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Molecular Mechanisms and the Interplay of Important Chronic Obstructive Pulmonary Disease Biomarkers Reveals Novel Therapeutic Targets
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Cite this: ACS Omega 2023, 8, 49, 46376–46389
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https://doi.org/10.1021/acsomega.3c07480
Published November 20, 2023

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Abstract

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Chronic Obstructive Pulmonary Disease (COPD) is a progressive, age-dependent, and unmet chronic inflammatory disease of the peripheral airways, leading to difficulty in exhalation. Several biomarkers have been tested in general towards the resolution for a long time, but no apparent success was achieved. Ongoing therapies of COPD have only symptomatic relief but no cure. Reactive oxygen species (ROS) are highly reactive species which include oxygen radicals and nonradical derivatives, and are the prominent players in COPD. They are produced as natural byproducts of cellular metabolism, but their levels can vary due to exposure to indoor air pollution, occupational pollution, and environmental pollutants such as cigarette smoke. In COPD, the lungs are continuously exposed to high levels of ROS thus leading to oxidative stress. ROS can cause damage to cells, proteins, lipids, and DNA which further contributes to the chronic inflammation in COPD and exacerbates the disease condition. Excessive ROS production can overwhelm cellular antioxidant systems and act as signaling molecules that regulate cellular processes, including antioxidant defense mechanisms involving glutathione and sirtuins which further leads to cellular apoptosis, cellular senescence, inflammation, and sarcopenia. In this review paper, we focused on COPD from different perspectives including potential markers and different cellular processes such as apoptosis, cellular senescence, inflammation, sirtuins, and sarcopenia, and tried to connect the dots between them so that novel therapeutic strategies to evaluate and target the possible underlying mechanisms in COPD could be explored.

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This paper published ASAP on November 20, 2023. Additonal corrections were received and a new version reposted on November 27, 2023.

1. Introduction

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COPD is an obstructive airway condition wherein a person feels difficulty exhaling the lungs’ air. As per the Global Initiative for Chronic Obstructive Lung Disease (GOLD), a person having forced expiratory volume 1% (FEV1%) < 0.7 is regarded as COPD. COPD is the third leading cause of the death in USA and second leading cause of death in India as per World Health Organiation (WHO) 2019 data.
Emphysema and chronic bronchitis are two such chronic conditions of the lungs that are commonly associated with COPD. Alveoli are the primary sites that are affected in emphysema. Interalveolar septa and elastic tissues of alveoli get destroyed due to protease–antiprotease imbalance, namely elastase-α1-antitrypsin (AAT). (1) Bronchial tubes, on the other hand, are a cause of concern in chronic bronchitis. Inflammation and remodeling of the bronchial tubes, chronic cough, and hypermucus secretion are the hallmarks of chronic bronchitis. Mucus plugging or mucus pooling is the prominent cause of air obstruction, which further impairs mucociliary clearance and is mainly observed due to hyperplasia and hypertrophy of goblet cells and submucosal glands, respectively. In short, emphysema deals with structural issues, whereas chronic bronchitis deals with mucus issues (Figure 1).

Figure 1

Figure 1. | Schematic representation of COPD.

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COPD develops and is diagnosed later in life, typically in those over the age of 65. COPD has also been observed in younger patients, those under the age of 55. In these cases, the severity distribution and disease progression are comparable to those reported in older patients. (2) Numerous factors have been reported so far, such as indoor air pollution, outdoor air pollution, and genetic factors such as deficiency of the α1-antitrypsin (AAT) gene, a person’s lifestyle, and many more. Cigarette smoke, on the other hand, is the major cause of COPD in which good lifestyle roles in curbing COPD’s underlying cause are even less. ROS generated from cigarette smoke destroys the cilia due to which cilia fails to push the mucus. (3) In turn, mucus buildup results in impaired mucociliary clearance, greater work of breathing, dyspnea, deteriorating airway resistance, and an inability to exercise. In severe situations, this stretchy mucus can create mucus plugs that are difficult to remove from the airways and are likely to lead to infection or localized atelectasis. (4,5) Millions of people have been diagnosed with COPD, but millions are unaware of having COPD.
Mitochondria are the major source of ROS in the mammalian cells. (6) In COPD, mitochondrial dysfunction can occur due to oxidative stress. The increased production of ROS and reduced antioxidant defenses in COPD lead to mitochondrial dysfunction. As a result, apoptosis can be dysregulated and leads to increased cell death in lung tissues. The deterioration of lung parenchyma and the development of emphysema, a common feature of COPD, can be attributed to excessive apoptosis of lung epithelial and endothelial cells, which further spills systemically as chronic inflammation. This chronic inflammation along with fasting, physical inactivity, and malnutrition, leads to the development of sarcopenia which reduces the respiratory function and exercise capacity in individuals with COPD. (7) In addition to apoptosis, oxidative stress also leads to nondividing senescent cells (SNCs). These SNCs further secretes senescence-associated secretory phenotypes (SASP) factors such as cytokines, chemokines, growth factors, and proteases, which further remodels the extracellular matrix (ECM), induces inflammation and fibrosis, triggers unwanted cell death, and directly mimics the process of natural aging. (8)
This Review will discuss the mechanism underlying the mitochondrial dysfunction, reduced antioxidant machinery, apoptosis, cellular senescence, DNA-associated inflammation, antiaging markers, and muscle wasting through a deeper understanding of the supporting literature and will try to develop the interplay between these components so that novel therapeutic strategies to curb COPD could be explored.

2. Mitochondria and Cytoplasm Interplay

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2.1. Reactive Oxygen Species (ROS) Generation

Mitochondria are not only the powerhouse of a cell but also the site of ROS generation. ROS generation in mitochondria is a natural process that usually happens due to oxidative phosphorylation that gives rise to ATP production within a cell. In general, ROS species such as superoxide (O2•–) and hydrogen peroxide (H2O2) get neutralized by superoxide dismutase and glutathione peroxidase using glutathione as a cofactor. Under stress conditions of exaggerated ROS such as cigarette smoke and many more, functionalities of the mitochondrial enzymes get impaired, and mitochondrial GSH (mGSH) gets reduced. As a result, ROS does not get neutralized by the mitochondrial machinery, leading to mitochondrial dysfunction and, eventually, cell death (6,9) (Figure 2).

Figure 2

Figure 2. | Mitochondria functionality. Reduced GSH due to ROS is translocated into the mitochondria, where it acts as a cofactor for GPx for the conversion of hydrogen peroxide into water. Due to reduced levels of GSH, H2O2 keeps on accumulating in the mitochondria, which diffuses from the mitochondria and starts causing cellular damage. Adaptor protein p66shc under stress conditions translocates into the mitochondria and starts producing H2O2 on its own in the absence of superoxide dismutase, which further leads to higher levels of H2O2. Stress conditions generated due to lower mitochondrial glutathione levels cause the oxidation of the cardiolipin–cytochrome c complex. As a result, cytochrome c diffuses through the mitochondria via BAX/BAK created pores and starts the apoptosis via caspase-3. P66shc also reduces the membrane potential to release cyt c into the cytosol. Upper head arrows show increased expression, while lower head arrows represent a decreased expression. Green circles with negative symbol represents membrane negative potential whereas green circles with plus symbol presents reduction in the membrane potential. O2•–, superoxide; SOD, superoxide dismutase; H2O2, hydrogen peroxide; GPx, glutathione peroxidase; GSH, glutathione; GSSG, glutathione disulfide; CLOOH, oxidized cardiolipin; BAX, B-cell lymphoma-2(Bcl-2)-associated X protein; BAK, Bcl-2 antagonist/killer; cty c, cytochrome c; p66shc, 66 kDa adaptor protein and member of the Src homologous-collagen homologue.

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2.2. Glutathione and Its Role

Glutathione (GSH) is a potent thiol-based antioxidant that normalizes the ROS levels in mitochondria. GSH is also essential for cell growth and other metabolic activities. GSH is synthesized in the cytoplasm via the γ-glutamyl cycle utilizing Adenosine triphosphate (ATP). Apart from mitochondria, GSH is also localized in the endoplasmic reticulum (ER) and nucleus. In the mitochondria and the nucleus, GSH is present in the reduced form, where it accounts for 10–15% of the total GSH pool and functions as redox stabilizer and DNA repair moiety, respectively. (10,11) However, in ER, GSH is present in the oxidized form, where it forms disulfide bond in proteins and helps in protein folding. (12)
Mitochondria do not have the machinery for the GSH synthesis, as GSH is synthesized exclusively in the cytosol. So, in order to neutralize ROS to normal levels, GSH is imported from the cytoplasm. GSH is anionic at physiological pH, and mitochondria, too, have a negative membrane potential because of oxidative phosphorylation. As a result, GSH cannot cross the mitochondrial membrane on its own. Therefore, it is transported by electroneutral antiport carriers or polypeptides such as 2-oxoglutarate and dicarboxylate to neutralize the ROS in the mitochondria. Imported GSH is regarded as mitochondrial GSH (mGSH). Mitochondrial enzymes such as glutathione peroxidase prevent lipid peroxidation and oxidative damage to the cell components by converting H2O2 into the water using GSH as a cofactor. Disulfide GSH (GSSG) formed after conversion of H2O2 into the water cannot cross the mitochondrial membrane, so it gets converted back to GSH by GSH reductase (GR) using nicotinamide adenine dinucleotide phosphate (NADPH) as a coenzyme (11,13−18) which is further reused as a cofactor in H2O2 neutralization (Figure 2).
Therefore, the role of gluathione is of utmost importance in COPD as it acts as a free radical scavenger and detoxifies the harmful molecules which contribute to the inflammation in the airways and also prevents the lung damage exacerbations. Additionally, it maintains the fluidity of the airway mucus to allow for the propulsion of the foreign substances, thus reducing infection susceptibility.

2.3. Apoptosis

Apoptosis or programmed cell death is the cascade of events that leads to dysfunctional cells’ death. Caspases are known to be critical enzymes involved in apoptosis. Caspases are further categorized into initiator caspases and executioner or effector caspases. Caspases-2, 8, 9, and 10 are among the initiator caspases that initiate apoptosis, whereas caspases-3, 6, and 7 are among the executioner caspases that executes apoptosis. (19−21) Apoptosis, as a whole, works in two different pathways, namely, the intrinsic pathway and the extrinsic pathway.
Intrinsic or the mitochondrial pathway of apoptosis is a mitochondrial associated event involving the mitochondrial outer membrane’s permeabilization. As mitochondria lack catalase enzyme for the metabolism of H2O2. So, it mainly utilizes imported GSH for the breakdown of H2O2 via glutathione peroxidase. (11) Under normal circumstances, GSH neutralizes ROS. Under stress conditions of cigarette smoke and exaggerated ROS, the amount of cholesterol increases, which may decrease the membrane fluidity and increase the membrane rigidity. (22) As a result, GSH may not be imported much from the cytosol to compensate for the mitochondria’s ROS. Due to this, H2O2 does not get neutralized by glutathione peroxidase. As a result, accumulated H2O2 diffuses into the cytosol and starts damaging the DNA and cell components through the Fenton process. (23) Another phenomenon is also reported that involves adaptor protein p66shc. Under normal circumstances, p66shc resides in the cytosol, but under stress conditions, it translocates into the mitochondria and generates H2O2 in the absence of superoxide through cytochrome c oxidation. (24,25) It is also believed that p66shc drops the membrane potential to release cytochrome c into the cytoplasm (26) (Figure 2).
Lower mGSH loosens the electrostatic bond between positively charged cytochrome c at physiological pH and anionic phospholipid, cardiolipin, in the inner mitochondrial membrane. Cardiolipin provides fluidity and stability to the mitochondrial membrane, but once cardiolipin is oxidized due to lower mGSH. Association between cardiolipin and cytochrome c gets broken. As a result, cytochrome c diffuses into the cytoplasm. Cardiolipin is also observed to be oxidized by phospholipase A2, cytochrome c and cardiolipin complex itself, and ROS. Calcium also interferes with the electrostatic interaction between the cardiolipin and cytochrome c, resulting in the detachment of cytochrome c from the cardiolipin. Cytochrome c detachment results in the disruption of the electron transport chain, which causes the burst in ROS, thus further amplifies the oxidative stress loop. (27−31)
B-cells lymphoma protein-2 (Bcl-2) keeps the pore-forming proteins such as BAX/BAK in the cytosol under normal conditions. Under an apoptotic environment, tumor suppressor protein, p53, blocks activity of Bcl-2 protein and recruits BAX/BAK in the mitochondria. (32) BAX/BAK translocates into the outer mitochondrial membrane and forms a pore through which cytochrome c gets released into the cytosol (33,34) (Figure 2). Cytochrome c, along with apoptotic protease activating factor-1 (Apaf-1) and ATP, activates caspase-9, thus forming a complex known as the apoptosome. Apoptosome further activates executioner caspase-3, (35) which leads to the activation of proteases and nucleases, leading to cell fragmentation and other structural changes such as flipping of phosphatidylserine on the outer leaflet of cells, which serves as a signal for phagocytes to perform opsonization. This phosphatidylserine is usually detected under early apoptosis by flow cytometry using Annexin V staining. (36)
In the extrinsic or death-receptor pathway, the apoptotic signal is associated with an extracellular ligand binding to a transmembrane receptor. A death-inducing signaling complex (DISC) is formed after receiving the apoptotic signal, which further activates caspase-8. Caspase-8 then activates caspase-3, which serves as the same function as caspase-3 does in the intrinsic pathway (11) (Figure 2). Thus, caspase-3 is the common caspase in both apoptotic pathways. Caspase-8 also turns truncated BID (tBID) into the proapoptotic protein BID. BID further activates BAX and BAK. In this way, caspase-8 cross-talks with an intrinsic pathway. (20,21)
Apoptosis dysregulation has been linked to the etiology of COPD. Apoptosis normally maintains tissue integrity by removing damaged cells, but in COPD, this integrity is disrupted by an imbalance between cell survival and cell death, which results in the exaggerated death of structural cells like fibroblasts and epithelial cells in the lungs. This results in the disruption of normal lung tissue repair and matrix remodeling processes, which causes the progressive loss of lung function that is typically observed in COPD. The main factor for the deregulation of apoptosis is increased ROS-mediated oxidative stress. Understanding apoptosis and its dysregulation is crucial for identifying the precise apoptotic pathway components that can be targeted as therapeutic targets to reduce lung tissue damage and slow the progression of COPD.

3. Cellular Senescence-Associated Aging Markers

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Cellular senescence is a condition of permanent cell cycle arrest in response to irreparable damage, typically DNA damage. Senescent cells (SNCs) gets accumulated over time and damage the nearby tissues, which are associated with the features of natural aging, by releasing the metalloproteinases, cytokines, growth factors, chemokines, and many more factors, collectively known as senescent-associated secretory phenotype (SASP) (37−42) (Figure 3). Senolysis, or the selective removal of SNCs, increases “healthspan”, or the amount of time an organism can survive without developing chronic illnesses of aging. It is now being thought of as a potential treatment option for diseases of aging to interfere with the pro-aging effects of SNCs, either by completely deleting SNCs or by turning off the SNC secretory machinery.

Figure 3

Figure 3. | Interplay of signaling pathway and COPD biomarkers. Myostatin on binding to its receptor ActRIIB causes the phosphorylation of the Smad2 and Smad3, which further recruits Smad4 and forms a trio-complex which via gene transcription in the nucleus results in sarcopenia. On the other hand, myostatin binding also reduces the Akt activity, which usually keeps the FOXO in the cytosol by phosphorylating it under normal conditions. FOXO on dephosphorylation due to reduced Akt activity translocates into the nucleus and transcribes the genes involved in sarcopenia via proteolysis. Activated FOXO also reduces the expression of PGC-1α, which via atrophy leads to sarcopenia. ROS causes a reduction in the levels of SIRT1 and the endogenous antioxidant GSH. SIRT1 inhibits NF-kß signaling under normal conditions, but under stress conditions, it is unable to do so; thus, NF-kß translocates into the nucleus and starts its downstream effects, such as a reduction in the PGC-1α expression. SIRT1 under normal circumstances increases the PGC-1α expression, but under stress conditions, it cannot do so; thus, the expression of PGC-1α gets suppressed. ROS also increases the lysosomal SA-ß-gal, and tumor suppressors p16INK4A and p53 levels associated with cellular senescence, which further secrete SASP. ROS mediated inflammation is caused by reduction in the levels of HDAC2 under stress conditions via activated NF-kß. ROS also reduces the level of PI3K/Akt/mTOR pathway expression, typically involved in protein synthesis. However, under stress conditions, protein synthesis is reduced and causes the skeletal muscle protein desmin’s proteolysis, which is involved in muscle wasting via atrophy. Upper head arrows show increased expression, while lower head arrows represent the decreased expression. Different colored arrows are used to indicate the paths of different markers and their outcomes. N represents no significant change. ActRIIB, activin A receptor, type IIB; PI3K, phosphatidylinositol 3-kinase; Akt, serine/threonine protein kinase B; mTOR, mammalian target of rapamycin; NF-kß, nuclear factor kappa light chain enhancer of activated B cells; SASP, senescence associated secretory phenotype; HDAC2, histone deacetylase 2; HAT, histone acetyltransferase; p16INK4A, cyclin-dependent kinase inhibitor 2A; p53, 53 kDa tumor protein; PGC-1α, peroxisome proliferator-activated receptor c coactivator 1; SIRT1, sirtuin 1; Smad2, mothers against decapentaplegic homologue 2; FOXO, forkhead box protein O; GSH, glutathione.

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3.1. Cyclin-Dependent Kinase Inhibitor 2A or P16INK4A

Universal markers to detect SNCs have not been reported so far. Tumor suppressors such as P16INK4A is known to be an inhibitor of cyclin-dependent kinases (CDKs) such as CDK4/6, which are essential for the cell to enter from one phase to another phase of the cell cycle. These tumor suppressors promote wound healing and inhibit the abnormal cells from dividing and entering into S phase from the G1 phase of the cell cycle by binding to cyclin-D. (43−51)
SNCs diminish the stem cell pool in COPD. As a result, the alveolar type I cells with a gaseous exchange role do not renew once they get damaged under stress condition of cigarette smoke. Around 10-fold increase was observed in the expression of p16 mRNA in p16+/+ mice compared to p16–/– mice upon four months of cigarette smoke exposure. It was found that p16 was increased by 30% in COPD patient lungs compared to the healthy patients across interstitial, alveolar, and bronchial samples, resulting in a reduced number of alveolar type II cells. Thus, it was observed found that p16–/– mice promote the stem cell pool and further increase alveolar regeneration. (51) Human bronchial epithelial cells (BEAS2B) showed a 5-fold increase in the p16 mRNA expression after induction with 0.5% cigarette smoke extract (CSE). Thus, apart from natural senescence, external stress factors such as cigarette smoke also trigger cellular senescence rather than natural phenomena. (52)
Other tumor suppressors, such as p19ARF (tumor suppressor in mouse) and p14ARF (tumor suppressor in humans), are also reported for cellular senescence. In mice, around 4-fold increase in the expression of p19ARF was reported using cigarettes smoke exposure in the epithelial cells of mice lungs. (53) More extensive research is still needed to understand its potential in cellular senescence. So far, no significant information about p14ARF has been reported in COPD patients and in BEAS2B cell lines by using cigarette smoke exposure.

3.2. Senescence-Associated β-Galactosidase (SA-ß-gal) Activity

SA-ß-gal is another biomarker used to stain SNCs both in vitro and in vivo. SA-ß-gal is a hydrolase enzyme of the lysosome, which shows its optimal activity at pH 6 while, on the other hand, peak enzymatic activity at pH 4–4.5 of ß-galactosidase was reported for its common isoforms. (42)
Four months cigarette smoke-exposed mice showed a ∼1.4 fold increase in the SA-ß-gal activity in lung homogenate against room air-exposed mice. (51) BEAS2B cell showed a 2- and 4-fold increase in the SA-ß-gal activity for 5% and 10% CSE exposure, respectively (54,55) while on the other hand, lung fibroblast cells from COPD patients showed 2-fold higher SA-ß-gal activity against healthy patients. (56) The levels of SA-ß-gal are not significantly increased as P16INK4A even after more extended duration studies of cigarette smoke, thus indicating that other cell cycle arrest points need to be checked for better insights into cellular senescence associated with SA-ß-gal activity.
Senolytics must have negligible off-target effects in non-SNCs in order to be considered safe. Though the possibility of therapeutically targeting SNCs is just beginning to become apparent, our knowledge of how SNCs may actively contribute to aging and age-related disorders is still in its infancy. Traditional thinking has not viewed aging as an illness per se, and there have been no studies done to date that have specifically examined how various treatments affect aging as a whole.
However, a number of technical obstacles must be removed in order to make therapies a reality. First off, cellular senescence is not always harmful and can assist a number of positive processes, such as the prevention of tumors, the speedy healing of wounds, the development of embryos (57−59) and tissues, (60) and the stimulation of pancreatic-ß cells (61) ability to secrete insulin as they get older. Second, despite the fact that numerous moieties have been found to eradicate SNCs in vivo, some of these substances have unfavorable side effects, like thrombocytopenia. (62) Third, the vulnerabilities of SNCs from various tissue origins vary, necessitating the development of special compounds that not only target the right cell type in vivo but also accumulate in the tissue where these SNCs are found. Finally, as SNCs would persist even after treatment, it would be necessary to continuously ingest chemicals that inhibit the SNC secretome. Because these compounds have been found to be immunosuppressive, (63) long-term use of them could pose safety issues.

4. Inflammatory Markers

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4.1. Histone Acetylation and Deacetylation

Histone belongs to the class of basic proteins that gives a structural role to the DNA. Nearly six feet long DNA wraps around the histone octamer thus forming the nucleosome assembly (64,65) and further condenses to form chromatin. DNA with its negatively charged phosphate group winds tightly around the positively charged histone lysine residues, thus acting as a barrier for transcription. Histone acetylation and deacetylation are associated with gene regulation. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the two major nuclear enzymes that are involved in gene transcription and gene silencing, respectively, (66,67) and thus are involved in modifying the expression of the genes involved in inflammation by regulating the chromatin structure. (68)
HAT reduces the positive charge on the histone lysine by transferring its acetyl group, resulting in DNA unwrapping around the histones. As a result, DNA gets relaxed. Thus, gene transcription sites on the relaxed DNA are then accessible to the RNA polymerase and the transcription factors, whereas HDAC performs opposite functions of compressing the DNA around the histone so that gene transcription sites are not accessible to RNA polymerase for transcription. Resistance towards corticosteroids in COPD is mainly contributed to the reduced expression of HDAC2. Peroxynitrite (ONOO–) formed from the combination of superoxide radical (O2•–) and nitric oxide (NO) from cigarette smoke leads to the nitration of the tyrosine residue of HDAC2, resulting in the inactivation of the HDAC2 and thus the relaxation of the DNA. (69−71)
In COPD patients, peripheral lung tissues showed around 7-fold lower HDAC2 levels against healthy patients. These levels further decrease with increasing COPD severity. This reduced HDAC2 trend was also observed in the alveolar macrophages, and bronchial biopsy samples from COPD patients. (72)
Reduced HDAC2 expression was also observed even after 4 h in BEAS2B cell lines after induction with 5% cigarette smoke extract (CSE), and a similar trend also followed in rat COPD model of lipopolysaccharide (LPS) and cigarette smoke exposure model for 30 days. (73−75) HAT, on the other hand, did not show significant differences among all the stages of COPD and even in alveolar macrophages and bronchial biopsies samples from COPD patients. (72) Thus, decreased HDAC2 expression is associated with increased expression of inflammatory genes via NF-kß pathway (71) (Figure 3).

4.2. Granulocyte-Colony Stimulating Factor (G-CSF)

G-CSF is known to be the principal regulator involved in the development, production, and release of neutrophils from the bone marrow. (76) Neutrophils are short-lived, terminally differentiated, and abundantly present leukocytes in humans. For bacterial and fungal infections, neutrophils are considered as the first-line defense support to the body. (77)
Interleukin 6 (IL-6), along with IL-23, triggers the release of stromal IL-17 from Th-17 cells. This IL-17, in turn, releases neutrophils from the G-CSF. G-CSF deficient mice model showed reduced lung tissue destruction, systemic inflammation, bone osteoporosis, reduced airway inflammation, and attenuated right heart hypertrophy. Bronchoalveolar lavage fluid (BALF) from COPD patients showed around a 3-fold increase in the G-CSF levels. (78) Neutrophils, on arrival at the site of inflammation, release their genomic DNA, which increases the viscosity and viscoelasticity of the sputum, which causes airway obstruction and thus impairs the mucociliary clearance. This form of genomic DNA extrusion serves as a trap known as neutrophil extracellular traps (NETs), which traps and kills bacteria. (79) It also plays prominent roles in inflammatory diseases. (80) NETosis (NET formation) is associated with gasdermin D, neutrophil elastase, peptidylarginine deaminase 4 (PAD4), and and myeloperoxidase (MPO). Thus, these four constituents of NETs are the targets for inflammatory conditions. (81−83) Thus, G-CSF and neutrophils’ play prominent in inflammation (77) and may serve as a distinguished marker in differentiating the different stages of COPD.

5. Oxidative Stress Associated Antiaging Markers

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5.1. Sirtuins (SIRTs)

Sirtuins or SIRTs are nicotinamide adenine dinucleotide (NAD) dependent protein deacetylases that mainly belongs to class III HDACs. (84,85) SIRTs are known for their antioxidant and oxidative stress antagonism involved in longevity, mitochondrial functions, metabolism, and DNA damage repair. (86)
Seven SIRTs family members have been reported in the literature and are known for their different roles. SIRT1, 3, and 5 are anti-ROS agents, whereas SIRT2, 6, and 7 are involved in the modulation of oxidative stress genes and metabolism. Interestingly, SIRT4 has both ROS inducing and antioxidant properties as well. (87)
SIRT1 is a well-studied member of the mammalian SIRTs family. They are found in both nuclei as well as in the cytoplasm. (88,89) They are known for their role in cellular senescence, development, cell death, calorie restriction, DNA repair, and longevity. (87,90) Increased matrix metalloproteinase-9 (MMP-9) mRNA expression was directly correlated with reduced SIRT1 in emphysema. (91) SIRT1 also promotes muscle mass, growth, maintenance, and repair. Attenuation in the NF-kß transcription activity was also observed by deacetylating the p53 subunit of NF-kß at lysine 310 residue. (92) The 2-fold decrease in the levels of SIRT1 was seen in the COPD serum patients and rat lung tissues from the LPS and cigarette smoke-induced model which was strongly correlated with the stress condition generated in COPD (93,94) and levels may increase with disease severity. To confirm the role of SIRT1 as an oxidative stress antagonist, BEAS2B cells were pretreated with buthionine sulfoximine (BSO), which is an intracellular glutathione depeletor, before induction with cigarette smoke extract. As anticipated, SIRT1 levels were decreased by 7-fold than the normal, thus proved the fact that SIRT1 has an antioxidant role as well (95) (Figure 3). SIRT1 also increases the expression of PGC-1α which further results in the mitochondrial and peroxisome biogenesis (87) (Figure 3).
SIRT2 is found in the cytoplasm and nucleus. (96) It is expressed in the organs related to metabolism, such as the brain, kidneys, liver, testes, pancreases, and mice’s fat tissues. It has been found that SIRT2 has a role in cell’s fuel detection, and its expressions are based on the cell’s energy state: suppressed in high energy state while expressed in low energy state. (97) Under stress conditions, SIRT2 deacetylases and activates the key enzymes of pentose phosphate pathway involved in NADPH production as NADPH is essential to combat the oxidative stress by keeping GSH in reduced form. (87,98)
SIRT3 is a nucleus sirtuin, but it gets translocated to the mitochondria under stress conditions of DNA damage, where it gets activated by the mitochondrial peptidase, thus designated as the mitochondrial sirtuin as it is localized in its active form in mitochondria. (99) SIRT3 is also believed to have antitumor activities through ROS modulation. SIRT3, on the other hand, is also known for repairing the mitochondrial DNA by replenishing the activity of human 8-oxoguanine-DNA glycosylase 1 (OGG1) that repairs the damaged DNA. (100) In antioxidant and redox signaling (ARS), SIRT3 is known as a genotoxic and oxidative stress antagonist. (87)
SIRT4 is designated as the mitochondrial sirtuin, whose primary function is to ribosylate the adenosine diphosphate (ADP). (96,101) SIRT4 may have enhanced roles in the kidneys, brain, liver, and heart, as it is predominantly found in these organ tissues. (102) All of the sirtuins except SIRT4 have a role in mitigating the mitochondrial stress through the calorie restriction process. Knockout and overexpression of SIRT4 decreased and increased the ROS levels in angiotensin II-induced cardiac hypertrophy in mice. It was also found that SIRT4 reduced the activity of SOD2 as it inhibits the binding of SOD2 to SIRT3. (103) In one of the studies conducted in 2010, SIRT4 knockdown resulted in enhanced oxygen consumption and fatty acid oxidation, possibly in primary mouse hepatocytes, by regulating the expression of SIRT1. As fatty acid oxidation leads to mitochondrial ROS and is also linked to the kidney damage in diabetes. (104,105) Due to its role as an oxidative metabolism, SIRT4 is being evaluated as a biomarker in coronary artery disease, but more studies need to be conducted to verify this finding. More robust studies are needed to clarify the role of SIRT4 in ARS.
SIRT5 is a mitochondrial sirtuin where it demalonylates, deacetylate, and desuccinylates various proteins. (96,106) They are known for their roles in regulating oxidative stress, a mediator in the apoptosis pathway, detoxification, energy production, and cellular metabolism. (107) SIRT5 is involved in converting ammonia into nontoxic urea by increasing the activity of carbamoyl phosphate synthetase (CPS1), which is involved in the detoxification of ammonia in the urea cycle. As ammonia is a ROS inducer and involved in decreasing the antioxidant GSH content. Increased levels of ammonia were seen in SIRT5 knockout mice during fasting, thus indicating its essential role in ARS. (108−110)
SIRT6 is designated as the nuclear sirtuin whose primary function is to deacetylase the lysine 9 and 56 residues on histone 3 abbreviated as H3K9 and H3K56. (111−116) The first evidence of SIRT6 in regulating mammalian aging was observed in SIRT6 knockout mice. (87,96) SIRT6 overexpression curbs the cellular senescence and inhibits fibrosis in COPD. (117) Reduced SIRT6 expression was found in the lung homogenate. SIRT6 overexpression inhibits cigarette smoke-induced senescence in human bronchial epithelial cells. It was also seen that SIRT6 overexpression induces autophagy through the attenuation of the insulin-like growth factor-Akt-mammalian target of rapamycin (IGF-Akt-mTOR) signaling. Thus, implying that increased expression of the IGF-Akt-mTOR pathway leads to insufficient autophagic elimination of dysfunctional cellular components, which may be involved in COPD development, thus making the role of SIRT6 important in mitigating the development and progression of COPD. (117,118) SIRT6 not only works as chromatin regulator and recruiter of transcription factors such as NF-kß but also involved in DNA repair, gene expression, and glucose homeostasis. (115,119−122)
The last member of the sirtuin family, SIRT7, is designated as the nucleoli sirtuin. This protein directly attaches to the histones and is involved in the positive regulation of the transcription of rDNA (rDNA). (96) SIRT7 is differentially expressed in all tissues with enhanced expression in higher metabolic activities and reduced expression as the age progresses. (123,124) Very little is known about the role of SIRT7 as it is a recent area of research and needs more robust studies to understand its substrates on which it acts and its proper mechanism of action. Although, the past few pieces of research indicated its minor role in the regulation of oxidative stress. (87) Further studies are needed to explore the deeper understanding of SIRT7.

6. Sarcopenia Markers

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Sarco in Greek is “flesh”, and -penia is “deficiency”. So, sarcopenia refers to muscle wasting or the gradual loss of skeletal muscle with age. The possible reason for the muscle mass is excessive proteolysis with reduced protein synthesis. It is predominantly observed in older people or due to factors such as fasting or malnutrition. Sarcopenia is also associated with specific disease conditions such as COPD, diabetes, renal failure, cardiac failure, cancer-associated cachexia, and many more. (7)

6.1. Myostatin and Myogenin

Myostatin, a member of the transforming growth factor-beta (TGF-ß) family, is expressed predominantly in skeletal muscles and expressed in low levels in cardiac and adipose tissues. (125) Myostatin is known as an autocrine inhibitor for normal muscle growth. Enhanced levels of myostatin and its homologue activin A causes the rapid loss of muscle mass. (125−127) Myostatin is the negative regulator of satellite cells which are the muscle stem cells required in repair and regeneration of the muscle after injury. (128−131) Myostatin on binding to its receptor, activin A receptor, type IIB (ActRIIB) on muscle cells activates Smad2 and Smad3 by phosphorylation. Activated Smad2 and Smad3 complexes recruit Smad4 in their complexes and form the trio-complex. This complex translocates into the nucleus and starts the transcription of genes, resulting in muscle wasting. PI3K/Akt/mTOR pathway promotes protein synthesis and prevents proteolysis, but myostatin on binding to its receptors on muscle cells reduces the PI3K/Akt/mTOR pathway expression. Akt keeps forkhead box protein O (FOXO) in the cytosol by phosphorylating it. However, due to reduced activity of Akt, FOXO gets dephosphorylated and translocates into the nucleus and start the transcription of the Atrogin 1, muscle-specific RING-finger 1(MURF 1), autophagy-related genes (ATGs) which via the ubiquitin-proteasome system (UPS) and autophagy promotes the muscle wasting (7,125) (Figure 3). NF-kß is also known as the potent inducer of myostatin or the inhibitor of myogenesis. (7) Although myostatin is a skeletal muscle marker but a 2-fold decrease in the serum of COPD patients was also reported. (132) A 5-fold decrease in the myostatin levels in COPD patients’ diaphragm was reported thus indicating its potential of muscle wasting in COPD patients. (133) Around 10-fold decreases in myostatin levels in gastrocnemius muscle (lower leg muscle) were reported in the 16-week cigarette smoke-induced rat model by immunohistochemistry. In contrast, a 4-fold decrease in myogenin was observed in the gastrocnemius muscle, which is the transcription factor involved in the development of muscles/myogenesis. (134) These findings are a proof of concept that muscle wasting is predominantly present in COPD and thus represents a therapeutic potential in treating COPD.

6.2. Forkhead Box Protein O (FOXO)

Forkhead box protein O and FOXOs are the transcription factors involved in regulating oxidative stress resistance, cell-cycle progression, and apoptosis. The expression of FOXO is majorly regulated by Akt-mediated phosphorylation in response to growth factors. (135) Akt inactivates the FOXO1 and -3 by phosphorylating it, and as a result, FOXO1 and -3 remain sequestered from the nucleus in the cytosol (Figure 3) to prevent the transcription of the muscle-specific E3 ubiquitin ligases gene. (136,137) A 4-fold increase in the FOXO1 in quadriceps femoris mRNA expression was observed in COPD patients associated with muscle loss via proteolysis, which ultimately leads to muscle atrophy. (138) Cigarette smoke condensate (CSC) induced autophagy leads to around a 7-fold increase in the levels of acetylated FOXO3a. Smokers’ lung and mice lungs exposed to cigarette smoke also showed increased expression of acetylated FOXO3a. (139,140) FOXOs are mediators in the pathway of oxidative stress, as other pathways or factors may be associated with its activation. More extensive research is needed to obtain more precise information about the FOXO proteins in COPD.

6.3. PGC1α

The peroxisome proliferator-activated receptor c coactivator 1 (PGC1) is a family of transcription factors involved in metabolism. The family consists of three members known as PGC1α, PGC1ß, and the PGC related coactivator (PRC). Among three members, PGC1α protein (encoded by PPARGC1A) is the well-studied member who is known for mitochondrial biogenesis and increased respiration for the detoxification of ROS, gluconeogenesis, and adaptive thermogenesis. (141−144)
The primary organelle that supports the functions of the mitochondria during oxidative metabolism is the peroxisome. Peroxisomes are known for the metabolism of complex fatty acids that cannot be metabolized by mitochondria. They do not fully metabolize the fatty acids, but they export the short-chained fatty acids to the mitochondria for complete breakdown. Thus, mitochondria and peroxisome aids each other in oxidative metabolism. (145) Muscle cell PGC1α enhances the SOD2 and glutathione peroxidase expression to remove the superoxide and hydrogen peroxide, respectively. (142) Elevated PGC1α levels enhance peroxisome and mitochondrial biogenesis, increasing the number of mitochondria and ROS-associated detoxification enzymes. In particular, PGC1α acts as a coactivator for nuclear respiratory factor 1 (NRF1) which is a regulator of antioxidant response elements (AREs) which encodes antioxidant associated enzymes. (146,147) In other words, PGC1α gives increased respiration to tackle the ROS and helps attenuates the process of aging. (148) Reduced levels of PGC1α is associated with atrophy by activating NF-kß and FOXO transcription factors (Figure 3), which in turn accelerates protein degradation induced by fasting or denervation. (149,150) PGC1α also activates the expression of the mitochondrial sirtuins, such as SIRT3. (151,152) Deacetylation and methylation increase the activity of PGC1α while, on the other hand; acetylation and sumoylation decrease its activity. There is growing evidence of organelle remodeling via PGC1α. It is believed that the mitochondria and the peroxisomes that are newly produced from the biogenesis via PGC-1α have different intrinsic compositions and properties as compared to the original organelles. (148) Enhanced levels of PGC-1α in muscles could delay the kick-off of the aging process linked with sarcopenia. PGC1α is a recent area of research working towards the mitigation of the mitochondrial ROS. PGC1α could be one of the markers to resolve sarcopenia associated with COPD.

6.4. Desmin

Desmin proteins are the intermediate filaments of the sarcomere architecture that are required for the mechanochemical signaling, efficient force transmission, and maintenance of cell integrity within the myocytes. Proteolysis causes the collapse of the muscle architecture, thus reducing the force generation ability and the force transmission capacity along and across the muscle fiber. As a result, muscles become weak and prone to damage. (153,154) Desmin associated atrophy can be explained with two ubiquitin ligases, such as ubiquitin tripartite motif-containing protein 32 (TRIM32) and MURF1. MURF1 catalyzes the breakdown of the thick myosin filament’s proteins, whereas TRIM32 catalyzes the Z-band and the desmin cytoskeleton’s breakdown. TRIM32 reduces the PI3K/Akt/mTOR pathway expression, thus triggering the proteolysis via FOXO, ultimately leading to atrophy. (7) Other muscle proteins might also be prone to proteolysis under stress/diseased conditions, but not much work is reported in that area. Desmin could be one of the potential markers to study the sarcopenia associated tremor in COPD.

7. Therapeutic Interplay of Potential Markers

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COPD is an age-specific disease, and its underlying cause is still not fully understood. Current medications are symptomatic relievers. Maintaining the ROS equilibrium while treating COPD could be a breakthrough in the disease’s management. Therapies such as antioxidants or the factors that can raise the downregulated expression of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) under diseased conditions would be beneficial. Different strategies were devised to target the dysfunctional mitochondria, such as targeting mitochondria based on its biophysical properties of high membrane negative potential, targeting locations within the mitochondria that are specific for particular enzymes that convert prodrugs into active drugs, and targeting the transporter-based delivery of prodrugs. (155) Antioxidant-based mitochondrial targeting may prevent cardiolipin oxidation, thereby maintaining cardiolipin–cytochrome c association and further preventing apoptosis (Figure 2). Heat-shock proteins (HSP) such as HSP27 prevent the release of the cytochrome c into the cytoplasm and prevent its downstream effects. (29,156,157) Therapies that can address these issues will be able to control apoptosis and the underlying ROS that are common in age-related illnesses.
Senotherapies are being evaluated to prevent the proaging effects associated with SNCs. Senotherapies are classified into three categories: senolytics to selectively kills the SNCs, senomorphics that modulate the SNC associated morphology and functions, delayed progression of young cells to SNCs, and the immune system based clearance of SNCs. (158) Senotherapies are based mostly on the optimistic premise that the harmful effects of SASPs connected to SNCs might be eliminated and there will be no risk of tumor escape from senescence once SNCs are eliminated which is otherwise possible if SNCs are allowed to linger indefinitely, and clearance of SNCs extends the healthspan which is a global measure of aging in mice (41,159) thus it is suggested that senotherapies retards aging and reduces the age-related illnesses. (42)
Anti-inflammatory therapies cannot reverse COPD. Poor clinical response was observed for corticosteroids in COPD patients. (160) Bronchodilators also fail to target the underlying inflammatory cause of COPD patients. The magnitude of inflammation in COPD progresses with the disease stage with a higher number of lymphocytes, neutrophils, and macrophages. (161) This inflammation “spillover” into the systemic circulation from the peripheral airways, thus giving rise to the systemic inflammation, which is associated with several comorbidities such as cardiovascular disease. (162) The lower respiratory tract of severe COPD patients is colonized with Streptococcus pneumoniae and Haemophilus influenzae, and this bacterial colonization is associated with defective phagocytosis of bacteria and thus may be the cause of persistent inflammation and immune response in COPD. (163) Targeting specific cytokines gave disappointing results in COPD patients. Emphysema escalates the lung aging, thus giving rise to the faulty endogenous antiaging mechanism involving sirtuins and FOXO. (164) Thus, targeting oxidative stress could have the therapeutic potential against the inflammatory factors such as increased expression of NF-kß, p38 mitogen-activated protein kinase (p38 MAPK), a higher amount of autoantibodies (165) against carbonylated proteins (166) and reduced aging factors such as reduced expression of SIRT1, HDAC2 (Figure 3), and the reduced expression of antiproteases that leads to fibrosis and emphysema with overexpressed transforming growth factor-beta (TGF-ß).
Reduced expression of proteins associated with atrophy leads to a decreased muscle mass. Proteins such as SIRT1, PGC1α (149,150) and many more are among those that induce during exercise and promote hypertrophy, and maintains the skeletal muscle mass. Therapies that block the wasting of these proteins or increase the level of these proteins could be promising to prevent COPD associated sarcopenia (Figure 3). Myostatin–activin A-growth differentiation factor 11 (GDF11) signaling inhibitions could have therapeutic potential in muscle wasting associated diseases. Antagonists such as follistatin (167,168) soluble forms of activin A receptor, type IIB (ActRIIB) (169) myostatin antibodies that can block its receptors (170) and many more could be the potential antagonists for myostatin or activin A. The loss of cytoskeletal proteins, such as desmin, is activated by phosphorylation. The agents that can block desmin phosphorylation could help stop atrophy by preventing the collapse of the desmin and the myofibrils (Figure 3). (7,171) During fasting, TRIM32 reduces the expression of the PI3K/Akt/FOXO signaling pathway that is associated with protein synthesis and prevents the proteolysis. (171,172) Thus, TRIM32 inhibitors could prevent the cytoskeletal collapse associated with desmin and myofibrils, but so far, no success has been attained in developing the TRIM32 inhibitor. Such inhibitors, once developed, may have good potential for COPD treatment.

8. Conclusion and Future Directions

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COPD has become a burden for older people and economy. Current COPD treatments, including bronchodilators, vaccines, corticosteroids, phosphodiesterases (PDEs), and long-term antibiotics, give symptomatic relief but cannot halt the progression of COPD due to it is progressive nature. Due to age factor, targeting, reduced antioxidant capacity, increased cellular senescence, and enhanced sarcopenia would be among those factors that may be beneficial in treating COPD. Daily chore or exercise is decisive for COPD patients as there are some essential biomarkers such as PGC-1α whose levels get increased during exercise thus, giving beneficial downstream effects by raising the levels of NRF-1 factors associated with endogenous antioxidant mechanisms. Patients with heart, joint, liver, kidney, brain, and gastrointestinal (GI) tract problems should also be mandatedly checked for COPD using a pulmonary function test (PFT) to validate the health of the lungs in order to lessen the worldwide burden of COPD. This strategy would be ideal for detecting COPD at an early stage since early stage COPD treatments, such as corticosteroids, are most effective; however, as the disease progresses, these treatments lose their effectiveness. The early detection and treatment of COPD may be possible with these strategies.

Author Information

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  • Corresponding Author
  • Authors
    • Gautam Sharma - Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Maharashtra 400076, India;  Orcidhttps://orcid.org/0000-0003-3321-637X
    • ⊥Rinti Banerjee - Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Maharashtra 400076, India
  • Notes
    The authors declare no competing financial interest.
    ⊥Prof. Rinti Banerjee passed away in July 2021 due to post-COVID-19 complications.

Acknowledgments

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The authors extend their thanks to the late Prof. Rinti Banerjee for providing the opportunity to initiate this review paper and Prof. Sanjeeva Srivastava to carry forward this review paper. Also, G.S. acknowledges Indian Institute of Technology Bombay for providing the platform to dissiminate the scientific knowledge to the global research community. G.S. also thanks Debarghya Pratim Gupta and Amrita Mukhjerjee from Protoemics Lab IIT Bombay for reviewing the manuscript and giving critical input to make the manuscript comprehendible for the readers. The authors also acknowledge Servier Medical Art. Parts of the graphical abstract and table of contents graphic, Figure 1, Figure 2, and Figure 3 were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

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    Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
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    Marí, M.; Morales, A.; Colell, A.; García-Ruiz, C.; Ferná Ndez-Checa, J. C. Mitochondrial Glutathione, a Key Survival Antioxidant. Antioxid. Redox Signal. 2009, 11 (11), 2685– 2700,  DOI: 10.1089/ars.2009.2695
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    11
    Mitochondrial glutathione, a key survival antioxidant
    Mari Montserrat; Morales Albert; Colell Anna; Garcia-Ruiz Carmen; Fernandez-Checa Jose C
    Antioxidants & redox signaling (2009), 11 (11), 2685-700 ISSN:.
    Mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain. Among the arsenal of antioxidants and detoxifying enzymes existing in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death. mGSH importance is based not only on its abundance, but also on its versatility to counteract hydrogen peroxide, lipid hydroperoxides, or xenobiotics, mainly as a cofactor of enzymes such as glutathione peroxidase or glutathione-S-transferase (GST). Many death-inducing stimuli interact with mitochondria, causing oxidative stress; in addition, numerous pathologies are characterized by a consistent decrease in mGSH levels, which may sensitize to additional insults. From the evaluation of mGSH influence on different pathologic settings such as hypoxia, ischemia/reperfusion injury, aging, liver diseases, and neurologic disorders, it is becoming evident that it has an important role in the pathophysiology and biomedical strategies aimed to boost mGSH levels.
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  12. 12
    Hwang, C.; Sinskey, A. J.; Lodish, H. F. Oxidized Redox State of Glutathione in the Endoplasmic Reticulum. Science (80-.). 1992, 257 (5076), 1496– 1502,  DOI: 10.1126/science.1523409
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    Chen, Z.; Lash, L. H. Evidence for Mitochondrial Uptake of Glutathione by Dicarboxylate and 2-Oxoglutarate Carriers 1. J. Pharmacol. Exp. Ther. 1998, 285 (2), 608– 618
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    13
    Evidence for mitochondrial uptake of glutathione by dicarboxylate and 2-oxoglutarate carriers
    Chen, Zhifeng; Lash, Lawrence H.
    Journal of Pharmacology and Experimental Therapeutics (1998), 285 (2), 608-618CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)
    The role of org. anion transporters in the mitochondrial uptake of glutathione (GSH) was investigated by assessing competition with substrates or inhibition with inhibitors of specific carriers and modulation of mitochondrial energetics. Potential artifacts in the transport methodol., including contamination of matrix space with extramitochondrial fluid, changes in matrix vol. during incubations, efflux of transported GSH during sample processing, induction of the membrane permeability transition, contamination of the mitochondrial prepn. with plasma membranes and GSH degrdn., were cor. or eliminated. Substrates (i.e., malate, succinate) and an inhibitor (i.e., butylmalonate) of the dicarboxylate carrier, an inhibitor (i.e., phenylsuccinate) of the 2-oxoglutarate carrier, and glutamate produced significant inhibition of GSH uptake whereas substrates and inhibitors of the mono- and tricarboxylate carriers were generally without effect. Phosphoenolpyruvate, which is a substrate for the tricarboxylate carrier, inhibited GSH uptake, but this was due to induction of the membrane permeability transition and not to competition for uptake. Although glutamate inhibited GSH uptake, the converse did not occur. GSH uptake was pH-independent and aspartate had no effect, which suggest that the glutamate and glutamate-aspartate carriers are not involved in GSH uptake but that the glutamyl residue of GSH may be important in its transport. GSH uptake was dependent on phosphate and ATP generation. Hence, we conclude that both the dicarboxylate and 2-oxoglutarate carriers of the inner membrane can catalyze uptake of GSH into the matrix. The function of an addnl., novel transporter cannot be excluded at present. This is the first study to define the function of mitochondrial anion carriers in GSH transport.
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  14. 14
    Chen, Z.; Putt, D. A.; Lash, L. H. Enrichment and Functional Reconstitution of Glutathione Transport Activity from Rabbit Kidney Mitochondria: Further Evidence for the Role of the Dicarboxylate and 2-Oxoglutarate Carriers in Mitochondrial Glutathione Transport. Arch. Biochem. Biophys. 2000, 373 (1), 193– 202,  DOI: 10.1006/abbi.1999.1527
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    14
    Enrichment and Functional Reconstitution of Glutathione Transport Activity from Rabbit Kidney Mitochondria: Further Evidence for the Role of the Dicarboxylate and 2-Oxoglutarate Carriers in Mitochondrial Glutathione Transport
    Chen, Zhifeng; Putt, David A.; Lash, Lawrence H.
    Archives of Biochemistry and Biophysics (2000), 373 (1), 193-202CODEN: ABBIA4; ISSN:0003-9861. (Academic Press)
    In previous studies, we provided evidence for uptake of glutathione (GSH) by the dicarboxylate and the 2-oxoglutarate carriers in rat kidney mitochondria. To investigate further the role of these two carriers, GSH transport activity was enriched from rabbit kidney mitochondria and functionally reconstituted into phospholipid vesicles. Starting with 200 mg of mitoplast protein, 2 mg of partially enriched proteins were obtained after Triton X-114 solubilization and hydroxyapatite chromatog. The reconstituted proteoliposomes catalyzed butylmalonate-sensitive uptake of [14C]malonate, phenylsuccinate-sensitive uptake of [14C]2-oxoglutarate, and transport activity with [3H]GSH. The initial rate of uptake of 5 mM GSH was approx. 170 nmol/min per mg protein, with a first-order rate const. of 0.3 min-1, which is very close to that previously detd. in freshly isolated rat kidney mitochondria. The enrichment procedure resulted in an approx. 60-fold increase in the specific activity of GSH transport. Substrates and inhibitors for the dicarboxylate and the 2-oxoglutarate carriers (i.e., malate, malonate, 2-oxoglutarate, butylmalonate, phenylsuccinate) significantly inhibited the uptake of [3H]GSH, whereas most substrates for the tricarboxylate and monocarboxylate carriers had no effect. GSH uptake exhibited an apparent Km of 2.8 mM and a Vmax of 260 nmol/min per mg protein. Anal. of mutual inhibition between GSH and the dicarboxylates suggested that the dicarboxylate carrier contributes a somewhat higher proportion to overall GSH uptake and that both carriers account for 70 to 80% of total GSH uptake. These results provide further evidence for the function of the dicarboxylate and 2-oxoglutarate carriers in the mitochondrial transport of GSH. (c) 2000 Academic Press.
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  15. 15
    Coll, O.; Colell, A.; García-Ruiz, C.; Kaplowitz, N.; Fernández-Checa, J. C. Sensitivity of the 2-Oxoglutarate Carrier to Alcohol Intake Contributes to Mitochondrial Glutathione Depletion. Hepatology 2003, 38 (3), 692– 702,  DOI: 10.1053/jhep.2003.50351
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    15
    Sensitivity of the 2-oxoglutarate carrier to alcohol intake contributes to mitochondrial glutathione depletion
    Coll, Olga; Colell, Anna; Garcia-Ruiz, Carmen; Kaplowitz, Neil; Fernandez-Checa, J. C.
    Hepatology (Philadelphia, PA, United States) (2003), 38 (3), 692-702CODEN: HPTLD9; ISSN:0270-9139. (W. B. Saunders Co.)
    The mitochondrial pool of reduced glutathione (mGSH) is known to play a protective role against liver injury and cytokine-mediated cell death. However, the identification of the mitochondrial carriers involved in its transport in hepatocellular mitochondria remains unestablished. In this study, the authors show that the functional expression of the 2-oxoglutarate carrier from HepG2 cells in mitochondria from Xenopus laevis oocytes conferred a reduced glutathione (GSH) transport activity that was inhibited by phenylsuccinate, a specific inhibitor of the carrier. In addn., the mitochondrial transport of GSH and 2-oxoglutarate in isolated mitochondria from rat liver exhibited mutual competition and sensitivity to glutamate and phenylsuccinate. Interestingly, the kinetics of 2-oxoglutarate transport in rat liver mitochondria displayed a single Michaelis-Menten component with a Michaelis const. of 3.1 ± 0.3 mmol/L and max. velocity of 1.9 ± 0.1 nmol/mg protein/25 s. Furthermore, the initial rate of 2-oxoglutarate was reduced in mitochondria from alc.-fed rat livers, an effect that was not accompanied by an alc.-induced decrease in the 2-oxoglutarate mRNA levels but rather by changes in mitochondrial membrane dynamics induced by alc. The fluidization of mitochondria by the fluidizing agent 2-(2-methoxyethoxy) Et 8-(cis-2-n-octylcyclopropyl) (A2C) restored the initial transport rate of both GSH and 2-oxoglutarate. Finally, these changes were reproduced in normal liver mitochondria enriched in cholesterol where the fluidization of cholesterol-enriched mitochondria with A2C restored the order membrane parameter and the mitochondrial 2-oxoglutarate uptake. In conclusion, these findings provide unequivocal evidence for 2-oxoglutarate as a GSH carrier and its sensitivity to membrane dynamics perturbation contributes in part to the alc.-induced mGSH depletion.
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  16. 16
    García-Ruiz, C.; Morales, A.; Colell, A.; Rodes, J.; Yi, J. R.; Kaplowitz, N.; Fernandez-Checa, J. C. Evidence That the Rat Hepatic Mitochondrial Carrier Is Distinct from the Sinusoidal and Canalicular Transporters for Reduced Glutathione: EXPRESSION STUDIES IN XENOPUS LAEVIS OOCYTES. J. Biol. Chem. 1995, 270 (27), 15946– 15949,  DOI: 10.1074/jbc.270.27.15946
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    16
    Evidence that the rat hepatic mitochondrial carrier is distinct from the sinusoidal and canalicular transporters for reduced glutathione. Expression studies in Xenopus laevis oocytes
    Garcia-Ruiz, Carmen; Morales, Albert; Colell, Anna; Rodes, Joan; Yi, Jiau-R.; Kaplowitz, Neil; Fernandez-Checa, Jose C.
    Journal of Biological Chemistry (1995), 270 (27), 15946-9CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Mitochondrial GSH derives from a mitochondrial transport system (RmGshT), which translocates cytosol GSH into the mitochondrial matrix. Mitochondria of oocytes, isolated 3-4 days after microinjection of total liver mRNA, expressed a RmGshT compared with water-injected oocytes. The expressed RmGshT exhibited similar functional features as reported in isolated mitochondria of rat liver such as ATP stimulation, inhibition by glutamate, and insensitivity to inhibition by sulfobromophthalein-glutathione (BSP-GSH) and S-(2,4-dinitrophenyl)glutathione (DNP-GSH). The expressed RmGshT is localized in the inner mitochondrial membrane since expression is still obsd. in mitoplasts prepd. from total liver mRNA-injected oocytes. Fractionation of poly(A)+ RNA identified a single mRNA species of ∼3-3.5 kilobases encoding for the RmGshT, which was stimulated by ATP and inhibited by glutamate but not by BSP-GSH or DNP-GSH. Microinjection of this fraction did not lead to expression of plasma membrane GSH transport in intact oocytes, and conversely, oocytes microinjected with cRNA for rat liver sinusoidal GSH transporter (RsGshT) or rat liver canalicular GSH transporter (RcGshT) did not express mitochondrial GSH transport activity. Thus, our results show the successful expression of the rat hepatic mitochondrial GSH carrier, which is different from RsGshT and RcGshT, and provide the strategic basis for the cloning of this important carrier.
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  17. 17
    Lash, L. H. Mitochondrial Glutathione Transport: Physiological, Pathological and Toxicological Implications. Chem. Biol. Interact. 2006, 163 (1–2), 54– 67,  DOI: 10.1016/j.cbi.2006.03.001
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    17
    Mitochondrial glutathione transport: Physiological, pathological and toxicological implications
    Lash, Lawrence H.
    Chemico-Biological Interactions (2006), 163 (1-2), 54-67CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
    A review. Although most cellular glutathione (GSH) is in the cytoplasm, a distinctly regulated pool is present in mitochondria. Inasmuch as GSH synthesis is primarily restricted to the cytoplasm, the mitochondrial pool must derive from transport of cytoplasmic GSH across the mitochondrial inner membrane. Early studies in liver mitochondria primarily focused on the relationship between GSH status and membrane permeability and energetics. Because GSH is an anion at physiol. pH, this suggested that some of the org. anion carriers present in the inner membrane could function in GSH transport. Indeed, studies by Lash and colleagues in isolated mitochondria from rat kidney showed that most of the transport (>80%) in that tissue could be accounted for by function of the dicarboxylate carrier (DIC, Slc25a10) and the oxoglutarate carrier (OGC, Slc25a11), which mediate electroneutral exchange of dicarboxylates for inorg. phosphate and 2-oxoglutarate for other dicarboxylates, resp. The identity and function of specific carrier proteins in other tissues is less certain, although the OGC is expressed in heart, liver, and brain and the DIC is expressed in liver and kidney. An addnl. carrier that transports 2-oxoglutarate, the oxodicarboxylate or oxoadipate carrier (ODC; Slc25a21), has been described in rat and human liver and its expression has a wide tissue distribution, although its potential function in GSH transport has not been investigated. Overexpression of the cDNA for the DIC and OGC in a renal proximal tubule-derived cell line, NRK-52E cells, showed that enhanced carrier expression and activity protects against oxidative stress and chem. induced apoptosis. This has implications for development of novel therapeutic approaches for treatment of human diseases and pathol. states. Several conditions, such as alc. liver disease, cirrhosis or other chronic biliary obstructive diseases, and diabetic nephropathy, are assocd. with depletion or oxidn. of the mitochondrial GSH pool in liver or kidney.
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  18. 18
    Mårtensson, J.; Lai, J. C. K.; Meister, A. High-Affinity Transport of Glutathione Is Part of a Multicomponent System Essential for Mitochondrial Function. Proc. Natl. Acad. Sci. U. S. A. 1990, 87 (18), 7185,  DOI: 10.1073/pnas.87.18.7185
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    18
    High-affinity transport of glutathione is part of a multicomponent system essential for mitochondrial function
    Martensson, Johannes; Lai, James C. K.; Meister, Alton
    Proceedings of the National Academy of Sciences of the United States of America (1990), 87 (18), 7185-9CODEN: PNASA6; ISSN:0027-8424.
    Glutathione (GSH), an essential cellular antioxidant required for mitochondrial function, is not synthesized by mitochondria but is imported from the cytosol. Rat liver mitochondria have a multicomponent system that underlies the remarkable ability of mitochondria to take up and retain GSH. At external GSH levels of <1 mM, GSH is transported into the mitochondrial matrix by a high-affinity component (Km = ∼60 μM; Vmax = ∼0.5 nmol/min/mg protein), which is satd. at levels of 1-2 mM and stimulated by ATP. Another component had lower affinity (Km = ∼5.4 mM; Vmax, = ∼5.9 nmol/min/mg protein) and was stimulated by ATP and ADP. Both components were inhibited by carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), glutamate, and ophthalmic acid. An increase of extramitochondrial GSH promoted uptake and exchange; the intermembranous space appeared to function as a recovery zone that promotes efficient recycling of matrix GSH. The findings were in accord with in vivo data showing that (i) rapid exchange occurs between mitochondrial and cytosolic GSH, (ii) lowering of cytosolic GSH levels (produced by administration of buthionine sulfoximine) decreases export of GSH from mitochondria to cytosol, and (iii) administration of GSH esters increases GSH levels in mitochondria more than those in the cytosol.
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    Boldin, M. P.; Goncharov, T. M.; Goltseve, Y. V.; Wallach, D. Involvement of MACH, a Novel MORT1/FADD-Interacting Protease, in Fas/APO-1- and TNF Receptor-Induced Cell Death. Cell 1996, 85 (6), 803– 815,  DOI: 10.1016/S0092-8674(00)81265-9
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    19
    Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death
    Boldin, Mark P.; Goncharov, Tanya M.; Goltsev, Yury V.; Wallach, David
    Cell (Cambridge, Massachusetts) (1996), 85 (6), 803-815CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Fas/APO-1 and p55 tumor necrosis factor (TNF) receptor (p55-R) activate cellular mechanisms that results in cell death. Upon activation of these receptors, Fas/APO-1 binds a protein called MORT1 (or FADD) and p55-R binds a protein called TRADD. MORT1 and TRADD can also bind to each other. We have cloned a novel protein, MACH, that binds to MORT1. This protein exists in multiple isoforms, some of which contain a region that has proteolytic activity and shows marked sequence homol. to proteases of the ICE/CED-3 family. Cellular expression of the proteolytic MACH isoforms results in cell death. Expression of MACH isoforms that contain an incomplete ICE/CED-3 region provides effective protection against the cytotoxicity induced by Fas/APO-1 or p55-R triggering. These findings suggest that MACH is the most upstream enzymic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades.
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  20. 20
    Muzio, M.; Chinnaiyan, A. M.; Kischkel, F. C.; O’Rourke, K. FLICE, A Novel FADD-Homologous ICE/CED-3-like Protease, Is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex. Cell 1996, 85, 817– 827,  DOI: 10.1016/S0092-8674(00)81266-0
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    20
    FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex
    Muzio, Marta; Chinnaiyan, Arul M.; Kischkel, Frank C.; O'Rourke, Karen; Shevchenko, Andrej; Ni, Jian; Scaffidi, Carsten; Bretz, James D.; Zhang, Mei; et al.
    Cell (Cambridge, Massachusetts) (1996), 85 (6), 817-827CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Nano-electrospray tandem mass spectrometry, a recently developed technique to sequence femtomole quantities of polyacrylamide gel-sepd. proteins, was used to identify CAP3 and CAP4, components of the CD95 (Fas/APO-1) death-inducing signaling complex. Interestingly, CAP4 encodes a novel 55-kDa protein, designated FLICE, which has homol. to both FADD and the ICE/CED-3 family of cysteine proteases. FLICE binds to the death effector domain of FADD and upon overexpression induces apoptosis that is blocked by the ICE family inhibitors, CrmA and z-VAD-fmk. CAP3 was identified as the FLICE prodomain which likely remains bound to the receptor after proteolytic activation. Taken together, this is unique biochem. evidence to link a death receptor phys. to the proapoptotic proteases of the ICE/CED-3 family.
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    Zhivotovsky, B. Caspases: The Enzymes of Death. Essays Biochem. 2003, 39, 25– 40,  DOI: 10.1042/bse0390025
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    Caspases: the enzymes of death
    Zhivotovsky, Boris
    Essays in Biochemistry (2003), 39 (), 25-40CODEN: ESBIAV; ISSN:0071-1365. (Portland Press Ltd.)
    A review. The caspases are a unique family of cysteine proteases, which cleave proteins next to an Asp residue. Among all known mammalian proteases, only the serine protease, granzyme B, has a similar substrate specificity. In addn. to a central role of caspases in the initiation and execution phases of apoptosis, these enzymes have some other non-apoptotic functions in living cells. During apoptosis, upon activation, caspases cleave specific substrates and thereby mediate many of the typical biochem. and morphol. changes in apoptotic cells, such as cell shrinkage, chromatin condensation, DNA fragmentation, and plasma membrane blebbing. Thus, detection of activated caspases can be used as a biochem. marker for apoptosis induced by diverse stimuli in many types of cells.
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    Srinivasa Rao, C.; Emmanuel Subash, Y. The Effect of Chronic Tobacco Smoking and Chewing on the Lipid Profile. J. Clin. Diagn. Res. 2013, 7 (1), 31– 34,  DOI: 10.7860/JCDR/2012/5086.2663
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    The effect of chronic tobacco smoking and chewing on the lipid profile
    Srinivasa, Rao Ch.; Emmanuel, Subash Y.
    Journal of Clinical and Diagnostic Research (2013), 7 (1), 31-34CODEN: JCDRAB; ISSN:0973-709X. (JCDR Research and Publications (Pvt) Ltd.)
    Background: A worldwide epidemic of cardio vascular diseases is evolving, out of which atherosclerosis appears to be the most frequent underlying cause. Cigarette smoking remains the most important cause of the preventable morbidity and the early mortality. Nicotine is highly addictive, it raises the brain levels of dopamine and it produces withdrawal symptoms on its discontinuation. Aim: To study the effect of tobacco smoking & chewing on serum lipid profile. Methods: Although a genetic predisposition to atherosclerosis may be the cause, a vast majority of the atherosclerotic related diseases, which include coronary heart diseases, are acquired. Those which usually appear later in life are largely preventable. Tobacco is the major and the single most preventable risk factor for atherosclerotic related, clin. events like coronary heart disease. This study was conducted on three groups of male subjects, with each group contg. 25 individuals of 25 to 35 years of age and who weighed 50-70 kgs. Group-I: non smokers and non chewers. Group-II: smokers and non chewers. Group-III: chewers and non smokers. To est. the triglycerides, glycerol which is derived from the sapon. of triglycerides is oxidized to formaldehyde, which in turn is made to react with ammonia and acetylacetone to give rise to a chromogen (3.5 diacetyle-1,4 dihydrolutidine). It is quantified spectro-photometrically (the HANTZSCH reaction). Results: The mean serum total cholesterol level in the subjects of Group II was more by about 16.94% (p<0.001) and that in the subjects of Group-III was more by 23.21% (p<0.001). The mean serum VLDL level in the subjects of Group II had an increase of about 27.54% (p<0.01) and in Group-III, it had increased by 11.82% (p<0.01). The mean serum LDL level in the subjects of Group II showed an increase of about 34.64% (p<0.001) and in Group-III, it had increased by 16.27% (p<0.001). The mean serum HDL level in the subjects of Group II showed a decrease in the mean serum HDL level by about 9.78% (p<0.01) and in Group-III, it had decreased by 22.12% (p<0.01). The mean serum triglyceride level in the subjects of Group II showed an increase of about 25.40% (p<0.001) and in Group-III, it was more by 33.35% (p<0.001). Conclusion: There was a significant increase in total cholesterol and LDL-C in tobacco users, as compared to non tobacco users.
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    Imlay, J. A.; Chin, S. M.; Linn, S. Toxic DNA Damage by Hydrogen Peroxide through the Fenton Reaction in Vivo and in Vitro. Science 1988, 240 (4852), 640– 642,  DOI: 10.1126/science.2834821
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    Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro
    Imlay, James A.; Chin, Sherman M.; Linn, Stuart
    Science (Washington, DC, United States) (1988), 240 (4852), 640-2CODEN: SCIEAS; ISSN:0036-8075.
    An in vitro Fenton system was established that generates DNA strand breaks and inactivates bacteriophage and also reproduces the suppression of DNA damage by high concns. of H2O2. The direct DNA oxidant both in vivo and in this in vitro system exhibits reactivity unlike that of a free hydroxyl radical and may instead be a ferryl radical.
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    Giorgio, M.; Migliaccio, E.; Orsini, F.; Paolucci, D.; Moroni, M.; Contursi, C.; Pelliccia, G.; Luzi, L.; Minucci, S.; Marcaccio, M.; Pinton, P.; Rizzuto, R.; Bernardi, P.; Paolucci, F.; Pelicci, P. G. Electron Transfer between Cytochrome c and P66Shc Generates Reactive Oxygen Species That Trigger Mitochondrial Apoptosis. Cell 2005, 122 (2), 221– 233,  DOI: 10.1016/j.cell.2005.05.011
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    Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis
    Giorgio, Marco; Migliaccio, Enrica; Orsini, Francesca; Paolucci, Demis; Moroni, Maurizio; Contursi, Cristina; Pelliccia, Giovanni; Luzi, Lucilla; Minucci, Saverio; Marcaccio, Massimo; Pinton, Paolo; Rizzuto, Rosario; Bernardi, Paolo; Paolucci, Francesco; Pelicci, Pier Giuseppe
    Cell (Cambridge, MA, United States) (2005), 122 (2), 221-233CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Reactive oxygen species (ROS) are potent inducers of oxidative damage and have been implicated in the regulation of specific cellular functions, including apoptosis. Mitochondrial ROS increase markedly after proapoptotic signals, though the biol. significance and the underlying mol. mechanisms remain undetd. P66Shc is a genetic determinant of life span in mammals, which regulates ROS metab. and apoptosis. The authors report that p66Shc is a redox enzyme that generates mitochondrial ROS (hydrogen peroxide) as signaling mols. for apoptosis. For this function, p66Shc utilizes reducing equiv. of the mitochondrial electron transfer chain through the oxidn. of cytochrome c. Redox-defective mutants of p66Shc are unable to induce mitochondrial ROS generation and swelling in vitro or to mediate mitochondrial apoptosis in vivo. These data demonstrate the existence of alternative redox reactions of the mitochondrial electron transfer chain, which evolved to generate proapoptotic ROS in response to specific stress signals.
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    Ribas, V.; García-Ruiz, C.; Fernández-Checa, J. C. Glutathione and Mitochondria. Front. Pharmacol. 2014, 5, 151,  DOI: 10.3389/fphar.2014.00151
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    Glutathione and mitochondria
    Ribas Vicent; Garcia-Ruiz Carmen; Fernandez-Checa Jose C
    Frontiers in pharmacology (2014), 5 (), 151 ISSN:1663-9812.
    Glutathione (GSH) is the main non-protein thiol in cells whose functions are dependent on the redox-active thiol of its cysteine moiety that serves as a cofactor for a number of antioxidant and detoxifying enzymes. While synthesized exclusively in the cytosol from its constituent amino acids, GSH is distributed in different compartments, including mitochondria where its concentration in the matrix equals that of the cytosol. This feature and its negative charge at physiological pH imply the existence of specific carriers to import GSH from the cytosol to the mitochondrial matrix, where it plays a key role in defense against respiration-induced reactive oxygen species and in the detoxification of lipid hydroperoxides and electrophiles. Moreover, as mitochondria play a central strategic role in the activation and mode of cell death, mitochondrial GSH has been shown to critically regulate the level of sensitization to secondary hits that induce mitochondrial membrane permeabilization and release of proteins confined in the intermembrane space that once in the cytosol engage the molecular machinery of cell death. In this review, we summarize recent data on the regulation of mitochondrial GSH and its role in cell death and prevalent human diseases, such as cancer, fatty liver disease, and Alzheimer's disease.
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    Galimov, E. R. The Role of P66shc in Oxidative Stress and Apoptosis. Acta Naturae 2010, 2 (4), 44,  DOI: 10.32607/20758251-2010-2-4-44-51
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    The Role of p66shc in Oxidative Stress and Apoptosis
    Galimov E R
    Acta naturae (2010), 2 (4), 44-51 ISSN:2075-8251.
    p66shcis a gene that regulates the level of reactive oxygen species (ROS), apoptosis induction, and lifespan in mammals. Miceknocked out forp66shchave a lifespan~30% longeranddemonstrate an enhanced resistance to oxidative stress and age-related pathologies such as hypercholesterolemia, ischemia, and hyperglycemia. In this respect, p66shc is a promising pharmacological target for the treatment of age-related diseases. In this review, an attempt has been made to survey and put to a critical analysis data concerning the involvement of p66sh.scy. in the different signaling pathways that regulate oxidative stress and apoptosis.
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    Kagan, V. E.; Tyurin, V. A.; Jiang, J.; Tyurina, Y. Y.; Ritov, V. B.; Amoscato, A. A.; Osipov, A. N.; Belikova, N. A.; Kapralov, A. A.; Kini, V.; Vlasova, I. I.; Zhao, Q.; Zou, M.; Di, P.; Svistunenko, D. A.; Kurnikov, I. V.; Borisenko, G. G. Cytochrome c Acts as a Cardiolipin Oxygenase Required for Release of Proapoptotic Factors. Nat. Chem. Biol. 2005, 1 (4), 223– 232,  DOI: 10.1038/nchembio727
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    Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors
    Kagan, Valerian E.; Tyurin, Vladimir A.; Jiang, Jianfei; Tyurina, Yulia Y.; Ritov, Vladimir B.; Amoscato, Andrew A.; Osipov, Anatoly N.; Belikova, Natalia A.; Kapralov, Alexandr A.; Kini, Vidisha; Vlasova, Irina I.; Zhao, Qing; Zou, Meimei; Di, Peter; Svistunenko, Dimitry A.; Kurnikov, Igor V.; Borisenko, Gregory G.
    Nature Chemical Biology (2005), 1 (4), 223-232CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
    Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascades. The release mechanisms include interactions of B-cell/lymphoma 2 family proteins with a mitochondria-specific phospholipid, cardiolipin, to cause permeabilization of the outer mitochondrial membrane. Using oxidative lipidomics, we showed that cardiolipin is the only phospholipid in mitochondria that undergoes early oxidn. during apoptosis. The oxidn. is catalyzed by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. In a previously undescribed step in apoptosis, we showed that oxidized cardiolipin is required for the release of proapoptotic factors. These results provide insight into the role of reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation.
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    Ott, M.; Robertson, J. D.; Gogvadze, V.; Zhivotovsky, B.; Orrenius, S. Cytochrome c Release from Mitochondria Proceeds by a Two-Step Process. Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (3), 1259– 1263,  DOI: 10.1073/pnas.241655498
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    Cytochrome c release from mitochondria proceeds by a two-step process
    Ott, Martin; Robertson, John D.; Gogvadze, Vladimir; Zhivotovsky, Boris; Orrenius, Sten
    Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (3), 1259-1263CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Cytochrome c is often released from mitochondria during the early stages of apoptosis, although the precise mechanisms regulating this event remain unclear. In this study, with isolated liver mitochondria, we demonstrate that cytochrome c release requires a two-step process. Because cytochrome c is present as loosely and tightly bound pools attached to the inner membrane by its assocn. with cardiolipin, this interaction must first be disrupted to generate a sol. pool of this protein. Specifically, solubilization of cytochrome c involves a breaching of the electrostatic and/or hydrophobic affiliations that this protein usually maintains with cardiolipin. Once cytochrome c is solubilized, permeabilization of the outer mitochondrial membrane by Bax is sufficient to allow the extrusion of this protein into the extramitochondrial environment. Neither disrupting the interaction of cytochrome c with cardiolipin, nor permeabilizing the outer membrane with Bax, alone, is sufficient to trigger this protein's release. This mechanism also extends to conditions of mitochondrial permeability transition insofar as cytochrome c release is significantly depressed when the electrostatic interaction between cytochrome c and cardiolipin remains intact. Our results indicate that the release of cytochrome c involves a distinct two-step process that is undermined when either step is compromised.
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    Ow, Y. L. P.; Green, D. R.; Hao, Z.; Mak, T. W. Cytochrome c: Functions beyond Respiration. Nat. Rev. Mol. Cell Biol. 2008, 9 (7), 532– 542,  DOI: 10.1038/nrm2434
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    Cytochrome c: functions beyond respiration
    Ow, Yong-Ling P.; Green, Douglas R.; Hao, Zhenyue; Mak, Tak W.
    Nature Reviews Molecular Cell Biology (2008), 9 (7), 532-542CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
    A review. Cytochrome c is primarily known for its function in the mitochondria as a key participant in the life-supporting function of ATP synthesis. However, when a cell receives an apoptotic stimulus, cytochrome c is released into the cytosol and triggers programmed cell death through apoptosis. The release of cytochrome c and cytochrome c-mediated apoptosis are controlled by multiple layers of regulation, the most prominent players being members of the B-cell lymphoma protein-2 (BCL2) family. As well as its role in canonical intrinsic apoptosis, cytochrome c amplifies signals that are generated by other apoptotic pathways and participates in certain non-apoptotic functions.
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    Mootha, V. K.; Wei, M. C.; Buttle, K. F.; Scorrano, L.; Panoutsakopoulou, V.; Mannella, C. A.; Korsmeyer, S. J. A Reversible Component of Mitochondrial Respiratory Dysfunction in Apoptosis Can Be Rescued by Exogenous Cytochrome C. EMBO J. 2001, 20 (4), 661– 671,  DOI: 10.1093/emboj/20.4.661
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    A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c
    Mootha, Vamsi K.; Wei, Michael C.; Buttle, Karolyn F.; Scorrano, Luca; Panoutsakopoulou, Vily; Mannella, Carmen A.; Korsmeyer, Stanley J.
    EMBO Journal (2001), 20 (4), 661-671CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)
    Multiple apoptotic pathways release cytochrome c from the mitochondrial intermembrane space, resulting in the activation of downstream caspases. In vivo activation of Fas (CD95) resulted in increased permeability of the mitochondrial outer membrane and depletion of cytochrome c stores. Serial measurements of oxygen consumption, NADH redox state and membrane potential revealed a loss of respiratory state transitions. This tBID-induced respiratory failure did not require any caspase activity. At early time points, re-addn. of exogenous cytochrome c markedly restored respiratory functions. Over time, however, mitochondria showed increasing irreversible respiratory dysfunction as well as diminished calcium buffering. Electron microscopy and tomog. reconstruction revealed asym. mitochondria with blebs of herniated matrix, distended inner membrane and partial loss of cristae structure. Thus, apoptogenic redistribution of cytochrome c is responsible for a distinct program of mitochondrial respiratory dysfunction, in addn. to the activation of downstream caspases.
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    Zhao, Y.; Wang, Z. B.; Xu, J. X. Effect of Cytochrome c on the Generation and Elimination of O2*- and H2O2 in Mitochondria. J. Biol. Chem. 2003, 278 (4), 2356– 2360,  DOI: 10.1074/jbc.M209681200
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    Effect of Cytochrome c on the Generation and Elimination of O and H2O2 in Mitochondria
    Zhao, Yungang; Wang, Zhi-Bo; Xu, Jian-Xing
    Journal of Biological Chemistry (2003), 278 (4), 2356-2360CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    The primary recognized function of cytochrome c is to act as an electron carrier transferring electrons from complex III to complex IV in the respiratory chain of mitochondria. Recent studies on cell apoptosis reveal that cytochrome c is responsible for the programmed cell death when it is released from mitochondria to cytoplasm. In this study we present evidence showing that cytochrome c plays an antioxidative role by acting on the generation and elimination of O and H2O2 in mitochondria. The O and H2O2 generation in cytochrome c-depleted Keilin-Hartree heart muscle prepn. (HMP) is 7-8 times higher than that in normal HMP. The reconstitution of cytochrome c to the cytochrome c-depleted HMP causes the O and H2O2 generation to exponentially decrease. An alternative electron-leak pathway of the respiratory chain is suggested to explain how cytochrome c affects on the generation and elimination of O and H2O2 in mitochondria. Enough cytochrome c in the respiratory chain is needed for keeping O and H2O2 at a lower physiol. level. A dramatic increase of O and H2O2 generation occurs when cytochrome c is released from the respiratory chain. The burst of O and H2O2, which happens at the same time as cytochrome c release from the respiratory chain, should have some role in the early stage of cell apoptosis.
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    Hemann, M. T.; Lowe, S. W. The P53-Bcl-2 Connection. Cell Death Differ. 2006, 13 (8), 1256– 1259,  DOI: 10.1038/sj.cdd.4401962
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    The p53-Bcl-2 connection
    Hemann, M. T.; Lowe, S. W.
    Cell Death and Differentiation (2006), 13 (8), 1256-1259CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)
    A review discusses p53 transactivation of proapoptotic Bcl-2 family members and transactivation-independent p53 regulation of Bcl-2/. The relevance of the p53-Bcl-2 pathway to cancer is discussed.
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    Muñoz-Pinedo, C.; Guío-Carrión, A.; Goldstein, J. C.; Fitzgerald, P.; Newmeyer, D. D.; Green, D. R. Different Mitochondrial Intermembrane Space Proteins Are Released during Apoptosis in a Manner That Is Coordinately Initiated but Can Vary in Duration. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (31), 11573– 11578,  DOI: 10.1073/pnas.0603007103
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    Different mitochondrial intermembrane space proteins are released during apoptosis in a manner that is coordinately initiated but can vary in duration
    Munoz-Pinedo, Cristina; Guio-Carrion, Ana; Goldstein, Joshua C.; Fitzgerald, Patrick; Newmeyer, Donald D.; Green, Douglas R.
    Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (31), 11573-11578CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The release of mitochondrial intermembrane space proteins to the cytosol is a key event during apoptosis. We used in situ fluorescent labeling of proteins tagged with a short tetracysteine-contg. sequence to follow the release of Smac, Omi, adenylate kinase-2, cytochrome c, and apoptosis-inducing factor (AIF) during apoptosis and compared the release with that of cytochrome c tagged with GFP in individual cells obsd. over time. We obsd. a caspase-independent, simultaneous release of cytochrome c, Smac, Omi, and adenylate kinase-2. Although AIF release also was caspase-independent and commenced with that of the other proteins, it proceeded much more slowly and incompletely from mitochondria, perhaps because of a requirement for a secondary event. These results suggest that these proteins are released through the same mitochondrial pore and that apoptosis may not be regulated through a selective release of individual mitochondrial proteins. The timing and extent of AIF release makes it unlikely that it is involved in the induction of apoptosis, either upstream or down-stream of mitochondrial outer membrane permeabilization.
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    Scorrano, L.; Ashiya, M.; Buttle, K.; Weiler, S.; Oakes, S. A.; Mannella, C. A.; Korsmeyer, S. J. A Distinct Pathway Remodels Mitochondrial Cristae and Mobilizes Cytochrome c during Apoptosis. Dev. Cell 2002, 2 (1), 55– 67,  DOI: 10.1016/S1534-5807(01)00116-2
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    A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis
    Scorrano, Luca; Ashiya, Mona; Buttle, Karolyn; Weiler, Solly; Oakes, Scott A.; Mannella, Carmen A.; Korsmeyer, Stanley J.
    Developmental Cell (2002), 2 (1), 55-67CODEN: DCEEBE; ISSN:1534-5807. (Cell Press)
    The mechanism during apoptosis by which cytochrome c is rapidly and completely released in the absence of mitochondrial swelling is uncertain. Here, we show that two distinct pathways are involved. One mediates release of cytochrome c across the outer mitochondrial membrane, and another, characterized in this study, is responsible for the redistribution of cytochrome c stored in intramitochondrial cristae. We have found that the "BH3-only" mol. tBID induces a striking remodeling of mitochondrial structure with mobilization of the cytochrome c stores (∼ 85%) in cristae. This reorganization does not require tBID's BH3 domain and is independent of BAK, but is inhibited by CsA. During this process, individual cristae become fused and the junctions between the cristae and the intermembrane space are opened.
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    Li, P.; Nijhawan, D.; Budihardjo, I.; Srinivasula, S. M.; Ahmad, M.; Alnemri, E. S.; Wang, X. Cytochrome c and DATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade. Cell 1997, 91 (4), 479– 489,  DOI: 10.1016/S0092-8674(00)80434-1
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    Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade
    Li, Peng; Nijhawan, Deepak; Budihardjo, Imawati; Alnemri, Emad S.; Wang, Xiaodong
    Cell (Cambridge, Massachusetts) (1997), 91 (4), 479-489CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    The purifn. from HeLa cell S-100 cytosolic fraction of the 3rd protein factor, Apaf-3, that participates in caspase-3 activation in vitro, is reported. Here, Apaf-3 is identified as a member of the caspase family, caspase-9. Caspase-9 and Apaf-1 bind to each other via their resp. N-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. Activated caspase-9 in turn cleaves and activates caspase-3. Depletion of caspase-9 from the S-100 exts. was found to diminish caspase-3 activation. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP.
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    Lakshmanan, I.; Batra, S. K. Protocol for Apoptosis Assay by Flow Cytometry Using Annexin V Staining Method Materials and Reagents. BIO-PROTOCOL 2013, 3, e374,  DOI: 10.21769/BioProtoc.374
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    Campisi, J. Aging, Cellular Senescence, and Cancer. Annu. Rev. Physiol. 2013, 75, 685– 705,  DOI: 10.1146/annurev-physiol-030212-183653
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    Aging, cellular senescence, and cancer
    Campisi, Judith
    Annual Review of Physiology (2013), 75 (), 685-705CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews Inc.)
    A review. For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, esp. among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biol. phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
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    Muñoz-Espín, D.; Serrano, M. Cellular Senescence: From Physiology to Pathology. Nat. Rev. Mol. Cell Biol. 2014, 15 (7), 482– 496,  DOI: 10.1038/nrm3823
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    Cellular senescence: from physiology to pathology
    Munoz-Espin, Daniel; Serrano, Manuel
    Nature Reviews Molecular Cell Biology (2014), 15 (7), 482-496CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
    A review. Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events - senescence, followed by clearance and then regeneration - may not be efficiently completed in aged tissues or in pathol. contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro-senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, resp. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.
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    Van Deursen, J. M. The Role of Senescent Cells in Ageing. Nature 2014, 509 (7501), 439– 446,  DOI: 10.1038/nature13193
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    The role of senescent cells in ageing
    van Deursen, Jan M.
    Nature (London, United Kingdom) (2014), 509 (7501), 439-446CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    A review. Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biol. processes such as development, tissue repair, ageing and age-related disorders. New insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. A deeper understanding of the mol. mechanisms underlying the multi-step progression of senescence and the development and function of acute vs. chronic senescent cells may lead to new therapeutic strategies for age-related pathologies and extend healthy lifespan.
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    Sharpless, N. E.; Sherr, C. J. Forging a Signature of in Vivo Senescence. Nat. Rev. Cancer 2015, 15 (7), 397– 408,  DOI: 10.1038/nrc3960
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    Forging a signature of in vivo senescence
    Sharpless, Norman E.; Sherr, Charles J.
    Nature Reviews Cancer (2015), 15 (7), 397-408CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
    A review. 'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest induced by disparate stress factors. Proposed relationships between cellular senescence, tumor suppression, loss of tissue regenerative capacity and aging suffer from lack of uniform definition and consistently applied criteria. Here, we highlight caveats in interpreting the importance of suboptimal senescence-assocd. biomarkers, expressed either alone or in combination. We advocate that more-specific descriptors be substituted for the now broadly applied umbrella term 'senescence' in defining the suite of diverse physiol. responses to cellular stress.
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    Baker, D. J.; Childs, B. G.; Durik, M.; Wijers, M. E.; Sieben, C. J.; Zhong, J.; Saltness, R. A.; Jeganathan, K. B.; Verzosa, G. C.; Pezeshki, A.-M.; Khazaie, K.; Miller, J. D.; Van Deursen, J. M. Naturally Occurring P16 Ink4a-Positive Cells Shorten Healthy Lifespan HHS Public Access. Nature 2016, 530 (7589), 184– 189,  DOI: 10.1038/nature16932
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    Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
    Baker, Darren J.; Childs, Bennett G.; Durik, Matej; Wijers, Melinde E.; Sieben, Cynthia J.; Zhong, Jian; Saltness, Rachel A.; Jeganathan, Karthik B.; Verzosa, Grace Casaclang; Pezeshki, Abdulmohammad; Khazaie, Khashayarsha; Miller, Jordan D.; van Deursen, Jan M.
    Nature (London, United Kingdom) (2016), 530 (7589), 184-189CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16Ink4a (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiol. relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-pos. cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, resp. Thus, p16Ink4a-pos. cells that accumulate during adulthood neg. influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
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    Childs, B. G.; Gluscevic, M.; Baker, D. J.; Laberge, R. M.; Marquess, D.; Dananberg, J.; Van Deursen, J. M. Senescent Cells: An Emerging Target for Diseases of Ageing. Nat. Rev. Drug Discovery 2017, 16 (10), 718– 735,  DOI: 10.1038/nrd.2017.116
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    Senescent cells: an emerging target for diseases of ageing
    Childs, Bennett G.; Gluscevic, Martina; Baker, Darren J.; Laberge, Remi-Martin; Marquess, Dan; Dananberg, Jamie; van Deursen, Jan M.
    Nature Reviews Drug Discovery (2017), 16 (10), 718-735CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)
    Chronol. age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programs now nearing human clin. studies.
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    Kumar, M.; Seeger, W.; Voswinckel, R. Senescence-Associated Secretory Phenotype and Its Possible Role in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell Mol. Biol. 2014, 51 (3), 323– 333,  DOI: 10.1165/rcmb.2013-0382PS
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    43
    Senescence-associated secretory phenotype and its possible role in chronic obstructive pulmonary disease
    Kumar, Manish; Seeger, Werner; Voswinckel, Robert
    American Journal of Respiratory Cell and Molecular Biology (2014), 51 (3), 323-333, 11 pp.CODEN: AJRBEL; ISSN:1044-1549. (American Thoracic Society)
    A review. Chronic obstructive pulmonary disease (COPD) is a major disease of the lungs. It primarily occurs after a prolonged period of cigarette smoking. Chronic inflammation of airways and the alveolar space as well as lung tissue destruction are the hallmarks of COPD. Recently it has been shown that cellular senescence might play a role in the pathogenesis of COPD. Cellular senescence comprises signal transduction program, leading to irreversible cell cycle arrest. The growth arrest in senescence can be triggered by many different mechanisms, including DNA damage and its recognition by cellular sensors, leading to the activation of cell cycle checkpoint responses and activation of DNA repair machinery. Senescence can be induced by several genotoxic factors apart from telomere attrition. When senescence induction is based on DNA damage, senescent cells display a unique phenotype, which has been termed "senescence-assocd. secretory phenotype" (SASP). SASP may be an important driver of chronic inflammation and therefore may be part of a vicious cycle of inflammation, DNA damage, and senescence. This research perspective aims to showcase cellular senescence with relevance to COPD and the striking similarities between the mediators and secretory phenotype in COPD and SASP.
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    Campisi, J. Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors. Cell 2005, 120 (4), 513– 522,  DOI: 10.1016/j.cell.2005.02.003
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    Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
    Campisi, Judith
    Cell (Cambridge, MA, United States) (2005), 120 (4), 513-522CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    A review. Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
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    Ogrodnik, M.; Miwa, S.; Tchkonia, T.; Tiniakos, D.; Wilson, C. L.; Lahat, A.; Day, C. P.; Burt, A.; Palmer, A.; Anstee, Q. M.; Grellscheid, S. N.; Hoeijmakers, J. H. J.; Barnhoorn, S.; Mann, D. A.; Bird, T. G.; Vermeij, W. P.; Kirkland, J. L.; Passos, J. F.; Von Zglinicki, T.; Jurk, D. Cellular Senescence Drives Age-Dependent Hepatic Steatosis. Nat. Commun. 2017 81 2017, 8 (1), 1– 12,  DOI: 10.1038/ncomms15691
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    Tchkonia, T.; Zhu, Y.; Van Deursen, J.; Campisi, J.; Kirkland, J. L. Cellular Senescence and the Senescent Secretory Phenotype: Therapeutic Opportunities. J. Clin. Invest. 2013, 123 (3), 966– 972,  DOI: 10.1172/JCI64098
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    Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
    Tchkonia, Tamara; Zhu, Yi; van Deursen, Jan; Campisi, Judith; Kirkland, James L.
    Journal of Clinical Investigation (2013), 123 (3), 966-972CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
    A review. Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-assocd. secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their assocns. with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clin. interventions.
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    Campisi, J.; D’Adda Di Fagagna, F. Cellular Senescence: When Bad Things Happen to Good Cells. Nat. Rev. Mol. Cell Biol. 2007, 8 (9), 729– 740,  DOI: 10.1038/nrm2233
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    Cellular senescence: when bad things happen to good cells
    Campisi, Judith; d'Adda di Fagagna, Fabrizio
    Nature Reviews Molecular Cell Biology (2007), 8 (9), 729-740CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
    A review. Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an addnl. response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, esp. genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and aging.
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    Lebrasseur, N. K.; Tchkonia, T.; Kirkland, J. L. Cellular Senescence and the Biology of Aging, Disease, and Frailty. Nestle Nutr. Inst. Workshop Ser. 2015, 83, 11– 18,  DOI: 10.1159/000382054
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    Cellular Senescence and the Biology of Aging, Disease, and Frailty
    LeBrasseur Nathan K; Tchkonia Tamara; Kirkland James L
    Nestle Nutrition Institute workshop series (2015), 83 (), 11-8 ISSN:.
    Population aging simultaneously highlights the remarkable advances in science, medicine, and public policy, and the formidable challenges facing society. Indeed, aging is the primary risk factor for many of the most common chronic diseases and frailty, which result in profound social and economic costs. Population aging also reveals an opportunity, i.e. interventions to disrupt the fundamental biology of aging could significantly delay the onset of age-related conditions as a group, and, as a result, extend the healthy life span, or health span. There is now considerable evidence that cellular senescence is an underlying mechanism of aging and age-related conditions. Cellular senescence is a process in which cells lose the ability to divide and damage neighboring cells by the factors they secrete, collectively referred to as the senescence-associated secretory phenotype (SASP). Herein, we discuss the concept of cellular senescence, review the evidence that implicates cellular senescence and SASP in age-related deterioration, hyperproliferation, and inflammation, and propose that this underlying mechanism of aging may play a fundamental role in the biology of frailty.
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    VanArsdale, T.; Boshoff, C.; Arndt, K. T.; Abraham, R. T. Molecular Pathways: Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment. Clin. Cancer Res. 2015, 21 (13), 2905– 2910,  DOI: 10.1158/1078-0432.CCR-14-0816
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    Molecular Pathways: Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment
    VanArsdale Todd; Abraham Robert T; Boshoff Chris; Arndt Kim T
    Clinical cancer research : an official journal of the American Association for Cancer Research (2015), 21 (13), 2905-10 ISSN:.
    Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. The retinoblastoma tumor suppressor protein (pRb) governs a key cell-cycle checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals. Cancer cells frequently overcome pRb-dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase (CDK) 4 or CDK6 partnered with D-type cyclins. Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non-small cell lung cancer. The emerging, positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D-CDK4/6 pathway is a rational target for cancer therapy.
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    Liu, Y.; Johnson, S. M.; Fedoriw, Y.; Rogers, A. B.; Yuan, H.; Krishnamurthy, J.; Sharpless, N. E. Expression of P16INK4a Prevents Cancer and Promotes Aging in Lymphocytes. Blood 2011, 117 (12), 3257,  DOI: 10.1182/blood-2010-09-304402
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    Expression of p16INK4a prevents cancer and promotes aging in lymphocytes
    Liu, Yan; Johnson, Soren M.; Fedoriw, Yuri; Rogers, Arlin B.; Yuan, Hong; Krishnamurthy, Janakiraman; Sharpless, Norman E.
    Blood (2011), 117 (12), 3257-3267CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)
    Previous authors have suggested that tumor suppressor expression promotes aging while preventing cancer, but direct exptl. support for this cancer-aging hypothesis has been elusive. Here, by using somatic, tissue-specific inactivation of the p16INK4a tumor suppressor in murine T- or B-lymphoid progenitors, we report that ablation of p16INK4a can either rescue aging or promote cancer in a lineage-specific manner. Deletion of p16INK4a in the T lineage ameliorated several aging phenotypes, including thymic involution, decreased prodn. of naive T cells, redn. in homeostatic T-cell proliferation, and attenuation of antigen-specific immune responses. Increased T-cell neoplasia was not obsd. with somatic p16INK4a inactivation in T cells. In contrast, B lineage-specific ablation of p16INK4a was assocd. with a markedly increased incidence of systemic, high-grade B-cell neoplasms, which limited studies of the effects of somatic p16INK4a ablation on B-cell aging. Together, these data show that expression of p16INK4a can promote aging and prevent cancer in related lymphoid progeny of a common stem cell.
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    Cottage, C. T.; Peterson, N.; Kearley, J.; Berlin, A.; Xiong, X.; Huntley, A.; Zhao, W.; Brown, C.; Migneault, A.; Zerrouki, K.; Criner, G.; Kolbeck, R.; Connor, J.; Lemaire, R. Targeting P16-Induced Senescence Prevents Cigarette Smoke-Induced Emphysema by Promoting IGF1/Akt1 Signaling in Mice. Commun Biol 2019, 2, 307,  DOI: 10.1038/s42003-019-0532-1
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    Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice
    Cottage Christopher T; Peterson Norman; Kearley Jennifer; Berlin Aaron; Xiong Ximing; Huntley Anna; Zhao Weiguang; Brown Charles; Migneault Annik; Zerrouki Kamelia; Kolbeck Roland; Connor Jane; Lemaire Raphael; Criner Gerald
    Communications biology (2019), 2 (), 307 ISSN:.
    Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke (CS) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to CS-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. CS induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas CS-exposed p16(-/-) mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16(-/-) mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.
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    Cheng, X.-Y.; Li, Y.-Y.; Huang, C.; Li, J.; Yao, H.-W. AMP-Activated Protein Kinase Reduces Inflammatory Responses and Cellular Senescence in Pulmonary Emphysema. Oncotarget 2017, 8 (14), 22513– 22523,  DOI: 10.18632/oncotarget.15116
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    AMP-activated protein kinase reduces inflammatory responses and cellular senescence in pulmonary emphysema
    Cheng Xiao-Yu; Li Yang-Yang; Huang Cheng; Li Jun; Yao Hong-Wei
    Oncotarget (2017), 8 (14), 22513-22523 ISSN:.
    Current drug therapy fails to reduce lung destruction of chronic obstructive pulmonary disease (COPD). AMP-activated protein kinase (AMPK) has emerged as an important integrator of signals that control energy balance and lipid metabolism. However, there are no studies regarding the role of AMPK in reducing inflammatory responses and cellular senescence during the development of emphysema. Therefore, we hypothesize that AMPK reduces inflammatroy responses, senescence, and lung injury. To test this hypothesis, human bronchial epithelial cells (BEAS-2B) and small airway epithelial cells (SAECs) were treated with cigarette smoke extract (CSE) in the presence of a specific AMPK activator (AICAR, 1 mM) and inhibitor (Compound C, 5 μM). Elastase injection was performed to induce mouse emphysema, and these mice were treated with a specific AMPK activator metformin as well as Compound C. AICAR reduced, whereas Compound C increased CSE-induced increase in IL-8 and IL-6 release and expression of genes involved in cellular senescence. Knockdown of AMPKα1/α2 increased expression of pro-senescent genes (e.g., p16, p21, and p66shc) in BEAS-2B cells. Prophylactic administration of an AMPK activator metformin (50 and 250 mg/kg) reduced while Compound C (4 and 20 mg/kg) aggravated elastase-induced airspace enlargement, inflammatory responses and cellular senescence in mice. This is in agreement with therapeutic effect of metformin (50 mg/kg) on airspace enlargement. Furthermore, metformin prophylactically protected against but Compound C further reduced mitochondrial proteins SOD2 and SIRT3 in emphysematous lungs. In conclusion, AMPK reduces abnormal inflammatory responses and cellular senescence, which implicates as a potential therapeutic target for COPD/emphysema.
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    Mikawa, R.; Sato, T.; Suzuki, Y.; Baskoro, H.; Kawaguchi, K.; Sugimoto, M. P19Arf Exacerbates Cigarette Smoke-Induced Pulmonary Dysfunction. Biomolecules 2020, 10 (3), 462,  DOI: 10.3390/biom10030462
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    p19Arf exacerbates cigarette smoke-induced pulmonary dysfunction
    Mikawa, Ryuta; Sato, Tadashi; Suzuki, Yohei; Baskoro, Hario; Kawaguchi, Koichiro; Sugimoto, Masataka
    Biomolecules (2020), 10 (3), 462CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
    Senescent cells accumulate in tissues during aging or pathol. settings. The semi- genetic or pharmacol. targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-assocd. phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-assocd. pulmonary dysfunction. We herein report that the elimination of Arf-expressing cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf-expressing cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke ext. lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-assocd. lung disease.
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    Bodas, M.; Pehote, G.; Silverberg, D.; Gulbins, E.; Vij, N. Autophagy Augmentation Alleviates Cigarette Smoke-Induced CFTR-Dysfunction, Ceramide-Accumulation and COPD-Emphysema Pathogenesis. Free Radic. Biol. Med. 2019, 131, 81– 97,  DOI: 10.1016/j.freeradbiomed.2018.11.023
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    Autophagy augmentation alleviates cigarette smoke-induced CFTR-dysfunction, ceramide-accumulation and COPD-emphysema pathogenesis
    Bodas, Manish; Pehote, Garrett; Silverberg, David; Gulbins, Erich; Vij, Neeraj
    Free Radical Biology & Medicine (2019), 131 (), 81-97CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
    In this study, we aimed to investigate precise mechanism(s) of sphingolipid-imbalance and resulting ceramide-accumulation in COPD-emphysema. Where, human and murine emphysema lung tissues or human bronchial epithelial cells (Beas2b) were used for exptl. anal. We found that lungs of smokers and COPD-subjects with increasing emphysema severity demonstrate sphingolipid-imbalance, resulting in significant ceramide-accumulation and increased ceramide/sphingosine ratio, as compared to non-emphysema/non-smoker controls. Next, we found a substantial increase in emphysema chronicity-related ceramide-accumulation in murine (C57BL/6) lungs, while sphingosine levels only slightly increased. In accordance, the expression of the acid ceramidase decreased after CS-exposure. Moreover, CS-induced (sub-chronic) ceramide-accumulation was significantly (p < 0.05) reduced by treatment with TFEB/autophagy-inducing drug, gemfibrozil (GEM), suggesting that autophagy regulates CS-induced ceramide-accumulation. Next, we validated exptl. that autophagy/lipophagy-induction using an anti-oxidant, cysteamine, significantly (p < 0.05) reduces CS-ext. (CSE)-mediated intracellular-ceramide-accumulation in p62 + aggresome-bodies. In addn. to intracellular-accumulation, we found that CSE also induces membrane-ceramide-accumulation by ROS-dependent acid-sphingomyelinase (ASM) activation and plasma-membrane translocation, which was significantly controlled (p < 0.05) by cysteamine (an anti-oxidant) and amitriptyline (AMT, an inhibitor of ASM). Cysteamine-mediated and CSE-induced membrane-ceramide regulation was nullified by CFTR-inhibitor-172, demonstrating that CFTR controls redox impaired-autophagy dependent membrane-ceramide accumulation. In summary, our data shows that CS-mediated autophagy/lipophagy-dysfunction results in intracellular-ceramide-accumulation, while acquired CFTR-dysfunction-induced ASM causes membrane ceramide-accumulation. Thus, CS-exposure alters the sphingolipid-rheostat leading to the increased membrane- and intracellular- ceramide-accumulation inducing COPD-emphysema pathogenesis that is alleviated by treatment with cysteamine, a potent anti-oxidant with CFTR/autophagy-augmenting properties.
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    Vij, N.; Chandramani-Shivalingappa, P.; Van Westphal, C.; Hole, R.; Bodas, M. Cigarette Smoke-Induced Autophagy Impairment Accelerates Lung Aging, COPD-Emphysema Exacerbations and Pathogenesis. Am. J. Physiol. Cell Physiol. 2018, 314 (1), C73– C87,  DOI: 10.1152/ajpcell.00110.2016
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    Woldhuis, R. R.; de Vries, M.; Timens, W.; van den Berge, M.; Demaria, M.; Oliver, B. G. G.; Heijink, I. H.; Brandsma, C. A. Link between Increased Cellular Senescence and Extracellular Matrix Changes in COPD. Am. J. Physiol. Lung Cell. Mol. Physiol. 2020, 319 (1), L48– L60,  DOI: 10.1152/ajplung.00028.2020
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    Storer, M.; Mas, A.; Robert-Moreno, A.; Pecoraro, M.; Ortells, M. C.; Di Giacomo, V.; Yosef, R.; Pilpel, N.; Krizhanovsky, V.; Sharpe, J.; Keyes, W. M. Senescence Is a Developmental Mechanism That Contributes to Embryonic Growth and Patterning. Cell 2013, 155 (5), 1119,  DOI: 10.1016/j.cell.2013.10.041
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    Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning
    Storer, Mekayla; Mas, Alba; Robert-Moreno, Alexandre; Pecoraro, Matteo; Ortells, M. Carmen; Di'Giacomo, Valeria; Yosef, Reut; Pilpel, Noam; Krizhanovsky, Valery; Sharpe, James; Keyes, William M.
    Cell (Cambridge, MA, United States) (2013), 155 (5), 1119-1130CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathol. states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-assocd. secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.
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    Mosteiro, L.; Pantoja, C.; Alcazar, N.; Marión, R. M.; Chondronasiou, D.; Rovira, M.; Fernandez-Marcos, P. J.; Muñoz-Martin, M.; Blanco-Aparicio, C.; Pastor, J.; Gómez-López, G.; De Martino, A.; Blasco, M. A.; Abad, M.; Serrano, M. Tissue Damage and Senescence Provide Critical Signals for Cellular Reprogramming in Vivo. Science 2016, 354 (6315), aaf4445,  DOI: 10.1126/science.aaf4445
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    Muñoz-Espín, D.; Cañamero, M.; Maraver, A.; Gómez-López, G.; Contreras, J.; Murillo-Cuesta, S.; Rodríguez-Baeza, A.; Varela-Nieto, I.; Ruberte, J.; Collado, M.; Serrano, M. Programmed Cell Senescence during Mammalian Embryonic Development. Cell 2013, 155 (5), 1104,  DOI: 10.1016/j.cell.2013.10.019
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    Programmed Cell Senescence during Mammalian Embryonic Development
    Munoz-Espin, Daniel; Canamero, Marta; Maraver, Antonio; Gomez-Lopez, Gonzalo; Contreras, Julio; Murillo-Cuesta, Silvia; Rodriguez-Baeza, Alfonso; Varela-Nieto, Isabel; Ruberte, Jesus; Collado, Manuel; Serrano, Manuel
    Cell (Cambridge, MA, United States) (2013), 155 (5), 1104-1118CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence.
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    Li, T.; Kon, N.; Jiang, L.; Tan, M.; Ludwig, T.; Zhao, Y.; Baer, R.; Gu, W. Tumor Suppression in the Absence of P53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence. Cell 2012, 149 (6), 1269– 1283,  DOI: 10.1016/j.cell.2012.04.026
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    Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence
    Li, Tongyuan; Kon, Ning; Jiang, Le; Tan, Minjia; Ludwig, Thomas; Zhao, Yingming; Baer, Richard; Gu, Wei
    Cell (Cambridge, MA, United States) (2012), 149 (6), 1269-1283CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are the rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53K117R) or three (p533KR; K117R+K161R+K162R) of p53 acetylation sites. Although p53K117R/K117R cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p533KR/3KR cells. Surprisingly, unlike p53 null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53K117R/K117R or p533KR/3KR animals. Notably, p533KR retains the ability to regulate energy metab. and reactive oxygen species prodn. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are crit. for suppression of early-onset spontaneous tumorigenesis.
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    Helman, A.; Klochendler, A.; Azazmeh, N.; Gabai, Y.; Horwitz, E.; Anzi, S.; Swisa, A.; Condiotti, R.; Granit, R. Z.; Nevo, Y.; Fixler, Y.; Shreibman, D.; Zamir, A.; Tornovsky-Babeay, S.; Dai, C.; Glaser, B.; Powers, A. C.; Shapiro, A. M. J.; Magnuson, M. A.; Dor, Y.; Ben-Porath, I. P16(Ink4a)-Induced Senescence of Pancreatic Beta Cells Enhances Insulin Secretion. Nat. Med. 2016, 22 (4), 412– 420,  DOI: 10.1038/nm.4054
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    p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion
    Helman, Aharon; Klochendler, Agnes; Azazmeh, Narmen; Gabai, Yael; Horwitz, Elad; Anzi, Shira; Swisa, Avital; Condiotti, Reba; Granit, Roy Z.; Nevo, Yuval; Fixler, Yaakov; Shreibman, Dorin; Zamir, Amit; Tornovsky-Babeay, Sharona; Dai, Chunhua; Glaser, Benjamin; Powers, Alvin C.; Shapiro, A. M. James; Magnuson, Mark A.; Dor, Yuval; Ben-Porath, Ittai
    Nature Medicine (New York, NY, United States) (2016), 22 (4), 412-420CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    Cellular senescence is thought to contribute to age-assocd. deterioration of tissue physiol. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16Ink4a in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16Ink4a in beta cells induces hallmarks of senescence-including cell enlargement, and greater glucose uptake and mitochondrial activity-which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.
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    Rudin, C. M.; Hann, C. L.; Garon, E. B.; Ribeiro De Oliveira, M.; Bonomi, P. D.; Camidge, D. R.; Chu, Q.; Giaccone, G.; Khaira, D.; Ramalingam, S. S.; Ranson, M. R.; Dive, C.; McKeegan, E. M.; Chyla, B. J.; Dowell, B. L.; Chakravartty, A.; Nolan, C. E.; Rudersdorf, N.; Busman, T. A.; Mabry, M. H.; Krivoshik, A. P.; Humerickhouse, R. A.; Shapiro, G. I.; Gandhi, L. Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer. Clin. Cancer Res. 2012, 18 (11), 3163– 3169,  DOI: 10.1158/1078-0432.CCR-11-3090
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    Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
    Rudin, Charles M.; Hann, Christine L.; Garon, Edward B.; Ribeiro de Oliveira, Moacyr; Bonomi, Philip D.; Camidge, D. Ross; Chu, Quincy; Giaccone, Giuseppe; Khaira, Divis; Ramalingam, Suresh S.; Ranson, Malcolm R.; Dive, Caroline; McKeegan, Evelyn M.; Chyla, Brenda J.; Dowell, Barry L.; Chakravartty, Arunava; Nolan, Cathy E.; Rudersdorf, Niki; Busman, Todd A.; Mabry, Mack H.; Krivoshik, Andrew P.; Humerickhouse, Rod A.; Shapiro, Geoffrey I.; Gandhi, Leena
    Clinical Cancer Research (2012), 18 (11), 3163-3169CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
    Purpose: Bcl-2 is a crit. regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-xL. The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. Exptl. Design: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results: The most common toxicity assocd. with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was obsd. in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 mo and median OS was 3.2 mo. A strong assocn. between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy no. (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell no. as correlates of clin. benefit. Conclusion: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clin. benefit. Preclin. models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to std. cytotoxics. Future studies will focus on combination therapies. Clin Cancer Res; 18(11); 3163-9. ©2012 AACR.
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    Laberge, R. M.; Sun, Y.; Orjalo, A. V.; Patil, C. K.; Freund, A.; Zhou, L.; Curran, S. C.; Davalos, A. R.; Wilson-Edell, K. A.; Liu, S.; Limbad, C.; Demaria, M.; Li, P.; Hubbard, G. B.; Ikeno, Y.; Javors, M.; Desprez, P. Y.; Benz, C. C.; Kapahi, P.; Nelson, P. S.; Campisi, J. MTOR Regulates the Pro-Tumorigenic Senescence-Associated Secretory Phenotype by Promoting IL1A Translation. Nat. Cell Biol. 2015, 17 (8), 1049– 1061,  DOI: 10.1038/ncb3195
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    MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation
    Laberge, Remi-Martin; Sun, Yu; Orjalo, Arturo V.; Patil, Christopher K.; Freund, Adam; Zhou, Lili; Curran, Samuel C.; Davalos, Albert R.; Wilson-Edell, Kathleen A.; Liu, Su; Limbad, Chandani; Demaria, Marco; Li, Patrick; Hubbard, Gene B.; Ikeno, Yuji; Javors, Martin; Desprez, Pierre-Yves; Benz, Christopher C.; Kapahi, Pankaj; Nelson, Peter S.; Campisi, Judith
    Nature Cell Biology (2015), 17 (8), 1049-1061CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)
    The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-assocd. secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumor growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-assocd. inflammation.
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    Truss, M.; Bartsch, J.; Mows, C.; Chavez, S.; Beato, M. Chromatin Structure of the MMTV Promoter and Its Changes during Hormonal Induction. Cell. Mol. Neurobiol. 1996, 16 (2), 85– 101,  DOI: 10.1007/BF02088169
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    Chromatin structure of the MMTV promoter and its changes during hormonal induction
    Truss, Mathias; Bartsch, Joerg; Moews, Christian; Chavez, Sebastian; Beato, Miguel
    Cellular and Molecular Neurobiology (1996), 16 (2), 85-101CODEN: CMNEDI; ISSN:0272-4340. (Plenum)
    A review, with 112 refs., which discusses: the MMTV system; the hormone (glucocorticoid) responsive region; the NF1 binding sites; the octamer motifs; other elements; cell-free transcription; nucleosome structure of the MMTV promoter; changes in chromatin structure after hormone induction; and mechanism for chromatin remodeling.
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    Beato, M.; Eisfeld, K. Transcription Factor Access to Chromatin. Nucleic Acids Res. 1997, 25 (18), 3559– 3563,  DOI: 10.1093/nar/25.18.3559
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    Transcription factor access to chromatin
    Beato, Miguel; Eisfeld, Karin
    Nucleic Acids Research (1997), 25 (18), 3559-3563CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    The question of how sequence-specific transcription factors access their cognate sites in nucleosomally organized DNA is discussed on the basis of genomic footprinting data and chromatin reconstitution expts. A classification of factors into two categories is proposed: (i) initiator factors which are able to bind their target sequences within regular nucleosomes and initiate events leading to chromatin remodelling and transactivation; (ii) effector factors which are unable to bind regular nucleosomes and depend on initiator factors or on a pre-set nucleosomal structure for accessing their target sequences in chromatin. Studies with the MMTV promoter suggest that the extent and no. of protein-DNA contacts det. whether a factor belongs to one or the other category. Initiator factors have only a few DNA contracts clustered on one side of the double helix, whereas effector factors have extensive contacts distributed throughout the whole circumference of the DNA helix. Thus, the nature of DNA, recognition confers to sequence-specific factors their specific place in the sequential hierarchy of gene regulatory events.
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    Ura, K.; Kurumizaka, H.; Dimitrov, S.; Almouzni, G.; Wolffe, A. P. Histone Acetylation: Influence on Transcription, Nucleosome Mobility and Positioning, and Linker Histone-Dependent Transcriptional Repression. EMBO J. 1997, 16 (8), 2096– 2107,  DOI: 10.1093/emboj/16.8.2096
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    Histone acetylation: influence on transcription, nucleosome mobility and positioning, and linker histone-dependent transcriptional repression
    Ura, Kiyoe; Kurumizaka, Hitoshi; Dimitrov, Stefan; Almouzni, Genevieve; Wolffe, Alan P.
    EMBO Journal (1997), 16 (8), 2096-2107CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)
    We demonstrate using a dinucleosome template that acetylation of the core histones enhances transcription by RNA polymerase III. This effect is not dependent on an increased mobility of the core histone octamer with respect to DNA sequence. When linker histone is subsequently bound, we find both a redn. in nucleosome mobility and a repression of transcription. These effects of linker histone binding are independent of core histone acetylation, indicating that core histone acetylation does not prevent linker histone binding and the concomitant transcriptional repression. These studies are complemented by the use of a Xenopus egg ext. competent both for chromatin assembly on replicating DNA and for RNA polymerase III transcription. Incorporation of acetylated histones and lack of linker histones together facilitate transcription by >10-fold in this system; however, they have little independent effect on transcription. Thus core histone acetylation significantly facilitates transcription, but this effect is inhibited by the assembly of linker histones into chromatin.
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    Wolffe, A. P. Sinful Repression. Nat. 1997 3876628 1997, 387 (6628), 16– 17,  DOI: 10.1038/387016a0
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    Urnov, F. D.; Wolffe, A. P. Chromatin Remodeling and Transcriptional Activation: The Cast (in Order of Appearance). Oncogene 2001, 20 (24), 2991– 3006,  DOI: 10.1038/sj.onc.1204323
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    Chromatin remodeling and transcriptional activation: the cast (in order of appearance)
    Urnov, Fyodor D.; Wolffe, Alan P.
    Oncogene (2001), 20 (24), 2991-3006CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
    A review, with ∼150 refs. The no. of chromatin modifying and remodeling complexes implicated in genome control is growing faster than our understanding of the functional roles they play. We discuss recent in vitro expts. with biochem. defined chromatin templates that illuminate new aspects of action by histone acetyltransferases and ATP-dependent chromatin remodeling engines in facilitating transcription. We review a no. of studies that present an "ordered recruitment" view of transcriptional activation, according to which various complexes enter and exit their target promoter in a set sequence, and at specific times, such that action by one complex sets the stage for the arrival of the next one. A consensus emerging from all these expts. is that the joint action by several types of chromatin remodeling machines can lead to a more profound alteration of the infrastructure of chromatin over a target promoter than could be obtained by these enzymes acting independently. In addn., it appears that in specific cases one type of chromatin structure alteration (e.g., histone hyperacetylation) is contingent upon prior alterations of a different sort (i.e., ATP-dependent remodeling of histone-DNA contacts). The striking differences between the precise sequence of action by various cofactors obsd. in these studies may be - at least in part - due to differences between the specific promoters studied, and distinct requirements exhibited by specific loci for chromatin remodeling based on their pre-existing nucleoprotein architecture.
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    Workman, J. L.; Buchman, A. R. Multiple Functions of Nucleosomes and Regulatory Factors in Transcription. Trends Biochem. Sci. 1993, 18 (3), 90– 95,  DOI: 10.1016/0968-0004(93)90160-O
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    Multiple functions of nucleosomes and regulatory factors in transcription
    Workman, Jerry L.; Buchman, Andrew R.
    Trends in Biochemical Sciences (1993), 18 (3), 90-5CODEN: TBSCDB; ISSN:0968-0004.
    A review, with 30 refs. The in vivo packaging of DNA with histone proteins to form chromatin makes its transcription a difficult process. Biochem. and genetic studies are beginning to reveal mechanistic details of how transcriptional regulatory factors confront at least two hurdles created by nucleosomes, the primary structural unit of chromatin. Regulatory factors must gain access to their resp. binding sites and activate the formation of transcription complexes at core promoter elements. Distinct regulatory factors may be specialized to perform these functions.
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    Barnes, P. J. New Anti-Inflammatory Targets for Chronic Obstructive Pulmonary Disease. Nat. Rev. Drug Discovery 2013, 12 (7), 543– 559,  DOI: 10.1038/nrd4025
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    New anti-inflammatory targets for chronic obstructive pulmonary disease
    Barnes Peter J
    Nature reviews. Drug discovery (2013), 12 (7), 543-59 ISSN:.
    Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of the peripheral airways and lung parenchyma, which leads to progressive obstruction of the airways. Current management with long-acting bronchodilators does not reduce disease progression, and there are no treatments that effectively suppress chronic inflammation in COPD. An increased understanding of the inflammatory processes that are involved in the pathophysiology of COPD has identified several new therapeutic targets. This Review discusses some of the most promising of these targets, including new antioxidants, kinase inhibitors and drugs that target cellular senescence, microbial colonization, epigenetic regulation of inflammatory gene expression and corticosteroid resistance.
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    Ito, K.; Barnes, P. J.; Adcock, I. M. Glucocorticoid Receptor Recruitment of Histone Deacetylase 2 Inhibits Interleukin-1beta-Induced Histone H4 Acetylation on Lysines 8 and 12. Mol. Cell. Biol. 2000, 20 (18), 6891– 6903,  DOI: 10.1128/MCB.20.18.6891-6903.2000
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    Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1β-induced histone H4 acetylation on lysines 8 and 12
    Ito, Kazuhiro; Barnes, Peter J.; Adcock, Ian M.
    Molecular and Cellular Biology (2000), 20 (18), 6891-6903CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
    We have investigated the ability of dexamethasone to regulate interleukin-1β (IL-1β)-induced gene expression, histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity. Low concns. of dexamethasone (10-10 M) repress IL-1β-stimulated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression and fail to stimulate secretory leukocyte proteinase inhibitor expression. Dexamethasone (10-7 M) and IL-1β (1 ng/mL) both stimulated HAT activity but showed a different pattern of histone H4 acetylation. Dexamethasone targeted lysines K5 and K16, whereas IL-1β targeted K8 and K12. Low concns. of dexamethasone (10-10 M), which do not transactivate, repressed IL-1β-stimulated K8 and K12 acetylation. Using chromatin immunopptn. assays, we show that dexamethasone inhibits IL-1β-enhanced acetylated K8-assocd. GM-CSF promoter enrichment in a concn.-dependent manner. Neither IL-1β nor dexamethasone elicited any GM-CSF promoter assocn. at acetylated K5 residues. Furthermore, we show that GR acts both as a direct inhibitor of CREB binding protein (CBP)-assocd. HAT activity and also by recruiting HDAC2 to the p65-CBP HAT complex. This action does not involve de novo synthesis of HDAC protein or altered expression of CBP or p300/CBP-assocd. factor. This mechanism for glucocorticoid repression is novel and establishes that inhibition of histone acetylation is an addnl. level of control of inflammatory gene expression. This further suggests that pharmacol. manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases.
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    Ito, K.; Ito, M.; Elliott, W. M.; Cosio, B.; Caramori, G.; Kon, O. M.; Barczyk, A.; Hayashi, S.; Adcock, I. M.; Hogg, J. C.; Barnes, P. J. Decreased Histone Deacetylase Activity in Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 2005, 352 (19), 1967– 1976,  DOI: 10.1056/NEJMoa041892
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    Decreased histone deacetylase activity in chronic obstructive pulmonary disease
    Ito, Kazuhiro; Ito, Misako; Elliott, W. Mark; Cosio, Borja; Caramori, Gaetano; Kon, Onn Min; Barczyk, Adam; Hayashi, Shizu; Adcock, Lan M.; Hogg, James C.; Barnes, Peter J.
    New England Journal of Medicine (2005), 352 (19), 1967-1976CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
    Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the redn. in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key mol. in the repression of prodn. of proinflammatory cytokines in alveolar macrophages. HDAC activity and histone acetyltransferase (HAT) activity were detd. in nuclear exts. of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examd. Total RNA extd. from lung tissue and macrophages was used for quant. reverse-transcriptase- PCR assay of HDAC1 through HDAC8 and interleukin-8. Expression of HDAC2 protein was quantified with the use of Western blotting. Histone-4 acetylation at the interleukin-8 promoter was evaluated with the use of a chromatin immunopptn. assay. Specimens of lung tissue obtained from patients with increasing clin. stages of COPD had graded redns. in HDAC activity and increases in interleukin-8 mRNA and histone-4 acetylation at the interleukin-8 promoter. The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia. Patients with COPD have a progressive redn. in total HDAC activity that reflects the severity of the disease.
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    Hu, L.; Liu, F.; Li, L.; Zhang, L.; Yan, C.; Li, Q.; Qiu, J.; Dong, J.; Sun, J.; Zhang, H. Effects of Icariin on Cell Injury and Glucocorticoid Resistance in BEAS-2B Cells Exposed to Cigarette Smoke Extract. Exp. Ther. Med. 2020, 20 (1), 283– 292,  DOI: 10.3892/etm.2020.8702
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    Effects of icariin on cell injury and glucocorticoid resistance in BEAS-2B cells exposed to cigarette smoke extract
    Hu, Lingli; Liu, Feng; Li, Lulu; Zhang, Li; Yan, Chen; Li, Qiuping; Qiu, Jian; Dong, Jingcheng; Sun, Jing; Zhang, Hongying
    Experimental and Therapeutic Medicine (2020), 20 (1), 283-292CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)
    Glucocorticoids (GCs) exert a therapeutic effect in numerous chronic inflammatory diseases. However, chronic obstructive pulmonary disease (COPD) tends to be GC-resistant. Icariin, a major component of flavonoids isolated from Epimedium brevicornum Maxim (Berberidaceae), significantly relieves symptoms in patients with COPD. However, the mechanism of action remains unclear and further investigation is required to establish whether it may serve as an alternative or complementary therapy for COPD. The aim of the present study was to det. the effects of icariin in human bronchial epithelial cells exposed to cigarette smoke ext. (CSE) and to det. whether icariin reverses GC resistance. The results revealed that icariin significantly increased the proliferation of CSE-exposed cells. Furthermore, icariin significantly increased protein expression of the anti-inflammatory factor interleukin (IL)-10 and significantly decreased protein expression of the pro-inflammatory factors IL-8 and tumor necrosis factor α. Icariin also attenuated the expression of the cellular matrix remodelling biomarkers matrix metallopeptidase 9 and tissue inhibitor of metalloproteinase 1, and decreased the prodn. of reactive oxygen species (ROS). In addn., icariin regulated the expression of GC resistance-related factors, such as GC receptors, histone deacetylase 2, nuclear factor erythroid-2-related factor 2 and nuclear factor κ B. The results obtained in the present study suggested that icariin may decrease CSE-induced inflammation, airway remodelling and ROS prodn. by mitigating GC resistance. In conclusion, icariin may potentially be used in combination with GCs to increase therapeutic efficacy and reduce GC resistance in COPD.
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    Wu, J.; Li, X.; Qin, Y.; Cheng, J.; Hao, G.; Jin, R.; Zhu, C. Jinwei Tang Modulates HDAC2 Expression in a Rat Model of COPD. Exp. Ther. Med. 2018, 15 (3), 2604,  DOI: 10.3892/etm.2018.5707
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    Jinwei Tang modulates HDAC2 expression in a rat model of COPD
    Wu, Jianjun; Li, Xin; Qin, Yang; Cheng, Juan; Hao, Gaimei; Jin, Ruifeng; Zhu, Chenjun
    Experimental and Therapeutic Medicine (2018), 15 (3), 2604-2610CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)
    The aim of the present study was to investigate the effect of a Traditional Chinese Herbal Medicine (TCHM), named Jinwei Tang on histone deacetylase 2 (HDAC2) and its role in the regulation of corticosteroid resistance in a rat model of chronic obstructive pulmonary disease (COPD). Male Wistar rats were divided into five groups (each n = 10): COPD group, established by the intratracheal instillation of lipopolysaccharide and passive smoke exposure, and control, budesonide, theophylline + budesonide and Jinwei Tang + budesonide groups. Lung function was measured, lung tissue histopathol. was examd. and HDAC2 expression in the lung was assessed by immunohistochem. In addn., protein levels of interleukin-8 (IL-8), tumor necrosis factor (TNF)-α and HDAC2 in lung homogenate were quantified by ELISA. The rat COPD model exhibited alterations of the ratio of forced expiratory vol. in 0.2 s (FEV0.2) to the forced vital capacity, FEV0.2, dynamic compliance and airway resistance. HDAC2 expression was markedly reduced in the lung tissue of the COPD group compared with the control group, and treatment with Jinwei Tang + budesonide or theophylline + budesonide resulted in significant attenuation of the redn. of HDAC2 expression in the lungs (P<0.05). However, treatment with budesonide alone did not significantly alter HDAC2 expression. In the Jinwei Tang + budesonide and theophylline + budesonide groups, IL-8 and TNF-α expression was significantly decreased (P<0.05) and the HDAC2 level increased (P<0.05) compared with that in the COPD group.
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    Miao, L.; Gao, Z.; Huang, F.; Huang, S.; Zhang, R.; Ma, D.; Wu, Q.; Li, F.; Chen, H.; Wang, J. Erythromycin Enhances the Anti-Inflammatory Activity of Budesonide in COPD Rat Model. Int. J. Clin. Exp. Med. 2015, 8 (12), 22217
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    Erythromycin enhances the anti-inflammatory activity of budesonide in COPD rat model
    Miao, Lijun; Gao, Zengyan; Huang, Fengxiang; Huang, Shifu; Zhang, Ruixia; Ma, Dongbo; Wu, Qiuge; Li, Fang; Chen, Hongjie; Wang, Jing
    International Journal of Clinical and Experimental Medicine (2015), 8 (12), 22217-22226CODEN: IJCEFA; ISSN:1940-5901. (e-Century Publishing Corp.)
    Glucocorticoids (GCs) have been widely applied to treat patients with chronic obstructive pulmonary disease (COPD). But the effect of GCs was not ideal. This study was to observe whether erythromycin could enhance the anti-inflammatory activity of budesonide in COPD model rats and to explore the mechanism involved. In this study, male Sprague-Dawley rats were divided into five groups: healthy control group (H group), COPD model group (C group), erythromycin group (E group), budesonide group (B group) and erythromycin + budesonide group (E+B group). The rats in groups of C, E, B and E+B were developed into COPD models. Different groups were given different drug interventions. The levels of 8-iso-PGF2 α, IL-8, and TNF- α in BALF and serum were measured with ELISA. The protein expression levels of HDAC2, PI3K, and p-AKT in lung tissue were measured with Western-blot and immunohistochem. The levels of 8-iso-PGF2 α, IL-8, and TNF- α in BALF and serum were lower in E+B group than those in B group and C group (all P<0.001).The protein expression level of HDAC2 was higher and PI3K and p-AKT were lower in E+B group than those in B group and C group (all P<0.001). Moreover, the expression levels of HDAC2 were neg. correlated with the levels of 8-iso-PGF2 α, IL-8 and TNF- α both in serum and BALF and the expression levels of PI3K and p-AKT among the five groups, with all P<0.001. We conclude that erythromycin can enhance the anti-inflammatory activity of budesonide in COPD model rats, possibly through inhibiting the PI3K/AKT pathway and enhancing the activity of HDAC2.
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    Manz, M. G.; Boettcher, S. Emergency Granulopoiesis. Nat. Rev. Immunol. 2014, 14 (5), 302– 314,  DOI: 10.1038/nri3660
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    Emergency granulopoiesis
    Manz, Markus G.; Boettcher, Steffen
    Nature Reviews Immunology (2014), 14 (5), 302-314CODEN: NRIABX; ISSN:1474-1733. (Nature Publishing Group)
    A review. Neutrophils are a key cell type of the innate immune system. They are short-lived and need to be continuously generated in steady-state conditions from haematopoietic stem and progenitor cells in the bone marrow to ensure their immediate availability for the containment of invading pathogens. However, if microbial infection cannot be controlled locally, and consequently develops into a life-threatening condition, neutrophils are used up in large quantities and the haematopoietic system has to rapidly adapt to the increased demand by switching from steady-state to emergency granulopoiesis. This involves the markedly increased de novo prodn. of neutrophils, which results from enhanced myeloid precursor cell proliferation in the bone marrow. In this Review, we discuss the mol. and cellular events that regulate emergency granulopoiesis, a process that is crucial for host survival.
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    Németh, T.; Sperandio, M.; Mócsai, A. Neutrophils as Emerging Therapeutic Targets. Nat. Rev. Drug Discovery 2020, 19 (4), 253– 275,  DOI: 10.1038/s41573-019-0054-z
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    Neutrophils as emerging therapeutic targets
    Nemeth, Tamas; Sperandio, Markus; Mocsai, Attila
    Nature Reviews Drug Discovery (2020), 19 (4), 253-275CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)
    A review. Neutrophils are the most abundant circulating leukocytes, being the first line of defense against bacterial and fungal infections. However, neutrophils also contribute to tissue damage during various autoimmune and inflammatory diseases, and play important roles in cancer progression. The intimate but complex involvement of neutrophils in various diseases makes them exciting targets for therapeutic intervention but also necessitates differentiation of beneficial responses from potentially detrimental side effects. A variety of approaches to therapeutically target neutrophils have emerged, including strategies to enhance, inhibit or restore neutrophil function, with several agents entering clin. trials. However, challenges and controversies in the field remain.
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    Tsantikos, E.; Lau, M.; Castelino, C. M. N.; Maxwell, M. J.; Passey, S. L.; Hansen, M. J.; McGregor, N. E.; Sims, N. A.; Steinfort, D. P.; Irving, L. B.; Anderson, G. P.; Hibbs, M. L. Granulocyte-CSF Links Destructive Inflammation and Comorbidities in Obstructive Lung Disease. J. Clin. Invest. 2018, 128 (6), 2406– 2418,  DOI: 10.1172/JCI98224
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    Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease
    Tsantikos Evelyn; Lau Maverick; Castelino Cassandra Mn; Maxwell Mhairi J; Hibbs Margaret L; Lau Maverick; Passey Samantha L; Hansen Michelle J; Anderson Gary P; McGregor Narelle E; Sims Natalie A; Steinfort Daniel P; Irving Louis B
    The Journal of clinical investigation (2018), 128 (6), 2406-2418 ISSN:.
    Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that afflicts millions of people worldwide, and it is the fourth leading cause of death. Systemic comorbidities affecting the heart, skeletal muscle, bone, and metabolism are major contributors to morbidity and mortality. Given the surprising finding in large prospective clinical biomarker studies that peripheral white blood cell count is more closely associated with disease than inflammatory biomarkers, we probed the role of blood growth factors. Using the SHIP-1-deficient COPD mouse model, which manifests a syndrome of destructive lung disease and a complex of comorbid pathologies, we have identified a critical and unexpected role for granulocyte-CSF (G-CSF) in linking these conditions. Deletion of G-CSF greatly reduced airway inflammation and lung tissue destruction, and attenuated systemic inflammation, right heart hypertrophy, loss of fat reserves, and bone osteoporosis. In human clinical translational studies, bronchoalveolar lavage fluid of patients with COPD demonstrated elevated G-CSF levels. These studies suggest that G-CSF may play a central and unforeseen pathogenic role in COPD and its complex comorbidities, and identify G-CSF and its regulators as potential therapeutic targets.
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    Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D. S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil Extracellular Traps Kill Bacteria. Science 2004, 303 (5663), 1532– 1535,  DOI: 10.1126/science.1092385
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    Neutrophil Extracellular Traps Kill Bacteria
    Brinkmann, Volker; Reichard, Ulrike; Goosmann, Christian; Fauler, Beatrix; Uhlemann, Yvonne; Weiss, David S.; Weinrauch, Yvette; Zychlinsky, Arturo
    Science (Washington, DC, United States) (2004), 303 (5663), 1532-1535CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, the authors describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-pos. and -neg. bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in exptl. dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concn. of antimicrobial agents to degrade virulence factors and kill bacteria.
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    Daniel, C.; Leppkes, M.; Muñoz, L. E.; Schley, G.; Schett, G.; Herrmann, M. Extracellular DNA Traps in Inflammation, Injury and Healing. Nat. Rev. Nephrol. 2019, 15 (9), 559– 575,  DOI: 10.1038/s41581-019-0163-2
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    Extracellular DNA traps in inflammation, injury and healing
    Daniel, Christoph; Leppkes, Moritz; Munoz, Luis E.; Schley, Gunnar; Schett, Georg; Herrmann, Martin
    Nature Reviews Nephrology (2019), 15 (9), 559-575CODEN: NRNABO; ISSN:1759-5061. (Nature Research)
    A review. Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is esp. prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathol. roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of patholologyl assocd. with the release of extracellular DNA traps is mainly detd. by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.
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    Porto, B. N.; Stein, R. T. Neutrophil Extracellular Traps in Pulmonary Diseases: Too Much of a Good Thing?. Front. Immunol. 2016, 7 (AUG), 311,  DOI: 10.3389/fimmu.2016.00311
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    Neutrophil extracellular traps in pulmonary diseases: too much of a good thing?
    Porto, Barbara Nery; Stein, Renato Tetelbom
    Frontiers in Immunology (2016), 7 (), 311/1-311/13CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    Neutrophil extracellular traps (NETs) arise from the release of granular and nuclear contents of neutrophils in the extracellular space in response to different classes of microorganisms, sol. factors, and host mols. NETs are composed by decondensed chromatin fibers coated with antimicrobial granular and cytoplasmic proteins, such as myeloperoxidase, neutrophil elastase (NE), and α-defensins. Besides being expressed on NET fibers, NE and MPO also regulate NET formation. Furthermore, histone deimination by peptidylarginine deiminase 4 (PAD4) is a central step to NET formation. NET formation has been widely demonstrated to be an effective mechanism to fight against invading microorganisms, as deficiency in NET release or dismantling NET backbone by bacterial DNases renders the host susceptible to infections. Therefore, the primary role of NETs is to prevent microbial dissemination, avoiding overwhelming infections. However, an excess of NET formation has a dark side. The pathogenic role of NETs has been described for many human diseases, infectious and non-infectious. The detrimental effect of excessive NET release is particularly important to lung diseases, because NETs can expand more easily in the pulmonary alveoli, causing lung injury. Moreover, NETs and its assocd. mols. are able to directly induce epithelial and endothelial cell death. In this regard, massive NET formation has been reported in several pulmonary diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory syncytial virus bronchiolitis, influenza, bacterial pneumonia, and tuberculosis, among others. Thus, NET formation must be tightly regulated in order to avoid NET-mediated tissue damage. Recent development of therapies targeting NETs in pulmonary diseases includes DNA disintegration with recombinant human DNase, neutralization of NET proteins, with anti-histone antibodies and protease inhibitors. In this review, we summarize the recent knowledge on the pathophysiol. role of NETs in pulmonary diseases as well as some exptl. and clin. approaches to modulate their detrimental effects.
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    Sollberger, G.; Choidas, A.; Burn, G. L.; Habenberger, P.; Di Lucrezia, R.; Kordes, S.; Menninger, S.; Eickhoff, J.; Nussbaumer, P.; Klebl, B.; Krüger, R.; Herzig, A.; Zychlinsky, A. Gasdermin D Plays a Vital Role in the Generation of Neutrophil Extracellular Traps. Sci. Immunol. 2018, 3 (26), eaar6689,  DOI: 10.1126/sciimmunol.aar6689
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    Chen, K. W.; Monteleone, M.; Boucher, D.; Sollberger, G.; Ramnath, D.; Condon, N. D.; von Pein, J. B.; Broz, P.; Sweet, M. J.; Schroder, K. Noncanonical Inflammasome Signaling Elicits Gasdermin D-Dependent Neutrophil Extracellular Traps. Sci. Immunol. 2018, 3 (26), eaar6676,  DOI: 10.1126/sciimmunol.aar6676
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    Frye, R. A. Phylogenetic Classification of Prokaryotic and Eukaryotic Sir2-like Proteins. Biochem. Biophys. Res. Commun. 2000, 273 (2), 793– 798,  DOI: 10.1006/bbrc.2000.3000
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    Phylogenetic Classification of Prokaryotic and Eukaryotic Sir2-like Proteins
    Frye, Roy A.
    Biochemical and Biophysical Research Communications (2000), 273 (2), 793-798CODEN: BBRCA9; ISSN:0006-291X. (Academic Press)
    Sirtuins (Sir2-like proteins) are present in prokaryotes and eukaryotes. Here, two new human sirtuins (SIRT6 and SIRT7) are found to be similar to a particular subset of insect, nematode, plant, and protozoan sirtuins. Mol. phylogenetic anal. of 60 sirtuin conserved core domain sequences from a diverse array of organisms (including archaeans, bacteria, yeasts, plants, protozoans, and metazoans) shows that eukaryotic Sir2-like proteins group into four main branches designated here as classes I-IV. Prokaryotic sirtuins include members of classes II and III. A fifth class of sirtuin is present in gram pos. bacteria and Thermotoga maritima. Saccharomyces cerevisiae has five class I sirtuins. Caenorhabditis elegans and Drosophila melanogaster have sirtuin genes from classes I, II, and IV. The seven human sirtuin genes include all four classes: SIRT1, SIRT2, and SIRT3 are class I; SIRT4 is class II; SIRT5 is class III; and SIRT6 and SIRT7 are class IV. (c) 2000 Academic Press.
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    Singh, C. K.; Nihal, M.; Ahmad, N. Histone Deacetylase Inhibitory Approaches for the Management of Osteoarthritis. Am. J. Pathol. 2016, 186 (10), 2555,  DOI: 10.1016/j.ajpath.2016.08.001
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    Histone Deacetylase Inhibitory Approaches for the Management of Osteoarthritis
    Singh, Chandra K.; Nihal, Minakshi; Ahmad, Nihal
    American Journal of Pathology (2016), 186 (10), 2555-2558CODEN: AJPAA4; ISSN:0002-9440. (Elsevier B.V.)
    A polemic in response to Makki et al is given.,. This paper discusses about the histone deacetylase inhibitory approaches for management of osteoarthritis.
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    Nakagawa, T.; Guarente, L. Sirtuins at a Glance. J. Cell Sci. 2011, 124 (6), 833– 838,  DOI: 10.1242/jcs.081067
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    Sirtuins at a glance
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    Journal of Cell Science (2011), 124 (6), 833-838CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
    A review. The enzymic activity and characterization of sirtuins and recent data relating to their role in aging and aging-related diseases are summarized and the underlying mechanisms are described.
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    Singh, C. K.; Chhabra, G.; Ndiaye, M. A.; Garcia-Peterson, L. M.; MacK, N. J.; Ahmad, N. The Role of Sirtuins in Antioxidant and Redox Signaling. Antioxid. Redox Signal. 2018, 28 (8), 643,  DOI: 10.1089/ars.2017.7290
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    The Role of Sirtuins in Antioxidant and Redox Signaling
    Singh Chandra K; Chhabra Gagan; Ndiaye Mary Ann; Garcia-Peterson Liz Mariely; Mack Nicholas J; Ahmad Nihal
    Antioxidants & redox signaling (2018), 28 (8), 643-661 ISSN:.
    SIGNIFICANCE: Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1-7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets. Recent studies show that sirtuins modulate the regulation of a variety of cellular processes associated with ARS. SIRT1, SIRT3, and SIRT5 protect the cell from ROS, and SIRT2, SIRT6, and SIRT7 modulate key oxidative stress genes and mechanisms. Interestingly, SIRT4 has been shown to induce ROS production and has antioxidative roles as well. CRITICAL ISSUES: A complete understanding of the roles of sirtuins in redox homeostasis of the cell is very important to understand the normal functioning as well as pathological manifestations. In this review, we have provided a critical discussion on the role of sirtuins in the regulation of ARS. We have also discussed mechanistic interactions among different sirtuins. Indeed, a complete understanding of sirtuin biology could be critical at multiple fronts. FUTURE DIRECTIONS: Sirtuins are emerging to be important in normal mammalian physiology and in a variety of oxidative stress-mediated pathological situations. Studies are needed to dissect the mechanisms of sirtuins in maintaining redox homeostasis. Efforts are also required to assess the targetability of sirtuins in the management of redox-regulated diseases. Antioxid. Redox Signal. 28, 643-661.
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    Bai, W.; Zhang, X. Nucleus or Cytoplasm? The Mysterious Case of SIRT1’s Subcellular Localization. Cell Cycle 2016, 15 (24), 3337,  DOI: 10.1080/15384101.2016.1237170
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    Nucleus or cytoplasm? The mysterious case of SIRT1's subcellular localization
    Bai, Wenlong; Zhang, Xiaohong
    Cell Cycle (2016), 15 (24), 3337-3338CODEN: CCEYAS; ISSN:1551-4005. (Taylor & Francis Ltd.)
    There is no expanded citation for this reference.
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    Wilking, M. J.; Singh, C.; Nihal, M.; Zhong, W.; Ahmad, N. SIRT1 Deacetylase Is Overexpressed in Human Melanoma and Its Small Molecule Inhibition Imparts Anti-Proliferative Response via P53 Activation. Arch. Biochem. Biophys. 2014, 563, 94– 100,  DOI: 10.1016/j.abb.2014.04.001
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    SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation
    Wilking, Melissa J.; Singh, Chandra; Nihal, Minakshi; Zhong, Weixiong; Ahmad, Nihal
    Archives of Biochemistry and Biophysics (2014), 563 (), 94-100CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)
    Melanoma causes more deaths than any other skin cancer, and its incidence in the US continues to rise. Current medical therapies are insufficient to control this deadly neoplasm, necessitating the development of new target-based approaches. The objective of this study was to det. the role and functional significance of the class III histone deacetylase SIRT1 in melanoma. We have found that SIRT1 is overexpressed in clin. human melanoma tissues and human melanoma cell lines (Sk-Mel-2, WM35, G361, A375, and Hs294T) compared to normal skin and normal melanocytes, resp. In addn., treatment of melanoma cell lines A375, Hs294T, and G361 with Tenovin-1, a small mol. SIRT1 inhibitor, resulted in a significant decrease in cell growth and cell viability. Further, Tenovin-1 treatment also resulted in a marked decrease in the clonogenic survival of melanoma cells. Further expts. showed that the anti-proliferative response of Tenovin-1 was accompanied by an increase in the protein as well as activity of the tumor suppressor p53. This increase in p53 activity was substantiated by an increase in the protein level of its downstream target p21. Overall, these data suggest that small mol. inhibition of SIRT1 causes anti-proliferative effects in melanoma cells. SIRT1 appears to be acting through the activity of the tumor suppressor p53, which is not mutated in the majority of melanomas. However, future detailed studies are needed to further explore the role and mechanism of SIRT1 in melanoma development and progression and its usefulness in melanoma treatment.
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    Yu, J.; Auwerx, J. Protein Deacetylation by SIRT1: An Emerging Key Post-Translational Modification in Metabolic Regulation. Pharmacol. Res. 2010, 62 (1), 35– 41,  DOI: 10.1016/j.phrs.2009.12.006
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    Protein deacetylation by SIRT1: An emerging key post-translational modification in metabolic regulation
    Yu, Jiujiu; Auwerx, Johan
    Pharmacological Research (2010), 62 (1), 35-41CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)
    A review. The biol. function of most proteins relies on reversible post-translational modifications, among which phosphorylation is most prominently studied and well recognized. Recently, a growing amt. of evidence indicates that acetylation-deacetylation reactions, when applied to crucial mediators, can also robustly affect the function of target proteins and thereby have wide-ranging physiol. impacts. Sirtuin 1 (SIRT1), which functions as a NAD (NAD+)-dependent protein deacetylase, deacetylates a wide variety of metabolic mols. in response to the cellular energy and redox status and as such causes significant changes in metabolic homeostasis. This review surveys the evidence for the emerging role of SIRT1-mediated deacetylation in the control of metabolic homeostasis.
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    Yao, H.; Hwang, J. W.; Sundar, I. K.; Friedman, A. E.; McBurney, M. W.; Guarente, L.; Gu, W.; Kinnula, V. L.; Rahman, I. SIRT1 Redresses the Imbalance of Tissue Inhibitor of Matrix Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Development of Mouse Emphysema and Human COPD. Am. J. Physiol. - Lung Cell. Mol. Physiol. 2013, 305 (9), L615,  DOI: 10.1152/ajplung.00249.2012
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    Yang, H.; Zhang, W.; Pan, H.; Feldser, H. G.; Lainez, E.; Miller, C.; Leung, S.; Zhong, Z.; Zhao, H.; Sweitzer, S.; Considine, T.; Riera, T.; Suri, V.; White, B.; Ellis, J. L.; Vlasuk, G. P.; Loh, C. SIRT1 Activators Suppress Inflammatory Responses through Promotion of P65 Deacetylation and Inhibition of NF-ΚB Activity. PLoS One 2012, 7 (9), e46364,  DOI: 10.1371/journal.pone.0046364
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    SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-κB activity
    Yang, Hongying; Zhang, Wei; Pan, Heng; Feldser, Heidi G.; Lainez, Elden; Miller, Christine; Leung, Stewart; Zhong, Zhong; Zhao, Huizhen; Sweitzer, Sharon; Considine, Thomas; Riera, Thomas; Suri, Vipin; White, Brian; Ellis, James L.; Vlasuk, George P.; Loh, Christine
    PLoS One (2012), 7 (9), e46364CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Chronic inflammation is a major contributing factor in the pathogenesis of many age-assocd. diseases. One central protein that regulates inflammation is NF-κB, the activity of which is modulated by post-translational modifications as well as by assocn. with co-activator and co-repressor proteins. SIRT1, an NAD+-dependent protein deacetylase, has been shown to suppress NF-κB signaling through deacetylation of the p65 subunit of NF-κB resulting in the redn. of the inflammatory responses mediated by this transcription factor. The role of SIRT1 in the regulation of NF-κB provides the necessary validation for the development of pharmacol. strategies for activating SIRT1 as an approach for the development of a new class of anti-inflammatory therapeutics. We report herein the development of a quant. assay to assess compd. effects on acetylated p65 protein in the cell. We demonstrate that small mol. activators of SIRT1 (STACs) enhance deacetylation of cellular p65 protein, which results in the suppression of TNFα-induced NF-κB transcriptional activation and redn. of LPS-stimulated TNFα secretion in a SIRT1-dependent manner. In an acute mouse model of LPS-induced inflammation, the STAC SRTCX1003 decreased the prodn. of the proinflammatory cytokines TNFα and IL-12. Our studies indicate that increasing SIRT1-mediated NF-κB deacetylation using small mol. activating compds. is a novel approach to the development of a new class of therapeutic anti-inflammatory agents.
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  93. 93
    Yanagisawa, S.; Papaioannou, A. I.; Papaporfyriou, A.; Baker, J. R.; Vuppusetty, C.; Loukides, S.; Barnes, P. J.; Ito, K. Decreased Serum Sirtuin-1 in COPD. Chest 2017, 152 (2), 343– 352,  DOI: 10.1016/j.chest.2017.05.004
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    93
    Decreased Serum Sirtuin-1 in COPD
    Yanagisawa Satoru; Baker Jonathan R; Vuppusetty Chaitanya; Barnes Peter J; Papaioannou Andriana I; Papaporfyriou Anastasia; Loukides Stelios; Ito Kazuhiro
    Chest (2017), 152 (2), 343-352 ISSN:.
    BACKGROUND: The protein deacetylase sirtuin-1 (SIRT1) is an antiaging molecule that is decreased in the lung in patients with COPD. Recently, SIRT1 was reported to be detectable in serum, but serum SIRT1 (s120S) levels have not yet been reported in patients with COPD. METHODS: Serum SIRT1 protein of all samples was measured by Western blot, and the SIRT1 protein band densities were calculated and compared with clinical parameters. RESULTS: Several molecular sizes of SIRT1, including 120 kDa (actual size) and fragments (102 and 75 kDa) were quantified by Western blot. Among them, only the 120-kDa s120S was significantly decreased in patients with COPD compared with the control subjects without COPD (s120S ratio in healthy subjects = 0.90 ± 0.34 vs those with COPD = 0.68 ± 0.24; P = .014) and was positively correlated with airway obstruction (FEV1/FVC, r = 0.31; P = .020); its severity measured by FEV1 % predicted (r = 0.29; P = .029). s120S also showed a positive correlation with BMI (r = 0.36; P = .0077) and diffusing capacity of the lung per unit volume (the carbon monoxide transfer coefficient: KCO%) (r = 0.32; P = .025). It was also significantly decreased with increasing severity of lung emphysema (r = -0.40; P = .027) and with a clinical history of frequent COPD exacerbations (infrequent vs frequent, 0.76 ± 0.20 vs 0.56 ± 0.26; P = .027). SIRT1 was not detected in supernatant of A549 and primary epithelial cells in normal culture conditions. CONCLUSIONS: s120S was decreased in the patients with COPD, potentially as reflected by the reduced SIRT1 within cells as a result of oxidative stress, and might be a potential biomarker for certain disease characteristics of COPD.
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  94. 94
    Peng, Z.; Zhang, W.; Qiao, J.; He, B. Melatonin Attenuates Airway Inflammation via SIRT1 Dependent Inhibition of NLRP3 Inflammasome and IL-1β in Rats with COPD. Int. Immunopharmacol. 2018, 62, 23– 28,  DOI: 10.1016/j.intimp.2018.06.033
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    94
    Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD
    Peng, Zhenyu; Zhang, Wenxuan; Qiao, Jianfeng; He, Baimei
    International Immunopharmacology (2018), 62 (), 23-28CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)
    Chronic airway inflammation is a characteristic feature of chronic obstructive pulmonary disease (COPD). Previous studies demonstrated that melatonin had a protective effect against COPD. In addn., silent information regulator 1 (SIRT1) was reported to be beneficial in COPD. However, whether SIRT1 is involved in the protective effect of melatonin against COPD remains unclear. In this study, we investigated the effect of melatonin on a rat model of COPD and explored the potential mechanisms. Twenty eight male Wistar rats were randomly assigned to four groups: control group, COPD group, COPD+Mel group and COPD+Mel+EX527 group. Rats were challenged with cigarette smoke and lipopolysaccharide (LPS) for 28 days with or without melatonin or EX527. The pulmonary function, lung histopathol., inflammatory cells count and the concn. of IL-1β in the BALF as well as the protein expressions of SIRT1, NLRP3, cleaved caspase-1 and ASC in the lung tissues were measured. The results demonstrated that melatonin prevented the development of COPD, which was attributed to the inhibition of airway inflammation by attenuating NLRP3 inflammasome and IL-1β. Furthermore, melatonin increased the expression of SIRT1 in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 abolished the protective effect of melatonin against COPD. In conclusion, these findings suggested that melatonin attenuated airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD.
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  95. 95
    Yanagisawa, S.; Baker, J. R.; Vuppusetty, C.; Koga, T.; Colley, T.; Fenwick, P.; Donnelly, L. E.; Barnes, P. J.; Ito, K. The Dynamic Shuttling of SIRT1 between Cytoplasm and Nuclei in Bronchial Epithelial Cells by Single and Repeated Cigarette Smoke Exposure. PLoS ONE 2018, 13, e0193921,  DOI: 10.1371/journal.pone.0193921
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    95
    The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure
    Yanagisawa, Satoru; Baker, Jonathan R.; Vuppusetty, Chaitanya; Koga, Takeshi; Colley, Thomas; Fenwick, Peter; Donnelly, Louise E.; Barnes, Peter J.; Ito, Kazuhiro
    PLoS One (2018), 13 (3), e0193921/1-e0193921/20CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein esp. in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke ext. (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was assocd. with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concn. of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-assocd. lung disease such as chronic obstructive pulmonary disease.
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  96. 96
    Grabowska, W.; Sikora, E.; Bielak-Zmijewska, A. Sirtuins, a Promising Target in Slowing down the Ageing Process. Biogerontology 2017, 18 (4), 447,  DOI: 10.1007/s10522-017-9685-9
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    96
    Sirtuins, a promising target in slowing down the ageing process
    Grabowska, Wioleta; Sikora, Ewa; Bielak-Zmijewska, Anna
    Biogerontology (2017), 18 (4), 447-476CODEN: BIOGCN; ISSN:1389-5729. (Springer)
    A review. Ageing is a plastic process and can be successfully modulated by some biomedical approaches or pharmaceutics. In this manner it is possible to delay or even prevent some age-related pathologies. There are some defined interventions, which give promising results in animal models or even in human studies, resulting in lifespan elongation or healthspan improvement. One of the most promising targets for anti-ageing approaches are proteins belonging to the sirtuin family. Sirtuins were originally discovered as transcription repressors in yeast, however, nowadays they are known to occur in bacteria and eukaryotes (including mammals). In humans the family consists of seven members (SIRT1-7) that possess either mono-ADP ribosyltransferase or deacetylase activity. It is believed that sirtuins play key role during cell response to a variety of stresses, such as oxidative or genotoxic stress and are crucial for cell metab. Although some data put in question direct involvement of sirtuins in extending human lifespan, it was documented that proper lifestyle including phys. activity and diet can influence healthspan via increasing the level of sirtuins. The search for an activator of sirtuins is one of the most extensive and robust topic of research. Some hopes are put on natural compds., including curcumin. In this review we summarize the involvement and usefulness of sirtuins in anti-ageing interventions and discuss the potential role of curcumin in sirtuins regulation.
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  97. 97
    Gomes, P.; Fleming Outeiro, T.; Cavadas, C. Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism. Trends Pharmacol. Sci. 2015, 36 (11), 756– 768,  DOI: 10.1016/j.tips.2015.08.001
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    97
    Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism
    Gomes, Pedro; Fleming Outeiro, Tiago; Cavadas, Claudia
    Trends in Pharmacological Sciences (2015), 36 (11), 756-768CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)
    A review. Sirtuins are an evolutionarily conserved family of NAD+-dependent deacylases that display diversity in subcellular localization and function. SIRT2, the predominantly cytosolic sirtuin, is among the least understood of the seven mammalian sirtuin isoforms described (SIRT1-7). The purpose of this review is to summarize the most recent findings about the potential roles and effects of SIRT2 in mammalian metabolic homeostasis. We discuss the different functions and targets of SIRT2 in various physiol. processes, including adipogenesis, fatty acid oxidn., gluconeogenesis, and insulin sensitivity. We also cover the role of SIRT2 in inflammation and oxidative stress due to the possible implications for metabolic disorders. Finally, we consider its potential as a therapeutic target for the prevention and treatment of type 2 diabetes.
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  98. 98
    Wang, Y. P.; Zhou, L. S.; Zhao, Y. Z.; Wang, S. W.; Chen, L. L.; Liu, L. X.; Ling, Z. Q.; Hu, F. J.; Sun, Y. P.; Zhang, J. Y.; Yang, C.; Yang, Y.; Xiong, Y.; Guan, K. L.; Ye, D. Regulation of G6PD Acetylation by SIRT2 and KAT9Modulates NADPH Homeostasis and Cell Survival during Oxidative Stress. EMBO J. 2014, 33 (12), 1304,  DOI: 10.1002/embj.201387224
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    98
    Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress
    Wang, Yi-Ping; Zhou, Li-Sha; Zhao, Yu-Zheng; Wang, Shi-Wen; Chen, Lei-Lei; Liu, Li-Xia; Ling, Zhi-Qiang; Hu, Fu-jun; Sun, Yi-Ping; Zhang, Jing-Ye; Yang, Chen; Yang, Yi; Xiong, Yue; Guan, Kun-Liang; Ye, Dan
    EMBO Journal (2014), 33 (12), 1304-1320CODEN: EMJODG; ISSN:0261-4189. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Glucose 6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular reductant in G6PD deficiency, which is the most common human enzyme defect, affecting >400 million people worldwide. Here, the authors show that G6PD is neg. regulated by acetylation on Lys-403, an evolutionarily conserved residue. Lys-403-acetylated G6PD was incapable of forming active dimers and displayed a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re-expression of wild-type G6PD, but not the Lys-403 acetylation mimetic mutant, rescued cells from oxidative injury. Moreover, the authors showed that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulated the PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. The authors also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Thus, this study uncovered a previously unknown mechanism by which acetylation neg. regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress.
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  99. 99
    Iwahara, T.; Bonasio, R.; Narendra, V.; Reinberg, D. SIRT3 Functions in the Nucleus in the Control of Stress-Related Gene Expression. Mol. Cell. Biol. 2012, 32 (24), 5022– 5034,  DOI: 10.1128/MCB.00822-12
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    99
    SIRT3 functions in the nucleus in the control of stress-related gene expression
    Iwahara, Toshinori; Bonasio, Roberto; Narendra, Varun; Reinberg, Danny
    Molecular and Cellular Biology (2012), 32 (24), 5022-5034CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
    SIRT3 is a member of the Sir2 family of NAD+-dependent protein deacetylases that promotes longevity in many organisms. The processed short form of SIRT3 is a well-established mitochondrial protein whose deacetylase activity regulates various metabolic processes. However, the presence of full-length (FL) SIRT3 in the nucleus and its functional importance remain controversial. Our previous studies demonstrated that nuclear FL SIRT3 functions as a histone deacetylase and is transcriptionally repressive when artificially recruited to a reporter gene. Here, we report that nuclear FL SIRT3 is subjected to rapid degrdn. under conditions of cellular stress, including oxidative stress and UV irradn., whereas the mitochondrial processed form is unaffected. FL SIRT3 degrdn. is mediated by the ubiquitin-proteasome pathway, at least partially through the ubiquitin protein ligase (E3) activity of SKP2. Finally, we show by chromatin immunopptn. that some target genes of nuclear SIRT3 are derepressed upon degrdn. of SIRT3 caused by stress stimuli. Thus, SIRT3 exhibits a previously unappreciated role in the nucleus, modulating the expression of some stress-related and nuclear-encoded mitochondrial genes.
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  100. 100
    Cheng, Y.; Ren, X.; Gowda, A. S. P.; Shan, Y.; Zhang, L.; Yuan, Y. S.; Patel, R.; Wu, H.; Huber-Keener, K.; Yang, J. W.; Liu, D.; Spratt, T. E.; Yang, J. M. Interaction of Sirt3 with OGG1 Contributes to Repair of Mitochondrial DNA and Protects from Apoptotic Cell Death under Oxidative Stress. Cell Death Dis. 2013, 4 (7), e731,  DOI: 10.1038/cddis.2013.254
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    100
    Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress
    Cheng, Y.; Ren, X.; Gowda, A. SP; Shan, Y.; Zhang, L.; Yuan, Y-S.; Patel, R.; Wu, H.; Huber-Keener, K.; Yang, J. W.; Liu, D.; Spratt, T. E.; Yang, J-M.
    Cell Death & Disease (2013), 4 (July), e731CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)
    Sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, targets various mitochondrial proteins for lysine deacetylation and regulates important cellular functions such as energy metab., aging, and stress response. In this study, we identified the human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine (8-oxoG) from damaged genome, as a new target protein for Sirt3. We found that Sirt3 phys. assocd. with OGG1 and deacetylated this DNA glycosylase and that deacetylation by Sirt3 prevented the degrdn. of the OGG1 protein and controlled its incision activity. We further showed that regulation of the acetylation and turnover of OGG1 by Sirt3 played a crit. role in repairing mitochondrial DNA (mtDNA) damage, protecting mitochondrial integrity, and preventing apoptotic cell death under oxidative stress. We obsd. that following ionizing radiation, human tumor cells with silencing of Sirt3 expression exhibited deteriorated oxidative damage of mtDNA, as measured by the accumulation of 8-oxoG and 4977 common deletion, and showed more severe mitochondrial dysfunction and underwent greater apoptosis in comparison with the cells without silencing of Sirt3 expression. The results reported here not only reveal a new function and mechanism for Sirt3 in defending the mitochondrial genome against oxidative damage and protecting from the genotoxic stress-induced apoptotic cell death but also provide evidence supporting a new mtDNA repair pathway.
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  101. 101
    Anderson, K. A.; Huynh, F. K.; Fisher-Wellman, K.; Stuart, J. D.; Peterson, B. S.; Douros, J. D.; Wagner, G. R.; Thompson, J. W.; Madsen, A. S.; Green, M. F.; Sivley, R. M.; Ilkayeva, O. R.; Stevens, R. D.; Backos, D. S.; Capra, J. A.; Olsen, C. A.; Campbell, J. E.; Muoio, D. M.; Grimsrud, P. A.; Hirschey, M. D. SIRT4 Is a Lysine Deacylase That Controls Leucine Metabolism and Insulin Secretion. Cell Metab. 2017, 25 (4), 838– 855,  DOI: 10.1016/j.cmet.2017.03.003
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    101
    SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion
    Anderson, Kristin A.; Huynh, Frank K.; Fisher-Wellman, Kelsey; Stuart, J. Darren; Peterson, Brett S.; Douros, Jonathan D.; Wagner, Gregory R.; Thompson, J. Will; Madsen, Andreas S.; Green, Michelle F.; Sivley, R. Michael; Ilkayeva, Olga R.; Stevens, Robert D.; Backos, Donald S.; Capra, John A.; Olsen, Christian A.; Campbell, Jonathan E.; Muoio, Deborah M.; Grimsrud, Paul A.; Hirschey, Matthew D.
    Cell Metabolism (2017), 25 (4), 838-855.e15CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)
    Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metab. and aging. In contrast to the other mammalian sirtuins, the primary enzymic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biol., and enzymol., we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidn., and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metab. in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.
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  102. 102
    Haigis, M. C.; Mostoslavsky, R.; Haigis, K. M.; Fahie, K.; Christodoulou, D. C.; Murphy, A. J. J.; Valenzuela, D. M.; Yancopoulos, G. D.; Karow, M.; Blander, G.; Wolberger, C.; Prolla, T. A.; Weindruch, R.; Alt, F. W.; Guarente, L. SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic Beta Cells. Cell 2006, 126 (5), 941– 954,  DOI: 10.1016/j.cell.2006.06.057
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    102
    SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells
    Haigis, Marcia C.; Mostoslavsky, Raul; Haigis, Kevin M.; Fahie, Kamau; Christodoulou, Danos C.; Murphy, Andrew J.; Valenzuela, David M.; Yancopoulos, George D.; Karow, Margaret; Blander, Gil; Wolberger, Cynthia; Prolla, Tomas A.; Weindruch, Richard; Alt, Frederick W.; Guarente, Leonard
    Cell (Cambridge, MA, United States) (2006), 126 (5), 941-954CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Sir2 is an NAD-dependent deacetylase that connects metab. with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metab. of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is obsd. in pancreatic β cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in β cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
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  103. 103
    Luo, Y. X.; Tang, X.; An, X. Z.; Xie, X. M.; Chen, X. F.; Zhao, X.; Hao, D. L.; Chen, H. Z.; Liu, D. P. SIRT4 Accelerates Ang II-Induced Pathological Cardiac Hypertrophy by Inhibiting Manganese Superoxide Dismutase Activity. Eur. Heart J. 2016, 38 (18), 1389– 1398,  DOI: 10.1093/eurheartj/ehw138
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    Nasrin, N.; Wu, X.; Fortier, E.; Feng, Y.; Baré, O. C.; Chen, S.; Ren, X.; Wu, Z.; Streeper, R. S.; Bordone, L. SIRT4 Regulates Fatty Acid Oxidation and Mitochondrial Gene Expression in Liver and Muscle Cells. J. Biol. Chem. 2010, 285 (42), 31995– 32002,  DOI: 10.1074/jbc.M110.124164
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    104
    SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells
    Nasrin, Nargis; Wu, Xiaoping; Fortier, Eric; Feng, Yajun; Bare', Olivia Claire; Chen, Sumiao; Ren, Xianglin; Wu, Zhidan; Streeper, Ryan S.; Bordone, Laura
    Journal of Biological Chemistry (2010), 285 (42), 31995-32002CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    SIRT4, a member of the sirtuin family, has been implicated in the regulation of insulin secretion by modulation of glutamate dehydrogenase. However, the role of this enzyme in the regulation of metab. in other tissues is unknown. In this study we investigated whether depletion of SIRT4 would enhance liver and muscle metabolic functions. To do this SIRT4 was knocked down using an adenoviral shRNA in mouse primary hepatocytes and myotubes. We obsd. a significant increase in gene expression of mitochondrial and fatty acid metab. enzymes in hepatocytes with reduced SIRT4 levels. SIRT4 knockdown also increased SIRT1 mRNA and protein levels both in vitro and in vivo. In agreement with the increased fatty acid oxidn. (FAO) gene expression, we showed a significant increase in FAO in SIRT4 knockdown primary hepatocytes compared with control, and this effect was dependent on SIRT1. In primary myotubes, knockdown of SIRT4 resulted in increased FAO, cellular respiration, and pAMPK levels. When SIRT4 was knocked down in vivo by tail vein injection of a shRNA adenovirus, we obsd. a significant increase in hepatic mitochondrial and FAO gene expression consistent with the findings in primary hepatocytes. Taken together these findings demonstrate that SIRT4 inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases assocd. with ectopic lipid storage such as type 2 diabetes.
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  105. 105
    Rosca, M. G.; Vazquez, E. J.; Chen, Q.; Kerner, J.; Kern, T. S.; Hoppel, C. L. Oxidation of Fatty Acids Is the Source of Increased Mitochondrial Reactive Oxygen Species Production in Kidney Cortical Tubules in Early Diabetes. Diabetes 2012, 61 (8), 2074– 2083,  DOI: 10.2337/db11-1437
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    105
    Oxidation of fatty acids is the source of increased mitochondrial reactive oxygen species production in kidney cortical tubules in early diabetes
    Rosca, Mariana G.; Vazquez, Edwin J.; Chen, Qun; Kerner, Janos; Kern, Timothy S.; Hoppel, Charles L.
    Diabetes (2012), 61 (8), 2074-2083CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)
    Mitochondrial reactive oxygen species (ROS) cause kidney damage in diabetes. We investigated the source and site of ROS prodn. by kidney cortical tubule mitochondria in streptozotocin-induced type 1 diabetes in rats. In diabetic mitochondria, the increased amts. and activities of selective fatty acid oxidn. enzymes is assocd. with increased oxidative phosphorylation and net ROS prodn. with fatty acid substrates (by 40% and 30%, resp.), whereas pyruvate oxidn. is decreased and pyruvate-supported ROS prodn. is unchanged. Oxidn. of substrates that donate electrons at specific sites in the electron transport chain (ETC) is unchanged. The increased maximal prodn. of ROS with fatty acid oxidn. is not affected by limiting the electron flow from complex I into complex III. The maximal capacity of the ubiquinol oxidn. site in complex III in generating ROS does not differ between the control and diabetic mitochondria. In conclusion, the mitochondrial ETC is neither the target nor the site of ROS prodn. in kidney tubule mitochondria in short-term diabetes. Mitochondrial fatty acid oxidn. is the source of the increased net ROS prodn., and the site of electron leakage is located proximal to coenzyme Q at the electron transfer flavoprotein that shuttles electrons from acyl-CoA dehydrogenases to coenzyme Q.
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  106. 106
    Du, J.; Zhou, Y.; Su, X.; Yu, J. J.; Khan, S.; Jiang, H.; Kim, J.; Woo, J.; Kim, J. H.; Choi, B. H.; He, B.; Chen, W.; Zhang, S.; Cerione, R. A.; Auwerx, J.; Hao, Q.; Lin, H. Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase. Science (80-.). 2011, 334 (6057), 806– 809,  DOI: 10.1126/science.1207861
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    Liu, B.; Che, W.; Zheng, C.; Liu, W.; Wen, J.; Fu, H.; Tang, K.; Zhang, J.; Xu, Y. SIRT5: A Safeguard against Oxidative Stress-Induced Apoptosis in Cardiomyocytes. Cell. Physiol. Biochem. 2013, 32 (4), 1050– 1059,  DOI: 10.1159/000354505
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    107
    SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes
    Liu, Ban; Che, Wenliang; Zheng, Changzhu; Liu, Weijing; Wen, Jing; Fu, Haitao; Tang, Kai; Zhang, Jinying; Xu, Yawei
    Cellular Physiology and Biochemistry (2013), 32 (4), 1050-1059CODEN: CEPBEW; ISSN:1015-8987. (S. Karger AG)
    Background: SIRT5 is located in the mitochondria, and plays a crucial role in the regulation of metabolic process and cellular apoptosis. Cardiomyocytes are abundant in mitochondria. However, the role of SIRT5 in oxidative stress-induced apoptosis is still unknown in cardiomyocytes. Methods and Results: Western blots anal. revealed that SIRT5 is significantly down-regulated in cardiomyocytes upon oxidative stress. MTT assay, DAPI staining, and caspase 3/7 activity assay were used to est. apoptosis development. The result suggested that compared with the wild-type group, SIRT5 knockdown results in a marked redn. in cell viability, and a significant increase in the no. of apoptotic cells and the caspase 3/7 activity. Protein immunopptn. revealed a direct interaction between Bcl-Xl and SIRT5. Apoptosis assay and western blot anal. suggested that SIRT5 levels could affect the levels of Bcl-Xl expression, but have no effect on the apoptosis development in Bcl-Xl knockdown cells. Conclusion: This study reveals a novel role of SIRT5 in the regulation of oxidative stress-induced apoptosis in cardiomyocytes. Pharmacol. interventions on SIRT5 expression may be useful in the treatment of oxidative stress-related cardiac injury.
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  108. 108
    Bobermin, L. D.; Wartchow, K. M.; Flores, M. P.; Leite, M. C.; Quincozes-Santos, A.; Gonçalves, C. A. Ammonia-Induced Oxidative Damage in Neurons Is Prevented by Resveratrol and Lipoic Acid with Participation of Heme Oxygenase 1. Neurotoxicology 2015, 49, 28– 35,  DOI: 10.1016/j.neuro.2015.05.005
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    108
    Ammonia-induced oxidative damage in neurons is prevented by resveratrol and lipoic acid with participation of heme oxygenase 1
    Bobermin, Larissa Daniele; Wartchow, Krista Mineia; Flores, Marianne Pires; Leite, Marina Concli; Quincozes-Santos, Andre; Goncalves, Carlos-Alberto
    NeuroToxicology (2015), 49 (), 28-35CODEN: NRTXDN; ISSN:0161-813X. (Elsevier Inc.)
    Ammonia is a metabolite that, at high concns., is implicated in neurol. disorders, such as hepatic encephalopathy (HE), which is assocd. with acute or chronic liver failure. Astrocytes are considered the primary target of ammonia toxicity in the central nervous system (CNS) because glutamine synthetase (GS), responsible for ammonia metab. in CNS, is an astrocytic enzyme. Thus, neuronal dysfunction has been assocd. as secondary to astrocytic impairment. However, we demonstrated that ammonia can induce direct effects on neuronal cells. The cell viability was decreased by ammonia in SH-SY5Y cells and cerebellar granule neurons. In addn., ammonia induced increased reactive oxygen species (ROS) prodn. and decreased GSH intracellular content, the main antioxidant in CNS. As ammonia neurotoxicity is strongly assocd. with oxidative stress, we also investigated the potential neuroprotective roles of the antioxidants, resveratrol (RSV) and lipoic acid (LA), against ammonia toxicity in cerebellar granule neurons. RSV and LA were able to prevent the oxidative damage induced by ammonia, maintaining the levels of ROS prodn. and GSH close to basal values. Both antioxidants also decreased ROS prodn. and increased GSH content under basal conditions (in the absence of ammonia). Moreover, we showed that heme oxygenase 1 (HO1), a protein assocd. with protection against stress conditions, is involved in the beneficial effects of RSV and LA in cerebellar granule neurons. Thus, this study reinforces the neuroprotective effects of RSV and LA. Although more studies in vivo are required, RSV and LA could represent interesting therapeutic strategies for the management of HE.
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  109. 109
    Nakagawa, T.; Lomb, D. J.; Haigis, M. C.; Guarente, L. SIRT5 Deacetylates Carbamoyl Phosphate Synthetase 1 and Regulates the Urea Cycle. Cell 2009, 137 (3), 560– 570,  DOI: 10.1016/j.cell.2009.02.026
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    109
    SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle
    Nakagawa, Takashi; Lomb, David J.; Haigis, Marcia C.; Guarente, Leonard
    Cell (Cambridge, MA, United States) (2009), 137 (3), 560-570CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Sirtuins are NAD-dependent protein deacetylases that connect metab. and aging. In mammals, there are 7 sirtuins (SIRT1-7), 3 of which are assocd. with mitochondria. Here, the authors show that SIRT5 localizes in the mitochondrial matrix and interacts with carbamoylphosphate synthetase 1 (CPS1), which catalyzes the initial step of the urea cycle for NH3 detoxification and disposal. SIRT5 deacetylates CPS1 and up-regulates its activity. During fasting, NAD in liver mitochondria increases, thereby triggering SIRT5 deacetylation of CPS1 and adaptation to the increase in amino acid catabolism. Indeed, SIRT5-KO mice fail to up-regulate CPS1 activity and show elevated blood NH3 during fasting. Similar effects occur during long-term calorie restriction or a high protein diet. These findings demonstrate that SIRT5 plays a pivotal role in NH3 detoxification and disposal by activating CPS1.
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  110. 110
    Ogura, M.; Nakamura, Y.; Tanaka, D.; Zhuang, X.; Fujita, Y.; Obara, A.; Hamasaki, A.; Hosokawa, M.; Inagaki, N. Overexpression of SIRT5 Confirms Its Involvement in Deacetylation and Activation of Carbamoyl Phosphate Synthetase 1. Biochem. Biophys. Res. Commun. 2010, 393 (1), 73– 78,  DOI: 10.1016/j.bbrc.2010.01.081
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    110
    Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1
    Ogura, Masahito; Nakamura, Yasuhiko; Tanaka, Daisuke; Zhuang, Xiaotong; Fujita, Yoshihito; Obara, Akio; Hamasaki, Akihiro; Hosokawa, Masaya; Inagaki, Nobuya
    Biochemical and Biophysical Research Communications (2010), 393 (1), 73-78CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
    SIR2 protein, an NAD-dependent deacetylase, is localized to nucleus and is involved in life span extension by calorie restriction in yeast. In mammals, among the 7 SIR2 homologs (SIRT1-7), SIRT3, SIRT4, and SIRT5 are localized to mitochondria. As SIRT5 mRNA levels in liver were increased by fasting, the physiol. role of SIRT5 was investigated in liver of SIRT5-overexpressing transgenic (SIRT5 Tg) mice. The authors identified carbamoyl phosphate synthetase 1 (CPS1), a key enzyme of the urea cycle that catalyzes condensation of NH3 with HCO3- to form carbamoyl phosphate, as a target of SIRT5 by 2-dimensional electrophoresis comparing mitochondrial proteins in livers of SIRT5 Tg and wild-type mice. CPS1 protein was more deacetylated and activated in liver of SIRT5 Tg mice than in wild-type mice. In addn., urea prodn. was up-regulated in hepatocytes of SIRT5 Tg mice. These results agreed with those of a previous study using SIRT5-knockout (KO) mice. Because NH3 generated during fasting is toxic, SIRT5 protein might play a protective role by converting NH3 to non-toxic urea through deacetylation and activation of CPS1.
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  111. 111
    Michishita, E.; McCord, R. A.; Berber, E.; Kioi, M.; Padilla-Nash, H.; Damian, M.; Cheung, P.; Kusumoto, R.; Kawahara, T. L. A.; Barrett, J. C.; Chang, H. Y.; Bohr, V. A.; Ried, T.; Gozani, O.; Chua, K. F. SIRT6 Is a Histone H3 Lysine 9 Deacetylase That Modulates Telomeric Chromatin. Nature 2008, 452 (7186), 492– 496,  DOI: 10.1038/nature06736
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    111
    SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
    Michishita, Eriko; McCord, Ronald A.; Berber, Elisabeth; Kioi, Mitomu; Padilla-Nash, Hesed; Damian, Mara; Cheung, Peggie; Kusumoto, Rika; Kawahara, Tiara L. A.; Barrett, J. Carl; Chang, Howard Y.; Bohr, Vilhelm A.; Ried, Thomas; Gozani, Or; Chua, Katrin F.
    Nature (London, United Kingdom) (2008), 452 (7186), 492-496CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature aging-like phenotype. However, the mol. mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-assocd. protein, but no enzymic activity of SIRT6 at chromatin has yet been detected, and the identity of physiol. SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 assocs. specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects obsd. in Werner syndrome, a premature aging disorder. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable assocn. of WRN, the factor that is mutated in Werner syndrome. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metab. and function. Our findings constitute the first identification of a physiol. enzymic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature aging syndrome.
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  112. 112
    Michishita, E.; McCord, R. A.; Boxer, L. D.; Barber, M. F.; Hong, T.; Gozani, O.; Chua, K. F. Cell Cycle-Dependent Deacetylation of Telomeric Histone H3 Lysine K56 by Human SIRT6. Cell Cycle 2009, 8 (16), 2664– 2666,  DOI: 10.4161/cc.8.16.9367
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    112
    Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6
    Michishita, Eriko; McCord, Ronald A.; Boxer, Lisa D.; Barber, Matthew F.; Hong, Tao; Gozani, Or; Chua, Katrin F.
    Cell Cycle (2009), 8 (16), 2664-2666CODEN: CCEYAS; ISSN:1538-4101. (Landes Bioscience)
    A second substrate of SIRT6 at chromotin, lysine 56 on the globular core of histone H3 (H3K56Ac) was examd. It was found that SIRT6 deacetylates H3K56Ac in vitro and in cells, and detd. a physiol. role for this activity in maintaining dynamic changes of H3K56 acetylation levels at telomeric chromatin over the cell cycle. Results showed that H3K56Ac was the new substrate for SIRT6. It also presented the antibody-independent mass spectrometry validation of the H3K56Ac deacetylase activities of both SIRT6 and SIRT1. The obsd. new data indicate that SIRT6 deacelylation of H3K56Ac might operate at chromatin directly at such sites of damaged DNA, and defects in such a mechanism could underlie aspects of the genomic instability, DNA damage hypersensitivity, and defective DNA repair phenotypes that are obsd. in SIRT6-deficient cells.
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    Michishita, E.; Park, J. Y.; Burneskis, J. M.; Barrett, J. C.; Horikawa, I. Evolutionarily Conserved and Nonconserved Cellular Localizations and Functions of Human SIRT Proteins. Mol. Biol. Cell 2005, 16 (10), 4623,  DOI: 10.1091/mbc.e05-01-0033
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    113
    Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins
    Michishita, Eriko; Park, Jean Y.; Burneskis, Jenna M.; Barrett, J. Carl; Horikawa, Izumi
    Molecular Biology of the Cell (2005), 16 (10), 4623-4635CODEN: MBCEEV; ISSN:1059-1524. (American Society for Cell Biology)
    Sir2 is a NAD+-dependent protein deacetylase that extends lifespan in yeast and worms. This study examines seven human proteins homologous to Sir2 (SIRT1 through SIRT7) for cellular localization, expression profiles, protein deacetylation activity, and effects on human cell lifespan. We found that: (1) three nuclear SIRT proteins (SIRT1, SIRT6, and SIRT7) show different subnuclear localizations: SIRT6 and SIRT7 are assocd. with heterochromatic regions and nucleoli, resp., where yeast Sir2 functions; (2) SIRT3, SIRT4, and SIRT5 are localized in mitochondria, an organelle that links aging and energy metab.; (3) cellular p53 is a major in vivo substrate of SIRT1 deacetylase, but not the other six SIRT proteins; (4) SIRT1, but not the other two nuclear SIRT proteins, shows an in vitro deacetylase activity on histone H4 and p53 peptides; and (5) overexpression of any one of the seven SIRT proteins does not extend cellular replicative lifespan in normal human fibroblasts or prostate epithelial cells. This study supports the notion that multiple human SIRT proteins have evolutionarily conserved and nonconserved functions at different cellular locations and reveals that the lifespan of normal human cells, in contrast to that of lower eukaryotes, cannot be manipulated by increased expression of a single SIRT protein.
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    Tennen, R. I.; Bua, D. J.; Wright, W. E.; Chua, K. F. SIRT6 Is Required for Maintenance of Telomere Position Effect in Human Cells. Nat. Commun. 2011, 2 (1), 433,  DOI: 10.1038/ncomms1443
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    114
    SIRT6 is required for maintenance of telomere position effect in human cells
    Tennen Ruth I; Bua Dennis J; Wright Woodring E; Chua Katrin F
    Nature communications (2011), 2 (), 433 ISSN:.
    In Saccharomyces cerevisiae, the repressive chromatin environment at telomeres gives rise to telomere position effect (TPE), the epigenetic silencing of telomere-proximal genes. Chromatin-modifying factors that control TPE in yeast have been extensively studied, and, among these, the lifespan regulator and silencing protein Sir2 has a pivotal role. In contrast, the factors that generate and maintain silent telomeric chromatin in human cells remain largely unknown. Here we show that the Sir2 family member SIRT6 is required for maintenance of TPE in human cells. RNAi-mediated depletion of SIRT6 abrogates silencing of both an integrated telomeric transgene and an endogenous telomere-proximal gene. Moreover, enhanced telomeric silencing in response to telomere elongation is associated with increased repressive chromatin marks, and this heterochromatic milieu is lost in SIRT6-deficient cells. Together, these findings establish a new role for SIRT6 in regulating an ageing-associated epigenetic silencing process and provide new mechanistic insight into chromatin silencing at telomeres.
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    Tennen, R. I.; Chua, K. F. Chromatin Regulation and Genome Maintenance by Mammalian SIRT6. Trends Biochem. Sci. 2011, 36 (1), 39– 46,  DOI: 10.1016/j.tibs.2010.07.009
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    Chromatin regulation and genome maintenance by mammalian SIRT6
    Tennen, Ruth I.; Chua, Katrin F.
    Trends in Biochemical Sciences (2011), 36 (1), 39-46CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)
    A review. Saccharomyces cerevisiae Sir2 is an NAD+-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metab. and lifespan regulation. In mice, deficiency for the Sir2 family member SIRT6 leads to genomic instability, metabolic defects and degenerative pathologies assocd. with aging. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. However, new mechanistic insights have come from the discovery that SIRT6 is a highly substrate-specific histone deacetylase that promotes proper chromatin function in several physiol. contexts, including telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian genome, SIRT6 thus serves several roles that parallel Sir2 function. In this article, we review recent advances in understanding the mechanisms of SIRT6 action and their implications for human biol. and disease.
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    Van Meter, M.; Mao, Z.; Gorbunova, V.; Seluanov, A. Repairing Split Ends: SIRT6, Mono-ADP Ribosylation and DNA Repair. Aging (Albany. NY). 2011, 3 (9), 829– 835,  DOI: 10.18632/aging.100389
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    116
    Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair
    Van Meter Michael; Mao Zhiyong; Gorbunova Vera; Seluanov Andrei
    Aging (2011), 3 (9), 829-35 ISSN:.
    The sirtuin gene family comprises an evolutionarily ancient set of NAD+ dependent protein deacetylase and mono-ADP ribosyltransferase enzymes. Found in all domains of life, sirtuins regulate a diverse array of biological processes, including DNA repair, gene silencing, apoptosis and metabolism. Studies in multiple model organisms have indicated that sirtuins may also function to extend lifespan and attenuate age-related pathologies. To date, most of these studies have focused on the deacetylase activity of sirtuins, and relatively little is known about the other biochemical activity of sirtuins, mono-ADP ribosylation. We recently reported that the mammalian sirtuin, SIRT6, mono-ADP ribosylates PARP1 to promote DNA repair in response to oxidative stress. In this research perspective we review the role of SIRT6 in DNA repair and discuss the emerging implications for sirtuin directed mono-ADP ribosylation in aging and age-related diseases.
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    Chun, P. Role of Sirtuins in Chronic Obstructive Pulmonary Disease. Arch. Pharm. Res. 2015, 38 (1), 1– 10,  DOI: 10.1007/s12272-014-0494-2
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    117
    Role of sirtuins in chronic obstructive pulmonary disease
    Chun, Pusoon
    Archives of Pharmacal Research (2015), 38 (1), 1-10CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)
    A review. Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is assocd. with chronic inflammatory response to noxious particles or gases. The airflow limitation may be explained by hypersecretion of mucus, thickening and fibrosis of small airways and alveolar wall destruction in emphysema. Sirtuins, a group of class III deacetylases, have gained considerable attention for their pos. effects on aging-related disease, such as cancer, cardiovascular disease, neurodegenerative diseases, osteoporosis and COPD. Among the seven mammalian sirtuins, SIRT1-SIRT7, SIRT1 and SIRT6 are considered to have protective effects against COPD. In the lungs, SIRT1 inhibits autophagy, cellular senescence, fibrosis, and inflammation by deacetylation of target proteins using NAD+ as co-substrate and is therefore linked to the redox state. In addn. to SIRT1, SIRT6 have also been shown to improve or slow down COPD. SIRT6 Escherichia is assocd. with redox state and inhibits cellular senescence and fibrosis. Therefore, activation of SIRT1 and SIRT6 might be an attractive approach for novel therapeutic targets for COPD. The present review describes the protective effects of SIRT1 and SIRT6 against COPD and their target proteins involved in the pathophysiol. of COPD.
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  118. 118
    Takasaka, N.; Araya, J.; Hara, H.; Ito, S.; Kobayashi, K.; Kurita, Y.; Wakui, H.; Yoshii, Y.; Yumino, Y.; Fujii, S.; Minagawa, S.; Tsurushige, C.; Kojima, J.; Numata, T.; Shimizu, K.; Kawaishi, M.; Kaneko, Y.; Kamiya, N.; Hirano, J.; Odaka, M.; Morikawa, T.; Nishimura, S. L.; Nakayama, K.; Kuwano, K. Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence. J. Immunol. 2014, 192 (3), 958– 968,  DOI: 10.4049/jimmunol.1302341
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    118
    Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence
    Takasaka, Naoki; Araya, Jun; Hara, Hiromichi; Ito, Saburo; Kobayashi, Kenji; Kurita, Yusuke; Wakui, Hiroshi; Yoshii, Yutaka; Yumino, Yoko; Fujii, Satoko; Minagawa, Shunsuke; Tsurushige, Chikako; Kojima, Jun; Numata, Takanori; Shimizu, Kenichiro; Kawaishi, Makoto; Kaneko, Yumi; Kamiya, Noriki; Hirano, Jun; Odaka, Makoto; Morikawa, Toshiaki; Nishimura, Stephen L.; Nakayama, Katsutoshi; Kuwano, Kazuyoshi
    Journal of Immunology (2014), 192 (3), 958-968CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
    Cigarette smoke (CS)-induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is neg. regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-assocd. β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory vol. in 1 s/forced vital capacity. CS ext. (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.
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    Finkel, T.; Deng, C. X.; Mostoslavsky, R. Recent Progress in the Biology and Physiology of Sirtuins. Nature 2009, 460 (7255), 587– 591,  DOI: 10.1038/nature08197
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    Recent progress in the biology and physiology of sirtuins
    Finkel, Toren; Deng, Chu-Xia; Mostoslavsky, Raul
    Nature (London, United Kingdom) (2009), 460 (7255), 587-591CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    A review. The sirtuins are a highly conserved family of NAD-dependent deacetylases that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis, and energy metab. Here, the authors review recent progress in sirtuin biol., the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long humans live.
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    Jia, G.; Su, L.; Singhal, S.; Liu, X. Emerging Roles of SIRT6 on Telomere Maintenance, DNA Repair, Metabolism and Mammalian Aging. Mol. Cell. Biochem. 2012, 364 (1–2), 345– 350,  DOI: 10.1007/s11010-012-1236-8
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    120
    Emerging roles of SIRT6 on telomere maintenance, DNA repair, metabolism and mammalian aging
    Jia, Gaoxiang; Su, Ling; Singhal, Sunil; Liu, Xiangguo
    Molecular and Cellular Biochemistry (2012), 364 (1-2), 345-350CODEN: MCBIB8; ISSN:0300-8177. (Springer)
    A review. With the characterization of Sir2 gene in yeast aging, its mammalian homologs Sirtuins 1-7 have been attracting attention from scientists with various research backgrounds. Among Sirtuins, SIRT1 is the most extensively studied. Recent progress on mammalian Sirtuins has shown that SIRT6 as a histone deacetylase may also play a crit. role in regulating mammalian aging. This review summarizes recent advances on SIRT6 as a key modulator of telomere structure, DNA repair, metab., and NF-kappa B pathway in aging. In addn., we discuss the challenges that remain to be studied in SIRT6 biol.
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    Michan, S.; Sinclair, D. Sirtuins in Mammals: Insights into Their Biological Function. Biochem. J. 2007, 404 (1), 1– 13,  DOI: 10.1042/BJ20070140
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    Sirtuins in mammals: Insights into their biological function
    Michan, Shaday; Sinclair, David
    Biochemical Journal (2007), 404 (1), 1-13CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
    A review. Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologs also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiol., since they may provide novel targets for treating diseases assocd. with aging and perhaps extend human lifespan. In this review, we describe our current understanding of the biol. function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacol. targets to delay and treat human age-related diseases.
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    Toiber, D.; Sebastian, C.; Mostoslavsky, R. Characterization of Nuclear Sirtuins: Molecular Mechanisms and Physiological Relevance. Handb. Exp. Pharmacol. 2011, 206, 189– 224,  DOI: 10.1007/978-3-642-21631-2_9
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    Characterization of nuclear sirtuins: Molecular mechanisms and physiological relevance
    Toiber, Debra; Sebastian, Carlos; Mostoslavsky, Raul
    Handbook of Experimental Pharmacology (2011), 206 (Histone Deacetylases), 189-224CODEN: HEPHD2; ISSN:0171-2004. (Springer GmbH)
    A review. Sirtuins are protein deacetylases/mono-ADP-ribosyltransferases found in organisms ranging from bacteria to humans. This group of enzymes relies on NAD as a cofactor linking their activity to the cellular metabolic status. Originally found in yeast, sirtuin 2 was discovered as a silencing factor and has been shown to mediate the effects of calorie restriction on lifespan extension. In mammals, 7 homologs (SIRT1-7) exist which evolved to have specific biol. outcomes depending on the particular cellular context, their interacting proteins, and the genomic loci to where they are actively targeted. The biol. roles of sirtuins are highlighted in early lethal phenotypes obsd. in deficient murine models. Here, the authors summarize current concepts on non-metabolic functions for sirtuins, depicting this broad family from yeast to mammals.
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    Ford, E.; Voit, R.; Liszt, G.; Magin, C.; Grummt, I.; Guarente, L. Mammalian Sir2 Homolog SIRT7 Is an Activator of RNA Polymerase I Transcription. Genes Dev. 2006, 20 (9), 1075– 1080,  DOI: 10.1101/gad.1399706
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    Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription
    Ford, Ethan; Voit, Renate; Liszt, Gregory; Magin, Cornelia; Grummt, Ingrid; Guarente, Leonard
    Genes & Development (2006), 20 (9), 1075-1080CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)
    We investigated the role of SIRT7, one of the seven members of the mammalian sirtuin family. We show that SIRT7 is a widely expressed nucleolar protein that is assocd. with active rRNA genes (rDNA), where it interacts with RNA polymerase I (Pol I) as well as with histones. Overexpression of SIRT7 increases Pol I-mediated transcription, whereas knockdown of SIRT7 or inhibition of the catalytic activity results in decreased assocn. of Pol I with rDNA and a redn. of Pol I transcription. Depletion of SIRT7 stops cell proliferation and triggers apoptosis. Our findings suggest that SIRT7 is a pos. regulator of Pol I transcription and is required for cell viability in mammals.
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    Kiran, S.; Anwar, T.; Kiran, M.; Ramakrishna, G. Sirtuin 7 in Cell Proliferation, Stress and Disease: Rise of the Seventh Sirtuin!. Cell. Signal. 2015, 27 (3), 673– 682,  DOI: 10.1016/j.cellsig.2014.11.026
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    Sirtuin 7 in cell proliferation, stress and disease: Rise of the Seventh Sirtuin!
    Kiran, Shashi; Anwar, Tarique; Kiran, Manjari; Ramakrishna, Gayatri
    Cellular Signalling (2015), 27 (3), 673-682CODEN: CESIEY; ISSN:0898-6568. (Elsevier)
    A review. Sirtuin 7 is a member of the sirtuin family of proteins. Sirtuins were originally discovered in yeast for its role in prolonging replicative lifespan. Until recently SIRT7 happened to be the least studied sirtuin of the seven mammalian sirtuins. However, a no. of recent breakthrough reports have provided significant clarity to SIRT7 biol. SIRT7 is now seen as a vital regulator of rRNA and protein synthesis for maintenance of normal cellular homeostasis. Proteins like p53, H3K18, PAF53, NPM1 and GABP-β1 are the known substrates for the deacetylase activity of SIRT7, thereby making it a key mediator of many cellular activities. Studies using in vitro based assays and also knockout mice have revealed a role of SIRT7 in certain disease pathologies as well. High expression of SIRT7 has been reported in few cancer types and is steadily propelling SIRT7 towards an oncogene status. The role of SIRT7 as a pro-survival adaptor mol. in conditions of cellular stress has recently emerged in view of the fact that SIRT7 can regulate mols. like HIF and IRE1α. Addnl., SIRT7 plays a key role in maintenance of the epigenome as it caused the deacetylation of histone (H3K18) and global proteomics studies have shown its interaction with many chromatin remodelling complexes such as B-WICH and other proteins. Lately, the role of SIRT7 in hepatic lipid metab. has been debated. This review attempts to summarize these recent findings and present the role of SIRT7 as an important cellular regulator.
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    Han, H. Q.; Zhou, X.; Mitch, W. E.; Goldberg, A. L. Myostatin/Activin Pathway Antagonism: Molecular Basis and Therapeutic Potential. Int. J. Biochem. Cell Biol. 2013, 45 (10), 2333– 2347,  DOI: 10.1016/j.biocel.2013.05.019
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    Myostatin/activin pathway antagonism: Molecular basis and therapeutic potential
    Han, H. Q.; Zhou, Xiaolan; Mitch, William E.; Goldberg, Alfred L.
    International Journal of Biochemistry & Cell Biology (2013), 45 (10), 2333-2347CODEN: IJBBFU; ISSN:1357-2725. (Elsevier Ltd.)
    A review. Muscle wasting is assocd. with a wide range of catabolic diseases. This debilitating loss of muscle mass and functional capacity reduces the quality of life and increases the risks of morbidity and mortality. Major progress has been made in understanding the biochem. mechanisms and signaling pathways regulating muscle protein balance under normal conditions and the enhanced protein loss in atrophying muscles. It is now clear that activation of myostatin/activin signaling is crit. in triggering the accelerated muscle catabolism that causes muscle loss in multiple disease states. Binding of myostatin and activin to the ActRIIB receptor complex on muscle cell membrane leads to activation of Smad2/3-mediated transcription, which in turn stimulates FoxO-dependent transcription and enhanced muscle protein breakdown via ubiquitin-proteasome system and autophagy. In addn., Smad activation inhibits muscle protein synthesis by suppressing Akt signaling. Pharmacol. blockade of the myostatin/activin-ActRIIB pathway has been shown to prevent or reverse the loss of muscle mass and strength in various disease models including cancer cachexia and renal failure. Moreover, it can markedly prolong the lifespan of animals with cancer-assocd. muscle loss. Furthermore, inhibiting myostatin/activin actions also improves insulin sensitivity, reduces excessive adiposity, attenuates systemic inflammation, and accelerates bone fracture healing in disease models. Based on these exciting advances, the potential therapeutic benefits of myostatin/activin antagonism are now being tested in multiple clin. settings.This article is part of a Directed Issue entitled: Mol. basis of muscle wasting.
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    Sartori, R.; Milan, G.; Patron, M.; Mammucari, C.; Blaauw, B.; Abraham, R.; Sandri, M. Smad2 and 3 Transcription Factors Control Muscle Mass in Adulthood. Am. J. Physiol. Cell Physiol. 2009, 296 (6), C1248,  DOI: 10.1152/ajpcell.00104.2009
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    Trendelenburg, A. U.; Meyer, A.; Rohner, D.; Boyle, J.; Hatakeyama, S.; Glass, D. J. Myostatin Reduces Akt/TORC1/P70S6K Signaling, Inhibiting Myoblast Differentiation and Myotube Size. Am. J. Physiol. Cell Physiol. 2009, 296 (6), C1258,  DOI: 10.1152/ajpcell.00105.2009
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    McCroskery, S.; Thomas, M.; Maxwell, L.; Sharma, M.; Kambadur, R. Myostatin Negatively Regulates Satellite Cell Activation and Self-Renewal. J. Cell Biol. 2003, 162 (6), 1135– 1147,  DOI: 10.1083/jcb.200207056
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    Myostatin negatively regulates satellite cell activation and self-renewal
    McCroskery, Seumas; Thomas, Mark; Maxwell, Linda; Sharma, Mridula; Kambadur, Ravi
    Journal of Cell Biology (2003), 162 (6), 1135-1147CODEN: JCLBA3; ISSN:0021-9525. (Rockefeller University Press)
    Satellite cells are quiescent muscle stem cells that promote postnatal muscle growth and repair. Myostatin, a TGF-β member, signals satellite cell quiescence and also neg. regulates satellite cell self-renewal. BrdU labeling in vivo revealed that, among the Myostatin-deficient satellite cells, higher nos. of satellite cells are activated as compared with wild type. In contrast, addn. of Myostatin to myofiber explant cultures inhibits satellite cell activation. Cell cycle anal. confirms that Myostatin up-regulated p21, a Cdk inhibitor, and decreased the levels and activity of Cdk2 protein in satellite cells. Hence, Myostatin neg. regulates the G1 to S progression and thus maintains the quiescent status of satellite cells. Immunohistochem. anal. with CD34 antibodies indicates that there is an increased no. of satellite cells per unit length of freshly isolated Mstn-/- muscle fibers. Detn. of proliferation rate suggests that this elevation in satellite cell no. could be due to increased self-renewal and delayed expression of the differentiation gene (myogenin) in Mstn-/- adult myoblasts. Taken together, these results suggest that Myostatin is a potent neg. regulator of satellite cell activation and thus signals the quiescence of satellite cells.
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    MAURO, A. Satellite Cell of Skeletal Muscle Fibers. J. Biophys. Biochem. Cytol. 1961, 9 (2), 493– 495,  DOI: 10.1083/jcb.9.2.493
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    Satellite cell of skeletal muscle fibers
    MAURO A
    The Journal of biophysical and biochemical cytology (1961), 9 (), 493-5 ISSN:0095-9901.
    There is no expanded citation for this reference.
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    Dhawan, J.; Rando, T. A. Stem Cells in Postnatal Myogenesis: Molecular Mechanisms of Satellite Cell Quiescence, Activation and Replenishment. Trends Cell Biol. 2005, 15 (12), 666– 673,  DOI: 10.1016/j.tcb.2005.10.007
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    Stem cells in postnatal myogenesis: molecular mechanisms of satellite cell quiescence, activation and replenishment
    Dhawan, Jyotsna; Rando, Thomas A.
    Trends in Cell Biology (2005), 15 (12), 666-673CODEN: TCBIEK; ISSN:0962-8924. (Elsevier)
    A review. Satellite cells are the primary stem cells in adult skeletal muscle, and are responsible for postnatal muscle growth, hypertrophy and regeneration. In mature muscle, most satellite cells are in a quiescent state, but they activate and begin proliferating in response to extrinsic signals. Following activation, a subset of satellite cell progeny returns to the quiescent state during the process of self-renewal. Here, we review recent studies of satellite cell biol. and focus on the key transitions from the quiescent state to the state of proliferative activation and myogenic lineage progression and back to the quiescent state. The mol. mechanisms of these transitions are considered in the context of the biol. of the satellite cell niche, changes with age, and interactions with established pathways of myogenic commitment and differentiation.
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    Kuang, S.; Gillespie, M. A.; Rudnicki, M. A. Niche Regulation of Muscle Satellite Cell Self-Renewal and Differentiation. Cell Stem Cell 2008, 2 (1), 22– 31,  DOI: 10.1016/j.stem.2007.12.012
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    Niche regulation of muscle satellite cell self-renewal and differentiation
    Kuang, Shihuan; Gillespie, Mark A.; Rudnicki, Michael A.
    Cell Stem Cell (2008), 2 (1), 22-31CODEN: CSCEC4; ISSN:1934-5909. (Cell Press)
    A review. Muscle satellite cells have been shown to be a heterogeneous population of committed myogenic progenitors and noncommitted stem cells. This hierarchical compn. of differentiating progenitors and self-renewable stem cells assures the extraordinary regenerative capacity of skeletal muscles. Recent studies have revealed a role for asym. division in satellite cell maintenance and offer novel insights into the regulation of satellite cell function by the niche. A thorough understanding of the mol. regulation and cell fate detn. of satellite cells and other potential stem cells resident in muscle is essential for successful stem cell-based therapies to treat muscular diseases.
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    Ju, C. R.; Chen, R. C. Serum Myostatin Levels and Skeletal Muscle Wasting in Chronic Obstructive Pulmonary Disease. Respir. Med. 2012, 106 (1), 102– 108,  DOI: 10.1016/j.rmed.2011.07.016
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    132
    Serum myostatin levels and skeletal muscle wasting in chronic obstructive pulmonary disease
    Ju Chun-Rong; Chen Rong-Chang
    Respiratory medicine (2012), 106 (1), 102-8 ISSN:.
    INTRODUCTION: It is well confirmed that myostatin is a negative regulator of skeletal muscle mass and implicated in several diseases involved in muscle wasting and cachexia. Skeletal muscle wasting is an important systemic manifestation of chronic obstructive pulmonary disease (COPD), while the expression of circulating myostatin in COPD remains unclear. The aim of this study was to investigate the expression of circulating myostatin and its relationship with skeletal muscle wasting in COPD. METHODS: Seventy-one patients with stable COPD and sixty age-matched, healthy control subjects participated in the study. Total skeletal muscle mass (SMM) were calculated according to a validated formula by using age and anthropometric measurements. Serum levels of myostatin, tumor necrosis factor (TNF)-α and interleukin-6 were determined by ELISA. RESULTS: Serum myostatin levels were significantly elevated in COPD patients when compared to controls [(11.85 ± 4.01) ng/ml vs. (7.46 ± 2.21) ng/ml, p < 0.01], while total SMM was significantly decreased in COPD patients when compared to controls [(20.81 ± 1.74) kg vs. (27.31 ± 2.18) kg for male, and (11.70 ± 0.56) kg vs. (19.89 ± 1.47) kg for female] (both p < 0.05). Regression correlation analysis on all COPD patients showed that serum myostatin levels weren't significantly correlated with SMM, but correlated with TNF-α levels (R(2) = 0.042, p = 0.048). However, when stratified for gender, serum myostatin levels were correlated inversely both with SMM (R(2) = 0.20, p = 0.000) and with BMI (R(2) = 0.084, p = 0.019) in subgroup of male patients. CONCLUSION: This study demonstrates that circulating myostatin levels are elevated in COPD and related to SMM in male patients, suggesting that myostatin contributes to skeletal muscle wasting in COPD.
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    Testelmans, D.; Crul, T.; Maes, K.; Agten, A.; Crombach, M.; Decramer, M.; Gayan-Ramirez, G. Atrophy and Hypertrophy Signalling in the Diaphragm of Patients with COPD. Eur. Respir. J. 2010, 35 (3), 549– 556,  DOI: 10.1183/09031936.00091108
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    Atrophy and hypertrophy signalling in the diaphragm of patients with COPD
    Testelmans, D.; Crul, T.; Maes, K.; Agten, A.; Crombach, M.; Decramer, M.; Gayan-Ramirez, G.
    European Respiratory Journal (2010), 35 (3), 549-556CODEN: ERJOEI; ISSN:0903-1936. (European Respiratory Society)
    We investigated whether atrophy and hypertrophy signalling were altered in the diaphragm of chronic obstructive pulmonary disease (COPD) patients. We studied diaphragm fiber dimensions and proportion, expression of markers of the ubiquitin-proteasome pathway, nuclear factor (NF)-κB pathways, muscle regulatory factors and myostatin in diaphragm biopsies from 19 patients with severe COPD and 13 patients without COPD. Type I proportion was significantly increased in the diaphragm of COPD patients while type II proportion was decreased. The cross-sectional area of all fiber types was reduced in the COPD patients. In addn., MAFbx mRNA was higher in the diaphragm of COPD patients while Nedd4 mRNA decreased. Cytoplasmatic levels of inhibitor protein IκBα and IκBβ were decreased in the COPD patients as was NF-κB p50 DNA-binding activity. MyoD mRNA and its nuclear protein content were decreased in the diaphragm of COPD patients and myogenin mRNA and protein levels remained unchanged. Myostatin mRNA was decreased but its protein levels in the nuclear and cytoplasmic fraction were significantly increased in the COPD patients. These data show that the ubiquitin-proteasome pathway, the NF-κB pathway and myostatin protein were up-regulated in the diaphragm of COPD patients while MyoD expression was reduced. These alterations may contribute to diaphragm remodeling in COPD.
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    Zhang, D.; Cao, L.; Wang, Z.; Feng, H.; Cai, X.; Xu, M.; Li, M.; Yu, N.; Yin, Y.; Wang, W.; Kang, J. Salidroside Mitigates Skeletal Muscle Atrophy in Rats with Cigarette Smoke-Induced COPD by up-Regulating Myogenin and down-Regulating Myostatin Expression. Biosci. Rep. 2019, 39 (11), BSR20190440,  DOI: 10.1042/BSR20190440
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    Carter, M. E.; Brunet, A. FOXO Transcription Factors. Curr. Biol. 2007, 17 (4), R113,  DOI: 10.1016/j.cub.2007.01.008
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    FOXO transcription factors
    Carter, Matthew E.; Brunet, Anne
    Current Biology (2007), 17 (4), R113-R114CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)
    There is no expanded citation for this reference.
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    Stitt, T. N.; Drujan, D.; Clarke, B. A.; Panaro, F.; Timofeyva, Y.; Kline, W. O.; Gonzalez, M.; Yancopoulos, G. D.; Glass, D. J. The IGF-1/PI3K/Akt Pathway Prevents Expression of Muscle Atrophy-Induced Ubiquitin Ligases by Inhibiting FOXO Transcription Factors. Mol. Cell 2004, 14 (3), 395– 403,  DOI: 10.1016/S1097-2765(04)00211-4
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    The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors
    Stitt, Trevor N.; Drujan, Doreen; Clarke, Brian A.; Panaro, Frank; Timofeyva, Yekatarina; Kline, William O.; Gonzalez, Michael; Yancopoulos, George D.; Glass, David J.
    Molecular Cell (2004), 14 (3), 395-403CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)
    Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the mol. mediators of atrophy and hypertrophy had been reported. The authors demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of MuRF1 and MAFbx upregulation. The authors' study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.
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    Sandri, M.; Sandri, C.; Gilbert, A.; Skurk, C.; Calabria, E.; Picard, A.; Walsh, K.; Schiaffino, S.; Lecker, S. H.; Goldberg, A. L. Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy. Cell 2004, 117 (3), 399– 412,  DOI: 10.1016/S0092-8674(04)00400-3
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    137
    Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy
    Sandri, Marco; Sandri, Claudia; Gilbert, Alex; Skurk, Carsten; Calabria, Elisa; Picard, Anne; Walsh, Kenneth; Schiaffino, Stefano; Lecker, Stewart H.; Goldberg, Alfred L.
    Cell (Cambridge, MA, United States) (2004), 117 (3), 399-412CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Skeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-neg. construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a crit. role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting.
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    Doucet, M.; Russell, A. P.; Léger, B.; Debigaré, R.; Joanisse, D. R.; Caron, M. A.; LeBlanc, P.; Maltais, F. Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2007, 176 (3), 261– 269,  DOI: 10.1164/rccm.200605-704OC
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    Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease
    Doucet, Marieve; Russell, Aaron P.; Leger, Bertrand; Debigare, Richard; Joanisse, Denis R.; Caron, Marc-Andre; LeBlanc, Pierre; Maltais, Francois
    American Journal of Respiratory and Critical Care Medicine (2007), 176 (3), 261-269CODEN: AJCMED; ISSN:1073-449X. (American Thoracic Society)
    Rationale: The mol. mechanisms of muscle atrophy in chronic obstructive pulmonary disease (COPD) are poorly understood. In wasted animals, muscle mass is regulated by several AKT-related signaling pathways. Objectives: To measure the protein expression of AKT, forkhead box class O (FoxO)-1 and -3, atrogin-1, the phosphophrylated form of AKT, p70S6K glycogen synthase kinase-3β (GSK-3β), eukaryotic translation initiation factor 4E binding protein-1 (4E-BP1), and the mRNA expression of atrogin-1, muscle ring finger (MuRF) protein 1, and FoxO-1 and -3 in the quadriceps of 12 patients with COPD with muscle atrophy and 10 healthy control subjects. Five patients with COPD with preserved muscle mass were subsequently recruited and were compared with six patients with low muscle mass. Methods: Protein contents and mRNA expression were measured by Western blot and quant. polymerase chain reaction, resp. Measurements and Main Results: The levels of atrogin-1 and MuRF1 mRNA, and of phosphorylated AKT and 4E-BP1 and FoxO-1 proteins, were increased in patients with COPD with muscle atrophy compared with healthy control subjects, whereas atrogin-1, p70S6K, GSK-3β, and FoxO-3 protein levels were similar. Patients with COPD with muscle atrophy showed an increased expression of p70S6K, GSK-3β, and 4E-BP1 compared with patients with COPD with preserved muscle mass. Conclusions: An increase in atrogin-1 and MuRF1 mRNA and FoxO-1 protein content was obsd. in the quadriceps of patients with COPD. The transcriptional regulation of atrogin-1 and MuRF1 may occur via FoxO-1, but independently of AKT. The overexpression of the muscle hypertrophic signaling pathways found in patients with COPD with muscle atrophy could represent an attempt to restore muscle mass.
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  139. 139
    Hwang, J.; Rajendrasozhan, S.; Yao, H.; Chung, S.; Sundar, I. K.; Huyck, H. L.; Pryhuber, G. S.; Kinnula, V. L.; Rahman, I. FoxO3 Deficiency Leads to Increased Susceptibility to Cigarette Smoke-Induced Inflammation, Airspace Enlargement, and Chronic Obstructive Pulmonary Disease. J. Immunol. 2011, 187 (2), 987,  DOI: 10.4049/jimmunol.1001861
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    139
    FOXO3 Deficiency Leads to Increased Susceptibility to Cigarette Smoke-Induced Inflammation, Airspace Enlargement, and Chronic Obstructive Pulmonary Disease
    Hwang, Jae-woong; Rajendrasozhan, Saravanan; Yao, Hongwei; Chung, Sangwoon; Sundar, Isaac K.; Huyck, Heidie L.; Pryhuber, Gloria S.; Kinnula, Vuokko L.; Rahman, Irfan
    Journal of Immunology (2011), 187 (2), 987-998CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
    Forkhead box class O 3a (FOXO3) is a member of the FoxO transcription factor subfamily, which regulates the expression of target genes not only through DNA binding as a transcription factor, but also through protein-protein interaction. Although FoxO3 is a well-known transcription factor involved in diverse biol. processes, the role of FoxO3 in cigarette smoke (CS)-induced lung inflammation and injury has not been studied. It is, therefore, hypothesized that deficiency of FoxO3 leads to increased susceptibility to CS-induced lung inflammatory response and airspace enlargement. In this article, we show that the levels of FOXO3 are significantly decreased in lungs of smokers and patients with chronic obstructive pulmonary disease, as well as in lungs of mice exposed to CS. Genetic ablation of FoxO3 led to pulmonary emphysema and exaggerated inflammatory response in lungs of mice exposed to CS. We further showed that CS induced the translocation of FoxO3 into the nucleus where FoxO3 interacted with NF-κB and disrupted NF-κB DNA-binding ability, leading to inhibition of its activity. Targeted disruption of FoxO3 also resulted in downregulation of antioxidant genes in mouse lungs in response to CS exposure. These results suggest that FoxO3 plays a pivotal role in regulation of lung inflammatory response and antioxidant genes, and deficiency of FoxO3 results in development of chronic obstructive pulmonary disease/emphysema.
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  140. 140
    Shi, J.; Yin, N.; Xuan, L. L.; Yao, C. S.; Meng, A. M.; Hou, Q. Vam3, a Derivative of Resveratrol, Attenuates Cigarette Smoke-Induced Autophagy. Acta Pharmacol. Sin. 2012, 33 (7), 888– 896,  DOI: 10.1038/aps.2012.73
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    Vam3, a derivative of resveratrol, attenuates cigarette smoke-induced autophagy
    Shi, Ji; Yin, Ning; Xuan, Ling-ling; Yao, Chun-suo; Meng, Ai-min; Hou, Qi
    Acta Pharmacologica Sinica (2012), 33 (7), 888-896CODEN: APSCG5; ISSN:1671-4083. (Nature Publishing Group)
    To appraise the efficacy of Vam3 (Amurensis H), a dimeric deriv. of resveratrol, at inhibiting cigarette smoke-induced autophagy. Human bronchial epithelial cells were treated with cigarette smoke condensates, and a chronic obstructive pulmonary disease (COPD) model was established by exposing male BALB/c mice to cigarette smoke. The protein levels of the autophagic marker microtubule-assocd. protein 1A/1B-light chain 3 (LC3), Sirtuin 1 (Sirt1), and foxhead box O 3a (FoxO3a) were examd. using Western blotting and Immunohistochem. LC3 punctae were detected by immunofluorescence. The levels of FoxO3a acetylation were examd. by immunopptn. The level of intracellular oxidn. was assessed by detecting ROS and GSH-Px. Results: Vam3 attenuated cigarette smoke condensate-induced autophagy in human bronchial epithelial cells, and restored the expression levels of Sirt1 and FoxO3a that had been reduced by cigarette smoke condensates. Similar protective effects of Vam3, reducing autophagy and restoring the levels of Sirt1 and FoxO3a, were obsd. in the COPD animal model. Addnl., Vam3 also diminished the oxidative stress that was induced by the cigarette smoke condensates. Conclusion: Vam3 decreases cigarette smoke-induced autophagy via up-regulating/restoring the levels of Sirt1 and FoxO3a and inhibiting the induced oxidative stress.
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    Handschin, C.; Spiegelman, B. M. Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Coactivators, Energy Homeostasis, and Metabolism. Endocr. Rev. 2006, 27 (7), 728– 735,  DOI: 10.1210/er.2006-0037
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    141
    Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism
    Handschin, Christoph; Spiegelman, Bruce M.
    Endocrine Reviews (2006), 27 (7), 728-735CODEN: ERVIDP; ISSN:0163-769X. (Endocrine Society)
    A review. Many biol. programs are regulated at the transcriptional level. This is generally achieved by the concerted actions of several transcription factors. Recent findings have shown that, in many cases, transcriptional coactivators coordinate the overall regulation of the biol. programs. One of the best-studied examples of coactivator control of metabolic pathways is the peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) family. These proteins are strong activators of mitochondrial function and are thus dominant regulators of oxidative metab. in a variety of tissues. The PGC-1 coactivators themselves are subject to powerful regulation at the transcriptional and posttranslational levels. Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration.
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    St-Pierre, J.; Lin, J.; Krauss, S.; Tarr, P. T.; Yang, R.; Newgard, C. B.; Spiegelman, B. M. Bioenergetic Analysis of Peroxisome Proliferator-Activated Receptor γ Coactivators 1α and 1β (PGC-1α and PGC-1β) in Muscle Cells. J. Biol. Chem. 2003, 278 (29), 26597– 26603,  DOI: 10.1074/jbc.M301850200
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    142
    Bioenergetic Analysis of Peroxisome Proliferator-activated Receptor γ Coactivators 1α and 1β (PGC-1α and PGC-1β) in Muscle Cells
    St-Pierre, Julie; Lin, Jiandie; Krauss, Stefan; Tarr, Paul T.; Yang, Ruojing; Newgard, Christopher B.; Spiegelman, Bruce M.
    Journal of Biological Chemistry (2003), 278 (29), 26597-26603CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α is a coactivator of nuclear receptors and other transcription factors that regulates several components of energy metab., particularly certain aspects of adaptive thermogenesis in brown fat and skeletal muscle, hepatic gluconeogenesis, and fiber type switching in skeletal muscle. PGC-1α has been shown to induce mitochondrial biogenesis when expressed in muscle cells, and preliminary anal. has suggested that this mol. may specifically increase the fraction of uncoupled vs. coupled respiration. In this paper, we have performed detailed bioenergetic analyses of the function of PGC-1α and its homolog PGC-1β in muscle cells by monitoring simultaneously oxygen consumption and membrane potential. Cells expressing PGC-1α or PGC-1β display higher proton leak rates at any given membrane potential than control cells. However, cells expressing PGC-1α have a higher proportion of their mitochondrial respiration linked to proton leak than cells expressing PGC-1β. Although these two proteins cause a similar increase in the expression of many mitochondrial genes, PGC-1β preferentially induces certain genes involved in the removal of reactive oxygen species, recently recognized as activators of uncoupling proteins. Together, these data indicate that PGC-1α and PGC-1β profoundly alter mitochondrial metab. and suggest that these proteins are likely to play different physiol. functions.
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    St-Pierre, J.; Drori, S.; Uldry, M.; Silvaggi, J. M.; Rhee, J.; Jäger, S.; Handschin, C.; Zheng, K.; Lin, J.; Yang, W.; Simon, D. K.; Bachoo, R.; Spiegelman, B. M. Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators. Cell 2006, 127 (2), 397– 408,  DOI: 10.1016/j.cell.2006.09.024
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    Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators
    St-Pierre, Julie; Drori, Stavit; Uldry, Marc; Silvaggi, Jessica M.; Rhee, James; Jager, Sibylle; Handschin, Christoph; Zheng, Kangni; Lin, Jiandie; Yang, Wenli; Simon, David K.; Bachoo, Robert; Spiegelman, Bruce M.
    Cell (Cambridge, MA, United States) (2006), 127 (2), 397-408CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    PPARγ coactivator 1α (PGC-1α) is a potent stimulator of mitochondrial biogenesis and respiration. Since the mitochondrial electron transport chain is the main producer of reactive oxygen species (ROS) in most cells, we examd. the effect of PGC-1α on the metab. of ROS. PGC-1α is co-induced with several key ROS-detoxifying enzymes upon treatment of cells with an oxidative stressor; studies with RNAi or null cells indicate that PGC-1α is required for the induction of many ROS-detoxifying enzymes, including GPx1 and SOD2. PGC-1α null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, resp. Increasing PGC-1α levels dramatically protects neural cells in culture from oxidative-stressor-mediated death. These studies reveal that PGC-1α is a broad and powerful regulator of ROS metab., providing a potential target for the therapeutic manipulation of these important endogenous toxins.
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    Valle, I.; Álvarez-Barrientos, A.; Arza, E.; Lamas, S.; Monsalve, M. PGC-1alpha Regulates the Mitochondrial Antioxidant Defense System in Vascular Endothelial Cells. Cardiovasc. Res. 2005, 66 (3), 562– 573,  DOI: 10.1016/j.cardiores.2005.01.026
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    PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells
    Valle, Inmaculada; Alvarez-Barrientos, Alberto; Arza, Elvira; Lamas, Santiago; Monsalve, Maria
    Cardiovascular Research (2005), 66 (3), 562-573CODEN: CVREAU; ISSN:0008-6363. (Elsevier B.V.)
    Objective: Mitochondrial prodn. of oxidants contributes to a variety of pathol. conditions including the vascular complications of diabetes, neurodegenerative diseases, and cellular senescence. The authors postulated that a transcriptional coactivator, peroxisome proliferator activated receptor-γ coactivator 1α (PGC-1α), a major regulator of oxidative metab. and mitochondrial biogenesis, could be involved in the transcriptional regulation of the mitochondrial antioxidant defense system in vascular endothelial cells. Methods and results: The authors show that PGC-1α is present in human, bovine, and mouse endothelial cells and pos. modulates the expression of the mitochondrial detoxification system. Endothelial cells that overexpress PGC-1α show reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death both in basal and oxidative stress conditions. Downregulation of PGC-1α levels by siRNA reduces the expression of mitochondrial detoxification proteins. Conclusions: These results unveil a novel regulatory pathway that links mitochondrial activity and mitochondrial oxidative stress protective systems. In addn., they suggest that PGC-1α could play a crucial protective role in vascular complications of diabetes, where the mitochondrial metab. of glucose has been shown to result in oxidative stress and vascular endothelial cell dysfunction.
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    Schrader, M.; Yoon, Y. Mitochondria and Peroxisomes: Are the ‘Big Brother’ and the ‘Little Sister’ Closer than Assumed?. BioEssays 2007, 29 (11), 1105– 1114,  DOI: 10.1002/bies.20659
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    Mitochondria and peroxisomes: are the 'big brother' and the 'little sister' closer than assumed?
    Schrader, Michael; Yoon, Yisang
    BioEssays (2007), 29 (11), 1105-1114CODEN: BIOEEJ; ISSN:0265-9247. (John Wiley & Sons, Inc.)
    A review. Mitochondria and peroxisomes are essential subcellular organelles in mammals. Despite obvious differences, both organelles display certain morphol. and functional similarities. Recent studies have elucidated that these highly dynamic and plastic organelles share components of their division machinery. Mitochondria and peroxisomes are metabolically linked organelles, which are cooperating and cross-talking. This review addresses the dynamics and division of mitochondria and peroxisomes as well as their functional similarities to provide insight as to why these organelles share the fission machinery in evolutionary aspects.
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    Wu, Z.; Puigserver, P.; Andersson, U.; Zhang, C.; Adelmant, G.; Mootha, V.; Troy, A.; Cinti, S.; Lowell, B.; Scarpulla, R. C.; Spiegelman, B. M. Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1. Cell 1999, 98 (1), 115– 124,  DOI: 10.1016/S0092-8674(00)80611-X
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    Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
    Wu, Zhidan; Puigserver, Pere; Andersson, Ulf; Zhang, Chenyu; Adelmant, Guillaume; Mootha, Vamsi; Troy, Amy; Cinti, Saverio; Lowell, Bradford; Scarpulla, Richard C.; Spiegelman, Bruce M.
    Cell (Cambridge, Massachusetts) (1999), 98 (1), 115-124CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Mitochondrial no. and function are altered in response to external stimuli in eukaryotes. While several transcription/replication factors directly regulate mitochondrial genes, the coordination of these factors into a program responsive to the environment is not understood. We show here that PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs). PGC-1 stimulates a powerful induction of NRF-1 and NRF-2 gene expression; in addn., PGC-1 binds to and coactivates the transcriptional function of NRF-1 on the promoter for mitochondrial transcription factor A (mtTFA), a direct regulator of mitochondrial DNA replication/transcription. These data elucidate a pathway that directly links external physiol. stimuli to the regulation of mitochondrial biogenesis and function.
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    Chepelev, N. L.; Enikanolaiye, M. I.; Chepelev, L. L.; Almohaisen, A.; Chen, Q.; Scoggan, K. A.; Coughlan, M. C.; Cao, X. L.; Jin, X.; Willmore, W. G. Bisphenol A Activates the Nrf1/2-Antioxidant Response Element Pathway in HEK 293 Cells. Chem. Res. Toxicol. 2013, 26 (3), 498– 506,  DOI: 10.1021/tx400036v
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    Bisphenol A Activates the Nrf1/2-Antioxidant Response Element Pathway in HEK 293 Cells
    Chepelev, Nikolai L.; Enikanolaiye, Mutiat I.; Chepelev, Leonid L.; Almohaisen, Abdulrahman; Chen, QiXuan; Scoggan, Kylie A.; Coughlan, Melanie C.; Cao, Xu-Liang; Jin, Xiaolei; Willmore, William G.
    Chemical Research in Toxicology (2013), 26 (3), 498-506CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
    Bisphenol A (BPA) is used in the prodn. of polycarbonate plastics and epoxy resins for baby bottles, liners of canned food, and many other consumer products. Previously, BPA has been shown to reduce the activity of several antioxidant enzymes, which may contribute to oxidative stress. However, the underlying mechanism of the BPA-mediated effect upon antioxidant enzyme activity is unknown. Antioxidant and phase II metabolizing enzymes protect cells from oxidative stress and are transcriptionally activated by Nrf1 and Nrf2 factors through their cis-regulatory antioxidant response elements (AREs). In this work, we have assessed the effect of BPA on the Nrf1/2-ARE pathway in cultured human embryonic kidney (HEK) 293 cells. Surprisingly, glutathione and reactive oxygen species assays revealed that BPA application created a more reduced intracellular environment in cultured HEK 293 cells. Furthermore, BPA increased the transactivation activity of ectopic Nrf1 and Nrf2 and increased the expression of ARE-target genes ho-1 and nqo1 at high (100-200 μM) BPA concns. only. Our study suggests that BPA activates the Nrf1/2-ARE pathway at high (>10 μM) micromolar concns.
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    Austin, S.; St-Pierre, J. PGC1α and Mitochondrial Metabolism-Emerging Concepts and Relevance in Ageing and Neurodegenerative Disorders. J. Cell Sci. 2012, 125 (21), 4963– 4971,  DOI: 10.1242/jcs.113662
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    PGC1α and mitochondrial metabolism - emerging concepts and relevance in ageing and neurodegenerative disorders
    Austin, Shane; St-Pierre, Julie
    Journal of Cell Science (2012), 125 (21), 4963-4971CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
    A review. PGC1α is a transcriptional coactivator that is a central inducer of mitochondrial biogenesis in cells. Recent work highlighted that PGC1α can also modulate the compn. and functions of individual mitochondria. Therefore, it is emerging that PGC1α is controlling global oxidative metab. by performing two types of remodelling: (1) cellular remodelling through mitochondrial biogenesis, and (2) organelle remodelling through alteration in the intrinsic properties of mitochondria. The elevated oxidative metab. assocd. with increased PGC1α activity could be accompanied by an increase in reactive oxygen species (ROS) that are primarily generated by mitochondria. However, increasing evidence suggests that this is not the case, as PGC1α is also a powerful regulator of ROS removal by increasing the expression of numerous ROS-detoxifying enzymes. Therefore, PGC1α, by controlling both the induction of mitochondrial metab. and the removal of its ROS byproducts, would elevate oxidative metab. and minimize the impact of ROS on cell physiol. In this Commentary, we discuss how the biogenesis and remodelling of mitochondria that are elicited by PGC1α contribute to an increase in oxidative metab. and the preservation of ROS homeostasis. Finally, we examine the importance of these findings in ageing and neurodegenerative disorders, conditions that are assocd. with impaired mitochondrial functions and ROS balance.
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    Sandri, M.; Lin, J.; Handschin, C.; Yang, W.; Arany, Z. P.; Lecker, S. H.; Goldberg, A. L.; Spiegelman, B. M. PGC-1alpha Protects Skeletal Muscle from Atrophy by Suppressing FoxO3 Action and Atrophy-Specific Gene Transcription. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (44), 16260– 16265,  DOI: 10.1073/pnas.0607795103
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    PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription
    Sandri, Marco; Lin, Jiandie; Handschin, Christoph; Yang, Wenli; Arany, Zoltan P.; Lecker, Stewart H.; Goldberg, Alfred L.; Spiegelman, Bruce M.
    Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (44), 16260-16265CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Maintaining muscle size and fiber compn. requires contractile activity. Increased activity stimulates expression of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which promotes fiber-type switching from glycolytic toward more oxidative fibers. In response to disuse or denervation, but also in fasting and many systemic diseases, muscles undergo marked atrophy through a common set of transcriptional changes. FoxO family transcription factors play a crit. role in this loss of cell protein, and when activated, FoxO3 causes expression of the atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 and profound loss of muscle mass. To understand how exercise might retard muscle atrophy, we investigated the possible interplay between PGC-1α and the FoxO family in regulation of muscle size. Rodent muscles showed a large decrease in PGC-1α mRNA during atrophy induced by denervation as well as by cancer cachexia, diabetes, and renal failure. Furthermore, in transgenic mice overexpressing PGC-1α, denervation and fasting caused a much smaller decrease in muscle fiber diam. and a smaller induction of atrogin-1 and MuRF-1 than in control mice. Increased expression of PGC-la also increased mRNA for several genes involved in energy metab. whose expression decreases during atrophy. Transfection of PGC-1α into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter. Thus, the high levels of PGC-1α in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1α during atrophy should enhance the FoxO-dependent loss of muscle mass.
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    Brault, J. J.; Jespersen, J. G.; Goldberg, A. L. Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1alpha or 1beta Overexpression Inhibits Muscle Protein Degradation, Induction of Ubiquitin Ligases, and Disuse Atrophy. J. Biol. Chem. 2010, 285 (25), 19460– 19471,  DOI: 10.1074/jbc.M110.113092
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    Peroxisome Proliferator-activated Receptor γ Coactivator 1α or 1β Overexpression Inhibits Muscle Protein Degradation, Induction of Ubiquitin Ligases, and Disuse Atrophy
    Brault, Jeffrey J.; Jespersen, Jakob G.; Goldberg, Alfred L.
    Journal of Biological Chemistry (2010), 285 (25), 19460-19471CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Overexpression of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), like exercise, increases mitochondrial content and inhibits muscle atrophy. To understand these actions, we tested whether PGC-1α or its close homolog, PGC-1β, influences muscle protein turnover. In myotubes, overexpression of either coactivator increased protein content by decreasing overall protein degrdn. without altering protein synthesis rates. Elevated PGC-1α or PGC-1β also prevented the acceleration of proteolysis induced by starvation or FoxO transcription factors and prevented the induction of autophagy and atrophy-specific ubiquitin ligases by a constitutively active FoxO3. In mouse muscles, overexpression of PGC-1β (like PGC-1α) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFκB. However, increasing muscle PGC-1α levels pharmacol. by treatment of mice with 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside failed to block loss of muscle mass or induction of ubiquitin ligases upon denervation atrophy, although it prevented loss of mitochondria. This capacity of PGC-1α and PGC-1β to inhibit FoxO3 and NFκB actions and proteolysis helps explain how exercise prevents muscle atrophy.
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    Houten, S. M.; Auwerx, J. PGC-1alpha: Turbocharging Mitochondria. Cell 2004, 119 (1), 5– 7,  DOI: 10.1016/j.cell.2004.09.016
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    PGC-1α: Turbocharging mitochondria
    Houten, Sander M.; Auwerx, Johan
    Cell (Cambridge, MA, United States) (2004), 119 (1), 5-7CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    A review. PGC-1α plays essential and diverse functions in the control of metab. ranging from mitochondrial biogenesis and respiration to hepatic gluconeogenesis and muscle fiber-type switching. In a paper by Lin et al., the characterization of PGC-1α-/- mice illustrates these pleiotropic functions and reveals an unexpected role for PGC-1α in the brain.
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    Giralt, A.; Hondares, E.; Villena, J. A.; Ribas, F.; Díaz-Delfín, J.; Giralt, M.; Iglesias, R.; Villarroya, F. Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Controls Transcription of the Sirt3 Gene, an Essential Component of the Thermogenic Brown Adipocyte Phenotype. J. Biol. Chem. 2011, 286 (19), 16958,  DOI: 10.1074/jbc.M110.202390
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    Peroxisome proliferator-activated receptor-γ coactivator-1α controls transcription of the Sirt3 gene, an essential component of the thermogenic brown adipocyte phenotype
    Giralt, Albert; Hondares, Elayne; Villena, Josep A.; Ribas, Francesc; Diaz-Delfin, Julieta; Giralt, Marta; Iglesias, Roser; Villarroya, Francesc
    Journal of Biological Chemistry (2011), 286 (19), 16958-16966CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Sirt3 protein, a member of the sirtuin family of protein deacetylases with multiple actions on metab. and gene expression, was expressed in assocn. with brown adipocyte differentiation. Using Sirt3-null brown adipocytes, the authors detd. that Sirt3 was required for an appropriate responsiveness of cells to noradrenergic, cAMP-mediated activation of the expression of brown adipose tissue thermogenic genes. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) induced Sirt3 gene expression in white adipocytes and embryonic fibroblasts as part of its overall induction of a brown adipose tissue-specific pattern of gene expression. In cells lacking Sirt3, PGC-1α failed to fully induce the expression of brown fat-specific thermogenic genes. Pgc-1α activated Sirt3 gene transcription through coactivation of orphan nuclear receptor Errα, which bound the proximal Sirt3 gene promoter region. Errα knockdown assays indicated that Errα was required for full induction of Sirt3 gene expression in response to PGC-1α. The present results indicate that PGC-1α controls Sirt3 gene expression and this action is an essential component of the overall mechanisms by which PGC-1α induces the full acquisition of a brown adipocyte differentiated phenotype.
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  153. 153
    Lovering, R. M.; O’Neill, A.; Muriel, J. M.; Prosser, B. L.; Strong, J.; Bloch, R. J. Physiology, Structure, and Susceptibility to Injury of Skeletal Muscle in Mice Lacking Keratin 19-Based and Desmin-Based Intermediate Filaments. Am. J. Physiol. - Cell Physiol. 2011, 300 (4), C803,  DOI: 10.1152/ajpcell.00394.2010
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    Marzuca-Nassr, G. N.; Vitzel, K. F.; Mancilla-Solorza, E.; Márquez, J. L. Sarcomere Structure: The Importance of Desmin Protein in Muscle Atrophy. Int. J. Morphol. 2018, 36 (2), 576– 583,  DOI: 10.4067/S0717-95022018000200576
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    Sheu, S. S.; Nauduri, D.; Anders, M. W. Targeting Antioxidants to Mitochondria: A New Therapeutic Direction. Biochim. Biophys. Acta 2006, 1762 (2), 256– 265,  DOI: 10.1016/j.bbadis.2005.10.007
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    155
    Targeting antioxidants to mitochondria: A new therapeutic direction
    Sheu, Shey-Shing; Nauduri, Dhananjaya; Anders, M. W.
    Biochimica et Biophysica Acta, Molecular Basis of Disease (2006), 1762 (2), 256-265CODEN: BBADEX; ISSN:0925-4439. (Elsevier B.V.)
    A review. Mitochondria play an important role in controlling the life and death of a cell. Consequently, mitochondrial dysfunction leads to a range of human diseases such as ischemia-reperfusion injury, sepsis, and diabetes. Although the mol. mechanisms responsible for mitochondria-mediated disease processes are not fully elucidated yet, the oxidative stress appears to be crit. Accordingly, strategies are being developed for the targeted delivery of antioxidants to mitochondria. In this review, we shall briefly discuss cellular reactive oxygen species metab. and its role in pathophysiol.; the currently existing antioxidants and possible reasons why they are not effective in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially targeted antioxidants and their future promise for disease treatment.
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  156. 156
    Paul, C.; Manero, F.; Gonin, S.; Kretz-Remy, C.; Virot, S.; Arrigo, A.-P. Hsp27 as a Negative Regulator of Cytochrome c Release. Mol. Cell. Biol. 2002, 22 (3), 816,  DOI: 10.1128/MCB.22.3.816-834.2002
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    156
    Hsp27 as a negative regulator of cytochrome c release
    Paul, Catherine; Manero, Florence; Gonin, Sandrine; Kretz-Remy, Carole; Virot, Sophie; Arrigo, Andre-Patrick
    Molecular and Cellular Biology (2002), 22 (3), 816-834CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
    We previously showed that Hsp27 protects against apoptosis through its interaction with cytosolic cytochrome c. We have revisited this protective activity in murine cell lines expressing different levels of Hsp27. We report that Hsp27 also interferes, in a manner dependent on level of expression, with the release of cytochrome c from mitochondria. Moreover, a decreased level of endogenous Hsp27, which sensitized HeLa cells to apoptosis, reduced the delay required for cytochrome c release and procaspase 3 activation. The mol. mechanism regulating this function of Hsp27 is unknown. In our cell systems, Hsp27 is mainly cytosolic and only a small fraction of this protein colocalized with mitochondria. Moreover, we show that only a very small fraction of cytochrome c interacts with Hsp27, hence excluding a role of this interaction in the retention of cytochrome c in mitochondria. We also report that Bid intracellular relocalization was altered by changes in Hsp27 level of expression, suggesting that Hsp27 interferes with apoptotic signals upstream of mitochondria. We therefore investigated if the ability of Hsp27 to act as an expression-dependent modulator of F-actin microfilaments integrity was linked to the retention of cytochrome c in mitochondria. We show here that the F-actin depolymg. agent cytochalasin D rapidly induced the release of cytochrome c from mitochondria and caspase activation. This phenomenon was delayed in cells pretreated with the F-actin stabilizer phalloidin and in cells expressing a high level of Hsp27. This suggests the existence of an apoptotic signaling pathway linking cytoskeleton damages to mitochondria. This pathway, which induces Bid intracellular redistribution, is neg. regulated by the ability of Hsp27 to protect F-actin network integrity. However, this upstream pathway is probably not the only one to be regulated by Hsp27 since, in staurosporine-treated cells, phalloidin only partially inhibited cytochrome c release and caspase activation. Moreover, in etoposide-treated cells, Hsp27 still delayed the release of cytochrome c from mitochondria and Bid intracellular redistribution in conditions where F-actin was not altered.
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  157. 157
    Bruey, J. M.; Ducasse, C.; Bonniaud, P.; Ravagnan, L.; Susin, S. A.; Diaz-Latoud, C.; Gurbuxani, S.; Arrigo, A. P.; Kroemer, G.; Solary, E.; Garrido, C. Hsp27 Negatively Regulates Cell Death by Interacting with Cytochrome C. Nat. Cell Biol. 2000, 2 (9), 645– 652,  DOI: 10.1038/35023595
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    157
    Hsp27 negatively regulates cell death by interacting with cytochrome c
    Bruey, Jean-Marie; Ducasse, Cecile; Bonniaud, Philippe; Ravagnan, Luigi; Susin, Santos A.; Diaz-Latoud, Chantal; Gurbuxani, Sandeep; Arrigo, Andre-Patrick; Kroemer, Guido; Solary, Eric; Garrido, Carmen
    Nature Cell Biology (2000), 2 (9), 645-652CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)
    Mammalian cells respond to stress by accumulating or activating a set of highly conserved proteins known as heat-shock proteins (HSPs). Several of these proteins interfere neg. with apoptosis. We show that the small HSP known as Hsp27 inhibits cytochrome-c-mediated activation of caspases in the cytosol. Hsp27 does not interfere with granzyme-B-induced activation of caspases, nor with apoptosis-inducing factor-mediated, caspase-independent, nuclear changes. Hsp27 binds to cytochrome c released from the mitochondria to the cytosol and prevents cytochrome-c-mediated interaction of Apaf-1 with procaspase-9. Thus, Hsp27 interferes specifically with the mitochondrial pathway of caspase-dependent cell death.
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  158. 158
    Kim, E. C.; Kim, J. R. Senotherapeutics: Emerging Strategy for Healthy Aging and Age-Related Disease. BMB Rep. 2019, 52 (1), 47– 55,  DOI: 10.5483/BMBRep.2019.52.1.293
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    158
    Senotherapeutics: emerging strategy for healthy aging and age-related disease
    Kim, Eok-Cheon; Kim, Jae-Ryong
    BMB Reports (2019), 52 (1), 47-55CODEN: BRMEC2; ISSN:1976-670X. (Korean Society for Biochemistry and Molecular Biology)
    Cellular senescence (CS) is one of hallmarks of aging and accumulation of senescent cells (SCs) with age contributes to tissue or organismal aging, as well as the pathophysiologies of diverse age-related diseases (ARDs). Genetic ablation of SCs in tissues lengthened health span and reduced the risk of age-related pathologies in a mouse model, suggesting a direct link between SCs, longevity, and ARDs. Therefore, senotherapeutics, medicines targeting SCs, might be an emerging strategy for the extension of health span, and prevention or treatment of ARDs. Senotherapeutics are classified as senolytics which kills SCs selectively; senomorphics which modulate functions and morphol. of SCs to those of young cells, or delays the progression of young cells to SCs in tissues; and immune-system mediators of the clearance of SCs. Some senolytics and senomorphics have been proven to markedly prevent or treat ARDs in animal models. This review will present the current status of the development of senotherapeutics, in relation to aging itself and ARDs. Finally, future directions and opportunities for senotherapeutics use will discussed. This knowledge will provide information that can be used to develop novel senotherapeutics for health span and ARDs.
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  159. 159
    Baker, D. J.; Wijshake, T.; Tchkonia, T.; Lebrasseur, N. K.; Childs, B. G.; Van De Sluis, B.; Kirkland, J. L.; Van Deursen, J. M. Clearance of P16Ink4a-Positive Senescent Cells Delays Ageing-Associated Disorders. Nature 2011, 479 (7372), 232– 236,  DOI: 10.1038/nature10600
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    159
    Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
    Baker, Darren J.; Wijshake, Tobias; Tchkonia, Tamar; LeBrasseur, Nathan K.; Childs, Bennett G.; van de Sluis, Bart; Kirkland, James L.; van Deursen, Jan M.
    Nature (London, United Kingdom) (2011), 479 (7372), 232-236CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive aging remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumor cells. Senescent cells accumulate in various tissues and organs with aging and were hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-pos. senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-pos. senescent cells upon drug treatment. In tissues-such as adipose tissue, skeletal muscle and eye-in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
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  160. 160
    Culpitt, S. V.; Rogers, D. F.; Shah, P.; De Matos, C.; Russell, R. E. K.; Donnelly, L. E.; Barnes, P. J. Impaired Inhibition by Dexamethasone of Cytokine Release by Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2003, 167 (1), 24– 31,  DOI: 10.1164/rccm.200204-298OC
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    160
    Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease
    Culpitt Sarah V; Rogers Duncan F; Shah Pallav; De Matos Carmen; Russell Richard E K; Donnelly Louise E; Barnes Peter J
    American journal of respiratory and critical care medicine (2003), 167 (1), 24-31 ISSN:1073-449X.
    Chronic obstructive pulmonary disease (COPD) is characterized by inflammation of the respiratory tract in which macrophages are the predominant inflammatory cell and for which the efficacy of treatment with corticosteroids is controversial. We investigated the effect of dexamethasone on basal and interleukin (IL)-1beta or cigarette smoke media (CSM)-stimulated release of IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF) by bronchoalveolar lavage macrophages from cigarette smokers and patients with COPD (n = 15). Basal release of IL-8 was approximately fivefold greater in patients with COPD than smokers, whereas GM-CSF was similar for each group. IL-1beta and CSM increased IL-8 and GM-CSF release by macrophages from both smokers and patients with COPD. Dexamethasone did not inhibit basal or stimulated IL-8 release from macrophages from patients with COPD but inhibited release in smokers. In contrast, basal and IL-1beta-stimulated GM-CSF release, but not CSM-stimulated release, was inhibited by dexamethasone. We conclude that the lack of efficacy of corticosteroids in COPD might be due to the relative steroid insensitivity of macrophages in the respiratory tract.
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  161. 161
    Hogg, J. C.; Chu, F.; Utokaparch, S.; Woods, R.; Elliott, W. M.; Buzatu, L.; Cherniack, R. M.; Rogers, R. M.; Sciurba, F. C.; Coxson, H. O.; Paré, P. D. The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 2004, 350 (26), 2645– 2653,  DOI: 10.1056/NEJMoa032158
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    The nature of small-airway obstruction in chronic obstructive pulmonary disease
    Hogg, James C.; Chu, Fanny; Utokaparch, Soraya; Woods, Ryan; Elliott, W. Mark; Buzatu, Liliana; Cherniack, Ruben M.; Rogers, Robert M.; Sciurba, Frank C.; Coxson, Harvey O.; Pare, Peter D.
    New England Journal of Medicine (2004), 350 (26), 2645-2653CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
    BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health problem assocd. with long-term exposure to toxic gases and particles. We examd. the evolution of the pathol. effects of airway obstruction in patients with COPD. METHODS: The small airways were assessed in surgically resected lung tissue from 159 patients -39 with stage 0 (at risk), 39 with stage 1, 22 with stage 2, 16 with stage 3, and 43 with stage 4 (very severe) COPD, according to the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). RESULTS: The progression of COPD was strongly assocd. with an increase in the vol. of tissue in the wall (P<0.001) and the accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways. The percentage of the airways that contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells (P<0.001), and lymphoid aggregates contg. follicles (P=0.003) and the abs. vol. of B cells (P=0.03) and CD8 cells (P=0.02) also increased as COPD progressed. CONCLUSIONS: Progression of COPD is assocd. with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles. These changes are coupled to a repair or remodeling process that thickens the walls of these airways.
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    Barnes, P. J. Chronic Obstructive Pulmonary Disease: Effects beyond the Lungs. PLoS Med. 2010, 7 (3), e1000220,  DOI: 10.1371/journal.pmed.1000220
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    Taylor, A. E.; Finney-Hayward, T. K.; Quint, J. K.; Thomas, C. M. R.; Tudhope, S. J.; Wedzicha, J. A.; Barnes, P. J.; Donnelly, L. E. Defective Macrophage Phagocytosis of Bacteria in COPD. Eur. Respir. J. 2010, 35 (5), 1039– 1047,  DOI: 10.1183/09031936.00036709
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    Defective macrophage phagocytosis of bacteria in COPD
    Taylor A E; Finney-Hayward T K; Quint J K; Thomas C M R; Tudhope S J; Wedzicha J A; Barnes P J; Donnelly L E
    The European respiratory journal (2010), 35 (5), 1039-47 ISSN:.
    Exacerbations of chronic obstructive pulmonary disease (COPD) are an increasing cause of hospitalisations and are associated with accelerated progression of airflow obstruction. Approximately half of COPD exacerbations are associated with bacteria and many patients have lower airways colonisation. This suggests that bacterial infection in COPD could be due to reduced pathogen removal. This study investigated whether bacterial clearance by macrophages is defective in COPD. Phagocytosis of fluorescently labelled polystyrene beads and Haemophillus influenzae and Streptococcus pneumoniae by alveolar macrophages and monocyte-derived macrophages (MDM) was assessed by fluorimetry and flow cytometry. Receptor expression was measured by flow cytometry. Alveolar macrophages and MDM phagocytosed polystyrene beads similarly. There was no difference in phagocytosis of beads by MDM from COPD patients compared with cells from smokers and nonsmokers. MDM from COPD patients showed reduced phagocytic responses to S. pneumoniae and H. influenzae compared with nonsmokers and smokers. This was not associated with alterations in cell surface receptor expression of toll-like receptor (TLR)2, TLR4, macrophage receptor with collagenous structure, cluster of differentiation (CD)163, CD36 or mannose receptor. Budesonide, formoterol or azithromycin did not suppress phagocytosis suggesting that reduced responses in COPD MDM were not due to medications. COPD macrophage innate responses are suppressed and may lead to bacterial colonisation and increased exacerbation frequency.
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  164. 164
    Nakamaru, Y.; Vuppusetty, C.; Wada, H.; Milne, J. C.; Ito, M.; Rossios, C.; Elliot, M.; Hogg, J.; Kharitonov, S.; Goto, H.; Bemis, J. E.; Elliott, P.; Barnes, P. J.; Ito, K. A Protein Deacetylase SIRT1 Is a Negative Regulator of Metalloproteinase-9. FASEB J. 2009, 23 (9), 2810– 2819,  DOI: 10.1096/fj.08-125468
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    A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9
    Nakamaru, Yuji; Vuppusetty, Chaitanya; Wada, Hiroo; Milne, Jill C.; Ito, Misako; Rossios, Christos; Elliot, Mark; Hogg, James; Kharitonov, Sergei; Goto, Hajime; Bemis, Jean E.; Elliott, Peter; Barnes, Peter J.; Ito, Kazuhiro
    FASEB Journal (2009), 23 (9), 2810-2819, 10.1096/fj.08-125468CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
    Inappropriate elevation of matrix metalloproteinase-9 (MMP9) is reported to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The object of this study was to identify the mol. mechanism underlying this increase of MMP9 expression, and here we show that oxidative stress-dependent redn. of a protein deacetylase, SIRT1, known as a putative antiaging enzyme, causes elevation of MMP9 expression. A sirtuin inhibitor, splitomycin, and SIRT1 knockdown by RNA interference led an increase in MMP9 expression in human monocytic U937 cells and in primary sputum macrophages, which was detected by RT-PCR, Western blot, activity assay, and zymog. In fact, the SIRT1 level was significantly decreased in peripheral lungs of patients with COPD, and this increase was inversely correlated with MMP9 expression and MMP9 promoter activation detected by a chromatin immunopptn. assay. H2O2 reduced SIRT1 expression and activity in U937 cells; furthermore, cigarette smoke exposure also caused redn. of SIRT1 expression in lung tissue of A/J mice, with concomitant elevation of MMP9. Intranasal treatment of a selective and novel SIRT1 small mol. activator, SRT2172, blocked the increase of MMP9 expression in the lung as well as pulmonary neutrophilia and the redn. in exercise tolerance. Thus, SIRT1 is a neg. regulator of MMP9 expression, and SIRT1 activation is implicated as a novel therapeutic approach to treating chronic inflammatory diseases, in which MMP9 is abundant.
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  165. 165
    Donovan, C.; Hansbro, P. M. IL-33 in Chronic Respiratory Disease: From Preclinical to Clinical Studies. ACS Pharmacol. Transl. Sci. 2020, 3 (1), 56– 62,  DOI: 10.1021/acsptsci.9b00099
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    165
    IL-33 in Chronic Respiratory Disease: From Preclinical to Clinical Studies
    Donovan, Chantal; Hansbro, Philip M.
    ACS Pharmacology & Translational Science (2020), 3 (1), 56-62CODEN: APTSFN; ISSN:2575-9108. (American Chemical Society)
    A review. IL-33 has been deorphanized as a member of the IL-1 family and has key roles as an alarmin and cytokine with potent capacity to drive type 2 inflammation. This has led to a plethora of studies surrounding its' role in chronic diseases with a type 2 inflammatory component. Here, we review the roles of IL-33 in two chronic respiratory diseases, asthma and chronic obstructive pulmonary disease (COPD). We discuss the hallmark and paradigm-shifting studies that have contributed to our understanding of IL-33 biol. We cover animal studies that have elucidated the mechanisms of IL-33 and assessed the role of anti-IL-33 treatment and immunization against IL-33. We highlight key clin. evidence for the potential of targeting increased IL-33 in respiratory diseases including exacerbations, and outline current clin. trials using anti-IL-33 monoclonal antibody in asthma patients. Finally, we discuss some of the challenges that have arisen in IL-33 biol. and highlight potential future directions in targeting this cytokine in chronic respiratory diseases.
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  166. 166
    Kirkham, P. A.; Caramori, G.; Casolari, P.; Papi, A. A.; Edwards, M.; Shamji, B.; Triantaphyllopoulos, K.; Hussain, F.; Pinart, M.; Khan, Y.; Heinemann, L.; Stevens, L.; Yeadon, M.; Barnes, P. J.; Chung, K. F.; Adcock, I. M. Oxidative Stress-Induced Antibodies to Carbonyl-Modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2011, 184 (7), 796– 802,  DOI: 10.1164/rccm.201010-1605OC
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    166
    Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease
    Kirkham, Paul A.; Caramori, Gaetano; Casolari, Paolo; Papi, Alberto A.; Edwards, Matt; Shamji, Betty; Triantaphyllopoulos, Kostas; Hussain, Farhana; Pinart, Mariona; Khan, Younis; Heinemann, Lucy; Stevens, Laurie; Yeadon, Mike; Barnes, Peter J.; Chung, Kian F.; Adcock, Ian M.
    American Journal of Respiratory and Critical Care Medicine (2011), 184 (7), 796-802CODEN: AJCMED; ISSN:1073-449X. (American Thoracic Society)
    Rationale. There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on "self" proteins. Objectives: To det. the presence of autoantibodies to carbonyl-modified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins. Methods: Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 wk. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochem., and cellular activation by ELISA and fluorescence-activated cell sorter. Measurements and Main Results: Antibody titer against carbonyl-modified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also obsd. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonyl-modified protein. Conclusions: Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody prodn., providing a link by which oxidative stress could drive an autoimmune response in COPD.
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  167. 167
    Lee, S. J.; McPherron, A. C. Regulation of Myostatin Activity and Muscle Growth. Proc. Natl. Acad. Sci. U. S. A. 2001, 98 (16), 9306– 9311,  DOI: 10.1073/pnas.151270098
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    Regulation of myostatin activity and muscle growth
    Lee, Se-Jin; McPherron, Alexandra C.
    Proceedings of the National Academy of Sciences of the United States of America (2001), 98 (16), 9306-9311CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Myostatin is a transforming growth factor-β family member that acts as a neg. regulator of skeletal muscle mass. To identify possible myostatin inhibitors that may have applications for promoting muscle growth, we investigated the regulation of myostatin signaling. Myostatin protein purified from mammalian cells consisted of a noncovalently held complex of the N-terminal propeptide and a disulfide-linked dimer of C-terminal fragments. The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA. Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concns., by the myostatin propeptide. To det. the functional significance of these interactions in vivo, we generated transgenic mice expressing high levels of the propeptide, follistatin, or a dominant-neg. form of Act RIIB by using a skeletal muscle-specific promoter. Independent transgenic mouse lines for each construct exhibited dramatic increases in muscle mass comparable to those seen in myostatin knockout mice. Our findings suggest that the propeptide, follistatin, or other mols. that block signaling through this pathway may be useful agents for enhancing muscle growth for both human therapeutic and agricultural applications.
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  168. 168
    Kota, J.; Handy, C. R.; Haidet, A. M.; Montgomery, C. L.; Eagle, A.; Rodino-Klapac, L. R.; Tucker, D.; Shilling, C. J.; Therlfall, W. R.; Walker, C. M.; Weisbrode, S. E.; Janssen, P. M. L.; Clark, K. R.; Sahenk, Z.; Mendell, J. R.; Kaspar, B. K. Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates. Sci. Transl. Med. 2009, 1 (6), 6ra15,  DOI: 10.1126/scitranslmed.3000112
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    Zhou, X.; Wang, J. L.; Lu, J.; Song, Y.; Kwak, K. S.; Jiao, Q.; Rosenfeld, R.; Chen, Q.; Boone, T.; Simonet, W. S.; Lacey, D. L.; Goldberg, A. L.; Han, H. Q. Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival. Cell 2010, 142 (4), 531– 543,  DOI: 10.1016/j.cell.2010.07.011
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    Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival
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  • Abstract

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    Figure 1

    Figure 1. | Schematic representation of COPD.

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    Figure 2

    Figure 2. | Mitochondria functionality. Reduced GSH due to ROS is translocated into the mitochondria, where it acts as a cofactor for GPx for the conversion of hydrogen peroxide into water. Due to reduced levels of GSH, H2O2 keeps on accumulating in the mitochondria, which diffuses from the mitochondria and starts causing cellular damage. Adaptor protein p66shc under stress conditions translocates into the mitochondria and starts producing H2O2 on its own in the absence of superoxide dismutase, which further leads to higher levels of H2O2. Stress conditions generated due to lower mitochondrial glutathione levels cause the oxidation of the cardiolipin–cytochrome c complex. As a result, cytochrome c diffuses through the mitochondria via BAX/BAK created pores and starts the apoptosis via caspase-3. P66shc also reduces the membrane potential to release cyt c into the cytosol. Upper head arrows show increased expression, while lower head arrows represent a decreased expression. Green circles with negative symbol represents membrane negative potential whereas green circles with plus symbol presents reduction in the membrane potential. O2•–, superoxide; SOD, superoxide dismutase; H2O2, hydrogen peroxide; GPx, glutathione peroxidase; GSH, glutathione; GSSG, glutathione disulfide; CLOOH, oxidized cardiolipin; BAX, B-cell lymphoma-2(Bcl-2)-associated X protein; BAK, Bcl-2 antagonist/killer; cty c, cytochrome c; p66shc, 66 kDa adaptor protein and member of the Src homologous-collagen homologue.

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    Figure 3

    Figure 3. | Interplay of signaling pathway and COPD biomarkers. Myostatin on binding to its receptor ActRIIB causes the phosphorylation of the Smad2 and Smad3, which further recruits Smad4 and forms a trio-complex which via gene transcription in the nucleus results in sarcopenia. On the other hand, myostatin binding also reduces the Akt activity, which usually keeps the FOXO in the cytosol by phosphorylating it under normal conditions. FOXO on dephosphorylation due to reduced Akt activity translocates into the nucleus and transcribes the genes involved in sarcopenia via proteolysis. Activated FOXO also reduces the expression of PGC-1α, which via atrophy leads to sarcopenia. ROS causes a reduction in the levels of SIRT1 and the endogenous antioxidant GSH. SIRT1 inhibits NF-kß signaling under normal conditions, but under stress conditions, it is unable to do so; thus, NF-kß translocates into the nucleus and starts its downstream effects, such as a reduction in the PGC-1α expression. SIRT1 under normal circumstances increases the PGC-1α expression, but under stress conditions, it cannot do so; thus, the expression of PGC-1α gets suppressed. ROS also increases the lysosomal SA-ß-gal, and tumor suppressors p16INK4A and p53 levels associated with cellular senescence, which further secrete SASP. ROS mediated inflammation is caused by reduction in the levels of HDAC2 under stress conditions via activated NF-kß. ROS also reduces the level of PI3K/Akt/mTOR pathway expression, typically involved in protein synthesis. However, under stress conditions, protein synthesis is reduced and causes the skeletal muscle protein desmin’s proteolysis, which is involved in muscle wasting via atrophy. Upper head arrows show increased expression, while lower head arrows represent the decreased expression. Different colored arrows are used to indicate the paths of different markers and their outcomes. N represents no significant change. ActRIIB, activin A receptor, type IIB; PI3K, phosphatidylinositol 3-kinase; Akt, serine/threonine protein kinase B; mTOR, mammalian target of rapamycin; NF-kß, nuclear factor kappa light chain enhancer of activated B cells; SASP, senescence associated secretory phenotype; HDAC2, histone deacetylase 2; HAT, histone acetyltransferase; p16INK4A, cyclin-dependent kinase inhibitor 2A; p53, 53 kDa tumor protein; PGC-1α, peroxisome proliferator-activated receptor c coactivator 1; SIRT1, sirtuin 1; Smad2, mothers against decapentaplegic homologue 2; FOXO, forkhead box protein O; GSH, glutathione.

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      Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M. T. D.; Mazur, M.; Telser, J. Free Radicals and Antioxidants in Normal Physiological Functions and Human Disease. Int. J. Biochem. Cell Biol. 2007, 39 (1), 44– 84,  DOI: 10.1016/j.biocel.2006.07.001
      10
      Free radicals and antioxidants in normal physiological functions and human disease
      Valko Marian; Leibfritz Dieter; Moncol Jan; Cronin Mark T D; Mazur Milan; Telser Joshua
      The international journal of biochemistry & cell biology (2007), 39 (1), 44-84 ISSN:1357-2725.
      Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
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    11. 11
      Marí, M.; Morales, A.; Colell, A.; García-Ruiz, C.; Ferná Ndez-Checa, J. C. Mitochondrial Glutathione, a Key Survival Antioxidant. Antioxid. Redox Signal. 2009, 11 (11), 2685– 2700,  DOI: 10.1089/ars.2009.2695
      11
      Mitochondrial glutathione, a key survival antioxidant
      Mari Montserrat; Morales Albert; Colell Anna; Garcia-Ruiz Carmen; Fernandez-Checa Jose C
      Antioxidants & redox signaling (2009), 11 (11), 2685-700 ISSN:.
      Mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain. Among the arsenal of antioxidants and detoxifying enzymes existing in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death. mGSH importance is based not only on its abundance, but also on its versatility to counteract hydrogen peroxide, lipid hydroperoxides, or xenobiotics, mainly as a cofactor of enzymes such as glutathione peroxidase or glutathione-S-transferase (GST). Many death-inducing stimuli interact with mitochondria, causing oxidative stress; in addition, numerous pathologies are characterized by a consistent decrease in mGSH levels, which may sensitize to additional insults. From the evaluation of mGSH influence on different pathologic settings such as hypoxia, ischemia/reperfusion injury, aging, liver diseases, and neurologic disorders, it is becoming evident that it has an important role in the pathophysiology and biomedical strategies aimed to boost mGSH levels.
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    12. 12
      Hwang, C.; Sinskey, A. J.; Lodish, H. F. Oxidized Redox State of Glutathione in the Endoplasmic Reticulum. Science (80-.). 1992, 257 (5076), 1496– 1502,  DOI: 10.1126/science.1523409
      There is no corresponding record for this reference.
    13. 13
      Chen, Z.; Lash, L. H. Evidence for Mitochondrial Uptake of Glutathione by Dicarboxylate and 2-Oxoglutarate Carriers 1. J. Pharmacol. Exp. Ther. 1998, 285 (2), 608– 618
      13
      Evidence for mitochondrial uptake of glutathione by dicarboxylate and 2-oxoglutarate carriers
      Chen, Zhifeng; Lash, Lawrence H.
      Journal of Pharmacology and Experimental Therapeutics (1998), 285 (2), 608-618CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)
      The role of org. anion transporters in the mitochondrial uptake of glutathione (GSH) was investigated by assessing competition with substrates or inhibition with inhibitors of specific carriers and modulation of mitochondrial energetics. Potential artifacts in the transport methodol., including contamination of matrix space with extramitochondrial fluid, changes in matrix vol. during incubations, efflux of transported GSH during sample processing, induction of the membrane permeability transition, contamination of the mitochondrial prepn. with plasma membranes and GSH degrdn., were cor. or eliminated. Substrates (i.e., malate, succinate) and an inhibitor (i.e., butylmalonate) of the dicarboxylate carrier, an inhibitor (i.e., phenylsuccinate) of the 2-oxoglutarate carrier, and glutamate produced significant inhibition of GSH uptake whereas substrates and inhibitors of the mono- and tricarboxylate carriers were generally without effect. Phosphoenolpyruvate, which is a substrate for the tricarboxylate carrier, inhibited GSH uptake, but this was due to induction of the membrane permeability transition and not to competition for uptake. Although glutamate inhibited GSH uptake, the converse did not occur. GSH uptake was pH-independent and aspartate had no effect, which suggest that the glutamate and glutamate-aspartate carriers are not involved in GSH uptake but that the glutamyl residue of GSH may be important in its transport. GSH uptake was dependent on phosphate and ATP generation. Hence, we conclude that both the dicarboxylate and 2-oxoglutarate carriers of the inner membrane can catalyze uptake of GSH into the matrix. The function of an addnl., novel transporter cannot be excluded at present. This is the first study to define the function of mitochondrial anion carriers in GSH transport.
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    14. 14
      Chen, Z.; Putt, D. A.; Lash, L. H. Enrichment and Functional Reconstitution of Glutathione Transport Activity from Rabbit Kidney Mitochondria: Further Evidence for the Role of the Dicarboxylate and 2-Oxoglutarate Carriers in Mitochondrial Glutathione Transport. Arch. Biochem. Biophys. 2000, 373 (1), 193– 202,  DOI: 10.1006/abbi.1999.1527
      14
      Enrichment and Functional Reconstitution of Glutathione Transport Activity from Rabbit Kidney Mitochondria: Further Evidence for the Role of the Dicarboxylate and 2-Oxoglutarate Carriers in Mitochondrial Glutathione Transport
      Chen, Zhifeng; Putt, David A.; Lash, Lawrence H.
      Archives of Biochemistry and Biophysics (2000), 373 (1), 193-202CODEN: ABBIA4; ISSN:0003-9861. (Academic Press)
      In previous studies, we provided evidence for uptake of glutathione (GSH) by the dicarboxylate and the 2-oxoglutarate carriers in rat kidney mitochondria. To investigate further the role of these two carriers, GSH transport activity was enriched from rabbit kidney mitochondria and functionally reconstituted into phospholipid vesicles. Starting with 200 mg of mitoplast protein, 2 mg of partially enriched proteins were obtained after Triton X-114 solubilization and hydroxyapatite chromatog. The reconstituted proteoliposomes catalyzed butylmalonate-sensitive uptake of [14C]malonate, phenylsuccinate-sensitive uptake of [14C]2-oxoglutarate, and transport activity with [3H]GSH. The initial rate of uptake of 5 mM GSH was approx. 170 nmol/min per mg protein, with a first-order rate const. of 0.3 min-1, which is very close to that previously detd. in freshly isolated rat kidney mitochondria. The enrichment procedure resulted in an approx. 60-fold increase in the specific activity of GSH transport. Substrates and inhibitors for the dicarboxylate and the 2-oxoglutarate carriers (i.e., malate, malonate, 2-oxoglutarate, butylmalonate, phenylsuccinate) significantly inhibited the uptake of [3H]GSH, whereas most substrates for the tricarboxylate and monocarboxylate carriers had no effect. GSH uptake exhibited an apparent Km of 2.8 mM and a Vmax of 260 nmol/min per mg protein. Anal. of mutual inhibition between GSH and the dicarboxylates suggested that the dicarboxylate carrier contributes a somewhat higher proportion to overall GSH uptake and that both carriers account for 70 to 80% of total GSH uptake. These results provide further evidence for the function of the dicarboxylate and 2-oxoglutarate carriers in the mitochondrial transport of GSH. (c) 2000 Academic Press.
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    15. 15
      Coll, O.; Colell, A.; García-Ruiz, C.; Kaplowitz, N.; Fernández-Checa, J. C. Sensitivity of the 2-Oxoglutarate Carrier to Alcohol Intake Contributes to Mitochondrial Glutathione Depletion. Hepatology 2003, 38 (3), 692– 702,  DOI: 10.1053/jhep.2003.50351
      15
      Sensitivity of the 2-oxoglutarate carrier to alcohol intake contributes to mitochondrial glutathione depletion
      Coll, Olga; Colell, Anna; Garcia-Ruiz, Carmen; Kaplowitz, Neil; Fernandez-Checa, J. C.
      Hepatology (Philadelphia, PA, United States) (2003), 38 (3), 692-702CODEN: HPTLD9; ISSN:0270-9139. (W. B. Saunders Co.)
      The mitochondrial pool of reduced glutathione (mGSH) is known to play a protective role against liver injury and cytokine-mediated cell death. However, the identification of the mitochondrial carriers involved in its transport in hepatocellular mitochondria remains unestablished. In this study, the authors show that the functional expression of the 2-oxoglutarate carrier from HepG2 cells in mitochondria from Xenopus laevis oocytes conferred a reduced glutathione (GSH) transport activity that was inhibited by phenylsuccinate, a specific inhibitor of the carrier. In addn., the mitochondrial transport of GSH and 2-oxoglutarate in isolated mitochondria from rat liver exhibited mutual competition and sensitivity to glutamate and phenylsuccinate. Interestingly, the kinetics of 2-oxoglutarate transport in rat liver mitochondria displayed a single Michaelis-Menten component with a Michaelis const. of 3.1 ± 0.3 mmol/L and max. velocity of 1.9 ± 0.1 nmol/mg protein/25 s. Furthermore, the initial rate of 2-oxoglutarate was reduced in mitochondria from alc.-fed rat livers, an effect that was not accompanied by an alc.-induced decrease in the 2-oxoglutarate mRNA levels but rather by changes in mitochondrial membrane dynamics induced by alc. The fluidization of mitochondria by the fluidizing agent 2-(2-methoxyethoxy) Et 8-(cis-2-n-octylcyclopropyl) (A2C) restored the initial transport rate of both GSH and 2-oxoglutarate. Finally, these changes were reproduced in normal liver mitochondria enriched in cholesterol where the fluidization of cholesterol-enriched mitochondria with A2C restored the order membrane parameter and the mitochondrial 2-oxoglutarate uptake. In conclusion, these findings provide unequivocal evidence for 2-oxoglutarate as a GSH carrier and its sensitivity to membrane dynamics perturbation contributes in part to the alc.-induced mGSH depletion.
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    16. 16
      García-Ruiz, C.; Morales, A.; Colell, A.; Rodes, J.; Yi, J. R.; Kaplowitz, N.; Fernandez-Checa, J. C. Evidence That the Rat Hepatic Mitochondrial Carrier Is Distinct from the Sinusoidal and Canalicular Transporters for Reduced Glutathione: EXPRESSION STUDIES IN XENOPUS LAEVIS OOCYTES. J. Biol. Chem. 1995, 270 (27), 15946– 15949,  DOI: 10.1074/jbc.270.27.15946
      16
      Evidence that the rat hepatic mitochondrial carrier is distinct from the sinusoidal and canalicular transporters for reduced glutathione. Expression studies in Xenopus laevis oocytes
      Garcia-Ruiz, Carmen; Morales, Albert; Colell, Anna; Rodes, Joan; Yi, Jiau-R.; Kaplowitz, Neil; Fernandez-Checa, Jose C.
      Journal of Biological Chemistry (1995), 270 (27), 15946-9CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Mitochondrial GSH derives from a mitochondrial transport system (RmGshT), which translocates cytosol GSH into the mitochondrial matrix. Mitochondria of oocytes, isolated 3-4 days after microinjection of total liver mRNA, expressed a RmGshT compared with water-injected oocytes. The expressed RmGshT exhibited similar functional features as reported in isolated mitochondria of rat liver such as ATP stimulation, inhibition by glutamate, and insensitivity to inhibition by sulfobromophthalein-glutathione (BSP-GSH) and S-(2,4-dinitrophenyl)glutathione (DNP-GSH). The expressed RmGshT is localized in the inner mitochondrial membrane since expression is still obsd. in mitoplasts prepd. from total liver mRNA-injected oocytes. Fractionation of poly(A)+ RNA identified a single mRNA species of ∼3-3.5 kilobases encoding for the RmGshT, which was stimulated by ATP and inhibited by glutamate but not by BSP-GSH or DNP-GSH. Microinjection of this fraction did not lead to expression of plasma membrane GSH transport in intact oocytes, and conversely, oocytes microinjected with cRNA for rat liver sinusoidal GSH transporter (RsGshT) or rat liver canalicular GSH transporter (RcGshT) did not express mitochondrial GSH transport activity. Thus, our results show the successful expression of the rat hepatic mitochondrial GSH carrier, which is different from RsGshT and RcGshT, and provide the strategic basis for the cloning of this important carrier.
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    17. 17
      Lash, L. H. Mitochondrial Glutathione Transport: Physiological, Pathological and Toxicological Implications. Chem. Biol. Interact. 2006, 163 (1–2), 54– 67,  DOI: 10.1016/j.cbi.2006.03.001
      17
      Mitochondrial glutathione transport: Physiological, pathological and toxicological implications
      Lash, Lawrence H.
      Chemico-Biological Interactions (2006), 163 (1-2), 54-67CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)
      A review. Although most cellular glutathione (GSH) is in the cytoplasm, a distinctly regulated pool is present in mitochondria. Inasmuch as GSH synthesis is primarily restricted to the cytoplasm, the mitochondrial pool must derive from transport of cytoplasmic GSH across the mitochondrial inner membrane. Early studies in liver mitochondria primarily focused on the relationship between GSH status and membrane permeability and energetics. Because GSH is an anion at physiol. pH, this suggested that some of the org. anion carriers present in the inner membrane could function in GSH transport. Indeed, studies by Lash and colleagues in isolated mitochondria from rat kidney showed that most of the transport (>80%) in that tissue could be accounted for by function of the dicarboxylate carrier (DIC, Slc25a10) and the oxoglutarate carrier (OGC, Slc25a11), which mediate electroneutral exchange of dicarboxylates for inorg. phosphate and 2-oxoglutarate for other dicarboxylates, resp. The identity and function of specific carrier proteins in other tissues is less certain, although the OGC is expressed in heart, liver, and brain and the DIC is expressed in liver and kidney. An addnl. carrier that transports 2-oxoglutarate, the oxodicarboxylate or oxoadipate carrier (ODC; Slc25a21), has been described in rat and human liver and its expression has a wide tissue distribution, although its potential function in GSH transport has not been investigated. Overexpression of the cDNA for the DIC and OGC in a renal proximal tubule-derived cell line, NRK-52E cells, showed that enhanced carrier expression and activity protects against oxidative stress and chem. induced apoptosis. This has implications for development of novel therapeutic approaches for treatment of human diseases and pathol. states. Several conditions, such as alc. liver disease, cirrhosis or other chronic biliary obstructive diseases, and diabetic nephropathy, are assocd. with depletion or oxidn. of the mitochondrial GSH pool in liver or kidney.
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    18. 18
      Mårtensson, J.; Lai, J. C. K.; Meister, A. High-Affinity Transport of Glutathione Is Part of a Multicomponent System Essential for Mitochondrial Function. Proc. Natl. Acad. Sci. U. S. A. 1990, 87 (18), 7185,  DOI: 10.1073/pnas.87.18.7185
      18
      High-affinity transport of glutathione is part of a multicomponent system essential for mitochondrial function
      Martensson, Johannes; Lai, James C. K.; Meister, Alton
      Proceedings of the National Academy of Sciences of the United States of America (1990), 87 (18), 7185-9CODEN: PNASA6; ISSN:0027-8424.
      Glutathione (GSH), an essential cellular antioxidant required for mitochondrial function, is not synthesized by mitochondria but is imported from the cytosol. Rat liver mitochondria have a multicomponent system that underlies the remarkable ability of mitochondria to take up and retain GSH. At external GSH levels of <1 mM, GSH is transported into the mitochondrial matrix by a high-affinity component (Km = ∼60 μM; Vmax = ∼0.5 nmol/min/mg protein), which is satd. at levels of 1-2 mM and stimulated by ATP. Another component had lower affinity (Km = ∼5.4 mM; Vmax, = ∼5.9 nmol/min/mg protein) and was stimulated by ATP and ADP. Both components were inhibited by carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), glutamate, and ophthalmic acid. An increase of extramitochondrial GSH promoted uptake and exchange; the intermembranous space appeared to function as a recovery zone that promotes efficient recycling of matrix GSH. The findings were in accord with in vivo data showing that (i) rapid exchange occurs between mitochondrial and cytosolic GSH, (ii) lowering of cytosolic GSH levels (produced by administration of buthionine sulfoximine) decreases export of GSH from mitochondria to cytosol, and (iii) administration of GSH esters increases GSH levels in mitochondria more than those in the cytosol.
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    19. 19
      Boldin, M. P.; Goncharov, T. M.; Goltseve, Y. V.; Wallach, D. Involvement of MACH, a Novel MORT1/FADD-Interacting Protease, in Fas/APO-1- and TNF Receptor-Induced Cell Death. Cell 1996, 85 (6), 803– 815,  DOI: 10.1016/S0092-8674(00)81265-9
      19
      Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death
      Boldin, Mark P.; Goncharov, Tanya M.; Goltsev, Yury V.; Wallach, David
      Cell (Cambridge, Massachusetts) (1996), 85 (6), 803-815CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Fas/APO-1 and p55 tumor necrosis factor (TNF) receptor (p55-R) activate cellular mechanisms that results in cell death. Upon activation of these receptors, Fas/APO-1 binds a protein called MORT1 (or FADD) and p55-R binds a protein called TRADD. MORT1 and TRADD can also bind to each other. We have cloned a novel protein, MACH, that binds to MORT1. This protein exists in multiple isoforms, some of which contain a region that has proteolytic activity and shows marked sequence homol. to proteases of the ICE/CED-3 family. Cellular expression of the proteolytic MACH isoforms results in cell death. Expression of MACH isoforms that contain an incomplete ICE/CED-3 region provides effective protection against the cytotoxicity induced by Fas/APO-1 or p55-R triggering. These findings suggest that MACH is the most upstream enzymic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades.
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    20. 20
      Muzio, M.; Chinnaiyan, A. M.; Kischkel, F. C.; O’Rourke, K. FLICE, A Novel FADD-Homologous ICE/CED-3-like Protease, Is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex. Cell 1996, 85, 817– 827,  DOI: 10.1016/S0092-8674(00)81266-0
      20
      FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex
      Muzio, Marta; Chinnaiyan, Arul M.; Kischkel, Frank C.; O'Rourke, Karen; Shevchenko, Andrej; Ni, Jian; Scaffidi, Carsten; Bretz, James D.; Zhang, Mei; et al.
      Cell (Cambridge, Massachusetts) (1996), 85 (6), 817-827CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Nano-electrospray tandem mass spectrometry, a recently developed technique to sequence femtomole quantities of polyacrylamide gel-sepd. proteins, was used to identify CAP3 and CAP4, components of the CD95 (Fas/APO-1) death-inducing signaling complex. Interestingly, CAP4 encodes a novel 55-kDa protein, designated FLICE, which has homol. to both FADD and the ICE/CED-3 family of cysteine proteases. FLICE binds to the death effector domain of FADD and upon overexpression induces apoptosis that is blocked by the ICE family inhibitors, CrmA and z-VAD-fmk. CAP3 was identified as the FLICE prodomain which likely remains bound to the receptor after proteolytic activation. Taken together, this is unique biochem. evidence to link a death receptor phys. to the proapoptotic proteases of the ICE/CED-3 family.
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    21. 21
      Zhivotovsky, B. Caspases: The Enzymes of Death. Essays Biochem. 2003, 39, 25– 40,  DOI: 10.1042/bse0390025
      21
      Caspases: the enzymes of death
      Zhivotovsky, Boris
      Essays in Biochemistry (2003), 39 (), 25-40CODEN: ESBIAV; ISSN:0071-1365. (Portland Press Ltd.)
      A review. The caspases are a unique family of cysteine proteases, which cleave proteins next to an Asp residue. Among all known mammalian proteases, only the serine protease, granzyme B, has a similar substrate specificity. In addn. to a central role of caspases in the initiation and execution phases of apoptosis, these enzymes have some other non-apoptotic functions in living cells. During apoptosis, upon activation, caspases cleave specific substrates and thereby mediate many of the typical biochem. and morphol. changes in apoptotic cells, such as cell shrinkage, chromatin condensation, DNA fragmentation, and plasma membrane blebbing. Thus, detection of activated caspases can be used as a biochem. marker for apoptosis induced by diverse stimuli in many types of cells.
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    22. 22
      Srinivasa Rao, C.; Emmanuel Subash, Y. The Effect of Chronic Tobacco Smoking and Chewing on the Lipid Profile. J. Clin. Diagn. Res. 2013, 7 (1), 31– 34,  DOI: 10.7860/JCDR/2012/5086.2663
      22
      The effect of chronic tobacco smoking and chewing on the lipid profile
      Srinivasa, Rao Ch.; Emmanuel, Subash Y.
      Journal of Clinical and Diagnostic Research (2013), 7 (1), 31-34CODEN: JCDRAB; ISSN:0973-709X. (JCDR Research and Publications (Pvt) Ltd.)
      Background: A worldwide epidemic of cardio vascular diseases is evolving, out of which atherosclerosis appears to be the most frequent underlying cause. Cigarette smoking remains the most important cause of the preventable morbidity and the early mortality. Nicotine is highly addictive, it raises the brain levels of dopamine and it produces withdrawal symptoms on its discontinuation. Aim: To study the effect of tobacco smoking & chewing on serum lipid profile. Methods: Although a genetic predisposition to atherosclerosis may be the cause, a vast majority of the atherosclerotic related diseases, which include coronary heart diseases, are acquired. Those which usually appear later in life are largely preventable. Tobacco is the major and the single most preventable risk factor for atherosclerotic related, clin. events like coronary heart disease. This study was conducted on three groups of male subjects, with each group contg. 25 individuals of 25 to 35 years of age and who weighed 50-70 kgs. Group-I: non smokers and non chewers. Group-II: smokers and non chewers. Group-III: chewers and non smokers. To est. the triglycerides, glycerol which is derived from the sapon. of triglycerides is oxidized to formaldehyde, which in turn is made to react with ammonia and acetylacetone to give rise to a chromogen (3.5 diacetyle-1,4 dihydrolutidine). It is quantified spectro-photometrically (the HANTZSCH reaction). Results: The mean serum total cholesterol level in the subjects of Group II was more by about 16.94% (p<0.001) and that in the subjects of Group-III was more by 23.21% (p<0.001). The mean serum VLDL level in the subjects of Group II had an increase of about 27.54% (p<0.01) and in Group-III, it had increased by 11.82% (p<0.01). The mean serum LDL level in the subjects of Group II showed an increase of about 34.64% (p<0.001) and in Group-III, it had increased by 16.27% (p<0.001). The mean serum HDL level in the subjects of Group II showed a decrease in the mean serum HDL level by about 9.78% (p<0.01) and in Group-III, it had decreased by 22.12% (p<0.01). The mean serum triglyceride level in the subjects of Group II showed an increase of about 25.40% (p<0.001) and in Group-III, it was more by 33.35% (p<0.001). Conclusion: There was a significant increase in total cholesterol and LDL-C in tobacco users, as compared to non tobacco users.
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    23. 23
      Imlay, J. A.; Chin, S. M.; Linn, S. Toxic DNA Damage by Hydrogen Peroxide through the Fenton Reaction in Vivo and in Vitro. Science 1988, 240 (4852), 640– 642,  DOI: 10.1126/science.2834821
      23
      Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro
      Imlay, James A.; Chin, Sherman M.; Linn, Stuart
      Science (Washington, DC, United States) (1988), 240 (4852), 640-2CODEN: SCIEAS; ISSN:0036-8075.
      An in vitro Fenton system was established that generates DNA strand breaks and inactivates bacteriophage and also reproduces the suppression of DNA damage by high concns. of H2O2. The direct DNA oxidant both in vivo and in this in vitro system exhibits reactivity unlike that of a free hydroxyl radical and may instead be a ferryl radical.
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    24. 24
      Giorgio, M.; Migliaccio, E.; Orsini, F.; Paolucci, D.; Moroni, M.; Contursi, C.; Pelliccia, G.; Luzi, L.; Minucci, S.; Marcaccio, M.; Pinton, P.; Rizzuto, R.; Bernardi, P.; Paolucci, F.; Pelicci, P. G. Electron Transfer between Cytochrome c and P66Shc Generates Reactive Oxygen Species That Trigger Mitochondrial Apoptosis. Cell 2005, 122 (2), 221– 233,  DOI: 10.1016/j.cell.2005.05.011
      24
      Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis
      Giorgio, Marco; Migliaccio, Enrica; Orsini, Francesca; Paolucci, Demis; Moroni, Maurizio; Contursi, Cristina; Pelliccia, Giovanni; Luzi, Lucilla; Minucci, Saverio; Marcaccio, Massimo; Pinton, Paolo; Rizzuto, Rosario; Bernardi, Paolo; Paolucci, Francesco; Pelicci, Pier Giuseppe
      Cell (Cambridge, MA, United States) (2005), 122 (2), 221-233CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Reactive oxygen species (ROS) are potent inducers of oxidative damage and have been implicated in the regulation of specific cellular functions, including apoptosis. Mitochondrial ROS increase markedly after proapoptotic signals, though the biol. significance and the underlying mol. mechanisms remain undetd. P66Shc is a genetic determinant of life span in mammals, which regulates ROS metab. and apoptosis. The authors report that p66Shc is a redox enzyme that generates mitochondrial ROS (hydrogen peroxide) as signaling mols. for apoptosis. For this function, p66Shc utilizes reducing equiv. of the mitochondrial electron transfer chain through the oxidn. of cytochrome c. Redox-defective mutants of p66Shc are unable to induce mitochondrial ROS generation and swelling in vitro or to mediate mitochondrial apoptosis in vivo. These data demonstrate the existence of alternative redox reactions of the mitochondrial electron transfer chain, which evolved to generate proapoptotic ROS in response to specific stress signals.
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    25. 25
      Ribas, V.; García-Ruiz, C.; Fernández-Checa, J. C. Glutathione and Mitochondria. Front. Pharmacol. 2014, 5, 151,  DOI: 10.3389/fphar.2014.00151
      25
      Glutathione and mitochondria
      Ribas Vicent; Garcia-Ruiz Carmen; Fernandez-Checa Jose C
      Frontiers in pharmacology (2014), 5 (), 151 ISSN:1663-9812.
      Glutathione (GSH) is the main non-protein thiol in cells whose functions are dependent on the redox-active thiol of its cysteine moiety that serves as a cofactor for a number of antioxidant and detoxifying enzymes. While synthesized exclusively in the cytosol from its constituent amino acids, GSH is distributed in different compartments, including mitochondria where its concentration in the matrix equals that of the cytosol. This feature and its negative charge at physiological pH imply the existence of specific carriers to import GSH from the cytosol to the mitochondrial matrix, where it plays a key role in defense against respiration-induced reactive oxygen species and in the detoxification of lipid hydroperoxides and electrophiles. Moreover, as mitochondria play a central strategic role in the activation and mode of cell death, mitochondrial GSH has been shown to critically regulate the level of sensitization to secondary hits that induce mitochondrial membrane permeabilization and release of proteins confined in the intermembrane space that once in the cytosol engage the molecular machinery of cell death. In this review, we summarize recent data on the regulation of mitochondrial GSH and its role in cell death and prevalent human diseases, such as cancer, fatty liver disease, and Alzheimer's disease.
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    26. 26
      Galimov, E. R. The Role of P66shc in Oxidative Stress and Apoptosis. Acta Naturae 2010, 2 (4), 44,  DOI: 10.32607/20758251-2010-2-4-44-51
      26
      The Role of p66shc in Oxidative Stress and Apoptosis
      Galimov E R
      Acta naturae (2010), 2 (4), 44-51 ISSN:2075-8251.
      p66shcis a gene that regulates the level of reactive oxygen species (ROS), apoptosis induction, and lifespan in mammals. Miceknocked out forp66shchave a lifespan~30% longeranddemonstrate an enhanced resistance to oxidative stress and age-related pathologies such as hypercholesterolemia, ischemia, and hyperglycemia. In this respect, p66shc is a promising pharmacological target for the treatment of age-related diseases. In this review, an attempt has been made to survey and put to a critical analysis data concerning the involvement of p66sh.scy. in the different signaling pathways that regulate oxidative stress and apoptosis.
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    27. 27
      Kagan, V. E.; Tyurin, V. A.; Jiang, J.; Tyurina, Y. Y.; Ritov, V. B.; Amoscato, A. A.; Osipov, A. N.; Belikova, N. A.; Kapralov, A. A.; Kini, V.; Vlasova, I. I.; Zhao, Q.; Zou, M.; Di, P.; Svistunenko, D. A.; Kurnikov, I. V.; Borisenko, G. G. Cytochrome c Acts as a Cardiolipin Oxygenase Required for Release of Proapoptotic Factors. Nat. Chem. Biol. 2005, 1 (4), 223– 232,  DOI: 10.1038/nchembio727
      27
      Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors
      Kagan, Valerian E.; Tyurin, Vladimir A.; Jiang, Jianfei; Tyurina, Yulia Y.; Ritov, Vladimir B.; Amoscato, Andrew A.; Osipov, Anatoly N.; Belikova, Natalia A.; Kapralov, Alexandr A.; Kini, Vidisha; Vlasova, Irina I.; Zhao, Qing; Zou, Meimei; Di, Peter; Svistunenko, Dimitry A.; Kurnikov, Igor V.; Borisenko, Gregory G.
      Nature Chemical Biology (2005), 1 (4), 223-232CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
      Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascades. The release mechanisms include interactions of B-cell/lymphoma 2 family proteins with a mitochondria-specific phospholipid, cardiolipin, to cause permeabilization of the outer mitochondrial membrane. Using oxidative lipidomics, we showed that cardiolipin is the only phospholipid in mitochondria that undergoes early oxidn. during apoptosis. The oxidn. is catalyzed by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. In a previously undescribed step in apoptosis, we showed that oxidized cardiolipin is required for the release of proapoptotic factors. These results provide insight into the role of reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation.
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    28. 28
      Ott, M.; Robertson, J. D.; Gogvadze, V.; Zhivotovsky, B.; Orrenius, S. Cytochrome c Release from Mitochondria Proceeds by a Two-Step Process. Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (3), 1259– 1263,  DOI: 10.1073/pnas.241655498
      28
      Cytochrome c release from mitochondria proceeds by a two-step process
      Ott, Martin; Robertson, John D.; Gogvadze, Vladimir; Zhivotovsky, Boris; Orrenius, Sten
      Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (3), 1259-1263CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Cytochrome c is often released from mitochondria during the early stages of apoptosis, although the precise mechanisms regulating this event remain unclear. In this study, with isolated liver mitochondria, we demonstrate that cytochrome c release requires a two-step process. Because cytochrome c is present as loosely and tightly bound pools attached to the inner membrane by its assocn. with cardiolipin, this interaction must first be disrupted to generate a sol. pool of this protein. Specifically, solubilization of cytochrome c involves a breaching of the electrostatic and/or hydrophobic affiliations that this protein usually maintains with cardiolipin. Once cytochrome c is solubilized, permeabilization of the outer mitochondrial membrane by Bax is sufficient to allow the extrusion of this protein into the extramitochondrial environment. Neither disrupting the interaction of cytochrome c with cardiolipin, nor permeabilizing the outer membrane with Bax, alone, is sufficient to trigger this protein's release. This mechanism also extends to conditions of mitochondrial permeability transition insofar as cytochrome c release is significantly depressed when the electrostatic interaction between cytochrome c and cardiolipin remains intact. Our results indicate that the release of cytochrome c involves a distinct two-step process that is undermined when either step is compromised.
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    29. 29
      Ow, Y. L. P.; Green, D. R.; Hao, Z.; Mak, T. W. Cytochrome c: Functions beyond Respiration. Nat. Rev. Mol. Cell Biol. 2008, 9 (7), 532– 542,  DOI: 10.1038/nrm2434
      29
      Cytochrome c: functions beyond respiration
      Ow, Yong-Ling P.; Green, Douglas R.; Hao, Zhenyue; Mak, Tak W.
      Nature Reviews Molecular Cell Biology (2008), 9 (7), 532-542CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
      A review. Cytochrome c is primarily known for its function in the mitochondria as a key participant in the life-supporting function of ATP synthesis. However, when a cell receives an apoptotic stimulus, cytochrome c is released into the cytosol and triggers programmed cell death through apoptosis. The release of cytochrome c and cytochrome c-mediated apoptosis are controlled by multiple layers of regulation, the most prominent players being members of the B-cell lymphoma protein-2 (BCL2) family. As well as its role in canonical intrinsic apoptosis, cytochrome c amplifies signals that are generated by other apoptotic pathways and participates in certain non-apoptotic functions.
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    30. 30
      Mootha, V. K.; Wei, M. C.; Buttle, K. F.; Scorrano, L.; Panoutsakopoulou, V.; Mannella, C. A.; Korsmeyer, S. J. A Reversible Component of Mitochondrial Respiratory Dysfunction in Apoptosis Can Be Rescued by Exogenous Cytochrome C. EMBO J. 2001, 20 (4), 661– 671,  DOI: 10.1093/emboj/20.4.661
      30
      A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c
      Mootha, Vamsi K.; Wei, Michael C.; Buttle, Karolyn F.; Scorrano, Luca; Panoutsakopoulou, Vily; Mannella, Carmen A.; Korsmeyer, Stanley J.
      EMBO Journal (2001), 20 (4), 661-671CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)
      Multiple apoptotic pathways release cytochrome c from the mitochondrial intermembrane space, resulting in the activation of downstream caspases. In vivo activation of Fas (CD95) resulted in increased permeability of the mitochondrial outer membrane and depletion of cytochrome c stores. Serial measurements of oxygen consumption, NADH redox state and membrane potential revealed a loss of respiratory state transitions. This tBID-induced respiratory failure did not require any caspase activity. At early time points, re-addn. of exogenous cytochrome c markedly restored respiratory functions. Over time, however, mitochondria showed increasing irreversible respiratory dysfunction as well as diminished calcium buffering. Electron microscopy and tomog. reconstruction revealed asym. mitochondria with blebs of herniated matrix, distended inner membrane and partial loss of cristae structure. Thus, apoptogenic redistribution of cytochrome c is responsible for a distinct program of mitochondrial respiratory dysfunction, in addn. to the activation of downstream caspases.
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    31. 31
      Zhao, Y.; Wang, Z. B.; Xu, J. X. Effect of Cytochrome c on the Generation and Elimination of O2*- and H2O2 in Mitochondria. J. Biol. Chem. 2003, 278 (4), 2356– 2360,  DOI: 10.1074/jbc.M209681200
      31
      Effect of Cytochrome c on the Generation and Elimination of O and H2O2 in Mitochondria
      Zhao, Yungang; Wang, Zhi-Bo; Xu, Jian-Xing
      Journal of Biological Chemistry (2003), 278 (4), 2356-2360CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      The primary recognized function of cytochrome c is to act as an electron carrier transferring electrons from complex III to complex IV in the respiratory chain of mitochondria. Recent studies on cell apoptosis reveal that cytochrome c is responsible for the programmed cell death when it is released from mitochondria to cytoplasm. In this study we present evidence showing that cytochrome c plays an antioxidative role by acting on the generation and elimination of O and H2O2 in mitochondria. The O and H2O2 generation in cytochrome c-depleted Keilin-Hartree heart muscle prepn. (HMP) is 7-8 times higher than that in normal HMP. The reconstitution of cytochrome c to the cytochrome c-depleted HMP causes the O and H2O2 generation to exponentially decrease. An alternative electron-leak pathway of the respiratory chain is suggested to explain how cytochrome c affects on the generation and elimination of O and H2O2 in mitochondria. Enough cytochrome c in the respiratory chain is needed for keeping O and H2O2 at a lower physiol. level. A dramatic increase of O and H2O2 generation occurs when cytochrome c is released from the respiratory chain. The burst of O and H2O2, which happens at the same time as cytochrome c release from the respiratory chain, should have some role in the early stage of cell apoptosis.
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    32. 32
      Hemann, M. T.; Lowe, S. W. The P53-Bcl-2 Connection. Cell Death Differ. 2006, 13 (8), 1256– 1259,  DOI: 10.1038/sj.cdd.4401962
      32
      The p53-Bcl-2 connection
      Hemann, M. T.; Lowe, S. W.
      Cell Death and Differentiation (2006), 13 (8), 1256-1259CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)
      A review discusses p53 transactivation of proapoptotic Bcl-2 family members and transactivation-independent p53 regulation of Bcl-2/. The relevance of the p53-Bcl-2 pathway to cancer is discussed.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvFaitLw%253D&md5=9a47f9c9a6750b60c1006279dd50e154
    33. 33
      Muñoz-Pinedo, C.; Guío-Carrión, A.; Goldstein, J. C.; Fitzgerald, P.; Newmeyer, D. D.; Green, D. R. Different Mitochondrial Intermembrane Space Proteins Are Released during Apoptosis in a Manner That Is Coordinately Initiated but Can Vary in Duration. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (31), 11573– 11578,  DOI: 10.1073/pnas.0603007103
      33
      Different mitochondrial intermembrane space proteins are released during apoptosis in a manner that is coordinately initiated but can vary in duration
      Munoz-Pinedo, Cristina; Guio-Carrion, Ana; Goldstein, Joshua C.; Fitzgerald, Patrick; Newmeyer, Donald D.; Green, Douglas R.
      Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (31), 11573-11578CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The release of mitochondrial intermembrane space proteins to the cytosol is a key event during apoptosis. We used in situ fluorescent labeling of proteins tagged with a short tetracysteine-contg. sequence to follow the release of Smac, Omi, adenylate kinase-2, cytochrome c, and apoptosis-inducing factor (AIF) during apoptosis and compared the release with that of cytochrome c tagged with GFP in individual cells obsd. over time. We obsd. a caspase-independent, simultaneous release of cytochrome c, Smac, Omi, and adenylate kinase-2. Although AIF release also was caspase-independent and commenced with that of the other proteins, it proceeded much more slowly and incompletely from mitochondria, perhaps because of a requirement for a secondary event. These results suggest that these proteins are released through the same mitochondrial pore and that apoptosis may not be regulated through a selective release of individual mitochondrial proteins. The timing and extent of AIF release makes it unlikely that it is involved in the induction of apoptosis, either upstream or down-stream of mitochondrial outer membrane permeabilization.
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    34. 34
      Scorrano, L.; Ashiya, M.; Buttle, K.; Weiler, S.; Oakes, S. A.; Mannella, C. A.; Korsmeyer, S. J. A Distinct Pathway Remodels Mitochondrial Cristae and Mobilizes Cytochrome c during Apoptosis. Dev. Cell 2002, 2 (1), 55– 67,  DOI: 10.1016/S1534-5807(01)00116-2
      34
      A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis
      Scorrano, Luca; Ashiya, Mona; Buttle, Karolyn; Weiler, Solly; Oakes, Scott A.; Mannella, Carmen A.; Korsmeyer, Stanley J.
      Developmental Cell (2002), 2 (1), 55-67CODEN: DCEEBE; ISSN:1534-5807. (Cell Press)
      The mechanism during apoptosis by which cytochrome c is rapidly and completely released in the absence of mitochondrial swelling is uncertain. Here, we show that two distinct pathways are involved. One mediates release of cytochrome c across the outer mitochondrial membrane, and another, characterized in this study, is responsible for the redistribution of cytochrome c stored in intramitochondrial cristae. We have found that the "BH3-only" mol. tBID induces a striking remodeling of mitochondrial structure with mobilization of the cytochrome c stores (∼ 85%) in cristae. This reorganization does not require tBID's BH3 domain and is independent of BAK, but is inhibited by CsA. During this process, individual cristae become fused and the junctions between the cristae and the intermembrane space are opened.
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    35. 35
      Li, P.; Nijhawan, D.; Budihardjo, I.; Srinivasula, S. M.; Ahmad, M.; Alnemri, E. S.; Wang, X. Cytochrome c and DATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade. Cell 1997, 91 (4), 479– 489,  DOI: 10.1016/S0092-8674(00)80434-1
      35
      Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade
      Li, Peng; Nijhawan, Deepak; Budihardjo, Imawati; Alnemri, Emad S.; Wang, Xiaodong
      Cell (Cambridge, Massachusetts) (1997), 91 (4), 479-489CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      The purifn. from HeLa cell S-100 cytosolic fraction of the 3rd protein factor, Apaf-3, that participates in caspase-3 activation in vitro, is reported. Here, Apaf-3 is identified as a member of the caspase family, caspase-9. Caspase-9 and Apaf-1 bind to each other via their resp. N-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. Activated caspase-9 in turn cleaves and activates caspase-3. Depletion of caspase-9 from the S-100 exts. was found to diminish caspase-3 activation. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP.
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    36. 36
      Lakshmanan, I.; Batra, S. K. Protocol for Apoptosis Assay by Flow Cytometry Using Annexin V Staining Method Materials and Reagents. BIO-PROTOCOL 2013, 3, e374,  DOI: 10.21769/BioProtoc.374
      There is no corresponding record for this reference.
    37. 37
      Campisi, J. Aging, Cellular Senescence, and Cancer. Annu. Rev. Physiol. 2013, 75, 685– 705,  DOI: 10.1146/annurev-physiol-030212-183653
      37
      Aging, cellular senescence, and cancer
      Campisi, Judith
      Annual Review of Physiology (2013), 75 (), 685-705CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews Inc.)
      A review. For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, esp. among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biol. phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
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    38. 38
      Muñoz-Espín, D.; Serrano, M. Cellular Senescence: From Physiology to Pathology. Nat. Rev. Mol. Cell Biol. 2014, 15 (7), 482– 496,  DOI: 10.1038/nrm3823
      38
      Cellular senescence: from physiology to pathology
      Munoz-Espin, Daniel; Serrano, Manuel
      Nature Reviews Molecular Cell Biology (2014), 15 (7), 482-496CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
      A review. Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events - senescence, followed by clearance and then regeneration - may not be efficiently completed in aged tissues or in pathol. contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro-senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, resp. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.
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    39. 39
      Van Deursen, J. M. The Role of Senescent Cells in Ageing. Nature 2014, 509 (7501), 439– 446,  DOI: 10.1038/nature13193
      39
      The role of senescent cells in ageing
      van Deursen, Jan M.
      Nature (London, United Kingdom) (2014), 509 (7501), 439-446CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      A review. Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biol. processes such as development, tissue repair, ageing and age-related disorders. New insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. A deeper understanding of the mol. mechanisms underlying the multi-step progression of senescence and the development and function of acute vs. chronic senescent cells may lead to new therapeutic strategies for age-related pathologies and extend healthy lifespan.
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    40. 40
      Sharpless, N. E.; Sherr, C. J. Forging a Signature of in Vivo Senescence. Nat. Rev. Cancer 2015, 15 (7), 397– 408,  DOI: 10.1038/nrc3960
      40
      Forging a signature of in vivo senescence
      Sharpless, Norman E.; Sherr, Charles J.
      Nature Reviews Cancer (2015), 15 (7), 397-408CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
      A review. 'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest induced by disparate stress factors. Proposed relationships between cellular senescence, tumor suppression, loss of tissue regenerative capacity and aging suffer from lack of uniform definition and consistently applied criteria. Here, we highlight caveats in interpreting the importance of suboptimal senescence-assocd. biomarkers, expressed either alone or in combination. We advocate that more-specific descriptors be substituted for the now broadly applied umbrella term 'senescence' in defining the suite of diverse physiol. responses to cellular stress.
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    41. 41
      Baker, D. J.; Childs, B. G.; Durik, M.; Wijers, M. E.; Sieben, C. J.; Zhong, J.; Saltness, R. A.; Jeganathan, K. B.; Verzosa, G. C.; Pezeshki, A.-M.; Khazaie, K.; Miller, J. D.; Van Deursen, J. M. Naturally Occurring P16 Ink4a-Positive Cells Shorten Healthy Lifespan HHS Public Access. Nature 2016, 530 (7589), 184– 189,  DOI: 10.1038/nature16932
      41
      Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
      Baker, Darren J.; Childs, Bennett G.; Durik, Matej; Wijers, Melinde E.; Sieben, Cynthia J.; Zhong, Jian; Saltness, Rachel A.; Jeganathan, Karthik B.; Verzosa, Grace Casaclang; Pezeshki, Abdulmohammad; Khazaie, Khashayarsha; Miller, Jordan D.; van Deursen, Jan M.
      Nature (London, United Kingdom) (2016), 530 (7589), 184-189CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16Ink4a (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiol. relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-pos. cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, resp. Thus, p16Ink4a-pos. cells that accumulate during adulthood neg. influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
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    42. 42
      Childs, B. G.; Gluscevic, M.; Baker, D. J.; Laberge, R. M.; Marquess, D.; Dananberg, J.; Van Deursen, J. M. Senescent Cells: An Emerging Target for Diseases of Ageing. Nat. Rev. Drug Discovery 2017, 16 (10), 718– 735,  DOI: 10.1038/nrd.2017.116
      42
      Senescent cells: an emerging target for diseases of ageing
      Childs, Bennett G.; Gluscevic, Martina; Baker, Darren J.; Laberge, Remi-Martin; Marquess, Dan; Dananberg, Jamie; van Deursen, Jan M.
      Nature Reviews Drug Discovery (2017), 16 (10), 718-735CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)
      Chronol. age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programs now nearing human clin. studies.
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    43. 43
      Kumar, M.; Seeger, W.; Voswinckel, R. Senescence-Associated Secretory Phenotype and Its Possible Role in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell Mol. Biol. 2014, 51 (3), 323– 333,  DOI: 10.1165/rcmb.2013-0382PS
      43
      Senescence-associated secretory phenotype and its possible role in chronic obstructive pulmonary disease
      Kumar, Manish; Seeger, Werner; Voswinckel, Robert
      American Journal of Respiratory Cell and Molecular Biology (2014), 51 (3), 323-333, 11 pp.CODEN: AJRBEL; ISSN:1044-1549. (American Thoracic Society)
      A review. Chronic obstructive pulmonary disease (COPD) is a major disease of the lungs. It primarily occurs after a prolonged period of cigarette smoking. Chronic inflammation of airways and the alveolar space as well as lung tissue destruction are the hallmarks of COPD. Recently it has been shown that cellular senescence might play a role in the pathogenesis of COPD. Cellular senescence comprises signal transduction program, leading to irreversible cell cycle arrest. The growth arrest in senescence can be triggered by many different mechanisms, including DNA damage and its recognition by cellular sensors, leading to the activation of cell cycle checkpoint responses and activation of DNA repair machinery. Senescence can be induced by several genotoxic factors apart from telomere attrition. When senescence induction is based on DNA damage, senescent cells display a unique phenotype, which has been termed "senescence-assocd. secretory phenotype" (SASP). SASP may be an important driver of chronic inflammation and therefore may be part of a vicious cycle of inflammation, DNA damage, and senescence. This research perspective aims to showcase cellular senescence with relevance to COPD and the striking similarities between the mediators and secretory phenotype in COPD and SASP.
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    44. 44
      Campisi, J. Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors. Cell 2005, 120 (4), 513– 522,  DOI: 10.1016/j.cell.2005.02.003
      44
      Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
      Campisi, Judith
      Cell (Cambridge, MA, United States) (2005), 120 (4), 513-522CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      A review. Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
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    45. 45
      Ogrodnik, M.; Miwa, S.; Tchkonia, T.; Tiniakos, D.; Wilson, C. L.; Lahat, A.; Day, C. P.; Burt, A.; Palmer, A.; Anstee, Q. M.; Grellscheid, S. N.; Hoeijmakers, J. H. J.; Barnhoorn, S.; Mann, D. A.; Bird, T. G.; Vermeij, W. P.; Kirkland, J. L.; Passos, J. F.; Von Zglinicki, T.; Jurk, D. Cellular Senescence Drives Age-Dependent Hepatic Steatosis. Nat. Commun. 2017 81 2017, 8 (1), 1– 12,  DOI: 10.1038/ncomms15691
      There is no corresponding record for this reference.
    46. 46
      Tchkonia, T.; Zhu, Y.; Van Deursen, J.; Campisi, J.; Kirkland, J. L. Cellular Senescence and the Senescent Secretory Phenotype: Therapeutic Opportunities. J. Clin. Invest. 2013, 123 (3), 966– 972,  DOI: 10.1172/JCI64098
      46
      Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
      Tchkonia, Tamara; Zhu, Yi; van Deursen, Jan; Campisi, Judith; Kirkland, James L.
      Journal of Clinical Investigation (2013), 123 (3), 966-972CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
      A review. Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-assocd. secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their assocns. with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clin. interventions.
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    47. 47
      Campisi, J.; D’Adda Di Fagagna, F. Cellular Senescence: When Bad Things Happen to Good Cells. Nat. Rev. Mol. Cell Biol. 2007, 8 (9), 729– 740,  DOI: 10.1038/nrm2233
      47
      Cellular senescence: when bad things happen to good cells
      Campisi, Judith; d'Adda di Fagagna, Fabrizio
      Nature Reviews Molecular Cell Biology (2007), 8 (9), 729-740CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
      A review. Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an addnl. response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, esp. genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and aging.
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    48. 48
      Lebrasseur, N. K.; Tchkonia, T.; Kirkland, J. L. Cellular Senescence and the Biology of Aging, Disease, and Frailty. Nestle Nutr. Inst. Workshop Ser. 2015, 83, 11– 18,  DOI: 10.1159/000382054
      48
      Cellular Senescence and the Biology of Aging, Disease, and Frailty
      LeBrasseur Nathan K; Tchkonia Tamara; Kirkland James L
      Nestle Nutrition Institute workshop series (2015), 83 (), 11-8 ISSN:.
      Population aging simultaneously highlights the remarkable advances in science, medicine, and public policy, and the formidable challenges facing society. Indeed, aging is the primary risk factor for many of the most common chronic diseases and frailty, which result in profound social and economic costs. Population aging also reveals an opportunity, i.e. interventions to disrupt the fundamental biology of aging could significantly delay the onset of age-related conditions as a group, and, as a result, extend the healthy life span, or health span. There is now considerable evidence that cellular senescence is an underlying mechanism of aging and age-related conditions. Cellular senescence is a process in which cells lose the ability to divide and damage neighboring cells by the factors they secrete, collectively referred to as the senescence-associated secretory phenotype (SASP). Herein, we discuss the concept of cellular senescence, review the evidence that implicates cellular senescence and SASP in age-related deterioration, hyperproliferation, and inflammation, and propose that this underlying mechanism of aging may play a fundamental role in the biology of frailty.
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    49. 49
      VanArsdale, T.; Boshoff, C.; Arndt, K. T.; Abraham, R. T. Molecular Pathways: Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment. Clin. Cancer Res. 2015, 21 (13), 2905– 2910,  DOI: 10.1158/1078-0432.CCR-14-0816
      49
      Molecular Pathways: Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment
      VanArsdale Todd; Abraham Robert T; Boshoff Chris; Arndt Kim T
      Clinical cancer research : an official journal of the American Association for Cancer Research (2015), 21 (13), 2905-10 ISSN:.
      Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. The retinoblastoma tumor suppressor protein (pRb) governs a key cell-cycle checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals. Cancer cells frequently overcome pRb-dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase (CDK) 4 or CDK6 partnered with D-type cyclins. Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non-small cell lung cancer. The emerging, positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D-CDK4/6 pathway is a rational target for cancer therapy.
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    50. 50
      Liu, Y.; Johnson, S. M.; Fedoriw, Y.; Rogers, A. B.; Yuan, H.; Krishnamurthy, J.; Sharpless, N. E. Expression of P16INK4a Prevents Cancer and Promotes Aging in Lymphocytes. Blood 2011, 117 (12), 3257,  DOI: 10.1182/blood-2010-09-304402
      50
      Expression of p16INK4a prevents cancer and promotes aging in lymphocytes
      Liu, Yan; Johnson, Soren M.; Fedoriw, Yuri; Rogers, Arlin B.; Yuan, Hong; Krishnamurthy, Janakiraman; Sharpless, Norman E.
      Blood (2011), 117 (12), 3257-3267CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)
      Previous authors have suggested that tumor suppressor expression promotes aging while preventing cancer, but direct exptl. support for this cancer-aging hypothesis has been elusive. Here, by using somatic, tissue-specific inactivation of the p16INK4a tumor suppressor in murine T- or B-lymphoid progenitors, we report that ablation of p16INK4a can either rescue aging or promote cancer in a lineage-specific manner. Deletion of p16INK4a in the T lineage ameliorated several aging phenotypes, including thymic involution, decreased prodn. of naive T cells, redn. in homeostatic T-cell proliferation, and attenuation of antigen-specific immune responses. Increased T-cell neoplasia was not obsd. with somatic p16INK4a inactivation in T cells. In contrast, B lineage-specific ablation of p16INK4a was assocd. with a markedly increased incidence of systemic, high-grade B-cell neoplasms, which limited studies of the effects of somatic p16INK4a ablation on B-cell aging. Together, these data show that expression of p16INK4a can promote aging and prevent cancer in related lymphoid progeny of a common stem cell.
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    51. 51
      Cottage, C. T.; Peterson, N.; Kearley, J.; Berlin, A.; Xiong, X.; Huntley, A.; Zhao, W.; Brown, C.; Migneault, A.; Zerrouki, K.; Criner, G.; Kolbeck, R.; Connor, J.; Lemaire, R. Targeting P16-Induced Senescence Prevents Cigarette Smoke-Induced Emphysema by Promoting IGF1/Akt1 Signaling in Mice. Commun Biol 2019, 2, 307,  DOI: 10.1038/s42003-019-0532-1
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      Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice
      Cottage Christopher T; Peterson Norman; Kearley Jennifer; Berlin Aaron; Xiong Ximing; Huntley Anna; Zhao Weiguang; Brown Charles; Migneault Annik; Zerrouki Kamelia; Kolbeck Roland; Connor Jane; Lemaire Raphael; Criner Gerald
      Communications biology (2019), 2 (), 307 ISSN:.
      Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke (CS) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to CS-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. CS induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas CS-exposed p16(-/-) mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16(-/-) mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.
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    52. 52
      Cheng, X.-Y.; Li, Y.-Y.; Huang, C.; Li, J.; Yao, H.-W. AMP-Activated Protein Kinase Reduces Inflammatory Responses and Cellular Senescence in Pulmonary Emphysema. Oncotarget 2017, 8 (14), 22513– 22523,  DOI: 10.18632/oncotarget.15116
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      AMP-activated protein kinase reduces inflammatory responses and cellular senescence in pulmonary emphysema
      Cheng Xiao-Yu; Li Yang-Yang; Huang Cheng; Li Jun; Yao Hong-Wei
      Oncotarget (2017), 8 (14), 22513-22523 ISSN:.
      Current drug therapy fails to reduce lung destruction of chronic obstructive pulmonary disease (COPD). AMP-activated protein kinase (AMPK) has emerged as an important integrator of signals that control energy balance and lipid metabolism. However, there are no studies regarding the role of AMPK in reducing inflammatory responses and cellular senescence during the development of emphysema. Therefore, we hypothesize that AMPK reduces inflammatroy responses, senescence, and lung injury. To test this hypothesis, human bronchial epithelial cells (BEAS-2B) and small airway epithelial cells (SAECs) were treated with cigarette smoke extract (CSE) in the presence of a specific AMPK activator (AICAR, 1 mM) and inhibitor (Compound C, 5 μM). Elastase injection was performed to induce mouse emphysema, and these mice were treated with a specific AMPK activator metformin as well as Compound C. AICAR reduced, whereas Compound C increased CSE-induced increase in IL-8 and IL-6 release and expression of genes involved in cellular senescence. Knockdown of AMPKα1/α2 increased expression of pro-senescent genes (e.g., p16, p21, and p66shc) in BEAS-2B cells. Prophylactic administration of an AMPK activator metformin (50 and 250 mg/kg) reduced while Compound C (4 and 20 mg/kg) aggravated elastase-induced airspace enlargement, inflammatory responses and cellular senescence in mice. This is in agreement with therapeutic effect of metformin (50 mg/kg) on airspace enlargement. Furthermore, metformin prophylactically protected against but Compound C further reduced mitochondrial proteins SOD2 and SIRT3 in emphysematous lungs. In conclusion, AMPK reduces abnormal inflammatory responses and cellular senescence, which implicates as a potential therapeutic target for COPD/emphysema.
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    53. 53
      Mikawa, R.; Sato, T.; Suzuki, Y.; Baskoro, H.; Kawaguchi, K.; Sugimoto, M. P19Arf Exacerbates Cigarette Smoke-Induced Pulmonary Dysfunction. Biomolecules 2020, 10 (3), 462,  DOI: 10.3390/biom10030462
      53
      p19Arf exacerbates cigarette smoke-induced pulmonary dysfunction
      Mikawa, Ryuta; Sato, Tadashi; Suzuki, Yohei; Baskoro, Hario; Kawaguchi, Koichiro; Sugimoto, Masataka
      Biomolecules (2020), 10 (3), 462CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
      Senescent cells accumulate in tissues during aging or pathol. settings. The semi- genetic or pharmacol. targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-assocd. phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-assocd. pulmonary dysfunction. We herein report that the elimination of Arf-expressing cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf-expressing cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke ext. lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-assocd. lung disease.
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    54. 54
      Bodas, M.; Pehote, G.; Silverberg, D.; Gulbins, E.; Vij, N. Autophagy Augmentation Alleviates Cigarette Smoke-Induced CFTR-Dysfunction, Ceramide-Accumulation and COPD-Emphysema Pathogenesis. Free Radic. Biol. Med. 2019, 131, 81– 97,  DOI: 10.1016/j.freeradbiomed.2018.11.023
      54
      Autophagy augmentation alleviates cigarette smoke-induced CFTR-dysfunction, ceramide-accumulation and COPD-emphysema pathogenesis
      Bodas, Manish; Pehote, Garrett; Silverberg, David; Gulbins, Erich; Vij, Neeraj
      Free Radical Biology & Medicine (2019), 131 (), 81-97CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
      In this study, we aimed to investigate precise mechanism(s) of sphingolipid-imbalance and resulting ceramide-accumulation in COPD-emphysema. Where, human and murine emphysema lung tissues or human bronchial epithelial cells (Beas2b) were used for exptl. anal. We found that lungs of smokers and COPD-subjects with increasing emphysema severity demonstrate sphingolipid-imbalance, resulting in significant ceramide-accumulation and increased ceramide/sphingosine ratio, as compared to non-emphysema/non-smoker controls. Next, we found a substantial increase in emphysema chronicity-related ceramide-accumulation in murine (C57BL/6) lungs, while sphingosine levels only slightly increased. In accordance, the expression of the acid ceramidase decreased after CS-exposure. Moreover, CS-induced (sub-chronic) ceramide-accumulation was significantly (p < 0.05) reduced by treatment with TFEB/autophagy-inducing drug, gemfibrozil (GEM), suggesting that autophagy regulates CS-induced ceramide-accumulation. Next, we validated exptl. that autophagy/lipophagy-induction using an anti-oxidant, cysteamine, significantly (p < 0.05) reduces CS-ext. (CSE)-mediated intracellular-ceramide-accumulation in p62 + aggresome-bodies. In addn. to intracellular-accumulation, we found that CSE also induces membrane-ceramide-accumulation by ROS-dependent acid-sphingomyelinase (ASM) activation and plasma-membrane translocation, which was significantly controlled (p < 0.05) by cysteamine (an anti-oxidant) and amitriptyline (AMT, an inhibitor of ASM). Cysteamine-mediated and CSE-induced membrane-ceramide regulation was nullified by CFTR-inhibitor-172, demonstrating that CFTR controls redox impaired-autophagy dependent membrane-ceramide accumulation. In summary, our data shows that CS-mediated autophagy/lipophagy-dysfunction results in intracellular-ceramide-accumulation, while acquired CFTR-dysfunction-induced ASM causes membrane ceramide-accumulation. Thus, CS-exposure alters the sphingolipid-rheostat leading to the increased membrane- and intracellular- ceramide-accumulation inducing COPD-emphysema pathogenesis that is alleviated by treatment with cysteamine, a potent anti-oxidant with CFTR/autophagy-augmenting properties.
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    55. 55
      Vij, N.; Chandramani-Shivalingappa, P.; Van Westphal, C.; Hole, R.; Bodas, M. Cigarette Smoke-Induced Autophagy Impairment Accelerates Lung Aging, COPD-Emphysema Exacerbations and Pathogenesis. Am. J. Physiol. Cell Physiol. 2018, 314 (1), C73– C87,  DOI: 10.1152/ajpcell.00110.2016
      There is no corresponding record for this reference.
    56. 56
      Woldhuis, R. R.; de Vries, M.; Timens, W.; van den Berge, M.; Demaria, M.; Oliver, B. G. G.; Heijink, I. H.; Brandsma, C. A. Link between Increased Cellular Senescence and Extracellular Matrix Changes in COPD. Am. J. Physiol. Lung Cell. Mol. Physiol. 2020, 319 (1), L48– L60,  DOI: 10.1152/ajplung.00028.2020
      There is no corresponding record for this reference.
    57. 57
      Storer, M.; Mas, A.; Robert-Moreno, A.; Pecoraro, M.; Ortells, M. C.; Di Giacomo, V.; Yosef, R.; Pilpel, N.; Krizhanovsky, V.; Sharpe, J.; Keyes, W. M. Senescence Is a Developmental Mechanism That Contributes to Embryonic Growth and Patterning. Cell 2013, 155 (5), 1119,  DOI: 10.1016/j.cell.2013.10.041
      57
      Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning
      Storer, Mekayla; Mas, Alba; Robert-Moreno, Alexandre; Pecoraro, Matteo; Ortells, M. Carmen; Di'Giacomo, Valeria; Yosef, Reut; Pilpel, Noam; Krizhanovsky, Valery; Sharpe, James; Keyes, William M.
      Cell (Cambridge, MA, United States) (2013), 155 (5), 1119-1130CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathol. states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-assocd. secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.
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    58. 58
      Mosteiro, L.; Pantoja, C.; Alcazar, N.; Marión, R. M.; Chondronasiou, D.; Rovira, M.; Fernandez-Marcos, P. J.; Muñoz-Martin, M.; Blanco-Aparicio, C.; Pastor, J.; Gómez-López, G.; De Martino, A.; Blasco, M. A.; Abad, M.; Serrano, M. Tissue Damage and Senescence Provide Critical Signals for Cellular Reprogramming in Vivo. Science 2016, 354 (6315), aaf4445,  DOI: 10.1126/science.aaf4445
      There is no corresponding record for this reference.
    59. 59
      Muñoz-Espín, D.; Cañamero, M.; Maraver, A.; Gómez-López, G.; Contreras, J.; Murillo-Cuesta, S.; Rodríguez-Baeza, A.; Varela-Nieto, I.; Ruberte, J.; Collado, M.; Serrano, M. Programmed Cell Senescence during Mammalian Embryonic Development. Cell 2013, 155 (5), 1104,  DOI: 10.1016/j.cell.2013.10.019
      59
      Programmed Cell Senescence during Mammalian Embryonic Development
      Munoz-Espin, Daniel; Canamero, Marta; Maraver, Antonio; Gomez-Lopez, Gonzalo; Contreras, Julio; Murillo-Cuesta, Silvia; Rodriguez-Baeza, Alfonso; Varela-Nieto, Isabel; Ruberte, Jesus; Collado, Manuel; Serrano, Manuel
      Cell (Cambridge, MA, United States) (2013), 155 (5), 1104-1118CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence.
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    60. 60
      Li, T.; Kon, N.; Jiang, L.; Tan, M.; Ludwig, T.; Zhao, Y.; Baer, R.; Gu, W. Tumor Suppression in the Absence of P53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence. Cell 2012, 149 (6), 1269– 1283,  DOI: 10.1016/j.cell.2012.04.026
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      Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence
      Li, Tongyuan; Kon, Ning; Jiang, Le; Tan, Minjia; Ludwig, Thomas; Zhao, Yingming; Baer, Richard; Gu, Wei
      Cell (Cambridge, MA, United States) (2012), 149 (6), 1269-1283CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are the rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53K117R) or three (p533KR; K117R+K161R+K162R) of p53 acetylation sites. Although p53K117R/K117R cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p533KR/3KR cells. Surprisingly, unlike p53 null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53K117R/K117R or p533KR/3KR animals. Notably, p533KR retains the ability to regulate energy metab. and reactive oxygen species prodn. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are crit. for suppression of early-onset spontaneous tumorigenesis.
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    61. 61
      Helman, A.; Klochendler, A.; Azazmeh, N.; Gabai, Y.; Horwitz, E.; Anzi, S.; Swisa, A.; Condiotti, R.; Granit, R. Z.; Nevo, Y.; Fixler, Y.; Shreibman, D.; Zamir, A.; Tornovsky-Babeay, S.; Dai, C.; Glaser, B.; Powers, A. C.; Shapiro, A. M. J.; Magnuson, M. A.; Dor, Y.; Ben-Porath, I. P16(Ink4a)-Induced Senescence of Pancreatic Beta Cells Enhances Insulin Secretion. Nat. Med. 2016, 22 (4), 412– 420,  DOI: 10.1038/nm.4054
      61
      p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion
      Helman, Aharon; Klochendler, Agnes; Azazmeh, Narmen; Gabai, Yael; Horwitz, Elad; Anzi, Shira; Swisa, Avital; Condiotti, Reba; Granit, Roy Z.; Nevo, Yuval; Fixler, Yaakov; Shreibman, Dorin; Zamir, Amit; Tornovsky-Babeay, Sharona; Dai, Chunhua; Glaser, Benjamin; Powers, Alvin C.; Shapiro, A. M. James; Magnuson, Mark A.; Dor, Yuval; Ben-Porath, Ittai
      Nature Medicine (New York, NY, United States) (2016), 22 (4), 412-420CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
      Cellular senescence is thought to contribute to age-assocd. deterioration of tissue physiol. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16Ink4a in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16Ink4a in beta cells induces hallmarks of senescence-including cell enlargement, and greater glucose uptake and mitochondrial activity-which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.
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    62. 62
      Rudin, C. M.; Hann, C. L.; Garon, E. B.; Ribeiro De Oliveira, M.; Bonomi, P. D.; Camidge, D. R.; Chu, Q.; Giaccone, G.; Khaira, D.; Ramalingam, S. S.; Ranson, M. R.; Dive, C.; McKeegan, E. M.; Chyla, B. J.; Dowell, B. L.; Chakravartty, A.; Nolan, C. E.; Rudersdorf, N.; Busman, T. A.; Mabry, M. H.; Krivoshik, A. P.; Humerickhouse, R. A.; Shapiro, G. I.; Gandhi, L. Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer. Clin. Cancer Res. 2012, 18 (11), 3163– 3169,  DOI: 10.1158/1078-0432.CCR-11-3090
      62
      Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
      Rudin, Charles M.; Hann, Christine L.; Garon, Edward B.; Ribeiro de Oliveira, Moacyr; Bonomi, Philip D.; Camidge, D. Ross; Chu, Quincy; Giaccone, Giuseppe; Khaira, Divis; Ramalingam, Suresh S.; Ranson, Malcolm R.; Dive, Caroline; McKeegan, Evelyn M.; Chyla, Brenda J.; Dowell, Barry L.; Chakravartty, Arunava; Nolan, Cathy E.; Rudersdorf, Niki; Busman, Todd A.; Mabry, Mack H.; Krivoshik, Andrew P.; Humerickhouse, Rod A.; Shapiro, Geoffrey I.; Gandhi, Leena
      Clinical Cancer Research (2012), 18 (11), 3163-3169CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      Purpose: Bcl-2 is a crit. regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-xL. The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. Exptl. Design: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results: The most common toxicity assocd. with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was obsd. in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 mo and median OS was 3.2 mo. A strong assocn. between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy no. (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell no. as correlates of clin. benefit. Conclusion: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clin. benefit. Preclin. models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to std. cytotoxics. Future studies will focus on combination therapies. Clin Cancer Res; 18(11); 3163-9. ©2012 AACR.
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    63. 63
      Laberge, R. M.; Sun, Y.; Orjalo, A. V.; Patil, C. K.; Freund, A.; Zhou, L.; Curran, S. C.; Davalos, A. R.; Wilson-Edell, K. A.; Liu, S.; Limbad, C.; Demaria, M.; Li, P.; Hubbard, G. B.; Ikeno, Y.; Javors, M.; Desprez, P. Y.; Benz, C. C.; Kapahi, P.; Nelson, P. S.; Campisi, J. MTOR Regulates the Pro-Tumorigenic Senescence-Associated Secretory Phenotype by Promoting IL1A Translation. Nat. Cell Biol. 2015, 17 (8), 1049– 1061,  DOI: 10.1038/ncb3195
      63
      MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation
      Laberge, Remi-Martin; Sun, Yu; Orjalo, Arturo V.; Patil, Christopher K.; Freund, Adam; Zhou, Lili; Curran, Samuel C.; Davalos, Albert R.; Wilson-Edell, Kathleen A.; Liu, Su; Limbad, Chandani; Demaria, Marco; Li, Patrick; Hubbard, Gene B.; Ikeno, Yuji; Javors, Martin; Desprez, Pierre-Yves; Benz, Christopher C.; Kapahi, Pankaj; Nelson, Peter S.; Campisi, Judith
      Nature Cell Biology (2015), 17 (8), 1049-1061CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)
      The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-assocd. secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumor growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-assocd. inflammation.
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    64. 64
      Truss, M.; Bartsch, J.; Mows, C.; Chavez, S.; Beato, M. Chromatin Structure of the MMTV Promoter and Its Changes during Hormonal Induction. Cell. Mol. Neurobiol. 1996, 16 (2), 85– 101,  DOI: 10.1007/BF02088169
      64
      Chromatin structure of the MMTV promoter and its changes during hormonal induction
      Truss, Mathias; Bartsch, Joerg; Moews, Christian; Chavez, Sebastian; Beato, Miguel
      Cellular and Molecular Neurobiology (1996), 16 (2), 85-101CODEN: CMNEDI; ISSN:0272-4340. (Plenum)
      A review, with 112 refs., which discusses: the MMTV system; the hormone (glucocorticoid) responsive region; the NF1 binding sites; the octamer motifs; other elements; cell-free transcription; nucleosome structure of the MMTV promoter; changes in chromatin structure after hormone induction; and mechanism for chromatin remodeling.
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    65. 65
      Beato, M.; Eisfeld, K. Transcription Factor Access to Chromatin. Nucleic Acids Res. 1997, 25 (18), 3559– 3563,  DOI: 10.1093/nar/25.18.3559
      65
      Transcription factor access to chromatin
      Beato, Miguel; Eisfeld, Karin
      Nucleic Acids Research (1997), 25 (18), 3559-3563CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      The question of how sequence-specific transcription factors access their cognate sites in nucleosomally organized DNA is discussed on the basis of genomic footprinting data and chromatin reconstitution expts. A classification of factors into two categories is proposed: (i) initiator factors which are able to bind their target sequences within regular nucleosomes and initiate events leading to chromatin remodelling and transactivation; (ii) effector factors which are unable to bind regular nucleosomes and depend on initiator factors or on a pre-set nucleosomal structure for accessing their target sequences in chromatin. Studies with the MMTV promoter suggest that the extent and no. of protein-DNA contacts det. whether a factor belongs to one or the other category. Initiator factors have only a few DNA contracts clustered on one side of the double helix, whereas effector factors have extensive contacts distributed throughout the whole circumference of the DNA helix. Thus, the nature of DNA, recognition confers to sequence-specific factors their specific place in the sequential hierarchy of gene regulatory events.
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    66. 66
      Ura, K.; Kurumizaka, H.; Dimitrov, S.; Almouzni, G.; Wolffe, A. P. Histone Acetylation: Influence on Transcription, Nucleosome Mobility and Positioning, and Linker Histone-Dependent Transcriptional Repression. EMBO J. 1997, 16 (8), 2096– 2107,  DOI: 10.1093/emboj/16.8.2096
      66
      Histone acetylation: influence on transcription, nucleosome mobility and positioning, and linker histone-dependent transcriptional repression
      Ura, Kiyoe; Kurumizaka, Hitoshi; Dimitrov, Stefan; Almouzni, Genevieve; Wolffe, Alan P.
      EMBO Journal (1997), 16 (8), 2096-2107CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)
      We demonstrate using a dinucleosome template that acetylation of the core histones enhances transcription by RNA polymerase III. This effect is not dependent on an increased mobility of the core histone octamer with respect to DNA sequence. When linker histone is subsequently bound, we find both a redn. in nucleosome mobility and a repression of transcription. These effects of linker histone binding are independent of core histone acetylation, indicating that core histone acetylation does not prevent linker histone binding and the concomitant transcriptional repression. These studies are complemented by the use of a Xenopus egg ext. competent both for chromatin assembly on replicating DNA and for RNA polymerase III transcription. Incorporation of acetylated histones and lack of linker histones together facilitate transcription by >10-fold in this system; however, they have little independent effect on transcription. Thus core histone acetylation significantly facilitates transcription, but this effect is inhibited by the assembly of linker histones into chromatin.
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    67. 67
      Wolffe, A. P. Sinful Repression. Nat. 1997 3876628 1997, 387 (6628), 16– 17,  DOI: 10.1038/387016a0
      There is no corresponding record for this reference.
    68. 68
      Urnov, F. D.; Wolffe, A. P. Chromatin Remodeling and Transcriptional Activation: The Cast (in Order of Appearance). Oncogene 2001, 20 (24), 2991– 3006,  DOI: 10.1038/sj.onc.1204323
      68
      Chromatin remodeling and transcriptional activation: the cast (in order of appearance)
      Urnov, Fyodor D.; Wolffe, Alan P.
      Oncogene (2001), 20 (24), 2991-3006CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
      A review, with ∼150 refs. The no. of chromatin modifying and remodeling complexes implicated in genome control is growing faster than our understanding of the functional roles they play. We discuss recent in vitro expts. with biochem. defined chromatin templates that illuminate new aspects of action by histone acetyltransferases and ATP-dependent chromatin remodeling engines in facilitating transcription. We review a no. of studies that present an "ordered recruitment" view of transcriptional activation, according to which various complexes enter and exit their target promoter in a set sequence, and at specific times, such that action by one complex sets the stage for the arrival of the next one. A consensus emerging from all these expts. is that the joint action by several types of chromatin remodeling machines can lead to a more profound alteration of the infrastructure of chromatin over a target promoter than could be obtained by these enzymes acting independently. In addn., it appears that in specific cases one type of chromatin structure alteration (e.g., histone hyperacetylation) is contingent upon prior alterations of a different sort (i.e., ATP-dependent remodeling of histone-DNA contacts). The striking differences between the precise sequence of action by various cofactors obsd. in these studies may be - at least in part - due to differences between the specific promoters studied, and distinct requirements exhibited by specific loci for chromatin remodeling based on their pre-existing nucleoprotein architecture.
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    69. 69
      Workman, J. L.; Buchman, A. R. Multiple Functions of Nucleosomes and Regulatory Factors in Transcription. Trends Biochem. Sci. 1993, 18 (3), 90– 95,  DOI: 10.1016/0968-0004(93)90160-O
      69
      Multiple functions of nucleosomes and regulatory factors in transcription
      Workman, Jerry L.; Buchman, Andrew R.
      Trends in Biochemical Sciences (1993), 18 (3), 90-5CODEN: TBSCDB; ISSN:0968-0004.
      A review, with 30 refs. The in vivo packaging of DNA with histone proteins to form chromatin makes its transcription a difficult process. Biochem. and genetic studies are beginning to reveal mechanistic details of how transcriptional regulatory factors confront at least two hurdles created by nucleosomes, the primary structural unit of chromatin. Regulatory factors must gain access to their resp. binding sites and activate the formation of transcription complexes at core promoter elements. Distinct regulatory factors may be specialized to perform these functions.
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    70. 70
      Barnes, P. J. New Anti-Inflammatory Targets for Chronic Obstructive Pulmonary Disease. Nat. Rev. Drug Discovery 2013, 12 (7), 543– 559,  DOI: 10.1038/nrd4025
      70
      New anti-inflammatory targets for chronic obstructive pulmonary disease
      Barnes Peter J
      Nature reviews. Drug discovery (2013), 12 (7), 543-59 ISSN:.
      Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of the peripheral airways and lung parenchyma, which leads to progressive obstruction of the airways. Current management with long-acting bronchodilators does not reduce disease progression, and there are no treatments that effectively suppress chronic inflammation in COPD. An increased understanding of the inflammatory processes that are involved in the pathophysiology of COPD has identified several new therapeutic targets. This Review discusses some of the most promising of these targets, including new antioxidants, kinase inhibitors and drugs that target cellular senescence, microbial colonization, epigenetic regulation of inflammatory gene expression and corticosteroid resistance.
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    71. 71
      Ito, K.; Barnes, P. J.; Adcock, I. M. Glucocorticoid Receptor Recruitment of Histone Deacetylase 2 Inhibits Interleukin-1beta-Induced Histone H4 Acetylation on Lysines 8 and 12. Mol. Cell. Biol. 2000, 20 (18), 6891– 6903,  DOI: 10.1128/MCB.20.18.6891-6903.2000
      71
      Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1β-induced histone H4 acetylation on lysines 8 and 12
      Ito, Kazuhiro; Barnes, Peter J.; Adcock, Ian M.
      Molecular and Cellular Biology (2000), 20 (18), 6891-6903CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
      We have investigated the ability of dexamethasone to regulate interleukin-1β (IL-1β)-induced gene expression, histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity. Low concns. of dexamethasone (10-10 M) repress IL-1β-stimulated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression and fail to stimulate secretory leukocyte proteinase inhibitor expression. Dexamethasone (10-7 M) and IL-1β (1 ng/mL) both stimulated HAT activity but showed a different pattern of histone H4 acetylation. Dexamethasone targeted lysines K5 and K16, whereas IL-1β targeted K8 and K12. Low concns. of dexamethasone (10-10 M), which do not transactivate, repressed IL-1β-stimulated K8 and K12 acetylation. Using chromatin immunopptn. assays, we show that dexamethasone inhibits IL-1β-enhanced acetylated K8-assocd. GM-CSF promoter enrichment in a concn.-dependent manner. Neither IL-1β nor dexamethasone elicited any GM-CSF promoter assocn. at acetylated K5 residues. Furthermore, we show that GR acts both as a direct inhibitor of CREB binding protein (CBP)-assocd. HAT activity and also by recruiting HDAC2 to the p65-CBP HAT complex. This action does not involve de novo synthesis of HDAC protein or altered expression of CBP or p300/CBP-assocd. factor. This mechanism for glucocorticoid repression is novel and establishes that inhibition of histone acetylation is an addnl. level of control of inflammatory gene expression. This further suggests that pharmacol. manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases.
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    72. 72
      Ito, K.; Ito, M.; Elliott, W. M.; Cosio, B.; Caramori, G.; Kon, O. M.; Barczyk, A.; Hayashi, S.; Adcock, I. M.; Hogg, J. C.; Barnes, P. J. Decreased Histone Deacetylase Activity in Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 2005, 352 (19), 1967– 1976,  DOI: 10.1056/NEJMoa041892
      72
      Decreased histone deacetylase activity in chronic obstructive pulmonary disease
      Ito, Kazuhiro; Ito, Misako; Elliott, W. Mark; Cosio, Borja; Caramori, Gaetano; Kon, Onn Min; Barczyk, Adam; Hayashi, Shizu; Adcock, Lan M.; Hogg, James C.; Barnes, Peter J.
      New England Journal of Medicine (2005), 352 (19), 1967-1976CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
      Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the redn. in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key mol. in the repression of prodn. of proinflammatory cytokines in alveolar macrophages. HDAC activity and histone acetyltransferase (HAT) activity were detd. in nuclear exts. of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examd. Total RNA extd. from lung tissue and macrophages was used for quant. reverse-transcriptase- PCR assay of HDAC1 through HDAC8 and interleukin-8. Expression of HDAC2 protein was quantified with the use of Western blotting. Histone-4 acetylation at the interleukin-8 promoter was evaluated with the use of a chromatin immunopptn. assay. Specimens of lung tissue obtained from patients with increasing clin. stages of COPD had graded redns. in HDAC activity and increases in interleukin-8 mRNA and histone-4 acetylation at the interleukin-8 promoter. The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia. Patients with COPD have a progressive redn. in total HDAC activity that reflects the severity of the disease.
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    73. 73
      Hu, L.; Liu, F.; Li, L.; Zhang, L.; Yan, C.; Li, Q.; Qiu, J.; Dong, J.; Sun, J.; Zhang, H. Effects of Icariin on Cell Injury and Glucocorticoid Resistance in BEAS-2B Cells Exposed to Cigarette Smoke Extract. Exp. Ther. Med. 2020, 20 (1), 283– 292,  DOI: 10.3892/etm.2020.8702
      73
      Effects of icariin on cell injury and glucocorticoid resistance in BEAS-2B cells exposed to cigarette smoke extract
      Hu, Lingli; Liu, Feng; Li, Lulu; Zhang, Li; Yan, Chen; Li, Qiuping; Qiu, Jian; Dong, Jingcheng; Sun, Jing; Zhang, Hongying
      Experimental and Therapeutic Medicine (2020), 20 (1), 283-292CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)
      Glucocorticoids (GCs) exert a therapeutic effect in numerous chronic inflammatory diseases. However, chronic obstructive pulmonary disease (COPD) tends to be GC-resistant. Icariin, a major component of flavonoids isolated from Epimedium brevicornum Maxim (Berberidaceae), significantly relieves symptoms in patients with COPD. However, the mechanism of action remains unclear and further investigation is required to establish whether it may serve as an alternative or complementary therapy for COPD. The aim of the present study was to det. the effects of icariin in human bronchial epithelial cells exposed to cigarette smoke ext. (CSE) and to det. whether icariin reverses GC resistance. The results revealed that icariin significantly increased the proliferation of CSE-exposed cells. Furthermore, icariin significantly increased protein expression of the anti-inflammatory factor interleukin (IL)-10 and significantly decreased protein expression of the pro-inflammatory factors IL-8 and tumor necrosis factor α. Icariin also attenuated the expression of the cellular matrix remodelling biomarkers matrix metallopeptidase 9 and tissue inhibitor of metalloproteinase 1, and decreased the prodn. of reactive oxygen species (ROS). In addn., icariin regulated the expression of GC resistance-related factors, such as GC receptors, histone deacetylase 2, nuclear factor erythroid-2-related factor 2 and nuclear factor κ B. The results obtained in the present study suggested that icariin may decrease CSE-induced inflammation, airway remodelling and ROS prodn. by mitigating GC resistance. In conclusion, icariin may potentially be used in combination with GCs to increase therapeutic efficacy and reduce GC resistance in COPD.
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    74. 74
      Wu, J.; Li, X.; Qin, Y.; Cheng, J.; Hao, G.; Jin, R.; Zhu, C. Jinwei Tang Modulates HDAC2 Expression in a Rat Model of COPD. Exp. Ther. Med. 2018, 15 (3), 2604,  DOI: 10.3892/etm.2018.5707
      74
      Jinwei Tang modulates HDAC2 expression in a rat model of COPD
      Wu, Jianjun; Li, Xin; Qin, Yang; Cheng, Juan; Hao, Gaimei; Jin, Ruifeng; Zhu, Chenjun
      Experimental and Therapeutic Medicine (2018), 15 (3), 2604-2610CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)
      The aim of the present study was to investigate the effect of a Traditional Chinese Herbal Medicine (TCHM), named Jinwei Tang on histone deacetylase 2 (HDAC2) and its role in the regulation of corticosteroid resistance in a rat model of chronic obstructive pulmonary disease (COPD). Male Wistar rats were divided into five groups (each n = 10): COPD group, established by the intratracheal instillation of lipopolysaccharide and passive smoke exposure, and control, budesonide, theophylline + budesonide and Jinwei Tang + budesonide groups. Lung function was measured, lung tissue histopathol. was examd. and HDAC2 expression in the lung was assessed by immunohistochem. In addn., protein levels of interleukin-8 (IL-8), tumor necrosis factor (TNF)-α and HDAC2 in lung homogenate were quantified by ELISA. The rat COPD model exhibited alterations of the ratio of forced expiratory vol. in 0.2 s (FEV0.2) to the forced vital capacity, FEV0.2, dynamic compliance and airway resistance. HDAC2 expression was markedly reduced in the lung tissue of the COPD group compared with the control group, and treatment with Jinwei Tang + budesonide or theophylline + budesonide resulted in significant attenuation of the redn. of HDAC2 expression in the lungs (P<0.05). However, treatment with budesonide alone did not significantly alter HDAC2 expression. In the Jinwei Tang + budesonide and theophylline + budesonide groups, IL-8 and TNF-α expression was significantly decreased (P<0.05) and the HDAC2 level increased (P<0.05) compared with that in the COPD group.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFGjsr%252FE&md5=b93ae564602e5b01d97b66d0dd63647e
    75. 75
      Miao, L.; Gao, Z.; Huang, F.; Huang, S.; Zhang, R.; Ma, D.; Wu, Q.; Li, F.; Chen, H.; Wang, J. Erythromycin Enhances the Anti-Inflammatory Activity of Budesonide in COPD Rat Model. Int. J. Clin. Exp. Med. 2015, 8 (12), 22217
      75
      Erythromycin enhances the anti-inflammatory activity of budesonide in COPD rat model
      Miao, Lijun; Gao, Zengyan; Huang, Fengxiang; Huang, Shifu; Zhang, Ruixia; Ma, Dongbo; Wu, Qiuge; Li, Fang; Chen, Hongjie; Wang, Jing
      International Journal of Clinical and Experimental Medicine (2015), 8 (12), 22217-22226CODEN: IJCEFA; ISSN:1940-5901. (e-Century Publishing Corp.)
      Glucocorticoids (GCs) have been widely applied to treat patients with chronic obstructive pulmonary disease (COPD). But the effect of GCs was not ideal. This study was to observe whether erythromycin could enhance the anti-inflammatory activity of budesonide in COPD model rats and to explore the mechanism involved. In this study, male Sprague-Dawley rats were divided into five groups: healthy control group (H group), COPD model group (C group), erythromycin group (E group), budesonide group (B group) and erythromycin + budesonide group (E+B group). The rats in groups of C, E, B and E+B were developed into COPD models. Different groups were given different drug interventions. The levels of 8-iso-PGF2 α, IL-8, and TNF- α in BALF and serum were measured with ELISA. The protein expression levels of HDAC2, PI3K, and p-AKT in lung tissue were measured with Western-blot and immunohistochem. The levels of 8-iso-PGF2 α, IL-8, and TNF- α in BALF and serum were lower in E+B group than those in B group and C group (all P<0.001).The protein expression level of HDAC2 was higher and PI3K and p-AKT were lower in E+B group than those in B group and C group (all P<0.001). Moreover, the expression levels of HDAC2 were neg. correlated with the levels of 8-iso-PGF2 α, IL-8 and TNF- α both in serum and BALF and the expression levels of PI3K and p-AKT among the five groups, with all P<0.001. We conclude that erythromycin can enhance the anti-inflammatory activity of budesonide in COPD model rats, possibly through inhibiting the PI3K/AKT pathway and enhancing the activity of HDAC2.
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    76. 76
      Manz, M. G.; Boettcher, S. Emergency Granulopoiesis. Nat. Rev. Immunol. 2014, 14 (5), 302– 314,  DOI: 10.1038/nri3660
      76
      Emergency granulopoiesis
      Manz, Markus G.; Boettcher, Steffen
      Nature Reviews Immunology (2014), 14 (5), 302-314CODEN: NRIABX; ISSN:1474-1733. (Nature Publishing Group)
      A review. Neutrophils are a key cell type of the innate immune system. They are short-lived and need to be continuously generated in steady-state conditions from haematopoietic stem and progenitor cells in the bone marrow to ensure their immediate availability for the containment of invading pathogens. However, if microbial infection cannot be controlled locally, and consequently develops into a life-threatening condition, neutrophils are used up in large quantities and the haematopoietic system has to rapidly adapt to the increased demand by switching from steady-state to emergency granulopoiesis. This involves the markedly increased de novo prodn. of neutrophils, which results from enhanced myeloid precursor cell proliferation in the bone marrow. In this Review, we discuss the mol. and cellular events that regulate emergency granulopoiesis, a process that is crucial for host survival.
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    77. 77
      Németh, T.; Sperandio, M.; Mócsai, A. Neutrophils as Emerging Therapeutic Targets. Nat. Rev. Drug Discovery 2020, 19 (4), 253– 275,  DOI: 10.1038/s41573-019-0054-z
      77
      Neutrophils as emerging therapeutic targets
      Nemeth, Tamas; Sperandio, Markus; Mocsai, Attila
      Nature Reviews Drug Discovery (2020), 19 (4), 253-275CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)
      A review. Neutrophils are the most abundant circulating leukocytes, being the first line of defense against bacterial and fungal infections. However, neutrophils also contribute to tissue damage during various autoimmune and inflammatory diseases, and play important roles in cancer progression. The intimate but complex involvement of neutrophils in various diseases makes them exciting targets for therapeutic intervention but also necessitates differentiation of beneficial responses from potentially detrimental side effects. A variety of approaches to therapeutically target neutrophils have emerged, including strategies to enhance, inhibit or restore neutrophil function, with several agents entering clin. trials. However, challenges and controversies in the field remain.
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    78. 78
      Tsantikos, E.; Lau, M.; Castelino, C. M. N.; Maxwell, M. J.; Passey, S. L.; Hansen, M. J.; McGregor, N. E.; Sims, N. A.; Steinfort, D. P.; Irving, L. B.; Anderson, G. P.; Hibbs, M. L. Granulocyte-CSF Links Destructive Inflammation and Comorbidities in Obstructive Lung Disease. J. Clin. Invest. 2018, 128 (6), 2406– 2418,  DOI: 10.1172/JCI98224
      78
      Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease
      Tsantikos Evelyn; Lau Maverick; Castelino Cassandra Mn; Maxwell Mhairi J; Hibbs Margaret L; Lau Maverick; Passey Samantha L; Hansen Michelle J; Anderson Gary P; McGregor Narelle E; Sims Natalie A; Steinfort Daniel P; Irving Louis B
      The Journal of clinical investigation (2018), 128 (6), 2406-2418 ISSN:.
      Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that afflicts millions of people worldwide, and it is the fourth leading cause of death. Systemic comorbidities affecting the heart, skeletal muscle, bone, and metabolism are major contributors to morbidity and mortality. Given the surprising finding in large prospective clinical biomarker studies that peripheral white blood cell count is more closely associated with disease than inflammatory biomarkers, we probed the role of blood growth factors. Using the SHIP-1-deficient COPD mouse model, which manifests a syndrome of destructive lung disease and a complex of comorbid pathologies, we have identified a critical and unexpected role for granulocyte-CSF (G-CSF) in linking these conditions. Deletion of G-CSF greatly reduced airway inflammation and lung tissue destruction, and attenuated systemic inflammation, right heart hypertrophy, loss of fat reserves, and bone osteoporosis. In human clinical translational studies, bronchoalveolar lavage fluid of patients with COPD demonstrated elevated G-CSF levels. These studies suggest that G-CSF may play a central and unforeseen pathogenic role in COPD and its complex comorbidities, and identify G-CSF and its regulators as potential therapeutic targets.
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    79. 79
      Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D. S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil Extracellular Traps Kill Bacteria. Science 2004, 303 (5663), 1532– 1535,  DOI: 10.1126/science.1092385
      79
      Neutrophil Extracellular Traps Kill Bacteria
      Brinkmann, Volker; Reichard, Ulrike; Goosmann, Christian; Fauler, Beatrix; Uhlemann, Yvonne; Weiss, David S.; Weinrauch, Yvette; Zychlinsky, Arturo
      Science (Washington, DC, United States) (2004), 303 (5663), 1532-1535CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, the authors describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-pos. and -neg. bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in exptl. dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concn. of antimicrobial agents to degrade virulence factors and kill bacteria.
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    80. 80
      Daniel, C.; Leppkes, M.; Muñoz, L. E.; Schley, G.; Schett, G.; Herrmann, M. Extracellular DNA Traps in Inflammation, Injury and Healing. Nat. Rev. Nephrol. 2019, 15 (9), 559– 575,  DOI: 10.1038/s41581-019-0163-2
      80
      Extracellular DNA traps in inflammation, injury and healing
      Daniel, Christoph; Leppkes, Moritz; Munoz, Luis E.; Schley, Gunnar; Schett, Georg; Herrmann, Martin
      Nature Reviews Nephrology (2019), 15 (9), 559-575CODEN: NRNABO; ISSN:1759-5061. (Nature Research)
      A review. Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is esp. prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathol. roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of patholologyl assocd. with the release of extracellular DNA traps is mainly detd. by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.
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    81. 81
      Porto, B. N.; Stein, R. T. Neutrophil Extracellular Traps in Pulmonary Diseases: Too Much of a Good Thing?. Front. Immunol. 2016, 7 (AUG), 311,  DOI: 10.3389/fimmu.2016.00311
      81
      Neutrophil extracellular traps in pulmonary diseases: too much of a good thing?
      Porto, Barbara Nery; Stein, Renato Tetelbom
      Frontiers in Immunology (2016), 7 (), 311/1-311/13CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
      Neutrophil extracellular traps (NETs) arise from the release of granular and nuclear contents of neutrophils in the extracellular space in response to different classes of microorganisms, sol. factors, and host mols. NETs are composed by decondensed chromatin fibers coated with antimicrobial granular and cytoplasmic proteins, such as myeloperoxidase, neutrophil elastase (NE), and α-defensins. Besides being expressed on NET fibers, NE and MPO also regulate NET formation. Furthermore, histone deimination by peptidylarginine deiminase 4 (PAD4) is a central step to NET formation. NET formation has been widely demonstrated to be an effective mechanism to fight against invading microorganisms, as deficiency in NET release or dismantling NET backbone by bacterial DNases renders the host susceptible to infections. Therefore, the primary role of NETs is to prevent microbial dissemination, avoiding overwhelming infections. However, an excess of NET formation has a dark side. The pathogenic role of NETs has been described for many human diseases, infectious and non-infectious. The detrimental effect of excessive NET release is particularly important to lung diseases, because NETs can expand more easily in the pulmonary alveoli, causing lung injury. Moreover, NETs and its assocd. mols. are able to directly induce epithelial and endothelial cell death. In this regard, massive NET formation has been reported in several pulmonary diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory syncytial virus bronchiolitis, influenza, bacterial pneumonia, and tuberculosis, among others. Thus, NET formation must be tightly regulated in order to avoid NET-mediated tissue damage. Recent development of therapies targeting NETs in pulmonary diseases includes DNA disintegration with recombinant human DNase, neutralization of NET proteins, with anti-histone antibodies and protease inhibitors. In this review, we summarize the recent knowledge on the pathophysiol. role of NETs in pulmonary diseases as well as some exptl. and clin. approaches to modulate their detrimental effects.
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    82. 82
      Sollberger, G.; Choidas, A.; Burn, G. L.; Habenberger, P.; Di Lucrezia, R.; Kordes, S.; Menninger, S.; Eickhoff, J.; Nussbaumer, P.; Klebl, B.; Krüger, R.; Herzig, A.; Zychlinsky, A. Gasdermin D Plays a Vital Role in the Generation of Neutrophil Extracellular Traps. Sci. Immunol. 2018, 3 (26), eaar6689,  DOI: 10.1126/sciimmunol.aar6689
      There is no corresponding record for this reference.
    83. 83
      Chen, K. W.; Monteleone, M.; Boucher, D.; Sollberger, G.; Ramnath, D.; Condon, N. D.; von Pein, J. B.; Broz, P.; Sweet, M. J.; Schroder, K. Noncanonical Inflammasome Signaling Elicits Gasdermin D-Dependent Neutrophil Extracellular Traps. Sci. Immunol. 2018, 3 (26), eaar6676,  DOI: 10.1126/sciimmunol.aar6676
      There is no corresponding record for this reference.
    84. 84
      Frye, R. A. Phylogenetic Classification of Prokaryotic and Eukaryotic Sir2-like Proteins. Biochem. Biophys. Res. Commun. 2000, 273 (2), 793– 798,  DOI: 10.1006/bbrc.2000.3000
      84
      Phylogenetic Classification of Prokaryotic and Eukaryotic Sir2-like Proteins
      Frye, Roy A.
      Biochemical and Biophysical Research Communications (2000), 273 (2), 793-798CODEN: BBRCA9; ISSN:0006-291X. (Academic Press)
      Sirtuins (Sir2-like proteins) are present in prokaryotes and eukaryotes. Here, two new human sirtuins (SIRT6 and SIRT7) are found to be similar to a particular subset of insect, nematode, plant, and protozoan sirtuins. Mol. phylogenetic anal. of 60 sirtuin conserved core domain sequences from a diverse array of organisms (including archaeans, bacteria, yeasts, plants, protozoans, and metazoans) shows that eukaryotic Sir2-like proteins group into four main branches designated here as classes I-IV. Prokaryotic sirtuins include members of classes II and III. A fifth class of sirtuin is present in gram pos. bacteria and Thermotoga maritima. Saccharomyces cerevisiae has five class I sirtuins. Caenorhabditis elegans and Drosophila melanogaster have sirtuin genes from classes I, II, and IV. The seven human sirtuin genes include all four classes: SIRT1, SIRT2, and SIRT3 are class I; SIRT4 is class II; SIRT5 is class III; and SIRT6 and SIRT7 are class IV. (c) 2000 Academic Press.
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    85. 85
      Singh, C. K.; Nihal, M.; Ahmad, N. Histone Deacetylase Inhibitory Approaches for the Management of Osteoarthritis. Am. J. Pathol. 2016, 186 (10), 2555,  DOI: 10.1016/j.ajpath.2016.08.001
      85
      Histone Deacetylase Inhibitory Approaches for the Management of Osteoarthritis
      Singh, Chandra K.; Nihal, Minakshi; Ahmad, Nihal
      American Journal of Pathology (2016), 186 (10), 2555-2558CODEN: AJPAA4; ISSN:0002-9440. (Elsevier B.V.)
      A polemic in response to Makki et al is given.,. This paper discusses about the histone deacetylase inhibitory approaches for management of osteoarthritis.
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    86. 86
      Nakagawa, T.; Guarente, L. Sirtuins at a Glance. J. Cell Sci. 2011, 124 (6), 833– 838,  DOI: 10.1242/jcs.081067
      86
      Sirtuins at a glance
      Nakagawa, Takashi; Guarente, Leonard
      Journal of Cell Science (2011), 124 (6), 833-838CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
      A review. The enzymic activity and characterization of sirtuins and recent data relating to their role in aging and aging-related diseases are summarized and the underlying mechanisms are described.
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    87. 87
      Singh, C. K.; Chhabra, G.; Ndiaye, M. A.; Garcia-Peterson, L. M.; MacK, N. J.; Ahmad, N. The Role of Sirtuins in Antioxidant and Redox Signaling. Antioxid. Redox Signal. 2018, 28 (8), 643,  DOI: 10.1089/ars.2017.7290
      87
      The Role of Sirtuins in Antioxidant and Redox Signaling
      Singh Chandra K; Chhabra Gagan; Ndiaye Mary Ann; Garcia-Peterson Liz Mariely; Mack Nicholas J; Ahmad Nihal
      Antioxidants & redox signaling (2018), 28 (8), 643-661 ISSN:.
      SIGNIFICANCE: Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1-7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets. Recent studies show that sirtuins modulate the regulation of a variety of cellular processes associated with ARS. SIRT1, SIRT3, and SIRT5 protect the cell from ROS, and SIRT2, SIRT6, and SIRT7 modulate key oxidative stress genes and mechanisms. Interestingly, SIRT4 has been shown to induce ROS production and has antioxidative roles as well. CRITICAL ISSUES: A complete understanding of the roles of sirtuins in redox homeostasis of the cell is very important to understand the normal functioning as well as pathological manifestations. In this review, we have provided a critical discussion on the role of sirtuins in the regulation of ARS. We have also discussed mechanistic interactions among different sirtuins. Indeed, a complete understanding of sirtuin biology could be critical at multiple fronts. FUTURE DIRECTIONS: Sirtuins are emerging to be important in normal mammalian physiology and in a variety of oxidative stress-mediated pathological situations. Studies are needed to dissect the mechanisms of sirtuins in maintaining redox homeostasis. Efforts are also required to assess the targetability of sirtuins in the management of redox-regulated diseases. Antioxid. Redox Signal. 28, 643-661.
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    88. 88
      Bai, W.; Zhang, X. Nucleus or Cytoplasm? The Mysterious Case of SIRT1’s Subcellular Localization. Cell Cycle 2016, 15 (24), 3337,  DOI: 10.1080/15384101.2016.1237170
      88
      Nucleus or cytoplasm? The mysterious case of SIRT1's subcellular localization
      Bai, Wenlong; Zhang, Xiaohong
      Cell Cycle (2016), 15 (24), 3337-3338CODEN: CCEYAS; ISSN:1551-4005. (Taylor & Francis Ltd.)
      There is no expanded citation for this reference.
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    89. 89
      Wilking, M. J.; Singh, C.; Nihal, M.; Zhong, W.; Ahmad, N. SIRT1 Deacetylase Is Overexpressed in Human Melanoma and Its Small Molecule Inhibition Imparts Anti-Proliferative Response via P53 Activation. Arch. Biochem. Biophys. 2014, 563, 94– 100,  DOI: 10.1016/j.abb.2014.04.001
      89
      SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation
      Wilking, Melissa J.; Singh, Chandra; Nihal, Minakshi; Zhong, Weixiong; Ahmad, Nihal
      Archives of Biochemistry and Biophysics (2014), 563 (), 94-100CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)
      Melanoma causes more deaths than any other skin cancer, and its incidence in the US continues to rise. Current medical therapies are insufficient to control this deadly neoplasm, necessitating the development of new target-based approaches. The objective of this study was to det. the role and functional significance of the class III histone deacetylase SIRT1 in melanoma. We have found that SIRT1 is overexpressed in clin. human melanoma tissues and human melanoma cell lines (Sk-Mel-2, WM35, G361, A375, and Hs294T) compared to normal skin and normal melanocytes, resp. In addn., treatment of melanoma cell lines A375, Hs294T, and G361 with Tenovin-1, a small mol. SIRT1 inhibitor, resulted in a significant decrease in cell growth and cell viability. Further, Tenovin-1 treatment also resulted in a marked decrease in the clonogenic survival of melanoma cells. Further expts. showed that the anti-proliferative response of Tenovin-1 was accompanied by an increase in the protein as well as activity of the tumor suppressor p53. This increase in p53 activity was substantiated by an increase in the protein level of its downstream target p21. Overall, these data suggest that small mol. inhibition of SIRT1 causes anti-proliferative effects in melanoma cells. SIRT1 appears to be acting through the activity of the tumor suppressor p53, which is not mutated in the majority of melanomas. However, future detailed studies are needed to further explore the role and mechanism of SIRT1 in melanoma development and progression and its usefulness in melanoma treatment.
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    90. 90
      Yu, J.; Auwerx, J. Protein Deacetylation by SIRT1: An Emerging Key Post-Translational Modification in Metabolic Regulation. Pharmacol. Res. 2010, 62 (1), 35– 41,  DOI: 10.1016/j.phrs.2009.12.006
      90
      Protein deacetylation by SIRT1: An emerging key post-translational modification in metabolic regulation
      Yu, Jiujiu; Auwerx, Johan
      Pharmacological Research (2010), 62 (1), 35-41CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)
      A review. The biol. function of most proteins relies on reversible post-translational modifications, among which phosphorylation is most prominently studied and well recognized. Recently, a growing amt. of evidence indicates that acetylation-deacetylation reactions, when applied to crucial mediators, can also robustly affect the function of target proteins and thereby have wide-ranging physiol. impacts. Sirtuin 1 (SIRT1), which functions as a NAD (NAD+)-dependent protein deacetylase, deacetylates a wide variety of metabolic mols. in response to the cellular energy and redox status and as such causes significant changes in metabolic homeostasis. This review surveys the evidence for the emerging role of SIRT1-mediated deacetylation in the control of metabolic homeostasis.
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    91. 91
      Yao, H.; Hwang, J. W.; Sundar, I. K.; Friedman, A. E.; McBurney, M. W.; Guarente, L.; Gu, W.; Kinnula, V. L.; Rahman, I. SIRT1 Redresses the Imbalance of Tissue Inhibitor of Matrix Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Development of Mouse Emphysema and Human COPD. Am. J. Physiol. - Lung Cell. Mol. Physiol. 2013, 305 (9), L615,  DOI: 10.1152/ajplung.00249.2012
      There is no corresponding record for this reference.
    92. 92
      Yang, H.; Zhang, W.; Pan, H.; Feldser, H. G.; Lainez, E.; Miller, C.; Leung, S.; Zhong, Z.; Zhao, H.; Sweitzer, S.; Considine, T.; Riera, T.; Suri, V.; White, B.; Ellis, J. L.; Vlasuk, G. P.; Loh, C. SIRT1 Activators Suppress Inflammatory Responses through Promotion of P65 Deacetylation and Inhibition of NF-ΚB Activity. PLoS One 2012, 7 (9), e46364,  DOI: 10.1371/journal.pone.0046364
      92
      SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-κB activity
      Yang, Hongying; Zhang, Wei; Pan, Heng; Feldser, Heidi G.; Lainez, Elden; Miller, Christine; Leung, Stewart; Zhong, Zhong; Zhao, Huizhen; Sweitzer, Sharon; Considine, Thomas; Riera, Thomas; Suri, Vipin; White, Brian; Ellis, James L.; Vlasuk, George P.; Loh, Christine
      PLoS One (2012), 7 (9), e46364CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Chronic inflammation is a major contributing factor in the pathogenesis of many age-assocd. diseases. One central protein that regulates inflammation is NF-κB, the activity of which is modulated by post-translational modifications as well as by assocn. with co-activator and co-repressor proteins. SIRT1, an NAD+-dependent protein deacetylase, has been shown to suppress NF-κB signaling through deacetylation of the p65 subunit of NF-κB resulting in the redn. of the inflammatory responses mediated by this transcription factor. The role of SIRT1 in the regulation of NF-κB provides the necessary validation for the development of pharmacol. strategies for activating SIRT1 as an approach for the development of a new class of anti-inflammatory therapeutics. We report herein the development of a quant. assay to assess compd. effects on acetylated p65 protein in the cell. We demonstrate that small mol. activators of SIRT1 (STACs) enhance deacetylation of cellular p65 protein, which results in the suppression of TNFα-induced NF-κB transcriptional activation and redn. of LPS-stimulated TNFα secretion in a SIRT1-dependent manner. In an acute mouse model of LPS-induced inflammation, the STAC SRTCX1003 decreased the prodn. of the proinflammatory cytokines TNFα and IL-12. Our studies indicate that increasing SIRT1-mediated NF-κB deacetylation using small mol. activating compds. is a novel approach to the development of a new class of therapeutic anti-inflammatory agents.
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    93. 93
      Yanagisawa, S.; Papaioannou, A. I.; Papaporfyriou, A.; Baker, J. R.; Vuppusetty, C.; Loukides, S.; Barnes, P. J.; Ito, K. Decreased Serum Sirtuin-1 in COPD. Chest 2017, 152 (2), 343– 352,  DOI: 10.1016/j.chest.2017.05.004
      93
      Decreased Serum Sirtuin-1 in COPD
      Yanagisawa Satoru; Baker Jonathan R; Vuppusetty Chaitanya; Barnes Peter J; Papaioannou Andriana I; Papaporfyriou Anastasia; Loukides Stelios; Ito Kazuhiro
      Chest (2017), 152 (2), 343-352 ISSN:.
      BACKGROUND: The protein deacetylase sirtuin-1 (SIRT1) is an antiaging molecule that is decreased in the lung in patients with COPD. Recently, SIRT1 was reported to be detectable in serum, but serum SIRT1 (s120S) levels have not yet been reported in patients with COPD. METHODS: Serum SIRT1 protein of all samples was measured by Western blot, and the SIRT1 protein band densities were calculated and compared with clinical parameters. RESULTS: Several molecular sizes of SIRT1, including 120 kDa (actual size) and fragments (102 and 75 kDa) were quantified by Western blot. Among them, only the 120-kDa s120S was significantly decreased in patients with COPD compared with the control subjects without COPD (s120S ratio in healthy subjects = 0.90 ± 0.34 vs those with COPD = 0.68 ± 0.24; P = .014) and was positively correlated with airway obstruction (FEV1/FVC, r = 0.31; P = .020); its severity measured by FEV1 % predicted (r = 0.29; P = .029). s120S also showed a positive correlation with BMI (r = 0.36; P = .0077) and diffusing capacity of the lung per unit volume (the carbon monoxide transfer coefficient: KCO%) (r = 0.32; P = .025). It was also significantly decreased with increasing severity of lung emphysema (r = -0.40; P = .027) and with a clinical history of frequent COPD exacerbations (infrequent vs frequent, 0.76 ± 0.20 vs 0.56 ± 0.26; P = .027). SIRT1 was not detected in supernatant of A549 and primary epithelial cells in normal culture conditions. CONCLUSIONS: s120S was decreased in the patients with COPD, potentially as reflected by the reduced SIRT1 within cells as a result of oxidative stress, and might be a potential biomarker for certain disease characteristics of COPD.
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    94. 94
      Peng, Z.; Zhang, W.; Qiao, J.; He, B. Melatonin Attenuates Airway Inflammation via SIRT1 Dependent Inhibition of NLRP3 Inflammasome and IL-1β in Rats with COPD. Int. Immunopharmacol. 2018, 62, 23– 28,  DOI: 10.1016/j.intimp.2018.06.033
      94
      Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD
      Peng, Zhenyu; Zhang, Wenxuan; Qiao, Jianfeng; He, Baimei
      International Immunopharmacology (2018), 62 (), 23-28CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)
      Chronic airway inflammation is a characteristic feature of chronic obstructive pulmonary disease (COPD). Previous studies demonstrated that melatonin had a protective effect against COPD. In addn., silent information regulator 1 (SIRT1) was reported to be beneficial in COPD. However, whether SIRT1 is involved in the protective effect of melatonin against COPD remains unclear. In this study, we investigated the effect of melatonin on a rat model of COPD and explored the potential mechanisms. Twenty eight male Wistar rats were randomly assigned to four groups: control group, COPD group, COPD+Mel group and COPD+Mel+EX527 group. Rats were challenged with cigarette smoke and lipopolysaccharide (LPS) for 28 days with or without melatonin or EX527. The pulmonary function, lung histopathol., inflammatory cells count and the concn. of IL-1β in the BALF as well as the protein expressions of SIRT1, NLRP3, cleaved caspase-1 and ASC in the lung tissues were measured. The results demonstrated that melatonin prevented the development of COPD, which was attributed to the inhibition of airway inflammation by attenuating NLRP3 inflammasome and IL-1β. Furthermore, melatonin increased the expression of SIRT1 in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 abolished the protective effect of melatonin against COPD. In conclusion, these findings suggested that melatonin attenuated airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD.
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    95. 95
      Yanagisawa, S.; Baker, J. R.; Vuppusetty, C.; Koga, T.; Colley, T.; Fenwick, P.; Donnelly, L. E.; Barnes, P. J.; Ito, K. The Dynamic Shuttling of SIRT1 between Cytoplasm and Nuclei in Bronchial Epithelial Cells by Single and Repeated Cigarette Smoke Exposure. PLoS ONE 2018, 13, e0193921,  DOI: 10.1371/journal.pone.0193921
      95
      The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure
      Yanagisawa, Satoru; Baker, Jonathan R.; Vuppusetty, Chaitanya; Koga, Takeshi; Colley, Thomas; Fenwick, Peter; Donnelly, Louise E.; Barnes, Peter J.; Ito, Kazuhiro
      PLoS One (2018), 13 (3), e0193921/1-e0193921/20CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein esp. in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke ext. (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was assocd. with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concn. of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-assocd. lung disease such as chronic obstructive pulmonary disease.
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    96. 96
      Grabowska, W.; Sikora, E.; Bielak-Zmijewska, A. Sirtuins, a Promising Target in Slowing down the Ageing Process. Biogerontology 2017, 18 (4), 447,  DOI: 10.1007/s10522-017-9685-9
      96
      Sirtuins, a promising target in slowing down the ageing process
      Grabowska, Wioleta; Sikora, Ewa; Bielak-Zmijewska, Anna
      Biogerontology (2017), 18 (4), 447-476CODEN: BIOGCN; ISSN:1389-5729. (Springer)
      A review. Ageing is a plastic process and can be successfully modulated by some biomedical approaches or pharmaceutics. In this manner it is possible to delay or even prevent some age-related pathologies. There are some defined interventions, which give promising results in animal models or even in human studies, resulting in lifespan elongation or healthspan improvement. One of the most promising targets for anti-ageing approaches are proteins belonging to the sirtuin family. Sirtuins were originally discovered as transcription repressors in yeast, however, nowadays they are known to occur in bacteria and eukaryotes (including mammals). In humans the family consists of seven members (SIRT1-7) that possess either mono-ADP ribosyltransferase or deacetylase activity. It is believed that sirtuins play key role during cell response to a variety of stresses, such as oxidative or genotoxic stress and are crucial for cell metab. Although some data put in question direct involvement of sirtuins in extending human lifespan, it was documented that proper lifestyle including phys. activity and diet can influence healthspan via increasing the level of sirtuins. The search for an activator of sirtuins is one of the most extensive and robust topic of research. Some hopes are put on natural compds., including curcumin. In this review we summarize the involvement and usefulness of sirtuins in anti-ageing interventions and discuss the potential role of curcumin in sirtuins regulation.
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    97. 97
      Gomes, P.; Fleming Outeiro, T.; Cavadas, C. Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism. Trends Pharmacol. Sci. 2015, 36 (11), 756– 768,  DOI: 10.1016/j.tips.2015.08.001
      97
      Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism
      Gomes, Pedro; Fleming Outeiro, Tiago; Cavadas, Claudia
      Trends in Pharmacological Sciences (2015), 36 (11), 756-768CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)
      A review. Sirtuins are an evolutionarily conserved family of NAD+-dependent deacylases that display diversity in subcellular localization and function. SIRT2, the predominantly cytosolic sirtuin, is among the least understood of the seven mammalian sirtuin isoforms described (SIRT1-7). The purpose of this review is to summarize the most recent findings about the potential roles and effects of SIRT2 in mammalian metabolic homeostasis. We discuss the different functions and targets of SIRT2 in various physiol. processes, including adipogenesis, fatty acid oxidn., gluconeogenesis, and insulin sensitivity. We also cover the role of SIRT2 in inflammation and oxidative stress due to the possible implications for metabolic disorders. Finally, we consider its potential as a therapeutic target for the prevention and treatment of type 2 diabetes.
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    98. 98
      Wang, Y. P.; Zhou, L. S.; Zhao, Y. Z.; Wang, S. W.; Chen, L. L.; Liu, L. X.; Ling, Z. Q.; Hu, F. J.; Sun, Y. P.; Zhang, J. Y.; Yang, C.; Yang, Y.; Xiong, Y.; Guan, K. L.; Ye, D. Regulation of G6PD Acetylation by SIRT2 and KAT9Modulates NADPH Homeostasis and Cell Survival during Oxidative Stress. EMBO J. 2014, 33 (12), 1304,  DOI: 10.1002/embj.201387224
      98
      Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress
      Wang, Yi-Ping; Zhou, Li-Sha; Zhao, Yu-Zheng; Wang, Shi-Wen; Chen, Lei-Lei; Liu, Li-Xia; Ling, Zhi-Qiang; Hu, Fu-jun; Sun, Yi-Ping; Zhang, Jing-Ye; Yang, Chen; Yang, Yi; Xiong, Yue; Guan, Kun-Liang; Ye, Dan
      EMBO Journal (2014), 33 (12), 1304-1320CODEN: EMJODG; ISSN:0261-4189. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Glucose 6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular reductant in G6PD deficiency, which is the most common human enzyme defect, affecting >400 million people worldwide. Here, the authors show that G6PD is neg. regulated by acetylation on Lys-403, an evolutionarily conserved residue. Lys-403-acetylated G6PD was incapable of forming active dimers and displayed a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re-expression of wild-type G6PD, but not the Lys-403 acetylation mimetic mutant, rescued cells from oxidative injury. Moreover, the authors showed that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulated the PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. The authors also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Thus, this study uncovered a previously unknown mechanism by which acetylation neg. regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress.
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    99. 99
      Iwahara, T.; Bonasio, R.; Narendra, V.; Reinberg, D. SIRT3 Functions in the Nucleus in the Control of Stress-Related Gene Expression. Mol. Cell. Biol. 2012, 32 (24), 5022– 5034,  DOI: 10.1128/MCB.00822-12
      99
      SIRT3 functions in the nucleus in the control of stress-related gene expression
      Iwahara, Toshinori; Bonasio, Roberto; Narendra, Varun; Reinberg, Danny
      Molecular and Cellular Biology (2012), 32 (24), 5022-5034CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
      SIRT3 is a member of the Sir2 family of NAD+-dependent protein deacetylases that promotes longevity in many organisms. The processed short form of SIRT3 is a well-established mitochondrial protein whose deacetylase activity regulates various metabolic processes. However, the presence of full-length (FL) SIRT3 in the nucleus and its functional importance remain controversial. Our previous studies demonstrated that nuclear FL SIRT3 functions as a histone deacetylase and is transcriptionally repressive when artificially recruited to a reporter gene. Here, we report that nuclear FL SIRT3 is subjected to rapid degrdn. under conditions of cellular stress, including oxidative stress and UV irradn., whereas the mitochondrial processed form is unaffected. FL SIRT3 degrdn. is mediated by the ubiquitin-proteasome pathway, at least partially through the ubiquitin protein ligase (E3) activity of SKP2. Finally, we show by chromatin immunopptn. that some target genes of nuclear SIRT3 are derepressed upon degrdn. of SIRT3 caused by stress stimuli. Thus, SIRT3 exhibits a previously unappreciated role in the nucleus, modulating the expression of some stress-related and nuclear-encoded mitochondrial genes.
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    100. 100
      Cheng, Y.; Ren, X.; Gowda, A. S. P.; Shan, Y.; Zhang, L.; Yuan, Y. S.; Patel, R.; Wu, H.; Huber-Keener, K.; Yang, J. W.; Liu, D.; Spratt, T. E.; Yang, J. M. Interaction of Sirt3 with OGG1 Contributes to Repair of Mitochondrial DNA and Protects from Apoptotic Cell Death under Oxidative Stress. Cell Death Dis. 2013, 4 (7), e731,  DOI: 10.1038/cddis.2013.254
      100
      Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress
      Cheng, Y.; Ren, X.; Gowda, A. SP; Shan, Y.; Zhang, L.; Yuan, Y-S.; Patel, R.; Wu, H.; Huber-Keener, K.; Yang, J. W.; Liu, D.; Spratt, T. E.; Yang, J-M.
      Cell Death & Disease (2013), 4 (July), e731CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)
      Sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, targets various mitochondrial proteins for lysine deacetylation and regulates important cellular functions such as energy metab., aging, and stress response. In this study, we identified the human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine (8-oxoG) from damaged genome, as a new target protein for Sirt3. We found that Sirt3 phys. assocd. with OGG1 and deacetylated this DNA glycosylase and that deacetylation by Sirt3 prevented the degrdn. of the OGG1 protein and controlled its incision activity. We further showed that regulation of the acetylation and turnover of OGG1 by Sirt3 played a crit. role in repairing mitochondrial DNA (mtDNA) damage, protecting mitochondrial integrity, and preventing apoptotic cell death under oxidative stress. We obsd. that following ionizing radiation, human tumor cells with silencing of Sirt3 expression exhibited deteriorated oxidative damage of mtDNA, as measured by the accumulation of 8-oxoG and 4977 common deletion, and showed more severe mitochondrial dysfunction and underwent greater apoptosis in comparison with the cells without silencing of Sirt3 expression. The results reported here not only reveal a new function and mechanism for Sirt3 in defending the mitochondrial genome against oxidative damage and protecting from the genotoxic stress-induced apoptotic cell death but also provide evidence supporting a new mtDNA repair pathway.
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    101. 101
      Anderson, K. A.; Huynh, F. K.; Fisher-Wellman, K.; Stuart, J. D.; Peterson, B. S.; Douros, J. D.; Wagner, G. R.; Thompson, J. W.; Madsen, A. S.; Green, M. F.; Sivley, R. M.; Ilkayeva, O. R.; Stevens, R. D.; Backos, D. S.; Capra, J. A.; Olsen, C. A.; Campbell, J. E.; Muoio, D. M.; Grimsrud, P. A.; Hirschey, M. D. SIRT4 Is a Lysine Deacylase That Controls Leucine Metabolism and Insulin Secretion. Cell Metab. 2017, 25 (4), 838– 855,  DOI: 10.1016/j.cmet.2017.03.003
      101
      SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion
      Anderson, Kristin A.; Huynh, Frank K.; Fisher-Wellman, Kelsey; Stuart, J. Darren; Peterson, Brett S.; Douros, Jonathan D.; Wagner, Gregory R.; Thompson, J. Will; Madsen, Andreas S.; Green, Michelle F.; Sivley, R. Michael; Ilkayeva, Olga R.; Stevens, Robert D.; Backos, Donald S.; Capra, John A.; Olsen, Christian A.; Campbell, Jonathan E.; Muoio, Deborah M.; Grimsrud, Paul A.; Hirschey, Matthew D.
      Cell Metabolism (2017), 25 (4), 838-855.e15CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)
      Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metab. and aging. In contrast to the other mammalian sirtuins, the primary enzymic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biol., and enzymol., we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidn., and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metab. in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.
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    102. 102
      Haigis, M. C.; Mostoslavsky, R.; Haigis, K. M.; Fahie, K.; Christodoulou, D. C.; Murphy, A. J. J.; Valenzuela, D. M.; Yancopoulos, G. D.; Karow, M.; Blander, G.; Wolberger, C.; Prolla, T. A.; Weindruch, R.; Alt, F. W.; Guarente, L. SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic Beta Cells. Cell 2006, 126 (5), 941– 954,  DOI: 10.1016/j.cell.2006.06.057
      102
      SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells
      Haigis, Marcia C.; Mostoslavsky, Raul; Haigis, Kevin M.; Fahie, Kamau; Christodoulou, Danos C.; Murphy, Andrew J.; Valenzuela, David M.; Yancopoulos, George D.; Karow, Margaret; Blander, Gil; Wolberger, Cynthia; Prolla, Tomas A.; Weindruch, Richard; Alt, Frederick W.; Guarente, Leonard
      Cell (Cambridge, MA, United States) (2006), 126 (5), 941-954CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Sir2 is an NAD-dependent deacetylase that connects metab. with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metab. of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is obsd. in pancreatic β cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in β cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
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    103. 103
      Luo, Y. X.; Tang, X.; An, X. Z.; Xie, X. M.; Chen, X. F.; Zhao, X.; Hao, D. L.; Chen, H. Z.; Liu, D. P. SIRT4 Accelerates Ang II-Induced Pathological Cardiac Hypertrophy by Inhibiting Manganese Superoxide Dismutase Activity. Eur. Heart J. 2016, 38 (18), 1389– 1398,  DOI: 10.1093/eurheartj/ehw138
      There is no corresponding record for this reference.
    104. 104
      Nasrin, N.; Wu, X.; Fortier, E.; Feng, Y.; Baré, O. C.; Chen, S.; Ren, X.; Wu, Z.; Streeper, R. S.; Bordone, L. SIRT4 Regulates Fatty Acid Oxidation and Mitochondrial Gene Expression in Liver and Muscle Cells. J. Biol. Chem. 2010, 285 (42), 31995– 32002,  DOI: 10.1074/jbc.M110.124164
      104
      SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells
      Nasrin, Nargis; Wu, Xiaoping; Fortier, Eric; Feng, Yajun; Bare', Olivia Claire; Chen, Sumiao; Ren, Xianglin; Wu, Zhidan; Streeper, Ryan S.; Bordone, Laura
      Journal of Biological Chemistry (2010), 285 (42), 31995-32002CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      SIRT4, a member of the sirtuin family, has been implicated in the regulation of insulin secretion by modulation of glutamate dehydrogenase. However, the role of this enzyme in the regulation of metab. in other tissues is unknown. In this study we investigated whether depletion of SIRT4 would enhance liver and muscle metabolic functions. To do this SIRT4 was knocked down using an adenoviral shRNA in mouse primary hepatocytes and myotubes. We obsd. a significant increase in gene expression of mitochondrial and fatty acid metab. enzymes in hepatocytes with reduced SIRT4 levels. SIRT4 knockdown also increased SIRT1 mRNA and protein levels both in vitro and in vivo. In agreement with the increased fatty acid oxidn. (FAO) gene expression, we showed a significant increase in FAO in SIRT4 knockdown primary hepatocytes compared with control, and this effect was dependent on SIRT1. In primary myotubes, knockdown of SIRT4 resulted in increased FAO, cellular respiration, and pAMPK levels. When SIRT4 was knocked down in vivo by tail vein injection of a shRNA adenovirus, we obsd. a significant increase in hepatic mitochondrial and FAO gene expression consistent with the findings in primary hepatocytes. Taken together these findings demonstrate that SIRT4 inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases assocd. with ectopic lipid storage such as type 2 diabetes.
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    105. 105
      Rosca, M. G.; Vazquez, E. J.; Chen, Q.; Kerner, J.; Kern, T. S.; Hoppel, C. L. Oxidation of Fatty Acids Is the Source of Increased Mitochondrial Reactive Oxygen Species Production in Kidney Cortical Tubules in Early Diabetes. Diabetes 2012, 61 (8), 2074– 2083,  DOI: 10.2337/db11-1437
      105
      Oxidation of fatty acids is the source of increased mitochondrial reactive oxygen species production in kidney cortical tubules in early diabetes
      Rosca, Mariana G.; Vazquez, Edwin J.; Chen, Qun; Kerner, Janos; Kern, Timothy S.; Hoppel, Charles L.
      Diabetes (2012), 61 (8), 2074-2083CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)
      Mitochondrial reactive oxygen species (ROS) cause kidney damage in diabetes. We investigated the source and site of ROS prodn. by kidney cortical tubule mitochondria in streptozotocin-induced type 1 diabetes in rats. In diabetic mitochondria, the increased amts. and activities of selective fatty acid oxidn. enzymes is assocd. with increased oxidative phosphorylation and net ROS prodn. with fatty acid substrates (by 40% and 30%, resp.), whereas pyruvate oxidn. is decreased and pyruvate-supported ROS prodn. is unchanged. Oxidn. of substrates that donate electrons at specific sites in the electron transport chain (ETC) is unchanged. The increased maximal prodn. of ROS with fatty acid oxidn. is not affected by limiting the electron flow from complex I into complex III. The maximal capacity of the ubiquinol oxidn. site in complex III in generating ROS does not differ between the control and diabetic mitochondria. In conclusion, the mitochondrial ETC is neither the target nor the site of ROS prodn. in kidney tubule mitochondria in short-term diabetes. Mitochondrial fatty acid oxidn. is the source of the increased net ROS prodn., and the site of electron leakage is located proximal to coenzyme Q at the electron transfer flavoprotein that shuttles electrons from acyl-CoA dehydrogenases to coenzyme Q.
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    106. 106
      Du, J.; Zhou, Y.; Su, X.; Yu, J. J.; Khan, S.; Jiang, H.; Kim, J.; Woo, J.; Kim, J. H.; Choi, B. H.; He, B.; Chen, W.; Zhang, S.; Cerione, R. A.; Auwerx, J.; Hao, Q.; Lin, H. Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase. Science (80-.). 2011, 334 (6057), 806– 809,  DOI: 10.1126/science.1207861
      There is no corresponding record for this reference.
    107. 107
      Liu, B.; Che, W.; Zheng, C.; Liu, W.; Wen, J.; Fu, H.; Tang, K.; Zhang, J.; Xu, Y. SIRT5: A Safeguard against Oxidative Stress-Induced Apoptosis in Cardiomyocytes. Cell. Physiol. Biochem. 2013, 32 (4), 1050– 1059,  DOI: 10.1159/000354505
      107
      SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes
      Liu, Ban; Che, Wenliang; Zheng, Changzhu; Liu, Weijing; Wen, Jing; Fu, Haitao; Tang, Kai; Zhang, Jinying; Xu, Yawei
      Cellular Physiology and Biochemistry (2013), 32 (4), 1050-1059CODEN: CEPBEW; ISSN:1015-8987. (S. Karger AG)
      Background: SIRT5 is located in the mitochondria, and plays a crucial role in the regulation of metabolic process and cellular apoptosis. Cardiomyocytes are abundant in mitochondria. However, the role of SIRT5 in oxidative stress-induced apoptosis is still unknown in cardiomyocytes. Methods and Results: Western blots anal. revealed that SIRT5 is significantly down-regulated in cardiomyocytes upon oxidative stress. MTT assay, DAPI staining, and caspase 3/7 activity assay were used to est. apoptosis development. The result suggested that compared with the wild-type group, SIRT5 knockdown results in a marked redn. in cell viability, and a significant increase in the no. of apoptotic cells and the caspase 3/7 activity. Protein immunopptn. revealed a direct interaction between Bcl-Xl and SIRT5. Apoptosis assay and western blot anal. suggested that SIRT5 levels could affect the levels of Bcl-Xl expression, but have no effect on the apoptosis development in Bcl-Xl knockdown cells. Conclusion: This study reveals a novel role of SIRT5 in the regulation of oxidative stress-induced apoptosis in cardiomyocytes. Pharmacol. interventions on SIRT5 expression may be useful in the treatment of oxidative stress-related cardiac injury.
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    108. 108
      Bobermin, L. D.; Wartchow, K. M.; Flores, M. P.; Leite, M. C.; Quincozes-Santos, A.; Gonçalves, C. A. Ammonia-Induced Oxidative Damage in Neurons Is Prevented by Resveratrol and Lipoic Acid with Participation of Heme Oxygenase 1. Neurotoxicology 2015, 49, 28– 35,  DOI: 10.1016/j.neuro.2015.05.005
      108
      Ammonia-induced oxidative damage in neurons is prevented by resveratrol and lipoic acid with participation of heme oxygenase 1
      Bobermin, Larissa Daniele; Wartchow, Krista Mineia; Flores, Marianne Pires; Leite, Marina Concli; Quincozes-Santos, Andre; Goncalves, Carlos-Alberto
      NeuroToxicology (2015), 49 (), 28-35CODEN: NRTXDN; ISSN:0161-813X. (Elsevier Inc.)
      Ammonia is a metabolite that, at high concns., is implicated in neurol. disorders, such as hepatic encephalopathy (HE), which is assocd. with acute or chronic liver failure. Astrocytes are considered the primary target of ammonia toxicity in the central nervous system (CNS) because glutamine synthetase (GS), responsible for ammonia metab. in CNS, is an astrocytic enzyme. Thus, neuronal dysfunction has been assocd. as secondary to astrocytic impairment. However, we demonstrated that ammonia can induce direct effects on neuronal cells. The cell viability was decreased by ammonia in SH-SY5Y cells and cerebellar granule neurons. In addn., ammonia induced increased reactive oxygen species (ROS) prodn. and decreased GSH intracellular content, the main antioxidant in CNS. As ammonia neurotoxicity is strongly assocd. with oxidative stress, we also investigated the potential neuroprotective roles of the antioxidants, resveratrol (RSV) and lipoic acid (LA), against ammonia toxicity in cerebellar granule neurons. RSV and LA were able to prevent the oxidative damage induced by ammonia, maintaining the levels of ROS prodn. and GSH close to basal values. Both antioxidants also decreased ROS prodn. and increased GSH content under basal conditions (in the absence of ammonia). Moreover, we showed that heme oxygenase 1 (HO1), a protein assocd. with protection against stress conditions, is involved in the beneficial effects of RSV and LA in cerebellar granule neurons. Thus, this study reinforces the neuroprotective effects of RSV and LA. Although more studies in vivo are required, RSV and LA could represent interesting therapeutic strategies for the management of HE.
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    109. 109
      Nakagawa, T.; Lomb, D. J.; Haigis, M. C.; Guarente, L. SIRT5 Deacetylates Carbamoyl Phosphate Synthetase 1 and Regulates the Urea Cycle. Cell 2009, 137 (3), 560– 570,  DOI: 10.1016/j.cell.2009.02.026
      109
      SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle
      Nakagawa, Takashi; Lomb, David J.; Haigis, Marcia C.; Guarente, Leonard
      Cell (Cambridge, MA, United States) (2009), 137 (3), 560-570CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Sirtuins are NAD-dependent protein deacetylases that connect metab. and aging. In mammals, there are 7 sirtuins (SIRT1-7), 3 of which are assocd. with mitochondria. Here, the authors show that SIRT5 localizes in the mitochondrial matrix and interacts with carbamoylphosphate synthetase 1 (CPS1), which catalyzes the initial step of the urea cycle for NH3 detoxification and disposal. SIRT5 deacetylates CPS1 and up-regulates its activity. During fasting, NAD in liver mitochondria increases, thereby triggering SIRT5 deacetylation of CPS1 and adaptation to the increase in amino acid catabolism. Indeed, SIRT5-KO mice fail to up-regulate CPS1 activity and show elevated blood NH3 during fasting. Similar effects occur during long-term calorie restriction or a high protein diet. These findings demonstrate that SIRT5 plays a pivotal role in NH3 detoxification and disposal by activating CPS1.
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    110. 110
      Ogura, M.; Nakamura, Y.; Tanaka, D.; Zhuang, X.; Fujita, Y.; Obara, A.; Hamasaki, A.; Hosokawa, M.; Inagaki, N. Overexpression of SIRT5 Confirms Its Involvement in Deacetylation and Activation of Carbamoyl Phosphate Synthetase 1. Biochem. Biophys. Res. Commun. 2010, 393 (1), 73– 78,  DOI: 10.1016/j.bbrc.2010.01.081
      110
      Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1
      Ogura, Masahito; Nakamura, Yasuhiko; Tanaka, Daisuke; Zhuang, Xiaotong; Fujita, Yoshihito; Obara, Akio; Hamasaki, Akihiro; Hosokawa, Masaya; Inagaki, Nobuya
      Biochemical and Biophysical Research Communications (2010), 393 (1), 73-78CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
      SIR2 protein, an NAD-dependent deacetylase, is localized to nucleus and is involved in life span extension by calorie restriction in yeast. In mammals, among the 7 SIR2 homologs (SIRT1-7), SIRT3, SIRT4, and SIRT5 are localized to mitochondria. As SIRT5 mRNA levels in liver were increased by fasting, the physiol. role of SIRT5 was investigated in liver of SIRT5-overexpressing transgenic (SIRT5 Tg) mice. The authors identified carbamoyl phosphate synthetase 1 (CPS1), a key enzyme of the urea cycle that catalyzes condensation of NH3 with HCO3- to form carbamoyl phosphate, as a target of SIRT5 by 2-dimensional electrophoresis comparing mitochondrial proteins in livers of SIRT5 Tg and wild-type mice. CPS1 protein was more deacetylated and activated in liver of SIRT5 Tg mice than in wild-type mice. In addn., urea prodn. was up-regulated in hepatocytes of SIRT5 Tg mice. These results agreed with those of a previous study using SIRT5-knockout (KO) mice. Because NH3 generated during fasting is toxic, SIRT5 protein might play a protective role by converting NH3 to non-toxic urea through deacetylation and activation of CPS1.
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    111. 111
      Michishita, E.; McCord, R. A.; Berber, E.; Kioi, M.; Padilla-Nash, H.; Damian, M.; Cheung, P.; Kusumoto, R.; Kawahara, T. L. A.; Barrett, J. C.; Chang, H. Y.; Bohr, V. A.; Ried, T.; Gozani, O.; Chua, K. F. SIRT6 Is a Histone H3 Lysine 9 Deacetylase That Modulates Telomeric Chromatin. Nature 2008, 452 (7186), 492– 496,  DOI: 10.1038/nature06736
      111
      SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
      Michishita, Eriko; McCord, Ronald A.; Berber, Elisabeth; Kioi, Mitomu; Padilla-Nash, Hesed; Damian, Mara; Cheung, Peggie; Kusumoto, Rika; Kawahara, Tiara L. A.; Barrett, J. Carl; Chang, Howard Y.; Bohr, Vilhelm A.; Ried, Thomas; Gozani, Or; Chua, Katrin F.
      Nature (London, United Kingdom) (2008), 452 (7186), 492-496CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature aging-like phenotype. However, the mol. mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-assocd. protein, but no enzymic activity of SIRT6 at chromatin has yet been detected, and the identity of physiol. SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 assocs. specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects obsd. in Werner syndrome, a premature aging disorder. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable assocn. of WRN, the factor that is mutated in Werner syndrome. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metab. and function. Our findings constitute the first identification of a physiol. enzymic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature aging syndrome.
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    112. 112
      Michishita, E.; McCord, R. A.; Boxer, L. D.; Barber, M. F.; Hong, T.; Gozani, O.; Chua, K. F. Cell Cycle-Dependent Deacetylation of Telomeric Histone H3 Lysine K56 by Human SIRT6. Cell Cycle 2009, 8 (16), 2664– 2666,  DOI: 10.4161/cc.8.16.9367
      112
      Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6
      Michishita, Eriko; McCord, Ronald A.; Boxer, Lisa D.; Barber, Matthew F.; Hong, Tao; Gozani, Or; Chua, Katrin F.
      Cell Cycle (2009), 8 (16), 2664-2666CODEN: CCEYAS; ISSN:1538-4101. (Landes Bioscience)
      A second substrate of SIRT6 at chromotin, lysine 56 on the globular core of histone H3 (H3K56Ac) was examd. It was found that SIRT6 deacetylates H3K56Ac in vitro and in cells, and detd. a physiol. role for this activity in maintaining dynamic changes of H3K56 acetylation levels at telomeric chromatin over the cell cycle. Results showed that H3K56Ac was the new substrate for SIRT6. It also presented the antibody-independent mass spectrometry validation of the H3K56Ac deacetylase activities of both SIRT6 and SIRT1. The obsd. new data indicate that SIRT6 deacelylation of H3K56Ac might operate at chromatin directly at such sites of damaged DNA, and defects in such a mechanism could underlie aspects of the genomic instability, DNA damage hypersensitivity, and defective DNA repair phenotypes that are obsd. in SIRT6-deficient cells.
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    113. 113
      Michishita, E.; Park, J. Y.; Burneskis, J. M.; Barrett, J. C.; Horikawa, I. Evolutionarily Conserved and Nonconserved Cellular Localizations and Functions of Human SIRT Proteins. Mol. Biol. Cell 2005, 16 (10), 4623,  DOI: 10.1091/mbc.e05-01-0033
      113
      Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins
      Michishita, Eriko; Park, Jean Y.; Burneskis, Jenna M.; Barrett, J. Carl; Horikawa, Izumi
      Molecular Biology of the Cell (2005), 16 (10), 4623-4635CODEN: MBCEEV; ISSN:1059-1524. (American Society for Cell Biology)
      Sir2 is a NAD+-dependent protein deacetylase that extends lifespan in yeast and worms. This study examines seven human proteins homologous to Sir2 (SIRT1 through SIRT7) for cellular localization, expression profiles, protein deacetylation activity, and effects on human cell lifespan. We found that: (1) three nuclear SIRT proteins (SIRT1, SIRT6, and SIRT7) show different subnuclear localizations: SIRT6 and SIRT7 are assocd. with heterochromatic regions and nucleoli, resp., where yeast Sir2 functions; (2) SIRT3, SIRT4, and SIRT5 are localized in mitochondria, an organelle that links aging and energy metab.; (3) cellular p53 is a major in vivo substrate of SIRT1 deacetylase, but not the other six SIRT proteins; (4) SIRT1, but not the other two nuclear SIRT proteins, shows an in vitro deacetylase activity on histone H4 and p53 peptides; and (5) overexpression of any one of the seven SIRT proteins does not extend cellular replicative lifespan in normal human fibroblasts or prostate epithelial cells. This study supports the notion that multiple human SIRT proteins have evolutionarily conserved and nonconserved functions at different cellular locations and reveals that the lifespan of normal human cells, in contrast to that of lower eukaryotes, cannot be manipulated by increased expression of a single SIRT protein.
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    114. 114
      Tennen, R. I.; Bua, D. J.; Wright, W. E.; Chua, K. F. SIRT6 Is Required for Maintenance of Telomere Position Effect in Human Cells. Nat. Commun. 2011, 2 (1), 433,  DOI: 10.1038/ncomms1443
      114
      SIRT6 is required for maintenance of telomere position effect in human cells
      Tennen Ruth I; Bua Dennis J; Wright Woodring E; Chua Katrin F
      Nature communications (2011), 2 (), 433 ISSN:.
      In Saccharomyces cerevisiae, the repressive chromatin environment at telomeres gives rise to telomere position effect (TPE), the epigenetic silencing of telomere-proximal genes. Chromatin-modifying factors that control TPE in yeast have been extensively studied, and, among these, the lifespan regulator and silencing protein Sir2 has a pivotal role. In contrast, the factors that generate and maintain silent telomeric chromatin in human cells remain largely unknown. Here we show that the Sir2 family member SIRT6 is required for maintenance of TPE in human cells. RNAi-mediated depletion of SIRT6 abrogates silencing of both an integrated telomeric transgene and an endogenous telomere-proximal gene. Moreover, enhanced telomeric silencing in response to telomere elongation is associated with increased repressive chromatin marks, and this heterochromatic milieu is lost in SIRT6-deficient cells. Together, these findings establish a new role for SIRT6 in regulating an ageing-associated epigenetic silencing process and provide new mechanistic insight into chromatin silencing at telomeres.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MjmvFShsw%253D%253D&md5=6484129a28a0fe3c8cc3bfd199d39dff
    115. 115
      Tennen, R. I.; Chua, K. F. Chromatin Regulation and Genome Maintenance by Mammalian SIRT6. Trends Biochem. Sci. 2011, 36 (1), 39– 46,  DOI: 10.1016/j.tibs.2010.07.009
      115
      Chromatin regulation and genome maintenance by mammalian SIRT6
      Tennen, Ruth I.; Chua, Katrin F.
      Trends in Biochemical Sciences (2011), 36 (1), 39-46CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)
      A review. Saccharomyces cerevisiae Sir2 is an NAD+-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metab. and lifespan regulation. In mice, deficiency for the Sir2 family member SIRT6 leads to genomic instability, metabolic defects and degenerative pathologies assocd. with aging. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. However, new mechanistic insights have come from the discovery that SIRT6 is a highly substrate-specific histone deacetylase that promotes proper chromatin function in several physiol. contexts, including telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian genome, SIRT6 thus serves several roles that parallel Sir2 function. In this article, we review recent advances in understanding the mechanisms of SIRT6 action and their implications for human biol. and disease.
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    116. 116
      Van Meter, M.; Mao, Z.; Gorbunova, V.; Seluanov, A. Repairing Split Ends: SIRT6, Mono-ADP Ribosylation and DNA Repair. Aging (Albany. NY). 2011, 3 (9), 829– 835,  DOI: 10.18632/aging.100389
      116
      Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair
      Van Meter Michael; Mao Zhiyong; Gorbunova Vera; Seluanov Andrei
      Aging (2011), 3 (9), 829-35 ISSN:.
      The sirtuin gene family comprises an evolutionarily ancient set of NAD+ dependent protein deacetylase and mono-ADP ribosyltransferase enzymes. Found in all domains of life, sirtuins regulate a diverse array of biological processes, including DNA repair, gene silencing, apoptosis and metabolism. Studies in multiple model organisms have indicated that sirtuins may also function to extend lifespan and attenuate age-related pathologies. To date, most of these studies have focused on the deacetylase activity of sirtuins, and relatively little is known about the other biochemical activity of sirtuins, mono-ADP ribosylation. We recently reported that the mammalian sirtuin, SIRT6, mono-ADP ribosylates PARP1 to promote DNA repair in response to oxidative stress. In this research perspective we review the role of SIRT6 in DNA repair and discuss the emerging implications for sirtuin directed mono-ADP ribosylation in aging and age-related diseases.
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    117. 117
      Chun, P. Role of Sirtuins in Chronic Obstructive Pulmonary Disease. Arch. Pharm. Res. 2015, 38 (1), 1– 10,  DOI: 10.1007/s12272-014-0494-2
      117
      Role of sirtuins in chronic obstructive pulmonary disease
      Chun, Pusoon
      Archives of Pharmacal Research (2015), 38 (1), 1-10CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)
      A review. Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is assocd. with chronic inflammatory response to noxious particles or gases. The airflow limitation may be explained by hypersecretion of mucus, thickening and fibrosis of small airways and alveolar wall destruction in emphysema. Sirtuins, a group of class III deacetylases, have gained considerable attention for their pos. effects on aging-related disease, such as cancer, cardiovascular disease, neurodegenerative diseases, osteoporosis and COPD. Among the seven mammalian sirtuins, SIRT1-SIRT7, SIRT1 and SIRT6 are considered to have protective effects against COPD. In the lungs, SIRT1 inhibits autophagy, cellular senescence, fibrosis, and inflammation by deacetylation of target proteins using NAD+ as co-substrate and is therefore linked to the redox state. In addn. to SIRT1, SIRT6 have also been shown to improve or slow down COPD. SIRT6 Escherichia is assocd. with redox state and inhibits cellular senescence and fibrosis. Therefore, activation of SIRT1 and SIRT6 might be an attractive approach for novel therapeutic targets for COPD. The present review describes the protective effects of SIRT1 and SIRT6 against COPD and their target proteins involved in the pathophysiol. of COPD.
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    118. 118
      Takasaka, N.; Araya, J.; Hara, H.; Ito, S.; Kobayashi, K.; Kurita, Y.; Wakui, H.; Yoshii, Y.; Yumino, Y.; Fujii, S.; Minagawa, S.; Tsurushige, C.; Kojima, J.; Numata, T.; Shimizu, K.; Kawaishi, M.; Kaneko, Y.; Kamiya, N.; Hirano, J.; Odaka, M.; Morikawa, T.; Nishimura, S. L.; Nakayama, K.; Kuwano, K. Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence. J. Immunol. 2014, 192 (3), 958– 968,  DOI: 10.4049/jimmunol.1302341
      118
      Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence
      Takasaka, Naoki; Araya, Jun; Hara, Hiromichi; Ito, Saburo; Kobayashi, Kenji; Kurita, Yusuke; Wakui, Hiroshi; Yoshii, Yutaka; Yumino, Yoko; Fujii, Satoko; Minagawa, Shunsuke; Tsurushige, Chikako; Kojima, Jun; Numata, Takanori; Shimizu, Kenichiro; Kawaishi, Makoto; Kaneko, Yumi; Kamiya, Noriki; Hirano, Jun; Odaka, Makoto; Morikawa, Toshiaki; Nishimura, Stephen L.; Nakayama, Katsutoshi; Kuwano, Kazuyoshi
      Journal of Immunology (2014), 192 (3), 958-968CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
      Cigarette smoke (CS)-induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is neg. regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-assocd. β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory vol. in 1 s/forced vital capacity. CS ext. (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.
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    119. 119
      Finkel, T.; Deng, C. X.; Mostoslavsky, R. Recent Progress in the Biology and Physiology of Sirtuins. Nature 2009, 460 (7255), 587– 591,  DOI: 10.1038/nature08197
      119
      Recent progress in the biology and physiology of sirtuins
      Finkel, Toren; Deng, Chu-Xia; Mostoslavsky, Raul
      Nature (London, United Kingdom) (2009), 460 (7255), 587-591CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      A review. The sirtuins are a highly conserved family of NAD-dependent deacetylases that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis, and energy metab. Here, the authors review recent progress in sirtuin biol., the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long humans live.
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    120. 120
      Jia, G.; Su, L.; Singhal, S.; Liu, X. Emerging Roles of SIRT6 on Telomere Maintenance, DNA Repair, Metabolism and Mammalian Aging. Mol. Cell. Biochem. 2012, 364 (1–2), 345– 350,  DOI: 10.1007/s11010-012-1236-8
      120
      Emerging roles of SIRT6 on telomere maintenance, DNA repair, metabolism and mammalian aging
      Jia, Gaoxiang; Su, Ling; Singhal, Sunil; Liu, Xiangguo
      Molecular and Cellular Biochemistry (2012), 364 (1-2), 345-350CODEN: MCBIB8; ISSN:0300-8177. (Springer)
      A review. With the characterization of Sir2 gene in yeast aging, its mammalian homologs Sirtuins 1-7 have been attracting attention from scientists with various research backgrounds. Among Sirtuins, SIRT1 is the most extensively studied. Recent progress on mammalian Sirtuins has shown that SIRT6 as a histone deacetylase may also play a crit. role in regulating mammalian aging. This review summarizes recent advances on SIRT6 as a key modulator of telomere structure, DNA repair, metab., and NF-kappa B pathway in aging. In addn., we discuss the challenges that remain to be studied in SIRT6 biol.
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    121. 121
      Michan, S.; Sinclair, D. Sirtuins in Mammals: Insights into Their Biological Function. Biochem. J. 2007, 404 (1), 1– 13,  DOI: 10.1042/BJ20070140
      121
      Sirtuins in mammals: Insights into their biological function
      Michan, Shaday; Sinclair, David
      Biochemical Journal (2007), 404 (1), 1-13CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
      A review. Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologs also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiol., since they may provide novel targets for treating diseases assocd. with aging and perhaps extend human lifespan. In this review, we describe our current understanding of the biol. function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacol. targets to delay and treat human age-related diseases.
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    122. 122
      Toiber, D.; Sebastian, C.; Mostoslavsky, R. Characterization of Nuclear Sirtuins: Molecular Mechanisms and Physiological Relevance. Handb. Exp. Pharmacol. 2011, 206, 189– 224,  DOI: 10.1007/978-3-642-21631-2_9
      122
      Characterization of nuclear sirtuins: Molecular mechanisms and physiological relevance
      Toiber, Debra; Sebastian, Carlos; Mostoslavsky, Raul
      Handbook of Experimental Pharmacology (2011), 206 (Histone Deacetylases), 189-224CODEN: HEPHD2; ISSN:0171-2004. (Springer GmbH)
      A review. Sirtuins are protein deacetylases/mono-ADP-ribosyltransferases found in organisms ranging from bacteria to humans. This group of enzymes relies on NAD as a cofactor linking their activity to the cellular metabolic status. Originally found in yeast, sirtuin 2 was discovered as a silencing factor and has been shown to mediate the effects of calorie restriction on lifespan extension. In mammals, 7 homologs (SIRT1-7) exist which evolved to have specific biol. outcomes depending on the particular cellular context, their interacting proteins, and the genomic loci to where they are actively targeted. The biol. roles of sirtuins are highlighted in early lethal phenotypes obsd. in deficient murine models. Here, the authors summarize current concepts on non-metabolic functions for sirtuins, depicting this broad family from yeast to mammals.
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    123. 123
      Ford, E.; Voit, R.; Liszt, G.; Magin, C.; Grummt, I.; Guarente, L. Mammalian Sir2 Homolog SIRT7 Is an Activator of RNA Polymerase I Transcription. Genes Dev. 2006, 20 (9), 1075– 1080,  DOI: 10.1101/gad.1399706
      123
      Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription
      Ford, Ethan; Voit, Renate; Liszt, Gregory; Magin, Cornelia; Grummt, Ingrid; Guarente, Leonard
      Genes & Development (2006), 20 (9), 1075-1080CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)
      We investigated the role of SIRT7, one of the seven members of the mammalian sirtuin family. We show that SIRT7 is a widely expressed nucleolar protein that is assocd. with active rRNA genes (rDNA), where it interacts with RNA polymerase I (Pol I) as well as with histones. Overexpression of SIRT7 increases Pol I-mediated transcription, whereas knockdown of SIRT7 or inhibition of the catalytic activity results in decreased assocn. of Pol I with rDNA and a redn. of Pol I transcription. Depletion of SIRT7 stops cell proliferation and triggers apoptosis. Our findings suggest that SIRT7 is a pos. regulator of Pol I transcription and is required for cell viability in mammals.
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    124. 124
      Kiran, S.; Anwar, T.; Kiran, M.; Ramakrishna, G. Sirtuin 7 in Cell Proliferation, Stress and Disease: Rise of the Seventh Sirtuin!. Cell. Signal. 2015, 27 (3), 673– 682,  DOI: 10.1016/j.cellsig.2014.11.026
      124
      Sirtuin 7 in cell proliferation, stress and disease: Rise of the Seventh Sirtuin!
      Kiran, Shashi; Anwar, Tarique; Kiran, Manjari; Ramakrishna, Gayatri
      Cellular Signalling (2015), 27 (3), 673-682CODEN: CESIEY; ISSN:0898-6568. (Elsevier)
      A review. Sirtuin 7 is a member of the sirtuin family of proteins. Sirtuins were originally discovered in yeast for its role in prolonging replicative lifespan. Until recently SIRT7 happened to be the least studied sirtuin of the seven mammalian sirtuins. However, a no. of recent breakthrough reports have provided significant clarity to SIRT7 biol. SIRT7 is now seen as a vital regulator of rRNA and protein synthesis for maintenance of normal cellular homeostasis. Proteins like p53, H3K18, PAF53, NPM1 and GABP-β1 are the known substrates for the deacetylase activity of SIRT7, thereby making it a key mediator of many cellular activities. Studies using in vitro based assays and also knockout mice have revealed a role of SIRT7 in certain disease pathologies as well. High expression of SIRT7 has been reported in few cancer types and is steadily propelling SIRT7 towards an oncogene status. The role of SIRT7 as a pro-survival adaptor mol. in conditions of cellular stress has recently emerged in view of the fact that SIRT7 can regulate mols. like HIF and IRE1α. Addnl., SIRT7 plays a key role in maintenance of the epigenome as it caused the deacetylation of histone (H3K18) and global proteomics studies have shown its interaction with many chromatin remodelling complexes such as B-WICH and other proteins. Lately, the role of SIRT7 in hepatic lipid metab. has been debated. This review attempts to summarize these recent findings and present the role of SIRT7 as an important cellular regulator.
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    125. 125
      Han, H. Q.; Zhou, X.; Mitch, W. E.; Goldberg, A. L. Myostatin/Activin Pathway Antagonism: Molecular Basis and Therapeutic Potential. Int. J. Biochem. Cell Biol. 2013, 45 (10), 2333– 2347,  DOI: 10.1016/j.biocel.2013.05.019
      125
      Myostatin/activin pathway antagonism: Molecular basis and therapeutic potential
      Han, H. Q.; Zhou, Xiaolan; Mitch, William E.; Goldberg, Alfred L.
      International Journal of Biochemistry & Cell Biology (2013), 45 (10), 2333-2347CODEN: IJBBFU; ISSN:1357-2725. (Elsevier Ltd.)
      A review. Muscle wasting is assocd. with a wide range of catabolic diseases. This debilitating loss of muscle mass and functional capacity reduces the quality of life and increases the risks of morbidity and mortality. Major progress has been made in understanding the biochem. mechanisms and signaling pathways regulating muscle protein balance under normal conditions and the enhanced protein loss in atrophying muscles. It is now clear that activation of myostatin/activin signaling is crit. in triggering the accelerated muscle catabolism that causes muscle loss in multiple disease states. Binding of myostatin and activin to the ActRIIB receptor complex on muscle cell membrane leads to activation of Smad2/3-mediated transcription, which in turn stimulates FoxO-dependent transcription and enhanced muscle protein breakdown via ubiquitin-proteasome system and autophagy. In addn., Smad activation inhibits muscle protein synthesis by suppressing Akt signaling. Pharmacol. blockade of the myostatin/activin-ActRIIB pathway has been shown to prevent or reverse the loss of muscle mass and strength in various disease models including cancer cachexia and renal failure. Moreover, it can markedly prolong the lifespan of animals with cancer-assocd. muscle loss. Furthermore, inhibiting myostatin/activin actions also improves insulin sensitivity, reduces excessive adiposity, attenuates systemic inflammation, and accelerates bone fracture healing in disease models. Based on these exciting advances, the potential therapeutic benefits of myostatin/activin antagonism are now being tested in multiple clin. settings.This article is part of a Directed Issue entitled: Mol. basis of muscle wasting.
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    126. 126
      Sartori, R.; Milan, G.; Patron, M.; Mammucari, C.; Blaauw, B.; Abraham, R.; Sandri, M. Smad2 and 3 Transcription Factors Control Muscle Mass in Adulthood. Am. J. Physiol. Cell Physiol. 2009, 296 (6), C1248,  DOI: 10.1152/ajpcell.00104.2009
      There is no corresponding record for this reference.
    127. 127
      Trendelenburg, A. U.; Meyer, A.; Rohner, D.; Boyle, J.; Hatakeyama, S.; Glass, D. J. Myostatin Reduces Akt/TORC1/P70S6K Signaling, Inhibiting Myoblast Differentiation and Myotube Size. Am. J. Physiol. Cell Physiol. 2009, 296 (6), C1258,  DOI: 10.1152/ajpcell.00105.2009
      There is no corresponding record for this reference.
    128. 128
      McCroskery, S.; Thomas, M.; Maxwell, L.; Sharma, M.; Kambadur, R. Myostatin Negatively Regulates Satellite Cell Activation and Self-Renewal. J. Cell Biol. 2003, 162 (6), 1135– 1147,  DOI: 10.1083/jcb.200207056
      128
      Myostatin negatively regulates satellite cell activation and self-renewal
      McCroskery, Seumas; Thomas, Mark; Maxwell, Linda; Sharma, Mridula; Kambadur, Ravi
      Journal of Cell Biology (2003), 162 (6), 1135-1147CODEN: JCLBA3; ISSN:0021-9525. (Rockefeller University Press)
      Satellite cells are quiescent muscle stem cells that promote postnatal muscle growth and repair. Myostatin, a TGF-β member, signals satellite cell quiescence and also neg. regulates satellite cell self-renewal. BrdU labeling in vivo revealed that, among the Myostatin-deficient satellite cells, higher nos. of satellite cells are activated as compared with wild type. In contrast, addn. of Myostatin to myofiber explant cultures inhibits satellite cell activation. Cell cycle anal. confirms that Myostatin up-regulated p21, a Cdk inhibitor, and decreased the levels and activity of Cdk2 protein in satellite cells. Hence, Myostatin neg. regulates the G1 to S progression and thus maintains the quiescent status of satellite cells. Immunohistochem. anal. with CD34 antibodies indicates that there is an increased no. of satellite cells per unit length of freshly isolated Mstn-/- muscle fibers. Detn. of proliferation rate suggests that this elevation in satellite cell no. could be due to increased self-renewal and delayed expression of the differentiation gene (myogenin) in Mstn-/- adult myoblasts. Taken together, these results suggest that Myostatin is a potent neg. regulator of satellite cell activation and thus signals the quiescence of satellite cells.
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    129. 129
      MAURO, A. Satellite Cell of Skeletal Muscle Fibers. J. Biophys. Biochem. Cytol. 1961, 9 (2), 493– 495,  DOI: 10.1083/jcb.9.2.493
      129
      Satellite cell of skeletal muscle fibers
      MAURO A
      The Journal of biophysical and biochemical cytology (1961), 9 (), 493-5 ISSN:0095-9901.
      There is no expanded citation for this reference.
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    130. 130
      Dhawan, J.; Rando, T. A. Stem Cells in Postnatal Myogenesis: Molecular Mechanisms of Satellite Cell Quiescence, Activation and Replenishment. Trends Cell Biol. 2005, 15 (12), 666– 673,  DOI: 10.1016/j.tcb.2005.10.007
      130
      Stem cells in postnatal myogenesis: molecular mechanisms of satellite cell quiescence, activation and replenishment
      Dhawan, Jyotsna; Rando, Thomas A.
      Trends in Cell Biology (2005), 15 (12), 666-673CODEN: TCBIEK; ISSN:0962-8924. (Elsevier)
      A review. Satellite cells are the primary stem cells in adult skeletal muscle, and are responsible for postnatal muscle growth, hypertrophy and regeneration. In mature muscle, most satellite cells are in a quiescent state, but they activate and begin proliferating in response to extrinsic signals. Following activation, a subset of satellite cell progeny returns to the quiescent state during the process of self-renewal. Here, we review recent studies of satellite cell biol. and focus on the key transitions from the quiescent state to the state of proliferative activation and myogenic lineage progression and back to the quiescent state. The mol. mechanisms of these transitions are considered in the context of the biol. of the satellite cell niche, changes with age, and interactions with established pathways of myogenic commitment and differentiation.
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    131. 131
      Kuang, S.; Gillespie, M. A.; Rudnicki, M. A. Niche Regulation of Muscle Satellite Cell Self-Renewal and Differentiation. Cell Stem Cell 2008, 2 (1), 22– 31,  DOI: 10.1016/j.stem.2007.12.012
      131
      Niche regulation of muscle satellite cell self-renewal and differentiation
      Kuang, Shihuan; Gillespie, Mark A.; Rudnicki, Michael A.
      Cell Stem Cell (2008), 2 (1), 22-31CODEN: CSCEC4; ISSN:1934-5909. (Cell Press)
      A review. Muscle satellite cells have been shown to be a heterogeneous population of committed myogenic progenitors and noncommitted stem cells. This hierarchical compn. of differentiating progenitors and self-renewable stem cells assures the extraordinary regenerative capacity of skeletal muscles. Recent studies have revealed a role for asym. division in satellite cell maintenance and offer novel insights into the regulation of satellite cell function by the niche. A thorough understanding of the mol. regulation and cell fate detn. of satellite cells and other potential stem cells resident in muscle is essential for successful stem cell-based therapies to treat muscular diseases.
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    132. 132
      Ju, C. R.; Chen, R. C. Serum Myostatin Levels and Skeletal Muscle Wasting in Chronic Obstructive Pulmonary Disease. Respir. Med. 2012, 106 (1), 102– 108,  DOI: 10.1016/j.rmed.2011.07.016
      132
      Serum myostatin levels and skeletal muscle wasting in chronic obstructive pulmonary disease
      Ju Chun-Rong; Chen Rong-Chang
      Respiratory medicine (2012), 106 (1), 102-8 ISSN:.
      INTRODUCTION: It is well confirmed that myostatin is a negative regulator of skeletal muscle mass and implicated in several diseases involved in muscle wasting and cachexia. Skeletal muscle wasting is an important systemic manifestation of chronic obstructive pulmonary disease (COPD), while the expression of circulating myostatin in COPD remains unclear. The aim of this study was to investigate the expression of circulating myostatin and its relationship with skeletal muscle wasting in COPD. METHODS: Seventy-one patients with stable COPD and sixty age-matched, healthy control subjects participated in the study. Total skeletal muscle mass (SMM) were calculated according to a validated formula by using age and anthropometric measurements. Serum levels of myostatin, tumor necrosis factor (TNF)-α and interleukin-6 were determined by ELISA. RESULTS: Serum myostatin levels were significantly elevated in COPD patients when compared to controls [(11.85 ± 4.01) ng/ml vs. (7.46 ± 2.21) ng/ml, p < 0.01], while total SMM was significantly decreased in COPD patients when compared to controls [(20.81 ± 1.74) kg vs. (27.31 ± 2.18) kg for male, and (11.70 ± 0.56) kg vs. (19.89 ± 1.47) kg for female] (both p < 0.05). Regression correlation analysis on all COPD patients showed that serum myostatin levels weren't significantly correlated with SMM, but correlated with TNF-α levels (R(2) = 0.042, p = 0.048). However, when stratified for gender, serum myostatin levels were correlated inversely both with SMM (R(2) = 0.20, p = 0.000) and with BMI (R(2) = 0.084, p = 0.019) in subgroup of male patients. CONCLUSION: This study demonstrates that circulating myostatin levels are elevated in COPD and related to SMM in male patients, suggesting that myostatin contributes to skeletal muscle wasting in COPD.
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    133. 133
      Testelmans, D.; Crul, T.; Maes, K.; Agten, A.; Crombach, M.; Decramer, M.; Gayan-Ramirez, G. Atrophy and Hypertrophy Signalling in the Diaphragm of Patients with COPD. Eur. Respir. J. 2010, 35 (3), 549– 556,  DOI: 10.1183/09031936.00091108
      133
      Atrophy and hypertrophy signalling in the diaphragm of patients with COPD
      Testelmans, D.; Crul, T.; Maes, K.; Agten, A.; Crombach, M.; Decramer, M.; Gayan-Ramirez, G.
      European Respiratory Journal (2010), 35 (3), 549-556CODEN: ERJOEI; ISSN:0903-1936. (European Respiratory Society)
      We investigated whether atrophy and hypertrophy signalling were altered in the diaphragm of chronic obstructive pulmonary disease (COPD) patients. We studied diaphragm fiber dimensions and proportion, expression of markers of the ubiquitin-proteasome pathway, nuclear factor (NF)-κB pathways, muscle regulatory factors and myostatin in diaphragm biopsies from 19 patients with severe COPD and 13 patients without COPD. Type I proportion was significantly increased in the diaphragm of COPD patients while type II proportion was decreased. The cross-sectional area of all fiber types was reduced in the COPD patients. In addn., MAFbx mRNA was higher in the diaphragm of COPD patients while Nedd4 mRNA decreased. Cytoplasmatic levels of inhibitor protein IκBα and IκBβ were decreased in the COPD patients as was NF-κB p50 DNA-binding activity. MyoD mRNA and its nuclear protein content were decreased in the diaphragm of COPD patients and myogenin mRNA and protein levels remained unchanged. Myostatin mRNA was decreased but its protein levels in the nuclear and cytoplasmic fraction were significantly increased in the COPD patients. These data show that the ubiquitin-proteasome pathway, the NF-κB pathway and myostatin protein were up-regulated in the diaphragm of COPD patients while MyoD expression was reduced. These alterations may contribute to diaphragm remodeling in COPD.
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    134. 134
      Zhang, D.; Cao, L.; Wang, Z.; Feng, H.; Cai, X.; Xu, M.; Li, M.; Yu, N.; Yin, Y.; Wang, W.; Kang, J. Salidroside Mitigates Skeletal Muscle Atrophy in Rats with Cigarette Smoke-Induced COPD by up-Regulating Myogenin and down-Regulating Myostatin Expression. Biosci. Rep. 2019, 39 (11), BSR20190440,  DOI: 10.1042/BSR20190440
      There is no corresponding record for this reference.
    135. 135
      Carter, M. E.; Brunet, A. FOXO Transcription Factors. Curr. Biol. 2007, 17 (4), R113,  DOI: 10.1016/j.cub.2007.01.008
      135
      FOXO transcription factors
      Carter, Matthew E.; Brunet, Anne
      Current Biology (2007), 17 (4), R113-R114CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)
      There is no expanded citation for this reference.
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    136. 136
      Stitt, T. N.; Drujan, D.; Clarke, B. A.; Panaro, F.; Timofeyva, Y.; Kline, W. O.; Gonzalez, M.; Yancopoulos, G. D.; Glass, D. J. The IGF-1/PI3K/Akt Pathway Prevents Expression of Muscle Atrophy-Induced Ubiquitin Ligases by Inhibiting FOXO Transcription Factors. Mol. Cell 2004, 14 (3), 395– 403,  DOI: 10.1016/S1097-2765(04)00211-4
      136
      The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors
      Stitt, Trevor N.; Drujan, Doreen; Clarke, Brian A.; Panaro, Frank; Timofeyva, Yekatarina; Kline, William O.; Gonzalez, Michael; Yancopoulos, George D.; Glass, David J.
      Molecular Cell (2004), 14 (3), 395-403CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)
      Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the mol. mediators of atrophy and hypertrophy had been reported. The authors demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of MuRF1 and MAFbx upregulation. The authors' study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.
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    137. 137
      Sandri, M.; Sandri, C.; Gilbert, A.; Skurk, C.; Calabria, E.; Picard, A.; Walsh, K.; Schiaffino, S.; Lecker, S. H.; Goldberg, A. L. Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy. Cell 2004, 117 (3), 399– 412,  DOI: 10.1016/S0092-8674(04)00400-3
      137
      Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy
      Sandri, Marco; Sandri, Claudia; Gilbert, Alex; Skurk, Carsten; Calabria, Elisa; Picard, Anne; Walsh, Kenneth; Schiaffino, Stefano; Lecker, Stewart H.; Goldberg, Alfred L.
      Cell (Cambridge, MA, United States) (2004), 117 (3), 399-412CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Skeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-neg. construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a crit. role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting.
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    138. 138
      Doucet, M.; Russell, A. P.; Léger, B.; Debigaré, R.; Joanisse, D. R.; Caron, M. A.; LeBlanc, P.; Maltais, F. Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2007, 176 (3), 261– 269,  DOI: 10.1164/rccm.200605-704OC
      138
      Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease
      Doucet, Marieve; Russell, Aaron P.; Leger, Bertrand; Debigare, Richard; Joanisse, Denis R.; Caron, Marc-Andre; LeBlanc, Pierre; Maltais, Francois
      American Journal of Respiratory and Critical Care Medicine (2007), 176 (3), 261-269CODEN: AJCMED; ISSN:1073-449X. (American Thoracic Society)
      Rationale: The mol. mechanisms of muscle atrophy in chronic obstructive pulmonary disease (COPD) are poorly understood. In wasted animals, muscle mass is regulated by several AKT-related signaling pathways. Objectives: To measure the protein expression of AKT, forkhead box class O (FoxO)-1 and -3, atrogin-1, the phosphophrylated form of AKT, p70S6K glycogen synthase kinase-3β (GSK-3β), eukaryotic translation initiation factor 4E binding protein-1 (4E-BP1), and the mRNA expression of atrogin-1, muscle ring finger (MuRF) protein 1, and FoxO-1 and -3 in the quadriceps of 12 patients with COPD with muscle atrophy and 10 healthy control subjects. Five patients with COPD with preserved muscle mass were subsequently recruited and were compared with six patients with low muscle mass. Methods: Protein contents and mRNA expression were measured by Western blot and quant. polymerase chain reaction, resp. Measurements and Main Results: The levels of atrogin-1 and MuRF1 mRNA, and of phosphorylated AKT and 4E-BP1 and FoxO-1 proteins, were increased in patients with COPD with muscle atrophy compared with healthy control subjects, whereas atrogin-1, p70S6K, GSK-3β, and FoxO-3 protein levels were similar. Patients with COPD with muscle atrophy showed an increased expression of p70S6K, GSK-3β, and 4E-BP1 compared with patients with COPD with preserved muscle mass. Conclusions: An increase in atrogin-1 and MuRF1 mRNA and FoxO-1 protein content was obsd. in the quadriceps of patients with COPD. The transcriptional regulation of atrogin-1 and MuRF1 may occur via FoxO-1, but independently of AKT. The overexpression of the muscle hypertrophic signaling pathways found in patients with COPD with muscle atrophy could represent an attempt to restore muscle mass.
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    139. 139
      Hwang, J.; Rajendrasozhan, S.; Yao, H.; Chung, S.; Sundar, I. K.; Huyck, H. L.; Pryhuber, G. S.; Kinnula, V. L.; Rahman, I. FoxO3 Deficiency Leads to Increased Susceptibility to Cigarette Smoke-Induced Inflammation, Airspace Enlargement, and Chronic Obstructive Pulmonary Disease. J. Immunol. 2011, 187 (2), 987,  DOI: 10.4049/jimmunol.1001861
      139
      FOXO3 Deficiency Leads to Increased Susceptibility to Cigarette Smoke-Induced Inflammation, Airspace Enlargement, and Chronic Obstructive Pulmonary Disease
      Hwang, Jae-woong; Rajendrasozhan, Saravanan; Yao, Hongwei; Chung, Sangwoon; Sundar, Isaac K.; Huyck, Heidie L.; Pryhuber, Gloria S.; Kinnula, Vuokko L.; Rahman, Irfan
      Journal of Immunology (2011), 187 (2), 987-998CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
      Forkhead box class O 3a (FOXO3) is a member of the FoxO transcription factor subfamily, which regulates the expression of target genes not only through DNA binding as a transcription factor, but also through protein-protein interaction. Although FoxO3 is a well-known transcription factor involved in diverse biol. processes, the role of FoxO3 in cigarette smoke (CS)-induced lung inflammation and injury has not been studied. It is, therefore, hypothesized that deficiency of FoxO3 leads to increased susceptibility to CS-induced lung inflammatory response and airspace enlargement. In this article, we show that the levels of FOXO3 are significantly decreased in lungs of smokers and patients with chronic obstructive pulmonary disease, as well as in lungs of mice exposed to CS. Genetic ablation of FoxO3 led to pulmonary emphysema and exaggerated inflammatory response in lungs of mice exposed to CS. We further showed that CS induced the translocation of FoxO3 into the nucleus where FoxO3 interacted with NF-κB and disrupted NF-κB DNA-binding ability, leading to inhibition of its activity. Targeted disruption of FoxO3 also resulted in downregulation of antioxidant genes in mouse lungs in response to CS exposure. These results suggest that FoxO3 plays a pivotal role in regulation of lung inflammatory response and antioxidant genes, and deficiency of FoxO3 results in development of chronic obstructive pulmonary disease/emphysema.
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    140. 140
      Shi, J.; Yin, N.; Xuan, L. L.; Yao, C. S.; Meng, A. M.; Hou, Q. Vam3, a Derivative of Resveratrol, Attenuates Cigarette Smoke-Induced Autophagy. Acta Pharmacol. Sin. 2012, 33 (7), 888– 896,  DOI: 10.1038/aps.2012.73
      140
      Vam3, a derivative of resveratrol, attenuates cigarette smoke-induced autophagy
      Shi, Ji; Yin, Ning; Xuan, Ling-ling; Yao, Chun-suo; Meng, Ai-min; Hou, Qi
      Acta Pharmacologica Sinica (2012), 33 (7), 888-896CODEN: APSCG5; ISSN:1671-4083. (Nature Publishing Group)
      To appraise the efficacy of Vam3 (Amurensis H), a dimeric deriv. of resveratrol, at inhibiting cigarette smoke-induced autophagy. Human bronchial epithelial cells were treated with cigarette smoke condensates, and a chronic obstructive pulmonary disease (COPD) model was established by exposing male BALB/c mice to cigarette smoke. The protein levels of the autophagic marker microtubule-assocd. protein 1A/1B-light chain 3 (LC3), Sirtuin 1 (Sirt1), and foxhead box O 3a (FoxO3a) were examd. using Western blotting and Immunohistochem. LC3 punctae were detected by immunofluorescence. The levels of FoxO3a acetylation were examd. by immunopptn. The level of intracellular oxidn. was assessed by detecting ROS and GSH-Px. Results: Vam3 attenuated cigarette smoke condensate-induced autophagy in human bronchial epithelial cells, and restored the expression levels of Sirt1 and FoxO3a that had been reduced by cigarette smoke condensates. Similar protective effects of Vam3, reducing autophagy and restoring the levels of Sirt1 and FoxO3a, were obsd. in the COPD animal model. Addnl., Vam3 also diminished the oxidative stress that was induced by the cigarette smoke condensates. Conclusion: Vam3 decreases cigarette smoke-induced autophagy via up-regulating/restoring the levels of Sirt1 and FoxO3a and inhibiting the induced oxidative stress.
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    141. 141
      Handschin, C.; Spiegelman, B. M. Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Coactivators, Energy Homeostasis, and Metabolism. Endocr. Rev. 2006, 27 (7), 728– 735,  DOI: 10.1210/er.2006-0037
      141
      Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism
      Handschin, Christoph; Spiegelman, Bruce M.
      Endocrine Reviews (2006), 27 (7), 728-735CODEN: ERVIDP; ISSN:0163-769X. (Endocrine Society)
      A review. Many biol. programs are regulated at the transcriptional level. This is generally achieved by the concerted actions of several transcription factors. Recent findings have shown that, in many cases, transcriptional coactivators coordinate the overall regulation of the biol. programs. One of the best-studied examples of coactivator control of metabolic pathways is the peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) family. These proteins are strong activators of mitochondrial function and are thus dominant regulators of oxidative metab. in a variety of tissues. The PGC-1 coactivators themselves are subject to powerful regulation at the transcriptional and posttranslational levels. Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration.
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    142. 142
      St-Pierre, J.; Lin, J.; Krauss, S.; Tarr, P. T.; Yang, R.; Newgard, C. B.; Spiegelman, B. M. Bioenergetic Analysis of Peroxisome Proliferator-Activated Receptor γ Coactivators 1α and 1β (PGC-1α and PGC-1β) in Muscle Cells. J. Biol. Chem. 2003, 278 (29), 26597– 26603,  DOI: 10.1074/jbc.M301850200
      142
      Bioenergetic Analysis of Peroxisome Proliferator-activated Receptor γ Coactivators 1α and 1β (PGC-1α and PGC-1β) in Muscle Cells
      St-Pierre, Julie; Lin, Jiandie; Krauss, Stefan; Tarr, Paul T.; Yang, Ruojing; Newgard, Christopher B.; Spiegelman, Bruce M.
      Journal of Biological Chemistry (2003), 278 (29), 26597-26603CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α is a coactivator of nuclear receptors and other transcription factors that regulates several components of energy metab., particularly certain aspects of adaptive thermogenesis in brown fat and skeletal muscle, hepatic gluconeogenesis, and fiber type switching in skeletal muscle. PGC-1α has been shown to induce mitochondrial biogenesis when expressed in muscle cells, and preliminary anal. has suggested that this mol. may specifically increase the fraction of uncoupled vs. coupled respiration. In this paper, we have performed detailed bioenergetic analyses of the function of PGC-1α and its homolog PGC-1β in muscle cells by monitoring simultaneously oxygen consumption and membrane potential. Cells expressing PGC-1α or PGC-1β display higher proton leak rates at any given membrane potential than control cells. However, cells expressing PGC-1α have a higher proportion of their mitochondrial respiration linked to proton leak than cells expressing PGC-1β. Although these two proteins cause a similar increase in the expression of many mitochondrial genes, PGC-1β preferentially induces certain genes involved in the removal of reactive oxygen species, recently recognized as activators of uncoupling proteins. Together, these data indicate that PGC-1α and PGC-1β profoundly alter mitochondrial metab. and suggest that these proteins are likely to play different physiol. functions.
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    143. 143
      St-Pierre, J.; Drori, S.; Uldry, M.; Silvaggi, J. M.; Rhee, J.; Jäger, S.; Handschin, C.; Zheng, K.; Lin, J.; Yang, W.; Simon, D. K.; Bachoo, R.; Spiegelman, B. M. Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators. Cell 2006, 127 (2), 397– 408,  DOI: 10.1016/j.cell.2006.09.024
      143
      Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators
      St-Pierre, Julie; Drori, Stavit; Uldry, Marc; Silvaggi, Jessica M.; Rhee, James; Jager, Sibylle; Handschin, Christoph; Zheng, Kangni; Lin, Jiandie; Yang, Wenli; Simon, David K.; Bachoo, Robert; Spiegelman, Bruce M.
      Cell (Cambridge, MA, United States) (2006), 127 (2), 397-408CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      PPARγ coactivator 1α (PGC-1α) is a potent stimulator of mitochondrial biogenesis and respiration. Since the mitochondrial electron transport chain is the main producer of reactive oxygen species (ROS) in most cells, we examd. the effect of PGC-1α on the metab. of ROS. PGC-1α is co-induced with several key ROS-detoxifying enzymes upon treatment of cells with an oxidative stressor; studies with RNAi or null cells indicate that PGC-1α is required for the induction of many ROS-detoxifying enzymes, including GPx1 and SOD2. PGC-1α null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, resp. Increasing PGC-1α levels dramatically protects neural cells in culture from oxidative-stressor-mediated death. These studies reveal that PGC-1α is a broad and powerful regulator of ROS metab., providing a potential target for the therapeutic manipulation of these important endogenous toxins.
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    144. 144
      Valle, I.; Álvarez-Barrientos, A.; Arza, E.; Lamas, S.; Monsalve, M. PGC-1alpha Regulates the Mitochondrial Antioxidant Defense System in Vascular Endothelial Cells. Cardiovasc. Res. 2005, 66 (3), 562– 573,  DOI: 10.1016/j.cardiores.2005.01.026
      144
      PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells
      Valle, Inmaculada; Alvarez-Barrientos, Alberto; Arza, Elvira; Lamas, Santiago; Monsalve, Maria
      Cardiovascular Research (2005), 66 (3), 562-573CODEN: CVREAU; ISSN:0008-6363. (Elsevier B.V.)
      Objective: Mitochondrial prodn. of oxidants contributes to a variety of pathol. conditions including the vascular complications of diabetes, neurodegenerative diseases, and cellular senescence. The authors postulated that a transcriptional coactivator, peroxisome proliferator activated receptor-γ coactivator 1α (PGC-1α), a major regulator of oxidative metab. and mitochondrial biogenesis, could be involved in the transcriptional regulation of the mitochondrial antioxidant defense system in vascular endothelial cells. Methods and results: The authors show that PGC-1α is present in human, bovine, and mouse endothelial cells and pos. modulates the expression of the mitochondrial detoxification system. Endothelial cells that overexpress PGC-1α show reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death both in basal and oxidative stress conditions. Downregulation of PGC-1α levels by siRNA reduces the expression of mitochondrial detoxification proteins. Conclusions: These results unveil a novel regulatory pathway that links mitochondrial activity and mitochondrial oxidative stress protective systems. In addn., they suggest that PGC-1α could play a crucial protective role in vascular complications of diabetes, where the mitochondrial metab. of glucose has been shown to result in oxidative stress and vascular endothelial cell dysfunction.
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    145. 145
      Schrader, M.; Yoon, Y. Mitochondria and Peroxisomes: Are the ‘Big Brother’ and the ‘Little Sister’ Closer than Assumed?. BioEssays 2007, 29 (11), 1105– 1114,  DOI: 10.1002/bies.20659
      145
      Mitochondria and peroxisomes: are the 'big brother' and the 'little sister' closer than assumed?
      Schrader, Michael; Yoon, Yisang
      BioEssays (2007), 29 (11), 1105-1114CODEN: BIOEEJ; ISSN:0265-9247. (John Wiley & Sons, Inc.)
      A review. Mitochondria and peroxisomes are essential subcellular organelles in mammals. Despite obvious differences, both organelles display certain morphol. and functional similarities. Recent studies have elucidated that these highly dynamic and plastic organelles share components of their division machinery. Mitochondria and peroxisomes are metabolically linked organelles, which are cooperating and cross-talking. This review addresses the dynamics and division of mitochondria and peroxisomes as well as their functional similarities to provide insight as to why these organelles share the fission machinery in evolutionary aspects.
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    146. 146
      Wu, Z.; Puigserver, P.; Andersson, U.; Zhang, C.; Adelmant, G.; Mootha, V.; Troy, A.; Cinti, S.; Lowell, B.; Scarpulla, R. C.; Spiegelman, B. M. Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1. Cell 1999, 98 (1), 115– 124,  DOI: 10.1016/S0092-8674(00)80611-X
      146
      Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
      Wu, Zhidan; Puigserver, Pere; Andersson, Ulf; Zhang, Chenyu; Adelmant, Guillaume; Mootha, Vamsi; Troy, Amy; Cinti, Saverio; Lowell, Bradford; Scarpulla, Richard C.; Spiegelman, Bruce M.
      Cell (Cambridge, Massachusetts) (1999), 98 (1), 115-124CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Mitochondrial no. and function are altered in response to external stimuli in eukaryotes. While several transcription/replication factors directly regulate mitochondrial genes, the coordination of these factors into a program responsive to the environment is not understood. We show here that PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs). PGC-1 stimulates a powerful induction of NRF-1 and NRF-2 gene expression; in addn., PGC-1 binds to and coactivates the transcriptional function of NRF-1 on the promoter for mitochondrial transcription factor A (mtTFA), a direct regulator of mitochondrial DNA replication/transcription. These data elucidate a pathway that directly links external physiol. stimuli to the regulation of mitochondrial biogenesis and function.
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    147. 147
      Chepelev, N. L.; Enikanolaiye, M. I.; Chepelev, L. L.; Almohaisen, A.; Chen, Q.; Scoggan, K. A.; Coughlan, M. C.; Cao, X. L.; Jin, X.; Willmore, W. G. Bisphenol A Activates the Nrf1/2-Antioxidant Response Element Pathway in HEK 293 Cells. Chem. Res. Toxicol. 2013, 26 (3), 498– 506,  DOI: 10.1021/tx400036v
      147
      Bisphenol A Activates the Nrf1/2-Antioxidant Response Element Pathway in HEK 293 Cells
      Chepelev, Nikolai L.; Enikanolaiye, Mutiat I.; Chepelev, Leonid L.; Almohaisen, Abdulrahman; Chen, QiXuan; Scoggan, Kylie A.; Coughlan, Melanie C.; Cao, Xu-Liang; Jin, Xiaolei; Willmore, William G.
      Chemical Research in Toxicology (2013), 26 (3), 498-506CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
      Bisphenol A (BPA) is used in the prodn. of polycarbonate plastics and epoxy resins for baby bottles, liners of canned food, and many other consumer products. Previously, BPA has been shown to reduce the activity of several antioxidant enzymes, which may contribute to oxidative stress. However, the underlying mechanism of the BPA-mediated effect upon antioxidant enzyme activity is unknown. Antioxidant and phase II metabolizing enzymes protect cells from oxidative stress and are transcriptionally activated by Nrf1 and Nrf2 factors through their cis-regulatory antioxidant response elements (AREs). In this work, we have assessed the effect of BPA on the Nrf1/2-ARE pathway in cultured human embryonic kidney (HEK) 293 cells. Surprisingly, glutathione and reactive oxygen species assays revealed that BPA application created a more reduced intracellular environment in cultured HEK 293 cells. Furthermore, BPA increased the transactivation activity of ectopic Nrf1 and Nrf2 and increased the expression of ARE-target genes ho-1 and nqo1 at high (100-200 μM) BPA concns. only. Our study suggests that BPA activates the Nrf1/2-ARE pathway at high (>10 μM) micromolar concns.
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    148. 148
      Austin, S.; St-Pierre, J. PGC1α and Mitochondrial Metabolism-Emerging Concepts and Relevance in Ageing and Neurodegenerative Disorders. J. Cell Sci. 2012, 125 (21), 4963– 4971,  DOI: 10.1242/jcs.113662
      148
      PGC1α and mitochondrial metabolism - emerging concepts and relevance in ageing and neurodegenerative disorders
      Austin, Shane; St-Pierre, Julie
      Journal of Cell Science (2012), 125 (21), 4963-4971CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
      A review. PGC1α is a transcriptional coactivator that is a central inducer of mitochondrial biogenesis in cells. Recent work highlighted that PGC1α can also modulate the compn. and functions of individual mitochondria. Therefore, it is emerging that PGC1α is controlling global oxidative metab. by performing two types of remodelling: (1) cellular remodelling through mitochondrial biogenesis, and (2) organelle remodelling through alteration in the intrinsic properties of mitochondria. The elevated oxidative metab. assocd. with increased PGC1α activity could be accompanied by an increase in reactive oxygen species (ROS) that are primarily generated by mitochondria. However, increasing evidence suggests that this is not the case, as PGC1α is also a powerful regulator of ROS removal by increasing the expression of numerous ROS-detoxifying enzymes. Therefore, PGC1α, by controlling both the induction of mitochondrial metab. and the removal of its ROS byproducts, would elevate oxidative metab. and minimize the impact of ROS on cell physiol. In this Commentary, we discuss how the biogenesis and remodelling of mitochondria that are elicited by PGC1α contribute to an increase in oxidative metab. and the preservation of ROS homeostasis. Finally, we examine the importance of these findings in ageing and neurodegenerative disorders, conditions that are assocd. with impaired mitochondrial functions and ROS balance.
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    149. 149
      Sandri, M.; Lin, J.; Handschin, C.; Yang, W.; Arany, Z. P.; Lecker, S. H.; Goldberg, A. L.; Spiegelman, B. M. PGC-1alpha Protects Skeletal Muscle from Atrophy by Suppressing FoxO3 Action and Atrophy-Specific Gene Transcription. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (44), 16260– 16265,  DOI: 10.1073/pnas.0607795103
      149
      PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription
      Sandri, Marco; Lin, Jiandie; Handschin, Christoph; Yang, Wenli; Arany, Zoltan P.; Lecker, Stewart H.; Goldberg, Alfred L.; Spiegelman, Bruce M.
      Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (44), 16260-16265CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Maintaining muscle size and fiber compn. requires contractile activity. Increased activity stimulates expression of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which promotes fiber-type switching from glycolytic toward more oxidative fibers. In response to disuse or denervation, but also in fasting and many systemic diseases, muscles undergo marked atrophy through a common set of transcriptional changes. FoxO family transcription factors play a crit. role in this loss of cell protein, and when activated, FoxO3 causes expression of the atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 and profound loss of muscle mass. To understand how exercise might retard muscle atrophy, we investigated the possible interplay between PGC-1α and the FoxO family in regulation of muscle size. Rodent muscles showed a large decrease in PGC-1α mRNA during atrophy induced by denervation as well as by cancer cachexia, diabetes, and renal failure. Furthermore, in transgenic mice overexpressing PGC-1α, denervation and fasting caused a much smaller decrease in muscle fiber diam. and a smaller induction of atrogin-1 and MuRF-1 than in control mice. Increased expression of PGC-la also increased mRNA for several genes involved in energy metab. whose expression decreases during atrophy. Transfection of PGC-1α into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter. Thus, the high levels of PGC-1α in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1α during atrophy should enhance the FoxO-dependent loss of muscle mass.
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    150. 150
      Brault, J. J.; Jespersen, J. G.; Goldberg, A. L. Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1alpha or 1beta Overexpression Inhibits Muscle Protein Degradation, Induction of Ubiquitin Ligases, and Disuse Atrophy. J. Biol. Chem. 2010, 285 (25), 19460– 19471,  DOI: 10.1074/jbc.M110.113092
      150
      Peroxisome Proliferator-activated Receptor γ Coactivator 1α or 1β Overexpression Inhibits Muscle Protein Degradation, Induction of Ubiquitin Ligases, and Disuse Atrophy
      Brault, Jeffrey J.; Jespersen, Jakob G.; Goldberg, Alfred L.
      Journal of Biological Chemistry (2010), 285 (25), 19460-19471CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Overexpression of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), like exercise, increases mitochondrial content and inhibits muscle atrophy. To understand these actions, we tested whether PGC-1α or its close homolog, PGC-1β, influences muscle protein turnover. In myotubes, overexpression of either coactivator increased protein content by decreasing overall protein degrdn. without altering protein synthesis rates. Elevated PGC-1α or PGC-1β also prevented the acceleration of proteolysis induced by starvation or FoxO transcription factors and prevented the induction of autophagy and atrophy-specific ubiquitin ligases by a constitutively active FoxO3. In mouse muscles, overexpression of PGC-1β (like PGC-1α) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFκB. However, increasing muscle PGC-1α levels pharmacol. by treatment of mice with 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside failed to block loss of muscle mass or induction of ubiquitin ligases upon denervation atrophy, although it prevented loss of mitochondria. This capacity of PGC-1α and PGC-1β to inhibit FoxO3 and NFκB actions and proteolysis helps explain how exercise prevents muscle atrophy.
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    151. 151
      Houten, S. M.; Auwerx, J. PGC-1alpha: Turbocharging Mitochondria. Cell 2004, 119 (1), 5– 7,  DOI: 10.1016/j.cell.2004.09.016
      151
      PGC-1α: Turbocharging mitochondria
      Houten, Sander M.; Auwerx, Johan
      Cell (Cambridge, MA, United States) (2004), 119 (1), 5-7CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      A review. PGC-1α plays essential and diverse functions in the control of metab. ranging from mitochondrial biogenesis and respiration to hepatic gluconeogenesis and muscle fiber-type switching. In a paper by Lin et al., the characterization of PGC-1α-/- mice illustrates these pleiotropic functions and reveals an unexpected role for PGC-1α in the brain.
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    152. 152
      Giralt, A.; Hondares, E.; Villena, J. A.; Ribas, F.; Díaz-Delfín, J.; Giralt, M.; Iglesias, R.; Villarroya, F. Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Controls Transcription of the Sirt3 Gene, an Essential Component of the Thermogenic Brown Adipocyte Phenotype. J. Biol. Chem. 2011, 286 (19), 16958,  DOI: 10.1074/jbc.M110.202390
      152
      Peroxisome proliferator-activated receptor-γ coactivator-1α controls transcription of the Sirt3 gene, an essential component of the thermogenic brown adipocyte phenotype
      Giralt, Albert; Hondares, Elayne; Villena, Josep A.; Ribas, Francesc; Diaz-Delfin, Julieta; Giralt, Marta; Iglesias, Roser; Villarroya, Francesc
      Journal of Biological Chemistry (2011), 286 (19), 16958-16966CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Sirt3 protein, a member of the sirtuin family of protein deacetylases with multiple actions on metab. and gene expression, was expressed in assocn. with brown adipocyte differentiation. Using Sirt3-null brown adipocytes, the authors detd. that Sirt3 was required for an appropriate responsiveness of cells to noradrenergic, cAMP-mediated activation of the expression of brown adipose tissue thermogenic genes. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) induced Sirt3 gene expression in white adipocytes and embryonic fibroblasts as part of its overall induction of a brown adipose tissue-specific pattern of gene expression. In cells lacking Sirt3, PGC-1α failed to fully induce the expression of brown fat-specific thermogenic genes. Pgc-1α activated Sirt3 gene transcription through coactivation of orphan nuclear receptor Errα, which bound the proximal Sirt3 gene promoter region. Errα knockdown assays indicated that Errα was required for full induction of Sirt3 gene expression in response to PGC-1α. The present results indicate that PGC-1α controls Sirt3 gene expression and this action is an essential component of the overall mechanisms by which PGC-1α induces the full acquisition of a brown adipocyte differentiated phenotype.
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    153. 153
      Lovering, R. M.; O’Neill, A.; Muriel, J. M.; Prosser, B. L.; Strong, J.; Bloch, R. J. Physiology, Structure, and Susceptibility to Injury of Skeletal Muscle in Mice Lacking Keratin 19-Based and Desmin-Based Intermediate Filaments. Am. J. Physiol. - Cell Physiol. 2011, 300 (4), C803,  DOI: 10.1152/ajpcell.00394.2010
      There is no corresponding record for this reference.
    154. 154
      Marzuca-Nassr, G. N.; Vitzel, K. F.; Mancilla-Solorza, E.; Márquez, J. L. Sarcomere Structure: The Importance of Desmin Protein in Muscle Atrophy. Int. J. Morphol. 2018, 36 (2), 576– 583,  DOI: 10.4067/S0717-95022018000200576
      There is no corresponding record for this reference.
    155. 155
      Sheu, S. S.; Nauduri, D.; Anders, M. W. Targeting Antioxidants to Mitochondria: A New Therapeutic Direction. Biochim. Biophys. Acta 2006, 1762 (2), 256– 265,  DOI: 10.1016/j.bbadis.2005.10.007
      155
      Targeting antioxidants to mitochondria: A new therapeutic direction
      Sheu, Shey-Shing; Nauduri, Dhananjaya; Anders, M. W.
      Biochimica et Biophysica Acta, Molecular Basis of Disease (2006), 1762 (2), 256-265CODEN: BBADEX; ISSN:0925-4439. (Elsevier B.V.)
      A review. Mitochondria play an important role in controlling the life and death of a cell. Consequently, mitochondrial dysfunction leads to a range of human diseases such as ischemia-reperfusion injury, sepsis, and diabetes. Although the mol. mechanisms responsible for mitochondria-mediated disease processes are not fully elucidated yet, the oxidative stress appears to be crit. Accordingly, strategies are being developed for the targeted delivery of antioxidants to mitochondria. In this review, we shall briefly discuss cellular reactive oxygen species metab. and its role in pathophysiol.; the currently existing antioxidants and possible reasons why they are not effective in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially targeted antioxidants and their future promise for disease treatment.
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    156. 156
      Paul, C.; Manero, F.; Gonin, S.; Kretz-Remy, C.; Virot, S.; Arrigo, A.-P. Hsp27 as a Negative Regulator of Cytochrome c Release. Mol. Cell. Biol. 2002, 22 (3), 816,  DOI: 10.1128/MCB.22.3.816-834.2002
      156
      Hsp27 as a negative regulator of cytochrome c release
      Paul, Catherine; Manero, Florence; Gonin, Sandrine; Kretz-Remy, Carole; Virot, Sophie; Arrigo, Andre-Patrick
      Molecular and Cellular Biology (2002), 22 (3), 816-834CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
      We previously showed that Hsp27 protects against apoptosis through its interaction with cytosolic cytochrome c. We have revisited this protective activity in murine cell lines expressing different levels of Hsp27. We report that Hsp27 also interferes, in a manner dependent on level of expression, with the release of cytochrome c from mitochondria. Moreover, a decreased level of endogenous Hsp27, which sensitized HeLa cells to apoptosis, reduced the delay required for cytochrome c release and procaspase 3 activation. The mol. mechanism regulating this function of Hsp27 is unknown. In our cell systems, Hsp27 is mainly cytosolic and only a small fraction of this protein colocalized with mitochondria. Moreover, we show that only a very small fraction of cytochrome c interacts with Hsp27, hence excluding a role of this interaction in the retention of cytochrome c in mitochondria. We also report that Bid intracellular relocalization was altered by changes in Hsp27 level of expression, suggesting that Hsp27 interferes with apoptotic signals upstream of mitochondria. We therefore investigated if the ability of Hsp27 to act as an expression-dependent modulator of F-actin microfilaments integrity was linked to the retention of cytochrome c in mitochondria. We show here that the F-actin depolymg. agent cytochalasin D rapidly induced the release of cytochrome c from mitochondria and caspase activation. This phenomenon was delayed in cells pretreated with the F-actin stabilizer phalloidin and in cells expressing a high level of Hsp27. This suggests the existence of an apoptotic signaling pathway linking cytoskeleton damages to mitochondria. This pathway, which induces Bid intracellular redistribution, is neg. regulated by the ability of Hsp27 to protect F-actin network integrity. However, this upstream pathway is probably not the only one to be regulated by Hsp27 since, in staurosporine-treated cells, phalloidin only partially inhibited cytochrome c release and caspase activation. Moreover, in etoposide-treated cells, Hsp27 still delayed the release of cytochrome c from mitochondria and Bid intracellular redistribution in conditions where F-actin was not altered.
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    157. 157
      Bruey, J. M.; Ducasse, C.; Bonniaud, P.; Ravagnan, L.; Susin, S. A.; Diaz-Latoud, C.; Gurbuxani, S.; Arrigo, A. P.; Kroemer, G.; Solary, E.; Garrido, C. Hsp27 Negatively Regulates Cell Death by Interacting with Cytochrome C. Nat. Cell Biol. 2000, 2 (9), 645– 652,  DOI: 10.1038/35023595
      157
      Hsp27 negatively regulates cell death by interacting with cytochrome c
      Bruey, Jean-Marie; Ducasse, Cecile; Bonniaud, Philippe; Ravagnan, Luigi; Susin, Santos A.; Diaz-Latoud, Chantal; Gurbuxani, Sandeep; Arrigo, Andre-Patrick; Kroemer, Guido; Solary, Eric; Garrido, Carmen
      Nature Cell Biology (2000), 2 (9), 645-652CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)
      Mammalian cells respond to stress by accumulating or activating a set of highly conserved proteins known as heat-shock proteins (HSPs). Several of these proteins interfere neg. with apoptosis. We show that the small HSP known as Hsp27 inhibits cytochrome-c-mediated activation of caspases in the cytosol. Hsp27 does not interfere with granzyme-B-induced activation of caspases, nor with apoptosis-inducing factor-mediated, caspase-independent, nuclear changes. Hsp27 binds to cytochrome c released from the mitochondria to the cytosol and prevents cytochrome-c-mediated interaction of Apaf-1 with procaspase-9. Thus, Hsp27 interferes specifically with the mitochondrial pathway of caspase-dependent cell death.
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    158. 158
      Kim, E. C.; Kim, J. R. Senotherapeutics: Emerging Strategy for Healthy Aging and Age-Related Disease. BMB Rep. 2019, 52 (1), 47– 55,  DOI: 10.5483/BMBRep.2019.52.1.293
      158
      Senotherapeutics: emerging strategy for healthy aging and age-related disease
      Kim, Eok-Cheon; Kim, Jae-Ryong
      BMB Reports (2019), 52 (1), 47-55CODEN: BRMEC2; ISSN:1976-670X. (Korean Society for Biochemistry and Molecular Biology)
      Cellular senescence (CS) is one of hallmarks of aging and accumulation of senescent cells (SCs) with age contributes to tissue or organismal aging, as well as the pathophysiologies of diverse age-related diseases (ARDs). Genetic ablation of SCs in tissues lengthened health span and reduced the risk of age-related pathologies in a mouse model, suggesting a direct link between SCs, longevity, and ARDs. Therefore, senotherapeutics, medicines targeting SCs, might be an emerging strategy for the extension of health span, and prevention or treatment of ARDs. Senotherapeutics are classified as senolytics which kills SCs selectively; senomorphics which modulate functions and morphol. of SCs to those of young cells, or delays the progression of young cells to SCs in tissues; and immune-system mediators of the clearance of SCs. Some senolytics and senomorphics have been proven to markedly prevent or treat ARDs in animal models. This review will present the current status of the development of senotherapeutics, in relation to aging itself and ARDs. Finally, future directions and opportunities for senotherapeutics use will discussed. This knowledge will provide information that can be used to develop novel senotherapeutics for health span and ARDs.
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    159. 159
      Baker, D. J.; Wijshake, T.; Tchkonia, T.; Lebrasseur, N. K.; Childs, B. G.; Van De Sluis, B.; Kirkland, J. L.; Van Deursen, J. M. Clearance of P16Ink4a-Positive Senescent Cells Delays Ageing-Associated Disorders. Nature 2011, 479 (7372), 232– 236,  DOI: 10.1038/nature10600
      159
      Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
      Baker, Darren J.; Wijshake, Tobias; Tchkonia, Tamar; LeBrasseur, Nathan K.; Childs, Bennett G.; van de Sluis, Bart; Kirkland, James L.; van Deursen, Jan M.
      Nature (London, United Kingdom) (2011), 479 (7372), 232-236CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive aging remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumor cells. Senescent cells accumulate in various tissues and organs with aging and were hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-pos. senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-pos. senescent cells upon drug treatment. In tissues-such as adipose tissue, skeletal muscle and eye-in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
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    160. 160
      Culpitt, S. V.; Rogers, D. F.; Shah, P.; De Matos, C.; Russell, R. E. K.; Donnelly, L. E.; Barnes, P. J. Impaired Inhibition by Dexamethasone of Cytokine Release by Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2003, 167 (1), 24– 31,  DOI: 10.1164/rccm.200204-298OC
      160
      Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease
      Culpitt Sarah V; Rogers Duncan F; Shah Pallav; De Matos Carmen; Russell Richard E K; Donnelly Louise E; Barnes Peter J
      American journal of respiratory and critical care medicine (2003), 167 (1), 24-31 ISSN:1073-449X.
      Chronic obstructive pulmonary disease (COPD) is characterized by inflammation of the respiratory tract in which macrophages are the predominant inflammatory cell and for which the efficacy of treatment with corticosteroids is controversial. We investigated the effect of dexamethasone on basal and interleukin (IL)-1beta or cigarette smoke media (CSM)-stimulated release of IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF) by bronchoalveolar lavage macrophages from cigarette smokers and patients with COPD (n = 15). Basal release of IL-8 was approximately fivefold greater in patients with COPD than smokers, whereas GM-CSF was similar for each group. IL-1beta and CSM increased IL-8 and GM-CSF release by macrophages from both smokers and patients with COPD. Dexamethasone did not inhibit basal or stimulated IL-8 release from macrophages from patients with COPD but inhibited release in smokers. In contrast, basal and IL-1beta-stimulated GM-CSF release, but not CSM-stimulated release, was inhibited by dexamethasone. We conclude that the lack of efficacy of corticosteroids in COPD might be due to the relative steroid insensitivity of macrophages in the respiratory tract.
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    161. 161
      Hogg, J. C.; Chu, F.; Utokaparch, S.; Woods, R.; Elliott, W. M.; Buzatu, L.; Cherniack, R. M.; Rogers, R. M.; Sciurba, F. C.; Coxson, H. O.; Paré, P. D. The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 2004, 350 (26), 2645– 2653,  DOI: 10.1056/NEJMoa032158
      161
      The nature of small-airway obstruction in chronic obstructive pulmonary disease
      Hogg, James C.; Chu, Fanny; Utokaparch, Soraya; Woods, Ryan; Elliott, W. Mark; Buzatu, Liliana; Cherniack, Ruben M.; Rogers, Robert M.; Sciurba, Frank C.; Coxson, Harvey O.; Pare, Peter D.
      New England Journal of Medicine (2004), 350 (26), 2645-2653CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
      BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health problem assocd. with long-term exposure to toxic gases and particles. We examd. the evolution of the pathol. effects of airway obstruction in patients with COPD. METHODS: The small airways were assessed in surgically resected lung tissue from 159 patients -39 with stage 0 (at risk), 39 with stage 1, 22 with stage 2, 16 with stage 3, and 43 with stage 4 (very severe) COPD, according to the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). RESULTS: The progression of COPD was strongly assocd. with an increase in the vol. of tissue in the wall (P<0.001) and the accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways. The percentage of the airways that contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells (P<0.001), and lymphoid aggregates contg. follicles (P=0.003) and the abs. vol. of B cells (P=0.03) and CD8 cells (P=0.02) also increased as COPD progressed. CONCLUSIONS: Progression of COPD is assocd. with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles. These changes are coupled to a repair or remodeling process that thickens the walls of these airways.
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    162. 162
      Barnes, P. J. Chronic Obstructive Pulmonary Disease: Effects beyond the Lungs. PLoS Med. 2010, 7 (3), e1000220,  DOI: 10.1371/journal.pmed.1000220
      There is no corresponding record for this reference.
    163. 163
      Taylor, A. E.; Finney-Hayward, T. K.; Quint, J. K.; Thomas, C. M. R.; Tudhope, S. J.; Wedzicha, J. A.; Barnes, P. J.; Donnelly, L. E. Defective Macrophage Phagocytosis of Bacteria in COPD. Eur. Respir. J. 2010, 35 (5), 1039– 1047,  DOI: 10.1183/09031936.00036709
      163
      Defective macrophage phagocytosis of bacteria in COPD
      Taylor A E; Finney-Hayward T K; Quint J K; Thomas C M R; Tudhope S J; Wedzicha J A; Barnes P J; Donnelly L E
      The European respiratory journal (2010), 35 (5), 1039-47 ISSN:.
      Exacerbations of chronic obstructive pulmonary disease (COPD) are an increasing cause of hospitalisations and are associated with accelerated progression of airflow obstruction. Approximately half of COPD exacerbations are associated with bacteria and many patients have lower airways colonisation. This suggests that bacterial infection in COPD could be due to reduced pathogen removal. This study investigated whether bacterial clearance by macrophages is defective in COPD. Phagocytosis of fluorescently labelled polystyrene beads and Haemophillus influenzae and Streptococcus pneumoniae by alveolar macrophages and monocyte-derived macrophages (MDM) was assessed by fluorimetry and flow cytometry. Receptor expression was measured by flow cytometry. Alveolar macrophages and MDM phagocytosed polystyrene beads similarly. There was no difference in phagocytosis of beads by MDM from COPD patients compared with cells from smokers and nonsmokers. MDM from COPD patients showed reduced phagocytic responses to S. pneumoniae and H. influenzae compared with nonsmokers and smokers. This was not associated with alterations in cell surface receptor expression of toll-like receptor (TLR)2, TLR4, macrophage receptor with collagenous structure, cluster of differentiation (CD)163, CD36 or mannose receptor. Budesonide, formoterol or azithromycin did not suppress phagocytosis suggesting that reduced responses in COPD MDM were not due to medications. COPD macrophage innate responses are suppressed and may lead to bacterial colonisation and increased exacerbation frequency.
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    164. 164
      Nakamaru, Y.; Vuppusetty, C.; Wada, H.; Milne, J. C.; Ito, M.; Rossios, C.; Elliot, M.; Hogg, J.; Kharitonov, S.; Goto, H.; Bemis, J. E.; Elliott, P.; Barnes, P. J.; Ito, K. A Protein Deacetylase SIRT1 Is a Negative Regulator of Metalloproteinase-9. FASEB J. 2009, 23 (9), 2810– 2819,  DOI: 10.1096/fj.08-125468
      164
      A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9
      Nakamaru, Yuji; Vuppusetty, Chaitanya; Wada, Hiroo; Milne, Jill C.; Ito, Misako; Rossios, Christos; Elliot, Mark; Hogg, James; Kharitonov, Sergei; Goto, Hajime; Bemis, Jean E.; Elliott, Peter; Barnes, Peter J.; Ito, Kazuhiro
      FASEB Journal (2009), 23 (9), 2810-2819, 10.1096/fj.08-125468CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
      Inappropriate elevation of matrix metalloproteinase-9 (MMP9) is reported to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The object of this study was to identify the mol. mechanism underlying this increase of MMP9 expression, and here we show that oxidative stress-dependent redn. of a protein deacetylase, SIRT1, known as a putative antiaging enzyme, causes elevation of MMP9 expression. A sirtuin inhibitor, splitomycin, and SIRT1 knockdown by RNA interference led an increase in MMP9 expression in human monocytic U937 cells and in primary sputum macrophages, which was detected by RT-PCR, Western blot, activity assay, and zymog. In fact, the SIRT1 level was significantly decreased in peripheral lungs of patients with COPD, and this increase was inversely correlated with MMP9 expression and MMP9 promoter activation detected by a chromatin immunopptn. assay. H2O2 reduced SIRT1 expression and activity in U937 cells; furthermore, cigarette smoke exposure also caused redn. of SIRT1 expression in lung tissue of A/J mice, with concomitant elevation of MMP9. Intranasal treatment of a selective and novel SIRT1 small mol. activator, SRT2172, blocked the increase of MMP9 expression in the lung as well as pulmonary neutrophilia and the redn. in exercise tolerance. Thus, SIRT1 is a neg. regulator of MMP9 expression, and SIRT1 activation is implicated as a novel therapeutic approach to treating chronic inflammatory diseases, in which MMP9 is abundant.
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    165. 165
      Donovan, C.; Hansbro, P. M. IL-33 in Chronic Respiratory Disease: From Preclinical to Clinical Studies. ACS Pharmacol. Transl. Sci. 2020, 3 (1), 56– 62,  DOI: 10.1021/acsptsci.9b00099
      165
      IL-33 in Chronic Respiratory Disease: From Preclinical to Clinical Studies
      Donovan, Chantal; Hansbro, Philip M.
      ACS Pharmacology & Translational Science (2020), 3 (1), 56-62CODEN: APTSFN; ISSN:2575-9108. (American Chemical Society)
      A review. IL-33 has been deorphanized as a member of the IL-1 family and has key roles as an alarmin and cytokine with potent capacity to drive type 2 inflammation. This has led to a plethora of studies surrounding its' role in chronic diseases with a type 2 inflammatory component. Here, we review the roles of IL-33 in two chronic respiratory diseases, asthma and chronic obstructive pulmonary disease (COPD). We discuss the hallmark and paradigm-shifting studies that have contributed to our understanding of IL-33 biol. We cover animal studies that have elucidated the mechanisms of IL-33 and assessed the role of anti-IL-33 treatment and immunization against IL-33. We highlight key clin. evidence for the potential of targeting increased IL-33 in respiratory diseases including exacerbations, and outline current clin. trials using anti-IL-33 monoclonal antibody in asthma patients. Finally, we discuss some of the challenges that have arisen in IL-33 biol. and highlight potential future directions in targeting this cytokine in chronic respiratory diseases.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVekur3L&md5=5edb2e81c8ab3dcfa960d5db489dbf62
    166. 166
      Kirkham, P. A.; Caramori, G.; Casolari, P.; Papi, A. A.; Edwards, M.; Shamji, B.; Triantaphyllopoulos, K.; Hussain, F.; Pinart, M.; Khan, Y.; Heinemann, L.; Stevens, L.; Yeadon, M.; Barnes, P. J.; Chung, K. F.; Adcock, I. M. Oxidative Stress-Induced Antibodies to Carbonyl-Modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2011, 184 (7), 796– 802,  DOI: 10.1164/rccm.201010-1605OC
      166
      Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease
      Kirkham, Paul A.; Caramori, Gaetano; Casolari, Paolo; Papi, Alberto A.; Edwards, Matt; Shamji, Betty; Triantaphyllopoulos, Kostas; Hussain, Farhana; Pinart, Mariona; Khan, Younis; Heinemann, Lucy; Stevens, Laurie; Yeadon, Mike; Barnes, Peter J.; Chung, Kian F.; Adcock, Ian M.
      American Journal of Respiratory and Critical Care Medicine (2011), 184 (7), 796-802CODEN: AJCMED; ISSN:1073-449X. (American Thoracic Society)
      Rationale. There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on "self" proteins. Objectives: To det. the presence of autoantibodies to carbonyl-modified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins. Methods: Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 wk. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochem., and cellular activation by ELISA and fluorescence-activated cell sorter. Measurements and Main Results: Antibody titer against carbonyl-modified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also obsd. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonyl-modified protein. Conclusions: Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody prodn., providing a link by which oxidative stress could drive an autoimmune response in COPD.
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    167. 167
      Lee, S. J.; McPherron, A. C. Regulation of Myostatin Activity and Muscle Growth. Proc. Natl. Acad. Sci. U. S. A. 2001, 98 (16), 9306– 9311,  DOI: 10.1073/pnas.151270098
      167
      Regulation of myostatin activity and muscle growth
      Lee, Se-Jin; McPherron, Alexandra C.
      Proceedings of the National Academy of Sciences of the United States of America (2001), 98 (16), 9306-9311CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Myostatin is a transforming growth factor-β family member that acts as a neg. regulator of skeletal muscle mass. To identify possible myostatin inhibitors that may have applications for promoting muscle growth, we investigated the regulation of myostatin signaling. Myostatin protein purified from mammalian cells consisted of a noncovalently held complex of the N-terminal propeptide and a disulfide-linked dimer of C-terminal fragments. The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA. Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concns., by the myostatin propeptide. To det. the functional significance of these interactions in vivo, we generated transgenic mice expressing high levels of the propeptide, follistatin, or a dominant-neg. form of Act RIIB by using a skeletal muscle-specific promoter. Independent transgenic mouse lines for each construct exhibited dramatic increases in muscle mass comparable to those seen in myostatin knockout mice. Our findings suggest that the propeptide, follistatin, or other mols. that block signaling through this pathway may be useful agents for enhancing muscle growth for both human therapeutic and agricultural applications.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlvFSrsL0%253D&md5=786113fd0e78342e48a69cb5a82d50e6
    168. 168
      Kota, J.; Handy, C. R.; Haidet, A. M.; Montgomery, C. L.; Eagle, A.; Rodino-Klapac, L. R.; Tucker, D.; Shilling, C. J.; Therlfall, W. R.; Walker, C. M.; Weisbrode, S. E.; Janssen, P. M. L.; Clark, K. R.; Sahenk, Z.; Mendell, J. R.; Kaspar, B. K. Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates. Sci. Transl. Med. 2009, 1 (6), 6ra15,  DOI: 10.1126/scitranslmed.3000112
      There is no corresponding record for this reference.
    169. 169
      Zhou, X.; Wang, J. L.; Lu, J.; Song, Y.; Kwak, K. S.; Jiao, Q.; Rosenfeld, R.; Chen, Q.; Boone, T.; Simonet, W. S.; Lacey, D. L.; Goldberg, A. L.; Han, H. Q. Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival. Cell 2010, 142 (4), 531– 543,  DOI: 10.1016/j.cell.2010.07.011
      169
      Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival
      Zhou, Xiaolan; Wang, Jin Lin; Lu, John; Song, Yanping; Kwak, Keith S.; Jiao, Qingsheng; Rosenfeld, Robert; Chen, Qing; Boone, Thomas; Simonet, W. Scott; Lacey, David L.; Goldberg, Alfred L.; Han, H. Q.
      Cell (Cambridge, MA, United States) (2010), 142 (4), 531-543CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Summary: Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct exptl. evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacol. blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and prodn. of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.
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    170. 170
      Lach-Trifilieff, E.; Minetti, G. C.; Sheppard, K.; Ibebunjo, C.; Feige, J. N.; Hartmann, S.; Brachat, S.; Rivet, H.; Koelbing, C.; Morvan, F.; Hatakeyama, S.; Glass, D. J. An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy. Mol. Cell. Biol. 2014, 34 (4), 606– 618,  DOI: 10.1128/MCB.01307-13
      170
      An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy
      Lach-Trifilieff, Estelle; Minetti, Giulia C.; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome M.; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederick; Hatakeyama, Shinji; Glass, David J.
      Molecular and Cellular Biology (2014), 34 (4), 606-618, 14 pp.CODEN: MCEBD4; ISSN:1098-5549. (American Society for Microbiology)
      The myostatin/activin type II receptor (ActRII) pathway has been identified to be crit. in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degrdn. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtVSktbc%253D&md5=b886aea45113b0c2ed7b1635e613f313
    171. 171
      Cohen, S.; Lee, D.; Zhai, B.; Gygi, S. P.; Goldberg, A. L. Trim32 Reduces PI3K-Akt-FoxO Signaling in Muscle Atrophy by Promoting Plakoglobin-PI3K Dissociation. J. Cell Biol. 2014, 204 (5), 747– 758,  DOI: 10.1083/jcb.201304167
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      Trim32 reduces PI3K-Akt-FoxO signaling in muscle atrophy by promoting plakoglobin-PI3K dissociation
      Cohen, Shenhav; Lee, Donghoon; Zhai, Bo; Gygi, Steven P.; Goldberg, Alfred L.
      Journal of Cell Biology (2014), 204 (5), 747-758CODEN: JCLBA3; ISSN:0021-9525. (Rockefeller University Press)
      Activation of the PI3K-Akt-FoxO pathway induces cell growth, whereas its inhibition reduces cell survival and, in muscle, causes atrophy. Here, we report a novel mechanism that suppresses PI3K-Akt-FoxO signaling. Although skeletal muscle lacks desmosomes, it contains multiple desmosomal components, including plakoglobin. In normal muscle plakoglobin binds the insulin receptor and PI3K subunit p85 and promotes PI3K-Akt-FoxO signaling. During atrophy, however, its interaction with PI3K-p85 is reduced by the ubiquitin ligase Trim32 (tripartite motif contg. protein 32). Inhibition of Trim32 enhanced plakoglobin binding to PI3K-p85 and promoted PI3K-Akt-FoxO signaling. Surprisingly, plakoglobin overexpression alone enhanced PI3K-Akt-FoxO signaling. Furthermore, Trim32 inhibition in normal muscle increased PI3K-Akt-FoxO signaling, enhanced glucose uptake, and induced fiber growth, whereas plakoglobin down-regulation reduced PI3K-Akt-FoxO signaling, decreased glucose uptake, and caused atrophy. Thus, by promoting plakoglobin-PI3K dissocn., Trim32 reduces PI3K-Akt-FoxO signaling in normal and atrophying muscle. This mechanism probably contributes to insulin resistance during fasting and catabolic diseases and perhaps to the myopathies and cardiomyopathies seen with Trim32 and plakoglobin mutations.
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    172. 172
      Sandri, M. Signaling in Muscle Atrophy and Hypertrophy. Physiology (Bethesda). 2008, 23 (3), 160– 170,  DOI: 10.1152/physiol.00041.2007
      172
      Signaling in muscle atrophy and hypertrophy
      Sandri Marco
      Physiology (Bethesda, Md.) (2008), 23 (), 160-70 ISSN:1548-9213.
      Muscle performance is influenced by turnover of contractile proteins. Production of new myofibrils and degradation of existing proteins is a delicate balance, which, depending on the condition, can promote muscle growth or loss. Protein synthesis and protein degradation are coordinately regulated by pathways that are influenced by mechanical stress, physical activity, availability of nutrients, and growth factors. Understanding the signaling that regulates muscle mass may provide potential therapeutic targets for the prevention and treatment of muscle wasting in metabolic and neuromuscular diseases.
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