Low-Molecular Weight Metabolites from Polyphenols as Effectors for Attenuating Neuroinflammation
- Diogo CarregosaDiogo CarregosaCEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Avenida da República, Apartado 12, 2781-901 Oeiras, PortugalMore by Diogo Carregosa,
- Rafael CarechoRafael CarechoCEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade NOVA de Lisboa, Avenida da República, 2780-157 Oeiras, PortugalMore by Rafael Carecho,
- Inês FigueiraInês FigueiraiBET, Instituto de Biologia Experimental e Tecnológica, Avenida da República, Apartado 12, 2781-901 Oeiras, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade NOVA de Lisboa, Avenida da República, 2780-157 Oeiras, PortugalMore by Inês Figueira, and
- Cláudia N Santos*Cláudia N Santos*E-mail: [email protected]. Phone: +351 218 803 101. Fax: +351 218 851 920.CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Avenida da República, Apartado 12, 2781-901 Oeiras, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade NOVA de Lisboa, Avenida da República, 2780-157 Oeiras, PortugalMore by Cláudia N Santos
Copyright © 2019 American Chemical Society
Abstract
Age-associated pathophysiological changes such as neurodegenerative diseases are multifactorial conditions with increasing incidence and no existing cure. The possibility of altering the progression and development of these multifactorial diseases through diet is an attractive approach with increasing supporting data. Epidemiological and clinical studies have highlighted the health potential of diets rich in fruits and vegetables. Such food sources are rich in (poly)phenols, natural compounds increasingly associated with health benefits, having the potential to prevent or retard the development of various diseases. However, absorption and the blood concentration of (poly)phenols is very low when compared with their corresponding (poly)phenolic metabolites. Therefore, these serum-bioavailable metabolites are much more promising candidates to overcome cellular barriers and reach target tissues, such as the brain. Bearing this in mind, it will be reviewed that the molecular mechanisms underlying (poly)phenolic metabolites effects, range from 0.1 to <50 μM and their role on neuroinflammation, a central hallmark in neurodegenerative diseases.
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1. Neurodegenerative Disorders and Dietary (Poly)Phenols
ARTICLE SECTIONS
Neurodegenerative diseases (NDs) are chronic and progressive neurological syndromes, a consequence of nervous system dysfunction that ultimately leads to neuronal cell failure. These disorders are incapacitating and are characterized by impaired mental and movement function.(1) These diseases present a deeply complex pathophysiology prompting atrophy of structures of the central or peripheral nervous system and can be caused by hereditary or sporadic conditions.(2) However, we still do not have available disease-modifying therapies to delay or reverse disease progression, and their pharmacotherapy strategies are only dealing with symptomatic relief. Overall, NDs represent a current burden in the developed world which is projected to accelerate over time. These factors make the discovery of novel therapies to delay and prevent the development of these diseases an urgent but yet an unmet need.
A huge number of diseases are known to affect the nervous system, with most of them considered heterogeneous and multifactorial disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain cancer, degenerative nerve diseases, encephalitis, epilepsy, among others. They develop alterations in different brain regions and have different etiologies. The aggregation of misfolded proteins is one of the most common pathological processes, shared in AD, PD, HD, and others, commonly denominated as protein conformational disorders.(2) Besides the determinant role of protein aggregation, several other factors are common across major NDs. A new paradigm has begun to emerge to develop interventions targeting common mechanisms associated with aging to delay the onset of more than one age-related disease at the same time.(3) Increased oxidative stress, protein carbonylation, lipid peroxidation, DNA damage, mitochondrial dysfunction, vascular dysfunction, endoplasmic reticulum (ER) stress, unfolded protein response (UPR) dysregulation, and imbalanced proteostasis and neuroinflammation are common ND hallmarks which may require multitargeted interventions to tackle disease progression.
Neuroinflammation appears as one of the key processes involved in the major NDs and is a double-edged sword, being not only essential for recovery from several conditions but also playing detrimental roles contributing to disease progression. This process is controlled by microglia cells, the innate immune cells of the central nervous system (CNS), which can be stimulated to protect or act as a self-propelling mechanism of progressive neurodegeneration (Figure 1).(4,5) The primary role of microglia cells is to maintain the normal functions of the CNS by continuous surveillance of their surrounding microenvironment by extending and retracting their highly motile processes, maintaining homeostasis and neuronal integrity. Under detrimental stimuli, microglia cells are activated, losing their surveillance phenotype and their ramified morphology which is converted to an amoeboid-like structure that responds accordingly to the nature of the stimuli (Figure 1). Under moderate or transient damage, microglia cells behave as protective cells, i.e., play immune resolving, anti-inflammatory functions and support cell renewal by secreting trophic factors (Figure 1). In contrast, under intensive acute or chronic activation, usually associated with NDs, microglia cells become neurotoxic and secrete an array of pro-inflammatory cytokines and reactive oxygen and nitrogen species (ROS, NOS) that may potentially impair neuronal activity (Figure 1).(5) The neurotoxic phenotype of microglia cells blocks their ability to circumvent inflammatory damage, feeding instead a vicious cycle of toxicity. Activation of microglia cells by low concentrations of cytokines, such as interferon-γ (IFN-γ), interleukin (IL)-4, or IL-10, supports differentiation and provides neuroprotection by regulating the levels of both insulin-like growth factor 1 (IGF-1) and tumor necrosis factor-α (TNF-α). However, stimulation with either toxic protein aggregates, e.g., amyloid β 42 (Aβ 42) and α-synuclein (αsyn), hallmarks of AD and PD, respectively, glutamate or lipopolysaccharide (LPS, only used in vitro) exacerbates the inflammatory response. Whenever facing strong “toxic” stimuli, short-lived microglia cells can potentially manage the neurotoxic factors, supporting regeneration and secreting neurotrophic factors. Nevertheless, when upon a chronic stimulus, microglia cells develop this neurotoxic phenotype. Different markers have been associated with the neurotoxic phenotype [e.g., TNF-α, IL-1β, IL-6, prostaglandins (COX-2), ROS, and NO] and with the neuroprotective phenotype [e.g., IL-10, transforming growth factor-β (TGF-β), enzymes able to inhibit ROS production (e.g., arginase-1), proteins that maintain the extracellular matrix (Ym-1) or perform phagocytic removal of toxic protein aggregates and of cellular debris] (Figure 1).(5,6) The main signaling cascade behind the activation of microglia cells involves Nuclear Factor kappa B (NF-κB) through a mitogen-activated protein kinase (MAPK) signal transduction pathway.(7) MAPK is a common signaling hub to transduce extracellular signals to the nucleus in microglia cells. Major MAPK cascades involved in gene expression alterations are ERK1/2, Jun N-terminal Kinase (JNK), and p38.(7,8)
Figure 1
Figure 1. Microglia cell phenotypes at resting surveillance state (gray ramified) and upon activation by signals to the neuroprotective (green amoeboid) and neurotoxic (red amoeboid) phenotypes. IL, interleukin; IFN-γ, interferon gamma; LPS, lipopolysaccharides; αsyn, alpha-synuclein; Aβ42, amyloid beta 42; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; COX, cyclooxygenase; ROS, reactive oxygen species.
Several epidemiological studies from the last decades illustrate that diets rich in fruits and vegetables can have beneficial effects in human health,(9,10) preventing degenerative disorders and cognitive decline.(11,12) Dietary phenolics are described to modulate different aspects of synaptic plasticity, e.g., memory and/or learning improvement in both animals and humans,(10,13,14) albeit their mechanism of action on CNS remains poorly understood.(15) Their long-term supplementation in animal models suggests they can activate neuronal receptors, interact with signaling pathways (e.g., MAPK), and control the expression of specific genes.(16)
In fact, emerging evidence indicates that adherence to the Mediterranean diet, rich in polyphenols, is associated with a reduction of markers of inflammation. Therefore, the impact of (poly)phenol metabolites present in the Mediterranean diet on the innate immune system cannot be overlooked. Recently, a number of studies have described the contribution of this diet to the decrease of several markers of systemic inflammation which can have knock-on effects on the neuroinflammation status of the brain.(17) Another example is the effects of increased consumption of berries on a large prospective cohort of older women, establishing a relation with a reduced gradual progression of cognitive decline.(18) Moreover, it was shown that consumption of high levels of anthocyanin is associated with a reduced risk of PD development.(19) Various studies also show significant cognitive benefits of phenolics consumption in humans.(20−22) In fact, diet supplementation with wild blueberry was proven to improve cognitive function in older adults.(23) A recent study have shown that chronic blueberry supplementation improved brain perfusion, task-related activation, and cognitive function in healthy older adults, suggesting that supplementation with an anthocyanin-rich concentrate can improve brain activation in areas associated with cognitive function.(24) Moreover, in a double-blind, placebo controlled trial, the addition of easily achievable quantities of blueberry to the diets of older adults improved some aspects of cognition.(25) The results shown in these studies are supporting the idea that diets rich in (poly)phenols may have a positive impact on neurodegenerative diseases.
2. (Poly)Phenol Metabolites and Their Brain Permeability
ARTICLE SECTIONS
Research accumulating recently has suggested the huge potential of (poly)phenols toward health benefits.(26) Still for a profound understanding of (poly)phenols’ effects on human health and their underlying mechanisms of action, their absorption, distribution, metabolism, and excretion in the human digestive tract must be considered and the ensuing circulating metabolites evaluated for their potential.
The term (poly)phenols represent a class of compounds possessing multiple aromatic rings and at least one hydroxyl group.(27) Nevertheless, this definition was not consensual since a multitude of authors referred to the metabolic monomeric units as polyphenolic. To avoid confusion, the term polyphenols was recently updated to (poly)phenols in order to engulf a wider range of structurally and metabolic related phenolics.(28,29) Inside the (poly)phenol family, several branches are present, namely, flavonoids, lignans, tannins, stilbenes, ellagic acid, phenolic acids, and many others. Among these, flavonoids and phenolic acids represent the most biologically relevant class of compounds, due to their significant presence in dietary products and their ability to reach circulation.
Flavonoids are composed of three rings, A, B, and C (Figure 2). Depending upon the chemical groups present on the C ring or the position of the B ring, flavonoids can be classified into different classes: flavones, flavonols, flavan-3-ols, isoflavones, flavanones, and anthocyanins. Chalcones and dihydrochalcones although not having a C ring are also classified by many as flavonoids, due to their similar backbone. All of the above-mentioned classes represent the high percentage of flavonoids in dietary products including tea, citrus fruit, berries, red wine, apples, and legumes.(30) These flavonoids mainly occur naturally in fruit and vegetables as glycosides, with the exception for flavan-3-ols that can be found conjugated with gallic acid such is the case of (epi)catechin gallate.(31) Other flavonoids like dihydroflavonols, flavan-3,4-diols, coumarins, aurones, and neoflavonols also represent compounds with interesting properties and biological activities. Yet their lower presence in dietary products makes them less important from a nutritional perspective.
Figure 2
Figure 2. Different flavonoid classes with nutritional relevance. Flavonoid classes are represented as their 5,7-dihydroxyflavonoid derivatives. Red labeled bonds and chemical groups represent the major chemical characteristics of the flavonoid class.
Results from intervention studies have shown that flavonoids are subjected to a series of metabolic events, resulting in a huge variety of low-molecular weight phenolic metabolites that reach circulation at considerably higher concentrations than their parent compounds.(32)
Even though the full mechanism behind the metabolism of (poly)phenols into low molecular weight phenolic metabolites has not been fully unveiled, some consensus has been established. Phenolic metabolites resulting from digestive and hepatic activity usually differ from their parent compounds, which are found in fruits and vegetables.(10,33) Absorption events are accompanied by multiple metabolic reactions, which occur in the small and large intestines, in the liver, and in cells, resulting in a wide variety of derivatives (e.g., sulfated, methylated, and glucuronidated). Upon ingestion, flavonoid aglycones can be absorbed in the small intestine due to the action of glycosidases such as lactase phloridzin hydrolase (LPH) in the brush border of the small intestine epithelial cells or cytosolic β-glucosidase (CBG) within epithelial cells.(34) (Poly)phenol conjugates with sugar moieties that are resistant to the action of LPH/CBG and that are not absorbed in the small intestine to any degree reach the colon.(34) In the colon, the remaining conjugates are cleaved and the resulting aglycones undergo ring fission by the action of host microbiota producing several low-molecular weight phenolic metabolites.(35) Ring fission sites are dependent on the structure of phenolic parent compounds (Figure 3). For example, ring fission of flavan-3-ols like catechin, epicatechin, and epigallocatechin produce 5-(hydroxyphenyl)valeric acid and 5-(hydroxyphenyl)-γ-valerolactones, which are not produced by any other flavonoid classes. Furthermore, only ring fission of flavanones produce 3-hydroxypropionic acid (3-(hydroxyphenyl)hydracrylic acid), while isoflavones produce 2-(hydroxyphenyl)propanoic acid. Another exclusive class of metabolites are urolithins that are the result of ellagic acid metabolism. The production of urolithin A, B, or no urolithin production is dependent on the host microbiota composition, which can divide the host into metabotypes A, B, and 0.(36) Also, urolithins, unlike other low-molecular weight phenolic metabolites, are not further metabolized into smaller compounds but rather excreted intact in urine as phase II conjugates.(37)
Figure 3
Figure 3. Conversion pathway demonstrating the metabolism of the most representative flavonoids in dietary products (black boxes) into low-molecular weight phenolic metabolites. Red arrows inside the black boxes indicate the possible microbiota mediated ring fission sites for each flavonoid. Red arrows emerging from the black boxes indicate ring fission metabolites. Compounds inside dotted black boxes represent the general structure of the low molecular weight phenolic metabolites subjected to further metabolism. Further metabolic reactions are represented by the black arrows reinforcing the convergence into more low-molecular weight phenolic metabolites with the potential to accumulate in higher concentrations than the remaining upstream compounds, like hydroxybenenes and (hydroxy)hippuric acids. Part of these metabolic reactions seem to be shared between both microbial and hepatic enzymes. Note that these metabolites can undergo phases I and II metabolism into sulfate and glucuronide conjugates. α-Ox, alpha oxidation; β-Ox, beta oxidation; dOH, dehydroxylation; dCOOH, decarboxylation; red, reduction; Glyc, glycination.
Ring fission of most flavonoids happens on the C ring leading to the formation of 3-(hydroxyphenyl)cinnammic acids, such as ferulic acid and caffeic acid, from the B ring and hydroxybenzenes or benzaldehydes, such as phloroglucinol or phloroglucinaldehyde, and from the A ring.(38) The 2,3 double bonds of the B ring derived phenolic compounds can be reduced leading to the formation of the saturated 3-(hydroxyphenyl)propionic acids, such as dihydroferulic and dihydrocaffeic acid.(38) Of note, the mechanism of formation of 3-(hydroxyphenyl)propionic acid from flavanones is not still fully elucidated and could be produced by 3-(hydroxyphenyl)cinnamic acid reduction or dihydroxylation of 3-(hydroxyphenyl)hydracrylic acid.
Further oxidation of 3-(hydroxyphenyl)propionic acids can produce 2-(hydroxyphenyl)acetic acid. Several authors suggest that 3-(hydroxyphenyl)hydracrylic acid can be dehydroxylated to 2-(hydroxyphenyl)mandelic acid that can also generate 2-(hydroxyphenyl)acetic acid, although this route is not so well characterized. The same is valid for the conversion of 2-(hydroxyphenyl)propanoic acid originating from isoflavones into 2-(hydroxyphenyl)acetic acid. Moreover 2-(hydroxyphenyl)acetic acid can be oxidized into hydroxybenzoic acids, such as protocatechuic acid, gallic acid, and syringic acid. These components can be further converted into two different sets of metabolites, hippuric acids through glycination and hydroxybenzenes, such as catechol and pyrogallol, through decarboxylation.
Therefore, these low molecular weight phenolic metabolites are the culmination of multiple steps, involving both microbiota and human metabolism. The convergence of multiple flavonoid classes happens during several hours after ingestion. Flavonoid conjugates and their first metabolites like 3-(hydroxyphenyl)cinnamic acid appear in circulation in minutes to an hour after ingestion.(39) Meanwhile end-point metabolites like hippuric acid and hydroxybenzoics can be present up to 24 h after ingestion of edible fruits.
In any step of their catabolism, circulating phenolic metabolites can undergo phase II metabolism in the liver, leading to the formation of sulfate, glucuronide, and methylated conjugates through the action of sulfotransferases (SULTs), uridine-5′-diphosphate glucuronosyltransferases (UGTs), and catechol-O-methyltransferases (COMTs), respectively.(40) It is however still not fully understood if phase II conjugates can still be catabolized into smaller metabolites or if they are directly excreted in the urine without further modifications. Moreover, since both endogenous human and microbiota metabolism play important roles in producing low-molecular weight phenolic compounds in blood circulation, it is difficult to unravel the origin of one compound. For example, ferulic acid in blood could arise from direct ingestion of dietary conjugated ferulic acid, from ring fission of flavonoids, or from the action of COMT on caffeic acid.(41)
Overall, the correlation between parent compounds and the derived gut-phenolic metabolites is puzzling; many low-molecular weight phenolic metabolites can arise through the metabolism of a wide group of structurally diverse parent compounds (e.g., flavonols, flavan-3-ols, anthocyanins, chalcones, isoflavones, flavanones, and flavones) (Figure 3 and Table 1), whereas few are associated with an unique gut-phenolic metabolites (e.g., urolithins from ellagitannins).(42) For other (poly)phenolic components, data is still lacking (e.g., pyranoanthocyanins, coumarins, and other minor dietary components).(42) In general, the role of gut microbiota in the metabolism of (poly)phenols and the generation of low-molecular weight metabolites is rapidly consolidating and is of great importance.(43)
Table 1. Low-Molecular Weight Phenolic Metabolites Resulting from Dietary Sources Rich in (Poly)Phenolic Content, Mainly Flavonoids
a
The compounds mentioned in this class are representing the (E) isomer.
b
This compound have more than one structural isomer.
A very important aspect when considering the bioactivity of (poly)phenol metabolites is their circulating concentrations. Parent (poly)phenols or their phase II conjugates only reach the circulation in concentrations in the nanomolar range. On the other hand, low-molecular weight phenolic metabolites which can originate from different flavonoid classes (Figure 3) tend to be present in concentrations vastly superior when compared to the parent compounds. Czank et al. found that ingestion of 500 mg of 13C cyanidin-3-glucoside provided 42-fold higher abundance of 13C-labeled metabolites relative to 13C cyanidin-3-glucoside at their respective maximum serum concentration.(44) The flavonoid conjugate was present in serum at a maximum concentration of 141 nM at 1.8 h. Meanwhile, 14 different metabolites were also detected, with the most abundant, hippuric acid, reaching a concentration of 1962 nM at 15.7 h.(44) Pimpão et al., in a human intervention study using 500 mL of a puree of berries, have found that hydroxybenzoic phase II metabolites reached concentrations of over 20 μM in some volunteers.(45) Moreover, hippuric acid has been found in circulation up to 24 h and reaching concentrations well above 25 μM.(46)
The ability of any dietary phenolic to directly influence the nervous system will be dictated by the ability of its ensuing phenolic metabolites to cross the blood-brain barrier (BBB).(35,47) The BBB is a very dynamic and complex interface, carrying the responsibility of protecting the CNS from toxic agents. It controls the molecular exchanges between the blood and the neuronal tissue, hence playing a key role in the control of the accessibility of nutrients and other compounds to the brain.(48) Evidence of BBB capacity to uptake some phenolic metabolites is growing in the literature, alongside studies consistent with potential activity of phenolic metabolites in the brain.(49,50) The majority of these studies that focused on oral administration of dietary phenolics, directly or their derived phenolic metabolites, have reported their capacity to reach the brain, e.g., (−)epicatechin,(51) hesperetin, naringenin,(52) quercetin,(53) and anthocyanins.(49,54) To date, despite the fact that gut-phenolic metabolites are in general accepted to comprise a considerable percentage of the total diversity of phenolic metabolites,(44,45) only a very limited number of studies have specifically focused on bioaccessibility of gut-phenolic metabolites to the brain (e.g., valerolactones and phenolic acids).(55) In a recent pharmacokinetic study in rats, upon intravenous administration, some gut-phenolic metabolites were observed to reach the brain.(50) Recent methods now being implemented, such as microdialysis sampling, give the ability to recover (poly)phenols in vivo. Using this system coupled with HPLC with chemiluminescence detection, Liang Wu et al. demonstrated the ability of (+)catechin and (−)epicatechin to reach the brain.(56) Using a similar system, Zhang et al. showed that nearly 30% of orally administered protocatechuic acid can be recovered in the rat brain.(57)
BBB permeation has also been ascertained by using in vitro assays with immortalized human microvascular endothelial cells such as hBMEC or hCMEC/D3 in monolayers in transwell inserts to test for apical and basal presence of the compounds. Faria et al. have shown that (+)catechin and (−)epicatechin are able to cross hCMEC/D3.(58) Hydroxycinammic acids such as ferulic acid have also been shown to cross these BBB models,(59) and the same was demonstrated for hydroxybenzenes and benzoic acid derivatives.(15) Transport through the BBB varies between 5 and 10% for the tested low-molecular weight polyphenol metabolites. Additionally, two of the gut-phenolic metabolites, namely, catechol-sulfate and pyrogallol-sulfate, lead to new end-point metabolites in human brain endothelial cells.(15)
Whether the effects induced by dietary phenolics on brain functions are mediated directly in the brain or involve other mechanisms triggered from cells in the periphery remains unclear. Some reports indicated that the effects of flavonoids and metabolites on the brain do not seem to be exclusively dependent on their blood-brain barrier permeation.(16) (Poly)phenols have been shown to impact cardiovascular functions modulating blood pressure, vasodilation, and the presence of inflammatory markers in circulation that can directly affect the brain.(60,61) However, if phenolic metabolites do have a direct effect on the brain, then the low molecular weight phenolic metabolites may have the capacity to have a major contribution, due to their higher circulating concentrations. This review will be focused on the data available only for the direct effects of low-molecular weight phenolic metabolites (Table 1) in the context of the molecular mechanisms associated with neuroinflammation.
3. Low-Molecular Weight (Poly)Phenol Metabolites as Effectors for Attenuating Neuroinflammation
ARTICLE SECTIONS
For a full comprehension of dietary (poly)phenols effects on NDs, an unified view of in vitro, cellular, and animal model studies is required to reveal the complete panorama of their molecular targets and mechanisms. Associations between higher intakes of flavonoid-rich diets with lower levels of inflammatory biomarkers have been established.(62) However, inconsistent results on the preventive anti-inflammatory effects of flavonoid supplementation reinforce the necessity for more prospective randomized trials with larger sample sizes and under rigorous clinical conditions.(62) Moreover, while human trials are more reliable and the closest to the real scenario, they are time-consuming and costly and it is difficult to assess the direct effect of the (poly)phenols in trials related to neurodegenerative diseases. Animal and cellular models have provided unparalleled tools for compound screening assays to reveal their mechanisms of action. Despite of the importance of animal studies with isolated compounds, it does not reflect a nutritional scenario but, in most cases, a pharmacological perspective. Besides that, nutritional studies reveal overall effects and pathways affected but most of them do not identify the relevant metabolites that can comprise the true effectors against neurodegeneration acting in the brain, especially since their presence on the brain has been overlooked. In vitro assays are of most importance to reveal crucial interactions of (poly)phenols with other small molecules, proteins or even metals. They can prove an indispensable tool to get a comprehensive picture and tune our understanding in vivo. We will highlight and discuss our recent knowledge on cellular studies focused on the low molecular weight (poly)phenol metabolites (Table 1) to delineate their main molecular mechanisms of attenuation of neuroinflammation and identify their putative targets. Cellular models are starting points to reveal the molecular mechanisms of (poly)phenol metabolites and the role on cellular homeostasis when considered under experimental conditions close to physiological conditions. We will not address nutritional studies in animals for the reasons described above.
Accumulating evidence highlights the molecular and cellular pathways modulated by parent (poly)phenols, which, though not always nutritionally relevant, can give us clues about the putative mode of action of their (poly)phenol metabolites in a nutritional context. Flavonoids have been shown to inhibit the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1 in microglial cells, suggesting close involvement in pathways such as NF-κB or MAPK.(63) In addition, there is strong evidence that blueberry (poly)phenols inhibit the production of NO, IL-1β, and TNF-α in activated microglia cells.(64) Another example of a parent compound with anti-inflammatory activity, however with poor bioavailability, is caffeic acid phenethyl ester (CAPE). Some studies highlight its potential to modulate NF-κB activation in microglia cell models stimulated with TNF-α and significantly attenuate TNF-α-induced Toll-like receptor (TLR) 2 expression.(65) However, CAPE has low solubility and poor bioavailability that limits in vivo efficacy. Consequently some nanotechnologies strategies are emerging to enhance bioavailability and improve the clinical use of CAPE.(66) Nevertheless, in a nutritional scenario, the current trend is to analyze the effect of defined (poly)phenol metabolites in specific cells/tissues, instead of those of their parent dietary phenolics, under near physiological concentrations and residence time. The potential to reduce LPS-induced TNF-α secretion in THP-1 monocytes was evaluated, demonstrating that some metabolites of flavonoids, individually and in combination, appear to present more anti-inflammatory effects than their parent compounds.(67) Importantly, the study of isolated polyphenol metabolites is often limited to their molecular mechanisms in neurodegeneration cell models and their specific biological effects in animal models, and such studies miss the synergetic effects of the diversity of (poly)phenol metabolites that coexist in serum. The overall diet complexity, the potential synergy that may occur in compounds derived from the metabolism cannot be fully depicted in studies using isolated pure compounds.(68) Studies with (poly)phenol-enriched fractions or with the bulk of digested/metabolized compounds may be useful to approach these interactions and depict the molecular effects of the overall metabolites in cells.(15,69,70) For instance, simulated gastro-intestinal digestion blackberry extracts revealed neuronal protection to oxidative insult that was not related to the levels of ROS and glutathione (GSH), suggesting a preconditioning effect by the induction of caspase activity.(69,71) Moreover, bioaccessible raspberry metabolites resulting from the in vitro digestion of raspberry extract significantly inhibited microglial pro-inflammatory activation by LPS through the inhibition of Iba1 expression, TNF-α release, and NO production.(72)
A plethora of mammalian cell models have been used to study the protective action of (poly)phenol metabolites toward NDs. Although there is some evidence mainly highlighting the ability of several circulating metabolites to reduce oxidative stress, lipid peroxidation, and cytotoxicity in neuronal models, few studies have explored their antineuroinflammatory properties.(73,74) On the other hand, more complex models have addressed effects of (poly)phenols in particular pathological processes associated with each disease as well as toxicity of specific disease proteins.(75,76) Cellular models to access the anti-inflammatory potential of (poly)phenols for neurodegeneration are in general based on using microglia cells and explore the therapeutic potential of metabolites to mitigate inflammation induced by LPS or TNF-α. Since microglia are the resident innate immune cells of the CNS, microglial cell lines such as N9 and BV-2 have been preferred. Although the evidence for modulatory effects of (poly)phenol metabolites in microglial cells is still very scarce, the ability of the low-molecular weight phenolic metabolites to reduce neuroinflammatory markers has been reported (Table 2) and in some cases the underlying involved pathways have been proposed.
Table 2. Neuroprotective Evidence (in Vitro) for Some Bioavailable (Poly)Phenol Metabolites
a
The concentration tested was 2 μg/mL, and it was converted to molar for comparison purposes.
b
3-Morpholinosydnonimine (SIN-1) is a peroxynitrite generator described as inducing phosphorylation of protein tyrosine residues in brain cells and has been used as a neuronal damage inductor. In the study, SIN-1-induced nitrosative stress in a human neuroblastoma cell line (SH-SY5Y) and was used as a model of neuroinflammation.
Benzene diols and triols and their conjugates (Table 1) are abundant low-molecular weight flavonoid metabolites since they can appear in circulation either by ring fission from the A and B rings (Figure 3). Moreover, some are present in specific foods, e.g., catechol, guaiacol, pyrogallol, and 4-methylcatechol occur in coffee, beer, and cocoa.(30) A study from 2008 reported the beneficial effects of catechol and its conjugates (Figure 4, Table 2) that consistently decreased LPS-induced NO and TNF-α production in the BV-2 microglia cell line. Moreover, these compounds also inhibited the expression of inducible nitric oxide synthase (iNOS) as well as nuclear translocation of the p65 subunit of NF-κB, IκB degradation, and phosphorylation of p38 MAPK,(77) key players in inflammatory processes. Other substituted catechols (3-methylcatechol and 4-tert-butylcatechol) are equally effective, which opens the window to inspire further modifications for pharmacological applications. A more recent study, using a different microglia cell line (N9), showed that catechol and pyrogallol conjugates (both methyl and sulfates, Figure 4, Table 2) improved cellular responses to oxidative and inflammatory injuries via modulation of the NF-κB pathway.(15) In the same study, catechol-sulfate was ineffective to interfere with the key players of the NF-κB pathway, suggesting that the slight modification of sulfation of one hydroxyl, leaving only a single free hydroxyl, could alter its activity.(15) It will be interesting to have more data for further physiological conjugates.
Figure 4
A different view of the effect of benzene diols and triols on neuronal cells came from the 60s. Although pyrogallol is a bioavailable polyphenol metabolite which results from the consumption of polyphenol-rich meals, it also has toxic and pro-oxidant effects at higher concentrations. Pyrogallol was seen as a potent modulator of neurotransmitter levels in the brain.(78) The understanding of its brain penetration(79) and effects on monoamine oxidase and catechol-O-methyltransferase(80) highlighted the fact that pyrogallol is undoubtfully a brain bioavailable metabolite, appearing to be a versatile molecule with an evident modulatory potential in brain activity. Such potential led to the understanding of how pyrogallol can influence several fine-tuned mechanisms such as blood pressure,(81) dopamine levels,(82) and iron homeostasis and, consequently, cellular oxidative stress.(83) As such, pyrogallol was used as a neurotoxic agent at nonphysiological concentrations both in vitro and in vivo,(84,85) reviewed in ref (86). This duality of roles for pyrogallol may rely on the fact that at low concentrations, as it is detected circulating after consumption of polyphenol-rich meals, may be preconditioning the cells to a later insult. Pyrogallol is priming the cells to better respond to more hostile alterations in cell environment that may arise. It might be plausible that there are similar mechanisms for other low-molecular weight phenolic metabolites.
Benzoic acids conjugates were also studied as attenuators of neuroinflammation (Table 2). This is a very important class not only because the majority of flavonoids’ metabolism converge to benzoic acid derivatives (Figure 3) but also because they are very well represented in diverse foods and therefore could be ingested directly (e.g., gallic acid and protocatechuic acid in beer, wine, berries, cereals, grape, apple, kiwi, olive oil, vinegar, chicory).(30,87,88) Mi-Jeong Kim and colleagues have demonstrated the neuroprotective effects of gallic acid (Figure 5, Table 2) using the BV-2 cell line and primary microglia cells prior to Aβ stimulation. Conditioned media was transferred to Neuro-2A cells, and in both situations, gallic acid prevented Aβ neurotoxicity by inhibiting the expression levels of iNOS, COX-2, IL-1β, and TNF-α.(89) Gallic acid conjugates (methyl and sulfate) (Figure 5, Table 2) also proved efficacy in reducing LPS-induced NO as well the levels of intracellular superoxide,(88) which suggests that these further metabolic alterations do not affect its ability to modulate the inflammatory markers. In addition, protocatechuic acid, that differs from gallic acid in only one hydroxyl (Figure 5, Table 2), has also presented potent anti-inflammatory effects in BV-2 LPS-stimulated microglia. Mechanistic assays have revealed its ability to inhibit the production of TNF-α, IL-6, IL-1β, and PGE2. Protocatechuic acid also suppressed the activation of NF-κB and MAPKs, and it was also able to inhibit the TLR4 expression.(87)
Figure 5
Figure 5. Benzoic acids evaluated as attenuators of neuroinflammation in microglia cells.
Although there are many food sources of free and conjugated ferulic acid, its bioavailability depends on the form in which it is ingested as free ferulic acid has limited solubility in water and hence poor bioavailability. However, ferulic acid appears in circulation as a result of the metabolism of caffeic acid, chlorogenic acid, and anthocyanins.(30,90) Some studies have evaluated the ability of ferulic acid to attenuate inflammatory markers in microglia cells (Figure 6Table 2).(91,92) While the trend observed for this compound was to reduce more than one pro-inflammatory mediators in microglia cells (Table 2), only the study of Byung-Wook Kim and colleagues had nutritional relevance, since they tested physiologically relevant levels of ferulic acid likely to reach the circulation.(91) In another microglia cell line, ferulic acid was ineffective in reducing LPS stimulated production of NO, TNF-α, and IL-6 and was only effective in other mediators at nonphysiological concentrations over 50 μM (Table 2).(93) Similarly, another study observed that ferulic acid attenuated the JNK/NF-κB inflammatory signaling pathway and apoptosis in LPS-induced BV-2 microglia cells at both 10 μM and 100 μM but then focused on assessing effects on the TLR4-mediated signaling pathway but only for the most effective concentration (100 μM).(92) Cinnamic acid (Figure 6, Table 2) is another example of an effective metabolite tested for reducing several pro-inflammatory markers although at levels (>100 μM) only suitable for pharmacological approaches.(94) The data gathered reveals ferulic acid potential for attenuating pro-inflammatory mediators in microglia. Although relevant metabolites, ferulic and isoferulic acid are not the major metabolites derived from coffee consumption,(95) as sulfates are the dominant conjugates over the glucuronides(95) Therefore, it will be very important to fill the gap in evaluating the activity of these circulating bioavailable conjugates as attenuators of neuroinflammation.
Figure 6
Figure 6. Cinnamic acids evaluated as attenuators of neuroinflammation in microglia cells.
Phenylacetic acids and phenylpropionic acids metabolites found in blood after wine consumption,(96) such as 2-(3,4-dihydroxyphenyl)acetic acid, 2-(3-hydroxyphenyl)acetic acid, 3-(4-hydroxyphenyl)propionic acid, and 3-(3-hydroxyphenyl)propionic acid (Figure 7, Table 2), have shown to be neuroprotective by significantly decreasing ERK 1/2 activation. Moreover 2-(3-hydroxyphenyl)acetic acid and 3-(4-hydroxyphenyl)propionic acid also reduce mitogen-activated protein kinase (MAPK) p38 and in SH-SY5Y cells modulate neuroinflammatory pathways normally triggered by nitrosative stress.(97)
Figure 7
Figure 7. Phenylacetic acids and phenylpropionic acids evaluated as attenuators of neuroinflammation in microglia cells.
Other studies evaluated the anti-inflammatory potential in microglia cells for other compounds similar to low molecular (poly)phenol metabolites. For example, phloroglucinol derivatives have potent anti-inflammatory effects and can effectively cross the blood-brain barrier.(98) Mechanistic studies have revealed neuroinflammation inhibition potential by targeting Src/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt signaling.(98) Notably, these results were supported using two more complex cellular approaches as primary mixed mesencephalic neuronal/glial cultures and primary rat microglia cultures, both stimulated with LPS.(98)
In general, we may infer that the main molecular targets of the low-molecular weight (poly)phenol metabolites in stimulated microglia cells includes (Figure 8): (1) inhibiting the microglial activation of inflammatory cytokines, including TNF-α, IL-1β, IL-6; (2) inhibiting iNOS induction and subsequent nitric oxide (NO) production in response to glial activation; (3) inhibiting expression of COX-2 and resulting reduction of prostaglandins; and (4) downregulating activity of pro-inflammatory transcription factors such as NF-κB through modulation of glial and neuronal signaling pathways.
Figure 8
Figure 8. Main molecular targets of the low-molecular weight (poly)phenols metabolites in stimulated microglia cells. The pathways are the main entries highlighted in Table 2 as affected by the indicated physiological concentrations (also indicated in Table 2, ranging from 0.1 to <50 μM) of the metabolites in microglia cell systems.
Overall, cellular studies taking into consideration (poly)phenol metabolism and biological activity against neurodegeneration, using physiologically relevant concentrations and relevant resident times, mark a mentality shift and the beginning of a new era in (poly)phenol health benefits research.
4. Final Considerations
ARTICLE SECTIONS
Many studies corroborate the theory that (poly)phenol-rich supplements or foods have a positive impact preventing or attenuating neuroinflammation and therefore ameliorating NDs development and progression. A large amount of evidence has come from in vitro research using single flavonoids, typically aglycones, at supra-physiological concentrations which have given valuable clues for further studies with relevant circulating metabolites. In fact, increasing evidence suggests that metabolism of (poly)phenols may actually increase their biological activity. The anti-inflammatory effects of physiologically attainable (poly)phenol metabolites in healthy subjects is starting to be unveiled.
The sustained release of pro-inflammatory mediators that characterize neuroinflammation is harmful to microglia cells. Therefore, having compounds that can promote a shift in cells from inflammatory and neurotoxic phenotype to an anti-inflammatory and neuroprotective phenotype are crucial to efficiently repair the damage and restore the homeostasis, downregulating inflammation. The data gathered has identified the main molecular targets of the low-molecular weight (poly)phenol metabolites in stimulated microglia cells and highlighted their potential to attenuate neuroinflammation. These low-molecular weight (poly)phenol metabolites produced by gut microbiota are well absorbed in the intestine and persist in the plasma for a substantial time. Therefore, they could play a relevant role and alter our perspective of an effective prevention and cotreatment for NDs.
Still, the uncovering of the neuroprotective potential of (poly)phenol metabolites to attenuate neuroinflammation and their mode of action in neuronal cells is in its infancy. More studies to examine the diversity of the metabolites and evaluate how and when various types of conjugates (sulfates, glucuronides, and methylated) may alter their efficacy of the metabolites are needed. Moreover, metabolites have different pharmacokinetics and some of them may circulate simultaneously in specific time window, which increases the complexity of possible interactions and synergistic actions. Another layer of complexity needed to embrace the physiological environment where the metabolites act in vivo inside the brain is to use more biologically relevant cellular models. Current cell culture methodologies (2D) used to assess (poly)phenol metabolites biological activity are limited in their ability to reconstruct and mimic the cellular environment that is present in vivo. In vitro models for preclinical research using stem cells, patient-specific induced pluripotent stem cells, and reprogrammed somatic cells from patients are already applied in disease modeling and drug discovery and may be applicable to test the brain benefits of (poly)phenol metabolites. Three-dimensional (3D) culture systems represent a more physiologically accurate model allowing more relevant cell–cell and cell–matrix interactions. The development of increasingly robust advanced model systems is a fast-growing field fed by the demands of the pharmaceutical industry. Some attempts have already evaluated cytoprotection by (poly)phenol metabolites in a 3D model containing neurons and astrocytes.(15,99) Approaching the missing link between (poly)phenol metabolites and neuroglia signaling and communication is crucial for tuning translation of how diet can modify age-related neurological diseases, like PD and AD.(15,99)
In the future, (poly)phenol research may accelerate the discovery of bioactive molecules with potential application in the prevention and therapeutics of neurodegenerative conditions. To design nutritional or pharmaceutical approaches using (poly)phenols, it is imperative to explore their benefits in animal models to examine their effects at the whole organism level. This is a promising area and will definitely provide knowledge of particular added value to postpone the development of NDs. Translation of these concepts could contribute to designing new dietary recommendations, and the established knowledge on bioactivity of phenolic metabolites can leverage future development of cost-effective nutraceutical/pharmaceutical therapies toward NDs. Both approaches may contribute to increase healthy life expectancy by delaying the onset of neurodegenerative diseases.
This work has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 804229. The iNOVA4Health Research Unit (Grant LISBOA-01-0145-FEDER-007344), which is cofunded by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement is acknowledged. The authors would like to acknowledge FCT for financial support of R.C. (Grant PD/BD/135492/2018).
The authors declare no competing financial interest.
Acknowledgments
ARTICLE SECTIONS
We acknowledge the language revision by Gordon McDougall (James Hutton Institute).
| Abbreviations Used | |
| AD | Alzheimer’s disease |
| ALS | amyotrophic lateral sclerosis |
| Aβ | amyloid beta |
| CAPE | caffeic acid phenethyl ester |
| COX-2 | cyclooxygenase 2 |
| ER | endoplasmic reticulum |
| HD | Huntington disease |
| IFN-γ | interferon gamma |
| IGF1 | insulin-like growth factor 1 |
| IL | interleukin |
| iNOS | inducible nitric oxide synthase |
| JNK | c-Jun N-terminal kinases |
| LPS | lipopolysaccharides |
| MAPK | mitogen-activated protein kinase |
| ND | neurological disease |
| NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cells |
| PD | Parkinson’s disease |
| ROS | reactive oxygen species |
| TGF-β | transforming growth factor beta |
| TLR | toll like receptor |
| TNF-α | tumor necrosis factor alpha |
| UPR | unfolded protein response |
| αsyn | alpha synuclein |
References
ARTICLE SECTIONS
This article references 120 other publications.
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- 10Rodriguez-Mateos, A.; Vauzour, D.; Krueger, C. G.; Shanmuganayagam, D.; Reed, J.; Calani, L.; Mena, P.; Del Rio, D.; Crozier, A. Bioavailability, Bioactivity and Impact on Health of Dietary Flavonoids and Related Compounds: An Update. Arch. Toxicol. 2014, 88 (10), 1803– 1853, DOI: 10.1007/s00204-014-1330-7[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsV2ntbjJ&md5=df6d1fa73d98f2ff363fa2e42212940eBioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an updateRodriguez-Mateos, Ana; Vauzour, David; Krueger, Christian G.; Shanmuganayagam, Dhanansayan; Reed, Jess; Calani, Luca; Mena, Pedro; Del Rio, Daniele; Crozier, AlanArchives of Toxicology (2014), 88 (10), 1803-1853CODEN: ARTODN; ISSN:0340-5761. (Springer)A review. There is substantial interest in the role of plant secondary metabolites as protective dietary agents. In particular, the involvement of flavonoids and related compds. has become a major topic in human nutrition research. Evidence from epidemiol. and human intervention studies is emerging regarding the protective effects of various (poly)phenol-rich foods against several chronic diseases, including neurodegeneration, cancer and cardiovascular diseases. In recent years, the use of HPLC-MS for the anal. of flavonoids and related compds. in foods and biol. samples has significantly enhanced our understanding of (poly)phenol bioavailability. These advancements have also led to improvements in the available food compn. and metabolomic databases, and consequently in the development of biomarkers of (poly)phenol intake to use in epidemiol. studies. Efforts to create adequate standardised materials and well-matched controls to use in randomised controlled trials have also improved the quality of the available data. In vitro investigations using physiol. achievable concns. of (poly)phenol metabolites and catabolites with appropriate model test systems have provided new and interesting insights on potential mechanisms of actions. This article will summarise recent findings on the bioavailability and biol. activity of (poly)phenols, focusing on the epidemiol. and clin. evidence of beneficial effects of flavonoids and related compds. on urinary tract infections, cognitive function and age-related cognitive decline, cancer and cardiovascular disease.
- 11Nooyens, A. C. J.; Bueno-de-Mesquita, H. B.; van Boxtel, M. P. J.; van Gelder, B. M.; Verhagen, H.; Verschuren, W. M. M. Fruit and Vegetable Intake and Cognitive Decline in Middle-Aged Men and Women: The Doetinchem Cohort Study. Br. J. Nutr. 2011, 106 (5), 752– 761, DOI: 10.1017/S0007114511001024[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1Srs7fK&md5=ec6bc7ec1f43e399264a383d05939485Fruit and vegetable intake and cognitive decline in middle-aged men and women: the Doetinchem Cohort StudyNooyens, Astrid C. J.; Bueno-de-Mesquita, H. Bas; van Boxtel, Martin P. J.; van Gelder, Boukje M.; Verhagen, Hans; Verschuren, W. M. MoniqueBritish Journal of Nutrition (2011), 106 (5), 752-761CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)To postpone cognitive decline and dementia in old age, primary prevention is required earlier in life during middle age. Dietary components may be modifiable determinants of mental performance. In the present study, habitual fruit and vegetable intake was studied in assocn. with cognitive function and cognitive decline during middle age. In the Doetinchem Cohort Study, 2613 men and women aged 43-70 years at baseline (1995-2002) were examd. for cognitive function twice, with a 5-yr time interval. Global cognitive function and the domains memory, information processing speed and cognitive flexibility were assessed. Dietary intake was assessed with a semi-quant. FFQ. In multivariate linear regression analyses, habitual fruit and vegetable intake was studied in assocn. with baseline and change in cognitive function. Higher reported vegetable intake was assocd. with lower information processing speed (P = 0·02) and worse cognitive flexibility (P = 0·03) at baseline, but with smaller decline in information processing speed (P < 0·01) and global cognitive function (P = 0·02) at follow-up. Total intakes of fruits, legumes and juices were not assocd. with baseline or change in cognitive function. High intakes of some subgroups of fruits and vegetables (i.e. nuts, cabbage and root vegetables) were assocd. with better cognitive function at baseline and/or smaller decline in cognitive domains. In conclusion, total intake of fruits and vegetables was not or inconsistently assocd. with cognitive function and cognitive decline. A high habitual consumption of some specific fruits and vegetables may diminish age-related cognitive decline in middle-aged individuals. Further research is needed to verify these findings before recommendations can be made.
- 12Psaltopoulou, T.; Sergentanis, T. N.; Panagiotakos, D. B.; Sergentanis, I. N.; Kosti, R.; Scarmeas, N. Mediterranean Diet, Stroke, Cognitive Impairment, and Depression: A Meta-Analysis. Ann. Neurol. 2013, 74 (4), 580– 591, DOI: 10.1002/ana.23944[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3snnvFOhsg%253D%253D&md5=9c858627b3b04f60cbffe23c5c707554Mediterranean diet, stroke, cognitive impairment, and depression: A meta-analysisPsaltopoulou Theodora; Sergentanis Theodoros N; Panagiotakos Demosthenes B; Sergentanis Ioannis N; Kosti Rena; Scarmeas NikolaosAnnals of neurology (2013), 74 (4), 580-91 ISSN:.OBJECTIVE: This meta-analysis aims to quantitatively synthesize all studies that examine the association between adherence to a Mediterranean diet and risk of stroke, depression, cognitive impairment, and Parkinson disease. METHODS: Potentially eligible publications were those providing effect estimates of relative risk (RR) for the association between Mediterranean diet and the aforementioned outcomes. Studies were sought in PubMed up to October 31, 2012. Maximally adjusted effect estimates were extracted; separate analyses were performed for high and moderate adherence. RESULTS: Twenty-two eligible studies were included (11 covered stroke, 9 covered depression, and 8 covered cognitive impairment; only 1 pertained to Parkinson's disease). High adherence to Mediterranean diet was consistently associated with reduced risk for stroke (RR = 0.71, 95% confidence interval [CI] = 0.57-0.89), depression (RR = 0.68, 95% CI = 0.54-0.86), and cognitive impairment (RR = 0.60, 95% CI = 0.43-0.83). Moderate adherence was similarly associated with reduced risk for depression and cognitive impairment, whereas the protective trend concerning stroke was only marginal. Subgroup analyses highlighted the protective actions of high adherence in terms of reduced risk for ischemic stroke, mild cognitive impairment, dementia, and particularly Alzheimer disease. Meta-regression analysis indicated that the protective effects of Mediterranean diet in stroke prevention seemed more sizeable among males. Concerning depression, the protective effects of high adherence seemed independent of age, whereas the favorable actions of moderate adherence seemed to fade away with more advanced age. INTERPRETATION: Adherence to a Mediterranean diet may contribute to the prevention of a series of brain diseases; this may be of special value given the aging of Western societies.
- 13Spencer, J. P. E. Food for Thought: The Role of Dietary Flavonoids in Enhancing Human Memory, Learning and Neuro-Cognitive Performance. Proc. Nutr. Soc. 2008, 67 (2), 238– 252, DOI: 10.1017/S0029665108007088[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntVSnsLk%253D&md5=05f2f507f8e66050755dfc4a72169b23Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performanceSpencer, Jeremy P. E.Proceedings of the Nutrition Society (2008), 67 (2), 238-252CODEN: PNUSA4; ISSN:0029-6651. (Cambridge University Press)A review. Emerging evidence suggests that dietary-derived flavonoids have the potential to improve human memory and neuro-cognitive performance via their ability to protect vulnerable neurons, enhance existing neuronal function and stimulate neuronal regeneration. Long-term potentiation (LTP) is widely considered to be one of the major mechanisms underlying memory acquisition, consolidation and storage in the brain and is known to be controlled at the mol. level by the activation of a no. of neuronal signalling pathways. These pathways include the phosphatidylinositol-3 kinase/protein kinase B/Akt (Akt), protein kinase C, protein kinase A, Ca-calmodulin kinase and mitogen-activated protein kinase pathways. Growing evidence suggests that flavonoids exert effects on LTP, and consequently memory and cognitive performance, through their interactions with these signalling pathways. Of particular interest is the ability of flavonoids to activate the extracellular signal-regulated kinase and the Akt signalling pathways leading to the activation of the cAMP-response element-binding protein, a transcription factor responsible for increasing the expression of a no. of neurotrophins important in LTP and long-term memory. One such neurotrophin is brain-derived neurotrophic factor, which is known to be crucial in controlling synapse growth, in promoting an increase in dendritic spine d. and in enhancing synaptic receptor d. The present review explores the potential of flavonoids and their metabolite forms to promote memory and learning through their interactions with neuronal signalling pathways pivotal in controlling LTP and memory in human subjects.
- 14Williams, R. J.; Spencer, J. P. E. Flavonoids, Cognition, and Dementia: Actions, Mechanisms, and Potential Therapeutic Utility for Alzheimer Disease. Free Radical Biol. Med. 2012, 52 (1), 35– 45, DOI: 10.1016/j.freeradbiomed.2011.09.010[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitlyntQ%253D%253D&md5=80351e6c4110bf1be1724376dd2d8196Flavonoids, cognition, and dementia: Actions, mechanisms, and potential therapeutic utility for Alzheimer diseaseWilliams, Robert J.; Spencer, Jeremy P. E.Free Radical Biology & Medicine (2012), 52 (1), 35-45CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)A review. There is increasing evidence that the consumption of flavonoid-rich foods can beneficially influence normal cognitive function. In addn., a growing no. of flavonoids have been shown to inhibit the development of Alzheimer disease (AD)-like pathol. and to reverse deficits in cognition in rodent models, suggestive of potential therapeutic utility in dementia. The actions of flavonoid-rich foods (e.g., green tea, blueberry, and cocoa) seem to be mediated by the direct interactions of absorbed flavonoids and their metabolites with a no. of cellular and mol. targets. For example, their specific interactions within the ERK and PI3-kinase/Akt signaling pathways, at the level of receptors or kinases, have been shown to increase the expression of neuroprotective and neuromodulatory proteins and increase the no. of, and strength of, connections between neurons. Concurrently, their effects on the vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Addnl. mechanisms have been suggested for the ability of flavonoids to delay the initiation of and/or slow the progression of AD-like pathol. and related neurodegenerative disorders, including a potential to inhibit neuronal apoptosis triggered by neurotoxic species (e.g., oxidative stress and neuroinflammation) or disrupt amyloid β aggregation and effects on amyloid precursor protein processing through the inhibition of β-secretase (BACE-1) and/or activation of α-secretase (ADAM10). Together, these processes act to maintain the no. and quality of synaptic connections in key brain regions and thus flavonoids have the potential to prevent the progression of neurodegenerative pathologies and to promote cognitive performance.
- 15Figueira, I.; Garcia, G.; Pimpão, R. C.; Terrasso, A. P.; Costa, I.; Almeida, A. F.; Tavares, L.; Pais, T. F.; Pinto, P.; Ventura, M. R. Polyphenols Journey through Blood-Brain Barrier towards Neuronal Protection. Sci. Rep. 2017, 7 (1), 11456, DOI: 10.1038/s41598-017-11512-6[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cbnvFCltg%253D%253D&md5=fd9d6a0e6d1ece906009b0723a1fc760Polyphenols journey through blood-brain barrier towards neuronal protectionFigueira I; Garcia G; Pimpao R C; Terrasso A P; Costa I; Almeida A F; Tavares L; Pinto P; Ventura M R; Brito C; Santos C N; Figueira I; Garcia G; Pimpao R C; Terrasso A P; Costa I; Almeida A F; Tavares L; Brito C; Santos C N; Pais T F; Pinto P; Filipe A; McDougall G J; Stewart D; Stewart D; Stewart D; Kim K S; Palmela I; Brites D; Brito M A; Brites D; Brito M AScientific reports (2017), 7 (1), 11456 ISSN:.Age-related complications such as neurodegenerative disorders are increasing and remain cureless. The possibility of altering the progression or the development of these multifactorial diseases through diet is an emerging and attractive approach with increasing experimental support. We examined the potential of known bioavailable phenolic sulfates, arising from colonic metabolism of berries, to influence hallmarks of neurodegenerative processes. In silico predictions and in vitro transport studies across blood-brain barrier (BBB) endothelial cells, at circulating concentrations, provided evidence for differential transport, likely related to chemical structure. Moreover, endothelial metabolism of these phenolic sulfates produced a plethora of novel chemical entities with further potential bioactivies. Pre-conditioning with phenolic sulfates improved cellular responses to oxidative, excitotoxicity and inflammatory injuries and this attenuation of neuroinflammation was achieved via modulation of NF-κB pathway. Our results support the hypothesis that these small molecules, derived from dietary (poly)phenols may cross the BBB, reach brain cells, modulate microglia-mediated inflammation and exert neuroprotective effects, with potential for alleviation of neurodegenerative diseases.
- 16Rendeiro, C.; Rhodes, J. S.; Spencer, J. P. E. The Mechanisms of Action of Flavonoids in the Brain: Direct versus Indirect Effects. Neurochem. Int. 2015, 89, 126– 139, DOI: 10.1016/j.neuint.2015.08.002[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlGrs73M&md5=6968318868a2d7a5646f7eb98eb6dadbThe mechanisms of action of flavonoids in the brain: Direct versus indirect effectsRendeiro, Catarina; Rhodes, Justin S.; Spencer, Jeremy P. E.Neurochemistry International (2015), 89 (), 126-139CODEN: NEUIDS; ISSN:0197-0186. (Elsevier Ltd.)A review. The projected increase in the incidence of dementia in the population highlights the urgent need for a more comprehensive understanding of how different aspects of lifestyle, in particular exercise and diet, may affect neural function and consequent cognitive performance throughout the life course. In this regard, flavonoids, found in a variety of fruits, vegetables and derived beverages, have been identified as a group of promising bioactive compds. capable of influencing different aspects of brain function, including cerebrovascular blood flow and synaptic plasticity, both resulting in improvements in learning and memory in mammalian species. However, the precise mechanisms by which flavonoids exert these actions are yet to be fully established, although accumulating data indicate an ability to interact with neuronal receptors and kinase signaling pathways which are key to neuronal activation and communication and synaptic strengthening. Alternatively or concurrently, there is also compelling evidence derived from human clin. studies suggesting that flavonoids can pos. affect peripheral and cerebrovascular blood flow, which may be an indirect effective mechanism by which dietary flavonoids can impact on brain health and cognition. The current review examines the beneficial effects of flavonoids on both human and animal brain function and attempts to address and link direct and indirect actions of flavonoids and their derivs. within the central nervous system (CNS).
- 17Mayr, H. L.; Thomas, C. J.; Tierney, A. C.; Kucianski, T.; George, E. S.; Ruiz-Canela, M.; Hebert, J. R.; Shivappa, N.; Itsiopoulos, C. Randomization to 6-Month Mediterranean Diet Compared with a Low-Fat Diet Leads to Improvement in Dietary Inflammatory Index Scores in Patients with Coronary Heart Disease: The AUSMED Heart Trial. Nutr. Res. (N. Y., NY, U. S.) 2018, 55, 94– 107, DOI: 10.1016/j.nutres.2018.04.006[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXptlyrsLo%253D&md5=a2f06b09498e417016e4ccbb3c30c8f4Randomization to 6-month Mediterranean diet compared with a low-fat diet leads to improvement in Dietary Inflammatory Index scores in patients with coronary heart disease: the AUSMED Heart TrialMayr, Hannah L.; Thomas, Colleen J.; Tierney, Audrey C.; Kucianski, Teagan; George, Elena S.; Ruiz-Canela, Miguel; Hebert, James R.; Shivappa, Nitin; Itsiopoulos, CatherineNutrition Research (New York, NY, United States) (2018), 55 (), 94-107CODEN: NTRSDC; ISSN:0271-5317. (Elsevier)A higher dietary inflammatory index (DII) score is assocd. with inflammation and incidence of coronary heart disease (CHD). We hypothesized that a Mediterranean diet (MedDiet) intervention would reduce DII score. We assessed dietary data from a randomized controlled trial comparing 6-mo MedDiet vs. low-fat diet intervention, in patients with CHD. We aimed to det. the DII scores of the prescribed diets' model meal plans, followed by whether dietary intervention led to lower (i.e., more anti-inflammatory) DII scores and consequently lower high sensitivity C-reactive protein (hs-CRP) and interleukin-6 (hs-IL-6). DII scores were calcd. from 7-day food diaries. The MedDiet meal plan had a markedly lower DII score than the low-fat diet meal plan (-4.55 vs. -0.33, resp.). In 56 participants who completed the trial (84% male, mean age 62 ± 9 years), the MedDiet group significantly reduced DII scores at 6 mo (n = 27; -0.40 ± 3.14 to -1.74 ± 2.81, P = .008) and the low-fat diet group did not change (n = 29; -0.17 ± 2.27 to 0.05 ± 1.89, P = .65). There was a significant post-intervention adjusted difference in DII score between groups (compared to low-fat, MedDiet decreased by -1.69 DII points; P = .004). When compared to the low-fat diet, the MedDiet non-significantly reduced hs-IL-6 (-0.32 pg/mL, P = .29) and increased hs-CRP (+0.09 mg/L, P = .84). These findings demonstrated that MedDiet intervention significantly reduced DII scores compared to a low-fat diet. However, in this small cohort of patients with CHD this did not translate to a significant improvement in measured inflammatory markers. The effect of improvement in DII with MedDiet should be tested in larger intervention trials and observational cohorts.
- 18Devore, E. E.; Kang, J. H.; Breteler, M. M. B.; Grodstein, F. Dietary Intakes of Berries and Flavonoids in Relation to Cognitive Decline. Ann. Neurol. 2012, 72 (1), 135– 143, DOI: 10.1002/ana.23594[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOgsLfI&md5=423cad845b370619f69d33b93cae170eDietary intakes of berries and flavonoids in relation to cognitive declineDevore, Elizabeth E.; Kang, Jae Hee; Breteler, Monique M. B.; Grodstein, FrancineAnnals of Neurology (2012), 72 (1), 135-143CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)Objective: : Berries are high in flavonoids, esp. anthocyanidins, and improve cognition in exptl. studies. We prospectively evaluated whether greater long-term intakes of berries and flavonoids are assocd. with slower rates of cognitive decline in older women. Methods: : Beginning in 1980, a semiquant. food frequency questionnaire was administered every 4 years to Nurses' Health Study participants. In 1995-2001, we began measuring cognitive function in 16,010 participants, aged ≥70 years; follow-up assessments were conducted twice, at 2-yr intervals. To ascertain long-term diet, we averaged dietary variables from 1980 through the initial cognitive interview. Using multivariate-adjusted, mixed linear regression, we estd. mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes. Results: : Greater intakes of blueberries and strawberries were assocd. with slower rates of cognitive decline (eg, for a global score averaging all 6 cognitive tests, for blueberries: p-trend = 0.014 and mean difference = 0.04, 95% confidence interval [CI] = 0.01-0.07, comparing extreme categories of intake; for strawberries: p-trend = 0.022 and mean difference = 0.03, 95% CI = 0.00-0.06, comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect ests. were equiv. to those we found for approx. 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Addnl., in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were assocd. with slower rates of cognitive decline (p-trends = 0.015 and 0.053, resp., for the global score). Interpretation: : Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults. ANN NEUROL 2012.
- 19Gao, X.; Cassidy, A.; Schwarzschild, M. A.; Rimm, E. B.; Ascherio, A. Habitual Intake of Dietary Flavonoids and Risk of Parkinson Disease. Neurology 2012, 78 (15), 1138– 1145, DOI: 10.1212/WNL.0b013e31824f7fc4[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsVaksbs%253D&md5=57abb8d8842c5913696b7e25b794e28eHabitual intake of dietary flavonoids and risk of Parkinson diseaseGao, X.; Cassidy, A.; Schwarzschild, M. A.; Rimm, E. B.; Ascherio, A.Neurology (2012), 78 (15), 1138-1145CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: To prospectively examine whether higher intakes of total flavonoids and their subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, and polymers) were assocd. with a lower risk of developing Parkinson disease (PD). Methods: In the current anal., we included 49,281 men in the Health Professional Follow-up Study and 80,336 women from the Nurses' Health Study. Five major sources of flavonoid-rich foods (tea, berry fruits, apples, red wine, and orange/orange juice) were also examd. Flavonoid intake was assessed using an updated food compn. database and a validated food frequency questionnaire. Results: We identified 805 participants (438 men and 367 women) who developed PD during 20-22 years of follow-up. In men, after adjusting for multiple confounders, participants in the highest quintile of total flavonoids had a 40%lower PD risk than those in the lowest quintile (hazard ratio [HR] = 0.60; 95% confidence interval 0.43, 0.83; p trend = 0.001). No significant relationship was obsd. in women (p trend = 0.62) or in pooled analyses (p trend = 0.23). In the pooled analyses for the subclasses, intakes of anthocyanins and a rich dietary source, berries, were significantly assocd. with a lower PD risk (HR comparing 2 extreme intake quintiles were 0.76 for anthocyanins and 0.77 for berries, resp.; p trend < 0.02 for both). Conclusions: Our findings suggest that intake of some flavonoids may reduce PD risk, particularly in men, but a protective effect of other constituents of plant foods cannot be excluded.
- 20Kennedy, D. O. Polyphenols and the Human Brain: Plant “Secondary Metabolite” Ecologic Roles and Endogenous Signaling Functions Drive Benefits. Adv. Nutr. 2014, 5 (5), 515– 533, DOI: 10.3945/an.114.006320[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVClt7zP&md5=3544d29309c20612794cd3cf215b0ccbPolyphenols and the human brain: plant "Secondary Metabolite" ecologic roles and endogenous signaling functions drive benefitsKennedy, David O.Advances in Nutrition (2014), 5 (5), 515-533CODEN: ANDUAW; ISSN:2156-5376. (American Society for Nutrition)A review. Flavonoids and other polyphenols are ubiquitous plant chems. that fulfill a range of ecol. roles for their home plant, including protection from a range of biotic and abiotic stressors and a pivotal role in the management of pathogenic and symbiotic soil bacteria and fungi. They form a natural part of the human diet, and evidence suggests that their consumption is assocd. with the beneficial modulation of a no. of health-related variables, including those related to cardiovascular and brain function. Over recent years, the consensus as to the mechanisms responsible for these effects in humans has shifted away from polyphenols having direct antioxidant effects and toward their modulation of cellular signal transduction pathways. To date, little consideration was given to the question of why, rather than how, these plant-derived chems. might exert these effects. Therefore, this review summarizes the evidence suggesting that polyphenols beneficially affect human brain function and describes the current mechanistic hypotheses explaining these effects. It then goes on to describe the ecol. roles and potential endogenous signaling functions that these ubiquitous phytochems. play within their home plant and discusses whether these functions drive their beneficial effects in humans via a process of "cross-kingdom" signaling predicated on the many conserved similarities in plant, microbial, and human cellular signal transduction pathways.
- 21Macready, A. L.; Kennedy, O. B.; Ellis, J. A.; Williams, C. M.; Spencer, J. P. E.; Butler, L. T. Flavonoids and Cognitive Function: A Review of Human Randomized Controlled Trial Studies and Recommendations for Future Studies. Genes Nutr. 2009, 4 (4), 227– 242, DOI: 10.1007/s12263-009-0135-4[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtl2ks77K&md5=980b8412fcc66290f6db44aa7c17361aFlavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studiesMacready, Anna L.; Kennedy, Orla B.; Ellis, Judi A.; Williams, Claire M.; Spencer, Jeremy P. E.; Butler, Laurie T.Genes and Nutrition (2009), 4 (4), 227-242CODEN: GNEUAZ; ISSN:1555-8932. (Springer)A review. Evidence in support of the neuroprotective effects of flavonoids has increased significantly in recent years, although to date much of this evidence has emerged from animal rather than human studies. Nonetheless, with a view to making recommendations for future good practice, we review 15 existing human dietary intervention studies that have examd. the effects of particular types of flavonoid on cognitive performance. The studies employed a total of 55 different cognitive tests covering a broad range of cognitive domains. Most studies incorporated at least one measure of executive function/working memory, with nine reporting significant improvements in performance as a function of flavonoid supplementation compared to a control group. However, some domains were overlooked completely (e.g. implicit memory, prospective memory), and for the most part there was little consistency in terms of the particular cognitive tests used making across study comparisons difficult. Furthermore, there was some confusion concerning what aspects of cognitive function particular tests were actually measuring. Overall, while initial results are encouraging, future studies need to pay careful attention when selecting cognitive measures, esp. in terms of ensuring that tasks are actually sensitive enough to detect treatment effects.
- 22Nehlig, A. The Neuroprotective Effects of Cocoa Flavanol and Its Influence on Cognitive Performance. Br. J. Clin. Pharmacol. 2013, 75 (3), 716– 727, DOI: 10.1111/j.1365-2125.2012.04378.x[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1WjsrY%253D&md5=ecb7837e3da51412fa499001797cdcdeThe neuroprotective effects of cocoa flavanol and its influence on cognitive performanceNehlig, AstridBritish Journal of Clinical Pharmacology (2013), 75 (3), 716-727CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)A review. Cocoa powder and chocolate contain numerous substances among which there is a quite large percentage of antioxidant mols., mainly flavonoids, most abundantly found in the form of epicatechin. These substances display several beneficial actions on the brain. They enter the brain and induce widespread stimulation of brain perfusion. They also provoke angiogenesis, neurogenesis and changes in neuron morphol., mainly in regions involved in learning and memory. Epicatechin improves various aspects of cognition in animals and humans. Chocolate also induces pos. effects on mood and is often consumed under emotional stress. In addn., flavonoids preserve cognitive abilities during ageing in rats, lower the risk for developing Alzheimer's disease and decrease the risk of stroke in humans. In addn. to their beneficial effects on the vascular system and on cerebral blood flow, flavonoids interact with signalization cascades involving protein and lipid kinases that lead to the inhibition of neuronal death by apoptosis induced by neurotoxicants such as oxygen radicals, and promote neuronal survival and synaptic plasticity. The present review intends to review the data available on the effects of cocoa and chocolate on brain health and cognitive abilities.
- 23Krikorian, R.; Shidler, M. D.; Nash, T. A.; Kalt, W.; Vinqvist-Tymchuk, M. R.; Shukitt-Hale, B.; Joseph, J. A. Blueberry Supplementation Improves Memory in Older Adults. J. Agric. Food Chem. 2010, 58 (7), 3996– 4000, DOI: 10.1021/jf9029332[ACS Full Text
], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFSm&md5=b5b5191927dfacb3f7c281f48b9680d7Blueberry supplementation improves memory in older adultsKrikorian, Robert; Shidler, Marcelle D.; Nash, Tiffany A.; Kalt, Wilhelmina; Vinqvist-Tymchuk, Melinda R.; Shukitt-Hale, Barbara; Joseph, James A.Journal of Agricultural and Food Chemistry (2010), 58 (7), 3996-4000CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The prevalence of dementia is increasing in the older adult population. In the absence of effective therapy, preventive approaches are essential to address this public health problem. Blueberries (Vaccinium angustifolium) contain polyphenol compds., esp. anthocyanins (estd. as cyanidin 3-glucoside), with antioxidant and anti-inflammatory effects. Anthocyanins have been assocd. with increased neuronal signaling in brain centers, mediation of memory functions , and improved glucose disposal; these benefits could mitigate neurodegeneration. The effects of daily consumption of wild blueberry juice were studied in 9 older adult humans (76.2±5.2 yr) with early memory changes. After 12 wk, improved paired assoc. learning and word list recall were obsd. There were also trends suggesting decreased depressive symptoms and lower blood serum glucose levels. The memory performance of the blueberry subjects was compared with a demog. matched sample who consumed a berry placebo beverage in a companion trial of identical design and comparable results for paired assoc. learning was obsd. Thus, moderate-term blueberry supplementation can have neurocognitive benefits. - 24Bowtell, J. L.; Aboo-Bakkar, Z.; Conway, M. E.; Adlam, A.-L. R.; Fulford, J. Enhanced Task-Related Brain Activation and Resting Perfusion in Healthy Older Adults after Chronic Blueberry Supplementation. Appl. Physiol., Nutr., Metab. 2017, 42 (7), 773– 779, DOI: 10.1139/apnm-2016-0550[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFGmu74%253D&md5=aac1dc9976e228f42c16356564ca3262Enhanced task-related brain activation and resting perfusion in healthy older adults after chronic blueberry supplementationBowtell, Joanna L.; Aboo-Bakkar, Zainie; Conway, Myra E.; Adlam, Anna-Lynne R.; Fulford, JonathanApplied Physiology, Nutrition, and Metabolism (2017), 42 (7), 773-779CODEN: APNMC6; ISSN:1715-5312. (Canadian Science Publishing)Blueberries are rich in flavonoids, which possess antioxidant and anti-inflammatory properties. High flavonoid intakes attenuate age-related cognitive decline, but data from human intervention studies are sparse. We investigated whether 12 wk of blueberry conc. supplementation improved brain perfusion, task-related activation, and cognitive function in healthy older adults. Participants were randomized to consume either 30 mL blueberry conc. providing 387 mg anthocyanidins (5 female, 7 male; age 67.5 ± 3.0 y; body mass index, 25.9 ± 3.3 kg·m-2) or isoenergetic placebo (8 female, 6 male; age 69.0 ± 3.3 y; body mass index, 27.1 ± 4.0 kg·m-2). Pre- and postsupplementation, participants undertook a battery of cognitive function tests and a numerical Stroop test within a 1.5T magnetic resonance imaging scanner while functional magnetic resonance images were continuously acquired. Quant. resting brain perfusion was detd. using an arterial spin labeling technique, and blood biomarkers of inflammation and oxidative stress were measured. Significant increases in brain activity were obsd. in response to blueberry supplementation relative to the placebo group within Brodmann areas 4/6/10/21/40/44/45, precuneus, anterior cingulate, and insula/thalamus (p < 0.001) as well as significant improvements in gray matter perfusion in the parietal (5.0 ± 1.8 vs -2.9 ± 2.4%, p = 0.013) and occipital (8.0 ± 2.6 vs -0.7 ± 3.2%, p = 0.031) lobes. There was also evidence suggesting improvement in working memory (2-back test) after blueberry vs. placebo supplementation (p = 0.05). Supplementation with an anthocyanin-rich blueberry conc. improved brain perfusion and activation in brain areas assocd. with cognitive function in healthy older adults.
- 25Miller, M. G.; Hamilton, D. A.; Joseph, J. A.; Shukitt-Hale, B. Dietary Blueberry Improves Cognition among Older Adults in a Randomized, Double-Blind, Placebo-Controlled Trial. Eur. J. Nutr. 2018, 57 (3), 1169– 1180, DOI: 10.1007/s00394-017-1400-8[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktFWjtr8%253D&md5=234b00becc15199365a1ab16294ba55aDietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trialMiller, Marshall G.; Hamilton, Derek A.; Joseph, James A.; Shukitt-Hale, BarbaraEuropean Journal of Nutrition (2018), 57 (3), 1169-1180CODEN: EJNUFZ; ISSN:1436-6207. (Springer)Purpose: As populations shift to include a larger proportion of older adults, the necessity of research targeting older populations is becoming increasingly apparent. Dietary interventions with blueberry have been assocd. with pos. outcomes in cell and rodent models of aging. We hypothesized that dietary blueberry would improve mobility and cognition among older adults. Methods: In this study, 13 men and 24 women, between the ages of 60 and 75 years, were recruited into a randomized, double-blind, placebo-controlled trial in which they consumed either freeze-dried blueberry (24 g/day, equiv. to 1 cup of fresh blueberries) or a blueberry placebo for 90 days. Participants completed a battery of balance, gait, and cognitive tests at baseline and again at 45 and 90 days of intervention. Results: Significant supplement group by study visit interactions were obsd. on tests of executive function. Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal Learning test (p = 0.031, ηp2 = 0.126) and reduced switch cost on a task-switching test (p = 0.033, ηp2 = 0.09) across study visits, relative to controls. However, no improvement in gait or balance was obsd. Conclusions: These findings show that the addn. of easily achievable quantities of blueberry to the diets of older adults can improve some aspects of cognition.
- 26Arts, I. C.; Hollman, P. C. Polyphenols and Disease Risk in Epidemiologic Studies. Am. J. Clin. Nutr. 2005, 81 (1), 317S– 325S, DOI: 10.1093/ajcn/81.1.317S[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvFKktQ%253D%253D&md5=bace162ff1361dccc462917b6526297dPolyphenols and disease risk in epidemiologic studiesArts, Ilja C. W.; Hollman, Peter C. H.American Journal of Clinical Nutrition (2005), 81 (1S), 317S-325SCODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)A review. Plant polyphenols, a large group of natural antioxidants, are candidates for explanation of the protective effects of dietary vegetables and fruits against cancer and cardiovascular diseases. Epidemiol. studies are useful for evaluation of human health effects of long-term exposure to physiol. concns. of polyphenols, but reliable data on polyphenol contents of foods are scarce. Epidemiol. data on health effects of polyphenols are examd. with focus on the flavonoid subclasses of flavonols, flavones, and catechins and on lignans. The data suggest beneficial effects of both flavonoids and lignans on cardiovascular diseases, but not on cancer, with possible exception of lung cancer. There is a need for more research on stroke and lung diseases, such as asthma and chronic obstructive pulmonary disease. Most studies have included only flavonols and flavones. With data becoming available for other polyphenols, these compds. should be included in future studies. Careful design of prospective studies is important to offset some of the major drawbacks of epidemiol. studies, including residual confounding (smoking, other dietary factors) and exposure assessment.
- 27Tsao, R. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2010, 2 (12), 1231– 1246, DOI: 10.3390/nu2121231[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1WiurfP&md5=66c81de74dee653ab2032353b7839563Chemistry and biochemistry of dietary polyphenolsTsao, RongNutrients (2010), 2 (), 1231-1246CODEN: NUTRHU; ISSN:2072-6643. (Molecular Diversity Preservation International)A review. Polyphenols are the biggest group of phytochems., and many of them have been found in plant-based foods. Polyphenol-rich diets have been linked to many health benefits. This paper is intended to review the chem. and biochem. of polyphenols as related to classification, extn., sepn. and anal. methods, their occurrence and biosynthesis in plants, and the biol. activities and implications in human health. The discussions are focused on important and most recent advances in the above aspects, and challenges are identified for future research.
- 28Feliciano, R. P.; Boeres, A.; Massacessi, L.; Istas, G.; Ventura, M. R.; Nunes dos Santos, C.; Heiss, C.; Rodriguez-Mateos, A. Identification and Quantification of Novel Cranberry-Derived Plasma and Urinary (Poly)Phenols. Arch. Biochem. Biophys. 2016, 599, 31– 41, DOI: 10.1016/j.abb.2016.01.014[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFGisLY%253D&md5=9173e5818c01cc39afdfa89adcde9e27Identification and quantification of novel cranberry-derived plasma and urinary (poly)phenolsFeliciano, Rodrigo P.; Boeres, Albert; Massacessi, Luca; Istas, Geoffrey; Ventura, M. Rita; Nunes dos Santos, Claudia; Heiss, Christian; Rodriguez-Mateos, AnaArchives of Biochemistry and Biophysics (2016), 599 (), 31-41CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)Cranberries are a rich source of (poly)phenols, in particular proanthocyanidins, anthocyanins, flavonols, and phenolic acids. However, little is known about their bioavailability in humans. We investigated the absorption, metab., and excretion of cranberry (poly)phenols in plasma and urine of healthy young men after consumption of a cranberry juice (787 mg (poly)phenols). A total of 60 cranberry-derived phenolic metabolites were identified using UPLC-Q-TOF-MS anal. with authentic stds. These included sulfates of pyrogallol, valerolactone, benzoic acids, phenylacetic acids, glucuronides of flavonols, as well as sulfates and glucuronides of cinnamic acids. The most abundant plasma metabolites were small phenolic compds., in particular hippuric acid, catechol-O-sulfate, 2,3-dihydroxybenzoic acid, phenylacetic acid, isoferulic acid, 4-methylcatechol-O-sulfate, α-hydroxyhippuric acid, ferulic acid 4-O-sulfate, benzoic acid, 4-hydroxyphenyl acetic acid, dihydrocaffeic acid 3-O-sulfate, and vanillic acid-4-O-sulfate. Some benzoic acids, cinnamic acids, and flavonol metabolites appeared in plasma early, at 1-2 h post-consumption. Others such as phenylacetic acids, benzaldehydes, pyrogallols, catechols, hippuric and dihydrocinnamic acid derivs. appear in plasma later (Tmax 4-22 h). The 24 h urinary recovery with respect to the amt. of (poly)phenols consumed was 6.2%. Our extensive description of the bioavailability of cranberry (poly)phenols lays important groundwork necessary to start understanding the fate of these compds. in humans.
- 29Rodriguez-Mateos, A.; Heiss, C.; Borges, G.; Crozier, A. Berry (Poly)Phenols and Cardiovascular Health. J. Agric. Food Chem. 2014, 62 (18), 3842– 3851, DOI: 10.1021/jf403757g[ACS Full Text], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsV2it7%252FN&md5=f3907a2817de424fda1e7a646b90b51aBerry (poly)phenols and cardiovascular healthRodriguez-Mateos, Ana; Heiss, Christian; Borges, Gina; Crozier, AlanJournal of Agricultural and Food Chemistry (2014), 62 (18), 3842-3851CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)A review. Berries are rich sources of polyphenols, including anthocyanins, flavan-3-ols, procyanidins, flavonols, ellagitannins, and hydroxycinnamates. Epidemiol. evidence indicates that the cardiovascular health benefits of diets rich in berries are related to their polyphenol content. These findings are supported by small-scale randomized controlled studies that show improvements in several surrogate markers of cardiovascular disease risk, such as blood pressure, endothelial function, arterial stiffness, and blood lipids after acute and short-term consumption of blueberries, strawberries, cranberries, or purified anthocyanin exts. in healthy or diseased individuals. Firm conclusions on the preventive value of berry polyphenols cannot be drawn due to the small no. of existing studies and limitations of the available data, such as lack of controls or failure to assess the absorption and metab. of polyphenols. Although the current evidence is promising, more long-term studies are needed to establish the role of berry polyphenols in support of cardiovascular health.
- 30Rothwell, J. A.; Perez-Jimenez, J.; Neveu, V.; Medina-Remon, A.; M’Hiri, N.; Garcia-Lobato, P.; Manach, C.; Knox, C.; Eisner, R.; Wishart, D. S. Phenol-Explorer 3.0: A Major Update of the Phenol-Explorer Database to Incorporate Data on the Effects of Food Processing on Polyphenol Content. Database 2013, 2013, bat070, DOI: 10.1093/database/bat070
- 31Mena, P.; Bresciani, L.; Brindani, N.; Ludwig, I. A.; Pereira-Caro, G.; Angelino, D.; Llorach, R.; Calani, L.; Brighenti, F.; Clifford, M. N. Phenyl-γ-Valerolactones and Phenylvaleric Acids, the Main Colonic Metabolites of Flavan-3-Ols: Synthesis, Analysis, Bioavailability, and Bioactivity. Nat. Prod. Rep. 2019, 36, 714– 752, DOI: 10.1039/C8NP00062J[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlSru7jI&md5=1d8dd5c3f552f1715dfbe831eca899e5Phenyl-γ-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: synthesis, analysis, bioavailability, and bioactivityMena, Pedro; Bresciani, Letizia; Brindani, Nicoletta; Ludwig, Iziar A.; Pereira-Caro, Gema; Angelino, Donato; Llorach, Rafael; Calani, Luca; Brighenti, Furio; Clifford, Michael N.; Gill, Chris I. R.; Crozier, Alan; Curti, Claudio; Del Rio, DanieleNatural Product Reports (2019), 36 (5), 714-752CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)Covering: 1958 to June 2018Phenyl-γ-valerolactones (PVLs) and their related phenylvaleric acids (PVAs) are the main metabolites of flavan-3-ols, the major class of flavonoids in the human diet. Despite their presumed importance, these gut microbiota-derived compds. have, to date, in terms of biol. activity, been considered subordinate to their parent dietary compds., the flavan-3-ol monomers and proanthocyanidins. In this review, the role and prospects of PVLs and PVAs as key metabolites in the understanding of the health features of flavan-3-ols have been critically assessed. Among the topics covered, are proposals for a standardised nomenclature for PVLs and PVAs. The formation, bioavailability and pharmacokinetics of PVLs and PVAs from different types of flavan-3-ols are discussed, taking into account in vitro and animal studies, as well as inter-individual differences and the existence of putative flavan-3-ol metabotypes. Synthetic strategies used for the prepn. of PVLs are considered and the methodologies for their identification and quantification assessed. Metabolomic approaches unravelling the role of PVLs and PVAs as biomarkers of intake are also described. Finally, the biol. activity of these microbial catabolites in different exptl. models is summarised. Knowledge gaps and future research are considered in this key area of dietary (poly)phenol research.
- 32Williamson, G.; Manach, C. Bioavailability and Bioefficacy of Polyphenols in Humans. II. Review of 93 Intervention Studies. Am. J. Clin. Nutr. 2005, 81 (1), 243S– 255S, DOI: 10.1093/ajcn/81.1.243S[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvFKltQ%253D%253D&md5=a7b2d3f99f5ef967fc4dbc0ff30e3d90Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studiesWilliamson, Gary; Manach, ClaudineAmerican Journal of Clinical Nutrition (2005), 81 (1S), 243S-255SCODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)A review. For some classes of dietary polyphenols, there are now sufficient data from intervention studies to indicate the type and magnitude of in vivo effects in humans on the basis of short-term changes in biomarkers. Isoflavones (soybean genistein and daidzein) have significant effects on bone health in postmenopausal women, together with some weak hormonal effects. Monomeric catechins (found at high concns. in tea) have effects on blood plasma antioxidant biomarkers and energy metab. Procyanidins (oligomeric catechins found at high concns. in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system, including but not limited to blood plasma antioxidant activity. Quercetin (representative of flavonols found at high concns. in onions, apples, red wine, broccoli, tea, and Ginkgo biloba) influences some carcinogenesis markers and has small effects on plasma antioxidant biomarkers in vivo, although some studies failed to find this effect. Compared with the effects of polyphenols in vitro, the effects in vivo are more limited. The reasons for this are lack of validated in vivo biomarkers (esp. in carcinogenesis), lack of long-term studies, and lack of understanding or consideration of bioavailability in vitro which are subsequently used for the design of in vivo expts. It is time to rethink the design of in vitro and in vivo studies, so that these issues are carefully considered. The length of human intervention studies should be increased to more closely reflect the long-term dietary consumption of polyphenols.
- 33Stalmach, A.; Edwards, C. A.; Wightman, J. D.; Crozier, A. Gastrointestinal Stability and Bioavailability of (Poly)Phenolic Compounds Following Ingestion of Concord Grape Juice by Humans. Mol. Nutr. Food Res. 2012, 56 (3), 497– 509, DOI: 10.1002/mnfr.201100566[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xit1Wmtbk%253D&md5=ee4a140a8836848881a39b61b7235f62Gastrointestinal stability and bioavailability of (poly)phenolic compounds following ingestion of Concord grape juice by humansStalmach, Angelique; Edwards, Christine A.; Wightman, JoLynne D.; Crozier, AlanMolecular Nutrition & Food Research (2012), 56 (3), 497-509CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)The in vitro gastrointestinal stability of (poly)phenolic compds. in Concord grape juice was compared with recoveries in ileal fluid after the ingestion of the juice by ileostomists. Recoveries in ileal fluid indicated that 67% of hydroxycinnamate tartarate esters, and smaller percentages of the intake of other (poly)phenolic compds., pass from the small intestine to the colon. The juice was also ingested by healthy subjects with an intact functioning colon. Peak plasma concns. (Cmax) ranged from 1.0 nmol/L for petunidin-3-O-glucoside to 355 nmol/L for dihydrocoumaric acid. Urinary excretion, as an indicator of bioavailability, varied from 0.26% for total anthocyanins to 24% for metabolites of hydroxycinnamate tartarate esters. The Cmax times of the anthocyanins indicated that their low level absorption occurred in the small intestine in contrast to hydroxycinnamate metabolites which were absorbed in both the small and the large intestine where the colonic microflora appeared responsible for hydrogenation of the hydroxycinnamate side chain. The bioavailability of the complex mixt. of (poly)phenolic compds. in Concord grape juice, was very similar to that obsd. in previous studies when compds. were either fed individually or as major components in products contg. a restricted spectrum of (poly)phenolic compds.
- 34Day, A. J; Canada, F.J.; Dıaz, J. C; Kroon, P. A; Mclauchlan, R.; Faulds, C. B; Plumb, G. W; Morgan, M. R.A; Williamson, G. Dietary Flavonoid and Isoflavone Glycosides Are Hydrolysed by the Lactase Site of Lactase Phlorizin Hydrolase. FEBS Lett. 2000, 468 (2–3), 166– 170, DOI: 10.1016/S0014-5793(00)01211-4[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1OitbY%253D&md5=4fb10628f5800a8eb739c25ae45f1b79Dietary flavonoid and isoflavone glycosides are hydrolyzed by the lactase site of lactase phlorizin hydrolaseDay, A. J.; Canada, F. J.; Diaz, J. C.; Kroon, P. A.; Mclauchlan, R.; Faulds, C. B.; Plumb, G. W.; Morgan, M. R. A.; Williamson, G.FEBS Letters (2000), 468 (2,3), 166-170CODEN: FEBLAL; ISSN:0014-5793. (Elsevier Science B.V.)Lactase phlorizin hydrolase (LPH; EC 3.2.1.62) is a membrane-bound, family 1 β-glycosidase found on the brush border of the mammalian small intestine. LPH, purified from sheep small intestine, was capable of hydrolyzing a range of flavonol and isoflavone glycosides. The catalytic efficiency (kcat/Km) for the hydrolysis of quercetin-4'-glucoside, quercetin-3-glucoside, genistein-7-glucoside and daidzein-7-glucoside was 170, 137, 77, and 14 (mM-1 s-1) resp. The majority of the activity occurred at the lactase and not phlorizin hydrolase site. The ability of LPH to deglycosylate dietary (iso)flavonoid glycosides suggests a possible role for this enzyme in the metab. of these biol. active compds.
- 35Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J. P. E.; Tognolini, M.; Borges, G.; Crozier, A. Dietary (Poly)Phenolics in Human Health: Structures, Bioavailability, and Evidence of Protective Effects Against Chronic Diseases. Antioxid. Redox Signaling 2013, 18 (14), 1818– 1892, DOI: 10.1089/ars.2012.4581[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltlKltLY%253D&md5=581508c16b497392e129fd795aee9b91Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseasesDel Rio, Daniele; Rodriguez-Mateos, Ana; Spencer, Jeremy P. E.; Tognolini, Massimiliano; Borges, Gina; Crozier, AlanAntioxidants & Redox Signaling (2013), 18 (14), 1818-1892CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)A review. Human intervention trials have provided evidence for protective effects of various (poly)phenol-rich foods against chronic disease, including cardiovascular disease, neurodegeneration, and cancer. While there are considerable data suggesting benefits of (poly)phenol intake, conclusions regarding their preventive potential remain unresolved due to several limitations in existing studies. Bioactivity investigations using cell lines have made an extensive use of both (poly)phenolic aglycons and sugar conjugates, these being the typical forms that exist in planta, at concns. in the low-μM-to-mM range. However, after ingestion, dietary (poly)phenolics appear in the circulatory system not as the parent compds., but as phase II metabolites, and their presence in plasma after dietary intake rarely exceeds nM concns. Substantial quantities of both the parent compds. and their metabolites pass to the colon where they are degraded by the action of the local microbiota, giving rise principally to small phenolic acid and arom. catabolites that are absorbed into the circulatory system. This comprehensive review describes the different groups of compds. that have been reported to be involved in human nutrition, their fate in the body as they pass through the gastrointestinal tract and are absorbed into the circulatory system, the evidence of their impact on human chronic diseases, and the possible mechanisms of action through which (poly)phenol metabolites and catabolites may exert these protective actions. It is concluded that better performed in vivo intervention and in vitro mechanistic studies are needed to fully understand how these mols. interact with human physiol. and pathol. processes. Antioxid. Redox Signal. 18, 1818-1892.
- 36González-Sarrías, A.; García-Villalba, R.; Romo-Vaquero, M.; Alasalvar, C.; Örem, A.; Zafrilla, P.; Tomás-Barberán, F. A.; Selma, M. V.; Espín, J. C. Clustering According to Urolithin Metabotype Explains the Interindividual Variability in the Improvement of Cardiovascular Risk Biomarkers in Overweight-Obese Individuals Consuming Pomegranate: A Randomized Clinical Trial. Mol. Nutr. Food Res. 2017, 61 (5), 1600830, DOI: 10.1002/mnfr.201600830
- 37Espín, J. C.; Larrosa, M.; García-Conesa, M. T.; Tomás-Barberán, F. Biological Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The Evidence So Far. Evidence-Based Complement. Altern. Med. 2013, 2013, 1– 15, DOI: 10.1155/2013/270418
- 38Plant Phenolics and Human Health; Fraga, C. G., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2009; DOI: 10.1002/9780470531792 .
- 39Bialonska, D.; Kasimsetty, S. G.; Khan, S. I.; Ferreira, D. Urolithins, Intestinal Microbial Metabolites of Pomegranate Ellagitannins, Exhibit Potent Antioxidant Activity in a Cell-Based Assay. J. Agric. Food Chem. 2009, 57 (21), 10181– 10186, DOI: 10.1021/jf9025794[ACS Full Text], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1GgsbzE&md5=f152e36a43cafaa2e8330439c573e67aUrolithins, Intestinal Microbial Metabolites of Pomegranate Ellagitannins, Exhibit Potent Antioxidant Activity in a Cell-Based AssayBialonska, Dobroslawa; Kasimsetty, Sashi G.; Khan, Shabana I.; Ferreira, DaneelJournal of Agricultural and Food Chemistry (2009), 57 (21), 10181-10186CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Many health benefits of pomegranate products have been attributed to the potent antioxidant action of their tannin components, mainly punicalagins and ellagic acid. While moving through the intestines, ellagitannins are metabolized by gut bacteria into urolithins that readily enter systemic circulation. In this study, the antioxidant properties of seven urolithin derivs. were evaluated in a cell-based assay. This method is biol. more relevant because it reflects bioavailability of the test compd. to the cells, and the antioxidant action is detd. in the cellular environment. Our results showed that the antioxidant activity of urolithins was correlated with the no. of hydroxy groups as well as the lipophilicity of the mol. The most potent antioxidants are urolithins C and D with IC50 values of 0.16 and 0.33 μM, resp., when compared to IC50 values of 1.1 and 1.4 μM of the parent ellagic acid and punicalagins, resp. The dihydroxylated urolithin A showed weaker antioxidant activity, with an IC50 value 13.6 μM, however, the potency was within the range of urolithin A plasma concns. Therefore, products of the intestinal microbial transformation of pomegranate ellagitannins may account for systemic antioxidant effects.
- 40Brinquin, L.; Philip, Y.; Le Gulluche, Y.; Bonsignour, J. P.; Buffat, J. J. Anesthésie Pour Chirurgie d’un Phéochromocytome Malin. Accès Hypertensif Après Administration de Dropéridol. Ann. Fr. Anesth. Reanim. 1987, 6 (3), 204– 206, DOI: 10.1016/S0750-7658(87)80080-1[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s3ps12hsg%253D%253D&md5=858cb6ece15c51600d16d83e221b0cf1Anesthesia for the surgery of malignant pheochromocytoma. Hypertensive crisis after the administration of droperidolBrinquin L; Philip Y; Le Gulluche Y; Bonsignour J P; Buffat J JAnnales francaises d'anesthesie et de reanimation (1987), 6 (3), 204-6 ISSN:0750-7658.A case of malignant phaeochromocytoma is reported. Computerized tomography and scintigraphy using metaiodobenzylguanidine localized the tumour and metastases. The anesthetic management included invasive monitoring of pulmonary pressures with a Swan-Ganz catheter and arterial pressure with a radial arterial cannula. Plasma catecholamine concentrations were measured before and during adrenalectomy and resection of a metastatic lesion on the fourth right rib. Induction of anaesthesia was carried out with droperidol, phenoperidine, thiopentone and pancuronium. After intravenous administration of droperidol, blood pressure increased together with the heart rate, vascular resistances and pulmonary pressure, whilst cardiac output decreased. Plasma noradrenaline levels were also greatly increased at the same time. The mechanism of this paradoxic pressor effect of droperidol is discussed.
- 41Perez-Ternero, C.; Macià, A.; de Sotomayor, M. A.; Parrado, J.; Motilva, M.-J.; Herrera, M.-D. Bioavailability of the Ferulic Acid-Derived Phenolic Compounds of a Rice Bran Enzymatic Extract and Their Activity against Superoxide Production. Food Funct. 2017, 8 (6), 2165– 2174, DOI: 10.1039/C7FO00243B[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVSmtbs%253D&md5=8b79e23e6d7763c2739e67845d9d1597Bioavailability of the ferulic acid-derived phenolic compounds of a rice bran enzymatic extract and their activity against superoxide productionPerez-Ternero, Cristina; Macia, Alba; de Sotomayor, Maria Alvarez; Parrado, Juan; Motilva, Maria-Jose; Herrera, Maria-DoloresFood & Function (2017), 8 (6), 2165-2174CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)Rice bran is an exceptional source of such antioxidant mols. as γ-oryzanol and ferulic acid, but their bioavailability and metab. within this matrix remain unknown. The aims of this work were to describe the oral bioavailability and metabolic pathways of the ferulic acid-derived phenolic compds. contained in a rice bran enzymic ext. (RBEE), and to det. its effect on NADPH oxidase activity. Wistar rats were administered with RBEE and sacrificed at different times over a period of 24 h to obtain plasma. An addnl. group was used for collection of urine and faeces over a period of 48 h. The phenolic metabolites were detd. by ultra-performance liq. chromatog. coupled to tandem mass spectrometry (UPLC-MS/MS), and plasma pharmacokinetic parameters were calcd. In parallel, aortic rings were incubated in the plasma of rats sacrificed 30 min after RBEE gavage, or in the presence of RBEE, ferulic acid or γ-oryzanol. Endothelin-1-induced superoxide prodn. was recorded by lucigenin-enhanced luminescence. Twenty-five ferulic acid metabolites showing biphasic behavior were found in the plasma, most of which were found in the urine as well, while in the faeces, colonic metab. led to simpler phenolic compds. Superoxide prodn. was abrogated by phenolic compd.-enriched plasma and by RBEE and ferulic acid, thus showing the biol. potential of RBEE as a nutraceutical ingredient.
- 42Williamson, G.; Clifford, M. N. Role of the Small Intestine, Colon and Microbiota in Determining the Metabolic Fate of Polyphenols. Biochem. Pharmacol. 2017, 139, 24– 39, DOI: 10.1016/j.bcp.2017.03.012[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXksFeqsLs%253D&md5=d121ba41e2dba5a13401611ac4e07251Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenolsWilliamson, Gary; Clifford, Michael N.Biochemical Pharmacology (Amsterdam, Netherlands) (2017), 139 (), 24-39CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)A review. (Poly)phenols are a large group of compds., found in food, beverages, dietary supplements and herbal medicines. Owing to interest in their biol. activities, absorption and metab. of the most abundant compds. in humans are well understood. Both the chem. structure of the phenolic moiety and any attached chem. groups define whether the polyphenol is absorbed in the small intestine, or reaches the colon and is subject to extensive catabolism by colonic microbiota. Untransformed substrates may be absorbed, appearing in plasma primarily as methylated, sulfated and glucuronidated derivs., with in some cases the unchanged substrate. Many of the catabolites are well absorbed from the colon and appear in the plasma either similarly conjugated, or as glycine conjugates, or in some cases unchanged. Although many (poly)phenol catabolites have been identified in human plasma and/or urine, the exact pathways from substrate to final microbial catabolite, and the species of bacteria and enzymes involved, are still scarcely reported. While it is clear that the compn. of the human gut microbiota can be modulated in vivo by supplementation with some (poly)phenol-rich commodities, such modulation is definitely not an inevitable consequence of supplementation; it depends on the treatment, length of time and on the individual metabotype, and it is not clear whether the modulation is sustained when supplementation ceases. Some catabolites have been recorded in plasma of volunteers at concns. similar to those shown to be effective in in vitro studies suggesting that some benefit may be achieved in vivo by diets yielding such catabolites.
- 43Pasinetti, G. M.; Singh, R.; Westfall, S.; Herman, F.; Faith, J.; Ho, L. The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. J. Alzheimer's Dis. 2018, 63 (2), 409– 421, DOI: 10.3233/JAD-171151[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotlCnurc%253D&md5=d3f916ceec8f68c3ee6a4ecf17dbad96The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic MicePasinetti, Giulio Maria; Singh, Risham; Westfall, Susan; Herman, Francis; Faith, Jeremiah; Ho, LapJournal of Alzheimer's Disease (2018), 63 (2), 409-421CODEN: JADIF9; ISSN:1387-2877. (IOS Press)A growing body of exptl. data suggests that microbes in the gut influence behavior and can alter brain physiol. and neurochem. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurol. disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metab. and bioavailability of certain dietary compds. and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms assocd. with the promotion of resilience against psychol. and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.
- 44Czank, C.; Cassidy, A.; Zhang, Q.; Morrison, D. J.; Preston, T.; Kroon, P. A.; Botting, N. P.; Kay, C. D. Human Metabolism and Elimination of the Anthocyanin, Cyanidin-3-Glucoside: A 13C-Tracer Study. Am. J. Clin. Nutr. 2013, 97 (5), 995– 1003, DOI: 10.3945/ajcn.112.049247[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmvFSmtrw%253D&md5=699339119331251badae3f046c78144cHuman metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a 13C-tracer studyCzank, Charles; Cassidy, Aedin; Zhang, Qingzhi; Morrison, Douglas J.; Preston, Tom; Kroon, Paul A.; Botting, Nigel P.; Kay, Colin D.American Journal of Clinical Nutrition (2013), 97 (5), 995-1003CODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)Background: Evidence suggests that the consumption of anthocyanin-rich foods beneficially affects cardiovascular health; however, the absorption, distribution, metab., and elimination (ADME) of anthocyanin-rich foods are relatively unknown. Objective: We investigated the ADME of a 13C5-labeled anthocyanin in humans. Design: Eight male participants consumed 500 mg isotopically labeled cyanidin-3-glucoside (6,8,10,3',5'-13C5-C3G). Biol. samples were collected over 48 h, and 13C and 13C-labeled metabolite concns. were measured by using isotope-ratio mass spectrometry and liq. chromatog.-tandem mass spectrometry. Results: The mean ± SE percentage of 13C recovered in urine, breath, and feces was 43.9 ± 25.9% (range: 15.1-99.3% across participants). The relative bioavailability was 12.38 ± 1.38% (5.37 ± 0.67% excreted in urine and 6.91 ± 1.59% in breath). Maximum rates of 13C elimination were achieved 30 min after ingestion (32.53 ± 14.24 μg13C/h), whereas 13C-labeled metabolites peaked (max. serum concn.: 5.97 ± 2.14 μmol/L) at 10.25 ± 4.14 h. The half-life for 13C-labeled metabolites ranged between 12.44 ± 4.22 and 51.62 ± 22.55 h. 13C elimination was greatest between 0 and 1 h for urine (90.30 ± 15.28 μg/h), at 6 h for breath (132.87 ± 32.23 μg/h), and between 6 and 24 h for feces (557.28 ± 247.88 μg/h), whereas the highest concns. of 13C-labeled metabolites were identified in urine (10.77 ± 4.52 μmol/L) and fecal samples (43.16 ± 18.00 μmol/L) collected between 6 and 24 h. Metabolites were identified as degrdn. products, phenolic, hippuric, phenylacetic, and phenylpropenoic acids. Conclusion: Anthocyanins are more bioavailable than previously perceived, and their metabolites are present in the circulation for ≤48 h after ingestion.
- 45Pimpão, R. C.; Ventura, M. R.; Ferreira, R. B.; Williamson, G.; Santos, C. N. Phenolic Sulfates as New and Highly Abundant Metabolites in Human Plasma after Ingestion of a Mixed Berry Fruit Purée. Br. J. Nutr. 2015, 113 (3), 454– 463, DOI: 10.1017/S0007114514003511[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit1CmsL0%253D&md5=19f03a84514b541a235bda5b69715ed6Phenolic sulfates as new and highly abundant metabolites in human plasma after ingestion of a mixed berry fruit pureePimpao, Rui C.; Ventura, M. Rita; Ferreira, Ricardo B.; Williamson, Gary; Santos, Claudia N.British Journal of Nutrition (2015), 113 (3), 454-463CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)Bioavailability studies are vital to assess the potential impact of bioactive compds. on human health. Although conjugated phenolic metabolites derived from colonic metab. have been identified in the urine, the quantification and appearance of these compds. in plasma is less well studied. In this regard, it is important to further assess their potential biol. activity in vivo. To address this gap, a cross-over intervention study with a mixed fruit puree (blueberry, blackberry, raspberry, strawberry tree fruit and Portuguese crowberry) and a std. polyphenol-free meal was conducted in thirteen volunteers (ten females and three males), who received each test meal once, and plasma metabolites were identified by HPLC-MS/MS. Sulfated compds. were chem. synthesized and used as stds. to facilitate quantification. Gallic and caffeic acid conjugates were absorbed rapidly, reaching a max. concn. between 1 and 2 h. The concns. of sulfated metabolites resulting from the colonic degrdn. of more complex polyphenols increased in plasma from 4 h, and pyrogallol sulfate and catechol sulfate reached concns. ranging from 5 to 20 μm at 6 h. In conclusion, phenolic sulfates reached high concns. in plasma, as opposed to their undetected parent compds. These compds. have potential use as biomarkers of polyphenol intake, and their biol. activities need to be considered.
- 46Penczynski, K. J.; Krupp, D.; Bring, A.; Bolzenius, K.; Remer, T.; Buyken, A. E. Relative Validation of 24-h Urinary Hippuric Acid Excretion as a Biomarker for Dietary Flavonoid Intake from Fruit and Vegetables in Healthy Adolescents. Eur. J. Nutr. 2017, 56 (2), 757– 766, DOI: 10.1007/s00394-015-1121-9[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVGrsbvK&md5=33ecba4768848db7f233e6d46e633ca4Relative validation of 24-h urinary hippuric acid excretion as a biomarker for dietary flavonoid intake from fruit and vegetables in healthy adolescentsPenczynski, Katharina J.; Krupp, Danika; Bring, Anna; Bolzenius, Katja; Remer, Thomas; Buyken, Anette E.European Journal of Nutrition (2017), 56 (2), 757-766CODEN: EJNUFZ; ISSN:1436-6207. (Springer)Purpose: A biomarker for dietary flavonoid intake from fruit and vegetables (FlavFV) is needed to elucidate the relevance of flavonoids from these sources for the prevention of chronic diseases. Urinary hippuric acid (HA)-a major metabolite of flavonoids-is promising in this respect as it was shown to satisfyingly indicate fruit and vegetable consumption in different age groups. Therefore, we validated urinary HA as a biomarker for intake of FlavFV. Methods: Analyses included data from 287 healthy adolescents of the DONALD Study (aged 9-16 years) for whom a min. of two pairs of HA measurements from 24-h urine samples (test method) and FlavFV intake estd. from 3-day weighed dietary records (ref. method) existed. Agreement between both methods was assessed by Spearman correlation and cross-classification analyses. Possible confounders of the assocn. were identified by linear regression models. Analyses were performed using a split-sample approach allowing for consecutive exploration (n = 192) and confirmation (n = 95) of results. Results: Agreement between urinary HA excretion and FlavFV intake was moderate according to correlation anal. in the exploratory sample (runadjusted = 0.47, P < 0.0001). Yet, 79 % of the subjects were classified into same/adjacent quartiles, and only 5 % were misclassified into opposite quartiles. These findings were corroborated by analyses in the confirmatory sample (runadjusted = 0.64; 88 % in same/adjacent vs. 4 % in opposite quartiles). Body surface area (BSA) was the only relevant covariate in the exploratory sample, and its adjustment improved cross-classification ests. in both subsamples. Conclusions: BSA-adjusted 24-h urinary HA excretion represents a suitable biomarker of habitual FlavFV intake in healthy adolescents.
- 47Schaffer, S.; Halliwell, B. Do Polyphenols Enter the Brain and Does It Matter? Some Theoretical and Practical Considerations. Genes Nutr. 2012, 7 (2), 99– 109, DOI: 10.1007/s12263-011-0255-5[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XltVKitr8%253D&md5=b5e38a6f0afba9830f0b14ade3aaf41eDo polyphenols enter the brain and does it matter? Some theoretical and practical considerationsSchaffer, Sebastian; Halliwell, BarryGenes and Nutrition (2012), 7 (2), 99-109CODEN: GNEUAZ; ISSN:1555-8932. (Springer)A review. Although several epidemiol. and intervention studies suggest that polyphenols (PPs) and PP-rich foods may improve memory and cognition in animals and humans, PPs' mode of action is only poorly understood. To help distinguish between the different modes of action that have been proposed for PPs, it is obviously important to know how much PPs can accumulate in the brain, if any at all. However, reliable data on PP uptake into the brain of animals are limited as many studies failed to report important control procedures during data acquisition. In this paper, we summarize published data on the penetration of PPs into animal brain and review some hypotheses to explain the biol. basis of potentially health-beneficial effects of PPs to the brain. Finally, we highlight promising new approaches, esp. those of a hormetic dose-response and gut microbiota-brain interaction, which may allow a better understanding of PPs' mode of action in animals and humans.
- 48Cardoso, C. G., Jr; Gomides, R. S.; Queiroz, A. C. C.; Pinto, L. G.; Lobo, F. da S.; Tinucci, T.; Mion, D., Jr; Forjaz, C. L. de M. Acute and Chronic Effects of Aerobic and Resistance Exercise on Ambulatory Blood Pressure. Clinics 2010, 65 (3), 317– 325, DOI: 10.1590/S1807-59322010000300013[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3jtFeltw%253D%253D&md5=8b8aa1c3b96401e88301dc38b06b67a6Acute and chronic effects of aerobic and resistance exercise on ambulatory blood pressureCardoso Crivaldo Gomes Jr; Gomides Ricardo Saraceni; Queiroz Andreia Cristiane Carrenho; Pinto Luiz Gustavo; da Silveira Lobo Fernando; Tinucci Tais; Mion Decio Jr; de Moraes Forjaz Claudia LuciaClinics (Sao Paulo, Brazil) (2010), 65 (3), 317-25 ISSN:.Hypertension is a ubiquitous and serious disease. Regular exercise has been recommended as a strategy for the prevention and treatment of hypertension because of its effects in reducing clinical blood pressure; however, ambulatory blood pressure is a better predictor of target-organ damage than clinical blood pressure, and therefore studying the effects of exercise on ambulatory blood pressure is important as well. Moreover, different kinds of exercise might produce distinct effects that might differ between normotensive and hypertensive subjects.The aim of this study was to review the current literature on the acute and chronic effects of aerobic and resistance exercise on ambulatory blood pressure in normotensive and hypertensive subjects. It has been conclusively shown that a single episode of aerobic exercise reduces ambulatory blood pressure in hypertensive patients. Similarly, regular aerobic training also decreases ambulatory blood pressure in hypertensive individuals. In contrast, data on the effects of resistance exercise is both scarce and controversial. Nevertheless, studies suggest that resistance exercise might acutely decrease ambulatory blood pressure after exercise, and that this effect seems to be greater after low-intensity exercise and in patients receiving anti-hypertensive drugs. On the other hand, only two studies investigating resistance training in hypertensive patients have been conducted, and neither has demonstrated any hypotensive effect. Thus, based on current knowledge, aerobic training should be recommended to decrease ambulatory blood pressure in hypertensive individuals, while resistance exercise could be prescribed as a complementary strategy.
- 49Milbury, P. E.; Kalt, W. Xenobiotic Metabolism and Berry Flavonoid Transport across the Blood–Brain Barrier. J. Agric. Food Chem. 2010, 58 (7), 3950– 3956, DOI: 10.1021/jf903529m[ACS Full Text], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGitrg%253D&md5=f42ac0eef009ab3c23752d14d4c6719aXenobiotic Metabolism and Berry Flavonoid Transport across the Blood-Brain BarrierMilbury, Paul E.; Kalt, WilhelminaJournal of Agricultural and Food Chemistry (2010), 58 (7), 3950-3956CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)A compelling body of literature suggests berry phytochems. play beneficial roles in reversing age-related cognitive impairment and protect against neurodegenerative disorders. Anthocyanins are bioactive phytochems. in berries suspected to be responsible for some of these neuroprotective effects. The plausible mechanisms of anthocyanin bioactivity in brain tissue are dependent on their bioavailability to the brain. Pigs were fed 2% whole freeze-dried, powd. blueberry in the diet for 8 wk. Anthocyanin and anthocyanin glucuronides were measured in the cortex, cerebellum, and midbrain and diencephalon by LC-MS/MS. Anthocyanins and their glucuronides were found in the range of femtomoles per g of fresh wt. of tissue at 18 h postprandial, after anthocyanins had been removed from the blood by xenobiotic metab. Xenobiotic metab., anthocyanin interaction, and transporter barriers to brain bioavailability are briefly discussed. The plausible mechanism of neuroprotective action of anthocyanins may be via modulation of signal transduction processes and/or gene expression in brain tissue rather than by direct antioxidant radical quenching.
- 50Gasperotti, M.; Passamonti, S.; Tramer, F.; Masuero, D.; Guella, G.; Mattivi, F.; Vrhovsek, U. Fate of Microbial Metabolites of Dietary Polyphenols in Rats: Is the Brain Their Target Destination?. ACS Chem. Neurosci. 2015, 6 (8), 1341– 1352, DOI: 10.1021/acschemneuro.5b00051[ACS Full Text], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXms1Ogsbo%253D&md5=cbc5a1644ee09f6fe8e3070cfdfd0f7eFate of microbial metabolites of dietary polyphenols in rats: Is the brain their target destination?Gasperotti, Mattia; Passamonti, Sabina; Tramer, Federica; Masuero, Domenico; Guella, Graziano; Mattivi, Fulvio; Vrhovsek, UrskaACS Chemical Neuroscience (2015), 6 (8), 1341-1352CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Different polyphenol compds. are ingested when consuming a serving of fruits rich in polyphenols, spanning from one-phenol hydroxybenzoic acid to more complex polymeric compds. Only a minor quantity of the polyphenols (5-10%) is absorbed. The remainder reaches the colon and is extensively metabolized by gut microbiota to low-mol. wt. metabolites. Their subsequent tissue distribution is still undefined, although these microbial metabolites are currently believed to play a role in human health and disease states. To fill this knowledge gap, we performed a pharmacokinetics expt. in which a single bolus of 23 polyphenol microbial metabolites (total 2.7 μmol) was administered i.v. to rats to reliably reproduce a physiol. postabsorption situation. Tissues and urine were collected shortly thereafter (15 s to 15 min) and were analyzed by UHPLC-MS/MS to quant. track these compds. Remarkably, the brain was found to be a specific target organ for 10 of the 23 polyphenol metabolites injected, which significantly increased in the treated animals. In most cases, their appearance in the brain was biphasic, with an early wave at 2 min (4 compds.) and a second wave starting at 5 min; at 15 min, 9 compds. were still detectable. Most compds. were excreted into the urine. The concns. in the brain of the treated animals were compared against those of the control group by Student's t test, with p-values < 0.1 considered to be statistically significant. These findings provide new perspectives for understanding the role of diet on brain chem. Our exptl. approach has enabled us to obtain rich metabolomics information from a single expt. involving a limited no. of animals.
- 51van Praag, H.; Lucero, M. J.; Yeo, G. W.; Stecker, K.; Heivand, N.; Zhao, C.; Yip, E.; Afanador, M.; Schroeter, H.; Hammerstone, J. Plant-Derived Flavanol (−)Epicatechin Enhances Angiogenesis and Retention of Spatial Memory in Mice. J. Neurosci. 2007, 27 (22), 5869– 5878, DOI: 10.1523/JNEUROSCI.0914-07.2007[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsVWktrw%253D&md5=faf4e569bec8271be1b03b9baddb4a04Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in micevan Praag, Henriette; Lucero, Melanie J.; Yeo, Gene W.; Stecker, Kimberly; Heivand, Neema; Zhao, Chunmei; Yip, Ed; Afanador, Mia; Schroeter, Hagen; Hammerstone, John; Gage, Fred H.Journal of Neuroscience (2007), 27 (22), 5869-5878CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Diet and exercise have a profound impact on brain function. In particular, natural nutrients found in plants may influence neuronal survival and plasticity. Here, we tested whether consumption of a plant-derived flavanol, (-)epicatechin, enhances cognition in sedentary or wheel-running female C57BL/6 mice. Retention of spatial memory in the water maze was enhanced by ingestion of (-)epicatechin, esp. in combination with exercise. Improved spatial memory was assocd. with increased angiogenesis and neuronal spine d., but not newborn cell survival, in the dentate gyrus of the hippocampus. Moreover, microarray anal. showed upregulation of genes assocd. with learning and downregulation of markers of neurodegeneration in the hippocampus. Together, our data show that ingestion of a single flavanol improves spatial memory retention in adult mammals.
- 52El Mohsen, M. A.; Marks, J.; Kuhnle, G.; Rice-Evans, C.; Moore, K.; Gibson, G.; Debnam, E.; Srai, S. K. The Differential Tissue Distribution of the Citrus Flavanone Naringenin Following Gastric Instillation. Free Radical Res. 2004, 38 (12), 1329– 1340, DOI: 10.1080/10715760400017293[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFCqur%252FN&md5=22051b933e598c51b7438f9c61c60a95The Differential Tissue Distribution of the Citrus Flavanone Naringenin Following Gastric InstillationEl Mohsen, Manal Abd; Marks, Joanne; Kuhnle, Gunter; Rice-Evans, Catherine; Moore, Kevin; Gibson, Glenn; Debnam, Edward; Srai, S. KailaFree Radical Research (2004), 38 (12), 1329-1340CODEN: FRARER; ISSN:1071-5762. (Taylor & Francis Ltd.)Citrus flavonoids have been investigated for their biol. activity, with both anti-inflammatory and -carcinogenic effects being reported. However, little information is known on the bioavailability of these compds. in vivo. The objectives of this study were to det. the tissue distribution of naringenin after gastric gavage of [3H]-naringenin to rats. Unlabeled naringenin was also used to quantify the levels of naringenin and its major metabolites in tissues and eliminated in the urine and feces. Significant radioactivity was detected in the plasma as well as all tissues examd. 2 h post-gavage. After 18 h, higher levels of radioactivity were retained in plasma and tissues (55% of the administered radioactivity). Investigation of the nature of metabolites, using unlabeled naringenin, revealed that the glucuronides were the major components in plasma, tissues and urine, in addn. to the colonic metabolite 3-(4-hydroxyphenyl) propionic acid, detected in the urine. The aglycon was the form extensively retained in tissues after 18 h post-gavage. Total identified metabolites detected after 18 h in most tissues were only 1-5% of the levels detected after 2 h. However, the brain, lungs and heart retained 27, 20 and 11%, resp., relative to the total metabolites detected at 2 h. While radioactive detection suggests increased levels of breakdown products of naringenin after 18 h vs. 2 h, the products identified using unlabeled naringenin are not consistent with this, suggesting that a predominant proportion of the naringenin breakdown products at 18 h are retained as smaller decompn. mols. which cannot yet be identified.
- 53Ishisaka, A.; Ichikawa, S.; Sakakibara, H.; Piskula, M. K.; Nakamura, T.; Kato, Y.; Ito, M.; Miyamoto, K.; Tsuji, A.; Kawai, Y. Accumulation of Orally Administered Quercetin in Brain Tissue and Its Antioxidative Effects in Rats. Free Radical Biol. Med. 2011, 51 (7), 1329– 1336, DOI: 10.1016/j.freeradbiomed.2011.06.017[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFSjsLbL&md5=26c4264c0b30ed01546d63ecc2a2ed8fAccumulation of orally administered quercetin in brain tissue and its antioxidative effects in ratsIshisaka, Akari; Ichikawa, Satomi; Sakakibara, Hiroyuki; Piskula, Mariusz K.; Nakamura, Toshiyuki; Kato, Yoji; Ito, Mikiko; Miyamoto, Ken-ichi; Tsuji, Akira; Kawai, Yoshichika; Terao, JunjiFree Radical Biology & Medicine (2011), 51 (7), 1329-1336CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)Quercetin is widely distributed in vegetables and herbs and has been suggested to act as a neuroprotective agent. Here, we demonstrate that quercetin can accumulate enough to exert biol. activity in rat brain tissues. Homogenates of perfused rat brain without detectable Hb contaminants were treated with β-glucuronidase/sulfatase and the released quercetin and its methylated form were analyzed using high-performance liq. chromatog. (HPLC) with three different detection methods. Both quercetin and the methylated form were detected in the brain of quercetin-administered rats using HPLC-UV and HPLC with electrochem. detection and were further identified using HPLC-tandem mass spectrometry. Oral administration of quercetin (50 mg/kg body wt) attenuated the increased oxidative stress in the hippocampus and striatum of rats exposed to chronic forced swimming. The possible transport of quercetin derivs. into the brain tissue was reproduced in vitro by using a rat brain capillary endothelial cell line, a model of the blood-brain barrier. These results show that quercetin could be a potent nutrient that can access the brain and protect it from disorders assocd. with oxidative stress.
- 54Talavéra, S.; Felgines, C.; Texier, O.; Besson, C.; Gil-Izquierdo, A.; Lamaison, J.-L.; Rémésy, C. Anthocyanin Metabolism in Rats and Their Distribution to Digestive Area, Kidney, and Brain. J. Agric. Food Chem. 2005, 53 (10), 3902– 3908, DOI: 10.1021/jf050145v[ACS Full Text], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtFSjtbw%253D&md5=7802c502c089132ee8984d71187f50f0Anthocyanin metabolism in rats and their distribution to digestive area, kidney, and brainTalavera, Severine; Felgines, Catherine; Texier, Odile; Besson, Catherine; Gil-Izquierdo, Angel; Lamaison, Jean-Louis; Remesy, ChristianJournal of Agricultural and Food Chemistry (2005), 53 (10), 3902-3908CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Anthocyanins are present in human diets due to their wide occurrence in fruits and vegetables. They have antioxidant activities and could have several health effects. The anthocyanin metab. and tissue distribution in the digestive organs (stomach, jejunum, liver), kidney, and brain were studied in male Wistar rats fed diet with blackberry (Rubus fruticosus) anthocyanins for 15 days. Identification and quantification of anthocyanin metabolites was done by HPLC-ESI-MS-MS and HPLC-DAD, resp. The stomach contained only native blackberry anthocyanins (cyanidin 3-O-glucoside, cyanidin 3-O-pentose), while in other organs (jejunum, liver, kidney) contained native and methylated anthocyanins and conjugated anthocyanidins (cyanidin and peonidin monoglucuronides). Proportions of anthocyanin derivs. differed according to the organs, with the liver having the highest proportion of methylated forms. Jejunum and blood plasma also contained aglycon forms. In the brain, the total anthocyanin content (blackberry anthocyanins and peonidin 3-O-glucoside) reached 0.25±0.05 nmol/g tissue. The urinary excretion of total anthocyanins was low (0.19±0.02% of ingested amt.). Thus, digestive organs have metabolic pathways for anthocyanins with enzymic conversions (methylation and/or glucuronide conjugation). Following consumption of an anthocyanin-rich diet, anthocyanins also enter the brain.
- 55Bo, C. D.; Ciappellano, S.; Klimis-Zacas, D.; Martini, D.; Gardana, C.; Riso, P.; Porrini, M. Anthocyanin Absorption, Metabolism, and Distribution from a Wild Blueberry-Enriched Diet (Vaccinium Angustifolium) Is Affected by Diet Duration in the Sprague–Dawley Rat. J. Agric. Food Chem. 2010, 58 (4), 2491– 2497, DOI: 10.1021/jf903472x
- 56Wu, L.; Zhang, Q.-L.; Zhang, X.-Y.; Lv, C.; Li, J.; Yuan, Y.; Yin, F.-X. Pharmacokinetics and Blood–Brain Barrier Penetration of (+)-Catechin and (−)-Epicatechin in Rats by Microdialysis Sampling Coupled to High-Performance Liquid Chromatography with Chemiluminescence Detection. J. Agric. Food Chem. 2012, 60 (37), 9377– 9383, DOI: 10.1021/jf301787f[ACS Full Text], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1Ghu73P&md5=ffcbc7080fad39a1a7165331b9b246bbPharmacokinetics and Blood-Brain Barrier Penetration of (+)-Catechin and (-)-Epicatechin in Rats by Microdialysis Sampling Coupled to High-Performance Liquid Chromatography with Chemiluminescence DetectionWu, Liang; Zhang, Qun-Lin; Zhang, Xiao-Yue; Lv, Chen; Li, Jun; Yuan, Ye; Yin, Fang-XiongJournal of Agricultural and Food Chemistry (2012), 60 (37), 9377-9383CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)(+)-Catechin (C) and (-)-epicatechin (EC), as the basic monomer units of flavanols, can be widely found in natural products or medicinal herbs. Recent pharmacol. studies have revealed that C and EC exhibit good neuroprotective effects. However, there is little information about pharmacokinetic profiles in the brain and in vivo BBB penetration of C and EC. In this paper, an ultrasensitive method using high-performance liq. chromatog. (HPLC) with chemiluminescence (CL) detection was developed for the anal. of microdialysis samples. The detection limits for C and EC in Ringer's soln. were 1.0 and 1.2 ng/mL, resp. The intraday and interday accuracies for C and EC in Ringer's soln. ranged from -3.0 to 4.4%, and the intraday and interday precisions were below 5.2%. The mean in vivo recoveries of C and EC in microdialysis probes were 33.7% and 26.5% in blood while 38.3% and 29.1% in brain. Pharmacokinetic parameters were estd. using the statistical moment method after iv administration (C and EC, 20 mg/kg of body wt.) in rats. Brain-to-blood (AUCbrain/AUCblood) distribution ratios were 0.0726 ± 0.0376 for C and 0.1065 ± 0.0531 for EC, indicating that C and EC could pass through the BBB, which is further evidence of their neuroprotective effects.
- 57Zhao, W.; Wang, J.; Bi, W.; Ferruzzi, M.; Yemul, S.; Freire, D.; Mazzola, P.; Ho, L.; Dubner, L.; Pasinetti, G. M. Novel Application of Brain-Targeting Polyphenol Compounds in Sleep Deprivation-Induced Cognitive Dysfunction. Neurochem. Int. 2015, 89, 191– 197, DOI: 10.1016/j.neuint.2015.07.023[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlWlt7rN&md5=45c0662cbe339b6f9ee86faec614d0cdNovel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunctionZhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freirea, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio MariaNeurochemistry International (2015), 89 (), 191-197CODEN: NEUIDS; ISSN:0197-0186. (Elsevier Ltd.)Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Prepn. (BDPP), comprised of grape seed polyphenol ext., Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compds. derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction.
- 58Faria, A.; Pestana, D.; Teixeira, D.; Couraud, P.-O.; Romero, I.; Weksler, B.; de Freitas, V.; Mateus, N.; Calhau, C. Insights into the Putative Catechin and Epicatechin Transport across Blood-Brain Barrier. Food Funct. 2011, 2 (1), 39– 44, DOI: 10.1039/C0FO00100G[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVGgtg%253D%253D&md5=4ed5870b17006f90c290a4b0a6296d1eInsights into the putative catechin and epicatechin transport across blood-brain barrierFaria, Ana; Pestana, Diogo; Teixeira, Diana; Couraud, Pierre-Olivier; Romero, Ignacio; Weksler, Babette; de Freitas, Victor; Mateus, Nuno; Calhau, ConceicaoFood & Function (2011), 2 (1), 39-44CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)The identification of mechanisms assocd. with phenolic neuroprotection is delayed due to a lack of information regarding the ability of phenolic compds. to enter the central nervous system (CNS). The aim of this work was to evaluate the transmembrane transport of catechin and epicatechin across blood-brain barrier (BBB). Two BBB cell lines, RBE-4 cells (immortalized cell line of rat capillary cerebral endothelial cells) and hCMEC/D3 (immortalized human cerebral microvessel endothelial cell line), were used. HPLC-DAD/MS was used to detect these compds. and their metabolites in the studied samples. The metabolites of the tested flavan-3-ols were synthesized to be used as stds. Catechin and epicatechin could cross both cells in a time-dependent manner. This transport was stereoselective (epicatechin » catechin), involving one or more stereoselective entities. Addnl., these cells were capable of metabolizing these compds., particularly by conjugation with glucuronic acid, since this metabolite was detected in the basolateral media. Several studies suggest that blood levels of catechin and epicatechin are far below the levels used in this study and that these compds. appeared mainly as Me, sulfate and glucuronide metabolites. Nevertheless, the information obtained by this study is valuable for the new insights about flavan-3-ols transport. In conclusion: (i) catechin and epicatechin are capable of crossing the BBB; (ii) a stereoselective process was involved in the passage of these compds. across BBB cells; (iii) endothelial cells have enzymes capable of metabolizing these compds.
- 59Wu, K.; Wang, Z.-Z.; Liu, D.; Qi, X.-R. Pharmacokinetics, Brain Distribution, Release and Blood–brain Barrier Transport of Shunaoxin Pills. J. Ethnopharmacol. 2014, 151 (3), 1133– 1140, DOI: 10.1016/j.jep.2013.12.027[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlGqu7w%253D&md5=df2324c90db8689c5da378af64517a35Pharmacokinetics, brain distribution, release and blood-brain barrier transport of Shunaoxin pillsWu, Kai; Wang, Zhan-Zhang; Liu, Dan; Qi, Xian-RongJournal of Ethnopharmacology (2014), 151 (3), 1133-1140CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)Shunaoxin pills, a traditional Chinese medicine (TCM) product, have been used to treat cerebrovascular diseases in China since 2005. The main active components of Shunaoxin pills are ferulic acid and ligustilide from Chuanxiong (Ligusticum chuanxiong Hort, Umbelliferae) and Danggui (Angelica sinensis radix, Umbelliferae). As Shunaoxin shows excellent activity in the central nervous system (CNS), the extent to which the major constituents of Shunaoxin reach the CNS should be investigated. Moreover, the in vivo-in vitro correlations (IVIVC) of the formulation should be studied to elucidate the mechanisms of action of TCM in the CNS. However, these data have not previously been available. Thus we intended to investigate what the extent when these constituents of Shunaoxin pills reach the CNS, and evaluate the IVIVC of release and pharmacokinetics. In this study, we evaluated the release of ferulic acid and ligustilide from Shunaoxin pills, and their transport across an in vitro model of the BBB. We also evaluated their pharmacokinetics and brain distribution in vivo. High-performance liq. chromatog. (HPLC) was used to quantify both compds. simultaneously. Based on the release in vitro and absorption of ferulic acid and ligustilide in vivo, IVIVC permitted prediction of the pharmacokinetics of these compds. The release of ferulic acid and ligustilide reached a platform phase within 1 h. Ferulic acid and ligustilide rapidly crossed the BBB in different patterns; the transport ratio increased over time. After intragastric (i.g.) administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed into brain, which may result in a rapid onset of action. Ferulic acid and ligustilide were transported across a model BBB. After i.g. administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed in brain; this may lead to rapid pharmacol. onset. The IVIVC can be used to predict in vivo pharmacokinetics from in vitro exptl. results. These results provide support for the clin. use of Shunaoxin pills.
- 60Bauer, S. R.; Ding, E. L.; Smit, L. A. Cocoa Consumption, Cocoa Flavonoids, and Effects on Cardiovascular Risk Factors: An Evidence-Based Review. Curr. Cardiovasc. Risk Rep. 2011, 5 (2), 120– 127, DOI: 10.1007/s12170-011-0157-5
- 61Monagas, M.; Khan, N.; Andres-Lacueva, C.; Casas, R.; Urpí-Sardà, M.; Llorach, R.; Lamuela-Raventós, R. M.; Estruch, R. Effect of Cocoa Powder on the Modulation of Inflammatory Biomarkers in Patients at High Risk of Cardiovascular Disease. Am. J. Clin. Nutr. 2009, 90 (5), 1144– 1150, DOI: 10.3945/ajcn.2009.27716[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlentLfP&md5=ba6ce24d871f5a08303b5f9705cf7cd8Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular diseaseMonagas, Maria; Khan, Nasiruddin; Andres-Lacueva, Cristina; Casas, Rosa; Urpi-Sarda, Mireia; Llorach, Rafael; Lamuela-Raventos, Rosa Maria; Estruch, RamonAmerican Journal of Clinical Nutrition (2009), 90 (5), 1144-1150CODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)Background: Epidemiol. studies have suggested that flavonoid intake plays a crit. role in the prevention of coronary heart disease. Because atherosclerosis is considered a low-grade inflammatory disease, some feeding trials have analyzed the effects of cocoa (an important source of flavonoids) on inflammatory biomarkers, but the results have been controversial. Objective: The objective was to evaluate the effects of chronic cocoa consumption on cellular and serum biomarkers related to atherosclerosis in high-risk patients. Design: Forty-two high-risk volunteers (19 men and 23 women; mean ± SD age: 69.7 ± 11.5 y) were included in a randomized crossover feeding trial. All subjects received 40 g cocoa powder with 500 mL skim milk/d (C+M) or only 500 mL skim milk/d (M) for 4 wk. Before and after each intervention period, cellular and serum inflammatory biomarkers related to atherosclerosis were evaluated. Results: Adherence to the dietary protocol was excellent. No significant changes in the expression of adhesion mols. on T lymphocyte surfaces were found between the C+M and M groups. However, in monocytes, the expression of VLA-4, CD40, and CD36 was significantly lower (P = 0.005, 0.028, and 0.001, resp.) after C+M intake than after M intake. In addn., serum concns. of the sol. endothelium-derived adhesion mols. P-selectin and intercellular adhesion mol.-1 were significantly lower (both P = 0.007) after C+M intake than after M intake. Conclusions: These results suggest that the intake of cocoa polyphenols may modulate inflammatory mediators in patients at high risk of cardiovascular disease. These antiinflammatory effects may contribute to the overall benefits of cocoa consumption against atherosclerosis.
- 62Flanagan, E.; Müller, M.; Hornberger, M.; Vauzour, D. Impact of Flavonoids on Cellular and Molecular Mechanisms Underlying Age-Related Cognitive Decline and Neurodegeneration. Curr. Nutr. Rep. 2018, 7 (2), 49– 57, DOI: 10.1007/s13668-018-0226-1[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MbmtlGltA%253D%253D&md5=8157db2b091d810018bc22b146e0b6bbImpact of Flavonoids on Cellular and Molecular Mechanisms Underlying Age-Related Cognitive Decline and NeurodegenerationFlanagan Emma; Muller Michael; Hornberger Michael; Vauzour DavidCurrent nutrition reports (2018), 7 (2), 49-57 ISSN:.PURPOSE OF REVIEW: This review summarises the most recent evidence regarding the effects of dietary flavonoids on age-related cognitive decline and neurodegenerative diseases. RECENT FINDINGS: Recent evidence indicates that plant-derived flavonoids may exert powerful actions on mammalian cognition and protect against the development of age-related cognitive decline and pathological neurodegeneration. The neuroprotective effects of flavonoids have been suggested to be due to interactions with the cellular and molecular architecture of brain regions responsible for memory. Mechanisms for the beneficial effects of flavonoids on age-related cognitive decline and dementia are discussed, including modulating signalling pathways critical in controlling synaptic plasticity, reducing neuroinflammation, promoting vascular effects capable of stimulating new nerve cell growth in the hippocampus, bidirectional interactions with gut microbiota and attenuating the extracellular accumulation of pathological proteins. These processes are known to be important in maintaining optimal neuronal function and preventing age-related cognitive decline and neurodegeneration.
- 63Poulose, S. M.; Fisher, D. R.; Larson, J.; Bielinski, D. F.; Rimando, A. M.; Carey, A. N.; Schauss, A. G.; Shukitt-Hale, B. Anthocyanin-Rich Açai (Euterpe Oleracea Mart.) Fruit Pulp Fractions Attenuate Inflammatory Stress Signaling in Mouse Brain BV-2 Microglial Cells. J. Agric. Food Chem. 2012, 60 (4), 1084– 1093, DOI: 10.1021/jf203989k[ACS Full Text], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVGrtA%253D%253D&md5=1b710b1ec57388c05755fc25db3fe7a0Anthocyanin-rich Acai (Euterpe oleracea Mart.) fruit pulp fractions attenuate inflammatory stress signaling in mouse brain BV-2 microglial cellsPoulose, Shibu M.; Fisher, Derek R.; Larson, Jessica; Bielinski, Donna F.; Rimando, Agnes M.; Carey, Amanda N.; Schauss, Alexander G.; Shukitt-Hale, BarbaraJournal of Agricultural and Food Chemistry (2012), 60 (4), 1084-1093CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Age-related diseases of the brain compromise memory, learning, and movement and are directly linked with increases in oxidative stress and inflammation. Previous research has shown that supplementation with berries can modulate signaling in primary hippocampal neurons or BV-2 mouse microglial cells. Because of their high polyphenolic content, fruit pulp fractions of acai (Euterpe oleracea Mart.) were explored for their protective effect on BV-2 mouse microglial cells. Freeze-dried acai pulp was fractionated using solvents with different polarities and analyzed using HPLC for major anthocyanins and other phenolics. Fractions extd. using methanol (MEOH) and ethanol (ETOH) were particularly rich in anthocyanins such as cyanidin, delphinidin, malvidin, pelargonidin, and peonidin, whereas the fraction extd. using acetone (ACE) was rich in other phenolics such as catechin, ferulic acid, quercetin, resveratrol, and syringic and vanillic acids. Studies were conducted to investigate the mitigating effects of acai pulp exts. on lipopolysaccharide (LPS, 100 ng/mL) induced oxidative stress and inflammation; treatment of BV-2 cells with acai fractions resulted in significant (p < 0.05) decreases in nitrite prodn., accompanied by a redn. in inducible nitric oxide synthase (iNOS) expression. The inhibition pattern was emulated with the ferulic acid content among the fractions. The protection of microglial cells by acai pulp exts., particularly that of MEOH, ETOH, and ACE fractions, was also accompanied by a significant concn.-dependent redn. in cyclooxygenase-2 (COX-2), p38 mitogen-activated protein kinase (p38-MAPK), tumor necrosis factor-α (TNFα), and nuclear factor κB (NF-κB). The current study offers valuable insights into the protective effects of acai pulp fractions on brain cells, which could have implications for improved cognitive and motor functions.
- 64Lau, F. C.; Bielinski, D. F.; Joseph, J. A. Inhibitory Effects of Blueberry Extract on the Production of Inflammatory Mediators in Lipopolysaccharide-Activated BV2Microglia. J. Neurosci. Res. 2007, 85 (5), 1010– 1017, DOI: 10.1002/jnr.21205[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXks1Ohtr8%253D&md5=c0846886721b8867e1ea7165544f1580Inhibitory effects of blueberry extract on the production of inflammatory mediators in lipopolysaccharide-activated BV2 microgliaLau, Francis C.; Bielinski, Donna F.; Joseph, James A.Journal of Neuroscience Research (2007), 85 (5), 1010-1017CODEN: JNREDK; ISSN:0360-4012. (Wiley-Liss, Inc.)Sustained microglial activation in the central nervous system (CNS) has been extensively investigated in age-related neurodegenerative diseases and has been postulated to lead to neuronal cell loss in these conditions. Recent studies have shown that antiinflammatory drugs may suppress microglial activation and thus protect against microglial overactivation and subsequent cell loss. Research also suggests that fruits such as berries may contain both antioxidant and antiinflammatory polyphenols that may be important in this regard. Our previous research showed that blueberry ext. was effective in preventing oxidant-induced calcium response deficits in M1 (muscarinic receptor)-transfected COS-7 cells. Extrapolating from these findings, the current study investigated the effect of blueberry ext. on preventing inflammation-induced activation of microglia. Results indicated that treatments with blueberry ext. inhibited the prodn. of the inflammatory mediator nitric oxide (NO) as well as the cytokines interleukin-1β and tumor necrosis factor-α, in cell conditioned media from lipopolysaccharide (LPS)-activated BV2 microglia. Also, mRNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-activated BV2 cells were significantly reduced by treatments with blueberry ext. The results suggest that blueberry polyphenols attenuate inflammatory responses of brain microglia and could be potentially useful in modulation of inflammatory conditions in the CNS.
- 65Syed, M. M.; Phulwani, N. K.; Kielian, T. Tumor Necrosis Factor-Alpha (TNF-α) Regulates Toll-like Receptor 2 (TLR2) Expression in Microglia. J. Neurochem. 2007, 103 (4), 1461– 1471, DOI: 10.1111/j.1471-4159.2007.04838.x[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtl2jurjL&md5=0f5539426b037b023707d79751980b9fTumor necrosis factor-alpha (TNF-α) regulates Toll-like receptor 2 (TLR2) expression in microgliaSyed, Mohsin Md.; Phulwani, Nirmal K.; Kielian, TammyJournal of Neurochemistry (2007), 103 (4), 1461-1471CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)Microglia represent one effector arm of CNS innate immunity as evident by their role in pathogen recognition. We previously reported that exposure of microglia to Staphylococcus aureus (S. aureus), a prevalent CNS pathogen, led to elevated Toll-like receptor 2 (TLR2) expression, a pattern recognition receptor capable of recognizing conserved structural motifs assocd. with gram-pos. bacteria such as S. aureus. In this study, we demonstrate that the proinflammatory cytokine tumor necrosis factor-α (TNF-α) enhances TLR2 expression in microglia, whereas interleukin-1β has no significant effect. To det. the downstream signaling events responsible for elevated microglial TLR2 expression in response to TNF-α, a series of signal transduction inhibitors were employed. Treatment with caffeic acid phenethyl ester, an inhibitor of redox-mediated nuclear factor-kappa B activation, significantly attenuated TNF-α-induced TLR2 expression. Similar results were obsd. with the IKK-2 and IκB-α inhibitors SC-514 and BAY 11-7082, resp. In contrast, no significant alterations in TLR2 expression were obsd. with protein kinase C or p38 mitogen-activated protein kinase inhibitors. A definitive role for TNF-α was demonstrated by the inability of S. aureus to augment TLR2 expression in microglia isolated from TNF-α knockout mice. In addn., TLR2 expression was significantly attenuated in brain abscesses of TNF-α knockout mice. Collectively, these results indicate that in response to S. aureus, TNF-α acts in an autocrine/paracrine manner to enhance TLR2 expression in microglia and that this effect is mediated, in part, by activation of the nuclear factor-kappa B pathway.
- 66Tambuwala, M. M.; Khan, M. N.; Thompson, P.; McCarron, P. A. Albumin Nano-Encapsulation of Caffeic Acid Phenethyl Ester and Piceatannol Potentiated Its Ability to Modulate HIF and NF-KB Pathways and Improves Therapeutic Outcome in Experimental Colitis. Drug Delivery Transl. Res. 2019, 9 (1), 14– 24, DOI: 10.1007/s13346-018-00597-9[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlShsLbP&md5=ef5f94bd7c96fef97433944211937d98Albumin nano-encapsulation of caffeic acid phenethyl ester and piceatannol potentiated its ability to modulate HIF and NF-κB pathways and improves therapeutic outcome in experimental colitisTambuwala, Murtaza M.; Khan, Mohammed N.; Thompson, Paul; McCarron, Paul A.Drug Delivery and Translational Research (2019), 9 (1), 14-24CODEN: DDTRCY; ISSN:2190-3948. (Springer)Hypoxia inducible factor and nuclear factor-kappa beta pathways have been proposed as therapeutic targets for several inflammatory diseases. Caffeic acid phenethyl ester (CAPE) and piceatannol (PIC) are natural anti-inflammatory compds.; however, poor bioavailability and limited understanding of biomol. mechanistic limits its clin. use. The aims of this study are to enhance bioavailability and investigate their impact on nuclear p65 and HIF-1α for the first time in exptl. colitis. Dextran sulfate sodium was used to induce colitis in mice and effect of either free CAPE/PIC or CAPE/PIC loaded albumin nanoparticles treatment was obsd. on disease development and levels of cellular p65 and HIF-1α. Our results indicate that albumin nano-encapsulation of CAPE/PIC not only enhances its anti-inflammatory potential but also potentiates its ability to effectively modulate inflammation related biomol. pathways. Hence, combining nanotechnol. with natural compds. could result in development of new therapeutic options for IBD.
- 67di Gesso, J. L.; Kerr, J. S.; Zhang, Q.; Raheem, S.; Yalamanchili, S. K.; O’Hagan, D.; Kay, C. D.; O’Connell, M. A. Flavonoid Metabolites Reduce Tumor Necrosis Factor-α Secretion to a Greater Extent than Their Precursor Compounds in Human THP-1 Monocytes. Mol. Nutr. Food Res. 2015, 59 (6), 1143– 1154, DOI: 10.1002/mnfr.201400799[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnsFyjt7Y%253D&md5=75bcf04367646f3d27cbbb49a4b75f24Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytesdi Gesso, Jessica L.; Kerr, Jason S.; Zhang, Qingzhi; Raheem, Saki; Yalamanchili, Sai Krishna; O'Hagan, David; Kay, Colin D.; O'Connell, Maria A.Molecular Nutrition & Food Research (2015), 59 (6), 1143-1154CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)Scope : Flavonoids are generally studied in vitro, in isolation, and as unmetabolized precursor structures. However, in the habitual diet, multiple flavonoids are consumed together and found present in the circulation as complex mixts. of metabolites. Using a unique study design, we investigated the potential for singular or additive anti-inflammatory effects of flavonoid metabolites relative to their precursor structures. Methods and results : Six flavonoids, 14 flavonoid metabolites, and 29 combinations of flavonoids and their metabolites (0.1-10 μM) were screened for their ability to reduce LPS-induced tumor necrosis factor-α (TNF-α) secretion in THP-1 monocytes. One micromolar peonidin-3-glucoside, cyanidin-3-glucoside, and the metabolites isovanillic acid (IVA), IVA-glucuronide, vanillic acid-glucuronide, protocatechuic acid-3-sulfate, and benzoic acid-sulfate significantly reduced TNF-α secretion when in isolation, while there was no effect on TNF-α mRNA expression. Four combinations of metabolites that included 4-hydroxybenzoic acid (4HBA) and/or protocatechuic acid also significantly reduced TNF-α secretion to a greater extent than the precursors or metabolites alone. The effects on LPS-induced IL-1β and IL-10 secretion and mRNA expression were also examd. 4HBA significantly reduced IL-1β secretion but none of the flavonoids or metabolites significantly modified IL-10 secretion. Conclusion : This study provides novel evidence suggesting flavonoid bioactivity results from cumulative or additive effects of circulating metabolites.
- 68Verpoorte, R.; Choi, Y. H.; Kim, H. K. Ethnopharmacology and Systems Biology: A Perfect Holistic Match. J. Ethnopharmacol. 2005, 100 (1–2), 53– 56, DOI: 10.1016/j.jep.2005.05.033[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2Mzps1eiug%253D%253D&md5=14404d358fb72ae66957b9b4ab8fa09fEthnopharmacology and systems biology: a perfect holistic matchVerpoorte R; Choi Y H; Kim H KJournal of ethnopharmacology (2005), 100 (1-2), 53-6 ISSN:0378-8741.Traditional medical doctors often apply a holistic approach in prescribing medicines to the patient. Each individual patient gets his own optimalized medicine, usually a mixture of different ingredients. The present day paradigm of drug development of <single target, single compound>, is based on a super reductionist approach which involves mostly tests of compounds at the molecular level in, e.g., receptor binding assays. This approach is not the best for studies on traditional medicines. A more holistic approach using systems biology seems much more suited to proof efficacy and to obtain information that might lead to understanding the mode of action. Synergy, prodrugs, novel targets, all these might be detected by a systems biology approach whereas the reductioinist approach only will recognize activity on already known targets, and will not detect synergism and prodrugs. Metabolomics will be a major tool in recognizing compounds connected with activity in the traditional medicines, and will also be very useful in recognizing the effect on the test organism, which can be the patient in case of clinical trials with well established traditional medicines.
- 69Tavares, L.; Figueira, I.; McDougall, G. J.; Vieira, H. L. A.; Stewart, D.; Alves, P. M.; Ferreira, R. B.; Santos, C. N. Neuroprotective Effects of Digested Polyphenols from Wild Blackberry Species. Eur. J. Nutr. 2013, 52 (1), 225– 236, DOI: 10.1007/s00394-012-0307-7[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVelsb4%253D&md5=b209e815112b958208d827e54910664cNeuroprotective effects of digested polyphenols from wild blackberry speciesTavares, Lucelia; Figueira, Ines; McDougall, Gordon J.; Vieira, Helena L. A.; Stewart, Derek; Alves, Paula M.; Ferreira, Ricardo B.; Santos, Claudia N.European Journal of Nutrition (2013), 52 (1), 225-236CODEN: EJNUFZ; ISSN:1436-6207. (Springer)Purpose Blackberry ingestion has been demonstrated to attenuate brain degenerative processes with the benefits ascribed to the (poly)phenolic components. The aim of this work was to evaluate the neuroprotective potential of two wild blackberry species in a neurodegeneration cell model and compare them with a com. variety. Methods This work encompasses chem. characterization before and after an in vitro digestion and the assessment of neuroprotection by digested metabolites. Some studies targeting redox/cell death systems were also performed to assess possible neuroprotective mol. mechanisms. Results The three blackberry exts. presented some quant. differences in polyphenol compn. that could be responsible for the different responses in the neurodegeneration cell model. Com. blackberry exts. were ineffective but both wild blackberries, Rubus brigantinus and Rubus vagabundus, presented neuroprotective effects. It was verified that a diminishment of intracellular ROS levels, modulation of glutathione levels and activation of caspases occurred during treatment. The last effect suggests a preconditioning effect since caspase activation was not accompanied by diminution in cell death and loss of functionality. Conclusions This is the first time that metabolites obtained from an in vitro digested food matrix, and tested at levels approaching the concns. found in human plasma, have been described as inducing an adaptative response.
- 70Giampieri, F.; Afrin, S.; Stewart, D.; McDougall, G.; Brennan, R.; Blyth, L.; Gasparrini, M.; Mazzoni, L.; Capocasa, F.; Alvarez-Suarez, J. Phytochemical Composition and Cytotoxic Effects on Liver Hepatocellular Carcinoma Cells of Different Berries Following a Simulated In Vitro Gastrointestinal Digestion. Molecules 2018, 23 (8), 1918, DOI: 10.3390/molecules23081918[Crossref], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVSnurjP&md5=fddde832754a07ca5bad18eab4bd1584Phytochemical composition and cytotoxic effects on liver hepatocellular carcinoma cells of different berries following a simulated in vitro gastrointestinal digestionGiampieri, Francesca; Afrin, Sadia; Stewart, Derek; McDougall, Gordon J.; Brennan, Rex; Blyth, Lesley; Gasparrini, Massimiliano; Mazzoni, Luca; Capocasa, Franco; Alvarez-Suarez, Jose Miguel; Bompadre, Stefano; Bras de Oliveira, Pedro Nogueira; Santos, Claudia N.; Masias, Manuel; Agudo, Pablo; Crespo, Jorge; Mezzetti, Bruno; Forbes-Hernandez, Tamara Y.; Battino, MaurizioMolecules (2018), 23 (8), 1918/1-1918/14CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Berry fruits are rich in nutrients and polyphenols, providing potential health benefits. Understanding the factors that affect their bioavailability is becoming of utmost importance for evaluating their biol. significance and efficacy as functional food. In this study, the phytochem. compn. and the total antioxidant capacity of different varieties of five berries (blackberry, blackcurrant, blueberry, raspberry, and strawberry) were evaluated after an in vitro gastrointestinal digestion process. The cultivar of each berry that showed the higher content of total phenols and flavonoids was selected to study its cytotoxic effect on human hepatoma cells. Digestion resulted in a high redn. (p< 0.05) of total phenolic, flavonoid andanthocyanin contents and total antioxidant capacity, in the "IN" samples compared to the "OUT" exts., which represent the "serum-available" and the "colon-available" fractions, resp. Incubation of the digested fraction for 24 h didn't exert any effect on cellular viability, while a dose- and time-dependent cytotoxicity was obsd. after 48 h and 72 h of incubation for all the berries analyzed. Our results suggest that the approach proposed in this work may represent a rapid tool for evaluating and identifying new berries with increased phytochem. bioavailability, highlighting their antiproliferative agents after an in vitro digestion.
- 71Tavares, L.; Figueira, I.; Macedo, D.; McDougall, G. J.; Leitão, M. C.; Vieira, H. L. A.; Stewart, D.; Alves, P. M.; Ferreira, R. B.; Santos, C. N. Neuroprotective Effect of Blackberry (Rubus Sp.) Polyphenols Is Potentiated after Simulated Gastrointestinal Digestion. Food Chem. 2012, 131 (4), 1443– 1452, DOI: 10.1016/j.foodchem.2011.10.025[Crossref], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVyktrrJ&md5=8d79820d7aec91dbd37c510633bca7c7Neuroprotective effect of blackberry (Rubus sp.) polyphenols is potentiated after simulated gastrointestinal digestionTavares, Lucelia; Figueira, Ines; Macedo, Diana; McDougall, Gordon J.; Leitao, Maria Cristina; Vieira, Helena L. A.; Stewart, Derek; Alves, Paula M.; Ferreira, Ricardo B.; Santos, Claudia N.Food Chemistry (2012), 131 (4), 1443-1452CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)Blackberry ingestion has been demonstrated to attenuate brain degenerative processes in rodents with the benefits ascribed to the (poly)phenolic components. The aim of this work was to assess the efficacy of blackberry polyphenolics in a neurodegeneration cell model before and after simulated gastrointestinal digestion. Digested blackberry metabolites protected neuroblastoma cells from H2O2-induced death at low, non-toxic levels that approach physiol.-relevant serum concns. However, the original exts. were not protective even at fivefold higher concns. This potentiation may reflect alterations in the polyphenolic compn. caused by the digestion procedure, as detected by liq.-chromatog.-mass spectrometric anal. This protection was not caused by modulation of the intracellular antioxidant capacity or through alteration of glutathione levels, although the original ext. influenced both of these parameters. This work reinforces the importance of evaluating digested metabolites in disease cell models and highlights the possible involvement of other mechanisms beyond antioxidant systems.
- 72Garcia, G.; Nanni, S.; Figueira, I.; Ivanov, I.; McDougall, G. J.; Stewart, D.; Ferreira, R. B.; Pinto, P.; Silva, R. F. M.; Brites, D. Bioaccessible (Poly)Phenol Metabolites from Raspberry Protect Neural Cells from Oxidative Stress and Attenuate Microglia Activation. Food Chem. 2017, 215, 274– 283, DOI: 10.1016/j.foodchem.2016.07.128[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSgur3F&md5=fd27e5c909a0a5854b05caf0ffeca700Bioaccessible (poly)phenol metabolites from raspberry protect neural cells from oxidative stress and attenuate microglia activationGarcia, Goncalo; Nanni, Sara; Figueira, Ines; Ivanov, Ines; McDougall, Gordon J.; Stewart, Derek; Ferreira, Ricardo B.; Pinto, Paula; Silva, Rui F. M.; Brites, Dora; Santos, Claudia N.Food Chemistry (2017), 215 (), 274-283CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)Neuroinflammation is an integral part of the neurodegeneration process inherent to several aging dysfunctions. Within the central nervous system, microglia are the effective immune cells, responsible for neuroinflammatory responses. In this study, raspberries were subjected to in vitro digestion simulation to obtain the components that result from the gastrointestinal (GI) conditions, which would be bioaccessible and available for blood uptake. Both the original raspberry ext. and the gastrointestinal bioaccessible (GIB) fraction protected neuronal and microglia cells against H2O2-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation, at low concns. Furthermore, this neuroprotective capacity was independent of intracellular ROS scavenging mechanisms. We show for the first time that raspberry metabolites present in the GIB fraction significantly inhibited microglial pro-inflammatory activation by LPS, through the inhibition of Iba1 expression, TNF-α release and NO prodn. Altogether, this study reveals that raspberry polyphenols may present a dietary route to the retardation or amelioration of neurodegenerative-related dysfunctions.
- 73Kuo, P.-C.; Liao, Y.-R.; Hung, H.-Y.; Chuang, C.-W.; Hwang, T.-L.; Huang, S.-C.; Shiao, Y.-J.; Kuo, D.-H.; Wu, T.-S. Anti-Inflammatory and Neuroprotective Constituents from the Peels of Citrus Grandis. Molecules 2017, 22 (6), 967, DOI: 10.3390/molecules22060967[Crossref], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1KnsLvP&md5=ca46de5817645866efbf8eaa713ee94eAnti-inflammatory and neuroprotective constituents from the peels of Citrus grandisKuo, Ping-Chung; Liao, Yu-Ren; Hung, Hsin-Yi; Chuang, Chia-Wei; Hwang, Tsong-Long; Huang, Shiow-Chyn; Shiao, Young-Ji; Kuo, Daih-Huang; Wu, Tian-ShungMolecules (2017), 22 (6), 967/1-967/11CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A series of chromatog. sepns. performed on the ethanol exts. of the peels of Citrus grandis has led to the characterization of forty compds., including seventeen coumarins, eight flavonoids, two triterpenoids, four benzenoids, two steroids, one lignan, one amide, and five other compds., resp. The chem. structures of the purified constituents were identified on the basis of spectroscopic elucidation, including 1D- and 2D-NMR, UV, IR, and mass spectrometric anal. Most of the isolated compds. were examd. for their inhibition of superoxide anion generation and elastase release by human neutrophils. Among the isolates, isomeranzin (3), 17,18-dihydroxybergamottin (12), epoxybergamottin (13), rhoifolin (19), vitexicarpin (22) and 4-hydroxybenzaldehyde (29) displayed the most significant inhibition of superoxide anion generation and elastase release with IC50 values ranged from 0.54 to 7.57 μM, and 0.43 to 4.33 μM, resp. In addn., 7-hydroxy-8-(2'-hydroxy-3'-methylbut-3'-enyl)coumarin (8) and 17,18-dihydroxybergamottin (12) also exhibited the protection of neurons against Aβ-mediated neurotoxicity at 50 μM.
- 74Kim, H. J.; Hwang, I. K.; Won, M. H. Vanillin, 4-Hydroxybenzyl Aldehyde and 4-Hydroxybenzyl Alcohol Prevent Hippocampal CA1 Cell Death Following Global Ischemia. Brain Res. 2007, 1181, 130– 141, DOI: 10.1016/j.brainres.2007.08.066[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1yls7%252FO&md5=3032426b0fd56cf0ec148fd79ea0d6a9Vanillin, 4-hydroxybenzyl aldehyde and 4-hydroxybenzyl alcohol prevent hippocampal CA1 cell death following global ischemiaKim, Hyeon Ju; Hwang, In Koo; Won, Moo HoBrain Research (2007), 1181 (), 130-141CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)Mongolian gerbils subjected to transient global ischemia exhibit neuroprotection against ischemic neuronal cell death in the hippocampal CA1 region when treated with vanillin, 4-hydroxybenzyl aldehyde (4-HBAL) and 4-hydroxybenzyl alc. (4-HBA), which are active components of Gastrodia elata Blume. Pre- and post-insult vanillin, 4-HBAL and 4-HBA treated-animals showed a significant increase in neuronal survival (66.32%, 43.21% and 64.58%, resp.) compared to vehicle-treated animals. Animals exhibited a gender difference in this neuroprotective effect. To study the neuroprotective mechanism of 4-HBA, we investigated N-methyl-D-aspartate (NMDA) receptor 1 (NR1), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and γ-aminobutyric acid transaminase (GABA-T) immunoreactivity at various times after ischemic insults. Treatment with 4-HBA did not affect NR1 expression levels, down-regulated 8-OHdG immunoreactivity, and increased GABA-T expression levels after global ischemia, suggesting that 4-HBA inhibited NR1 stimulation. Moreover, GABA-T was rapidly increased in the early stage after ischemia, which might enhance the survival of cells by supplying energy to the CA1 region. These results suggest that 4-HBA inhibits oxidative stress and excitotoxicity for at least 12 h and suppresses neuronal death in CA1 region. Di-Et ether fractions of GE scavenged hydroxyl radical (OH·) and showed antioxidant activity on lipid peroxidn. Vanillin and 4-HBA treatment blocked oxidative damage in PC12 cells. The neuroprotective effect has therapeutic significance and these compds. need to be evaluated for potential use in protecting against neuronal cell damage during stroke.
- 75Cuadrado, A. NRF2 in Neurodegenerative Diseases. Curr. Opin. Toxicol. 2016, 1, 46– 53, DOI: 10.1016/j.cotox.2016.09.004
- 76Doig, A. J.; Derreumaux, P. Inhibition of Protein Aggregation and Amyloid Formation by Small Molecules. Curr. Opin. Struct. Biol. 2015, 30, 50– 56, DOI: 10.1016/j.sbi.2014.12.004[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFygsL7J&md5=ce48f45a925b2545a63d37dc32983f18Inhibition of protein aggregation and amyloid formation by small moleculesDoig, Andrew J.; Derreumaux, PhilippeCurrent Opinion in Structural Biology (2015), 30 (), 50-56CODEN: COSBEF; ISSN:0959-440X. (Elsevier Ltd.)For decades, drug after drug has failed to slow the progression of Alzheimer's disease in human trials. How compds. reducing fibril formation in vitro and toxicity in transgenic mice and flies bind to the Aβ toxic oligomers, is unknown. This account reviews recent drugs mainly targeting Aβ, how they were identified and report their successes from in vitro and in vivo exptl. studies and their current status in clin. trials. We then focus on recent in vitro and simulation results on how inhibitors interact with Aβ monomers and oligomers, highly desirable knowledge for predicting new efficient drugs. We conclude with a perspective on the future of the inhibition of amyloid formation by small mols.
- 77Zheng, L. T.; Ryu, G.-M.; Kwon, B.-M.; Lee, W.-H.; Suk, K. Anti-Inflammatory Effects of Catechols in Lipopolysaccharide-Stimulated Microglia Cells: Inhibition of Microglial Neurotoxicity. Eur. J. Pharmacol. 2008, 588 (1), 106– 113, DOI: 10.1016/j.ejphar.2008.04.035[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmsFKltbk%253D&md5=74fdf818eb20e550a640604c1b3a51b3Anti-inflammatory effects of catechols in lipopolysaccharide-stimulated microglia cells: Inhibition of microglial neurotoxicityZheng, Long Tai; Ryu, Geun-Mu; Kwon, Byoung-Mog; Lee, Won-Ha; Suk, KyounghoEuropean Journal of Pharmacology (2008), 588 (1), 106-113CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Microglial activation plays a pivotal role in the pathogenesis of neurodegenerative diseases by producing various proinflammatory cytokines and nitric oxide (NO). In the present study, the anti-inflammatory and subsequent neuroprotective effects of catechol and its derivs. including 3-methylcatechol, 4-methylcatechol, and 4-tert-butylcatechol were investigated in microglia and neuroblastoma cells in culture. The four catechol compds. showed anti-inflammatory effects with different potency. The catechols significantly decreased lipopolysaccharide (LPS)-induced NO and tumor necrosis factor (TNF)-α prodn. in BV-2 microglia cells. The catechols also inhibited the expression of inducible nitric oxide synthase (iNOS) and TNF-α at mRNA or protein levels in the LPS-stimulated BV-2 cells. In addn., the catechols inhibited LPS-induced nuclear translocation of p65 subunit of nuclear factor (NF)-κB, IκB degrdn., and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in BV-2 cells. Moreover, the catechols attenuated the cytotoxicity of LPS-stimulated BV-2 microglia toward co-cultured rat B35 neuroblastoma cells. The catechols, however, did not protect B35 cells against H2O2 toxicity, indicating that the compds. exerted the neuroprotective effect by inhibiting the inflammatory activation of microglia in the co-culture. The anti-inflammatory and neuroprotective properties of the catechols in cultured microglia and neuroblastoma cells suggest a therapeutic potential of these compds. for the treatment of neurodegenerative diseases that are assocd. with an excessive microglial activation.
- 78Weil-Malherbe, H.; Posner, H. S.; Bowles, G. R. Changes in the Concentration and Intracellular Distribution of Brain Catecholamines: The Effects of Reserpine. Beta-Phenyliso-Propylhydrazine, Pyrogallol and 3,4-Dihydroxyphenyl Alanine, Alone and in Combination. J. Pharmacol. Exp. Ther. 1961, 132, 278– 286[PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXhtVOhsb0%253D&md5=8ee4130622d16f95ff7b205f41fe6f63Changes in concentration and intracellular distribution of brain catechol amines. Effects of reserpine, 1-(1-methyl-2-phenylethyl)hydrazine (Catron), pyrogallol, and 3,4-dihydroxyphenylalanine (dopa), alone and in combinationWeil-Malherbe, H.; Posner, Robert S.; Bowles, Grace R.Journal of Pharmacology and Experimental Therapeutics (1961), 132 (), 278-86CODEN: JPETAB; ISSN:0022-3565.cf. CA 54, 2591d, 15665b. Effects on the concns. of norepinephrine (I) and dopamine (II) in the particulate and sol. fractions of rabbit brain were studied. After injection of reserpine (III) the concns. of I and II decreased faster in the sol. fraction than in the granular fraction. Catron (IV) suppressed the depleting effect of III, while III abolished a moderate rise of I concn. evoked by IV. Pyrogallol (V) alone had no effect on the concn. of catechol amines and did not affect the activity of III or IV. When III, IV, and V were injected into the rabbit together, V potentiated the effect of IV and elicited a rise of I concn. in the sol. fraction to above normal without depletion of I in the particulate fraction. Dopa alone had no significant effect, but after pretreatment with either IV or V it produced a marked rise in II in both the sol. and the particulate fractions. The concns. of I in both fractions were increased by dopa after IV, but not after V, and were increased still more by dopa after IV + V. The results are discussed in relation to the mechanism of action of III, the roles of monoamine oxidase and catechol-O-methyl transferase in metabolism of brain catechol amines, and the factors limiting the synthesis and storage of catechol amines.
- 79Rogers, K. J.; Angel, A.; Butterfield, L. The Penetration of Catechol and Pyrogallol into Mouse Brain and the Effect on Cerebral Monoamine Levels. J. Pharm. Pharmacol. 1968, 20 (9), 727– 729, DOI: 10.1111/j.2042-7158.1968.tb09845.x[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXkvFCqsL0%253D&md5=63c64b58e05f60005145cf59cb160965Penetration of catechol and pyrogallol into mouse brain and the effect on cerebral monoamine levelsRogers, K. J.; Angel, A.; Butterfield, LindaJournal of Pharmacy and Pharmacology (1968), 20 (9), 727-9CODEN: JPPMAB; ISSN:0022-3573.Catechol (60 mg./kg. i.p.) when administered to mice elicited convulsions consisting of violent jerks and tremors, which commenced within 15-20 sec. of injection; the duration of this convulsive activity was transient, lasting ∼8 min., and the peak convulsive activity occurred at 2-3 min. The time course of catechol penetration into the brain followed closely that of the convulsive activity. Mice receiving pyrogallol (120 mg./kg. i.p.) showed no change in motor activity, even though this dose of pyrogallol produced cerebral concns. which were about the same as those produced by the convulsive dose of catechol. The concns. of noradrenaline, dopamine, and 5-hydroxytryptamine in the brains of mice treated with either catechol or pyrogallol were not significantly different from the levels in control mice. Thus, both catechol and pyrogallol enter the brains of mice after i.p. injections, catechol alone evoking convulsions. Neither of these hydroxyphenolic catechol O-methyltransferase inhibitors produced changes in the gross levels of noradrenaline, dopamine, or 5-hydroxytryptamine in mouse brain.
- 80Baldessarini, R. J.; Greiner, E. Inhibition of Catechol-o-Methyl Transferase by Catechols and Polyphenols. Biochem. Pharmacol. 1973, 22 (2), 247– 256, DOI: 10.1016/0006-2952(73)90277-3[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXhtF2it74%253D&md5=7933bf9de871b35dcfc7531550f0eff3Inhibition of catechol-O-methyl transferase by catechols and polyphenolsBaldessarini, Ross J.; Greiner, EllenBiochemical Pharmacology (1973), 22 (2), 247-56CODEN: BCPCA6; ISSN:0006-2952.The inhibitory action of N1-(DL-seryl)-N2-(2,3,4-trihydroxybenzyl) hydrazine (RO4-4602) (I) [322-35-0] on catechol-O-methyl transferase (EC 2.1.1.6) [9012-25-3] was compared with the inhibitory action of dopa [59-92-7] and pyrogallol [87-66-1]. The apparent Km for 3H-labeled norepinephrine [51-41-2] as transferase substrate was 0.36mM. L-dopa [59-92-7] weakly inhibited the transferase (Ki = 0.42mM) and seemed to be competitive with norepinephrine. D-dopa [5796-17-8] was slightly less potent. In contrast pyrogallol was a partially noncompetitive inhibitor of the transferase with respect to substrate (Ki = 30μM). I exhibited similar noncompetitive inhibitory kinetics (Ki = 60μM). In vivo I markedly increased the recovery of labeled catechol products from the brain of rats injected peripherally with labeled L-dopa, probably because I inhibited decarboxylation as well as methylation. I increased recovery of catechol products of labeled norepinephrine from the heart for periods up to 3-5 hr. I weakly inhibited monoamine oxidase [9001-66-5] in vitro (IC50 about 1mM) but was inactive in vivo in doses up to 100 mg/kg, i.p. I seems to be similar to pyrogallol in its ability to inhibit transferase in vitro and is able to inhibit the enzyme in vivo. This property may be partly responsible for its beneficial effects in Parkinsonian patients treated with L-dopa.
- 81Lai, F. M.; Spector, S. The Potentiating Effect of Clorgyline and Pyrogallol on the Blood Pressure Responses to Norepinephrine. Arch. Int. Pharmacodyn. Ther. 1978, 234 (2), 279– 286[PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXlsVU%253D&md5=ee5ed5b4b7ea1e7eb40c2ea2eaccbc16The potentiating effect of clorgyline and pyrogallol on the blood pressure responses to norepinephrineLai, F. M.; Spector, S.Archives Internationales de Pharmacodynamie et de Therapie (1978), 234 (2), 279-86CODEN: AIPTAK; ISSN:0003-9780.Intraventricular administration of norepinephrine (NE) [51-41-2] into pentobarbital anesthetized rats elicits a pressor or a depressor effect depending on the dose injected; after a low dose, a depressor response is seen while after a high dose, a pressor response is obsd. In the animal pretreated intraventricularly with clorgyline [17780-72-2] or pyrogallol [87-66-1], the hypotensive effect of a low dose NE was reversed to a hypertensive effect, while the hypertensive effect of a high dose of NE was markedly potentiated. Brain monoamine oxidase [9001-66-5] and catechol-o-methyltransferase [9012-25-3] can metabolize centrally released NE before it leaks into the peripheral circulation.
- 82Kita, T.; Wagner, G. C.; Philbert, M. A.; King, L. A.; Lowndes, H. E. Effects of Pargyline and Pyrogallol on the Methamphetamine-Induced Dopamine Depletion. Mol. Chem. Neuropathol. 1995, 24 (1), 31– 41, DOI: 10.1007/BF03160110[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXkvVGntrc%253D&md5=0fa7bc9a2e34efff5641751336694666Effects of pargyline and pyrogallol on the methamphetamine-induced dopamine depletionKita, Taizo; Wagner, George C.; Philbert, Martin A.; King, Linda A.; Lowndes, Herbert E.Molecular and Chemical Neuropathology (1995), 24 (1), 31-41CODEN: MCHNEM; ISSN:1044-7393.The formation of 6-hydroxydopamine (6-OHDA) from dopamine (DA) was investigated in the striatum of male Sprague-Dawley rats following a single administration of methamphetamine hydrochloride (100 mg/kg, s.c.). Rats were sacrificed 30, 60, and 90 min, and 1 wk after injection, and striatal 6-OHDA, DA, and 3,4-dihydroxyphenyl-acetic acid (DOPAC) were measured by HPLC with electrochem. detection. Methamphetamine decreased striatal DA and DOPAC levels (to 65 and 50% at 90 min, resp.) in the time-course study and also resulted in a long-lasting dopamine depletion (34%) 1 wk after its administration. However, endogenous 6-OHDA formation proved difficult to detect after administration of the methamphetamine alone. Pretreatment with the monoamine oxidase (MAO) inhibitor pargyline (100 mg/kg, i.p.) and the catechol-O-methyltransferase (COMT) inhibitor pyrogallol (25 mg/kg, i.p.) resulted in the HPLC detection of a 6-OHDA-like substance 30 min after methamphetamine administration when the oxidizing potential was set at 0.5 V, but not when it was set at 0.2 V. Moreover, pargyline (25 mg/kg, i.p.) alone or in combination with pyrogallol exacerbated the long-lasting dopamine depletion induced by methamphetamine (50 mg/kg, s.c.). These results indicate that simultaneous inhibition of MAO and COMT provides a cellular environment that encourages the autoxidn. of dopamine to a 6-OHDA-like substance.
- 83Agrawal, R.; Sharma, P. K.; Rao, G. S. Release of Iron from Ferritin by Metabolites of Benzene and Superoxide Radical Generating Agents. Toxicology 2001, 168 (3), 223– 230, DOI: 10.1016/S0300-483X(01)00412-7[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvFGru78%253D&md5=2628da58889ecfe1dfb82b61d66589b9Release of iron from ferritin by metabolites of benzene and superoxide radical generating agentsAgrawal, Rashmi; Sharma, Pankaj K.; Rao, Gondi S.Toxicology (2001), 168 (3), 223-230CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Science Ltd.)The release of iron from ferritin in the presence of benzene metabolites, viz. phenol (P), catechol (CT), hydroquinone (HQ) and superoxide radical generating compds., viz. pyrogallol (PL), phloroglucinol (PG), phenylhydrazine (PH) or phenylenediamine (PD) was studied in acetate buffer, pH 5.6. Monitoring the formation of the iron-ferrozine complex quantitated the release of iron from ferritin. The presence of P (125 μM) did not result in the release of iron from ferritin, whereas the same concn. of CT, HQ, PL, PH or PD resulted in the release of significant amts. of iron from ferritin and a marginal amt. of iron in the presence of PG, CT, HQ, PL, PH or PD concn. and time-dependent increase in iron release from ferritin were obsd. although the increase was not linear as a function of time and concn. of the compds. studied. The presence of superoxide dismutase inhibited significantly the release of iron from ferritin by CT, HQ, PL, PH or PD. The iron released from ferritin by CT, HQ, PL, PH or PD enhanced lipid peroxidn. in rat brain homogenate and released aldehydic products from bleomycin-dependent degrdn. of DNA and also caused single strand nicks to pUC18 DNA. These studies indicate that CT and HQ, the two principal polyphenolic metabolites of benzene and PL, PH or PD, the superoxide radical generating compds. were capable of reducing ferric iron from ferritin and also mobilizing and releasing iron from ferritin core. The release of iron from ferritin by these compds. is a result of direct redn. of ferritin iron by electron transfer and also redn. via superoxide radical. The release of iron from ferritin by CT and HQ may have toxicol. implications in relation to benzene toxicity. The release of iron by superoxide radical generating agents suggests that oxidative stress may play a role as this could lead to disruption of intracellular iron homeostasis.
- 84Yamada, J.; Yoshimura, S.; Yamakawa, H.; Sawada, M.; Nakagawa, M.; Hara, S.; Kaku, Y.; Iwama, T.; Naganawa, T.; Banno, Y. Cell Permeable ROS Scavengers, Tiron and Tempol, Rescue PC12 Cell Death Caused by Pyrogallol or Hypoxia/Reoxygenation. Neurosci. Res. 2003, 45 (1), 1– 8, DOI: 10.1016/S0168-0102(02)00196-7[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpvVaisbw%253D&md5=cf5e095c8016434f53263e69ade58d5fCell permeable ROS scavengers, Tiron and Tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenationYamada, Jun; Yoshimura, Shinichi; Yamakawa, Haruki; Sawada, Motoshi; Nakagawa, Masanori; Hara, Shigeru; Kaku, Yasuhiko; Iwama, Toru; Naganawa, Takashi; Banno, Yoshiko; Nakashima, Shigeru; Sakai, NoboruNeuroscience Research (Oxford, United Kingdom) (2003), 45 (1), 1-8CODEN: NERADN; ISSN:0168-0102. (Elsevier Science Ltd.)The role of superoxide anion (O2•-) in neuronal cell injury induced by reactive oxygen species (ROS) was examd. in PC12 cells using pyrogallol (1,2,3-benzenetrior), a donor to release O2•-. Pyrogallol induced PC12 cell death at concns., which evidently increased intracellular O2•-, as assessed by O2•--sensitive fluorescent precursor hydroethidine (HEt). Caspase inhibitors, Z-VAD-FMK and Z-Asp-CH2-DCB, failed to protect cells from injury caused by elevation of intracellular O2•-, although these inhibitors had effects on hypoxia- or hydrogen peroxide (H2O2)-induced PC12 cell death. Two known O2•- scavengers, Tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid) and Tempol (4-hydroxy-2,2,6,6-tetramethylpiperydine-1-oxyl) rescued PC12 cells from pyrogallol-induced cell death. Hypoxia/reoxygenation injury of PC12 cells was also blocked by Tiron and Tempol. Further understanding of the underlying mechanism of the protective effects of these radical scavengers reducing intracellular O2•- on neuronal cell death may lead to development of new therapeutic treatments for hypoxic/ischemic brain injury.
- 85Liao, P.-C.; Kuo, Y.-M.; Chang, Y.-C.; Lin, C.; Cherng, C.-F. G.; Yu, L. Striatal Formation of 6-Hydroxydopamine in Mice Treated with Pargyline, Pyrogallol and Methamphetamine. J. Neural Transm. 2003, 110 (5), 487– 494, DOI: 10.1007/s00702-002-0829-x[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjt1Omurg%253D&md5=5b31e1a45e7bfc4711ece4233433434cStriatal formation of 6-hydroxydopamine in mice treated with pargyline, pyrogallol and methamphetamineLiao, P.-C.; Kuo, Y.-M.; Chang, Y.-C.; Lin, C.; Cherng, C.-F. G.; Yu, L.Journal of Neural Transmission (2003), 110 (5), 487-494CODEN: JNTRF3; ISSN:0300-9564. (Springer-Verlag Wien)Formation of 6-hydroxydopamine (6-OHDA) has been posited in the striatum following methamphetamine treatment and plays a crit. role in methamphetamine-induced nigrostriatal dopaminergic toxicity. We used high performance liq. chromatog. electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) to det. the formation of 6-OHDA by the treatments of methamphetamine combined with pargyline, a monoamine oxidase inhibitor, and pyrogallol, a catechol-O-methyltransferase inhibitor, in female C57BL/6J mouse striatum. A substantial amt. of 6-OHDA (9.9 ± 0.7 pg/mg wet tissue) was detected in mice treated with pargyline (100 mg/kg) and pyrogallol (25 mg/kg) in combination. Greater striatal 6-OHDA levels were obsd. in mice treated with combined pargyline, pyrogallol and methamphetamine (50 mg/kg) as compared to mice treated with combined pargyline and pyrogallol. However, mice treated with pargyline and pyrogallol in combination followed by one and two doses of methamphetamine exhibited comparable striatal 6-OHDA levels (23.2 ± 4.3, 27.3 ± 1.3 pg/mg wet tissue) in our protocol. We conclude that blockade of the primary metabolic pathways of dopamine by inhibiting both monoamine oxidase and catechol-O-methyltransferase activities is sufficient to induce 6-OHDA formation in the striatum. Acute 6-OHDA accumulation in the striatum can be potentiated by methamphetamine, a potent dopamine releaser, administration following such metabolic inhibitions.
- 86Upadhyay, G.; Gupta, S. P.; Prakash, O.; Singh, M. P. Pyrogallol-Mediated Toxicity and Natural Antioxidants: Triumphs and Pitfalls of Preclinical Findings and Their Translational Limitations. Chem.-Biol. Interact. 2010, 183 (3), 333– 340, DOI: 10.1016/j.cbi.2009.11.028[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFagtQ%253D%253D&md5=98fb7012f8ec460cd9e44d641335d7d9Pyrogallol-mediated toxicity and natural antioxidants: Triumphs and pitfalls of preclinical findings and their translational limitationsUpadhyay, Ghanshyam; Gupta, Satya Prakash; Prakash, Om; Singh, Mahendra PratapChemico-Biological Interactions (2010), 183 (3), 333-340CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)A review. Pyrogallol, a potent anti-psoriatic drug, produces toxicity due to its ability to generate free radicals, besides its beneficial effects. Oxidative stress is implicated in pyrogallol-mediated toxicity in general and hepatotoxicity in particular. Naturally occurring antioxidants including, resveratrol and silymarin were proposed as potential supplements to counteract pyrogallol-mediated toxicity, without reducing its efficacy. Due to increase in the popularity of natural antioxidants in combating pyrogallol-mediated toxicity, a literature-based survey was performed to assess their role in exptl. studies and possible implications in real life situations. Although preclin. studies revealed the boons of naturally occurring antioxidants in attenuating/abolishing the undesirable effects of pyrogallol exposure, limited studies were conducted to evaluate their role in clinics. In this review, an update on the recent development in assessing the potential of natural antioxidants in pyrogallol-mediated toxicity in preclin. interventions, triumphs and pitfalls of such investigations, their translational challenges and future possibilities are discussed.
- 87Wang, H.; Wang, H.; Wang, J.; Wang, Q.; Ma, Q.-F.; Chen, Y.-Y. Protocatechuic Acid Inhibits Inflammatory Responses in LPS-Stimulated BV2Microglia via NF-KB and MAPKs Signaling Pathways. Neurochem. Res. 2015, 40 (8), 1655– 1660, DOI: 10.1007/s11064-015-1646-6[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWju73N&md5=4d169ed4309ee3c589a222347396d901Protocatechuic Acid Inhibits Inflammatory Responses in LPS-Stimulated BV2 Microglia via NF-κB and MAPKs Signaling PathwaysWang, Huan-yu; Wang, Hong; Wang, Jin-huan; Wang, Qiong; Ma, Quan-feng; Chen, Yi-yangNeurochemical Research (2015), 40 (8), 1655-1660CODEN: NEREDZ; ISSN:0364-3190. (Springer)Protocatechuic acid (PA), a major metabolite of anthocyanins, has been reported to possess antioxidant and anti-inflammatory activities. However, the effects of PA on LPS-induced inflammatory responses in microglia have not been reported. The aim of this study was to investigate the anti-inflammatory effects and mol. mechanisms of PA on LPS-stimulated BV2 microglia. The prodn. of inflammatory mediators TNF-α, IL-6, IL-1β, and PGE2 were detected by ELISA. TLR4, NF-κB and MAPKs activation were detected by western blotting. Our results demonstrated that PA dose-dependently inhibited LPS-induced TNF-α, IL-6, IL-1β, and PGE2 prodn. In addn., PA suppressed LPS-induced TLR4 expression, NF-κB and MAPKs activation, which resulted in the inhibition of inflammatory mediators. In conclusion, these results suggested that PA exhibited anti-inflammatory effects on LPS-stimulated BV2 microglia and the mechanisms were involved in the inhibition of TLR4-mediated NF-κB and MAPKs signaling pathways.
- 88Ren, Z.; Zhang, R.; Li, Y.; Li, Y.; Yang, Z.; Yang, H. Ferulic Acid Exerts Neuroprotective Effects against Cerebral Ischemia/Reperfusion-Induced Injury via Antioxidant and Anti-Apoptotic Mechanisms in Vitro and in Vivo. Int. J. Mol. Med. 2017, 40 (5), 1444– 1456, DOI: 10.3892/ijmm.2017.3127[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVOru77I&md5=dddc5fbf640e21cdd583d583e1bdecafFerulic acid exerts neuroprotective effects against cerebral ischemia/reperfusion-induced injury via antioxidant and anti-apoptotic mechanisms in vitro and in vivoRen, Zhongkun; Zhang, Rongping; Li, Yuanyuan; Li, Yu; Yang, Zhiyong; Yang, HuiInternational Journal of Molecular Medicine (2017), 40 (5), 1444-1456CODEN: IJMMFG; ISSN:1791-244X. (Spandidos Publications Ltd.)Ferulic acid (FA) is a deriv. of cinnamic acid. It is used in the treatment of heart head blood-vessel disease and exerts protective effects against hypoxia/ischemiainduced cell injury in the brain. This study investigated the potential neuroprotective effects of FA against ischemia/reperfusion (I/R)-induced brain injury in vivo and in vitro through hematoxylin and eosin (H&E) and Nissl staining assays, flow cytometry, Hoechst 33258 staining, quant. PCR, western blot anal. and fluorescence microscopic anal. In this study, models of cerebral I/R injury were established using rats and pheochromocytoma (PC-12) cells. The results revealed that treatment with FA significantly attenuated memory impairment, and reduced hippocampal neuronal apoptosis and oxidative stress in a dose-dependent manner. The results from in vitro expts. also indicated that FA protected the PC-12 cells against I/R-induced reactive oxygen species (ROS) generation and apoptosis by inhibiting apoptosis, Ca2+ influx, superoxide anion (O2-), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) prodn. in a concn.-dependent manner. Moreover, FA inactivated the Toll-like receptor (TLR)/myeloid differentiation factor 88 (MyD88) pathway. MyD88 overexpression abolished the neuroprotective effects of FA. On the whole, we found that FA attenuated memory dysfunction and exerted protective effects against oxidative stress and apoptosis induced by I/R injury by inhibiting the TLR4/MyD88 signaling pathway. This study supports the view that FA may be a promising neuroprotective agent for use in the treatment of cerebral ischemia.
- 89Kim, M.-J.; Seong, A.-R.; Yoo, J.-Y.; Jin, C.-H.; Lee, Y.-H.; Kim, Y. J.; Lee, J.; Jun, W. J.; Yoon, H.-G. Gallic Acid, a Histone Acetyltransferase Inhibitor, Suppresses β-Amyloid Neurotoxicity by Inhibiting Microglial-Mediated Neuroinflammation. Mol. Nutr. Food Res. 2011, 55 (12), 1798– 1808, DOI: 10.1002/mnfr.201100262[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlygtbvJ&md5=9e51b40ec36311b9e0b14caa5cfc4aaeGallic acid, a histone acetyltransferase inhibitor, suppresses β-amyloid neurotoxicity by inhibiting microglial-mediated neuroinflammationKim, Mi-Jeong; Seong, Ah-Reum; Yoo, Jung-Yoon; Jin, Cheng-Hao; Lee, Yoo-Hyun; Kim, Young Jun; Lee, Jeongmin; Jun, Woo Jin; Yoon, Ho-GeunMolecular Nutrition & Food Research (2011), 55 (12), 1798-1808CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)Scope: We examd. the biol. effect of gallic acid (GA) as a nuclear factor (NF)-κB acetyltransferase inhibitor on microglial-mediated β-amyloid neurotoxicity and restorative effects on the Aβ-induced cognitive dysfunction. Methods and results: The protective effects of GA on the survival of neuronal cells were assessed with an MTT assay and a co-culture system. For the co-culture expts., both BV-2 and primary microglia cells were treated with GA prior to Aβ stimulation, and conditioned media were transferred to Neuro-2A cells. The mRNA and protein levels of inflammatory cytokines in both microglia and Neuro-2A cells were assessed with real-time polymerase chain reaction and western blotting. Inhibition of nuclear factor kappa B (NF-κB) acetylation with GA treatment resulted in reduced cytokine prodn. in microglia cells and protection of neuronal cells from Aβ-induced neurotoxicity. Furthermore, we obsd. a restorative effect of GA on Aβ-induced cognitive dysfunction in mice with Y-maze and passive avoidance tests. Finally, we found that GA treatment efficiently blocked neuronal cell death by downregulating the expression of cytokines and the in vivo levels of NF-κB acetylation. Conclusion: These results suggest that selective inhibition of NF-κB acetylation by the histone acetyltransferase inhibitor GA is a possible therapeutic approach for alleviating the inflammatory progression of Alzheimer disease.
- 90da Silva, A.; Giacomoni, F.; Pavot, B.; Fillâtre, Y.; Rothwell, J. A.; Sualdea, B. B.; Veyrat, C.; Garcia-Villalba, R.; Gladine, C.; Kopec, R.; PhytoHub V1. 4: A New Release for the Online Database Dedicated to Food Phytochemicals and Their Human Metabolites. In Proceedings of the 1st International Conference on Food Bioactivities & Health, Norwich, U.K., 2016; pp 13– 15.Google ScholarThere is no corresponding record for this reference.
- 91Kim, B.-W.; Koppula, S.; Park, S.-Y.; Kim, Y.-S.; Park, P.-J.; Lim, J.-H.; Kim, I.-S.; Choi, D.-K. Attenuation of Neuroinflammatory Responses and Behavioral Deficits by Ligusticum Officinale (Makino) Kitag in Stimulated Microglia and MPTP-Induced Mouse Model of Parkinson’s Disease. J. Ethnopharmacol. 2015, 164, 388– 397, DOI: 10.1016/j.jep.2014.11.004[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mzis1Wnug%253D%253D&md5=502b59303505f16fd53aff3a7ffe91c0Attenuation of neuroinflammatory responses and behavioral deficits by Ligusticum officinale (Makino) Kitag in stimulated microglia and MPTP-induced mouse model of Parkinson's diseaseKim Byung-Wook; Koppula Sushruta; Park Shin-Young; Kim Yon-Suk; Park Pyo-Jam; Kim In-Su; Lim Ji-Hong; Choi Dong-KugJournal of ethnopharmacology (2015), 164 (), 388-97 ISSN:.ETHNOPHARMACOLOGICAL RELEVANCE: Ligusticum officinale (Makino) Kitag (L. officinale) is one of the important traditional herbs used in traditional Oriental medicine for the treatment of various disorders including pain and inflammation. However, there is limited scientific basis for its activity and mechanism in brain inflammation. AIM OF THE STUDY: This study aimed to evaluate the effects of L. officinale on microglia-mediated neuroinflammation and behavioral impairments using in vitro cellular and in vivo mouse model of PD, as well as investigate the molecular mechanisms involved including the finger printing analysis of its ethanol extract. MATERIALS AND METHODS: Lipopolysaccharide (LPS) was used to stimulate BV-2 microglial cells. The changes in neuroinflammatory expressional levels were measured by Western blotting and immunofluorescence techniques. 1-methyl-4 phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mice model of PD was developed to evaluate the behavioral impairments and the brain tissues were used for immunohistochemical studies. High performance liquid chromatography (HPLC) technique was performed for finger printing analysis of L. officinale extract used in the study. RESULTS: L. officinale significantly attenuated the LPS-stimulated increase in inflammatory mediators in BV-2 cells. L. officinale also inhibited the LPS-induced activation of nuclear factor-kappa beta by blocking the degradation of IκB-α and suppressing the increase in p38-mitogen-activated protein kinase phosphorylation in BV-2 cells. Furthermore, L. officinale exhibited significant antioxidant properties by inhibiting the 1-diphenyl-2-picrylhydrazyl radicals. An in vivo evaluation in MPTP (20mg/kg, four times, 1 day, i.p.) intoxicated mice resulted in brain microglial activation and significant behavioral deficits. Prophylactic treatment with L. officinale prevented microglial activation and attenuated PD-like behavioral changes as assessed by the pole test. HPLC finger printing analysis revealed that L. officinale extract contained ferulic acid (FA) as one of the major constituents compared with reference standard. FA also inhibited the LPS-stimulated excessive release of NO and suppressed the increased the expressional levels of proinflammatory mediators in BV-2 microglia. CONCLUSIONS: The findings observed in this study indicated that L. officinale extract significantly attenuated the neuroinflammatory processes in stimulated microglia and restored the behavioral impairments in a mouse model of PD providing a scientific basis for its traditional claims.
- 92Rehman, S. U.; Ali, T.; Alam, S. I.; Ullah, R.; Zeb, A.; Lee, K. W.; Rutten, B. P. F.; Kim, M. O. Ferulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse Hippocampus. Mol. Neurobiol. 2019, 56 (4), 2774– 2790, DOI: 10.1007/s12035-018-1280-9[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVShtb%252FP&md5=ea05349dd282ad10ab4822738671cefeFerulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse HippocampusRehman, Shafiq Ur; Ali, Tahir; Alam, Sayed Ibrar; Ullah, Rahat; Zeb, Amir; Lee, Keun Woo; Rutten, Bart P. F.; Kim, Myeong OkMolecular Neurobiology (2019), 56 (4), 2774-2790CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Microglia play a crucial role in the inflammatory brain response to infection. However, overactivation of microglia is neurotoxic. Toll-like receptor 4 (TLR4) is involved in microglial activation via lipopolysaccharide (LPS), which triggers a variety of cytotoxic pro-inflammatory markers that produce deleterious effects on neuronal cells. Ferulic acid (FA) is a phenolic compd. that exerts antioxidant and anti-inflammatory effects in neurodegenerative disease. However, the manner in which FA inhibits neuroinflammation-induced neurodegeneration is poorly understood. Therefore, we investigated the anti-inflammatory effects of FA against LPS-induced neuroinflammation in the mouse brain. First, we provide evidence that FA interferes with TLR4 interaction sites, which are required for the activation of microglia-induced neuroinflammation, and further examd. the potential mechanism of its neuroprotective effects in the mouse hippocampus using mol. docking simulation and immunoblot anal. Our results indicated that FA treatment inhibited glial cell activation, p-JNK, p-NFKB, and downstream signaling mols., such as iNOS, COX-2, TNF-α, and IL-1β, in the mouse hippocampus and BV2 microglial cells. FA treatment strongly inhibited mitochondrial apoptotic signaling mols., such as Bax, cytochrome C, caspase-3, and PARP-1, and reversed deregulated synaptic proteins, including PSD-95, synaptophysin, SNAP-25, and SNAP-23, and synaptic dysfunction in LPS-treated mice. These findings demonstrated that FA treatment interfered with the TLR4/MD2 complex binding site, which is crucial for evoking neuroinflammation via microglia activation and inhibited NFKB likely via a JNK-dependent mechanism, which suggests a therapeutic implication for neuroinflammation-induced neurodegeneration.
- 93Koshiguchi, M.; Komazaki, H.; Hirai, S.; Egashira, Y. Ferulic Acid Suppresses Expression of Tryptophan Metabolic Key Enzyme Indoleamine 2, 3-Dioxygenase via NFκB and P38 MAPK in Lipopolysaccharide-Stimulated Microglial Cells. Biosci., Biotechnol., Biochem. 2017, 81 (5), 966– 971, DOI: 10.1080/09168451.2016.1274636[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpslKhuw%253D%253D&md5=9e3544267ac670d37238d34c4ec20318Ferulic acid suppresses expression of tryptophan metabolic key enzyme indoleamine 2, 3-dioxygenase via NFκB and p38 MAPK in lipopolysaccharide-stimulated microglial cellsKoshiguchi, Manami; Komazaki, Hitoshi; Hirai, Shizuka; Egashira, YukariBioscience, Biotechnology, and Biochemistry (2017), 81 (5), 966-971CODEN: BBBIEJ; ISSN:1347-6947. (Taylor & Francis Ltd.)Ferulic acid (FA) is a phenol compd. found in plants that has anti-inflammatory properties. Indoleamine 2, 3-dioxygenase (IDO) is a tryptophan catabolic enzyme induced in immune cells, including glial cells, during inflammation. Enhanced IDO expression leads to reduced tryptophan levels and increased levels of toxic metabolites, including quinolinic acid. Therefore, inhibition of IDO expression may be effective in suppressing progression of neurodegenerative diseases. In this study, we examd. the effect of FA in microglial cells on IDO expression levels and related inflammatory signal mols. FA suppressed LPS-induced IDO mRNA expression and also suppressed nuclear translocation of NF-κB and phosphorylation of p38 MAPK. However, FA did not affect the prodn. of LPS-induced inflammatory mediators and phosphorylation of JNK. Our results indicate that FA suppresses LPS-induced IDO mRNA expression, which may be mediated by inhibition of the NF-κB and p38 MAPK pathways in microglial cells.
- 94Chakrabarti, S.; Jana, M.; Roy, A.; Pahan, K. Upregulation of Suppressor of Cytokine Signaling 3 in Microglia by Cinnamic Acid. Curr. Alzheimer Res. 2018, 15 (10), 894– 904, DOI: 10.2174/1567205015666180507104755[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1OmtrbI&md5=fd81ce41e95d64302459736b616e282bUpregulation of Suppressor of Cytokine Signaling 3 in Microglia by Cinnamic AcidChakrabarti, Sudipta; Jana, Malabendu; Roy, Avik; Pahan, KalipadaCurrent Alzheimer Research (2018), 15 (10), 894-904CODEN: CARUBY; ISSN:1567-2050. (Bentham Science Publishers Ltd.)Neuroinflammation plays an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer's disease (AD). Suppressor of cytokine signaling 3 (SOCS3) is an anti-inflammatory mol. that suppresses cytokine signaling and inflammatory gene expression in different cells including microglia. The pathways through which SOCS3 could be upregulated are poorly described. Cinnamic acid is a metabolite of cinnamon, a natural compd. that is being widely used all over the world as a spice or flavoring agent. Here, we examd. if cinnamic acid could upregulate SOCS3 in microglia. Microglia and astroglia isolated from mouse brain as well as BV-2 microglial cells were treated with cinnamic acid followed by monitoring the level of SOCS3 and different proinflammatory mols. by RT-PCR and real-time PCR. To nail down the mechanism, we also performed ChIP anal. to monitore the recruitment of cAMP response element binding (CREB) to the socs3 gene promoter and carried out siRNA knockdown of CREB. Cinnamic acid upregulated the expression of SOCS3 mRNA and protein in mouse BV-2 microglial cells in dose- and time-dependent manner. Accordingly, cinnamic acid also increased the level of SOCS3 and suppressed the expression of inducible nitric oxide synthase and proinflammatory cytokines (TNFα, IL-1 β and IL-6) in LPSstimulated BV-2 microglial cells. Similar to BV-2 microglial cells, cinnamic acid also increased the expression of SOCS3 in primary mouse microglia and astrocytes. We have seen that cAMP response element is present in the promoter of socs3 gene, that cinnamic acid induces the activation of CREB, that siRNA knockdown of CREB abrogates cinnamic acid-mediated upregulation of SOCS3, and that cinnamic acid treatment leads to the recruitment of CREB to the socs3 gene. These studies suggest that cinnamic acid upregulates the expression of SOCS3 in glial cells via CREB pathway, which may be of importance in neuroinflammatory and neurodegenerative disorders.
- 95Stalmach, A.; Mullen, W.; Barron, D.; Uchida, K.; Yokota, T.; Cavin, C.; Steiling, H.; Williamson, G.; Crozier, A. Metabolite Profiling of Hydroxycinnamate Derivatives in Plasma and Urine after the Ingestion of Coffee by Humans: Identification of Biomarkers of Coffee Consumption. Drug Metab. Dispos. 2009, 37 (8), 1749– 1758, DOI: 10.1124/dmd.109.028019[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXps1ygtLg%253D&md5=c5ec0019752498c656d752d23dc92afaMetabolite profiling of hydroxycinnamate derivatives in plasma and urine after the ingestion of coffee by humans: identification of biomarkers of coffee consumptionStalmach, Angelique; Mullen, William; Barron, Denis; Uchida, Kenichi; Yokota, Takao; Cavin, Christophe; Steiling, Heike; Williamson, Gary; Crozier, AlanDrug Metabolism and Disposition (2009), 37 (8), 1749-1758CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)Human subjects drank coffee contg. 412 μmol of chlorogenic acids, and plasma and urine were collected 0 to 24 h after ingestion and were analyzed by HPLC -mass spectrometry. Within 1 h, some of the components in the coffee reached nanomole peak plasma concns. (Cmax), whereas chlorogenic acid metabolites, including caffeic acid-3-O-sulfate and ferulic acid-4-O-sulfate and sulfates of 3- and 4-caffeoylquinic acid lactones, had higher Cmax values. The shor time to reach Cmax (Tmax) indicates absorption of these compds. in the small intestine. In contrast, dihydroferulic acid, its 4-O-sulfate, and dihydrocaffeic acid-3-O-sulfate exhibited much higher Cmax values (145-385 nM) with Tmax values in excess of 4 h, indicating absorption in the large intestine and the probable involvement of catabolism by colonic bacteria. These 3 compds., along with ferulic acid-4-O-sulfate and dihydroferulic acid-4-O-glucuronide, were also major components to be excreted in urine (8.4-37.1 μmol) after coffee intake. Feruloylglycine, which is not detected in plasma, was also a major urinary component (20.7 μmol excreted). Other compds., not accumulating in plasma but excreted in smaller quantities, included the 3-O-sulfate and 3-O-glucuronide of isoferulic acid, dihydro(iso)ferulic acid-3-O-glucuronide, and dihydrocaffeic acid-3-O-glucuronide. Overall, the 119.9 μmol excretion of the chlorogenic acid metabolites corresponded to 29.1% of intake, indicating that as well as being subject to extensive metab., chlorogenic acids in coffee are well absorbed. Pathways for the formation of the various metabolites within the body are proposed. Urinary dihydrocaffeic acid-3-O-sulfate and feruloylglycine are potentially very sensitive biomarkers for the consumption of relatively small amts. of coffee.
- 96van Dorsten, F. A.; Grün, C. H.; van Velzen, E. J. J.; Jacobs, D. M.; Draijer, R.; van Duynhoven, J. P. M. The Metabolic Fate of Red Wine and Grape Juice Polyphenols in Humans Assessed by Metabolomics. Mol. Nutr. Food Res. 2010, 54 (7), 897– 908, DOI: 10.1002/mnfr.200900212[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXosF2isr0%253D&md5=cea03e5632fb32db042214119a3b2dc2The metabolic fate of red wine and grape juice polyphenols in humans assessed by metabolomicsvan Dorsten, Ferdinand A.; Gruen, Christian H.; van Velzen, Ewoud J. J.; Jacobs, Doris M.; Draijer, Richard; van Duynhoven, John P. M.Molecular Nutrition & Food Research (2010), 54 (7), 897-908CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)The metabolic impact of polyphenol-rich red wine and grape juice consumption in humans was studied using a metabolomics approach. Fifty-eight men and women participated in a placebo-controlled, double-crossover study in which they consumed during a period of 4 wk, either a polyphenol-rich 2:1 dry mix of red wine and red grape juice exts. (MIX) or only a grape juice ext. (GJX). Twenty-four-hour urine samples were collected after each intervention. 1H NMR spectroscopy was applied for global metabolite profiling, while GC-MS was used for focused profiling of urinary phenolic acids. Urine metabolic profiles after intake of both polyphenol-rich exts. were significantly differentiated from placebo using multilevel partial least squares discriminant anal. (ML-PLS-DA). A significant 35% increase in hippuric acid excretion (p<0.001) in urine was measured after the MIX consumption compared with placebo, whereas no change was found after GJX consumption. GC-MS-based metabolomics of urine allowed identification of 18 different phenolic acids, which were significantly elevated following intake of either ext. Syringic acid, 3- and 4-hydroxyhippuric acid and 4-hydroxymandelic acid were the strongest urinary markers for both exts. MIX and GJX consumption had a slightly different effect on the excreted phenolic acid profile and on endogenous metabolite excretion, possibly reflecting their different polyphenol compn.
- 97Esteban-Fernández, A.; Rendeiro, C.; Spencer, J. P. E.; del Coso, D. G.; de Llano, M. D. G.; Bartolomé, B.; Moreno-Arribas, M. V. Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of Action. Front. Nutr. 2017, 4, 3, DOI: 10.3389/fnut.2017.00003[Crossref], [PubMed], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cvitFGhtQ%253D%253D&md5=eb1678b2c3971b714d30e03a944717a6Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of ActionEsteban-Fernandez A; Rendeiro C; Spencer J P E; Del Coso D Gigorro; de Llano M D Gonzalez; Bartolome B; Moreno-Arribas M VFrontiers in nutrition (2017), 4 (), 3 ISSN:2296-861X.Moderate wine consumption has shown the potential to delay the onset of neurodegenerative diseases. This study investigates the molecular mechanisms underlying the protective effects of wine-derived phenolic and aroma compounds in a neuroinflammation model based on SIN-1 stress-induced injury in SH-SY5Y neuroblastoma cells. Cell pretreatment with microbial metabolites found in blood after wine consumption, 3,4-dihydroxyphenylacetic (3,4-DHPA), 3-hydroxyphenylacetic acids and salicylic β-d-O-glucuronide, at physiologically concentrations (0.1-10 μM) resulted in increased cell viability versus SIN-1 control group (p < 0.05). Results also showed significant decreases in mitogen-activated protein kinase (MAPK) p38 and ERK1/2 activation as well as in downstream pro-apoptotic caspase-3 activity by some of the studied compounds. Moreover, pretreatment with p38, MEK, and ERK1/2-specific inhibitors, which have a phenolic-like structure, also resulted in an increase on cell survival and a reduction on caspase-3 activity levels. Overall, these results contribute with new evidences related to the neuroprotective actions of wine, pointing out that wine-derived human metabolites and aroma compounds may be effective at protecting neuroblastoma cells from nitrosative stress injury by inhibiting neuronal MAPK p38 and ERK1/2, as well as downstream caspase 3 activity.
- 98Wang, Y.-D.; Bao, X.-Q.; Xu, S.; Yu, W.-W.; Cao, S.-N.; Hu, J.-P.; Li, Y.; Wang, X.-L.; Zhang, D.; Yu, S.-S. A Novel Parkinson’s Disease Drug Candidate with Potent Anti-Neuroinflammatory Effects through the Src Signaling Pathway. J. Med. Chem. 2016, 59 (19), 9062– 9079, DOI: 10.1021/acs.jmedchem.6b00976[ACS Full Text], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyqtb7O&md5=8ceb592d04332b3dbde41a29c9304019A Novel Parkinson's Disease Drug Candidate with Potent Anti-neuroinflammatory Effects through the Src Signaling PathwayWang, Ya-Dan; Bao, Xiu-Qi; Xu, Song; Yu, Wen-Wen; Cao, Sheng-Nan; Hu, Jin-Ping; Li, Yan; Wang, Xiao-Liang; Zhang, Dan; Yu, Shi-ShanJournal of Medicinal Chemistry (2016), 59 (19), 9062-9079CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Numerous drug treatments are available for Parkinson's disease (PD), an age-related neurodegenerative disease, but most cause serious side effects. Therefore, novel therapeutic strategies that halt disease progression and allow for long-term administration are urgently needed. Neuroinflammation critically contributes to the pathogenesis of PD. Here, we report the discovery and optimization of phloroglucinol derivs., a novel class of anti-neuroinflammatory compds. Structural modifications of the hit compd. 3-methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one produced 43 derivs., including a preclin. candidate (compd. 21), that exhibited potent in vitro anti-neuroinflammatory effects, good blood-brain barrier penetration, and desirable safety margins in mice at a median LD (LD50) >5000 mg/kg. Its in vivo efficacy was demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and MPTP/probenecid (prob)-induced subacute and chronic PD models, resp., and α-synuclein transgenic mice. Mechanistic studies revealed neuroinflammation inhibition by targeting Src/phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/Akt signaling might be promising. We highlighted the potential usefulness of phloroglucinol derivs. in PD treatment.
- 99Figueira, I.; Tavares, L.; Jardim, C.; Costa, I.; Terrasso, A. P.; Almeida, A. F.; Govers, C.; Mes, J. J.; Gardner, R.; Becker, J. D. Blood–brain Barrier Transport and Neuroprotective Potential of Blackberry-Digested Polyphenols: An in Vitro Study. Eur. J. Nutr. 2019, 58 (1), 113– 130, DOI: 10.1007/s00394-017-1576-y[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVaru77F&md5=99a87eee4f37a5fba81fdcc8c68ad468Blood-brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro studyFigueira, Ines; Tavares, Lucelia; Jardim, Carolina; Costa, Ines; Terrasso, Ana P.; Almeida, Andreia F.; Govers, Coen; Mes, Jurriaan J.; Gardner, Rui; Becker, Jorg D.; McDougall, Gordon J.; Stewart, Derek; Filipe, Augusto; Kim, Kwang S.; Brites, Dora; Brito, Catarina; Brito, M. Alexandra; Santos, Claudia N.European Journal of Nutrition (2019), 58 (1), 113-130CODEN: EJNUFZ; ISSN:1436-6207. (Springer)Purpose: Epidemiol. and intervention studies have attempted to link the health effects of a diet rich in fruits and vegetables with the consumption of polyphenols and their impact in neurodegenerative diseases. Studies have shown that polyphenols can cross the intestinal barrier and reach concns. in the bloodstream able to exert effects in vivo. However, the effective uptake of polyphenols into the brain is still regarded with some reservations. Here we describe a combination of approaches to examine the putative transport of blackberry-digested polyphenols (BDP) across the blood-brain barrier (BBB) and ultimate evaluation of their neuroprotective effects. Methods: BDP was obtained by in vitro digestion of blackberry ext. and BDP major aglycons (hBDP) were obtained by enzymic hydrolysis. Chem. characterization and BBB transport of exts. were evaluated by LC-MSn. BBB transport and cytoprotection of both exts. was assessed in HBMEC monolayers. Neuroprotective potential of BDP was assessed in NT2-derived 3D co-cultures of neurons and astrocytes and in primary mouse cerebellar granule cells. BDP-modulated genes were evaluated by microarray anal. Results: Components from BDP and hBDP were shown to be transported across the BBB. Physiol. relevant concns. of both exts. were cytoprotective at endothelial level and BDP was neuroprotective in primary neurons and in an advanced 3D cell model. The major canonical pathways involved in the neuroprotective effect of BDP were unveiled, including mTOR signaling and the unfolded protein response pathway. Genes such as ASNS and ATF5 emerged as novel BDP-modulated targets. Conclusions: BBB transport of BDP and hBDP components reinforces the health benefits of a diet rich in polyphenols in neurodegenerative disorders. Our results suggest some novel pathways and genes that may be involved in the neuroprotective mechanism of the BDP polyphenol components.
- 100Loke, W. M.; Jenner, A. M.; Proudfoot, J. M.; McKinley, A. J.; Hodgson, J. M.; Halliwell, B.; Croft, K. D. A Metabolite Profiling Approach to Identify Biomarkers of Flavonoid Intake in Humans. J. Nutr. 2009, 139 (12), 2309– 2314, DOI: 10.3945/jn.109.113613[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFeis7o%253D&md5=a240236b587ca2fee84c41988b278b28A metabolite profiling approach to identify biomarkers of flavonoid intake in humansLoke, Wai Mun; Jenner, Andrew M.; Proudfoot, Julie M.; McKinley, Allan J.; Hodgson, Jonathan M.; Halliwell, Barry; Croft, Kevin D.Journal of Nutrition (2009), 139 (12), 2309-2314CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutrition)Flavonoids are phytochems. that are widespread in the human diet. Despite limitations in their bioavailability, exptl. and epidemiol. data suggest health benefits of flavonoid consumption. Valid biomarkers of flavonoid intake may be useful for estg. exposure in a range of settings. However, to date, few useful flavonoid biomarkers have been identified. In this study, we used a metabolite profiling approach to examine the arom. and phenolic profile of plasma and urine of healthy men after oral consumption of 200 mg of the pure flavonoids, quercetin, (-)-epicatechin, and epigallocatechin gallate, which represent major flavonoid constituents in the diet. Following enzymic hydrolysis, 71 arom. compds. were quantified in plasma and urine at 2 and 5 h, resp., after flavonoid ingestion. Plasma concns. of different arom. compds. ranged widely, from 0.01 to 10 μmol/L, with variation among volunteers. None of the arom. compds. was significantly elevated in plasma 2 h after consumption of either flavonoid compared with water placebo. This indicates that flavonoid-derived arom. compds. are not responsible for the acute physiol. effects reported within 2 h in previous human intervention studies involving flavonoids or flavonoid-rich food consumption. These effects are more likely due to absorption of the intact flavonoid. Our urine anal. suggested that urinary 4-ethylphenol, benzoic acid, and 4-ethylbenzoic acid may be potential biomarkers of quercetin intake and 1,3,5-trimethoxybenzene, 4-O-methylgallic acid, 3-O-methylgallic acid, and gallic acid may be potential markers of epigallocatechin gallate intake. Potential biomarkers of (-)-epicatechin were not identified. These urinary biomarkers may provide an accurate indication of flavonoid exposure.
- 101Cialdella-Kam, L.; Nieman, D. C.; Sha, W.; Meaney, M. P.; Knab, A. M.; Shanely, R. A. Dose–response to 3 Months of Quercetin-Containing Supplements on Metabolite and Quercetin Conjugate Profile in Adults. Br. J. Nutr. 2013, 109 (11), 1923– 1933, DOI: 10.1017/S0007114512003972[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvVGht78%253D&md5=6c2ec6c19830b91d1d957f06cf8f0ba8Dose-response to 3 months of quercetin-containing supplements on metabolite and quercetin conjugate profile in adultsCialdella-Kam, Lynn; Nieman, David C.; Sha, Wei; Meaney, Mary Pat; Knab, Amy M.; Shanely, R. AndrewBritish Journal of Nutrition (2013), 109 (11), 1923-1933CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)Quercetin, a flavonol in fruits and vegetables, has been demonstrated to have antioxidant, anti-inflammatory and immunomodulating influences. The purpose of the present study was to det. if quercetin, vitamin C and niacin supplements (Q-500 = 500 mg/d of quercetin, 125 mg/d of vitamin C and 5 mg/d of niacin; Q-1000 = 1000 mg/d of quercetin, 250 mg/d of vitamin C and 10 mg/d of niacin) would alter small-mol. metabolite profiles and serum quercetin conjugate levels in adults. Healthy adults (fifty-eight women and forty-two men; aged 40-83 years) were assigned using a randomised double-blinded placebo-controlled trial to one of three supplement groups (Q-1000, Q-500 or placebo). Overnight fasted blood samples were collected at 0, 1 and 3 mo. Quercetin conjugate concns. were measured using ultra-performance liq. chromatog. (UPLC)-MS/MS, and metabolite profiles were measured using two MS platforms (UPLC-quadrupole time-of-flight MS (TOFMS) and GC-TOFMS). Statistical procedures included partial least square discriminant anal. (PLS-DA) and linear mixed model anal. with repeated measures. After accounting for age, sex and BMI, quercetin supplementation was assocd. with significant shifts in 163 metabolites/quercetin conjugates (false discovery rate, P< 0·05). The top five metabolite shifts were an increase in serum guaiacol, 2-oxo-4-methylthiobutanoic acid, allocystathionine and two bile acids. Inflammatory and oxidative stress metabolites were not affected. PLS-DA revealed a clear sepn. only between the 1000 mg/d and placebo groups (Q 2 Y= 0·763). The quercetin conjugate, isorhamnetin-3-glucuronide, had the highest concn. at 3 mo followed by quercetin-3-glucuronide, quercetin-3-sulfate and quercetin diglucuronide. In human subjects, long-term quercetin supplementation exerts disparate and wide-ranging metabolic effects and changes in quercetin conjugate concns. Metabolic shifts were apparent at the 1000 mg/d dose; further research is required to understand the health implications of these shifts.
- 102van der Hooft, J. J. J.; de Vos, R. C. H.; Mihaleva, V.; Bino, R. J.; Ridder, L.; de Roo, N.; Jacobs, D. M.; van Duynhoven, J. P. M.; Vervoort, J. Structural Elucidation and Quantification of Phenolic Conjugates Present in Human Urine after Tea Intake. Anal. Chem. 2012, 84 (16), 7263– 7271, DOI: 10.1021/ac3017339[ACS Full Text], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOjsr3E&md5=bbb9f23847403e210e88212d60aa1e0aStructural Elucidation and Quantification of Phenolic Conjugates Present in Human Urine after Tea Intakevan der Hooft, Justin J. J.; de Vos, Ric C. H.; Mihaleva, Velitchka; Bino, Raoul J.; Ridder, Lars; de Roo, Niels; Jacobs, Doris M.; van Duynhoven, John P. M.; Vervoort, JacquesAnalytical Chemistry (Washington, DC, United States) (2012), 84 (16), 7263-7271CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)In dietary polyphenol exposure studies, annotation and identification of urinary metabolites present at low (micromolar) concns. are major obstacles. To det. the biol. activity of specific components, it is necessary to have the correct structures and the quantification of the polyphenol-derived conjugates present in the human body. We present a procedure for identification and quantification of metabolites and conjugates excreted in human urine after single bolus intake of black or green tea. A combination of a solid-phase extn. (SPE) prepn. step and two high pressure liq. chromatog. (HPLC)-based anal. platforms was used, namely, accurate mass fragmentation (HPLC-FTMSn) and mass-guided SPE-trapping of selected compds. for NMR spectroscopy (NMR) measurements (HPLC-TOFMS-SPE-NMR). HPLC-FTMSn anal. led to the annotation of 138 urinary metabolites, including 48 valerolactone and valeric acid conjugates. By combining the results from MSn fragmentation with the one-dimensional (1D)-1H NMR spectra of HPLC-TOFMS-SPE-trapped compds., we elucidated the structures of 36 phenolic conjugates, including the glucuronides of 3',4'-di- and 3',4',5'-trihydroxyphenyl-γ-valerolactone, three urolithin glucuronides, and indole-3-acetic acid glucuronide. We also obtained 26 h-quant. excretion profiles for specific valerolactone conjugates. The combination of the HPLC-FTMSn and HPLC-TOFMS-SPE-NMR platforms results in the efficient identification and quantification of less abundant phenolic conjugates down to nanomoles of trapped amts. of metabolite corresponding to micromolar metabolite concns. in urine.
- 103Welsch, F. Routes and Modes of Administration of Resorcinol and Their Relationship to Potential Manifestations of Thyroid Gland Toxicity in Animals and Man. Int. J. Toxicol. 2008, 27 (1), 59– 63, DOI: 10.1080/10915810701876687[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXit1Cms7s%253D&md5=56eaf6baf6eadea7368210c70c37ceecRoutes and modes of administration of resorcinol and their relationship to potential manifestations of thyroid gland toxicity in animals and manWelsch, FrankInternational Journal of Toxicology (2008), 27 (1), 59-63CODEN: IJTOFN; ISSN:1091-5818. (Informa Healthcare)A review. Medical case reports published in the 20th century over the course of several decades show that resorcinol caused reversible adverse effects on the human thyroid gland (TG) manifested as hypothyroidism. Affected patients had ulcerating leg varicosities and underwent prolonged treatment with ointments contg. high concns. of resorcinol. In animal studies resorcinol failed to induce TG toxicity, unless pharmacokinetic/toxicokinetic (PK/TK) conditions were manipulated (e.g., injection of resorcinol in oil or application in a slow release formulation). A recently completed two-generation reproductive toxicity study in rats did not detect any adverse effects on either reproductive or TG end points (Welsch, Nemec, and Lawrence, 2008, Int. J. Toxicol. 37, this issue). Resorcinol intake via drinking water up to the palatability limit had resulted in av. daily intakes (mg/kg) of 233 in F0 and F1 males and 304 (premating/gestation) or 660 (lactation) in females. Free resorcinol in blood plasma was barely detectable in a few parental animals, indicating rapid metab. This short review communication offers a perspective on compromised human skin barrier function as a likely cause of drastic increases in resorcinol absorption. In conjunction with multiple daily applications over many months to hyperemic, inflamed, and lesioned human skin much higher absorption was likely responsible for the reported human TG toxicity.
- 104Curzon, G.; Pratt, R. T. C. Origin of Urinary Resorcinol Sulphate. Nature 1964, 204 (4956), 383– 384, DOI: 10.1038/204383a0[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXks1Cr&md5=e1cff3980d900f25d4d9ed7976fa906aOrigin of urinary resorcinol sulfateCurzon, G.; Pratt, R. T. C.Nature (London, United Kingdom) (1964), 204 (4956), 383-4CODEN: NATUAS; ISSN:0028-0836.cf. CA 59, 9173f. Human urinary resorcinol monosulfate (I) appeared to be a product of the metabolism of a constituent of tea by certain people, since excretion of I stopped after removal of tea from the diet. The ingestion of large vols. of tea did not cause the excretion of I by one person. Oral administration of the intestinal antibiotic framycetin (soframycin) (II) (500 mg. 3 times/day) caused the excretion of I to cease after 6 days. Even 21 months after the end of II treatment, I was not excreted. The results suggested that I was formed in vivo by a particular intestinal bacteria from dietary vegetable matter. Once established, the bacteria may persist indefinitely but antibiotic treatment may result in their permanent disappearance.
- 105Guo, K.; Li, L. Differential 12 C-/ 13 C-Isotope Dansylation Labeling and Fast Liquid Chromatography/Mass Spectrometry for Absolute and Relative Quantification of the Metabolome. Anal. Chem. 2009, 81 (10), 3919– 3932, DOI: 10.1021/ac900166a[ACS Full Text], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsFKktrg%253D&md5=e6094091a162e20d77df94de4eb9d9baDifferential 12C-/13C-Isotope Dansylation Labeling and Fast Liquid Chromatography/Mass Spectrometry for Absolute and Relative Quantification of the MetabolomeGuo, Kevin; Li, LiangAnalytical Chemistry (Washington, DC, United States) (2009), 81 (10), 3919-3932CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)The authors report a new quant. metabolome profiling technique based on differential 12C-/13C-isotope dansylation labeling of metabolites, fast liq. chromatog. (LC) sepn. and electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) detection. An isotope reagent, 13C-dansyl chloride, can be readily synthesized. This reagent, along with 12C-dansyl chloride, provides a simple and robust means of labeling metabolites contg. primary amine, secondary amine, or phenolic hydroxyl group(s). It is shown that dansylation labeling offers 1-3 orders of magnitude ESI signal enhancement over the underivatized counterparts. Dansylation alters the chromatog. behaviors of polar and ionic metabolites normally not retainable on a reversed phase (RP) column to an extent that they can be retained and sepd. by RPLC with high efficiency. There is no isotopic effect on RPLC sepn. of the differential isotope labeled metabolites, and 12C-/13C-labeled isoforms of metabolites are coeluted and detected by MS for precise and accurate quantification and confident metabolite identification. It is demonstrated that, in the anal. of 20 amino acids, a linear response of over 2 orders of magnitude is achieved for relative metabolite quantification with an av. relative std. deviation (RSD) of about 5.3% from replicate expts. A dansylation std. compd. library consisting of 121 known amines and phenols has been constructed and is proven to be useful for abs. metabolite quantification and MS-based metabolite identification in biol. samples. As an example, the abs. concns. of 93 metabolites, ranging from 30 nM to 2510 μM, can be detd. from a pooled sample of human urines collected in 5 consecutive days labeled with 12C-dansylation and spiked with the 121 13C-dansylated stds. Relative concn. variations of these metabolites in individual urine samples can also be monitored by mixing the 13C-dansylated pooled urine sample with the 12C-dansylated individual sample. With a 12 min fast LC sepn. combined with FTICR MS, 672 metabolites were detected in a human urine sample with each metabolite peak having a signal-to-noise ratio of greater than 20; the identities of most of the metabolites remain to be detd. This work illustrates that dansylation labeling and fast LC/FTICR MS can be a powerful technique for quant. profiling of at least 672 metabolites in urine samples in 12 min.
- 106Toshimitsu, N.; Kenji, M.; Toyokazu, O.; Akira, S.; Kaizo, K. A Gas Chromatographic-Mass Spectrometric Analysis for Phenols in Uremic Serum. Clin. Chim. Acta 1981, 110 (1), 51– 57, DOI: 10.1016/0009-8981(81)90299-0
- 107Baldrick, F. R.; McFadden, K.; Ibars, M.; Sung, C.; Moffatt, T.; Megarry, K.; Thomas, K.; Mitchell, P.; Wallace, J. M. W.; Pourshahidi, L. K. Impact of a (Poly)Phenol-Rich Extract from the Brown Algae Ascophyllum Nodosum on DNA Damage and Antioxidant Activity in an Overweight or Obese Population: A Randomized Controlled Trial. Am. J. Clin. Nutr. 2018, 108 (4), 688– 700, DOI: 10.1093/ajcn/nqy147[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czptlGnsQ%253D%253D&md5=40a6c78bb774680672f9dd86bfdb28d0Impact of a (poly)phenol-rich extract from the brown algae Ascophyllum nodosum on DNA damage and antioxidant activity in an overweight or obese population: a randomized controlled trialBaldrick Francina R; McFadden Kevin; Ibars Maria; Sung Chris; Moffatt Tanya; Megarry Kate; Mitchell Peter; Wallace Julie M W; Pourshahidi L Kirsty; Ternan Nigel G; Gill Chris I R; Thomas Keith; Corona Giulia; Spencer Jeremy; Yaqoob Parveen; Rowland Ian; Corona Giulia; Hotchkiss Sarah; Campbell Ross; Moreno-Rojas Jose Manuel; Cuevas Francisco Julian; Pereira-Caro GemaThe American journal of clinical nutrition (2018), 108 (4), 688-700 ISSN:.Background: Epidemiologic evidence suggests that a diet rich in (poly)phenols has beneficial effects on many chronic diseases. Brown seaweed is a rich source of (poly)phenols. Objective: The aim of this study was to investigate the bioavailability and effect of a brown seaweed (Ascophyllum nodosum) (poly)phenol extract on DNA damage, oxidative stress, and inflammation in vivo. Design: A randomized, double-blind, placebo-controlled crossover trial was conducted in 80 participants aged 30-65 y with a body mass index (in kg/m2) ≥25. The participants consumed either a 400-mg capsule containing 100 mg seaweed (poly)phenol and 300 mg maltodextrin or a 400-mg maltodextrin placebo control capsule daily for an 8-wk period. Bioactivity was assessed with a panel of blood-based markers including lymphocyte DNA damage, plasma oxidant capacity, C-reactive protein (CRP), and inflammatory cytokines. To explore the bioavailability of seaweed phenolics, an untargeted metabolomics analysis of urine and plasma samples after seaweed consumption was determined by ultra-high-performance liquid chromatography-high-resolution mass spectrometry. Results: Consumption of the seaweed (poly)phenols resulted in a modest decrease in DNA damage but only in a subset of the total population who were obese. There were no significant changes in CRP, antioxidant status, or inflammatory cytokines. We identified phlorotannin metabolites that are considered potential biomarkers of seaweed consumption including pyrogallol/phloroglucinol-sulfate, hydroxytrifurahol A-glucuronide, dioxinodehydroeckol-glucuronide, diphlorethol sulfates, C-O-C dimer of phloroglucinol sulfate, and C-O-C dimer of phloroglucinol. Conclusions: To the best of our knowledge, this work represents the first comprehensive study investigating the bioactivity and bioavailability of seaweed (poly)phenolics in human participants. We identified several potential biomarkers of seaweed consumption. Intriguingly, the modest improvements in DNA damage were observed only in the obese subset of the total population. The subgroup analysis should be considered exploratory because it was not preplanned; therefore, it was not powered adequately. Elucidation of the biology underpinning this observation will require participant stratification according to weight in future studies. This trial was registered at clinicaltrials.gov as NCT02295878.
- 108Mateo Anson, N.; Aura, A.-M.; Selinheimo, E.; Mattila, I.; Poutanen, K.; van den Berg, R.; Havenaar, R.; Bast, A.; Haenen, G. R. M. M. Bioprocessing of Wheat Bran in Whole Wheat Bread Increases the Bioavailability of Phenolic Acids in Men and Exerts Antiinflammatory Effects Ex Vivo. J. Nutr. 2011, 141 (1), 137– 143, DOI: 10.3945/jn.110.127720[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252FlsFGntQ%253D%253D&md5=15c154ffb7324da4973c58f4df5b4c97Bioprocessing of wheat bran in whole wheat bread increases the bioavailability of phenolic acids in men and exerts antiinflammatory effects ex vivoMateo Anson Nuria; Aura Anna-Marja; Selinheimo Emilia; Mattila Ismo; Poutanen Kaisa; van den Berg Robin; Havenaar Robert; Bast Aalt; Haenen Guido R M MThe Journal of nutrition (2011), 141 (1), 137-43 ISSN:.Whole grain consumption has been linked to a lower risk of metabolic syndrome, which is normally associated with a low-grade chronic inflammation. The benefits of whole grain are in part related to the inclusion of the bran, rich in phenolic acids and fiber. However, the phenols are poorly bioaccessible from the cereal matrix. The aim of the present study was to investigate the effect of bioprocessing of the bran in whole wheat bread on the bioavailability of phenolic acids, the postprandial plasma antioxidant capacity, and ex vivo antiinflammatory properties. After consumption of a low phenolic acid diet for 3 d and overnight fasting, 8 healthy men consumed 300 g of whole wheat bread containing native bran (control bread) or bioprocessed bran (bioprocessed bread) in a cross-over design. Urine and blood samples were collected for 24 h to analyze the phenolic acids and metabolites. Trolox equivalent antioxidant capacity was measured in plasma. Cytokines were measured in blood after ex vivo stimulation with LPS. The bioavailabilities of ferulic acid, vanillic acid, sinapic acid, and 3,4-dimethoxybenzoic acid from the bioprocessed bread were 2- to 3-fold those from the control bread. Phenylpropionic acid and 3-hydroxyphenylpropionic acid were the main colonic metabolites of the nonbioaccessible phenols. The ratios of pro-:antiinflammatory cytokines were significantly lower in LPS-stimulated blood after the consumption of the bioprocessed bread. In conclusion, bioprocessing can remarkably increase the bioavailability of phenolic acids and their circulating metabolites, compounds which have immunomodulatory effects ex vivo.
- 109Clark, A.; Mach, N. Exercise-Induced Stress Behavior, Gut-Microbiota-Brain Axis and Diet: A Systematic Review for Athletes. J. Int. Soc. Sports Nutr. 2016, 13 (1), 43, DOI: 10.1186/s12970-016-0155-6[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVyltro%253D&md5=97b8110ff1817b5578e558535c14c485Exercise-induced stress behavior, gutmicrobiota- brain axis and diet: a systematic review for athletesClark, Allison; Mach, NuriaJournal of the International Society of Sports Nutrition (2016), 13 (), 43/1-43/21CODEN: JISSCV; ISSN:1550-2783. (BioMed Central Ltd.)Fatigue, mood disturbances, under performance and gastrointestinal distress are common among athletes during training and competition. The psychosocial and phys. demands during intense exercise can initiate a stress response activating the sympathetic-adrenomedullary and hypothalamus-pituitary-adrenal (HPA) axes, resulting in the release of stress and catabolic hormones, inflammatory cytokines and microbial mols. The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biol., including metab., endocrine, neuronal and immune function. The gut microbiome and its influence on host behavior, intestinal barrier and immune function are believed to be a crit. aspect of the brain-gut axis. Recent evidence in murine models shows that there is a high correlation between phys. and emotional stress during exercise and changes in gastrointestinal microbiota compn. For instance, induced exercise-stress decreased cecal levels of Turicibacter spp and increased Ruminococcus gnavus, which have well defined roles in intestinal mucus degrdn. and immune function. Diet is known to dramatically modulate the compn. of the gut microbiota. Due to the considerable complexity of stress responses in elite athletes (from leaky gut to increased catabolism and depression), defining std. diet regimes is difficult. However, some preliminary exptl. data obtained from studies using probiotics and prebiotics studies show some interesting results, indicating that the microbiota acts like an endocrine organ (e.g. secreting serotonin, dopamine or other neurotransmitters) and may control the HPA axis in athletes. What is troubling is that dietary recommendations for elite athletes are primarily based on a low consumption of plant polysaccharides, which is assocd. with reduced microbiota diversity and functionality (e.g. less synthesis of byproducts such as short chain fatty acids and neurotransmitters). As more elite athletes suffer from psychol. and gastrointestinal conditions that can be linked to the gut, targeting the microbiota therapeutically may need to be incorporated in athletes' diets that take into consideration dietary fiber as well as microbial taxa not currently present in athlete's gut.
- 110de Ferrars, R. M.; Czank, C.; Zhang, Q.; Botting, N. P.; Kroon, P. A.; Cassidy, A.; Kay, C. D. The Pharmacokinetics of Anthocyanins and Their Metabolites in Humans. Br. J. Pharmacol. 2014, 171 (13), 3268– 3282, DOI: 10.1111/bph.12676[Crossref], [PubMed], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpsVKrt70%253D&md5=5c01f6133547dee57e7a7be6190b9360The pharmacokinetics of anthocyanins and their metabolites in humansde Ferrars, R. M.; Czank, C.; Zhang, Q.; Botting, N. P.; Kroon, P. A.; Cassidy, A.; Kay, C. D.British Journal of Pharmacology (2014), 171 (13), 3268-3282CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Background and Purpose : Anthocyanins are phytochems. with reported vasoactive bioactivity. However, given their instability at neutral pH, they are presumed to undergo significant degrdn. and subsequent biotransformation. The aim of the present study was to establish the pharmacokinetics of the metabolites of cyanidin-3-glucoside (C3G), a widely consumed dietary phytochem. with potential cardioprotective properties. Exptl. Approach : A 500 mg oral bolus dose of 6,8,10,3',5'-13C5-C3G was fed to eight healthy male participants, followed by a 48 h collection (0, 0.5, 1, 2, 4, 6, 24, 48 h) of blood, urine and faecal samples. Samples were analyzed by HPLC-ESI-MS/MS with elimination kinetics established using non-compartmental pharmacokinetic modeling. Key Results : Seventeen 13C-labeled compds. were identified in the serum, including 13C5-C3G, its degrdn. products, protocatechuic acid (PCA) and phloroglucinaldehyde (PGA), 13 metabolites of PCA and 1 metabolite derived from PGA. The maximal concns. of the phenolic metabolites (Cmax) ranged from 10 to 2000 nM, between 2 and 30 h (tmax) post-consumption, with half-lives of elimination obsd. between 0.5 and 96 h. The major phenolic metabolites identified were hippuric acid and ferulic acid, which peaked in the serum at approx. 16 and 8 h resp. Conclusions and Implications : Anthocyanins are metabolized to a structurally diverse range of metabolites that exhibit dynamic kinetic profiles. Understanding the elimination kinetics of these metabolites is key to the design of future studies examg. their utility in dietary interventions or as therapeutics for disease risk redn.
- 111Blacklock, C. J. Salicylic Acid in the Serum of Subjects Not Taking Aspirin. Comparison of Salicylic Acid Concentrations in the Serum of Vegetarians, Non-Vegetarians, and Patients Taking Low Dose Aspirin. J. Clin. Pathol. 2001, 54 (7), 553– 555, DOI: 10.1136/jcp.54.7.553[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3Mznt1Kqug%253D%253D&md5=1247368b239927ce248da07e288f701fSalicylic acid in the serum of subjects not taking aspirin. Comparison of salicylic acid concentrations in the serum of vegetarians, non-vegetarians, and patients taking low dose aspirinBlacklock C J; Lawrence J R; Wiles D; Malcolm E A; Gibson I H; Kelly C J; Paterson J RJournal of clinical pathology (2001), 54 (7), 553-5 ISSN:0021-9746.AIMS: To determine serum salicylic acid concentrations in non-vegetarians and vegetarians not taking salicylate drugs, and to compare these concentrations with those found in patients taking aspirin, 75 mg daily. METHODS: Serum samples were obtained from vegetarians (n = 37) and non-vegetarians (n = 39) not taking salicylate drugs. Non-vegetarians and vegetarians were recruited from the community and from a Buddhist monastery, respectively, in Dumfries and Galloway, Scotland. Patients (n = 14) taking aspirin (75 mg daily) were recruited from the Dumfries diabetic clinic. Serum salicylic acid concentrations were determined using a high performance liquid chromatography method with electrochemical detection. RESULTS: Salicylic acid was detected in every serum sample analysed. Higher serum concentrations of salicylic acid were found in vegetarians than non-vegetarians: median concentrations of 0.11 (range, 0.04-2.47) micromol/litre and 0.07 (range, 0.02-0.20) micromol/litre, respectively; the median of the difference was 0.05 micromol/litre (95% confidence interval for difference, 0.03 to 0.08; p < 0.0001). The median serum concentration of salicylic acid in patients taking aspirin (75 mg daily) was 10.03 (range, 0.23-25.40) micromol/litre, which was significantly higher than that found in non-vegetarians and vegetarians. There was overlap in serum salicylic acid concentrations between the vegetarians and patients taking aspirin. CONCLUSIONS: Salicylic acid, a non-steroidal anti-inflammatory drug, is present in fruits and vegetables and is found in higher concentrations in vegetarians than non-vegetarians. This suggests that a diet rich in fruits and vegetables contributes to the presence of salicylic acid in vivo. There is overlap between the serum concentrations of salicylic acid in vegetarians and patients taking aspirin, 75 mg daily. These findings may explain, in part, the health promoting effects of dietary fruits and vegetables.
- 112Boto-Ordóñez, M.; Urpi-Sarda, M.; Queipo-Ortuño, M. I.; Corella, D.; Tinahones, F. J.; Estruch, R.; Andres-Lacueva, C. Microbial Metabolomic Fingerprinting in Urine after Regular Dealcoholized Red Wine Consumption in Humans. J. Agric. Food Chem. 2013, 61 (38), 9166– 9175, DOI: 10.1021/jf402394c[ACS Full Text], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlakt7%252FE&md5=7b5a3434c8813d4f12f0ca21aa7b3c4fMicrobial metabolomic fingerprinting in urine after regular dealcoholized red wine consumption in humansBoto-Ordonez, Maria; Urpi-Sarda, Mireia; Queipo-Ortuno, Maria Isabel; Corella, Dolores; Tinahones, Francisco J.; Estruch, Ramon; Andres-Lacueva, CristinaJournal of Agricultural and Food Chemistry (2013), 61 (38), 9166-9175CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The regular consumption of dealcoholized red wine (DRW) has demonstrated benefits in cardiovascular risk factors. The anal. of phenolic metabolites formed in the organism, esp. those that could come from microbiota metab., would help to understand these benefits. The aim of this study was to det. the widest urinary metabolomic fingerprinting of phenolics and microbial-derived phenolic acids (n = 61) after regular intake of DRW in men at high cardiovascular risk by UPLC-MS/MS using a targeted approach. Up to 49 metabolites, including phase II and microbial phenolic metabolites, increased after DRW consumption compared to baseline (P < 0.05). The highest percentage of increase was found for microbial metabolites from anthocyanin degrdn. such as syringic, p-coumaric, gallic acids and pyrogallol and from flavan-3-ols degrdn. such as hydroxyphenylvalerolactones and (epi)-catechins. These findings provide the most complete metabolic fingerprinting after wine consumption, amplifying the spectrum of microbial derived metabolites and their potential bioactivity related with health benefits.
- 113Olthof, M. R.; Hollman, P. C. H.; Buijsman, M. N. C. P.; van Amelsvoort, J. M. M.; Katan, M. B. Chlorogenic Acid, Quercetin-3-Rutinoside and Black Tea Phenols Are Extensively Metabolized in Humans. J. Nutr. 2003, 133 (6), 1806– 1814, DOI: 10.1093/jn/133.6.1806[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXks1Gkuro%253D&md5=dec89ddb8f0a75b7ced305e0dfed8a0fChlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humansOlthof, Margreet R.; Hollman, Peter C. H.; Buijsman, Michel N. C. P.; van Amelsvoort, Johan M. M.; Katan, Martijn B.Journal of Nutrition (2003), 133 (6), 1806-1814CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)Dietary phenols are antioxidants and their consumption may contribute to the prevention of cardiovascular diseases. Coffee and tea are major dietary sources of phenols. Dietary phenols are metabolized extensively in the body. Lack of quant. data on their metabolites hinders proper evaluation of the potential biol. effects of dietary phenols in vivo. This study examd. the phenolic acid metabolites of chlorogenic acid (major phenol in coffee), quercetin-3-rutinoside (major flavonol in tea), and black tea phenols and detd. the site of metab. in 20 healthy humans with an intact colon. The study identified and quantified ∼60 potential phenolic acid metabolites in urine using ref. stds. and GC-MS. Half of the ingested chlorogenic acid and 43% of the tea phenols were metabolized to hippuric acid. Quercetin-3-rutinoside was metabolized mainly to phenylacetic acids, i.e. 3-hydroxyphenylacetic acid (36%), 3-methoxy-4-hydroxyphenylacetic acid (8%), and 3,4-dihydroxyphenylacetic acid (5%). In 7 other humans without the colon, only traces of phenolic acid metabolites were found in urine after they had ingested chlorogenic acid and quercetin-3-rutinoside. This implies that the colonic microflora convert most of these dietary phenols into metabolites that then reach the body circulation. Metabolites of dietary phenols have lower antioxidant activity than their parent compds., thus the contribution of dietary phenols to antioxidant activity in vivo may be lower than expected from in vitro tests.
- 114Clifford, M. N.; Copeland, E. L.; Bloxsidge, J. P.; Mitchell, L. A. Hippuric Acid as a Major Excretion Product Associated with Black Tea Consumption. Xenobiotica 2000, 30 (3), 317– 326, DOI: 10.1080/004982500237703[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjs1Omtbw%253D&md5=cdf067dc0d2ff5a162b7d9a41e176568Hippuric acid as a major excretion product associated with black tea consumptionClifford, M. N.; Copeland, E. L.; Bloxsidge, J. P.; Mitchell, L. A.Xenobiotica (2000), 30 (3), 317-326CODEN: XENOBH; ISSN:0049-8254. (Taylor & Francis Ltd.)Nine humans (2 men, 7 women; age 25-28 yr) habitually drinking tea were asked to follow a low-polyphenol/low-caffeine diet for 6 days and to provide daily 24-h urine samples. On day 4 of the expt., strong black tea brewed under standardized conditions was reintroduced to their diet. HPLC and 1H-NMR profiling of urine samples indicated that black tea consumption (6-10 cups/day) was assocd. with increased hippuric acid excretion relative to controls, increasing from 153-512 to 742-1374 mg/day. The excretion of substantial amts. of hippuric acid has not previously been assocd. with black tea consumption. In some subjects the quantity of benzoic acid processed in this metabolic route exceeded the acceptable daily intakes, but this was not considered a hazard. A mass-balance anal. indicated that the necessary quantity of benzoic acid could not be obtained from the black tea contents of gallic acid, flavanols, flavonol glycosides, and theaflavins even if 100% transformation was reached, suggesting that the thearubigins (major chem. ill-defined polyphenols of black tea) may be an important source.
- 115Guertin, K. A.; Loftfield, E.; Boca, S. M.; Sampson, J. N.; Moore, S. C.; Xiao, Q.; Huang, W.-Y.; Xiong, X.; Freedman, N. D.; Cross, A. J. Serum Biomarkers of Habitual Coffee Consumption May Provide Insight into the Mechanism Underlying the Association between Coffee Consumption and Colorectal Cancer. Am. J. Clin. Nutr. 2015, 101 (5), 1000– 1011, DOI: 10.3945/ajcn.114.096099[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptlGhur4%253D&md5=948f3fdac658d3e329b02482bc0e8a3aSerum biomarkers of habitual coffee consumption may provide insight into the mechanism underlying the association between coffee consumption and colorectal cancerGuertin, Kristin A.; Loftfield, Erikka; Boca, Simina M.; Sampson, Joshua N.; Moore, Steven C.; Xiao, Qian; Huang, Wen-Yi; Xiong, Xiaoqin; Freedman, Neal D.; Cross, Amanda J.; Sinha, RashmiAmerican Journal of Clinical Nutrition (2015), 101 (5), 1000-1011CODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)Background: Coffee intake may be inversely assocd. with colorectal cancer; however, previous studies have been inconsistent. Serum coffee metabolites are integrated exposure measures that may clarify assocns. with cancer and elucidate underlying mechanisms. Objectives: Our aims were 2-fold as follows: (1) to identify serum metabolites assocd. with coffee intake and (2) to examine these metabolites in relation to colorectal cancer. Design: In a nested case-control study of 251 colorectal cancer cases and 247 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we conducted untargeted metabolomics analyses of baseline serum by using ultrahigh-performance liq.-phase chromatog.-tandem mass spectrometry and gas chromatog.-mass spectrometry. Usual coffee intake was self-reported in a food-frequency questionnaire. We used partial Pearson correlations and linear regression to identify serum metabolites assocd. with coffee intake and conditional logistic regression to evaluate assocns. between coffee metabolites and colorectal cancer. Results: After Bonferroni correction for multiple comparisons (P = 0.05 ÷ 657 metabolites), 29 serum metabolites were pos. correlated with coffee intake (partial correlation coeffs.: 0.18-0.61; P < 7.61 × 10-5); serum metabolites most highly correlated with coffee intake (partial correlation coeffs. >0.40) included trigonelline (N'-methylnicotinate), quinate, and 7 unknown metabolites. Of 29 serum metabolites, 8 metabolites were directly related to caffeine metab., and 3 of these metabolites, theophylline (OR for 90th compared with 10th percentiles: 0.44; 95% CI: 0.25, 0.79; P-linear trend = 0.006), caffeine (OR for 90th compared with 10th percentiles: 0.56; 95% CI: 0.35, 0.89; P-linear trend = 0.015), and paraxanthine (OR for 90th compared with 10th percentiles: 0.58; 95% CI: 0.36, 0.94; P-linear trend = 0.027), were inversely assocd. with colorectal cancer. Conclusions: Serum metabolites can distinguish coffee drinkers from nondrinkers; some caffeine-related metabolites were inversely assocd. with colorectal cancer and should be studied further to clarify the role of coffee in the cause of colorectal cancer.
- 116Guy, P. A.; Renouf, M.; Barron, D.; Cavin, C.; Dionisi, F.; Kochhar, S.; Rezzi, S.; Williamson, G.; Steiling, H. Quantitative Analysis of Plasma Caffeic and Ferulic Acid Equivalents by Liquid Chromatography Tandem Mass Spectrometry. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2009, 877 (31), 3965– 3974, DOI: 10.1016/j.jchromb.2009.10.006[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVWlsr7O&md5=6d9953bc0f9549bb51c5be2fde3ad562Quantitative analysis of plasma caffeic and ferulic acid equivalents by liquid chromatography tandem mass spectrometryGuy, Philippe A.; Renouf, Mathieu; Barron, Denis; Cavin, Christophe; Dionisi, Fabiola; Kochhar, Sunil; Rezzi, Serge; Williamson, Gary; Steiling, HeikeJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2009), 877 (31), 3965-3974CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)A validated method was developed for the simultaneous detn. of the hydroxycinnamates caffeic acid (CA), dihydrocaffeic acid (DHCA), ferulic acid (FA), dihydroferulic acid (DHFA), and isoferulic acid (IFA) in human plasma as metabolites derived from coffee consumption. The method includes a protein pptn. step prior to enzymic hydrolysis of the conjugated metabolites (sulfate, glucuronide, and/or ester) back to their aglycon forms. After liq.-liq. extn., the reconstituted ext. was analyzed byHPLC coupled to neg. electrospray ionization tandem mass spectrometry. Calibration curves were constructed from spiked human plasma samples in the range of 0-4800 nM for each of the targeted analytes. Two internal stds., 3-(4-hydroxyphenyl)-propionic acid (500 nM) and 1,3-dicaffeoylquinic acid (200 nM), were spiked at the beginning of the sample prepn. and before anal., resp. Good performance data were obtained with limits of detection and quantification of the five hydroxycinnamates ranging between 1-15 nM and 3-50 nM, resp. Within and between-days precisions were resp. calcd. between 8-18% and 8-30% (at 50 nM added initially), between 6-9% and 6-12% (at 200 nM), and between 5-9% and 5-9% (at 500 nM). Precision calcd. from different analysts ranged from 18% to 44% (at 50 nM), from 8% to 16% (at 200 nM), and from 4% to 8% (at 500 nM). Using this method, we detd. plasma levels in humans and measured the efficiency of deconjugation using our enzymic cocktail.
- 117Zamora-Ros, R.; Achaintre, D.; Rothwell, J. A.; Rinaldi, S.; Assi, N.; Ferrari, P.; Leitzmann, M.; Boutron-Ruault, M.-C.; Fagherazzi, G.; Auffret, A. Urinary Excretions of 34 Dietary Polyphenols and Their Associations with Lifestyle Factors in the EPIC Cohort Study. Sci. Rep. 2016, 6 (1), 26905, DOI: 10.1038/srep26905[Crossref], [PubMed], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xps1ynsrY%253D&md5=deb7676f535c33d9ead9bcc62399663bUrinary excretions of 34 dietary polyphenols and their associations with lifestyle factors in the EPIC cohort studyZamora-Ros, Raul; Achaintre, David; Rothwell, Joseph A.; Rinaldi, Sabina; Assi, Nada; Ferrari, Pietro; Leitzmann, Michael; Boutron-Ruault, Marie-Christine; Fagherazzi, Guy; Auffret, Aurelie; Kuhn, Tilman; Katzke, Verena; Boeing, Heiner; Trichopoulou, Antonia; Naska, Androniki; Vasilopoulou, Effie; Palli, Domenico; Grioni, Sara; Mattiello, Amalia; Tumino, Rosario; Ricceri, Fulvio; Slimani, Nadia; Romieu, Isabelle; Scalbert, AugustinScientific Reports (2016), 6 (), 26905CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Urinary excretion of 34 dietary polyphenols and their variations according to diet and other lifestyle factors were measured by tandem mass spectrometry in 475 adult participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cross-sectional study. A single 24-h urine sample was analyzed for each subject from 4 European countries. The highest median levels were obsd. for phenolic acids such as 4-hydroxyphenylacetic acid (157 μmol/24 h), followed by 3-hydroxyphenylacetic, ferulic, vanillic and homovanillic acids (20-50 μmol/24 h). The lowest concns. were obsd. for equol, apigenin and resveratrol (<0.1 μmol/24 h). Urinary polyphenols significantly varied by center, followed by alc. intake, sex, educational level, and energy intake. This variability is largely explained by geog. variations in the diet, as suggested by the high correlations (r > 0.5) obsd. between urinary polyphenols and the intake of their main food sources (e.g., resveratrol and gallic acid Et ester with red wine intake; caffeic, protocatechuic and ferulic acids with coffee consumption; and hesperetin and naringenin with citrus fruit intake). The large variations in urinary polyphenols obsd. are largely detd. by food preferences. These polyphenol biomarkers should allow more accurate evaluation of the relationships between polyphenol exposure and the risk of chronic diseases in large epidemiol. studies.
- 118Kern, S. M.; Bennett, R. N.; Mellon, F. A.; Kroon, P. A.; Garcia-Conesa, M.-T. Absorption of Hydroxycinnamates in Humans after High-Bran Cereal Consumption. J. Agric. Food Chem. 2003, 51 (20), 6050– 6055, DOI: 10.1021/jf0302299[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmsVOns7g%253D&md5=84a99c4b766a4a1850619fe7f9a0cd94Absorption of hydroxycinnamates in humans after high-bran cereal consumptionKern, Sandra M.; Bennett, Richard N.; Mellon, Fred A.; Kroon, Paul Anthony; Garcia-Conesa, Maria-TeresaJournal of Agricultural and Food Chemistry (2003), 51 (20), 6050-6055CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The present work investigated the absorption in humans of hydroxycinnamic acids from high-bran breakfast cereal (wheat). Plasma and urine samples from six volunteers were collected before and after cereal consumption and analyzed for total hydroxycinnamic acids content after β-glucuronidase/sulfatase treatment both by HPLC-DAD and by LC-MS (SIM monitoring). High-bran cereal administration resulted in increased plasma ferulic and sinapic acid concns. (max. levels detected of ∼200 and ∼40 nM, resp.) with absorption peaks between 1 and 3 h. Increases of ∼4-fold in ferulic acid and ∼5-fold in feruloylglycine were detected in 24-h urine after consumption of the cereal. Most of the ferulic acid detected in urine and plasma was present as conjugates (feruloylglycine and/or glucuronides). Diferulic acids were undetectable. The data show that ferulic and sinapic acids are taken up in humans from dietary high bran wheat but that absorption is limited and may originate only from the free and sol. portions present in the cereal.
- 119Roowi, S.; Mullen, W.; Edwards, C. A.; Crozier, A. Yoghurt Impacts on the Excretion of Phenolic Acids Derived from Colonic Breakdown of Orange Juice Flavanones in Humans. Mol. Nutr. Food Res. 2009, 53 (S1), S68– S75, DOI: 10.1002/mnfr.200800287
- 120Del Rio, D.; Stalmach, A.; Calani, L.; Crozier, A. Bioavailability of Coffee Chlorogenic Acids and Green Tea Flavan-3-Ols. Nutrients 2010, 2 (8), 820– 833, DOI: 10.3390/nu2080820[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvV2qsLk%253D&md5=93a1225c5cb0f8de15f5184c345d9315Bioavailability of coffee chlorogenic acids and green tea flavan-3-olsDel Rio, Daniele; Stalmach, Angelique; Calani, Luca; Crozier, AlanNutrients (2010), 2 (), 820-833CODEN: NUTRHU; ISSN:2072-6643. (Molecular Diversity Preservation International)A review. This paper reviews recent human studies on the bioavailability of chlorogenic acids in coffee and green tea flavan-3-ols in which the identification of metabolites, catabolites and parent compds. in plasma, urine and ileal fluid was based on mass spectrometric methodol. Both the chlorogenic acids and the flavan-3-ols are absorbed in the small intestine and appear in the circulatory system predominantly as glucuronide, sulfate and methylated metabolites. Even when absorption occurs in the small intestine, feeding studies with ileostomists reveal that substantial amts. of the parent compds. and some of their metabolites appear in ileal fluid indicating that in volunteers with a functioning colon these compds. will pass to the large intestine where they are subjected to the action of the colonic microflora. A diversity of colonic-derived catabolites are absorbed into the bloodstream and pass through the body prior to excretion in urine. There is growing evidence that these compds., which were little investigated until recently, are produced in quantity in the colon and form a key part of the bioavailability equation of flavonoids and related compds. that occur in fruits, vegetables and beverages. Recent evidence indicates that some colon-derived phenolic acids have in vitro anti-inflammatory activity.
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Abstract
Figure 1
Figure 1. Microglia cell phenotypes at resting surveillance state (gray ramified) and upon activation by signals to the neuroprotective (green amoeboid) and neurotoxic (red amoeboid) phenotypes. IL, interleukin; IFN-γ, interferon gamma; LPS, lipopolysaccharides; αsyn, alpha-synuclein; Aβ42, amyloid beta 42; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; COX, cyclooxygenase; ROS, reactive oxygen species.
Figure 2
Figure 2. Different flavonoid classes with nutritional relevance. Flavonoid classes are represented as their 5,7-dihydroxyflavonoid derivatives. Red labeled bonds and chemical groups represent the major chemical characteristics of the flavonoid class.
Figure 3
Figure 3. Conversion pathway demonstrating the metabolism of the most representative flavonoids in dietary products (black boxes) into low-molecular weight phenolic metabolites. Red arrows inside the black boxes indicate the possible microbiota mediated ring fission sites for each flavonoid. Red arrows emerging from the black boxes indicate ring fission metabolites. Compounds inside dotted black boxes represent the general structure of the low molecular weight phenolic metabolites subjected to further metabolism. Further metabolic reactions are represented by the black arrows reinforcing the convergence into more low-molecular weight phenolic metabolites with the potential to accumulate in higher concentrations than the remaining upstream compounds, like hydroxybenenes and (hydroxy)hippuric acids. Part of these metabolic reactions seem to be shared between both microbial and hepatic enzymes. Note that these metabolites can undergo phases I and II metabolism into sulfate and glucuronide conjugates. α-Ox, alpha oxidation; β-Ox, beta oxidation; dOH, dehydroxylation; dCOOH, decarboxylation; red, reduction; Glyc, glycination.
Figure 4
Figure 5
Figure 5. Benzoic acids evaluated as attenuators of neuroinflammation in microglia cells.
Figure 6
Figure 6. Cinnamic acids evaluated as attenuators of neuroinflammation in microglia cells.
Figure 7
Figure 7. Phenylacetic acids and phenylpropionic acids evaluated as attenuators of neuroinflammation in microglia cells.
Figure 8
Figure 8. Main molecular targets of the low-molecular weight (poly)phenols metabolites in stimulated microglia cells. The pathways are the main entries highlighted in Table 2 as affected by the indicated physiological concentrations (also indicated in Table 2, ranging from 0.1 to <50 μM) of the metabolites in microglia cell systems.
References
ARTICLE SECTIONSThis article references 120 other publications.
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- 7Kaminska, B.; Mota, M.; Pizzi, M. Signal Transduction and Epigenetic Mechanisms in the Control of Microglia Activation during Neuroinflammation. Biochim. Biophys. Acta, Mol. Basis Dis. 2016, 1862 (3), 339– 351, DOI: 10.1016/j.bbadis.2015.10.026[Crossref], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslKkt7bE&md5=7c6e13fb8c28fd97912b1366024013daSignal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammationKaminska, Bozena; Mota, Mariana; Pizzi, MarinaBiochimica et Biophysica Acta, Molecular Basis of Disease (2016), 1862 (3), 339-351CODEN: BBADEX; ISSN:0925-4439. (Elsevier B. V.)A review. Activation of microglia is a common denominator and a pathophysiol. hallmark of the central nervous system (CNS) disorders. Damage or CNS disorders can trigger inflammatory responses in resident microglia and initiate a systemic immune system response. Although a repertoire of inflammatory responses differs in those diseases, there is a spectrum of transcriptionally activated genes that encode various mediators such as growth factors, inflammatory cytokines, chemokines, matrix metalloproteinases, enzymes producing lipid mediators, toxic molocules, all of which contribute to neuroinflammation. The initiation, progression and termination of inflammation requires global activation of gene expression, postranscriptional regulation, epigenetic modifications, changes in chromatin structure and these processes are tightly regulated by specific signaling pathways. This review focuses on the function of "master regulators" and epigenetic mechanisms in microglia activation during neuroinflammation. The authors review studies showing impact of epigenetic enzyme inhibitors on microglia activation in vitro and in vivo, and critically discuss potential of such mols. to prevent/moderate pathol. events mediated by microglia under brain pathologies.1This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.
- 8ElAli, A.; Rivest, S. Microglia Ontology and Signaling. Front. Cell Dev. Biol. 2016, 4, 72, DOI: 10.3389/fcell.2016.00072[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s3jsFalsA%253D%253D&md5=316ed057585a3331ec91c2a7bca7d5ceMicroglia Ontology and SignalingElAli Ayman; Rivest SergeFrontiers in cell and developmental biology (2016), 4 (), 72 ISSN:2296-634X.Microglia constitute the powerhouse of the innate immune system in the brain. It is now widely accepted that they are monocytic-derived cells that infiltrate the developing brain at the early embryonic stages, and acquire a resting phenotype characterized by the presence of dense branching processes, called ramifications. Microglia use these dynamic ramifications as sentinels to sense and detect any occurring alteration in brain homeostasis. Once a danger signal is detected, such as molecular factors associated to brain damage or infection, they get activated by acquiring a less ramified phenotype, and mount adequate responses that range from phagocyting cell debris to secreting inflammatory and trophic factors. Here, we review the origin of microglia and we summarize the main molecular signals involved in controlling their function under physiological conditions. In addition, their implication in the pathogenesis of multiple sclerosis and stress is discussed.
- 9Medina-Remón, A.; Tresserra-Rimbau, A.; Pons, A.; Tur, J. A.; Martorell, M.; Ros, E.; Buil-Cosiales, P.; Sacanella, E.; Covas, M. I.; Corella, D. Effects of Total Dietary Polyphenols on Plasma Nitric Oxide and Blood Pressure in a High Cardiovascular Risk Cohort. The PREDIMED Randomized Trial. Nutr., Metab. Cardiovasc. Dis. 2015, 25 (1), 60– 67, DOI: 10.1016/j.numecd.2014.09.001[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1KgsbvM&md5=2a07d06cd1971f64619cbdeb79959bbaEffects of total dietary polyphenols on plasma nitric oxide and blood pressure in a high cardiovascular risk cohort. The PREDIMED randomized trialMedina-Remon, A.; Tresserra-Rimbau, A.; Pons, A.; Tur, J. A.; Martorell, M.; Ros, E.; Buil-Cosiales, P.; Sacanella, E.; Covas, M. I.; Corella, D.; Salas-Salvado, J.; Gomez-Gracia, E.; Ruiz-Gutierrez, V.; Ortega-Calvo, M.; Garcia-Valdueza, M.; Aros, F.; Saez, G. T.; Serra-Majem, L.; Pinto, X.; Vinyoles, E.; Estruch, R.; Lamuela-Raventos, R. M.Nutrition, Metabolism & Cardiovascular Diseases (2015), 25 (1), 60-67CODEN: NMCDEE; ISSN:0939-4753. (Elsevier B.V.)Hypertension is one of the main cardiovascular risk factors in the elderly. The aims of this work were to evaluate if a one-year intervention with two Mediterranean diets (Med-diet) could decrease blood pressure (BP) due to a high polyphenol consumption, and if the decrease in BP was mediated by plasma nitric oxide (NO) prodn.An intervention substudy of 200 participants at high cardiovascular risk was carried out within the PREDIMED trial. They were randomly assigned to a low-fat control diet or to two Med-diets, one supplemented with extra virgin olive oil (Med-EVOO) and the other with nuts (Med-nuts). Anthropometrics and clin. parameters were measured at baseline and after one year of intervention, as well as BP, plasma NO and total polyphenol excretion (TPE) in urine samples. Systolic and diastolic BP decreased significantly after a one-year dietary intervention with Med-EVOO and Med-nuts. These changes were assocd. with a significant increase in TPE and plasma NO. Addnl., a significant pos. correlation was obsd. between changes in urinary TPE, a biomarker of TP intake, and in plasma NO (Beta = 4.84; 95% CI: 0.57-9.10).TPE in spot urine sample was pos. correlated with plasma NO in Med-diets supplemented with either EVOO or nuts. The statistically significant increases in plasma NO were assocd. with a redn. in systolic and diastolic BP levels, adding to the growing evidence that polyphenols might protect the cardiovascular system by improving the endothelial function and enhancing endothelial synthesis of NO.
- 10Rodriguez-Mateos, A.; Vauzour, D.; Krueger, C. G.; Shanmuganayagam, D.; Reed, J.; Calani, L.; Mena, P.; Del Rio, D.; Crozier, A. Bioavailability, Bioactivity and Impact on Health of Dietary Flavonoids and Related Compounds: An Update. Arch. Toxicol. 2014, 88 (10), 1803– 1853, DOI: 10.1007/s00204-014-1330-7[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsV2ntbjJ&md5=df6d1fa73d98f2ff363fa2e42212940eBioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an updateRodriguez-Mateos, Ana; Vauzour, David; Krueger, Christian G.; Shanmuganayagam, Dhanansayan; Reed, Jess; Calani, Luca; Mena, Pedro; Del Rio, Daniele; Crozier, AlanArchives of Toxicology (2014), 88 (10), 1803-1853CODEN: ARTODN; ISSN:0340-5761. (Springer)A review. There is substantial interest in the role of plant secondary metabolites as protective dietary agents. In particular, the involvement of flavonoids and related compds. has become a major topic in human nutrition research. Evidence from epidemiol. and human intervention studies is emerging regarding the protective effects of various (poly)phenol-rich foods against several chronic diseases, including neurodegeneration, cancer and cardiovascular diseases. In recent years, the use of HPLC-MS for the anal. of flavonoids and related compds. in foods and biol. samples has significantly enhanced our understanding of (poly)phenol bioavailability. These advancements have also led to improvements in the available food compn. and metabolomic databases, and consequently in the development of biomarkers of (poly)phenol intake to use in epidemiol. studies. Efforts to create adequate standardised materials and well-matched controls to use in randomised controlled trials have also improved the quality of the available data. In vitro investigations using physiol. achievable concns. of (poly)phenol metabolites and catabolites with appropriate model test systems have provided new and interesting insights on potential mechanisms of actions. This article will summarise recent findings on the bioavailability and biol. activity of (poly)phenols, focusing on the epidemiol. and clin. evidence of beneficial effects of flavonoids and related compds. on urinary tract infections, cognitive function and age-related cognitive decline, cancer and cardiovascular disease.
- 11Nooyens, A. C. J.; Bueno-de-Mesquita, H. B.; van Boxtel, M. P. J.; van Gelder, B. M.; Verhagen, H.; Verschuren, W. M. M. Fruit and Vegetable Intake and Cognitive Decline in Middle-Aged Men and Women: The Doetinchem Cohort Study. Br. J. Nutr. 2011, 106 (5), 752– 761, DOI: 10.1017/S0007114511001024[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1Srs7fK&md5=ec6bc7ec1f43e399264a383d05939485Fruit and vegetable intake and cognitive decline in middle-aged men and women: the Doetinchem Cohort StudyNooyens, Astrid C. J.; Bueno-de-Mesquita, H. Bas; van Boxtel, Martin P. J.; van Gelder, Boukje M.; Verhagen, Hans; Verschuren, W. M. MoniqueBritish Journal of Nutrition (2011), 106 (5), 752-761CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)To postpone cognitive decline and dementia in old age, primary prevention is required earlier in life during middle age. Dietary components may be modifiable determinants of mental performance. In the present study, habitual fruit and vegetable intake was studied in assocn. with cognitive function and cognitive decline during middle age. In the Doetinchem Cohort Study, 2613 men and women aged 43-70 years at baseline (1995-2002) were examd. for cognitive function twice, with a 5-yr time interval. Global cognitive function and the domains memory, information processing speed and cognitive flexibility were assessed. Dietary intake was assessed with a semi-quant. FFQ. In multivariate linear regression analyses, habitual fruit and vegetable intake was studied in assocn. with baseline and change in cognitive function. Higher reported vegetable intake was assocd. with lower information processing speed (P = 0·02) and worse cognitive flexibility (P = 0·03) at baseline, but with smaller decline in information processing speed (P < 0·01) and global cognitive function (P = 0·02) at follow-up. Total intakes of fruits, legumes and juices were not assocd. with baseline or change in cognitive function. High intakes of some subgroups of fruits and vegetables (i.e. nuts, cabbage and root vegetables) were assocd. with better cognitive function at baseline and/or smaller decline in cognitive domains. In conclusion, total intake of fruits and vegetables was not or inconsistently assocd. with cognitive function and cognitive decline. A high habitual consumption of some specific fruits and vegetables may diminish age-related cognitive decline in middle-aged individuals. Further research is needed to verify these findings before recommendations can be made.
- 12Psaltopoulou, T.; Sergentanis, T. N.; Panagiotakos, D. B.; Sergentanis, I. N.; Kosti, R.; Scarmeas, N. Mediterranean Diet, Stroke, Cognitive Impairment, and Depression: A Meta-Analysis. Ann. Neurol. 2013, 74 (4), 580– 591, DOI: 10.1002/ana.23944[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3snnvFOhsg%253D%253D&md5=9c858627b3b04f60cbffe23c5c707554Mediterranean diet, stroke, cognitive impairment, and depression: A meta-analysisPsaltopoulou Theodora; Sergentanis Theodoros N; Panagiotakos Demosthenes B; Sergentanis Ioannis N; Kosti Rena; Scarmeas NikolaosAnnals of neurology (2013), 74 (4), 580-91 ISSN:.OBJECTIVE: This meta-analysis aims to quantitatively synthesize all studies that examine the association between adherence to a Mediterranean diet and risk of stroke, depression, cognitive impairment, and Parkinson disease. METHODS: Potentially eligible publications were those providing effect estimates of relative risk (RR) for the association between Mediterranean diet and the aforementioned outcomes. Studies were sought in PubMed up to October 31, 2012. Maximally adjusted effect estimates were extracted; separate analyses were performed for high and moderate adherence. RESULTS: Twenty-two eligible studies were included (11 covered stroke, 9 covered depression, and 8 covered cognitive impairment; only 1 pertained to Parkinson's disease). High adherence to Mediterranean diet was consistently associated with reduced risk for stroke (RR = 0.71, 95% confidence interval [CI] = 0.57-0.89), depression (RR = 0.68, 95% CI = 0.54-0.86), and cognitive impairment (RR = 0.60, 95% CI = 0.43-0.83). Moderate adherence was similarly associated with reduced risk for depression and cognitive impairment, whereas the protective trend concerning stroke was only marginal. Subgroup analyses highlighted the protective actions of high adherence in terms of reduced risk for ischemic stroke, mild cognitive impairment, dementia, and particularly Alzheimer disease. Meta-regression analysis indicated that the protective effects of Mediterranean diet in stroke prevention seemed more sizeable among males. Concerning depression, the protective effects of high adherence seemed independent of age, whereas the favorable actions of moderate adherence seemed to fade away with more advanced age. INTERPRETATION: Adherence to a Mediterranean diet may contribute to the prevention of a series of brain diseases; this may be of special value given the aging of Western societies.
- 13Spencer, J. P. E. Food for Thought: The Role of Dietary Flavonoids in Enhancing Human Memory, Learning and Neuro-Cognitive Performance. Proc. Nutr. Soc. 2008, 67 (2), 238– 252, DOI: 10.1017/S0029665108007088[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntVSnsLk%253D&md5=05f2f507f8e66050755dfc4a72169b23Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performanceSpencer, Jeremy P. E.Proceedings of the Nutrition Society (2008), 67 (2), 238-252CODEN: PNUSA4; ISSN:0029-6651. (Cambridge University Press)A review. Emerging evidence suggests that dietary-derived flavonoids have the potential to improve human memory and neuro-cognitive performance via their ability to protect vulnerable neurons, enhance existing neuronal function and stimulate neuronal regeneration. Long-term potentiation (LTP) is widely considered to be one of the major mechanisms underlying memory acquisition, consolidation and storage in the brain and is known to be controlled at the mol. level by the activation of a no. of neuronal signalling pathways. These pathways include the phosphatidylinositol-3 kinase/protein kinase B/Akt (Akt), protein kinase C, protein kinase A, Ca-calmodulin kinase and mitogen-activated protein kinase pathways. Growing evidence suggests that flavonoids exert effects on LTP, and consequently memory and cognitive performance, through their interactions with these signalling pathways. Of particular interest is the ability of flavonoids to activate the extracellular signal-regulated kinase and the Akt signalling pathways leading to the activation of the cAMP-response element-binding protein, a transcription factor responsible for increasing the expression of a no. of neurotrophins important in LTP and long-term memory. One such neurotrophin is brain-derived neurotrophic factor, which is known to be crucial in controlling synapse growth, in promoting an increase in dendritic spine d. and in enhancing synaptic receptor d. The present review explores the potential of flavonoids and their metabolite forms to promote memory and learning through their interactions with neuronal signalling pathways pivotal in controlling LTP and memory in human subjects.
- 14Williams, R. J.; Spencer, J. P. E. Flavonoids, Cognition, and Dementia: Actions, Mechanisms, and Potential Therapeutic Utility for Alzheimer Disease. Free Radical Biol. Med. 2012, 52 (1), 35– 45, DOI: 10.1016/j.freeradbiomed.2011.09.010[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitlyntQ%253D%253D&md5=80351e6c4110bf1be1724376dd2d8196Flavonoids, cognition, and dementia: Actions, mechanisms, and potential therapeutic utility for Alzheimer diseaseWilliams, Robert J.; Spencer, Jeremy P. E.Free Radical Biology & Medicine (2012), 52 (1), 35-45CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)A review. There is increasing evidence that the consumption of flavonoid-rich foods can beneficially influence normal cognitive function. In addn., a growing no. of flavonoids have been shown to inhibit the development of Alzheimer disease (AD)-like pathol. and to reverse deficits in cognition in rodent models, suggestive of potential therapeutic utility in dementia. The actions of flavonoid-rich foods (e.g., green tea, blueberry, and cocoa) seem to be mediated by the direct interactions of absorbed flavonoids and their metabolites with a no. of cellular and mol. targets. For example, their specific interactions within the ERK and PI3-kinase/Akt signaling pathways, at the level of receptors or kinases, have been shown to increase the expression of neuroprotective and neuromodulatory proteins and increase the no. of, and strength of, connections between neurons. Concurrently, their effects on the vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Addnl. mechanisms have been suggested for the ability of flavonoids to delay the initiation of and/or slow the progression of AD-like pathol. and related neurodegenerative disorders, including a potential to inhibit neuronal apoptosis triggered by neurotoxic species (e.g., oxidative stress and neuroinflammation) or disrupt amyloid β aggregation and effects on amyloid precursor protein processing through the inhibition of β-secretase (BACE-1) and/or activation of α-secretase (ADAM10). Together, these processes act to maintain the no. and quality of synaptic connections in key brain regions and thus flavonoids have the potential to prevent the progression of neurodegenerative pathologies and to promote cognitive performance.
- 15Figueira, I.; Garcia, G.; Pimpão, R. C.; Terrasso, A. P.; Costa, I.; Almeida, A. F.; Tavares, L.; Pais, T. F.; Pinto, P.; Ventura, M. R. Polyphenols Journey through Blood-Brain Barrier towards Neuronal Protection. Sci. Rep. 2017, 7 (1), 11456, DOI: 10.1038/s41598-017-11512-6[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cbnvFCltg%253D%253D&md5=fd9d6a0e6d1ece906009b0723a1fc760Polyphenols journey through blood-brain barrier towards neuronal protectionFigueira I; Garcia G; Pimpao R C; Terrasso A P; Costa I; Almeida A F; Tavares L; Pinto P; Ventura M R; Brito C; Santos C N; Figueira I; Garcia G; Pimpao R C; Terrasso A P; Costa I; Almeida A F; Tavares L; Brito C; Santos C N; Pais T F; Pinto P; Filipe A; McDougall G J; Stewart D; Stewart D; Stewart D; Kim K S; Palmela I; Brites D; Brito M A; Brites D; Brito M AScientific reports (2017), 7 (1), 11456 ISSN:.Age-related complications such as neurodegenerative disorders are increasing and remain cureless. The possibility of altering the progression or the development of these multifactorial diseases through diet is an emerging and attractive approach with increasing experimental support. We examined the potential of known bioavailable phenolic sulfates, arising from colonic metabolism of berries, to influence hallmarks of neurodegenerative processes. In silico predictions and in vitro transport studies across blood-brain barrier (BBB) endothelial cells, at circulating concentrations, provided evidence for differential transport, likely related to chemical structure. Moreover, endothelial metabolism of these phenolic sulfates produced a plethora of novel chemical entities with further potential bioactivies. Pre-conditioning with phenolic sulfates improved cellular responses to oxidative, excitotoxicity and inflammatory injuries and this attenuation of neuroinflammation was achieved via modulation of NF-κB pathway. Our results support the hypothesis that these small molecules, derived from dietary (poly)phenols may cross the BBB, reach brain cells, modulate microglia-mediated inflammation and exert neuroprotective effects, with potential for alleviation of neurodegenerative diseases.
- 16Rendeiro, C.; Rhodes, J. S.; Spencer, J. P. E. The Mechanisms of Action of Flavonoids in the Brain: Direct versus Indirect Effects. Neurochem. Int. 2015, 89, 126– 139, DOI: 10.1016/j.neuint.2015.08.002[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlGrs73M&md5=6968318868a2d7a5646f7eb98eb6dadbThe mechanisms of action of flavonoids in the brain: Direct versus indirect effectsRendeiro, Catarina; Rhodes, Justin S.; Spencer, Jeremy P. E.Neurochemistry International (2015), 89 (), 126-139CODEN: NEUIDS; ISSN:0197-0186. (Elsevier Ltd.)A review. The projected increase in the incidence of dementia in the population highlights the urgent need for a more comprehensive understanding of how different aspects of lifestyle, in particular exercise and diet, may affect neural function and consequent cognitive performance throughout the life course. In this regard, flavonoids, found in a variety of fruits, vegetables and derived beverages, have been identified as a group of promising bioactive compds. capable of influencing different aspects of brain function, including cerebrovascular blood flow and synaptic plasticity, both resulting in improvements in learning and memory in mammalian species. However, the precise mechanisms by which flavonoids exert these actions are yet to be fully established, although accumulating data indicate an ability to interact with neuronal receptors and kinase signaling pathways which are key to neuronal activation and communication and synaptic strengthening. Alternatively or concurrently, there is also compelling evidence derived from human clin. studies suggesting that flavonoids can pos. affect peripheral and cerebrovascular blood flow, which may be an indirect effective mechanism by which dietary flavonoids can impact on brain health and cognition. The current review examines the beneficial effects of flavonoids on both human and animal brain function and attempts to address and link direct and indirect actions of flavonoids and their derivs. within the central nervous system (CNS).
- 17Mayr, H. L.; Thomas, C. J.; Tierney, A. C.; Kucianski, T.; George, E. S.; Ruiz-Canela, M.; Hebert, J. R.; Shivappa, N.; Itsiopoulos, C. Randomization to 6-Month Mediterranean Diet Compared with a Low-Fat Diet Leads to Improvement in Dietary Inflammatory Index Scores in Patients with Coronary Heart Disease: The AUSMED Heart Trial. Nutr. Res. (N. Y., NY, U. S.) 2018, 55, 94– 107, DOI: 10.1016/j.nutres.2018.04.006[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXptlyrsLo%253D&md5=a2f06b09498e417016e4ccbb3c30c8f4Randomization to 6-month Mediterranean diet compared with a low-fat diet leads to improvement in Dietary Inflammatory Index scores in patients with coronary heart disease: the AUSMED Heart TrialMayr, Hannah L.; Thomas, Colleen J.; Tierney, Audrey C.; Kucianski, Teagan; George, Elena S.; Ruiz-Canela, Miguel; Hebert, James R.; Shivappa, Nitin; Itsiopoulos, CatherineNutrition Research (New York, NY, United States) (2018), 55 (), 94-107CODEN: NTRSDC; ISSN:0271-5317. (Elsevier)A higher dietary inflammatory index (DII) score is assocd. with inflammation and incidence of coronary heart disease (CHD). We hypothesized that a Mediterranean diet (MedDiet) intervention would reduce DII score. We assessed dietary data from a randomized controlled trial comparing 6-mo MedDiet vs. low-fat diet intervention, in patients with CHD. We aimed to det. the DII scores of the prescribed diets' model meal plans, followed by whether dietary intervention led to lower (i.e., more anti-inflammatory) DII scores and consequently lower high sensitivity C-reactive protein (hs-CRP) and interleukin-6 (hs-IL-6). DII scores were calcd. from 7-day food diaries. The MedDiet meal plan had a markedly lower DII score than the low-fat diet meal plan (-4.55 vs. -0.33, resp.). In 56 participants who completed the trial (84% male, mean age 62 ± 9 years), the MedDiet group significantly reduced DII scores at 6 mo (n = 27; -0.40 ± 3.14 to -1.74 ± 2.81, P = .008) and the low-fat diet group did not change (n = 29; -0.17 ± 2.27 to 0.05 ± 1.89, P = .65). There was a significant post-intervention adjusted difference in DII score between groups (compared to low-fat, MedDiet decreased by -1.69 DII points; P = .004). When compared to the low-fat diet, the MedDiet non-significantly reduced hs-IL-6 (-0.32 pg/mL, P = .29) and increased hs-CRP (+0.09 mg/L, P = .84). These findings demonstrated that MedDiet intervention significantly reduced DII scores compared to a low-fat diet. However, in this small cohort of patients with CHD this did not translate to a significant improvement in measured inflammatory markers. The effect of improvement in DII with MedDiet should be tested in larger intervention trials and observational cohorts.
- 18Devore, E. E.; Kang, J. H.; Breteler, M. M. B.; Grodstein, F. Dietary Intakes of Berries and Flavonoids in Relation to Cognitive Decline. Ann. Neurol. 2012, 72 (1), 135– 143, DOI: 10.1002/ana.23594[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOgsLfI&md5=423cad845b370619f69d33b93cae170eDietary intakes of berries and flavonoids in relation to cognitive declineDevore, Elizabeth E.; Kang, Jae Hee; Breteler, Monique M. B.; Grodstein, FrancineAnnals of Neurology (2012), 72 (1), 135-143CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)Objective: : Berries are high in flavonoids, esp. anthocyanidins, and improve cognition in exptl. studies. We prospectively evaluated whether greater long-term intakes of berries and flavonoids are assocd. with slower rates of cognitive decline in older women. Methods: : Beginning in 1980, a semiquant. food frequency questionnaire was administered every 4 years to Nurses' Health Study participants. In 1995-2001, we began measuring cognitive function in 16,010 participants, aged ≥70 years; follow-up assessments were conducted twice, at 2-yr intervals. To ascertain long-term diet, we averaged dietary variables from 1980 through the initial cognitive interview. Using multivariate-adjusted, mixed linear regression, we estd. mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes. Results: : Greater intakes of blueberries and strawberries were assocd. with slower rates of cognitive decline (eg, for a global score averaging all 6 cognitive tests, for blueberries: p-trend = 0.014 and mean difference = 0.04, 95% confidence interval [CI] = 0.01-0.07, comparing extreme categories of intake; for strawberries: p-trend = 0.022 and mean difference = 0.03, 95% CI = 0.00-0.06, comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect ests. were equiv. to those we found for approx. 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Addnl., in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were assocd. with slower rates of cognitive decline (p-trends = 0.015 and 0.053, resp., for the global score). Interpretation: : Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults. ANN NEUROL 2012.
- 19Gao, X.; Cassidy, A.; Schwarzschild, M. A.; Rimm, E. B.; Ascherio, A. Habitual Intake of Dietary Flavonoids and Risk of Parkinson Disease. Neurology 2012, 78 (15), 1138– 1145, DOI: 10.1212/WNL.0b013e31824f7fc4[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsVaksbs%253D&md5=57abb8d8842c5913696b7e25b794e28eHabitual intake of dietary flavonoids and risk of Parkinson diseaseGao, X.; Cassidy, A.; Schwarzschild, M. A.; Rimm, E. B.; Ascherio, A.Neurology (2012), 78 (15), 1138-1145CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: To prospectively examine whether higher intakes of total flavonoids and their subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, and polymers) were assocd. with a lower risk of developing Parkinson disease (PD). Methods: In the current anal., we included 49,281 men in the Health Professional Follow-up Study and 80,336 women from the Nurses' Health Study. Five major sources of flavonoid-rich foods (tea, berry fruits, apples, red wine, and orange/orange juice) were also examd. Flavonoid intake was assessed using an updated food compn. database and a validated food frequency questionnaire. Results: We identified 805 participants (438 men and 367 women) who developed PD during 20-22 years of follow-up. In men, after adjusting for multiple confounders, participants in the highest quintile of total flavonoids had a 40%lower PD risk than those in the lowest quintile (hazard ratio [HR] = 0.60; 95% confidence interval 0.43, 0.83; p trend = 0.001). No significant relationship was obsd. in women (p trend = 0.62) or in pooled analyses (p trend = 0.23). In the pooled analyses for the subclasses, intakes of anthocyanins and a rich dietary source, berries, were significantly assocd. with a lower PD risk (HR comparing 2 extreme intake quintiles were 0.76 for anthocyanins and 0.77 for berries, resp.; p trend < 0.02 for both). Conclusions: Our findings suggest that intake of some flavonoids may reduce PD risk, particularly in men, but a protective effect of other constituents of plant foods cannot be excluded.
- 20Kennedy, D. O. Polyphenols and the Human Brain: Plant “Secondary Metabolite” Ecologic Roles and Endogenous Signaling Functions Drive Benefits. Adv. Nutr. 2014, 5 (5), 515– 533, DOI: 10.3945/an.114.006320[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVClt7zP&md5=3544d29309c20612794cd3cf215b0ccbPolyphenols and the human brain: plant "Secondary Metabolite" ecologic roles and endogenous signaling functions drive benefitsKennedy, David O.Advances in Nutrition (2014), 5 (5), 515-533CODEN: ANDUAW; ISSN:2156-5376. (American Society for Nutrition)A review. Flavonoids and other polyphenols are ubiquitous plant chems. that fulfill a range of ecol. roles for their home plant, including protection from a range of biotic and abiotic stressors and a pivotal role in the management of pathogenic and symbiotic soil bacteria and fungi. They form a natural part of the human diet, and evidence suggests that their consumption is assocd. with the beneficial modulation of a no. of health-related variables, including those related to cardiovascular and brain function. Over recent years, the consensus as to the mechanisms responsible for these effects in humans has shifted away from polyphenols having direct antioxidant effects and toward their modulation of cellular signal transduction pathways. To date, little consideration was given to the question of why, rather than how, these plant-derived chems. might exert these effects. Therefore, this review summarizes the evidence suggesting that polyphenols beneficially affect human brain function and describes the current mechanistic hypotheses explaining these effects. It then goes on to describe the ecol. roles and potential endogenous signaling functions that these ubiquitous phytochems. play within their home plant and discusses whether these functions drive their beneficial effects in humans via a process of "cross-kingdom" signaling predicated on the many conserved similarities in plant, microbial, and human cellular signal transduction pathways.
- 21Macready, A. L.; Kennedy, O. B.; Ellis, J. A.; Williams, C. M.; Spencer, J. P. E.; Butler, L. T. Flavonoids and Cognitive Function: A Review of Human Randomized Controlled Trial Studies and Recommendations for Future Studies. Genes Nutr. 2009, 4 (4), 227– 242, DOI: 10.1007/s12263-009-0135-4[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtl2ks77K&md5=980b8412fcc66290f6db44aa7c17361aFlavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studiesMacready, Anna L.; Kennedy, Orla B.; Ellis, Judi A.; Williams, Claire M.; Spencer, Jeremy P. E.; Butler, Laurie T.Genes and Nutrition (2009), 4 (4), 227-242CODEN: GNEUAZ; ISSN:1555-8932. (Springer)A review. Evidence in support of the neuroprotective effects of flavonoids has increased significantly in recent years, although to date much of this evidence has emerged from animal rather than human studies. Nonetheless, with a view to making recommendations for future good practice, we review 15 existing human dietary intervention studies that have examd. the effects of particular types of flavonoid on cognitive performance. The studies employed a total of 55 different cognitive tests covering a broad range of cognitive domains. Most studies incorporated at least one measure of executive function/working memory, with nine reporting significant improvements in performance as a function of flavonoid supplementation compared to a control group. However, some domains were overlooked completely (e.g. implicit memory, prospective memory), and for the most part there was little consistency in terms of the particular cognitive tests used making across study comparisons difficult. Furthermore, there was some confusion concerning what aspects of cognitive function particular tests were actually measuring. Overall, while initial results are encouraging, future studies need to pay careful attention when selecting cognitive measures, esp. in terms of ensuring that tasks are actually sensitive enough to detect treatment effects.
- 22Nehlig, A. The Neuroprotective Effects of Cocoa Flavanol and Its Influence on Cognitive Performance. Br. J. Clin. Pharmacol. 2013, 75 (3), 716– 727, DOI: 10.1111/j.1365-2125.2012.04378.x[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1WjsrY%253D&md5=ecb7837e3da51412fa499001797cdcdeThe neuroprotective effects of cocoa flavanol and its influence on cognitive performanceNehlig, AstridBritish Journal of Clinical Pharmacology (2013), 75 (3), 716-727CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)A review. Cocoa powder and chocolate contain numerous substances among which there is a quite large percentage of antioxidant mols., mainly flavonoids, most abundantly found in the form of epicatechin. These substances display several beneficial actions on the brain. They enter the brain and induce widespread stimulation of brain perfusion. They also provoke angiogenesis, neurogenesis and changes in neuron morphol., mainly in regions involved in learning and memory. Epicatechin improves various aspects of cognition in animals and humans. Chocolate also induces pos. effects on mood and is often consumed under emotional stress. In addn., flavonoids preserve cognitive abilities during ageing in rats, lower the risk for developing Alzheimer's disease and decrease the risk of stroke in humans. In addn. to their beneficial effects on the vascular system and on cerebral blood flow, flavonoids interact with signalization cascades involving protein and lipid kinases that lead to the inhibition of neuronal death by apoptosis induced by neurotoxicants such as oxygen radicals, and promote neuronal survival and synaptic plasticity. The present review intends to review the data available on the effects of cocoa and chocolate on brain health and cognitive abilities.
- 23Krikorian, R.; Shidler, M. D.; Nash, T. A.; Kalt, W.; Vinqvist-Tymchuk, M. R.; Shukitt-Hale, B.; Joseph, J. A. Blueberry Supplementation Improves Memory in Older Adults. J. Agric. Food Chem. 2010, 58 (7), 3996– 4000, DOI: 10.1021/jf9029332[ACS Full Text], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFSm&md5=b5b5191927dfacb3f7c281f48b9680d7Blueberry supplementation improves memory in older adultsKrikorian, Robert; Shidler, Marcelle D.; Nash, Tiffany A.; Kalt, Wilhelmina; Vinqvist-Tymchuk, Melinda R.; Shukitt-Hale, Barbara; Joseph, James A.Journal of Agricultural and Food Chemistry (2010), 58 (7), 3996-4000CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The prevalence of dementia is increasing in the older adult population. In the absence of effective therapy, preventive approaches are essential to address this public health problem. Blueberries (Vaccinium angustifolium) contain polyphenol compds., esp. anthocyanins (estd. as cyanidin 3-glucoside), with antioxidant and anti-inflammatory effects. Anthocyanins have been assocd. with increased neuronal signaling in brain centers, mediation of memory functions , and improved glucose disposal; these benefits could mitigate neurodegeneration. The effects of daily consumption of wild blueberry juice were studied in 9 older adult humans (76.2±5.2 yr) with early memory changes. After 12 wk, improved paired assoc. learning and word list recall were obsd. There were also trends suggesting decreased depressive symptoms and lower blood serum glucose levels. The memory performance of the blueberry subjects was compared with a demog. matched sample who consumed a berry placebo beverage in a companion trial of identical design and comparable results for paired assoc. learning was obsd. Thus, moderate-term blueberry supplementation can have neurocognitive benefits.
- 24Bowtell, J. L.; Aboo-Bakkar, Z.; Conway, M. E.; Adlam, A.-L. R.; Fulford, J. Enhanced Task-Related Brain Activation and Resting Perfusion in Healthy Older Adults after Chronic Blueberry Supplementation. Appl. Physiol., Nutr., Metab. 2017, 42 (7), 773– 779, DOI: 10.1139/apnm-2016-0550[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFGmu74%253D&md5=aac1dc9976e228f42c16356564ca3262Enhanced task-related brain activation and resting perfusion in healthy older adults after chronic blueberry supplementationBowtell, Joanna L.; Aboo-Bakkar, Zainie; Conway, Myra E.; Adlam, Anna-Lynne R.; Fulford, JonathanApplied Physiology, Nutrition, and Metabolism (2017), 42 (7), 773-779CODEN: APNMC6; ISSN:1715-5312. (Canadian Science Publishing)Blueberries are rich in flavonoids, which possess antioxidant and anti-inflammatory properties. High flavonoid intakes attenuate age-related cognitive decline, but data from human intervention studies are sparse. We investigated whether 12 wk of blueberry conc. supplementation improved brain perfusion, task-related activation, and cognitive function in healthy older adults. Participants were randomized to consume either 30 mL blueberry conc. providing 387 mg anthocyanidins (5 female, 7 male; age 67.5 ± 3.0 y; body mass index, 25.9 ± 3.3 kg·m-2) or isoenergetic placebo (8 female, 6 male; age 69.0 ± 3.3 y; body mass index, 27.1 ± 4.0 kg·m-2). Pre- and postsupplementation, participants undertook a battery of cognitive function tests and a numerical Stroop test within a 1.5T magnetic resonance imaging scanner while functional magnetic resonance images were continuously acquired. Quant. resting brain perfusion was detd. using an arterial spin labeling technique, and blood biomarkers of inflammation and oxidative stress were measured. Significant increases in brain activity were obsd. in response to blueberry supplementation relative to the placebo group within Brodmann areas 4/6/10/21/40/44/45, precuneus, anterior cingulate, and insula/thalamus (p < 0.001) as well as significant improvements in gray matter perfusion in the parietal (5.0 ± 1.8 vs -2.9 ± 2.4%, p = 0.013) and occipital (8.0 ± 2.6 vs -0.7 ± 3.2%, p = 0.031) lobes. There was also evidence suggesting improvement in working memory (2-back test) after blueberry vs. placebo supplementation (p = 0.05). Supplementation with an anthocyanin-rich blueberry conc. improved brain perfusion and activation in brain areas assocd. with cognitive function in healthy older adults.
- 25Miller, M. G.; Hamilton, D. A.; Joseph, J. A.; Shukitt-Hale, B. Dietary Blueberry Improves Cognition among Older Adults in a Randomized, Double-Blind, Placebo-Controlled Trial. Eur. J. Nutr. 2018, 57 (3), 1169– 1180, DOI: 10.1007/s00394-017-1400-8[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktFWjtr8%253D&md5=234b00becc15199365a1ab16294ba55aDietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trialMiller, Marshall G.; Hamilton, Derek A.; Joseph, James A.; Shukitt-Hale, BarbaraEuropean Journal of Nutrition (2018), 57 (3), 1169-1180CODEN: EJNUFZ; ISSN:1436-6207. (Springer)Purpose: As populations shift to include a larger proportion of older adults, the necessity of research targeting older populations is becoming increasingly apparent. Dietary interventions with blueberry have been assocd. with pos. outcomes in cell and rodent models of aging. We hypothesized that dietary blueberry would improve mobility and cognition among older adults. Methods: In this study, 13 men and 24 women, between the ages of 60 and 75 years, were recruited into a randomized, double-blind, placebo-controlled trial in which they consumed either freeze-dried blueberry (24 g/day, equiv. to 1 cup of fresh blueberries) or a blueberry placebo for 90 days. Participants completed a battery of balance, gait, and cognitive tests at baseline and again at 45 and 90 days of intervention. Results: Significant supplement group by study visit interactions were obsd. on tests of executive function. Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal Learning test (p = 0.031, ηp2 = 0.126) and reduced switch cost on a task-switching test (p = 0.033, ηp2 = 0.09) across study visits, relative to controls. However, no improvement in gait or balance was obsd. Conclusions: These findings show that the addn. of easily achievable quantities of blueberry to the diets of older adults can improve some aspects of cognition.
- 26Arts, I. C.; Hollman, P. C. Polyphenols and Disease Risk in Epidemiologic Studies. Am. J. Clin. Nutr. 2005, 81 (1), 317S– 325S, DOI: 10.1093/ajcn/81.1.317S[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvFKktQ%253D%253D&md5=bace162ff1361dccc462917b6526297dPolyphenols and disease risk in epidemiologic studiesArts, Ilja C. W.; Hollman, Peter C. H.American Journal of Clinical Nutrition (2005), 81 (1S), 317S-325SCODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)A review. Plant polyphenols, a large group of natural antioxidants, are candidates for explanation of the protective effects of dietary vegetables and fruits against cancer and cardiovascular diseases. Epidemiol. studies are useful for evaluation of human health effects of long-term exposure to physiol. concns. of polyphenols, but reliable data on polyphenol contents of foods are scarce. Epidemiol. data on health effects of polyphenols are examd. with focus on the flavonoid subclasses of flavonols, flavones, and catechins and on lignans. The data suggest beneficial effects of both flavonoids and lignans on cardiovascular diseases, but not on cancer, with possible exception of lung cancer. There is a need for more research on stroke and lung diseases, such as asthma and chronic obstructive pulmonary disease. Most studies have included only flavonols and flavones. With data becoming available for other polyphenols, these compds. should be included in future studies. Careful design of prospective studies is important to offset some of the major drawbacks of epidemiol. studies, including residual confounding (smoking, other dietary factors) and exposure assessment.
- 27Tsao, R. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2010, 2 (12), 1231– 1246, DOI: 10.3390/nu2121231[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1WiurfP&md5=66c81de74dee653ab2032353b7839563Chemistry and biochemistry of dietary polyphenolsTsao, RongNutrients (2010), 2 (), 1231-1246CODEN: NUTRHU; ISSN:2072-6643. (Molecular Diversity Preservation International)A review. Polyphenols are the biggest group of phytochems., and many of them have been found in plant-based foods. Polyphenol-rich diets have been linked to many health benefits. This paper is intended to review the chem. and biochem. of polyphenols as related to classification, extn., sepn. and anal. methods, their occurrence and biosynthesis in plants, and the biol. activities and implications in human health. The discussions are focused on important and most recent advances in the above aspects, and challenges are identified for future research.
- 28Feliciano, R. P.; Boeres, A.; Massacessi, L.; Istas, G.; Ventura, M. R.; Nunes dos Santos, C.; Heiss, C.; Rodriguez-Mateos, A. Identification and Quantification of Novel Cranberry-Derived Plasma and Urinary (Poly)Phenols. Arch. Biochem. Biophys. 2016, 599, 31– 41, DOI: 10.1016/j.abb.2016.01.014[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFGisLY%253D&md5=9173e5818c01cc39afdfa89adcde9e27Identification and quantification of novel cranberry-derived plasma and urinary (poly)phenolsFeliciano, Rodrigo P.; Boeres, Albert; Massacessi, Luca; Istas, Geoffrey; Ventura, M. Rita; Nunes dos Santos, Claudia; Heiss, Christian; Rodriguez-Mateos, AnaArchives of Biochemistry and Biophysics (2016), 599 (), 31-41CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)Cranberries are a rich source of (poly)phenols, in particular proanthocyanidins, anthocyanins, flavonols, and phenolic acids. However, little is known about their bioavailability in humans. We investigated the absorption, metab., and excretion of cranberry (poly)phenols in plasma and urine of healthy young men after consumption of a cranberry juice (787 mg (poly)phenols). A total of 60 cranberry-derived phenolic metabolites were identified using UPLC-Q-TOF-MS anal. with authentic stds. These included sulfates of pyrogallol, valerolactone, benzoic acids, phenylacetic acids, glucuronides of flavonols, as well as sulfates and glucuronides of cinnamic acids. The most abundant plasma metabolites were small phenolic compds., in particular hippuric acid, catechol-O-sulfate, 2,3-dihydroxybenzoic acid, phenylacetic acid, isoferulic acid, 4-methylcatechol-O-sulfate, α-hydroxyhippuric acid, ferulic acid 4-O-sulfate, benzoic acid, 4-hydroxyphenyl acetic acid, dihydrocaffeic acid 3-O-sulfate, and vanillic acid-4-O-sulfate. Some benzoic acids, cinnamic acids, and flavonol metabolites appeared in plasma early, at 1-2 h post-consumption. Others such as phenylacetic acids, benzaldehydes, pyrogallols, catechols, hippuric and dihydrocinnamic acid derivs. appear in plasma later (Tmax 4-22 h). The 24 h urinary recovery with respect to the amt. of (poly)phenols consumed was 6.2%. Our extensive description of the bioavailability of cranberry (poly)phenols lays important groundwork necessary to start understanding the fate of these compds. in humans.
- 29Rodriguez-Mateos, A.; Heiss, C.; Borges, G.; Crozier, A. Berry (Poly)Phenols and Cardiovascular Health. J. Agric. Food Chem. 2014, 62 (18), 3842– 3851, DOI: 10.1021/jf403757g[ACS Full Text], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsV2it7%252FN&md5=f3907a2817de424fda1e7a646b90b51aBerry (poly)phenols and cardiovascular healthRodriguez-Mateos, Ana; Heiss, Christian; Borges, Gina; Crozier, AlanJournal of Agricultural and Food Chemistry (2014), 62 (18), 3842-3851CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)A review. Berries are rich sources of polyphenols, including anthocyanins, flavan-3-ols, procyanidins, flavonols, ellagitannins, and hydroxycinnamates. Epidemiol. evidence indicates that the cardiovascular health benefits of diets rich in berries are related to their polyphenol content. These findings are supported by small-scale randomized controlled studies that show improvements in several surrogate markers of cardiovascular disease risk, such as blood pressure, endothelial function, arterial stiffness, and blood lipids after acute and short-term consumption of blueberries, strawberries, cranberries, or purified anthocyanin exts. in healthy or diseased individuals. Firm conclusions on the preventive value of berry polyphenols cannot be drawn due to the small no. of existing studies and limitations of the available data, such as lack of controls or failure to assess the absorption and metab. of polyphenols. Although the current evidence is promising, more long-term studies are needed to establish the role of berry polyphenols in support of cardiovascular health.
- 30Rothwell, J. A.; Perez-Jimenez, J.; Neveu, V.; Medina-Remon, A.; M’Hiri, N.; Garcia-Lobato, P.; Manach, C.; Knox, C.; Eisner, R.; Wishart, D. S. Phenol-Explorer 3.0: A Major Update of the Phenol-Explorer Database to Incorporate Data on the Effects of Food Processing on Polyphenol Content. Database 2013, 2013, bat070, DOI: 10.1093/database/bat070
- 31Mena, P.; Bresciani, L.; Brindani, N.; Ludwig, I. A.; Pereira-Caro, G.; Angelino, D.; Llorach, R.; Calani, L.; Brighenti, F.; Clifford, M. N. Phenyl-γ-Valerolactones and Phenylvaleric Acids, the Main Colonic Metabolites of Flavan-3-Ols: Synthesis, Analysis, Bioavailability, and Bioactivity. Nat. Prod. Rep. 2019, 36, 714– 752, DOI: 10.1039/C8NP00062J[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlSru7jI&md5=1d8dd5c3f552f1715dfbe831eca899e5Phenyl-γ-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: synthesis, analysis, bioavailability, and bioactivityMena, Pedro; Bresciani, Letizia; Brindani, Nicoletta; Ludwig, Iziar A.; Pereira-Caro, Gema; Angelino, Donato; Llorach, Rafael; Calani, Luca; Brighenti, Furio; Clifford, Michael N.; Gill, Chris I. R.; Crozier, Alan; Curti, Claudio; Del Rio, DanieleNatural Product Reports (2019), 36 (5), 714-752CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)Covering: 1958 to June 2018Phenyl-γ-valerolactones (PVLs) and their related phenylvaleric acids (PVAs) are the main metabolites of flavan-3-ols, the major class of flavonoids in the human diet. Despite their presumed importance, these gut microbiota-derived compds. have, to date, in terms of biol. activity, been considered subordinate to their parent dietary compds., the flavan-3-ol monomers and proanthocyanidins. In this review, the role and prospects of PVLs and PVAs as key metabolites in the understanding of the health features of flavan-3-ols have been critically assessed. Among the topics covered, are proposals for a standardised nomenclature for PVLs and PVAs. The formation, bioavailability and pharmacokinetics of PVLs and PVAs from different types of flavan-3-ols are discussed, taking into account in vitro and animal studies, as well as inter-individual differences and the existence of putative flavan-3-ol metabotypes. Synthetic strategies used for the prepn. of PVLs are considered and the methodologies for their identification and quantification assessed. Metabolomic approaches unravelling the role of PVLs and PVAs as biomarkers of intake are also described. Finally, the biol. activity of these microbial catabolites in different exptl. models is summarised. Knowledge gaps and future research are considered in this key area of dietary (poly)phenol research.
- 32Williamson, G.; Manach, C. Bioavailability and Bioefficacy of Polyphenols in Humans. II. Review of 93 Intervention Studies. Am. J. Clin. Nutr. 2005, 81 (1), 243S– 255S, DOI: 10.1093/ajcn/81.1.243S[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvFKltQ%253D%253D&md5=a7b2d3f99f5ef967fc4dbc0ff30e3d90Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studiesWilliamson, Gary; Manach, ClaudineAmerican Journal of Clinical Nutrition (2005), 81 (1S), 243S-255SCODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)A review. For some classes of dietary polyphenols, there are now sufficient data from intervention studies to indicate the type and magnitude of in vivo effects in humans on the basis of short-term changes in biomarkers. Isoflavones (soybean genistein and daidzein) have significant effects on bone health in postmenopausal women, together with some weak hormonal effects. Monomeric catechins (found at high concns. in tea) have effects on blood plasma antioxidant biomarkers and energy metab. Procyanidins (oligomeric catechins found at high concns. in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system, including but not limited to blood plasma antioxidant activity. Quercetin (representative of flavonols found at high concns. in onions, apples, red wine, broccoli, tea, and Ginkgo biloba) influences some carcinogenesis markers and has small effects on plasma antioxidant biomarkers in vivo, although some studies failed to find this effect. Compared with the effects of polyphenols in vitro, the effects in vivo are more limited. The reasons for this are lack of validated in vivo biomarkers (esp. in carcinogenesis), lack of long-term studies, and lack of understanding or consideration of bioavailability in vitro which are subsequently used for the design of in vivo expts. It is time to rethink the design of in vitro and in vivo studies, so that these issues are carefully considered. The length of human intervention studies should be increased to more closely reflect the long-term dietary consumption of polyphenols.
- 33Stalmach, A.; Edwards, C. A.; Wightman, J. D.; Crozier, A. Gastrointestinal Stability and Bioavailability of (Poly)Phenolic Compounds Following Ingestion of Concord Grape Juice by Humans. Mol. Nutr. Food Res. 2012, 56 (3), 497– 509, DOI: 10.1002/mnfr.201100566[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xit1Wmtbk%253D&md5=ee4a140a8836848881a39b61b7235f62Gastrointestinal stability and bioavailability of (poly)phenolic compounds following ingestion of Concord grape juice by humansStalmach, Angelique; Edwards, Christine A.; Wightman, JoLynne D.; Crozier, AlanMolecular Nutrition & Food Research (2012), 56 (3), 497-509CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)The in vitro gastrointestinal stability of (poly)phenolic compds. in Concord grape juice was compared with recoveries in ileal fluid after the ingestion of the juice by ileostomists. Recoveries in ileal fluid indicated that 67% of hydroxycinnamate tartarate esters, and smaller percentages of the intake of other (poly)phenolic compds., pass from the small intestine to the colon. The juice was also ingested by healthy subjects with an intact functioning colon. Peak plasma concns. (Cmax) ranged from 1.0 nmol/L for petunidin-3-O-glucoside to 355 nmol/L for dihydrocoumaric acid. Urinary excretion, as an indicator of bioavailability, varied from 0.26% for total anthocyanins to 24% for metabolites of hydroxycinnamate tartarate esters. The Cmax times of the anthocyanins indicated that their low level absorption occurred in the small intestine in contrast to hydroxycinnamate metabolites which were absorbed in both the small and the large intestine where the colonic microflora appeared responsible for hydrogenation of the hydroxycinnamate side chain. The bioavailability of the complex mixt. of (poly)phenolic compds. in Concord grape juice, was very similar to that obsd. in previous studies when compds. were either fed individually or as major components in products contg. a restricted spectrum of (poly)phenolic compds.
- 34Day, A. J; Canada, F.J.; Dıaz, J. C; Kroon, P. A; Mclauchlan, R.; Faulds, C. B; Plumb, G. W; Morgan, M. R.A; Williamson, G. Dietary Flavonoid and Isoflavone Glycosides Are Hydrolysed by the Lactase Site of Lactase Phlorizin Hydrolase. FEBS Lett. 2000, 468 (2–3), 166– 170, DOI: 10.1016/S0014-5793(00)01211-4[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1OitbY%253D&md5=4fb10628f5800a8eb739c25ae45f1b79Dietary flavonoid and isoflavone glycosides are hydrolyzed by the lactase site of lactase phlorizin hydrolaseDay, A. J.; Canada, F. J.; Diaz, J. C.; Kroon, P. A.; Mclauchlan, R.; Faulds, C. B.; Plumb, G. W.; Morgan, M. R. A.; Williamson, G.FEBS Letters (2000), 468 (2,3), 166-170CODEN: FEBLAL; ISSN:0014-5793. (Elsevier Science B.V.)Lactase phlorizin hydrolase (LPH; EC 3.2.1.62) is a membrane-bound, family 1 β-glycosidase found on the brush border of the mammalian small intestine. LPH, purified from sheep small intestine, was capable of hydrolyzing a range of flavonol and isoflavone glycosides. The catalytic efficiency (kcat/Km) for the hydrolysis of quercetin-4'-glucoside, quercetin-3-glucoside, genistein-7-glucoside and daidzein-7-glucoside was 170, 137, 77, and 14 (mM-1 s-1) resp. The majority of the activity occurred at the lactase and not phlorizin hydrolase site. The ability of LPH to deglycosylate dietary (iso)flavonoid glycosides suggests a possible role for this enzyme in the metab. of these biol. active compds.
- 35Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J. P. E.; Tognolini, M.; Borges, G.; Crozier, A. Dietary (Poly)Phenolics in Human Health: Structures, Bioavailability, and Evidence of Protective Effects Against Chronic Diseases. Antioxid. Redox Signaling 2013, 18 (14), 1818– 1892, DOI: 10.1089/ars.2012.4581[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltlKltLY%253D&md5=581508c16b497392e129fd795aee9b91Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseasesDel Rio, Daniele; Rodriguez-Mateos, Ana; Spencer, Jeremy P. E.; Tognolini, Massimiliano; Borges, Gina; Crozier, AlanAntioxidants & Redox Signaling (2013), 18 (14), 1818-1892CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)A review. Human intervention trials have provided evidence for protective effects of various (poly)phenol-rich foods against chronic disease, including cardiovascular disease, neurodegeneration, and cancer. While there are considerable data suggesting benefits of (poly)phenol intake, conclusions regarding their preventive potential remain unresolved due to several limitations in existing studies. Bioactivity investigations using cell lines have made an extensive use of both (poly)phenolic aglycons and sugar conjugates, these being the typical forms that exist in planta, at concns. in the low-μM-to-mM range. However, after ingestion, dietary (poly)phenolics appear in the circulatory system not as the parent compds., but as phase II metabolites, and their presence in plasma after dietary intake rarely exceeds nM concns. Substantial quantities of both the parent compds. and their metabolites pass to the colon where they are degraded by the action of the local microbiota, giving rise principally to small phenolic acid and arom. catabolites that are absorbed into the circulatory system. This comprehensive review describes the different groups of compds. that have been reported to be involved in human nutrition, their fate in the body as they pass through the gastrointestinal tract and are absorbed into the circulatory system, the evidence of their impact on human chronic diseases, and the possible mechanisms of action through which (poly)phenol metabolites and catabolites may exert these protective actions. It is concluded that better performed in vivo intervention and in vitro mechanistic studies are needed to fully understand how these mols. interact with human physiol. and pathol. processes. Antioxid. Redox Signal. 18, 1818-1892.
- 36González-Sarrías, A.; García-Villalba, R.; Romo-Vaquero, M.; Alasalvar, C.; Örem, A.; Zafrilla, P.; Tomás-Barberán, F. A.; Selma, M. V.; Espín, J. C. Clustering According to Urolithin Metabotype Explains the Interindividual Variability in the Improvement of Cardiovascular Risk Biomarkers in Overweight-Obese Individuals Consuming Pomegranate: A Randomized Clinical Trial. Mol. Nutr. Food Res. 2017, 61 (5), 1600830, DOI: 10.1002/mnfr.201600830
- 37Espín, J. C.; Larrosa, M.; García-Conesa, M. T.; Tomás-Barberán, F. Biological Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The Evidence So Far. Evidence-Based Complement. Altern. Med. 2013, 2013, 1– 15, DOI: 10.1155/2013/270418
- 38Plant Phenolics and Human Health; Fraga, C. G., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2009; DOI: 10.1002/9780470531792 .
- 39Bialonska, D.; Kasimsetty, S. G.; Khan, S. I.; Ferreira, D. Urolithins, Intestinal Microbial Metabolites of Pomegranate Ellagitannins, Exhibit Potent Antioxidant Activity in a Cell-Based Assay. J. Agric. Food Chem. 2009, 57 (21), 10181– 10186, DOI: 10.1021/jf9025794[ACS Full Text], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1GgsbzE&md5=f152e36a43cafaa2e8330439c573e67aUrolithins, Intestinal Microbial Metabolites of Pomegranate Ellagitannins, Exhibit Potent Antioxidant Activity in a Cell-Based AssayBialonska, Dobroslawa; Kasimsetty, Sashi G.; Khan, Shabana I.; Ferreira, DaneelJournal of Agricultural and Food Chemistry (2009), 57 (21), 10181-10186CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Many health benefits of pomegranate products have been attributed to the potent antioxidant action of their tannin components, mainly punicalagins and ellagic acid. While moving through the intestines, ellagitannins are metabolized by gut bacteria into urolithins that readily enter systemic circulation. In this study, the antioxidant properties of seven urolithin derivs. were evaluated in a cell-based assay. This method is biol. more relevant because it reflects bioavailability of the test compd. to the cells, and the antioxidant action is detd. in the cellular environment. Our results showed that the antioxidant activity of urolithins was correlated with the no. of hydroxy groups as well as the lipophilicity of the mol. The most potent antioxidants are urolithins C and D with IC50 values of 0.16 and 0.33 μM, resp., when compared to IC50 values of 1.1 and 1.4 μM of the parent ellagic acid and punicalagins, resp. The dihydroxylated urolithin A showed weaker antioxidant activity, with an IC50 value 13.6 μM, however, the potency was within the range of urolithin A plasma concns. Therefore, products of the intestinal microbial transformation of pomegranate ellagitannins may account for systemic antioxidant effects.
- 40Brinquin, L.; Philip, Y.; Le Gulluche, Y.; Bonsignour, J. P.; Buffat, J. J. Anesthésie Pour Chirurgie d’un Phéochromocytome Malin. Accès Hypertensif Après Administration de Dropéridol. Ann. Fr. Anesth. Reanim. 1987, 6 (3), 204– 206, DOI: 10.1016/S0750-7658(87)80080-1[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s3ps12hsg%253D%253D&md5=858cb6ece15c51600d16d83e221b0cf1Anesthesia for the surgery of malignant pheochromocytoma. Hypertensive crisis after the administration of droperidolBrinquin L; Philip Y; Le Gulluche Y; Bonsignour J P; Buffat J JAnnales francaises d'anesthesie et de reanimation (1987), 6 (3), 204-6 ISSN:0750-7658.A case of malignant phaeochromocytoma is reported. Computerized tomography and scintigraphy using metaiodobenzylguanidine localized the tumour and metastases. The anesthetic management included invasive monitoring of pulmonary pressures with a Swan-Ganz catheter and arterial pressure with a radial arterial cannula. Plasma catecholamine concentrations were measured before and during adrenalectomy and resection of a metastatic lesion on the fourth right rib. Induction of anaesthesia was carried out with droperidol, phenoperidine, thiopentone and pancuronium. After intravenous administration of droperidol, blood pressure increased together with the heart rate, vascular resistances and pulmonary pressure, whilst cardiac output decreased. Plasma noradrenaline levels were also greatly increased at the same time. The mechanism of this paradoxic pressor effect of droperidol is discussed.
- 41Perez-Ternero, C.; Macià, A.; de Sotomayor, M. A.; Parrado, J.; Motilva, M.-J.; Herrera, M.-D. Bioavailability of the Ferulic Acid-Derived Phenolic Compounds of a Rice Bran Enzymatic Extract and Their Activity against Superoxide Production. Food Funct. 2017, 8 (6), 2165– 2174, DOI: 10.1039/C7FO00243B[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVSmtbs%253D&md5=8b79e23e6d7763c2739e67845d9d1597Bioavailability of the ferulic acid-derived phenolic compounds of a rice bran enzymatic extract and their activity against superoxide productionPerez-Ternero, Cristina; Macia, Alba; de Sotomayor, Maria Alvarez; Parrado, Juan; Motilva, Maria-Jose; Herrera, Maria-DoloresFood & Function (2017), 8 (6), 2165-2174CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)Rice bran is an exceptional source of such antioxidant mols. as γ-oryzanol and ferulic acid, but their bioavailability and metab. within this matrix remain unknown. The aims of this work were to describe the oral bioavailability and metabolic pathways of the ferulic acid-derived phenolic compds. contained in a rice bran enzymic ext. (RBEE), and to det. its effect on NADPH oxidase activity. Wistar rats were administered with RBEE and sacrificed at different times over a period of 24 h to obtain plasma. An addnl. group was used for collection of urine and faeces over a period of 48 h. The phenolic metabolites were detd. by ultra-performance liq. chromatog. coupled to tandem mass spectrometry (UPLC-MS/MS), and plasma pharmacokinetic parameters were calcd. In parallel, aortic rings were incubated in the plasma of rats sacrificed 30 min after RBEE gavage, or in the presence of RBEE, ferulic acid or γ-oryzanol. Endothelin-1-induced superoxide prodn. was recorded by lucigenin-enhanced luminescence. Twenty-five ferulic acid metabolites showing biphasic behavior were found in the plasma, most of which were found in the urine as well, while in the faeces, colonic metab. led to simpler phenolic compds. Superoxide prodn. was abrogated by phenolic compd.-enriched plasma and by RBEE and ferulic acid, thus showing the biol. potential of RBEE as a nutraceutical ingredient.
- 42Williamson, G.; Clifford, M. N. Role of the Small Intestine, Colon and Microbiota in Determining the Metabolic Fate of Polyphenols. Biochem. Pharmacol. 2017, 139, 24– 39, DOI: 10.1016/j.bcp.2017.03.012[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXksFeqsLs%253D&md5=d121ba41e2dba5a13401611ac4e07251Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenolsWilliamson, Gary; Clifford, Michael N.Biochemical Pharmacology (Amsterdam, Netherlands) (2017), 139 (), 24-39CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)A review. (Poly)phenols are a large group of compds., found in food, beverages, dietary supplements and herbal medicines. Owing to interest in their biol. activities, absorption and metab. of the most abundant compds. in humans are well understood. Both the chem. structure of the phenolic moiety and any attached chem. groups define whether the polyphenol is absorbed in the small intestine, or reaches the colon and is subject to extensive catabolism by colonic microbiota. Untransformed substrates may be absorbed, appearing in plasma primarily as methylated, sulfated and glucuronidated derivs., with in some cases the unchanged substrate. Many of the catabolites are well absorbed from the colon and appear in the plasma either similarly conjugated, or as glycine conjugates, or in some cases unchanged. Although many (poly)phenol catabolites have been identified in human plasma and/or urine, the exact pathways from substrate to final microbial catabolite, and the species of bacteria and enzymes involved, are still scarcely reported. While it is clear that the compn. of the human gut microbiota can be modulated in vivo by supplementation with some (poly)phenol-rich commodities, such modulation is definitely not an inevitable consequence of supplementation; it depends on the treatment, length of time and on the individual metabotype, and it is not clear whether the modulation is sustained when supplementation ceases. Some catabolites have been recorded in plasma of volunteers at concns. similar to those shown to be effective in in vitro studies suggesting that some benefit may be achieved in vivo by diets yielding such catabolites.
- 43Pasinetti, G. M.; Singh, R.; Westfall, S.; Herman, F.; Faith, J.; Ho, L. The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. J. Alzheimer's Dis. 2018, 63 (2), 409– 421, DOI: 10.3233/JAD-171151[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotlCnurc%253D&md5=d3f916ceec8f68c3ee6a4ecf17dbad96The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic MicePasinetti, Giulio Maria; Singh, Risham; Westfall, Susan; Herman, Francis; Faith, Jeremiah; Ho, LapJournal of Alzheimer's Disease (2018), 63 (2), 409-421CODEN: JADIF9; ISSN:1387-2877. (IOS Press)A growing body of exptl. data suggests that microbes in the gut influence behavior and can alter brain physiol. and neurochem. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurol. disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metab. and bioavailability of certain dietary compds. and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms assocd. with the promotion of resilience against psychol. and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.
- 44Czank, C.; Cassidy, A.; Zhang, Q.; Morrison, D. J.; Preston, T.; Kroon, P. A.; Botting, N. P.; Kay, C. D. Human Metabolism and Elimination of the Anthocyanin, Cyanidin-3-Glucoside: A 13C-Tracer Study. Am. J. Clin. Nutr. 2013, 97 (5), 995– 1003, DOI: 10.3945/ajcn.112.049247[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmvFSmtrw%253D&md5=699339119331251badae3f046c78144cHuman metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a 13C-tracer studyCzank, Charles; Cassidy, Aedin; Zhang, Qingzhi; Morrison, Douglas J.; Preston, Tom; Kroon, Paul A.; Botting, Nigel P.; Kay, Colin D.American Journal of Clinical Nutrition (2013), 97 (5), 995-1003CODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)Background: Evidence suggests that the consumption of anthocyanin-rich foods beneficially affects cardiovascular health; however, the absorption, distribution, metab., and elimination (ADME) of anthocyanin-rich foods are relatively unknown. Objective: We investigated the ADME of a 13C5-labeled anthocyanin in humans. Design: Eight male participants consumed 500 mg isotopically labeled cyanidin-3-glucoside (6,8,10,3',5'-13C5-C3G). Biol. samples were collected over 48 h, and 13C and 13C-labeled metabolite concns. were measured by using isotope-ratio mass spectrometry and liq. chromatog.-tandem mass spectrometry. Results: The mean ± SE percentage of 13C recovered in urine, breath, and feces was 43.9 ± 25.9% (range: 15.1-99.3% across participants). The relative bioavailability was 12.38 ± 1.38% (5.37 ± 0.67% excreted in urine and 6.91 ± 1.59% in breath). Maximum rates of 13C elimination were achieved 30 min after ingestion (32.53 ± 14.24 μg13C/h), whereas 13C-labeled metabolites peaked (max. serum concn.: 5.97 ± 2.14 μmol/L) at 10.25 ± 4.14 h. The half-life for 13C-labeled metabolites ranged between 12.44 ± 4.22 and 51.62 ± 22.55 h. 13C elimination was greatest between 0 and 1 h for urine (90.30 ± 15.28 μg/h), at 6 h for breath (132.87 ± 32.23 μg/h), and between 6 and 24 h for feces (557.28 ± 247.88 μg/h), whereas the highest concns. of 13C-labeled metabolites were identified in urine (10.77 ± 4.52 μmol/L) and fecal samples (43.16 ± 18.00 μmol/L) collected between 6 and 24 h. Metabolites were identified as degrdn. products, phenolic, hippuric, phenylacetic, and phenylpropenoic acids. Conclusion: Anthocyanins are more bioavailable than previously perceived, and their metabolites are present in the circulation for ≤48 h after ingestion.
- 45Pimpão, R. C.; Ventura, M. R.; Ferreira, R. B.; Williamson, G.; Santos, C. N. Phenolic Sulfates as New and Highly Abundant Metabolites in Human Plasma after Ingestion of a Mixed Berry Fruit Purée. Br. J. Nutr. 2015, 113 (3), 454– 463, DOI: 10.1017/S0007114514003511[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit1CmsL0%253D&md5=19f03a84514b541a235bda5b69715ed6Phenolic sulfates as new and highly abundant metabolites in human plasma after ingestion of a mixed berry fruit pureePimpao, Rui C.; Ventura, M. Rita; Ferreira, Ricardo B.; Williamson, Gary; Santos, Claudia N.British Journal of Nutrition (2015), 113 (3), 454-463CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)Bioavailability studies are vital to assess the potential impact of bioactive compds. on human health. Although conjugated phenolic metabolites derived from colonic metab. have been identified in the urine, the quantification and appearance of these compds. in plasma is less well studied. In this regard, it is important to further assess their potential biol. activity in vivo. To address this gap, a cross-over intervention study with a mixed fruit puree (blueberry, blackberry, raspberry, strawberry tree fruit and Portuguese crowberry) and a std. polyphenol-free meal was conducted in thirteen volunteers (ten females and three males), who received each test meal once, and plasma metabolites were identified by HPLC-MS/MS. Sulfated compds. were chem. synthesized and used as stds. to facilitate quantification. Gallic and caffeic acid conjugates were absorbed rapidly, reaching a max. concn. between 1 and 2 h. The concns. of sulfated metabolites resulting from the colonic degrdn. of more complex polyphenols increased in plasma from 4 h, and pyrogallol sulfate and catechol sulfate reached concns. ranging from 5 to 20 μm at 6 h. In conclusion, phenolic sulfates reached high concns. in plasma, as opposed to their undetected parent compds. These compds. have potential use as biomarkers of polyphenol intake, and their biol. activities need to be considered.
- 46Penczynski, K. J.; Krupp, D.; Bring, A.; Bolzenius, K.; Remer, T.; Buyken, A. E. Relative Validation of 24-h Urinary Hippuric Acid Excretion as a Biomarker for Dietary Flavonoid Intake from Fruit and Vegetables in Healthy Adolescents. Eur. J. Nutr. 2017, 56 (2), 757– 766, DOI: 10.1007/s00394-015-1121-9[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVGrsbvK&md5=33ecba4768848db7f233e6d46e633ca4Relative validation of 24-h urinary hippuric acid excretion as a biomarker for dietary flavonoid intake from fruit and vegetables in healthy adolescentsPenczynski, Katharina J.; Krupp, Danika; Bring, Anna; Bolzenius, Katja; Remer, Thomas; Buyken, Anette E.European Journal of Nutrition (2017), 56 (2), 757-766CODEN: EJNUFZ; ISSN:1436-6207. (Springer)Purpose: A biomarker for dietary flavonoid intake from fruit and vegetables (FlavFV) is needed to elucidate the relevance of flavonoids from these sources for the prevention of chronic diseases. Urinary hippuric acid (HA)-a major metabolite of flavonoids-is promising in this respect as it was shown to satisfyingly indicate fruit and vegetable consumption in different age groups. Therefore, we validated urinary HA as a biomarker for intake of FlavFV. Methods: Analyses included data from 287 healthy adolescents of the DONALD Study (aged 9-16 years) for whom a min. of two pairs of HA measurements from 24-h urine samples (test method) and FlavFV intake estd. from 3-day weighed dietary records (ref. method) existed. Agreement between both methods was assessed by Spearman correlation and cross-classification analyses. Possible confounders of the assocn. were identified by linear regression models. Analyses were performed using a split-sample approach allowing for consecutive exploration (n = 192) and confirmation (n = 95) of results. Results: Agreement between urinary HA excretion and FlavFV intake was moderate according to correlation anal. in the exploratory sample (runadjusted = 0.47, P < 0.0001). Yet, 79 % of the subjects were classified into same/adjacent quartiles, and only 5 % were misclassified into opposite quartiles. These findings were corroborated by analyses in the confirmatory sample (runadjusted = 0.64; 88 % in same/adjacent vs. 4 % in opposite quartiles). Body surface area (BSA) was the only relevant covariate in the exploratory sample, and its adjustment improved cross-classification ests. in both subsamples. Conclusions: BSA-adjusted 24-h urinary HA excretion represents a suitable biomarker of habitual FlavFV intake in healthy adolescents.
- 47Schaffer, S.; Halliwell, B. Do Polyphenols Enter the Brain and Does It Matter? Some Theoretical and Practical Considerations. Genes Nutr. 2012, 7 (2), 99– 109, DOI: 10.1007/s12263-011-0255-5[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XltVKitr8%253D&md5=b5e38a6f0afba9830f0b14ade3aaf41eDo polyphenols enter the brain and does it matter? Some theoretical and practical considerationsSchaffer, Sebastian; Halliwell, BarryGenes and Nutrition (2012), 7 (2), 99-109CODEN: GNEUAZ; ISSN:1555-8932. (Springer)A review. Although several epidemiol. and intervention studies suggest that polyphenols (PPs) and PP-rich foods may improve memory and cognition in animals and humans, PPs' mode of action is only poorly understood. To help distinguish between the different modes of action that have been proposed for PPs, it is obviously important to know how much PPs can accumulate in the brain, if any at all. However, reliable data on PP uptake into the brain of animals are limited as many studies failed to report important control procedures during data acquisition. In this paper, we summarize published data on the penetration of PPs into animal brain and review some hypotheses to explain the biol. basis of potentially health-beneficial effects of PPs to the brain. Finally, we highlight promising new approaches, esp. those of a hormetic dose-response and gut microbiota-brain interaction, which may allow a better understanding of PPs' mode of action in animals and humans.
- 48Cardoso, C. G., Jr; Gomides, R. S.; Queiroz, A. C. C.; Pinto, L. G.; Lobo, F. da S.; Tinucci, T.; Mion, D., Jr; Forjaz, C. L. de M. Acute and Chronic Effects of Aerobic and Resistance Exercise on Ambulatory Blood Pressure. Clinics 2010, 65 (3), 317– 325, DOI: 10.1590/S1807-59322010000300013[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3jtFeltw%253D%253D&md5=8b8aa1c3b96401e88301dc38b06b67a6Acute and chronic effects of aerobic and resistance exercise on ambulatory blood pressureCardoso Crivaldo Gomes Jr; Gomides Ricardo Saraceni; Queiroz Andreia Cristiane Carrenho; Pinto Luiz Gustavo; da Silveira Lobo Fernando; Tinucci Tais; Mion Decio Jr; de Moraes Forjaz Claudia LuciaClinics (Sao Paulo, Brazil) (2010), 65 (3), 317-25 ISSN:.Hypertension is a ubiquitous and serious disease. Regular exercise has been recommended as a strategy for the prevention and treatment of hypertension because of its effects in reducing clinical blood pressure; however, ambulatory blood pressure is a better predictor of target-organ damage than clinical blood pressure, and therefore studying the effects of exercise on ambulatory blood pressure is important as well. Moreover, different kinds of exercise might produce distinct effects that might differ between normotensive and hypertensive subjects.The aim of this study was to review the current literature on the acute and chronic effects of aerobic and resistance exercise on ambulatory blood pressure in normotensive and hypertensive subjects. It has been conclusively shown that a single episode of aerobic exercise reduces ambulatory blood pressure in hypertensive patients. Similarly, regular aerobic training also decreases ambulatory blood pressure in hypertensive individuals. In contrast, data on the effects of resistance exercise is both scarce and controversial. Nevertheless, studies suggest that resistance exercise might acutely decrease ambulatory blood pressure after exercise, and that this effect seems to be greater after low-intensity exercise and in patients receiving anti-hypertensive drugs. On the other hand, only two studies investigating resistance training in hypertensive patients have been conducted, and neither has demonstrated any hypotensive effect. Thus, based on current knowledge, aerobic training should be recommended to decrease ambulatory blood pressure in hypertensive individuals, while resistance exercise could be prescribed as a complementary strategy.
- 49Milbury, P. E.; Kalt, W. Xenobiotic Metabolism and Berry Flavonoid Transport across the Blood–Brain Barrier. J. Agric. Food Chem. 2010, 58 (7), 3950– 3956, DOI: 10.1021/jf903529m[ACS Full Text], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGitrg%253D&md5=f42ac0eef009ab3c23752d14d4c6719aXenobiotic Metabolism and Berry Flavonoid Transport across the Blood-Brain BarrierMilbury, Paul E.; Kalt, WilhelminaJournal of Agricultural and Food Chemistry (2010), 58 (7), 3950-3956CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)A compelling body of literature suggests berry phytochems. play beneficial roles in reversing age-related cognitive impairment and protect against neurodegenerative disorders. Anthocyanins are bioactive phytochems. in berries suspected to be responsible for some of these neuroprotective effects. The plausible mechanisms of anthocyanin bioactivity in brain tissue are dependent on their bioavailability to the brain. Pigs were fed 2% whole freeze-dried, powd. blueberry in the diet for 8 wk. Anthocyanin and anthocyanin glucuronides were measured in the cortex, cerebellum, and midbrain and diencephalon by LC-MS/MS. Anthocyanins and their glucuronides were found in the range of femtomoles per g of fresh wt. of tissue at 18 h postprandial, after anthocyanins had been removed from the blood by xenobiotic metab. Xenobiotic metab., anthocyanin interaction, and transporter barriers to brain bioavailability are briefly discussed. The plausible mechanism of neuroprotective action of anthocyanins may be via modulation of signal transduction processes and/or gene expression in brain tissue rather than by direct antioxidant radical quenching.
- 50Gasperotti, M.; Passamonti, S.; Tramer, F.; Masuero, D.; Guella, G.; Mattivi, F.; Vrhovsek, U. Fate of Microbial Metabolites of Dietary Polyphenols in Rats: Is the Brain Their Target Destination?. ACS Chem. Neurosci. 2015, 6 (8), 1341– 1352, DOI: 10.1021/acschemneuro.5b00051[ACS Full Text], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXms1Ogsbo%253D&md5=cbc5a1644ee09f6fe8e3070cfdfd0f7eFate of microbial metabolites of dietary polyphenols in rats: Is the brain their target destination?Gasperotti, Mattia; Passamonti, Sabina; Tramer, Federica; Masuero, Domenico; Guella, Graziano; Mattivi, Fulvio; Vrhovsek, UrskaACS Chemical Neuroscience (2015), 6 (8), 1341-1352CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Different polyphenol compds. are ingested when consuming a serving of fruits rich in polyphenols, spanning from one-phenol hydroxybenzoic acid to more complex polymeric compds. Only a minor quantity of the polyphenols (5-10%) is absorbed. The remainder reaches the colon and is extensively metabolized by gut microbiota to low-mol. wt. metabolites. Their subsequent tissue distribution is still undefined, although these microbial metabolites are currently believed to play a role in human health and disease states. To fill this knowledge gap, we performed a pharmacokinetics expt. in which a single bolus of 23 polyphenol microbial metabolites (total 2.7 μmol) was administered i.v. to rats to reliably reproduce a physiol. postabsorption situation. Tissues and urine were collected shortly thereafter (15 s to 15 min) and were analyzed by UHPLC-MS/MS to quant. track these compds. Remarkably, the brain was found to be a specific target organ for 10 of the 23 polyphenol metabolites injected, which significantly increased in the treated animals. In most cases, their appearance in the brain was biphasic, with an early wave at 2 min (4 compds.) and a second wave starting at 5 min; at 15 min, 9 compds. were still detectable. Most compds. were excreted into the urine. The concns. in the brain of the treated animals were compared against those of the control group by Student's t test, with p-values < 0.1 considered to be statistically significant. These findings provide new perspectives for understanding the role of diet on brain chem. Our exptl. approach has enabled us to obtain rich metabolomics information from a single expt. involving a limited no. of animals.
- 51van Praag, H.; Lucero, M. J.; Yeo, G. W.; Stecker, K.; Heivand, N.; Zhao, C.; Yip, E.; Afanador, M.; Schroeter, H.; Hammerstone, J. Plant-Derived Flavanol (−)Epicatechin Enhances Angiogenesis and Retention of Spatial Memory in Mice. J. Neurosci. 2007, 27 (22), 5869– 5878, DOI: 10.1523/JNEUROSCI.0914-07.2007[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsVWktrw%253D&md5=faf4e569bec8271be1b03b9baddb4a04Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in micevan Praag, Henriette; Lucero, Melanie J.; Yeo, Gene W.; Stecker, Kimberly; Heivand, Neema; Zhao, Chunmei; Yip, Ed; Afanador, Mia; Schroeter, Hagen; Hammerstone, John; Gage, Fred H.Journal of Neuroscience (2007), 27 (22), 5869-5878CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Diet and exercise have a profound impact on brain function. In particular, natural nutrients found in plants may influence neuronal survival and plasticity. Here, we tested whether consumption of a plant-derived flavanol, (-)epicatechin, enhances cognition in sedentary or wheel-running female C57BL/6 mice. Retention of spatial memory in the water maze was enhanced by ingestion of (-)epicatechin, esp. in combination with exercise. Improved spatial memory was assocd. with increased angiogenesis and neuronal spine d., but not newborn cell survival, in the dentate gyrus of the hippocampus. Moreover, microarray anal. showed upregulation of genes assocd. with learning and downregulation of markers of neurodegeneration in the hippocampus. Together, our data show that ingestion of a single flavanol improves spatial memory retention in adult mammals.
- 52El Mohsen, M. A.; Marks, J.; Kuhnle, G.; Rice-Evans, C.; Moore, K.; Gibson, G.; Debnam, E.; Srai, S. K. The Differential Tissue Distribution of the Citrus Flavanone Naringenin Following Gastric Instillation. Free Radical Res. 2004, 38 (12), 1329– 1340, DOI: 10.1080/10715760400017293[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFCqur%252FN&md5=22051b933e598c51b7438f9c61c60a95The Differential Tissue Distribution of the Citrus Flavanone Naringenin Following Gastric InstillationEl Mohsen, Manal Abd; Marks, Joanne; Kuhnle, Gunter; Rice-Evans, Catherine; Moore, Kevin; Gibson, Glenn; Debnam, Edward; Srai, S. KailaFree Radical Research (2004), 38 (12), 1329-1340CODEN: FRARER; ISSN:1071-5762. (Taylor & Francis Ltd.)Citrus flavonoids have been investigated for their biol. activity, with both anti-inflammatory and -carcinogenic effects being reported. However, little information is known on the bioavailability of these compds. in vivo. The objectives of this study were to det. the tissue distribution of naringenin after gastric gavage of [3H]-naringenin to rats. Unlabeled naringenin was also used to quantify the levels of naringenin and its major metabolites in tissues and eliminated in the urine and feces. Significant radioactivity was detected in the plasma as well as all tissues examd. 2 h post-gavage. After 18 h, higher levels of radioactivity were retained in plasma and tissues (55% of the administered radioactivity). Investigation of the nature of metabolites, using unlabeled naringenin, revealed that the glucuronides were the major components in plasma, tissues and urine, in addn. to the colonic metabolite 3-(4-hydroxyphenyl) propionic acid, detected in the urine. The aglycon was the form extensively retained in tissues after 18 h post-gavage. Total identified metabolites detected after 18 h in most tissues were only 1-5% of the levels detected after 2 h. However, the brain, lungs and heart retained 27, 20 and 11%, resp., relative to the total metabolites detected at 2 h. While radioactive detection suggests increased levels of breakdown products of naringenin after 18 h vs. 2 h, the products identified using unlabeled naringenin are not consistent with this, suggesting that a predominant proportion of the naringenin breakdown products at 18 h are retained as smaller decompn. mols. which cannot yet be identified.
- 53Ishisaka, A.; Ichikawa, S.; Sakakibara, H.; Piskula, M. K.; Nakamura, T.; Kato, Y.; Ito, M.; Miyamoto, K.; Tsuji, A.; Kawai, Y. Accumulation of Orally Administered Quercetin in Brain Tissue and Its Antioxidative Effects in Rats. Free Radical Biol. Med. 2011, 51 (7), 1329– 1336, DOI: 10.1016/j.freeradbiomed.2011.06.017[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFSjsLbL&md5=26c4264c0b30ed01546d63ecc2a2ed8fAccumulation of orally administered quercetin in brain tissue and its antioxidative effects in ratsIshisaka, Akari; Ichikawa, Satomi; Sakakibara, Hiroyuki; Piskula, Mariusz K.; Nakamura, Toshiyuki; Kato, Yoji; Ito, Mikiko; Miyamoto, Ken-ichi; Tsuji, Akira; Kawai, Yoshichika; Terao, JunjiFree Radical Biology & Medicine (2011), 51 (7), 1329-1336CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)Quercetin is widely distributed in vegetables and herbs and has been suggested to act as a neuroprotective agent. Here, we demonstrate that quercetin can accumulate enough to exert biol. activity in rat brain tissues. Homogenates of perfused rat brain without detectable Hb contaminants were treated with β-glucuronidase/sulfatase and the released quercetin and its methylated form were analyzed using high-performance liq. chromatog. (HPLC) with three different detection methods. Both quercetin and the methylated form were detected in the brain of quercetin-administered rats using HPLC-UV and HPLC with electrochem. detection and were further identified using HPLC-tandem mass spectrometry. Oral administration of quercetin (50 mg/kg body wt) attenuated the increased oxidative stress in the hippocampus and striatum of rats exposed to chronic forced swimming. The possible transport of quercetin derivs. into the brain tissue was reproduced in vitro by using a rat brain capillary endothelial cell line, a model of the blood-brain barrier. These results show that quercetin could be a potent nutrient that can access the brain and protect it from disorders assocd. with oxidative stress.
- 54Talavéra, S.; Felgines, C.; Texier, O.; Besson, C.; Gil-Izquierdo, A.; Lamaison, J.-L.; Rémésy, C. Anthocyanin Metabolism in Rats and Their Distribution to Digestive Area, Kidney, and Brain. J. Agric. Food Chem. 2005, 53 (10), 3902– 3908, DOI: 10.1021/jf050145v[ACS Full Text], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtFSjtbw%253D&md5=7802c502c089132ee8984d71187f50f0Anthocyanin metabolism in rats and their distribution to digestive area, kidney, and brainTalavera, Severine; Felgines, Catherine; Texier, Odile; Besson, Catherine; Gil-Izquierdo, Angel; Lamaison, Jean-Louis; Remesy, ChristianJournal of Agricultural and Food Chemistry (2005), 53 (10), 3902-3908CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Anthocyanins are present in human diets due to their wide occurrence in fruits and vegetables. They have antioxidant activities and could have several health effects. The anthocyanin metab. and tissue distribution in the digestive organs (stomach, jejunum, liver), kidney, and brain were studied in male Wistar rats fed diet with blackberry (Rubus fruticosus) anthocyanins for 15 days. Identification and quantification of anthocyanin metabolites was done by HPLC-ESI-MS-MS and HPLC-DAD, resp. The stomach contained only native blackberry anthocyanins (cyanidin 3-O-glucoside, cyanidin 3-O-pentose), while in other organs (jejunum, liver, kidney) contained native and methylated anthocyanins and conjugated anthocyanidins (cyanidin and peonidin monoglucuronides). Proportions of anthocyanin derivs. differed according to the organs, with the liver having the highest proportion of methylated forms. Jejunum and blood plasma also contained aglycon forms. In the brain, the total anthocyanin content (blackberry anthocyanins and peonidin 3-O-glucoside) reached 0.25±0.05 nmol/g tissue. The urinary excretion of total anthocyanins was low (0.19±0.02% of ingested amt.). Thus, digestive organs have metabolic pathways for anthocyanins with enzymic conversions (methylation and/or glucuronide conjugation). Following consumption of an anthocyanin-rich diet, anthocyanins also enter the brain.
- 55Bo, C. D.; Ciappellano, S.; Klimis-Zacas, D.; Martini, D.; Gardana, C.; Riso, P.; Porrini, M. Anthocyanin Absorption, Metabolism, and Distribution from a Wild Blueberry-Enriched Diet (Vaccinium Angustifolium) Is Affected by Diet Duration in the Sprague–Dawley Rat. J. Agric. Food Chem. 2010, 58 (4), 2491– 2497, DOI: 10.1021/jf903472x
- 56Wu, L.; Zhang, Q.-L.; Zhang, X.-Y.; Lv, C.; Li, J.; Yuan, Y.; Yin, F.-X. Pharmacokinetics and Blood–Brain Barrier Penetration of (+)-Catechin and (−)-Epicatechin in Rats by Microdialysis Sampling Coupled to High-Performance Liquid Chromatography with Chemiluminescence Detection. J. Agric. Food Chem. 2012, 60 (37), 9377– 9383, DOI: 10.1021/jf301787f[ACS Full Text], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1Ghu73P&md5=ffcbc7080fad39a1a7165331b9b246bbPharmacokinetics and Blood-Brain Barrier Penetration of (+)-Catechin and (-)-Epicatechin in Rats by Microdialysis Sampling Coupled to High-Performance Liquid Chromatography with Chemiluminescence DetectionWu, Liang; Zhang, Qun-Lin; Zhang, Xiao-Yue; Lv, Chen; Li, Jun; Yuan, Ye; Yin, Fang-XiongJournal of Agricultural and Food Chemistry (2012), 60 (37), 9377-9383CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)(+)-Catechin (C) and (-)-epicatechin (EC), as the basic monomer units of flavanols, can be widely found in natural products or medicinal herbs. Recent pharmacol. studies have revealed that C and EC exhibit good neuroprotective effects. However, there is little information about pharmacokinetic profiles in the brain and in vivo BBB penetration of C and EC. In this paper, an ultrasensitive method using high-performance liq. chromatog. (HPLC) with chemiluminescence (CL) detection was developed for the anal. of microdialysis samples. The detection limits for C and EC in Ringer's soln. were 1.0 and 1.2 ng/mL, resp. The intraday and interday accuracies for C and EC in Ringer's soln. ranged from -3.0 to 4.4%, and the intraday and interday precisions were below 5.2%. The mean in vivo recoveries of C and EC in microdialysis probes were 33.7% and 26.5% in blood while 38.3% and 29.1% in brain. Pharmacokinetic parameters were estd. using the statistical moment method after iv administration (C and EC, 20 mg/kg of body wt.) in rats. Brain-to-blood (AUCbrain/AUCblood) distribution ratios were 0.0726 ± 0.0376 for C and 0.1065 ± 0.0531 for EC, indicating that C and EC could pass through the BBB, which is further evidence of their neuroprotective effects.
- 57Zhao, W.; Wang, J.; Bi, W.; Ferruzzi, M.; Yemul, S.; Freire, D.; Mazzola, P.; Ho, L.; Dubner, L.; Pasinetti, G. M. Novel Application of Brain-Targeting Polyphenol Compounds in Sleep Deprivation-Induced Cognitive Dysfunction. Neurochem. Int. 2015, 89, 191– 197, DOI: 10.1016/j.neuint.2015.07.023[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlWlt7rN&md5=45c0662cbe339b6f9ee86faec614d0cdNovel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunctionZhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freirea, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio MariaNeurochemistry International (2015), 89 (), 191-197CODEN: NEUIDS; ISSN:0197-0186. (Elsevier Ltd.)Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Prepn. (BDPP), comprised of grape seed polyphenol ext., Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compds. derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction.
- 58Faria, A.; Pestana, D.; Teixeira, D.; Couraud, P.-O.; Romero, I.; Weksler, B.; de Freitas, V.; Mateus, N.; Calhau, C. Insights into the Putative Catechin and Epicatechin Transport across Blood-Brain Barrier. Food Funct. 2011, 2 (1), 39– 44, DOI: 10.1039/C0FO00100G[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVGgtg%253D%253D&md5=4ed5870b17006f90c290a4b0a6296d1eInsights into the putative catechin and epicatechin transport across blood-brain barrierFaria, Ana; Pestana, Diogo; Teixeira, Diana; Couraud, Pierre-Olivier; Romero, Ignacio; Weksler, Babette; de Freitas, Victor; Mateus, Nuno; Calhau, ConceicaoFood & Function (2011), 2 (1), 39-44CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)The identification of mechanisms assocd. with phenolic neuroprotection is delayed due to a lack of information regarding the ability of phenolic compds. to enter the central nervous system (CNS). The aim of this work was to evaluate the transmembrane transport of catechin and epicatechin across blood-brain barrier (BBB). Two BBB cell lines, RBE-4 cells (immortalized cell line of rat capillary cerebral endothelial cells) and hCMEC/D3 (immortalized human cerebral microvessel endothelial cell line), were used. HPLC-DAD/MS was used to detect these compds. and their metabolites in the studied samples. The metabolites of the tested flavan-3-ols were synthesized to be used as stds. Catechin and epicatechin could cross both cells in a time-dependent manner. This transport was stereoselective (epicatechin » catechin), involving one or more stereoselective entities. Addnl., these cells were capable of metabolizing these compds., particularly by conjugation with glucuronic acid, since this metabolite was detected in the basolateral media. Several studies suggest that blood levels of catechin and epicatechin are far below the levels used in this study and that these compds. appeared mainly as Me, sulfate and glucuronide metabolites. Nevertheless, the information obtained by this study is valuable for the new insights about flavan-3-ols transport. In conclusion: (i) catechin and epicatechin are capable of crossing the BBB; (ii) a stereoselective process was involved in the passage of these compds. across BBB cells; (iii) endothelial cells have enzymes capable of metabolizing these compds.
- 59Wu, K.; Wang, Z.-Z.; Liu, D.; Qi, X.-R. Pharmacokinetics, Brain Distribution, Release and Blood–brain Barrier Transport of Shunaoxin Pills. J. Ethnopharmacol. 2014, 151 (3), 1133– 1140, DOI: 10.1016/j.jep.2013.12.027[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlGqu7w%253D&md5=df2324c90db8689c5da378af64517a35Pharmacokinetics, brain distribution, release and blood-brain barrier transport of Shunaoxin pillsWu, Kai; Wang, Zhan-Zhang; Liu, Dan; Qi, Xian-RongJournal of Ethnopharmacology (2014), 151 (3), 1133-1140CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)Shunaoxin pills, a traditional Chinese medicine (TCM) product, have been used to treat cerebrovascular diseases in China since 2005. The main active components of Shunaoxin pills are ferulic acid and ligustilide from Chuanxiong (Ligusticum chuanxiong Hort, Umbelliferae) and Danggui (Angelica sinensis radix, Umbelliferae). As Shunaoxin shows excellent activity in the central nervous system (CNS), the extent to which the major constituents of Shunaoxin reach the CNS should be investigated. Moreover, the in vivo-in vitro correlations (IVIVC) of the formulation should be studied to elucidate the mechanisms of action of TCM in the CNS. However, these data have not previously been available. Thus we intended to investigate what the extent when these constituents of Shunaoxin pills reach the CNS, and evaluate the IVIVC of release and pharmacokinetics. In this study, we evaluated the release of ferulic acid and ligustilide from Shunaoxin pills, and their transport across an in vitro model of the BBB. We also evaluated their pharmacokinetics and brain distribution in vivo. High-performance liq. chromatog. (HPLC) was used to quantify both compds. simultaneously. Based on the release in vitro and absorption of ferulic acid and ligustilide in vivo, IVIVC permitted prediction of the pharmacokinetics of these compds. The release of ferulic acid and ligustilide reached a platform phase within 1 h. Ferulic acid and ligustilide rapidly crossed the BBB in different patterns; the transport ratio increased over time. After intragastric (i.g.) administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed into brain, which may result in a rapid onset of action. Ferulic acid and ligustilide were transported across a model BBB. After i.g. administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed in brain; this may lead to rapid pharmacol. onset. The IVIVC can be used to predict in vivo pharmacokinetics from in vitro exptl. results. These results provide support for the clin. use of Shunaoxin pills.
- 60Bauer, S. R.; Ding, E. L.; Smit, L. A. Cocoa Consumption, Cocoa Flavonoids, and Effects on Cardiovascular Risk Factors: An Evidence-Based Review. Curr. Cardiovasc. Risk Rep. 2011, 5 (2), 120– 127, DOI: 10.1007/s12170-011-0157-5
- 61Monagas, M.; Khan, N.; Andres-Lacueva, C.; Casas, R.; Urpí-Sardà, M.; Llorach, R.; Lamuela-Raventós, R. M.; Estruch, R. Effect of Cocoa Powder on the Modulation of Inflammatory Biomarkers in Patients at High Risk of Cardiovascular Disease. Am. J. Clin. Nutr. 2009, 90 (5), 1144– 1150, DOI: 10.3945/ajcn.2009.27716[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlentLfP&md5=ba6ce24d871f5a08303b5f9705cf7cd8Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular diseaseMonagas, Maria; Khan, Nasiruddin; Andres-Lacueva, Cristina; Casas, Rosa; Urpi-Sarda, Mireia; Llorach, Rafael; Lamuela-Raventos, Rosa Maria; Estruch, RamonAmerican Journal of Clinical Nutrition (2009), 90 (5), 1144-1150CODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)Background: Epidemiol. studies have suggested that flavonoid intake plays a crit. role in the prevention of coronary heart disease. Because atherosclerosis is considered a low-grade inflammatory disease, some feeding trials have analyzed the effects of cocoa (an important source of flavonoids) on inflammatory biomarkers, but the results have been controversial. Objective: The objective was to evaluate the effects of chronic cocoa consumption on cellular and serum biomarkers related to atherosclerosis in high-risk patients. Design: Forty-two high-risk volunteers (19 men and 23 women; mean ± SD age: 69.7 ± 11.5 y) were included in a randomized crossover feeding trial. All subjects received 40 g cocoa powder with 500 mL skim milk/d (C+M) or only 500 mL skim milk/d (M) for 4 wk. Before and after each intervention period, cellular and serum inflammatory biomarkers related to atherosclerosis were evaluated. Results: Adherence to the dietary protocol was excellent. No significant changes in the expression of adhesion mols. on T lymphocyte surfaces were found between the C+M and M groups. However, in monocytes, the expression of VLA-4, CD40, and CD36 was significantly lower (P = 0.005, 0.028, and 0.001, resp.) after C+M intake than after M intake. In addn., serum concns. of the sol. endothelium-derived adhesion mols. P-selectin and intercellular adhesion mol.-1 were significantly lower (both P = 0.007) after C+M intake than after M intake. Conclusions: These results suggest that the intake of cocoa polyphenols may modulate inflammatory mediators in patients at high risk of cardiovascular disease. These antiinflammatory effects may contribute to the overall benefits of cocoa consumption against atherosclerosis.
- 62Flanagan, E.; Müller, M.; Hornberger, M.; Vauzour, D. Impact of Flavonoids on Cellular and Molecular Mechanisms Underlying Age-Related Cognitive Decline and Neurodegeneration. Curr. Nutr. Rep. 2018, 7 (2), 49– 57, DOI: 10.1007/s13668-018-0226-1[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MbmtlGltA%253D%253D&md5=8157db2b091d810018bc22b146e0b6bbImpact of Flavonoids on Cellular and Molecular Mechanisms Underlying Age-Related Cognitive Decline and NeurodegenerationFlanagan Emma; Muller Michael; Hornberger Michael; Vauzour DavidCurrent nutrition reports (2018), 7 (2), 49-57 ISSN:.PURPOSE OF REVIEW: This review summarises the most recent evidence regarding the effects of dietary flavonoids on age-related cognitive decline and neurodegenerative diseases. RECENT FINDINGS: Recent evidence indicates that plant-derived flavonoids may exert powerful actions on mammalian cognition and protect against the development of age-related cognitive decline and pathological neurodegeneration. The neuroprotective effects of flavonoids have been suggested to be due to interactions with the cellular and molecular architecture of brain regions responsible for memory. Mechanisms for the beneficial effects of flavonoids on age-related cognitive decline and dementia are discussed, including modulating signalling pathways critical in controlling synaptic plasticity, reducing neuroinflammation, promoting vascular effects capable of stimulating new nerve cell growth in the hippocampus, bidirectional interactions with gut microbiota and attenuating the extracellular accumulation of pathological proteins. These processes are known to be important in maintaining optimal neuronal function and preventing age-related cognitive decline and neurodegeneration.
- 63Poulose, S. M.; Fisher, D. R.; Larson, J.; Bielinski, D. F.; Rimando, A. M.; Carey, A. N.; Schauss, A. G.; Shukitt-Hale, B. Anthocyanin-Rich Açai (Euterpe Oleracea Mart.) Fruit Pulp Fractions Attenuate Inflammatory Stress Signaling in Mouse Brain BV-2 Microglial Cells. J. Agric. Food Chem. 2012, 60 (4), 1084– 1093, DOI: 10.1021/jf203989k[ACS Full Text], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVGrtA%253D%253D&md5=1b710b1ec57388c05755fc25db3fe7a0Anthocyanin-rich Acai (Euterpe oleracea Mart.) fruit pulp fractions attenuate inflammatory stress signaling in mouse brain BV-2 microglial cellsPoulose, Shibu M.; Fisher, Derek R.; Larson, Jessica; Bielinski, Donna F.; Rimando, Agnes M.; Carey, Amanda N.; Schauss, Alexander G.; Shukitt-Hale, BarbaraJournal of Agricultural and Food Chemistry (2012), 60 (4), 1084-1093CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Age-related diseases of the brain compromise memory, learning, and movement and are directly linked with increases in oxidative stress and inflammation. Previous research has shown that supplementation with berries can modulate signaling in primary hippocampal neurons or BV-2 mouse microglial cells. Because of their high polyphenolic content, fruit pulp fractions of acai (Euterpe oleracea Mart.) were explored for their protective effect on BV-2 mouse microglial cells. Freeze-dried acai pulp was fractionated using solvents with different polarities and analyzed using HPLC for major anthocyanins and other phenolics. Fractions extd. using methanol (MEOH) and ethanol (ETOH) were particularly rich in anthocyanins such as cyanidin, delphinidin, malvidin, pelargonidin, and peonidin, whereas the fraction extd. using acetone (ACE) was rich in other phenolics such as catechin, ferulic acid, quercetin, resveratrol, and syringic and vanillic acids. Studies were conducted to investigate the mitigating effects of acai pulp exts. on lipopolysaccharide (LPS, 100 ng/mL) induced oxidative stress and inflammation; treatment of BV-2 cells with acai fractions resulted in significant (p < 0.05) decreases in nitrite prodn., accompanied by a redn. in inducible nitric oxide synthase (iNOS) expression. The inhibition pattern was emulated with the ferulic acid content among the fractions. The protection of microglial cells by acai pulp exts., particularly that of MEOH, ETOH, and ACE fractions, was also accompanied by a significant concn.-dependent redn. in cyclooxygenase-2 (COX-2), p38 mitogen-activated protein kinase (p38-MAPK), tumor necrosis factor-α (TNFα), and nuclear factor κB (NF-κB). The current study offers valuable insights into the protective effects of acai pulp fractions on brain cells, which could have implications for improved cognitive and motor functions.
- 64Lau, F. C.; Bielinski, D. F.; Joseph, J. A. Inhibitory Effects of Blueberry Extract on the Production of Inflammatory Mediators in Lipopolysaccharide-Activated BV2Microglia. J. Neurosci. Res. 2007, 85 (5), 1010– 1017, DOI: 10.1002/jnr.21205[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXks1Ohtr8%253D&md5=c0846886721b8867e1ea7165544f1580Inhibitory effects of blueberry extract on the production of inflammatory mediators in lipopolysaccharide-activated BV2 microgliaLau, Francis C.; Bielinski, Donna F.; Joseph, James A.Journal of Neuroscience Research (2007), 85 (5), 1010-1017CODEN: JNREDK; ISSN:0360-4012. (Wiley-Liss, Inc.)Sustained microglial activation in the central nervous system (CNS) has been extensively investigated in age-related neurodegenerative diseases and has been postulated to lead to neuronal cell loss in these conditions. Recent studies have shown that antiinflammatory drugs may suppress microglial activation and thus protect against microglial overactivation and subsequent cell loss. Research also suggests that fruits such as berries may contain both antioxidant and antiinflammatory polyphenols that may be important in this regard. Our previous research showed that blueberry ext. was effective in preventing oxidant-induced calcium response deficits in M1 (muscarinic receptor)-transfected COS-7 cells. Extrapolating from these findings, the current study investigated the effect of blueberry ext. on preventing inflammation-induced activation of microglia. Results indicated that treatments with blueberry ext. inhibited the prodn. of the inflammatory mediator nitric oxide (NO) as well as the cytokines interleukin-1β and tumor necrosis factor-α, in cell conditioned media from lipopolysaccharide (LPS)-activated BV2 microglia. Also, mRNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-activated BV2 cells were significantly reduced by treatments with blueberry ext. The results suggest that blueberry polyphenols attenuate inflammatory responses of brain microglia and could be potentially useful in modulation of inflammatory conditions in the CNS.
- 65Syed, M. M.; Phulwani, N. K.; Kielian, T. Tumor Necrosis Factor-Alpha (TNF-α) Regulates Toll-like Receptor 2 (TLR2) Expression in Microglia. J. Neurochem. 2007, 103 (4), 1461– 1471, DOI: 10.1111/j.1471-4159.2007.04838.x[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtl2jurjL&md5=0f5539426b037b023707d79751980b9fTumor necrosis factor-alpha (TNF-α) regulates Toll-like receptor 2 (TLR2) expression in microgliaSyed, Mohsin Md.; Phulwani, Nirmal K.; Kielian, TammyJournal of Neurochemistry (2007), 103 (4), 1461-1471CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)Microglia represent one effector arm of CNS innate immunity as evident by their role in pathogen recognition. We previously reported that exposure of microglia to Staphylococcus aureus (S. aureus), a prevalent CNS pathogen, led to elevated Toll-like receptor 2 (TLR2) expression, a pattern recognition receptor capable of recognizing conserved structural motifs assocd. with gram-pos. bacteria such as S. aureus. In this study, we demonstrate that the proinflammatory cytokine tumor necrosis factor-α (TNF-α) enhances TLR2 expression in microglia, whereas interleukin-1β has no significant effect. To det. the downstream signaling events responsible for elevated microglial TLR2 expression in response to TNF-α, a series of signal transduction inhibitors were employed. Treatment with caffeic acid phenethyl ester, an inhibitor of redox-mediated nuclear factor-kappa B activation, significantly attenuated TNF-α-induced TLR2 expression. Similar results were obsd. with the IKK-2 and IκB-α inhibitors SC-514 and BAY 11-7082, resp. In contrast, no significant alterations in TLR2 expression were obsd. with protein kinase C or p38 mitogen-activated protein kinase inhibitors. A definitive role for TNF-α was demonstrated by the inability of S. aureus to augment TLR2 expression in microglia isolated from TNF-α knockout mice. In addn., TLR2 expression was significantly attenuated in brain abscesses of TNF-α knockout mice. Collectively, these results indicate that in response to S. aureus, TNF-α acts in an autocrine/paracrine manner to enhance TLR2 expression in microglia and that this effect is mediated, in part, by activation of the nuclear factor-kappa B pathway.
- 66Tambuwala, M. M.; Khan, M. N.; Thompson, P.; McCarron, P. A. Albumin Nano-Encapsulation of Caffeic Acid Phenethyl Ester and Piceatannol Potentiated Its Ability to Modulate HIF and NF-KB Pathways and Improves Therapeutic Outcome in Experimental Colitis. Drug Delivery Transl. Res. 2019, 9 (1), 14– 24, DOI: 10.1007/s13346-018-00597-9[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlShsLbP&md5=ef5f94bd7c96fef97433944211937d98Albumin nano-encapsulation of caffeic acid phenethyl ester and piceatannol potentiated its ability to modulate HIF and NF-κB pathways and improves therapeutic outcome in experimental colitisTambuwala, Murtaza M.; Khan, Mohammed N.; Thompson, Paul; McCarron, Paul A.Drug Delivery and Translational Research (2019), 9 (1), 14-24CODEN: DDTRCY; ISSN:2190-3948. (Springer)Hypoxia inducible factor and nuclear factor-kappa beta pathways have been proposed as therapeutic targets for several inflammatory diseases. Caffeic acid phenethyl ester (CAPE) and piceatannol (PIC) are natural anti-inflammatory compds.; however, poor bioavailability and limited understanding of biomol. mechanistic limits its clin. use. The aims of this study are to enhance bioavailability and investigate their impact on nuclear p65 and HIF-1α for the first time in exptl. colitis. Dextran sulfate sodium was used to induce colitis in mice and effect of either free CAPE/PIC or CAPE/PIC loaded albumin nanoparticles treatment was obsd. on disease development and levels of cellular p65 and HIF-1α. Our results indicate that albumin nano-encapsulation of CAPE/PIC not only enhances its anti-inflammatory potential but also potentiates its ability to effectively modulate inflammation related biomol. pathways. Hence, combining nanotechnol. with natural compds. could result in development of new therapeutic options for IBD.
- 67di Gesso, J. L.; Kerr, J. S.; Zhang, Q.; Raheem, S.; Yalamanchili, S. K.; O’Hagan, D.; Kay, C. D.; O’Connell, M. A. Flavonoid Metabolites Reduce Tumor Necrosis Factor-α Secretion to a Greater Extent than Their Precursor Compounds in Human THP-1 Monocytes. Mol. Nutr. Food Res. 2015, 59 (6), 1143– 1154, DOI: 10.1002/mnfr.201400799[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnsFyjt7Y%253D&md5=75bcf04367646f3d27cbbb49a4b75f24Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytesdi Gesso, Jessica L.; Kerr, Jason S.; Zhang, Qingzhi; Raheem, Saki; Yalamanchili, Sai Krishna; O'Hagan, David; Kay, Colin D.; O'Connell, Maria A.Molecular Nutrition & Food Research (2015), 59 (6), 1143-1154CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)Scope : Flavonoids are generally studied in vitro, in isolation, and as unmetabolized precursor structures. However, in the habitual diet, multiple flavonoids are consumed together and found present in the circulation as complex mixts. of metabolites. Using a unique study design, we investigated the potential for singular or additive anti-inflammatory effects of flavonoid metabolites relative to their precursor structures. Methods and results : Six flavonoids, 14 flavonoid metabolites, and 29 combinations of flavonoids and their metabolites (0.1-10 μM) were screened for their ability to reduce LPS-induced tumor necrosis factor-α (TNF-α) secretion in THP-1 monocytes. One micromolar peonidin-3-glucoside, cyanidin-3-glucoside, and the metabolites isovanillic acid (IVA), IVA-glucuronide, vanillic acid-glucuronide, protocatechuic acid-3-sulfate, and benzoic acid-sulfate significantly reduced TNF-α secretion when in isolation, while there was no effect on TNF-α mRNA expression. Four combinations of metabolites that included 4-hydroxybenzoic acid (4HBA) and/or protocatechuic acid also significantly reduced TNF-α secretion to a greater extent than the precursors or metabolites alone. The effects on LPS-induced IL-1β and IL-10 secretion and mRNA expression were also examd. 4HBA significantly reduced IL-1β secretion but none of the flavonoids or metabolites significantly modified IL-10 secretion. Conclusion : This study provides novel evidence suggesting flavonoid bioactivity results from cumulative or additive effects of circulating metabolites.
- 68Verpoorte, R.; Choi, Y. H.; Kim, H. K. Ethnopharmacology and Systems Biology: A Perfect Holistic Match. J. Ethnopharmacol. 2005, 100 (1–2), 53– 56, DOI: 10.1016/j.jep.2005.05.033[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2Mzps1eiug%253D%253D&md5=14404d358fb72ae66957b9b4ab8fa09fEthnopharmacology and systems biology: a perfect holistic matchVerpoorte R; Choi Y H; Kim H KJournal of ethnopharmacology (2005), 100 (1-2), 53-6 ISSN:0378-8741.Traditional medical doctors often apply a holistic approach in prescribing medicines to the patient. Each individual patient gets his own optimalized medicine, usually a mixture of different ingredients. The present day paradigm of drug development of <single target, single compound>, is based on a super reductionist approach which involves mostly tests of compounds at the molecular level in, e.g., receptor binding assays. This approach is not the best for studies on traditional medicines. A more holistic approach using systems biology seems much more suited to proof efficacy and to obtain information that might lead to understanding the mode of action. Synergy, prodrugs, novel targets, all these might be detected by a systems biology approach whereas the reductioinist approach only will recognize activity on already known targets, and will not detect synergism and prodrugs. Metabolomics will be a major tool in recognizing compounds connected with activity in the traditional medicines, and will also be very useful in recognizing the effect on the test organism, which can be the patient in case of clinical trials with well established traditional medicines.
- 69Tavares, L.; Figueira, I.; McDougall, G. J.; Vieira, H. L. A.; Stewart, D.; Alves, P. M.; Ferreira, R. B.; Santos, C. N. Neuroprotective Effects of Digested Polyphenols from Wild Blackberry Species. Eur. J. Nutr. 2013, 52 (1), 225– 236, DOI: 10.1007/s00394-012-0307-7[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVelsb4%253D&md5=b209e815112b958208d827e54910664cNeuroprotective effects of digested polyphenols from wild blackberry speciesTavares, Lucelia; Figueira, Ines; McDougall, Gordon J.; Vieira, Helena L. A.; Stewart, Derek; Alves, Paula M.; Ferreira, Ricardo B.; Santos, Claudia N.European Journal of Nutrition (2013), 52 (1), 225-236CODEN: EJNUFZ; ISSN:1436-6207. (Springer)Purpose Blackberry ingestion has been demonstrated to attenuate brain degenerative processes with the benefits ascribed to the (poly)phenolic components. The aim of this work was to evaluate the neuroprotective potential of two wild blackberry species in a neurodegeneration cell model and compare them with a com. variety. Methods This work encompasses chem. characterization before and after an in vitro digestion and the assessment of neuroprotection by digested metabolites. Some studies targeting redox/cell death systems were also performed to assess possible neuroprotective mol. mechanisms. Results The three blackberry exts. presented some quant. differences in polyphenol compn. that could be responsible for the different responses in the neurodegeneration cell model. Com. blackberry exts. were ineffective but both wild blackberries, Rubus brigantinus and Rubus vagabundus, presented neuroprotective effects. It was verified that a diminishment of intracellular ROS levels, modulation of glutathione levels and activation of caspases occurred during treatment. The last effect suggests a preconditioning effect since caspase activation was not accompanied by diminution in cell death and loss of functionality. Conclusions This is the first time that metabolites obtained from an in vitro digested food matrix, and tested at levels approaching the concns. found in human plasma, have been described as inducing an adaptative response.
- 70Giampieri, F.; Afrin, S.; Stewart, D.; McDougall, G.; Brennan, R.; Blyth, L.; Gasparrini, M.; Mazzoni, L.; Capocasa, F.; Alvarez-Suarez, J. Phytochemical Composition and Cytotoxic Effects on Liver Hepatocellular Carcinoma Cells of Different Berries Following a Simulated In Vitro Gastrointestinal Digestion. Molecules 2018, 23 (8), 1918, DOI: 10.3390/molecules23081918[Crossref], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVSnurjP&md5=fddde832754a07ca5bad18eab4bd1584Phytochemical composition and cytotoxic effects on liver hepatocellular carcinoma cells of different berries following a simulated in vitro gastrointestinal digestionGiampieri, Francesca; Afrin, Sadia; Stewart, Derek; McDougall, Gordon J.; Brennan, Rex; Blyth, Lesley; Gasparrini, Massimiliano; Mazzoni, Luca; Capocasa, Franco; Alvarez-Suarez, Jose Miguel; Bompadre, Stefano; Bras de Oliveira, Pedro Nogueira; Santos, Claudia N.; Masias, Manuel; Agudo, Pablo; Crespo, Jorge; Mezzetti, Bruno; Forbes-Hernandez, Tamara Y.; Battino, MaurizioMolecules (2018), 23 (8), 1918/1-1918/14CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Berry fruits are rich in nutrients and polyphenols, providing potential health benefits. Understanding the factors that affect their bioavailability is becoming of utmost importance for evaluating their biol. significance and efficacy as functional food. In this study, the phytochem. compn. and the total antioxidant capacity of different varieties of five berries (blackberry, blackcurrant, blueberry, raspberry, and strawberry) were evaluated after an in vitro gastrointestinal digestion process. The cultivar of each berry that showed the higher content of total phenols and flavonoids was selected to study its cytotoxic effect on human hepatoma cells. Digestion resulted in a high redn. (p< 0.05) of total phenolic, flavonoid andanthocyanin contents and total antioxidant capacity, in the "IN" samples compared to the "OUT" exts., which represent the "serum-available" and the "colon-available" fractions, resp. Incubation of the digested fraction for 24 h didn't exert any effect on cellular viability, while a dose- and time-dependent cytotoxicity was obsd. after 48 h and 72 h of incubation for all the berries analyzed. Our results suggest that the approach proposed in this work may represent a rapid tool for evaluating and identifying new berries with increased phytochem. bioavailability, highlighting their antiproliferative agents after an in vitro digestion.
- 71Tavares, L.; Figueira, I.; Macedo, D.; McDougall, G. J.; Leitão, M. C.; Vieira, H. L. A.; Stewart, D.; Alves, P. M.; Ferreira, R. B.; Santos, C. N. Neuroprotective Effect of Blackberry (Rubus Sp.) Polyphenols Is Potentiated after Simulated Gastrointestinal Digestion. Food Chem. 2012, 131 (4), 1443– 1452, DOI: 10.1016/j.foodchem.2011.10.025[Crossref], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVyktrrJ&md5=8d79820d7aec91dbd37c510633bca7c7Neuroprotective effect of blackberry (Rubus sp.) polyphenols is potentiated after simulated gastrointestinal digestionTavares, Lucelia; Figueira, Ines; Macedo, Diana; McDougall, Gordon J.; Leitao, Maria Cristina; Vieira, Helena L. A.; Stewart, Derek; Alves, Paula M.; Ferreira, Ricardo B.; Santos, Claudia N.Food Chemistry (2012), 131 (4), 1443-1452CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)Blackberry ingestion has been demonstrated to attenuate brain degenerative processes in rodents with the benefits ascribed to the (poly)phenolic components. The aim of this work was to assess the efficacy of blackberry polyphenolics in a neurodegeneration cell model before and after simulated gastrointestinal digestion. Digested blackberry metabolites protected neuroblastoma cells from H2O2-induced death at low, non-toxic levels that approach physiol.-relevant serum concns. However, the original exts. were not protective even at fivefold higher concns. This potentiation may reflect alterations in the polyphenolic compn. caused by the digestion procedure, as detected by liq.-chromatog.-mass spectrometric anal. This protection was not caused by modulation of the intracellular antioxidant capacity or through alteration of glutathione levels, although the original ext. influenced both of these parameters. This work reinforces the importance of evaluating digested metabolites in disease cell models and highlights the possible involvement of other mechanisms beyond antioxidant systems.
- 72Garcia, G.; Nanni, S.; Figueira, I.; Ivanov, I.; McDougall, G. J.; Stewart, D.; Ferreira, R. B.; Pinto, P.; Silva, R. F. M.; Brites, D. Bioaccessible (Poly)Phenol Metabolites from Raspberry Protect Neural Cells from Oxidative Stress and Attenuate Microglia Activation. Food Chem. 2017, 215, 274– 283, DOI: 10.1016/j.foodchem.2016.07.128[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSgur3F&md5=fd27e5c909a0a5854b05caf0ffeca700Bioaccessible (poly)phenol metabolites from raspberry protect neural cells from oxidative stress and attenuate microglia activationGarcia, Goncalo; Nanni, Sara; Figueira, Ines; Ivanov, Ines; McDougall, Gordon J.; Stewart, Derek; Ferreira, Ricardo B.; Pinto, Paula; Silva, Rui F. M.; Brites, Dora; Santos, Claudia N.Food Chemistry (2017), 215 (), 274-283CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)Neuroinflammation is an integral part of the neurodegeneration process inherent to several aging dysfunctions. Within the central nervous system, microglia are the effective immune cells, responsible for neuroinflammatory responses. In this study, raspberries were subjected to in vitro digestion simulation to obtain the components that result from the gastrointestinal (GI) conditions, which would be bioaccessible and available for blood uptake. Both the original raspberry ext. and the gastrointestinal bioaccessible (GIB) fraction protected neuronal and microglia cells against H2O2-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation, at low concns. Furthermore, this neuroprotective capacity was independent of intracellular ROS scavenging mechanisms. We show for the first time that raspberry metabolites present in the GIB fraction significantly inhibited microglial pro-inflammatory activation by LPS, through the inhibition of Iba1 expression, TNF-α release and NO prodn. Altogether, this study reveals that raspberry polyphenols may present a dietary route to the retardation or amelioration of neurodegenerative-related dysfunctions.
- 73Kuo, P.-C.; Liao, Y.-R.; Hung, H.-Y.; Chuang, C.-W.; Hwang, T.-L.; Huang, S.-C.; Shiao, Y.-J.; Kuo, D.-H.; Wu, T.-S. Anti-Inflammatory and Neuroprotective Constituents from the Peels of Citrus Grandis. Molecules 2017, 22 (6), 967, DOI: 10.3390/molecules22060967[Crossref], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1KnsLvP&md5=ca46de5817645866efbf8eaa713ee94eAnti-inflammatory and neuroprotective constituents from the peels of Citrus grandisKuo, Ping-Chung; Liao, Yu-Ren; Hung, Hsin-Yi; Chuang, Chia-Wei; Hwang, Tsong-Long; Huang, Shiow-Chyn; Shiao, Young-Ji; Kuo, Daih-Huang; Wu, Tian-ShungMolecules (2017), 22 (6), 967/1-967/11CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A series of chromatog. sepns. performed on the ethanol exts. of the peels of Citrus grandis has led to the characterization of forty compds., including seventeen coumarins, eight flavonoids, two triterpenoids, four benzenoids, two steroids, one lignan, one amide, and five other compds., resp. The chem. structures of the purified constituents were identified on the basis of spectroscopic elucidation, including 1D- and 2D-NMR, UV, IR, and mass spectrometric anal. Most of the isolated compds. were examd. for their inhibition of superoxide anion generation and elastase release by human neutrophils. Among the isolates, isomeranzin (3), 17,18-dihydroxybergamottin (12), epoxybergamottin (13), rhoifolin (19), vitexicarpin (22) and 4-hydroxybenzaldehyde (29) displayed the most significant inhibition of superoxide anion generation and elastase release with IC50 values ranged from 0.54 to 7.57 μM, and 0.43 to 4.33 μM, resp. In addn., 7-hydroxy-8-(2'-hydroxy-3'-methylbut-3'-enyl)coumarin (8) and 17,18-dihydroxybergamottin (12) also exhibited the protection of neurons against Aβ-mediated neurotoxicity at 50 μM.
- 74Kim, H. J.; Hwang, I. K.; Won, M. H. Vanillin, 4-Hydroxybenzyl Aldehyde and 4-Hydroxybenzyl Alcohol Prevent Hippocampal CA1 Cell Death Following Global Ischemia. Brain Res. 2007, 1181, 130– 141, DOI: 10.1016/j.brainres.2007.08.066[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1yls7%252FO&md5=3032426b0fd56cf0ec148fd79ea0d6a9Vanillin, 4-hydroxybenzyl aldehyde and 4-hydroxybenzyl alcohol prevent hippocampal CA1 cell death following global ischemiaKim, Hyeon Ju; Hwang, In Koo; Won, Moo HoBrain Research (2007), 1181 (), 130-141CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)Mongolian gerbils subjected to transient global ischemia exhibit neuroprotection against ischemic neuronal cell death in the hippocampal CA1 region when treated with vanillin, 4-hydroxybenzyl aldehyde (4-HBAL) and 4-hydroxybenzyl alc. (4-HBA), which are active components of Gastrodia elata Blume. Pre- and post-insult vanillin, 4-HBAL and 4-HBA treated-animals showed a significant increase in neuronal survival (66.32%, 43.21% and 64.58%, resp.) compared to vehicle-treated animals. Animals exhibited a gender difference in this neuroprotective effect. To study the neuroprotective mechanism of 4-HBA, we investigated N-methyl-D-aspartate (NMDA) receptor 1 (NR1), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and γ-aminobutyric acid transaminase (GABA-T) immunoreactivity at various times after ischemic insults. Treatment with 4-HBA did not affect NR1 expression levels, down-regulated 8-OHdG immunoreactivity, and increased GABA-T expression levels after global ischemia, suggesting that 4-HBA inhibited NR1 stimulation. Moreover, GABA-T was rapidly increased in the early stage after ischemia, which might enhance the survival of cells by supplying energy to the CA1 region. These results suggest that 4-HBA inhibits oxidative stress and excitotoxicity for at least 12 h and suppresses neuronal death in CA1 region. Di-Et ether fractions of GE scavenged hydroxyl radical (OH·) and showed antioxidant activity on lipid peroxidn. Vanillin and 4-HBA treatment blocked oxidative damage in PC12 cells. The neuroprotective effect has therapeutic significance and these compds. need to be evaluated for potential use in protecting against neuronal cell damage during stroke.
- 75Cuadrado, A. NRF2 in Neurodegenerative Diseases. Curr. Opin. Toxicol. 2016, 1, 46– 53, DOI: 10.1016/j.cotox.2016.09.004
- 76Doig, A. J.; Derreumaux, P. Inhibition of Protein Aggregation and Amyloid Formation by Small Molecules. Curr. Opin. Struct. Biol. 2015, 30, 50– 56, DOI: 10.1016/j.sbi.2014.12.004[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFygsL7J&md5=ce48f45a925b2545a63d37dc32983f18Inhibition of protein aggregation and amyloid formation by small moleculesDoig, Andrew J.; Derreumaux, PhilippeCurrent Opinion in Structural Biology (2015), 30 (), 50-56CODEN: COSBEF; ISSN:0959-440X. (Elsevier Ltd.)For decades, drug after drug has failed to slow the progression of Alzheimer's disease in human trials. How compds. reducing fibril formation in vitro and toxicity in transgenic mice and flies bind to the Aβ toxic oligomers, is unknown. This account reviews recent drugs mainly targeting Aβ, how they were identified and report their successes from in vitro and in vivo exptl. studies and their current status in clin. trials. We then focus on recent in vitro and simulation results on how inhibitors interact with Aβ monomers and oligomers, highly desirable knowledge for predicting new efficient drugs. We conclude with a perspective on the future of the inhibition of amyloid formation by small mols.
- 77Zheng, L. T.; Ryu, G.-M.; Kwon, B.-M.; Lee, W.-H.; Suk, K. Anti-Inflammatory Effects of Catechols in Lipopolysaccharide-Stimulated Microglia Cells: Inhibition of Microglial Neurotoxicity. Eur. J. Pharmacol. 2008, 588 (1), 106– 113, DOI: 10.1016/j.ejphar.2008.04.035[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmsFKltbk%253D&md5=74fdf818eb20e550a640604c1b3a51b3Anti-inflammatory effects of catechols in lipopolysaccharide-stimulated microglia cells: Inhibition of microglial neurotoxicityZheng, Long Tai; Ryu, Geun-Mu; Kwon, Byoung-Mog; Lee, Won-Ha; Suk, KyounghoEuropean Journal of Pharmacology (2008), 588 (1), 106-113CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Microglial activation plays a pivotal role in the pathogenesis of neurodegenerative diseases by producing various proinflammatory cytokines and nitric oxide (NO). In the present study, the anti-inflammatory and subsequent neuroprotective effects of catechol and its derivs. including 3-methylcatechol, 4-methylcatechol, and 4-tert-butylcatechol were investigated in microglia and neuroblastoma cells in culture. The four catechol compds. showed anti-inflammatory effects with different potency. The catechols significantly decreased lipopolysaccharide (LPS)-induced NO and tumor necrosis factor (TNF)-α prodn. in BV-2 microglia cells. The catechols also inhibited the expression of inducible nitric oxide synthase (iNOS) and TNF-α at mRNA or protein levels in the LPS-stimulated BV-2 cells. In addn., the catechols inhibited LPS-induced nuclear translocation of p65 subunit of nuclear factor (NF)-κB, IκB degrdn., and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in BV-2 cells. Moreover, the catechols attenuated the cytotoxicity of LPS-stimulated BV-2 microglia toward co-cultured rat B35 neuroblastoma cells. The catechols, however, did not protect B35 cells against H2O2 toxicity, indicating that the compds. exerted the neuroprotective effect by inhibiting the inflammatory activation of microglia in the co-culture. The anti-inflammatory and neuroprotective properties of the catechols in cultured microglia and neuroblastoma cells suggest a therapeutic potential of these compds. for the treatment of neurodegenerative diseases that are assocd. with an excessive microglial activation.
- 78Weil-Malherbe, H.; Posner, H. S.; Bowles, G. R. Changes in the Concentration and Intracellular Distribution of Brain Catecholamines: The Effects of Reserpine. Beta-Phenyliso-Propylhydrazine, Pyrogallol and 3,4-Dihydroxyphenyl Alanine, Alone and in Combination. J. Pharmacol. Exp. Ther. 1961, 132, 278– 286[PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXhtVOhsb0%253D&md5=8ee4130622d16f95ff7b205f41fe6f63Changes in concentration and intracellular distribution of brain catechol amines. Effects of reserpine, 1-(1-methyl-2-phenylethyl)hydrazine (Catron), pyrogallol, and 3,4-dihydroxyphenylalanine (dopa), alone and in combinationWeil-Malherbe, H.; Posner, Robert S.; Bowles, Grace R.Journal of Pharmacology and Experimental Therapeutics (1961), 132 (), 278-86CODEN: JPETAB; ISSN:0022-3565.cf. CA 54, 2591d, 15665b. Effects on the concns. of norepinephrine (I) and dopamine (II) in the particulate and sol. fractions of rabbit brain were studied. After injection of reserpine (III) the concns. of I and II decreased faster in the sol. fraction than in the granular fraction. Catron (IV) suppressed the depleting effect of III, while III abolished a moderate rise of I concn. evoked by IV. Pyrogallol (V) alone had no effect on the concn. of catechol amines and did not affect the activity of III or IV. When III, IV, and V were injected into the rabbit together, V potentiated the effect of IV and elicited a rise of I concn. in the sol. fraction to above normal without depletion of I in the particulate fraction. Dopa alone had no significant effect, but after pretreatment with either IV or V it produced a marked rise in II in both the sol. and the particulate fractions. The concns. of I in both fractions were increased by dopa after IV, but not after V, and were increased still more by dopa after IV + V. The results are discussed in relation to the mechanism of action of III, the roles of monoamine oxidase and catechol-O-methyl transferase in metabolism of brain catechol amines, and the factors limiting the synthesis and storage of catechol amines.
- 79Rogers, K. J.; Angel, A.; Butterfield, L. The Penetration of Catechol and Pyrogallol into Mouse Brain and the Effect on Cerebral Monoamine Levels. J. Pharm. Pharmacol. 1968, 20 (9), 727– 729, DOI: 10.1111/j.2042-7158.1968.tb09845.x[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXkvFCqsL0%253D&md5=63c64b58e05f60005145cf59cb160965Penetration of catechol and pyrogallol into mouse brain and the effect on cerebral monoamine levelsRogers, K. J.; Angel, A.; Butterfield, LindaJournal of Pharmacy and Pharmacology (1968), 20 (9), 727-9CODEN: JPPMAB; ISSN:0022-3573.Catechol (60 mg./kg. i.p.) when administered to mice elicited convulsions consisting of violent jerks and tremors, which commenced within 15-20 sec. of injection; the duration of this convulsive activity was transient, lasting ∼8 min., and the peak convulsive activity occurred at 2-3 min. The time course of catechol penetration into the brain followed closely that of the convulsive activity. Mice receiving pyrogallol (120 mg./kg. i.p.) showed no change in motor activity, even though this dose of pyrogallol produced cerebral concns. which were about the same as those produced by the convulsive dose of catechol. The concns. of noradrenaline, dopamine, and 5-hydroxytryptamine in the brains of mice treated with either catechol or pyrogallol were not significantly different from the levels in control mice. Thus, both catechol and pyrogallol enter the brains of mice after i.p. injections, catechol alone evoking convulsions. Neither of these hydroxyphenolic catechol O-methyltransferase inhibitors produced changes in the gross levels of noradrenaline, dopamine, or 5-hydroxytryptamine in mouse brain.
- 80Baldessarini, R. J.; Greiner, E. Inhibition of Catechol-o-Methyl Transferase by Catechols and Polyphenols. Biochem. Pharmacol. 1973, 22 (2), 247– 256, DOI: 10.1016/0006-2952(73)90277-3[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXhtF2it74%253D&md5=7933bf9de871b35dcfc7531550f0eff3Inhibition of catechol-O-methyl transferase by catechols and polyphenolsBaldessarini, Ross J.; Greiner, EllenBiochemical Pharmacology (1973), 22 (2), 247-56CODEN: BCPCA6; ISSN:0006-2952.The inhibitory action of N1-(DL-seryl)-N2-(2,3,4-trihydroxybenzyl) hydrazine (RO4-4602) (I) [322-35-0] on catechol-O-methyl transferase (EC 2.1.1.6) [9012-25-3] was compared with the inhibitory action of dopa [59-92-7] and pyrogallol [87-66-1]. The apparent Km for 3H-labeled norepinephrine [51-41-2] as transferase substrate was 0.36mM. L-dopa [59-92-7] weakly inhibited the transferase (Ki = 0.42mM) and seemed to be competitive with norepinephrine. D-dopa [5796-17-8] was slightly less potent. In contrast pyrogallol was a partially noncompetitive inhibitor of the transferase with respect to substrate (Ki = 30μM). I exhibited similar noncompetitive inhibitory kinetics (Ki = 60μM). In vivo I markedly increased the recovery of labeled catechol products from the brain of rats injected peripherally with labeled L-dopa, probably because I inhibited decarboxylation as well as methylation. I increased recovery of catechol products of labeled norepinephrine from the heart for periods up to 3-5 hr. I weakly inhibited monoamine oxidase [9001-66-5] in vitro (IC50 about 1mM) but was inactive in vivo in doses up to 100 mg/kg, i.p. I seems to be similar to pyrogallol in its ability to inhibit transferase in vitro and is able to inhibit the enzyme in vivo. This property may be partly responsible for its beneficial effects in Parkinsonian patients treated with L-dopa.
- 81Lai, F. M.; Spector, S. The Potentiating Effect of Clorgyline and Pyrogallol on the Blood Pressure Responses to Norepinephrine. Arch. Int. Pharmacodyn. Ther. 1978, 234 (2), 279– 286[PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXlsVU%253D&md5=ee5ed5b4b7ea1e7eb40c2ea2eaccbc16The potentiating effect of clorgyline and pyrogallol on the blood pressure responses to norepinephrineLai, F. M.; Spector, S.Archives Internationales de Pharmacodynamie et de Therapie (1978), 234 (2), 279-86CODEN: AIPTAK; ISSN:0003-9780.Intraventricular administration of norepinephrine (NE) [51-41-2] into pentobarbital anesthetized rats elicits a pressor or a depressor effect depending on the dose injected; after a low dose, a depressor response is seen while after a high dose, a pressor response is obsd. In the animal pretreated intraventricularly with clorgyline [17780-72-2] or pyrogallol [87-66-1], the hypotensive effect of a low dose NE was reversed to a hypertensive effect, while the hypertensive effect of a high dose of NE was markedly potentiated. Brain monoamine oxidase [9001-66-5] and catechol-o-methyltransferase [9012-25-3] can metabolize centrally released NE before it leaks into the peripheral circulation.
- 82Kita, T.; Wagner, G. C.; Philbert, M. A.; King, L. A.; Lowndes, H. E. Effects of Pargyline and Pyrogallol on the Methamphetamine-Induced Dopamine Depletion. Mol. Chem. Neuropathol. 1995, 24 (1), 31– 41, DOI: 10.1007/BF03160110[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXkvVGntrc%253D&md5=0fa7bc9a2e34efff5641751336694666Effects of pargyline and pyrogallol on the methamphetamine-induced dopamine depletionKita, Taizo; Wagner, George C.; Philbert, Martin A.; King, Linda A.; Lowndes, Herbert E.Molecular and Chemical Neuropathology (1995), 24 (1), 31-41CODEN: MCHNEM; ISSN:1044-7393.The formation of 6-hydroxydopamine (6-OHDA) from dopamine (DA) was investigated in the striatum of male Sprague-Dawley rats following a single administration of methamphetamine hydrochloride (100 mg/kg, s.c.). Rats were sacrificed 30, 60, and 90 min, and 1 wk after injection, and striatal 6-OHDA, DA, and 3,4-dihydroxyphenyl-acetic acid (DOPAC) were measured by HPLC with electrochem. detection. Methamphetamine decreased striatal DA and DOPAC levels (to 65 and 50% at 90 min, resp.) in the time-course study and also resulted in a long-lasting dopamine depletion (34%) 1 wk after its administration. However, endogenous 6-OHDA formation proved difficult to detect after administration of the methamphetamine alone. Pretreatment with the monoamine oxidase (MAO) inhibitor pargyline (100 mg/kg, i.p.) and the catechol-O-methyltransferase (COMT) inhibitor pyrogallol (25 mg/kg, i.p.) resulted in the HPLC detection of a 6-OHDA-like substance 30 min after methamphetamine administration when the oxidizing potential was set at 0.5 V, but not when it was set at 0.2 V. Moreover, pargyline (25 mg/kg, i.p.) alone or in combination with pyrogallol exacerbated the long-lasting dopamine depletion induced by methamphetamine (50 mg/kg, s.c.). These results indicate that simultaneous inhibition of MAO and COMT provides a cellular environment that encourages the autoxidn. of dopamine to a 6-OHDA-like substance.
- 83Agrawal, R.; Sharma, P. K.; Rao, G. S. Release of Iron from Ferritin by Metabolites of Benzene and Superoxide Radical Generating Agents. Toxicology 2001, 168 (3), 223– 230, DOI: 10.1016/S0300-483X(01)00412-7[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvFGru78%253D&md5=2628da58889ecfe1dfb82b61d66589b9Release of iron from ferritin by metabolites of benzene and superoxide radical generating agentsAgrawal, Rashmi; Sharma, Pankaj K.; Rao, Gondi S.Toxicology (2001), 168 (3), 223-230CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Science Ltd.)The release of iron from ferritin in the presence of benzene metabolites, viz. phenol (P), catechol (CT), hydroquinone (HQ) and superoxide radical generating compds., viz. pyrogallol (PL), phloroglucinol (PG), phenylhydrazine (PH) or phenylenediamine (PD) was studied in acetate buffer, pH 5.6. Monitoring the formation of the iron-ferrozine complex quantitated the release of iron from ferritin. The presence of P (125 μM) did not result in the release of iron from ferritin, whereas the same concn. of CT, HQ, PL, PH or PD resulted in the release of significant amts. of iron from ferritin and a marginal amt. of iron in the presence of PG, CT, HQ, PL, PH or PD concn. and time-dependent increase in iron release from ferritin were obsd. although the increase was not linear as a function of time and concn. of the compds. studied. The presence of superoxide dismutase inhibited significantly the release of iron from ferritin by CT, HQ, PL, PH or PD. The iron released from ferritin by CT, HQ, PL, PH or PD enhanced lipid peroxidn. in rat brain homogenate and released aldehydic products from bleomycin-dependent degrdn. of DNA and also caused single strand nicks to pUC18 DNA. These studies indicate that CT and HQ, the two principal polyphenolic metabolites of benzene and PL, PH or PD, the superoxide radical generating compds. were capable of reducing ferric iron from ferritin and also mobilizing and releasing iron from ferritin core. The release of iron from ferritin by these compds. is a result of direct redn. of ferritin iron by electron transfer and also redn. via superoxide radical. The release of iron from ferritin by CT and HQ may have toxicol. implications in relation to benzene toxicity. The release of iron by superoxide radical generating agents suggests that oxidative stress may play a role as this could lead to disruption of intracellular iron homeostasis.
- 84Yamada, J.; Yoshimura, S.; Yamakawa, H.; Sawada, M.; Nakagawa, M.; Hara, S.; Kaku, Y.; Iwama, T.; Naganawa, T.; Banno, Y. Cell Permeable ROS Scavengers, Tiron and Tempol, Rescue PC12 Cell Death Caused by Pyrogallol or Hypoxia/Reoxygenation. Neurosci. Res. 2003, 45 (1), 1– 8, DOI: 10.1016/S0168-0102(02)00196-7[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpvVaisbw%253D&md5=cf5e095c8016434f53263e69ade58d5fCell permeable ROS scavengers, Tiron and Tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenationYamada, Jun; Yoshimura, Shinichi; Yamakawa, Haruki; Sawada, Motoshi; Nakagawa, Masanori; Hara, Shigeru; Kaku, Yasuhiko; Iwama, Toru; Naganawa, Takashi; Banno, Yoshiko; Nakashima, Shigeru; Sakai, NoboruNeuroscience Research (Oxford, United Kingdom) (2003), 45 (1), 1-8CODEN: NERADN; ISSN:0168-0102. (Elsevier Science Ltd.)The role of superoxide anion (O2•-) in neuronal cell injury induced by reactive oxygen species (ROS) was examd. in PC12 cells using pyrogallol (1,2,3-benzenetrior), a donor to release O2•-. Pyrogallol induced PC12 cell death at concns., which evidently increased intracellular O2•-, as assessed by O2•--sensitive fluorescent precursor hydroethidine (HEt). Caspase inhibitors, Z-VAD-FMK and Z-Asp-CH2-DCB, failed to protect cells from injury caused by elevation of intracellular O2•-, although these inhibitors had effects on hypoxia- or hydrogen peroxide (H2O2)-induced PC12 cell death. Two known O2•- scavengers, Tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid) and Tempol (4-hydroxy-2,2,6,6-tetramethylpiperydine-1-oxyl) rescued PC12 cells from pyrogallol-induced cell death. Hypoxia/reoxygenation injury of PC12 cells was also blocked by Tiron and Tempol. Further understanding of the underlying mechanism of the protective effects of these radical scavengers reducing intracellular O2•- on neuronal cell death may lead to development of new therapeutic treatments for hypoxic/ischemic brain injury.
- 85Liao, P.-C.; Kuo, Y.-M.; Chang, Y.-C.; Lin, C.; Cherng, C.-F. G.; Yu, L. Striatal Formation of 6-Hydroxydopamine in Mice Treated with Pargyline, Pyrogallol and Methamphetamine. J. Neural Transm. 2003, 110 (5), 487– 494, DOI: 10.1007/s00702-002-0829-x[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjt1Omurg%253D&md5=5b31e1a45e7bfc4711ece4233433434cStriatal formation of 6-hydroxydopamine in mice treated with pargyline, pyrogallol and methamphetamineLiao, P.-C.; Kuo, Y.-M.; Chang, Y.-C.; Lin, C.; Cherng, C.-F. G.; Yu, L.Journal of Neural Transmission (2003), 110 (5), 487-494CODEN: JNTRF3; ISSN:0300-9564. (Springer-Verlag Wien)Formation of 6-hydroxydopamine (6-OHDA) has been posited in the striatum following methamphetamine treatment and plays a crit. role in methamphetamine-induced nigrostriatal dopaminergic toxicity. We used high performance liq. chromatog. electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) to det. the formation of 6-OHDA by the treatments of methamphetamine combined with pargyline, a monoamine oxidase inhibitor, and pyrogallol, a catechol-O-methyltransferase inhibitor, in female C57BL/6J mouse striatum. A substantial amt. of 6-OHDA (9.9 ± 0.7 pg/mg wet tissue) was detected in mice treated with pargyline (100 mg/kg) and pyrogallol (25 mg/kg) in combination. Greater striatal 6-OHDA levels were obsd. in mice treated with combined pargyline, pyrogallol and methamphetamine (50 mg/kg) as compared to mice treated with combined pargyline and pyrogallol. However, mice treated with pargyline and pyrogallol in combination followed by one and two doses of methamphetamine exhibited comparable striatal 6-OHDA levels (23.2 ± 4.3, 27.3 ± 1.3 pg/mg wet tissue) in our protocol. We conclude that blockade of the primary metabolic pathways of dopamine by inhibiting both monoamine oxidase and catechol-O-methyltransferase activities is sufficient to induce 6-OHDA formation in the striatum. Acute 6-OHDA accumulation in the striatum can be potentiated by methamphetamine, a potent dopamine releaser, administration following such metabolic inhibitions.
- 86Upadhyay, G.; Gupta, S. P.; Prakash, O.; Singh, M. P. Pyrogallol-Mediated Toxicity and Natural Antioxidants: Triumphs and Pitfalls of Preclinical Findings and Their Translational Limitations. Chem.-Biol. Interact. 2010, 183 (3), 333– 340, DOI: 10.1016/j.cbi.2009.11.028[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFagtQ%253D%253D&md5=98fb7012f8ec460cd9e44d641335d7d9Pyrogallol-mediated toxicity and natural antioxidants: Triumphs and pitfalls of preclinical findings and their translational limitationsUpadhyay, Ghanshyam; Gupta, Satya Prakash; Prakash, Om; Singh, Mahendra PratapChemico-Biological Interactions (2010), 183 (3), 333-340CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)A review. Pyrogallol, a potent anti-psoriatic drug, produces toxicity due to its ability to generate free radicals, besides its beneficial effects. Oxidative stress is implicated in pyrogallol-mediated toxicity in general and hepatotoxicity in particular. Naturally occurring antioxidants including, resveratrol and silymarin were proposed as potential supplements to counteract pyrogallol-mediated toxicity, without reducing its efficacy. Due to increase in the popularity of natural antioxidants in combating pyrogallol-mediated toxicity, a literature-based survey was performed to assess their role in exptl. studies and possible implications in real life situations. Although preclin. studies revealed the boons of naturally occurring antioxidants in attenuating/abolishing the undesirable effects of pyrogallol exposure, limited studies were conducted to evaluate their role in clinics. In this review, an update on the recent development in assessing the potential of natural antioxidants in pyrogallol-mediated toxicity in preclin. interventions, triumphs and pitfalls of such investigations, their translational challenges and future possibilities are discussed.
- 87Wang, H.; Wang, H.; Wang, J.; Wang, Q.; Ma, Q.-F.; Chen, Y.-Y. Protocatechuic Acid Inhibits Inflammatory Responses in LPS-Stimulated BV2Microglia via NF-KB and MAPKs Signaling Pathways. Neurochem. Res. 2015, 40 (8), 1655– 1660, DOI: 10.1007/s11064-015-1646-6[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWju73N&md5=4d169ed4309ee3c589a222347396d901Protocatechuic Acid Inhibits Inflammatory Responses in LPS-Stimulated BV2 Microglia via NF-κB and MAPKs Signaling PathwaysWang, Huan-yu; Wang, Hong; Wang, Jin-huan; Wang, Qiong; Ma, Quan-feng; Chen, Yi-yangNeurochemical Research (2015), 40 (8), 1655-1660CODEN: NEREDZ; ISSN:0364-3190. (Springer)Protocatechuic acid (PA), a major metabolite of anthocyanins, has been reported to possess antioxidant and anti-inflammatory activities. However, the effects of PA on LPS-induced inflammatory responses in microglia have not been reported. The aim of this study was to investigate the anti-inflammatory effects and mol. mechanisms of PA on LPS-stimulated BV2 microglia. The prodn. of inflammatory mediators TNF-α, IL-6, IL-1β, and PGE2 were detected by ELISA. TLR4, NF-κB and MAPKs activation were detected by western blotting. Our results demonstrated that PA dose-dependently inhibited LPS-induced TNF-α, IL-6, IL-1β, and PGE2 prodn. In addn., PA suppressed LPS-induced TLR4 expression, NF-κB and MAPKs activation, which resulted in the inhibition of inflammatory mediators. In conclusion, these results suggested that PA exhibited anti-inflammatory effects on LPS-stimulated BV2 microglia and the mechanisms were involved in the inhibition of TLR4-mediated NF-κB and MAPKs signaling pathways.
- 88Ren, Z.; Zhang, R.; Li, Y.; Li, Y.; Yang, Z.; Yang, H. Ferulic Acid Exerts Neuroprotective Effects against Cerebral Ischemia/Reperfusion-Induced Injury via Antioxidant and Anti-Apoptotic Mechanisms in Vitro and in Vivo. Int. J. Mol. Med. 2017, 40 (5), 1444– 1456, DOI: 10.3892/ijmm.2017.3127[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVOru77I&md5=dddc5fbf640e21cdd583d583e1bdecafFerulic acid exerts neuroprotective effects against cerebral ischemia/reperfusion-induced injury via antioxidant and anti-apoptotic mechanisms in vitro and in vivoRen, Zhongkun; Zhang, Rongping; Li, Yuanyuan; Li, Yu; Yang, Zhiyong; Yang, HuiInternational Journal of Molecular Medicine (2017), 40 (5), 1444-1456CODEN: IJMMFG; ISSN:1791-244X. (Spandidos Publications Ltd.)Ferulic acid (FA) is a deriv. of cinnamic acid. It is used in the treatment of heart head blood-vessel disease and exerts protective effects against hypoxia/ischemiainduced cell injury in the brain. This study investigated the potential neuroprotective effects of FA against ischemia/reperfusion (I/R)-induced brain injury in vivo and in vitro through hematoxylin and eosin (H&E) and Nissl staining assays, flow cytometry, Hoechst 33258 staining, quant. PCR, western blot anal. and fluorescence microscopic anal. In this study, models of cerebral I/R injury were established using rats and pheochromocytoma (PC-12) cells. The results revealed that treatment with FA significantly attenuated memory impairment, and reduced hippocampal neuronal apoptosis and oxidative stress in a dose-dependent manner. The results from in vitro expts. also indicated that FA protected the PC-12 cells against I/R-induced reactive oxygen species (ROS) generation and apoptosis by inhibiting apoptosis, Ca2+ influx, superoxide anion (O2-), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) prodn. in a concn.-dependent manner. Moreover, FA inactivated the Toll-like receptor (TLR)/myeloid differentiation factor 88 (MyD88) pathway. MyD88 overexpression abolished the neuroprotective effects of FA. On the whole, we found that FA attenuated memory dysfunction and exerted protective effects against oxidative stress and apoptosis induced by I/R injury by inhibiting the TLR4/MyD88 signaling pathway. This study supports the view that FA may be a promising neuroprotective agent for use in the treatment of cerebral ischemia.
- 89Kim, M.-J.; Seong, A.-R.; Yoo, J.-Y.; Jin, C.-H.; Lee, Y.-H.; Kim, Y. J.; Lee, J.; Jun, W. J.; Yoon, H.-G. Gallic Acid, a Histone Acetyltransferase Inhibitor, Suppresses β-Amyloid Neurotoxicity by Inhibiting Microglial-Mediated Neuroinflammation. Mol. Nutr. Food Res. 2011, 55 (12), 1798– 1808, DOI: 10.1002/mnfr.201100262[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlygtbvJ&md5=9e51b40ec36311b9e0b14caa5cfc4aaeGallic acid, a histone acetyltransferase inhibitor, suppresses β-amyloid neurotoxicity by inhibiting microglial-mediated neuroinflammationKim, Mi-Jeong; Seong, Ah-Reum; Yoo, Jung-Yoon; Jin, Cheng-Hao; Lee, Yoo-Hyun; Kim, Young Jun; Lee, Jeongmin; Jun, Woo Jin; Yoon, Ho-GeunMolecular Nutrition & Food Research (2011), 55 (12), 1798-1808CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)Scope: We examd. the biol. effect of gallic acid (GA) as a nuclear factor (NF)-κB acetyltransferase inhibitor on microglial-mediated β-amyloid neurotoxicity and restorative effects on the Aβ-induced cognitive dysfunction. Methods and results: The protective effects of GA on the survival of neuronal cells were assessed with an MTT assay and a co-culture system. For the co-culture expts., both BV-2 and primary microglia cells were treated with GA prior to Aβ stimulation, and conditioned media were transferred to Neuro-2A cells. The mRNA and protein levels of inflammatory cytokines in both microglia and Neuro-2A cells were assessed with real-time polymerase chain reaction and western blotting. Inhibition of nuclear factor kappa B (NF-κB) acetylation with GA treatment resulted in reduced cytokine prodn. in microglia cells and protection of neuronal cells from Aβ-induced neurotoxicity. Furthermore, we obsd. a restorative effect of GA on Aβ-induced cognitive dysfunction in mice with Y-maze and passive avoidance tests. Finally, we found that GA treatment efficiently blocked neuronal cell death by downregulating the expression of cytokines and the in vivo levels of NF-κB acetylation. Conclusion: These results suggest that selective inhibition of NF-κB acetylation by the histone acetyltransferase inhibitor GA is a possible therapeutic approach for alleviating the inflammatory progression of Alzheimer disease.
- 90da Silva, A.; Giacomoni, F.; Pavot, B.; Fillâtre, Y.; Rothwell, J. A.; Sualdea, B. B.; Veyrat, C.; Garcia-Villalba, R.; Gladine, C.; Kopec, R.; PhytoHub V1. 4: A New Release for the Online Database Dedicated to Food Phytochemicals and Their Human Metabolites. In Proceedings of the 1st International Conference on Food Bioactivities & Health, Norwich, U.K., 2016; pp 13– 15.Google ScholarThere is no corresponding record for this reference.
- 91Kim, B.-W.; Koppula, S.; Park, S.-Y.; Kim, Y.-S.; Park, P.-J.; Lim, J.-H.; Kim, I.-S.; Choi, D.-K. Attenuation of Neuroinflammatory Responses and Behavioral Deficits by Ligusticum Officinale (Makino) Kitag in Stimulated Microglia and MPTP-Induced Mouse Model of Parkinson’s Disease. J. Ethnopharmacol. 2015, 164, 388– 397, DOI: 10.1016/j.jep.2014.11.004[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mzis1Wnug%253D%253D&md5=502b59303505f16fd53aff3a7ffe91c0Attenuation of neuroinflammatory responses and behavioral deficits by Ligusticum officinale (Makino) Kitag in stimulated microglia and MPTP-induced mouse model of Parkinson's diseaseKim Byung-Wook; Koppula Sushruta; Park Shin-Young; Kim Yon-Suk; Park Pyo-Jam; Kim In-Su; Lim Ji-Hong; Choi Dong-KugJournal of ethnopharmacology (2015), 164 (), 388-97 ISSN:.ETHNOPHARMACOLOGICAL RELEVANCE: Ligusticum officinale (Makino) Kitag (L. officinale) is one of the important traditional herbs used in traditional Oriental medicine for the treatment of various disorders including pain and inflammation. However, there is limited scientific basis for its activity and mechanism in brain inflammation. AIM OF THE STUDY: This study aimed to evaluate the effects of L. officinale on microglia-mediated neuroinflammation and behavioral impairments using in vitro cellular and in vivo mouse model of PD, as well as investigate the molecular mechanisms involved including the finger printing analysis of its ethanol extract. MATERIALS AND METHODS: Lipopolysaccharide (LPS) was used to stimulate BV-2 microglial cells. The changes in neuroinflammatory expressional levels were measured by Western blotting and immunofluorescence techniques. 1-methyl-4 phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mice model of PD was developed to evaluate the behavioral impairments and the brain tissues were used for immunohistochemical studies. High performance liquid chromatography (HPLC) technique was performed for finger printing analysis of L. officinale extract used in the study. RESULTS: L. officinale significantly attenuated the LPS-stimulated increase in inflammatory mediators in BV-2 cells. L. officinale also inhibited the LPS-induced activation of nuclear factor-kappa beta by blocking the degradation of IκB-α and suppressing the increase in p38-mitogen-activated protein kinase phosphorylation in BV-2 cells. Furthermore, L. officinale exhibited significant antioxidant properties by inhibiting the 1-diphenyl-2-picrylhydrazyl radicals. An in vivo evaluation in MPTP (20mg/kg, four times, 1 day, i.p.) intoxicated mice resulted in brain microglial activation and significant behavioral deficits. Prophylactic treatment with L. officinale prevented microglial activation and attenuated PD-like behavioral changes as assessed by the pole test. HPLC finger printing analysis revealed that L. officinale extract contained ferulic acid (FA) as one of the major constituents compared with reference standard. FA also inhibited the LPS-stimulated excessive release of NO and suppressed the increased the expressional levels of proinflammatory mediators in BV-2 microglia. CONCLUSIONS: The findings observed in this study indicated that L. officinale extract significantly attenuated the neuroinflammatory processes in stimulated microglia and restored the behavioral impairments in a mouse model of PD providing a scientific basis for its traditional claims.
- 92Rehman, S. U.; Ali, T.; Alam, S. I.; Ullah, R.; Zeb, A.; Lee, K. W.; Rutten, B. P. F.; Kim, M. O. Ferulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse Hippocampus. Mol. Neurobiol. 2019, 56 (4), 2774– 2790, DOI: 10.1007/s12035-018-1280-9[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVShtb%252FP&md5=ea05349dd282ad10ab4822738671cefeFerulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse HippocampusRehman, Shafiq Ur; Ali, Tahir; Alam, Sayed Ibrar; Ullah, Rahat; Zeb, Amir; Lee, Keun Woo; Rutten, Bart P. F.; Kim, Myeong OkMolecular Neurobiology (2019), 56 (4), 2774-2790CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Microglia play a crucial role in the inflammatory brain response to infection. However, overactivation of microglia is neurotoxic. Toll-like receptor 4 (TLR4) is involved in microglial activation via lipopolysaccharide (LPS), which triggers a variety of cytotoxic pro-inflammatory markers that produce deleterious effects on neuronal cells. Ferulic acid (FA) is a phenolic compd. that exerts antioxidant and anti-inflammatory effects in neurodegenerative disease. However, the manner in which FA inhibits neuroinflammation-induced neurodegeneration is poorly understood. Therefore, we investigated the anti-inflammatory effects of FA against LPS-induced neuroinflammation in the mouse brain. First, we provide evidence that FA interferes with TLR4 interaction sites, which are required for the activation of microglia-induced neuroinflammation, and further examd. the potential mechanism of its neuroprotective effects in the mouse hippocampus using mol. docking simulation and immunoblot anal. Our results indicated that FA treatment inhibited glial cell activation, p-JNK, p-NFKB, and downstream signaling mols., such as iNOS, COX-2, TNF-α, and IL-1β, in the mouse hippocampus and BV2 microglial cells. FA treatment strongly inhibited mitochondrial apoptotic signaling mols., such as Bax, cytochrome C, caspase-3, and PARP-1, and reversed deregulated synaptic proteins, including PSD-95, synaptophysin, SNAP-25, and SNAP-23, and synaptic dysfunction in LPS-treated mice. These findings demonstrated that FA treatment interfered with the TLR4/MD2 complex binding site, which is crucial for evoking neuroinflammation via microglia activation and inhibited NFKB likely via a JNK-dependent mechanism, which suggests a therapeutic implication for neuroinflammation-induced neurodegeneration.
- 93Koshiguchi, M.; Komazaki, H.; Hirai, S.; Egashira, Y. Ferulic Acid Suppresses Expression of Tryptophan Metabolic Key Enzyme Indoleamine 2, 3-Dioxygenase via NFκB and P38 MAPK in Lipopolysaccharide-Stimulated Microglial Cells. Biosci., Biotechnol., Biochem. 2017, 81 (5), 966– 971, DOI: 10.1080/09168451.2016.1274636[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpslKhuw%253D%253D&md5=9e3544267ac670d37238d34c4ec20318Ferulic acid suppresses expression of tryptophan metabolic key enzyme indoleamine 2, 3-dioxygenase via NFκB and p38 MAPK in lipopolysaccharide-stimulated microglial cellsKoshiguchi, Manami; Komazaki, Hitoshi; Hirai, Shizuka; Egashira, YukariBioscience, Biotechnology, and Biochemistry (2017), 81 (5), 966-971CODEN: BBBIEJ; ISSN:1347-6947. (Taylor & Francis Ltd.)Ferulic acid (FA) is a phenol compd. found in plants that has anti-inflammatory properties. Indoleamine 2, 3-dioxygenase (IDO) is a tryptophan catabolic enzyme induced in immune cells, including glial cells, during inflammation. Enhanced IDO expression leads to reduced tryptophan levels and increased levels of toxic metabolites, including quinolinic acid. Therefore, inhibition of IDO expression may be effective in suppressing progression of neurodegenerative diseases. In this study, we examd. the effect of FA in microglial cells on IDO expression levels and related inflammatory signal mols. FA suppressed LPS-induced IDO mRNA expression and also suppressed nuclear translocation of NF-κB and phosphorylation of p38 MAPK. However, FA did not affect the prodn. of LPS-induced inflammatory mediators and phosphorylation of JNK. Our results indicate that FA suppresses LPS-induced IDO mRNA expression, which may be mediated by inhibition of the NF-κB and p38 MAPK pathways in microglial cells.
- 94Chakrabarti, S.; Jana, M.; Roy, A.; Pahan, K. Upregulation of Suppressor of Cytokine Signaling 3 in Microglia by Cinnamic Acid. Curr. Alzheimer Res. 2018, 15 (10), 894– 904, DOI: 10.2174/1567205015666180507104755[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1OmtrbI&md5=fd81ce41e95d64302459736b616e282bUpregulation of Suppressor of Cytokine Signaling 3 in Microglia by Cinnamic AcidChakrabarti, Sudipta; Jana, Malabendu; Roy, Avik; Pahan, KalipadaCurrent Alzheimer Research (2018), 15 (10), 894-904CODEN: CARUBY; ISSN:1567-2050. (Bentham Science Publishers Ltd.)Neuroinflammation plays an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer's disease (AD). Suppressor of cytokine signaling 3 (SOCS3) is an anti-inflammatory mol. that suppresses cytokine signaling and inflammatory gene expression in different cells including microglia. The pathways through which SOCS3 could be upregulated are poorly described. Cinnamic acid is a metabolite of cinnamon, a natural compd. that is being widely used all over the world as a spice or flavoring agent. Here, we examd. if cinnamic acid could upregulate SOCS3 in microglia. Microglia and astroglia isolated from mouse brain as well as BV-2 microglial cells were treated with cinnamic acid followed by monitoring the level of SOCS3 and different proinflammatory mols. by RT-PCR and real-time PCR. To nail down the mechanism, we also performed ChIP anal. to monitore the recruitment of cAMP response element binding (CREB) to the socs3 gene promoter and carried out siRNA knockdown of CREB. Cinnamic acid upregulated the expression of SOCS3 mRNA and protein in mouse BV-2 microglial cells in dose- and time-dependent manner. Accordingly, cinnamic acid also increased the level of SOCS3 and suppressed the expression of inducible nitric oxide synthase and proinflammatory cytokines (TNFα, IL-1 β and IL-6) in LPSstimulated BV-2 microglial cells. Similar to BV-2 microglial cells, cinnamic acid also increased the expression of SOCS3 in primary mouse microglia and astrocytes. We have seen that cAMP response element is present in the promoter of socs3 gene, that cinnamic acid induces the activation of CREB, that siRNA knockdown of CREB abrogates cinnamic acid-mediated upregulation of SOCS3, and that cinnamic acid treatment leads to the recruitment of CREB to the socs3 gene. These studies suggest that cinnamic acid upregulates the expression of SOCS3 in glial cells via CREB pathway, which may be of importance in neuroinflammatory and neurodegenerative disorders.
- 95Stalmach, A.; Mullen, W.; Barron, D.; Uchida, K.; Yokota, T.; Cavin, C.; Steiling, H.; Williamson, G.; Crozier, A. Metabolite Profiling of Hydroxycinnamate Derivatives in Plasma and Urine after the Ingestion of Coffee by Humans: Identification of Biomarkers of Coffee Consumption. Drug Metab. Dispos. 2009, 37 (8), 1749– 1758, DOI: 10.1124/dmd.109.028019[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXps1ygtLg%253D&md5=c5ec0019752498c656d752d23dc92afaMetabolite profiling of hydroxycinnamate derivatives in plasma and urine after the ingestion of coffee by humans: identification of biomarkers of coffee consumptionStalmach, Angelique; Mullen, William; Barron, Denis; Uchida, Kenichi; Yokota, Takao; Cavin, Christophe; Steiling, Heike; Williamson, Gary; Crozier, AlanDrug Metabolism and Disposition (2009), 37 (8), 1749-1758CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)Human subjects drank coffee contg. 412 μmol of chlorogenic acids, and plasma and urine were collected 0 to 24 h after ingestion and were analyzed by HPLC -mass spectrometry. Within 1 h, some of the components in the coffee reached nanomole peak plasma concns. (Cmax), whereas chlorogenic acid metabolites, including caffeic acid-3-O-sulfate and ferulic acid-4-O-sulfate and sulfates of 3- and 4-caffeoylquinic acid lactones, had higher Cmax values. The shor time to reach Cmax (Tmax) indicates absorption of these compds. in the small intestine. In contrast, dihydroferulic acid, its 4-O-sulfate, and dihydrocaffeic acid-3-O-sulfate exhibited much higher Cmax values (145-385 nM) with Tmax values in excess of 4 h, indicating absorption in the large intestine and the probable involvement of catabolism by colonic bacteria. These 3 compds., along with ferulic acid-4-O-sulfate and dihydroferulic acid-4-O-glucuronide, were also major components to be excreted in urine (8.4-37.1 μmol) after coffee intake. Feruloylglycine, which is not detected in plasma, was also a major urinary component (20.7 μmol excreted). Other compds., not accumulating in plasma but excreted in smaller quantities, included the 3-O-sulfate and 3-O-glucuronide of isoferulic acid, dihydro(iso)ferulic acid-3-O-glucuronide, and dihydrocaffeic acid-3-O-glucuronide. Overall, the 119.9 μmol excretion of the chlorogenic acid metabolites corresponded to 29.1% of intake, indicating that as well as being subject to extensive metab., chlorogenic acids in coffee are well absorbed. Pathways for the formation of the various metabolites within the body are proposed. Urinary dihydrocaffeic acid-3-O-sulfate and feruloylglycine are potentially very sensitive biomarkers for the consumption of relatively small amts. of coffee.
- 96van Dorsten, F. A.; Grün, C. H.; van Velzen, E. J. J.; Jacobs, D. M.; Draijer, R.; van Duynhoven, J. P. M. The Metabolic Fate of Red Wine and Grape Juice Polyphenols in Humans Assessed by Metabolomics. Mol. Nutr. Food Res. 2010, 54 (7), 897– 908, DOI: 10.1002/mnfr.200900212[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXosF2isr0%253D&md5=cea03e5632fb32db042214119a3b2dc2The metabolic fate of red wine and grape juice polyphenols in humans assessed by metabolomicsvan Dorsten, Ferdinand A.; Gruen, Christian H.; van Velzen, Ewoud J. J.; Jacobs, Doris M.; Draijer, Richard; van Duynhoven, John P. M.Molecular Nutrition & Food Research (2010), 54 (7), 897-908CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)The metabolic impact of polyphenol-rich red wine and grape juice consumption in humans was studied using a metabolomics approach. Fifty-eight men and women participated in a placebo-controlled, double-crossover study in which they consumed during a period of 4 wk, either a polyphenol-rich 2:1 dry mix of red wine and red grape juice exts. (MIX) or only a grape juice ext. (GJX). Twenty-four-hour urine samples were collected after each intervention. 1H NMR spectroscopy was applied for global metabolite profiling, while GC-MS was used for focused profiling of urinary phenolic acids. Urine metabolic profiles after intake of both polyphenol-rich exts. were significantly differentiated from placebo using multilevel partial least squares discriminant anal. (ML-PLS-DA). A significant 35% increase in hippuric acid excretion (p<0.001) in urine was measured after the MIX consumption compared with placebo, whereas no change was found after GJX consumption. GC-MS-based metabolomics of urine allowed identification of 18 different phenolic acids, which were significantly elevated following intake of either ext. Syringic acid, 3- and 4-hydroxyhippuric acid and 4-hydroxymandelic acid were the strongest urinary markers for both exts. MIX and GJX consumption had a slightly different effect on the excreted phenolic acid profile and on endogenous metabolite excretion, possibly reflecting their different polyphenol compn.
- 97Esteban-Fernández, A.; Rendeiro, C.; Spencer, J. P. E.; del Coso, D. G.; de Llano, M. D. G.; Bartolomé, B.; Moreno-Arribas, M. V. Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of Action. Front. Nutr. 2017, 4, 3, DOI: 10.3389/fnut.2017.00003[Crossref], [PubMed], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cvitFGhtQ%253D%253D&md5=eb1678b2c3971b714d30e03a944717a6Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of ActionEsteban-Fernandez A; Rendeiro C; Spencer J P E; Del Coso D Gigorro; de Llano M D Gonzalez; Bartolome B; Moreno-Arribas M VFrontiers in nutrition (2017), 4 (), 3 ISSN:2296-861X.Moderate wine consumption has shown the potential to delay the onset of neurodegenerative diseases. This study investigates the molecular mechanisms underlying the protective effects of wine-derived phenolic and aroma compounds in a neuroinflammation model based on SIN-1 stress-induced injury in SH-SY5Y neuroblastoma cells. Cell pretreatment with microbial metabolites found in blood after wine consumption, 3,4-dihydroxyphenylacetic (3,4-DHPA), 3-hydroxyphenylacetic acids and salicylic β-d-O-glucuronide, at physiologically concentrations (0.1-10 μM) resulted in increased cell viability versus SIN-1 control group (p < 0.05). Results also showed significant decreases in mitogen-activated protein kinase (MAPK) p38 and ERK1/2 activation as well as in downstream pro-apoptotic caspase-3 activity by some of the studied compounds. Moreover, pretreatment with p38, MEK, and ERK1/2-specific inhibitors, which have a phenolic-like structure, also resulted in an increase on cell survival and a reduction on caspase-3 activity levels. Overall, these results contribute with new evidences related to the neuroprotective actions of wine, pointing out that wine-derived human metabolites and aroma compounds may be effective at protecting neuroblastoma cells from nitrosative stress injury by inhibiting neuronal MAPK p38 and ERK1/2, as well as downstream caspase 3 activity.
- 98Wang, Y.-D.; Bao, X.-Q.; Xu, S.; Yu, W.-W.; Cao, S.-N.; Hu, J.-P.; Li, Y.; Wang, X.-L.; Zhang, D.; Yu, S.-S. A Novel Parkinson’s Disease Drug Candidate with Potent Anti-Neuroinflammatory Effects through the Src Signaling Pathway. J. Med. Chem. 2016, 59 (19), 9062– 9079, DOI: 10.1021/acs.jmedchem.6b00976[ACS Full Text], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyqtb7O&md5=8ceb592d04332b3dbde41a29c9304019A Novel Parkinson's Disease Drug Candidate with Potent Anti-neuroinflammatory Effects through the Src Signaling PathwayWang, Ya-Dan; Bao, Xiu-Qi; Xu, Song; Yu, Wen-Wen; Cao, Sheng-Nan; Hu, Jin-Ping; Li, Yan; Wang, Xiao-Liang; Zhang, Dan; Yu, Shi-ShanJournal of Medicinal Chemistry (2016), 59 (19), 9062-9079CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Numerous drug treatments are available for Parkinson's disease (PD), an age-related neurodegenerative disease, but most cause serious side effects. Therefore, novel therapeutic strategies that halt disease progression and allow for long-term administration are urgently needed. Neuroinflammation critically contributes to the pathogenesis of PD. Here, we report the discovery and optimization of phloroglucinol derivs., a novel class of anti-neuroinflammatory compds. Structural modifications of the hit compd. 3-methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one produced 43 derivs., including a preclin. candidate (compd. 21), that exhibited potent in vitro anti-neuroinflammatory effects, good blood-brain barrier penetration, and desirable safety margins in mice at a median LD (LD50) >5000 mg/kg. Its in vivo efficacy was demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and MPTP/probenecid (prob)-induced subacute and chronic PD models, resp., and α-synuclein transgenic mice. Mechanistic studies revealed neuroinflammation inhibition by targeting Src/phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/Akt signaling might be promising. We highlighted the potential usefulness of phloroglucinol derivs. in PD treatment.
- 99Figueira, I.; Tavares, L.; Jardim, C.; Costa, I.; Terrasso, A. P.; Almeida, A. F.; Govers, C.; Mes, J. J.; Gardner, R.; Becker, J. D. Blood–brain Barrier Transport and Neuroprotective Potential of Blackberry-Digested Polyphenols: An in Vitro Study. Eur. J. Nutr. 2019, 58 (1), 113– 130, DOI: 10.1007/s00394-017-1576-y[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVaru77F&md5=99a87eee4f37a5fba81fdcc8c68ad468Blood-brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro studyFigueira, Ines; Tavares, Lucelia; Jardim, Carolina; Costa, Ines; Terrasso, Ana P.; Almeida, Andreia F.; Govers, Coen; Mes, Jurriaan J.; Gardner, Rui; Becker, Jorg D.; McDougall, Gordon J.; Stewart, Derek; Filipe, Augusto; Kim, Kwang S.; Brites, Dora; Brito, Catarina; Brito, M. Alexandra; Santos, Claudia N.European Journal of Nutrition (2019), 58 (1), 113-130CODEN: EJNUFZ; ISSN:1436-6207. (Springer)Purpose: Epidemiol. and intervention studies have attempted to link the health effects of a diet rich in fruits and vegetables with the consumption of polyphenols and their impact in neurodegenerative diseases. Studies have shown that polyphenols can cross the intestinal barrier and reach concns. in the bloodstream able to exert effects in vivo. However, the effective uptake of polyphenols into the brain is still regarded with some reservations. Here we describe a combination of approaches to examine the putative transport of blackberry-digested polyphenols (BDP) across the blood-brain barrier (BBB) and ultimate evaluation of their neuroprotective effects. Methods: BDP was obtained by in vitro digestion of blackberry ext. and BDP major aglycons (hBDP) were obtained by enzymic hydrolysis. Chem. characterization and BBB transport of exts. were evaluated by LC-MSn. BBB transport and cytoprotection of both exts. was assessed in HBMEC monolayers. Neuroprotective potential of BDP was assessed in NT2-derived 3D co-cultures of neurons and astrocytes and in primary mouse cerebellar granule cells. BDP-modulated genes were evaluated by microarray anal. Results: Components from BDP and hBDP were shown to be transported across the BBB. Physiol. relevant concns. of both exts. were cytoprotective at endothelial level and BDP was neuroprotective in primary neurons and in an advanced 3D cell model. The major canonical pathways involved in the neuroprotective effect of BDP were unveiled, including mTOR signaling and the unfolded protein response pathway. Genes such as ASNS and ATF5 emerged as novel BDP-modulated targets. Conclusions: BBB transport of BDP and hBDP components reinforces the health benefits of a diet rich in polyphenols in neurodegenerative disorders. Our results suggest some novel pathways and genes that may be involved in the neuroprotective mechanism of the BDP polyphenol components.
- 100Loke, W. M.; Jenner, A. M.; Proudfoot, J. M.; McKinley, A. J.; Hodgson, J. M.; Halliwell, B.; Croft, K. D. A Metabolite Profiling Approach to Identify Biomarkers of Flavonoid Intake in Humans. J. Nutr. 2009, 139 (12), 2309– 2314, DOI: 10.3945/jn.109.113613[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFeis7o%253D&md5=a240236b587ca2fee84c41988b278b28A metabolite profiling approach to identify biomarkers of flavonoid intake in humansLoke, Wai Mun; Jenner, Andrew M.; Proudfoot, Julie M.; McKinley, Allan J.; Hodgson, Jonathan M.; Halliwell, Barry; Croft, Kevin D.Journal of Nutrition (2009), 139 (12), 2309-2314CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutrition)Flavonoids are phytochems. that are widespread in the human diet. Despite limitations in their bioavailability, exptl. and epidemiol. data suggest health benefits of flavonoid consumption. Valid biomarkers of flavonoid intake may be useful for estg. exposure in a range of settings. However, to date, few useful flavonoid biomarkers have been identified. In this study, we used a metabolite profiling approach to examine the arom. and phenolic profile of plasma and urine of healthy men after oral consumption of 200 mg of the pure flavonoids, quercetin, (-)-epicatechin, and epigallocatechin gallate, which represent major flavonoid constituents in the diet. Following enzymic hydrolysis, 71 arom. compds. were quantified in plasma and urine at 2 and 5 h, resp., after flavonoid ingestion. Plasma concns. of different arom. compds. ranged widely, from 0.01 to 10 μmol/L, with variation among volunteers. None of the arom. compds. was significantly elevated in plasma 2 h after consumption of either flavonoid compared with water placebo. This indicates that flavonoid-derived arom. compds. are not responsible for the acute physiol. effects reported within 2 h in previous human intervention studies involving flavonoids or flavonoid-rich food consumption. These effects are more likely due to absorption of the intact flavonoid. Our urine anal. suggested that urinary 4-ethylphenol, benzoic acid, and 4-ethylbenzoic acid may be potential biomarkers of quercetin intake and 1,3,5-trimethoxybenzene, 4-O-methylgallic acid, 3-O-methylgallic acid, and gallic acid may be potential markers of epigallocatechin gallate intake. Potential biomarkers of (-)-epicatechin were not identified. These urinary biomarkers may provide an accurate indication of flavonoid exposure.
- 101Cialdella-Kam, L.; Nieman, D. C.; Sha, W.; Meaney, M. P.; Knab, A. M.; Shanely, R. A. Dose–response to 3 Months of Quercetin-Containing Supplements on Metabolite and Quercetin Conjugate Profile in Adults. Br. J. Nutr. 2013, 109 (11), 1923– 1933, DOI: 10.1017/S0007114512003972[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvVGht78%253D&md5=6c2ec6c19830b91d1d957f06cf8f0ba8Dose-response to 3 months of quercetin-containing supplements on metabolite and quercetin conjugate profile in adultsCialdella-Kam, Lynn; Nieman, David C.; Sha, Wei; Meaney, Mary Pat; Knab, Amy M.; Shanely, R. AndrewBritish Journal of Nutrition (2013), 109 (11), 1923-1933CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)Quercetin, a flavonol in fruits and vegetables, has been demonstrated to have antioxidant, anti-inflammatory and immunomodulating influences. The purpose of the present study was to det. if quercetin, vitamin C and niacin supplements (Q-500 = 500 mg/d of quercetin, 125 mg/d of vitamin C and 5 mg/d of niacin; Q-1000 = 1000 mg/d of quercetin, 250 mg/d of vitamin C and 10 mg/d of niacin) would alter small-mol. metabolite profiles and serum quercetin conjugate levels in adults. Healthy adults (fifty-eight women and forty-two men; aged 40-83 years) were assigned using a randomised double-blinded placebo-controlled trial to one of three supplement groups (Q-1000, Q-500 or placebo). Overnight fasted blood samples were collected at 0, 1 and 3 mo. Quercetin conjugate concns. were measured using ultra-performance liq. chromatog. (UPLC)-MS/MS, and metabolite profiles were measured using two MS platforms (UPLC-quadrupole time-of-flight MS (TOFMS) and GC-TOFMS). Statistical procedures included partial least square discriminant anal. (PLS-DA) and linear mixed model anal. with repeated measures. After accounting for age, sex and BMI, quercetin supplementation was assocd. with significant shifts in 163 metabolites/quercetin conjugates (false discovery rate, P< 0·05). The top five metabolite shifts were an increase in serum guaiacol, 2-oxo-4-methylthiobutanoic acid, allocystathionine and two bile acids. Inflammatory and oxidative stress metabolites were not affected. PLS-DA revealed a clear sepn. only between the 1000 mg/d and placebo groups (Q 2 Y= 0·763). The quercetin conjugate, isorhamnetin-3-glucuronide, had the highest concn. at 3 mo followed by quercetin-3-glucuronide, quercetin-3-sulfate and quercetin diglucuronide. In human subjects, long-term quercetin supplementation exerts disparate and wide-ranging metabolic effects and changes in quercetin conjugate concns. Metabolic shifts were apparent at the 1000 mg/d dose; further research is required to understand the health implications of these shifts.
- 102van der Hooft, J. J. J.; de Vos, R. C. H.; Mihaleva, V.; Bino, R. J.; Ridder, L.; de Roo, N.; Jacobs, D. M.; van Duynhoven, J. P. M.; Vervoort, J. Structural Elucidation and Quantification of Phenolic Conjugates Present in Human Urine after Tea Intake. Anal. Chem. 2012, 84 (16), 7263– 7271, DOI: 10.1021/ac3017339[ACS Full Text], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOjsr3E&md5=bbb9f23847403e210e88212d60aa1e0aStructural Elucidation and Quantification of Phenolic Conjugates Present in Human Urine after Tea Intakevan der Hooft, Justin J. J.; de Vos, Ric C. H.; Mihaleva, Velitchka; Bino, Raoul J.; Ridder, Lars; de Roo, Niels; Jacobs, Doris M.; van Duynhoven, John P. M.; Vervoort, JacquesAnalytical Chemistry (Washington, DC, United States) (2012), 84 (16), 7263-7271CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)In dietary polyphenol exposure studies, annotation and identification of urinary metabolites present at low (micromolar) concns. are major obstacles. To det. the biol. activity of specific components, it is necessary to have the correct structures and the quantification of the polyphenol-derived conjugates present in the human body. We present a procedure for identification and quantification of metabolites and conjugates excreted in human urine after single bolus intake of black or green tea. A combination of a solid-phase extn. (SPE) prepn. step and two high pressure liq. chromatog. (HPLC)-based anal. platforms was used, namely, accurate mass fragmentation (HPLC-FTMSn) and mass-guided SPE-trapping of selected compds. for NMR spectroscopy (NMR) measurements (HPLC-TOFMS-SPE-NMR). HPLC-FTMSn anal. led to the annotation of 138 urinary metabolites, including 48 valerolactone and valeric acid conjugates. By combining the results from MSn fragmentation with the one-dimensional (1D)-1H NMR spectra of HPLC-TOFMS-SPE-trapped compds., we elucidated the structures of 36 phenolic conjugates, including the glucuronides of 3',4'-di- and 3',4',5'-trihydroxyphenyl-γ-valerolactone, three urolithin glucuronides, and indole-3-acetic acid glucuronide. We also obtained 26 h-quant. excretion profiles for specific valerolactone conjugates. The combination of the HPLC-FTMSn and HPLC-TOFMS-SPE-NMR platforms results in the efficient identification and quantification of less abundant phenolic conjugates down to nanomoles of trapped amts. of metabolite corresponding to micromolar metabolite concns. in urine.
- 103Welsch, F. Routes and Modes of Administration of Resorcinol and Their Relationship to Potential Manifestations of Thyroid Gland Toxicity in Animals and Man. Int. J. Toxicol. 2008, 27 (1), 59– 63, DOI: 10.1080/10915810701876687[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXit1Cms7s%253D&md5=56eaf6baf6eadea7368210c70c37ceecRoutes and modes of administration of resorcinol and their relationship to potential manifestations of thyroid gland toxicity in animals and manWelsch, FrankInternational Journal of Toxicology (2008), 27 (1), 59-63CODEN: IJTOFN; ISSN:1091-5818. (Informa Healthcare)A review. Medical case reports published in the 20th century over the course of several decades show that resorcinol caused reversible adverse effects on the human thyroid gland (TG) manifested as hypothyroidism. Affected patients had ulcerating leg varicosities and underwent prolonged treatment with ointments contg. high concns. of resorcinol. In animal studies resorcinol failed to induce TG toxicity, unless pharmacokinetic/toxicokinetic (PK/TK) conditions were manipulated (e.g., injection of resorcinol in oil or application in a slow release formulation). A recently completed two-generation reproductive toxicity study in rats did not detect any adverse effects on either reproductive or TG end points (Welsch, Nemec, and Lawrence, 2008, Int. J. Toxicol. 37, this issue). Resorcinol intake via drinking water up to the palatability limit had resulted in av. daily intakes (mg/kg) of 233 in F0 and F1 males and 304 (premating/gestation) or 660 (lactation) in females. Free resorcinol in blood plasma was barely detectable in a few parental animals, indicating rapid metab. This short review communication offers a perspective on compromised human skin barrier function as a likely cause of drastic increases in resorcinol absorption. In conjunction with multiple daily applications over many months to hyperemic, inflamed, and lesioned human skin much higher absorption was likely responsible for the reported human TG toxicity.
- 104Curzon, G.; Pratt, R. T. C. Origin of Urinary Resorcinol Sulphate. Nature 1964, 204 (4956), 383– 384, DOI: 10.1038/204383a0[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXks1Cr&md5=e1cff3980d900f25d4d9ed7976fa906aOrigin of urinary resorcinol sulfateCurzon, G.; Pratt, R. T. C.Nature (London, United Kingdom) (1964), 204 (4956), 383-4CODEN: NATUAS; ISSN:0028-0836.cf. CA 59, 9173f. Human urinary resorcinol monosulfate (I) appeared to be a product of the metabolism of a constituent of tea by certain people, since excretion of I stopped after removal of tea from the diet. The ingestion of large vols. of tea did not cause the excretion of I by one person. Oral administration of the intestinal antibiotic framycetin (soframycin) (II) (500 mg. 3 times/day) caused the excretion of I to cease after 6 days. Even 21 months after the end of II treatment, I was not excreted. The results suggested that I was formed in vivo by a particular intestinal bacteria from dietary vegetable matter. Once established, the bacteria may persist indefinitely but antibiotic treatment may result in their permanent disappearance.
- 105Guo, K.; Li, L. Differential 12 C-/ 13 C-Isotope Dansylation Labeling and Fast Liquid Chromatography/Mass Spectrometry for Absolute and Relative Quantification of the Metabolome. Anal. Chem. 2009, 81 (10), 3919– 3932, DOI: 10.1021/ac900166a[ACS Full Text], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsFKktrg%253D&md5=e6094091a162e20d77df94de4eb9d9baDifferential 12C-/13C-Isotope Dansylation Labeling and Fast Liquid Chromatography/Mass Spectrometry for Absolute and Relative Quantification of the MetabolomeGuo, Kevin; Li, LiangAnalytical Chemistry (Washington, DC, United States) (2009), 81 (10), 3919-3932CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)The authors report a new quant. metabolome profiling technique based on differential 12C-/13C-isotope dansylation labeling of metabolites, fast liq. chromatog. (LC) sepn. and electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) detection. An isotope reagent, 13C-dansyl chloride, can be readily synthesized. This reagent, along with 12C-dansyl chloride, provides a simple and robust means of labeling metabolites contg. primary amine, secondary amine, or phenolic hydroxyl group(s). It is shown that dansylation labeling offers 1-3 orders of magnitude ESI signal enhancement over the underivatized counterparts. Dansylation alters the chromatog. behaviors of polar and ionic metabolites normally not retainable on a reversed phase (RP) column to an extent that they can be retained and sepd. by RPLC with high efficiency. There is no isotopic effect on RPLC sepn. of the differential isotope labeled metabolites, and 12C-/13C-labeled isoforms of metabolites are coeluted and detected by MS for precise and accurate quantification and confident metabolite identification. It is demonstrated that, in the anal. of 20 amino acids, a linear response of over 2 orders of magnitude is achieved for relative metabolite quantification with an av. relative std. deviation (RSD) of about 5.3% from replicate expts. A dansylation std. compd. library consisting of 121 known amines and phenols has been constructed and is proven to be useful for abs. metabolite quantification and MS-based metabolite identification in biol. samples. As an example, the abs. concns. of 93 metabolites, ranging from 30 nM to 2510 μM, can be detd. from a pooled sample of human urines collected in 5 consecutive days labeled with 12C-dansylation and spiked with the 121 13C-dansylated stds. Relative concn. variations of these metabolites in individual urine samples can also be monitored by mixing the 13C-dansylated pooled urine sample with the 12C-dansylated individual sample. With a 12 min fast LC sepn. combined with FTICR MS, 672 metabolites were detected in a human urine sample with each metabolite peak having a signal-to-noise ratio of greater than 20; the identities of most of the metabolites remain to be detd. This work illustrates that dansylation labeling and fast LC/FTICR MS can be a powerful technique for quant. profiling of at least 672 metabolites in urine samples in 12 min.
- 106Toshimitsu, N.; Kenji, M.; Toyokazu, O.; Akira, S.; Kaizo, K. A Gas Chromatographic-Mass Spectrometric Analysis for Phenols in Uremic Serum. Clin. Chim. Acta 1981, 110 (1), 51– 57, DOI: 10.1016/0009-8981(81)90299-0
- 107Baldrick, F. R.; McFadden, K.; Ibars, M.; Sung, C.; Moffatt, T.; Megarry, K.; Thomas, K.; Mitchell, P.; Wallace, J. M. W.; Pourshahidi, L. K. Impact of a (Poly)Phenol-Rich Extract from the Brown Algae Ascophyllum Nodosum on DNA Damage and Antioxidant Activity in an Overweight or Obese Population: A Randomized Controlled Trial. Am. J. Clin. Nutr. 2018, 108 (4), 688– 700, DOI: 10.1093/ajcn/nqy147[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czptlGnsQ%253D%253D&md5=40a6c78bb774680672f9dd86bfdb28d0Impact of a (poly)phenol-rich extract from the brown algae Ascophyllum nodosum on DNA damage and antioxidant activity in an overweight or obese population: a randomized controlled trialBaldrick Francina R; McFadden Kevin; Ibars Maria; Sung Chris; Moffatt Tanya; Megarry Kate; Mitchell Peter; Wallace Julie M W; Pourshahidi L Kirsty; Ternan Nigel G; Gill Chris I R; Thomas Keith; Corona Giulia; Spencer Jeremy; Yaqoob Parveen; Rowland Ian; Corona Giulia; Hotchkiss Sarah; Campbell Ross; Moreno-Rojas Jose Manuel; Cuevas Francisco Julian; Pereira-Caro GemaThe American journal of clinical nutrition (2018), 108 (4), 688-700 ISSN:.Background: Epidemiologic evidence suggests that a diet rich in (poly)phenols has beneficial effects on many chronic diseases. Brown seaweed is a rich source of (poly)phenols. Objective: The aim of this study was to investigate the bioavailability and effect of a brown seaweed (Ascophyllum nodosum) (poly)phenol extract on DNA damage, oxidative stress, and inflammation in vivo. Design: A randomized, double-blind, placebo-controlled crossover trial was conducted in 80 participants aged 30-65 y with a body mass index (in kg/m2) ≥25. The participants consumed either a 400-mg capsule containing 100 mg seaweed (poly)phenol and 300 mg maltodextrin or a 400-mg maltodextrin placebo control capsule daily for an 8-wk period. Bioactivity was assessed with a panel of blood-based markers including lymphocyte DNA damage, plasma oxidant capacity, C-reactive protein (CRP), and inflammatory cytokines. To explore the bioavailability of seaweed phenolics, an untargeted metabolomics analysis of urine and plasma samples after seaweed consumption was determined by ultra-high-performance liquid chromatography-high-resolution mass spectrometry. Results: Consumption of the seaweed (poly)phenols resulted in a modest decrease in DNA damage but only in a subset of the total population who were obese. There were no significant changes in CRP, antioxidant status, or inflammatory cytokines. We identified phlorotannin metabolites that are considered potential biomarkers of seaweed consumption including pyrogallol/phloroglucinol-sulfate, hydroxytrifurahol A-glucuronide, dioxinodehydroeckol-glucuronide, diphlorethol sulfates, C-O-C dimer of phloroglucinol sulfate, and C-O-C dimer of phloroglucinol. Conclusions: To the best of our knowledge, this work represents the first comprehensive study investigating the bioactivity and bioavailability of seaweed (poly)phenolics in human participants. We identified several potential biomarkers of seaweed consumption. Intriguingly, the modest improvements in DNA damage were observed only in the obese subset of the total population. The subgroup analysis should be considered exploratory because it was not preplanned; therefore, it was not powered adequately. Elucidation of the biology underpinning this observation will require participant stratification according to weight in future studies. This trial was registered at clinicaltrials.gov as NCT02295878.
- 108Mateo Anson, N.; Aura, A.-M.; Selinheimo, E.; Mattila, I.; Poutanen, K.; van den Berg, R.; Havenaar, R.; Bast, A.; Haenen, G. R. M. M. Bioprocessing of Wheat Bran in Whole Wheat Bread Increases the Bioavailability of Phenolic Acids in Men and Exerts Antiinflammatory Effects Ex Vivo. J. Nutr. 2011, 141 (1), 137– 143, DOI: 10.3945/jn.110.127720[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252FlsFGntQ%253D%253D&md5=15c154ffb7324da4973c58f4df5b4c97Bioprocessing of wheat bran in whole wheat bread increases the bioavailability of phenolic acids in men and exerts antiinflammatory effects ex vivoMateo Anson Nuria; Aura Anna-Marja; Selinheimo Emilia; Mattila Ismo; Poutanen Kaisa; van den Berg Robin; Havenaar Robert; Bast Aalt; Haenen Guido R M MThe Journal of nutrition (2011), 141 (1), 137-43 ISSN:.Whole grain consumption has been linked to a lower risk of metabolic syndrome, which is normally associated with a low-grade chronic inflammation. The benefits of whole grain are in part related to the inclusion of the bran, rich in phenolic acids and fiber. However, the phenols are poorly bioaccessible from the cereal matrix. The aim of the present study was to investigate the effect of bioprocessing of the bran in whole wheat bread on the bioavailability of phenolic acids, the postprandial plasma antioxidant capacity, and ex vivo antiinflammatory properties. After consumption of a low phenolic acid diet for 3 d and overnight fasting, 8 healthy men consumed 300 g of whole wheat bread containing native bran (control bread) or bioprocessed bran (bioprocessed bread) in a cross-over design. Urine and blood samples were collected for 24 h to analyze the phenolic acids and metabolites. Trolox equivalent antioxidant capacity was measured in plasma. Cytokines were measured in blood after ex vivo stimulation with LPS. The bioavailabilities of ferulic acid, vanillic acid, sinapic acid, and 3,4-dimethoxybenzoic acid from the bioprocessed bread were 2- to 3-fold those from the control bread. Phenylpropionic acid and 3-hydroxyphenylpropionic acid were the main colonic metabolites of the nonbioaccessible phenols. The ratios of pro-:antiinflammatory cytokines were significantly lower in LPS-stimulated blood after the consumption of the bioprocessed bread. In conclusion, bioprocessing can remarkably increase the bioavailability of phenolic acids and their circulating metabolites, compounds which have immunomodulatory effects ex vivo.
- 109Clark, A.; Mach, N. Exercise-Induced Stress Behavior, Gut-Microbiota-Brain Axis and Diet: A Systematic Review for Athletes. J. Int. Soc. Sports Nutr. 2016, 13 (1), 43, DOI: 10.1186/s12970-016-0155-6[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVyltro%253D&md5=97b8110ff1817b5578e558535c14c485Exercise-induced stress behavior, gutmicrobiota- brain axis and diet: a systematic review for athletesClark, Allison; Mach, NuriaJournal of the International Society of Sports Nutrition (2016), 13 (), 43/1-43/21CODEN: JISSCV; ISSN:1550-2783. (BioMed Central Ltd.)Fatigue, mood disturbances, under performance and gastrointestinal distress are common among athletes during training and competition. The psychosocial and phys. demands during intense exercise can initiate a stress response activating the sympathetic-adrenomedullary and hypothalamus-pituitary-adrenal (HPA) axes, resulting in the release of stress and catabolic hormones, inflammatory cytokines and microbial mols. The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biol., including metab., endocrine, neuronal and immune function. The gut microbiome and its influence on host behavior, intestinal barrier and immune function are believed to be a crit. aspect of the brain-gut axis. Recent evidence in murine models shows that there is a high correlation between phys. and emotional stress during exercise and changes in gastrointestinal microbiota compn. For instance, induced exercise-stress decreased cecal levels of Turicibacter spp and increased Ruminococcus gnavus, which have well defined roles in intestinal mucus degrdn. and immune function. Diet is known to dramatically modulate the compn. of the gut microbiota. Due to the considerable complexity of stress responses in elite athletes (from leaky gut to increased catabolism and depression), defining std. diet regimes is difficult. However, some preliminary exptl. data obtained from studies using probiotics and prebiotics studies show some interesting results, indicating that the microbiota acts like an endocrine organ (e.g. secreting serotonin, dopamine or other neurotransmitters) and may control the HPA axis in athletes. What is troubling is that dietary recommendations for elite athletes are primarily based on a low consumption of plant polysaccharides, which is assocd. with reduced microbiota diversity and functionality (e.g. less synthesis of byproducts such as short chain fatty acids and neurotransmitters). As more elite athletes suffer from psychol. and gastrointestinal conditions that can be linked to the gut, targeting the microbiota therapeutically may need to be incorporated in athletes' diets that take into consideration dietary fiber as well as microbial taxa not currently present in athlete's gut.
- 110de Ferrars, R. M.; Czank, C.; Zhang, Q.; Botting, N. P.; Kroon, P. A.; Cassidy, A.; Kay, C. D. The Pharmacokinetics of Anthocyanins and Their Metabolites in Humans. Br. J. Pharmacol. 2014, 171 (13), 3268– 3282, DOI: 10.1111/bph.12676[Crossref], [PubMed], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpsVKrt70%253D&md5=5c01f6133547dee57e7a7be6190b9360The pharmacokinetics of anthocyanins and their metabolites in humansde Ferrars, R. M.; Czank, C.; Zhang, Q.; Botting, N. P.; Kroon, P. A.; Cassidy, A.; Kay, C. D.British Journal of Pharmacology (2014), 171 (13), 3268-3282CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Background and Purpose : Anthocyanins are phytochems. with reported vasoactive bioactivity. However, given their instability at neutral pH, they are presumed to undergo significant degrdn. and subsequent biotransformation. The aim of the present study was to establish the pharmacokinetics of the metabolites of cyanidin-3-glucoside (C3G), a widely consumed dietary phytochem. with potential cardioprotective properties. Exptl. Approach : A 500 mg oral bolus dose of 6,8,10,3',5'-13C5-C3G was fed to eight healthy male participants, followed by a 48 h collection (0, 0.5, 1, 2, 4, 6, 24, 48 h) of blood, urine and faecal samples. Samples were analyzed by HPLC-ESI-MS/MS with elimination kinetics established using non-compartmental pharmacokinetic modeling. Key Results : Seventeen 13C-labeled compds. were identified in the serum, including 13C5-C3G, its degrdn. products, protocatechuic acid (PCA) and phloroglucinaldehyde (PGA), 13 metabolites of PCA and 1 metabolite derived from PGA. The maximal concns. of the phenolic metabolites (Cmax) ranged from 10 to 2000 nM, between 2 and 30 h (tmax) post-consumption, with half-lives of elimination obsd. between 0.5 and 96 h. The major phenolic metabolites identified were hippuric acid and ferulic acid, which peaked in the serum at approx. 16 and 8 h resp. Conclusions and Implications : Anthocyanins are metabolized to a structurally diverse range of metabolites that exhibit dynamic kinetic profiles. Understanding the elimination kinetics of these metabolites is key to the design of future studies examg. their utility in dietary interventions or as therapeutics for disease risk redn.
- 111Blacklock, C. J. Salicylic Acid in the Serum of Subjects Not Taking Aspirin. Comparison of Salicylic Acid Concentrations in the Serum of Vegetarians, Non-Vegetarians, and Patients Taking Low Dose Aspirin. J. Clin. Pathol. 2001, 54 (7), 553– 555, DOI: 10.1136/jcp.54.7.553[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3Mznt1Kqug%253D%253D&md5=1247368b239927ce248da07e288f701fSalicylic acid in the serum of subjects not taking aspirin. Comparison of salicylic acid concentrations in the serum of vegetarians, non-vegetarians, and patients taking low dose aspirinBlacklock C J; Lawrence J R; Wiles D; Malcolm E A; Gibson I H; Kelly C J; Paterson J RJournal of clinical pathology (2001), 54 (7), 553-5 ISSN:0021-9746.AIMS: To determine serum salicylic acid concentrations in non-vegetarians and vegetarians not taking salicylate drugs, and to compare these concentrations with those found in patients taking aspirin, 75 mg daily. METHODS: Serum samples were obtained from vegetarians (n = 37) and non-vegetarians (n = 39) not taking salicylate drugs. Non-vegetarians and vegetarians were recruited from the community and from a Buddhist monastery, respectively, in Dumfries and Galloway, Scotland. Patients (n = 14) taking aspirin (75 mg daily) were recruited from the Dumfries diabetic clinic. Serum salicylic acid concentrations were determined using a high performance liquid chromatography method with electrochemical detection. RESULTS: Salicylic acid was detected in every serum sample analysed. Higher serum concentrations of salicylic acid were found in vegetarians than non-vegetarians: median concentrations of 0.11 (range, 0.04-2.47) micromol/litre and 0.07 (range, 0.02-0.20) micromol/litre, respectively; the median of the difference was 0.05 micromol/litre (95% confidence interval for difference, 0.03 to 0.08; p < 0.0001). The median serum concentration of salicylic acid in patients taking aspirin (75 mg daily) was 10.03 (range, 0.23-25.40) micromol/litre, which was significantly higher than that found in non-vegetarians and vegetarians. There was overlap in serum salicylic acid concentrations between the vegetarians and patients taking aspirin. CONCLUSIONS: Salicylic acid, a non-steroidal anti-inflammatory drug, is present in fruits and vegetables and is found in higher concentrations in vegetarians than non-vegetarians. This suggests that a diet rich in fruits and vegetables contributes to the presence of salicylic acid in vivo. There is overlap between the serum concentrations of salicylic acid in vegetarians and patients taking aspirin, 75 mg daily. These findings may explain, in part, the health promoting effects of dietary fruits and vegetables.
- 112Boto-Ordóñez, M.; Urpi-Sarda, M.; Queipo-Ortuño, M. I.; Corella, D.; Tinahones, F. J.; Estruch, R.; Andres-Lacueva, C. Microbial Metabolomic Fingerprinting in Urine after Regular Dealcoholized Red Wine Consumption in Humans. J. Agric. Food Chem. 2013, 61 (38), 9166– 9175, DOI: 10.1021/jf402394c[ACS Full Text], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlakt7%252FE&md5=7b5a3434c8813d4f12f0ca21aa7b3c4fMicrobial metabolomic fingerprinting in urine after regular dealcoholized red wine consumption in humansBoto-Ordonez, Maria; Urpi-Sarda, Mireia; Queipo-Ortuno, Maria Isabel; Corella, Dolores; Tinahones, Francisco J.; Estruch, Ramon; Andres-Lacueva, CristinaJournal of Agricultural and Food Chemistry (2013), 61 (38), 9166-9175CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The regular consumption of dealcoholized red wine (DRW) has demonstrated benefits in cardiovascular risk factors. The anal. of phenolic metabolites formed in the organism, esp. those that could come from microbiota metab., would help to understand these benefits. The aim of this study was to det. the widest urinary metabolomic fingerprinting of phenolics and microbial-derived phenolic acids (n = 61) after regular intake of DRW in men at high cardiovascular risk by UPLC-MS/MS using a targeted approach. Up to 49 metabolites, including phase II and microbial phenolic metabolites, increased after DRW consumption compared to baseline (P < 0.05). The highest percentage of increase was found for microbial metabolites from anthocyanin degrdn. such as syringic, p-coumaric, gallic acids and pyrogallol and from flavan-3-ols degrdn. such as hydroxyphenylvalerolactones and (epi)-catechins. These findings provide the most complete metabolic fingerprinting after wine consumption, amplifying the spectrum of microbial derived metabolites and their potential bioactivity related with health benefits.
- 113Olthof, M. R.; Hollman, P. C. H.; Buijsman, M. N. C. P.; van Amelsvoort, J. M. M.; Katan, M. B. Chlorogenic Acid, Quercetin-3-Rutinoside and Black Tea Phenols Are Extensively Metabolized in Humans. J. Nutr. 2003, 133 (6), 1806– 1814, DOI: 10.1093/jn/133.6.1806[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXks1Gkuro%253D&md5=dec89ddb8f0a75b7ced305e0dfed8a0fChlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humansOlthof, Margreet R.; Hollman, Peter C. H.; Buijsman, Michel N. C. P.; van Amelsvoort, Johan M. M.; Katan, Martijn B.Journal of Nutrition (2003), 133 (6), 1806-1814CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)Dietary phenols are antioxidants and their consumption may contribute to the prevention of cardiovascular diseases. Coffee and tea are major dietary sources of phenols. Dietary phenols are metabolized extensively in the body. Lack of quant. data on their metabolites hinders proper evaluation of the potential biol. effects of dietary phenols in vivo. This study examd. the phenolic acid metabolites of chlorogenic acid (major phenol in coffee), quercetin-3-rutinoside (major flavonol in tea), and black tea phenols and detd. the site of metab. in 20 healthy humans with an intact colon. The study identified and quantified ∼60 potential phenolic acid metabolites in urine using ref. stds. and GC-MS. Half of the ingested chlorogenic acid and 43% of the tea phenols were metabolized to hippuric acid. Quercetin-3-rutinoside was metabolized mainly to phenylacetic acids, i.e. 3-hydroxyphenylacetic acid (36%), 3-methoxy-4-hydroxyphenylacetic acid (8%), and 3,4-dihydroxyphenylacetic acid (5%). In 7 other humans without the colon, only traces of phenolic acid metabolites were found in urine after they had ingested chlorogenic acid and quercetin-3-rutinoside. This implies that the colonic microflora convert most of these dietary phenols into metabolites that then reach the body circulation. Metabolites of dietary phenols have lower antioxidant activity than their parent compds., thus the contribution of dietary phenols to antioxidant activity in vivo may be lower than expected from in vitro tests.
- 114Clifford, M. N.; Copeland, E. L.; Bloxsidge, J. P.; Mitchell, L. A. Hippuric Acid as a Major Excretion Product Associated with Black Tea Consumption. Xenobiotica 2000, 30 (3), 317– 326, DOI: 10.1080/004982500237703[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjs1Omtbw%253D&md5=cdf067dc0d2ff5a162b7d9a41e176568Hippuric acid as a major excretion product associated with black tea consumptionClifford, M. N.; Copeland, E. L.; Bloxsidge, J. P.; Mitchell, L. A.Xenobiotica (2000), 30 (3), 317-326CODEN: XENOBH; ISSN:0049-8254. (Taylor & Francis Ltd.)Nine humans (2 men, 7 women; age 25-28 yr) habitually drinking tea were asked to follow a low-polyphenol/low-caffeine diet for 6 days and to provide daily 24-h urine samples. On day 4 of the expt., strong black tea brewed under standardized conditions was reintroduced to their diet. HPLC and 1H-NMR profiling of urine samples indicated that black tea consumption (6-10 cups/day) was assocd. with increased hippuric acid excretion relative to controls, increasing from 153-512 to 742-1374 mg/day. The excretion of substantial amts. of hippuric acid has not previously been assocd. with black tea consumption. In some subjects the quantity of benzoic acid processed in this metabolic route exceeded the acceptable daily intakes, but this was not considered a hazard. A mass-balance anal. indicated that the necessary quantity of benzoic acid could not be obtained from the black tea contents of gallic acid, flavanols, flavonol glycosides, and theaflavins even if 100% transformation was reached, suggesting that the thearubigins (major chem. ill-defined polyphenols of black tea) may be an important source.
- 115Guertin, K. A.; Loftfield, E.; Boca, S. M.; Sampson, J. N.; Moore, S. C.; Xiao, Q.; Huang, W.-Y.; Xiong, X.; Freedman, N. D.; Cross, A. J. Serum Biomarkers of Habitual Coffee Consumption May Provide Insight into the Mechanism Underlying the Association between Coffee Consumption and Colorectal Cancer. Am. J. Clin. Nutr. 2015, 101 (5), 1000– 1011, DOI: 10.3945/ajcn.114.096099[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptlGhur4%253D&md5=948f3fdac658d3e329b02482bc0e8a3aSerum biomarkers of habitual coffee consumption may provide insight into the mechanism underlying the association between coffee consumption and colorectal cancerGuertin, Kristin A.; Loftfield, Erikka; Boca, Simina M.; Sampson, Joshua N.; Moore, Steven C.; Xiao, Qian; Huang, Wen-Yi; Xiong, Xiaoqin; Freedman, Neal D.; Cross, Amanda J.; Sinha, RashmiAmerican Journal of Clinical Nutrition (2015), 101 (5), 1000-1011CODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)Background: Coffee intake may be inversely assocd. with colorectal cancer; however, previous studies have been inconsistent. Serum coffee metabolites are integrated exposure measures that may clarify assocns. with cancer and elucidate underlying mechanisms. Objectives: Our aims were 2-fold as follows: (1) to identify serum metabolites assocd. with coffee intake and (2) to examine these metabolites in relation to colorectal cancer. Design: In a nested case-control study of 251 colorectal cancer cases and 247 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we conducted untargeted metabolomics analyses of baseline serum by using ultrahigh-performance liq.-phase chromatog.-tandem mass spectrometry and gas chromatog.-mass spectrometry. Usual coffee intake was self-reported in a food-frequency questionnaire. We used partial Pearson correlations and linear regression to identify serum metabolites assocd. with coffee intake and conditional logistic regression to evaluate assocns. between coffee metabolites and colorectal cancer. Results: After Bonferroni correction for multiple comparisons (P = 0.05 ÷ 657 metabolites), 29 serum metabolites were pos. correlated with coffee intake (partial correlation coeffs.: 0.18-0.61; P < 7.61 × 10-5); serum metabolites most highly correlated with coffee intake (partial correlation coeffs. >0.40) included trigonelline (N'-methylnicotinate), quinate, and 7 unknown metabolites. Of 29 serum metabolites, 8 metabolites were directly related to caffeine metab., and 3 of these metabolites, theophylline (OR for 90th compared with 10th percentiles: 0.44; 95% CI: 0.25, 0.79; P-linear trend = 0.006), caffeine (OR for 90th compared with 10th percentiles: 0.56; 95% CI: 0.35, 0.89; P-linear trend = 0.015), and paraxanthine (OR for 90th compared with 10th percentiles: 0.58; 95% CI: 0.36, 0.94; P-linear trend = 0.027), were inversely assocd. with colorectal cancer. Conclusions: Serum metabolites can distinguish coffee drinkers from nondrinkers; some caffeine-related metabolites were inversely assocd. with colorectal cancer and should be studied further to clarify the role of coffee in the cause of colorectal cancer.
- 116Guy, P. A.; Renouf, M.; Barron, D.; Cavin, C.; Dionisi, F.; Kochhar, S.; Rezzi, S.; Williamson, G.; Steiling, H. Quantitative Analysis of Plasma Caffeic and Ferulic Acid Equivalents by Liquid Chromatography Tandem Mass Spectrometry. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2009, 877 (31), 3965– 3974, DOI: 10.1016/j.jchromb.2009.10.006[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVWlsr7O&md5=6d9953bc0f9549bb51c5be2fde3ad562Quantitative analysis of plasma caffeic and ferulic acid equivalents by liquid chromatography tandem mass spectrometryGuy, Philippe A.; Renouf, Mathieu; Barron, Denis; Cavin, Christophe; Dionisi, Fabiola; Kochhar, Sunil; Rezzi, Serge; Williamson, Gary; Steiling, HeikeJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2009), 877 (31), 3965-3974CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)A validated method was developed for the simultaneous detn. of the hydroxycinnamates caffeic acid (CA), dihydrocaffeic acid (DHCA), ferulic acid (FA), dihydroferulic acid (DHFA), and isoferulic acid (IFA) in human plasma as metabolites derived from coffee consumption. The method includes a protein pptn. step prior to enzymic hydrolysis of the conjugated metabolites (sulfate, glucuronide, and/or ester) back to their aglycon forms. After liq.-liq. extn., the reconstituted ext. was analyzed byHPLC coupled to neg. electrospray ionization tandem mass spectrometry. Calibration curves were constructed from spiked human plasma samples in the range of 0-4800 nM for each of the targeted analytes. Two internal stds., 3-(4-hydroxyphenyl)-propionic acid (500 nM) and 1,3-dicaffeoylquinic acid (200 nM), were spiked at the beginning of the sample prepn. and before anal., resp. Good performance data were obtained with limits of detection and quantification of the five hydroxycinnamates ranging between 1-15 nM and 3-50 nM, resp. Within and between-days precisions were resp. calcd. between 8-18% and 8-30% (at 50 nM added initially), between 6-9% and 6-12% (at 200 nM), and between 5-9% and 5-9% (at 500 nM). Precision calcd. from different analysts ranged from 18% to 44% (at 50 nM), from 8% to 16% (at 200 nM), and from 4% to 8% (at 500 nM). Using this method, we detd. plasma levels in humans and measured the efficiency of deconjugation using our enzymic cocktail.
- 117Zamora-Ros, R.; Achaintre, D.; Rothwell, J. A.; Rinaldi, S.; Assi, N.; Ferrari, P.; Leitzmann, M.; Boutron-Ruault, M.-C.; Fagherazzi, G.; Auffret, A. Urinary Excretions of 34 Dietary Polyphenols and Their Associations with Lifestyle Factors in the EPIC Cohort Study. Sci. Rep. 2016, 6 (1), 26905, DOI: 10.1038/srep26905[Crossref], [PubMed], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xps1ynsrY%253D&md5=deb7676f535c33d9ead9bcc62399663bUrinary excretions of 34 dietary polyphenols and their associations with lifestyle factors in the EPIC cohort studyZamora-Ros, Raul; Achaintre, David; Rothwell, Joseph A.; Rinaldi, Sabina; Assi, Nada; Ferrari, Pietro; Leitzmann, Michael; Boutron-Ruault, Marie-Christine; Fagherazzi, Guy; Auffret, Aurelie; Kuhn, Tilman; Katzke, Verena; Boeing, Heiner; Trichopoulou, Antonia; Naska, Androniki; Vasilopoulou, Effie; Palli, Domenico; Grioni, Sara; Mattiello, Amalia; Tumino, Rosario; Ricceri, Fulvio; Slimani, Nadia; Romieu, Isabelle; Scalbert, AugustinScientific Reports (2016), 6 (), 26905CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Urinary excretion of 34 dietary polyphenols and their variations according to diet and other lifestyle factors were measured by tandem mass spectrometry in 475 adult participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cross-sectional study. A single 24-h urine sample was analyzed for each subject from 4 European countries. The highest median levels were obsd. for phenolic acids such as 4-hydroxyphenylacetic acid (157 μmol/24 h), followed by 3-hydroxyphenylacetic, ferulic, vanillic and homovanillic acids (20-50 μmol/24 h). The lowest concns. were obsd. for equol, apigenin and resveratrol (<0.1 μmol/24 h). Urinary polyphenols significantly varied by center, followed by alc. intake, sex, educational level, and energy intake. This variability is largely explained by geog. variations in the diet, as suggested by the high correlations (r > 0.5) obsd. between urinary polyphenols and the intake of their main food sources (e.g., resveratrol and gallic acid Et ester with red wine intake; caffeic, protocatechuic and ferulic acids with coffee consumption; and hesperetin and naringenin with citrus fruit intake). The large variations in urinary polyphenols obsd. are largely detd. by food preferences. These polyphenol biomarkers should allow more accurate evaluation of the relationships between polyphenol exposure and the risk of chronic diseases in large epidemiol. studies.
- 118Kern, S. M.; Bennett, R. N.; Mellon, F. A.; Kroon, P. A.; Garcia-Conesa, M.-T. Absorption of Hydroxycinnamates in Humans after High-Bran Cereal Consumption. J. Agric. Food Chem. 2003, 51 (20), 6050– 6055, DOI: 10.1021/jf0302299[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmsVOns7g%253D&md5=84a99c4b766a4a1850619fe7f9a0cd94Absorption of hydroxycinnamates in humans after high-bran cereal consumptionKern, Sandra M.; Bennett, Richard N.; Mellon, Fred A.; Kroon, Paul Anthony; Garcia-Conesa, Maria-TeresaJournal of Agricultural and Food Chemistry (2003), 51 (20), 6050-6055CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The present work investigated the absorption in humans of hydroxycinnamic acids from high-bran breakfast cereal (wheat). Plasma and urine samples from six volunteers were collected before and after cereal consumption and analyzed for total hydroxycinnamic acids content after β-glucuronidase/sulfatase treatment both by HPLC-DAD and by LC-MS (SIM monitoring). High-bran cereal administration resulted in increased plasma ferulic and sinapic acid concns. (max. levels detected of ∼200 and ∼40 nM, resp.) with absorption peaks between 1 and 3 h. Increases of ∼4-fold in ferulic acid and ∼5-fold in feruloylglycine were detected in 24-h urine after consumption of the cereal. Most of the ferulic acid detected in urine and plasma was present as conjugates (feruloylglycine and/or glucuronides). Diferulic acids were undetectable. The data show that ferulic and sinapic acids are taken up in humans from dietary high bran wheat but that absorption is limited and may originate only from the free and sol. portions present in the cereal.
- 119Roowi, S.; Mullen, W.; Edwards, C. A.; Crozier, A. Yoghurt Impacts on the Excretion of Phenolic Acids Derived from Colonic Breakdown of Orange Juice Flavanones in Humans. Mol. Nutr. Food Res. 2009, 53 (S1), S68– S75, DOI: 10.1002/mnfr.200800287
- 120Del Rio, D.; Stalmach, A.; Calani, L.; Crozier, A. Bioavailability of Coffee Chlorogenic Acids and Green Tea Flavan-3-Ols. Nutrients 2010, 2 (8), 820– 833, DOI: 10.3390/nu2080820[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvV2qsLk%253D&md5=93a1225c5cb0f8de15f5184c345d9315Bioavailability of coffee chlorogenic acids and green tea flavan-3-olsDel Rio, Daniele; Stalmach, Angelique; Calani, Luca; Crozier, AlanNutrients (2010), 2 (), 820-833CODEN: NUTRHU; ISSN:2072-6643. (Molecular Diversity Preservation International)A review. This paper reviews recent human studies on the bioavailability of chlorogenic acids in coffee and green tea flavan-3-ols in which the identification of metabolites, catabolites and parent compds. in plasma, urine and ileal fluid was based on mass spectrometric methodol. Both the chlorogenic acids and the flavan-3-ols are absorbed in the small intestine and appear in the circulatory system predominantly as glucuronide, sulfate and methylated metabolites. Even when absorption occurs in the small intestine, feeding studies with ileostomists reveal that substantial amts. of the parent compds. and some of their metabolites appear in ileal fluid indicating that in volunteers with a functioning colon these compds. will pass to the large intestine where they are subjected to the action of the colonic microflora. A diversity of colonic-derived catabolites are absorbed into the bloodstream and pass through the body prior to excretion in urine. There is growing evidence that these compds., which were little investigated until recently, are produced in quantity in the colon and form a key part of the bioavailability equation of flavonoids and related compds. that occur in fruits, vegetables and beverages. Recent evidence indicates that some colon-derived phenolic acids have in vitro anti-inflammatory activity.