Phenolic Lipids Derived from Cashew Nut Shell Liquid to Treat Metabolic Diseases

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1. 1

   Saklayen, M. G. The global epidemic of the metabolic syndrome. Curr. Hypertens. Rep. 2018, 20, 12  DOI: 10.1007/s11906-018-0812-z

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   The Global Epidemic of the Metabolic Syndrome

   Saklayen Mohammad G

   Current hypertension reports (2018), 20 (2), 12 ISSN:.

   Metabolic syndrome, variously known also as syndrome X, insulin resistance, etc., is defined by WHO as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Though there is some variation in the definition by other health care organization, the differences are minor. With the successful conquest of communicable infectious diseases in most of the world, this new non-communicable disease (NCD) has become the major health hazard of modern world. Though it started in the Western world, with the spread of the Western lifestyle across the globe, it has become now a truly global problem. The prevalence of the metabolic syndrome is often more in the urban population of some developing countries than in its Western counterparts. The two basic forces spreading this malady are the increase in consumption of high calorie-low fiber fast food and the decrease in physical activity due to mechanized transportations and sedentary form of leisure time activities. The syndrome feeds into the spread of the diseases like type 2 diabetes, coronary diseases, stroke, and other disabilities. The total cost of the malady including the cost of health care and loss of potential economic activity is in trillions. The present trend is not sustainable unless a magic cure is found (unlikely) or concerted global/governmental/societal efforts are made to change the lifestyle that is promoting it. There are certainly some elements in the causation of the metabolic syndrome that cannot be changed but many are amenable for corrections and curtailments. For example, better urban planning to encourage active lifestyle, subsidizing consumption of whole grains and possible taxing high calorie snacks, restricting media advertisement of unhealthy food, etc. Revitalizing old fashion healthier lifestyle, promoting old-fashioned foods using healthy herbs rather than oil and sugar, and educating people about choosing healthy/wholesome food over junks are among the steps that can be considered.
2. 2

   Nolan, P. B.; Carrick-Ranson, G.; Stinear, J. W.; Reading, S. A.; Dalleck, L. C. Prevalence of metabolic syndrome and metabolic syndrome components in young adults: A pooled analysis. Prev. Med. Rep. 2017, 7, 211– 215,  DOI: 10.1016/j.pmedr.2017.07.004

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   Prevalence of metabolic syndrome and metabolic syndrome components in young adults: A pooled analysis

   Nolan Paul B; Carrick-Ranson Graeme; Stinear James W; Reading Stacey A; Dalleck Lance C

   Preventive medicine reports (2017), 7 (), 211-215 ISSN:2211-3355.

   Metabolic syndrome (MetSyn) represents a clustering of different metabolic abnormalities. MetSyn prevalence is present in approximately 25% of all adults with increased prevalence in advanced ages. The presence of one component of MetSyn increases the risk of developing MetSyn later in life and likely represents a high lifetime burden of cardiovascular disease risk. Therefore we pooled data from multiple studies to establish the prevalence of MetSyn and MetSyn component prevalence across a broad range of ethnicities. PubMed, SCOPUS and Medline databases were searched to find papers presenting MetSyn and MetSyn component data for 18-30 year olds who were apparently healthy, free of disease, and MetSyn was assessed using either the harmonized, National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII), American Heart Association/National Heart, Blood and Lung Institute (AHA/NHBLI), or International Diabetes Federation (IDF) definitions of MetSyn. After reviewing returned articles, 26,609 participants' data from 34 studies were included in the analysis and the data were pooled. MetSyn was present in 4.8-7% of young adults. Atherogenic dyslipidaemia defined as low high density lipoprotein (HDL) cholesterol was the most prevalent MetSyn component (26.9-41.2%), followed by elevated blood pressure (16.6-26.6%), abdominal obesity (6.8-23.6%), atherogenic dyslipidaemia defined as raised triglycerides (8.6-15.6%), and raised fasting glucose (2.8-15.4%). These findings highlight that MetSyn is prevalent in young adults. Establishing the reason why low HDL is the most prevalent component may represent an important step in promoting primary prevention of MetSyn and reducing the incidence of subsequent clinical disease.
3. 3

   Sathyaprakash, R.; Henry, R. R. Preventing diabetes by treating aspects of the metabolic syndrome. Curr. Diabetes Rep. 2002, 2, 416– 422,  DOI: 10.1007/s11892-002-0106-2

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   Preventing diabetes by treating aspects of the metabolic syndrome

   Sathyaprakash Roopa; Henry Robert R

   Current diabetes reports (2002), 2 (5), 416-22 ISSN:1534-4827.

   The metabolic syndrome often develops into and is usually present in type 2 diabetes in association with premature cardiovascular disease. Treating diabetes can prevent some of its devastating consequences, but it does not eliminate them all. With the goal to eliminate all the adverse consequences of the syndrome, the optimal approach would be through its prevention. Insulin resistance appears to be pivotal to development of the syndrome complex that includes features such as intra-abdominal or visceral obesity, hypertension, impaired glucose homeostasis, dyslipidemia with elevated triglycerides and low high-density lipoprotein without elevations of low-density lipoprotein, a procoagulant state, and impaired vascular function. Improving the insulin resistance needs to be the primary target of the therapy. Hyperglycemia, which is one feature of the metabolic syndrome, may range from impaired glucose tolerance (IGT) to overt diabetes. The risk of progression of the disease from IGT to diabetes is increased with time and the presence of various risk factors. Diabetes is a disease of serious concern because of the associated complication of the disease and the huge impact on the health care costs. Many short- and longer-term trials have shown promise in the prevention of diabetes and its metabolic and cardiovascular consequences.
4. 4

   Haffner, S. M. Dyslipidemia management in adults with diabetes. Diabetes Care 2004, 27, S68– S71,  DOI: 10.2337/diacare.27.2007.S68

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   Kahn, S. E.; Hull, R. L.; Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006, 444, 840– 846,  DOI: 10.1038/nature05482

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   Mechanisms linking obesity to insulin resistance and type 2 diabetes

   Kahn, Steven E.; Hull, Rebecca L.; Utzschneider, Kristina M.

   Nature (London, United Kingdom) (2006), 444 (7121), 840-846CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

   A review. Obesity is assocd. with an increased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissue releases increased amts. of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet β-cells - the cells that release insulin - failure to control blood glucose levels results. Abnormalities in β-cell function are therefore crit. in defining the risk and development of type 2 diabetes. This knowledge is fostering exploration of the mol. and genetic basis of the disease and new approaches to its treatment and prevention.
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   Ford, E. S.; Li, C.; Sattar, N. Metabolic syndrome and incident diabetes: Current state of the evidence. Diabetes Care 2008, 31, 1898– 1904,  DOI: 10.2337/dc08-0423

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   Metabolic syndrome and incident diabetes: current state of the evidence

   Ford Earl S; Li Chaoyang; Sattar Naveed

   Diabetes care (2008), 31 (9), 1898-904 ISSN:.

   OBJECTIVE: Our objective was to perform a quantitative review of prospective studies examining the association between the metabolic syndrome and incident diabetes. RESEARCH DESIGN AND METHODS: Using the title terms "diabetes" and "metabolic syndrome" in PubMed, we searched for articles published since 1998. RESULTS: Based on the results from 16 cohorts, we performed a meta-analysis of estimates of relative risk (RR) and incident diabetes. The random-effects summary RRs were 5.17 (95% CI 3.99-6.69) for the 1999 World Health Organization definition (ten cohorts); 4.45 (2.41-8.22) for the 1999 European Group for the Study of Insulin Resistance definition (four cohorts); 3.53 (2.84-4.39) for the 2001 National Cholesterol Education Program definition (thirteen cohorts); 5.12 (3.26-8.05) for the 2005 American Heart Association/National Heart, Lung, and Blood Institute definition (five cohorts); and 4.42 (3.30-5.92) for the 2005 International Diabetes Federation definition (nine cohorts). The fixed-effects summary RR for the 2004 National Heart, Lung, and Blood Institute/American Heart Association definition was 5.16 (4.43-6.00) (six cohorts). Higher number of abnormal components was strongly related to incident diabetes. Compared with participants without an abnormality, estimates of RR for those with four or more abnormal components ranged from 10.88 to 24.4. Limited evidence suggests fasting glucose alone may be as good as metabolic syndrome for diabetes prediction. CONCLUSIONS: The metabolic syndrome, however defined, has a stronger association with incident diabetes than that previously demonstrated for coronary heart disease. Its clinical value for diabetes prediction remains uncertain.
7. 7

   Eckel, R. H.; Alberti, K. G.; Grundy, S. M.; Zimmet, P. Z. The metabolic syndrome. Lancet 2010, 375, 181– 183,  DOI: 10.1016/S0140-6736(09)61794-3

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   The metabolic syndrome

   Eckel Robert H; Alberti K G M M; Grundy Scott M; Zimmet Paul Z

   Lancet (London, England) (2010), 375 (9710), 181-3 ISSN:.

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8. 8

   Evans, R. M.; Barish, G. D.; Wang, Y. X. Ppars and the complex journey to obesity. Nat. Med. 2004, 10, 355– 361,  DOI: 10.1038/nm1025

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   PPARs and the complex journey to obesity

   Evans, Ronald M.; Barish, Grant D.; Wang, Yong-Xu

   Nature Medicine (New York, NY, United States) (2004), 10 (4), 355-361CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)

   A review. Obesity and the related disorders of dyslipidemia and diabetes (components of syndrome X) have become global health epidemics. Over the past decade, the elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metab. and their intimate link. The three 'lipid-sensing' peroxisome proliferator-activated receptors (PPAR-α, PPAR-γ and PPAR-δ) exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bona fide therapeutic targets. With mol. underpinnings now in place, new pharmacol. approaches to metabolic disease and new questions are emerging.
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   Kersten, S.; Desvergne, B.; Wahli, W. Roles of ppars in health and disease. Nature 2000, 405, 421– 424,  DOI: 10.1038/35013000

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   Roles of PPARs in health and disease

   Kersten, Sander; Desvergne, Beatrice; Wahli, Walter

   Nature (London) (2000), 405 (6785), 421-424CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

   A review with 30 refs. In developed societies, chronic diseases such as diabetes, obesity, atherosclerosis and cancer are responsible for most deaths. These ailments have complex causes involving genetic, environmental and nutritional factors. There is evidence that a group of closely related nuclear receptors, called peroxisome proliferator-activated receptors (PPARs), may be involved in these diseases. This, together with the fact that PPAR activity can be modulated by drugs such as thiazolidinediones and fibrates, has instigated a huge research effort into PPARs. Here the authors present the latest developments in the PPAR field, with particular emphasis on the physiol. function of PPARs during various nutritional states, and the possible role of PPARs in several chronic diseases.
10. 10

    Gronemeyer, H.; Gustafsson, J. A.; Laudet, V. Principles for modulation of the nuclear receptor superfamily. Nat. Rev. Drug Discovery 2004, 3, 950– 964,  DOI: 10.1038/nrd1551

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    Principles for modulation of the nuclear receptor superfamily

    Gronemeyer, Hinrich; Gustafsson, Jan-A.; Laudet, Vincent

    Nature Reviews Drug Discovery (2004), 3 (11), 950-964CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)

    A review. Nuclear receptors are major targets for drug discovery and have key roles in development and homeostasis, as well as in many diseases such as obesity, diabetes and cancer. This review provides a general overview of the mechanism of action of nuclear receptors and explores the various factors that are instrumental in modulating their pharmacol. In most cases, the response of a given receptor to a particular ligand in a specific tissue will be dictated by the set of proteins with which the receptor is able to interact. One of the most promising aspects of nuclear receptor pharmacol. is that it is now possible to develop ligands with a large spectrum of full, partial or inverse agonist or antagonist activities, but also compds., called selective nuclear receptor modulators, that activate only a subset of the functions induced by the cognate ligand or that act in a cell-type-selective manner.
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    Mangelsdorf, D. J.; Thummel, C.; Beato, M.; Herrlich, P.; Schutz, G.; Umesono, K.; Blumberg, B.; Kastner, P.; Mark, M.; Chambon, P.; Evans, R. M. The nuclear receptor superfamily: The second decade. Cell 1995, 83, 835– 839,  DOI: 10.1016/0092-8674(95)90199-X

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    The nuclear receptor superfamily: The second decade

    Mangelsdorf, David J.; Thummel, Carl; Beato, Miguel; Herrlich, Peter; Schuetz, Guenther; Umesono, Kazuhiko; Blumberg, Bruce; Kastner, Philippe; Mark, Manuel; et al.

    Cell (Cambridge, Massachusetts) (1995), 83 (6), 835-9CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    A review with 21 refs. on the nuclear hormone receptor superfamily discussing ligands, common receptor structure/function domains, and the evolutionary relationships of receptor sequences.
12. 12

    Kliewer, S. A.; Sundseth, S. S.; Jones, S. A.; Brown, P. J.; Wisely, G. B.; Koble, C. S.; Devchand, P.; Wahli, W.; Willson, T. M.; Lenhard, J. M.; Lehmann, J. M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 4318– 4323,  DOI: 10.1073/pnas.94.9.4318

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    Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ

    Kliewer, Steven A.; Sundseth, Scott S.; Jones, Stacey A.; Brown, Peter J.; Wisely, G. Bruce; Koble, Cecilia; Devchand, Pallavi; Wahli, Walter; Willson, Timothy M.; Lenhard, James M.; Lehmann, Jurgen M.

    Proceedings of the National Academy of Sciences of the United States of America (1997), 94 (9), 4318-4323CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Peroxisome proliferator-activated receptors (PPARs) α and γ are key regulators of lipid homeostasis and are activated by a structurally diverse group of compds. including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-Δ12,14-prostaglandin J2 have been shown to bind to PPARγ, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, a novel fibrate designed GW2231 is described, that is a high-affinity ligand for both PPARα and PPARγ. Using GW2331 as a radioligand in competition binding assays, it is shown that certain mono- and polyunsatd. fatty acids bind directly to PPARα and PPARγ at physiol. concns., and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-Δ12,14-prostaglandin J2 can function as subtype-selective ligands for PPARα and PPARγ, resp. These data provide evidence that PPARs serve as physiol. sensors of lipid levels and suggest a mol. mechanism whereby dietary fatty acids can modulate lipid homeostasis.
13. 13

    Itoh, T.; Yamamoto, K. Peroxisome proliferator activated receptor gamma and oxidized docosahexaenoic acids as new class of ligand. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2008, 377, 541– 547,  DOI: 10.1007/s00210-007-0251-x

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    Peroxisome proliferator activated receptor γ and oxidized docosahexaenoic acids as new class of ligand

    Itoh, Toshimasa; Yamamoto, Keiko

    Naunyn-Schmiedeberg's Archives of Pharmacology (2008), 377 (4-6), 541-547CODEN: NSAPCC; ISSN:0028-1298. (Springer)

    A review. PPARγ regulates the expression of numerous genes. In addn. to their anti-diabetic activity, PPARγ agonists have been reported to have beneficial effects for cancer, inflammation including inflammatory bowel disease, atherosclerosis and brain inflammation, as well as bone turnover. To investigate a potential new class of ligands for PPARγ, we designed with ref. to the crystal structure of the ligand-binding domain of PPARγ oxidized docosahexaenoic acid (DHA) derivs., which have a hydrophilic substituent at the C(4)-position and are putative metabolites of DHA. We synthesized 14 compds. and evaluated their activities in vitro. We found that these DHA derivs. show PPARγ transactivation higher than, or comparable to, that of pioglitazone, which is a thiazolidinedione deriv. used as an antidiabetic agent. Furthermore, one of them showed anti-diabetic activity in animal models. In this paper, we review the potential of PPARγ as a drug target and oxidized DHA as a new class of ligand for PPARγ.
14. 14

    Berger, J.; Moller, D. E. The mechanisms of action of ppars. Annu. Rev. Med. 2002, 53, 409– 435,  DOI: 10.1146/annurev.med.53.082901.104018

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    The Mechanisms of Action of PPARs

    Berger, Joel; Moller, David E.

    Annual Review of Medicine (2002), 53 (), 409-435CODEN: ARMCAH; ISSN:0066-4219. (Annual Reviews Inc.)

    A review. The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with co-factors such that the rate of transcription initiation is increased. The PPARs play a crit. physiol. role as lipid sensors and regulators of lipid metab. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathol. states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the mol. mechanisms of PPAR action and the involvement of the PPARs in the etiol. and treatment of several chronic diseases.
15. 15

    Lefebvre, P.; Chinetti, G.; Fruchart, J. C.; Staels, B. Sorting out the roles of ppar alpha in energy metabolism and vascular homeostasis. J. Clin. Invest. 2006, 116, 571– 580,  DOI: 10.1172/JCI27989

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    Sorting out the roles of PPARα in energy metabolism and vascular homeostasis

    Lefebvre, Philippe; Chinetti, Giulia; Fruchart, Jean-Charles; Staels, Bart

    Journal of Clinical Investigation (2006), 116 (3), 571-580CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

    A review. PPARα is a nuclear receptor that regulates liver and skeletal muscle lipid metab. as well as glucose homeostasis. Acting as a mol. sensor of endogenous fatty acids (FAs) and their derivs., this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidn. and improving lipoprotein metab. PPARα also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARα help explain the clin. actions of fibrates, synthetic PPARα agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclin. studies cannot predict all of the effects of PPARα in humans, recent findings have revealed potential adverse effects of PPARα action, underlining the need for further study. This review will focus on the mechanisms of action of PPARα in metabolic diseases and their assocd. vascular pathologies.
16. 16

    Ahmadian, M.; Suh, J. M.; Hah, N.; Liddle, C.; Atkins, A. R.; Downes, M.; Evans, R. M. Ppar gamma signaling and metabolism: The good, the bad and the future. Nat. Med. 2013, 19, 557– 566,  DOI: 10.1038/nm.3159

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    PPARγ signaling and metabolism: the good, the bad and the future

    Ahmadian, Maryam; Suh, Jae Myoung; Hah, Nasun; Liddle, Christopher; Atkins, Annette R.; Downes, Michael; Evans, Ronald M.

    Nature Medicine (New York, NY, United States) (2013), 19 (5), 557-566CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)

    A review. Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, wt. gain, bone loss, and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiol. and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of mols. that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.
17. 17

    Wagner, K. D.; Wagner, N. Peroxisome proliferator-activated receptor beta/delta (pparbeta/delta) acts as regulator of metabolism linked to multiple cellular functions. Pharmacol. Ther. 2010, 125, 423– 435,  DOI: 10.1016/j.pharmthera.2009.12.001

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    Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) acts as regulator of metabolism linked to multiple cellular functions

    Wagner, Kay-Dietrich; Wagner, Nicole

    Pharmacology & Therapeutics (2010), 125 (3), 423-435CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)

    A review. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors. They function as ligand activated transcription factors. They exist in three isoforms, PPARα, PPARβ (formerly PPARδ), and PPARγ. For all PPARs lipids are endogenous ligands, linking them directly to metab. PPARs form heterodimers with retinoic X receptors, and, upon ligand binding, modulate gene expression of downstream target genes dependent on the presence of co-repressors or co-activators. This results in cell-type specific complex regulations of proliferation, differentiation and cell survival. Specific synthetic agonists for all PPARs are available. PPARα and PPARγ agonists are already in clin. use for the treatment of hyperlipidemia and type 2 diabetes, resp. More recently, PPARβ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and assocd. cardiovascular diseases. Although the initial notion was that PPARβ is expressed ubiquitously, more recently extensive investigations have been performed demonstrating high PPARβ expression in a variety of tissues, e.g. skin, skeletal muscle, adipose tissue, inflammatory cells, heart, and various types of cancer. In addn., in vitro and in vivo studies using specific PPARβ agonists, tissue-specific over-expression or knockout mouse models have demonstrated a variety of functions of PPARβ in adipose tissue, muscle, skin, inflammation, and cancer. We will focus here on functions of PPARβ in adipose tissue, skeletal muscle, heart, angiogenesis and cancer related to modifications in metab. and the identified underlying mol. mechanisms.
18. 18

    Wang, Y. X.; Zhang, C. L.; Yu, R. T.; Cho, H. K.; Nelson, M. C.; Bayuga-Ocampo, C. R.; Ham, J.; Kang, H.; Evans, R. M. Regulation of muscle fiber type and running endurance by ppardelta. PLoS Biol. 2004, 2, e294  DOI: 10.1371/journal.pbio.0020294

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    Regulation of muscle fiber type and running endurance by PPARdelta

    Wang Yong-Xu; Zhang Chun-Li; Yu Ruth T; Cho Helen K; Nelson Michael C; Bayuga-Ocampo Corinne R; Ham Jungyeob; Kang Heonjoong; Evans Ronald M

    PLoS biology (2004), 2 (10), e294 ISSN:.

    Endurance exercise training can promote an adaptive muscle fiber transformation and an increase of mitochondrial biogenesis by triggering scripted changes in gene expression. However, no transcription factor has yet been identified that can direct this process. We describe the engineering of a mouse capable of continuous running of up to twice the distance of a wild-type littermate. This was achieved by targeted expression of an activated form of peroxisome proliferator-activated receptor delta (PPARdelta) in skeletal muscle, which induces a switch to form increased numbers of type I muscle fibers. Treatment of wild-type mice with PPARdelta agonist elicits a similar type I fiber gene expression profile in muscle. Moreover, these genetically generated fibers confer resistance to obesity with improved metabolic profiles, even in the absence of exercise. These results demonstrate that complex physiologic properties such as fatigue, endurance, and running capacity can be molecularly analyzed and manipulated.
19. 19

    Michalik, L.; Auwerx, J.; Berger, J. P.; Chatterjee, V. K.; Glass, C. K.; Gonzalez, F. J.; Grimaldi, P. A.; Kadowaki, T.; Lazar, M. A.; O’Rahilly, S.; Palmer, C. N.; Plutzky, J.; Reddy, J. K.; Spiegelman, B. M.; Staels, B.; Wahli, W. International union of pharmacology. Lxi. Peroxisome proliferator-activated receptors. Pharmacol. Rev. 2006, 58, 726– 741,  DOI: 10.1124/pr.58.4.5

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    International union of pharmacology. LXI. Peroxisome proliferator-activated receptors

    Michalik, Liliane; Auwerx, Johan; Berger, Joel P.; Chatterjee, V. Krishna; Glass, Christopher K.; Gonzalez, Frank J.; Grimaldi, Paul A.; Kadowaki, Takashi; Lazar, Mitchell A.; O'Rahilly, Stephen; Palmer, Colin N. A.; Plutzky, Jorge; Reddy, Janardan K.; Spiegelman, Bruce M.; Staels, Bart; Wahli, Walter

    Pharmacological Reviews (2006), 58 (4), 726-741CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)

    A review. The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homol. with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARα is expressed at high levels in organs with significant catabolism of fatty acids. PPARβ/δ has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARγ is expressed as two isoforms, of which PPARγ2 is found at high levels in the adipose tissues, whereas PPARγ1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compds. was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARα and PPARγ agonists, resp., which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.
20. 20

    Fruchart, J. C. Peroxisome proliferator-activated receptor-alpha (pparalpha): At the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 2009, 205, 1– 8,  DOI: 10.1016/j.atherosclerosis.2009.03.008

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    Peroxisome proliferator-activated receptor-alpha (PPARα): At the crossroads of obesity, diabetes and cardiovascular disease

    Fruchart, Jean-Charles

    Atherosclerosis (Amsterdam, Netherlands) (2009), 205 (1), 1-8CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)

    A review. Cardiovascular disease is the leading cause of morbidity and mortality world-wide. The burden of disease is also increasing as a result of the global epidemics of diabetes and obesity. Peroxisome proliferator-activated receptor α (PPARα), a member of this nuclear receptor family, has emerged as an important player in this scenario, with evidence supporting a central coordinated role in the regulation of fatty acid oxidn., lipid and lipoprotein metab. and inflammatory and vascular responses, all of which would be predicted to reduce atherosclerotic risk. Addnl., the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has indicated the possibility of preventive effects in diabetes-related microvascular complications, although the mechanisms of these effects warrant further study. The multimodal pharmacol. profile of PPARα has prompted development of selective PPAR modulators (SPPARMs) to maximise therapeutic potential. It is anticipated that PPARα will continue to have important clin. application in addressing the major challenge of cardiometabolic risk assocd. with type 2 diabetes, obesity and metabolic syndrome.
21. 21

    Jones, D. Potential remains for ppar-targeted drugs. Nat. Rev. Drug Discovery 2010, 9, 668– 669,  DOI: 10.1038/nrd3271

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    Potential remains for PPAR-targeted drugs

    Jones, Dan

    Nature Reviews Drug Discovery (2010), 9 (9), 668-669CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)

    A review. The controversy over the diabetes drug rosiglitazone (Avandia; GlaxoSmithKline), a peroxisome proliferator-activated receptor-γ agonist, has undermined confidence in developing drugs that target this family of nuclear receptors, but some companies still see promise in the field.
22. 22

    Wright, M. B.; Bortolini, M.; Tadayyon, M.; Bopst, M. Minireview: Challenges and opportunities in development of ppar agonists. Mol. Endocrinol. 2014, 28, 1756– 1768,  DOI: 10.1210/me.2013-1427

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    Minireview: challenges and opportunities in development of PPAR agonists

    Wright, Matthew B.; Bortolini, Michele; Tadayyon, Moh; Bopst, Martin

    Molecular Endocrinology (2014), 28 (11), 1756-1768, 13 pp.CODEN: MOENEN; ISSN:1944-9917. (Endocrine Society)

    A review. The clin. impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.
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    Hiukka, A.; Maranghi, M.; Matikainen, N.; Taskinen, M. R. Pparalpha: An emerging therapeutic target in diabetic microvascular damage. Nat. Rev. Endocrinol. 2010, 6, 454– 463,  DOI: 10.1038/nrendo.2010.89

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    PPARα: an emerging therapeutic target in diabetic microvascular damage

    Hiukka, Anne; Maranghi, Marianna; Matikainen, Niina; Taskinen, Marja-Riitta

    Nature Reviews Endocrinology (2010), 6 (8), 454-463CODEN: NREABD; ISSN:1759-5029. (Nature Publishing Group)

    A review. Peroxisome proliferator-activated receptor α (PPARα) activation attenuates or inhibits several mediators of vascular damage, which indicates that PPARα could potentially be targeted by therapies to prevent microvascular disease in patients with diabetes. This Review focuses on the role of PPARα activation in diabetic microvascular disease and highlights the available exptl. and clin. evidence from studies of PPARα agonists. The global pandemic of diabetes mellitus portends an alarming rise in the prevalence of microvascular complications, despite advanced therapies for hyperglycemia, hypertension and dyslipidemia. Peroxisome proliferator-activated receptor α (PPARα) is expressed in organs affected by diabetic microvascular disease (retina, kidney and nerves), and its expression is regulated specifically in these tissues. Exptl. evidence suggests that PPARα activation attenuates or inhibits several mediators of vascular damage, including lipotoxicity, inflammation, reactive oxygen species generation, endothelial dysfunction, angiogenesis and thrombosis, and thus might influence intracellular signaling pathways that lead to microvascular complications. PPARα has emerged as a novel target to prevent microvascular disease, via both its lipid-related and lipid-unrelated actions. Despite strong exptl. evidence of the potential benefits of PPARα agonists in the prevention of vascular damage, the evidence from clin. studies in patients with diabetes mellitus remains limited. Promising findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study on microvascular outcomes are countered by elevations in participants' homocysteine and creatinine levels that might potentially attenuate the benefits of PPARα activation. This Review focuses on the role of PPARα activation in diabetic microvascular disease and highlights the available exptl. and clin. evidence from studies of PPARα agonists.
24. 24

    Chatterjee, S.; Majumder, A.; Ray, S. Observational study of effects of saroglitazar on glycaemic and lipid parameters on indian patients with type 2 diabetes. Sci. Rep. 2015, 5, 7706  DOI: 10.1038/srep07706

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    Observational Study of Effects of Saroglitazar on Glycaemic and Lipid Parameters on Indian Patients with Type 2 Diabetes

    Chatterjee, Sanjay; Majumder, Anirban; Ray, Subir

    Scientific Reports (2015), 5 (), 7706CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

    Cardiovascular risk redn. is an important issue in the management of patients with Type 2 diabetes mellitus. Peroxisome proliferator activated receptor (PPAR) agonists favorably influence glycemic and lipid parameters in patients with Type 2 diabetes and a dual PPAR agonist is expected to have favorable effect on both parameters. In this study we have analyzed the effect of Saroglitazar, a novel dual PPAR alpha & gamma agonist, on glycemic and lipid parameters in Indian patients with Type 2 diabetes. After a mean follow-up period of 14 wk in 34 patients, treatment with Saroglitazar, in a dose of 4 mg daily, resulted in significant improvement in both glycemic and lipid parameters. There were significant mean redns. of fasting plasma glucose (36.71 mg/dL; p = 0.0007), post-prandial plasma glucose (66.29 mg/dL; p = 0.0005), glycosylated Hb (1.13%; p < 0.0001), total cholesterol (48.16 mg/dL; p < 0.0001), low- d. lipoprotein cholesterol (24.04 mg/dL; p = 0.0048), triglyceride (192.78 mg/dL; p = 0.0001), non-high d. lipoprotein cholesterol (48.72 mg/dL; p < 0.0001) and the ratio of triglyceride and high d. lipoprotein cholesterol (5.30; p = 0.0006). There was no significant change in body wt., blood pressure, high-d. lipoprotein cholesterol and serum creatinine.
25. 25

    Gregoire, F. M.; Zhang, F.; Clarke, H. J.; Gustafson, T. A.; Sears, D. D.; Favelyukis, S.; Lenhard, J.; Rentzeperis, D.; Clemens, L. E.; Mu, Y.; Lavan, B. E. Mbx-102/jnj39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema. Mol. Endocrinol. 2009, 23, 975– 988,  DOI: 10.1210/me.2008-0473

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    25

    MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema

    Gregoire, Francine M.; Zhang, Fang; Clarke, Holly J.; Gustafson, Thomas A.; Sears, Dorothy D.; Favelyukis, Svetlana; Lenhard, James; Rentzeperis, Dennis; Clemens, L. Edward; Mu, Yi; Lavan, Brian E.

    Molecular Endocrinology (2009), 23 (7), 975-988CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)

    MBX-102/JNJ39659100 (MBX-102) is in clin. development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ that is differentiated from the TZDs structurally, mechanistically, preclinically and clin. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body wt. In vitro, in contrast with full PPAR-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-γ or α/γ agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer.
26. 26

    Fukui, Y.; Masui, S.; Osada, S.; Umesono, K.; Motojima, K. A new thiazolidinedione, nc-2100, which is a weak ppar-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of kkay obese mice. Diabetes 2000, 49, 759– 767,  DOI: 10.2337/diabetes.49.5.759

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    A new thiazolidinedione, NC-2100, which is a weak PPAR-γ activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice

    Fukui, Yuka; Masui, Sei-Ichiro; Osada, Shiho; Umesono, Kazuhiko; Motojima, Kiyoto

    Diabetes (2000), 49 (5), 759-767CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association)

    Thiazolidinediones (TZDs) reduce insulin resistance in type 2 diabetes by increasing peripheral uptake of glucose, and they bind to and activate the transcriptional factor peroxisome proliferator-activated receptor-γ (PPAR-γ). Studies have suggested that TZD-induced activation of PPAR-γ correlates with antidiabetic action, but the mechanism by which the activated PPAR-γ is involved in reducing insulin resistance is not known. To examine whether activation of PPAR-γ directly correlates with antidiabetic activities, we compared the effects of 4 TZDs (troglitazone, pioglitazone, BRL-49653, and a new deriv., NC-2100) on the activation of PPAR-γ in a reporter assay, transcription of the target genes, adipogenesis, plasma glucose and triglyceride levels, and body wt. using obese KKAy mice. There were 10- to 30-fold higher concns. of NC-2100 required for maximal activation of PPAR-γ in a reporter assay system, and only high concns. of NC-2100 weakly induced transcription of the PPAR-γ but not PPAR-α target genes in a whole mouse and adipogenesis of cultured 3T3L1 cells, which indicates that NC-2100 is a weak PPAR-γ activator. However, low concns. of NC-2100 efficiently lowered plasma glucose levels in KKAy obese mice. These results strongly suggest that TZD-induced activation of PPAR-γ does not directly correlate with antidiabetic (glucose-lowering) action. Furthermore, NC-2100 caused the smallest body wt. increase of the 4 TZDs, which may be partly explained by the finding that NC-2100 efficiently induces uncoupling protein (UCP)-2 mRNA and significantly induces UCP1 mRNA in white adipose tissue (WAT). NC-2100 induced UCP1 efficiently in mesenteric WAT and less efficiently in s.c. WAT, although pioglitazone and troglitazone also slightly induced UCP1 only in mesenteric WAT. These characteristics of NC-2100 should be beneficial for humans with limited amts. of brown adipose tissue.
27. 27

    DePaoli, A. M.; Higgins, L. S.; Henry, R. R.; Mantzoros, C.; Dunn, F. L.; INT131-007 Study Group Can a selective ppar gamma modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone?. Diabetes Care 2014, 37, 1918– 1923,  DOI: 10.2337/dc13-2480

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    Can a selective PPARγ modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone?

    DePaoli, Alex M.; Higgins, Linda S.; Henry, Robert R.; Mantzoros, Christos; Dunn, Fredrick L.

    Diabetes Care (2014), 37 (7), 1918-1923CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)

    Objective INT131 besylate is a potent, nonthiazolidinedione, selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) designed to improve glucose metab. while minimizing the side effects of full PPARγ agonists. This placebo-controlled study compared the efficacy and side effects of INT131 besylate vs. 45 mg pioglitazone HCl in subjects with type 2 diabetes (T2D). Research Design and Methods This was a 24-wk randomized, double-blind, placebo- and active-controlled study of 0.5-3.0 mg INT131 vs. 45 mg pioglitazone or placebo daily in 367 subjects with T2D on sulfonylurea or sulfonylurea plus metformin. The primary efficacy anal. was the comparison of change from baseline to week 24 in Hb A1c (HbA1c) across treatment groups. Fluid status was assessed with a prospective scoring system for lower-extremity pitting edema. Results INT131 had a steep dose response for efficacy as measured by changes in HbA1c. After 24 wk' treatment, the 0.5-mg dose demonstrated minimal efficacy (HbA1c -0.3 ± 0.12%) and the 2-mg dose demonstrated near-maximal efficacy (HbA1c -1.1 ± 0.12%), which was not statistically different from the efficacy of 45 mg pioglitazone (HbA1c -0.9 ± 0.12%; P < 0.01 for noninferiority). With the 1-mg dose, INT131 provided significant improvements in glycemic control (HbA1c 0.8 ± 0.12; P < 0.001 vs. placebo) but with less edema, wt. gain, and hemodilution than obsd. with 45 mg pioglitazone. Conclusions INT131 demonstrated dose-dependent redns. in HbA1c, equiv. to 45 mg pioglitazone, but with less fluid accumulation and wt. gain, consistent with its SPPARM design.
28. 28

    Choi, J. H.; Banks, A. S.; Estall, J. L.; Kajimura, S.; Bostrom, P.; Laznik, D.; Ruas, J. L.; Chalmers, M. J.; Kamenecka, T. M.; Bluher, M.; Griffin, P. R.; Spiegelman, B. M. Anti-diabetic drugs inhibit obesity-linked phosphorylation of ppargamma by cdk5. Nature 2010, 466, 451– 456,  DOI: 10.1038/nature09291

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    Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5

    Choi, Jang Hyun; Banks, Alexander S.; Estall, Jennifer L.; Kajimura, Shingo; Bostroem, Pontus; Laznik, Dina; Ruas, Jorge L.; Chalmers, Michael J.; Kamenecka, Theodore M.; Blueher, Matthias; Griffin, Patrick R.; Spiegelman, Bruce M.

    Nature (London, United Kingdom) (2010), 466 (7305), 451-456CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

    Obesity induced in mice by high-fat feeding activates the protein kinase Cdk5 (cyclin-dependent kinase 5) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARγ (peroxisome proliferator-activated receptor γ), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARγ does not alter its adipogenic capacity, but leads to dysregulation of a large no. of genes whose expression is altered in obesity, including a redn. in the expression of the insulin-sensitizing adipokine, adiponectin. The phosphorylation of PPARγ by Cdk5 is blocked by anti-diabetic PPARγ ligands, such as rosiglitazone and MRL24. This inhibition works both in vivo and in vitro, and is completely independent of classical receptor transcriptional agonism. Similarly, inhibition of PPARγ phosphorylation in obese patients by rosiglitazone is very tightly assocd. with the anti-diabetic effects of this drug. All these findings strongly suggest that Cdk5-mediated phosphorylation of PPARγ may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARγ.
29. 29

    Lemes, L. F. N.; de Andrade Ramos, G.; de Oliveira, A. S.; da Silva, F. M. R.; de Castro Couto, G.; da Silva Boni, M.; Guimaraes, M. J. R.; Souza, I. N. O.; Bartolini, M.; Andrisano, V.; do Nascimento Nogueira, P. C.; Silveira, E. R.; Brand, G. D.; Soukup, O.; Korabecny, J.; Romeiro, N. C.; Castro, N. G.; Bolognesi, M. L.; Romeiro, L. A. S. Cardanol-derived ache inhibitors: Towards the development of dual binding derivatives for Alzheimer’s disease. Eur. J. Med. Chem. 2016, 108, 687– 700,  DOI: 10.1016/j.ejmech.2015.12.024

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    Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease

    Lemes, Lais Flavia Nunes; Ramos, Giselle de Andrade; Souza de Oliveira, Andressa; da Silva, Fernanda Motta R.; Couto, Gina de Castro; Boni, Marina da Silva; Guimaraes, Marcos Jorge R.; Souza, Isis Nem O.; Bartolini, Manuela; Andrisano, Vincenza; Nogueira, Patricia Coelho do Nascimento; Silveira, Edilberto Rocha; Brand, Guilherme D.; Soukup, Ondrej; Korabecny, Jan; Romeiro, Nelilma C.; Castro, Newton G.; Bolognesi, Maria Laura; Romeiro, Luiz Antonio Soares

    European Journal of Medicinal Chemistry (2016), 108 (), 687-700CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    Cardanol is a phenolic lipid component of cashew nut shell liq. (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the prodn. of high-value chems., including drugs. On the basis of these findings and in connection with the authors' previous studies on cardanol derivs. as acetylcholinesterase (AChE) inhibitors, the authors designed a novel series of analogs by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new mols. to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new mols. showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compd. 26 (N-ethyl-N-(2-methoxybenzyl)-8-(3-methoxyphenyl)octan-1-amine), bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 μM, and a similar inhibition profile of the human isoform (IC50 = 5.7 μM). As another pos. feature, most of the derivs. did not show appreciable toxicity against HT-29 cells, up to a concn. of 100 μM, which indicates drug-conform behavior. Also, compd. 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.
30. 30

    Cerone, M.; Uliassi, E.; Prati, F.; Ebiloma, G. U.; Lemgruber, L.; Bergamini, C.; Watson, D. G.; Ferreira, T. d. A. M.; Roth Cardoso, G. S. H.; Soares Romeiro, L. A.; de Koning, H. P.; Bolognesi, M. L. Discovery of sustainable drugs for neglected tropical diseases: Cashew nut shell liquid (cnsl)-based hybrids target mitochondrial function and atp production in Trypanosoma brucei. ChemMedChem 2019, 14, 621– 635,  DOI: 10.1002/cmdc.201800790

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    Discovery of Sustainable Drugs for Neglected Tropical Diseases: Cashew Nut Shell Liquid (CNSL)-Based Hybrids Target Mitochondrial Function and ATP Production in Trypanosoma brucei

    Cerone, Michela; Uliassi, Elisa; Prati, Federica; Ebiloma, Godwin U.; Lemgruber, Leandro; Bergamini, Christian; Watson, David G.; Ferreira, Thais de A. M.; Roth Cardoso, Gabriella Simoes Heyn; Soares Romeiro, Luiz A.; de Koning, Harry P.; Bolognesi, Maria Laura

    ChemMedChem (2019), 14 (6), 621-635CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)

    In the search for effective and sustainable drugs for human African trypanosomiasis (HAT), we developed hybrid compds. by merging the structural features of quinone 4 (2-phenoxynaphthalene-1,4-dione) with those of phenolic constituents from cashew nut shell liq. (CNSL). CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compds. were tested against Trypanosoma brucei brucei, including three multi-drug-resistant strains, T. congolense, and a human cell line. The most potent activity was found against T. b. brucei, the causative agent of HAT. Shorter-chain derivs. 20 (2-(3-(8-hydroxyoctyl)phenoxy)-5-methoxynaphthalene-1,4-dione) and 22 (5-hydroxy-2-(3-(8-hydroxyoctyl)phenoxy)naphthalene-1,4-dione) were more active than 4, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species prodn. We envisage that such compds., obtained from a renewable and inexpensive material, might be promising bio-based sustainable hits for anti-trypanosomatid drug discovery.
31. 31

    Rossi, M.; Freschi, M.; de Camargo Nascente, L.; Salerno, A.; de Melo Viana Teixeira, S.; Nachon, F.; Chantegreil, F.; Soukup, O.; Prchal, L.; Malaguti, M.; Bergamini, C.; Bartolini, M.; Angeloni, C.; Hrelia, S.; Soares Romeiro, L. A.; Bolognesi, M. L. Sustainable drug discovery of multi-target-directed ligands for Alzheimer’s disease. J. Med. Chem. 2021, 64, 4972– 4990,  DOI: 10.1021/acs.jmedchem.1c00048

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    Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease

    Rossi, Michele; Freschi, Michela; de Camargo Nascente, Luciana; Salerno, Alessandra; de Melo Viana Teixeira, Sarah; Nachon, Florian; Chantegreil, Fabien; Soukup, Ondrej; Prchal, Lukas; Malaguti, Marco; Bergamini, Christian; Bartolini, Manuela; Angeloni, Cristina; Hrelia, Silvana; Soares Romeiro, Luiz Antonio; Bolognesi, Maria Laura

    Journal of Medicinal Chemistry (2021), 64 (8), 4972-4990CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liq. (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the obsd. activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01μM), confirming the design rationale.
32. 32

    de Andrade Ramos, G.; Souza de Oliveira, A.; Bartolini, M.; Naldi, M.; Liparulo, I.; Bergamini, C.; Uliassi, E.; Wu, L.; Fraser, P. E.; Abreu, M.; Kiametis, A. S.; Gargano, R.; Silveira, E. R.; Brand, G. D.; Prchal, L.; Soukup, O.; Korábečný, J.; Bolognesi, M. L.; Soares Romeiro, L. A. Discovery of sustainable drugs for Alzheimer’s disease: Cardanol-derived cholinesterase inhibitors with antioxidant and anti-amyloid properties. RSC Med. Chem. 2021, 12, 1154– 1163,  DOI: 10.1039/D1MD00046B

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    Discovery of sustainable drugs for Alzheimer's disease: cardanol-derived cholinesterase inhibitors with antioxidant and anti-amyloid properties

    de Andrade Ramos, Giselle; Souza de Oliveira, Andressa; Bartolini, Manuela; Naldi, Marina; Liparulo, Irene; Bergamini, Christian; Uliassi, Elisa; Wu, Ling; Fraser, Paul E.; Abreu, Monica; Kiametis, Alessandra Sofia; Gargano, Ricardo; Silveira, Edilberto Rocha; Brand, Guilherme D.; Prchal, Lukas; Soukup, Ondrej; Korabecny, Jan; Bolognesi, Maria Laura; Soares Romeiro, Luiz Antonio

    RSC Medicinal Chemistry (2021), 12 (7), 1154-1163CODEN: RMCSEZ; ISSN:2632-8682. (Royal Society of Chemistry)

    As part of our efforts to develop sustainable drugs for Alzheimer's disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liq. (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compds. with concomitant anti-amyloid and antioxidant activities. Ten new derivs., carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). 5 and 11 were found to inhibit human BChE at a single-digit micromolar concn. Transmission electron microscopy revealed the potential of five derivs. to modulate Aβ aggregation, including 5 and 11. In HORAC assays, 5 and 11 performed similarly to std. antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in in vitro studies in neuronal cell cultures, 5 and 11 were found to effectively inhibit reactive oxygen species prodn. at a 10 μM concn. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD.
33. 33

    de Souza, M. Q.; Teotonio, I.; de Almeida, F. C.; Heyn, G. S.; Alves, P. S.; Romeiro, L. A. S.; Pratesi, R.; de Medeiros Nobrega, Y. K.; Pratesi, C. B. Molecular evaluation of anti-inflammatory activity of phenolic lipid extracted from cashew nut shell liquid (cnsl). BMC Complementary Altern. Med. 2018, 18, 181  DOI: 10.1186/s12906-018-2247-0

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    Molecular evaluation of anti-inflammatory activity of phenolic lipid extracted from cashew nut shell liquid (CNSL)

    de Souza, Marilen Queiroz; Teotonio, Isabella Marcia Soares Nogueira; de Almeida, Fernanda Coutinho; Heyn, Gabriella Simoes; Alves, Priscilla Souza; Romeiro, Luiz Antonio Soares; Pratesi, Riccardo; de Medeiros Nobrega, Yanna Karla; Pratesi, Claudia B.

    BMC Complementary and Alternative Medicine (2018), 18 (), 181/1-181/11CODEN: BCAMCV; ISSN:1472-6882. (BioMed Central Ltd.)

    The objective of the present study was to evaluate the anti-inflammatory profile of a deriv., synthesized from LDT11, on an in vitro cellular model. Org. synthesis of the phenolic deriv. of CNSL that results in the hemi-synthetic compd. LDT11. The cytotoxicity of the planned compd., LDT11, was analyzed in murine macrophages cell line, RAW264.7. The anal. of the gene expression of inflammatory markers (TNFα, iNOS, COX-2, NF-κB,IL-1β and IL-6), nitric oxide (NO) dosage, and cytokine IL-6 were realized. He results showed that the phenolic deriv., LDT11, influenced the modulatory gene expression. The relative gene transcripts quantification demonstrated that the LDT11 disclosed an immunoprotective effect against inflammation by decreasing genes expression when compared with cells stimulated with LPS in the control group. The present study evaluated the immunoprotective effect of LDT11. In addn. to a significant redn. in the expression of inflammatory genes, LDT11 also had a faster and superior anti-inflammatory action than the com. products, and its response was already evident in the test carried out six hours after the treatment of the cells. This study demonstrated LDT11 is potentially valuable as a rapid immunoprotective anti-inflammatory agent. Treatment with LDT11 decreased the gene expression of inflammatory markers, and the NO, and IL-6 prodn. When compared to com. drugs, LDT11 showed a superior anti-inflammatory action.
34. 34

    Gomes Júnior, A. L.; Islam, M. T.; Nicolau, L. A. D.; de Souza, L. K. M.; Araujo, T. S. L.; Lopes de Oliveira, G. A.; de Melo Nogueira, K.; da Silva Lopes, L.; Medeiros, J. R.; Mubarak, M. S.; Melo-Cavalcante, A. A. C. Anti-inflammatory, antinociceptive, and antioxidant properties of anacardic acid in experimental models. ACS Omega 2020, 5, 19506– 19515,  DOI: 10.1021/acsomega.0c01775

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    Anti-Inflammatory, Antinociceptive, and Antioxidant Properties of Anacardic Acid in Experimental Models

    Gomes Junior, Antonio Luiz; Islam, Muhammad Torequl; Nicolau, Lucas Antonio Duarte; de Souza, Luan Kevin Miranda; Araujo, Tiago de Souza Lopes; Lopes de Oliveira, Guilherme Antonio; de Melo Nogueira, Kerolayne; da Silva Lopes, Luciano; Medeiros, Jand-Venes Rolim; Mubarak, Mohammad S.; Melo-Cavalcante, Ana Amelia de Carvalho

    ACS Omega (2020), 5 (31), 19506-19515CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)

    Anacardic acid (AA), a compd. extd. from cashew nut liq., exhibits numerous pharmacol. activities. The aim of the current investigation was to assess the anti-inflammatory, antinociceptive, and antioxidant activities of AA in mouse models. For this, Swiss albino mice were pretreated with AA (10, 25, 50 mg/kg, i.p., i.p.) 30 min prior to the administration of carrageenan, as well as 25 mg/kg of prostaglandin E2, dextran, histamine, and compd. 48/80. The antinociceptive activity was evaluated by formalin, abdominal, and hot plate tests, using antagonist of opioid receptors (naloxene, 3 mg/kg, i.p.) to identify antinociceptive mechanisms. Results from this study revealed that AA at 25 mg/kg inhibits carrageenan-induced edema. In addn., AA at 25 mg/kg reduced edema and leukocyte and neutrophilic migration to the i.p. cavity, diminished myeloperoxidase activity and malondialdehyde concn., and increased the levels of reduced glutathione. In nociceptive tests, it also decreased licking, abdominal writhing, and latency to thermal stimulation, possibly via interaction with opioid receptors. Taken together, these results indicate that AA exhibits anti-inflammatory and antinociceptive actions and also reduces oxidative stress in acute exptl. models, suggesting AA as a promising compd. in the pharmaceutical arena.
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    Stasiuk, M.; Kozubek, A. Biological activity of phenolic lipids. Cell. Mol. Life Sci. 2010, 67, 841– 860,  DOI: 10.1007/s00018-009-0193-1

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    Biological activity of phenolic lipids

    Stasiuk, Maria; Kozubek, A.

    Cellular and Molecular Life Sciences (2010), 67 (6), 841-860CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)

    A review. Phenolic lipids are a very diversified group of compds. derived from mono and dihydroxyphenols, i.e., phenol, catechol, resorcinol, and hydroquinone. Due to their strong amphiphilic character, these compds. can incorporate into erythrocytes and liposomal membranes. In this review, the antioxidant, antigenotoxic, and cytostatic activities of resorcinolic and other phenolic lipids are described. The ability of these compds. to inhibit bacterial, fungal, protozoan and parasite growth seems to depend on their interaction with proteins and/or on their membrane-disturbing properties.
36. 36

    Sung, B.; Pandey, M. K.; Ahn, K. S.; Yi, T.; Chaturvedi, M. M.; Liu, M.; Aggarwal, B. B. Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-kappab-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-kappabalpha kinase, leading to potentiation of apoptosis. Blood 2008, 111, 4880– 4891,  DOI: 10.1182/blood-2007-10-117994

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    Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-κB-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-κBα kinase, leading to potentiation of apoptosis

    Sung, Bokyung; Pandey, Manoj K.; Ahn, Kwang Seok; Yi, Tingfang; Chaturvedi, Madan M.; Liu, Mingyao; Aggarwal, Bharat B.

    Blood (2008), 111 (10), 4880-4891CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)

    Anacardic acid (6-pentadecylsalicylic acid) is derived from traditional medicinal plants, such as cashew nuts, and has been linked to anticancer, anti-inflammatory, and radiosensitization activities through a mechanism that is not yet fully understood. Because of the role of nuclear factor-κB (NF-κB) activation in these cellular responses, we postulated that anacardic acid might interfere with this pathway. We found that this salicylic acid potentiated the apoptosis induced by cytokine and chemotherapeutic agents, which correlated with the down-regulation of various gene products that mediate proliferation (cyclin D1 and cyclooxygenase-2), survival (Bcl-2, Bcl-xL, cFLIP, cIAP-1, and survivin), invasion (matrix metalloproteinase-9 and intercellular adhesion mol.-1), and angiogenesis (vascular endothelial growth factor), all known to be regulated by the NF-κB. We found that anacardic acid inhibited both inducible and constitutive NF-κB activation; suppressed the activation of IκBα kinase that led to abrogation of phosphorylation and degrdn. of IκBα; inhibited acetylation and nuclear translocation of p65; and suppressed NF-κB-dependent reporter gene expression. Down-regulation of the p300 histone acetyltransferase gene by RNA interference abrogated the effect of anacardic acid on NF-κB suppression, suggesting the crit. role of this enzyme. Overall, our results demonstrate a novel role for anacardic acid in potentially preventing or treating cancer through modulation of NF-κB signaling pathway.
37. 37

    Uliassi, E.; de Oliveira, A. S.; de Camargo Nascente, L.; Romeiro, L. A. S.; Bolognesi, M. L. Cashew nut shell liquid (CNSL) as a source of drugs for Alzheimer’s disease. Molecules 2021, 26, 5441  DOI: 10.3390/molecules26185441

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    Cashew Nut Shell Liquid (CNSL) as a Source of Drugs for Alzheimer's Disease

    Uliassi, Elisa; de Oliveira, Andressa Souza; de Camargo Nascente, Luciana; Romeiro, Luiz Antonio Soares; Bolognesi, Maria Laura

    Molecules (2021), 26 (18), 5441CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)

    A review. Alzheimer's disease (AD) is a complex neurodegenerative disorder with a multifaceted pathogenesis. This fact has long halted the development of effective anti-AD drugs. Recently, a therapeutic strategy based on the exploitation of Brazilian biodiversity was set with the aim of discovering new disease-modifying and safe drugs for AD. In this review, we will illustrate our efforts in developing new mols. derived from Brazilian cashew nut shell liq. (CNSL), a natural oil and a byproduct of cashew nut food processing, with a high content of phenolic lipids. The rational modification of their structures has emerged as a successful medicinal chem. approach to the development of novel anti-AD lead candidates. The biol. profile of the newly developed CNSL derivs. towards validated AD targets will be discussed together with the role of these mol. targets in the context of AD pathogenesis.
38. 38

    Proschak, E.; Heitel, P.; Kalinowsky, L.; Merk, D. Opportunities and challenges for fatty acid mimetics in drug discovery. J. Med. Chem. 2017, 60, 5235– 5266,  DOI: 10.1021/acs.jmedchem.6b01287

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    Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery

    Proschak, Ewgenij; Heitel, Pascal; Kalinowsky, Lena; Merk, Daniel

    Journal of Medicinal Chemistry (2017), 60 (13), 5235-5266CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling mols. regulating various physiol. effects in metab. and inflammation. Accordingly, the mol. targets involved in formation and physiol. activities of fatty acids hold significant therapeutic potential. A no. of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compds. orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compds. showing specific binding thermodn. and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.
39. 39

    Tontonoz, P.; Hu, E.; Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by ppar gamma 2, a lipid-activated transcription factor. Cell 1994, 79, 1147– 1156,  DOI: 10.1016/0092-8674(94)90006-X

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    Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor

    Tontonoz P; Hu E; Spiegelman B M

    Cell (1994), 79 (7), 1147-56 ISSN:0092-8674.

    Peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2) is an adipocyte-specific nuclear hormone receptor that has recently been identified as a key regulator of two fat cell enhancers. Transcriptional activation by PPAR gamma 2 is potentiated by a variety of lipids and lipid-like compounds, including naturally occurring polyunsaturated fatty acids. We demonstrate here that retroviral expression of PPAR gamma 2 stimulates adipose differentiation of cultured fibroblasts. PPAR activators promote the differentiation of PPAR gamma 2-expressing cells in a dose-dependent manner. C/EBP alpha, a second transcription factor induced during adipocyte differentiation, can cooperate with PPAR gamma 2 to stimulate the adipocyte program dramatically. Our results suggest that the physiologic role of PPAR gamma 2 is to regulate development of the adipose lineage in response to endogenous lipid activators and that this factor may serve to link the process of adipocyte differentiation to systemic lipid metabolism.
40. 40

    Nesto, R. W.; Bell, D.; Bonow, R. O.; Fonseca, V.; Grundy, S. M.; Horton, E. S.; Le Winter, M.; Porte, D.; Semenkovich, C. F.; Smith, S.; Young, L. H.; Kahn, R. Thiazolidinedione use, fluid retention, and congestive heart failure. Diabetes Care 2004, 27, 256– 263,  DOI: 10.2337/diacare.27.1.256

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    Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association

    Nesto, Richard W.; Bell, David; Bonow, Robert O.; Fonseca, Vivian; Grundy, Scott M.; Horton, Edward S.; Le Winter, Martin; Porte, Daniel; Semenkovich, Clay F.; Smith, Sidney; Young, Lawrence H.; Kahn, Richard

    Diabetes Care (2004), 27 (1), 256-263CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)

    The review discusses cardiovascular risk factors related to the use of antidiabetic agents rosiglitazone and pioglitazone.
41. 41

    Miyazaki, Y.; Mahankali, A.; Matsuda, M.; Mahankali, S.; Hardies, J.; Cusi, K.; Mandarino, L. J.; DeFronzo, R. A. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J. Clin. Endocrinol. Metab. 2002, 87, 2784– 2791,  DOI: 10.1210/jcem.87.6.8567

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    Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients

    Miyazaki, Yoshinori; Mahankali, Archana; Matsuda, Masafumi; Mahankali, Srikanth; Hardies, Jean; Cusi, Kenneth; Mandarino, Lawrence J.; DeFronzo, Ralph A.

    Journal of Clinical Endocrinology and Metabolism (2002), 87 (6), 2784-2791CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)

    We examd. the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52±3 yr; body mass index, 29.0±1.1 kg/m2), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m2 min) with [3H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4-5. After 16 wk of pioglitazone treatment, fasting plasma glucose (179±10 to 140±10 mg/dL; P < 0.01), mean plasma glucose during OGTT (295±13 to 233±14 mg/dL; P < 0.01), and Hb A1c (8.6±0.4% to 7.2±0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674±38 to 569±31 μEq/L; P < 0.05) and mean plasma FFA (539±20 to 396±29 μEq/L; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose prodn. (EGP) × basal plasma insulin concn.] decreased from 41±7 to 25±3 mg/kg fat-free mass (FFM)( min × μU/mL; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1±0.1 to 0.6±0.2 mg/kg FFM-min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5±0.5 to 4.4±0.4 mL/kg FFM-min (P < 0.05); second MCR, 8.7±1.0 to 11.3±1.1 mL/kg FFM min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body wt. (82±4 to 85±4 kg; P < 0.05) and fat mass (27±2 to 30±3 kg; P < 0.05). After pioglitazone treatment, s.c. fat area at L4-5 (301±44 to 342±44 cm2; P < 0.01) increased, whereas visceral fat area at L4-5 (144±13 to 131±16 cm2; P < 0.05) and the ratio of visceral to s.c. fat (0.59±0.08 to 0.44±0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP × basal immunoreactive insulin) correlated pos. with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = -0.45; P < 0.05) and second (r = -0.44; P < 0.05) insulin clamp steps were neg. correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to s.c. adipose depots after pioglitazone treatment is assocd. with improvements in hepatic and peripheral tissue sensitivity to insulin.
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    Stern, J. H.; Rutkowski, J. M.; Scherer, P. E. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 2016, 23, 770– 784,  DOI: 10.1016/j.cmet.2016.04.011

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    Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk

    Stern, Jennifer H.; Rutkowski, Joseph M.; Scherer, Philipp E.

    Cell Metabolism (2016), 23 (5), 770-784CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)

    Metab. research has made tremendous progress over the last several decades in establishing the adipocyte as a central rheostat in the regulation of systemic nutrient and energy homeostasis. Operating at multiple levels of control, the adipocyte communicates with organ systems to adjust gene expression, glucoregulatory hormone exocytosis, enzymic reactions, and nutrient flux to equilibrate the metabolic demands of a pos. or neg. energy balance. The identification of these mechanisms has great potential to identify novel targets for the treatment of diabetes and related metabolic disorders. Herein, we review the central role of the adipocyte in the maintenance of metabolic homeostasis, highlighting three crit. mediators: adiponectin, leptin, and fatty acids.
43. 43

    Maeda, N.; Takahashi, M.; Funahashi, T.; Kihara, S.; Nishizawa, H.; Kishida, K.; Nagaretani, H.; Matsuda, M.; Komuro, R.; Ouchi, N.; Kuriyama, H.; Hotta, K.; Nakamura, T.; Shimomura, I.; Matsuzawa, Y. Ppar gamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001, 50, 2094– 2099,  DOI: 10.2337/diabetes.50.9.2094

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    PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein

    Maeda, Norikazu; Takahashi, Masahiko; Funahashi, Tohru; Kihara, Shinji; Nishizawa, Hitoshi; Kishida, Ken; Nagaretani, Hiroyuki; Matsuda, Morihiro; Komuro, Ryutaro; Ouchi, Noriyuki; Kuriyama, Hiroshi; Hotta, Kikuko; Nakamura, Tadashi; Shimomura, Iichiro; Matsuzawa, Yuji

    Diabetes (2001), 50 (9), 2094-2099CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association)

    Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion mol. expression in vascular endothelial cells and cytokine prodn. from macrophages. Plasma adiponectin concns. are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPARγ ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concns. in insulin resistant humans and rodents without affecting their body wt. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivs. enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-α, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-α. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the prodn. of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-α on the adiponectin promoter.
44. 44

    Tiefenbach, J.; Moll, P. R.; Nelson, M. R.; Hu, C.; Baev, L.; Kislinger, T.; Krause, H. M. A live zebrafish-based screening system for human nuclear receptor ligand and cofactor discovery. PLoS One 2010, 5, e9797  DOI: 10.1371/journal.pone.0009797

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    Kamata, S.; Oyama, T.; Saito, K.; Honda, A.; Yamamoto, Y.; Suda, K.; Ishikawa, R.; Itoh, T.; Watanabe, Y.; Shibata, T.; Uchida, K.; Suematsu, M.; Ishii, I. Pparalpha ligand-binding domain structures with endogenous fatty acids and fibrates. iScience 2020, 23, 101727  DOI: 10.1016/j.isci.2020.101727

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    PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates

    Kamata, Shotaro; Oyama, Takuji; Saito, Kenta; Honda, Akihiro; Yamamoto, Yume; Suda, Keisuke; Ishikawa, Ryo; Itoh, Toshimasa; Watanabe, Yasuo; Shibata, Takahiro; Uchida, Koji; Suematsu, Makoto; Ishii, Isao

    iScience (2020), 23 (11), 101727CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)

    Most triacylglycerol-lowering fibrates have been developed in the 1960s-1980s before their mol. target, peroxisome proliferator-activated receptor alpha (PPARα), was identified. Twenty-one ligand-bound PPARα structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiol. ligands remain unknown. Here we show thirty-four X-ray crystallog. structures of the PPARα ligand-binding domain, which are composed of a "Center" and four "Arm" regions, in complexes with five endogenous fatty acids, six fibrates in clin. use, and six synthetic PPARα agonists. High-resoln. structural anal., in combination with coactivator recruitment and thermostability assays, demonstrate that stearic and palmitic acids are presumably physiol. ligands; coordination to Arm III is important for high PPARα potency/selectivity of pemafibrate and GW7647; and agonistic activities of four fibrates are enhanced by the partial agonist GW9662. These results renew our understanding of PPARα ligand recognition and contribute to the mol. design of next-generation PPAR-targeted drugs.
46. 46

    Itoh, T.; Fairall, L.; Amin, K.; Inaba, Y.; Szanto, A.; Balint, B. L.; Nagy, L.; Yamamoto, K.; Schwabe, J. W. Structural basis for the activation of ppargamma by oxidized fatty acids. Nat. Struct. Mol. Biol. 2008, 15, 924– 931,  DOI: 10.1038/nsmb.1474

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    Structural basis for the activation of PPARγ by oxidized fatty acids

    Itoh, Toshimasa; Fairall, Louise; Amin, Kush; Inaba, Yuka; Szanto, Attila; Balint, Balint L.; Nagy, Laszlo; Yamamoto, Keiko; Schwabe, John W. R.

    Nature Structural & Molecular Biology (2008), 15 (9), 924-931CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)

    PPARγ is a nuclear receptor that regulates metabolic homeostasis and whose physiol. ligands are nitrated and oxidized fatty acids. The crystal structures of the ligand binding domain of PPARγ in complex with several oxidized fatty acids are now described, showing differences with synthetic agonists that may have physiol. relevance. PPARγ is a nuclear receptor that regulates metabolic homeostasis and whose physiol. ligands are nitrated and oxidized fatty acids. The crystal structures of the ligand binding domain of PPARγ in complex with several oxidized fatty acids are now described, showing differences with synthetic agonists that may have physiol. relevance. The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) has important roles in adipogenesis and immune response as well as roles in both lipid and carbohydrate metab. Although synthetic agonists for PPARγ are widely used as insulin sensitizers, the identity of the natural ligand(s) for PPARγ is still not clear. Suggested natural ligands include 15-deoxy-Δ12,14-prostaglandin J2 and oxidized fatty acids such as 9-HODE and 13-HODE. Crystal structures of PPARγ have revealed the mode of recognition for synthetic compds. Here we report structures of PPARγ bound to oxidized fatty acids that are likely to be natural ligands for this receptor. These structures reveal that the receptor can (i) simultaneously bind two fatty acids and (ii) couple covalently with conjugated oxo fatty acids. Thermal stability and gene expression analyses suggest that such covalent ligands are particularly effective activators of PPARγ and thus may serve as potent and biol. relevant ligands.
47. 47

    Shang, J.; Brust, R.; Griffin, P. R.; Kamenecka, T. M.; Kojetin, D. J. Quantitative structural assessment of graded receptor agonism. Proc. Natl. Acad. Sci. U.S.A. 2019, 116, 22179– 22188,  DOI: 10.1073/pnas.1909016116

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    Quantitative structural assessment of graded receptor agonism

    Shang, Jinsai; Brust, Richard; Griffin, Patrick R.; Kamenecka, Theodore M.; Kojetin, Douglas J.

    Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (44), 22179-22188CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Ligan-receptor interactions, which are ubiquitous in physiol., are described by theor. models of receptor pharmacol. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is crit. to fully validate theor. models. We applied quant. structure-function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). For all ligands, agonist functional efficacy is correlated to a shift in the conformational ensemble equil. from a ground state toward an active state, which is detected by NMR spectroscopy but not obsd. in crystal structures. For the structurally similar ligands, ligand potency and affinity are also correlated to efficacy and conformation, indicating ligand residence times among related analogs may influence receptor conformation and function. Our results derived from quant. graded activity-conformation correlations provide exptl. evidence and a platform with which to extend and test theor. models of receptor pharmacol. to more accurately describe and predict ligand-dependent receptor activity.
48. 48

    Yoshikawa, C.; Ishida, H.; Ohashi, N.; Itoh, T. Synthesis of a coumarin-based ppargamma fluorescence probe for competitive binding assay. Int. J. Mol. Sci. 2021, 22, 4034  DOI: 10.3390/ijms22084034

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    Synthesis of a Coumarin-Based PPARγ Fluorescence Probe for Competitive Binding Assay

    Yoshikawa, Chisato; Ishida, Hiroaki; Ohashi, Nami; Itoh, Toshimasa

    International Journal of Molecular Sciences (2021), 22 (8), 4034CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    Peroxisome proliferator-activated receptorγ is a mol. target of metabolic syndrome and inflammatory disease. PPARγ is an important nuclear receptor and numerous & ligands were developed to date; thus, efficient assay methods are important. Here, we investigated the incorporation of 7-diethylamino coumarin into the PPARγ agonist rosiglitazone and used the compd. in a binding assay for PPARγ. PPARγ-ligand-incorporated 7-methoxycoumarin, 1, showed weak fluorescence intensity in a previous report. We synthesized PPARγ-ligand-incorporating coumarin, 2, in this report, and it enhanced the fluorescence intensity. The PPARγ ligand 2 maintained the rosiglitazone activity. The obtained partial agonist 6 appeared to act through a novel mechanism. The fluorescence intensity of 2 and 6 increased by binding to the ligand binding domain (LBD) of PPARγ and the affinity of reported PPARγ ligands were evaluated using the probe.
49. 49

    Wu, C. C.; Baiga, T. J.; Downes, M.; La Clair, J. J.; Atkins, A. R.; Richard, S. B.; Fan, W.; Stockley-Noel, T. A.; Bowman, M. E.; Noel, J. P.; Evans, R. M. Structural basis for specific ligation of the peroxisome proliferator-activated receptor delta. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, E2563– E2570,  DOI: 10.1073/pnas.1621513114

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    49

    Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ

    Wu, Chyuan-Chuan; Baiga, Thomas J.; Downes, Michael; La Clair, James J.; Atkins, Annette R.; Richard, Stephane B.; Fan, Weiwei; Stockley-Noel, Theresa A.; Bowman, Marianne E.; Noel, Joseph P.; Evans, Ronald M.

    Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (13), E2563-E2570CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    The peroxisome proliferator-activated receptor (PPAR) family comprises 3 subtypes: PPARα, PPARγ, and PPARδ. PPARδ transcriptionally modulates lipid metab. and the control of energy homeostasis; therefore, PPARδ agonists are promising agents for treating a variety of metabolic disorders. In the present study, we developed a panel of rationally designed PPARδ agonists. The modular motif afforded efficient syntheses using building blocks optimized for interactions with subtype-specific residues in the PPARδ ligand-binding domain (LBD). A combination of at.-resoln. protein x-ray crystallog. structures, ligand-dependent LBD stabilization assays, and cell-based transactivation measurements delineated structure-activity relations (SARs) for PPARδ-selective targeting and structural modulation. We identified key ligand-induced conformational transitions of a conserved Trp side-chain in the LBD that triggered reorganization of the H2'-H3 surface segment of PPARδ. The subtype-specific conservation of H2'-H3 sequences suggested that this architectural remodeling constitutes a previously unrecognized conformational switch accompanying ligand-dependent PPARδ transcriptional regulation.
50. 50

    Patel, R.; Patel, M.; Tsai, R.; Lin, V.; Bookout, A. L.; Zhang, Y.; Magomedova, L.; Li, T.; Chan, J. F.; Budd, C.; Mangelsdorf, D. J.; Cummins, C. L. LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. J Clin Invest. 2011, 121, 431– 441,  DOI: 10.1172/JCI41681

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    LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

    Patel, Rucha; Patel, Monika; Tsai, Ricky; Lin, Vicky; Bookout, Angie L.; Zhang, Yuan; Magomedova, Lilia; Li, Tingting; Chan, Jessica F.; Budd, Conrad; Mangelsdorf, David J.; Cummins, Carolyn L.

    Journal of Clinical Investigation (2011), 121 (1), 431-441CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

    Although widely prescribed for their potent antiinflammatory actions, glucocorticoid drugs (e.g., dexamethasone) cause undesirable side effects that are features of the metabolic syndrome, including hyperglycemia, fatty liver, insulin resistance, and type II diabetes. Liver x receptors (LXRs) are nuclear receptors that respond to cholesterol metabolites and regulate the expression of a subset of glucocorticoid target genes. Here, we show LXRβ is required to mediate many of the neg. side effects of glucocorticoids. Mice lacking LXRβ (but not LXRα) were resistant to dexamethasone-induced hyperglycemia, hyperinsulinemia, and hepatic steatosis, but remained sensitive to dexamethasone-dependent repression of the immune system. In vivo, LXRα/β knockout mice demonstrated reduced dexamethasone-induced expression of the key hepatic gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK). In perfused liver and primary mouse hepatocytes, LXRβ was required for glucocorticoid-induced recruitment of the glucocorticoid receptor to the PEPCK promoter. These findings suggest a new avenue for the design of safer glucocorticoid drugs through a mechanism of selective glucocorticoid receptor transactivation.