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Molecular Basis of the Beneficial Actions of Resveratrol
Archives of Medical Research
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REVIEW ARTICLE
Molecular Basis of the Beneficial Actions of Resveratrol Gast on Repossi,a Undurti N. Das,b and Aldo Renato Eynarda a
Instituto de Investigaciones en Ciencias de la Salud, Catedra de Biologıa Celular, Histologıa y Embriologıa, Facultad de Ciencias Medicas, Universidad Nacional de Cordoba, Ciudad Universitaria, Cordoba, Argentina b UND Life Sciences, Battle Ground, Washington, USA Received for publication December 31, 2019; accepted January 24, 2020 (ARCMED_2019_1186).
Resveratrol modulates the transcription factor NF-kB, cytochrome P450 isoenzyme CYP1A1, expression and activity of cyclooxygenase (COX) enzymes, Fas/Fas ligand mediated apoptosis, p53, mTOR and cyclins and various phospho-diesterases resulting in an increase in cytosolic cAMP levels. Cyclic AMP, in turn, activates Epac1/CaMKKb/ AMPK/SIRT1/PGC-1a pathway that facilitates increased oxidation of fatty acids, mitochondrial respiration and their biogenesis and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-a (TNF-a), interleukin-17 (IL-17) and other pro-inflammatory molecules and inhibits expression of hypoxia inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) that may explain its anti-inflammatory actions. Polyunsaturated fatty acids (PUFAs) and their anti-inflammatory metabolites lipoxin A4, resolvins, protectins and maresins have a significant role in obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome and cancer. We observed that PUFAs (especially arachidonic acid, AA) and BDNF (brain-derived neurotrophic factor) protect against the cytotoxic actions of alloxan, streptozotocin, benzo(a)pyrene (BP) and doxorubicin. Thus, there is an overlap in the beneficial actions of resveratrol, PUFAs and BDNF suggesting that these molecules may interact and augment synthesis and action of each other. This is supported by the observation that resveratrol and PUFAs modulate gut microbiota and influence stem cell proliferation and differentiation. Since resveratrol is not easily absorbed from the gut it is likely that it may act on endocannabinoid and light, odor, and taste receptors located in the gut, which, in turn, convey their messages to the various organs via vagus nerve. Ó 2020 IMSS. Published by Elsevier Inc. Key Words: Resveratrol, Polyunsaturated fatty acids, Brain-derived neurotrophic factor, Cytotoxic, Lipoxin A4, Metabolic syndrome, Cancer.
Introduction Resveratrol (3,5,40 -trihydroxy-trans-stilbene) (RSV) is a stilbenoid produced by several plants in response to injury or pathogens such as bacteria or fungi. Food sources of RSV include the skin of grapes, blueberries, raspberries, and mulberries. Highest concentrations of RSV are present in grape, and, more precisely, in grape skin. Thus, red wine is the most concentrated food source of RSV (1e3). Resveratrol exists as two geometric isomers: cis- (Z ) and trans- (E ). The trans- and cis resveratrol can be either free
Address reprint requests to: Undurti N. Das, UND Life Sciences, 2221 NW 5th St. Battle Ground, Washington, WA 98604, USA; Phone: (þ54) 0351 4334020; FAX: þ54 0351 4334021; E-mail: [email protected]
or bound to glucose. The trans- form seems to have the major biological effects. The anti-inflammatory actions of flavonoid RSV is mediated by its modulatory actions on transcription factor NF-kB, cytochrome P450 isoenzyme CYP1A1, cyclooxygenase (COX) enzymes, Fas/Fas ligand mediated apoptosis, p53, mTOR, cyclins, various phospho-diesterases and Epac1/CaMKKb/AMPK/SIRT1/PGC-1a pathway. These actions facilitate increased oxidation of fatty acids, mitochondrial biogenesis and respiration, and gluconeogenesis. RSV induces apoptosis of activated T cells and suppresses the production of pro-inflammatory tumor necrosis factor-a (TNF-a), interleukin-17 (IL-17) and other pro-inflammatory molecules. RSV inhibits expressions of hypoxia inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) leading to a decrease in
0188-4409/$ - see front matter. Copyright Ó 2020 IMSS. Published by Elsevier Inc. https://doi.org/10.1016/j.arcmed.2020.01.010
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neo-angiogenesis implying that it could be of benefit in diabetic retinopathy (DR) (4,5) and cancer (6). RSV activates Sirtuin 1 (SIRT1) (7), a molecule belonging to histone deacetylases, and peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) and thus, improves the function of mitochondria (8,9). Since SIRT1 may function as an antiageing molecule and delays age-associated diseases, it suggests that RSV may have similar function. Overexpression of SIRT1 and RSV enhances insulin sensitivity (10e13) and could be of benefit in DR (14e17) (Figures 1 and 2). RSV binds to tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) to enhance a poly (ADP-ribose) polymerase 1 (PARP1)/NADþ driven signaling cascade to activate p53 (18). Cells treated with RSV showed a 14 fold increase in the action of superoxide dismutase (SOD) (19) that led to reduced levels of superoxide anion resulting in restoration of mitochondrial dysfunction to normal. RSV by activating SIRT1 favors migration of FOXO transcription factors to the nucleus (20), which stimulates FOXO3a transcriptional activity (21). SOD is a target of FOXO3a, and MnSOD expression is strongly induced in cells overexpressing FOXO3a (20). High expression of SOD with mild changes in catalase (CAT) and glutathione peroxidase (GPX) expression in cancer cells results in the mitochondrial
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accumulation of H2O2 leading to cancer cell apoptosis (21). This is somewhat similar to the actions of exercise, which also causes strong up-regulation of SOD, CAT and GPX. These results are interesting since regular exercise decreases the incidence of cancer (6,22,23). Resveratrol Suppresses Inflammation and has Cytoprotective Properties RSV has anti-inflammatory actions. For example, RSV triggers apoptosis of activated T cells and downregulates TNFa, interferon-g (IFN-g), interleukin (IL)-2, IL-9, IL-12, IL17, macrophage inflammatory protein-1a (MIP-1 a), and monocyte chemoattractant protein-1 (MCP-1) secretion (24e30). RSV inhibits both HIF-1a and VEGF that are overexpressed in DR and in cancer that may explain some of its beneficial actions (31e33). The anti-inflammatory actions of RSV are in support of its beneficial actions in inflammatory and autoimmune diseases (34e38) (Figure 2). In addition, RSV has cytoprotective actions. Bisphenol, an endocrine disruptor present in plastics and the end product component of the degradation of industrial plasticrelated wastes, is known to promote development and progression of estrogen-dependent cancer and increase cell
Figure 1. Scheme showing various actions of resveratrol that may form the basis of its beneficial actions. (modified from https://https://doi.org/10.1016/j.nut. 2015.08.017).
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Figure 2. Scheme showing the actions of resveratrol. Macrophages (MF), Programmed Cell Death-1 protein (PD-1).
growth. The increased cell viability and growth induced by bisphenol A could be reversed by RSV (39). Bisphenol A decreased expression of p21, which promotes cell cycle arrest and plays an important role in halting cell proliferation and increased the expression of cell cycle-dependent kinase 2 (CDK2), which was reverted to normal by RSV. Furthermore, increase in cyclin D1 secondary to downregulation of p21 can also be restored to normal by RSV treatment, explaining its antiproliferative action on estrogen-dependent ovarian cancer (39). Bisphenol A plays a significant role in visceral obesityrelated low-grade chronic systemic inflammation (LGCI) (40) and autism (41). Prenatal exposure to bisphenol A induces DNA methylation changes in the transcriptionally relevant region of the BDNF gene in the hippocampus. Bisphenol activates stem cell Pax-6, an ectoderm marker, thus interferes with the development of eyes, other sensory organs, and certain neural and epidermal tissues usually derived from ectodermal tissues (42). Bisphenol A administered to zebra fish (43) and Xaenopus laevis (44) resulted in severe eye and retina malformations. Brain-derived neurotrophic factor (BDNF) methylation changes have been reported in the cord blood of humans exposed to high maternal bisphenol A levels in utero (45). BDNF expression and DNA methylation are altered in depression, schizophrenia, bipolar disorder, DR (46,47) and autism. Decreased plasma levels of BDNF has been reported in
obesity, type 2 diabetes mellitus, DR (48) and metabolic syndrome (49,50) indicating that environmental agents such as bisphenol and benzo(a)pyrene alter the expression and actions of BDNF that may lead to the development of several diseases. Our recent studies revealed that BDNF could function as a cytoprotective molecule preventing the cytotoxic actions of alloxan, streptozotocin, benzo(a) pyrene (BP), a common environmental pollutant, and anti-cancer drug doxorubicin (51). This cytoprotective action of BDNF is somewhat similar to the observed cytoprotective action of RSV against bisphenol A-induced autism, type 2 diabetes mellitus and metabolic syndrome (52e54). This suggest that in all probability RSV may augment BDNF synthesis (6,55). Recently, we observed that both plasma and vitreal fluid BDNF levels are low in subjects with type 2 diabetes mellitus and those with DR (48). This is supported by in vitro and bioinformatics studies that showed that BDNF interacts with various polyunsaturated fatty acids (PUFAs) and their anti-inflammatory metabolites such as lipoxin A4 (LXA4), resolvins and protectins (49,50,56). Subsequent studies revealed that BDNF enhances the production of LXA4, while LXA4 augmented the synthesis and release of BDNF (Unpublished data). Thus, a close interaction exists between BDNF and various PUFAs and together they may bring about that their cytoprotective, anti-inflammatory and anti-diabetic actions ((48e51,55e60)). BDNF and LXA4
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and other lipids AA, EPA, DHA, resolvins, protectins and maresins play a significant role in type 2 diabetes mellitus, DR, obesity and metabolic syndrome, autism, depression and schizophrenia, (6,49e51,55e60) and augment each other’s action(s) implying a close interaction(s) between several proteins and lipids. It is noteworthy that RSV (61) and LXA4, AA, EPA and DHA have anti-cancer actions (62e68). RSV and LXA4 inhibit the production of pro-inflammatory molecule PGE2 and inducible nitric oxide (iNO) synthesis (62,69e71). The similarity in the anti-cancer and antiinflammatory actions of RSV and LXA4 implies that RSV may augment the production of LXA4 that may be relevant to their beneficial actions in type 2 DM, DR, obesity, metabolic syndrome, autism, depression and schizophrenia (52,72e75). In addition, resveratrol, PUFAs and LXA4 modulate gut microbiota and proliferation and differentiation of stem cells (66,75e79) (Figures 1 and 2). Beneficial Activities of Resveratrol in DR It is well documented that inflammatory process has a role in the etiopathogenesis of DR and AMD (adult macular degeneration) (80,81). Persistence of hyperglycemia and other metabolic perturbations results in low-grade systemic inflammatory process that results in deterioration of retinal pigmentary epithelial (RPE) cells leading to the impairment of the blood-retinal barrier (BRB) and consequently the loss of central vision (82). Experimental and clinical studies indicated that in DM there could occur significant damage to the RPE- photoreceptors (PRs). RPE cells avidly phagocyte and digest oldest and damaged PR outer segments, a phenomenon abnormally increased in DM that requires large amounts of energy and oxygen. Outer segments of PRs are packed with membranous sacs notably enriched in LC-PUFAs; whose composition are altered in DM resulting in increased peroxidation. As a consequence, all retinal cell populations and vascular endothelial cells are exposed to significantly high levels of oxidative stress. This can lead to apoptosis of RPE cells and photoreceptors (Repossi et al, unpublished results). RSV can enhance the survival and improve phagocytic capacity of RPE cells that have been exposed to oxidants (83). Human RPE cells challenged with H2O2 can be protected by RSV by inducing a significant and dose-dependent increase in antioxidant defense system by enhancing the activity of reduced glutathione and suppressing the production of reactive oxygen species (ROS) by RPE cells. These evidences suggest that RSV exerts potent antioxidant action (84). RSV has significant antiangiogenic action. In general, neovascularization is a normal physiological event that is needed for repair and wound healing. But this could be a pathological event in DR and AMD. Using retinal pigment epithelial ARPE-19 cell line, Latruffe and co-workers
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showed that RSV exerts anti-angiogenic action (85) that seems to be mediated by its ability to inhibit VEGF-A secretion and COX activity (1,3). In a mouse model of pathological neovascular lesions, RSV treatment normalized VEGF mRNA level (86). Low-grade systemic inflammation is associated with abnormal oxidation that has been implicated in the pathobiology of several diseases including DM, metabolic syndrome, obesity, psoriasis, Crohn’s Disease, cardiovascular diseases, arthritis and cancer. Low serum BDNF and higher levels of ILe6 and IL-10 observed in vitreous of DM patients are considered risk factors for DR development (48). Interestingly, many polyphenols (resveratrol, epigallocatechin-gallate, curcumin, genistein, phtalates) inhibit COX-2 expression in a dose-dependent manner (2). RSV binds to the active site of COX enzyme and thus, block COX binding to AA and prevent its further catalysis (87). In addition, RSV down-regulates COX-2 expression by acting on NF-kB and the AP-1 complex transcription factors, which are under the control of the signaling kinases: IkkBa processing to IkBa p50/p65 and MAPK/ ERK/p38/JNK. RSV has been shown to prevent the phosphorylation of IkkBa and MAPK (29).
RSV and Endocannabinoids The fact that RSV is not easily absorbed but yet has shown several beneficial actions when given orally suggests that it may act locally in the gut that, in turn, produces systemic actions. One such possibility is that RSV may act on widely distributed gut associated endocannabinoid system—a family of endogenous ligands, receptors, and enzymes- that are present in the heart, liver, pancreas, skin, reproductive tract and nervous system. Endocannabinoids are associated with many disorders, including diabetes, hypertension, infertility, liver disease, appetite, inflammatory bowel disease and vomiting (88,89). The main endocannabinoid receptor, CB1 is the most abundant G proteinecoupled receptors in the neurons of the brain and is also present in the heart, liver, pancreas, skin, reproductive tract and other tissues. Chronic consumption of a high-fat and high-sugar diet elevates the levels of endocannabinoids in the gut and blood (90). Blocking endocannabinoids decreased overeating in the animals. Endocannabinoids interact with other neurotransmitters: in the reproductive tract with steroid hormones; in the muscles, with myokines; and so on. Endocannabinoids act as appetite-promoting signal, control food intake by way of signals generated in the gut and thus, may have a role in obesity and metabolic syndrome. In obesity, both CB1 and CB2 receptors are upregulated throughout the body, including liver and adipose tissue (91). Activation of CB1 receptors increases food intake and affects energy metabolism in peripheral tissues. In type 2 diabetes, endocannabinoids and their receptors are
Molecular Basis of the Actions of Resveratrol
upregulated in circulating macrophages and contribute to the loss of pancreatic beta cells. Endocannabinoids are Effective Pain Relievers and Have Anti-inflammatory Actions RSV and light, odor and taste receptors. Yet another possibility by which RSV may be able to produce its beneficial actions is by acting on the light, odor, and taste receptors present in the gut and other tissues (Figures 3 and 4). Light, odor and taste receptors (or receptors of similar nature) located in our eyes, noses, and tongues exist in many locations in the body, including skin, heart, lungs, kidneys, muscles, and sperm. They are involved in regulation of blood pressure and enhance muscle and skin regeneration. In the kidney, for example, short-chain fatty acids produced by gut bacteria (RSV can act on gut microbiota) can
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activate olfactory receptor 78 (Olfr78) and trigger changes in blood pressure. Short-chain fatty acids decrease blood pressure, suggesting that Olfr78 by itself normally increases blood pressure in response to the compounds. Nonolfactory receptor called Gpr41 that decreased blood pressure in response to short-chain fatty acids shows a stronger effect than Olfr78. It is likely that these two receptors interact with each other to regulate blood pressure (92). Olfactory receptors are expressed highly in a number of different types of cancer cells and stimulating those receptors can shrink tumors in vitro (93). Melanopsin gene Opn4 is present throughout the blood vessels, and Opn4 knockout mice and its pharmacological inhibitors showed that melanopsin mediates the relaxation of blood vessels in response to light. It is known that photorelaxation is regulated by G proteinecoupled receptor kinase 2 (GRK2). While exposure to light alone could
Figure 3. Mechanism(s) of development of tolerogenic microenvironment in the gut. Helminths and bacteria secretory products (HES) induce T regulatory cells (Tregs) generation in the gut and Foxp3 expression, which is dependent on signaling through T cell TGF-bR. Short chain fatty acids (SCFAs), such as butyric acid, secreted by gut microbiota induce IL-10eproducing Tregs in the colonic lamina propria and is dependent on the production of B. fragilis polysaccharide A (PSA) and the expression of T cell TLR2. T regulatory cells induction is at least, in part, due to the stimulation of TGF-b secretion by intestinal epithelial cells that may result in a tolerogenic intestinal environment in the gut. It is likely that RSV may act on gut microbiota and colonic cells to develop tolerogenic gut environment so that many gut-associated diseases are suppressed.
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Figure 4. Mechanism(s) of tuft cell-induced immune events in the gut. Tuft cells release IL-25 on exposure to gut bacteria and worms which stimulates ILC2s to produce IL-13 that stimulates stem cells to differentiate into Tuft cells. Tuft cells sense pathogens involving the mTORC1 complex and Raptor. Increased IL-25 release by Tuft cells drives IL-13edependent expansion of the Tuft cell lineage. Tuft cells contain light, odor and taste receptors that ender them to sense RSV and other polyphenols. SCFAs act on Tuft cells and their light, odor and taste (or similar) receptors to bring about the beneficial actions of gut microbiota. RSV acts on gut microbiota to enhance their production and secretion of SCFAs and both RSV and SCFAs stimulate light, odor and taste receptors present on the Tuft cells to bring about their beneficial actions that are carried to various other organs through the vagus nerve.
cause a 20e25%relaxation of blood vessels, coupling light with a GRK2 inhibitor resulted in a 75e100% relaxation. Human aortic smooth muscle cells produce melanopsin (Opsin4), a photopigment (that is normally seen in the human and mouse retina) that mediates relaxation of the vasculature in response to blue light. Melanopsin has been implicated in a number of light-induced phenomena including regulation of the circadian clock, constriction of the pupil in response to light, and effects on alertness, learning, and metabolism (94,95). Sweet and bitter taste receptors expressed in tuft cells in the small intestine’s epithelium detect parasites and stimulate the immune system response. Taste receptors in the gut detect nutrients from food. These taste receptors are also
present in mouse testes and sperm and knocking them out render mice infertile. Recent studies indicate a role for taste receptors in body’s immune reaction to certain bacteria and parasites. Solitary chemosensory cells expressing bitter taste receptors are present in the mouse upper respiratory tract and molecules produced by gram-negative bacteria to communicate with each other activated these receptors and stimulated the secretion of inflammatory peptides to initiate an innate immune response (96,97). Upper respiratory cells that have motile cilia express bitter taste receptors that can sense and respond to bacterial signaling molecules. These ciliated cells’ taste receptors can stimulate the innate immune system upon binding to bacterial compounds and are also likely have a role in immune responses in the
Molecular Basis of the Actions of Resveratrol
gut. Taste receptors are expressed by gut tuft cells, and so are likely to be involved in reacting to food and may play a role in detecting microbes (98e100). Since RSV is not easily absorbed yet has many actions, one potential possibility is that its actions in the gut are somehow transmitted to the various other tissues of the body. Assuming that very small amounts of RSV and its metabolites are absorbed from the gut, it can be suggested that they act on endocannabinoid and light, odor, and taste receptors located in the gut and elsewhere and bring about their actions. This proposal needs to be verified in future studies. It is also suggested that endocannabinoid, light, odor and taste receptors convey their messages to the various organs in the body and especially, to brain via vagus nerve. Helminths and bacteria induce Tregs (T regulatory cells) generation in the gut and Foxp3 expression by their secretory products (HES), which is dependent on signaling through T cell TGF-bR. SCFAs (short chain fatty acids such as butyric acid) secreted by gut microbiota induce IL-10eproducing Tregs in the colonic lamina propria and is dependent on the production of B. fragilis polysaccharide A (PSA) and the expression of T cell TLR2. Treg induction is at least, in part, due to the stimulation of TGF-b secretion by intestinal epithelial cells that may result in a tolerogenic intestinal environment in the gut. It is likely that RSV may act on gut microbiota and colonic cells to develop tolerogenic gut environment so that many gut-associated diseases are suppressed. Tuft cells release IL-25 on exposure to gut bacteria and worms which stimulates ILC2s to produce IL-13 that stimulates stem cells to differentiate into Tuft cells. Tuft cells sense pathogens involving the mTORC1 complex and Raptor. Increased IL-25 release by Tuft cells drives IL13edependent expansion of the Tuft cell lineage. Tuft cells contain light, odor and taste receptors that ender them to sense RSV and other polyphenols. SCFAs act on Tuft cells and their light, odor and taste (or similar) receptors to bring about the beneficial actions of gut microbiota. RSV acts on gut microbiota to enhance their production and secretion of SCFAs and both RSV and SCFAs stimulate light, odor and taste receptors present on the Tuft cells to bring about their beneficial actions that are carried to various other organs through the vagus.
Conclusions It is evident from the preceding discussion that RSV has many actions that may account for its beneficial actions in several diseases (Figures 1 and 2). RSV could be a promising therapeutic agent to prevent pathological neoangiogenesis seen in DR and AMD. Despite its many useful actions, the low bioavailability of RSV is a hindrance to its meaningful therapeutic application. Poor bioavailability of
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RSV is due to its extensive hepatic gluconuridation and sulfation. The low bioavailability of RSV also implies that its actions are predominantly in the gut rather than due to its availability in significant amounts in the circulation. In this context, action of RSV on gut microbiota and its ability to act on duodenal-mucosal SIRT1 and thus, enhance insulin sensitivity and lower hepatic glucose production needs special consideration. Studies revealed that in addition to its action on duodenal mucosa, RSV initiates a gut-brainliver axis that improves hypothalamic insulin sensitivity (52). These results are supported by the observation that acute central (medio-basal hypothalamus, MBH) or systemic injections of RSV induced marked improvement in insulin sensitivity by acting on hypothalamic SIRT1. Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central RSV on hepatic glucose production, suggesting that RSV improves glucose homeostasis mainly through a central SIRT1-dependent pathway and that the MBH is a major site of RSV action (101). Despite these impressive actions (seen mainly in vitro and experimental animals), RSV could not be brought to the clinic due to its poor systemic bioavailability and non-availability of relevant pre-clinical toxicological studies. There are very few studies that evaluated the actions of RSV when systemically administered (102). Such studies are needed to know the possible clinical implications of RSV and to exploit them in the clinic. To achieve these objectives, newer methods of delivery need to be developed that could include microencapsulation or nanoparticles of resveratrol such that they could be absorbed better from the gut to improve its bioavailability (103). Further research needs to be performed to know the halflife, tissue distribution, tissue affinity, and local metabolism and actions of RSV in various tissues of the body. In order to target specific tissues or cells, it (RSV) may be conjugated with specific monoclonal antibodies and administer it in situ. It may be possible to develop analogues of RSV that have increased affinity to CB1, light, odor, and taste receptors present in the gut. These receptors may have the ability to sense not only RSV and similar compounds present in our diet, but sense gut microbiota and their metabolites. This could be one of the mechanisms by which the actions of gut microbiota and their metabolites on various organs and diseases is elicited.
References 1. Latruffe N, Lanc¸on A, Limagne E, et al. Bioreactivity of resveratrol towards inflammation processes. In: Jacob C, Kirsch G, Slusarenko A, Winyard PG, Burkholz T, eds. Recent Advances in Redox Active Plant and Microbial Products. Heidelberg: Springer Science; 2014. pp. 193e207. 2. Latruffe N, Lanc¸on A, Frazzi R, et al. Exploring new ways of regulation by resveratrol involving miRNAs, with emphasis on inflammation. Ann NY Acad Sci 2015;1348:97e106.
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3. Latruffe N, Vervandier-Fasseur D. Strategic syntheses of vine and wine resveratrol derivatives to explore their effects on cell functions and dysfunctions. Diseases 2018;6:E110. 4. Popescu M, Bogdan C, Pintea A, et al. Antiangiogenic cytokines as potential new therapeutic targets for resveratrol in diabetic retinopathy. Drug Des Devel Ther 2018;12:1985e1996. 5. Chen Y, Meng J, Li H, et al. Resveratrol exhibits an effect on attenuating retina inflammatory condition and damage of diabetic retinopathy via PON1. Exp Eye Res 2018;181:356e366. 6. Diaz-Gerevini GT, Repossi G, Dain A, et al. Beneficial action of resveratrol: how and why? Nutrition 2016;32:174e178. 7. Alcaın FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Pat 2009;19:403e414. 8. Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006;127:1109e1122. 9. Denu JM. Fortifying the link between SIRT1, resveratrol, and mitochondrial function. Cell Metabolism 2012;15:566e567. 10. Banks AS, Kon N, Knight C, et al. SIRT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 2008;8: 333e341. 11. Tsuchiya T, Endo A, Tsujikado K, et al. Involvement of resveratrol and u-3 polyunsaturated fatty acids on Sirtuin 1 gene expression in THP1 cells. Am J Med Sci 2017;54:415e422. 12. Milne JC, Lambert PD, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007;450:712e716. 13. Pfluger PT, Herranz D, Velasco-Miguel S, et al. SIRT1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci USA 2008;105:9793e9798. 14. Stefani M, Markus MA, Lin RC, et al. The effect of resveratrol on a cell model of human aging. Annals NY Acad Sci 2007;1114: 407e418. 15. Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;303:2011e2015. 16. Zhou M, Luo J, Zhang H. Role of Sirtuin 1 in the pathogenesis of ocular disease. Int J Mol Med 2018;42:13e20. 17. Li YR, Li S, Lin CC. Effect of resveratrol and pterostilbene on aging and longevity. Biofactors 2018;44:69e82. 18. Sajish M, Schimmel P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 2015;519: 370e373. 19. Robb EL, Page MM, Wiens BE, et al. Molecular mechanisms of oxidative stress resistance induced by resveratrol: specific and progressive induction of MnSOD. Biochem Biophys Res Commun 2008;367:406e412. 20. Kops GJ, Dansen TB, Polderman PE, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 2002;419:316e321. 21. Khan MA, Chen HC, Wan XX, et al. Regulatory effects of resveratrol on antioxidant enzymes: a mechanism of growth inhibition and apoptosis induction in cancer cells. Mol Cells 2013;35:219e225. 22. Joris PJ, Mensink RP, Adam TC, et al. Cerebral blood flow measurements in adults: a review on the effects of dietary factors and exercise. Nutrients 2018;10(5):E530. 23. Das UN. Molecular, biochemical, and physiological basis of beneficial actions of exercise. In: Farooqui T, Farooqui AA, eds. Diet and Exercise in Cognitive Function and Neurological Diseases. New Jersey: John Wiley and Sons, Inc.; 2015. pp. 183e204. 24. Wang MJ, Huang HM, Hsieh SJ, et al. Resveratrol inhibits interleukin-6 production in cortical mixed glial cells under hypoxia/hypoglycemia followed by reoxygenation. J Neuroimmunol 2001;112:28e34.
-
(2020)
-
25. Bertelli AA, Baccalini R, Battaglia E, et al. Resveratrol inhibits TNF alpha-induced endothelial cell activation. Therapie 2001;56: 613e616. 26. Venkatachalam K, Mummidi S, Cortez DM, et al. Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin17 expression in primary mouse cardiac fibroblasts. Am J Physiol Heart Circ Physiol 2008;294:H2078eH2087. 27. Zhong LM, Zong Y, Sun L, et al. Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PLoS One 2012;7: e32195. 28. Ren Z, Wang L, Cui J, et al. Resveratrol inhibits NF-kB signaling through suppression of p65 and IkappaB kinase activities. Pharmazie 2013;68:689e694. 29. Kim MY, Lim JH, Youn HH, et al. Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1a axis in db/db mice. Diabetologia 2013; 56:204e217. 30. Liu Z, Jiang C, Zhang J. Resveratrol inhibits inflammation and ameliorates insulin resistant endothelial dysfunction via regulation of AMP-activated protein kinase and sirtuin 1 activities. J Diabetes 2015;8:324e335. 31. Zhang M, Li W, Yu L, et al. The suppressive effect of resveratrol on HIF-1a and VEGF expression after warm ischemia and reperfusion in rat liver. PLoS One 2014;9:e109589. 32. Seong H, Ryu J, Jeong JY, et al. Resveratrol suppresses vascular endothelial growth factor secretion via inhibition of CXCchemokine receptor 4 expression in ARPE-19 cells. Mol Med Rep 2015;12:1479e1484. 33. Trapp V, Parmakhtiar B, Papazian V, et al. Anti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1 expression in melanoma-endothelial cell co-culture. Angiogenesis 2010;13: 305e315. 34. Imler TJ Jr, Petro TM. Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17þIL-10þ T cells, CD4(-) IFN-gammaþ cells, and decreased macrophage IL-6 expression. Int Immunopharmacol 2009;9:134e143. 35. Lanzilli G, Cottarelli A, Nicotera G, et al. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation 2012;35:240e248. 36. Xuzhu G, Komai-Koma M, Leung BP, et al. Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann Rheum Dis 2012;71:129e135. 37. Kjær TN, Thorsen K, Jessen N, et al. Resveratrol ameliorates imiquimod-induced psoriasis-like skin inflammation in mice. PLoS One 2015;10:e0126599. 38. Yao J, Wei C, Wang JY, et al. Effect of resveratrol on Treg/Th17 signaling and ulcerative colitis treatment in mice. World J Gastroenterol 2015;21:6572e6581. 39. Kang NH, Hwang KA, Lee HR, et al. Resveratrol regulates the cell viability promoted by 17b-estradiol or bisphenol A via downregulation of the cross-talk between estrogen receptor a and insulin growth factor-1 receptor in BG-1 ovarian cancer cells. Food Chem Toxicol 2013;59:373e379. 40. Savastano S, Tarantino G, D’Esposito V, et al. Bisphenol-A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: a cross-sectional study on adult male population. J Transl Med 2015;13:169. 41. Stein T, P’ Schluter MD, Steer RA, et al. Bisphenol A exposure in children with autism spectrum disorders. Autism Res 2015;8: 272e283. 42. Yamamoto M, Tase N, Okuno T, et al. Monitoring of gene expression in differentiation of embryoid bodies from cynomolgus monkey
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43.
44.
45.
46.
47.
48.
49. 50. 51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
embryonic stem cells in the presence of bisphenol A. Toxicol Sci 2007;32:301e310. Liu W, Zhang X, Wei P, et al. Long-term exposure to bisphenol S damages the visual system and reduces the tracking capability of male zebrafish (Danio rerio). J Appl Toxicol 2018;38:248e258. Baba K, Okada K, Kinoshita T, et al. Bisphenol A disrupts Notch signaling by inhibiting gamma-secretase activity and causes eye dysplasia of Xenopus laevis. Toxicol Sci 2009;108:344e355. Kundakovic M, Gudsnuk K, Herbstman JB, et al. DNA methylation of BDNF as a biomarker of early-life adversity. Proc Natl Acad Sci USA 2015;112:6807e6813. Afarid M, Torabi-Nami M, Zare B. Neuroprotective and restorative effects of the brain-derived neurotrophic factor in retinal diseases. J Neurol Sci 2016;363:43e50. Behl T, Kotwani A. Downregulated brain-derived neurotrophic factor-induced oxidative stress in the pathophysiology of diabetic retinopathy. Can J Diabetes 2017;41:241e246. Kaviarasan K, Mohanlal J, Mohammad Mulla MA, et al. Low blood and vitreal BDNF, LXA4 and altered Th1/Th2 cytokine balance as potential risk factors for diabetic retinopathy. Metabolism 2015;64: 958e966. Das UN. Obesity: genes, brain, gut and environment. Nutrition 2010; 26:459e473. Siresha B, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci 2015;11:1164e1178. Siresha B, Srinivas N, Das UN. BDNF protects pancreatic b cells (RIN5F) against cytotoxic action of alloxan, streptozotocin, doxorubicin and benzo(a)pyrene in vitro. Metabolism 2016;65: 667e684. C^ ote CD, Rasmussen BA, Duca F, et al. Resveratrol activates duodenal SIRT1 to reverse insulin resistance in rats through a neuronal network. Nat Med 2015;21:498e505. Duca FA, C^ ote CD, Rasmussen BA, et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med 2015;21:506e511. Moore A, Beidler J, Hong MY. Resveratrol and depression in animal models: a systematic review of the biological mechanisms. Molecules 2018;23:E2197. Das UN. Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids. Nutrition 2013;29:1175e1185. Umashankar V, Sathya BR, Kaviarasan K, et al. Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on brainderived neurotrophic factor (BDNF) through molecular docking simulation. Lipids Health Dis 2012;11:109. Das UN. Arachidonic acid and lipoxin A4 as possible anti-diabetic molecules. Prostaglandins Leukot Essen Fatty Acids 2013;88: 201e210. Das UN. Polyunsaturated fatty acids and their metabolites in the pathobiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013;42:122e134. Das UN. Can perinatal supplementation of long-chain polyunsaturated fatty acids prevents schizophrenia in adult life? Med Sci Monit 2004;10:HY33eHY37. Dıaz-Gerevini GT, Daın A, Pasqualini ME, et al. Diabetic encephalopathy: beneficial effects of supplementation with fatty acids u3 and nordihydroguaiaretic acid in a spontaneous diabetes rat model. Lipids Health Dis 2019;18(1):43. Radhakrishnan S, Reddivari L, Sclafani R, et al. Resveratrol potentiates grape seed extract induced human colon cancer cell apoptosis. Front Biosci (Elite Ed) 2011;3:1509e1523. Poorani R, Bhatt AN, Dwarakanath BS, et al. COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance. Eur J Pharmacol 2016;785:116e132.
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63. Das UN. Polyunsaturated fatty acids in cancer and their influence on biochemical and metabolic events and body composition. Nutrition 2015;31:582e584. 64. Polavarapu S, Mani AM, Gundala NK, et al. Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro. PLoS One 2014;9:e114766. 65. Das UN. Radiation resistance, invasiveness and metastasis are inflammatory events that could be suppressed by lipoxin A4. Prostaglandins Leukot Essent Fatty Acids 2012;86:3e11. 66. Das UN. Essential fatty acids and their metabolites as modulators of stem cell biology with reference to inflammation, cancer, and metastasis. Cancer Metastasis Rev 2011;30:311e324. 67. Das UN, Madhavi N. Effect of polyunsaturated fatty acids on drugsensitive and resistant tumor cells in vitro. Lipids Health Dis 2011; 10:159. 68. Das UN. Gamma-linolenic acid therapy of human glioma-a review of in vitro, in vivo, and clinical studies. Med Sci Monit 2007;13: RA119eRA131. 69. Kim YA, Lim SY, Rhee SH, et al. Resveratrol inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in betaamyloid-treated C6 glioma cells. Int J Mol Med 2006;17: 1069e1075. 70. Kim YA, Kim GY, Park KY, et al. Resveratrol inhibits nitric oxide and prostaglandin E2 production by lipopolysaccharide-activated C6 microglia. J Med Food 2007;10:218e224. 71. Wendeburg L, de Oliveira AC, Bhatia HS, et al. Resveratrol inhibits prostaglandin formation in IL-1beta-stimulated SK-N-SH neuronal cells. J Neuroinflammation 2009;6:26. 72. Pasinetti GM, Wang J, Ho L, et al. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim Biophys Acta 2015;1852:1202e1208. 73. Qi Y, Shang L, Liao Z, et al. Intracerebroventricular injection of resveratrol ameliorated Ab-induced learning and cognitive decline in mice. Metab Brain Dis 2019;34:257e266. 74. Qiao Y, Sun J, Xia S, et al. Effects of resveratrol on gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Food Funct 2014;5:1241e1249. 75. Chen YB, Lan YW, Hung TH, et al. Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol promotes angiogenesis in a mouse model. Cell Stress Chaperones 2015;20: 643e652. 76. Pezzolla D, Lopez-Beas J, Lachaud CC, et al. Resveratrol ameliorates the maturation process of b-cell-like cells obtained from an optimized differentiation protocol of human embryonic stem cells. PLoS One 2015;10:e0119904. 77. Lee YL, Peng Q, Fong SW, et al. Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miR-34a and p53 pathways. PLoS One 2012; 7:e45633. 78. Yu HN, Zhu J, Pan WS, et al. Effects of fish oil with a high content of n-3 polyunsaturated fatty acids on mouse gut microbiota. Arch Med Res 2014;45:195e202. 79. Pusceddu MM, El Aidy S, Crispie F, et al. N-3 polyunsaturated fatty acids (PUFAs) reverse the impact of early-life stress on the gut microbiota. PLoS One 2015;10:e0139721. 80. Joussen AM, Smyth N, Niessen C. Pathophysiology of diabetic macular edema. Dev Ophthalmol 2007;39:1e12. 81. Das UN. Lipoxins, resolvins, and protectins in the prevention and treatment of diabetic macular edema and retinopathy. Nutrition 2013;29:1e7. 82. Eynard AR, Repossi G. Role of u3 polyunsaturated fatty acids in diabetic retinopathy: a morphological and metabolically cross talk among blood retina barriers damage, autoimmunity and chronic inflammation. Lipids Health Dis 2019;18:114.
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83. Sheu SJ, Liu NC, Chen JL. Resveratrol protects human retinal pigment epithelial cells from acrolein-induced damage. J Ocul Pharmacol Ther 2010;26:231e236. 84. Pintea A, Rugina D, Pop R, et al. Antioxidant effect of transresveratrol in cultured human retinal pigment epithelial cells. J Ocul Pharmacol Ther 2011;27:315e321. 85. Lanc¸on A, Frazzi R, Latruffe N. Anti-oxidant, anti-inflammatory and anti-angiogenic properties of resveratrol in ocular diseases. Molecules 2016;21:304. 86. Hua J, Guerin KI, Chen J, et al. Resveratrol inhibits pathologic retinal neovascularization in VLDLR(‒/‒) mice. Investig Ophthalmol Vis Sci 2011;52:2809e2816. 87. Ghiringhelli F, Rebe C, Hichami A, et al. Immunomodulation and anti-inflammatory roles of polyphenols as anticancer agents. Anticancer Agents Med Chem 2012;12:852e873. 88. Hassanzadeh P, Arbabi E, Atyabi F, et al. The endocannabinoid system and NGF are involved in the mechanism of action of resveratrol: a multi-target nutraceutical with therapeutic potential in neuropsychiatric disorders. Psychopharmacology 2016;233:1087e1096. 89. Dain A, Repossi G, Das UN, et al. Role of PUFAs, the precursors of endocannabinoids, in human obesity and type 2 diabetes. Front Biosci (Elite Ed) 2010;2:1432e1447. 90. Di Patrizio NV, Astarita G, Schwartz G, et al. Endocannabinoid signal in the gut controls dietary fat intake. Proc Natl Acad Sci USA 2011;108:12904e12908. 91. Argueta DA, Di Patrizio NV. Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity. Physiol Behav 2017;171:32e39. 92. Pluznick JL, Protzko RJ, Gevorgyan H, et al. Olfactory receptor responding to gut microbiotaederived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci USA 2013;110:4410e4415.
-
(2020)
-
93. Neuhaus EM, Zhang W, Gelis L, et al. Activation of an olfactory receptor inhibits proliferation of prostate cancer cells. J Biol Chem 2009;284:16218e16225. 94. Sikka G, Hussmann GP, Pandey D, et al. Melanopsin mediates lightdependent relaxation in blood vessels. Proc Natl Acad Sci USA 2014;111:17977e17982. 95. Spitschan M. Melanopsin contributions to non-visual and visual function. Curr Opin Behav Sci 2019;30:67e72. 96. Tizzano M, Gulbransen BD, Vandenbeuch A, et al. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci USA 2010;107:3210e3215. 97. Lee RJ, Kofonow JM, Rosen PL, et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J Clin Invest 2014;124:1393e1405. 98. Shah AS, Ben-Shahar Y, Moninger TO, et al. Motile cilia of human airway epithelia are chemosensory. Science 2009;325:1131e1134. 99. Lee RJ, Xiong G, Kofonow JM, et al. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J Clin Invest 2012;122:4145e4159. 100. Howitt MR, Lavoie S, Michaud M, et al. Tuft cells, tastechemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 2016;351:1329e1333. 101. Knight CM, Gutierrez-Juarez R, Lam TK, et al. Mediobasal hypothalamic SIRT1 is essential for resveratrol’s effects on insulin action in rats. Diabetes 2011;60:2691e2700. 102. Tabrizi R, Tamtaji OR, Lankarani KB, et al. The effects of resveratrol intake on weight loss: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr 2020;60:375e390. 103. Serini S, Cassano R, Corsetto PA, et al. Omega-3 PUFA loaded in resveratrol-based solid lipid nanoparticles: physicochemical properties and antineoplastic activities in human colorectal cancer cells in vitro. Int J Mol Sci 2018;19(2):E586.
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REVIEW ARTICLE
Molecular Basis of the Beneficial Actions of Resveratrol Gast on Repossi,a Undurti N. Das,b and Aldo Renato Eynarda a
Instituto de Investigaciones en Ciencias de la Salud, Catedra de Biologıa Celular, Histologıa y Embriologıa, Facultad de Ciencias Medicas, Universidad Nacional de Cordoba, Ciudad Universitaria, Cordoba, Argentina b UND Life Sciences, Battle Ground, Washington, USA Received for publication December 31, 2019; accepted January 24, 2020 (ARCMED_2019_1186).
Resveratrol modulates the transcription factor NF-kB, cytochrome P450 isoenzyme CYP1A1, expression and activity of cyclooxygenase (COX) enzymes, Fas/Fas ligand mediated apoptosis, p53, mTOR and cyclins and various phospho-diesterases resulting in an increase in cytosolic cAMP levels. Cyclic AMP, in turn, activates Epac1/CaMKKb/ AMPK/SIRT1/PGC-1a pathway that facilitates increased oxidation of fatty acids, mitochondrial respiration and their biogenesis and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-a (TNF-a), interleukin-17 (IL-17) and other pro-inflammatory molecules and inhibits expression of hypoxia inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) that may explain its anti-inflammatory actions. Polyunsaturated fatty acids (PUFAs) and their anti-inflammatory metabolites lipoxin A4, resolvins, protectins and maresins have a significant role in obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome and cancer. We observed that PUFAs (especially arachidonic acid, AA) and BDNF (brain-derived neurotrophic factor) protect against the cytotoxic actions of alloxan, streptozotocin, benzo(a)pyrene (BP) and doxorubicin. Thus, there is an overlap in the beneficial actions of resveratrol, PUFAs and BDNF suggesting that these molecules may interact and augment synthesis and action of each other. This is supported by the observation that resveratrol and PUFAs modulate gut microbiota and influence stem cell proliferation and differentiation. Since resveratrol is not easily absorbed from the gut it is likely that it may act on endocannabinoid and light, odor, and taste receptors located in the gut, which, in turn, convey their messages to the various organs via vagus nerve. Ó 2020 IMSS. Published by Elsevier Inc. Key Words: Resveratrol, Polyunsaturated fatty acids, Brain-derived neurotrophic factor, Cytotoxic, Lipoxin A4, Metabolic syndrome, Cancer.
Introduction Resveratrol (3,5,40 -trihydroxy-trans-stilbene) (RSV) is a stilbenoid produced by several plants in response to injury or pathogens such as bacteria or fungi. Food sources of RSV include the skin of grapes, blueberries, raspberries, and mulberries. Highest concentrations of RSV are present in grape, and, more precisely, in grape skin. Thus, red wine is the most concentrated food source of RSV (1e3). Resveratrol exists as two geometric isomers: cis- (Z ) and trans- (E ). The trans- and cis resveratrol can be either free
Address reprint requests to: Undurti N. Das, UND Life Sciences, 2221 NW 5th St. Battle Ground, Washington, WA 98604, USA; Phone: (þ54) 0351 4334020; FAX: þ54 0351 4334021; E-mail: [email protected]
or bound to glucose. The trans- form seems to have the major biological effects. The anti-inflammatory actions of flavonoid RSV is mediated by its modulatory actions on transcription factor NF-kB, cytochrome P450 isoenzyme CYP1A1, cyclooxygenase (COX) enzymes, Fas/Fas ligand mediated apoptosis, p53, mTOR, cyclins, various phospho-diesterases and Epac1/CaMKKb/AMPK/SIRT1/PGC-1a pathway. These actions facilitate increased oxidation of fatty acids, mitochondrial biogenesis and respiration, and gluconeogenesis. RSV induces apoptosis of activated T cells and suppresses the production of pro-inflammatory tumor necrosis factor-a (TNF-a), interleukin-17 (IL-17) and other pro-inflammatory molecules. RSV inhibits expressions of hypoxia inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) leading to a decrease in
0188-4409/$ - see front matter. Copyright Ó 2020 IMSS. Published by Elsevier Inc. https://doi.org/10.1016/j.arcmed.2020.01.010
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neo-angiogenesis implying that it could be of benefit in diabetic retinopathy (DR) (4,5) and cancer (6). RSV activates Sirtuin 1 (SIRT1) (7), a molecule belonging to histone deacetylases, and peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) and thus, improves the function of mitochondria (8,9). Since SIRT1 may function as an antiageing molecule and delays age-associated diseases, it suggests that RSV may have similar function. Overexpression of SIRT1 and RSV enhances insulin sensitivity (10e13) and could be of benefit in DR (14e17) (Figures 1 and 2). RSV binds to tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) to enhance a poly (ADP-ribose) polymerase 1 (PARP1)/NADþ driven signaling cascade to activate p53 (18). Cells treated with RSV showed a 14 fold increase in the action of superoxide dismutase (SOD) (19) that led to reduced levels of superoxide anion resulting in restoration of mitochondrial dysfunction to normal. RSV by activating SIRT1 favors migration of FOXO transcription factors to the nucleus (20), which stimulates FOXO3a transcriptional activity (21). SOD is a target of FOXO3a, and MnSOD expression is strongly induced in cells overexpressing FOXO3a (20). High expression of SOD with mild changes in catalase (CAT) and glutathione peroxidase (GPX) expression in cancer cells results in the mitochondrial
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accumulation of H2O2 leading to cancer cell apoptosis (21). This is somewhat similar to the actions of exercise, which also causes strong up-regulation of SOD, CAT and GPX. These results are interesting since regular exercise decreases the incidence of cancer (6,22,23). Resveratrol Suppresses Inflammation and has Cytoprotective Properties RSV has anti-inflammatory actions. For example, RSV triggers apoptosis of activated T cells and downregulates TNFa, interferon-g (IFN-g), interleukin (IL)-2, IL-9, IL-12, IL17, macrophage inflammatory protein-1a (MIP-1 a), and monocyte chemoattractant protein-1 (MCP-1) secretion (24e30). RSV inhibits both HIF-1a and VEGF that are overexpressed in DR and in cancer that may explain some of its beneficial actions (31e33). The anti-inflammatory actions of RSV are in support of its beneficial actions in inflammatory and autoimmune diseases (34e38) (Figure 2). In addition, RSV has cytoprotective actions. Bisphenol, an endocrine disruptor present in plastics and the end product component of the degradation of industrial plasticrelated wastes, is known to promote development and progression of estrogen-dependent cancer and increase cell
Figure 1. Scheme showing various actions of resveratrol that may form the basis of its beneficial actions. (modified from https://https://doi.org/10.1016/j.nut. 2015.08.017).
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Figure 2. Scheme showing the actions of resveratrol. Macrophages (MF), Programmed Cell Death-1 protein (PD-1).
growth. The increased cell viability and growth induced by bisphenol A could be reversed by RSV (39). Bisphenol A decreased expression of p21, which promotes cell cycle arrest and plays an important role in halting cell proliferation and increased the expression of cell cycle-dependent kinase 2 (CDK2), which was reverted to normal by RSV. Furthermore, increase in cyclin D1 secondary to downregulation of p21 can also be restored to normal by RSV treatment, explaining its antiproliferative action on estrogen-dependent ovarian cancer (39). Bisphenol A plays a significant role in visceral obesityrelated low-grade chronic systemic inflammation (LGCI) (40) and autism (41). Prenatal exposure to bisphenol A induces DNA methylation changes in the transcriptionally relevant region of the BDNF gene in the hippocampus. Bisphenol activates stem cell Pax-6, an ectoderm marker, thus interferes with the development of eyes, other sensory organs, and certain neural and epidermal tissues usually derived from ectodermal tissues (42). Bisphenol A administered to zebra fish (43) and Xaenopus laevis (44) resulted in severe eye and retina malformations. Brain-derived neurotrophic factor (BDNF) methylation changes have been reported in the cord blood of humans exposed to high maternal bisphenol A levels in utero (45). BDNF expression and DNA methylation are altered in depression, schizophrenia, bipolar disorder, DR (46,47) and autism. Decreased plasma levels of BDNF has been reported in
obesity, type 2 diabetes mellitus, DR (48) and metabolic syndrome (49,50) indicating that environmental agents such as bisphenol and benzo(a)pyrene alter the expression and actions of BDNF that may lead to the development of several diseases. Our recent studies revealed that BDNF could function as a cytoprotective molecule preventing the cytotoxic actions of alloxan, streptozotocin, benzo(a) pyrene (BP), a common environmental pollutant, and anti-cancer drug doxorubicin (51). This cytoprotective action of BDNF is somewhat similar to the observed cytoprotective action of RSV against bisphenol A-induced autism, type 2 diabetes mellitus and metabolic syndrome (52e54). This suggest that in all probability RSV may augment BDNF synthesis (6,55). Recently, we observed that both plasma and vitreal fluid BDNF levels are low in subjects with type 2 diabetes mellitus and those with DR (48). This is supported by in vitro and bioinformatics studies that showed that BDNF interacts with various polyunsaturated fatty acids (PUFAs) and their anti-inflammatory metabolites such as lipoxin A4 (LXA4), resolvins and protectins (49,50,56). Subsequent studies revealed that BDNF enhances the production of LXA4, while LXA4 augmented the synthesis and release of BDNF (Unpublished data). Thus, a close interaction exists between BDNF and various PUFAs and together they may bring about that their cytoprotective, anti-inflammatory and anti-diabetic actions ((48e51,55e60)). BDNF and LXA4
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and other lipids AA, EPA, DHA, resolvins, protectins and maresins play a significant role in type 2 diabetes mellitus, DR, obesity and metabolic syndrome, autism, depression and schizophrenia, (6,49e51,55e60) and augment each other’s action(s) implying a close interaction(s) between several proteins and lipids. It is noteworthy that RSV (61) and LXA4, AA, EPA and DHA have anti-cancer actions (62e68). RSV and LXA4 inhibit the production of pro-inflammatory molecule PGE2 and inducible nitric oxide (iNO) synthesis (62,69e71). The similarity in the anti-cancer and antiinflammatory actions of RSV and LXA4 implies that RSV may augment the production of LXA4 that may be relevant to their beneficial actions in type 2 DM, DR, obesity, metabolic syndrome, autism, depression and schizophrenia (52,72e75). In addition, resveratrol, PUFAs and LXA4 modulate gut microbiota and proliferation and differentiation of stem cells (66,75e79) (Figures 1 and 2). Beneficial Activities of Resveratrol in DR It is well documented that inflammatory process has a role in the etiopathogenesis of DR and AMD (adult macular degeneration) (80,81). Persistence of hyperglycemia and other metabolic perturbations results in low-grade systemic inflammatory process that results in deterioration of retinal pigmentary epithelial (RPE) cells leading to the impairment of the blood-retinal barrier (BRB) and consequently the loss of central vision (82). Experimental and clinical studies indicated that in DM there could occur significant damage to the RPE- photoreceptors (PRs). RPE cells avidly phagocyte and digest oldest and damaged PR outer segments, a phenomenon abnormally increased in DM that requires large amounts of energy and oxygen. Outer segments of PRs are packed with membranous sacs notably enriched in LC-PUFAs; whose composition are altered in DM resulting in increased peroxidation. As a consequence, all retinal cell populations and vascular endothelial cells are exposed to significantly high levels of oxidative stress. This can lead to apoptosis of RPE cells and photoreceptors (Repossi et al, unpublished results). RSV can enhance the survival and improve phagocytic capacity of RPE cells that have been exposed to oxidants (83). Human RPE cells challenged with H2O2 can be protected by RSV by inducing a significant and dose-dependent increase in antioxidant defense system by enhancing the activity of reduced glutathione and suppressing the production of reactive oxygen species (ROS) by RPE cells. These evidences suggest that RSV exerts potent antioxidant action (84). RSV has significant antiangiogenic action. In general, neovascularization is a normal physiological event that is needed for repair and wound healing. But this could be a pathological event in DR and AMD. Using retinal pigment epithelial ARPE-19 cell line, Latruffe and co-workers
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showed that RSV exerts anti-angiogenic action (85) that seems to be mediated by its ability to inhibit VEGF-A secretion and COX activity (1,3). In a mouse model of pathological neovascular lesions, RSV treatment normalized VEGF mRNA level (86). Low-grade systemic inflammation is associated with abnormal oxidation that has been implicated in the pathobiology of several diseases including DM, metabolic syndrome, obesity, psoriasis, Crohn’s Disease, cardiovascular diseases, arthritis and cancer. Low serum BDNF and higher levels of ILe6 and IL-10 observed in vitreous of DM patients are considered risk factors for DR development (48). Interestingly, many polyphenols (resveratrol, epigallocatechin-gallate, curcumin, genistein, phtalates) inhibit COX-2 expression in a dose-dependent manner (2). RSV binds to the active site of COX enzyme and thus, block COX binding to AA and prevent its further catalysis (87). In addition, RSV down-regulates COX-2 expression by acting on NF-kB and the AP-1 complex transcription factors, which are under the control of the signaling kinases: IkkBa processing to IkBa p50/p65 and MAPK/ ERK/p38/JNK. RSV has been shown to prevent the phosphorylation of IkkBa and MAPK (29).
RSV and Endocannabinoids The fact that RSV is not easily absorbed but yet has shown several beneficial actions when given orally suggests that it may act locally in the gut that, in turn, produces systemic actions. One such possibility is that RSV may act on widely distributed gut associated endocannabinoid system—a family of endogenous ligands, receptors, and enzymes- that are present in the heart, liver, pancreas, skin, reproductive tract and nervous system. Endocannabinoids are associated with many disorders, including diabetes, hypertension, infertility, liver disease, appetite, inflammatory bowel disease and vomiting (88,89). The main endocannabinoid receptor, CB1 is the most abundant G proteinecoupled receptors in the neurons of the brain and is also present in the heart, liver, pancreas, skin, reproductive tract and other tissues. Chronic consumption of a high-fat and high-sugar diet elevates the levels of endocannabinoids in the gut and blood (90). Blocking endocannabinoids decreased overeating in the animals. Endocannabinoids interact with other neurotransmitters: in the reproductive tract with steroid hormones; in the muscles, with myokines; and so on. Endocannabinoids act as appetite-promoting signal, control food intake by way of signals generated in the gut and thus, may have a role in obesity and metabolic syndrome. In obesity, both CB1 and CB2 receptors are upregulated throughout the body, including liver and adipose tissue (91). Activation of CB1 receptors increases food intake and affects energy metabolism in peripheral tissues. In type 2 diabetes, endocannabinoids and their receptors are
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upregulated in circulating macrophages and contribute to the loss of pancreatic beta cells. Endocannabinoids are Effective Pain Relievers and Have Anti-inflammatory Actions RSV and light, odor and taste receptors. Yet another possibility by which RSV may be able to produce its beneficial actions is by acting on the light, odor, and taste receptors present in the gut and other tissues (Figures 3 and 4). Light, odor and taste receptors (or receptors of similar nature) located in our eyes, noses, and tongues exist in many locations in the body, including skin, heart, lungs, kidneys, muscles, and sperm. They are involved in regulation of blood pressure and enhance muscle and skin regeneration. In the kidney, for example, short-chain fatty acids produced by gut bacteria (RSV can act on gut microbiota) can
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activate olfactory receptor 78 (Olfr78) and trigger changes in blood pressure. Short-chain fatty acids decrease blood pressure, suggesting that Olfr78 by itself normally increases blood pressure in response to the compounds. Nonolfactory receptor called Gpr41 that decreased blood pressure in response to short-chain fatty acids shows a stronger effect than Olfr78. It is likely that these two receptors interact with each other to regulate blood pressure (92). Olfactory receptors are expressed highly in a number of different types of cancer cells and stimulating those receptors can shrink tumors in vitro (93). Melanopsin gene Opn4 is present throughout the blood vessels, and Opn4 knockout mice and its pharmacological inhibitors showed that melanopsin mediates the relaxation of blood vessels in response to light. It is known that photorelaxation is regulated by G proteinecoupled receptor kinase 2 (GRK2). While exposure to light alone could
Figure 3. Mechanism(s) of development of tolerogenic microenvironment in the gut. Helminths and bacteria secretory products (HES) induce T regulatory cells (Tregs) generation in the gut and Foxp3 expression, which is dependent on signaling through T cell TGF-bR. Short chain fatty acids (SCFAs), such as butyric acid, secreted by gut microbiota induce IL-10eproducing Tregs in the colonic lamina propria and is dependent on the production of B. fragilis polysaccharide A (PSA) and the expression of T cell TLR2. T regulatory cells induction is at least, in part, due to the stimulation of TGF-b secretion by intestinal epithelial cells that may result in a tolerogenic intestinal environment in the gut. It is likely that RSV may act on gut microbiota and colonic cells to develop tolerogenic gut environment so that many gut-associated diseases are suppressed.
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Figure 4. Mechanism(s) of tuft cell-induced immune events in the gut. Tuft cells release IL-25 on exposure to gut bacteria and worms which stimulates ILC2s to produce IL-13 that stimulates stem cells to differentiate into Tuft cells. Tuft cells sense pathogens involving the mTORC1 complex and Raptor. Increased IL-25 release by Tuft cells drives IL-13edependent expansion of the Tuft cell lineage. Tuft cells contain light, odor and taste receptors that ender them to sense RSV and other polyphenols. SCFAs act on Tuft cells and their light, odor and taste (or similar) receptors to bring about the beneficial actions of gut microbiota. RSV acts on gut microbiota to enhance their production and secretion of SCFAs and both RSV and SCFAs stimulate light, odor and taste receptors present on the Tuft cells to bring about their beneficial actions that are carried to various other organs through the vagus nerve.
cause a 20e25%relaxation of blood vessels, coupling light with a GRK2 inhibitor resulted in a 75e100% relaxation. Human aortic smooth muscle cells produce melanopsin (Opsin4), a photopigment (that is normally seen in the human and mouse retina) that mediates relaxation of the vasculature in response to blue light. Melanopsin has been implicated in a number of light-induced phenomena including regulation of the circadian clock, constriction of the pupil in response to light, and effects on alertness, learning, and metabolism (94,95). Sweet and bitter taste receptors expressed in tuft cells in the small intestine’s epithelium detect parasites and stimulate the immune system response. Taste receptors in the gut detect nutrients from food. These taste receptors are also
present in mouse testes and sperm and knocking them out render mice infertile. Recent studies indicate a role for taste receptors in body’s immune reaction to certain bacteria and parasites. Solitary chemosensory cells expressing bitter taste receptors are present in the mouse upper respiratory tract and molecules produced by gram-negative bacteria to communicate with each other activated these receptors and stimulated the secretion of inflammatory peptides to initiate an innate immune response (96,97). Upper respiratory cells that have motile cilia express bitter taste receptors that can sense and respond to bacterial signaling molecules. These ciliated cells’ taste receptors can stimulate the innate immune system upon binding to bacterial compounds and are also likely have a role in immune responses in the
Molecular Basis of the Actions of Resveratrol
gut. Taste receptors are expressed by gut tuft cells, and so are likely to be involved in reacting to food and may play a role in detecting microbes (98e100). Since RSV is not easily absorbed yet has many actions, one potential possibility is that its actions in the gut are somehow transmitted to the various other tissues of the body. Assuming that very small amounts of RSV and its metabolites are absorbed from the gut, it can be suggested that they act on endocannabinoid and light, odor, and taste receptors located in the gut and elsewhere and bring about their actions. This proposal needs to be verified in future studies. It is also suggested that endocannabinoid, light, odor and taste receptors convey their messages to the various organs in the body and especially, to brain via vagus nerve. Helminths and bacteria induce Tregs (T regulatory cells) generation in the gut and Foxp3 expression by their secretory products (HES), which is dependent on signaling through T cell TGF-bR. SCFAs (short chain fatty acids such as butyric acid) secreted by gut microbiota induce IL-10eproducing Tregs in the colonic lamina propria and is dependent on the production of B. fragilis polysaccharide A (PSA) and the expression of T cell TLR2. Treg induction is at least, in part, due to the stimulation of TGF-b secretion by intestinal epithelial cells that may result in a tolerogenic intestinal environment in the gut. It is likely that RSV may act on gut microbiota and colonic cells to develop tolerogenic gut environment so that many gut-associated diseases are suppressed. Tuft cells release IL-25 on exposure to gut bacteria and worms which stimulates ILC2s to produce IL-13 that stimulates stem cells to differentiate into Tuft cells. Tuft cells sense pathogens involving the mTORC1 complex and Raptor. Increased IL-25 release by Tuft cells drives IL13edependent expansion of the Tuft cell lineage. Tuft cells contain light, odor and taste receptors that ender them to sense RSV and other polyphenols. SCFAs act on Tuft cells and their light, odor and taste (or similar) receptors to bring about the beneficial actions of gut microbiota. RSV acts on gut microbiota to enhance their production and secretion of SCFAs and both RSV and SCFAs stimulate light, odor and taste receptors present on the Tuft cells to bring about their beneficial actions that are carried to various other organs through the vagus.
Conclusions It is evident from the preceding discussion that RSV has many actions that may account for its beneficial actions in several diseases (Figures 1 and 2). RSV could be a promising therapeutic agent to prevent pathological neoangiogenesis seen in DR and AMD. Despite its many useful actions, the low bioavailability of RSV is a hindrance to its meaningful therapeutic application. Poor bioavailability of
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RSV is due to its extensive hepatic gluconuridation and sulfation. The low bioavailability of RSV also implies that its actions are predominantly in the gut rather than due to its availability in significant amounts in the circulation. In this context, action of RSV on gut microbiota and its ability to act on duodenal-mucosal SIRT1 and thus, enhance insulin sensitivity and lower hepatic glucose production needs special consideration. Studies revealed that in addition to its action on duodenal mucosa, RSV initiates a gut-brainliver axis that improves hypothalamic insulin sensitivity (52). These results are supported by the observation that acute central (medio-basal hypothalamus, MBH) or systemic injections of RSV induced marked improvement in insulin sensitivity by acting on hypothalamic SIRT1. Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central RSV on hepatic glucose production, suggesting that RSV improves glucose homeostasis mainly through a central SIRT1-dependent pathway and that the MBH is a major site of RSV action (101). Despite these impressive actions (seen mainly in vitro and experimental animals), RSV could not be brought to the clinic due to its poor systemic bioavailability and non-availability of relevant pre-clinical toxicological studies. There are very few studies that evaluated the actions of RSV when systemically administered (102). Such studies are needed to know the possible clinical implications of RSV and to exploit them in the clinic. To achieve these objectives, newer methods of delivery need to be developed that could include microencapsulation or nanoparticles of resveratrol such that they could be absorbed better from the gut to improve its bioavailability (103). Further research needs to be performed to know the halflife, tissue distribution, tissue affinity, and local metabolism and actions of RSV in various tissues of the body. In order to target specific tissues or cells, it (RSV) may be conjugated with specific monoclonal antibodies and administer it in situ. It may be possible to develop analogues of RSV that have increased affinity to CB1, light, odor, and taste receptors present in the gut. These receptors may have the ability to sense not only RSV and similar compounds present in our diet, but sense gut microbiota and their metabolites. This could be one of the mechanisms by which the actions of gut microbiota and their metabolites on various organs and diseases is elicited.
References 1. Latruffe N, Lanc¸on A, Limagne E, et al. Bioreactivity of resveratrol towards inflammation processes. In: Jacob C, Kirsch G, Slusarenko A, Winyard PG, Burkholz T, eds. Recent Advances in Redox Active Plant and Microbial Products. Heidelberg: Springer Science; 2014. pp. 193e207. 2. Latruffe N, Lanc¸on A, Frazzi R, et al. Exploring new ways of regulation by resveratrol involving miRNAs, with emphasis on inflammation. Ann NY Acad Sci 2015;1348:97e106.
8
Repossi et al./ Archives of Medical Research
3. Latruffe N, Vervandier-Fasseur D. Strategic syntheses of vine and wine resveratrol derivatives to explore their effects on cell functions and dysfunctions. Diseases 2018;6:E110. 4. Popescu M, Bogdan C, Pintea A, et al. Antiangiogenic cytokines as potential new therapeutic targets for resveratrol in diabetic retinopathy. Drug Des Devel Ther 2018;12:1985e1996. 5. Chen Y, Meng J, Li H, et al. Resveratrol exhibits an effect on attenuating retina inflammatory condition and damage of diabetic retinopathy via PON1. Exp Eye Res 2018;181:356e366. 6. Diaz-Gerevini GT, Repossi G, Dain A, et al. Beneficial action of resveratrol: how and why? Nutrition 2016;32:174e178. 7. Alcaın FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Pat 2009;19:403e414. 8. Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006;127:1109e1122. 9. Denu JM. Fortifying the link between SIRT1, resveratrol, and mitochondrial function. Cell Metabolism 2012;15:566e567. 10. Banks AS, Kon N, Knight C, et al. SIRT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 2008;8: 333e341. 11. Tsuchiya T, Endo A, Tsujikado K, et al. Involvement of resveratrol and u-3 polyunsaturated fatty acids on Sirtuin 1 gene expression in THP1 cells. Am J Med Sci 2017;54:415e422. 12. Milne JC, Lambert PD, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007;450:712e716. 13. Pfluger PT, Herranz D, Velasco-Miguel S, et al. SIRT1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci USA 2008;105:9793e9798. 14. Stefani M, Markus MA, Lin RC, et al. The effect of resveratrol on a cell model of human aging. Annals NY Acad Sci 2007;1114: 407e418. 15. Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;303:2011e2015. 16. Zhou M, Luo J, Zhang H. Role of Sirtuin 1 in the pathogenesis of ocular disease. Int J Mol Med 2018;42:13e20. 17. Li YR, Li S, Lin CC. Effect of resveratrol and pterostilbene on aging and longevity. Biofactors 2018;44:69e82. 18. Sajish M, Schimmel P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 2015;519: 370e373. 19. Robb EL, Page MM, Wiens BE, et al. Molecular mechanisms of oxidative stress resistance induced by resveratrol: specific and progressive induction of MnSOD. Biochem Biophys Res Commun 2008;367:406e412. 20. Kops GJ, Dansen TB, Polderman PE, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 2002;419:316e321. 21. Khan MA, Chen HC, Wan XX, et al. Regulatory effects of resveratrol on antioxidant enzymes: a mechanism of growth inhibition and apoptosis induction in cancer cells. Mol Cells 2013;35:219e225. 22. Joris PJ, Mensink RP, Adam TC, et al. Cerebral blood flow measurements in adults: a review on the effects of dietary factors and exercise. Nutrients 2018;10(5):E530. 23. Das UN. Molecular, biochemical, and physiological basis of beneficial actions of exercise. In: Farooqui T, Farooqui AA, eds. Diet and Exercise in Cognitive Function and Neurological Diseases. New Jersey: John Wiley and Sons, Inc.; 2015. pp. 183e204. 24. Wang MJ, Huang HM, Hsieh SJ, et al. Resveratrol inhibits interleukin-6 production in cortical mixed glial cells under hypoxia/hypoglycemia followed by reoxygenation. J Neuroimmunol 2001;112:28e34.
-
(2020)
-
25. Bertelli AA, Baccalini R, Battaglia E, et al. Resveratrol inhibits TNF alpha-induced endothelial cell activation. Therapie 2001;56: 613e616. 26. Venkatachalam K, Mummidi S, Cortez DM, et al. Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin17 expression in primary mouse cardiac fibroblasts. Am J Physiol Heart Circ Physiol 2008;294:H2078eH2087. 27. Zhong LM, Zong Y, Sun L, et al. Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PLoS One 2012;7: e32195. 28. Ren Z, Wang L, Cui J, et al. Resveratrol inhibits NF-kB signaling through suppression of p65 and IkappaB kinase activities. Pharmazie 2013;68:689e694. 29. Kim MY, Lim JH, Youn HH, et al. Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1a axis in db/db mice. Diabetologia 2013; 56:204e217. 30. Liu Z, Jiang C, Zhang J. Resveratrol inhibits inflammation and ameliorates insulin resistant endothelial dysfunction via regulation of AMP-activated protein kinase and sirtuin 1 activities. J Diabetes 2015;8:324e335. 31. Zhang M, Li W, Yu L, et al. The suppressive effect of resveratrol on HIF-1a and VEGF expression after warm ischemia and reperfusion in rat liver. PLoS One 2014;9:e109589. 32. Seong H, Ryu J, Jeong JY, et al. Resveratrol suppresses vascular endothelial growth factor secretion via inhibition of CXCchemokine receptor 4 expression in ARPE-19 cells. Mol Med Rep 2015;12:1479e1484. 33. Trapp V, Parmakhtiar B, Papazian V, et al. Anti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1 expression in melanoma-endothelial cell co-culture. Angiogenesis 2010;13: 305e315. 34. Imler TJ Jr, Petro TM. Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17þIL-10þ T cells, CD4(-) IFN-gammaþ cells, and decreased macrophage IL-6 expression. Int Immunopharmacol 2009;9:134e143. 35. Lanzilli G, Cottarelli A, Nicotera G, et al. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation 2012;35:240e248. 36. Xuzhu G, Komai-Koma M, Leung BP, et al. Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann Rheum Dis 2012;71:129e135. 37. Kjær TN, Thorsen K, Jessen N, et al. Resveratrol ameliorates imiquimod-induced psoriasis-like skin inflammation in mice. PLoS One 2015;10:e0126599. 38. Yao J, Wei C, Wang JY, et al. Effect of resveratrol on Treg/Th17 signaling and ulcerative colitis treatment in mice. World J Gastroenterol 2015;21:6572e6581. 39. Kang NH, Hwang KA, Lee HR, et al. Resveratrol regulates the cell viability promoted by 17b-estradiol or bisphenol A via downregulation of the cross-talk between estrogen receptor a and insulin growth factor-1 receptor in BG-1 ovarian cancer cells. Food Chem Toxicol 2013;59:373e379. 40. Savastano S, Tarantino G, D’Esposito V, et al. Bisphenol-A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: a cross-sectional study on adult male population. J Transl Med 2015;13:169. 41. Stein T, P’ Schluter MD, Steer RA, et al. Bisphenol A exposure in children with autism spectrum disorders. Autism Res 2015;8: 272e283. 42. Yamamoto M, Tase N, Okuno T, et al. Monitoring of gene expression in differentiation of embryoid bodies from cynomolgus monkey
Molecular Basis of the Actions of Resveratrol
43.
44.
45.
46.
47.
48.
49. 50. 51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
embryonic stem cells in the presence of bisphenol A. Toxicol Sci 2007;32:301e310. Liu W, Zhang X, Wei P, et al. Long-term exposure to bisphenol S damages the visual system and reduces the tracking capability of male zebrafish (Danio rerio). J Appl Toxicol 2018;38:248e258. Baba K, Okada K, Kinoshita T, et al. Bisphenol A disrupts Notch signaling by inhibiting gamma-secretase activity and causes eye dysplasia of Xenopus laevis. Toxicol Sci 2009;108:344e355. Kundakovic M, Gudsnuk K, Herbstman JB, et al. DNA methylation of BDNF as a biomarker of early-life adversity. Proc Natl Acad Sci USA 2015;112:6807e6813. Afarid M, Torabi-Nami M, Zare B. Neuroprotective and restorative effects of the brain-derived neurotrophic factor in retinal diseases. J Neurol Sci 2016;363:43e50. Behl T, Kotwani A. Downregulated brain-derived neurotrophic factor-induced oxidative stress in the pathophysiology of diabetic retinopathy. Can J Diabetes 2017;41:241e246. Kaviarasan K, Mohanlal J, Mohammad Mulla MA, et al. Low blood and vitreal BDNF, LXA4 and altered Th1/Th2 cytokine balance as potential risk factors for diabetic retinopathy. Metabolism 2015;64: 958e966. Das UN. Obesity: genes, brain, gut and environment. Nutrition 2010; 26:459e473. Siresha B, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci 2015;11:1164e1178. Siresha B, Srinivas N, Das UN. BDNF protects pancreatic b cells (RIN5F) against cytotoxic action of alloxan, streptozotocin, doxorubicin and benzo(a)pyrene in vitro. Metabolism 2016;65: 667e684. C^ ote CD, Rasmussen BA, Duca F, et al. Resveratrol activates duodenal SIRT1 to reverse insulin resistance in rats through a neuronal network. Nat Med 2015;21:498e505. Duca FA, C^ ote CD, Rasmussen BA, et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med 2015;21:506e511. Moore A, Beidler J, Hong MY. Resveratrol and depression in animal models: a systematic review of the biological mechanisms. Molecules 2018;23:E2197. Das UN. Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids. Nutrition 2013;29:1175e1185. Umashankar V, Sathya BR, Kaviarasan K, et al. Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on brainderived neurotrophic factor (BDNF) through molecular docking simulation. Lipids Health Dis 2012;11:109. Das UN. Arachidonic acid and lipoxin A4 as possible anti-diabetic molecules. Prostaglandins Leukot Essen Fatty Acids 2013;88: 201e210. Das UN. Polyunsaturated fatty acids and their metabolites in the pathobiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013;42:122e134. Das UN. Can perinatal supplementation of long-chain polyunsaturated fatty acids prevents schizophrenia in adult life? Med Sci Monit 2004;10:HY33eHY37. Dıaz-Gerevini GT, Daın A, Pasqualini ME, et al. Diabetic encephalopathy: beneficial effects of supplementation with fatty acids u3 and nordihydroguaiaretic acid in a spontaneous diabetes rat model. Lipids Health Dis 2019;18(1):43. Radhakrishnan S, Reddivari L, Sclafani R, et al. Resveratrol potentiates grape seed extract induced human colon cancer cell apoptosis. Front Biosci (Elite Ed) 2011;3:1509e1523. Poorani R, Bhatt AN, Dwarakanath BS, et al. COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance. Eur J Pharmacol 2016;785:116e132.
9
63. Das UN. Polyunsaturated fatty acids in cancer and their influence on biochemical and metabolic events and body composition. Nutrition 2015;31:582e584. 64. Polavarapu S, Mani AM, Gundala NK, et al. Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro. PLoS One 2014;9:e114766. 65. Das UN. Radiation resistance, invasiveness and metastasis are inflammatory events that could be suppressed by lipoxin A4. Prostaglandins Leukot Essent Fatty Acids 2012;86:3e11. 66. Das UN. Essential fatty acids and their metabolites as modulators of stem cell biology with reference to inflammation, cancer, and metastasis. Cancer Metastasis Rev 2011;30:311e324. 67. Das UN, Madhavi N. Effect of polyunsaturated fatty acids on drugsensitive and resistant tumor cells in vitro. Lipids Health Dis 2011; 10:159. 68. Das UN. Gamma-linolenic acid therapy of human glioma-a review of in vitro, in vivo, and clinical studies. Med Sci Monit 2007;13: RA119eRA131. 69. Kim YA, Lim SY, Rhee SH, et al. Resveratrol inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in betaamyloid-treated C6 glioma cells. Int J Mol Med 2006;17: 1069e1075. 70. Kim YA, Kim GY, Park KY, et al. Resveratrol inhibits nitric oxide and prostaglandin E2 production by lipopolysaccharide-activated C6 microglia. J Med Food 2007;10:218e224. 71. Wendeburg L, de Oliveira AC, Bhatia HS, et al. Resveratrol inhibits prostaglandin formation in IL-1beta-stimulated SK-N-SH neuronal cells. J Neuroinflammation 2009;6:26. 72. Pasinetti GM, Wang J, Ho L, et al. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim Biophys Acta 2015;1852:1202e1208. 73. Qi Y, Shang L, Liao Z, et al. Intracerebroventricular injection of resveratrol ameliorated Ab-induced learning and cognitive decline in mice. Metab Brain Dis 2019;34:257e266. 74. Qiao Y, Sun J, Xia S, et al. Effects of resveratrol on gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Food Funct 2014;5:1241e1249. 75. Chen YB, Lan YW, Hung TH, et al. Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol promotes angiogenesis in a mouse model. Cell Stress Chaperones 2015;20: 643e652. 76. Pezzolla D, Lopez-Beas J, Lachaud CC, et al. Resveratrol ameliorates the maturation process of b-cell-like cells obtained from an optimized differentiation protocol of human embryonic stem cells. PLoS One 2015;10:e0119904. 77. Lee YL, Peng Q, Fong SW, et al. Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miR-34a and p53 pathways. PLoS One 2012; 7:e45633. 78. Yu HN, Zhu J, Pan WS, et al. Effects of fish oil with a high content of n-3 polyunsaturated fatty acids on mouse gut microbiota. Arch Med Res 2014;45:195e202. 79. Pusceddu MM, El Aidy S, Crispie F, et al. N-3 polyunsaturated fatty acids (PUFAs) reverse the impact of early-life stress on the gut microbiota. PLoS One 2015;10:e0139721. 80. Joussen AM, Smyth N, Niessen C. Pathophysiology of diabetic macular edema. Dev Ophthalmol 2007;39:1e12. 81. Das UN. Lipoxins, resolvins, and protectins in the prevention and treatment of diabetic macular edema and retinopathy. Nutrition 2013;29:1e7. 82. Eynard AR, Repossi G. Role of u3 polyunsaturated fatty acids in diabetic retinopathy: a morphological and metabolically cross talk among blood retina barriers damage, autoimmunity and chronic inflammation. Lipids Health Dis 2019;18:114.
10
Repossi et al./ Archives of Medical Research
83. Sheu SJ, Liu NC, Chen JL. Resveratrol protects human retinal pigment epithelial cells from acrolein-induced damage. J Ocul Pharmacol Ther 2010;26:231e236. 84. Pintea A, Rugina D, Pop R, et al. Antioxidant effect of transresveratrol in cultured human retinal pigment epithelial cells. J Ocul Pharmacol Ther 2011;27:315e321. 85. Lanc¸on A, Frazzi R, Latruffe N. Anti-oxidant, anti-inflammatory and anti-angiogenic properties of resveratrol in ocular diseases. Molecules 2016;21:304. 86. Hua J, Guerin KI, Chen J, et al. Resveratrol inhibits pathologic retinal neovascularization in VLDLR(‒/‒) mice. Investig Ophthalmol Vis Sci 2011;52:2809e2816. 87. Ghiringhelli F, Rebe C, Hichami A, et al. Immunomodulation and anti-inflammatory roles of polyphenols as anticancer agents. Anticancer Agents Med Chem 2012;12:852e873. 88. Hassanzadeh P, Arbabi E, Atyabi F, et al. The endocannabinoid system and NGF are involved in the mechanism of action of resveratrol: a multi-target nutraceutical with therapeutic potential in neuropsychiatric disorders. Psychopharmacology 2016;233:1087e1096. 89. Dain A, Repossi G, Das UN, et al. Role of PUFAs, the precursors of endocannabinoids, in human obesity and type 2 diabetes. Front Biosci (Elite Ed) 2010;2:1432e1447. 90. Di Patrizio NV, Astarita G, Schwartz G, et al. Endocannabinoid signal in the gut controls dietary fat intake. Proc Natl Acad Sci USA 2011;108:12904e12908. 91. Argueta DA, Di Patrizio NV. Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity. Physiol Behav 2017;171:32e39. 92. Pluznick JL, Protzko RJ, Gevorgyan H, et al. Olfactory receptor responding to gut microbiotaederived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci USA 2013;110:4410e4415.
-
(2020)
-
93. Neuhaus EM, Zhang W, Gelis L, et al. Activation of an olfactory receptor inhibits proliferation of prostate cancer cells. J Biol Chem 2009;284:16218e16225. 94. Sikka G, Hussmann GP, Pandey D, et al. Melanopsin mediates lightdependent relaxation in blood vessels. Proc Natl Acad Sci USA 2014;111:17977e17982. 95. Spitschan M. Melanopsin contributions to non-visual and visual function. Curr Opin Behav Sci 2019;30:67e72. 96. Tizzano M, Gulbransen BD, Vandenbeuch A, et al. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci USA 2010;107:3210e3215. 97. Lee RJ, Kofonow JM, Rosen PL, et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J Clin Invest 2014;124:1393e1405. 98. Shah AS, Ben-Shahar Y, Moninger TO, et al. Motile cilia of human airway epithelia are chemosensory. Science 2009;325:1131e1134. 99. Lee RJ, Xiong G, Kofonow JM, et al. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J Clin Invest 2012;122:4145e4159. 100. Howitt MR, Lavoie S, Michaud M, et al. Tuft cells, tastechemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 2016;351:1329e1333. 101. Knight CM, Gutierrez-Juarez R, Lam TK, et al. Mediobasal hypothalamic SIRT1 is essential for resveratrol’s effects on insulin action in rats. Diabetes 2011;60:2691e2700. 102. Tabrizi R, Tamtaji OR, Lankarani KB, et al. The effects of resveratrol intake on weight loss: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr 2020;60:375e390. 103. Serini S, Cassano R, Corsetto PA, et al. Omega-3 PUFA loaded in resveratrol-based solid lipid nanoparticles: physicochemical properties and antineoplastic activities in human colorectal cancer cells in vitro. Int J Mol Sci 2018;19(2):E586.