Resveratrol

1 Fallopia sp. 2 Picea sp. 3 Polygonum sp. 4 Trifolium sp. 5 Veratrum sp. 6 Vitis sp.

Resveratrol is a phytoalexin produced naturally by several plants with anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects.

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.[Pubmed:22304913]

Cell. 2012 Feb 3;148(3):421-33.

Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of Resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKbeta-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, Resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of Resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.

Resveratrol upregulates Egr-1 expression and activity involving extracellular signal-regulated protein kinase and ternary complex factors.[Pubmed:25645941]

Exp Cell Res. 2015 Mar 1;332(1):116-27.

Many intracellular functions have been attributed to Resveratrol, a polyphenolic phytoalexin found in grapes and in other plants. Here, we show that Resveratrol induces the expression of the transcription factor Egr-1 in human embryonic kidney cells. Using a chromosomally embedded Egr-1-responsive reporter gene, we show that the Egr-1 activity was significantly elevated in Resveratrol-treated cells, indicating that the newly synthesized Egr-1 protein was biologically active. Stimulus-transcription coupling leading to the Resveratrol-induced upregulation of Egr-1 expression and activity requires the protein kinases Raf and extracellular signal-regulated protein kinase ERK, while MAP kinase phosphatase-1 functions as a nuclear shut-off device that interrupts the signaling cascade connecting Resveratrol stimulation with enhanced Egr-1 expression. On the transcriptional level, Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, connects the intracellular signaling cascade elicited by Resveratrol with transcription of the Egr-1 gene. These data were corroborated by the observation that stimulation of the cells with Resveratrol increased the transcriptional activation potential of Elk-1. The SRE as well as the GC-rich DNA binding site of Egr-1 function as Resveratrol-responsive elements. Thus, Resveratrol regulates gene transcription via activation of the stimulus-regulated protein kinases Raf and ERK and the stimulus-responsive transcription factors TCF and Egr-1.

Resveratrol induces cell apoptosis in adipocytes via AMPK activation.[Pubmed:25603053]

Biochem Biophys Res Commun. 2015 Feb 20;457(4):608-13.

Resveratrol is identified as polyphenolic compound with anti-inflammatory, antioxidant, anti-insulin resistance characteristics. Moreover, Resveratrol exerts pro-apoptotic effects in varieties of cancer cell lines. However, effects and mechanisms of Resveratrol on the regulation of adipocytes apoptosis remain largely unknown. In this study, we found that Resveratrol treatment could induce cell apoptosis in murine 3T3-L1 adipocytes. Furthermore, Resveratrol activated the mitochondrial apoptotic signaling pathway with the decrease in the mitochondrial membrane potential (MMP), and the activation of caspase 3. Mechanistically, we found that phosphorylation level of AMP-activated protein kinase alpha (AMPKalpha) was elevated, accompany with reduced level of phosphorylation of protein kinase B (AKT) when cells were exposed to Resveratrol. By using small interfering RNAs of AMPKalpha and specific inhibitor for p-AKT, it was shown that activation of AMPKalpha could inhibit downstream of p-AKT, consequently activating mitochondrion-mediated apoptotic pathway. Additionally, we observed similar pro-apoptotic effects of Res on mouse primary adipocytes. Our findings clarified the apoptotic effects and underlying mechanisms of Resveratrol in adipocytes, suggesting its potential therapeutic application in the treatment or prevention of obesity and related metabolic symptoms.

Resveratrol protects against arsenic trioxide-induced oxidative damage through maintenance of glutathione homeostasis and inhibition of apoptotic progression.[Pubmed:25339131]

Environ Mol Mutagen. 2015 Apr;56(3):333-46.

Arsenic trioxide (As2 O3 ) is commonly used to treat acute promyelocytic leukemia and solid tumors. However, the clinical application of the agent is limited by its cyto- and genotoxic effects on normal cells. Thus, relief of As2 O3 toxicity in normal cells is essentially necessary for improvement of As2 O3 -mediated chemotherapy. In this study, we have identified a series of protective effects of Resveratrol against As2 O3 -induced oxidative damage in normal human bronchial epithelial (HBE) cells. We showed that treatment of HBE cells with Resveratrol significantly reduced cellular levels of DNA damage, chromosomal breakage, and apoptosis induced by As2 O3 . The effect of Resveratrol against DNA damage was associated with a decreased level of reactive oxygen species and lipid peroxidation in cells treated by As2 O3 , suggesting that Resveratrol protects against As2 O3 toxicity via a cellular anti-oxidative stress pathway. Further analysis of the roles of Resveratrol demonstrated that it modulated biosynthesis, recycling, and consumption of glutathione (GSH), thereby promoting GSH homeostasis in HBE cells treated by As2 O3 . This was further supported by results showing that Resveratrol prevented an increase in the activities and levels of caspases, Fas, Fas-L, and cytochrome c proteins induced by As2 O3 . Our study indicates that Resveratrol relieves As2 O3 -induced oxidative damage in normal human lung cells via maintenance of GSH homeostasis and suppression of apoptosis.

Resveratrol at anti-angiogenesis/anticancer concentrations suppresses protein kinase G signaling and decreases IAPs expression in HUVECs.[Pubmed:25550561]

Anticancer Res. 2015 Jan;35(1):273-81.

BACKGROUND: Resveratrol increases nitric oxide (NO) production via increased expression and activation of endothelial-form-NO-synthase (eNOS) in endothelial cells. However, the role of downstream cGMP/protein kinase G (PKG) signaling, a pathway activated by NO/eNOS, in pro- and anti-angiogenic effects of Resveratrol is still unclear. MATERIALS AND METHODS: Endogenous NO/cGMP/PKG pathway and downstream cell-survival proteins (Inhibitor of Apoptosis Proteins, IAPs) were studied in relation to pro- and anti-angiogenic effects of Resveratrol in human umbilical vein endothelial cells (HUVECs). RESULTS: Resveratrol at higher/anti-angiogenic concentrations inhibits HUVEC tube formation and cell migration/invasion (indices of angiogenesis). Resveratrol at lower concentrations stimulates proliferation and protects HUVECs against spontaneous apoptosis. 8-Br-cGMP, a direct activator of PKG, protects against pro-apoptotic effects of high-concentration Resveratrol. Western blot analyses showed that anti-angiogenic concentrations of Resveratrol suppress endogenous PKG kinase activity and decrease the expression of four cell-survival proteins, c-IAP1, c-IAP2, livin and XIAP. CONCLUSION: Resveratrol-induced anti-angiogenesis/pro-apoptosis induced suppression of PKG signaling and decreased expression of the cell-survival proteins c-IAP1, c-IAP2, livin and XIAP.

Resveratrol restores the circadian rhythmic disorder of lipid metabolism induced by high-fat diet in mice.[Pubmed:25640840]

Biochem Biophys Res Commun. 2015 Feb 27;458(1):86-91.

Circadian rhythmic disorders induced by high-fat diet are associated with metabolic diseases. Resveratrol could improve metabolic disorder, but few reports focused on its effects on circadian rhythm disorders in a variety of studies. The aim of the present study was to analyze the potential effects of Resveratrol on high-fat diet-induced disorders about the rhythmic expression of clock genes and clock-controlled lipid metabolism. Male C57BL/6 mice were divided into three groups: a standard diet control group (CON), a high-fat diet (HFD) group and HFD supplemented with 0.1% (w/w) Resveratrol (RES). The body weight, fasting blood glucose and insulin, plasma lipids and leptin, whole body metabolic status and the expression of clock genes and clock-controlled lipogenic genes were analyzed at four different time points throughout a 24-h cycle (8:00, 14:00, 20:00, 2:00). Resveratrol, being associated with rhythmic restoration of fasting blood glucose and plasma insulin, significantly decreased the body weight in HFD mice after 11 weeks of feeding, as well as ameliorated the rhythmities of plasma leptin, lipid profiles and whole body metabolic status (respiratory exchange ratio, locomotor activity, and heat production). Meanwhile, Resveratrol modified the rhythmic expression of clock genes (Clock, Bmal1 and Per2) and clock-controlled lipid metabolism related genes (Sirt1, Pparalpha, Srebp-1c, Acc1 and Fas). The response pattern of mRNA expression for Acc1 was similar to the plasma triglyceride. All these results indicated that Resveratrol reduced lipogenesis and ultimately normalized rhythmic expression of plasma lipids, possibly via its action on clock machinery.

Regulation of histone H2A.Z expression is mediated by sirtuin 1 in prostate cancer.[Pubmed:24127549]

Oncotarget. 2013 Oct;4(10):1673-85.

Histone variants seem to play a major role in gene expression regulation. In prostate cancer, H2A.Z and its acetylated form are implicated in oncogenes' upregulation. SIRT1, which may act either as tumor suppressor or oncogene, reduces H2A.Z levels in cardiomyocytes, via proteasome-mediated degradation, and this mechanism might be impaired in prostate cancer cells due to sirtuin 1 downregulation. Thus, we aimed to characterize the mechanisms underlying H2A.Z and SIRT1 deregulation in prostate carcinogenesis and how they interact. We found that H2AFZ and SIRT1 were up- and downregulated, respectively, at transcript level in primary prostate cancer and high-grade prostatic intraepithelial neoplasia compared to normal prostatic tissues. Induced SIRT1 overexpression in prostate cancer cell lines resulted in almost complete absence of H2A.Z. Inhibition of mTOR had a modest effect on H2A.Z levels, but proteasome inhibition prevented the marked reduction of H2A.Z due to sirtuin 1 overexpression. Prostate cancer cells exposed to epigenetic modifying drugs trichostatin A, alone or combined with 5-aza-2'-deoxycytidine, increased H2AFZ transcript, although with a concomitant decrease in protein levels. Conversely, SIRT1 transcript and protein levels increased after exposure. ChIP revealed an increase of activation marks within the TSS region for both genes. Remarkably, inhibition of sirtuin 1 with nicotinamide, increased H2A.Z levels, whereas activation of sirtuin 1 by Resveratrol led to an abrupt decrease in H2A.Z. Finally, protein-ligation assay showed that exposure to epigenetic modifying drugs fostered the interaction between sirtuin 1 and H2A.Z. We concluded that sirtuin 1 and H2A.Z deregulation in prostate cancer are reciprocally related. Epigenetic mechanisms, mostly histone post-translational modifications, are likely involved and impair sirtuin 1-mediated downregulation of H2A.Z via proteasome-mediated degradation. Epigenetic modifying drugs in conjunction with enzymatic modulators are able to restore the normal functions of sirtuin 1 and might constitute relevant tools for targeted therapy of prostate cancer patients.

Therapeutic potential of resveratrol: the in vivo evidence.[Pubmed:16732220]

Nat Rev Drug Discov. 2006 Jun;5(6):493-506.

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that Resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on Resveratrol, and consider its potential as a therapeutic for humans.

Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta.[Pubmed:11014220]

Endocrinology. 2000 Oct;141(10):3657-67.

Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. At least some of these activities are mediated through the interaction of phytoestrogens with estrogen receptors alpha and beta (ERalpha and ERbeta). Resveratrol, trans-3,5,4'-trihydroxystilbene, is a phytoestrogen in grapes that is present in red wine. Resveratrol was shown to bind ER in cytosolic extracts from MCF-7 and rat uteri. However, the contribution of ERalpha vs. ERbeta in this binding is unknown. Here we report that Resveratrol binds ERbeta and ERalpha with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, Resveratrol differs from other phytoestrogens that bind ERbeta with higher affinity than ERalpha. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ERalpha or ERbeta. The estrogen agonist activity of Resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ERbeta has higher transcriptional activity than E2-liganded ERbeta at a single palindromic ERE. This indicates that those tissues that uniquely express ERbeta or that express higher levels of ERbeta than ERalpha may be more sensitive to Resveratrol's estrogen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, Resveratrol shows activity comparable to that induced by E2. We report that Resveratrol exhibits E2 antagonist activity for ERalpha with select EREs. In contrast, Resveratrol shows no E2 antagonist activity with ERbeta. These data indicate that Resveratrol differentially affects the transcriptional activity of ERalpha and ERbeta in an ERE sequence-dependent manner.

Biological effects of resveratrol.[Pubmed:10680575]

Life Sci. 2000 Jan 14;66(8):663-73.

Resveratrol (3, 4', 5 trihydroxystilbene) is a naturally occuring phytoalexin produced by some spermatophytes, such as grapevines, in response to injury. Given that it is present in grape berry skins but not in flesh, white wine contains very small amounts of Resveratrol, compared to red wine. The concentrations in the form of trans- and cis- isomers of aglycone and glucosides are subjected to numerous variables. In red wine, the concentrations of the trans-isomer, which is the major form, generally ranges between 0.1 and 15 mg/L. As phenolic compound, Resveratrol contributes to the antioxidant potential of red wine and thereby may play a role in the prevention of human cardiovascular diseases. Resveratrol has been shown to modulate the metabolism of lipids, and to inhibit the oxidation of low-density lipoproteins and the aggregation of platelets. Moreover, as phytoestrogen, Resveratrol may provide cardiovascular protection. This compound also possesses anti-inflammatory and anticancer properties. However, the bioavailability and metabolic pathways must be known before drawing any conclusions on the benefits of dietary Resveratrol to health.

Resveratrol is a selective human cytochrome P450 1A1 inhibitor.[Pubmed:10448061]

Biochem Biophys Res Commun. 1999 Aug 19;262(1):20-4.

Resveratrol (trans-3,4',5-trihydroxystilbene) is a phytoalexin compound found in juice and wine produced from dark-skinned grape cultivars and reported to have anti-inflammatory and anticarcinogenic activities. To investigate the mechanism of anticarcinogenic activities of Resveratrol, the effects on cytochrome P450 (P450) were determined in human liver microsomes and Escherichia coli membranes coexpressing human P450 1A1 or P450 1A2 with human NADPH-P450 reductase (bicistronic expression system). Resveratrol slightly inhibited ethoxyresorufin O-deethylation (EROD) activity in human liver microsomes with an IC(50) of 1.1 mM. Interestingly, Resveratrol exhibited potent inhibition of human P450 1A1 in a dose-dependent manner with IC(50) of 23 microM for EROD and IC(50) of 11 microM for methoxyresorufin O-demethylation (MROD). However, the inhibition of human P450 1A2 by Resveratrol was not so strong (IC(50) 1.2 mM for EROD and 580 microM for MROD). Resveratrol showed over 50-fold selectivity for P450 1A1 over P450 1A2. The activities of human NADPH-P450 reductase were not significantly changed by Resveratrol. In a human P450 1A1/reductase bicistronic expression system, Resveratrol inhibited human P450 1A1 activity in a mixed-type inhibition (competitive-noncompetitive) with a K(i) values of 9 and 89 microM. These results suggest that Resveratrol is a selective human P450 1A1 inhibitor, and may be considered for use as a strong cancer chemopreventive agent in humans.

Effects of stilbenes on arachidonate metabolism in leukocytes.[Pubmed:3922423]

Biochim Biophys Acta. 1985 Apr 25;834(2):275-8.

The effects of various stilbenes (i.e, 3,4',5-trihydroxystilbene, 3,4',5-trihydroxystilbene 3-O-D-glucoside and 2,3,4',5-tetrahydroxystilbene 2-O-D-glucoside) isolated from the roots of Polygonum species on rat peritoneal polymorphonuclear leukocyte lipoxygenase and cyclooxygenase activities were studied. Resveratrol (3,4',5-trihydroxystilbene) was found to inhibit the 5-lipoxygenase product, 5-HETE, and cyclooxygenase products, HHT and thromboxane B2; its concentrations for 50% inhibition (IC50) were 2.72 +/- 0.262 microM for the leukocyte lipoxygenase product, 5-HETE, 0.683 +/- 0.163 microM for the formations of HHT and 0.810 +/- 0.274 microM for the formation of thromboxane B2. Piceid (3,4',5-trihydroxystilbene 3-O-D-glucoside) and 2,3,4',5-tetrahydroxystilbene 2-O-D-glucoside also inhibited the formation of 5-HETE, HHT and thromboxane B2, although less strongly. Their IC50 values were, respectively, 55.3 +/- 15.3 microM and greater than 1000 microM for the formation of 5-HETE, 196.7 +/- 48.0 microM and 300.0 +/- 10.4 microM for the formation of HHT and 251.7 +/- 24.9 microM and 366.7 +/- 37.1 microM for the formation of thromboxane B2.

Resveratrol (trans-Resveratrol; SRT501), a natural polyphenolic phytoalexin that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anti-cancer properties. Resveratrol (SRT 501) has a wide spectrum of targets including mTOR, JAK, β-amyloid, Adenylyl cyclase, IKKβ, DNA polymerase. Resveratrol also is a specific SIRT1 activator. Resveratrol is a potent pregnane X receptor (PXR) inhibitor.

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