TITLE | ABSTRACT | LINK |
Anti‐diabetic effects of resveratrol | Diabetes mellitus is a complex metabolic disease affecting about 5% of people all over the world. Data from the literature indicate that resveratrol is a compound exerting numerous beneficial effects in organisms. Rodent studies, for example, have demonstrated that resveratrol decreases blood glucose in animals with hyperglycemia. This effect seems to predominantly result from increased intracellular transport of glucose. Resveratrol was also demonstrated to induce effects that may contribute to the protection of β cells in diabetes. In experiments on pancreatic islets, the ability of resveratrol to reduce insulin secretion was demonstrated; this effect was confirmed in animals with hyperinsulinemia, in which resveratrol decreased blood insulin levels. Moreover, inhibition of cytokine action and attenuation of the oxidative damage of the pancreatic tissue by resveratrol were recently shown. Studies of animals with insulin resistance indicate that resveratrol may also improve insulin action. The mechanism through which resveratrol improves insulin action is complex and involves reduced adiposity, changes in gene expression, and changes in the activities of some enzymes. These data indicate that resveratrol may be useful in preventing and treating diabetes. | |
Antioxidant properties of resveratrol: A structure–activity insight | Resveratrol, a natural product, is known to affect a broad range of intracellular mediators. In the present study, we clarified the antioxidant activity of resveratrol by employing various in vitro antioxidant assays such as DPPH•, ABTS•+, DMPD•+, O2•− and H2O2 scavenging activities, total antioxidant activity, reducing abilities, and Fe2+ chelating activities. Resveratrol inhibited 89.1% of the lipid peroxidation of linoleic acid emulsion at 30 µg/mL concentration. On the other hand, BHA, BHT, α-tocopherol, and trolox exhibited inhibitions of 83.3, 82.1, 68.1, and 81.3% against peroxidation of linoleic acid emulsion at the same concentration, respectively. In addition, resveratrol had effective DPPH•, ABTS•+, DMPD•+, O2•− and H2O2 scavenging activities, reducing power, and Fe2+ chelating activities. The present study found that resveratrol had effective in vitro antioxidant and radical scavenging activity. It can be used in pharmacological and food industry due to its antioxidant properties. Industrial relevance Antioxidants are often added to foods to prevent the radical chain reactions of oxidation and they act by inhibiting the initiation and propagation step leading to the termination of the reaction and delay the oxidation process. At the present time, the most commonly used antioxidants are BHA, BHT, propylgallate and tert-butyl hydroquinone. Besides that BHA and BHT are restricted by legislative rules because of doubts over their toxic and carcinogenic effects. Therefore, there is a growing interest on natural and safer antioxidants in food applications, and a growing trend in consumer preferences for natural antioxidants, all of which has given more impetus to explore natural sources of antioxidants. A variety of foods and beverages of vegetable origin contain several nonflavonoid classes of phenolic compounds synthesized by plants. Among them, resveratrol has been identified as the major active compound of stilbene phytoalexins and is presumed to be beneficial for human health. Resveratrol is naturally occurring in the fruits and leaves of edible plants, peanuts, mulberries, grapes and red wine. Resveratrol is currently in the limelight all over the world due to their beneficial effects on the human body. Resveratrol can be used for minimizing or preventing lipid oxidation in pharmaceutical products, retarding the formation of toxic oxidation products, maintaining nutritional quality and prolonging the shelf life of food products and pharmaceuticals instead of BHA and BHT and other antioxidant compounds because of their safer usage. | |
Bioactivity of Resveratrol | Resveratrol (3,5,4′‐trihydroxystilbene) is a natural polyphenolic phytochemical with a variety of bioactivities associated with health promotion. Resveratrol is readily absorbed with the other absorbable digestion products of its main human dietary sources (peanuts, peanut butter, grapes, and red wine). The polyphenolic structure of resveratrol confers antioxidant activity and may reduce oxidant‐induced apoptosis and low‐density lipoprotein (LDL) oxidation. Resveratrol may be responsible, in part, for the correlation between increased wine consumption and decreased risk of coronary heart disease. The cardioprotective activity of resveratrol is associated with the inhibition of platelet aggregation and LDL oxidation and the promotion of artery vasorelaxation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression, as well as inhibit the growth of cancerous cells through increased apoptosis and/or cell cycle blockage. Inflammatory processes are associated in the pathogenesis of many chronic diseases including heart disease and cancer. Resveratrol has been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase‐2 activity, and nuclear factor‐кB activity. In addition, the estrogenic activity of resveratrol may help prevent post‐menopausal bone loss. Modulation of cellular signal transduction pathways (such as mitogen‐activated protein kinases) may explain, in part, the diverse bioactivities associated with resveratrol. Scientific information summarized in this review supports the many potential health benefits of resveratrol; however, further understanding of the bioavailability, metabolism, and cellular effects of resveratrol is necessary. | https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1541-4337.2006.00001.x |
Bioavailability of resveratrol | This paper reviews our current understanding of the absorption, bioavailability, and metabolism of resveratrol,with an emphasis on humans. The oral absorption of resveratrol in humans is about 75% and is thought to occurmainly by transepithelial diffusion. Extensive metabolism in the intestine and liver results in an oral bioavailabilityconsiderably less than 1%. Dose escalation and repeated dose administration of resveratrol does not appear to alterthis significantly. Metabolic studies, both in plasma and in urine, have revealed major metabolites to be glucuronidesand sulfates of resveratrol. However, reduced dihydroresveratrol conjugates, in addition to highly polar unknownproducts, may account for as much as 50% of an oral resveratrol dose. Although major sites of metabolism includethe intestine and liver (as expected), colonic bacterial metabolism may be more important than previously thought.Deconjugation enzymes such asβ-glucuronidase and sulfatase, as well as specific tissue accumulation of resveratrol,may enhance resveratrol efficacy at target sites. Resveratrol analogs, such as methylated derivatives with improvedbioavailability, may be important in future research. | https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1749-6632.2010.05842.x |
Biological effects of resveratrol | 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. | https://media.ellinikahoaxes.gr/uploads/2016/11/Biological-Effects-of-Resveratrol.pdf |
Cancer Chemopreventive Activity of Resveratrol | Cancer chemopreventive agents are designed to reduce the incidence of tumorigenesis by intervening at one or more stages of carcinogenesis. Recently, resveratrol, a natural product found in the diet of humans, has been shown to function as a cancer chemopreventive agent. Resveratrol was first shown to act as an antioxidant and antimutagenic agent, thus acting as an antiinitiation agent. Further evidence indicated that resveratrol selectively suppresses the transcriptional activation of cytochrome P-450 1A1 and inhibits the formation of carcinogen-induced preneoplastic lesions in a mouse mammary organ culture model. Resveratrol also inhibits the formation of 12-Otetradecanoylphorbol-13-acetate (TPA)–promoted mouse skin tumors in the two-stage model. The enzymatic activities of COX-1 and -2 are inhibited by resveratrol in cell-free models, and COX-2 mRNA and TPA-induced activation of protein kinase C and AP-1–mediated gene expression are suppressed by resveratrol in mammary epithelial cells. In addition, resveratrol strongly inhibits nitric oxide generation and inducible nitric oxide synthase protein expression.NFkB is strongly linked to inflammatory and immune responses and is associated with oncogenesis in certain models of cancer, and resveratrol suppresses the induction of this transcription factor by a number of agents. The mechanism may involve decreasing the phosphorylation and degradation of IkBα. At the cellular level, resveratrol also induces apoptosis, cell cycle delay or a block in the G1→S transition phase in a number of cell lines. Thus, resveratrol holds great promise for future development as a chemopreventive agent that may be useful for several disorders. Preclinical toxicity studies are underway that should be followed by human clinical trials. | http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.476.2309&rep=rep1&type=pdf |
Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes | Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans. | https://www.jstor.org/stable/pdf/2891907.pdf |
Cancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives | A plant kingdom is considered as a gold mine for the discovery of many biologically active substances with therapeutic values. Resveratrol (3,5,4′-trihydroxystilbene), a naturally occurring polyphenol, exhibits pleiotropic health beneficial effects including anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. Currently, numerous preclinical findings suggest resveratrol as a promising nature’s arsenal for cancer prevention and treatment. A remarkable progress in dissecting the molecular mechanisms underlying anti-cancer properties of resveratrol has been achieved in the past decade. As a potential anti-cancer agent, resveratrol has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. The compound significantly inhibits experimental tumorigenesis in a wide range of animal models. Resveratrol targets many components of intracellular signaling pathways including pro-inflammatory mediators, regulators of cell survival and apoptosis, and tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. This review summarizes the diverse molecular targets of resveratrol with a special focus on those involved in fine-tuning of orchestrated intracellular signal transduction. | https://www.sciencedirect.com/science/article/pii/S0304383508002528/pdfft?md5=6584e960304c54fa5cceff14e87270e9&pid=1-s2.0-S0304383508002528-main.pdf |
Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes | Background: The major objective of the present study was to examine the cardioprotective effect of resveratrol, an antioxidant presents in red wines, in the rat after ischemia and ischemia–reperfusion (I–R). Methods: The left main coronary artery was occluded for 30 or 5 min followed by a 30-min reperfusion in anesthetized rats. Animals were preinfused with and without resveratrol before occlusion and the severity of ischemia- and I–R-induced arrhythmias and mortality were compared. Results: Resveratrol pretreatment had no effect on ischemia-induced arrhythmias nor on mortality. In contrast, a dramatic protective effects were observed against I–R-induced arrhythmias and mortality. Resveratrol pretreatment both reduced the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF). During the same period, resveratrol pretreatment also increased nitric oxide (NO) and decreased lactate dehydrogenase levels in the carotid blood. Conclusions: Resveratrol is a potent antiarrhythmic agent with cardioprotective properties in I–R rats. The cardioprotective effects of resveratrol in the I–R rats may be correlated with its antioxidant activity and upregulation of NO production. | https://academic.oup.com/cardiovascres/article-pdf/47/3/549/987512/47-3-549.pdf |
Cardiovascular Protective Effects of Resveratrol | Resveratrol (3,4′,5‐trihydroxy‐trans‐stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that at low doses (such as consumed in the common diet) resveratrol may have cardioprotective activity. In this article we describe recent in vitro and in vivo studies in animal models. The results of these studies suggest that resveratrol modulates vascular cell function, inhibits LDL oxidation, suppresses platelet aggregation and reduces myocardial damage during ischemia‐reperfusion. Although the reported biological data indicate that resveratrol is a highly promising cardiovascular protective agent, more studies are needed to establish its bioavailability and in vivo cardioprotective effects, particularly in humans. | https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1527-3466.2004.tb00139.x |
Chemosensitization of tumors by resveratrol | Because tumors develop resistance to chemotherapeutic agents, the cancer research community continues to search for effective chemosensitizers. One promising possibility is to use dietary agents that sensitize tumors to the chemotherapeutics. In this review, we discuss that the use of resveratrol can sensitize tumor cells to chemotherapeutic agents. The tumors shown to be sensitized by resveratrol include lung carcinoma, acute myeloid leukemia, promyelocytic leukemia, multiple myeloma, prostate cancer, oral epidermoid carcinoma, and pancreatic cancer. The chemotherapeutic agents include vincristine, adriamycin, paclitaxel, doxorubicin, cisplatin, gefitinib, 5-Fluorouracil (5-FU), velcade, and gemcitabine. The chemosensitization of tumor cells by resveratrol appears to be mediated through its ability to modulate multiple cell signaling molecules, including drug transporters, cell survival proteins, cell proliferative proteins, and members of the NF-κB and STAT-3 signaling pathways. Interestingly, however, this nutraceutical has also been reported to suppress apoptosis induced by paclitaxel, vincristine, and daunorubicin in some tumor cells. The potential mechanisms underlying this dual effect are discussed. Overall, studies suggest that resveratrol can be used to sensitize tumors to standard cancer chemotherapeutics. | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060406/pdf/nihms248745.pdf |
Clinical trials of resveratrol | An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol. Recent studies have also evaluated safety and potential mechanisms of activity following multiple dosing, and have found resveratrol to be safe and reasonably well‐tolerated at doses of up to 5 g/day. However, the occurrence of mild to moderate side effects is likely to limit the doses employed in future trials to significantly less than this amount. This review describes the available clinical data, outlines how it supports the continuing development of resveratrol, and suggests what additional information is needed to increase the chances of success in future clinical trials. | https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1749-6632.2010.05853.x |
Effects of Resveratrol in Inflammatory Arthritis | Summary: Nuclear factor kappa B (NF-κB), is a pivotal transcription factor involved in the activation of the TNF-α and IL-1β genes. Activation of NF-κB in synovial cells is a feature seen in arthritis patients. Resveratrol, a polyphenolic, natural phytoalexin found with particularly high levels in grape skin and red wine is potent and specific inhibitor of TNF-α and IL-1β induced NF-κB activation. We aimed to determine the in vivo effects of intra-articular injections of resveratrol on cartilage and synovium in an experimental rabbit inflammatory arthritis model. Materials and methods: Arthritis was induced by intra-articular injection of three times of 50 μg lipopolysaccharide (LPS) at day 0, 4 and 8 at 4-day intervals into the knee joints of rabbits. To the test group, 10 μMol/kg resveratrol in the DMSO was injected in the knees at day 0 and then it was continued once daily for 2 weeks. To the control group the same time and amount of DMSO was injected the knees of rabbits. All rabbits were killed 1 week after the last injection and cartilage tissue and synovium were evaluated with semiquantitative scoring histologically. Results: According to control group in the resveratrol group, significantly decreased cartilage destruction was determined by H&E staining (p = 0.04). Loss of matrix proteoglycan content in the cartilage was much lower, as determined by safranin O staining (p = 0.03). We also observed marked synovial inflammation after intra-articular injection to control knees, but not in the resveratrol treated group knees (p = 0.01). Conclusion: This study suggests that intra-articular injection of resveratrol may protect cartilage against the development of experimentally induced IA. | https://link.springer.com/content/pdf/10.1007%2Fs10753-006-9012-0.pdf |
High Absorption but Very Low Bioavailability of Oral Resveratrol in Humans | The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 ± 90 ng/ml (about 2 μM) and a plasma half-life of 9.2 ± 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects. | https://terraternal.com/content/ResveratrolAbsorptionAndBioavailability.pdf |
Human, Rat, and Mouse Metabolism of Resveratrol | Purpose. Resveratrol, a phenolic phytoalexin occurring in grapes, wine, peanuts, and cranberries, has been reported to have anticarcinogenic, antioxidative, phytoestrogenic, and cardioprotective activities. Because little is known about the metabolism of this potentially important compound, the in vitro and in vivo metabolism of trans-resveratrol were investigated. Methods. The in vitro experiments included incubation with human liver microsomes, human hepatocytes, and rat hepatocytes and the in vivo studies included oral or intraperitoneal administration of resveratrol to rats and mice. Methanol extracts of rat urine, mouse serum, human hepatocytes, rat hepatocytes, and human liver microsomes were analyzed for resveratrol metabolites using reversed-phase high-performance liquid chromatography with on-line ultraviolet-photodiode array detection and mass spectrometric detection (LC-DAD-MS and LC-UV-MS-MS). UV-photodiode array analysis facilitated the identification of cis- and trans-isomers of resveratrol and its metabolites. Negative ion electrospray mass spectrometric analysis provided molecular weight confirmation of resveratrol metabolites and tandem mass spectrometry allowed structural information to be obtained. Results. No resveratrol metabolites were detected in the microsomal incubations, and no phase I metabolites, such as oxidations, reductions, or hydrolyzes, were observed in any samples. However, abundant trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate were identified in rat urine, mouse serum, and incubations with rat and human hepatocytes. Incubation with β-glucuronidase and sulfatase to release free resveratrol was used to confirm the structures of these conjugates. Only trace amounts of cis-resveratrol were detected, indicating that isomerization was not an important factor in the metabolism and elimination of resveratrol. Conclusion. Our results indicate that trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate are the most abundant metabolites of resveratrol. Virtually no unconjugated resveratrol was detected in urine or serum samples, which might have implications regarding the significance of in vitro studies that used only unconjugated resveratrol. | https://link.springer.com/content/pdf/10.1023%2FA%3A1021414129280.pdf |
Mechanism of Human SIRT1 Activation by Resveratrol | The NAD+-dependent protein deacetylase family, Sir2 (or sirtuins), is important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and life span extension. Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro. In addition, resveratrol was shown to increase life span in three model organisms through a Sir2-dependent pathway. Here, we investigated the molecular basis for Sir2 activation by resveratrol. Among the three enzymes tested (yeast Sir2, human SIRT1, and human SIRT2), only SIRT1 exhibited significant enzyme activation (∼8-fold) using the commercially available Fluor de Lys kit (BioMol). To examine the requirements for resveratrol activation of SIRT1, we synthesized three p53 acetylpeptide substrates either lacking a fluorophore or containing a 7-amino-4-methylcoumarin (p53-AMC) or rhodamine 110 (p53-R110). Although SIRT1 activation was independent of the acetylpeptide sequence, resveratrol activation was completely dependent on the presence of a covalently attached fluorophore. Substrate competition studies indicated that the fluorophore decreased the binding affinity of the peptide, and, in the presence of resveratrol, fluorophore-containing substrates bound more tightly to SIRT1. Using available crystal structures, a model of SIRT1 bound to p53-AMC peptide was constructed. Without resveratrol, the coumarin of p53-AMC peptide is solvent-exposed and makes no significant contacts with SIRT1. We propose that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group. | https://www.jbc.org/content/280/17/17187.full.pdf |
Molecular mechanism of the chemopreventive effect of resveratrol | Chemoprevention is a promising approach to control human cancer. Resveratrol has been shown to have a potent chemopreventive effect in multiple carcinogenesis models. However, the precise mechanism explaining its anti-carcinogenic effect is not clear. This review summarizes recent studies from our laboratory on the mechanisms of resveratrol’s effects. In JB6 cells, resveratrol was found to induce apoptosis and inhibit tumor promoter-induced cell transformation. We also found that resveratrol-induced activation of p53 and resveratrol-induced apoptosis occurred through a p53-dependent pathway. The MAP kinases, ERKs, JNKs, or p38 kinases, are involved in resveratrol-induced activation of p53 and apoptosis. | http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.320.871&rep=rep1&type=pdf |
Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms | Plant-derived polyphenolic compounds, such as the stilbene resveratrol (trans-3,4′,5-trihydroxystilbene), have been identified as potent anti-cancer agents. Extensive in vitro studies revealed multiple intracellular targets of resveratrol, which affect cell growth, inflammation, apoptosis, angiogenesis, and invasion and metastasis. These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases ATM/ATR; transcription factors NF-κB, AP-1, c-Jun, and c-Fos; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators, Bax, Bak, PUMA, Noxa, TRAIL, APAF, survivin, Akt, Bcl2 and Bcl-XL. In addition to its well-documented anti-oxidant properties, there is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. This review summarizes in vitro mechanistic data available for resveratrol and discusses new potential anti-cancer targets and the anti-proliferative mechanisms of resveratrol. | https://www.sciencedirect.com/science/article/pii/S0003986109000216/pdfft?md5=06d65eeb9fd617285eae90af5a57db7c&pid=1-s2.0-S0003986109000216-main.pdf |
Neuroprotective action of resveratrol | Low-to-moderate red wine consumption appeared to reduce age-related neurological disorders including macular degeneration, stroke, and cognitive deficits with or without dementia. Resveratrol has been considered as one of the key ingredients responsible for the preventive action of red wine since the stilbene displays a neuroprotective action in various models of toxicity. Besides its well documented free radical scavenging and anti-inflammatory properties, resveratrol has been shown to increase the clearance of beta-amyloid, a key feature of Alzheimer's disease, and to modulate intracellular effectors associated with oxidative stress (e.g. heme oxygenase), neuronal energy homeostasis (e.g. AMP kinase), program cell death (i.e. AIF) and longevity (i.e. sirtuins). This article summarizes the most recent findings on mechanisms of action involved in the protective effects of this multi target polyphenol, and discusses its possible roles in the prevention of various age-related neurological disorders. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. | https://www.sciencedirect.com/science/article/pii/S0925443914002920/pdfft?md5=a00f947bb24db1530651a24531c1e44e&pid=1-s2.0-S0925443914002920-main.pdf |
Neuroprotective properties of resveratrol and derivatives | Stilbenoid compounds consist of a family of resveratrol derivatives. They have demonstrated promising activities in vitro and in vivo that indicate they may be useful in the prevention of a wide range of pathologies, such as cardiovascular diseases and cancers, as well have anti‐aging effects. More recently stilbenoid compounds have shown promise in the treatment and prevention of neurodegenerative disorders, such as Huntington’s, Parkinson’s, and Alzheimer's diseases. This paper primarily focuses on the impact of stilbenoids in Alzheimer's disease and more specifically on the inhibition of β‐amyloid peptide aggregation. | https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1749-6632.2010.05865.x |
Occurrence of Resveratrol in Edible Peanuts | Resveratrol has been associated with reduced cardiovascular disease and reduced cancer risk. This phytoalexin has been reported in a number of plant species, including grapes, and may be one of the compounds responsible for the health benefits of red wine. Analytical methods for measuring resveratrol in wine and peanuts were adapted to isolate, identify, and quantify resveratrol in several cultivars of peanuts. Aqueous ethanol (80% v/v) extracts from peanuts without seed coats were purified over alumina/silica gel columns and analyzed by reversed phase HPLC using a C-18 column. Peanuts from each market type, Virginia, runner, and Spanish, produced in four different locations contained from 0.03 to 0.14 μg of resveratrol/g. Seed coats from runner and Virginia types contained ∼0.65 μg/g of seed coat, which is equivalent to <0.04 μg/seed. Quantitative analysis of 15 cultivars representing 3 peanut market types, which had been cold stored for up to 3 years, indicated a range of 0.02−1.79 μg/g of peanut compared to 0.6−8.0 μg/mL in red wines. | https://pubs.acs.org/doi/pdf/10.1021/jf990737b |
Plant Foods and Herbal Sources of Resveratrol | Stilbenes, in particular trans-resveratrol and its glucoside, are widely reported to be beneficial to health, having been shown to possess antioxidative, anticarcinogenic, and antitumor properties. Major dietary sources include grapes, wine, peanuts, and soy; however, they can also be introduced into the diet through Itadori tea, which has long been used in Japan and China as a traditional herbal remedy for heart disease and strokes. Analysis of grapes, peanuts, and Itadori tea shows that they contain mainly trans-resveratrol glucoside. In contrast, red wines are primarily a source of the aglycones cis- and trans-resveratrol. While peanuts and grapes contain low levels of the stilbenes, Itadori tea and red wine both supply relatively high concentrations of resveratrol. For people who do not consume alcohol, Itadori tea may be a suitable substitute for red wine. However, further study on the potential biological effects of other endogenous compounds in Itadori tea is required and there is also a need for more information on the absorption and in vivo biomedical actions of free and conjugated resveratrol. | https://pubs.acs.org/doi/pdf/10.1021/jf0112973 |
Production of Resveratrol in Recombinant Microorganisms | Resveratrol production in Saccharomyces cerevisiae was compared to that in Escherichia coli. In both systems, 4-coumarate:coenzyme A ligase from tobacco and stilbene synthase from grapes were expressed. When p-coumaric acid was used as the precursor, resveratrol accumulations in the culture medium were observed to be comparable in E. coli (16 mg/liter) and yeast (6 mg/liter). | https://aem.asm.org/content/aem/72/8/5670.full.pdf |
Resveratrol alleviates alcoholic fatty liver in mice | Alcoholic fatty liver is associated with inhibition of sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK), two critical signaling molecules regulating the pathways of hepatic lipid metabolism in animals. Resveratrol, a dietary polyphenol, has been identified as a potent activator for both SIRT1 and AMPK. In the present study, we have carried out in vivo animal experiments that test the ability of resveratrol to reverse the inhibitory effects of chronic ethanol feeding on hepatic SIRT1-AMPK signaling system and to prevent the development of alcoholic liver steatosis. Resveratrol treatment increased SIRT1 expression levels and stimulated AMPK activity in livers of ethanol-fed mice. The resveratrol-mediated increase in activities of SIRT1 and AMPK was associated with suppression of sterol regulatory element binding protein 1 (SREBP-1) and activation of peroxisome proliferator-activated receptor γ coactivator α (PGC-1α). In parallel, in ethanol-fed mice, resveratrol administration markedly increased circulating adiponectin levels and enhanced mRNA expression of hepatic adiponectin receptors (AdipoR1/R2). In conclusion, resveratrol treatment led to reduced lipid synthesis and increased rates of fatty acid oxidation and prevented alcoholic liver steatosis. The protective action of resveratrol is in whole or in part mediated through the upregulation of a SIRT1-AMPK signaling system in the livers of ethanol-fed mice. Our study suggests that resveratrol may serve as a promising agent for preventing or treating human alcoholic fatty liver disease. | https://journals.physiology.org/doi/pdf/10.1152/ajpgi.90358.2008 |
Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases | 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 Ca2+ levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca2+-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. | https://www.sciencedirect.com/science/article/pii/S009286741200030X/pdfft?md5=fc6844f293b15e1015050615bb76a212&pid=1-s2.0-S009286741200030X-main.pdf |
Resveratrol and chemoprevention | Resveratrol is a phytoalexin, highly abundant in skins of red grapes and moderately abundant in peanuts and blueberries. Originally a constituent of oriental medicines, it has lately been rediscovered for a plethora of beneficial properties such as anti-cancer, anti-aging, antiviral, cardiovascular and neuroprotective effects, thereby making it one of the most sought after phytochemicals for supplementing human diet. Studies done in various laboratories have shown its modulatory effects on multitudes of cell signaling and gene expression pathways. Although most of its effects have been observed in cultured cells, quite a few have also been validated in whole animals as well. It is thus necessary to have a comprehensive look at all those effects of resveratrol in an organismal context. The following review summarizes the effects of resveratrol in the context of chemoprevention. | https://www.sciencedirect.com/science/article/pii/S0304383509000846/pdfft?md5=423dbfb2c51e0ba53ca055ba2f60ba19&pid=1-s2.0-S0304383509000846-main.pdf |
Resveratrol and life extension | Age is the most important risk factor for diseases affecting the Western world, and slowing age‐related degeneration would greatly improve the quality of human life. In rodents, caloric restriction (CR) extends lifespan by up to 50%. However, attempts to mimic the effects of CR pharmacologically have been limited by our poor understanding of the mechanisms involved. SIRT1 is proposed to mediate key aspects of CR, and small molecule activators may therefore act as CR mimetics. The polyphenol resveratrol activates SIRT1 in an in vitro assay, and produces changes that resemble CR in vivo, including improvements in insulin sensitivity, endurance, and overall survival in obese mice. However, resveratrol has numerous other targets that could contribute to its health benefits. Moreover, unlike bona fide CR, resveratrol has not been shown to extend lifespan in lean mice. Overexpression of SIRT1 or treatment with a novel activator is sufficient to improve metabolism, supporting the idea that resveratrol could act through this pathway. However, the poor phenotype of SIRT1 null mice has thus far precluded a more definitive test. | https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1749-6632.2010.05850.x |
Resveratrol bioavailability and toxicity in humans | Numerous data are now available on the beneficial properties of the polyphenolic compound resveratrol including its anti‐inflammatory and antitumor effects. However, few studies have been performed with resveratrol in humans, and the results of these studies appear fragmentary and sometimes contradictory due to variations in conditions of administration, protocols and methods of assessment. This review article presents the results of recent studies investigating the pharmacokinetics, bioavailability, and toxicity of resveratrol in humans. Resveratrol is well absorbed, rapidly metabolized, mainly into sulfo and glucuronides conjugates which are eliminated in urine. Resveratrol seems to be well tolerated and no marked toxicity was reported. These data are important in the context of human efficacy studies, and they provide further support for the use of resveratrol as a pharmacological drug in human medicine. | https://onlinelibrary.wiley.com/doi/epdf/10.1002/mnfr.200900437 |
Resveratrol improves health and survival of mice on a high-calorie diet | Resveratrol (3,5,4′-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor- γ coactivator 1α (PGC-1α) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing. | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990206/pdf/nihms763280.pdf |
Resveratrol increases vascular oxidative stress resistance | Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL and TNF-α elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10−6–10−4 mol/l). The protective effect of resveratrol was attenuated by inhibition of glutathione peroxidase and heme oxygenase-1, suggesting a role for antioxidant systems in the antiapoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H2O2 levels and H2O2-mediated apoptotic cell death induced by oxidative stressors (exogenous H2O2, paraquat, and UV light). Resveratrol treatment also attenuated UV-induced DNA damage (comet assay). Resveratrol treatment upregulated the expression of glutathione peroxidase, catalase, and heme oxygenase-1 in cultured arteries, whereas it had no significant effect on the expression of SOD isoforms. Resveratrol also effectively scavenged H2O2 in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H2O2 and preventing oxidative stress-induced endothelial cell death. We propose that the antioxidant and antiapoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects. | https://journals.physiology.org/doi/pdf/10.1152/ajpheart.01258.2006 |
Resveratrol inhibition of lipid peroxidation | To define the molecular mechanism(s) of resveratrol inhibition of lipid peroxidation we have utilized model systems that allow us to study the different reactions involved in this complex process. Resveratrol proved (a) to inhibit more efficiently than either Trolox or ascorbate the Fe2+ catalyzed lipid hydroperoxide-dependent peroxidation of sonicated phosphatidylcholine liposomes; (b) to be less effective than Trolox in inhibiting lipid peroxidation initiated by the water soluble AAPH peroxyl radicals; (c) when exogenously added to liposomes, to be more potent than α-tocopherol and Trolox, in the inhibition of peroxidation initiated by the lipid soluble AMVN peroxyl radicals; (d) when incorporated within liposomes, to be a less potent chain-breaking antioxidant than α-tocopherol; (e) to be a weaker antiradical than α-tocopherol in the reduction of the stable radical DPPH·. Resveratrol reduced Fe3+ but its reduction rate was much slower than that observed in the presence of either ascorbate or Trolox. However, at the concentration inhibiting iron catalyzed lipid peroxidation, resveratrol did not significantly reduce Fe3+, contrary to ascorbate. In their complex, our data indicate that resveratrol inhibits lipid peroxidation mainly by scavenging lipid peroxyl radicals within the membrane, like α-tocopherol. Although it is less effective, its capacity of spontaneously entering the lipid environment confers on it great antioxidant potential. | https://www.tandfonline.com/doi/pdf/10.1080/10715760000300661?needAccess=true |
Resveratrol Is Absorbed in the Small Intestine as Resveratrol Glucuronide | We have studied the absorption and metabolism of resveratrol in the jejunum in an isolated rat small intestine model. Only small amounts of resveratrol were absorbed across the enterocytes of the jejunum and ileum unmetabolised. The major compound detected on the serosal side was the glucuronide conjugate of resveratrol (96.5% 6 4.6 of the amount absorbed) indicating the susceptibility of resveratrol to glucuronidation during transfer across the rat jejunum. The presence of the glucuronide was confirmed using HPLC-PDA and nanoES-MS/MS techniques. These findings suggest that resveratrol is most likely to be in the form of a glucuronide conjugate after crossing the small intestine and entering the blood circulation. This will have important implications for the biological functions of resveratrol in vivo. | https://www.researchgate.net/profile/Gunter_Kuhnle/publication/233760433_Absorption_and_metabolism_of_resveratrol_in_the_small_intestine_Implications_for_resveratrol_in_vivo/links/545632a60cf2bccc490f2549.pdf |
Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid-β Peptides | Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4′,5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-β (Aβ) peptides produced from different cell lines. Resveratrol does not inhibit Aβ production, because it has no effect on the Aβ-producing enzymes β- and γ-secretases, but promotes instead intracellular degradation of Aβ via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Aβ could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit β5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease. | https://www.jbc.org/content/280/45/37377.full.pdf |
Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses | Scavenging or quenching of the reactive oxygen species (ROS) involved in oxidative stress has been the subject of many recent studies. Resveratrol, found in various natural food products, has been linked to decreased coronary artery disease and preventing cancer development. The present study measured the effect of resveratrol on several different systems involving the hydroxyl, superoxide, metal/enzymatic-induced, and cellular generated radicals. The rate constant for reaction of resveratrol with the hydroxyl radical was determined, and resveratrol was found to be an effective scavenger of hydroxyl, superoxide, and metal-induced radicals as well as showing antioxidant abilities in cells producing ROS. Resveratrol exhibits a protective effect against lipid peroxidation in cell membranes and DNA damage caused by ROS. Resveratrol was also found to have a significant inhibitory effect on the NF-κB signaling pathway after cellular exposure to metal-induced radicals. It was concluded that resveratrol in foods plays an important antioxidant role. | https://www.researchgate.net/profile/Stephen_Leonard/publication/5240069_Resveratrol_scavenges_reactive_oxygen_species_and_effects_radical-induced_cellular_responses/links/565326db08ae1ef92975da71.pdf |
Resveratrol stimulates AMP kinase activity in neurons | Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol. | https://www.pnas.org/content/pnas/104/17/7217.full.pdf |
Resveratrol-Associated Renal Toxicity | Resveratrol, (3,5,4′-trihydoxystilbene) a compound found in grapes, mulberries, and peanuts, has antimycotic, antiviral, and beneficial cardiovascular and cancer preventive activities. It is being developed for several clinical indications. To evaluate the potential toxicity of resveratrol, rats were administered by gavage 0, 300, 1000, and 3000 mg trans-resveratrol per kilogram body weight per day for 4 weeks. Most of the adverse events occurred in the rats administered 3000 mg per kilogram body weight per day. These included increased clinical signs of toxicity; reduced final body weights and food consumption; elevated BUN, creatinine, alkaline phosphatase, alanine aminotransferase, total bilirubin, and albumin; reduced hemoglobin, hematocrit, and red cell counts; and increased white cell counts. Increases in kidney weights and clinically significant renal lesions, including an increased incidence and severity of nephropathy, were observed. Diffuse epithelial hyperplasia in the bladder was considered, equivocal and of limited biological significance. No histological effects on the liver were observed, despite the clinical chemistry changes and increased liver weights in the females. Effects seen in the group administered 1000 mg resveratrol per kilogram body weight per day included reduced body weight gain (females only) and elevated white blood cell count (males only). Plasma resveratrol concentrations in blood collected 1 h after dose administration during week 4 were dose related but were relatively low given the high dosage levels; conjugates were not measured. Under the conditions of this study, the no observed adverse effect level was 300 mg resveratrol per kilogram body weight per day in rats. | https://academic.oup.com/toxsci/article-pdf/82/2/614/4663435/kfh263.pdf |
Resveratrol-induced Autophagocytosis in Ovarian Cancer Cells | Resveratrol (3,5,4-trihydroxystilbene), a natural phytoalexin present in grapes, nuts, and red wine, has antineoplastic activities. Several molecular mechanisms have been described to underlie its effects on cells in vitro and in vivo. In the present study, the response of ovarian cancer cells to resveratrol is explored. Resveratrol inhibited growth and induced death in a panel of five human ovarian carcinoma cell lines. The response was associated with mitochondrial release of cytochrome c, formation of the apoptosome complex, and caspase activation. Surprisingly, even with these molecular features of apoptosis, analysis of resveratrol-treated cells by light and electron microscopy revealed morphology and ultrastructural changes indicative of autophagocytic, rather than apoptotic, death. This suggests that resveratrol can induce cell death through two distinct pathways. Consistent with resveratrol’s ability to kill cells via nonapoptotic processes, cells transfected to express high levels of the antiapoptotic proteins Bcl-xL and Bcl-2 are equally sensitive as control cells to resveratrol. Together, these findings show that resveratrol induces cell death in ovarian cancer cells through a mechanism distinct from apoptosis, therefore suggesting that it may provide leverage to treat ovarian cancer that is chemoresistant on the basis of ineffective apoptosis. | https://cancerres.aacrjournals.org/content/canres/64/2/696.full.pdf |
Resveratrol, a remarkable inhibitor of ribonucleotide reductase | Resveratrol, a natural phytoalexin found in grapes, is well known for its presumed role in the prevention of heart disease, associated with red wine consumption. We show here that it is a remarkable inhibitor of ribonucleotide reductase and DNA synthesis in mammalian cells, which might have further applications as an antiproliferative or a cancer chemopreventive agent in humans. | https://febs.onlinelibrary.wiley.com/doi/full/10.1016/S0014-5793%2897%2901572-X |
Resveratrol, obesity and diabetes | Resveratrol belongs to the large group of biologically active substances found in plants. This compound is classified as phytoestrogen because of its ability to interact with estrogen receptor. Numerous beneficial effects of resveratrol described in the literature involve cardioprotective, anti-cancer, anti-inflammatory and antioxidant action. Recently, this broad spectrum of effects is enlarged by new data demonstrating a great potency of this compound in relation to obesity and diabetes. It is well established that resveratrol exerts beneficial effects in rodents fed a high-calorie diet. In some studies, resveratrol was reported to reduce body weight and adiposity in obese animals. The action of this compound involves favourable changes in gene expressions and in enzyme activities. The accumulating evidence also indicates the benefits of resveratrol in diabetes and diabetic complications. It is known that resveratrol affects insulin secretion and blood insulin concentration. In animals with hyperinsulinemia, resveratrol was found to reduce blood insulin. Moreover, numerous data indicate that in diabetic rats, resveratrol is able to reduce hyperglycemia. The mechanism of resveratrol's action is complex and is demonstrated to involve both insulin-dependent and insulin-independent effects. These data point to the potential possibility of use of resveratrol in preventing and/or treating both obesity and diabetes. | https://reader.elsevier.com/reader/sd/pii/S0014299910002001?token=59443884D532CA32C744DB9BD51B9E27DDBC3BA4A2AA6743A32431C80ACF280F0FD4AA89DB9008C5CA898DF8E5ECD95C |
Resveratrol, Pterostilbene, and Piceatannol in Vaccinium Berries | A study was conducted to determine the presence of resveratrol, pterostilbene, and piceatannol in Vaccinium berries. Samples representing selections and cultivars of 10 species from Mississippi, North Carolina, Oregon, and Canada were analyzed by gas chromatography/mass spectrometry. Resveratrol was found in Vaccinium angustifolium (lowbush blueberry), Vaccinium arboretum (sparkleberry), Vaccinium ashei (rabbiteye blueberry), Vaccinium corymbosum (highbush blueberry), Vaccinium elliottii (Elliott's blueberry), Vaccinium macrocarpon (cranberry), Vaccinium myrtillus (bilberry), Vaccinium stamineum (deerberry), Vaccinium vitis-ideae var. vitis-ideae (lingonberry), and Vaccinium vitis-ideae var. minor (partridgeberry) at levels between 7 and 5884 ng/g dry sample. Lingonberry was found to have the highest content, 5884 ng/g dry sample, comparable to that found in grapes, 6471 ng/g dry sample. Pterostilbene was found in two cultivars of V. ashei and in V. stamineum at levels of 99−520 ng/g dry sample. Piceatannol was found in V. corymbosum and V. stamineum at levels of 138−422 ng/g dry sample. These naturally occurring stilbenes, known to be strong antioxidants and to have cancer chemopreventive activities, will add to the purported health benefits derived from the consumption of these small fruits. | https://pubs.acs.org/doi/pdf/10.1021/jf040095e |
Resveratrol: Isomeric Molar Absorptivities and Stability | Resveratrol has attracted interest as a wine constituent that may reduce heart disease. Published data on the molar absorptivity and chemical stability of cis- and trans-resveratrol have varied greatly. Accurate values for UV absorbance for trans-resveratrol [UV λmax (EtOH) nm (ε) 308 (30 000)] and cis-resveratrol [UV λmax (EtOH) nm (ε) 288 (12 600)] were determined and are used to improve chromatographic quantitation methods. Trials conducted under a variety of commonly encountered laboratory conditions show that trans-resveratrol is stable for months, except in high-pH buffers, when protected from light. cis-Resveratrol was stable only near pH neutrality when completely protected from light. | https://pubs.acs.org/doi/pdf/10.1021/jf9504576 |
Resveratrol: a cardioprotective substance | Coronary heart disease (CHD) is a major and preventable cause of morbidity and death in the United States. Recently, significant research efforts have been directed at an epidemiological phenomenon known as the “French paradox.” This observation refers to the coexistence of high risk factors with unanticipated low incidence of CHD, and is postulated to be associated with low‐to‐moderate consumption of red wine. In vivo studies have shown that red wine intake is more CHD‐preventative in comparison to other alcoholic drinks; enhanced cardioprotection may be attributed to grape‐derived polyphenols, e.g., resveratrol, in red wine. This review summarizes results of in vitro and animal studies showing that resveratrol exerts multifaceted cardioprotective activities, as well as evidence demonstrating the presence of proteins specifically targeted by resveratrol, as exemplified by N‐ribosyldihydronicotinamide:quinone oxidoreductase, NQO2. A mechanism encompassing nongenomic and genomic effects and a research roadmap is proposed as a framework for uncovering further insights on cardioprotection by resveratrol. | https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1749-6632.2010.05854.x |
Resveratrol: A multitargeted agent for age-associated chronic diseases | Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NF-κB, STAT3, HIF-1α, β-catenin and PPAR-γ), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-XL, XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomrkers (e.g; TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metstatic gene products (e.g; MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g; p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol’s prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Ours review describes various targets of resveratrol and their therapeutic potential. | https://www.tandfonline.com/doi/pdf/10.4161/cc.7.8.5740?needAccess=true |
Resveratrol: A review of preclinical studies for human cancer prevention | The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4′,5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations. | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2083123/pdf/nihms33735.pdf |
Resveratrol: French paradox revisited | Resveratrol is a polyphenol that plays a potentially important role in many disorders and has been studied in different diseases. The research on this chemical started through the “French paradox,” which describes improved cardiovascular outcomes despite a high-fat diet in French people. Since then, resveratrol has been broadly studied and shown to have antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic effects, with those on oxidative stress possibly being most important and underlying some of the others, but many signaling pathways are among the molecular targets of resveratrol. In concert they may be beneficial in many disorders, particularly in diseases where oxidative stress plays an important role. The main focus of this review will be the pathways affected by resveratrol. Based on these mechanistic considerations, the involvement of resveratrol especially in cardiovascular diseases, cancer, neurodegenerative diseases, and possibly in longevity will be is addressed. | https://www.frontiersin.org/articles/10.3389/fphar.2012.00141 |
Resveratrol: from grapevines to mammalian biology | with the rapid advances made over the last two decades in biomedical research, there has been an unprecedented interest in unraveling the magical properties of some commonly used natural products. Consequently, a wide variety of natural products are under scrutiny for their clinical potential, both in terms of disease prevention and treatment. Among the compounds under investigation is a family of polymers given the name viniferin. These compounds elicit strong anti-fungal properties and are therefore included under the broad class of plant antibiotics known as phytoalexins (1)⤻. One remarkable compound in this list is resveratrol (RSV), a major active ingredient of stilbene phytoalexins, first isolated from the roots of the oriental medicinal plant Polygonum Capsidatum (Ko-jo-kon in Japanese) (2)⤻. Observations that this compound was an active ingredient of a folk plant known for its remedial effects against a host of human afflictions (2⤻, 3)⤻ and that it was synthesized by leaf tissue in response to fungal infection of grapevines (Vitis vinifera) (4)⤻ provided the impetus for the increase in activity surrounding RSV in the field of biomedical research. The relatively high concentration of RSV in wine (5⤻) and its documented cardioprotective effect (6)⤻ form the basis for the so-called “French paradox” (7)⤻. Most of the initial work on RSV was centered around its effects on metabolic pathways regulating cardiovascular biology, such as lipid metabolism and platelet function; however, since the reported cancer chemopreventive activity of RSV in animal models of carcinogenesis (8)⤻, recent investigations have been directed at understanding the molecular mechanism(s) of its diverse biological effects. As a result, the positive or negative effects of RSV on some important physiological pathways have been proposed as possible mechanisms for its observed cancer chemopreventive, cardioprotective, and neuroprotective activities. These include suppression of cellular proliferation via inhibition of key steps in the signal transduction pathways (9⤻10⤻11⤻12)⤻ and cyclin-dependent kinases (cdks) (13)⤻, promotion of cellular differentiation (14)⤻, scavenging/suppression of intracellular reactive oxygen intermediates (ROI) (15)⤻, induction of apoptotic cell death through activation of mitochondria-dependent or -independent pathways (16⤻17⤻18)⤻, anti-inflammatory activity via down-regulation of proinflammatory cytokines (19⤻, 20)⤻, and inhibition of androgen receptor function and estrogenic activity (21⤻, 22)⤻. This review is intended to provide the reader with an appreciation of the diverse biological effects of this remarkable compound, which could have tremendous potential as a chemopreventive and/or chemotherapeutic agent in clinical medicine. | http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.326.3682&rep=rep1&type=pdf |
Resveratrol: One molecule, many targets | Resveratrol is one of the numerous polyphenolic compounds found in several vegetal sources. In recent years, the interest in this molecule has increased exponentially following the major findings that resveratrol (i) is shown to be chemopreventive in some cancer models, (ii) is cardioprotective, and (iii) has positive effects on several aspects of metabolism, leading to increased lifespan in all the metazoan models tested thus far, including small mammals. Such remarkable properties have elicited a vast interest towards the identification of target proteins of resveratrol and have led to the identification of enzymes inhibited by resveratrol and others whose activation is enhanced. In the vast majority of cases, resveratrol displays inhibitory/activatory effects in the micromolar range, which is potentially attainable pharmacologically, although targets with affinities in the nanomolar range have also been reported. Here, we provide an overview of the various classes of enzymes known to be inhibited (or activated) by resveratrol. It appears that resveratrol, as a pharmacological agent, has a wide spectrum of targets. The biological activities of resveratrol may thus be dependent on its simultaneous activity on multiple molecular targets. | https://iubmb.onlinelibrary.wiley.com/doi/epdf/10.1002/iub.47 |
Substrate-specific Activation of Sirtuins by Resveratrol | Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined. | https://www.jbc.org/content/280/17/17038.full.pdf |
The molecular targets of resveratrol | Resveratrol has emerged in recent years as a compound conferring strong protection against metabolic, cardiovascular and other age-related complications, including neurodegeneration and cancer. This has generated the notion that resveratrol treatment acts as a calorie-restriction mimetic, based on the many overlapping health benefits observed upon both interventions in diverse organisms, including yeast, worms, flies and rodents. Though studied for over a decade, the molecular mechanisms governing the therapeutic properties of resveratrol still remain elusive. Elucidating how resveratrol exerts its effects would provide not only new insights in its fundamental biological actions but also new avenues for the design and development of more potent drugs to efficiently manage metabolic disorders. In this review we will cover the most recent advances in the field, with special focus on the metabolic actions of resveratrol and the potential role of SIRT1 and AMPK. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. | https://reader.elsevier.com/reader/sd/pii/S0925443914003111?token=3048F83F64322421DA71F4D52699F9D0A6FB6E911C937A2BF32CE7A3EC75D134BF9820E7BF2D7140DFD610BA1BC1A13F |
Therapeutic potential of resveratrol: the in vivo evidence | 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 | https://www.researchgate.net/profile/Andrei_Gonzales_I/post/Is_there_any_mechanism_on_the_influence_of_resveratrol_on_growth_hormone/attachment/59d623bf6cda7b8083a1e8fc/AS:347637640384512@1459894680107/download/Therapeutic_potential_of_resveratrol.pdf |