In a possible setback for scientists attempting to make drugs out of a substance found in red wine, GlaxoSmithKline PLC said a clinical trial of one drug in cancer patients has been halted due to safety concerns.

Glaxo acquired the drug in 2008 when it paid $720 million for Sirtris Pharmaceuticals, a biotech company in Cambridge, Mass. The drug, known as SRT501, contains a reformulated version of resveratrol, a substance found in low quantities in red wine. Glaxo and Sirtris have been testing the drug and others in several diseases, including diabetes and cancer, in the belief that they may provide health benefits by activating enzymes in the body called sirtuins.

Resveratrol Clinical Trial Halted because of safety concerns

BACKGROUND: The many putative beneficial effects of the polyphenol resveratrol include an ability to bolster endogenous antioxidant defenses, modulate nitric oxide synthesis, and promote vasodilation, which thereby improves blood flow. Resveratrol may therefore modulate aspects of brain function in humans. OBJECTIVE: The current study assessed the effects of oral resveratrol on cognitive performance and localized cerebral blood flow variables in healthy human adults. DESIGN: In this randomized, double-blind, placebo-controlled, crossover study, 22 healthy adults received placebo and 2 doses (250 and 500 mg) of trans-resveratrol in counterbalanced order on separate days. After a 45-min resting absorption period, the participants performed a selection of cognitive tasks that activate the frontal cortex for an additional 36 min. Cerebral blood flow and hemodynamics, as indexed by concentration changes in oxygenated and deoxygenated hemoglobin, were assessed in the frontal cortex throughout the posttreatment period with the use of near-infrared spectroscopy.

Since an article appeared in "Nature" in 2003 about the potential life-extension capabilities of resveratrol, many people both in and out inside of the life-extension community have been interested in this supplement. Red wine became touted even more as a heath drink due to its (meager) resveratrol content, and people began to have hope in this as a potential CR mimetic. The possibility to obtain the benefits of CR with out the actual calorie restriction made the ears of the nation perk.

By 2006 and 2007, the results from different groups were beginning to conflict. Studies began to indicate that while resveratrol had health benefits in elderly and obese mice, the longevity effects were not consistently observed in ad lib fed mice stared on the supplement midlife. However, a very interesting observation showed that resveratrol could improve insulin and glucose levels in mice on a high-fat (over-consumption) diet, but note that cholesterol and free fatty acid levels did not improve.

Efforts to slow the march of old age with a pill have been dealt a blow. Drugs that might treat disease by tampering with the biology of ageing are being tested, but new research questions whether they work as thought.

The compounds include resveratrol, a much-touted component of red wine that is thought to prevent the cellular damage that underlies ageing. Also under test are several chemicals intended to mimic resveratrol's effects by activating SIRT1, a protein implicated in ageing. Experiments have led some to conclude that these drugs ramp up the protein's activity, but the new studies suggest that those experiments suffered from errors.

AIM: To elucidate the effect of antioxidants, resveratrol (RVT) and astaxanthin (AXN), on hepatitis C virus (HCV) replication. METHODS: We investigated the effect of recent popular antioxidant supplements on replication of the HCV replicon system OR6. RVT is a strong antioxidant and a kind of polyphenol that inhibits replication of various viruses. AXN is also a strong antioxidant. The replication of HCV RNA was assessed by the luciferase reporter assay. An additive effect of antioxidants on antiviral effects of interferon (IFN) and ribavirin (RBV) was investigated. RESULTS: This is the first report to investigate the effect of RVT and AXN on HCV replication. In contrast to other reported viruses, RVT significantly enhanced HCV RNA replication. Vitamin E also enhanced HCV RNA replication as reported previously, although AXN did not affect replication. IFN and RBV significantly reduced HCV RNA replication, but these effects were dose-dependently hampered and attenuated by the addition of RVT. AXN did not affect antiviral effects of IFN or RBV. CONCLUSION: These results suggested that RVT is not suitable as an antioxidant therapy for chronic hepatitis C.

BACKGROUND: Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. METHODS AND FINDINGS: The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 +/- 1.0 y), overweight (body mass index, 27.8 +/- 0.7 kg/m(2)) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, -135 +/- 42 kcal/d, p = 0.002 and CREX, -117 +/- 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05).

An article in the Wall Street Journal about the craze over resveratrol (requires subscription) based on a couple of mice studies should give supplement buyers pause.

This resveratrol feeding frenzy reminds me of a similar situation a few years back with St. John’s Wort. As I’m sure most of you know, St. John’s Wort is an herb that offers a mild anti-depressant effect to its takers. Although St. John’s Wort has been around forever, it was primarily known only to herbalists and other hard-core natural food types until several years ago when a spate of popular books came out touting its advantages. These books provoked a run on St. John’s Wort similar to the rush to buy resveratrol today.

Read the whole article at proteinpower.com

The natural compounds genistein (G), quercetin (Q), and resveratrol (R) have been reported to each exhibit anti-adipogenic activities in adipocytes and antiproliferative and pro-apoptotic activities in several cell types. We studied the combined effects of G, Q, and R on adipogenesis and apoptosis in primary human adipocytes (HAs) and 3T3-L1 murine adipocyte (MAs). Combined treatment with 6.25 microM G, 12.5 microM Q, and 12.5 microM R during the 14-day differentiation period caused an enhanced inhibition of lipid accumulation in maturing HAs that was greater than the responses to individual compounds and to the calculated additive response. Glycerol 3-phosphate dehydrogenase activity, a marker of late adipocyte differentiation, was decreased markedly in HAs treated with the combination of G+Q+R. In addition, combined treatment with 50 microM G, 100 microM Q, and 100 microM R for 3 days decreased cell viability and induced apoptosis in early- and mid- phase maturing and lipid-filled mature HAs. In contrast, no compound alone induced apoptosis. Oil Red O stain and Hoechst 33342 stain were performed to confirm the effects on lipid accumulation and apoptosis, respectively.

Glioma is the most frequent and malignant primary human brain tumor with dismal prognosis despite multimodal therapy. Resveratrol and quercetin, two structurally related and naturally occurring polyphenols, are proposed to have anticancer effects. We report here that resveratrol and quercetin decreased the cell number in four glioma cell lines but not in rat astrocytes. Low doses of resveratrol (10 microM) or quercetin (25 microM) separately had no effect on apoptosis induction, but had a strong effect on caspase 3/7 activation when administered together. Western blot analyses showed that resveratrol (10 microM) and quercetin (25 microM) caused a reduction in phosphorylation of Akt, but this reduction was not sufficient by itself to mediate the effects of these polyphenols. Most important, resveratrol and quercetin chronically administered presented a strong synergism in inducing senescence-like growth arrest. These results suggest that the combination of polyphenols can potentialize their antitumoral activity, thereby reducing the therapeutic concentration needed for glioma treatment

Although trans-resveratrol appears to be well-absorbed by humans when taken orally, its bioavailability is relatively low due to its rapid metabolism and elimination (7, 8). Resveratrol metabolites are primarily detected upon oral exposure to trans-resveratrol. When six healthy men and women took an oral dose of 25 mg of trans-resveratrol, only traces of the unchanged resveratrol were detected in plasma (blood). Plasma concentrations of resveratrol and metabolites peaked around 60 minutes later at concentrations around 2 micromoles/liter (491 micrograms/liter) (7).

Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD(+)-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions. Based on these observations, we conclude that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme.

PURPOSE: Resveratrol, a polyphenolic compound mainly abundant in red wines, has beneficial cardiovascular effects on various pathological conditions. However, at present, the effect of resveratrol on health promotion remains unclear. Therefore, in this study, we assessed whether long-term resveratrol supplementation changes endothelial function, vascular contractility, nitric oxide and superoxide production in healthy male and female rats.

The responses of Vitis vinifera L. cv. Malbec to different solar ultraviolet-B radiation (UV-B) levels were assessed in two contrasting situations, under sunlight with full UV-B (+UV-B) and filtered UV-B (-UV-B), in three different locations at 500, 1000, and 1500 m above sea level (asl). To evaluate the effects of radiation, a simple, accurate, and rapid method for the separation and simultaneous determination of representative phenolic compounds in grape berry skins by capillary zone electrophoresis was developed. Separation was carried out in less than 20 min with 20 mM sodium tetraborate buffer containing 30% methanol, pH 9.00.