The effect of Resv on insulin sensitivity has been the subject in nine studies using rats or mice in which insulin sensitivity was reduced by high fat diets, using animal strains prone to developing insulin resistance or by chemically induced diabetes (treatment with streptozotocin). Nearly all experiments showed a reduced insulin level or increased insulin sensitivity using doses covering 2.5–400 mg/kg bw/day and exposure time covering 1–6 months [21,73,89,92,94,95]. One study, using AMPKa12/2 and wild-type C57BL/6J mice fed a high-fat diet and exposed to 400 mg Resv/ kg bw/day for 12 weeks found an effect of Resv on insulin sensitivity in wild-type, but not AMPKa12/2 mice [96]. In C57BL/6 male mice fed a high-calorie diet and a low dose of Resv (79.2 ng/day, infused intra-cerebro ventricularly) for five weeks, reduced the serum insulin levels significantly [97], indicating that the active dose of Resv for prevention of elevated insulin levels is low and may be mediated the central nervous system. Ten studies have been identified which investigated the effect of Resv on blood glucose levels, using genetically obese mice or rats, dietary induced obesity or chemically induced diabetes by STZ or alloxan [21,73,83,85,94,97–101]. Only one study [101], per- formed on rabbits with alloxan-induced diabetes, didn’t find a reduced blood glucose level following exposure to Resv for 5 days to 2 months. Neuroprotective action of resveratrol. Several animal studies have indicated that Resv has a neuroprotective effect (Table S4). In total, 12 studies test the effect of resveratrol after a single exposure and 28 studies investigated the effect of resveratrol af subchronic/chronic exposure. This effect of Resv has been documented in various animal models including rabbits [102], mice or rats and using different end points, such as reduced lipid peroxidation and neurological cell destruction [100,103–107], attenuation of induced lesion areas [82,108–115], induced tolerance to brain injury [116], reduced frequency of seizures [117], impairment of motor coordination [102,104,118–124] and enhancement of learning [125–127]. Only very few of these experiments found no or a marginal effect of Resv. A significant number of these studies use acute doses of Resv, ranging 5– 100 mg/kg using one dose or exposure to the animals for Resv up to 1 week. Thirteen studies unraveling the neuroprotective effect of Resv expose to the experimental animals for more than 3 weeks: 10–50 mg Resv/kg bw/day for 3–6 weeks [100,104,105, 126,128,129], 100–300 mg Resv/kg bw/day for 3–6 weeks [107,111,122], 10–40 mg/kg bw/day for 10 weeks [130], or three weeks exposure of 2.5 mg Resv (by intra-cerebroventricular injection) every 2–3 day for 3 weeks [125]. Modulation of inflammation by resveratrol. Inflammatory response is a well known mechanism of the diseases described above such as cancer, coronary-heart disease, diabetes and neurodegeneration. Resveratrol is shown to modulate the inflammatory response induced by various stimuli. Fourteen studies have investigated the effect of exposure of one week or more to Resv on various inflammatory markers in rats. The same number of studies has been identified using mice as an experimental model. Generally, Resv in nearly all models counteracted the increased levels of pro inflammatory biochemical markers, such as TNFa, IL-1b, IL-6 in nearly all models. Beside these cytokines, MCP-1, COX-2 and iNOS was most often found to be down- regulated by Resv when stimulated by the pro-inflammatory treatment. The estimates of inflammation were often performed as a part of a study with another aim, i.e. testing a chemopreventive effect, or the effect of Resv on diabetes or cardiovascular disease. Therefore, different inducers of the inflammatory status have been used; Resv reduced inflammation in several models such as obesity- induced [73], in diabetic mice [131] or chemically induced diabetes Recommendations on the Use of Resveratrol [124,132,133], but also dextran sulfate sodium induced colon colitis [55,134–138]. Other models were using induced hypertension [72,139], chemicals causing tissue injury (and act as carcinogen) in liver [140], lung [141,142] and colon [143–145] and showed decreased levels of inflammatory markers (Table S5). Besides the animal experiments described above which focused on chronic or near-chronic exposures, a long list of papers exist that analyze the effect of Resv after an acute exposure on biomarkers relevant for prevention of cancer, coronary-heart disease and diabetes. These articles are not included in the present review. The working group concluded (Table 4): N There is sufficient evidence for a chemopreventive effect of resveratrol on the development of skin cancer in mice. There are promising results on the prevention of colon cancer in animals. The effects of resveratrol on other cancer types besides skin cancer need to be investigated more in detail prior to recommending clinical trials. N There is sufficient evidence to suggest that resveratrol reduces the incidence of hypertension, heart failure, ischemia heart disease in experimental animal models. N There is sufficient evidence to suggest that resveratrol improves insulin sensitivity, reduces blood glucose levels, and reduces high fat diet-induced obesity in rodents. N Resveratrol showed neuroprotective effects in experimental animal models of injury or degeneration. N Resveratrol is well tolerated in rats and no toxicological effects are observed up to 700–1000 mg/kg bw/day. Which relevant (overall) mechanisms of action of resveratrol have been documented? Without going too much into details, and without giving the references, several mechanisms of action of Resv are relevant in relation to its proposed enhancement of human health. A number of mechanisms are relevant for several of the diseases mentioned herein, whereas others are more specific. The working group has identified twelve such mechanisms, as listed in Table 5. They are closely related and it is not possible to focus solely on one mechanism without taking the other mechanisms into consider- ation. Further, the indicated mechanisms are identified in in vitro, in experimental animals or both. Suppression of inflammation is a general mechanism relevant for prevention of cancer diseases, coronary heart diseases, diabetes and neurodegeneration, as indicated above. Similarly, modulation of the cellular redox status is closely related to several diseases and linked to the anti-inflammatory effect. Modulation of cell proliferation and apoptosis as well as modulation of angiogenesis, inhibition of metastasis and suppression of DNA damage are relevant especially in cancer diseases. Modulation of xenobiotic metabolism by Resv likely plays a significant role in cancer prevention but may also have an impact on metabolism of drugs used to treat the listed diseases. Modulation of mitochondrial activity seems crucial in obesity/diabetes but may also be relevant for understanding life extension as well as be related to the inhibition of cell proliferation. Suppression of adipogenesis and stimulation of adipocyte lipolysis by Resv is relevant when one consider the effect on obesity and diabetes. Relevant for neuroprotection by Resv is the modulation of glutamate metabolism. Resveratrol also stimulates osteogenesis which indicates an effect on bone biology. Estrogenic activity but also anti-estrogenic activity by Resv has been shown but the clinical significance of these observations is uncertain. PLoS ONE | www.plosone.org 7 June 2011 | Volume 6 | Issue 6 | e19881