Table 4. Recommendations for the use of resveratrol – part 4. What valid data are available regarding an effect in various species of experimental animals? N There is sufficient evidence for a chemopreventive effect of resveratrol on the development of cancer in skin of mice. There are promising results on the prevention of colon cancer in animals. The effects of resveratrol on other cancer types than skin cancer need to be investigated more in detail prior to recommending clinical trials. N There is sufficient evidence to suggest resveratrol reduces the incidence of hypertension, heart failure, ischemia heart disease in experimental animal models. N There is sufficient evidence to suggest 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. doi:10.1371/journal.pone.0019881.t004 preventive potential of Resv, in total 1191 papers were identified (Figure 1A), but by excluding non English papers, reviews and papers analyzing acute or in vitro effects only, 41 articles were found to test Resv in animal model systems, whereas two studies focused on the effect of Resv in human subjects. The effect of Resv on coronary heart diseases was investigated in 118 papers (Figure 1B); whereas only 26 papers show data from non acute animal experiments and one paper was identified investigating effect in humans. Focusing on the effect of Resv on obesity and related diseases such as diabetes, 218 articles were identified (Figure 1C), but only 19 animal studies and no human studies focused on non-acute effects of Resv. Neuroprotection by Resv was in focus of 163 papers (Figure 1D), but 40 papers concerned animal studies, including both acute exposure and sub- and chronic studies. Lastly, 559 papers focused on resveratrol and inflammation (Figure 1E), and of these 31 papers included sub chronic and chronic studies, whereas no human studies focusing on inflammation have been published. Table 5. Recommendations for the use of resveratrol – part 5. Which relevant (overall) mechanisms of action of resveratrol have been documented? N Modulation of cell proliferation and apoptosis N Modulation of angiogenesis N Inhibition of metastasis N Modulation of redox status N Suppression of adipogenesis and stimulation of adipocyte lipolysis N Stimulation of osteogenesis N Modulation of mitochondria activity N Suppression of inflammation N Modulation of DNA damage N Modulation of xenobiotic metabolism N Modulation of glutamate metabolism N Estrogenic activity/anti-estrogenic activity doi:10.1371/journal.pone.0019881.t005 Recommendations on the Use of Resveratrol 1 2 1 2 3 4 5 6 7 Table 6. Overall conclusions for the use of resveratrol. Published evidence today is not sufficiently strong to justify recommendation for the chronic administration of resveratrol to human beings, beyond the dose which can be obtained from dietary sources. Animal data are promising and indicate the need for further human clinical trials. doi:10.1371/journal.pone.0019881.t006 Discussion Can resveratrol be recommended in the prevention or treatment of human diseases? A major challenge for scientists investigating Resv is to prove that it has the health promoting effects, which have been suggested based on the in vitro and animal studies available. Clinical trials with Resv in human subjects focusing on the health promoting effect of Resv are lacking. Therefore, these studies have the highest priority in recommendations from the scientific working group (Table 7). Two clinical trials have been recently published analyzing the effect on biomarkers of intermediary metabolism: 2.5 g Resv/day for 29 days was found to significantly reduce the plasma level of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 indicating a possible cancer preventive effect [2], whereas daily doses of 0.5 and 1.0 g Resv/day for 29 days caused a reduction of cell proliferation in colon cancer tissue [3]. Most of the available clinical studies with Resv in humans focus on bioavailability, pharmacokinetics and metabolism of Resv [4–11]. These studies showed that Resv was rapidly absorbed after oral intake; a maximal plasma concentration of Resv obtained after 30 to 60 minutes. Further, the level of Resv in the blood Table 7. Recommendations for research on resveratrol for the coming years. Clinical studies should be initiated, especially with focus on the effect of resveratrol on the development of cancers in colon and skin Clinical studies should be initiated to test the potential cardio-vascular benefit of resveratrol Elucidating the biological effects of resveratrol metabolites Biodistribution and degradation of resveratrol in vivo, including the role of bacterial enzymes Preparation of a resveratrol reference (international standard) product for analytical purposes Standardized formulations for clinical studies Combinatory effects of resveratrol with other compounds. This include development of relevant models 8 Interaction of resveratrol with drug metabolism (especially cytochrome P450 metabolism) 9 Identification/development of relevant biomarkers, relevant for the disease- prevention rather than disease treatment, depending on the relevant disease 10 Effect of resveratrol on inflammation as general condition relevant for several lifestyle diseases 11 Long term preclinical studies in nonhuman primates may be appropriate to determine the effect of resveratrol on diet-induced metabolic disorders, such as development of insulin resistance doi:10.1371/journal.pone.0019881.t007 PLoS ONE | www.plosone.org 3 June 2011 | Volume 6 | Issue 6 | e19881