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Resveratrol has been proposed to be active in the prevention of various life style diseases such as cancer, coronary heart diseases and type 2 diabetes. Different mechanisms are likely involved besides the modulation of inflammation as a unifying mechanism. Because of different mechanisms and targets one must assume that the optimal dose will depend on the particular disease. As indicated above, only a few human studies have been performed, showing down-regulation of cancer biomarkers by 2.5 g Resv/day for 28 days [2] and reduced cell proliferation in colon cancer tissue was observed in humans at doses of 0.5 and 1.0 g Resv/day [3]. A single double-blind, randomized cross-over human study focused on the effect of Resv on flow-mediated dilatation of the brachial artery (as a biomarker of reduced endothelial function and cardiovascular health) in overweight/obese men and women: Resv, at sub chronic doses of 30, 90 and 270 mg/day for one week, showed a significant dose-dependent increase in flow-mediated dilation, significant even at the 30 mg dose.
Several human studies have investigated the effects of Resv containing food items. The exposure to Resv is likely in all cases less than 4 mg. Human acute or sub chronic (two weeks) intake of red wine, dealcoholized red wine or red grape juice did not show effect on Tumor necrosis factor (TNF) α, Interleukin (IL)-2 or IL-4 levels, indicating no anti-inflammatory response of the wine but the presence of Resv in the wine was not proven.Exposure of healthy volunteers to 36 µg Resv/day (combination of trans- and cis-Resv and cis-piceid) in the form of Chardonnay cava wine for 28 days caused a reduction of various inflammatory markers such as IL-6, high-sensitivity C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). Resveratrol is found to reduce the risk of colon cancer development in experimental animals (see below) using doses in the range of 0.2 to 8 mg/kg in rats and 2.4 to 60 mg/kg in mice. Applying the dose translations factors described by Reagan-Shaw et al. The corresponding daily ‘human equivalent doses’ (HED) are around 2 mg–78 mg (based on rat data) or 12–290 mg (based on mouse data) for a 60 kg person. Enhanced insulin sensitivity by Resv was observed in experimental animals when exposed to 2.5–400 mg/kg in mice and 1–100 mg/kg in rats (see below). The corresponding HED are 12–1945 mg (based on mouse data) or 10–973 mg/day for a 60 kg person.
The relevant effective dose of Resv needs to be established in humans in relation to the different diseases that it may counteract and the working group
concludes that:
The initial paper by Jang et al. showed a cancer preventive effect of Resv on skin cancer in a mice model. Seven animal studies have been identified studying the effect of Resv on skin cancer all showing reduction of the incidence of chemically induced skin cancer whereas no reduction was observed in a mouse line spontaneous to developing polyps. Only mice have been used in these studies with different Resv concentrations, dose regimens and exposure times (up to 28 week). A recent study supported this by showing reduction of skin hyperplasia by Resv alone and in synergism with other dietary components.
To test the effect of Resv on breast cancer, four studies used mice where Resv showed a reducing effect in three experiments (in chemical induced cancers, in a HER-2/neu transgenic mice model and injected Ehrlich ascites carcinoma cells), whereas Resv failed to show chemoprevention in a model where 4T1 mammary carcinoma cells were injected into the mice. In rats, three studies showed a chemopreventive effect of Resv whereas increased breast cancer incidence is observed in one study. The reason for these contradictory results is not obvious. Resveratrol reduced chemically-induced liver cancer in rats and in mice injected with carcinoma cells. A single experiment showed no reduction of the incidence of esophagus carcinoma formation by Resv. The effect of Resv on gastric cancers was evaluated with its effect on tumor growth after subcutaneous injection of cancer cells. Both studies in mice showed a reduced tumor volume as a consequence of Resv exposure.
To study the effect of Resv on colon cancer development in animals, four studies focus on chemically-induced colon cancer in rats or mice and three studies evaluated the effect of Resv on colon cancer in APC/Min mice strains. Three of the tests showed significant reduction of the aberrant crypt formation or incidence of adenomas, whereas two of the mouse studies did not show a significant reduction in colon cancer incidence or tumor load. Resveratrol showed a chemopreventive effect on development of prostate cancer using rat or mice strains prone to spontaneously developing prostate cancer and a mouse model with injected prostate cancer cells. In other studies focusing on lung carcinogenesis, Resv showed a chemopreventive effect only in a single experiment out of a total of four experiments. A single study focused on the effect of Resv on the development of neuroblastoma in mice, and found reduced tumor volume.
Risk reduction of cardiovascular events is one of the most well-known health promoting effects of Resv. It has been shown that Resv may modulate various aspects of cardio-vascular diseases, including atherosclerosis, hypertension, ischemia reperfusion injury and heart failure. Resveratrol reduced hypertension in various models including spontaneously hypertensive rats salt induced hypertension, hypertension induced by monocrotaline or obesity-induced hypertension. In nine out of eleven studies, Resv (at levels of 10 mg/kg bw/day or higher) was found to reduce the elevated blood pressure. The blood pressure reducing effect of Resv was observed after 3 weeks and maintained for 10 weeks. Low exposure to Resv (2.5 mg/kg bw/day for 10 weeks) was described in two experiments using spontaneous hypertensive rat where one experiment showed a preventive effect on hypertension whereas the other did not.
Several studies (five have been identified) showed a preventive effect of Resv on myocardial infarction induced by surgery. All studies showed a reduced infarct size effect and one experiment even at the low dose of 1 mg Resv/kg bw/day for four weeks. Chronic treatment with Resv reduced infarct area after middle cerebral artery occlusion. The diabetes-induced myocardial infarct size was significantly reduced by Resv (ranging from 1 to 5 mg/kg bw/day) in rats exposed to Resv for 5–15 days. Further, Resv may precondition the heart in a nitric oxide (NO)-dependent manner, which would reduce heart damage from ischemia. Resveratrol prevented the effects of ischemia at doses of 10 mg/kg, whereas higher doses were found to depress cardiac function and increase myocardial infarct size. A single experiment was performed in swine where the reduced inferolateral function induced by hypercholesterolemic diet was prevented by 100 mg Resv/kg bw/day.
Animal studies focusing on the effect of Resv on obesity and diabetes are shown in Some studies have indicated that intake of Resv may reduce body weight increase caused by high fat intake in mouse and grey mouse lemurs both exposed to high levels of Resv (200 or 400 mg/kg bw/day). Low doses, up to 60 mg/kg bw/day did not show any effect on body weight. On the other hand, low doses did affect lipid accumulation observed as reduced size of white adipose tissue reduced abdominal obesity reduced abdominal fat in obese rats and reduced grade of steatosis.
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. One study, using AMPKα1−/− 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 AMPKα1−/− mice. 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 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. Only one study performed on rabbits with alloxan-induced diabetes, didn't find a reduced blood glucose level following exposure to Resv for 5 days to 2 months.
Several animal studies have indicated that Resv has a neuroprotective effect. 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, mice or rats and using different end points, such as reduced lipid peroxidation and neurological cell destruction, attenuation of induced lesion areas induced tolerance to brain injury, reduced frequency of seizures, impairment of motor coordination and enhancement of learning. 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 100–300 mg Resv/kg bw/day for 3–6 weeks. 10–40 mg/kg bw/day for 10 weeks or three weeks exposure of 2.5 µg Resv (by intra-cerebroventricular injection) every 2–3 day for 3 weeks.
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 TNFα, IL-1β, 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 in diabetic mice or chemically induced diabetes, but also dextran sulfate sodium induced colon colitis. Other models were using induced hypertension chemicals causing tissue injury (and act as carcinogen) in liver, lung and colon and showed decreased levels of inflammatory markers.
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.
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. They are closely related and it is not possible to focus solely on one mechanism without taking the other mechanisms into consideration. 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.
It clearly follows from the recommendations for the use of Resv that evidence for the effect of Resv in humans is lacking. It shows the research in the field of Resv considered of highest priority. These recommendations naturally do not give space for a full list of relevant research projects, but only the most relevant from the point of view of the scientific working group of the Resveratrol2010 conference. The clinical studies with focus on cancer prevention might have a high priority, and as the most clear results have been shown in animal models of cancer in skin and colon these targets are the most relevant points of initiation. Furthermore, investigation of the effect of Resv on metabolic disorders evaluated in preclinical studies in nonhuman primates also has a high priority. Relevant clinical studies should be done soon and address the preventive effect of Resv on coronary heart disease. However, long term studies in animal models are still needed in order to evaluate the chronic effect of Resv to identify a probable NOAEL in human. Since chronic low grade inflammation is reduced by resveratrol and is a general characteristic of several of the life style disease, the effect of Resv on inflammatory biomarkers should be investigated in the coming clinical studies.
One of the major challenges in the clinical studies investigating the preventive effect of e.g. Resv is to show the absence or reduced incidence of a specific disease end point. Such intervention studies should then be long term and will therefore be very expensive. To overcome these challenges, new biomarkers need to be identified, developed and verified to analyze the long term disease prevention.
To make preclinical and clinical studies comparable, the working group suggests that a standard Resv formulation should be performed. Such standardized Resv formulation should be made based on very pure Resv preparations. The use of non-pure Resv samples for preclinical or clinical experiments makes their interpretation very difficult. On the other hand, elucidation of the combined effect of Resv together with other dietary or non-dietary compounds should be accelerated as combinatory effects may solve some of the possible draw backs of high doses of resveratrol. Besides using a standardized Resv formulation for the preclinical and clinical studies a Resv reference should be prepared for analytical purposes, such as analyzing metabolite formation and in the investigation of the bioavailability of Resv.
The bioavailability of Resv is described to some extent but have to be analyzed further to find the biodistribution and the degradation in vivo, which is very relevant to forecast the biological effect of Resv in humans. Several Resv metabolites have been identified but the biological activity of these metabolites formed in humans and experimental animals needs to be elucidated fully. Lastly, the combinatory effect of Resv with other bioactive compounds has only been studied in few cases in experimental animals or in vitro. These studies should be amplified, as the outcomes of the combinations are not only additive but also synergistic or even antagonistic. The effect of Resv on the metabolism of these compounds have to be addressed as well, e.g. regulation of Cytochrome P450 enzymes and activities.
The scientific literature cannot yet justify recommendation for the chronic administration of resveratrol to human beings. Humans are receiving resveratrol frequently in red wine, berries, peanuts etc. but these levels are low, less than 4 mg. Before having data from chronic exposure to higher levels of resveratrol or more chronic studies with experimental animals, intake of resveratrol at higher doses should be considered experimental. In contrast to the lacking data of resveratrol in humans, the animal data are promising and indicate the need for further human clinical trials. Therefore, the working group from the Resveratrol 2010 conference recommends that these human trials will be initiated soon.
Article Produced By
Department of Science, System and Models, Roskilde University, Department of Science, System and Models, Roskilde University, Department of Dermatology, University of Wisconsin, Madison, Wisconsin, United States of America, Department of Animal and Dairy Science, University of Georgia, Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Department of Cancer Studies and Molecular Medicine, The Biocentre, University of Leicester, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut, United States of America, INSERM U866, University of Burgundy, Department of Biochemistry, Postgraduate Programme of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Signal Transduction Laboratory, Ordway Research Institute, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Laboratory of Physiological Studies, Section on Oxidative Stress Tissue Injury, National Institutes of Health, Department of Biochemistry and Biotechnology, Annamalai University, College of Pharmacy, University of Hawaii at Hilo,15 UFR Pharmacie, University of Bordeaux, Proteomics Laboratory, Indian Institute of Toxicology Research, College of Pharmacy, Seoul National University, Clinical Institute of Medical and Chemical Laboratory Diagnostics, General Hospital of Vienna, Medical University of Vienna, Department of Animal Physiology and Biochemistry, August Cieszkowski University of Agriculture, Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Department of Biochemistry and Molecular Biology, New York Medical College,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116821/
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