RESVERATROL BENEFITS SIDE EFFECTS, REVIEWS
Resveratrol supplements, resveratrol dosages, weight loss zhion@zhion.com     December 4, 2011
Stability of Resveratrol
Resveratrol is a potent antioxidant, oxidation may occur during the manufacturing process or/and storage of the
finished products. It has long been thought that resveratrol supplements were not very effective in comparison with
wine. Recently, some manufacturers have developed a technique to solve the stability issues of resveratrol
supplements during manufacturing and storage. [1]

RESVERATROL DOSAGE
Resveratrol has been suggested to be safe at doses equivalent to 500 mg./day. [1] But, the resveratrol dosage needed
to be much higher than that to be effective for therapeutic use. On the other hand, dosages lower than 500 mg/day
definitely is OK for general support. Users must discuss with their medical doctor to see if resveratrol benefits them
before use.
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RESVERATROL SAFETY

Resveratrol Side Effects
Resveratrol is not known to be toxic or cause adverse effects in humans at low doses. Researchers administered rats
dosage of 0, 300, 1000, and 3000 mg trans-resveratrol per kilogram body weight per day for 4 weeks. Most of the
adverse or side events occurred in the rats administered 3000 mg per kilogram body weight per day. Signs of toxicity
included 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. They also observed renal lesions. No adverse or side effects were observed at 300 mg resveratrol
per kilogram body weight per day in rats. [12]

However, resveratrol was found to affect the activity of P450 and increase the absorption of certain drugs such as
diltiazem. The intake of high resveratrol dosages can offer serious unwanted side effects for patients on certain types of
medications. Resveratrol was also found to delay the recovery of gastric ulcer in an animal study. Finally, resveratrol is
also known as a metal chelator, high doses of resveratrol may prevent the absorption of copper or other metals.
Copper deficiency can cause muscle issues and even heart failure. Its side effect can be serious!

Resveratrol-Drug Interaction
Intake of resveratrol significantly increased the extent of the absorption (AUC) of diltiazem, except for resveratrol 0.5
mg/kg, in a rat study. The increased bioavailability of diltiazem is probably related to the inhibition of both the
cytochrome P450 3A4-mediated metabolism and the efflux pump P-glycoprotein in the intestine and/or liver. [s7]  
Further,resveratrol may slow down the metabolism of some drugs including statins, statins, erectile dysfunction
medicine, calcium channel blockers and some immune-system suppressants.

Estrogen Issues
There's some evidence that resveratrol may activate estrogen receptors on cells, spelling side effects or trouble for
women with a history of estrogen-sensitive tumours (often breast, ovarian and uterine). [s9]
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This web side discusses side effects and benefits of herbs, supplements or drug products. You are encouraged to
report adverse side effects of any resveratrol products to FDA, its website is www.fda.gov., or report the adverse side
effects to the manufacturer directly, you should be able to find the contact information on the label. There are always
new information. Please, send me an email (zhion@zhion.com) to correct my mistake(s). Reasonable care has been
taken in preparing this document and the information provided herein is believed to be accurate. The information is not
intended to be a substitute for professional medical advice. It is important to seek the advice of a physician about any
medical condition or symptom or the benefits and side effects of a resveratrol supplement or a resveratrol product.
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Resveratrol weight loss

Some marketers argue that resveratrol speeds up metabolism to help users burn more calories throughout the day.
Thus, resveratrol offers benefits of weight loss. Their argument sounds interesting but they do not list out what
evidence they have to support the idea that resveratrol helps weight loss. In a study, resveratrol in combination with
genistein and quercetin synergistically decreased adipogenesis in murine and human adipocytes. While, an in vivo
study showed that phytochemicals including resveratrol in combination with vitamin D prevented weight gain and bone
loss in a postmenopausal rat model. [WL1]

In another study of aged ovariectomized female rats, an high-dose treatment (dosage: vitamin D+400 mg/kg
resveratrol+2,000 mg/kg quercetin+1,040 mg/kg genistein) reduced body weight gain and the fat pad weights. This
treatment also increased the serum concentration of insulin-like growth factor-1 and the bone mineral content of the
femur. Thus, the synergistic effects of a combination of resveratrol with vitamin D may be effective in reducing bone
loss and weight gain after menopause. [WL2] These studies show that resveratrol may help prevent "weight gain"
under certain conditions. But, there is still no solid evidence to support resveratrol helps weight loss.

One of these online article actually suggest the readers not to consume sugary or starchy carbohydrates after 6 pm,
and the readers should eat often, do not over eat, and try 5 small meals daily. They even suggest protein diets and
exercise plan to readers. Sure, diet control and exercise can help weight loss!
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Resveratrol Reviews

According to a Oregon State University online publication [OSU], resveratrol (3,4',5-trihydroxystilbene) is a polyphenol, belongs to a class of
stilbenes. Resveratrol is a fat-soluble compound that occurs in a trans and a cis configuration. Resveratrol also occur as glucosides, such as
resveratrol-3-O-beta-glucoside (also called as piceid).

Resveratrol was first found in 1940 in the roots of a plant called Veratrum grandiflorum. Later on, in 1976, resveratrol was discovered in grapes,
and in 1992, resveratrol was also indentified in wine. [13] Resveratrol was interested by scientist, as it might have health benefits on various chronic
diseases. [1] Resveratrol exhibits a wide range of biological effects, including antiplatelet, anti-inflammatory, anticancer, antimutagenic and
antifungal properties. [4]

Resveratrol was also believed responsible for some of the beneficial effects of moderate red wine drinking on the cardiovascular system. However,
one liter of red wine contains only 1.5-3 mg of resveratrol, Consequently, resveratrol becomes popular in the US and other places in the world.

Resveratrol is considered as a dietary phytoalexin. Phyto comes from the word phyton which means a plant, while alexin means to defend.
Phytoalexin means plant antibiotic produced by a plant in response to the entry of a disease-producing substance. [8]

Metabolism and Absorption of Resveratrol
Oral dosage of trans-reveratrol is well-absorbed in the body, but it has a rapid metabolism and elimination leading to a low bioavailability.
Bioavailability is the fraction of an orally-administrated compound that reaches the circulatory system. A group of 6 subjects took 25 mg of
trans-resveratrol orally, only traces of the unchanged resveratrol were detected in blood stream. Plasma concentrations of resveratrol and
metabolites peaked around 60 minutes (T max) later. [OSU]
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Resveratrol Biological Activities and Potential Health Benefits

Arthritis
Yucca schidigera Roezl. (Agavaceae) has been traditionally used to treat arthritis and rheumatism and some other
diseases. Later on, resveratrol was found to be one of its key ingredients. [a3] Arthritis is the inflammation of the joints,
it is a chronic disease that results from dysregulation of pro-inflammatory cytokines (e.g. tumour necrosis factor and
interleukin-1beta) and pro-inflammatory enzymes that mediate the production of prostaglandins (e.g.
cyclooxygenase-2) and leukotrienes (e.g. lipooxygenase), together with the expression of adhesion molecules and
matrix metalloproteinases, and hyperproliferation of synovial fibroblasts. All of these factors are regulated by the
activation of the transcription factor nuclear factor-kappaB. Thus, any agent which can suppress the expression of
tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, lipooxygenase, matrix metalloproteinases or
adhesion molecules, or suppress the activation of NF-kappaB, have the potential to cure arthritis. [a6] Resveratrol was
found be an inhibitor or a mediator for some of these compounds in our body. Thus, resveratrol may benefit people
suffered from arthritis.

Cancer
Resveratrol may have benefits on those at risk of certain cancers. As early as 1997, researchers have proposed to use
resveratrol as a cancer-preventive agent. Resveratrol potentiates the growth inhibitory/anticancer activity of cisplatin
and doxorubicin in vitro and protects against doxorubicin-induced cardiac toxicity both in vitro and in mice.
[c3]Resveratrol acts on the process of carcinogenesis by affecting the three phases: tumor initiation, promotion and
progression phases and suppresses the final steps of carcinogenesis, i.e. angiogenesis and metastasis. Resveratrol is
also able to activate apoptosis, to arrest the cell cycle or to inhibit kinase pathways. [2,3, c2]

In addition to potentiate the benefit of anti-cancer drugs, resveratrol itself can be an anti-cancer agent. In a study,
resveratrol inhibited cyclooxygenase (COX) expression and/or activity; in endometrial cancer cells, COX-2 is
overexpressed and confers cellular resistance to apoptosis. High-doses of resveratrol triggered apoptosis in five out of
six uterine cancer cell lines. [c4] Resveratrol also exhibited a variety of molecular events in etoposide-based
combination therapy in HT-29 colon cancer cells including the activation of adenosine monophosphate
(AMP)-activated protein kinase, inhibition of cell growth, induction of apoptosis, and reactive oxygen species (ROS)
generation. [c5] In another study, resveratrol-induced growth inhibition in T47D human breast cancer cells.
Resveratrol-induced apoptosis is found to be associated with the activation of the p53 in a dose- and a time-dependent
manner. [c6] In another study, resveratrol significantly inhibited growth factor heregulin-beta1 (HRG-beta1)-mediated
Matrix metalloproteinase expression in human breast cancer cells. Resveratrol significantly suppressed
HRG-beta1-mediated phosphorylation of ERK1/2 and invasion of breast cancer cells. [c8] Transgenic Adenocarcinoma
Mouse Prostate males were fed with resveratrol (dosage- 625 mg resveratrol per kg AIN-76A diet) or
phytoestrogen-free, control diet (AIN-76A). Resveratrol in the diet significantly reduced the incidence of poorly
differentiated prostatic adenocarcinoma by 7.7-fold. [c9] Finally, resveratrol was shown as a potent inhibitor of A549
lung cancer cell growth based on a microarray gene expression study. [c10]
The studies on the potential health benefits of resveratrol on cancer were done in animals. One may ask what dosage needed for a human to
achieve such therapeutic effects? A phase I study of oral resveratrol (single dosages- 0.5, 1, 2.5, or 5 g) was conducted by Leicester University, UK,
in 10 healthy volunteers per dose level. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at
the highest dosage were 539 +/- 384 ng/mL (2.4 micromol/L), which occurred 1.5 h post-dose. Cancer preventive effects of resveratrol in cells in
vitro require levels of at least 5 micromol/L. The results suggest the requirement of consumption of very high-dose resveratrol to elicit systemic
levels commensurate with cancer preventive efficacy. [c7]

Cardiovascular Diseases
Resveratrol is a phytoestrogen, potent antioxidant, reactive oxygen species scavenger and metal chelators.  [4] Thus, resveratrol may have benefits
of protection of the cardiovascular system against ischemic-reperfusion injury; it may also protect and maintain the intact endothelium, exhibits
antiatherosclerotic properties inhibits the LDL oxidation, suppress the platelet aggregation and exhibits estrogen like action. [4, 7] Thus, resveratrol
may benefit people at risk of certain cardiovascular conditions.

Diabetes
Studies showed that resveratrol increased life span in lower organisms by activating the NAD (+)-dependent histone deacetylase Sirt1. And, it was
found that that resveratrol promoted longevity and improved glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the
transcriptional coactivator PGC-1alpha. [d7] In 2001, resveratrol (5-35 micromol/l) was found to induce concentration-dependent relaxation of
mesenteric arteries preconstricted with noradrenaline (8 micromol/l) or KCl (125 mmol/l) from both lean and dietary-obese rats. [d1]

Hyperglycemia, a symptom of diabetes mellitus, induces hyperosmotic responses, including apoptosis, in vascular endothelial cells and leukocytes.
Hyperosmotic shock often leads to apoptotic cell death. Resveratrol was found to attenuate high glucose-induced apoptotic changes by virtue of its
antioxidant property. [d2] Diabetic nephropathy is a serious vascular complication and one of the main causes of end-stage renal disease.
Increased oxidative stress plays an important role in the etiology of diabetic nephropathy. Treatment with resveratrol significantly attenuated renal
dysfunction and oxidative stress in diabetic rats. [d3]

Most of type 2 diabetes mellitus patients eventually become insulin dependent when insulin secretion by the islets of Langerhans is exhausted.
Resveratrol was found to possess hypoglycemic and hypolipidemic effects in streptozotocin-induced diabetes rats. In resveratrol-treated diabetic
rats, the plasma glucose concentration on day 14 was reduced by 25.3%, and the triglyceride concentration was reduced by 50.2% compared with
the placebo-treated rats. In nicotinamide-treated diabetic rats, the plasma glucose oncentration on day 14 was reduced only by 20.3 %, and the
triglyceride concentration was reduced by 33 %. Resveratrol administration ameliorates common DM symptoms, such as body weight loss,
polyphagia, and polydipsia. In STZ-nicotinamide DM rats, resveratrol administration significantly decreased insulin secretion and delayed the onset
of insulin resistance. [d4]

Fatty liver / liver protection
The prevalence of nonalcoholic fatty liver disease is high.nonalcoholic fatty liver disease is linked to obesity, diabetes mellitus, and
hypertriglyceridemia. Approximately 20% of patients with nonalcoholic fatty liver disease will eventually develop cirrhosis. Resveratrol was found to
decrease nonalcoholic fatty liver disease severity in rats. This effect was mediated, at least in part, by tumor necrosis factor alpha (TNF-alpha)
inhibition and antioxidant activities. Oral administration of resveratrol (dosage 20 mg/kg daily for 4 weeks) also remarkably prevented the DMN-
induced loss in body and liver weight, and inhibited the elevation of serum alanine transaminase, aspartate transaminase, alkaline phosphatase and
bilirubin levels. [LP1] Thus, resveratrol may have benefits of liver protection.

Skin
When topically applied, resveratrol cream limited the HSV-1 lesion formation in the skin of mice, resveratrol cream also reduced HSV replication in
the vagina of mice and limits extravaginal disease. Thus, resveratrol cream may have some potential benefits on skin health, but more studies are
needed to support this health benefit-claim.

Other Conditions
Because microcirculation occlusion and cytokines over-production is involved in many diseases such as acute pancreatitis, resveratrol as a platelet
and cytokines inhibitor may have benefits on acute pancreatitis. [5] Resveratrol has been shown to have an immuno-suppressive property as well
as protective effect on hepatocytes under allograft rejection in a study of Wistar rats. [11] Resveratrol has been shown to reduce ischemia-
reperfusion (I/R) injury of rat kidney both by antioxidant and anti-inflammatory mechanisms. [10] In a study, researchers administered dosage of 20
mg/(kg . d) of trans-resveratrol for 90 days. Compared to a control group, the diameter of the seminiferous tubules was significantly reduced from
437.5 +/- 0.1 mum in the controls to 310.9 +/- 0.1 mum. This decrease was accompanied by a significant increase in tubular density. Sperm counts
were significantly greater in the resveratrol-treated rats than in the control group, but sperm quality did not differ. [9] Some online articles claim that
resveratrol helps weight loss, but it also depends on the lifestyle.
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