RESVERATROL BENEFITS SIDE EFFECTS, REVIEWS
Resveratrol supplements, resveratrol dosages, weight loss zhion@zhion.com     February 17, 2012
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.

Recently, I have received a comment from a visitor about the hormesis of resveratrol. Hormesis is a dose response phenomenon characterized by a
low dose stimulation, high dose inhibition, resulting in either a J-shaped or an inverted U-shaped dose response curves. [RD1] resveratrol displays
hormesis-like biphasic dose responses in studies. Recognition of the widespread occurrence of the hormetic nature of many of the responses of
resveratrol can help optimize study design protocols, create a dose-response framework for better addressing dose-related biological complexities
and assist in the determination of an optimal dose for resveratrol.

Recent studies indicate the hormetic action of resveratrol, in which resveratrol protects the heart cells at a lower dose while kills them at relatively
higher doses. In an animal study, resveratrol formulation (Longevinex) was tested. A group of rats were fed with three different doses of resveratrol
or Longevinex (dosage 2.5 mg/kg, 25 mg/kg and 100 mg/kg) for up to 30 days, while the control group was only given placebo. The results showed
hormesis for pure resveratrol, which was cardioprotective at lower doses and detrimental for higher doses, but surprisingly Longevinex did not
display such hormetic action. [RD2]

It has been known that formulation can alter the absorption of a nutrient, a drug or a chemicals. It is not a surprise to see the effect of Longevinex. I
wonder if RD2 suggests that a tiny amount of pure resveratrol powder is already good enough to achieve a general purpose, why do we spend
extra money to purchase a high dose resveratrol formulation?
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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!
Any type of medication abuse can lead to major health risks, be aware there's always
drug rehabilitation centers that offer advice and treatment if
needed.

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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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
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zhion@zhion.com) to correct my mistake(s).
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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
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 scientists, as it might have health benefits on various
chronic diseases. [1] Some marketers promote resveratrol as an anti-aging remedy. 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] However, it is also found that resveratrol has hormesis properties. Frequently, low doses
of toxins and other stressors not only are harmless but also activate an adaptive stress response that raise the resistance of the organism against
high doses of the same agent. This phenomenon, which is known as "hormesis" When high doses of these chemicals are employed, cells undergo
mitochondrial outer membrane permeabilization and die. In contrast, low doses of such cytotoxic chgemicals can activate hormesis in several
paradigms, and this may explain the lifespan-prolonging potential of autophagy inducers including resveratrol and caloric restriction. [RD3]

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] Thus, resveratrol may benefit people at risk of type 2 diabetes.

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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