RESVERATROL REVIEWS
zhion@zhion.com     October 16, 2011

Resveratrol Reviews
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 is a
polyphenol compound that may have health benefits on various chronic diseases.  [1] It exhibits a wide range of
biological effects, including antiplatelet, anti-inflammatory, anticancer, antimutagenic and antifungal properties. [4]
This compound is also believed responsible for some of the beneficial effects of moderate red wine drinking on the
cardiovascular system. One liter of red wine contains 1.5-3 mg of resveratrol. Resveratrol also exists in grapes.
Resveratrol supplements are popular in the US and other countries.

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] This article reviews various aspects of resveratrol benefits and side effects.
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SCIENTIFIC EVFIDENCE FOR RESVERATROL BENEFITS REVIEWS

Resveratrol Benefits - Arthritis
Yucca schidigera Roezl. (Agavaceae) has been traditionally used to treat a variety of diseases including arthritis
and rheumatism. Resveratrol, one of the key ingredients in Yucca, is believed to contribute a part of its health
benefits. [a3]

Arthritis, an inflammation of the joints, 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 agents
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]

COX-1 and COX-2
Oxidative stress is related to a number of autoimmune diseases, including cancer and rheumatoid arthritis. The main
source of pathologic “reactive oxygen species” are the activated polymorphonuclear leukocytes. Resveratrol was
found to inhibit isolated polymorphonuclear leukocytes in a dose dependent manner. [a2] Resveratrol is able to
inhibit the expression of VEGF, MMP-3, MMP-9 and COX-2 in human articularchondrocytes stimulated with the pro-
inflammatory cytokine IL-1beta. Resveratrol is also able to suppress apoptosis and inflammatory signaling through
its actions on the NF-kappaB pathway in human chondrocytes. [a4] Resveratrol was found to possess COX-1
inhibition, COX-2 inhibitory potential and an LTB 4 formation inhibitory activity in an in vitro study. [a3]

Anabolic Mediator
Resveratrol is found to be a potent anabolic mediator of bovine intervertebral disc cartilage homeostasis from a vitro
study, revealing its potential as a unique biologic treatment to slow the progression of intervertebral disc
degeneration. [a1]

IL-1beta
The inflammatory process plays a pivotal role during the pathogenesis of osteoarthritis, dominated by catabolic
processes initiated by pro-inflammatory cytokines such as IL-1beta. Resveratrol is able to reverse significantly IL-
1beta-reduced cell proliferation and blocked IL-1beta-stimulated cell membrane bound- and mature IL-1beta
synthesis in chondrocytes. Furthermore, resveratrol is able to inhibit the IL-1beta-induced degradation of
mitochondria and apoptosis in chondrocytes in a time-dependent manner. Resveratrol is also able to reverse the IL-
1beta-induced up-regulation of reactive oxygen species (ROS) in chondrocytes. [a5]

Macrophage Migration Inhibitory Factor
Cytokine macrophage migration inhibitory factor is a crucial factor in the pathogenesis of rheumatoid arthritis.
Resveratrol is found to be a potent inhibitor as the antipyretic-analgetic drug acetaminophen. [a7]

Nuclear factor kappa B (NF-kappaB) / Animal Study
Nuclear factor kappa B (NF-kappaB), is a pivotal transcription factor involved inthe activation of the TNF-alpha and
IL-1beta genes. Activation of NF-kappaB insynovial cells is a feature seen in arthritis patients. Resveratrol is potent
and specific inhibitor of TNF-alpha and IL-1beta induced NF-kappaB activation. Intra-articular injections of
resveratrol on cartilage and synovium could significantly decreased cartilage destruction in an experimental rabbit
inflammatory arthritic model. [a8]

Resveratrol benefits - cancer
As early as 1997, researchers have proposed to use resveratrol as a cancer-preventive agent. Resveratrol was
shown to have anti-cancer activities in assays representing three major stages of carcinogenesis.

Resveratrol has been shown to inhibit cancer initiation and promotion [2] It acts as a selective estrogen receptor
modulator (SERM) and regulates proteins involved in DNA synthesis and cell cycle. Resveratrol also affects the
activity of transcriptional factors involved in proliferation and stress responses, such as NF-kB, AP1 and Egr1. [3]

Researchers from researchers at Cook County Hospital found that gastric adenocarcinoma cells respond to
resveratrol treatment with suppression of DNA synthesis, activation of nitric oxide synthase, induction of apoptosis
and inhibition of total PKC and PKC alpha activity. [6]

Observation (Epidemiological Studies)
Trans-resveratrol (RSVL; 3,4',5-trihydroxystilbene), a natural compound found in grapes, berries, peanuts and red
wine exerts certain anticancer roles in different human cancer types. Several epidemiological studies have revealed
that resveratrol is probably one of the active ingredients of wine responsible for its health benefits such as
prevention of vaso-coronary diseases and cancer. 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. It is also able to activate apoptosis, to arrest the cell cycle or to
inhibit kinase pathways. [c2]

Intensifying Anti-cancer Agents
Resveratrol adds to 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]

Endometrial Cancer/ Human Uterine Cancer Cells
Endometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world. At the
molecular level, resveratrol has been reported to inhibit cyclooxygenase (COX) expression and/or activity; in
endometrial cancer cells, COX-2 is overexpressed and confers cellular resistance to apoptosis. Researchers from
Université du Québec found that high-doses of resveratrol triggered apoptosis in five out of six uterine cancer cell
lines. [c4]

Colon Cancer / HT-29 Colon Cancer Cells
Resveratrol 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]

Breast Cancer / Human Breast Cancer Cells
Researchers from Kuwait University, found resveratrol-induced growth inhibition in T47D human breast cancer cells
was caused by apoptosis in a cell study. Resveratrol-induced apoptosis is associated with the activation of the p53
in a dose- and a time-dependent manner. [c6]

Researchers from China Medical University, Taiwan, found resveratrol significantly
inhibited growth factor heregulin-beta1 (HRG-beta1)-mediated Matrix metalloproteinase (MMP-9) expression in
human breast cancer cells. Resveratrol significantly suppressed HRG-beta1-mediated phosphorylation of ERK1/2
and invasion of breast cancer cells. [c8]

Prostate Cancer / Mouse
Researchers from University of Alabama at Birmingham fed transgenic Adenocarcinoma Mouse Prostate males with
resveratrol (625 mg resveratrol per kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A). They found
resveratrol in the diet significantly reduced the incidence of poorly differentiated prostatic adenocarcinoma by 7.7-
fold. [c9]

Lung Cancer / Microarray
Researchers from IIT Research Institute showed resveratrol as a potent inhibitor of A549 lung cancer cell growth
based on a microarray gene expression study. [c10]

Clinical Study in Human
A phase I study of oral resveratrol (single doses of 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 dose 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 that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with
cancer preventive efficacy. [c7]

Resveratrol Benefits - Cardiovascular Diseases
Resveratrol is a phytoestrogen, potent antioxidant, reactive oxygen species scavenger and metal chelators.  [4]
Thus, it 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]

Resveratrol Benefits - 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]
Researchers are interested to know if resveratrol benefits animals suffered from chronic diseases, such as diabetes.
The following is a summary of a few interesting research studies about the potential benefits of resveratrol on
chronic diseases, such as diabetes.

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 elicits a stress response in mammalian cells, often leading to
apoptotic cell death. Moreover, 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. In a study, researchers
found 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 because insulin secretion by the
islets of Langerhans becomes exhausted. Researchers from Chang Gung University, Taiwan, showed that
resveratrol (3,5,4'-trihydroxylstilbene) possesses 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]

Usually, diabetic rats exhibited a significant thermal hyperalgesia and cold allodynia along with increased plasma
glucose and decreased body weights. Allodynia means other pain. It is a painful response to a usually non-painful
stimulus. Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or
peripheral nerves. [Wikipedia] Sharma S and co-workers from Panjab University, India, reported treatment with
resveratrol (10mg/kg orally) from week 4 to week 6 significantly attenuated the cold allodynia and thermal
hyperalgesia, suggesting the application of resveratrol in diabetes, especially for diabetic neuropathy. [d5]

Researchers, at Boston University Medical Center, revealed inactivation of hepatic AMP-activated protein kinase
was a key event in the pathogenesis of hyperlipidemia in diabetes (based on a study of in type 1 diabetic LDL
receptor-deficient mice). They showed that resveratrol could lower lipid levels by activating AMP-activated protein
kinase. It was about 200 times the potency of Metformin! [d6]

Recent Research Studies of Resveratrol on Diabetes
Schmatz R and co-workers from Universidade Federal de Santa Maria, Brazil, found that treatment with resveratrol
prevented the increase in acetylcholinesterase activity and consequently memory impairment in diabetic rats. [d8]

Palsamy P and other India researchers found daily oral treatment of resveratrol to diabetic rats for 30 days
demonstrated a significant decline in blood glucose and glycosylated hemoglobin levels and a significant increase in
plasma insulin level. The administration of resveratrol also reverted the altered activities of the key enzymes of
carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase,
fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen
phosphorylase in liver and kidney tissues of diabetic rats to near normal levels. [d9]

Researchers from New York Medical College observed that resveratrol increased mitochondrial mass and mtDNA
content, up-regulated protein expression of electron transport chain constituents and induced mitochondrial
biogenesis factors (PGC-1alpha, Nrf-1, Tfam) in cultured human coronary arterial endothelial cells. They found
resveratrol treatment normalized impaired mitochondrial biogenesis in aortas of type 2 diabetic mice. This suggests
the potential benefits of resveratrol on diabetes or metabolic diseases. [d10]

Researchers from Dortmund University of Technology, Germany, observed that resveratrol could inhibit the
formation of islet amyloid polypeptide (IAPP) fibril. Following preferential partitioning of IAPP into the fluid lipid phase,
the membrane of beta-cells suffered irreversible damage and predominantly circularly-shaped lipid-containing IAPP
amyloid was formed. Deposition of amyloid in the extracellular matrix of beta-cells commonly occurs in type II
diabetes mellitus. Thus, resveratrol may benefit animals suffered from diabetes. [d11]

Rodella LF and co-workers from University of Brescia, Italy, found resveratrol and cobalt protoporphyrin
administration increased heme oxygenase-1 protein expression and heme oxygenase activity in the aorta and
significantly increased serum adiponectin levels, compared to untreated diabetic rats. Increased heme oxygenase-1
expression usually improves vascular function. [d12]

Resveratrol decreased blood glucose, glycosylated hemoglobin, blood urea, serum uric acid, serum creatinine and
diminished activities of pathophysiological enzymes such as aspartate transaminase (AST), alanine transaminase
(ALT) and alkaline phosphatase (ALP) in diabetic rats after 30 days of treatment. [d13]

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.
[d14]

Resveratrol benefits - 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 (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]

Resveratrol benefits - pancreatitis
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 benefits - liver transplant
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 benefits - kidney diseases
Resveratrol (RSV) has been shown to reduce ischemia-reperfusion (I/R) injury of rat kidney both by antioxidant and
anti-inflammatory mechanisms. [10]

Resveratrol benefits - sperm production
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]

Resveratrol weight loss
Resveratrol in combination with genistein and quercetin synergistically decreased adipogenesis in murine and
human adipocytes. A 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, the high-dose treatment (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 (P<.05) 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] Note, a very high dosage of resveratrol is needed to acheive this weight loss!

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] Then
what is the effective resveratrol dosage? Not sure. The resveratrol dosage used in the rat study is already high.
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RESVERATROL SIDE EFFECTS REVIEW
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] There are also other
potential resveratrol side effects at high doses such as drug interaction, hinderance of metal absorption, gastric
ulcer, pimples or even certain kinds of cancers. For details, please, review article - resveratrol side effects.
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RESVERATROL PRODUCT REVIEW
Resveratrol Cream
Brand: Resveratrol Cream 2 oz
Manufacturer/ Vender: Springboard; Manufacturer/ Vender: Health Pro Labs

Ingredients: Deionized Water, Glycerin, Caprylic/Capric Triglyceride, Sepigel 305, Lecithin, Alcohol, Resveratrol,
Sodium Hydroxymethylglycinate, Potassium Sorbate, Citric Acid

Brand: Sirtuin Skin, Resveratrol Cream Peptide Formula
Manufacturer: RevGenetics

Ingredient: Micronized resveratrol particles, acetyl hexapeptide-3, palmitoyl pentapeptide-4 (Matrixyl), sodium
hyaluronate (HA), cetearyl alcohol, glyceryl stearate, PEG 100 stearate, citrus aurantium dulcis (orange) fragrance,
phenoxyethanol, caprylyl glycol, stearic acid and potassium sorbate.

Claim: They provide the Sirtuin Skin formula (a resveratrol cream) to help fight the appearance of age, lines and to
help maintain user's healthy skin looking younger for a longer period of time.

Brand: MyChelle Supreme Polypeptide Cream Unscented - 1.2 fl oz
Vender: vitacost.com

Ingredients: Aqua (Water), Helianthus Annuus (Sunflower) Seed Oil, Squalane, Caprylic/Capric Triglyceride, Pisum
Sativum (Pea Peptide) Extract, Butyrospermum Parkii (Shea Butter), Polawax, Mangifera Indica (Mango) Seed
Butter, Palmitoyl Tripeptide-5, Ribes Nigrum (Black Currant) Seed Oil, Cetearyl Olivate, Sorbitan Olivate, Glycerin,
Rosa Canina (Rose Hip) Seed Extract, Simmondsia Chinensis (Jojoba) Seed Oil, C 18-36 Acid Triglyceride,
Collagen (Marine Oligopeptides), Oryza Sativa (Rice Peptide) Extract, Cassia Angustifolia Seed Polysaccharide,
Totarol, Astaxanthin, Camellia Sinensis (Green Tea) Leaf Extract, Deuterium Oxide (heavy water), Resveratrol,
Honey, Phospholipids, Sphingolipids, Sodium Hyaluronate (L), Elaeis Guineensis (Palm) Oil, Tocotrienols,
Tocopherol, Glucosamine HCL (D), Xanthan Gum, Citrus Aurantium ssp. Amara (Neroli) Oil, Cananga Odorata
(Ylang Ylang) Flower Oil, Pelargonium Graveolens (Geranium) Flower Oil, Citrus Aurantium Bergamia (Bergamot)
Fruit Oil, Salvia Sclarea (Clary) Oil, Alcohol Denat., Lavandula Angustifolia (Lavender) Oil, Potassium Sorbate,
Phenethyl Alcohol, Caprylyl Glycol, Trisodium Ethylenediamine Disuccinate.

Claim: Supreme Polypeptide Cream is the ultimate in combining organic ingredients with dermaceutical grade
peptides to smooth fine lines while softening deeper ones.

Resvinex 500
According to advertisement, Resvinex 500 is a high dose resveratrol supplement that Resvinex 500 contains 5 times
the potency of most resveratrol products on the market. Resvinex 500 is claimed to be manufactured in the United
States in an FDA licensed facility in full compliance with Good Manufacturing Practice (GMP) guidelines. 500 mg of
trans-resveratrol per serving; 2 capsules per serving; 30 servings per container.

Puritan's Pride - Resveratrol Supplements.
Puritan's Pride has 6 supplement products in resveratrol-resveratrol 50 mg, resveratrol red wine extract, resveratrol
100 mg, resveratrol 250 mg, resveratrol/grape extract 60 mg and resveratrol 250 mg.

Bioforte Resveratrol
Bioforte Resveratrol supplement - 250 mg per serving, 60 vcaps/bottle. Bioforte Transmax (high potency and purity)
- 500 mg of 99% resveratrol; 60 vcaps/bottle. Biotivia claims that it harvests its own raw materials from organic
sources, processes its products in its own CGMP and SFDA certified facilities and rigidly tests every bottle to insure
potency. Biotivia is also the only manufacturer to use a patented Oxygen scavenging packaging system to protect
our resveratrol supplements from destructive oxidation each time the bottle is opened.

Resveratrol Ultra and Now Foods Natural Resveratrol are also popular.
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Resveratrol is a polyphenol compound that may have health benefits on various chronic diseases.  [1]
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Different people may experience different side effects and benefits of a product. You are encouraged to report
adverse side effects to FDA, its website is www.fda.gov., or report the adverse side effects to the
manufacturer, 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 supplement or a drug product. Finally, please, do not transfer the article to other website. Thank
you. ALL RIGHTS RESERVED.