Dose-Dependency of Resveratrol in Providing Health Benefits

Abstract

This review describes the dose-dependent health benefits of resveratrol, a polyphenolic antioxidant that is found in a variety of foods, especially grape skin and red wine. Resveratrol provides diverse health benefits including cardioprotection, inhibition of low-density lipoprotein, activation of nitric oxide (NO) production, hindering of platelet aggregation [32] A.A.E. Bertelli, D.E. Giovannini, R.L. Caterina, W. Bernini, M. Migliori and M. Fregoni et al., Antiplatelet activity of cis-resveratrol, Drugs Exp Clin Res 22 (1996), pp. 61-63. View Record in Scopus | Cited By in Scopus (111) and promotion of anti-inflammatory effects. Studies have shown that at a lower dose, resveratrol acts as an anti-apoptotic agent, providing cardioprotection as evidenced by increased expression in cell survival proteins, improved postischemic ventricular recovery and reduction of myocardial infarct size and cardiomyocyte apoptosis and maintains a stable redox environment compared to control. At higher dose, resveratrol acts as a pro-apoptotic compound, inducing apoptosis in cancer cells by exerting a death signal. At higher doses, resveratrol depresses cardiac function, elevates levels of apoptotic protein expressions, results in an unstable redox environment, increases myocardial infarct size and number of apoptotic cells. At high dose, resveratrol not only hinders tumor growth but also inhibits the synthesis of RNA, DNA and protein, causes structural chromosome aberrations, chromatin breaks, chromatin exchanges, weak aneuploidy, higher S-phase arrest, blocks cell proliferation, decreases wound healing, endothelial cell growth by fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor, and angiogenesis in healthy tissue cells leading to cell death. Thus, at lower dose, resveratrol can be very useful in maintaining the human health whereas at higher dose, resveratrol has pro-apoptotic actions on healthy cells, but can kill tumor cells.

Full text

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DOSE-DEPENDENCY OF RESVERATROL IN PROVIDING HEALTH BENEFITS
Subhendu Mukherjee, Jocelyn I. Dudley, Dipak K. Das 䊐Cardiovascular
Research Center, University of Connecticut Health Center, School of Medicine,
263 Farmington Avenue, Farmington, CT 06030-1110, USA
䊐This review describes the dose-dependent health benefits of resveratrol, a polypheno-
lic antioxidant that is found in a variety of foods, especially grape skin and red wine.
Resveratrol provides diverse health benefits including cardioprotection, inhibition of low-
density lipoprotein, activation of nitric oxide (NO) production, hindering of platelet
aggregation [32] A.A.E. Bertelli, D.E. Giovannini, R.L. Caterina, W. Bernini, M. Migliori
and M. Fregoni et al., Antiplatelet activity of cis-resveratrol, Drugs Exp Clin Res 22 (1996),
pp. 61–63. View Record in Scopus | Cited By in Scopus (111) and promotion of anti-
inflammatory effects. Studies have shown that at a lower dose, resveratrol acts as an anti-
apoptotic agent, providing cardioprotection as evidenced by increased expression in cell
survival proteins, improved post-ischemic ventricular recover y and reduction of myocar-
dial infarct size and cardiomyocyte apoptosis and maintains a stable redox environment
compared to control. At higher dose, resveratrol acts as a pro-apoptotic compound, induc-
ing apoptosis in cancer cells by exerting a death signal. At higher doses, resveratrol
depresses cardiac function, elevates levels of apoptotic protein expressions, results in an
unstable redox environment, increases myocardial infarct size and number of apoptotic
cells. At high dose, resveratrol not only hinders tumor growth but also inhibits the syn-
thesis of RNA, DNA and protein, causes structural chromosome aberrations, chromatin
breaks, chromatin exchanges, weak aneuploidy, higher S-phase arrest, blocks cell prolif-
eration, decreases wound healing, endothelial cell growth by fibroblast growth factor-2
(FGF-2) and vascular endothelial growth factor, and angiogenesis in healthy tissue cells
leading to cell death. Thus, at lower dose, resveratrol can be very useful in maintaining the
human health whereas at higher dose, resveratrol has pro-apoptotic actions on healthy
cells, but can kill tumor cells.
INTRODUCTION
A growing body of evidence supports that nutrition plays a major role
in maintaining a healthy heart. A proper diet containing a variety of
grains, fruits, vegetables and foods that are low in saturated fat, trans fat
and cholesterol, help maintain a healthy heart. Coronary heart disease
(CHD) is one of the major causes of death worldwide. Epidemiologic and
human intervention studies have shown the inverse relationship between
the consumption of plant-based diets and deaths attributed to heart dis-
ease. Most dietitians and nutritionists around the world are recommend-
ing an increase in the consumption of plant foods for the prevention of
Dose-Response, 8:478–500, 2010
Formerly Nonlinearity in Biology, Toxicology, and Medicine
Copyright © 2010 University of Massachusetts
ISSN: 1559-3258
DOI: 10.2203/dose-response.09-015.Mukherjee
Address correspondence to Prof. Dipak K. Das PhD, Sc.D, FAHA; Cardiovascular Research
Center, School of Medicine, University of Connecticut Health Center, 263 Farmington Avenue,
Farmington, CT 06030-1110, USA; Tel: (860)-679-3687; Fax: (860)-679-4606; E-mail: ddas@neu-
ron.uchc.edu

Dose dependency of Resveratrol
479
CHD. Certain foods are well known for their ability to protect human
health from CHD. Grape is the most well known among them and has
been used in medicinal science from the time immemorial. Ayurveda, one
of the ancient medicinal books of Hindus, described “darakchasava” (fer-
mented juice of red grapes) as a cardio tonic (Paul et al. 1999). Grape
juice or red wine was also described as a “gift of god” in The Bible.
Resveratrol is a naturally occurring phytoalexin present in grape skin. Its
chemical name is trans-3,5,4’-trihydroxy stilbene (Figure 1). Resveratrol
occurs in two isoforms cis and trans – resveratrol, but trans- resveratrol is
more biologically active than its cis isoform. In last few decades, resvera-
trol gained the attention of scientists worldwide due to its anti-cancer,
anti-inflammatory, blood-sugar-lowering and other beneficial cardiovas-
cular effects. Resveratrol has been reported to show these properties in
experimental mouse and rat models. Most of these results have yet to be
replicated in humans. In this article we will discuss the sources, health
benefits, molecular targets and dose dependency in delivering health
benefits of resveratrol.
SOURCES OF RESVERATROL
Resveratrol was first identified as the principal active ingredient from
the dried roots of Polygonum cuspidatum, mainly found in Japan and China.
Polygonum extract has been used in Japanese and Chinese traditional med-
icine to treat fungal infection, various skin inflammations, liver disease and
cardiovascular disease (Arichi et al. 1982; Vastano et al. 2000). Grape skin is
the main source of resveratrol. In addition to grapes, resveratrol is present
in a large variety of fruits such as cranberry, mulberry, lingberry, bilberry,
partridgeberry, sparkleberry, deerberry, blueberry, jackfruit, peanut and
also in a wide variety of flowers and leaves including gnetum, butterfly
orchid tree, white hellebore, scots pine, corn lily, eucalyptus, spruce etc.
FIGURE 1. Chemical structure of cis-resveratrol and trans-resveratrol.

S. Mukherjee and others
480
Resveratrol is also synthesized in response to environmental stressors that
include water deprivation, UV irradiation and especially fungal infection
(Das and Maulik 2006). Apart from these naturally occurring substances,
red wine and white wine also contain resveratrol. All of the above men-
tioned substances demonstrate their cardioprotective activities (Baur et al.
2006) due to the presence of resveratrol. Table 1 shows the amount of
resveratrol found in natural foods (Dudley et al. 2008a).
HEALTH BENEFIT OF RESVERATROL
It is now well known that resveratrol protects human health by diverse
mechanisms. It received importance during early nineties in the context
of “French paradox”; the phenomena wherein certain population of
France, in spite of eating a regular high fat diet, was less susceptible to
heart diseases (Richard 1987). The apparent cardioprotection was attrib-
uted to the regular consumption of moderate doses of red wine rich in
resveratrol in their diet (Kopp 1998)[14] P. Kopp, Resveratrol a phytoe-
strogen found in red wine a possible explanation for the conundrum of
the ‘French paradox’, Eur. J. Endocrinol. 138 (1998), pp. 619–620. Full
Text via CrossRef | View Record in Scopus | Cited By in Scopus (118).
Resveratrol is a natural antioxidant; it can scavenge some intracellular
reactive oxygen species (ROS). Although resveratrol is not a potent
antioxidant in vitro, it functions as a potent antioxidant in vivo. Most like-
ly the in vivo antioxidant property of resveratrol is derived from its ability
to increase nitric oxide (NO) synthesis, which in turns acts as an antioxi-
dant. It has been shown that resveratrol induces NO synthesis in case of
ischemic reperfused heart, brain and kidney and lower the oxidative
stress (Hattori et al. 2002; Cadenas and Barja 1999). Certain wines, grape
TABLE 1: The amount of resveratrol found in natural foods.
Source Resveratrol concentration
100% Natural peanut butter ~0.65 μg/g
Bilberries ~16 ng/g
Blueberries ~32 ng/g
Boiled peanuts ~5.1 μg/g
Cranberry raw juice ~0.2 mg/L
Dry grape skin ~24.06 μg/g
Grapes 0.16–3.54 μg/g
Peanut butter 0.3–1.4 μg/g
Peanuts 0.02–1.92 μg/g
Pistachios 0.09–1.67 μg/g
Ports and sherries <0.1 mg/L
Ref grape juice ~0.50 mg/L
Red wines 0.1–14.3 mg/L
Roasted peanuts ~0.055 μg/g
White grape juice ~0.05 mg/L
White wines <0.1–2.1 mg/L

Dose dependency of Resveratrol
481
juices, especially grape skins can provide cardioprotective effects due to
presence of resveratrol. Studies have shown that resveratrol protects per-
fused rat hearts through an increase in inducible nitric oxide synthase
(iNOS) expression and this effect is abolished in case of iNOS knockout
mice (Hattori et al. 2002; Imamura et al. 2002). It was also shown that
resveratrol provides cardioprotection via upregulation of catalase activity
in the myocardium. Resveratrol has been found to pharmacologically
precondition hearts by a NO-dependent manner (Hattori et al., 2002 R.
Hattori, H. Otani, N. Maulik and D.K. Das, Pharmacological precondi-
tioning with resveratrol: role of nitric oxide, Am. J. Physiol. 282 (2002), pp.
H1988–H1995. View Record in Scopus | Cited By in Scopus (75)Hattori et
al. 2002; Imamura et al. 2002). In another study, Das et al. (2005a) showed
that resveratrol –induced preconditioning was derived through the
upregulation of the iNOS–vascular endothelial growth factor (VEGF)–
VEGF receptor-2/kinase insert domain-containing receptor
(KDR)–endothelial nitric oxide synthase (eNOS) pathway. A number of
studies have successfully demonstrated that in rat myocardial infarction
(MI) model resveratrol significantly upregulates the protein expression
profiles of vascular endothelial growth factor (VEGF) and its tyrosine
kinase receptor fetal liver kinase-1 (Flk-1), which in turn ameliorates
myocardial damage (Fukuda et al. 2006). Several studies from our labora-
tory have shown that resveratrol protects mammalian hearts from
ischemia/reperfusion-induced injury. Resveratrol improves postischemic
ventricular function, reduces myocardial infarction and cardiomyocyte
apoptosis, activates survival signal, and reduces death signal (Das et al.
2005b; Das and Maulik 2006; Dudley et al. 2008a, Dekkers et al. 2008). It
has been also shown that resveratrol increases GLUT-4 expression and
reduces endothelin expression in ischemic-reperfused hearts of Zucker
obese rats in the presence or absence of glucose intake (Lekli et al. 2008).
This study indicates that resveratrol could provide protection against obe-
sity related cardiac injury.
Resveratrol regulates the redox homeostasis in mammalian system by
maintaining the amounts of several antioxidant enzymes, including glu-
tathione peroxidase, glutathione–S-transferase and glutathione reductase
(Yen et al. 2003). It is also known that resveratrol prevents low density
lipoprotein (LDL) oxidation (Frankel et al. 1993). There is evidence that
resveratrol is a potent inhibitor of the oxidation of polyunsaturated fatty
acids (PUFA) found in LDL. In fact, resveratrol was shown to be more
potent than flavonoids in preventing copper-catalyzed oxidation, thus
preventing oxidative modification of LDL (Frankel et al. 1993). Hebbar et
al. (2005) showed that high doses (0.3, 1.0 and 3.0 g/kg day) of resvera-
trol upregulates phase II and antioxidant genes in female and male rats.
Due to high rate of oxygen consumption and low levels of antioxidant
defense enzymes, the brain and the heart are particularly vulnerable to

S. Mukherjee and others
482
hypoxic conditions and oxidative stress injuries. Heme oxygenase-1 (HO-
1) has been shown to be neuroprotective (Dore 2002), it degrades the
pro-oxidant heme into biliverdin/bilirubin, iron and carbon monoxide.
Bilirubin can scavenge free radicals. Carbon monoxide is a cell cycle
modulator and vasodilator. It has been reported that CO provides anti-
inflammatory and antiapoptotic effects via nuclear factor kappa B
(NF(B) regulation (Kim et al. 2006). Resveratrol induces HO-1 in primary
neuronal cultures (Zhuang et al. 2003) and aortic smooth muscle cells
(Juan et al. 2005) at low concentrations (1–10 mM). At higher concentra-
tions (>20 mM), NF(B activation was suppressed and HO-1 was inhibited.
Moderate resveratrol or red wine rich in resveratrol intake (presumably
low concentration) could, therefore, have a considerable neuro-protec-
tive and vascular-protective effect against oxidative stress.
Resveratrol inhibits platelet aggregation, which is a major contribu-
tor in the process of atherosclerosis (Olas et al. 2001; Orsini et al. 1997).
Platelets through the activation of the process of thrombus formation
and their aggregation could set into motion the process of vascular
occlusion. A dose dependent decrease in platelet aggregation was shown
with resveratrol treatment (Soleas et al. 1997). Resveratrol (0.15 and 0.25
micromole/l) was shown to inhibit collagen-induced platelet activation
accompanied by [Ca+2] immobilization, thromboxaneA2 formation,
phosphoinositide breakdown, and protein kinase C (PKC) activation
(Shen et al. 2007).
Resveratrol has been shown to possess potential anticancer activity in
various cancer cells at the initiation, promotion, and progression stages
(Jang et al. 1997). High dose resveratrol (50 mM) has been shown to
induce cell death in mouse xenograft models of human neuroblastoma
cells (SH-SY5Y, NGP, and SK-N-AS) (van Ginkel et al. 2007). Moreover, 48
h exposure of 100 mM resveratrol induced cell death in human colorec-
tal cancer cells (DLD1 and HT29 cells) (Trincheri et al. 2007). Inhibitory
effects of resveratrol against breast cancer progression has been reported
in both estrogen-positive (MCF-7) and estrogen-negative (MDA-MB-231)
breast cancer cells as a result of 1 mM resveratrol treatment in vitro and
in nude mice inoculated with any of these cell lines. Ten mg per kg body
weight (BW) resveratrol treatment for 2 days reduced the cancer pro-
gression (Su et al. 2007). Resveratrol is also well known to possess anti can-
cer properties in animal model. It was shown that 625 mg/kg body wt
resveratrol reduced the progression of prostate cancer in transgenic ade-
nocarcinoma prostate (TRAMP) mice (Harper et al. 2007). Bhardwaj et
al. (2007) showed that 50 (M resveratrol could reduce the proliferation
of human multiple myeloma. Most of its anticancer properties are attrib-
uted to its ability to induce apoptosis in cancer cells (Abd El-Mohsen et al.
2006; Trincheri et al. 2007; Bhardwaj et al. 2007; Sun et al. 2006; Busquets
et al. 2007). For example, resveratrol induces loss of mitochondrial mem-

Dose dependency of Resveratrol
483
brane potential, leading to release of cytochrome C and Smac/Diablo,
and subsequent activation of caspase-9 and caspase-3 (van Ginkel et al.
2007). In addition to these mechanisms, resveratrol can also induce cell
cycle arrest at G0/G1 phase and reduce the expression of cell growth fac-
tors in human prostate cancer cell lines (Benitez et al. 2007). Resveratrol
was also shown to activate proapoptotic Bax, p53, and p21waf in T-cell
acute lymphoblastic leukemia cells (Hwang et al. 2007), and to reduce the
levels of antiapoptotic Bcl-xL, Bcl-2, cyclin D1, and TNF receptor-associ-
ated factor (Benitez et al. 2007; Bhardwaj et al. 2007; Athar et al. 2007). In
case of human breast cancer cells resveratrol inhibited the anti-apoptotic
phosphatidylinositol 3_-kinase (PI3K)/Akt pathway (Cecchinato et al.
2007), and activated the Forkhead transcription factor (FOXO3a) (Su et
al. 2007), which mediates cellular apoptosis through the activation of
proapoptotic genes (Su et al. 2007). In addition, in earlier studies, resver-
atrol had been proposed to downregulate the expression of tumorigenic
nuclear factor NF(B and its regulated proapoptotic gene products as well
as growth factors in multiple myeloma cells (Sun et al. 2006).
In addition to its anticancer activity, resveratrol has displayed benefi-
cial activity against inflammatory responses via inhibition of cyclooxyge-
nase 1 (COX1) and cyclooxygenase (COX2) expression (Kundu et al.
2006). Resveratrol was reported to reduce the production of
prostaglandin E2 (PGE2) and the formation of ROS in lipopolysaccha-
ride (LPS)-activated microglial cells (Candelario-Jalil et al. 2007; Kim et al.
2007). Moreover, resveratrol was reported to suppress the activity of T-
and B-cells, and macrophages (Sharma et al. 2007). Singh et al (2007)
showed that resveratrol induced both caspase-dependent and caspase-
independent apoptosis in activated T-cells in experimental allergic
encephalomyelitis- induced mice. One study from our own laboratory
showed that resveratrol possesses analgesic property by inhibition of
COX1 and COX 2 (Bertelli et al. 2008).
Resveratrol also possesses neuroprotective properties. It has been
reported that resveratrol could protect against Huntington’s disease
(Parker et al. 2005), Alzheimer’s disease (Marambaud et al. 2005) and
Parkinson’s disease (Karlsson et al. 2000).
RESVERATROL AND LONGEVITY
A significant number of reports exist in the literature indicating that
resveratrol can activate the longevity assurance genes, Sirtuins (SirTs)
(Miyazaki et al. 2008; Borra et al. 2005; Kaeberlein et al. 2005; Jiang 2008;
Guarente 2007). Resveratrol was shown to extend the life span in
Drosophila (Griswold et al. 2008) and C. elegans (Gruber et al. 2007) as
well as in vertebrates such as short-lived fish Northobranchius (Terzibasi
et al. 2007). Bauer et al. showed for the first time that resveratrol could
extend life span in case of mammals also (Baur et al. 2006), In this study,

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484
high-calorie diets (60% of calories from fat) induced obesity, triggering
an inflammatory response and comorbidities, such as diabetes and ath-
erosclerosis, which decreased the life span in case of middle-aged (1-year-
old) mice, but resveratrol treatment (22.4 mg/kg/day) along with the
high-fat diets extended the life span by inducing Sirt1 similar to calorie-
restricted animals with greater SIRT1 coexpression (Nisoli et al. 2005).
Evidence is available to show the positive effects of resveratrol and SIRT1
activation on several age related disorders including type 2 diabetes, car-
diovascular disease, neurodegeneration, and inflammation (Baur and
Sinclair. 2006; Pearson et al. 2008; Lagouge et al. 2006; Milne et al. 2007).
Resveratrol increases longevity through SirT1, which is activated with
NAD+supplied by an anti-aging enzyme pre B cell-enhancing factor
(PBEF). SirT1 interacts with an anti-aging transcription factor, forkhead
box protein O1 (FoxO1), which is negatively regulated by Akt. We have
shown in one of our recent studies that resveratrol induced the activation
of SirT1, SirT3, and SirT4, and the phosphorylation of FoxO1 and fprk-
head box protein O3a (FoxO3a) as well as PBEF proteins (Mukherjee et
al. 2009). This study also showed that red wine and white wine induced
SirT1, SirT3, SirT4 and PBEF proteins as well as the phosphorylation of
FoxO1 and FoxO3a due to the presence of the common component
resveratrol (Mukherjee et al. 2009). Thus, resveratrol and red wine can
provide protection against age-related cardiac diseases.
MOLECULAR TARGETS OF RESVERATROL
In the vast majority of cases, resveratrol displays inhibitory/stimulato-
ry effects in the micromolar range, which is potentially attainable phar-
macologically. It appears that resveratrol, as a pharmacological agent, has
a wide spectrum of targets. The biological activities of resveratrol may
thus be dependent on its simultaneous activities on multiple molecular
targets. Cancer and inflammation are critically linked, and among the
enzymes that synthesize proinflammatory mediators from arachidonic
acid are the cyclooxygenases and lipooxygenases (COX and LOX)
(Aggarwal et al. 2006). Different studies demonstrate that resveratrol can
inhibit both 5-lipooxygenase and cyclooxygenase enzymes. The synthesis
of proinflammatory molecules by COX and LOX is an important step for
the initiation of tumorogenesis. Thus, the inhibitory effects of resveratrol
on COX/LOX catalytic activities are highly relevant to cancer chemo-
prevention (Subbaramaiah and Dannenberg 2003). Kinase is the other
enzyme family, which is moderated by resveratrol. It is known that resver-
atrol can inhibit tyrosine kinase (p56lck) and serine/threonine kinase
(PKC, with both ( and ( isoforms present in a mixture) (Jayatilake et al.,
1993). Resveratrol can inhibit both protein kinase C (PKC) and protein
kinase D (PKD). Inhibition of PKC isoforms by resveratrol is related to
growth inhibition and induction of apoptosis in various cancer cell mod-

Dose dependency of Resveratrol
485
els, including gastric cancer cells (Atten et al. 2005) and prostate cancer
cells (Stewart and O’Brian 2004). The inhibition by resveratrol of the
activities of receptor tyrosine kinases and Src kinase may be relevant to its
antitumor activity. Study on HER-2/neu transgenic mice has further
expanded the concept that chemopreventive activity of resveratrol is due
to targeting tyrosine kinase cascades (Muller et al. 1988). Another major
target of resveratrol is the mitogen-activated protein kinase (MAPK) fam-
ily, including the extracellular signal regulated kinases (Erk1/2) and the
stress activated kinases JNK1/2 and p38 MAPK. Resveratrol (30–50 (M)
inhibited endothelin-1 induced Erk1/2 enzymatic activity and Erk1/2,
JNK and p38 MAPK phosphorylation in coronary artery smooth muscle
cells (El-Mowafy and White 1999), thus suggesting a partial mechanism
for the beneficial cardiovascular effects of resveratrol. Since resveratrol
also acts as a cancer chemopreventive molecule and PI3K/PKB virtually
always activated in tumors, it can be expected that it resveratrol might
have an impact on the PI3K/PKB signaling pathway (Hennessy et al.
2005). Further studies on the inhibitory potential of resveratrol on can-
cer cells might eventually define PI3K as a target of resveratrol in cancer.
The improvement of insulin sensitivity due to long-term treatment with
resveratrol in mice was associated to AMPK phosphorylation (Baur et al.
2006). Furthermore, in a recent report resveratrol was shown to stimulate
glucose transport in C2C12 myotubes via adenosine monophosphate-acti-
vated protein kinase (AMPK) activation (Park et al. 2007). Sirtuin is
another potential target of resveratrol. Resveratrol activates Sirt1, which
is responsible for its life extending properties (Kaeberlein et al. 2005;
Borra et al. 2005). Besides the action of resveratrol on COX/LOX, kinas-
es and sirtuins, several other resveratrol targets have been identified, such
as ribonucleotide reductase, adenylyl cyclase, quinone reductase 2, aro-
matase and DNA polymerases (Pirola and Frojdo 2008) (Figure 2).
DOSE DEPENDENCY OF RESVERATROL
From the previous discussion it should be clear that resveratrol pro-
tects human health through chemoprevention to cardioprotection.
Resveratrol provides protection against cancer, cardiovascular diseases,
ageing related diseases and also possess chemoprotective, neuroprotec-
tive, anti-inflammatory properties. In case of myocardial injury and age-
ing related diseases, resveratrol protects cells from apoptosis thereby
working as an anti-apoptotic agent whereas in cancer prevention, resver-
atrol kills the cancer cell by inducing apoptosis, thus working as a pro-
apoptotic agent. So resveratrol can function both as pro-apoptotic and
anti-apoptotic agents. Here the question arises, how resveratrol can func-
tion as both pro-and anti-apoptotic agents?
Careful review of the studies on cancer prevention with resveratrol
reveals that in each case, resveratrol was used at high concentration/dose

S. Mukherjee and others
486
[10-40 mM] (Frémont et al. 1999; Bhat and Pezzuto 2001; Dong and Ren
2004; Aggarwal et al. 2004; Lee and Lee 2006). In contrast resveratrol pro-
tects hearts in a relatively low dose [5-20 µM](Penumathsa and Maulik
2009; Xi et al. 2009; Das et al. 2006a; Kaga et al. 2005). This would tend to
indicate that resveratrol provides diverse health benefits in a dose-
response manner. In this section, we will discuss the importance of such
dose dependency of resveratrol in providing health protection. There are
quite a few studies to describe the dose dependency of resveratrol towards
health benefit.
Wilson et al. (1996) showed that high dose [1 mg/kg] of resveratrol
promotes atherosclerosis in case of hypercholesterolemic rabbits. They
showed that resveratrol treatment did not adversely affect rabbit health
other than promoting atherosclerosis. Both control and high dose [1
mg/kg] of resveratrol-treated groups showed similar body weight, food
consumption, liver weight, serum chemistry profile or serum enzyme
activities, lipoprotein concentration and LDL oxidation. In contrast to
the anti-atherosclerotic effect for resveratrol, this study suggested that
oral administration of high dose [1mg/kg] of resveratrol to hypercholes-
terolemic rabbits promotes atherosclerosis independent of difference in
gross animal health, liver disease, lipoprotein cholesterol concentration
(Wilson et al. 1996). In a study by Crowell et al. (2004), resveratrol [3000
mg/kg] caused renal toxicity when used in high concentration. Renal
tubule dilatation, papillary necrosis, acute pelvic inflammation and
increased incidence and severity of nephropathy were seen in the animals
treated with high dose of resveratrol. Oral administration of high dose
(3000 mg/kg bw/day) of resveratrol to the rats for 28 days resulted in
FIGURE 2. Molecular Targets of Resveratrol: as a pharmacological agent, resveratrol has wide spec-
trum of targets.

Dose dependency of Resveratrol
487
nephrotoxicity observed as elevated blood urea nitrogen (BUN) and cre-
atinine level, increased kidney weights, gross renal pathology changes
and an increased incidence and severity of histopathological changes in
the kidneys. Low dose of resveratrol [300 µg/kg] did not result in
nephrotoxicity. Animals treated with high dose also showed higher serum
alanine aminotransferase (ALT) and alkaline phosphatase levels, signifi-
cant lower hemoglobin concentration and lower red blood cell counts.
High dose [3000 mg/kg] of resveratrol treated rats also showed reduc-
tion in weight of heart, lung/bronchi than those of the low dose resvera-
trol treated group (Crowell et al. 2004). The above study suggests that
resveratrol causes renal toxicity when administrated in high dose. One
study from France shows that at higher dose (60 µM), resveratrol inhibits
the growth and induces apoptosis in case of both normal (60 µM) and
leukemic (5-43 µM) hematopoietic cells (Ferry-Dumazet et al. 2002). In
this study, the authors have shown that resveratrol induced a dose
dependent decrease in cell number and cell proliferation by inducing
apoptosis via activation of caspase cascade. Thus, resveratrol can be con-
sidered as an inhibitor for the human myeloid of lymphoid leukemic cell
growth at high dose (43 µM). Resveratrol can reduce cell growth and
induce apoptosis in case of normal cell when administered in high dose
(60 µM) (Ferry-Dumazet et al. 2002). Thus, resveratrol has biphasic
effects over low to high spectrum of concentrations. At low concentration
(5 (M), resveratrol appears to increase cell proliferation, whereas apop-
tosis is induced in various cancer cells at 15 (M or higher concentration.
It was also reported that resveratrol activates extracellular signal regulat-
ed kinase (ERK), a member of the mitogen-activated protein kinase
(MAPK) family and stimulates endothelial nitric oxide synthase (eNOS)
at low concentration (50 nM) in endothelial cell (Klinge et al. 2005). In a
recent study from Korea, the authors have shown that resveratrol induced
apoptosis in endothelial cells with increasing concentration (2.5-100 µM)
(Kyungmin and Park 2006). This clearly indicates that resveratrol at a
high dose/concentration has a strong pro–apoptotic effect on endothe-
lial cells. In contrast, resveratrol inhibits oxidized LDL- induced cytotoxi-
city when used in low concentration (Ou et al. 2006). In case of human
cancer cells (HT29, SW-620, HT-1080) and endothelial cells, resveratrol
enhances proliferation when used at low dose (0.1-1 (g/ml) and induces
apoptosis and decreases mitotic activity when used at high dose (10-100
(g/ml) (Szende et al. 2000). Cell numbers of human umbilical vein
endothelial cells (HUVEC) cells in culture were shown to be decreased
drastically at 10 (g /ml and 100 (g/ml concentration of resveratrol treat-
ment. Szende et al (2000) showed that 1 (g/ml of resveratrol exerted a
slight anti-proliferative effect but when resveratrol was used in a very
small concentration (0.1 (g/ml) proliferation was stimulated. Kyungmin
and Park (2006) showed that 100 (M resveratrol induced apoptosis by

S. Mukherjee and others
488
cleavage of caspase 3. They have also shown that resveratrol has an
inhibitory effect on cell migration. It is known that resveratrol induces
the activation of ERK and reduces the activation of JNK when used in low
dose (Klinge et al. 2005). In contrast, high dose of resveratrol stimulates
JNK activity in variety of cancer cells (She et al. 2002). In the same study,
Kyungmin and Park (2006) have shown that 100 (M resveratrol treatment
declines the basal levels of Akt and eNOS phosphorylation in endothelial
cell, indicating that resveratrol induces endothelial cell apoptosis and
inhibits endothelial migration at a high dose. It is known that resveratrol
can induce the activation of Akt and eNOS when used in low concentra-
tion (Dudley et al. 2008a). In another study with androgen–sensitive
prostate cancer cells, resveratrol showed a proliferative activity at a low
dose (5 (M), whereas it had a pro-apoptotic activity at a high dose (15 (M
or higher) (Signorelli and Ghidoni 2005). One group from Italy showed
the effect of resveratrol on some activities of isolated and in whole blood
human neutrophils. In this study, the authors have shown that in volun-
teers with normal low basal O2
- production resveratrol showed an
inhibitory activity only at high concentrations (10-2 mg/ml). In case of
volunteers with natural high basal O2
-production, resveratrol inhibited
superoxide anion generation at all concentrations (both in low and high
concentration) (Cavallaro et al. 2003). In another study, Acquaviva et al.
(2002) have shown that free radical-scavenging capacity of resveratrol
depends on concentration. They have shown that antioxidant properties
of resveratrol is increased with increasing concentrations of resveratrol,
which was monitored by measuring the free radical–scavenging capacity
of resveratrol with different concentration of resveratrol. It is known that
in human esophageal carcinoma cells, resveratrol induces apoptosis
when used in high concentration (100 mM/lit) and this high dose of
resveratrol also downregulated Bcl2 protein expression and upregulated
Bax protein expression in EC-9706 cells (Zhou et al. 2003). Mnjoyan and
Fujise (2003) investigated the role of resveratrol in cell cycle progression
and apoptosis of vascular smooth muscle cells (VSMCs). They have shown
that resveratrol inhibited the growth of human aortic VSMCs at low con-
centrations (1 (M). That was due to the profound dose-dependent inhi-
bition of DNA synthesis by resveratrol. This study has shown that resvera-
trol caused a dose-dependent increase in intracellular p53 and
p21WAF1/CIP1 levels. When used at lower concentrations (6.25–12.5 (M),
resveratrol effectively blocked cell cycle progression of serum-stimulated
VSMCs without inducing apoptosis, while at higher concentrations,
resveratrol (25 (M) selectively induced apoptosis in the same VSMCs.
Intriguingly however, the same high concentration of resveratrol could
not induce apoptosis in quiescent VSMCs (Mnjoyan and Fujise 2003).
Recently, Caddeo et al. (2008) showed that the effect of resveratrol on the
cell proliferation, cell viability of HEK 293 cell before and after UV-B irra-

Dose dependency of Resveratrol
489
diation is dose dependent. When the cells were incubated with 10 (M
resveratrol, it activated the metabolic activity of the cells, but in case of 50
(M resveratrol dose, a slightly deteriorative effect was observed and when
the cells were incubated with 100 (M resveratrol, the metabolic activity
was completely inhibited. They have also shown that resveratrol could
protect cells from UV-B radiation much better when used in lower dose.
In case of UV radiated HEK cells, it was shown that 100 (M resveratrol
suppressed cell proliferation, whereas in case of 10 (M resveratrol treat-
ment, the cell proliferation was higher (Caddeo et al. 2008). This study
indicates that resveratrol is much more photoprotective when used in low
dose. In an another study, Howitz et al. (2003) showed that the photo-
protective effect of resveratrol from radiation induced apoptosis in HEK
293 cells was reversed at concentrations greater than 50 (M. Caddeo et al.
(2008) also showed that at low concentration, resveratrol increased the
number of cells without any evidence of toxicity. In contrast, cells treated
with higher concentration of resveratrol showed loss of membrane
integrity due to polymerized actin degradation and impaired functional
status of cell (Caddeo et al. 2008).
Limited data exist regarding the adverse effects of resveratrol in
aging. Juan et al. (2002) have shown that in rats, oral administration of 20
mg/kg resveratrol for 28 days produced no harmful effects as assessed by
growth, hematology, clinical chemistry, and histopathology. In contrast,
higher amounts of resveratrol (1000, and 3000 mg daily for 28 days) were
shown to cause kidney damage (Crowell et al. 2004). Consumption of
resveratrol at a modest dose results in an increase in the life span in case
of 1 year old mice. However, when mice consumed larger doses (1800
mg/kg) of resveratrol, animals were shown to die within 3–4 months
(Pearson et al. 2008).
As we discussed in previous section, several studies have shown that
resveratrol possess biphasic function depending on dose. The cardiopro-
tective properties of resveratrol also appear to be dose-dependent. At lower
dose of 5 µM, resveratrol functions as an antioxidant, while at higher dose
it may function as a pro-oxidant (Dudley et al., 2008a). Our previous stud-
ies regarding cardioprotection of resveratrol showed that in low doses (5-10
µM), resveratrol functions as a cardioprotective agent (Penumathsa and
Maulik 2009; Xi et al. 2009; Das et al. 2006b; Kaga et al. 2005). Red wines and
white wines that contain resveratrol also possess cardioprotective properties
at low to moderate doses (10-15 µM) (Sato et al. 2004, Dudley et al. 2008b).
At low concentration, resveratrol (<10 (M) can protect the heart from
ischemia/reperfusion related injury by making the heart pharmacological-
ly preconditioned in a NO-dependent manner (Hattori et al. 2002), which
was further confirmed by a subsequent study, which showed that the same
concentration of resveratrol could not protect the heart from
ischemia/reperfusion induced injury in case of iNOS knockout mice

S. Mukherjee and others
490
(Imamura et al. 2002). It has been shown that 10 (M resveratrol could pro-
tect the heart by activating the survival signal through PI3-Kinase- Akt- Bcl2
signaling pathway (Das et al., 2005b) and through adenosine A(3) receptor
signaling, which accelerates the CREB phosphorylation through both Akt-
dependent and -independent pathways (Das et al. 2005b). In related stud-
ies, low doses of resveratrol (e.g., 10 (M or 2.5 mg/kg) protected the mam-
malian hearts from ischemia/reperfusion injury by activating the phase II
enzymes, HO-1 and Trx-1 and by Map Kinase signaling (Das et al. 2006b;
Das et al. 2006c). In a related study, it was shown that 2.5 mg/kg resveratrol
alleviated cardiac dysfunction in streptozotocin-induced diabetes by upreg-
ulating NO, thioredoxin, and heme oxygenase and MnSOD activity
(Thirunavukkarasu et al. 2007). A specially designed study to determine the
optimal concentration of resveratrol where the authors showed that there
were no effects on ventricular function at 3.7 and 7.4 (M resveratrol, nor
did any effect on myocardial infarct size. The maximum beneficial effect of
resveratrol was noticed at 10 (M resveratrol. The higher dose (25 (M) of
resveratrol still exerts cardioprotective effects, but the effects tend to be
slightly reduced (Das et al, 2006c). In a more recent study, we randomly
assigned the rats in five groups: control group (vehicle treated), low dose
groups (treated with 2.5 mg/kg and 5.0 mg/kg resveratrol) and high dose
groups (treated with 25 mg/kg and 50 mg/kg resveratrol). All rats were
gavaged with either vehicle or different doses of resveratrol for 14 days.
After 14 days of gavaging all rats were sacrificed and isolated hearts were
perfused by working heart method in a working heart apparatus. All the
hearts were subjected to 30 min ischemia followed by 2h reperfusion to
examine the effects of different doses of resveratrol in ischemia/reperfu-
sion induced cardiac injury. We have shown in this paper (Dudley et al.
2008a) that post ischemic cardiac functional parameters were improved by
resveratrol treatment only at low doses (2.5 and 5 mg/kg). High dose
resveratrol (25 and 50 mg/kg) significantly reduced the recovery of func-
tional parameters like aortic flow, LVDP (left ventricular developed pres-
sure), and LVdp/dt (First Derivative of Left Ventricular Developed
Pressure). Cardiomyocyte apoptosis and myocardial infarction due to
ischemia/reperfusion injury were reduced only in the low doses of resver-
atrol treatment, but not with high doses resveratrol treatment. As resvera-
trol is a well known antioxidant, we determined the effects of different
doses of resveratrol on regulation of mRNA transcripts of some redox pro-
teins, which were directly related to cardioprotection, like Trx-1, Trx-2,
Grx-1 and Grx-2. These redox proteins play crucial role to maintain the
redox homeostasis in mammalian system. Our result showed that
ischemia/reperfusion reduced the level of mRNA transcript of these redox
proteins due to oxidative stress and low dose resveratrol could prevent this
reduction, whereas high dose resveratrol was unable to protect the reduc-
tion of redox protein mRNA transcript. Redox effector factor-1 (Ref-1) is

Dose dependency of Resveratrol
491
an important enzyme ubiquitously present in the mammalian system. Ref-
1 plays a major role in DNA base excision repair pathway (Evans et al. 2000;
Wilson and Barsky 2001)[2] D.M. Wilson III and D. Barsky, The major
human abasic endonuclease: formation, consequences, and repair of aba-
sic sites in DNA, Mutat. Res. 485 (2001), pp. 283–307. Article | PDF (720 K)
| View Record in Scopus | Cited By in Scopus (113) It also serves as a tran-
scriptional coactivator by stimulating the DNA binding activity of redox-
sensitive transcription factors such as AP-1, nuclear factor _B (NF_B), p53,
and cAMP response element binding protein (Xanthoudakis and Curran
1992; Huang and Adamson 1993). Consistently, Ref-1 enhanced Nrf2 bind-
ing to the ARE (Iwasaki et al. 2006), which in turn regulated the expression
of a variety of enzyme proteins (Chan 2000). A recent study showed that
ischemia/reperfusion could potentiate a rapid translocation of thioredox-
in-1 into the nucleus which then interacts with Ref-1, leading to the gener-
ation of a survival signal (Malik et al. 2006). The same author also showed
that Ref-1 induced a survival signal in ischemic heart via protein- protein
interaction between NF_B, Ref-1, Trx-1 and Nrf2. (Gurusamy et al. 2007)
Based on these studies we determined whether different doses of resvera-
trol could have diverse effects on Ref-1 profile in ischemic/reperfused
heart. We have shown that ischemia/reperfusion downregulated Ref-1
level, but resveratrol could induce Ref-1 expression, only at a low dose.
High dose resveratrol could not prevent the down-regulation of Ref-1 dur-
ing ischemia/reperfusion injury (Figure 3. Data taken from Dudley et al.
2008a). The above study suggested that low dose resveratrol activated Ref-
1 in ischemic heart and triggered Nrf-2 binding to ARE region and upreg-
ulated the expression of redox proteins like Trx and Grx. Upon ischemic
stress, these redox proteins translocate into nucleus and bind with Ref-1,
leading to activation of a survival signal to protect the heart. At low dose,
resveratrol treatment can activate the survival signal by inducing Akt phos-
phorylation, which in turn activates Bcl2 and triggers cardiac cell survival
whereas the reverse is true for the high dose of resveratrol (Figure 4. Data
reproduced from Dudley et al. 2008a). Thus resveratrol appears to be dose-
dependent in providing cardioprotection. Table 2 shows the effects of low
and high doses of resveratrol on health benefits. The precise reason for
generation of death signal at higher resveratrol dose is not clear. It is spec-
ulated that differential redox cycling of resveratrol between high and low
dose might be responsible for survival and death signal. Resveratrol con-
tains two phenol groups in it. A study by Boyer et al. (1988) showed that
phenol reduces Fe3+ to Fe2+. Iron plays a crucial role in free radical reac-
tions leading to iron–oxygen complexes that remove hydrogen atoms from
the polyunsaturated fatty acid membrane (Minotti and Aust 1989;
Sotomatsu et al., 1990; Rice-Evans and Burdon 1993). Miura et al. (2000)
found that resveratrol possesses both antioxidant and pro-oxidant effects.
Resveratrol promoted the reduction of Fe3+ by increasing the formation of

S. Mukherjee and others
492
hydroxyl radicals through the Fenton reaction producing hydroxyl radicals
and iron species (Yamazaki and Piette 1990). At higher doses, resveratrol
causes DNA strand breakage by the accumulation of reduced ADP-Fe3+ in
the presence of hydrogen peroxide. Fukuhara and Miyata (1998) found
that resveratrol could bind to DNA and promoted DNA plasmid cleavage
FIGURE 3. Effects of high and low doses of resveratrol on the myocardial infarct size and cardiomy-
ocyte apoptosis (Graphs are re-plotted from Dudley et al., 2008a). Myocardial infarction and car-
diomyocyte apoptosis were measured by TTC method and TUNEL method respectively.
FIGURE 4. Effects of low and high doses of resveratrol on the expression of some survival pathway
members like Akt, Bcl2 and Ref-1 (Graphs are re-plotted from Dudley et al., 2008b). Expression of
different proteins was measured by western blot technique. *p <0.05 vs. control; † p<0.05 vs. I/R.

Dose dependency of Resveratrol
493
TABLE 2: Effects of Low and High Doses of Resveratrol on Health Benefits.
Does of
resveratrol used Effects of resveratrol in health benefits References
50 nM Induces eNOS activity and activates ERK. Klinge at al. 2005
0.15/0.25 μM Inhibits collagen- induced platelet activation, Shen et al. 2007
phosphoinositide breakdown and protein
kinase C activation.
5 μM Increases cell proliferation. Jang et al. 1997,
Inhibits oxidized LDL- induced cytotoxicity in Ou et al. 2006,
HUVEC cells. Signorelli and
Increases cell proliferation in androgen sensitive Ghidoni 2005
prostate cancer cells.
6.25-12.5 μM Blocked cell cycle progression of serum-stimulated Mnjoyan and
VSMC without inducing apoptosis. Fujise 2003
10 μM Activates metabolic activity and proliferation in Caddeo et al. 2008,
HEK 293 cells. Hattori et al. 2002,
Improves cardiac functions after ischemia/ Das et al. 2005a,
reperfusion injury. Das et al. 2006a
Protects the heart from I/R related injury by making
the heart pharmacologically preconditioned.
Activates survival signal members like Akt Bcl-2
Activates phase II enzymes, HO-1, Trx-1,
Map kinase signal.
25 μM Exerts lesser degree of cardioprotection. Das et al. 2006b
1 mM Inhibits breast cancer progression in both Su et al. 2007
estrogen-positive and estrogen-negative
breast cancer cells.
1-10 mM Induces HO-1 in primary neuronal cultures Juan et al. 2005,
and aortic smooth muscle cells. Zhuang et al. 2003
0.1-1 μg/ml Enhances proliferation of human cancer cells Szende et al. 2000
and endothelial cells.
2.5 mg/kg bw Increases longevity through induction of proteins Mukherjee et al. 2009,
like Sirt, FoxO, and PBEF. Dudley et al. 2008a,
Induces the activation of Akt, eNOS. Das et al. 2006c,
Activates phase II enzymes, HO-1, Trx-1, Thirunavukkarasu
Map kinase signal. et al. 2007
Alleviates cardiac dysfunction in streptozotocin-induced
diabetes by up regulating nitric oxide, thioredoxin,
HO-1, MnSOD activity.
2.5-5 mg/kg bw Improves post ischemic cardiac functions. Dudley et al. 2008a
Increase LVDP, LV dp/dt Xanthoudakis and
Reduces myocardial infarction, cardiomyocytes Curran 1992
apoptosis. Huang and
Induces expression of redox gene Adamson 1993,
like Trx-1,Trx-2, Grx-1, Grx-2 Gurusamy et al. 2007
Increase the expression of Ref-1, Nrf2, NF_B, p53.
22.4 mg/kg bw Extends the life span, in case of high-calorie diets Nisoli et al. 2005
induce mice, by overexpressing SIRT1.
>5-100 μM Induces apoptosis in activated T-cells in experimental Singh et al. 2007
allergic encephalomyelitis- induced mice.
15 μM or more Induces apoptosis in various cancer cells. Jang et al. 1997,
Exhibits pro-apoptotic activity. Signorelli and
Ghidone 2005
cont.

S. Mukherjee and others
494
in presence of Cu2+ under aerobic conditions and neutral pH. Resveratrol
also reduces Cu2+ to Cu+in the presence of the reactive oxygen species.
CONCLUSION
There are numerous plant-derived natural components, vitamins and
minerals whose daily allowance requirement are safe and promote good
health when taken at a low dose. When the same substances are taken at
a high dose, they become toxic and produce adverse effects to the cells at
the subcellular levels. Similarly resveratrol is good for health but the
health benefit of resveratrol is dose-dependent. Low doses resveratrol
protect health from different types of diseases, while high doses resvera-
TABLE 2: continued.
25 μM Selectively induces apoptosis in the human Mnjoyan and
aortic VSMCs. Fujise 2003
25-100 μM Inhibits cell growth and proliferation by inducing Ferry-Dumazet et al.
apoptosis in both leukemic hematopoietic cells. 2002
50 μM Reduces the proliferation of human multiple myeloma. Bhardwaj et al. 2007
50-100 μM Inhibits metabolic activity and cell proliferation. Caddeo et al. 2008
50 μM-400 μM Shows a marked inhibitor y potential on cancer cell Hwang et al. 2007
proliferation in the presence of etoposide.
100 μM Induces apoptosis by cleavage of caspase 3, Kyungmin and
declines the basal levels of Akt and eNOS Park 2006
phosphorylation in endothelial cell.
>20 mM Reduces NF_B activation and inhibits HO-1 Juan et al. 2005
expression in neuronal cultures.
50 mM Induces cell death in mouse xenograft models van Ginkel et al. 2007
of human neuroblastoma (SH-SY5Y, NGP
and SK-N-AS) cells.
100 mM Induces cell death in human colorectal cancer cells Trincheri et al. 2007
(DLD1and HT29 cells). Zhou et al. 2003
Induces apoptosis, downregulates Bcl2 protein
expression and upregulates Bax protein expression
in human esophageal carcinoma cells (EC-9706 cells).
10-100 ug/ml Induces apoptosis and decreases mitotic activity in case Szende et al. 2000
of human cancer cells (HT29, SW-620, HT-1080)
and endothelial cells.
1 mg/kg bw Induces atherosclerosis in case of hypercholesterolemic Wilson et al. 1996
rabbits.
10 mg/kg bw Reduces cancer progression. Su et al. 2007
>25 mg/kg/bw Unable to induce post ischemic cardiac functions after Dudley et al. 2008b
ischemia/reperfusion injury. Reduces LVDP, LV dp/dt.
Unable to protect myocardial infarction, cardiomyocytes
apoptosis.
Reduces expression of redox gene
like Trx-1,Trx-2, Grx-1, Grx-2
Reduces the expression of Ref-1, Nrf2, NF_B.
625 mg/kg bw Reduces the progression of prostate cancer Harper et al. 2007
in transgenic adenocarcinoma prostate (TRAMP) mice.
3000 mg/kg bw Induce renal toxicity. Crowell et al. 2004

Dose dependency of Resveratrol
495
trol can be detrimental for health. However, high dose resveratrol may be
required in pathological conditions such as destroying cancer cells.
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