Resveratrol: A Unique Antioxidant Offering a Multi-Mechanistic Approach for Treating Aging Skin

Abstract

Resveratrol is a botanical antioxidant with diverse biologic effects. In this paper we will review the unique antioxidant activity of resveratrol including its effects on mitochondrial function. The molecular signaling of resveratrol and cellular mechanisms that make this botanical active an important anti-aging ingredient for topical application will be discussed.

J Drugs Dermatol. 2013;12(12):1389-1394.

Full text

December 2013 1389 VOLUME 12 • ISSUE 12
Copyright © 2013 ORIGINAL ARTICLE Journal of Drugs in Dermatology
Resveratrol: A Unique Antioxidant Offering a
Multi-Mechanistic Approach for Treating Aging
Skin
Patricia Farris MD,a,b Jean Krutmann MD,h Yuan-Hong Li MD PhD,i
David McDaniel MD,c,d,e,f,g and Yevgeniy Krolj
aDepartment of Dermatology, Tulane University, New Orleans, LA
bOld Metairie Dermatology, Metairie, LA
cMcDaniel Laser and Cosmetic Center and McDaniel Institute of Anti Aging Research, Virginia Beach, VA
dDepartment of Dermatology, Eastern Virginia Medical School, Hampton, VA
eHampton University Skin of Color Research Institute, Hampton, VA
fSchool of Science, Hampton University, Hampton, VA
gDepartment of Biological Sciences, Old Dominion University, Norfolk, VA
hIUF – Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
iDepartment of Dermatology, No.1 Hospital of China Medical University, Liaoning, Shenyang, China
jSkinCeuticals Inc., New York, NY
ABSTRACT
Resveratrol is a botanical antioxidant with diverse biologic effects. In this paper we will review the unique
antioxidant activity of resveratrol including its effects on mitochondrial function. The molecular signaling of
resveratrol and cellular mechanisms that make this botanical active an important anti-aging ingredient for
topical application will be discussed.
J Drugs Dermatol.
2013;12(12):1389-1394.
INTRODUCTION
Resveratrol (3,5,4’-trihydroxystilbene) was first isolated from the roots of white hellebore (
Veratrum
grandiflorum O. Loes
) and later from the roots of
Polygonum cuspidatum
.(1) This plant has long been used in
Chinese and Japanese medicine where it is valued for diverse therapeutic effects. Resveratrol is a natural
polyphenolic antioxidant of the stilbene family that is found in more than 70 plant species. Some of the more
common botanical sources include berries, peanuts and grapes. Resveratrol is a major constituent of red
wine as it is present in the skin of red grapes and concentrates as wine ferments. In nature, resveratrol is a
phytoalexin, which functions to protect plants from stress, ultraviolet light and certain fungal infections.
Medical interest in this compound sparked when it was postulated that resveratrol may be responsible for the
low incidence of heart disease seen in the French population whose diet is high in saturated fat.2 This
phenomenon, coined by Dr. Serge Renaud and Dr. Michel de Lorgerial as the French Paradox, was
attributed to a moderate intake of red wine. Since that time, resveratrol has been the subject of vigorous
ongoing research to confirm its health and anti-aging benefits. Studies have shown that resveratrol binds to
numerous cell-signaling molecules allowing it to modulate beneficial health effects through multiple
pathways.4 Resveratrol has anti-diabetic, anti-inflammatory and anti-cancer activity.3-5 It also acts as a
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.

vasodilator, platelet inhibitor and has important cardioprotective effects.6 Recent studies have suggested that
resveratrol may also be effective when applied topically to treat aged skin. In this review we will therefore
describe some of the important targets of resveratrol, their clinical implications for treating aging skin and the
challenges that have prevented resveratrol from being effectively incorporated into a topical formulation.
Resveratrol as an Antioxidant
Resveratrol is probably most recognized for its potent antioxidant activity. One of the more distinct features of
this polyphenol is that it exhibits dual antioxidant capacity. In addition to directly scavenging free radicals
resveratrol increases the intracellular expression of other naturally occurring enzymatic antioxidants.
Specifically, resveratrol up-regulates expression of nuclear factor-E2-related factor-2 (Nrf2), a transcription
factor, which regulates several genes responsible for detoxification of reactive oxygen species.7 For example,
Nrf2 is known to increase the production of glutathione synthetase (GSH), the enzyme that is the rate limiting
step in the synthesis of the antioxidant glutathione. Additionally, resveratrol has been shown to boost
naturally occurring enzymatic antioxidants including superoxide dismutase, catalase and hemoxygenase-1
thus increasing intracellular antioxidant capacity.8 The direct free radical scavenging properties of pure
resveratrol are well established and appear to be greatly dependent on the structural position of the hydroxyl
group.9 Studies have determined resveratrol to be an effective scaven-
ger of hydroxyl, superoxide and metal induced radicals.10 Finally, resveratrol prevents lipid peroxidation by
chelating copper and by working synergistically with antioxidants such as vitamin E.11 These combined
effects make resveratrol a unique antioxidant capable of both scavenging free radicals on its own and
increasing intrinsic antioxidant capabilities.
Resveratrol and Mitochondrial Function
Mitochondria are the organelles primarily responsible for generating cellular energy in the form of adenosine
triphosphate (ATP). Production of ATP involves a number of complex redox reactions that generate reactive
oxygen species as a byproduct. Multiple features of the mitochondria are unique; in contrast to other cellular
components whose DNA is found inside the nuclear envelope, the mitochondria has its own genome
localized to its innermost membrane. As of the main sources of endogenous reactive oxygen species,
mitochondria are very susceptible to oxidative damage, which can deteriorate the organelle’s function and
promote apoptosis. Mitochondrial DNA (mtDNA) is especially vulnerable to attack by reactive oxygen species
because of its proximity to ROS production, the lack of protection offered by histones and relatively slow
repair, as compared with nuclear DNA. Mitochondrial dysfunction is often attributed to various disease
pathologies along with the aging process.12 Resveratrol exhibits multiple properties beneficial for
mitochondrial vitality. Specifically, this phytoalexin promotes mitochondrial biogenesis and reduces
mitochondrial reactive oxygen species generation.13,14 Accordingly, there has been extensive research on
the use of resveratrol as anti-aging agent. This notion is supported by the fact that resveratrol effects appear
to mimic the health benefits of caloric restriction including reducing age related diseases such as cancer,
heart disease, diabetes, neurodegenerative disease and enhancing longevity in vitro and in organisms
ranging from worms through mice.15 The SIRT1 and Nrf2 pathways are two of the more widely studied
pathways associated with resveratrol’s biologic action and continue to be linked with its anti-aging potential.
It is now known that both dietary restriction and resveratrol exert their beneficial effects on health and
longevity by activating an important group of enzymes called sirtuins. Landmark resveratrol studies on
longevity showed that it was able to extend lifespan in yeast, fruit flies and worms. Sirtuins were first
discovered in yeast and have recently been identified in mammals.16 There are seven mammalian sirtuins
the most important of which is sirtuin 1 (SIRT1). SIRT1 is a NAD-dependent deacetylase that turns on and off
certain transcription factors that are essential for survival during times of stress. Resveratrol works by
activating SIRT1 that deacetylates peroxisome proliferator activator gamma co-activator 1 alpha (PGC-1α)
causing an increase in its activity.17,18 PGC-1α induces transcription of genes that regulate gluconeogenesis
and lipid metabolism. In addition, resveratrol through SIRT1 and PGC-1α increases mitochondrial function
and has a positive impact on energy homeostasis. Animal research established that resveratrol protects mice
against diet induced obesity and insulin resistance by increasing SIRT1 activity.19 Studies have confirmed
that similar mechanisms are in play in humans. One of the noteworthy human studies tested supplementation
with resveratrol for 30 days in obese males resulting in improved skeletal muscle mitochondrial function and
fat oxidative capacity that was not associated with weight loss. SIRT1 protein levels in skeletal muscle were
observed and fasting plasma glucose and insulin levels were decreased in test subjects receiving
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.

resveratrol.20 In addition, SIRT1 modulates DNA repair, gluconeogenesis, cell-cycle regulation, lipid
metabolism, insulin sensitivity, fat mobilization, cell survival and lifespan.21 Studies of multiple compounds
known to affect SIRT1 revealed that resveratrol is among the most potent natural sirtuin activators.22
More recent studies demonstrated that resveratrol prevents mitochondrial dysfunction and confers
cytoprotective benefits via the Nrf2 pathway.23 Since diminished mitochondrial function is associated with
reduced longevity, the ability of resveratrol to enhance mitochondrial function may be a key mechanism for its
anti-aging effects. At steady state, inactive Nrf2 is associated with Kelch-like erythroid cell-derived protein 1
(Keap-1) in the cytoplasm. Once activated, Nrf2 dissociates from Keap-1 and translocates to the nucleus
where it binds the antioxidant response element (ARE) initiating the cellular response to oxidative stress.
(Figure 1) While the exact method of Nrf2 translocation is unclear, it has been shown that under conditions of
oxidative stress, Nrf2 exhibits greater nuclear accumulation and transcriptional activity.24 The increase in the
Nrf2 induced gene expression will prompt the antioxidant defense response in order to maintain cellular
redox homeostasis.25 Resveratrol is believed to work in similar ways by stimulating the Nrf2 pathway,
promoting the subsequent translocation of Nrf2 into the nucleus, leading to downstream increase in
expression of Nrf2 target genes, specifically heme oxygenase-1 (HO-1).26
HO-1, along with the other genes, will subsequently activate the antioxidant defense system needed to
protect cellular components, especially the mitochondria, from oxidative damage. Studying cultured
endothelial cells, Zoltan Ungvari (2009) was able to demonstrate that resveratrol’s activation of Nrf2 induced
naturally occurring enzymatic antioxidants leading to significant reduction of mitochondrial oxidative stress.28
Other studies have linked resveratrol action with the Nrf2 pathway by demonstrating its protective role of
human epithelial cells.29
Resveratrol as a Chemoprotector
Within the last decade, a large portion of resveratrol medical research has focused on its potential as a
chemopreventive agent. Resveratrol exerts anti-tumor activity by affecting all three stages of tumor formation
including initiation, promotion and progression.30 The stilbene induces apoptosis of tumor cells by down
regulating expression of the inhibitor of apoptosis gene survivin and by inducing expression of the tumor
suppressing p53.31 Furthermore, studies have demonstrated that resveratrol has both in vivo and in vitro
cytotoxic activity against melanoma cells.32 Animal studies have also confirmed that topically applied
resveratrol inhibits non-melanoma skin cancer formation. Mice which were irradiated with daily UVB and had
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.

either pre- or post-treatment with topical resveratrol showed a delay in the onset of tumor formation and the
incidence of tumors.33 The fact that post-treatment with resveratrol conferred benefits similar to pre-treatment
demonstrates that chemoprevention is not due to the sunscreen effects. Other studies demonstrated that pre-
treatment of mouse skin with topical resveratrol reduced UVB-induced edema, erythema and leukocyte
infiltration and inhibited COX2 expression and ornithine decarboxylase activity.34 These studies suggest that
resveratrol may confer an added benefit through its anti-inflammatory activity.
"Studies have shown that resveratrol binds to numerous cell-signaling molecules allowing it to modulate
beneficial health effects through multiple pathways."
Resveratrol and Skin Aging
Skin aging is a complex sequence of events that reflects the changes occurring in both natural (intrinsic) and
extrinsic aging. While the clinical stigmata of natural aging differ significantly compared to extrinsic or
photoaging, the cellular and molecular mechanisms are similar. Skin aging is thought to be driven by an
increased in-situ production of reactive oxygen species (ROS), which result from both a disturbance of
mitochondrial function and acute stress responses to different environmental insults including solar
radiation.35 There is also good evidence that intrinsic as well as extrinsic skin aging are associated with a
depletion of naturally occurring antioxidants that serve as a defense mechanism against free radical
damage.36 When left unchecked, ROS can directly damage cell membranes, proteins and DNA. In addition,
ROS turn on cellular and molecular mechanisms that accelerate skin aging including up regulation of
transcription factors such as activator protein 1 (AP-1) and nuclear factor-kB (NF-kB).37,38 AP-1 is one of the
prominent transcription factors responsible for the production of metalloproteinases (MMPs), the enzymes
that break down collagen. The essential role of MMPs in promoting premature skin aging has been
demonstrated in pivotal scientific studies.39 Furthermore, multiple studies have shown that the decrease in
collagen production is associated with AP-1 and may involve the cytokine transforming growth factor beta
(TGF-β).40,41 This cumulative loss of dermal collagen is believed to be the primary cause of wrinkling.
Likewise, NF-kB is paramount in the production of pro-inflammatory mediators that contribute to skin
aging.42,43 In vitro studies have demonstrated that resveratrol effectively down regulates both AP-1 and NF-
kB and thus serves a key role in preserving dermal collagen and reducing skin inflammation.44,45
The stilbene chemical structure of resveratrol is similar to that of the synthetic estrogen diethylstilbesterol. In
view of this it is not surprising that resveratrol is a phytoestrogen and estrogen beta receptor agonist (ERβ).46
Post-menopausal women are known to lose collagen at a rate of 1% per year causing skin to become thin,
wrinkled and fragile.47 Estrogen replacement therapy mitigates collagen loss and improves the clinical signs
of skin aging. The use of phytoestrogens such as resveratrol, are of particular interest since they may provide
the skin benefits of estrogen without the associated risks.
Resveratrol also has potential use as a skin lightener. Studies have demonstrated that resveratrol and other
stilbenes have potent tyrosinase inhibitory activity.48 This activity has been shown to be a function of
chemical structure of the stilbenes including a double bond that is present in the parent molecule.49,50 In
view of these diverse properties, resveratrol provides a multi-mechanistic approach that makes it a
remarkably promising agent for the treatment of various skin aging symptoms.
Bioavailability, Formulation and Delivery of Resveratrol
While the inherent potential of resveratrol is undeniable, there are several challenges that prevent its broader
utilization in treating skin conditions. Resveratrol is absorbed quickly after oral ingestion with peak plasma
levels 30 minutes after consumption. 51 Up to 70% of resveratrol is bioavailable in the plasma after
absorption but rapid enterohepatic metabolism significantly reduces that level. Orally ingested resveratrol is
excreted primarily by the kidney and only a small fraction that is ingested reaches the tissues of various
bodily organs. This is especially problematic for skin tissue since it is the outermost organ of the body.
Multiple studies have attested to the challenges of systemic administration of resveratrol attributing this
difficulty to rapid metabolism and an inability to sustain meaningful plasma concentration.52 Researchers
have suggested that both naturally occurring and synthetic derivatives may be utilized to circumvent the issue
of rapid metabolism. Nonetheless, comprehensive clinical data on resveratrol derivatives is still under
investigation. Targeting resveratrol to the epidermal tissue via oral administration is clearly not the most
effective strategy to deliver this phytoalexin to the skin.
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.

Topical application of resveratrol represents a promising alternative to oral ingestion for use in treatment of
skin aging. In fact, while studying human keratinocytes cell lines, a collaboration of scientists at McGill
University and L’Oreal Open Research were able to confirm the existence of resveratrol binding sites located
in the epidermis.53 (Figure 2) Since topical applications are delivered directly to the affected area, this may
be an effective approach to combat resveratrol’s rapid metabolism and allow skin tissue to attain a
therapeutic concentration. However, utilizing a topical delivery system presents additional challenges. One of
the problems is specific to resveratrol’s strong photosensitivity. The polyphenol exists predominantly as two
isomers, cis-(Z)-resveratrol and trans-(E)-resveratrol. In this regard it is important to note that the trans-
isomer is more stable and biologically active.54
So to maximize the effect, resveratrol needs to be maintained as a trans-structural isomer. However,
Waterhouse et al 2009 demonstrated that UV irradiation (306 nm) caused approximately 90% isomerization
of trans-resveratrol to its less desired cis-isoform.55 (Figure 3) Resveratrol’s promise as a topical skin care
formulation may be severely limited by the consistent UV exposure of human skin. Unless protected from UV
rays by a broad-spectrum sunscreen or used exclusively in the evening, this instability caused by UV
irradiation will substantially diminish resveratrol’s biological activity.
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.

Furthermore, the physico-chemical properties of resveratrol have restricted its use in topical formulations.
One particular challenge is the stilbene’s relatively low water solubility, estimated around 0.05 mg/mL.56 This
property prevents incorporation of high concentrations of pure resveratrol into topical products. This is
supported by the fact that the leading topical resveratrol products often contain less that 1% of pure
resveratrol in the final formulation. Various solvents are often employed to increase the hydro-solubility of
solid ingredients. However, solubilizing agents may potentially introduce unknown and unwanted side effects.
Furthermore, resveratrol’s protonation state is integral to understanding the complexity of its biological role.
Studies have established that transport of resveratrol to the skin is limited by the type of vehicle used in the
formulation.57 Proper formulation parameters are essential since the ingredient is required to both escape
from its vehicle and penetrate the initial barrier to exert biologic action in the skin. Overcoming these
impediments is an area of ongoing resveratrol research that is essential for the development of effective
topical formulations.
CONCLUSION
Resveratrol is an important polyphenol with numerous known health benefits. Working through multiple
pathways this powerful antioxidant can improve the function of multiple organ systems including the skin.
Resveratrol holds great promise as a topical ingredient for treating skin as it can both prevent and improve
the clinical signs of aging. Many of its scientifically proven properties show great potential to ameliorate the
aesthetic problems of skin aging. However, further innovation is required to overcome the challenges to
effectively deliver resveratrol into the skin in order to transform this omnipotent extract into a proven
therapeutic product.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Christina Steel PhD for the critical reading and editing of this manuscript.
DISCLOSUREs
P.F. serves on the advisory board and has received consultancy fees from Beiersdorf, LaRoche
Posay/L’Oreal, L’Oreal Paris, NeoStrata Company, Skinceuticals/L’Oreal, and Skin- Medica; and is a
speaker/trainer for Allergan, Medicis. D.M. has grants/pending grants from Cynosure/Palomar, Fibrocell
Science, LifeSpan Extension, Skinceuticals/L’Oreal, US Cosmecuetechs, NorthCell Pharmaceutical, Allergan,
Priori SkinCare, Dr. Brandt® Skincare, Ulthera, BTL Aesthetics; has received consultancy fees from Allergan,
SkinCeuticals/ L’Oreal, Fibrocell Science; paid lectures fees from Fibrocell Science; and patents with
LifeSpan Extension, Cynosure/ Palomar, Light BioScience, Hampton University. J.K. has received
consultancy fees from SkinCeuticals/L’Oreal and paid lectures for SkinCeuticals/L’Oreal. Y.L. has received
consultancy fees from SkinCeuticals/L’Oreal. Y.K. is employed by SkinCeuticals/L’Oreal.
REFERENCES
Takaoka MJ. Of the phenolic substance of white hellebore (Veratrum grandiflorum Loes, fil.). J Faculty
Sci. Hokkaido Imperia University. 1940;3:1-16.
1.
Siemann EH, Creasy LL. Concentration of the phytoalexin resveratrol in wine. Am J Eno Vitic.
1992;43(1):49-52.
2.
Harikumar KB, Aggarwal BB. Resveratrol. A multitargeted agent for age-associated chronic diseases.
Cell Cycle. 2008;7(8):1020-1035.
3.
Su HC, Hung LM, Chen JK. Resveratrol, a red wine antioxidant, possessing an insulin-like effect in
streptozotiocin-induced diabetic rats. Am J Physiol Endocrinol Metab. 2006:290:1339-1346.
4.
Jang M, Cai L, Udeani Go, Slowing KV et al. Cancer chemopreventive activity of resveratrol, a natural
product derived from grapes. Science. 1997;275:218-220.
5.
Magyar K, Halmosi R, Palfi A, Feher G, et al. Cardioprotection by resveratrol: A human clinical trial in6.
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.

patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012;50(3):179-87.
Ungvari et al. Resveratrol increases vascular oxidative stress resistance. Am J Physiol Heart Circ
Physiol. 2007;292:H2417-H2424.
7.
Arikumar et al. Resveratrol: A multitargeted agent for age-associated chronic disease. Cell Cycle.
2008;7(8):1020-1035.
8.
Stojanovic S, Sprinz H, Brede O. Efficiency and mechanism of antioxidant action of trans-resveratrol
and its analogues in the radical liposome oxidation. Arch Biochem Biophys. 2001;391(1):79-89.
9.
Leonard SS, Xia C, Jiang BH, Stinetefelt, et al. Resveratrol scavenges reactive oxygen species and
effects radical-induced cellular responses. Biochem Biophys Res Commun. 2003;309(4):1017-26
10.
Fang JG, Lu M, Chen Zh et al. Antioxidant effects of resveratrol and its analogues against the free
radical induced peroxidation of linoleic acid in micelles. Chemistry. 2002;8(18):4191-4198.
11.
Wallace DC. Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen.
2012;51(5):440-450.
12.
Csiszar A et al. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart
Circ Physiol. 2009;297(1):H13-H20.
13.
Ungvari Z et al. Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial
cell. Am J Physiol Heart Circ Physiol. 2009;297(5):H1876-H1881.
14.
Baur JA. Resveratrol, sirtuins, and the promise of a DR mimetic. Mech Ageing Dev. 2010;131(4);261-
269.
15.
Dali-Youcef N, Lagouge M, Froelich S, et al. The “magnificent seven”: function, metabolism and
longevity. Ann Med. 2007;39(5):335-345.
16.
Gerhart-Hines et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation
through SIRT1/PGC-1 alpha. Embo J. 2007;26(7):1913-1923.
17.
Lagouge M, Argmann C, Gerhart-Hines, et al. Resveratrol improves mitochondrial function and
protects against metabolic disease by activating SIRT1 and PGC-1α. Cell. 2006;127(6):1109-1122.
18.
Barger JL, Kayo T, Vann JM, et al. A low dose of dietary resveratrol partially mimics calorie restriction
and retards ageing parameters in mice. Plos ONE. 2009;3(6):e2664.
19.
Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol
supplementation on energy metabolism and metabolic profile in obese human. Cell Metab.
2011;14(5):612-622.
20.
Michan S, Sinclair D: Sirtuins in mammals: Insights into their biological function. Biochem J.
2007;404(1):1-13.
21.
Howitz KT, Bitterman KJ, Cohen HY t al. Small molecule activators of sirtuins extend Saccharomyces
cerevisiae lifespan. Nature. 2003;425(6954);191-196.
22.
Ungvari Z et al 2010 Resveratrol confers endothelial protection via activation of the antioxidant
transcription factor NRF2. Am J Physiol Heart Circ Physiol. 2010;299(1):H18-H24.
23.
Nguyen T, Sherratt PJ, Nioi P, Yang CS, Pickett CB. Nrf2 controls constitutive and inducible
expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by
Keap1. J Biol Chem. 2005;280(37):32485-32492.
24.
25. Tufekci KU, Bayin EC, Genc S, Genc K. The Nrf2/ARE Pathway: A promising target to counteract
mitochondrial dysfunction in Parkinson’s Disease. Parkinsons Dis. 2010;2011:314082.
25.
26. Cheng AS, Cheng YH, Chiou CH, Chang TS. Resveratrol Upregulates Nrf2 Expression To
Attenuate Methylglyoxal-Induced Insulin Resistance in Hep G2 Cell. J Agric Food Chem.
2012;60(36):9180-9187.
26.
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.

Kim HJ, Vaziri ND. Contribution of impaired Nrf2-Keap1 pathway to oxidative stress inflammation in
chronic renal failure. Am J Physiol Renal Physiol. 2010;298(3):F662-671.
27.
Ungyari Z, Sonntag WE, Cabo R, Bauer JA, Csiszar A. Mitochondrial Protection by Resveratrol. Exerc
sport Sci Rev. 20122;39(3):128-132.
28.
Kode et al. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against
cigarette smoke-medicated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol
Physiol. 2008; 294(3):L478-L488.
29.
30. Aggarawal BB, Ghardwaj A, Aggarwal RS, et al. Role of resveratrol in prevention and therapy of
cancer; preclinical and clinical studies. Anticancer Res. 2004;24(5):2783-2840.
30.
Ulrich S, Wolter F, Stein JM. Molecular mechanisms of the chemopreventative effects of resveratrol
and its analogs in carcinogenesis. Mol Nutr Food Res. 2005;49(5):452-461.
31.
Osmund GW et al. Enhancing melanoma treatment with resveratrol. J Surg Res. 2010;2(1):109-115.32.
Aziz MH, Reagan-Shaw S, Wu J, et al. Chemoprevention of skin cancer by grape constituents
resveratrol: Relevance to human disease? FASEB J. 2005;(9)19:1193-1195.
33.
Afaq F, Adhami VM, Ahmad N Prevention of short-term ultraviolet B radiation-mediated damages by
resveratrol in SKH-1 hairless mice. Toxicol Appl Pharmacol. 2003;186(1):28-37.
34.
Krutmann J, Schroeder P: Role of mitochondria in photoaging of human skin: The defective
powerhouse moel. J Invest Dermatol Symp Proc. 2009;14:44-49.
35.
Sander CS, Chang H, Salzmann S, Muller CS, Ekanayake-Mudiyanselage S, Elsner P, et al.
Photaging is asscoaited with protein oxidation in human skin in vivo. J Invest Dermatol. (2002)
118:618-25
36.
Fisher GJ, Talwar HS, Lin J, P Lin, McPhillips F, Wang Z, Li X, Wan Y, Kang S, Voorhees JJ. Retinoic
acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of
mitogen-activated protein kinase pathways in human skin in vivo. J Clin Invest.
1998;101(6):1432–1440.
37.
Dhar A, Young MR, Colburn NH. The role of AP-1, NF-kappaB and ROS/ NOS in skin carcinogenesis:
the JB6 model is predictive. Mol Cell Biochem. 2002;234-235(1-2):185-193.
38.
Fisher GJ, Wang ZQ, Datta S,Varani J, Kang S, Voorhees JJ. Pathophysiology of premature skin
aging induced by ultraviolet light. N Engl J Med. 1997;337(20):1419-1428.
39.
Miyazaki Y, Tsukazaki T, Hirota Y, Yonekura A, Osaki M, Shindo H, Yamashita S. Dexamethasone
inhibition of TGF beta-induced cell growth and type II collagen mRNA expression through ERK-
integrated AP-1 activity in cultured rat articular chondrocytes. Osteoarthritis Cartilage. 2000;8(5):378-
385.
40.
Avouac J et al. Inhibition of activator protein 1 signaling abrogates transforming growth factor β-
mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum.
2012;64(5):1642-1652.
41.
Kaufman C and Fuchs E. It’s got you covered:Nf-kB in the epidermis. J Cell Biol. 2000;149(5):999-
1004.
42.
Tilstra JS et al. NF-kB inhibition delays DNA damage-induced senescence and aging in mice. J Clin
Invest. 2012;122(7):2601-2612.
43.
Kundu JK, Shin YK, Surh YJ, et al. Reveratrol modulates phorbol ester-induced pro-inflammatory
signal transduction pathways in mouse skin in vivo: NRkappaβ and AP-1 as prime targets. Biochem
Pharmacol. 2006;72(11):1506-1515.
44.
Adhami VM, Afaq F, Ahmad N. Suppression of Ultraviolet B Exposure-Mediated Activation of NF-kB in45.
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.

Normal Human Keratinocytes by Resveratrol. Neoplasia. 2003;5(1):74–82
Gehm BD, McAndrews JM, Chien PY, et al. Resveratrol, a polyphenolic compound found in grapes
and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci. USA 1997;94(25):14138-14143.
46.
Castelo-Branco C, Duran M, Gonzalez-Merlo J. Skin collagen changes related to age and hormone
replacement therapy. Maturitas. 1992;15(2):113-119.
47.
Newton RA, Cook AL, Roberts DW, Leonard JH, Sturm RA. Post-transcriptional regulation of melanin
biosynthesis enzymes by cAMP and resveratrol in human melanocytes. J Invest Dermatol.
2007;127(9):2216-2227.
48.
Ohguchi K, Tanka T, Ito T, et al. Inhibitory effects of resveratrol derivatives from dipterocarpaceae
plants on tyrosinase activity. Biosci Biotechnol Biochem. 200;67(7):1587-1589.
49.
Newton et al. Post-transcriptional regulation of melanin biosynthetic enzymes by cAMP and
resveratrol in human melanocytes. Invest Dermatol. 2007;127(9):2216-27.
50.
Goldberg DM, Yan J, Solease GJ. Absorption of three wine-related polyphenols in three different
matrices in healthy subjects. Clin Biochem. 2003;36(1):79-87.
51.
Cottart CH, Nivet-Antoine V, Laguillier-Morizot C, Beaudeux JL. Resveratrol bioavailability and toxicity
in humans. Mol Nutr Food Res. 2010;54(1):7–16.
52.
Bastianetto S, Dumont Y, Duranton A, Vercauteren F, Brenton L, Quirion R. Protective action of
resveratrol in human skin: Possible involvement of specific receptor binding sites. PLoS One.
2010;5(9):e12935 (McGill University and L’Oreal Open Research)
53.
Rius C et al. Trans- but not cis-resveratrol impairs angiotensin-II-mediated vascular inflammation
through inhibition of NF-kB activation and peroxisome proliferator-activated receptor-gamma
upregulation. J Immunol. 2010;185(6):3718-3727.
54.
Waterhouse AL, Trela BC. Resveratrol: isomeric molar absorptivities and stability. J Agric Food Chem.
1996;44(5):1253-1257.
55.
Belguendouz, L, Fremont & A. Linard. Resveratrol inhibits metal ion-dependent and independent
peroxidation of porcine low-density lipoproteins. Biochem. Pharmacol. 1997;53(9):1347-1355.
56.
Hung CF, Lin YK, Huang ZR, Fang JY., Delivery of resveratrol, a red wine polyphenol, from solutions
and hydrogels via the skin. Biol Pharm Bull. 2008 May;31(5):955-62.
57.
AUTHOR CORRESPONDENCE
Patricia Farris MD
E-mail: pkfarmd@gmail.com
© 2013-Jddonline. All Rights Reserved. This document contains proprietary information, images, and marks of the Jddonline. No reproduction or use
of any portion of the contents of these materials may be made without the express written consent of the Jddonline. Licensed to
kdogs@eden.rutgers.edu.