ArticlePDF AvailableLiterature Review

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

Authors:
  • McDaniel Institute of Aging Research

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.
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
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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
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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
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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.
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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.
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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.
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AUTHOR CORRESPONDENCE
Patricia Farris MD
E-mail: pkfarmd@gmail.com
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... Following oral administration in humans, 75% of resveratrol is absorbed possibly by transepithelial diffusion. However, oral bioavailability is low (<1%) due to rapid and extensive metabolism in the intestine and liver (first-pass effect, conjugation), resulting in exceptionally low circulating levels of active compound, which require large oral dosing between 0.5 and over 1 gram of supplementation per day to furnish plasma levels sufficient to be efficacious [126,127]. On the other hand, equol is not conjugated to the same extent as resveratrol, oral dosing for equol is dramatically lower, where 5-10 milligrams per day is effective in improving skin health [117]. Pharmacokinetic studies examining oral equol administration displayed similar profiles for r-equol and s-equol, where there was a rapid rise after 2-2.5 h of ingestion with half-life intervals for both isomers at 7 to 8 h [128]. ...
... Pharmacokinetic studies examining oral equol administration displayed similar profiles for r-equol and s-equol, where there was a rapid rise after 2-2.5 h of ingestion with half-life intervals for both isomers at 7 to 8 h [128]. Oral resveratrol administration displayed a similar pharmacokinetic profile to that of equol with a half-life of 8 to 9 h [124][125][126][127], but with much lower bioavailability. ...
... Several studies have been performed on both all-trans resveratrol and (racemic) equol, but the most novel aspects of each phytoestrogen will be summarized in this section emphasizing their protection against oxidative stress, since this plays a critical role in human skin aging and dermal damage [8,9,109,110,113,126]. It should be noted that both resveratrol and equol act as strong antioxidants with higher antioxidant activity than vitamin E or vitamin C [8,109,110,113,126,131]. ...
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The overarching theme for this review is perspective. Superfoods (a marketing term for fruits and vegetables, etc.) have a positive connotation, while many superfoods contain phytoestrogens, a term that is alarming to the public and has a negative connotation because phytoestrogens are endocrine-disruptors, even though they are strong antioxidants that have many health benefits. To understand phytoestrogens, this paper provides a brief summary of the characteristics of: (a) estrogens, (b) estrogen receptors (ER), (c) estrogen-deficient skin, (d) how perspective(s) get off track, (e) phytoestrogen food sources, and (f) misconceptions of phytoestrogens and food safety, in general, that influence person(s) away from what is true. Finally, a brief history of cosmetics to nutraceuticals is covered plus the characteristics of phytoestrogens, resveratrol and equol on: (g) estrogen receptor binding, (h) topical and oral dosing, and (i) in vitro, molecular mechanisms and select clinical evidence, where both phytoestrogens (resveratrol and equol) demonstrate promising applications to improve skin health is presented along with future directions of nutraceuticals. Perspective is paramount in understanding the controversies associated with superfoods, phytoestrogens, and endocrine-disruptors because they have both positive and negative connotations. Everyone is exposed to and consumes these molecules everyday regardless of age, gender, or geographic location around the world, and how we understand this is a matter of perspective.
... Their upregulation results in the induction of matrix metalloproteinase activity leading to the interference with intracellular signaling pathways responsible to the expression of genes regulating the process of collagen type I and III, resulting in hypertrophy and degradation of elastin and hyaluronic acid [45,48,50]. Resveratrol was found to reduce the expression of AP-1 and NF-kB transcription factors, limiting the degradation process of collagen and elastin in the skin, but also skin inflammation [48,49,51,52]. In addition, resveratrol has been to act as an NF-kB inhibitor [53] which can be activated by ROS playing and important role in the inflammatory response [54,55]. ...
... The other 3 subjects left were seen only to improve skin quality at the end of this study. In 2014, Farris P. [52] demonstrated also the efficacy of another resveratrol enhanced formulation (1% resveratrol, 0 1% Vitamin E and 0.5% baicalin) in the treatment of photodamaged skin. After a 12 weeks period an improvement in fine lines and wrinkles derived from photo aging processes were observed. ...
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Nowadays, resveratrol, a polyphenolic phytoalexin is increasingly included in the formulas of cosmetic products and dermatology as an active ingredient, as a consequence of the well-known health beneficial properties, namely antioxidant, anti-inflammatory, anti-viral and anti-bacterial effects. This important compound can be biosynthesized naturally by plants or by industrial synthetic processes. Apart from its anti-inflammatory and antioxidant effects, a broad spectrum of effects has been attributed to the use of this compound such as anti-aging, skin-whitening, anti-angiogenic, collagen I and III stimulation (in fibroblasts) and estrogen-like effects, as well as the ability to protect cells against hydrogen peroxide-induced oxidative stress and UV-irradiation-mediated cell death. In cosmetology and dermatology has been popular because of its ability to penetrate the skin barrier and its anti-aging activity. In fact, resveratrol as an important impact on the regulation of inflammation and, as consequence, repair-related processes in skin. Furthermore, when administered either topically or orally has been proven to be safe and also to overcome the skin barrier. This review will focus in its potential application on melasma treatment and in photo-aging. Resveratrol chemistry, pharmacology, mechanism of action and evidence of its efficacy as photo skin aging protector and its potential use in melasma is discussed.
... Through sirtuin 1, resveratrol directly increases the synthesis of new mitochondria in multiple tissues [94] . While this highlights resveratrol as an appealing option for topical therapy, current small trials of topical formulations have unclear evidence of benefit and the bioavailability of these formulations remains questionable [50,95,96] . ...
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Skin aging is a major cosmetic concern and associated with extensive changes in skin function and structure. The understanding of the basic science underlying skin aging is rapidly progressing, anchored around nine fundamental hallmarks of aging defined in 2013. Here we present the evidence for the relevance of each hallmark of aging to skin aging, emphasizing the uniquely prominent roles of oxidative damage and the extracellular matrix in photoaging. We review the existing evidence for how established treatments of skin aging target each fundamental hallmark and discuss targets for potential future treatments.
... [6,[9][10][11][12][13][14][15]. RSV also supports collagen activity and can act as UV photo-protection [16][17]. ...
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Resveratrol (RSV), a natural lipophilic phytoalexin, was reported as an antioxidant and anti-inflammatory agent, which has the potential to cure diabetic wounds. However, several studies suggested the limitation of RSV, such as poor aqueous solubility, poor stability, and poor oral bioavailability. To overcome the issues, RSV was formulated as a topical nanoemulsion. It is important to ensure the quality of the dosage form by evaluating RSV load in the nanoformulation and optimizing the formula. A reversed-phase HPLC method was developed and validated prior to the load determination of RSV in the nanoemulsion formulation. The composition of triacetin-eugenol, Kolliphor® RH 40, and Transcutol® was further optimized by employing a Box-Behnken Design (BBD) to achieve the optimum composition with expected viscosity and RSV load. The HPLC method for determining RSV load was successfully validated for parameters of selectivity with the resolution of 8.487, linearity and range (r = 0.9979), precision (0.12% of RSD), accuracy (109–110% of recovery), the limit of detection (0.574 µg/mL), and limit of quantitation (1.740 µg/mL). The result of formula optimization was promising, showing the optimum composition of triacetin-eugenol, Kolliphor® RH 40, and Transcutol® at 4.44 g, 30.97 g, and 11.39 g, respectively.
... Luebberding et al. [15] analyzed the mechanical properties of human skin during aging via Cutometer and demonstrated that all assessed parameters progressively decrease with increasing age. Collagen provides the structural framework of the dermal layer, which plays essential roles in maintaining good skin health [12] [20]. Sun-exposed aged skin is characterized by the solar elastosis (thickening, wrinkling). ...
... In cosmetics, polyphenol-containing sunscreen or skin care lotion may effectively reduce the oxidative stress caused by ultraviolet radiation due to excessive sun exposure. Although the skin has a perfect antioxidant defense system, long-term exposure to ultraviolet rays would destroy the skin's own antioxidant capacity, leading to skin aging, melanoma and non-melanin related skin diseases such as neoplastic skin cancer [19]. Therefore, the intervention of antioxidants can improve the problems caused by free radicals or oxidative stress in food consumption, disease defense and skin maintenance. ...
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The aim of this study was to investigate the effect of topology on the antioxidative activities of antioxidant-grafted polypeptides. The linear and star-shaped poly(L-glutamic acid) (PLG) polypeptides were synthesized by N-carboxyanhydrides (NCAs) ring opening polymerization (ROP) using primary amine and polyols as initiators, followed by deprotection. Graft copolypeptides (PLG-Dopa, PLG-GSH and PLG-Dopa-GSH) were obtained by EDC/NHS coupling chemistry using dopamine (Dopa) and glutathione (GSH). Successful synthesis of these polypeptides was confirmed by ¹H NMR, MALDI TOF, GPC, UV-vis and IR spectra analyses. The conformation of polypeptides was investigated by circular dichroism (CD) spectroscopy, demonstrating the grafting of Dopa and GSH onto PLG was accompanied by a conformational change from a random coil to α-helical structure. The results showed that the antioxidant activities of PLG-Dopa and PLG-Dopa-GSH were mainly ascribed to Dopa. It was found that the conjugation of Dopa resulted in the decrease in its antioxidant activity and the antioxidant-grafted polypeptides exhibited comparable antioxidant activity regardless the polypeptide arm number. The conjugation of GSH could prolong polypeptide antioxidant activity by preventing Dopa from oxidation. It was found that both PLG-Dopa and PLG-Dopa-GSH exhibited good hemocompatibility and biocompatibility.
Chapter
The mitochondrion is the energy plant of the cell, and the place of adenosine triphosphate production thanks to the process of respiration. This activity uses dioxygen and generates reactive oxygen species. Consequently, any dysfunction in the mitochondria can cause oxidative stress, which, when uncontrolled, can lead to further cellular and tissue damage. Mitochondrial dysfunctions are linked to many diseases from age-related and degenerative diseases to metabolic and cardiovascular diseases, in addition to genetic mitochondrial disorders. Nutritional interventions could represent interesting therapeutic strategies by targeting specific mitochondrial targets, pathways, and/or functions. The main classes of these nutrients are reviewed here, along with their main cellular, preclinical, and clinical data. A special focus is given to the topical use of certain nutrients for dermo-cosmetic applications.
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Therapeutically targeting B cells has received great attention in the treatment of B-cell malignancies and autoimmune diseases. The B-cell activating factor (BAFF) is critical to the survival of normal and neoplastic B cells, and excess production of BAFF contributes to autoimmune diseases. Resveratrol, a natural polyphenolic compound, has a positive effect on the treatment of autoimmune diseases. However, how resveratrol affects BAFF-stimulated B-cell proliferation and survival is poorly understood. Here, we show that resveratrol increased autophagosome formation and ATG5/LC3-II levels and decreased p62 level, promoting autophagic flux/autophagy and thereby suppressing the basal or human soluble BAFF (hsBAFF)-stimulated proliferation and survival of normal and B-lymphoid (Raji) cells. This is supported by the findings that inhibition of autophagy with 3-methyladenine (3-MA, an inhibitor of Vps34) or ATG5 shRNA attenuates resveratrol-induced autophagy and -reduced proliferation/viability in B-cells. Inhibition of mTOR with rapamycin or knockdown of mTOR potentiated resveratrol-induced autophagy and inhibition of hsBAFF-stimulated B-cell proliferation/viability, while overexpression of wild-type mTOR conferred resistance to the actions of resveratrol. Similarly, inhibition of Akt with Akt inhibitor X or ectopic expression of dominant negative Akt reinforced resveratrol-induced autophagy and inhibition of hsBAFF-stimulated B-cell proliferation/viability, whereas expression of constitutively active Akt conferred resistance to the actions of resveratrol. Taken together, these results indicate that resveratrol induces autophagy impeding BAFF-stimulated proliferation and survival via blocking the Akt/mTOR signaling pathway in normal and neoplastic B cells. Our findings highlight that resveratrol has a great potential for prevention and treatment of excessive BAFF-elicited aggressive B-cell disorders and autoimmune diseases.
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The long lifespan of the world’s population has been raising interest in the research for new solutions to delay the aging process. With the aim of skin aging prevention, solid lipid nanoparticles (SLNs) were developed in this work for the encapsulation of three lipophilic natural compounds extracted from vine cane—epigallocatechin gallate (EGCG), resveratrol and myricetin. The developed loaded-SLNs proved to be stable, maintaining their adequate physicochemical characteristics for 30 days. In addition, the loaded-SLNs formulations exhibited high encapsulation efficiencies and loading capacities and high intracellular antioxidant activity. The mixture of EGCG-loaded SLNs with resveratrol-loaded SLNs proved to have the highest protection against induced oxidative stress. The in vitro cytotoxicity of the loaded SLNs was also evaluated, showing that the developed formulations are biocompatible for concentrations up to 50 µg/mL and could be safe for use in cosmetics. The encapsulation of EGCG, resveratrol and myricetin in SLNs seems to be a suitable strategy for the delivery of these antioxidants to the skin, improving their bioavailability.
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To overcome the hydrophobicity and chemical instability of resveratrol (Rev), modified whey protein isolate (WPI) and gelatin (Gel) were used to loading Rev. Three treatments including the pH-shifting at pH 12 (S), pH-shifting at pH 12 combined with ultrasonication at pH 7 (SU7), and pH-shifting at pH 12 combined with ultrasonication at pH 12 (SU12) were conducted to obtain a series of modified proteins (WPI-S, WPI-SU7, WPI-SU12, Gel-S, Gel-SU7, Gel-SU12). Among them, WPI-SU12 and Gel-SU12 had the highest encapsulation efficiency (EE) and loading capacity (LC) for Rev. The EE and LC were 92.69±0.25% and 17.37±0.067 g/100 g protein in WPI-SU12-Rev nanocomposites, respectively, and 83.85±0.43% and 15.68±0.070 g/100 g protein in Gel-SU12-Rev nanocomposites, respectively. This might be related to the highest surface hydrophobicity of modified proteins in SU12 groups. The particle sizes of all nanocomposites were below 200 nm, while the higher absolute ζ-potential value of WPI-SU12-Rev nanocomposites than that of Gel-SU12-Rev nanocomposites indicate higher stability. Molecular interaction and secondary structure analysis verified that the proteins and Rev bound to each other. Moreover, protein nanocomposites can greatly improve the water solubility and antioxidant capacity of Rev. In summary, the WPI modified by ultrasonication at pH 12 showed the best loading capacity with Rev.
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Resveratrol has attracted interest as a wine constituent that may reduce heart disease. Published data on the molar absorptivity and chemical stability of cis- and trans-resveratrol have varied greatly. Accurate values for UV absorbance for trans-resveratrol [UV λmax (EtOH) nm (ε) 308 (30 000)] and cis-resveratrol [UV λmax (EtOH) nm (ε) 288 (12 600)] were determined and are used to improve chromatographic quantitation methods. Trials conducted under a variety of commonly encountered laboratory conditions show that trans-resveratrol is stable for months, except in high-pH buffers, when protected from light. cis-Resveratrol was stable only near pH neutrality when completely protected from light. Keywords: Antioxidant; phenolic; wine; grape; stilbene; isomer; UV spectroscopy; absorptivity
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The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.
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Several beneficial effects of resveratrol (RES), a natural antioxidant present in red wine have already been described. The aim of our study was to investigate if RES had a clinically measurable cardioprotective effect in patients after myocardial infarction. In this double-blind, placebo controlled trial 40 post-infarction Caucasian patients were randomized into two groups. One group received 10 mg RES capsule daily for 3 months. Systolic and diastolic left ventricular function, flow-mediated vasodilation (FMD), several laboratory and hemorheological parameters were measured before and after the treatment. Left ventricular ejection fraction showed an increasing tendency (ns) by RES treatment. However, left ventricular diastolic function was improved significantly (p < 0.01) by RES. A significant improvement in endothelial function measured by FMD was also observed (p < 0.05). Low-density lipoprotein (LDL) level significantly decreased (p < 0.05) in the RES treated group. Red blood cell deformability decreased and platelet aggregation increased significantly in the placebo group (p < 0.05), while resveratrol treatment has prevented these unfavourable changes. Concerning other measured parameters no significant changes were observed neither in placebo nor in RES group. Our results show that resveratrol improved left ventricle diastolic function, endothelial function, lowered LDL-cholesterol level and protected against unfavourable hemorheological changes measured in patients with coronary artery disease (CAD).
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Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
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Resveratrol has attracted interest as a wine constituent that may reduce heart disease. Published data on the molar absorptivity and chemical stability of cis- and trans-resveratrol have varied greatly. Accurate values for UV absorbance for trans-resveratrol [UV λmax (EtOH) nm (ε) 308 (30 000)] and cis-resveratrol [UV λmax (EtOH) nm (ε) 288 (12 600)] were determined and are used to improve Chromatographic quantitation methods. Trials conducted under a variety of commonly encountered laboratory conditions show that trans-resveratrol is stable for months, except in high-pH buffers, when protected from light. cis-Resveratrol was stable only near pH neutrality when completely protected from light.
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Nonmelanoma skin cancer is the most common cancer among humans and solar UV radiation, particularly its UVB component (290–320 nm), is its major cause. One way to reduce the occurrence of the cancer is via the use of substances (often antioxidants) termed “photochemopreventive agents”. Resveratrol (trans-3,4′,5-trihydroxystilbene), a phytoalexin found in grapes, nuts, fruits, and red wine, is a potent antioxidant with strong anti-inflammatory and antiproliferative properties. This study was designed to examine whether resveratrol possesses the potential to ameliorate the damages caused by short-term UVB exposure to mouse skin. Single topical application of resveratrol (25 μmol/0.2 ml acetone per mouse) to SKH-1 hairless mice was found to result in significant inhibition of UVB (180 mJ/cm2)-mediated increase in bifold skin thickness and skin edema. The resveratrol treatment to mouse skin was also found to result in significant inhibition of UVB-mediated induction of cyclooxygenase and ornithine decarboxylase (ODC) enzyme activities and protein expression of ODC, which are well-established markers for tumor promotion. We also observed that resveratrol inhibits UVB-mediated increased level of lipid peroxidation, a marker of oxidative stress. Taken together, our results suggest that resveratrol may afford substantial protection against the damages caused by UVB exposure, and these protective effects may be mediated via its antioxidant properties.
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Oxidative stress can result in insulin resistance, a primary cause of type-2 diabetes. Methylglyoxal (MG), a highly reactive dicarbonyl metabolite generated during glucose metabolism, has also been confirmed to cause pancreatic injury and induce inflammation, thereby resulting in insulin resistance. Recently, resveratrol has been reported to exert antioxidant properties, protecting cells from the generation of reactive oxygen species (ROS). The aim of this study was to evaluate resveratrol activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced insulin resistance in Hep G2 cells. Therefore, the molecular signaling events affecting resveratrol-mediated heme oxygenase-1 (HO-1) and glyoxalase expression levels were further investigated in this study. Our findings indicated that resveratrol activated the extracellular signal-regulated kinase (ERK) pathway but not the p38 or c-Jun N-terminal kinase (JNK) pathways, subsequently leading to Nrf2 nuclear translocation and elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. In contrast, depletion of Nrf2 by small interfering RNA (si-RNA) resulted in the abrogation of HO-1 and glyoxalase expression in the MG-treated resveratrol group in Hep G2 cells. Administration of an appropriate chemopreventive agent, such as resveratrol, may be an alternative strategy for protecting against MG-induced diabetes.