Review Article Polyphenol Stilbenes: Molecular Mechanisms ...downloads.hindawi.com/journals/omcl/2015/340520.pdfReview Article Polyphenol Stilbenes: Molecular Mechanisms of Defence

Review ArticlePolyphenol Stilbenes Molecular Mechanisms ofDefence against Oxidative Stress and Aging-Related Diseases

Mika Reinisalo1 Anna Karingrlund2 Ali Koskela12

Kai Kaarniranta13 and Reijo O Karjalainen2

1Department of Ophthalmology University of Eastern Finland PO Box 1627 70211 Kuopio Finland2Department of Biology University of Eastern Finland PO Box 1627 70211 Kuopio Finland3Department of Ophthalmology Kuopio University Hospital PO Box 1627 70211 Kuopio Finland

Correspondence should be addressed to Mika Reinisalo mikareinisaloueffi

Received 11 October 2014 Accepted 21 January 2015

Academic Editor David Vauzour

Copyright copy 2015 Mika Reinisalo et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Numerous studies have highlighted the key roles of oxidative stress and inflammation in aging-related diseases such as obesity type2 diabetes age-related macular degeneration (AMD) and Alzheimerrsquos disease (AD) In aging cells the natural antioxidant capacitydecreases and the overall efficiency of reparative systems against cell damage becomes impaired There is convincing data thatstilbene compounds a diverse group of natural defence phenolics abundant in grapes berries and conifer bark waste may confera protective effect against aging-related diseases This review highlights recent data helping to clarify the molecular mechanismsinvolved in the stilbene-mediated protection against oxidative stress The impact of stilbenes on the nuclear factor-erythroid-2-related factor-2 (Nrf2) mediated cellular defence against oxidative stress as well as the potential roles of SQSTM1p62 proteinin Nrf2Keap1 signaling and autophagy will be summarized The therapeutic potential of stilbene compounds against the mostcommon aging-related diseases is discussed

1 Introduction

Aging is one of the major risk factors for a wide range ofchronic metabolic and neurodegenerative diseases Duringthe course of aging reactive oxygen species (ROS) causeincreasing oxidative stress in cells leading to oxidative dam-age and to the induction of inflammatory cascades (Figure 1)Furthermore antioxidant defence systems against oxidativestress deteriorate during aging and many antioxidant phaseII genes are upregulated only marginally or may even bedownregulated Moreover the innate and adaptive immunedefence systems tend to deteriorate during aging and thismaycontribute to the degeneration process [1]

Activation of antioxidant defence and phase II enzymesis a key endogenous mechanism protecting cells from theoxidative damage associated with many common diseasessuch as obesity type 2 diabetes (T2D) age-related maculardegeneration (AMD) and Alzheimerrsquos disease (AD) Theactivation of cellular defence mechanisms by plant-derived

bioactive compounds is believed to attenuate cellular oxida-tive stress and thus this seems to represent a feasible therapeu-tic approach against age-related diseases There is increasingepidemiological and experimental data suggesting that theregular intake of berries vegetables and fruits containingsignificant amounts of polyphenols is a potential way toimprove the quality of life as an individual grows older [2ndash4] Polyphenols or polyphenol metabolites produced in thebody mediate their protective action via several mechanismsand different pathways that are currently under intensivestudy For example the beneficial effects of anthocyanin-rich bilberry and blackcurrant diets proanthocyanidin (laterreferred to as PAC) metabolites and grape-derived polyphe-nolic preparations have been extensively studied not only inanimal models but also in patients with T2D and AD [5ndash7]

Stilbene compounds are part of a vast group of naturaldefence polyphenols occurring inmany plant species Resver-atrol (3541015840-trihydroxy-trans-stilbene) is a well-known poly-phenol phytoalexin which is found mainly in the skin of

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 340520 24 pageshttpdxdoiorg1011552015340520

2 Oxidative Medicine and Cellular Longevity

Antioxidants

Stilbenes

Oxidativestress

ROS

Aging

Antioxidantdefence

cells

Healthycells

Aging-relateddiseases

Inflammation

Long and healthylifespan

Damaged

Figure 1 As an individual ages the balance between a longhealthy lifespan and suffering age-related diseases is believed to berelated to the interplay between the cellular antioxidant defencesystem and adverse effects related to oxidative stress In agingcells oxidative stress increases due to a progressive decline inthe efficiency of antioxidant defence systems There is convincingevidence to indicate that supplementation with polyphenols suchas stilbenes anthocyanins and catechins can increase cellularantioxidant defence and promote health of the individual

grapes it has attracted extensive scientific attention due toits potential health benefits related with its cardiovascu-lar (French paradox) chemopreventive antiobesity antidia-betic and neuroprotective properties However recent datahave highlighted that also other stilbene compounds suchas pterostilbene (35-dimethyl ether derivative of resver-atrol) may have higher bioavailability and possess betterneuroprotective activity against AD than resveratrol itself[8] Another interesting stilbene compound with potentialhealth-beneficial properties is pinosylvin (35-dihydroxy-trans-stilbene) a naturally occurring trans-stilbenoid whichis mainly found in the heartwood of Pinus species andoccurs in high concentrations in bark waste and thus thisstilbene compoundmay represent an inexpensive polyphenolwith considerable potential for diverse health-promotingapplications [9ndash11]

There are several comprehensive reviews available focus-ing on resveratrol but very few reports have analyzedthe bioactivity of other stilbenes Here we review shortlythe most recent data to clarify the molecular mechanismsinvolved in stilbene-mediated protection against oxidativestress emphasizing the potential roles of transcription fac-tor nuclear factor-erythroid-2-related factor-2 (Nrf2) andSQSTM1p62 protein (later referred to as p62) in the regula-tion of antioxidant enzymes and autophagy The therapeuticpotential of stilbene compounds to target the molecularpathways behind many common aging-related diseases willbe reviewed

2 Stilbene Compounds in Plants

Phenolic compounds are important mediators of adapta-tion and survival responses of plants in acute and chronicchallenges but polyphenols also act in plants regulating cellgrowth differentiation pollen fertility and nodulation andthus seem to be essential for plant health For example stil-benes are natural phenolic defence compounds occurring ina number of different plant species that possess antimicrobialand antioxidant activities against phytopathogens and ozoneor UV stress [12]

Stilbene compounds occur in many plant species(Table 1) including grape wine (Vitis vinifera) peanut(Arachis hypogaea) sorghum (Sorghum bicolor) and manytree species (Pinus and Picea) [13] Moreover commercialsources of stilbenes include many plants cultivated in Asia asfolk medicines such as Polygonum cuspidatum Rhodomyrtustomentosa Rheum undulatum Melaleuca leucadendronand Euphorbia lagascae while pterostilbene is found pre-dominantly in bilberries (Vaccinium myrtillus) blueberries(several Vaccinium species) and some other berries as wellas in grapes and juice residues which are important source ofthis stilbene when it is used in nutraceutical applications [14]Grape pomaces residues produced during wine makingand other grape juice solids contain high polyphenolconcentrations and are also attractive sources of manystilbene compounds not only resveratrol [15] The bark wasteof conifer trees contains substantial amount of stilbene com-pounds such as pinosylvin piceatannol and trans-resveratrol(t-Res)Thus this enormous amount of industrial byproductsrepresents a very attractive and inexpensive source of stil-benes with commercial applications [16 17] Genetic tools area very promising means to produce specific stilbenes such aspterostilbene via stilbene synthase and O-methyltransferasecoexpression in plants [18] These types of stilbenes maybe especially suitable for pharmacological applications Themajor stilbenes and their structures are described in Table 1and a more complete list can be found in reviews [12 19]

Stilbene synthase (STS) is the key enzyme that catalyzesthe biosynthesis of stilbenic compounds STS has evolvedfrom the chalcone synthases (CHSs) apparently several timesindependently in stilbene-producing plants [13 19] Interest-ingly different STS genes display different tissue and devel-opmental specific expression Thus it has been reported thatSTS genes exhibited lower expression levels in young grapeleaves than in old leaves while the transcript levels of eightSTS genes increased dramatically in the berry skin of grapecultivars Cabernet Sauvignon and Norton post veraisonreaching the highest level at the time of harvest [2] Theheartwood of pine trees contains high level of pinosylvin butas a response to stress induction (fungal or UV light) youngseedlings also accumulate high amounts of pinosylvin [20]

3 Bioavailability

At least a proportion of the stilbene compounds or theirmetabolites present in extracts may be sufficiently bioavail-able to reach even brain target cells and thus exert beneficial

Oxidative Medicine and Cellular Longevity 3

Table 1 Major stilbenes and their structures

Plant Compounds [reference]Cocoa (Theobroma cacao L) Resveratrol [21]Grape (Vitis vinifera L) Piceatannol resveratrol [22]Hop (Humulus lupulus L) Resveratrol [23]Peanut (Arachis hypogaea L) Resveratrol [24]Pinaceae trees (pines)PiceaMill Isorhapontigenin piceatannol [25]Pinus L Pinosylvin [16]Rhubarbs (Rheum L) Piceatannol rhapontigenin resveratrol [26]Strawberry (Fragaria x ananassa Duch) Resveratrol [27]Sugar cane (Saccharum spp) Piceatannol resveratrol [28]Tomato (Lycopersicon esculentumMill) Resveratrol [29]Vaccinium berriesBilberry (Vmyrtillus) Resveratrol [30]Cranberry (Vmacrocarpon) Resveratrol [30]Highbush blueberry (V corymbosum) Piceatannol resveratrol [30] pterostilbene [31]WinesRed Piceatannol resveratrol [32]White Resveratrol [33]

HO

OH

Pinosylvin trans-Resveratrol

HO

OH

OH

Piceatannol

HO

OH

OH

OH

H3C

Pterostilbene

OHCH3

O

O

CH3

O

Rhapontigenin

HO

OH

CH3

Isorhapontigenin

HO

OH

OCH3

OH

actions [7 34] Although the oral absorption of resvera-trol in humans has been claimed to be as high as 75[35] it is well known that stilbenes however are poorlybioavailable phenolic compounds after oral intake Due toextensive metabolism in the major sites in intestine andliver (glucuronides and sulfates are the major metabolites ofresveratrol) the oral bioavailability appears to be less than1 in a rat model The oral bioavailability of rhaponticin was

calculated to be 003 [36] In another rat study followingoral dosing plasma levels of pterostilbene and pterostilbenesulfate were markedly greater than the levels of resveratroland resveratrol sulfate indicating that the in vivo biologicalactivity of equimolar doses of pterostilbene may be greaterthan that of resveratrol [37] Moreover the absolute oralbioavailability of pterostilbene was found to be around 12in rat plasma with the values of terminal elimination half-life


and clearance of pterostilbene being 966 plusmn 237min and370 plusmn 25mLminkg suggesting that bioabsorption is veryrapid with peak concentration achieved at 05ndash2 h after theoral dose and excretion being complete a few hours afteringestion [38]

In a human trial 10 healthy volunteers received singledoses of 05 1 25 or 5 g resveratrol the peak levels ofresveratrol and six metabolites at the highest dose were 539 plusmn384 ngmL (24 micromolL mean plusmn SD 119899 = 10) analyzed15 h after dose [39] Interestingly the area under the plasmalevels curve (AUC) values for resveratrol-3-sulfate andresveratrol monoglucuronides was up to 23 times greaterthan that of resveratrol In the other human trial performedin 40 healthy volunteers repeated doses of resveratrol weretested with the volunteers ingesting 29 daily resveratrol dosesof 05 10 25 or 50 g [40]The data revealed that resveratrol-3-O-sulfate resveratrol-41015840-O-glucuronide and resveratrol-3-O-glucuronide were the major plasma metabolites Maximalplasma levels and areas under the concentration versus timecurve for the metabolites exceeded the levels of resveratrolby about 20-fold When resveratrol at doses of 05 or 10 gwas given to 20 patients suffering from colorectal cancerboth resveratrol and resveratrol-3-O-glucuronide wererecovered from tissues at maximal mean concentrations of674 and 860 nmolg respectively [41] Interestingly it wasclaimed by the authors that these daily doses of 05 or 10 gproduced levels in the human gastrointestinal tract at orderof magnitude sufficient to elicit anticarcinogenic effects

Low bioavailability poor solubility limited stability highrate of metabolic breakdown and low target specificity havebeen considered as major obstacles to the use of resveratroland its natural analogies in major pharmacological applica-tions However several research lines are currently underwayto improve these properties [42] A wide range of syntheticderivatives of resveratrol have been generated and some ofthe best derivatives have improved the target specificity downto the nanomolar range [43] There is a remarkable findingthat inhibition of aromatase activity was enhanced by over6000-fold when the central ring of resveratrol was substitutedwith 13-thiazole this suggests that this modified resveratrolmay be a potential drug for treating breast cancer

Recently it was reported that soluble galenic formimproved low absorption of t-Res as a dry powder [44]The efficacy of the new formulation was tested in 15 healthyvolunteers receiving 40mg of t-Res The single dose (40mg)of the soluble t-Res was found to be well absorbed andelicited biologically efficient blood levels (01ndash6120583M) forseveral hours the new soluble galenic-based formulation ledto 88-fold higher resveratrol levels in plasma versus thecontrol powder Interestingly this new formulation elicitedan intense anti-inflammatory response in various tissuesof mice fed a high-fat diet (HFD) while the control dietexhibited only a weak response suggesting that improvedplasma bioavailability confers significant enhancement ofbiological activity in the target cells In another recent work amodification of the liposome with polyethylene glycol (PEG)was used to improve the bioavailability of rhaponticin (RA)and its plasma protein binding ability [45] This experimentrevealed that the maximum plasma concentration (119879max)

of PEGL-RA was about 45 times higher than that of freeRA after oral administration due to the lower distributioninto the gastrointestinal tract Addition of piperine alkaloid(100mgkg oral gavage) + piperine (10mgkg oral gavage)in a mouse trial lead to a substantial increase (1544) in themaximum serum concentration (119862max) as compared with thestandard resveratrol dose [46] Recently it was reported thata higher concentration of resveratrol could be achieved inthe brain tissue by administrating the compound inside lipid-core nanocapsules [47]

The safety of food ingredients (dietary supplementsfunctional foods etc) containing substantial amounts ofpolyphenols is an important issue In the majority of studiesstilbene compounds such as resveratrol have appeared to bewell tolerated and nomarked toxicity has been reported [48]In a human trial 25 50 100 or 150mg of t-Res was givensix times a day but adverse events were mild in severityand similar between groups [49] Only at very high dosesused in some human studies such as repeated doses at 25and 5 g levels have there been reports of mild to moderategastrointestinal symptoms [48] but even such high levelsgiven as single doses did not cause any adverse events [39 40]However stilbene-drug interactions have not been clarifiedand remain to be determined

Gastrointestinal symptoms at a 1 g daily dose were alsoobserved and it has been suggested that 1 g of daily resveratroldose should not be exceeded in clinical trials [40] More-over administration of 2 g t-Res twice a day was recentlyfound to achieve adequate biological exposure and it waswell tolerated in healthy subjects although diarrhea wasfrequently observed thus it was proposed that to maximizet-Res exposure and safety these supplements should be takenwith a standard breakfast and not with a high-fat meal [50]

4 Molecular Basis of Oxidative Stress

41 The Nrf2ARE Pathway in Cellular Defence Nuclearfactor-erythroid-2-related factor-2 (Nrf2) a member of thebasic leucine zipper (bZIP) transcription factor family isan essential transcription factor for cellular detoxificationand defence against oxidative stress In the cell nucleusNrf2 is able to recognize the antioxidant response element(ARE) with the specific nucleotide binding sequence (51015840-TGACnnnGC-31015840) positioned in regulatory region of targetgenes [51 52] Role of other members of the Nrf-family suchas Nrf1 and Nrf3 has not been so thoroughly studied but cur-rent evidence suggests that these genes have partially differentfunctions target genes and tissue-specificities although theyrecognize the same ARE sequence as Nrf2 [51 53] By actingthrough the ARE element Nrf2 has a central role in theregulation of a large group of phase II metabolite conjugationand antioxidant genes (Figure 2) as well as in influencingsome of the genes involved in proteasome pathway andinflammation [52 54ndash57] Until now several Nrf2 targetgenes (see Table 2) such as heme oxygenase-1 (HO-1) [58]and NAD(P)H dehydrogenase quinone 1 (NQO1) [59] havebeen verified Under basal conditions theNrf2ARE pathwayis suppressed since Nrf2 is trapped in the cytosol as itforms a protein complex with Kelch-like ECH-associated


Keap1

Keap1Ub

Keap1

Ub

Nucleus mRNAsAntioxidant

enzymes

Target genes(p62 HO-1 Nrf2 etc)

Cell

Stilbenes

CUL3

Nrf2 ubiquitinationand proteasomal

degradation

No stress Keap1 CUL3p62

p62

NQO1Oxidative

stress

p62

PKA

CRE ARENrf2

CREB

CREB

Nrf2

Ub

GSTs

HO-1ARE

ARE

SIRT1

Autophagosome

Keap1Nrf2

CUL3 p62Keap1

+

HO-1

minus

ARE antioxidant response elementCRE cAMP response element in gene regulatory region

Nrf2

Maf

uarr cAMPuarr AMPK

darr PDE

uarr cAMP

Figure 2 The Nrf2ARE pathway and cAMP second messenger system together are the key regulators of cellular antioxidant defence Thesepathways can bemodulated by stilbenes Stilbenes can activate nuclear localization of Nrf2 and activation of Nrf2 target genes associated withantioxidant defence and autophagy Autophagy related protein p62 and Nrf2 form a regulatory loop where p62 enables the release of Nrf2from cytoplasmic Keap1 complex When cells are not stressed the excess of cytoplasmic Nrf2 is eliminated by proteasomal degradation Inaddition stilbenes are capable of activating cAMP response element-binding protein (CREB) target genes and the AMPK pathway by PDEinhibition mediated increase of cellular cAMP levels

protein 1 (Keap1) [55] Keap1 acts as a molecular switch sens-ing cellular electrophile and oxidant homeostasis [60] Withassistance of Cullin-3 (CUL3) the Nrf2-Keap1-CUL3 proteincomplexes are constantly exposed to ubiquitin conjugationand proteasomal degradation [55 61] In condition of stressor exposure to electrophiles Nrf2 dissociates from the Keap1-CUL3 complex and translocates into the nucleus The disso-ciation of Nrf2 is mediated via modification of specific Keap1cysteine residues by electrophiles oxidants and dietary sup-plements such as stilbenes [62] Alternatively dissociation ofNrf2 from cytoplasmic Nrf2-Keap1-CUL3 complex is enabledby p62 involved in autophagy process (see Section 42) Inthe nucleus Nrf2 heterodimerizes with small Maf (sMaf)proteins which seems to be indispensable partners requiredfor ARE binding and subsequent transactivation of targetgenes [52] In contrast in the nucleus the transcriptionalrepressor BACH1 seems to have an important role as anantagonist for Nrf2 mediated activation by binding ARE-like elements in Nrf2 target genes [63] It should be notedthat Keap1 has the capability to undergo nuclear localizationand to shuttle back to cytoplasm this suggests that Keap1is also involved in the regulation of Nrf2 in the cell nucleus[64] Interestingly in different species ARE elements are alsofound in the regulatory regions of Nrf2 itself as well as in

several regulators of the Nrf2ARE pathway such as Keap1sMaf and p62 [65 66] In addition it has been shown that theacetylation-deacetylation status of Nrf2 in the nucleus is alsoimportant for Nrf2 binding and target gene activation [67]Auxiliary mechanisms such as the cAMPCREB pathway[68] and the aryl hydrocarbon receptor (AhR) pathway [69]interactingwith theNrf2AREpathwaywill be discussed laterin this review (see Section 43)

Convincing evidence from knockout animal models hasproved that Nrf2 and Keap1 regulate numerous cellular func-tions [70 71] For example Nrf2 knockout mouse displaysprogressive degeneration of retina (see Section 53) character-istic for AMD [71] In Keap1 knockout mouse excessive accu-mulation of Nrf2 into nucleus stimulates aberrant expressionof Nrf2 target genes causing growth retardation and thedeath of pups soon after birth [54] The dramatic changesin growth indicate that Keap1 has an essential role in Nrf2regulation and expression of Nrf2 target genes For instanceKeap1 knockout mice displayed a constant overexpression ofcytoprotective proteins such as phase II enzymes NQO1 andglutathione S-transferases (GSTs) Moreover recent genome-wide studies have revealed numerous putative Nrf2 targetgenes [52 72] suggesting that the Nrf2ARE pathway maypossess several novel molecular targets for polyphenols stillto be found


Table 2 Selected Nrf2 target gene candidates in human associated with defence against oxidative stress and age-related diseases

Target gene Functionrole in defence against oxidative stress ReferenceNrf2 Transcription factor activator of detoxifying enzymes (autoregulation) [73]AhR Regulator of xenobiotic metabolizing enzymes [74]HO-1 Cytoprotection catabolize heme [75]GSTP1 Antioxidant enzyme xenobiotic metabolizing enzyme [76]NQO1 Antioxidant enzyme xenobiotic metabolizing enzyme [77ndash79]CBR3 Metabolizing enzyme of carbonyl compounds [80]UGT1A8 A10 Glucuronidation of xenobiotics [81]GCS Glutathione biosynthesis [82]TRX Antioxidant enzyme protein redox regulation [83]SLC7A11 Transports cysteine a precursor of antioxidant glutathione [52 84]SLC48A1 Heme transporter [85]

AMBP Heme binding free radical scavenger [72][85]

ABCB6 Mitochondrial porphyrin (heme) transporter [85]FECH Heme biosynthesis chelates ferrous iron [72 85]TBXAS1 Thromboxane A2 synthesis (cytochrome P450 family) [85]IL-6 Inflammation proinflammatory cytokine [52 86]Bcl-2 Antiapoptotic protein [87]p62 Adaptor protein proteasomal clearance autophagy [52 66]ABCB6 ATP-binding cassette subfamily B member 6 AhR aryl hydrocarbon receptor AMBP 1205721-microglobulinbikunin Bcl-2 B-cell lymphoma 2 proteinCBR3 carbonyl reductase 3 FECH ferrochelatase GCS 120574-glutamylcysteine synthetase GSTP1 glutathione S-transferase pi HO-1 heme oxygenase-1IL-6 interleukin-6 NQO1 NAD(P)H dehydrogenase quinone 1 Nrf2 nuclear factor-erythroid-2-related factor-2 p62 sequestosome 1 SLC7A11 solutecarrier family 7 member 11 SLC48A1 solute carrier family 48 member 1 TBXAS1 thromboxane A synthase 1 TRX thioredoxin and UGTs UDP-glucuronosyltransferases

42 Role of p62 Protein in Nrf2ARE Signaling and AutophagyCurrent data indicates that Nrf2 is involved in autophagy acatabolic process activated during starvation For instance inthe retinal pigment epithelial (RPE) cells of theNrf2 knockoutmouse eye the autophagy process and lysosome-dependentdegradation were disturbed with accumulated autophagyintermediates photoreceptor outer segments (POS) and anaging pigment lipofuscin [70] Autophagy supplies an energyresource of amino acids and other substrates via lysosomaldegradation and recycling of unnecessary cellular compo-nents [88] The impaired autophagy system has been shownto associate with aging-related neurodegenerative diseasessuch as Parkinsonrsquos disease (PD) [89] AMD [90] and AD[91] One sign of this impairment is the accumulation ofautophagy receptor p62 in AMD [90] In addition p62 is amultifunctional protein involved in other cellular functionssuch as bone metabolism inflammation and adipogenesis[92ndash94] In order to eliminate cellular waste and proteinaggregates during nutrient deprivation the cell may triggerthe complex autophagy process where the p62 protein has acentral role [88] In an experiment conducted in autophagydeficient mice it was found that p62 is involved in theformation of cellular protein aggregates which are normallyeliminated by autophagy [95]There is growing evidence thatp62 is also capable of interacting with the Nrf2ARE pathway(Figure 2) by disrupting the cytoplasmicNrf2-Keap1 complex[66] Moreover it has been shown that the functional AREelement is located in regulatory region of p62 gene [52 66]Nrf2-p62 couple seems to form a regulatory loop where Nrf2

is able to activate p62 expression and consequently Nrf2nuclear localization is facilitated by p62 [96 97] Interestinglythere is data that p62 is able to bind on specific Keap1motif required for Nrf2 binding [66 96] and that Keap1elimination is processed by p62 dependent autophagy [97]This was also shown in autophagy deficient mouse whereNrf2 became accumulated in cell nucleus [95] However thenuclear localization of Nrf2 was diminished when p62 wasabolished

It has been shown that AMP-activated protein kinase(AMPK) is the key regulator of autophagy [97] suggestingthat the AMPK pathway is also likely involved in the regu-lation of p62 and the Nrf2ARE pathway (Figure 2) AMPKis able to induce autophagosome formation by activatingnumerous downstream kinases and interacting proteins suchas autophagy-related proteins protein kinase ULK1 andmicrotubule-associated protein LC3 [93 98] finally achievingthe oligomerization of p62 within autophagosomes [99] Theactivation of autophagy is concurrently aided by AMPKmediated inhibition of mammalian target of rapamycin(mTOR) a known suppressor of autophagy [100] In contrastmTOR is capable of inhibiting autophagy via phosphory-lation of ULK1 [101] It is known that both AMPK andautophagy are activated upon starvation This pathway hasbeen verified by utilizing 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside ribonucleoside (AICAR) an activatorof AMPK autophagy and NAD-dependent deacetylase sir-tuin 1 (SIRT1) [90 102ndash104] For instance AICAR medi-ated activation of the AMPK pathway can increase HO-1


expression via Nrf2 [104] Interestingly also stilbenes suchas resveratrol can facilitate AMPK activation and autophagy[105]

43Modulation ofOther PathwaysUnderlying theAntioxidantDefence Systems There is growing data that polyphenols havealternativemolecular targets and this complicates elucidationof their role in cellular physiology and pathophysiologyRecently interesting information regarding novel molec-ular targets of stilbenes such as cellular cAMP secondmessenger signaling the AMPK pathway regulating energyhomeostasis estrogen-related receptor alpha (ERR120572) andestrogen receptors (ER) as well as the enzymatic cofactortetrahydrobiopterin (BH4) has become a focus of attentionApparently some of these targets may interact with theNrf2ARE pathway and the autophagic process

Stilbenes Can Restore the Cellular Bioavailability of theEnzymatic Cofactor Tetrahydrobiopterin (BH4) under ROSExposureThere is evidence that ROS are able to decrease thebioavailability of BH4 and coupling to aromatic amino acidhydroxylases enzymes essential in many of the metabolicpathways involved in vascular and neurotransmitter home-ostasis [106] It is noteworthy that BH4 is an essential cofactorof nitric oxide synthase enzymes (NOS) involved in nitrogenoxide (NO) synthesis in almost all tissues [107 108] It hasbeen shown that in NO synthesis the lack of BH4 initiatessuperoxide generation and further synthesis of the powerfuloxidant peroxynitrite [109] Moreover in the brain and theeye BH4 is required for the synthesis of tyrosine dihydrox-yphenylalanine (L-DOPA) dopamine and serotonin [110] byacting as an essential cofactor of the key enzymes pheny-lalanine hydroxylase tyrosine hydroxylase tyrosinase [111]and tryptophan hydroxylase [112] respectively InterestinglyBH4 is also pivotal for synthesis of two important neurotrans-mitters norepinephrine and epinephrine [113] and serotonin[114] It is noteworthy that serotonin derived melatonin canalso act as an efficient free radical scavenger in the eye [115]Therefore it can be concluded that by increasing cellularBH4 levels stilbenes can also contribute to the productionof endogenous antioxidants It has been shown in cell andanimal models that resveratrol can increase BH4 synthesisand decrease the oxidation of BH4 [116] In condition ofoxidative stress cellular BH4 stores are diminished and thisdisturbs several physiological functions [110] It has beenproposed that BH4 deficiency due to oxidative stress isassociated with PD and AD [110] whereas the role of BH4in AMD is unclear However in the retina BH4 may havean essential role in regulation of retinal neovascularizationvia L-DOPA since L-DOPA is capable of controlling levelsof vascular endothelial growth factor (VEGF) via secretionof antiangiogenic pigment epithelial derived factor (PEDF)[117 118]

Stilbene Mediated Activation of the cAMP Pathway Con-tributes to Autophagy and Defence against Oxidative Stress Itis known that resveratrol can increase cAMP levels in cellsand animal models by their ability to inhibit cAMP phospho-diesterase [105] Phosphodiesterases (PDE) are the enzymesresponsible for degradation of cAMPand cGMP [119] second

messengers involved in the regulation of numerous genes andcellular functions

Recent findings have verified that activation of thecAMP signaling targets by stilbenes such as resveratrol caninfluence important functions in aging cells associated withantioxidant defence First cAMP is able to induce Nrf2expression in cells [120] Similarly activation of Nrf2 viacAMP can be induced by 120572-melanocyte stimulating hor-mone (120572-MSH) a known hormonal activator of G protein-coupledmelanocortin receptors and the cAMP pathway [68]Apparently activation of Nrf2 transcription by cAMP ismediated via protein kinase A (PKA) and cAMP responseelement-binding protein (CREB) In the presence of cAMPstimuli CREB can transactivate Nrf2 as well as Nrf2 targetgenes such as glutathione S-transferase pi (GSTP1) and NOS[121 122] by binding on specific cAMP response element(CRE) in promoter region [123] Second by inhibiting PDEactivity resveratrol is able to increase cellular cAMP andCa2+ levels finally activating the AMPK pathway involvedin the regulation of nutrient homeostasis [105 124] suchas autophagy as described in Section 42 The AMPK canincrease cellular levels of NAD+ as well as the activity ofSIRT1 [105 125] It has been shown that SIRT1 can modulatethe activity of metabolic regulators peroxisome proliferator-activated receptor 120574 coactivator-1120572 (PGC-1120572) and ERR120572[102 126] However information regarding the interactionbetween theAMPK andNrf2ARE pathways is contradictoryIt was shown recently that known AMPK pathway inducersAICAR and berberine can also induce theNrf2ARE pathway[104 127] whereas in contrast it was shown that deacetylationof Nrf2 by SIRT1 decreases DNA binding activity of Nrf2causing decreased promoter activity of Nrf2 targets such asHO-1 and NQO1 [67] This was also verified with resveratrolwhich was shown to act as a SIRT1 activator

Polyphenols Are Involved in Regulation of Nuclear Recep-tors (NRs) The large family of NRs including nuclearhormone receptors and orphan receptors with somewhatunknown ligands is associated with multiple functions inthe human body from development to hormonal regulationand metabolism In particular NRs are also involved inthe metabolism of xenobiotics [128 129] and therefore NRsand their targets are under intense investigation in drugindustry Interestingly current data suggests that severalpolyphenolic compounds can activate different NRs Thisseems reasonable since the Nrf2ARE pathway and someNRs are activated by phytochemicals and xenobiotics andthey are thought to participate with regulation of xenobioticmetabolizing enzymes such as CYP3A4 and NQO1 [69 130131] In such interactions polyphenols can act as a ligandfor nuclear receptor (resveratrolERs) or activation of NRs ismediated via Nrf2 as has been found with retinoid X receptoralpha (RXRa) [72] For instance Nrf2 has been shown tobind aryl hydrocarbon receptor (AhR) promoter and viceversa AhR element is found from Nrf2 promoter [69] AhRis involved in cytokine and growth factor signaling andparticularly it is a regulator of several xenobioticmetabolizingenzymes activated by exogenous ligands such as dioxins [132]Furthermore Nrf2 and AhR have shared target genes such


as NQO1 GSTs and UDP-glucuronosyltransferases (UTGs)[78 133] It should be noted that activation of UTG1A8andUTG1A10 phase-II enzymes involved in glucuronidationmediated elimination of xenobiotics requires cooperativeinduction via both factors AhR and Nrf2 [81] Moreoveractivation of NRs can also be mediated via kinase pathwayssuch as the AMPK-SIRT1 pathway in case of ERR120572 regulation[102]

Estrogenic Activity of Stilbenes Interestingly it seems thatsome beneficial effects of stilbene derivatives in neuronaland vascular cells are mediated via ERs typically activatedby estrogens (17120573-estradiol) [134] In addition to estro-gens ERs can also bind nonsteroidal compounds such asphytoestrogens [135] For instance the ER-specific agonistfunctions of resveratrol are thought to be attributable to itsstructural similarities with estrogens thus resveratrol andsome stilbene derivatives can be classified as selective ERmodulators (SERMs) [135 136] Recently it has been shownthat resveratrol can act through estrogen receptors (ER120572and ER120573) to exert neuroprotective activity [137] and it canincrease the expression of the dopamine transporter (DAT) indopaminergic cells [138]Moreover it seems that ERs can alsomediate the beneficial effects of resveratrol in vascular cellssuch as vasodilatation by increasing cGMP synthesis eNOSactivity and NO production [106]

5 Therapeutic Potential of Stilbenes againstOxidative Stress and Age-Related Diseases

51 Obesity Obesity is a major global health problem forexample it is one of the major risk factors for T2D Thewestern life style including high energy food intake and inad-equate physical activity is the cause of adipocyte dysfunctionleading to the storage of extra energy as triglycerides Therelease of proinflammatory cytokines from visceral adiposetissue liver insulin resistance and inflammation lead to anincreasing risk of several metabolic diseases [139] Preventionof extra energy storage via caloric restriction is a well-documentedmeans to reduce obesity to increase the life span[140ndash142] and even to prevent the memory decline [143]However the current obesity problem indicates clearly thatalthough lifestyle changes are effective in practice they arevery difficult to achieveThemolecular mechanism of obesityhas not been fully clarified but an increase in the numberand size of adipocytes differentiated from preadipocytes inmature adipocytes seems to be a key pathway in the routetowards [144] It has long been known that resveratrol canmimic some of the impacts of calorie restriction (CR) butstilbene compounds may mediate their antiobesity actionalso by reducing the synthesis of lipids in adipocytes mod-ulating of lipolysis and reducing inflammation and oxidativestress in the target tissue [140] Although there are abundantdata suggesting that stilbene compounds such as resveratrolmay increase lifespan through the modulation of insulinsignaling even on a high-calorie diet the practical outcomesof these findings is far from clear [145 146] Moreovercomparison of the effectiveness of CR and resveratrol to theHFD-induced obesity and fatty liver formation in C57Bl6J

mice lead to the finding that CR provided superior protectionagainst diet-induced obesity and fatty liver formation com-pared with resveratrol [147]

Stilbene compounds presumably act on severalmoleculartargets in adipocytes eventually leading to the decreas-ing levels in adipocyte number and size With respectto the recently synthesized several stilbene analogues 3-hydroxy-trans stilbene inhibited adipocyte differentiationand enhanced glucose uptake resulting in a reduction ofobesity [148] The impact of resveratrol on fat cell apoptosishas not been intensively studied but it has been reported thatresveratrol inhibited human preadipocyte proliferation andadipogenic differentiation in a SIRT1-dependent manner andde novo lipogenesis was inhibited in parallel with a down-regulation of lipogenic gene expression [149] SIRT1 maywidely regulate fatty acid oxidation in liver fatmobilization inwhite adipose tissue insulin secretion in pancreas and sensenutrient availability in hypothalamus [150] However resver-atrol reduced fat cell number also via SIRT1-independentmechanism [151] Thus the apoptotic effects of stilbenes in3T3-L1 preadipocytes may be complex and involve severalpathways such as AMPK AKT and survivin [152]

Peroxisome proliferator-activated receptor-120574 (PPAR120574) isan important regulator of lipid and energy metabolism aswell as one of key factors in the differentiation of adipocytesIn a microarray analysis it was demonstrated that therewere changes identified in 35 genes involved in the PPAR120574signaling pathway lipid metabolism or adipogenesis inadipocytes treated with grape seed extract (GSE) [153]Most of these genes involved in PPAR120574 signaling AdipoqScd1 Nr1h3 Fabp5 Scd2 and Pparg decreased upon GSEtreatment whereas the expression of Ppargc1a was ele-vated [153 154] However lipid metabolism-associated genesMlxp1 Stat5a Hsl Plin1 and Vdr were downregulated ThusGSE containing resveratrol has been claimed to modulatekey transcription factors including peroxisome proliferator-activated receptor CCAATenhancer-binding proteins andtheir target genes (FAS aP2 SCD-1 and LPL) It remains to bedetermined whether a novel regulator of mammalian targetof rapamycin complex 1 (mTORC1) plays an important rolein the stilbene-mediated adipocyte differentiation of 3T3-L1preadipocytes and potential prevention of obesity as foundfor other polyphenols [155]

Lipolysis regulates the key metabolic roles in the for-mation of adipose tissue size weight and obesity and twoenzymes adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are involved in the lipolytic activityHSL is active against diglycerines while ATGL selectively acton the first step in the triglycerine hydrolysis resulting in theformation of diglycerines and free fatty acids [156] Stilbenecompounds can modulate lipogenesis in many ways forexample using knockout mice it was found that resveratrolregulates lipolytic activity in human and murine adipocytesas well as in white adipose tissue frommice mainly via ATGLat transcriptional and posttranscriptional levels [156] SIRT1and FOXO1 (Forkhead box proteinO1) involve the regulationof lipolysis so that SIRT1 probably affects the acetylationstatus and functional activity of FoxO1 so that it may directlybind to the ATGL promoter [157] thus it apparently regu-lates ATGL gene transcription Two other studies [158 159]


provide support for the important role of SIRTI and FOXO1in the regulation of transcriptional expression of ATGL inadipocytes Gene expression patterns of two human tissuesamples (subcutaneous abdominal adipose tissue SAT andvisceral adipose tissue VAT) derived from nonobese and classIII obese subjects were recently analyzed [160] Interestinglyadiponectin expression was lower only in VAT of obesesubjects while FOXO1 and PPAR120574 levels were decreased inVAT of both groups However there was no difference withregard to the SIRT1 levels in VAT or SAT in both groups

AMPK is an important regulator of energy metabolismand thus it is a key component in obesity regulation There isan abundance of data indicating that resveratrol can activateAMPK for example [145] Resveratrol may activate AMPKvia inhibition of ATP production but this action seems to bedependent on high doses of resveratrol [161] Importantly itwas shown that resveratrol increased cAMP levels by com-petitively inhibiting a number of cAMP phosphodiesterases(PDEs) [105 161] which degrade cAMP this suggests thatPDE4 inhibitorsmay be used to develop drugs or special foodsupplements for therapeutic options for obesitymanagement

Obesity is known to be related with chronic low-grade inflammation condition leading to the productionof a number of inflammatory cytokines chemokines andprostaglandins which eventually can lead to the developmentof insulin resistance Consequently targeting specific stilbenecompounds to prevent or inhibit the inflammation cascademay be attractive means to reduce obesity and T2D Thereis an extensive literature that different stilbenes includingpinosylvin piceatannol and resveratrol can reduce the devel-opment of inflammatory cytokines [9 162 163] Stilbenes andGSEs appear to mediate the attenuation of inflammation andinsulin resistance apparently by suppressing the activationof extracellular signal-regulated kinase (ERK) c-Jun N-terminal kinase (JNK) and NF-120581B (nuclear factor kappa-light-chain-enhancer of activated B cells) [164 165] butthe anti-inflammatory property may also involve the SIRT1pathway [166] In rats resveratrol may mediate body-fatreduction also via the modulation of thermogenesis as UCPprotein was increasingly expressed after resveratrol treatmentin the important thermogenic levels [167]

Collectively in vitro and animal studies suggest thatstilbenes mediate their antiobesity action via severalmechanisms including the inhibition of lipid synthesis inadipocytes modulation of lipolysis modulation of apoptosisor mTORC1 and activation of AMPK via inhibition of ATPproduction as well as reducing inflammation and oxidativestress in the target tissue The development of specificweight management food products focusing at multiplemolecular targets may be a promising avenue for enhancingthe antiobesity effect but this approach may benefit fromthe combination of distinct polyphenols in the product[168 169]

52 Type 2 Diabetes Type 2 diabetes mellitus (T2D) is arapidly and globally increasing complex metabolic disorderassociated with elevated insulin resistance decreased insulinsecretion impaired insulin signaling hepatic 120573-cell dys-function abnormal glucose and lipid metabolisms elevated

inflammatory burden and increased oxidative stress Drugsare widely used to maintain the normal blood glucose levelto prevent the development of hyperglycemia whichmay leadto a number of diabetic complications It is well documentedthat diet is one of major risk factors for the developmentof metabolic disorders leading to T2D and increasing datasuggests that a diet rich in polyphenols and fiber may lowerthe incidence of T2D by reducing the major predisposingmetabolic risk factors

A considerable amount of in vitro and preclinical dataimplicates that stilbene compounds may lower risk factorsbehind T2D via several mechanisms There are recent ani-mal trials suggesting that stilbene compounds particularlyresveratrol may reduce blood glucose levels in mice ratsand rodents with hyperglycemia and also modulate insulinlevels In a recent mice trial both low (0005) and highlevels (002) of resveratrol diet given for six weeks sig-nificantly decreased blood glucose plasma free fatty acidtriglyceride and apo Bapo AI levels and increased plasmaadiponectin levels [170] Decreased glucose levels were foundto be associated with activated levels of AMPK and itsdownstream targets leading to decreased blood HbA1c levelshepatic gluconeogenic enzyme activity and hepatic glycogenHowever only after high dose resveratrol supplementationthere were increases in levels of insulin pancreatic insulinprotein and skeletal muscle GLUT4 protein Furthermorethere is a report that although low dose (30mgkg dailyfor two weeks) treatment could lower fasting glucose levelthe resveratrol treatment enhanced insulin action only underinsulin-resistant conditions and the treatment efficacy wasfound to depend on the target tissue and its metabolic stage[171] In an experiment in T2D model dbdb mice anotherstilbene treatment (piceatannol) was noted to enhance glu-cose uptake AMPK phosphorylation and GLUT4 translo-cation to the plasma membrane in conditions of insulinabsence [172] Interestingly they found that piceatannolsuppressed the elevations in blood glucose levels in theearly stages and improved the impaired glucose tolerancein the later stages in dbdb mice In a rat trial it wasshown that resveratrol treatment inhibited HFD-inducedglucose intolerance and insulin resistance in ovariectomizedrats [173] Furthermore increased insulin-stimulated glu-cose uptake was demonstrated in isolated soleus musclein vivo and in C2C12 myotubes in vitro with mechanismattributed to enhancement of GLUT4 translocation to theplasma membrane rather than increasing GLUT4 proteinexpression Interestingly they were able to show that CAV-3protein (caveolin family proteins) expression was increasedafter resveratrol treatment which contributed to GLUT4translocation120572-Glucosidase and 120572-amylase are digestive enzymes

participating in starch and disaccharide degradation Byinhibiting the action of these enzymes with drugs (egacarbose and voglibose) it is possible to slow down glu-cose absorption from intestine to bloodstream and henceto reduce postprandial hyperglycemia In addition manypolyphenols are capable of inhibiting 120572-glucosidase and 120572-amylase enzyme activity Numerous vegetable herbal fruitand berry extracts especially those rich in flavonols ellagi-tannins anthocyanins phenolic acids and their derivatives


have demonstrated in vitro inhibitory activity with respectto both 120572-glucosidase and 120572-amylase [174ndash176] Howeverlittle is known about the impact of stilbenes on thesemolecular targets Some stilbenoids and stilbene glycosides(eg 41015840-O-methyl piceid rhapontin rhapontigenin anddesoxyrhapontigenin) from rhubarb (Rheum palmatum andRheum emodi Wall ex Meissn) have been observed toinhibit and modulate 120572-glucosidase activity [177 178] Inaddition trans-stilbenes resveratrol and rumexoid from theroots of buckwheatRumex bucephalophorous andmonomericand dimeric stilbenoids (eg piceatannol resveratrol andscirpusin) from the seeds of palm Syagrus romanzoffianahave revealed inhibitory activity against 120572-glucosidase [179180] For example piceatannol dimers trans double bondtetrahydrofuran ring and free adjacent phenolic dihydroxylsmay be important features in the inhibitory properties [181]Based on in vitro assay and docking studies resveratrol-3-O-glucosidase from grape skin extracts has been speculated tobind to 120572-amylase in an inhibitory manner [182] It has alsobeen postulated that biotransformation for example dimer-ization of stilbene compoundsmay be a way to enhance theirefficacies as antihyperglycemic agents [181]

Insulin suppresses lipolysis in both transcriptional andposttranscriptional levels in adipose tissue Apparentlyinsulin signaling acutely inhibits beta-adrenergic signalingby decreasing intracellular cyclic AMP (cAMP) levels andthe rate of lipolysis [183] Moreover in the case of insulinresistance and T2D attenuation of lipolysis by insulin actionis impaired leading to an increased rate of lipolysis andenhanced release of free fatty acids (FFA) in the circulation[183] A very interesting novel protective mechanism ofresveratrol against aging-related metabolic degeneration wasdescribed by Park et al [105] They hypothesized that themetabolic impact of resveratrol results fromcompetitive inhi-bition of cAMP-degrading phosphodiesterases Apparentlyelevated cAMP levels can activate a cAMP effector protein(Epac1) leading to higher concentrations of intracellularCa2 eventually this will lead to the increasing uptake ofresveratrol and elevated NAD+ levels and increased activityof SIRT1 It has therefore been postulated that the inhibitionof PDE4 activity via bioactive compounds may protect fromor ameliorate the symptoms of metabolic diseases associatedwith aging such as T2D

There is considerable data highlighting the vital role ofoxidative stress as an important risk factor in development ofT2D Activation of antioxidant defence and phase II enzymesis a keymechanism to protect cells from the oxidative damageinvolved in age-related diseases such as T2D By usingmethylglyoxal (MG) as a tool to induce insulin resistance inHepG2 cells Cheng et al [80] demonstrated that resveratrolactivated ERK pathway but not the p38 or JNK pathways andthis eventually led toNrf2 nuclear translocation and elevationof HO-1 and glyoxalase expression levels Furthermore theyfound that resveratrol significantly elevated glucose uptakeand protected HepG2 cells against MG-induced insulinresistance Recently when a 20mgkg daily dose of resveratrolwas administrated for 12 weeks to dbdb mice improvedglucose tolerance attenuated 120573-cell loss and reduced oxida-tive stress were documented [184]The protective function of

resveratrol against cellular oxidative stress through the SIRT1-FOXO pathway under high-glucose (HG) conditions wasrecently demonstrated [185] Under HG conditions in vitroSIRT1 and FOXO3a were significantly decreased comparedwith normal glucose conditions and this was reversed byresveratrol treatment concomitant with the reduction in HG-induced superoxide production and p47phox Thus the datasuggests that resveratrol decreases HG-induced superoxideproduction via upregulation of SIRT1 induction of FOXO3aand inhibition of p47phox in monocytes Although a vastnumber of in vitro and animal studies hint at the vital roleof oxidative stress in T2D more clinical data however areneeded to confirm this hypothesis

T2D is also an inflammation-related disease expandedvisceral adipose tissuemay disturb insulin signaling pathwaysby excreting inflammatory factors It has long been knownthat anti-inflammatory agents may be one therapeutic meansto reduce the risk of developing this disease A wide bodyof data indicates that stilbene compounds demonstrate anti-inflammatory properties in vitro

Overall the accumulated data suggest that stilbene-likepolyphenols can modulate blood glucose and insulin levelsand reduce oxidative stress and inflammation meaning thatthis represents a rational molecular target for novel target-specific food product development

Beneficial Role of Stilbenes on Diabetic Vascular DiseasesDiabetes has been shown to associatewith the development ofcardiovascular diseases (CVD) such as atherosclerosis [186]In CVD vascular inflammation increased platelet aggrega-tion and decreased levels of vascular nitrogen oxide (NO)production disturb the functions of the vascular endothelium[187] In vascular endothelium oxidative stress decreasesNO bioavailability and in the presence of superoxide anion(O2minus) it increases the formation of peroxynitrite (ONO

2

minus)a powerful oxidant [106] Although NO is a free radicalit is also an important cellular signaling molecule and amajor regulator of vascular functions such as vascular toneplatelet aggregation and vascular proliferation [106 187] Inthe vascular endothelium NO is synthesized by endothelialnitric oxide synthase enzyme (eNOS) with the assistance oftetrahydrobiopterin (BH4) an essential cofactor of eNOS[116] Importantly it has been shown that in CVD anddiabetes decreased NO levels are a result of ROS inducedelimination of BH4 stores in vascular endothelium [106 108188]

The cardioprotective functions of stilbene compoundssuch as piceatannol and resveratrol have been intensivelystudied in animals [145 189] and in humans [112 190ndash192]Several molecular targets for stilbenes with cardioprotectiveactivity such as cyclooxygenases (COX-1 and COX-2) eNOSNrf2 ERs and SIRT1 have been proposed [188] Resveratroland piceatannol can support endothelial functions such asvasorelaxation by increasing NO production and by reducingROS via eNOS and NADPH enzymes respectively [193ndash196]The beneficial effects of stilbenes in CVD are also mediatedvia regulation of cellular BH4 homeostasis It has been shownthat resveratrol decreases BH4 degradation in parallel withthe induction of BH4 synthesis via GTP cyclohydrolase 1


(GCH1) [116] Apparently the anti-inflammatory functions ofstilbenes can also be mediated via the COX enzymes [197] aswell as the Toll-like receptor 4 (TLR4) [198]

53 Neurodegenerative Diseases of the Aging Eye and BrainAMD and AD share common features with the neurode-generative aging diseases that is abnormal accumulationof insoluble protein aggregates (lipofuscin drusen and ADplaques) perturbation of autophagy clearance system andincreased cellular status of oxidative stress and inflammation[199ndash203] Moreover increased levels of labile cellular iron apowerful generator of ROS involved in oxidative stress havebeen observed in both diseases [204 205] It is noteworthythat although these diseases have similarities the geneticcomponent of AMD and AD seems to be specific for thedisease In this section the characteristics of AMD and ADthe beneficial functions of stilbenes and associated cellularmechanisms are discussed

531 Age-RelatedMacularDegeneration (AMD) Age-relatedmacular degeneration (AMD) is the leading cause of blind-ness in an aging population affecting the life of 30ndash50 mil-lion individuals [206] AMD is a multifactorial progressivedegeneration of the central retina with two distinct subforms[207] The atrophic form (dry AMD) with a prevalenceof 85ndash90 represents a major healthcare burden since noeffective cure is available The wet form of AMD (prevalence10ndash15) with choroidal neovascularization and leaky bloodvessels under the macula is more severe and has fasterprogression AMD initiates from the RPE eventually leadingto degeneration of photoreceptors

In AMD patients retinal changes such as the formationof extracellular deposits (drusens) [208] accumulation ofRPE lipofuscin [209] chronic inflammation [210] impairedautophagy [211] and neovascularization [212] are frequentlyobserved In addition to aging genetic component smokingextensive light exposure and decreased RPE pigmentationare known to be risk factors for AMD [213 214] In particularthe probability of increased chronic oxidative stress triggeredby several factors unique for the eye seems to play centralrole in development of AMD [215] First RPE is located inexceptionally oxygen rich environment next to the choroidalvasculature network [215] Second due to continuous phago-cytosis of photoreceptor outer segments (POS) RPE cellsare repeatedly exposed to lipid peroxidation products [216]and to the phototoxic lipofuscin intermediate bisretinoidA2E [217 218] Third during its lifespan RPE is exposed tointense stress and photobleaching of RPE melanin causedby sunlight and UV-radiation [214 219] In healthy RPEtissue melanin is a potent scavenger of free radicals whichalso inhibits lipid peroxidation absorbs UV-radiation andchelates metals such as labile iron [220 221] Labile ironis capable of inducing a Fenton reaction in cells which isa powerful generator of free radicals and oxidative stress[205 222 223] Reduced levels of RPE melanin pigment[219 224ndash226] are commonly observed in AMD patientswith concurrent increase of cytotoxic levels of labile ironin the RPE [204] In addition to the devastating generalactions of ROS in cells increased levels of oxidative stressmayspecifically disturb fundamental functions of the RPE such as

POS phagocytosis [227] visual cycle [93] and the integrity ofthe RPE barrier functions [228]

The reduced antioxidant capacity in the RPE is knownto associate with age For instance data from mouse modelsindicates that the Nrf2 system declines with age subjectingRPE cells to oxidative stress [229] It seems that Nrf2 isinvolved in the maintenance of retinal functions in general asrevealed by current data obtained fromNrf2 knockoutmousemodel showing that perturbation of the Nrf2ARE pathwayhas a remarkable role in development of age-related signs inretina AMD [71 230] Nrf2 knockout mouse seems to displayall of the typical hallmark retinal changes encountered inAMD such as drusens lipofuscin choroidal neovasculariza-tion (CNV) and changes in RPE pigmentation Experimentswith Nrf2 deficient mice indicate that Nrf2 is also involvedin reducing the chronic inflammation in the eye [231] Afterinflammation induced by lipopolysaccharide (LPS) Nrf2deficient mice displayed increased levels of inflammationmarkers (ICAM IL-6 TNFa MCP-1 COX-2 and iNOS) inthe retina in comparison to their wild-type counterparts

It is claimed that polyphenolic compounds can exert aprotective effect against the stress associated with aging ofretinal cells In particular the induction of phase II enzymesvia the Nrf2 pathway seems to play a key role in this defencesystem For instance pinosylvin was revealed to protectARPE-19 cells (human RPE cell line) against oxidative stressmediated via the Nrf2 pathway by inducing HO-1 expression[232] and quercetin reduced the levels of inflammationmarkers IL-6 and IL-1120573 after oxidative stress induction inARPE-19 cell line [233] Similarly hydroxytyrosol a phenoliccompound present in olive oil and red wine has beendemonstrated to activate Nrf2 HO-1 NQO-1 GCL GSHand p62 expression in ARPE-19 cells and interestingly GSHproduction was partially mediated via induced p62 expres-sion [234] Convincing evidence indicates that accumulationof p62 due to an impairment of the autophagy process isassociated with degeneration of RPE cells [90] Impairedautophagy clearance has been shown to associate with AMD[90 212] There is growing data that polyphenols can alsomodulate autophagy clearance mediated via the cAMP andAMPK pathways (see Section 43) [100 235]

There are interesting results indicating that polyphenolscan also influence the secretion of specific growth factorsassociated with AMD and other retinal diseases such asdiabetic retinopathy In a long-term trial of a small group ofelderly AMD patients daily administration of a polyphenolsupplement containing 100mg resveratrol quercetin api-genin ferulic acid and so forth exerted a beneficial effect onretinal integrity and anti-VEGF activity as well as an improve-ment of visual function [236] In mice resveratrol has beenshown to suppress angiogenesis [237] Similarly resveratrolwas able to decrease oxysterol induced VEGF secretion inARPE-19 cells [238] It is noteworthy that cigarette smokeis a major risk factor in AMD [230] Cigarette smokecontains abundance free radicals such as hydroquinone (HQ)and these can decrease the levels of antiangiogenic PEDFaccompanied by a simultaneous increase in the VEGF levelsin RPE cells of smoking AMD patients [239] This is feasiblebased on evidence detailing the role of PEDFas an inhibitor of


choroidal neovascularization (CNV) in the retina [117 240]A recent study conducted in ARPE-19 cells revealed that10 120583M resveratrol was able to prevent platelet-derived growthfactor (PDGF) induced RPE cell proliferation and migrationwhich are common phenomena in AMD diabetic retinopa-thy and proliferative vitreoretinopathy [241] The beneficialeffects of resveratrol have also been demonstrated in animalmodels where the animals were subjected to different retinalinjuries such as retinal detachment [240] retinal ischemicinjury [242 243] light-induced retinal degeneration [244]endoplasmic reticulum stress related vascular degeneration[245] and retinal ganglion cell degeneration associated opticnerve injury [246]Moreover the beneficial effects of resvera-trol against inflammation have been observed inmousemod-els For instance the activation of SIRT1 and the decreasednuclear localization of NF-120581B achieved by resveratrol wereassociated with reduced oxidative stress and a decrease ininflammation in the mouse retina [247] A similar type ofaction was found with the resveratrol analog piceatannol inthe retina In rodents this compound has been shown tosuppress endotoxin induced ocular inflammation [248] aswell as Toll-like receptor 4 (TLR4) mediated inflammatoryresponse and retinal damage occurring after retinal ischemia[249]

Taken together polyphenols seem to exert numerousbeneficial effects in retinal cells and thus they display apotential for the prevention of retinal diseases such as AMDIn addition to their direct antioxidant activity polyphenolsseem to display beneficial effects in the eye through anti-inflammatory activity and activation of autophagy as well asby induction of phase II enzymes via the Nrf2 pathway Thusone can speculate that polyphenols may support integrityof the retina by controlling the expression and secretion ofmany of the growth factors such as VEGF PEDF and PDGFinvolved in neovascularization and cell proliferation

532 Alzheimerrsquos Disease (AD) Alzheimerrsquos disease (AD) isa devastating neurodegenerative disorder exhibiting synapticchanges and neuronal loss in the hippocampus and cerebralcortex in the central areas of the brain involved in memoryand cognition Accumulation of extracellular plaques ofamyloid 120573 (A120573) peptide and aggregation of microtubule-associated protein tau into insoluble intracellular neurofib-rillary tangles are the characteristic hallmarks of AD About25 of the US population carries two genetic risk genes forApoE4 the cholesterol-carrying protein which increases therisk of developing AD by about 10-fold [250] Despite inten-sive research and drug development there is still no effectivetherapy against AD and at present preventive approaches arethought to be the best way to address this growing publichealth problemThere are epidemiological studies indicatingthat the consumption of phenolic-containing berries fruitand vegetables can lower the risk of AD [3 251] For exampleindividuals drinking three or more glasses of fruit or veg-etable juice per week have been shown to lower by over 50their risk of AD in comparison to individuals who consumedless than one serving per week [251] The protective activityconferred by the bioactive polyphenols in the juice is likelyto be a result of multiple-target properties such as impaired

insulin and insulin-like growth factor (IGF) signaling A120573and tau-protein accumulation synaptic disconnection andimpaired energy in addition to limiting damage due to ofoxidative stress and inflammation

Since polyphenols have difficulties passing through theblood-brain barrier following oral administration the result-ing low concentration of polyphenols in the brain tissue hasbeen thought as limiting their use againstAlzheimerrsquos diseasebut it was recently shown that resveratrol and particularlyresveratrol metabolites can reach such concentrations in thebrain capable of achieving beneficial physiological changes [747 252] For example a higher concentration of resveratrolwas achieved in the rat brain tissue when the compoundwas dispensed in lipid-core nanocapsules [47] Importantlythe enhanced penetration of resveratrol into the brain wasfound to protect tissue from the deleterious effect of A1205731-42 and the subsequent impairment of memory functionsmore effectively than resveratrol treatment without lipid-corenanocapsulation Furthermore the polyphenol metabolitequercetin-3-O-glucuronide was found to significantly reducethe generation of A120573 peptides by primary neuron culturesobtained from the Tg2576 AD mouse model [252] Interest-ingly quercetin-3-O-glucuronidewas also capable of interfer-ing with the initial protein-protein interaction of A120573 (1ndash40)and A120573 (1ndash42) necessary for the formation of the neurotoxicoligomeric A120573 species [252] These are important findingssince it is known that A120573 which is released after sequentialcleavage of amyloid precursor protein (APP) by 120573- and 120574-secretases is a key participant in AD pathogenesis [253] Tauprotein is known to be abnormally hyperphosphorylated inAD and aberrant tau phosphorylation contributes to the neu-ropathology of AD Administration of polyphenol-rich GSEhas been shown to interfere with the assembly of tau peptidesinto neurotoxic aggregates suggesting that polyphenols suchas stilbenes can directly modulate the aggregation process oftau [254] Interestingly feeding mice for four months witha protein restriction (nonessential amino acid) based dietachieved a cognitive improvement and reduced pathologicalchanges associated with altered tau phosphorylation anddisturbed levels of IGF-1 [255]This observation suggests thatprovision of polyphenols and a protein restriction diet maymediate their neuroprotective action via common molecularmechanisms There are recent findings indicating that onlythe apolipoprotein ApoE4 allele significantly decreases theratio of soluble amyloid precursor protein alpha (sAPP120572)to A120573 and is able to reduce SIRT1 expression resulting inmarkedly differing ratios of the levels of neuroprotective SirT1to the neurotoxic SIRT2 as well as also triggering Tau andAPP phosphorylation [250] Stimulation of innate immunityvia the Toll-like receptors such as TLR9 has been reported toeffectively reduce the amyloid burden [256] but it remains tobe determined whether stilbene compounds have sufficientefficacy to activate innate immunity

Brain-derived neurotrophic factor (BDNF) plays a keyrole in brain cell development growth and survival since thisgrowth factor promotes synaptic plasticity in the hippocam-pus For example BDNF mediates neuroprotective and cog-nitive function via inhibiting food intake and increasingenergy expenditure in the hypothalamus [257]There is some


data indicating that stilbenes may directly modulate brainsynaptic plasticity Treatment of rats for 3 10 and 30 dayswithresveratrol significantly and dose-dependently elevated thelevels of BDNFmRNA expression in hippocampal tissue sug-gesting that the resveratrol mediated neuroprotective impactmay be related with activation of the BDNF pathway [258]Recently grape powder extract was found to prevent oxida-tive stress-induced anxiety memory impairment and hyper-tension in rats by regulating also brain CREB and BDNFlevels [259] Furthermore blueberry-fed animals exhibited afaster rate of learning and better spatialmemory performanceas compared to those on the control diet providing furtherevidence that polyphenolsmaymediate their neuroprotectiveaction via BDNF [260] Importantly it was also observedthat the improved behavioral performance was associatedwith increases in total CREB and elevated levels of pro- andmature BDNF in the hippocampus Recent important find-ings have indicated that the monomeric proanthocyanidinmetabolites seem to be the key PAC metabolite that is ableto attain concentrations of sim400 nM in brain and improvecognitive function [7] They further revealed that one ofthe epicatechin metabolites 31015840-O-methyl-epicatechin-5-O-120573-glucuronide could enhance synaptic plasticity throughmechanisms associated with CREB signaling

Autophagy the lysosomal mediated degradative pathwayfor proteins and organelles may be essential for the survivalofmature neurons but the underlyingmechanisms remain tobe elucidated However Marambaud and coworkers reportedthat resveratrol could not inhibit A120573 production since ithad no apparent effect on the A120573-producing enzymes beta-and gamma-secretases but instead it promoted intracellulardegradation of A120573 via amechanism involving the proteasome[261] Subsequently considerable data have accumulated thatautophagy is involved in the resveratrol mediated protectionagainst oxidative stress inflammation and associated cardio-vascular cancer and neurological diseases [262] Resveratrol-mediated autophagy mechanisms may be dose-dependent[263] but their importance in neuroprotection however stillremains to be clarified

There is a growing body of experimental data stronglysupporting the hypothesis that CR is a significant way toextend longevity and delay many age-related diseases reviewby [143 264 265] The protective action of CR is potentiallymediated via a reduction of inflammation and oxidativestress but recent data have highlighted the possibility thatCR may modulate also critical signaling pathways such asIGF-1insulin signaling sirtuin AMPK and mTOR path-ways [255] These metabolic pathways are considered as keyrisk factors affecting brain health and AD However onerecent report suggested that part of the beneficial metabolicimpacts may not simply be due to general CR but alsothe food ingredients in the CR diet may play a role sincethose individuals consuming a CR diet had high intakesof vegetables berries and fruits which contain substantialamounts of bioactive compounds [265] Stilbenes such asresveratrol are considered to exhibit to some degree of CRmimetic properties via the action on sirtuin By using SAMP8(Senescence-accelerated mouse mice) it was revealed thatlong-term resveratrol treatment could reduce the cognitive

impairment by reducing the amyloid burden and tau hyper-phosphorylation [266] It was further demonstrated thatresveratrol activated AMPK pathways and prosurvival routessuch as SIRT1 in vivo However in the same SAMP8 micemodel resveratrol and another stilbene pterostilbene didnot increase SIRT1 expression although markers of cellularstress and inflammation and reduced AD pathology werepositively modulated by pterostilbene but not resveratrol [8]hence pterostilbenersquos higher bioavailability (ie better thanresveratrol) may have important protective implications

There is emerging evidence suggesting that AD is fun-damentally a metabolic disease and brain glucose utilizationand responsiveness to IGF stimulation may play key rolesbehind neuronal loss loss of synaptic connections tauhyperphosphorylation and A120573 accumulation [267] Thussuppression of energy expenditure by modulation AMPKglucose transport and the insulin pathway via stilbene-likepolyphenols may represent a promising avenue to delay theonset of AD and slow disease development Importantlyresveratrol was able to activate AMPK in neuronal cells invitro as well as in the brain and it enhanced activation ofmitochondrial biogenesis in an AMPK-dependent manner[268] There are several animal experiments indicating thatsupplementation with stilbenes (resveratrol and piceatannol)can enhance glucose uptake AMPK phosphorylation andGLUT4 translocation (see diabetes section) but very fewhuman trials have been performed Interestingly when mice(C57BL6 Jl) were fedwithHFD (high-fat diet) supplementedwith resveratrol for 20 weeks there were signs of reducedinsulin resistance lower levels of tumor necrosis factor-120572 andIba-1 in hippocampus as well as improvements in the normalmemory deficits in HFD-fed mice [269]

Taken together there is an impressive body of in vitro andanimal data to suggest that stilbenes mediate their neuropro-tective action via several mechanisms that is through themodulation of generation ofA120573 and tau peptidesmodulationof brain synaptic plasticity via BDNF modulation of brainenergy expenditure via AMPK glucose transport and insulinpathway and reducing inflammation and oxidative stressburden Experiments in mice models of ADs have indicatedthat polyphenol based diets can alleviate the spatial workingmemory deficit and some other cognitive traitsThese studiesprovide new ideas for the development of novel target-specificmedicinal foods and dietary supplements for the everincreasing elderly population

6 Lessons from Preclinical and Clinical Trials

There is convincing epidemiological data emphasizing that adiet rich in vegetables and fruits confersmany health benefitsThere is also increasing preclinical data obtained in variousanimal models indicating that polyphenols such as stilbenescan target critical sites involved in the disease process andultimately alleviate disease outcomes However very fewwell-planned clinical trials are available which would haveprovided solid evidence for the health benefits of stilbenes forhumans

Recently a very interesting long-term trial determiningthe impact of resveratrol supplementation on adipose tissue


insulin signaling and inflammatory response was reportedusing rhesus monkeys as the model [270] Two-year supple-mentation with 80 and 480mgday for the first and secondyear respectively was found to decrease adipocyte sizeincrease SIRT1 expression decrease NF-120581B activation andimprove insulin sensitivity in visceral but not subcutaneousWAT (white adipose tissue) in the HFS-fed animals Further-more the impact of resveratrol supplementation on obesityhas been evaluated in a few clinical trials For example11 healthy obese men were supplemented with 150mgdayresveratrol in a randomized double-blind crossover studyfor 30 days [271] Resveratrol treatment activated AMPKincreased SIRT1 and PGC-1120572 protein levels improvedmusclemitochondrial respiration on a fatty acid-derived substrateelevated intramyocellular lipid levels and decreased intra-hepatic lipid content reduced levels of circulating glucosetriglycerides alanine-aminotransferase and decreased thelevels of inflammation markers Furthermore declines wereobserved in the systolic blood pressure adipose tissue lipol-ysis and plasma fatty acid in the postprandial stage Interest-ingly resveratrol supplementation for 30 days in obese menmodulated postprandial glucagon responses [105] it is knownthat glucagon and related hormones may stimulate adenylatecyclases (AC) resulting in increased cAMP production [161]

In a long-term human trial molecular changes in periph-eral blood mononuclear cells (PBMCs) associated with theone-year daily intake of a resveratrol grape extract (GE) andGE enriched 8mg of resveratrol (GE-RES) in hypertensivemale patients was studied [272] This data revealed thatGE or GE-RES did not affect body weight blood pressureglucose HbA1c or lipids but a significant reduction in thelevels of ALP (alkaline phosphatase) and IL-6 was recordedThe expression of the proinflammatory cytokines CCL3IL-1120573 and TNF-120572 was significantly reduced and that ofthe transcriptional repressor LRRFIP-1 increased in PBMCsfrom patients consuming the GE-RES extract Furthermorea group of miRs (microRNA expression) involved in theregulation of the inflammatory response that ismiR-21miR-181b miR-663 miR-30c2 miR-155 and miR-34a were foundto be highly correlated and altered in the group consumingtheGE-RES for 12monthsThus this human trial provided thefirst indication that long-term supplementation with a GE-RES could downregulate the expression of key proinflamma-tory cytokines suggesting that this polyphenol treatmentmayhave a true beneficial immunomodulatory impact in humanssuffering from hypertension [272] A recent meta-analysisbased on eleven human clinical trials (involving a total of 388subjects) indicated that resveratrol supplementation couldsignificantly reduce fasting glucose insulin hemoglobin A

1cand insulin resistance levels in participants with diabetes butno significant impact on glycemic parameters was recordedin nondiabetic participants [4]

Epidemiological studies have indicated that greaterintakes of fruit and vegetable juices [251] as well as higherintakes of blueberries or its component anthocyanidins [3]were associated with slower rates of cognitive decline Con-sumption of the Mediterranean-type diet which consists offoods such as vegetables nuts and fish and combines micro-and macronutrients with substantial amounts of bioactive

Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1

Xenobioticmetabolism

Autophagy

Vascularendothelialfunction Neuronal

and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD

TH Hormonalregulation

Stilbenes

Figure 3 Schematic diagram showing the potential beneficialactions of stilbenes in prevention of age-related diseases

polyphenols has been also associated with decreased cogni-tive decline [273] New prospective studies performed withthe Mediterranean diet also provide evidence that not onlycan this diet slow down the progression of AD but it alsoreduces the risk of CVDs and othermetabolic disorders [274]However the therapeutic value of stilbene compounds inthe prevention of progression of AD remains to be demon-strated in long-term clinical trials with different stilbenesand variable doses There are animal trials suggesting thatdifferent stilbene compounds togethermay provide enhancedprotection above that obtained with the single compounds[275] perhaps through affecting different molecular targetsThus long-term human trials with different combinationsof stilbenes may be a promising avenue for revealing thepotential therapeutic value of stilbenes in AD managementSouvenaid a currently marketed medicinal food producthas achieved some improvements in cognitive function inpatients with AD in small human trials [276]

7 Conclusions

There is emerging in vitro and preclinical data to indicatethat stilbene compounds are capable of suppressing oxidativestress inflammation and energy expenditure as well asmodulating the secretion of neurotropic factors Howevermost of the available experimental data has concentrated onresveratrol and only limited research has been carried outwith the other stilbene compounds These other stilbenessuch as pinosylvin piceatannol and pterostilbene may havehigher biological activity than resveratrol and deserve toreceive more scientific attention The limited bioavailabilitythe low target specificity and the rapid metabolism of stil-benes represent obstacles to achieving high enough concen-trations of these compounds in plasma and the target tissuein order that they can exert their beneficial actions Howeverrecent investigations into the biological activity of polyphenolmetabolites have been promising Unlike drugs stilbene-likepolyphenols affect several keymetabolic pathways (Figure 3)


and promising therapeutic approaches may require focusingon multiple targets This may lead to the development ofnext-generation functional type foods and supplements forslowing down the increasingly common diseases such asobesity T2D AMD and AD

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors thank the Northern Savo ELY-center and theUniversity of Eastern Finland spearhead project ldquoChangingClimate and Biological Interactions Related to Forests CABIrdquofor financial support

References

[1] L Muller T Fulop and G Pawelec ldquoImmunosenescence invertebrates and invertebratesrdquo Immunity amp Ageing vol 10 no1 article 12 2013

[2] R Dai H Ge S Howard andW Qiu ldquoTranscriptional expres-sion of Stilbene synthase genes are regulated developmentallyand differentially in response to powderymildew inNorton andCabernet Sauvignon grapevinerdquo Plant Science vol 197 pp 70ndash76 2012

[3] E E Devore J H Kang M M B Breteler and F GrodsteinldquoDietary intakes of berries and flavonoids in relation to cog-nitive declinerdquo Annals of Neurology vol 72 no 1 pp 135ndash1432012

[4] K Liu R Zhou B Wang and M-T Mi ldquoEffect of resveratrolon glucose control and insulin sensitivity a meta-analysis of 11randomized controlled trialsrdquoThe American Journal of ClinicalNutrition vol 99 no 6 pp 1510ndash1519 2014

[5] M Takikawa S Inoue F Horio and T Tsuda ldquoDietaryanthocyanin-rich bilberry extract ameliorates hyperglycemiaand insulin sensitivity via activation of amp-activated proteinkinase in diabetic micerdquoThe Journal of Nutrition vol 140 no 3pp 527ndash533 2010

[6] S Vepsalainen H Koivisto E Pekkarinen et al ldquoAnthocyanin-enriched bilberry and blackcurrant extracts modulate amyloidprecursor protein processing and alleviate behavioral abnor-malities in the APPPS1 mouse model of Alzheimerrsquos diseaserdquoThe Journal of Nutritional Biochemistry vol 24 no 1 pp 360ndash370 2013

[7] J Wang M G Ferruzzi L Ho et al ldquoBrain-targeted proan-thocyanidinmetabolites for Alzheimerrsquos disease treatmentrdquoTheJournal of Neuroscience vol 32 no 15 pp 5144ndash5150 2012

[8] J Chang A Rimando M Pallas et al ldquoLow-dose pterostilbenebut not resveratrol is a potent neuromodulator in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 33 no 9 pp2062ndash2071 2012

[9] E Jeong H-R Lee J Pyee and H Park ldquoPinosylvin inducescell survival migration and anti-adhesiveness of endothelialcells via nitric oxide productionrdquo Phytotherapy Research vol 27no 4 pp 610ndash617 2013

[10] T Macickova K Drabikova R Nosalrsquo et al ldquoIn vivo effect ofpinosylvin and pterostilbene in the animal model of adjuvant

arthritisrdquo Neuroendocrinology Letters vol 31 no 2 pp 91ndash952010

[11] K Bauerova A Acquaviva S Ponist et al ldquoMarkers of inflam-mation and oxidative stress studied in adjuvant-induced arthri-tis in the rat on systemic and local level affected by pinosylvinand methotrexate and their combinationrdquo Autoimmunity vol48 no 1 pp 46ndash56 2015

[12] J Chong A Poutaraud and P Hugueney ldquoMetabolism androles of stilbenes in plantsrdquo Plant Science vol 177 no 3 pp 143ndash155 2009

[13] C Parage R Tavares S Rety et al ldquoStructural functional andevolutionary analysis of the unusually large stilbene synthasegene family in grapevinerdquo Plant Physiology vol 160 no 3 pp1407ndash1419 2012

[14] C Riviere A D Pawlus and J-M Merillon ldquoNatural stil-benoids distribution in the plant kingdom and chemotaxo-nomic interest in VitaceaerdquoNatural Product Reports vol 29 no11 pp 1317ndash1333 2012

[15] A R Fontana A Antoniolli and R Bottini ldquoGrape pomace asa sustainable source of bioactive compounds extraction char-acterization and biotechnological applications of phenolicsrdquoJournal of Agricultural and Food Chemistry vol 61 no 38 pp8987ndash9003 2013

[16] S P Pietarinen S M Willfor M O Ahotupa J E Hemmingand B R Holmbom ldquoKnotwood and bark extracts strongantioxidants fromwastematerialsrdquo Journal ofWood Science vol52 no 5 pp 436ndash444 2006

[17] M-E Garcıa-Perez M Royer G Herbette Y Desjardins RPouliot and T Stevanovic ldquoPicea mariana bark a new sourceof trans-resveratrol and other bioactive polyphenolsrdquo FoodChemistry vol 135 no 3 pp 1173ndash1182 2012

[18] A M Rimando Z Pan J J Polashock et al ldquoIn planta pro-duction of the highly potent resveratrol analogue pterostilbenevia stilbene synthase and O-methyltransferase co-expressionrdquoPlant Biotechnology Journal vol 10 no 3 pp 269ndash283 2012

[19] P Jeandet B Delaunois A Conreux et al ldquoBiosynthesismetabolismmolecular engineering and biological functions ofstilbene phytoalexins in plantsrdquoBiofactors vol 36 no 5 pp 331ndash341 2010

[20] R Preisig-Muller A Schwekendiek I Brehm H-J Reif andHKindl ldquoCharacterization of a pine multigene family containingelicitor-responsive stilbene synthase genesrdquo Plant MolecularBiology vol 39 no 2 pp 221ndash229 1999

[21] W J Hurst J A Glinski K B Miller J Apgar M H Davey andD A Stuart ldquoSurvey of the trans-resveratrol and trans-piceidcontent of cocoa-containing and chocolate productsrdquo Journal ofAgricultural and Food Chemistry vol 56 no 18 pp 8374ndash83782008

[22] R Flamini M de Rosso F de Marchi et al ldquoAn innovativeapproach to grape metabolomics stilbene profiling by suspectscreening analysisrdquo Metabolomics vol 9 no 6 pp 1243ndash12532013

[23] V Jerkovic D Callemien and S Collin ldquoDetermination ofstilbenes in hop pellets from different cultivarsrdquo Journal ofAgricultural and Food Chemistry vol 53 no 10 pp 4202ndash42062005

[24] O Tokusoglu M K Unal and F Yemis ldquoDetermination of thephytoalexin resveratrol (3541015840-Trihydroxystilbene) in peanutsand pistachios by High-Performance Liquid ChromatographicDiode Array (HPLC-DAD) and Gas Chromatography-MassSpectrometry (GC-MS)rdquo Journal of Agricultural and FoodChemistry vol 53 no 12 pp 5003ndash5009 2005


[25] H Latva-Maenpaa T Laakso T Sarjala K Wahala and PSaranpaa ldquoVariation of stilbene glucosides in bark extractsobtained from roots and stumps of Norway spruce (Picea abiesL Karst)rdquo Trees Structure and Function vol 27 no 1 pp 131ndash139 2013

[26] N KrafczykM Kotke N Lehnert andM A Glomb ldquoPhenoliccomposition of rhubarbrdquo European Food Research and Technol-ogy vol 228 no 2 pp 187ndash196 2008

[27] S Y Wang C-T Chen C Y Wang and P Chen ldquoResveratrolcontent in strawberry fruit is affected by preharvest conditionsrdquoJournal of Agricultural and Food Chemistry vol 55 no 20 pp8269ndash8274 2007

[28] S M Boue B Y Shih M E Burow et al ldquoPostharvestaccumulation of resveratrol and piceatannol in sugarcane withenhanced antioxidant activityrdquo Journal of Agricultural and FoodChemistry vol 61 no 35 pp 8412ndash8419 2013

[29] A S Ragab J van Fleet B Jankowski J-H Park and S CBobzin ldquoDetection and quantitation of resveratrol in tomatofruit (Lycopersicon esculentum Mill)rdquo Journal of Agriculturaland Food Chemistry vol 54 no 19 pp 7175ndash7179 2006

[30] AM RimandoW Kalt J B Magee J Dewey and J R Balling-ton ldquoResveratrol pterostilbene and piceatannol in Vacciniumberriesrdquo Journal of Agricultural and Food Chemistry vol 52 no15 pp 4713ndash4719 2004

[31] P Rodrıguez-Bonilla J M Lopez-Nicolas L Mendez-Cazorlaand F Garcıa-Carmona ldquoDevelopment of a reversed phasehigh performance liquid chromatography method based on theuse of cyclodextrins as mobile phase additives to determinepterostilbene in blueberriesrdquo Journal of Chromatography B vol879 no 15-16 pp 1091ndash1097 2011

[32] R Moss Q Mao D Taylor and C Saucier ldquoInvestigation ofmonomeric and oligomeric wine stilbenoids in red wines byultra-high-performance liquid chromatographyelectrosprayionization quadrupole time-of-flightmass spectrometryrdquoRapidCommunications in Mass Spectrometry vol 27 no 16 pp 1815ndash1827 2013

[33] N Landrault F Larronde J-C Delaunay et al ldquoLevels ofstilbene oligomers and astilbin in French varietal wines and ingrapes during noble rot developmentrdquo Journal of Agriculturaland Food Chemistry vol 50 no 7 pp 2046ndash2052 2002

[34] SDore ldquoUnique properties of polyphenol stilbenes in the brainmore than direct antioxidant actions geneprotein regulatoryactivityrdquo NeuroSignals vol 14 no 1-2 pp 61ndash70 2005

[35] T Walle ldquoBioavailability of resveratrolrdquo Annals of the New YorkAcademy of Sciences vol 1215 no 1 pp 9ndash15 2011

[36] Y-Y Zhao Q Su X-L Cheng X-J Tan X Bai and R-C Lin ldquoPharmacokinetics bioavailability and metabolism ofrhaponticin in rat plasma byUHPLC-Q-TOFMS andUHPLC-DAD-MSnrdquo Bioanalysis vol 4 no 6 pp 713ndash723 2012

[37] I M Kapetanovic M Muzzio Z Huang T N Thompson andD L McCormick ldquoPharmacokinetics oral bioavailability andmetabolic profile of resveratrol and its dimethylether analogpterostilbene in ratsrdquoCancer Chemotherapy and Pharmacologyvol 68 no 3 pp 593ndash601 2011

[38] H-S Lin B-D Yue and P C Ho ldquoDetermination of pteros-tilbene in rat plasma by a simple HPLC-UV method and itsapplication in pre-clinical pharmacokinetic studyrdquo BiomedicalChromatography vol 23 no 12 pp 1308ndash1315 2009

[39] D J Boocock K R Patel G E S Faust et al ldquoQuantitationof trans-resveratrol and detection of its metabolites in humanplasma and urine by high performance liquid chromatographyrdquo

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[40] V A Brown K R Patel M Viskaduraki et al ldquoRepeatdose study of the cancer chemopreventive agent resveratrol inhealthy volunteers safety pharmacokinetics and effect on theinsulin-like growth factor axisrdquo Cancer Research vol 70 no 22pp 9003ndash9011 2010

[41] K R Patel V A Brown D J L Jones et al ldquoClinicalpharmacology of resveratrol and its metabolites in colorectalcancer patientsrdquo Cancer Research vol 70 no 19 pp 7392ndash73992010

[42] A Amri J C Chaumeil S Sfar andC Charrueau ldquoAdministra-tion of resveratrol what formulation solutions to bioavailabilitylimitationsrdquo Journal of Controlled Release vol 158 no 2 pp182ndash193 2012

[43] T Ogas T P Kondratyuk and J M Pezzuto ldquoResveratrolanalogs promising chemopreventive agentsrdquoAnnals of the NewYork Academy of Sciences vol 1290 no 1 pp 21ndash29 2013

[44] M J Amiot B Romier T-M Anh Dao et al ldquoOptimization oftrans-resveratrol bioavailability for human therapyrdquo Biochimievol 95 no 6 pp 1233ndash1238 2013

[45] Y Sun and Y Zhao ldquoEnhanced pharmacokinetics and anti-tumor efficacy of PEGylated liposomal rhaponticin and plasmaprotein binding ability of rhaponticinrdquo Journal of Nanoscienceand Nanotechnology vol 12 no 10 pp 7677ndash7684 2012

[46] J J Johnson M Nihal I A Siddiqui et al ldquoEnhancing thebioavailability of resveratrol by combining it with piperinerdquoMolecular Nutrition amp Food Research vol 55 no 8 pp 1169ndash1176 2011

[47] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[48] C-H Cottart V Nivet-Antoine C Laguillier-Morizot and J-LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition amp Food Research vol 54 no 1 pp 7ndash162010

[49] L Almeida M Vaz-da-Silva A Falcao et al ldquoPharmacokineticand safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteersrdquo Molecular Nutrition amp FoodResearch vol 53 no 1 pp S7ndashS15 2009

[50] C La Porte N Voduc G Zhang et al ldquoSteady-state pharma-cokinetics and tolerability of trans-resveratrol 2000mg twicedaily with food quercetin and alcohol (Ethanol) in healthyhuman subjectsrdquo Clinical Pharmacokinetics vol 49 no 7 pp449ndash454 2010

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[53] M Biswas and J Y Chan ldquoRole of Nrf1 in antioxidant responseelement-mediated gene expression and beyondrdquoToxicology andApplied Pharmacology vol 244 no 1 pp 16ndash20 2010

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[55] M Kobayashi and M Yamamoto ldquoNrf2-Keap1 regulation ofcellular defense mechanisms against electrophiles and reactiveoxygen speciesrdquo Advances in Enzyme Regulation vol 46 no 1pp 113ndash140 2006

[56] T Nguyen P Nioi and C B Pickett ldquoThe Nrf2-antioxidantresponse element signaling pathway and its activation byoxidative stressrdquo The Journal of Biological Chemistry vol 284no 20 pp 13291ndash13295 2009

[57] M Zhang C An Y Gao R K Leak J Chen and F ZhangldquoEmerging roles of Nrf2 and phase II antioxidant enzymes inneuroprotectionrdquo Progress in Neurobiology vol 100 no 1 pp30ndash47 2013

[58] R Gozzelino V Jeney and M P Soares ldquoMechanisms of cellprotection by heme oxygenase-1rdquoAnnual Review of Pharmacol-ogy and Toxicology vol 50 pp 323ndash354 2010

[59] A T Dinkova-Kostova and P Talalay ldquoNAD(P)Hquinoneacceptor oxidoreductase 1 (NQO1) a multifunctional antioxi-dant enzyme and exceptionally versatile cytoprotectorrdquoArchivesof Biochemistry and Biophysics vol 501 no 1 pp 116ndash123 2010

[60] E Kansanen H-K Jyrkkanen and A-L Levonen ldquoActivationof stress signaling pathways by electrophilic oxidized andnitrated lipidsrdquo Free Radical Biology and Medicine vol 52 no6 pp 973ndash982 2012

[61] S B Cullinan J D Gordan J Jin J W Harper and J A DiehlldquoThe Keap1-BTB protein is an adaptor that bridges Nrf2 to aCul3-based E3 ligase oxidative stress sensing by a Cul3-Keap1ligaserdquoMolecular and Cellular Biology vol 24 no 19 pp 8477ndash8486 2004

[62] E Kansanen S M Kuosmanen H Leinonen and A-LLevonenn ldquoTheKeap1-Nrf2 pathwaymechanisms of activationand dysregulation in cancerrdquo Redox Biology vol 1 no 1 pp 45ndash49 2013

[63] J F Reichard G T Motz and A Puga ldquoHeme oxygenase-1induction by NRF2 requires inactivation of the transcriptionalrepressor BACH1rdquo Nucleic Acids Research vol 35 no 21 pp7074ndash7086 2007

[64] Z Sun T Wu F Zhao A Lau C M Birch and D D ZhangldquoKPNA6 (Importin 1205727)-mediated nuclear import of Keap1represses the Nrf2-dependent antioxidant responserdquoMolecularand Cellular Biology vol 31 no 9 pp 1800ndash1811 2011

[65] M-K Kwak K Itoh M Yamamoto and T W KenslerldquoEnhanced expression of the transcription factorNrf2 by cancerchemopreventive agents role of antioxidant response element-like sequences in the nrf2 promoterrdquo Molecular and CellularBiology vol 22 no 9 pp 2883ndash2892 2002

[66] A Jain T Lamark E Sjoslashttem et al ldquop62SQSTM1 is a targetgene for transcription factor NRF2 and creates a positivefeedback loop by inducing antioxidant response element-drivengene transcriptionrdquoThe Journal of Biological Chemistry vol 285no 29 pp 22576ndash22591 2010

[67] Y Kawai L Garduno M Theodore J Yang and I J ArinzeldquoAcetylation-deacetylation of the transcription factor Nrf2(nuclear factor erythroid 2-related factor 2) regulates its tran-scriptional activity and nucleocytoplasmic localizationrdquo TheJournal of Biological Chemistry vol 286 no 9 pp 7629ndash76402011

[68] A Kokot D Metze N Mouchet et al ldquoAlpha-melanocyte-stimulating hormone counteracts the suppressive effect of UVBon Nrf2 and Nrf-dependent gene expression in human skinrdquoEndocrinology vol 150 no 7 pp 3197ndash3206 2009

[69] N Wakabayashi S Shin S L Slocum et al ldquoRegulation ofNotch1 signaling by Nrf2 implications for tissue regenerationrdquoScience Signaling vol 3 no 130 p ra52 2010

[70] W O Osburn M S Yates P D Dolan et al ldquoGenetic orpharmacologic amplification of Nrf2 signaling inhibits acuteinflammatory liver injury in micerdquo Toxicological Sciences vol104 no 1 pp 218ndash227 2008

[71] Z Zhao Y Chen J Wang et al ldquoAge-related retinopathy inNRF2-deficient micerdquo PLoS ONE vol 6 no 4 Article IDe19456 2011

[72] B N Chorley M R Campbell X Wang et al ldquoIdentification ofnovel NRF2-regulated genes by ChiP-Seq influence on retinoidX receptor alphardquo Nucleic Acids Research vol 40 no 15 pp7416ndash7429 2012

[73] J M Marzec J D Christie S P Reddy et al ldquoFunctionalpolymorphisms in the transcription factor NRF2 in humansincrease the risk of acute lung injuryrdquo FASEB Journal vol 21no 9 pp 2237ndash2246 2007

[74] S Shin N Wakabayashi V Misra et al ldquoNRF2 modulates arylhydrocarbon receptor signaling influence on adipogenesisrdquoMolecular and Cellular Biology vol 27 no 20 pp 7188ndash71972007

[75] K L Cheung S Yu Z Pan J Ma T Y Wu and A-NT Kong ldquoTBHQ-induced HO-1 expression is mediated bycalcium through regulation of Nrf2 binding to enhancer andpolymerase II to promoter region of HO-1rdquo Chemical Researchin Toxicology vol 24 no 5 pp 670ndash676 2011

[76] T Nishinaka Y Ichijo M Ito et al ldquoCurcumin activates humanglutathione S-transferase P1 expression through antioxidantresponse elementrdquo Toxicology Letters vol 170 no 3 pp 238ndash247 2007

[77] P Nioi M McMahon K Itoh M Yamamoto and J D HayesldquoIdentification of a novel NRF2-regulated antioxidant responseelement (ARE) in the mouse NAD(P)Hquinone oxidoreduc-tase 1 gene reassessment of the ARE consensus sequencerdquoTheBiochemical Journal vol 374 no 2 pp 337ndash348 2003

[78] P Nioi and J D Hayes ldquoContribution of NAD(P)H quinoneoxidoreductase 1 to protection against carcinogenesis andregulation of its gene by the Nrf2 basic-region leucine zip-per and the arylhydrocarbon receptor basic helix-loop-helixtranscription factorsrdquo Mutation ResearchmdashFundamental andMolecular Mechanisms of Mutagenesis vol 555 no 1-2 pp 149ndash171 2004

[79] T-C Hsieh X Lu Z Wang and J M Wu ldquoInductionof quinone reductase NQO1 by resveratrol in human K562cells involves the antioxidant response element ARE and isaccompanied by nuclear translocation of transcription factorNrf2rdquoMedicinal Chemistry vol 2 no 3 pp 275ndash285 2006

[80] Q Cheng J L Kalabus J Zhang and J G Blanco ldquoA conservedantioxidant response element (ARE) in the promoter of humancarbonyl reductase 3 (CBR3) mediates induction by the masterredox switch Nrf2rdquo Biochemical Pharmacology vol 83 no 1 pp139ndash148 2012

[81] S Kalthoff U Ehmer N Freiberg M P Manns and CP Strassburg ldquoInteraction between oxidative stress sensorNrf2 and xenobiotic-activated aryl hydrocarbon receptor inthe regulation of the human phase II detoxifying UDP-glucuronosyltransferase 1A10rdquo The Journal of Biological Chem-istry vol 285 no 9 pp 5993ndash6002 2010

[82] A C Wild H R Moinova and R T Mulcahy ldquoRegulation of120574-glutamylcysteine synthetase subunit gene expression by the


transcription factor Nrf2rdquo The Journal of Biological Chemistryvol 274 no 47 pp 33627ndash33636 1999

[83] J-Y Im K-W Lee J-M Woo E Junn and M M MouradianldquoDj-1 induces thioredoxin 1 expression through the Nrf2 path-wayrdquo Human Molecular Genetics vol 21 no 13 pp 3013ndash30242012

[84] X Lin H Yang H Zhang L Zhou and Z Guo ldquoA novel tran-scription mechanism activated by ethanol induction of Slc7a11gene expression via inhibition of the DNA-binding activity oftranscriptional repressor octamer-binding transcription factor1 (OCT-1)rdquoThe Journal of Biological Chemistry vol 288 no 21pp 14815ndash14823 2013

[85] M R Campbell M Karaca K N Adamski B N Chorley XWang and D A Bell ldquoNovel hematopoietic target genes in theNRF2-Mediated transcriptional pathwayrdquo Oxidative Medicineand Cellular Longevity vol 2013 Article ID 120305 12 pages2013

[86] C JWruck K Streetz G Pavic et al ldquoNrf2 induces interleukin-6 (IL-6) expression via an antioxidant response element withinthe IL-6 promoterrdquoThe Journal of Biological Chemistry vol 286no 6 pp 4493ndash4499 2011

[87] S K Niture and A K Jaiswal ldquoNrf2 protein up-regulatesantiapoptotic protein bcl-2 and prevents cellular apoptosisrdquoTheJournal of Biological Chemistry vol 287 no 13 pp 9873ndash98862012

[88] M Komatsu S Kageyama and Y Ichimura ldquoP62SQSTM1A170 physiology and pathologyrdquoPharmacological Research vol66 no 6 pp 457ndash462 2012

[89] A M Cuervo L Stafanis R Fredenburg P T Lansbury andD Sulzer ldquoImpaired degradation of mutant 120572-synuclein bychaperone-mediated autophagyrdquo Science vol 305 no 5688 pp1292ndash1295 2004

[90] J Viiri M Amadio N Marchesi et al ldquoAutophagy activationclears ELAVL1HuR-mediated accumulation of SQSTM1p62during proteasomal inhibition in human retinal pigmentepithelial cellsrdquo PLoS ONE vol 8 no 7 Article ID e69563 2013

[91] A Salminen K Kaarniranta A Kauppinen et al ldquoImpairedautophagy and APP processing in Alzheimerrsquos disease thepotential role of Beclin 1 interactomerdquo Progress in Neurobiologyvol 106-107 pp 33ndash54 2013

[92] R Layfield J R Cavey D Najat et al ldquop62mutations ubiquitinrecognition and Pagetrsquos disease of bonerdquo Biochemical SocietyTransactions vol 34 no 5 pp 735ndash737 2006

[93] J-H Lee W H Yu A Kumar et al ldquoLysosomal proteolysis andautophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutationsrdquo Cell vol 141 no 7 pp 1146ndash1158 2010

[94] J Moscat M T Diaz-Meco and M W Wooten ldquoSignal inte-gration and diversification through the p62 scaffold proteinrdquoTrends in Biochemical Sciences vol 32 no 2 pp 95ndash100 2007

[95] M Komatsu S Waguri M Koike et al ldquoHomeostatic lev-els of p62 control cytoplasmic inclusion body formation inautophagy-deficient micerdquo Cell vol 131 no 6 pp 1149ndash11632007

[96] A Lau X-J Wang F Zhao et al ldquoA noncanonical mechanismof Nrf2 activation by autophagy deficiency direct interactionbetween keap1 and p62rdquoMolecular and Cellular Biology vol 30no 13 pp 3275ndash3285 2010

[97] K Taguchi N Fujikawa M Komatsu et al ldquoKeap1 degradationby autophagy for the maintenance of redox homeostasisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 34 pp 13561ndash13566 2012

[98] E Itakura and N Mizushima ldquop62 targeting to the autophago-some formation site requires self-oligomerization but not LC3bindingrdquo Journal of Cell Biology vol 192 no 1 pp 17ndash27 2011

[99] Y Ichimura and M Komatsu ldquoSelective degradation of p62 byautophagyrdquo Seminars in Immunopathology vol 32 no 4 pp431ndash436 2010

[100] J M T Hyttinen G Petrovski A Salminen and K Kaarni-ranta ldquo51015840-adenosine monophosphate-activated protein kinase-mammalian target of rapamycin axis as therapeutic target forage-related macular degenerationrdquo Rejuvenation Research vol14 no 6 pp 651ndash660 2011

[101] J Kim M Kundu B Viollet and K-L Guan ldquoAMPK andmTOR regulate autophagy through direct phosphorylation ofUlk1rdquo Nature Cell Biology vol 13 no 2 pp 132ndash141 2011

[102] C Canto Z Gerhart-Hines J N Feige et al ldquoAMPK regulatesenergy expenditure by modulating NAD+ metabolism andSIRT1 activityrdquo Nature vol 458 no 7241 pp 1056ndash1060 2009

[103] A Gormand E Henriksson K Strom T E Jensen KSakamoto and O Goransson ldquoRegulation of AMP-activatedprotein kinase by LKB1 and CaMKK in adipocytesrdquoThe Journalof Cellular Biochemistry vol 112 no 5 pp 1364ndash1375 2011

[104] X-M Liu K J Peyton A R Shebib H Wang R JKorthuis and W Durante ldquoActivation of AMPK stimulatesheme oxygenase-1 gene expression and human endothelialcell survivalrdquo The American Journal of PhysiologymdashHeart andCirculatory Physiology vol 300 no 1 pp H84ndashH93 2011

[105] S-J Park F Ahmad A Philp et al ldquoResveratrol amelioratesaging-related metabolic phenotypes by inhibiting cAMP phos-phodiesterasesrdquo Cell vol 148 no 3 pp 421ndash433 2012

[106] M Frombaum S Le Clanche D Bonnefont-Rousselot and DBorderie ldquoAntioxidant effects of resveratrol and other stilbenederivatives on oxidative stress and NO bioavailability potentialbenefits to cardiovascular diseasesrdquo Biochimie vol 94 no 2 pp269ndash276 2012

[107] F X Guix I Uribesalgo M Coma and F J Munoz ldquoThephysiology and pathophysiology of nitric oxide in the brainrdquoProgress in Neurobiology vol 76 no 2 pp 126ndash152 2005

[108] M J Crabtree and K M Channon ldquoSynthesis and recyclingof tetrahydrobiopterin in endothelial function and vasculardiseaserdquo Nitric Oxide Biology and Chemistry vol 25 no 2 pp81ndash88 2011

[109] J Vasquez-Vivar N Hogg P Martasek H Karoui K APritchard Jr and B Kalyanaraman ldquoTetrahydrobiopterin-dependent inhibition of superoxide generation from neuronalnitric oxide synthaserdquo The Journal of Biological Chemistry vol274 no 38 pp 26736ndash26742 1999

[110] R H Foxton J M Land and S J R Heales ldquoTetrahydro-biopterin availability in Parkinsonrsquos and Alzheimerrsquos diseasepotential pathogenic mechanismsrdquo Neurochemical Researchvol 32 no 4-5 pp 751ndash756 2007

[111] K U Schallreuter J Moore D J Tobin et al ldquo120572-MSH cancontrol the essential cofactor 6-tetrahydrobiopterin in melano-genesisrdquo Annals of the New York Academy of Sciences vol 885pp 329ndash341 1999

[112] L Wang H Erlandsen J Haavik P M Knappskog and RC Stevens ldquoThree-dimensional structure of human tryptophanhydroxylase and its implications for the biosynthesis of theneurotransmitters serotonin and melatoninrdquo Biochemistry vol41 no 42 pp 12569ndash12574 2002


[113] H K Kim S H Ha and J Han ldquoPotential therapeutic appli-cations of tetrahydrobiopterin from inherited hyperphenylala-ninemia to mitochondrial diseasesrdquo Annals of the New YorkAcademy of Sciences vol 1201 pp 177ndash182 2010

[114] J Z Nowak and J B Zawilska ldquoMelatonin and its physiologicaland therapeutic propertiesrdquo PharmacyWorld amp Science vol 20no 1 pp 18ndash27 1998

[115] P O Lundmark S R Pandi-Perumal V Srinivasan D P Car-dinali and R E Rosenstein ldquoMelatonin in the eye implicationsfor glaucomardquo Experimental Eye Research vol 84 no 6 pp1021ndash1030 2007

[116] N Xia A Daiber A Habermeier et al ldquoResveratrol reversesendothelial nitric-oxide synthase uncoupling in apolipoproteinE knockoutmicerdquoThe Journal of Pharmacology and Experimen-tal Therapeutics vol 335 no 1 pp 149ndash154 2010

[117] J Cai W G Jiang M B Grant and M Boulton ldquoPigmentepithelium-derived factor inhibits angiogenesis via regulatedintracellular proteolysis of vascular endothelial growth factorreceptor 1rdquo The Journal of Biological Chemistry vol 281 no 6pp 3604ndash3613 2006

[118] V M Lopez C L Decatur W D Stamer R M Lynch and BS McKay ldquoL-DOPA is an endogenous ligand for OA1rdquo PLoSBiology vol 6 no 9 article e236 2008

[119] B Omar E Zmuda-Trzebiatowska V Manganiello OGoransson and E Degerman ldquoRegulation of AMP-activated protein kinase by cAMP in adipocytes roles forphosphodiesterases protein kinase B protein kinase A Epacand lipolysisrdquo Cellular Signalling vol 21 no 5 pp 760ndash7662009

[120] S R Kulkarni A C Donepudi J Xu et al ldquoFasting inducesnuclear factor E2-related factor 2 and ATP-binding cassettetransporters via protein kinase a and sirtuin-1 in mouse andhumanrdquo Antioxidants amp Redox Signaling vol 20 no 1 pp 15ndash30 2014

[121] H-W Lo and F Ali-Osman ldquoCyclic AMPmediatedGSTP1 geneactivation in tumor cells involves the interaction of activatedCREB-1 with the GSTP1 CRE a novel mechanism of cellularGSTP1 gene regulationrdquo Journal of Cellular Biochemistry vol 87no 1 pp 103ndash116 2002

[122] H Si J Yu H Jiang H Lum and D Liu ldquoPhytoestrogen genis-tein up-regulates endothelial nitric oxide synthase expressionvia activation of cAMP response element-binding protein inhuman aortic endothelial cellsrdquo Endocrinology vol 153 no 7pp 3190ndash3198 2012

[123] D de Rasmo A Signorile F Papa E Roca and S PapaldquocAMPCa2+ response element-binding protein plays a centralrole in the biogenesis of respiratory chain proteins in mam-malian cellsrdquo IUBMB Life vol 62 no 6 pp 447ndash452 2010

[124] D G Hardie F A Ross and S A Hawley ldquoAMPK a nutrientand energy sensor that maintains energy homeostasisrdquo NatureReviews Molecular Cell Biology vol 13 no 4 pp 251ndash262 2012

[125] M Lagouge C Argmann Z Gerhart-Hines et al ldquoResver-atrol improves mitochondrial function and protects againstmetabolic disease by activating SIRT1 and PGC-1 alphardquo Cellvol 127 no 6 pp 1109ndash1122 2006

[126] B J Wilson A M Tremblay G Deblois G Sylvain-Drolet andVGiguere ldquoAn acetylation switchmodulates the transcriptionalactivity of estrogen-related receptor 120572rdquo Molecular Endocrinol-ogy vol 24 no 7 pp 1349ndash1358 2010

[127] CMo LWang J Zhang et al ldquoThe crosstalk betweenNrf2 andAMPK signal pathways is important for the anti-inflammatory

effect of Berberine in LPS-stimulated macrophages andendotoxin-shocked micerdquo Antioxidants amp Redox Signaling vol20 no 4 pp 574ndash588 2014

[128] C Handschin and U AMeyer ldquoInduction of drugmetabolismthe role of nuclear receptorsrdquo Pharmacological Reviews vol 55no 4 pp 649ndash673 2003

[129] J TMoore J L Collins andKH Pearce ldquoThe nuclear receptorsuperfamily and drug discoveryrdquo ChemMedChem vol 1 no 5pp 504ndash523 2006

[130] D Kluth A Banning I Paur R Blomhoff and R Brigelius-Flohe ldquoModulation of pregnane X receptor-and electrophileresponsive element-mediated gene expression by dietarypolyphenolic compoundsrdquo Free Radical Biology and Medicinevol 42 no 3 pp 315ndash325 2007

[131] K C Wu J Y Cui and C D Klaassen ldquoEffect of graded nrf2activation on phase-I and -II drug metabolizing enzymes andtransporters in mouse liverrdquo PLoS ONE vol 7 no 7 Article IDe39006 2012

[132] T Haarmann-Stemmann H Bothe and J Abel ldquoGrowthfactors cytokines and their receptors as downstream targets ofarylhydrocarbon receptor (AhR) signaling pathwaysrdquo Biochem-ical Pharmacology vol 77 no 4 pp 508ndash520 2009

[133] R L Yeager S A Reisman LMAleksunes andCD KlaassenldquoIntroducing the lsquoTCDD-inducible AhR-Nrf2 gene batteryrsquordquoToxicological Sciences vol 111 no 2 pp 238ndash246 2009

[134] E R Levin ldquoIntegration of the extranuclear and nuclear actionsof estrogenrdquo Molecular Endocrinology vol 19 no 8 pp 1951ndash1959 2005

[135] A L Ososki and E J Kennelly ldquoPhytoestrogens a review of thepresent state of researchrdquo Phytotherapy Research vol 17 no 8pp 845ndash869 2003

[136] R Lappano C Rosano A Madeo et al ldquoStructure-activityrelationships of resveratrol and derivatives in breast cancercellsrdquoMolecular Nutrition and Food Research vol 53 no 7 pp845ndash858 2009

[137] M C Saleh B J Connell and T M Saleh ldquoResveratrolinduced neuroprotection ismediated via both estrogen receptorsubtypes ER120572 and ER120573rdquoNeuroscience Letters vol 548 pp 217ndash221 2013

[138] V Di Liberto J Makela L Korhonen et al ldquoInvolvementof estrogen receptors in the resveratrol-mediated increase indopamine transporter in human dopaminergic neurons and instriatum of female micerdquoNeuropharmacology vol 62 no 2 pp1011ndash1018 2012

[139] A Tchernof and J-P Despres ldquoPathophysiology of humanvisceral obesity an updaterdquo Physiological Reviews vol 93 no1 pp 359ndash404 2013

[140] D A Sinclair ldquoToward a unified theory of caloric restrictionand longevity regulationrdquo Mechanisms of Ageing and Develop-ment vol 126 no 9 pp 987ndash1002 2005

[141] L Fontana L Partridge and V D Longo ldquoExtending healthylife span-from yeast to humansrdquo Science vol 328 no 5976 pp321ndash326 2010

[142] A Soare R Cangemi D Omodei J O Holloszy and LFontana ldquoLong-term calorie restriction but not enduranceexercise lowers core body temperature in humansrdquo Aging vol3 no 4 pp 374ndash379 2011

[143] A V Witte M Fobker R Gellner S Knecht and A FloelldquoCaloric restriction improves memory in elderly humansrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 106 no 4 pp 1255ndash1260 2009


[144] C-L Hsu and G-C Yen ldquoPhenolic compounds evidencefor inhibitory effects against obesity and their underlyingmolecular signaling mechanismrdquo Molecular Nutrition amp FoodResearch vol 52 no 1 pp 53ndash61 2008

[145] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006

[146] A-S Cheng Y-H Cheng C-H Chiou and T-L ChangldquoResveratrol upregulates Nrf2 expression to attenuatemethylglyoxal-induced insulin resistance in hep G2 cellsrdquoJournal of Agricultural and Food Chemistry vol 60 no 36 pp9180ndash9187 2012

[147] E Tauriainen M Luostarinen E Martonen et al ldquoDistincteffects of calorie restriction and resveratrol on diet-inducedobesity and fatty liver formationrdquo Journal of Nutrition andMetabolism vol 2011 Article ID 525094 10 pages 2011

[148] T Ito-Nagahata C KuriharaMHasebe et al ldquoStilbene analogsof resveratrol improve insulin resistance through activation ofAMPKrdquo Bioscience Biotechnology and Biochemistry vol 77 no6 pp 1229ndash1235 2013

[149] P Fischer-Posovszky V Kukulus D Tews et al ldquoResveratrolregulates human adipocyte number and function in a Sirt1-dependent mannerrdquoTheAmerican Journal of Clinical Nutritionvol 92 no 1 pp 5ndash15 2010

[150] T T Schug and X Li ldquoSirtuin 1 in lipidmetabolism and obesityrdquoAnnals of Medicine vol 43 no 3 pp 198ndash211 2011

[151] I Mader M Wabitsch K-M Debatin P Fischer-Posovszkyand S Fulda ldquoIdentification of a novel proapoptotic functionof resveratrol in fat cells SIRT1-independent sensitization toTRAIL-induced apoptosisrdquo The FASEB Journal vol 24 no 6pp 1997ndash2009 2010

[152] S Chen X Xiao X Feng et al ldquoResveratrol induces Sirt1-dependent apoptosis in 3T3-L1 preadipocytes by activatingAMPK and suppressing AKT activity and survivin expressionrdquoThe Journal of Nutritional Biochemistry vol 23 no 9 pp 1100ndash1112 2012

[153] Y S Jeong J H Hong K H Cho and H K Jung ldquoGrapeskin extract reduces adipogenesis- and lipogenesis-relatedgene expression in 3T3-L1 adipocytes through the peroxisomeproliferator-activated receptor-120574 signaling pathwayrdquo NutritionResearch vol 32 no 7 pp 514ndash521 2012

[154] X-H Zhang B Huang S-K Choi and J-S Seo ldquoAnti-obesityeffect of resveratrol-amplified grape skin extracts on 3T3-L1adipocytes differentiationrdquoNutrition Research and Practice vol6 no 4 pp 286ndash293 2012

[155] D Y Jung U Chalasani N Pan et al ldquoKLF15 is amolecular linkbetween endoplasmic reticulum stress and insulin resistancerdquoPLoS ONE vol 8 no 10 Article ID e77851 2013

[156] A Lasa M Schweiger P Kotzbeck et al ldquoResveratrol regulateslipolysis via adipose triglyceride lipaserdquo The Journal of Nutri-tional Biochemistry vol 23 no 4 pp 379ndash384 2012

[157] P Chakrabarti T English S Karki et al ldquoSIRT1 controls lipol-ysis in adipocytes via FOXO1-mediated expression of ATGLrdquoJournal of Lipid Research vol 52 no 9 pp 1693ndash1701 2011

[158] C D S Costa F Rohden T O Hammes et al ldquoResvera-trol upregulated SIRT1 FOXO1 and adiponectin and down-regulated PPAR1205741-3 mRNA expression in human visceraladipocytesrdquo Obesity Surgery vol 21 no 3 pp 356ndash361 2011

[159] T Shan Y Ren and Y Wang ldquoSirtuin 1 affects the tran-scriptional expression of adipose triglyceride lipase in porcineadipocytesrdquo Journal of Animal Science vol 91 no 3 pp 1247ndash1254 2013

[160] T O Hammes C D S Costa F Rohden et al ldquoParallel down-regulation of FOXO1 PPAR120574 and adiponectin mRNA expres-sion in visceral adipose tissue of class III obese individualsrdquoObesity Facts vol 5 no 3 pp 452ndash459 2012

[161] J H Chung V Manganiello and J R B Dyck ldquoResveratrol asa calorie restriction mimetic therapeutic implicationsrdquo Trendsin Cell Biology vol 22 no 10 pp 546ndash554 2012

[162] J Lee E Jung J Lim et al ldquoInvolvement of nuclear factor-120581Bin the inhibition of pro-inflammatorymediators by pinosylvinrdquoPlanta Medica vol 72 no 9 pp 801ndash806 2006

[163] M Frombaum P Therond R Djelidi J-L Beaudeux DBonnefont-Rousselot and D Borderie ldquoPiceatannol is moreeffective than resveratrol in restoring endothelial cell dimethy-larginine dimethylaminohydrolase expression and activity afterhigh-glucose oxidative stressrdquo Free Radical Research vol 45 no3 pp 293ndash302 2011

[164] A Overman A Bumrungpert A Kennedy et al ldquoPolyphenol-rich grape powder extract (GPE) attenuates inflammationin human macrophages and in human adipocytes exposedto macrophage-conditioned mediardquo International Journal ofObesity vol 34 no 5 pp 800ndash808 2010

[165] C-C Chuang A Bumrungpert A Kennedy et al ldquoGrapepowder extract attenuates tumor necrosis factor 120572-mediatedinflammation and insulin resistance in primary cultures ofhuman adipocytesrdquo Journal of Nutritional Biochemistry vol 22no 1 pp 89ndash94 2011

[166] J Ołlholm S K Paulsen K B Cullberg B Richelsen and S BPedersen ldquoAnti-inflammatory effect of resveratrol on adipokineexpression and secretion in human adipose tissue explantsrdquoInternational Journal of Obesity vol 34 no 10 pp 1546ndash15532010

[167] G Alberdi V M Rodrıguez J Miranda M T Macarulla IChurruca andM P Portillo ldquoThermogenesis is involved in thebody-fat lowering effects of resveratrol in ratsrdquo Food Chemistryvol 141 no 2 pp 1530ndash1535 2013

[168] H J Park J-Y Yang S Ambati et al ldquoCombined effectsof genistein quercetin and resveratrol in human and 3T3-L1adipocytesrdquo Journal of Medicinal Food vol 11 no 4 pp 773ndash783 2008

[169] M Herranz-Lopez S Fernandez-Arroyo A Perez-Sanchez etal ldquoSynergism of plant-derived polyphenols in adipogenesisperspectives and implicationsrdquo Phytomedicine vol 19 no 3-4pp 253ndash261 2012

[170] G-M Do U J Jung H-J Park et al ldquoResveratrol amelioratesdiabetes-related metabolic changes via activation of AMP-activated protein kinase and its downstream targets in dbdbmicerdquo Molecular Nutrition amp Food Research vol 56 no 8 pp1282ndash1291 2012

[171] W Kang H J Hong J Guan et al ldquoResveratrol improvesinsulin signaling in a tissue-specific manner under insulin-resistant conditions only in vitro and in vivo experiments inrodentsrdquo Metabolism Clinical and Experimental vol 61 no 3pp 424ndash433 2012

[172] M Minakawa Y Miura and K Yagasaki ldquoPiceatannol aresveratrol derivative promotes glucose uptake through glu-cose transporter 4 translocation to plasma membrane in L6myocytes and suppresses blood glucose levels in type 2 diabeticmodel dbdb micerdquo Biochemical and Biophysical Research Com-munications vol 422 no 3 pp 469ndash475 2012

[173] Z Tan L-J Zhou P-W Mu et al ldquoCaveolin-3 is involvedin the protection of resveratrol against high-fat-diet-inducedinsulin resistance by promoting GLUT4 translocation to the


plasma membrane in skeletal muscle of ovariectomized ratsrdquoThe Journal of Nutritional Biochemistry vol 23 no 12 pp 1716ndash1724 2012

[174] T Matsui T Ueda T Oki K Sugita N Terahara and KMatsumoto ldquo120572-glucosidase inhibitory action of natural acy-lated anthocyanins 1 Survey of natural pigments with potentinhibitory activityrdquo Journal of Agricultural and Food Chemistryvol 49 no 4 pp 1948ndash1951 2001

[175] A C L Barbosa M D S Pinto D Sarkar C AnkolekarD Greene and K Shetty ldquoVarietal influences on antihyper-glycemia properties of freshly harvested apples using in vitroassay modelsrdquo Journal of Medicinal Food vol 13 no 6 pp 1313ndash1323 2010

[176] D Grussu D Stewart and G J McDougall ldquoBerry polyphenolsinhibit 120572-amylase in vitro identifying active components inrowanberry and raspberryrdquo Journal of Agricultural and FoodChemistry vol 59 no 6 pp 2324ndash2331 2011

[177] I Kubo Y Murai I Soediro S Soetarno and S SastrodihardjoldquoEfficient isolation of glycosidase inhibitory stilbene glycosidesfromRheum palmatumrdquo Journal of Natural Products vol 54 no4 pp 1115ndash1118 1991

[178] K S Babu A K Tiwari P V Srinivas A Z Ali B C Rajuand J M Rao ldquoYeast and mammalian 120572-glucosidase inhibitoryconstituents from Himalayan rhubarb Rheum emodi WallexMeissonrdquo Bioorganic and Medicinal Chemistry Letters vol 14no 14 pp 3841ndash3845 2004

[179] Z Kerem I Bilkis M A Flaishman and L Sivan ldquoAntioxidantactivity and inhibition of 120572-glucosidase by trans-resveratrolpiceid and a novel trans-stilbene from the roots of IsraeliRumex bucephalophorus Lrdquo Journal of Agricultural and FoodChemistry vol 54 no 4 pp 1243ndash1247 2006

[180] S-H Lam J-M Chen C-J Kang C-H Chen and S-SLee ldquoAlpha-glucosidase inhibitors from the seeds of syagrusromanzoffianardquo Phytochemistry vol 69 no 5 pp 1173ndash11782008

[181] X Wan X-B Wang M-H Yang J-S Wang and L-Y KongldquoDimerization of piceatannol by Momordica charantia peroxi-dase and120572-glucosidase inhibitory activity of the biotransforma-tion productsrdquo Bioorganic and Medicinal Chemistry vol 19 no17 pp 5085ndash5092 2011

[182] M Miao H Jiang B Jiang T Zhang S W Cui and Z JinldquoPhytonutrients for controlling starch digestion evaluation ofgrape skin extractrdquo Food Chemistry vol 145 pp 205ndash211 2014

[183] P Chakrabarti and K V Kandror ldquoFoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression andlipolysis in adipocytesrdquoThe Journal of Biological Chemistry vol284 no 20 pp 13296ndash13300 2009

[184] Y-E Lee J-W Kim E-M Lee et al ldquoChronic resveratroltreatment protects pancreatic islets against oxidative stress indbdb micerdquo PLoS ONE vol 7 no 11 Article ID e50412 2012

[185] J-M Yun A Chien I Jialal and S Devaraj ldquoResveratrol up-regulates SIRT1 and inhibits cellular oxidative stress in thediabetic milieu mechanistic insightsrdquo Journal of NutritionalBiochemistry vol 23 no 7 pp 699ndash705 2012

[186] F Paneni J A Beckman M A Creager and F CosentinoldquoDiabetes and vascular disease pathophysiology clinical conse-quences and medical therapy Part Irdquo European Heart Journalvol 34 no 31 pp 2436ndash2446 2013

[187] B B Dokken ldquoThe pathophysiology of cardiovascular diseaseand diabetes beyond blood pressure and lipidsrdquo DiabetesSpectrum vol 21 no 3 pp 160ndash165 2008

[188] N J Alp S Mussa J Khoo et al ldquoTetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelialfunction in diabetes by targeted transgenic GTP-cyclohydrolaseI overexpressionrdquo Journal of Clinical Investigation vol 112 no 5pp 725ndash735 2003

[189] H Li N Xia and U Forstermann ldquoCardiovascular effectsandmolecular targets of resveratrolrdquoNitric OxidemdashBiology andChemistry vol 26 no 2 pp 102ndash110 2012

[190] A A E Bertelli L Giovannini D Giannessi M Migliori WBernini and M Fregoni ldquoAntiplatelet activity of synthetic andnatural resveratrol in red winerdquo International Journal of TissueReactions vol 17 no 1 pp 1ndash3 1995

[191] K R Patel E Scott V A Brown A J Gescher W P Stewardand K Brown ldquoClinical trials of resveratrolrdquo Annals of the NewYork Academy of Sciences vol 1215 no 1 pp 161ndash169 2011

[192] B Agarwal M J Campen M M Channell et al ldquoResveratrolfor primary prevention of atherosclerosis clinical trial evidencefor improved gene expression in vascular endotheliumrdquo Inter-national Journal of Cardiology vol 166 no 1 pp 246ndash248 2013

[193] T Wallerath G Deckert T Ternes et al ldquoResveratrol apolyphenolic phytoalexin present in red wine enhances expres-sion and activity of endothelial nitric oxide synthaserdquo Circula-tion vol 106 no 13 pp 1652ndash1658 2002

[194] P Gresele P Pignatelli G Guglielmini et al ldquoResveratrol atconcentrations attainable with moderate wine consumptionstimulates human platelet nitric oxide productionrdquoThe Journalof Nutrition vol 138 no 9 pp 1602ndash1608 2008

[195] G Spanier H Xu N Xia et al ldquoResveratrol reduces endothelialoxidative stress by modulating the gene expression of superox-ide dismutase 1 (SOD1) glutathione peroxidase 1 (GPx1) andNADPH oxidase subunit (Nox4)rdquo Journal of Physiology andPharmacology vol 60 pp 111ndash116 2009

[196] H Wang Y-J Yang H-Y Qian Q Zhang H Xu and J-JLi ldquoResveratrol in cardiovascular disease what is known fromcurrent researchrdquoHeart Failure Reviews vol 17 no 3 pp 437ndash448 2012

[197] M Jang L Cai G O Udeani et al ldquoCancer chemopreventiveactivity of resveratrol a natural product derived from grapesrdquoScience vol 275 no 5297 pp 218ndash220 1997

[198] H S Youn J Y Lee K A Fitzgerald H A Young S Akiraand D H Hwang ldquoSpecific inhibition of MyD88-independentsignaling pathways of TLR3 and TLR4 by resveratrol moleculartargets are TBK1 and RIP1 in TRIF complexrdquo The Journal ofImmunology vol 175 no 5 pp 3339ndash3346 2005

[199] L V Johnson W P Leitner A J Rivest M K Staples MJ Radeke and D H Anderson ldquoThe Alzheimerrsquos A120573-peptideis deposited at sites of complement activation in pathologicdeposits associated with aging and age-related macular degen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 18 pp 11830ndash11835 2002

[200] D Sulzer E Mosharov Z Talloczy F A Zucca J D Simon andL Zecca ldquoNeuronal pigmented autophagic vacuoles lipofuscinneuromelanin and ceroid as macroautophagic responses dur-ing aging and diseaserdquo Journal of Neurochemistry vol 106 no1 pp 24ndash36 2008

[201] J M Isas V Luibl L V Johnson et al ldquoSoluble and matureamyloid fibrils in drusen depositsrdquo Investigative Ophthalmologyand Visual Science vol 51 no 3 pp 1304ndash1310 2010

[202] K Kaarniranta A Salminen A Haapasalo H Soininenand M Hiltunen ldquoAge-related macular degeneration (AMD)alzheimerrsquos disease in the eyerdquo Journal of Alzheimerrsquos Diseasevol 24 no 4 pp 615ndash631 2011


[203] R A Nixon and D-S Yang ldquoAutophagy failure in Alzheimerrsquosdisease-locating the primary defectrdquo Neurobiology of Diseasevol 43 no 1 pp 38ndash45 2011

[204] P Hahn A H Milam and J L Dunaief ldquoMaculas affected byage-related macular degeneration contain increased chelatableiron in the retinal pigment epithelium and Bruchrsquos membranerdquoArchives of Ophthalmology vol 121 no 8 pp 1099ndash1105 2003

[205] S Oshiro M S Morioka and M Kikuchi ldquoDysregulation ofiron metabolism in Alzheimerrsquos disease Parkinsonrsquos diseaseand amyotrophic lateral sclerosisrdquoAdvances in PharmacologicalSciences vol 2011 Article ID 378278 8 pages 2011

[206] KMGehrs DHAnderson L V Johnson andG SHagemanldquoAge-related macular degenerationmdashemerging pathogeneticand therapeutic conceptsrdquo Annals of Medicine vol 38 no 7 pp450ndash471 2006

[207] J Z Nowak ldquoAge-relatedmacular degeneration (AMD) patho-genesis and therapyrdquo Pharmacological Reports vol 58 no 3 pp353ndash363 2006

[208] M AWilliams D Craig P Passmore and G Silvestri ldquoRetinaldrusen harbingers of age safe havens for troublerdquo Age andAgeing vol 38 no 6 pp 648ndash654 2009

[209] K P Ng B Gugiu K Renganathan et al ldquoRetinal pigmentepithelium lipofuscin proteomicsrdquoMolecular and Cellular Pro-teomics vol 7 no 7 pp 1397ndash1405 2008

[210] H Xu M Chen and J V Forrester ldquoPara-inflammation in theaging retinardquo Progress in Retinal and Eye Research vol 28 no 5pp 348ndash368 2009

[211] K Kaarniranta D Sinha J Blasiak et al ldquoAutophagy andheterophagy dysregulation leads to retinal pigment epitheliumdysfunction and development of age-related macular degener-ationrdquo Autophagy vol 9 no 7 pp 973ndash984 2013

[212] A Klettner A Kauppinen J Blasiak J Roider A Salminenand K Kaarniranta ldquoCellular and molecular mechanisms ofage-related macular degeneration from impaired autophagy toneovascularizationrdquoThe International Journal of BiochemistryampCell Biology vol 45 no 7 pp 1457ndash1497 2013

[213] S Binder B V Stanzel I Krebs andCGlittenberg ldquoTransplan-tation of the RPE in AMDrdquo Progress in Retinal and Eye Researchvol 26 no 5 pp 516ndash554 2007

[214] E Arnault C Barrau C Nanteau et al ldquoPhototoxic actionspectrum on a retinal pigment epithelium model of age-related macular degeneration exposed to sunlight normalizedconditionsrdquo PLoS ONE vol 8 no 8 Article ID e71398 2013

[215] S G Jarrett and M E Boulton ldquoConsequences of oxidativestress in age-related macular degenerationrdquo Molecular Aspectsof Medicine vol 33 no 4 pp 399ndash417 2012

[216] J Kopitz F G Holz E Kaemmerer and F Schutt ldquoLipids andlipid peroxidation products in the pathogenesis of age-relatedmacular degenerationrdquo Biochimie vol 86 no 11 pp 825ndash8312004

[217] J R Sparrow and M Boulton ldquoRPE lipofuscin and its role inretinal pathobiologyrdquo Experimental Eye Research vol 80 no 5pp 595ndash606 2005

[218] Y Wu E Yanase X Feng M M Siegel and J R SparrowldquoStructural characterization of bisretinoid A2E photocleavageproducts and implications for age-related macular degenera-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 16 pp 7275ndash7280 2010

[219] A Zadlo M B Rozanowska J M Burke and T J SarnaldquoPhotobleaching of retinal pigment epithelium melanosomesreduces their ability to inhibit iron-induced peroxidation oflipidsrdquo Pigment Cell Research vol 20 no 1 pp 52ndash60 2007

[220] S Memoli A Napolitano M DrsquoIschia A Palumbo andG Prota ldquoDiffusible melanin-related metabolites are potentinhibitors of lipid peroxidationrdquo Biochimica et Biophysica Actavol 1346 no 1 pp 61ndash68 1997

[221] L Hong and J D Simon ldquoCurrent understanding of the bindingsites capacity affinity and biological significance of metals inmelaninrdquo The Journal of Physical Chemistry B vol 111 no 28pp 7938ndash7947 2007

[222] P Kaczara M Zareba A Herrnreiter et al ldquoMelanosome-ironinteractions within retinal pigment epithelium-derived cellsrdquoPigment Cell and Melanoma Research vol 25 no 6 pp 804ndash814 2012

[223] K Jomova D Vondrakova M Lawson and M Valko ldquoMetalsoxidative stress and neurodegenerative disordersrdquo Molecularand Cellular Biochemistry vol 345 no 1-2 pp 91ndash104 2010

[224] T Sarna J M Burke W Korytowski et al ldquoLoss of melaninfrom human RPE with aging possible role of melanin photoox-idationrdquo Experimental Eye Research vol 76 no 1 pp 89ndash982003

[225] R Klein B E K Klein E K Marino et al ldquoEarly age-relatedmaculopathy in the cardiovascular health studyrdquo Ophthalmol-ogy vol 110 no 1 pp 25ndash33 2003

[226] C L Thompson G Jun B E K Klein et al ldquoGenetics ofpigment changes and geographic atrophyrdquo Investigative Oph-thalmology and Visual Science vol 48 no 7 pp 3005ndash30132007

[227] S Qin and G A Rodrigues ldquoRoles of 120572v1205735 FAK and MerTKin oxidative stress inhibition of RPE cell phagocytosisrdquo Experi-mental Eye Research vol 94 no 1 pp 63ndash70 2012

[228] T A Bailey N Kanuga I A Romero J Greenwood P JLuthert andM E Cheetham ldquoOxidative stress affects the junc-tional integrity of retinal pigment epithelial cellsrdquo InvestigativeOphthalmology and Visual Science vol 45 no 2 pp 675ndash6842004

[229] M M Sachdeva M Cano and J T Handa ldquoNrf2 signaling isimpaired in the aging RPE given an oxidative insultrdquo Experi-mental Eye Research vol 119 pp 111ndash114 2014

[230] M Cano R Thimmalappula M Fujihara et al ldquoCigarettesmoking oxidative stress the anti-oxidant response throughNrf2 signaling and age-related macular degenerationrdquo VisionResearch vol 50 no 7 pp 652ndash664 2010

[231] N Nagai R K Thimmulappa M Cano et al ldquoNrf2 is a criticalmodulator of the innate immune response in amodel of uveitisrdquoFree Radical Biology amp Medicine vol 47 no 3 pp 300ndash3062009

[232] A Koskela M Reinisalo J M Hyttinen K Kaarniranta andR O Karjalainen ldquoPinosylvin-mediated protection againstoxidative stress in human retinal pigment epithelial cellsrdquoMolecular Vision vol 20 pp 760ndash769 2014

[233] N M M Saviranta L Veeroos L J Granlund V H HassinenK Kaarniranta and R O Karjalainen ldquoPlant flavonol quercetinand isoflavone biochanin A differentially induce protectionagainst oxidative stress and inflammation in ARPE-19 cellsrdquoFood Research International vol 44 no 1 pp 109ndash113 2011

[234] X Zou Z Feng Y Li et al ldquoStimulation of GSH synthesis toprevent oxidative stress-induced apoptosis by hydroxytyrosolin human retinal pigment epithelial cells activation of Nrf2and JNK-p62SQSTM1 pathwaysrdquo The Journal of NutritionalBiochemistry vol 23 no 8 pp 994ndash1006 2012


[235] E-J Park H J Park H-J Chung et al ldquoAntimetastatic activityof pinosylvin a natural stilbenoid is associated with the sup-pression of matrix metalloproteinasesrdquo Journal of NutritionalBiochemistry vol 23 no 8 pp 946ndash952 2012

[236] S Richer W Stiles L Ulanski D Carroll and C PodellaldquoObservation of human retinal remodeling in octogenarianswith a resveratrol based nutritional supplementrdquoNutrients vol5 no 6 pp 1989ndash2005 2013

[237] E Brakenhielm R Cao and Y Cao ldquoSuppression of angiogen-esis tumor growth and wound healing by resveratrol a naturalcompound in red wine and grapesrdquoThe FASEB Journal vol 15no 10 pp 1798ndash1800 2001

[238] B Dugas S Charbonnier M Baarine et al ldquoEffects of oxys-terols on cell viability inflammatory cytokines VEGF andreactive oxygen species production on human retinal cellscytoprotective effects and prevention of VEGF secretion byresveratrolrdquo European Journal of Nutrition vol 49 no 7 pp435ndash446 2010

[239] M Pons and M E Marin-Castano ldquoCigarette smoke-relatedhydroquinone dysregulates MCP-1 VEGF and PEDF expres-sion in retinal pigment epithelium in vitro and in vivordquo PLoSONE vol 6 no 2 Article ID e16722 2011

[240] Z Ablonczy A Prakasam J Fant A Fauq C Crosson andK Sambamurti ldquoPigment epithelium-derived factor main-tains retinal pigment epithelium function by inhibiting vas-cular endothelial growth factor-R2 signaling through gamma-secretaserdquoThe Journal of Biological Chemistry vol 284 no 44pp 30177ndash30186 2009

[241] C-M Chan H-H Chang V-C Wang C-L Huang and C-FHung ldquoInhibitory effects of resveratrol on PDGF-BB-inducedretinal pigment epithelial cellmigration via PDGFR120573 PI3KAktand MAPK pathwaysrdquo PLoS ONE vol 8 no 2 Article IDe56819 2013

[242] X-Q Liu B-JWuWH T Pan et al ldquoResveratrol mitigates ratretinal ischemic injury the roles of matrix metalloproteinase-9inducible nitric oxide and heme oxygenase-1rdquo Journal of OcularPharmacology andTherapeutics vol 29 no 1 pp 33ndash40 2013

[243] A P Vin H Hu Y Zhai et al ldquoNeuroprotective effectof resveratrol prophylaxis on experimental retinal ischemicinjuryrdquo Experimental Eye Research vol 108 pp 72ndash75 2013

[244] S Kubota T Kurihara M Ebinuma et al ldquoResveratrol preventslight-induced retinal degeneration via suppressing activatorprotein-1 activationrdquo The American Journal of Pathology vol177 no 4 pp 1725ndash1731 2010

[245] C Li L Wang K Huang and L Zheng ldquoEndoplasmicreticulum stress in retinal vascular degeneration protective roleof resveratrolrdquo Investigative Ophthalmology amp Visual Sciencevol 53 no 6 pp 3241ndash3249 2012

[246] S H Kim J H Park Y J Kim and K H Park ldquoTheneuroprotective effect of resveratrol on retinal ganglion cellsafter optic nerve transectionrdquoMolecularVision vol 19 pp 1667ndash1676 2013

[247] S Kubota T Kurihara H Mochimar et al ldquoPrevention ofocular inflammation in endotoxin-induced uveitis with resver-atrol by inhibiting oxidative damage and nuclear factor-kappaBactivationrdquo Investigative Ophthalmology amp Visual Science vol50 no 7 pp 3512ndash3519 2009

[248] N M Kalariya M Shoeb A B M Reddy R Sawhney and KV Ramana ldquoPiceatannol suppresses endotoxin-induced ocularinflammation in ratsrdquo International Immunopharmacology vol17 no 2 pp 439ndash446 2013

[249] F Ishizuka M Shimazawa Y Inoue et al ldquoToll-like receptor4 mediates retinal ischemiareperfusion injury through nuclearfactor-120581B and spleen tyrosine kinase activationrdquo InvestigativeOphthalmology and Visual Science vol 54 no 8 pp 5807ndash58162013

[250] VTheendakara A Patent C A P Libeu et al ldquoNeuroprotectiveSirtuin ratio reversed by ApoE4rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 110 no45 pp 18303ndash18308 2013

[251] Q Dai A R Borenstein Y Wu J C Jackson and E B LarsonldquoFruit and vegetable juices and alzheimerrsquos disease the kameprojectrdquo The American Journal of Medicine vol 119 no 9 pp751ndash759 2006

[252] L Ho M G Ferruzzi E M Janle et al ldquoIdentification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novelintervention for Alzheimerrsquos diseaserdquo The FASEB Journal vol27 no 2 pp 769ndash781 2013

[253] R E Tanzi R D Moir and S L Wagner ldquoClearance ofAlzheimerrsquos A120573 peptide the many roads to perditionrdquo Neuronvol 43 no 5 pp 605ndash608 2004

[254] JWang I Santa-Maria LHo et al ldquoGrape derived polyphenolsattenuate Tau neuropathology in a mouse model of alzheimerrsquosdiseaserdquo Journal of Alzheimerrsquos Disease vol 22 no 2 pp 653ndash661 2010

[255] E Parrella T Maxim F Maialetti et al ldquoProtein restrictioncycles reduce IGF-1 and phosphorylated tau and improvebehavioral performance in an Alzheimerrsquos disease mousemodelrdquo Aging Cell vol 12 no 2 pp 257ndash268 2013

[256] H Scholtzova R J Kascsak K A Bates et al ldquoInductionof toll-like receptor 9 signaling as a method for amelioratingalzheimerrsquos disease-related pathologyrdquo Journal of Neurosciencevol 29 no 6 pp 1846ndash1854 2009

[257] S M Rothman and M P Mattson ldquoActivity-dependent stress-responsive BDNF signaling and the quest for optimal brainhealth and resilience throughout the lifespanrdquoNeuroscience vol239 pp 228ndash240 2013

[258] M Rahvar M Nikseresht S M Shafiee et al ldquoEffect of oralresveratrol on the BDNF gene expression in the hippocampusof the rat brainrdquoNeurochemical Research vol 36 no 5 pp 761ndash765 2011

[259] F Allam A T Dao G Chugh et al ldquoGrape powder supplemen-tation prevents oxidative stress-induced anxiety-like behaviormemory impairment and high blood pressure in ratsrdquo TheJournal of Nutrition vol 143 no 6 pp 835ndash842 2013

[260] C Rendeiro D Vauzour R J Kean et al ldquoBlueberry supple-mentation induces spatial memory improvements and region-specific regulation of hippocampal BDNFmRNA expression inyoung ratsrdquo Psychopharmacology vol 223 no 3 pp 319ndash3302012

[261] P Marambaud H Zhao and P Davies ldquoResveratrol promotesclearance of Alzheimerrsquos disease amyloid-120573 peptidesrdquoThe Jour-nal of Biological Chemistry vol 280 no 45 pp 37377ndash373822005

[262] K Pallauf and G Rimbach ldquoAutophagy polyphenols andhealthy ageingrdquo Ageing Research Reviews vol 12 no 1 pp 237ndash252 2013

[263] N Gurusamy I Lekli S Mukherjee et al ldquoCardioprotectionby resveratrol a novel mechanism via autophagy involving themTORC2 pathwayrdquo Cardiovascular Research vol 86 no 1 pp103ndash112 2010


[264] L Fontana ldquoThe scientific basis of caloric restriction leading tolonger liferdquo Current Opinion in Gastroenterology vol 25 no 2pp 144ndash150 2009

[265] W Rizza N Veronese and L Fontana ldquoWhat are the rolesof calorie restriction and diet quality in promoting healthylongevityrdquo Ageing Research Reviews vol 13 no 1 pp 38ndash452014

[266] D Porquet G Casadesus S Bayod et al ldquoDietary resveratrolprevents alzheimerrsquosmarkers and increases life span in SAMP8rdquoAge vol 35 no 5 pp 1851ndash1865 2013

[267] S M de la Monte ldquoBrain insulin resistance and deficiency astherapeutic targets in Alzheimerrsquos diseaserdquo Current AlzheimerResearch vol 9 no 1 pp 35ndash66 2012

[268] B Dasgupta and J Milbrandt ldquoResveratrol stimulates AMPkinase activity in neuronsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 104 no 17 pp7217ndash7222 2007

[269] B T Jeon E A Jeong H J Shin et al ldquoResveratrol attenuatesobesity-associated peripheral and central inflammation andimproves memory deficit in mice fed a high-fat dietrdquo Diabetesvol 61 no 6 pp 1444ndash1454 2012

[270] Y Jimenez-Gomez J A Mattison K J Pearson et al ldquoResvera-trol improves adipose insulin signaling and reduces the inflam-matory response in adipose tissue of rhesus monkeys on high-fat high-sugar dietrdquoCell Metabolism vol 18 no 4 pp 533ndash5452013

[271] S Timmers E Konings L Bilet et al ldquoCalorie restriction-like effects of 30 days of resveratrol supplementation on energymetabolism and metabolic profile in obese humansrdquo CellMetabolism vol 14 no 5 pp 612ndash622 2011

[272] J Tome-Carneiro M Gonzalvez M Larrosa et al ldquoGraperesveratrol increases serum adiponectin and downregulatesinflammatory genes in peripheral blood mononuclear cellsa triple-blind placebo-controlled one-year clinical trial inpatients with stable coronary artery diseaserdquo CardiovascularDrugs and Therapy vol 27 no 1 pp 37ndash48 2013

[273] V Solfrizzi V Frisardi D Seripa et al ldquoMediterranean dietin predementia and dementia syndromesrdquo Current AlzheimerResearch vol 8 no 5 pp 520ndash542 2011

[274] V Solfrizzi F Panza V Frisardi et al ldquoDiet and alzheimerrsquosdisease risk factors or prevention the current evidencerdquo ExpertReview of Neurotherapeutics vol 11 no 5 pp 677ndash708 2011

[275] L Ho L H Chen J Wang et al ldquoHeterogeneity in red winepolyphenolic contents differentially influences Alzheimerrsquosdisease-type neuropathology and cognitive deteriorationrdquo Jour-nal of Alzheimerrsquos Disease vol 16 no 1 pp 59ndash72 2009

[276] P Scheltens P J G H Kamphuis F R J Verhey et al ldquoEfficacyof a medical food in mild Alzheimerrsquos disease a randomizedcontrolled trialrdquoAlzheimerrsquos andDementia vol 6 no 1 pp 1e1ndash10e1 2010

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Antioxidants

Stilbenes

Oxidativestress

ROS

Aging

Antioxidantdefence

cells

Healthycells

Aging-relateddiseases

Inflammation

Long and healthylifespan

Damaged

Figure 1 As an individual ages the balance between a longhealthy lifespan and suffering age-related diseases is believed to berelated to the interplay between the cellular antioxidant defencesystem and adverse effects related to oxidative stress In agingcells oxidative stress increases due to a progressive decline inthe efficiency of antioxidant defence systems There is convincingevidence to indicate that supplementation with polyphenols suchas stilbenes anthocyanins and catechins can increase cellularantioxidant defence and promote health of the individual

grapes it has attracted extensive scientific attention due toits potential health benefits related with its cardiovascu-lar (French paradox) chemopreventive antiobesity antidia-betic and neuroprotective properties However recent datahave highlighted that also other stilbene compounds suchas pterostilbene (35-dimethyl ether derivative of resver-atrol) may have higher bioavailability and possess betterneuroprotective activity against AD than resveratrol itself[8] Another interesting stilbene compound with potentialhealth-beneficial properties is pinosylvin (35-dihydroxy-trans-stilbene) a naturally occurring trans-stilbenoid whichis mainly found in the heartwood of Pinus species andoccurs in high concentrations in bark waste and thus thisstilbene compoundmay represent an inexpensive polyphenolwith considerable potential for diverse health-promotingapplications [9ndash11]

There are several comprehensive reviews available focus-ing on resveratrol but very few reports have analyzedthe bioactivity of other stilbenes Here we review shortlythe most recent data to clarify the molecular mechanismsinvolved in stilbene-mediated protection against oxidativestress emphasizing the potential roles of transcription fac-tor nuclear factor-erythroid-2-related factor-2 (Nrf2) andSQSTM1p62 protein (later referred to as p62) in the regula-tion of antioxidant enzymes and autophagy The therapeuticpotential of stilbene compounds to target the molecularpathways behind many common aging-related diseases willbe reviewed

2 Stilbene Compounds in Plants

Phenolic compounds are important mediators of adapta-tion and survival responses of plants in acute and chronicchallenges but polyphenols also act in plants regulating cellgrowth differentiation pollen fertility and nodulation andthus seem to be essential for plant health For example stil-benes are natural phenolic defence compounds occurring ina number of different plant species that possess antimicrobialand antioxidant activities against phytopathogens and ozoneor UV stress [12]

Stilbene compounds occur in many plant species(Table 1) including grape wine (Vitis vinifera) peanut(Arachis hypogaea) sorghum (Sorghum bicolor) and manytree species (Pinus and Picea) [13] Moreover commercialsources of stilbenes include many plants cultivated in Asia asfolk medicines such as Polygonum cuspidatum Rhodomyrtustomentosa Rheum undulatum Melaleuca leucadendronand Euphorbia lagascae while pterostilbene is found pre-dominantly in bilberries (Vaccinium myrtillus) blueberries(several Vaccinium species) and some other berries as wellas in grapes and juice residues which are important source ofthis stilbene when it is used in nutraceutical applications [14]Grape pomaces residues produced during wine makingand other grape juice solids contain high polyphenolconcentrations and are also attractive sources of manystilbene compounds not only resveratrol [15] The bark wasteof conifer trees contains substantial amount of stilbene com-pounds such as pinosylvin piceatannol and trans-resveratrol(t-Res)Thus this enormous amount of industrial byproductsrepresents a very attractive and inexpensive source of stil-benes with commercial applications [16 17] Genetic tools area very promising means to produce specific stilbenes such aspterostilbene via stilbene synthase and O-methyltransferasecoexpression in plants [18] These types of stilbenes maybe especially suitable for pharmacological applications Themajor stilbenes and their structures are described in Table 1and a more complete list can be found in reviews [12 19]

Stilbene synthase (STS) is the key enzyme that catalyzesthe biosynthesis of stilbenic compounds STS has evolvedfrom the chalcone synthases (CHSs) apparently several timesindependently in stilbene-producing plants [13 19] Interest-ingly different STS genes display different tissue and devel-opmental specific expression Thus it has been reported thatSTS genes exhibited lower expression levels in young grapeleaves than in old leaves while the transcript levels of eightSTS genes increased dramatically in the berry skin of grapecultivars Cabernet Sauvignon and Norton post veraisonreaching the highest level at the time of harvest [2] Theheartwood of pine trees contains high level of pinosylvin butas a response to stress induction (fungal or UV light) youngseedlings also accumulate high amounts of pinosylvin [20]

3 Bioavailability

At least a proportion of the stilbene compounds or theirmetabolites present in extracts may be sufficiently bioavail-able to reach even brain target cells and thus exert beneficial




HO

OH


HO

OH

OH

Piceatannol

HO

OH

OH

OH

H3C

Pterostilbene

OHCH3

O

O

CH3

O

Rhapontigenin

HO

OH

CH3

Isorhapontigenin

HO

OH

OCH3

OH














Keap1

Keap1Ub

Keap1

Ub


enzymes


Cell

Stilbenes

CUL3


degradation


p62

NQO1Oxidative

stress

p62

PKA

CRE ARENrf2

CREB

CREB

Nrf2

Ub

GSTs

HO-1ARE

ARE

SIRT1

Autophagosome

Keap1Nrf2

CUL3 p62Keap1

+

HO-1

minus


Nrf2

Maf

uarr cAMPuarr AMPK

darr PDE

uarr cAMP















































2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















HO

OH


HO

OH

OH

Piceatannol

HO

OH

OH

OH

H3C

Pterostilbene

OHCH3

O

O

CH3

O

Rhapontigenin

HO

OH

CH3

Isorhapontigenin

HO

OH

OCH3

OH














Keap1

Keap1Ub

Keap1

Ub


enzymes


Cell

Stilbenes

CUL3


degradation


p62

NQO1Oxidative

stress

p62

PKA

CRE ARENrf2

CREB

CREB

Nrf2

Ub

GSTs

HO-1ARE

ARE

SIRT1

Autophagosome

Keap1Nrf2

CUL3 p62Keap1

+

HO-1

minus


Nrf2

Maf

uarr cAMPuarr AMPK

darr PDE

uarr cAMP















































2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























Keap1

Keap1Ub

Keap1

Ub


enzymes


Cell

Stilbenes

CUL3


degradation


p62

NQO1Oxidative

stress

p62

PKA

CRE ARENrf2

CREB

CREB

Nrf2

Ub

GSTs

HO-1ARE

ARE

SIRT1

Autophagosome

Keap1Nrf2

CUL3 p62Keap1

+

HO-1

minus


Nrf2

Maf

uarr cAMPuarr AMPK

darr PDE

uarr cAMP















































2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Keap1

Keap1Ub

Keap1

Ub


enzymes


Cell

Stilbenes

CUL3


degradation


p62

NQO1Oxidative

stress

p62

PKA

CRE ARENrf2

CREB

CREB

Nrf2

Ub

GSTs

HO-1ARE

ARE

SIRT1

Autophagosome

Keap1Nrf2

CUL3 p62Keap1

+

HO-1

minus


Nrf2

Maf

uarr cAMPuarr AMPK

darr PDE

uarr cAMP















































2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























2


































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Nrf2PDEs NRsBH4

cAMPAntioxidant

enzymes PAHeNOS

TYR

L-DOPA

NO

p62 SIRT1


Autophagy


and retinalfunction

Energyhomeostasis

AMPK

Obesity T2D ADAMD


Stilbenes



7 Conclusions






Acknowledgments


References








































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Acknowledgments


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of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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