Aggarwal

Birrell

Biswas

Cheng

Culpitt

Donnelly

Irfan Rahman

Kang

Marwick

Moodie

Pervaiz

Rahman

Shoba

Wahlstrom

Yang

English

PubMed

Crossref

Dietary polyphenols mediated regulation of oxidative stress and chromatin remodeling in inflammation

Rahman, Irfan

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      Dietary polyphenols mediated regulation of oxidative stress andchromatin remodeling in inflammationCitation for published version:Rahman, I 2008, 'Dietary polyphenols mediated regulation of oxidative stress and chromatin remodeling ininflammation' Nutrition Reviews, vol 66 , no. Suppl 1, pp. S42-5., 10.1111/j.1753-4887.2008.00067.xDigital Object Identifier (DOI):10.1111/j.1753-4887.2008.00067.xLink:Link to publication record in Edinburgh Research ExplorerDocument Version:Author final version (often known as postprint)Published In:Nutrition ReviewsGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 20. Feb. 2015Dietary polyphenols mediated regulation of oxidative stress andchromatin remodeling in inflammationIrfan RahmanDepartment of Environmental Medicine, University of Rochester Medical Center, Rochester, NewYork, USAReactive oxygen species (ROS) alter nuclear histone acetylation and deacetylation(chromatin remodeling) leading to increased NF-κB-dependent gene expression ofproinflammatory mediators. Naturally occurring dietary polyphenols such as curcumin(diferuloylmethane, an active component of spice turmeric) and resveratrol (phytoalexin, aflavanoid found in red wine) can directly scavenge ROS and modulate signaling pathwaysmediated via NF-κB and MAP kinase pathways, and upregulate glutathione biosynthesisgene via Nrf2 activation. They also downregulate expression of proinflammatory mediators,matrix metalloproteinases, adhesion molecules, and growth factor receptor genes byinhibiting histone acetyltransferase activity and activating histone deacetylase/sirtuins. Thus,these polyphenolic compounds have therapeutic value as antioxidant and anti-inflammatorytherapy against chronic inflammatory epigenetically regulated diseases.Reactive oxygen species play a key role in enhancing the inflammation through sustainedactivation and phosphorylation of MAP kinases and redox-sensitive transcription factors,such as NF-κB and AP-1, in various inflammatory diseases.1 Oxidative stress also altersnuclear histone acetylation and deacetylation (chromatin remodeling) leading to increasedgene expression of proinflammatory mediators.2,3 Recent studies from our laboratory showthat oxidative stress enhances lung inflammation via expression of proinflammatorymediators through the activation of intrinsic histone acetyltransferase (HAT) activity ofcoactivator molecules.4–7 Increased histone acetylation was associated with increasedactivation of IκB kinase-α and interaction of NF-κB with CBP, leading to increasedacetylation of RelA/p65 subunit of NF-κB. Oxidative stress also inhibits the activity ofhistone deacetylase (HDACs) (decreased HDAC2 levels), activates cells for NF-κBtransactivation, and enhances inflammatory gene expression, which leads to chronicinflammatory response both in monocytes and epithelial cells in vitro, and in lungs in vivo.5–7 Oxidative stress also plays a role in poor efficacy of corticosteroids in various chronicinflammatory diseases.2,8 Thus, oxidative stress-mediated aberrant chromatin remodeling orhistone modifications can lead to heightened abnormal inflammatory response. Thesechanges, despite being heritable and stably maintained, are also potentially reversible;therefore, there is scope for the development of ‘epigenetic therapies’ for such diseases.However, there is no specific therapeutic agent currently available to effectively inhibit bothoxidative stress and inflammatory responses in a variety of inflammatory conditions/disorders.Polyphenols in food plants are a versatile group of phytochemicals with many potentiallybeneficial activities in terms of disease prevention. Dietary polyphenols (bioflavanoids) haveantioxidant and anti-inflammatory properties that might explain their beneficial effects.Correspondence: Department of Environmental Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 850,Rochester, NY 14642, USA. E-mail: irfan_rahman@urmc.rochester.edu, Phone: +1-585-275-6911, Fax: +1-585-506-0239.NIH Public AccessAuthor ManuscriptNutr Rev. Author manuscript; available in PMC 2009 August 1.Published in final edited form as:Nutr Rev. 2008 August ; 66(Suppl 1): S42–S45. doi:10.1111/j.1753-4887.2008.00067.x.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptHowever, the actual therapeutic potential of these compounds remains to be translated forhuman use due to lack of knowledge of their complex mode of absorption,biotransformation, and bioavailability. Although several in vitro studies have yieldedexcellent results using polyphenols from plants, more detailed investigations are stillrequired to extrapolate these results to in vivo conditions. In this minireview, antioxidantand anti-inflammatory properties of some of the dietary polyphenols are briefly described inthe context of nuclear chromatin remodeling.CurcuminCurcumin (diferuloylmethane, a principal and active component of turmeric) is a yellow-colored polyphenolic pigment obtained from the rhizome of Curcuma longa Linn (Family-Zingiberaceae) and a member of the curcuminoid family of compounds. Several of itspharmacological properties and medicinal applications have been reported previously.9 Thehydroxyl and methoxy groups of curcumin have been considered to render antioxidant andanticarcinogenic activities, respectively. About 40–85% of the total amount of curcuminingested remains unaltered in the gastrointestinal tract, it is, however, metabolized in theintestinal mucosa and liver.10 Consumption of up to 10 g curcumin/day have been reportedto be devoid of any direct toxicity in humans11 and its bioavailability has been found to beincreased 20-fold when consumed along with piperin (an active ingredient of pepper).12 Arecent surge in research on oxidative stress-related diseases and the possibility thatantioxidants may help control such diseases (particularly in susceptible populations) havetriggered a remarkable increment in scientific investigations and knowledge regarding theantioxidant and anti-inflammatory roles of dietary polyphenols.Antioxidant properties of curcuminFree radicals (ROS and reactive nitrogen species) such as superoxide anion (O2–), hydrogenperoxide (H2O2), and nitric oxide (NO) have now been reported to be scavenged bycurcumin (in the micro to millimolar range) both in vitro and in vivo.9 Findings from ourown laboratory indicate that curcumin (1–50 μM) could scavenge ROS in 1–4 hours, asdetermined by electron paramagnetic resonance spectroscopy.13 Curcumin was found to bemuch faster in terms of quenching ROS when compared to other polyphenols tested(resveratrol and quercetin). More recently, curcumin has been demonstrated to induceantioxidant defenses through increases in glutathione production via Nrf2 activation andinduction of glutamate cysteine ligase transcription. Similarly, expression of phase IIenzymes such as glutathione-S-transferase is also induced by curcumin. The antioxidantproperties of curcumin are evident from its ability to lower lipid peroxidation and maintainthe activity status of various antioxidant enzymes. Since ROS have been implicated in thepathogenesis of various chronic and inflammatory conditions, curcumin therefore has thepotential to control these diseases through its potent antioxidant activity.Anti-inflammatory property of curcumin: its role in chromatin remodelingCurcumin has been reported to have both anti-cancer and anti-inflammatory properties andinhibit a wide range of inflammatory and signaling molecules.9 Recent studies have reportedthat curcumin inhibits NF-κB expression/activation, IL-8 release, and neutrophil recruitmentin lung cells.13 Curcumin inhibits NF-κB transactivation by inhibiting the nucleartranslocation of the p65 subunit of NF-κB, in association with the sequential suppression ofIκB kinase phosphorylation, IκB-α degradation, p65 phosphorylation, and p65acetylation9,13 (Figure 1). Since NF-κB regulates expression of a wide variety of genes thatare intimately involved in the process of inflammation, inhibition of NF-κB by curcuminmay be an interesting prospect for controlling chronic inflammatory diseases involving theNF-κB signaling pathway. In addition to the suppression of proinflammatory genes,Rahman Page 2Nutr Rev. Author manuscript; available in PMC 2009 August 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptcurcumin also downregulates the expression of iNOS, MMP-9, TNF-α, chemokines, cellsurface adhesion molecules, and growth factor receptors (such as epidermal growth factorreceptor). In addition, curcumin modulates a number of key kinase signaling pathways suchas mitogen-activated protein kinases (MAPK) and protein kinase C (PKC) in a wide varietyof different cell types. The pleiotropic nature of curcumin in targeting so many cell signalingpathways complicates the process of identifying which pathway is essential for the anti-inflammatory effects. On the other hand, it may be that the ability to prevent cross talkbetween the myriad signaling pathways is a prerequisite for its anti-inflammatory properties.We recently observed that curcumin can inhibit inflammation and restore glucocorticoidefficacy (which is lost under oxidative stress) through upregulation/restoration of HDAC2activity in monocytes/macrophages (U937 and MonoMac6 cells). Curcumin restored bothHDAC2 activity and corticosteroid resistance in a concentration-dependent manner with anEC50 of 15 nM and 200–300 nM, respectively, in the monocytes and macrophages. Thisrestoration facilitated steroid-mediated HDAC2 recruitment in the co-repressor complexattenuating NF-κB-mediated chromatin acetylation and subsequent proinflammatory geneexpression. Interestingly, it has recently been suggested that the anti-inflammatory actions ofcurcumin at 50 μM are propagated through inhibition of HAT activity, preventing NF-κB-mediated chromatin acetylation.14 Hence, it might be reasonable to propose that in additionto its role as an antioxidant/anti-inflammatory agent, curcumin may also assist in increasingthe efficacy of steroids via modulation of HDAC and HAT activity. Clearly, clinical trialsusing a combination approach of a steroid with curcumin are warranted.ResveratrolResveratrol (3, 4′-5- trihydroxystilbene), which is a phytoalexin found in the skin and seedsof grapes and produced by some spermatophytes, such as grapevines, in response to injuryor fungal attack, has been reported to possess antioxidant, anti-inflammatory, andanticarcinogenic properties.15 Studies have shown that resveratrol is more effective ininhibiting the oxidative damage than the conventional antioxidants and has also been shownto scavenge free radicals such as lipid hydroperoxyl, hydroxyl, and superoxide anionradicals.16 Our data show that resveratrol is a potent ROS scavenger and exerts antioxidantproperties through modulation of glutathione biosynthesis via Nrf2 antioxidant responseelement signaling.Anti-inflammatory property of resveratrolResveratrol is an effective inhibitor of inflammatory cytokine release from macrophages inpatients with chronic obstructive pulmonary disease.17 This anti-inflammatory property ofresveratrol may be due to its ability to induce sirtuins and HDAC activity. A recent in vivostudy has shown that resveratrol inhibits inflammatory cytokine expression in response tolipopolysaccharide in rat lungs.18 Furthermore, in both monocytic U937 cells and alveolarepithelial A549 cells, resveratrol inhibited NF-κB and AP-1 activation.19 The mechanismthrough which this occurs is still unclear. It is possible that resveratrol could induce histonedeacetylase activity via SIRT1 (sirtuin1) and inhibit proinflammatory genes.20ConclusionsDietary polyphenols such as curcumin and resveratrol have been shown to act both as anantioxidant as well as an anti-inflammatory agent. These polyphenols inhibit oxidant-induced NF-κB activation, histone acetylation, and proinflammatory cytokine release, andthey restore glucocorticoid functions via a mechanism involving upregulation of HDAC2/sirtuin activity. Thus, regulation of inflammatory response by dietary polyphenols andrestoration of glucocorticoid efficacy at the molecular level are possible ways forward toRahman Page 3Nutr Rev. Author manuscript; available in PMC 2009 August 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptdesign therapeutic strategies for the treatment of chronic inflammatory diseases, particularlyin susceptible populations. However, future studies on the bioavailability, absorption, tissuedistribution, and understanding of the in vivo molecular effects of curcumin and resveratrolare needed in order to consider these dietary polyphenols as natural therapy ‘nutraceuticals’for chronic inflammatory disorders.AcknowledgmentsFunding. NIH R01-HL085613, NIEHS Grant ES-01247, and NIEHS Toxicology Training grant # ES07026.AbbreviationsGC glucocorticoidAc acetylationP phosphateCBP CREB (cAMP response element binding protein)-binding proteinRelA/p65 NF-κB subunitSIRT1 Sirtuin1ROS reactive oxygen species+ inducting effects of polyphenols– inhibitory effects of polyphenolsReferences1. Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation andchronic lung disease. J Biochem Mol Biol. 2003; 36:95–109. [PubMed: 12542980]2. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. EurRespir J. 2006; 28:219–242. [PubMed: 16816350]3. Rahman I, Marwick JA, Kirkham PA. Redox modulation of histone acetylation and deacetylation invitro and in vivo: modulation of NF-κB and pro-inflammatory genes. Biochem Pharmacol. 2004;68:1255–1267. [PubMed: 15313424]4. Rahman I, Gilmour P, Jimenez LA, Mac Nee W. Oxidative stress and TNF-α induce histoneacetylation and AP-1/NF-κB in alveolar epithelial cells: potential mechanism in inflammatory genetranscription. Mol Cell Biochem. 2002; 234/235:239–248. [PubMed: 12162440]5. Marwick JA, Giddings J, Butler K, et al. Cigarette smoke induces inflammatory response and alterschromatin remodeling in rat lungs. Am J Respir Cell Mol Biol. 2004; 31:633–642. [PubMed:15333327]6. Moodie F, Marwick JA, Anderson C, et al. Oxidative stress and cigarette smoke alter chromatinremodeling but differentially regulate NF-κB activation and pro-inflammatory cytokine release inalveolar epithelial cells. FASEB J. 2004; 18:1897–1909. [PubMed: 15456740]7. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine releaseby activation of NF-kappaB and posttranslational modifications of histone deacetylase inmacrophages. Am J Physiol Lung Cell Mol Physiol. 2006; 291:L46–57. [PubMed: 16473865]8. Ito K, Lim G, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histonedeacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions inalveolar macrophages. FASEB J. 2001; 15:1110–1112. [PubMed: 11292684]9. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinicalstudies. Anticancer Res. 2003; 23:363–398. [PubMed: 12680238]10. Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol.1978; 43:86–92.Rahman Page 4Nutr Rev. Author manuscript; available in PMC 2009 August 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript11. Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, inpatients with high-risk or pre-malignant lesions. Anticancer Res. 2001; 21:2895–2900. [PubMed:11712783]12. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on thepharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998; 64:353–356.[PubMed: 9619120]13. Biswas SK, McClure D, Jimenez LA, Megson IL, Rahman I. Curcumin induces glutathionebiosynthesis and inhibits oxidant- and TNF-α-mediated NF-κB activation and chromatinremodeling in alveolar epithelial cells. Antioxid Redox Signal. 2005; 7:32–41. [PubMed:15650394]14. Kang J, Chen J, Shi Y, Jia J, Zhang Y. Curcumin-induced histone hypoacetylation: the role ofreactive oxygen species. Biochem Pharmacol. 2005; 69:1205–1213. [PubMed: 15794941]15. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrolin prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004;24:2783–2840. [PubMed: 15517885]16. Pervaiz S. Resveratrol: from grapevines to mammalian biology. FASEB J. 2003; 14:1975–1985.[PubMed: 14597667]17. Culpitt SV, Rogers DF, Fenwick PS, et al. Inhibition by red wine extract, resveratrol, of cytokinerelease by alveolar macrophages in COPD. Thorax. 2003; 58:942–946. [PubMed: 14586044]18. Birrell MA, McCluskie K, Wong S, Donnelly LE, Barnes PJ, Belvisi MG. Resveratrol, an extractof red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediatorsthrough an NF-KappaB-independent mechanism. FASEB J. 2005; 19:840–841. [PubMed:15734790]19. Donnelly LE, Newton R, Kennedy GE, et al. Anti-inflammatory effects of resveratrol in lungepithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol. 2004; 287:L774–783. [PubMed: 15180920]20. Yang SR, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I. Sirtuin regulates cigarettesmoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages invitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am J Physiol LungCell Mol Physiol. 2007; 292:L567–576. [PubMed: 17041012]Rahman Page 5Nutr Rev. Author manuscript; available in PMC 2009 August 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1. Impact of oxidative stress and dietary polyphenols on the regulation of chromatinmodifications and proinflammatory gene expressionOxidants and proinflammatory cytokines activate transcription factors, such as NF-κB, byrecruitment of transcriptional coactivator molecules CBP/p300, which possess intrinsichistone acetylase (HAT) activity, resulting in histone acetylation and DNA unwinding,allowing DNA polymerases access to the DNA leading to proinflammatory gene expression.Direct interaction between coactivators (such as HAT), histone deacetylase, and theglucocorticoid receptor (GR) may result in repression of expression of proinflammatorygenes. Histone deacetylase type II (HDAC2) forms a bridge with HAT and RelA/p65 toinhibit gene transcription. However, when the HDAC2 (by post-translational modification/disruption) is inhibited by cigarette smoke/oxidants and/or the NF-κB subunit RelA/p65 isacetylated, steroids may not be able to recruit HDAC2 into the transrepressor complex toinhibit proinflammatory gene expression. Dietary polyphenols, such as curcumin andresveratrol inhibit NF-κB activation, CBP-HAT activity, and restore glucocorticoid efficacyby upregulating HDAC2 and sirutin activity, culminating in inhibition of proinflammatorygene expression.Rahman Page 6Nutr Rev. Author manuscript; available in PMC 2009 August 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

4 Nutr Rev. Author manuscript; available in PMC

6 Nutr Rev. Author manuscript; available in PMC

Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic

Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res.

http://dx.doi.org/10.1111/j.1753-4887.2008.00067.x

Dietary polyphenols mediated regulation of oxidative stress and chromatin remodeling in inflammation

Abstract

Similar works

Full text

Available Versions

Crossref

Edinburgh Research Explorer