Elsevier

Biochemical Pharmacology

Volume 72, Issue 11, 30 November 2006, Pages 1439-1452
Biochemical Pharmacology

Regulation of inflammation and redox signaling by dietary polyphenols

https://doi.org/10.1016/j.bcp.2006.07.004Get rights and content

Abstract

Reactive oxygen species (ROS) play a key role in enhancing the inflammation through the activation of NF-κB and AP-1 transcription factors, and nuclear histone acetylation and deacetylation in various inflammatory diseases. Such undesired effects of oxidative stress have been found to be controlled by the antioxidant and/or anti-inflammatory effects of dietary polyphenols such as curcumin (diferuloylmethane, a principal component of tumeric) and resveratrol (a flavanoid found in red wine). The phenolic compounds in fruits, vegetables, tea and wine are mostly derivatives, and/or isomers of flavones, isoflavones, flavonols, catechins, tocopherols, and phenolic acids. Polyphenols modulate important cellular signaling processes such as cellular growth, differentiation and host of other cellular features. In addition, they modulate NF-κB activation, chromatin structure, glutathione biosynthesis, nuclear redox factor (Nrf2) activation, scavenge effect of ROS directly or via glutathione peroxidase activity and as a consequence regulate inflammatory genes in macrophages and lung epithelial cells. However, recent data suggest that dietary polyphenols can work as modifiers of signal transduction pathways to elicit their beneficial effects. The effects of polyphenols however, have been reported to be more pronounced in vitro using high concentrations which are not physiological in vivo. This commentary discusses the recent data on dietary polyphenols in the control of signaling and inflammation particularly during oxidative stress, their metabolism and bioavailability.

Section snippets

Polyphenols: an overview

A wide variety of dietary plants including grains, legumes, fruits, vegetables, tea, wine, etc. contain polyphenols [1]. The disease preventive abilities of fruit and vegetables have been attributed to the antioxidants/polyphenols present in these dietary sources [2]. It is noteworthy that most reports on the beneficial effects of polyphenols have been obtained from in vitro studies and more detailed investigations are required to extrapolate these results to in vivo situations. This is

Chemistry of polyphenols

Polyphenols, with over 8000 structural variants, are secondary metabolites of plants and denote a huge gamut of substances having aromatic ring(s) bearing one or more hydroxyl moieties. The structure of natural polyphenols varies from simple molecules, such as phenolic acids, to highly polymerized compounds, such as condensed tannins [3]. Polyphenols are effective free radical scavengers and metal chelators which are mediated by the presence of para-hydroxyl group. The most widely distributed

Absorption, pharmacokinetics, tissue distribution and metabolism of polyphenols

In view of polyphenols having complex absorption, biotransformation and bioavailability characteristics, it is important to probe these aspects before we embark on the investigation of the molecular mechanisms and therapeutic applications of these versatile compounds. A proper understanding of how polyphenols are absorbed and transformed pre- and post-absorption is helpful in understanding how in vitro observations can be translated into the in vivo context.

Bioavailability of polyphenols

Although the knowledge of absorption, bioavailability, biodistribution and metabolism of polyphenols is not entirely known, in general it appears that some polyphenols are bioactive and are absorbed through the intestine in their native or modified form. The absorbed forms are then metabolized and the end products may be detected in plasma in nanomolar ranges. The plasma forms of polyphenols may retain at least part of their antioxidant capacity before being excreted [16]. In general, the

Polyphenols as antioxidants

In recent years there has been a remarkable increment in scientific knowledge dealing with the beneficial role of polyphenols during oxidative stress. This is due to the identification of flavonoids and other dietary polyphenol antioxidants present in plant foods as bioactive molecules. Data supports the idea that the health benefits associated with fruits, vegetables and red wine in the diet are probably linked to the polyphenol antioxidants they contain. Indeed, the high content of polyphenol

Cellular signaling, NF-κB and polyphenols

Much of the earlier studies on polyphenols have viewed these compounds from the perspective of antioxidants. The antioxidant property of these molecules was later explained on the basis of the availability of –OH and the system of conjugated double bonds present in these molecules. However, many other effects of polyphenols such as anti-inflammatory, anti-tumor, anti-atherogenic abilities could not be explained solely on the basis of their antioxidant properties. Investigations into the

Polyphenols and cellular redox system

Since a variety of oxidants, free radicals and aldehydes are implicated in the pathogenesis of chronic inflammatory diseases, therapeutic intervention with a variety of polyphenolic antioxidants may therefore be an effective alternative for the treatment of chronic inflammatory diseases. An alternative mechanism may be that polyphenolic components of dietary plants may increase the endogenous antioxidant defense potential and thus modulate cellular redox state. It is therefore apt to consider

Polyphenols and glucocorticoid signaling

Although corticosteroids are highly effective in the control of asthma and other chronic inflammatory and immune diseases, a small proportion of patients with asthma fail to respond even to high doses of oral corticosteroids. Resistance to the therapeutic effects of corticosteroids is also recognized in other inflammatory and immune diseases, including rheumatoid arthritis and inflammatory bowel disease. Patients with corticosteroid-resistant asthma, although uncommon, present considerable

Challenges for research on polyphenols

Hundreds of polyphenols with antioxidant activity are potential contributors to the antioxidant mechanisms present in humans and animals. Although these compounds are excellent candidates to explain the health benefits of diets rich in fruits and vegetables, there is still not enough information on food composition data, bioavailability, interaction with other food components and their biological effects. There is evidence that polyphenols are metabolized by intestinal flora and that they and

Conclusions

Polyphenols and flavonoids seem to be important metabolic modulators by virtue of their ability to moderate and influence several cellular processes such as signaling, proliferation, apoptosis, redox balance, differentiation, etc. (Fig. 3). Although abundant in most dietary sources such as fruits, vegetables, tea and wine, more detailed studies are still required to determine their true absorption and bioavailability. It would serve well to remember that most studies and results on the effects

Acknowledgement

This work was supported by the Environmental Health Sciences Center Support #ES01247.

References (98)

  • C.G. Heijnen et al.

    Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups

    Toxicol In Vitro

    (2001)
  • H. Yoshida et al.

    Inhibitory effect of tea flavonoids on the ability of cells to oxidize low density lipoprotein

    Biochem Pharmacol

    (1999)
  • E.N. Frankel et al.

    Inhibition of human LDL oxidation by resveratrol

    Lancet

    (1993)
  • M.V. Clement et al.

    Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells

    Blood

    (1998)
  • J. Leiro et al.

    Effect of cis-resveratrol on genes involved in nuclear factor kappa B signaling

    Int Immunopharmacol

    (2005)
  • M. Miloso et al.

    Resveratrol-induced activation of the mitogen-activated protein kinases, ERK1 and ERK2, in human neuroblastoma SHSY5Y cells

    Neurosci Lett

    (1999)
  • A.M. El-Mowafy et al.

    Resveratrol inhibits MAPK activity and nuclear translocation in coronary artery smooth muscle: reversal of endothelin-1 stimulatory effects

    FEBS Lett

    (1999)
  • A. Duvoix et al.

    Chemopreventive and therapeutic effects of curcumin

    Cancer Lett

    (2005)
  • V.M. Adhami et al.

    Molecular targets for green tea in prostate cancer prevention

    J Nutr

    (2003)
  • N. Ahmad et al.

    Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells

    Arch Biochem Biophys

    (2000)
  • J.K. Lin et al.

    Cancer chemoprevention by tea polyphenols through mitotic signal transduction blockade

    Biochem Pharmacol

    (1999)
  • D.S. Wheeler et al.

    Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells

    J Nutr

    (2004)
  • J.S. Lee et al.

    Nrf2 as a novel molecular target for chemoprevention

    Cancer Lett

    (2005)
  • C.Y. Chen et al.

    Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells

    Biochem Biophys Res Commun

    (2005)
  • P. Kirkham et al.

    Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy

    Pharm Ther

    (2006)
  • I. Rahman et al.

    Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression

    Biochem Pharmacol

    (2004)
  • J. Kang et al.

    Curcumin-induced histone hypoacetylation: the role of reactive oxygen species

    Biochem Pharmacol

    (2005)
  • P. Knekt et al.

    Flavonoid intake and risk of chronic diseases

    Am J Clin Nutr

    (2002)
  • L. Bravo

    Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance

    Nutr Rev

    (1998)
  • M.A. Eastwood

    Interaction of dietary antioxidants in vivo: how fruit and vegetables prevent disease?

    Q J Med

    (1999)
  • J.B. Harborne

    Plant phenolics

  • E. Siemann et al.

    Concentration of the phytoalexin resveratrol in wine

    Am J Enol Vitic

    (1992)
  • B.C. Trela et al.

    Resveratrol: isomeric molar absorptivities and stability

    J Agric Food Chem

    (1996)
  • B.B. Aggarwal et al.

    Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies

    Anticancer Res

    (2004)
  • W. Andlauer et al.

    Assessment of resveratrol bioavailability in the perfused small intestine of the rat

    Drugs Exp Clin Res

    (2000)
  • C. Yu et al.

    Human, rat, and mouse metabolism of resveratrol

    Pharm Res

    (2002)
  • B. Wahlstrom et al.

    A study on the fate of curcumin in the rat

    Acta Pharmacol Toxicol

    (1978)
  • C.R. Ireson et al.

    Characterization of metabolites of the chemopreventive agent curcumin in humans and rat hepatocytes and in rat plasma and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production

    Cancer Res

    (2001)
  • L. Chen et al.

    Absorption, distribution, and elimination of tea polyphenols in rats

    Drug Metab Dispos

    (1997)
  • N.P. Das et al.

    Studies on flavonoid metabolism. Metabolism of (+)-[14C] catechin in the rat and guinea pig

    Biochem J

    (1969)
  • A.L. Cheng et al.

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

    Anticancer Res

    (2001)
  • G. Shoba et al.

    Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers

    Planta Med

    (1998)
  • J.M. van Amelsvoort et al.

    Plasma concentrations of individual tea catechins after a single oral dose in humans

    Xenobiotica

    (2001)
  • X. Meng et al.

    Identification and characterization of methylated and ring-fission metabolites of tea catechins formed in humans, mice, and rats

    Chem Res Toxicol

    (2002)
  • P. Mahakunakorn et al.

    Cytoprotective and cytotoxic effects of curcumin: dual action on H2O2 induced oxidative cell damage in NG108-15 cells

    Biol Pharm Bull

    (2003)
  • P.A. Reddy et al.

    Studies on spice principles as antioxidant in the inhibition of lipid peroxidation of rat liver microsomes

    Mol Cell Biochem

    (1992)
  • E.M. Starsser et al.

    The relationship between the anti-inflammatory effects of curcumin and cellular glutathione content in myelomonocytic cells

    Biochem Pharmacol

    (2005)
  • M.N. Sreejayan Rao

    Curcuminoids as potent inhibitors of lipid peroxidation

    J Pharm Pharmacol

    (1994)
  • C. Rice-Evans

    Implications of the mechanisms of action of tea polyphenols as antioxidants in vitro for chemoprevention in humans

    Proc Natl Acad Sci USA

    (1999)
  • Cited by (0)

    View full text