DK717X_half-series-title 8/31/05 9:25 AM Page A Resveratrol in Health and Disease DK717X_half-series-title 8/31/05 9:25 AM Page B OXIDATIVE STRESS AND DISEASE Series Editors LESTERPACKER, PH.D. ENRIQUECADENAS, M.D., PH.D. University of Southern California School of Pharmacy Los Angeles, California 1. Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases, edited by Luc Montagnier, René Olivier, and Catherine Pasquier 2. Understanding the Process of Aging:The Roles of Mitochondria, Free Radicals, and Antioxidants, edited by Enrique Cadenas and Lester Packer 3. Redox Regulation of Cell Signaling and Its Clinical Application, edited by Lester Packer and Junji Yodoi 4. Antioxidants in Diabetes Management, edited by Lester Packer, Peter Rösen, Hans J.Tritschler, George L.King, and Angelo Azzi 5. Free Radicals in Brain Pathophysiology, edited by Giuseppe Poli, Enrique Cadenas, and Lester Packer 6. Nutraceuticals in Health and Disease Prevention, edited by Klaus Krämer, Peter-Paul Hoppe, and Lester Packer 7. Environmental Stressors in Health and Disease, edited by Jürgen Fuchs and Lester Packer 8. Handbook of Antioxidants:Second Edition, Revised and Expanded, edited by Enrique Cadenas and Lester Packer 9. Flavonoids in Health and Disease:Second Edition, Revised and Expanded, edited by Catherine A.Rice-Evans and Lester Packer 10. Redox–Genome Interactions in Health and Disease, edited by Jürgen Fuchs, Maurizio Podda, and Lester Packer 11. Thiamine:Catalytic Mechanisms in Normal and Disease States, edited by Frank Jordan and Mulchand S.Patel 12. Phytochemicals in Health and Disease, edited by Yongping Bao and Roger Fenwick 13. Carotenoids in Health and Disease, edited by Norman I.Krinsky, Susan T.Mayne, and Helmut Sies DK717X_half-series-title 8/31/05 9:25 AM Page i 14. Herbal and Traditional Medicine:Molecular Aspects of Health, edited by Lester Packer, Choon Nam Ong, and Barry Halliwell 15. Nutrients and Cell Signaling, edited by Janos Zempleni and Krishnamurti Dakshinamurti 16. Mitochondria in Health and Disease, edited by Carolyn D.Berdanier 17. Nutrigenomics, edited by Gerald Rimbach, Jürgen Fuchs, and Lester Packer 18. Oxidative Stress, Inflammation, and Health, edited by Young-Joon Surh and Lester Packer 19. Nitric Oxide, Cell Signaling, and Gene Expression, edited by Santiago Lamas and Enrique Cadenas 20. Resveratrol in Health and Disease, edited by Bharat B.Aggarwal and Shishir Shishodia DK717X_half-series-title 8/31/05 9:25 AM Page i Resveratrol in Health and Disease editedby Bharat B. Aggarwal Shishir Shishodia Boca Raton London New York A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F Informa plc. DK717X_Discl.fm Page 1 Thursday, September 15, 2005 11:22 AM Published in 2006 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2006 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3371-7 (Hardcover) International Standard Book Number-13: 978-0-8493-3371-2 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Catalog record is available from the Library of Congress Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com Taylor & Francis Group and the CRC Press Web site at is the Academic Division of Informa plc. http://www.crcpress.com Series Introduction Oxygen is a dangerous friend. Through evolution, oxygen — itself a free radical — was chosen as the terminal electron acceptor for respiration. The two unpaired electrons of oxygen spin in the same direction; thus, oxygenisabiradical.Otheroxygen-derivedfreeradicals,suchassuperoxide anions or hydroxyl radicals, formed during metabolism or by ionizing radiationarestrongeroxidants,i.e.,endowedwithahigherchemicalreacti- vity. Oxygen-derived free radicals are generated during oxidative metabo- lism and energy production in the body and are involved in regulation of signal transduction and gene expression, activation of receptors and nuclear transcription factors, oxidative damage to cell components, the antimicrobialandcytotoxicactionofimmunesystemcells,neutrophils,and macrophages, as well as in aging and age-related degenerative diseases. Overwhelming evidence indicates that oxidative stress can lead to cell and tissue injury. However, the same free radicals that are generated during oxidativestressareproducedduringnormalmetabolismand,asacorollary, are involved in both human health and disease. In addition to reactive oxygen species, research on reactive nitrogen species has been gathering momentum to develop an area of enormous importance in biology and medicine. Nitric oxide or nitrogen monoxide (NO)isafreeradicalgeneratedbynitricoxidesynthase(NOS).Thisenzyme modulates physiological responses in the circulation such as vasodilation (eNOS)orsignalinginthebrain(nNOS).However,duringinflammation,a third isoenzyme is induced, iNOS, resulting in the overproduction of NO and causing damage totargeted infectious organismsand to healthytissues inthevicinity.Moreworrisome,however,isthefactthatNOcanreactwith the superoxide anion to yield a strong oxidant, peroxynitrite. Oxidation of lipids, proteins, and DNA by peroxynitrite increases the likelihood of tissue injury. Both reactive oxygen and nitrogen species are involved in the redox regulation of cell functions. Oxidative stress is increasingly viewed as a major upstream component in the signaling cascade involved in inflamma- tory responses and stimulation of adhesion molecule and chemoattractant production. Hydrogen peroxide decomposes in the presence of transition metalstothehighlyreactivehydroxylradical,whichbytwomajorreactions —hydrogenabstractionandaddition—accountsformostoftheoxidative damage to proteins, lipids, sugars, and nucleic acids. Hydrogen peroxide is also an important signaling molecule that, among others, can activate NF-kB, an important transcription factor involved in inflammatory responses.Atlowconcentrationshydrogenperoxideregulatescellsignaling viii Series Introduction and stimulates cell proliferation; at higher concentrations it triggers apoptosis and, at even higher levels, necrosis. Virtually all diseases thus far examined involve free radicals. In most cases, free radicals are secondary to the disease process, but in some instances free radicals are causal. Thus, there is a delicate balance between oxidants and antioxidants in health and disease. Their proper balance is essential for ensuring healthy aging. The term oxidative stress indicates that the antioxidant status of cells and tissues is altered by exposure to oxidants. The redox status is thus dependent on the degree to which a cell’s components are in the oxidized state. In general, the reducing environment inside cells helps to prevent oxidative damage. In this reducing environment, disulfide bonds (S–S) do not spontaneously form because sulfhydryl groups are maintained in the reducedstate(SH),thuspreventingproteinmisfoldingoraggregation.This reducing environment is maintained by oxidative metabolism and by the action of antioxidant enzymes and substances, such as glutathione, thioredoxin,vitaminsEandC,andenzymessuchassuperoxidedismutases, catalase,andtheselenium-dependentglutathionereductaseandglutathione and thioredoxin hydroperoxidases, which serve to remove reactive oxygen species (hydroperoxides). Changes in the redox status and depletion of antioxidants occur during oxidative stress. The thiol redox status is a useful index of oxidative stress mainly because metabolism and NADPH-dependent enzymes maintain cell glutathione (GSH) almost completely in its reduced state. Oxidized glutathione (glutathione disulfide, GSSG) accumulates under conditions of oxidant exposure and this changes the GSSG/GSH ratio; an increased ratio is usually taken as indicating oxidative stress. Other oxidative stress indicators are ratios of redox couples such as NADPH/NADP, NADH/ NAD, thioredoxin /thioredoxin , dihydrolipoic acid/(cid:1)-lipoic reduced oxidized acid, and lactate/pyruvate. Changes in these ratios affect the energy status ofthecell,largelydeterminedbytheratioATP/ADPþAMP.Manytissues contain large amounts of glutathione, 2 to 4mM in erythrocytes or neural tissues and up to 8mM in hepatic tissues. Reactive oxygen and nitrogen species can oxidize glutathione, thus lowering the levels of the most abundant nonprotein thiol, sometimes designated as the cell’s primary preventative antioxidant. Current hypotheses favor the idea that lowering oxidative stress can have a health benefit. Free radicals can be overproduced or the natural antioxidantsystemdefensesweakened,firstresultinginoxidativestress,and then leading to oxidative injury and disease. Examples of this process include heart disease, cancer, and neurodegenerative disorders. Oxidation of human low-density lipoproteins is considered an early step in the progression and eventual development of atherosclerosis, thus leading to cardiovasculardisease.OxidativeDNAdamagemayinitiatecarcinogenesis. Environmental sources of reactive oxygen species are also important in Series Introduction ix relation to oxidative stress and disease. For example, ultraviolet radiation, ozone,cigarettesmoke,andothersaresignificantsourcesofoxidativestress. Compelling support for the involvement of free radicals in disease development originates from epidemiological studies showing that an enhanced antioxidant status is associated with reduced risk of several diseases. Vitamins C and E and prevention of cardiovascular disease are a notable example. Elevated antioxidant status is also associated with decreased incidence of cataracts, cancer, and neurodegenerative disorders. Some recent reports have suggested an inverse correlation between antioxidant status and the occurrence of rheumatoid arthritis and diabetes mellitus. Indeed, the number of indications in which antioxidants may be useful in the prevention and/or the treatment of disease is increasing. Oxidative stress, rather than being the primary cause of disease, is more often a secondary complication in many disorders. Oxidative stress diseases include inflammatory bowel diseases, retinal ischemia, cardio- vascular disease and restenosis, AIDS, adult respiratory distress syndrome, and neurodegenerative diseases such as stroke, Parkinson’s disease, and Alzheimer’s disease. Such indications may prove amenable to antioxidant treatment (in combination with conventional therapies) because there is a clear involvement of oxidative injury in these disorders. In this series of books, the importance of oxidative stress and disease associated with organ systems of the body is highlighted by exploring the scientific evidence and the medical applications of this knowledge. The series also highlights the major natural antioxidant enzymes and anti- oxidant substances such as vitamins E, A, and C, flavonoids, polyphenols, carotenoids, lipoic acid, coenzyme Q , carnitine, and other micronutrients 10 present in food and beverages. Oxidative stress is an underlying factor in health and disease. More and more evidence indicates that a proper balance between oxidants and antioxidants is involved in maintaining healthandlongevityandthatalteringthisbalanceinfavorofoxidantsmay result in pathophysiological responses causing functional disorders and disease. This series is intended for researchers in the basic biomedical sciences and clinicians. The potential of such knowledge for healthy aging and disease prevention warrants further knowledge about how oxidants and antioxidants modulate cell and tissue function. Lester Packer Enrique Cadenas