Chronic inflammation is being shown to be increasingly involved in the onset and development of several pathological disturbances such as arteriosclerosis, obesity, diabetes, neurodegenerative diseases and even cancer. Treatment for chronic inflammatory disorders has not been solved, and there is an urgent need to find new and safe anti-inflammatory compounds. Flavonoids belong to a group of natural substances occurring normally in the diet that exhibit a variety of beneficial effects on health. The anti-inflammatory properties of flavonoids have been studied recently, in order to establish and characterize their potential utility as therapeutic agents in the treatment of inflammatory diseases. Several mechanisms of action have been proposed to explain in vivo flavonoid anti-inflammatory actions, such as antioxidant activity, inhibition of eicosanoid generating enzymes or the modulation of the production of proinflammatory molecules. Recent studies have also shown that some flavonoids are modulators of proinflammatory gene expression, thus leading to the attenuation of the inflammatory response. However, much work remains to be done in order to achieve definitive conclusions about their potential usefulness. This review summarizes the known mechanisms involved in the anti-inflammatory activity of flavonoids and the implications of these effects on the protection against cancer and cardiovascular disease.
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Nathan C. Points of control in inflammation. Nature. 2002;420:846–52.
Barton GM. A calculated response: control of inflammation by the innate immune system. J Clin Invest. 2008;118:413–20.
Haddad PS, Azar GA, Groom S, Boivin M. Natural health products, modulation of immune function and prevention of chronic disease. Evid Based Complement Alternat Med. 2005;2:513–20.
Yoon J-H, Baek SJ. Molecular targets of dietary polyphenols with anti-inflammatory properties. Yonsei Med J. 2005;46:585–96.
Robak J, Gryglewski RJ. Bioactivity of flavonoids. Pol J Pharmacol. 1996;48:555–64.
Russo A, Acquaviva R, Campisi A, Sorrenti V, Di Giacomo C, Virgata G, et al. Bioflavonoids as antiradicals, antioxidants and DNA cleavage protectors. Cell Biol Toxicol. 2000;16:91–8.
Havsteen B. The biochemistry and medical significance of the flavonoids. Pharmacol Ther. 2002;96:67–202.
Rotelli AE, Guardia T, Juárez AO, de la Rocha NE. Comparative study of flavonoids in experimental models of inflammation. Pharmacol Res. 2003;48:601–6.
Wang L, Tu YC, Lian TW, Hung JT, Yen JH, Wu MJ. Distinctive antioxidant and anti-inflammatory effects of flavonols. J Agric Food Chem. 2006;54:9798–804.
Bazzano LA, He J, Ogden LG, Loria CM, Vupputuri S, Myers L, et al. Fruit and vegetable intake and risk of cardiovascular disease in US adults: the first National Health and Nutrition Examination Survey Epidemiologic follow-up study. Am J Clin Nutr. 2002;76:93–9.
Joshipura KJ, Hu HB, Manson JE, Stampfer MJ, Rimm EB, Speizer FE, et al. The effect of fruit and vegetable intake on risk for coronary heart disease. Ann Intern Med. 2001;134:1106–14.
Liu S, Manson JE, Lee I-M, Cole SR, Hennekens CH, Willett WC, et al. Fruit and vegetable intake and risk of cardiovascular disease: the Women’s Health Study. Am J Clin Nutr. 2000;72:922–8.
Gandini S, Merzenich H, Robertson C, Boyle P. Meta-analysis of studies on breast cancer risk and diet: the role of fruit and vegetable consumption and the intake of associated micronutrients. Eur J Cancer. 2000;36:636–46.
Kolonel LN, Hankin J, Whittemore AS, Wu AH, Gallagher RP, Wilkens L, et al. Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study. Cancer Epidemiol Biomark Prev. 2000;9:795–804.
Feskanich D, Ziegler RG, Michaud DS, Giovannucci EL, Speizer FE, Willett WC, et al. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. J Natl Cancer Inst. 2000;92:1812–23.
Jiang F, Dusting GJ. Natural phenolic compounds as cardiovascular therapeutics: potential role of their anti-inflammatory effects. Curr Vasc Pharmacol. 2003;1:135–56.
Kim HP, Kun HS, Chang HW, Kang SS. Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci. 2004;96:229–45.
Beecher GR. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr. 2003;133:3248S–54S.
Paradkar PN, Blum PS, Berhow MA, Bauman H, Kuo SM. Dietary isoflavones suppress endotoxin-induced inflammatory reaction in liver and intestine. Cancer Lett. 2004;215:21–8.
Duan W, Kuo C, Selvarajan S, Chua KY, Bay BH, Wong WS. Anti-inflammatory effects of genistein, a tyrosine kinase inhibitor, on a guinea pig model of asthma. Am J Respir Crit Care Med. 2003;167:185–92.
Ruetten HT. Effects of tyrphostins and genistein on the circulatory failure and organ dysfunction caused by endotoxin in the rat: a possible role for protein tyrosine kinase. Br J Pharmacol. 1997;122:59–70.
Verdrengh M, Jonsson IM, Holmdahl R, Tarkowski A. Genistein as an anti-inflammatory agent. Inflamm Res. 2003;52:341–6.
Guardia T, Rotelli AE, Juárez AO, Pelzer LE. Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmacol. 2001;56:683–7.
Nishikawa M. Reactive oxygen species in tumor metastasis. Cancer Lett. 2008;266:53–9.
Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic disease. Crit Rev Food Sci Nutr. 2004;44:275–95.
Halliwell B. Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med. 1991;91:14S–22S.
Sies H. Oxidative stress: from basic research to clinical application. Am J Med. 1991;91:31S–8S.
de Groot H, Rauen U. Tissue injury by reactive oxygen species and the protective effects of flavonoids. Fundam Clin Pharmacol. 1998;12:249–55.
Fantone JC, Ward PA. Role of oxygen-derived free-radicals and metabolites in leukocyte-dependent inflammatory reactions. Am J Pathol. 1982;107:395–418.
Hart BA, Ram T, Vai Ching IP, Van DI H, Labodie RP. How flavonoids inhibit the generation of luminal-dependent chemiluminescence by activated human neutrophils. Chem Biol Interact. 1990;73:323–35.
Limasset B, Le Doucen C, Dore J-C, Ojasoo T, Damon M, De Paulet AC. Effects of flavonoid on the release of reactive oxygen species by stimulated human neutrophils. Multivariate analysis of structure activity relationships (SAR). Biochem Pharmacol. 1993;46:1257–71.
Jung HA, Jung MJ, Kim JY, Chung HY, Choi JS. Inhibitory activity of flavonoids from Prunus davidiana and other flavonoids on total ROS and hydroxyl radical generation. Arch Pharm Res. 2003;26:809–15.
Korkina LG, Afanas’ev IB. Antioxidant and chelating properties of flavonoids. Adv Pharmacol. 1997;38:151–63.
Haenen GR, Paquay JB, Korthouwer RE, Bast A. Peroxynitrite scavenging by flavonoids. Biochem Biophys Res Commun. 1997;236:591–3.
Lai HH, Yen GC. Inhibitory effect of isoflavones on peroxynitrite-mediated low density lipoprotein oxidation. Biosci Biotechnol Biochem. 2002;66:22–8.
Hanaski Y, Ogawa S, Fukui S. The correlation between active oxygen scavenging and antioxidative effects of flavonoids. Free Radic Biol Med. 1994;16:845–50.
Keery NL, Abbey M. Red wine and fractionated phenolic compounds prepared from red wine inhibit low density lipoprotein oxidation in vitro. Atherosclerosis. 1997;135:93–102.
Shutenko Z, Henry Y, Pinard E, Seylaz J, Potier P, Berthet F, et al. Influence of the antioxidant quercetin in vivo on the level of nitric oxide determined by electron paramagnetic resonance in rat brain during global ischemia and reperfusion. Biochem Pharmacol. 1999;57:199–208.
Van Acker SA, Tromp MN, Haenen GR, Van der Vijgh WJ, Bast A. Flavonoids as scavengers of nitric oxide radical. Biochem Biophys Res Commun. 1995;214:755–9.
Yen GC, Lai HH. Inhibition of reactive nitrogen species effects in vitro and in vivo isoflavones and soy-based food extracts. J Agric Food Chem. 2003;51:7892–900.
Sarkar A, Bhaduri A. Black tea is a powerful chemopreventor of reactive oxygen and nitrogen species: comparison with its individual constituents and green tea. Biochem Biophys Res Commun. 2001;284:173–8.
Chan MM, Fong D, Ho CT, Huang HT. Inhibition of inducible nitric oxide synthase gene expression and enzyme activity by epigallocatechin gallate, a natural product from green tea. Biochem Pharmacol. 1997;54:1281–6.
Hong J, Smith TJ, Ho CT, August DA, Yang CS. Effects of purified green and black tea polyphenols on cyclooxygenase and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Biochem Pharmacol. 2001;62:1175–83.
Agarwal SK, Agarwal R, Wood GS, Mukhtar H. Protection against ultraviolet B radiation induced effects in the skin of SKH-1 hairless mice by a polyphenolic fraction isolated from green tea. Photochem Photobiol. 1993;58:695–700.
Laughton MJ, Evans PJ, Moroney MA, Hoult JR, Halliwell B. Inhibition of mammalian 5-lipoxygenase and cyclooxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity to iron-reducing ability. Biochem Pharmacol. 1991;42:1673–81.
Nagao A, Seki M, Kobayashi H. Inhibition of xanthine oxidase by flavonoids. Biosci Biotechnol Biochem. 1999;63:1787–90.
Jolly CA. Diet manipulation and prevention of aging, cancer and autoimmune disease. Curr Opin Clin Nutr Metab Care. 2005;8:382–7.
Hance KW, Rogers CJ, Hursting SD, Greiner JW. Combination of physical activity, nutrition, or other metabolic factors and vaccine response. Front Biosci. 2007;12:4997–5029.
Volman JJ, Ramakers JD, Plat J. Dietary modulation of immune function by beta-glucans. Physiol Behav. 2008;94:276–84.
Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev. 2000;52:673–751.
Rudd CE. CD4, CD8 and the TCR-CD3 complex: a novel class of protein-tyrosine kinase receptor. Immunol Today. 1990;11:400–6.
Mustelin T, Abraham RT, Rudd CE, Alonso A, Merlo JJ. Protein tyrosine phosphorylation in T cell signaling. Front Biosci. 2002;1:918–69.
Campbell M-A, Sefton CM. Protein tyrosine phosphorylation is induced in murine B lymphocytes in response to stimulation with anti-immunoglobulin. EMBO J. 1990;9:2125–31.
Geng JY, Zhang B, Lotz M. Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J Immunol. 1993;151:6692–700.
Akiyama T, Ishida J, Nakagawa S, Ogawara H, Wanatabe S, Itoh N, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987;262:5592–5.
Trevillyan JM, Lu YL, Atluru D, Phillips CA, Bjorndahl JM. Differential inhibition of T cell receptor signal transduction and early activation events by selective inhibitor of protein-tyrosine kinase. J Immunol 1990;145.
Shapira L, Takashiba S, Champagne C, Amar S, Van Dyke TE. Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF-alpha and IL-1 beta production by human monocytes. J Immunol. 1994;153:1818–24.
Atluru D, Jackson TM, Atluru S. Genistein, a selective protein tyrosine kinase inhibitor, inhibits interleukin-2 and leukotriene B4 production from human mononuclear cells. Clin Immunol Immunopathol. 1991;59:379–87.
Comalada M, Ballester I, Bailón E, Sierra S, Xaus J, Gálvez J, et al. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship. Biochem Pharmacol. 2006;72:1010–21.
Bennet JP, Gomperst BD, Wollenweber E. Inhibitory effects of natural flavonoids on secretion from mast cells and neutrophils. Arzneimittelforschung. 1981;31:433–7.
Berton G, Schneider C, Romeo D. Inhibition by quercetin of activation of polymorphonuclear leukocyte functions. Stimulus-specific effects. Biochim Biophys Acta. 1980;595:47–55.
Kanashiro A, Souza JG, Kabeya LM, Azzolini AE, Lucisano-Valim YM. Elastase release by stimulet neutrophils inhibited by flavonoids: importance of the catechol group. Z Naturforsch 2007;62.
Selloum L, Bouriche H, Tigrine C, Boudoukha C. Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation. Exp Toxicol Pathol. 2003;54:313–8.
Tordera M, Ferrándiz ML, Alcaraz MJ. 1994. Influence of anti-inflammatory flavonoids on degranulation and arachidonic acid release in rat neutrophils. Z Naturforsch [C]. 49:235–40.
Chang HW, Baek SH, Chung KW, Son KH, Kim HP, Kang SS. Inactivation of phospholipase A2 by naturally ocurring biflavonoid, ochnaflavone. Biochem Biophys Res Commun. 1994;205:843–9.
Gil B, Sanz MJ, Terencio MC, Giunasegaran R, Playa M, Alcaraz MJ. Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase a2 with anti-inflammatory activity. Biochem Pharmacol. 1997;53:733–40.
Chi YS, Jong HG, Son KH, Chang HW, Kang SS, Kim HP. Effects of naturally prenylated flavonoids on enzymes metabolizing arachidonic acid: cyclooxygenases and lipoxygenases. Biochem Pharmacol. 2001;62:1185–91.
Kobuchi H, Virgili F, Packer L. Assay of inducible form of nitric oxide synthase activity: effect of flavonoids and plant extracts. Methods Enzymol. 1999;301:504–13.
Cheon BS, Kim YH, Son KS, Chang HW, Kang SS, Kim HP. Effects of prenilated flavonoids and biflavonoids on lipopolysaccharide-induced nitric oxide production from the mouse macrophage cell line RAW 264.7. Planta Med 2000; 66:596–600.
Lee T-P, Matteliano ML, Middleton E. Effect of quercitin on human polymorphonuclear leukocyte lysosomal enzyme release and phospholipid metabolism. Life Sci. 1982;31:2765–74.
Lanni C, Becker EL. Inhibition of neutrophil phospholipase A2 by p-bromophenylacyl bromide, nordihydroguaiaretic acid, 5,8,11,14-eicosatetrayenoic acid and quercetin. Inst Archs Allergy Appl Immunol. 1985;76:214–7.
Lindahl M, Tagesson C. Selective inhibition of group II phospholipase A2 by quercetin. Inflammation. 1993;17:573–82.
Süleyman H, Demircan B, Karagöz Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol Rep. 2007;59:247–58.
Khanapure SP, Garvey DS, Janero DR, Letts LG. Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers. Curr Top Med Chem. 2007;7:311–40.
Kuhn H. Biologic relevance of lipoxygenase isoforms in atherogenesis. Expert Rev Cardiovasc Ther. 2005;3:1099–110.
Bauman J, von Bruchhausen FV, Wurm G. Flavonoids and related compounds as inhibitors of arachidonic acid peroxidation. Prostaglandins. 1980;20:627–39.
Landorfi R, Mower RL, Steiner M. Modification of platelet function and arachidonic acid metabolism by biflavonoids. Structure–activity relations. Biochem Pharmacol. 1984;33:1525–30.
Wakabayashi I, Yasui K. Wogonin inhibits inducible prostaglandin E2 production in macrophages. Eur J Pharmacol. 2000;406:477–81.
Chi YS, Cheon BS, Kim HP. Effect of wogonin, a plant flavone from Scutellaria radix, on the suppression of cyclooxigenase-2 and the induction of inducible nitric oxide synthase in lipopolysaccharide-treated RAW 264.7 cells. Biochem Pharmacol 2001; 61:1195–203.
You KM, Jong HG, Kim HP. Inhibition of cyclooxygenase/lipoxygenase from human platelets by polyhydroxylated/methoxylated flavonoids isolated from medicinal plants. Arch Pharm Res. 1999;22:18–24.
Chung CP, Park JB, Bae KH. Pharmacological effects of methanolic extract from root of Scutellaria baicalensis and its flavonoids on human gingival fibroblasts. Planta Med. 1995;61:150–3.
Mashesha HG, Singh SA, Rao AR. Inhibition of lipoxygenase by soy isoflavones: Evidence of isoflavones as redox inhibitors. Arch Biochem Biophys. 2007;461:176–85.
Hong J, Bose M, Ju J, Ryu JH, Chen X, Sang S, et al. Modulation of arachidonic acid metabolism by curcumin and related beta-diketone derivates: effects on cytosolic phospholipase A2, cyclooxygenases and 5-lipoxygenase. Carcinogenesis. 2004;25:1671–9.
Moncada S, Palmer MJ, Higgs DA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1992;43:109–42.
Liang YC, Huang YT, Tsai SH, Lin-Shiau SY, Chen CF, Lin JK. 1999. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis. 20:1945–52.
Autore G, Rastrelli L, Lauro MR, Marzocco S, Sorrentino R, Pinto A, et al. Inhibition of nitric oxide synthase expression by a methanolic extract of Crescencia alata and its derived flavonols. Life Sci. 2001;70:523–34.
Kim HK, Cheon BS, Kim YH, Kim SY, Kim HP. Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structure–activity relationships. Biochem Pharmacol 1999;58.
Raso GM, Meli R, Di Carlo G, Pacilio M, Di Carlo R. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life Sci 2001; 68:921–31.
Sheu F, Lai HH, Yen GC. Suppression of effect of soy isoflavones on nitric oxide production in RAW 264.7 macrophages. J Agric Food Chem. 2001;49:1767–72.
Chen YC, Shen SC, Lee WR, Hou WC, Yang LL, Lee TJ. Inhibition of nitric oxide synthase inhibitors and lipopolysaccharide induced inducible NOS and cyclooxygenase-2 gene expression by rutin, quercetin, and quercetin pentaacetate in RAW 264.7 macrophages. J Cell Biochem. 2001;82:537–48.
Chen XW, FGraner SC, Anderson JJ. Isoflavones regulate interleukin-6 and osteoprotegerin synthesis during osteoblast cell differentiation via an estrogen-receptor-dependent pathway. Biochem Biophys Res Commun. 2002;295:417–22.
Ding SZ, Cho CH, Lam SK. Regulation of interleukin-6 production in a human gastric epithelial cell line MKN-28. Cytokine. 2000;12:1129–35.
Xagorari A, Papapetropoulos A, Mauromatis A, Economou M, Fostis T, Roussos C. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. J Pharmacol Exp Therap. 2001;296:181–7.
Cho JY, Kim PS, Park JB, Yoo ES, Baik KU, Kim YK, et al. Inhibitor of tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW264.7 cells from Amorpha fruticosa. J Ethnopharmacol. 2000;70:127–33.
Cho SY, Park SJ, Kwon MJ, Jeong TS, Bok SH, Choi WY, et al. Quercetin suppresses proinflammatory cytokines production through MAP kinases and NF-kappaB pathway in lipopolysaccharide-stimulated macrophage. Mol Cell Biochem. 2003;243:153–60.
Van Dien M, Takahashi K, Mu MM, Koide N, Sugiyama T, Mori I, et al. Protective effect of wogonin on endotoxin-induced lethal shock in d-galactosamine-sensitized mice. Microbiol Immunol. 2001;45:751–6.
Santangelo C, Vari R, Scazzocchio B, Di Benedetto R, Filesi C, Masella R. Polyphenols, intracellular signalling and inflammation. Ann Ist Super Sanita. 2007;43:394–405.
Mutoh M, Takahashi M, Fukuda K, Komatsu H, Enya T, Matsushima-Hibiya Y, et al. Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure–activity relationship. Jpn J Cancer Res. 2000;91:686–91.
Hooshmand S, Soung do Y, Lucas EA, Madihally SV, Levenson CW, Arjmandi BH. Genistein reduces the production of proinflammatory molecules in human chondrocytes. J Nutr Biochem 2007; 18:609–14.
Chen CY, Peng WH, Tsai KD, Hsu SL. Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages. Life Sci. 2007;81:1602–14.
Hämäläinen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E. Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediat Inflamm 2007; 2007:45673.
Su B, Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol. 1996;8:402–11.
Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol. 2002;20:55–72.
Herlaar E, Brown Z. MAPK signaling cascades in inflammatory disease. Mol Med Today. 1999;5:439–47.
Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal. 2000;12:1–13.
Branger J, van den Blink B, Weijer S, Madwed J, Bos CL, Gupta A, et al. The p38 signal transduction pathway: activation and function. J Immunol. 2002;168:4070–7.
Nieminen R, Leinonen S, Lahti A, Vuolteenaho K, Jalonen U, Kankaanranta H, et al. Inhibitors of mitogen-activated protein kinases downregulate COX-2 expression in human chondrocytes. Mediat Inflamm. 2005;5:249–55.
Feng GJ, Goodridge HS, Harnett MM, Wei SQ, Nikolaev AV, Higson AP, et al. Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase. J Immunol 1999; 163:6403–6412.
Xagorari A, Roussos C, Papapetropoulos A. Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin. Br J Pharmacol. 2002;136:1058–64.
Means TK, Pavlovich RP, Roca D, Vermuelen MW, Fenton MJ. Activation of TNF-alpha transcription utilizes distinct MAP kinase pathways in different macrophage populations. J Leuk Biol. 2000;67:885–93.
Baldassare JJ, Bi Y, Bellone CJ. The role of p38 mitogen-activated protein kinase in IL-1 beta transcription. J Immunol. 1999;162:5367–73.
van den Blink B, Juffermans NP, ten Hove T, Schultz MJ, van Deventer SJ, van der Poll T, et al. p38 mitogen-activated protein kinase inhibition increases cytokine release by macrophages in vitro and during infection in vivo. J Immunol. 2001;166:582–7.
Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut associated immunopathologies. Immunity. 1999;10:387–98.
Carter AB, Monick MM, Hunninghake GW. Both Erk and p38 kinases are necessary for cytokine gene transcription. Am J Resp Cell Mol Biol. 1999;20:751–8.
Pereira SG, Oakley F. Nuclear factor-kappaB1: regulation and function. Int J Biochem Cell Biol. 2008;40:1425–30.
Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997;336:1066–71.
Park E, Kum S, Wang C, Park SY, Kim BS, Schuller-Levis G. Anti-inflammatory activity of herbal medicines: inhibition of nitric oxide production and tumor necrosis factor-alpha secretion in an activated macrophage-like cell line. Am J Chin Med. 2005;33:415–24.
Kotanidou A, Xagorari A, Bagli E, Kitsanta P, Fostis T, Papapetropoulos A, et al. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice. Am J Resp Crit Care Med. 2002;165:818–23.
Kim JS, Jobin C. The flavonoid luteolin prevents lipopolysaccharide-induced NK-kappaB signaling and gene expression by blocking I-kappaB kinase activity in intestinal epithelial cells and bone-marrow derived dendritic cells. Immunology. 2005;115:373–87.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.
Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.
Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology. 2002;16:217–26.
Fox JG, Wang TC. Inflammation, atrophy and gastric cancer. J Clin Invest. 2007;117:60–9.
Dobrovolskaia MA, Kozlov SV. Inflammation and cancer: when NF-kappaB amalgamates the perilous partnership. Curr Cancer Drug Targets. 2005;5:325–544.
YC Xiao H. Combination regimen with statins and NSAIDs: a promising strategy for cancer chemoprevention. Int J Cancer. 2008;123:983–90.
Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer cell. 2005;7:211–7.
de Visser KE, Coussens LM. The inflammatory tumor microenvironment and its impact on cancer development. Contrib Microbiol. 2006;13:118–37.
Rivoli E, Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am J Clin Nutr. 2003;78:559S–69S.
Vainio H, Weiderpass E. Fruit and vegetables in cancer prevention. Nutr Cancer. 2006;54:111–42.
Yang CS, Landau JM, Huang MT, Newmark HL. Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr. 2001;21:381–406.
Le Marchand L. Cancer preventive effects of flavonoids—a review. Biomed Pharmacother. 2002;56:269–301.
Wang ZY, Huang HT, Lou YR, Xie JG, Reuhl KR, Newmark HL, et al. Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induce skin carcinogenesis in 7,12-dimethylbenz(a)anthracene-initiated SKH-1 mice. Cancer Res. 1994;52:1162–70.
Lu YP, Lou YR, Lin Y, Shih WJ, Huang MT, Yang CS, et al. Inhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet light (light-risk mice): relationship to decreased tissue fat. Cancer Res. 2001;61:5002–9.
Yamane T, Hagiwara N, Tateishi M, Akachi S, Kim M, Okuzumi J, et al. Inhibition of azoxymethane-induced colon carcinogenesis in rat by green tea polyphenol fraction. Jpn J Cancer Res. 1991;82:1336–9.
Kawabata K, Tanaka T, Honjo S, Kakumoto M, Hara A, Makita H, et al. Chemopreventive effects of dietary flavonoid morin on chemically induced rat tongue carcinogenesis. Int J Cancer. 1999;83:381–6.
Deschner EE, Ruperto J, Wong G, Newmark HL. Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis. 1991;12:1193–6.
Messina MJ, Persky V, Setchell KD, Barnes S. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer. 1994;21:113–31.
Wietrzyk J, Opolski A, Madej J, Radzikowski C. Antitumor and antimetastatic effect of genistein alone of combined with cyclophosphamide in mice transplanted with various tumors depends on the route of tumor transplantation. In Vivo. 2000;14:357–62.
Pollard M, Suckow MA. Dietary prevention of hormone refractory prostate cancer in Lobund–Wistar rats: a review of studies in a relevant animal model. Comp Med. 2006;56:461–7.
Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Therapeutics. 2001;90:157–77.
Fresco P, Borges F, Diniz C, Marques MPM. New insights on the anticancer properties of dietary polyphenols. Med Res Rev. 2006;26:747–66.
Kamaraj S, Vinodhkumar R, Anandakumar P, Jagan S, Ramakrishnan G, Devaki T. The effects of quercetin on antioxidant status and tumor markers in the lung and serum of mice treated with benzo(a)pyrene. Biol Pharm Bull 2007;30:2268–73.
D’Alessandro TL, Prasain J, Benton MR, Botting N, Moore R, Darley-Usmar V, et al. Polyphenols, inflammatory response, and cancer prevention: chlorination of isoflavones by human neutrophils. J Nutr 2003;133:3773S–7S.
Vanamala J, Leonardi T, Patil BS, Taddeo SS, Murphy ME, Pike LM, et al. Suppression of colon carcinogenesis by bioactive compounds in grapefruit. Carcinogenesis 2006;27:1257–65.
Cai H, Al-Fayez M, Tunstall RG, Platton S, Greaves P, Steward WP, et al. The rice bran constituent tricin potently inhibits cyclooxygenase enzymes and interferes with intestinal carcinogenesisin Apc Min mice. Mol Cancer Ther 2005;4:1287–92.
Horia E, Watkins BA. Complementary actions of docosahexanoic acid and genistein on COX-2, PGE2, and invasiveness in MDA-MB-231 breast cancer cells. Carcinogenesis 2007;28:809–15.
Van Dross RT, Hong X, Essengue S, Fischer SM, Pelling JC. Modulation of UVB-induced and basal cyclooxygenase-2 (COX-2) expression by apigenin in mouse keratinocytes: role of USF transcription factors. Mol Carcinog 2007;46:303–14.
Lin JK, Chen YC, Huang YT, Lin-Shiau SY. Suppression of protein kinase C and nuclear oncogene expression as possible molecular mechanisms of cancer chemoprevention by apigenin and curcumin. J Cell Biochem 1997;Suppl 28–29:39–48.
Lee LT, Huang YT, Hwang JJ, Lee PP, Ke FC, Nair MP, et al. Blockade of the epidrmal growth factor receptor tyrosine kinase activity by quercetin and luteolin leads to growth inhibition and apoptosis of pancreatic tumor cells. Anticancer Res 2002;22:1615–27.
Khan N, Afaq F, Mukhtar H. Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal 2008;10:475–510.
Shukla S, Gupta S. Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells. Cell cycle 2007;6:1102–14.
Yin F, Giuliano AE, Law RE, Van Herle AJ. Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells. Anticancer Res 2001;21:413–20.
Manna SK, Aggarwal RS, Sethi G, Agarwall BB, Ramesh GT. Morin (3,5,7,2′,4′-pentahydroxyflavone) abolishes nuclear factor-kappa B activation induced by various carcinogens and inflammatory stimuli, leading to suppression of nuclear factor-kappaB-regulated gene expression and up-regulation of apoptosis. Clin Cancer Res 2007;8:2290–7.
Li Y, Sarkar FH. Inhibition of nuclear factor kappaB activation in PC3 cells by genistenin is mediated via Akt signalling pathway. Clin Cancer Res 2002;8:2369–77.
Davis JN, Kucuk O, Sarkar FH. Genistein inhibits NF-kappaB activation in prostate cancer cells. Nutr Cancer 1999;35:167–74.
Rahman KW, Li Y, Sarkar FH. Inactivation of Akt and NF-kappaB play important roles during indole-3-carbinol-induced apoptosis in breast cancer cells. Nutr Cancer 2004;48:84–94.
Shukla S, Gupta S. Suppression of constitutive and tumor necrosis factor alpha-induced nuclear factor (NF)-kappaB activation and induction of apoptosis by apigenin in human prostate carcinoma PC-3 cells: correlation with down-regulation of NF-kappaB-responsive genes. Clin Cancer Res 2004;10:3169–78.
Kelloff GJ. Perspectives on cancer chemoprevention research and drug development. Adv Cancer Res. 2000;78:199–334.
Libby P. Inflammation and atherosclerosis. Nature. 2002;420:868–74.
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135–43.
Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. The combined role of P- and E-selectins in atherosclerosis. J Clin Invest. 1998;102:145–52.
Libby P. Changing concepts of atherogenesis. J Intern Med. 2000;247:349–58.
Bonomini F, Tengattin IS, Fabiano A, Bianchi R, Rezzani R. Atherosclerosis and oxidative stress. Histol Histopathol. 2008;23:381–90.
Hofnagel O, Luechtenborg B, Weissen-Plenz G, Robenek H. Statins and foam cell formation: impact on LDL oxidation and uptake of oxidized lipoproteins via scavenger receptors. Biochim Biophys Acta. 2007;1771:1117–24.
Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circ Res. 2004;95:858–66.
Szekanecz Z. Pro-inflammatory cytokines in atherosclerosis. Isr Med Assoc J. 2008;10:529–30.
Ohsuzu F. The roles of cytokines, inflammation and immunity in vascular diseases. J Atheroscler Thromb. 2004;11:313–21.
Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamaté C, Merval R, et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001;89:930–4.
Kaperonis EA, Liapis CD, Kakisis JD, Dimitroulis D, Papavassiliou VG. Inflammation and atherosclerosis. Eur J Vasc Endovasc Surg 2006;31.
Schonbeck U, Mach F, Sukhova GK, Murphy C, Bonnefoy JY, Fabunmi RP, et al. Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? Circ Res. 1997;81:448–54.
Wu L, Fan J, Matsumoto S, Watanabe T. Induction and regulation of matrix metalloproteinase-12 by cytokines and CD40 signaling in monocyte/macrophages. Biochem Biophys Res Commun. 2000;269:808–15.
Zebrack JS, Anderson JL. Role of inflammation in cardiovascular disease: how to use C-reactive protein in clinical practice. Prog Cardivasc Nurs. 2002;17:174–85.
Shishehbor MH, Bhatt DL. Inflammation and atherosclerosis. Curr Atheroscler Rep. 2004;6:131–9.
Hertog MGL, Kromhout D, Aravanis C, Blackburn H, Buzina R, Fidanza F, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med. 1995;155:381–6.
Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996;312:478–81.
Knekt P, Kumpulainen J, Järvinen R, Rissanen H, Heliövaara M, Reunanen A, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr. 2002;76:560–8.
Yochum L, Kushi LH, Meyer K, Folsom AR. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am J Epidemiol. 1999;149:943–9.
Rimm E, Katan M, Ascherio A, Stampfer MJ, Willett WC. Relation between intake of flavonoids and risk for coronary heart disease in male health professionals. Ann Intern Med. 1996;125:384–9.
Sesso HD, Gaziano JM, Liu S, Buring JE. Flavonoid intake and the risk of cardiovascular disease in women. Am J Clin Nutr. 2003;77:1400–8.
Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong CP, Nettleton JA, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr. 2007;85:895–909.
Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu KA, et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2008;88:38–50.
Mukamal KJ, Maclure M, Muller JE, Sherwood JB, Mittleman MA. Tea consumption and mortality after acute myocardial infarction. Circulation. 2002;105:2476–81.
Wiswedel I, Hirsch D, Kropf S, Gruening M, Pfister E, Schewe T, et al. Flavanol-rich cocoa drink lowers plasma F(2)-isoprostane concentrations in humans. Free Radic Biol Med. 2004;37:411–21.
Droke EA, Hager KA, Lerner MR, Lightfoot SA, Stoecker BJ, Brackett DJ, et al. Soy isoflavone averts chronic inflammation-induced bone loss and vascular disease. J Inflamm 2007;4:17.
Lotito SB, Frei B. Dietary flavonoids attenuate tumor necrosis factor alpha–induced adhesion molecule expression in human aortic endothelial cells. Structure–function relationships and activity after pass metabolism. J Biol Chem. 2006;281:37102–10.
Chacko BK, Chandler RT, D’Alessandro TL, Mundhekar A, Khoo NKH, Botting N, et al. Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell PPAR-gamma. J Nutr. 2007;137:351–6.
Osiecki H. The role of chronic inflammation in cardiovascular disease and its regulation by nutrients. Altern Med Rev. 2004;9:32–53.
The authors acknowledge funding from the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA) project AT07-003.
Responsible Editor: J. S. Skotnicki.
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García-Lafuente, A., Guillamón, E., Villares, A. et al. Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflamm. Res. 58, 537–552 (2009). https://doi.org/10.1007/s00011-009-0037-3