Isoflavones: Anti-inflammatory benefit and possible caveats

Nutrients

Volumn 8, Issue 6, 2016, Pages

  Yu, Jie ^a   Bi, Xiaojuan ^a   Yu, Bing ^a   Chen, Daiwen ^a  

^a SICHUAN AGRICULTURAL UNIVERSITY   (China)

Author keywords

Anti inflammation; Flavonoids; Health risks; Isoflavones

Indexed keywords

ARACHIDONIC ACID; CYCLOOXYGENASE 2; DAIDZEIN; GAMMA INTERFERON; GENISTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 12; INTERLEUKIN 6; ISOFLAVONE DERIVATIVE; LIPOXYGENASE; PHOSPHOLIPASE A2; TUMOR NECROSIS FACTOR ALPHA; ANTIINFLAMMATORY AGENT; ANTIOXIDANT;

ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ATHEROSCLEROSIS; CARCINOGENESIS; HUMAN; IMMUNE DEFICIENCY; INFLAMMATION; NEOPLASM; NONHUMAN; OBESITY; OSTEOPOROSIS; PHASE 2 CLINICAL TRIAL (TOPIC); POSTMENOPAUSE; PROTEIN EXPRESSION; REVIEW; RHEUMATOID ARTHRITIS; RISK FACTOR; SIGNAL TRANSDUCTION; ANIMAL; CARDIOVASCULAR DISEASES; CLINICAL TRIAL (TOPIC); DIET; DISEASE MODEL; NEOPLASMS;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTIOXIDANTS; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; DIET; DISEASE MODELS, ANIMAL; HUMANS; INFLAMMATION; ISOFLAVONES; NEOPLASMS; OBESITY;

EID: 84973596343     PISSN: None     EISSN: 20726643     Source Type: Journal    
DOI: 10.3390/nu8060361     Document Type: Review

References (141)

1. Barton, G. M. A calculated response: Control of inflammation by the innate immune system. J. Clin. Investig. 2008, 118, 413-420. [CrossRef] [PubMed]
2. Garcia-Lafuente, A.; Guillamon, E.; Villares, A.; Rostagno, M. A.; Martinez, J. A. Flavonoids as anti-inflammatory agents: Implications in cancer and cardiovascular disease. Inflamm. Res. 2009, 58, 537-552. [CrossRef] [PubMed]
3. Libby, P. Inflammation in atherosclerosis. Nature 2002, 420, 868-874. [CrossRef] [PubMed]
4. Samad, F.; Ruf, W. Inflammation, obesity, and thrombosis. Blood 2013, 122, 3415-3422. [CrossRef] [PubMed]
5. Khandpur, R.; Carmona-Rivera, C.; Vivekanandan-Giri, A.; Gizinski, A.; Yalavarthi, S.; Knight, J. S.; Friday, S.; Li, S.; Patel, R. M.; Subramanian, V.; et al. Nets are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 2013, 5, 178ra140. [CrossRef] [PubMed]
6. Shay, J.; Elbaz, H. A.; Lee, I.; Zielske, S. P.; Malek, M. H.; Huttemann, M. Molecular mechanisms and therapeutic effects of (-)-epicatechin and other polyphenols in cancer, inflammation, diabetes, and neurodegeneration. Oxidative Med. Cell. Longev. 2015, 2015, 181260. [CrossRef] [PubMed]
7. Elinav, E.; Nowarski, R.; Thaiss, C. A.; Hu, B.; Jin, C.; Flavell, R. A. Inflammation-induced cancer: Crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 2013, 13, 759-771. [CrossRef] [PubMed]
8. Coxib and traditional NSAID Trialists' (CNT) Collaboration; Bhala, N.; Emberson, J.; Merhi, A.; Abramson, S.; Arber, N.; Baron, J. A.; Bombardier, C.; Cannon, C.; Farkouh, M. E.; et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet 2013, 382, 769-779.
9. Trichopoulou, A.; Bamia, C.; Trichopoulos, D. Anatomy of health effects of mediterranean diet: Greek epic prospective cohort study. BMJ 2009, 338, b2337. [CrossRef] [PubMed]
10. Ros, E.; Hu, F. B. Consumption of plant seeds and cardiovascular health: Epidemiological and clinical trial evidence. Circulation 2013, 128, 553-565. [CrossRef] [PubMed]
11. Woo, K. S.; Kwok, T. C.; Celermajer, D. S. Vegan diet, subnormal vitamin b-12 status and cardiovascular health. Nutrients 2014, 6, 3259-3273. [CrossRef] [PubMed]
12. Li, S.; Zhang, B. Traditional Chinese medicine network pharmacology: Theory, methodology and application. Chin. J. Nat. Med. 2013, 11, 110-120. [CrossRef] [PubMed]
13. Yin, T.; Yang, G.; Ma, Y.; Xu, B.; Hu, M.; You, M.; Gao, S. Developing an activity and absorption-based quality control platform for chinese traditional medicine: Application to zeng-sheng-ping (antitumor b). J. Ethnopharmacol. 2015, 172, 195-201. [CrossRef] [PubMed]
14. Bo, Y.; Yuan, L. P.; Zhang, J. J.; Meng, D. D.; Jing, H.; Dai, H. J. Total flavonoids of bidens bipinnata l. A traditional Chinese medicine inhibits the production of inflammatory cytokines of vessel endothelial cells stimulated by sera from henoch-schonlein purpura patients. J. Pharm. Pharmacol. 2012, 64, 882-887. [CrossRef] [PubMed]
15. Dower, J. I.; Geleijnse, J. M.; Gijsbers, L.; Schalkwijk, C.; Kromhout, D.; Hollman, P. C. Supplementation of the pure flavonoids epicatechin and quercetin affects some biomarkers of endothelial dysfunction and inflammation in (pre)hypertensive adults: A randomized double-blind, placebo-controlled, crossover trial. J. Nutr. 2015, 145, 1459-1463. [CrossRef] [PubMed]
16. Dower, J. I.; Geleijnse, J. M.; Gijsbers, L.; Zock, P. L.; Kromhout, D.; Hollman, P. C. Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: A randomized, double-blind, placebo-controlled, crossover trial. Am. J. Clin. Nutr. 2015, 101, 914-921. [CrossRef] [PubMed]
17. Esposito, D.; Chen, A.; Grace, M. H.; Komarnytsky, S.; Lila, M. A. Inhibitory effects of wild blueberry anthocyanins and other flavonoids on biomarkers of acute and chronic inflammation in vitro. J. Agric. Food Chem. 2014, 62, 7022-7028. [CrossRef] [PubMed]
18. Terashima, M.; Kakuno, Y.; Kitano, N.; Matsuoka, C.; Murase, M.; Togo, N.; Watanabe, R.; Matsumura, S. Antioxidant activity of flavonoids evaluated with myoglobin method. Plant Cell Rep. 2012, 31, 291-298. [CrossRef] [PubMed]
19. Crozier, A.; Jaganath, I. B.; Clifford, M. N. Dietary phenolics: Chemistry, bioavailability and effects on health. Nat. Prod. Rep. 2009, 26, 1001-1043. [CrossRef] [PubMed]
20. Sakai, T.; Kogiso, M. Soy isoflavones and immunity. J. Med. Investig. 2008, 55, 167-173. [CrossRef]
21. Marzocchella, L.; Fantini, M.; Benvenuto, M.; Masuelli, L.; Tresoldi, I.; Modesti, A.; Bei, R. Dietary flavonoids: Molecular mechanisms of action as anti-inflammatory agents. Recent Pat. Inflamm. Allergy Drug Discov. 2011, 5, 200-220. [CrossRef] [PubMed]
22. Cassidy, A.; Hanley, B.; Lamuela-Raventos, R. M. Isoflavones, lignans and stilbenes-Origins, metabolism and potential importance to human health. J. Sci. Food Agric. 2000, 80, 1044-1062. [CrossRef]
23. Perez-Jimenez, J.; Neveu, V.; Vos, F.; Scalbert, A. Systematic analysis of the content of 502 polyphenols in 452 foods and beverages: An application of the phenol-explorer database. J. Agric. Food Chem. 2010, 58, 4959-4969. [CrossRef] [PubMed]
24. Setchell, K. D.; Nardi, E.; Battezzati, P.-M.; Asciutti, S.; Castellani, D.; Perriello, G.; Clerici, C. Novel soy germ pasta enriched in isoflavones ameliorates gastroparesis in type 2 diabetes a pilot study. Diabetes Care 2013, 36, 3495-3497. [CrossRef] [PubMed]
25. Barros, R. P.; Gustafsson, J. Å. Estrogen receptors and the metabolic network. Cell Metab. 2011, 14, 289-299. [CrossRef] [PubMed]
26. Vitale, D. C.; Piazza, C.; Melilli, B.; Drago, F.; Salomone, S. Isoflavones: Estrogenic activity, biological effect and bioavailability. Eur. J. Drug Metab. Pharmacokinet. 2013, 38, 15-25. [CrossRef] [PubMed]
27. Conklin, C. M.; Bechberger, J. F.; MacFabe, D.; Guthrie, N.; Kurowska, E. M.; Naus, C. C. Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis 2007, 28, 93-100. [CrossRef] [PubMed]
28. Dhayakaran, R. P. A.; Neethirajan, S.; Xue, J.; Shi, J. Characterization of antimicrobial efficacy of soy isoflavones against pathogenic biofilms. LWT Food Sci. Technol. 2015, 63, 859-865. [CrossRef]
29. Rodríguez-Roque, M. J.; Rojas-Graü, M. A.; Elez-Martínez, P.; Martín-Belloso, O. Soymilk phenolic compounds, isoflavones and antioxidant activity as affected by in vitro gastrointestinal digestion. Food Chem. 2013, 136, 206-212. [CrossRef] [PubMed]
30. Chacko, B. K.; Chandler, R. T.; D'Alessandro, T. L.; Mundhekar, A.; Khoo, N. K.; Botting, N.; Barnes, S.; Patel, R. P. Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell ppargamma. J. Nutr. 2007, 137, 351-356. [PubMed]
31. Kuiper, G. G.; Lemmen, J. G.; Carlsson, B.; Corton, J. C.; Safe, S. H.; van der Saag, P. T.; van der Burg, B.; Gustafsson, J.-A. K. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 1998, 139, 4252-4263. [PubMed]
32. Phetnoo, N.; Werawatganon, D.; Siriviriyakul, P. Genistein could have a therapeutic potential for gastrointestinal diseases. Thai J. Gastroenterol. 2013 2013, 14, 120-125.
33. Marugame, T.; Katanoda, K. International comparisons of cumulative risk of breast and prostate cancer, from cancer incidence in five continents vol. Viii. Jpn. J. Clin. Oncol. 2006, 36, 399-400. [CrossRef] [PubMed]
34. Medjakovic, S.; Mueller, M.; Jungbauer, A. Potential health-modulating effects of isoflavones and metabolites via activation of ppar and ahr. Nutrients 2010, 2, 241-279. [CrossRef] [PubMed]
35. Wu, A. H.; Ziegler, R. G.; Nomura, A.; West, D. W.; Kolonel, L. N.; Horn-Ross, P. L.; Hoover, R. N.; Pike, M. C. Soy intake and risk of breast cancer in asians and asian americans. Am. J. Clin. Nutr. 1998, 68, 1437S-1443S. [PubMed]
36. Nielsen, I. L.; Williamson, G. Review of the factors affecting bioavailability of soy isoflavones in humans. Nutr. Cancer 2007, 57, 1-10. [CrossRef] [PubMed]
37. Vergne, S.; Titier, K.; Bernard, V.; Asselineau, J.; Durand, M.; Lamothe, V.; Potier, M.; Perez, P.; Demotes-Mainard, J.; Chantre, P.; et al. Bioavailability and urinary excretion of isoflavones in humans: Effects of soy-based supplements formulation and equol production. J. Pharm. Biomed. Anal. 2007, 43, 1488-1494. [CrossRef] [PubMed]
38. Day, A. J.; DuPont, M. S.; Ridley, S.; Rhodes, M.; Rhodes, M. J.; Morgan, M. R.; Williamson, G. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver β-glucosidase activity. FEBS Lett. 1998, 436, 71-75. [CrossRef]
39. Setchell, K. D.; Brown, N. M.; Desai, P.; Zimmer-Nechemias, L.; Wolfe, B. E.; Brashear, W. T.; Kirschner, A. S.; Cassidy, A.; Heubi, J. E. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J. Nutr. 2001, 131, 1362S-1375S. [PubMed]
40. Barnes, S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. Lymphat. Res. Biol. 2010, 8, 89-98. [CrossRef] [PubMed]
41. Manach, C.; Williamson, G.; Morand, C.; Scalbert, A.; Rémésy, C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 2005, 81, 230S-242S. [PubMed]
42. Barnes, S. Evolution of the health benefits of soy isoflavones. Proc. Soc. Exp. Biol. Med. 1998, 217, 386-392. [CrossRef] [PubMed]
43. Messina, M. Soy foods, isoflavones, and the health of postmenopausal women. Am. J. Clin. Nutr. 2014, 100, 423S-430S. [CrossRef] [PubMed]
44. Verdrengh, M.; Jonsson, I. M.; Holmdahl, R.; Tarkowski, A. Genistein as an anti-inflammatory agent. Inflamm. Res. Off. J. Eur. Histamine Res. Soc. 2003, 52, 341-346. [CrossRef] [PubMed]
45. Paradkar, P. N.; Blum, P. S.; Berhow, M. A.; Baumann, H.; Kuo, S. M. Dietary isoflavones suppress endotoxin-induced inflammatory reaction in liver and intestine. Cancer Lett. 2004, 215, 21-28. [CrossRef] [PubMed]
46. Kao, T. H.; Wu, W. M.; Hung, C. F.; Wu, W. B.; Chen, B. H. Anti-inflammatory effects of isoflavone powder produced from soybean cake. J. Agric. Food Chem. 2007, 55, 11068-11079. [CrossRef] [PubMed]
47. Carrara, V. S.; Melo, J. O.; Filho, B.; Bersani-Amado, C. A.; Nakamura, C. V.; Mandarino, J.; Cortez, L.; Cortez, D. Anti-inflammatory activity of the soybean methanolic fraction containing isoflavones. Planta Medica 2008, 74, 1179. [CrossRef]
48. Lim, D. W.; Lee, C.; Kim, I. H.; Kim, Y. T. Anti-inflammatory effects of total isoflavones from pueraria lobata on cerebral ischemia in rats. Molecules 2013, 18, 10404-10412. [CrossRef] [PubMed]
49. Ganai, A. A.; Khan, A. A.; Malik, Z. A.; Farooqi, H. Genistein modulates the expression of nf-kappab and mapk (p-38 and erk1/2), thereby attenuating D-galactosamine induced fulminant hepatic failure in wistar rats. Toxicol. Appl. Pharmacol. 2015, 283, 139-146. [CrossRef] [PubMed]
50. Duan, W.; Kuo, I. C.; Selvarajan, S.; Chua, K. Y.; Bay, B. H.; Wong, W. S. Antiinflammatory effects of genistein, a tyrosine kinase inhibitor, on a guinea pig model of asthma. Am. J. Respir. Crit. Care Med. 2003, 167, 185-192. [CrossRef] [PubMed]
51. Hooshmand, S.; Soung do, Y.; Lucas, E. A.; Madihally, S. V.; Levenson, C. W.; Arjmandi, B. H. Genistein reduces the production of proinflammatory molecules in human chondrocytes. J. Nutr. Biochem. 2007, 18, 609-614. [CrossRef] [PubMed]
52. Li, H. Y.; Pan, L.; Ke, Y. S.; Batnasan, E.; Jin, X. Q.; Liu, Z. Y.; Ba, X. Q. Daidzein suppresses pro-inflammatory chemokine cxcl2 transcription in tnf-alpha-stimulated murine lung epithelial cells via depressing parp-1 activity. Acta Pharmacol. Sin. 2014, 35, 496-503. [CrossRef] [PubMed]
53. Tanaka, K.; Ohgo, Y.; Katayanagi, Y.; Yasui, K.; Hiramoto, S.; Ikemoto, H.; Nakata, Y.; Miyoshi, N.; Isemura, M.; Ohashi, N.; et al. Anti-inflammatory effects of green soybean extract irradiated with visible light. Sci. Rep. 2014, 4, 4732. [CrossRef] [PubMed]
54. Han, S.; Wu, H.; Li, W.; Gao, P. Protective effects of genistein in homocysteine-induced endothelial cell inflammatory injury. Mol. Cell. Biochem. 2015, 403, 43-49. [CrossRef] [PubMed]
55. Azadbakht, L.; Kimiagar, M.; Mehrabi, Y.; Esmaillzadeh, A.; Hu, F. B.; Willett, W. C. Soy consumption, markers of inflammation, and endothelial function a cross-over study in postmenopausal women with the metabolic syndrome. Diabetes Care 2007, 30, 967-973. [CrossRef] [PubMed]
56. Nasca, M. M.; Zhou, J.-R.; Welty, F. K. Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women. Am. J. Cardiol. 2008, 102, 84-86. [CrossRef] [PubMed]
57. Fanti, P.; Asmis, R.; Stephenson, T. J.; Sawaya, B. P.; Franke, A. A. Positive effect of dietary soy in esrd patients with systemic inflammation-Correlation between blood levels of the soy isoflavones and the acute-phase reactants. Nephrol. Dial. Transplant. 2006, 21, 2239-2246. [CrossRef] [PubMed]
58. Ferguson, J. F.; Ryan, M. F.; Gibney, E. R.; Brennan, L.; Roche, H. M.; Reilly, M. P. Dietary isoflavone intake is associated with evoked responses to inflammatory cardiometabolic stimuli and improved glucose homeostasis in healthy volunteers. Nutr. Metab. Cardiovasc. Dis. 2014, 24, 996-1003. [CrossRef] [PubMed]
59. Wu, S. H.; Shu, X. O.; Chow, W.-H.; Xiang, Y.-B.; Zhang, X.; Li, H.-L.; Cai, Q.; Ji, B.-T.; Cai, H.; Rothman, N. Soy food intake and circulating levels of inflammatory markers in Chinese women. J. Acad. Nutr. Diet. 2012, 112, 996-1004. [CrossRef] [PubMed]
60. Mangano, K. M.; Hutchins-Wiese, H. L.; Kenny, A. M.; Walsh, S. J.; Abourizk, R. H.; Bruno, R. S.; Lipcius, R.; Fall, P.; Kleppinger, A.; Kenyon-Pesce, L. Soy proteins and isoflavones reduce interleukin-6 but not serum lipids in older women: A randomized controlled trial. Nutr. Res. 2013, 33, 1026-1033. [CrossRef] [PubMed]
61. Acharjee, S.; Zhou, J.-R.; Elajami, T. K.; Welty, F. K. Effect of soy nuts and equol status on blood pressure, lipids and inflammation in postmenopausal women stratified by metabolic syndrome status. Metabolism 2015, 64, 236-243. [CrossRef] [PubMed]
62. Lee, D. J.; Kang, S. W. Reactive oxygen species and tumor metastasis. Mol. Cells 2013, 35, 93-98. [CrossRef] [PubMed]
63. Brown, G. C.; Neher, J. J. Microglial phagocytosis of live neurons. Nat. Rev. Neurosci. 2014, 15, 209-216. [CrossRef] [PubMed]
64. Halliwell, B.; Gutteridge, J. M. Free Radicals in Biology and Medicine; Oxford University Press: New York, NY, USA, 2015.
65. Niki, E. Role of vitamin E as a lipid-soluble peroxyl radical scavenger: In vitro and in vivo evidence. Free Radic. Biol. Med. 2014, 66, 3-12. [CrossRef] [PubMed]
66. Lee, I.-T.; Yang, C.-M. Role of nadph oxidase/ros in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochem. Pharmacol. 2012, 84, 581-590. [CrossRef] [PubMed]
67. Lengyel, J.; Rimarčík, J.; Vagánek, A.; Klein, E. On the radical scavenging activity of isoflavones: Thermodynamics of O-H bond cleavage. Phys. Chem. Chem. Phys. 2013, 15, 10895-10903. [CrossRef] [PubMed]
68. D'Alessandro, T.; Prasain, J.; Benton, M.; Botting, N.; Moore, R.; Darley-Usmar, V.; Patel, R.; Barnes, S. Polyphenols, inflammatory response, and cancer prevention: Chlorination of isoflavones by human neutrophils. J. Nutr. 2003, 133, 3773S-3777S. [PubMed]
69. Patel, R. P.; Boersma, B. J.; Crawford, J. H.; Hogg, N.; Kirk, M.; Kalyanaraman, B.; Parks, D. A.; Barnes, S.; Darley-Usmar, V. Antioxidant mechanisms of isoflavones in lipid systems: Paradoxical effects of peroxyl radical scavenging. Free Radic. Biol. Med. 2001, 31, 1570-1581. [CrossRef]
70. Boersma, B. J.; Patel, R. P.; Kirk, M.; Jackson, P. L.; Muccio, D.; Darley-Usmar, V. M.; Barnes, S. Chlorination and nitration of soy isoflavones. Arch. Biochem. Biophys. 1999, 368, 265-275. [CrossRef] [PubMed]
71. Lai, H. H.; Yen, G. C. Inhibitory effect of isoflavones on peroxynitrite-mediated low-density lipoprotein oxidation. Biosci. Biotechnol. Biochem. 2002, 66, 22-28. [CrossRef] [PubMed]
72. Tie, L.; An, Y.; Han, J.; Xiao, Y.; Xiaokaiti, Y.; Fan, S.; Liu, S.; Chen, A. F.; Li, X. Genistein accelerates refractory wound healing by suppressing superoxide and foxo1/inos pathway in type 1 diabetes. J. Nutr. Biochem. 2013, 24, 88-96. [CrossRef] [PubMed]
73. Kolodziejczyk-Czepas, J.; Wachowicz, B.; Moniuszko-Szajwaj, B.; Kowalska, I.; Oleszek, W.; Stochmal, A. Antioxidative effects of extracts from trifolium species on blood platelets exposed to oxidative stress. J. Physiol. Biochem. 2013, 69, 879-887. [CrossRef] [PubMed]
74. Yen, G. C.; Lai, H. H. Inhibition of reactive nitrogen species effects in vitro and in vivo by isoflavones and soy-based food extracts. J. Agric. Food Chem. 2003, 51, 7892-7900. [CrossRef] [PubMed]
75. Ma, X.; Jiang, Z.; Zhang, J.; Hu, Y.; Gao, K.; Wang, L.; Yang, X. Isoflavone ameliorates H2O2 induced injury by activating the antioxidant system of sow mammary gland cell. Nat. Sci. 2015, 7, 571.
76. Jin, L.; Zhao, X.; Qin, Y.; Zhu, W.; Zhang, W.; Liu, A.; Luo, Z. Soy isoflavones protect against H 2O2-induced injury in human umbilical vein endothelial cells. Mol. Med. Rep. 2015, 12, 4476-4482. [CrossRef] [PubMed]
77. Mann, G. E.; Bonacasa, B.; Ishii, T.; Siow, R. C. Targeting the redox sensitive nrf2-keap1 defense pathway in cardiovascular disease: Protection afforded by dietary isoflavones. Curr. Opin. Pharmacol. 2009, 9, 139-145. [CrossRef] [PubMed]
78. Zhai, X.; Lin, M.; Zhang, F.; Hu, Y.; Xu, X.; Li, Y.; Liu, K.; Ma, X.; Tian, X.; Yao, J. Dietary flavonoid genistein induces nrf2 and phase ii detoxification gene expression via erks and pkc pathways and protects against oxidative stress in caco-2 cells. Mol. Nutr. Food Res. 2013, 57, 249-259. [CrossRef] [PubMed]
79. Blay, M.; Espinel, A.; Delgado, M.; Baiges, I.; Blade, C.; Arola, L.; Salvado, J. Isoflavone effect on gene expression profile and biomarkers of inflammation. J. Pharm. Biomed. Anal. 2010, 51, 382-390. [CrossRef] [PubMed]
80. Ji, G.; Zhang, Y.; Yang, Q.; Cheng, S.; Hao, J.; Zhao, X.; Jiang, Z. Genistein suppresses lps-induced inflammatory response through inhibiting nf-κb following amp kinase activation in raw 264. 7 macrophages. PLoS ONE 2012, 7, e53101. [CrossRef] [PubMed]
81. Gao, Y.; Fang, L.; Liu, F.; Zong, C.; Cai, R.; Chen, X.; Qi, Y. Suppressive effects of irisflorentin on lps-induced inflammatory responses in raw 264. 7 macrophages. Exp. Biol. Med. 2014, 239, 1018-1024. [CrossRef] [PubMed]
82. Satsu, H.; Hyun, J. S.; Shin, H. S.; Shimizu, M. Suppressive effect of an isoflavone fraction on tumor necrosis factor-α-induced interleukin-8 production in human intestinal epithelial caco-2 cells. J. Nutr. Sci. Vitaminol. 2009, 55, 442-446. [CrossRef] [PubMed]
83. Morimoto, M.; Watanabe, T.; Yamori, M.; Takebe, M.; Wakatsuki, Y. Isoflavones regulate innate immunity and inhibit experimental colitis. J. Gastroenterol. Hepatol. 2009, 24, 1123-1129. [CrossRef] [PubMed]
84. Lesinski, G. B.; Reville, P. K.; Mace, T. A.; Young, G. S.; Ahn-Jarvis, J.; Thomas-Ahner, J.; Vodovotz, Y.; Ameen, Z.; Grainger, E.; Riedl, K.; et al. Consumption of soy isoflavone enriched bread in men with prostate cancer is associated with reduced proinflammatory cytokines and immunosuppressive cells. Cancer Prev. Res. 2015, 8, 1036-1044. [CrossRef] [PubMed]
85. De Paula, M. L.; Rodrigues, D. H.; Teixeira, H. C.; Barsante, M. M.; Souza, M. A.; Ferreira, A. P. Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis. Int. Immunopharmacol. 2008, 8, 1291-1297. [CrossRef] [PubMed]
86. Yoo, N. Y.; Jeon, S.; Nam, Y.; Park, Y. J.; Won, S. B.; Kwon, Y. H. Dietary supplementation of genistein alleviates liver inflammation and fibrosis mediated by a methionine-choline-deficient diet in db/db mice. J. Agric. Food Chem. 2015, 63, 4305-4311. [CrossRef] [PubMed]
87. Langenbach, R.; Morham, S. G.; Tiano, H. F.; Loftin, C. D.; Ghanayem, B. I.; Chulada, P. C.; Mahler, J. F.; Lee, C. A.; Goulding, E. H.; Kluckman, K. D. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995, 83, 483-492. [CrossRef]
88. Kuehl, F. A.; Egan, R. W. Prostaglandins, arachidonic acid, and inflammation. Science 1980, 210, 978-984. [CrossRef] [PubMed]
89. Vane, J. R.; Mitchell, J. A.; Appleton, I.; Tomlinson, A.; Bishop-Bailey, D.; Croxtall, J.; Willoughby, D. A. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc. Natl. Acad. Sci. USA 1994, 91, 2046-2050. [CrossRef] [PubMed]
90. Xiang, B.; Zhang, G.; Guo, L.; Li, X.-A.; Morris, A. J.; Daugherty, A.; Whiteheart, S. W.; Smyth, S. S.; Li, Z. Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway. Nat. Commun. 2013, 4, 2657. [CrossRef] [PubMed]
91. Middleton, E., Jr.; Kandaswami, C.; Theoharides, T. C. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol. Rev. 2000, 52, 673-751. [PubMed]
92. Dharmappa, K. K.; Mohamed, R.; Shivaprasad, H. V.; Vishwanath, B. S. Genistein, a potent inhibitor of secretory phospholipase a2: A new insight in down regulation of inflammation. Inflammopharmacology 2010, 18, 25-31. [CrossRef] [PubMed]
93. Ximenes, R. M.; Rabello, M. M.; Araújo, R. M.; Silveira, E. R.; Fagundes, F. H.; Diz-Filho, E.; Buzzo, S. C.; Soares, V. C.; Toyama, D. D. O.; Gaeta, H. H. Inhibition of neurotoxic secretory phospholipases a2 enzymatic, edematogenic, and myotoxic activities by harpalycin 2, an isoflavone isolated from harpalyce brasiliana benth. Evid. Based Complement. Altern. Med. 2012, 2012. [CrossRef] [PubMed]
94. Suleyman, H.; Demircan, B.; Karagoz, Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol. Rep. 2007, 59, 247-258. [PubMed]
95. Vera, R.; Galisteo, M.; Villar, I. C.; Sánchez, M.; Zarzuelo, A.; Pérez-Vizcaíno, F.; Duarte, J. Soy isoflavones improve endothelial function in spontaneously hypertensive rats in an estrogen-independent manner: Role of nitric-oxide synthase, superoxide, and cyclooxygenase metabolites. J. Pharmacol. Exp. Ther. 2005, 314, 1300-1309. [CrossRef] [PubMed]
96. Ahmad, A.; Ramasamy, K.; Jaafar, S. M.; Majeed, A. B.; Mani, V. Total isoflavones from soybean and tempeh reversed scopolamine-induced amnesia, improved cholinergic activities and reduced neuroinflammation in brain. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2014, 65, 120-128. [CrossRef] [PubMed]
97. Lau, T. Y.; Leung, L. K. Soya isoflavones suppress phorbol 12-myristate 13-acetate-induced cox-2 expression in mcf-7 cells. Br. J. Nutr. 2006, 96, 169-176. [CrossRef] [PubMed]
98. Li, Y. S.; Wu, L. P.; Li, K. H.; Liu, Y. P.; Xiang, R.; Zhang, S. B.; Zhu, L. Y.; Zhang, L. Y. Involvement of nuclear factor kappab (nf-kappab) in the downregulation of cyclooxygenase-2 (cox-2) by genistein in gastric cancer cells. J. Int. Med. Res. 2011, 39, 2141-2150. [CrossRef] [PubMed]
99. Mahesha, H.; Singh, S. A.; Rao, A. A. Inhibition of lipoxygenase by soy isoflavones: Evidence of isoflavones as redox inhibitors. Arch. Biochem. Biophys. 2007, 461, 176-185. [CrossRef] [PubMed]
100. Mascayano, C.; Espinosa, V.; Sepúlveda-Boza, S.; Hoobler, E. K.; Perry, S.; Diaz, G.; Holman, T. R. Enzymatic studies of isoflavonoids as selective and potent inhibitors of human leukocyte 5-lipo-oxygenase. Chem. Biol. Drug Des. 2015, 86, 114-121. [CrossRef] [PubMed]
101. Mascayano, C.; Espinosa, V.; Sepúlveda-Boza, S.; Hoobler, E. K.; Perry, S. In vitro study of isoflavones and isoflavans as potent inhibitors of human 12-and 15-lipoxygenases. Chem. Biol. Drug Des. 2013, 82, 317-325. [CrossRef] [PubMed]
102. Moncada, S.; Palmer, R.; Higgs, E. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 1991, 43, 109-142. [PubMed]
103. Salvemini, D.; Kim, S. F.; Mollace, V. Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: Relevance and clinical implications. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013, 304, R473-R487. [CrossRef] [PubMed]
104. Sheu, F.; Lai, H.-H.; Yen, G.-C. Suppression effect of soy isoflavones on nitric oxide production in raw 264. 7 macrophages. J. Agric. Food Chem. 2001, 49, 1767-1772. [CrossRef] [PubMed]
105. Park, J.-S.; Woo, M.-S.; Kim, D.-H.; Hyun, J.-W.; Kim, W.-K.; Lee, J.-C.; Kim, H.-S. Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells. J. Pharmacol. Exp. Ther. 2007, 320, 1237-1245. [CrossRef] [PubMed]
106. Chinta, S. J.; Ganesan, A.; Reis-Rodrigues, P.; Lithgow, G. J.; Andersen, J. K. Anti-inflammatory role of the isoflavone diadzein in lipopolysaccharide-stimulated microglia: Implications for Parkinson's disease. Neurotox. Res. 2013, 23, 145-153. [CrossRef] [PubMed]
107. Nakaya, M.; Tachibana, H.; Yamada, K. Isoflavone genistein and daidzein up-regulate lps-induced inducible nitric oxide synthase activity through estrogen receptor pathway in raw264. 7 cells. Biochem. Pharmacol. 2005, 71, 108-114. [CrossRef] [PubMed]
108. Valachovicova, T.; Slivova, V.; Bergman, H.; Shuherk, J.; Sliva, D. Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition of nf-κb/ap-1-dependent and-independent pathways. Int. J. Oncol. 2004, 25, 1389-1395. [CrossRef] [PubMed]
109. Pereira, S. G.; Oakley, F. Nuclear factor-kappab1: Regulation and function. Int. J. Biochem. Cell Biol. 2008, 40, 1425-1430. [CrossRef] [PubMed]
110. Barnes, P. J.; Karin, M. Nuclear factor-kappab: A pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 1997, 336, 1066-1071. [PubMed]
111. Yang, F.; Tang, E.; Guan, K.; Wang, C. Y. Ikk beta plays an essential role in the phosphorylation of rela/p65 on serine 536 induced by lipopolysaccharide. J. Immunol. 2003, 170, 5630-5635. [CrossRef] [PubMed]
112. Chen, Y.; Vallee, S.; Wu, J.; Vu, D.; Sondek, J.; Ghosh, G. Inhibition of nf-kappab activity by ikappabbeta in association with kappab-ras. Mol. Cell. Biol. 2004, 24, 3048-3056. [CrossRef] [PubMed]
113. Davis, J. N.; Kucuk, O.; Djuric, Z.; Sarkar, F. H. Soy isoflavone supplementation in healthy men prevents nf-κb activation by tnf-α in blood lymphocytes. Free Radic. Biol. Med. 2001, 30, 1293-1302. [CrossRef]
114. Kim, J. W.; Jin, Y. C.; Kim, Y. M.; Rhie, S.; Kim, H. J.; Seo, H. G.; Lee, J. H.; Ha, Y. L.; Chang, K. C. Daidzein administration in vivo reduces myocardial injury in a rat ischemia/reperfusion model by inhibiting nf-kb activation. Life Sci. 2009, 84, 227-234. [CrossRef] [PubMed]
115. Lu, H.; Shi, J.-X.; Zhang, D.-M.; Chen, H.-L.; Qi, M.; Yin, H.-X. Genistein, a soybean isoflavone, reduces the production of pro-inflammatory and adhesion molecules induced by hemolysate in brain microvascular endothelial cells. Acta Neurol. Belg. 2009, 109, 32. [PubMed]
116. Eo, H.; Ann, J.-Y.; Lim, Y. Dietary supplementation of genistein attenuates inflammatory responses and oxidative stress during cutaneous wound healing in diabetic mice. J. Agric. Sci. 2015, 7, 80. [CrossRef]
117. Hilakivi-Clarke, L.; Andrade, J. E.; Helferich, W. Is soy consumption good or bad for the breast? J. Nutr. 2010, 140, 2326S-2334S. [CrossRef] [PubMed]
118. Ravishankar, D.; Rajora, A. K.; Greco, F.; Osborn, H. M. Flavonoids as prospective compounds for anti-cancer therapy. Int. J. Biochem. Cell Biol. 2013, 45, 2821-2831. [CrossRef] [PubMed]
119. Boucher, B. A.; Cotterchio, M.; Anderson, L. N.; Kreiger, N.; Kirsh, V. A.; Thompson, L. U. Use of isoflavone supplements is associated with reduced postmenopausal breast cancer risk. Int. J. Cancer 2013, 132, 1439-1450. [CrossRef] [PubMed]
120. Yamamoto, S.; Sobue, T.; Kobayashi, M.; Sasaki, S.; Tsugane, S. Soy, isoflavones, and breast cancer risk in japan. J. Natl. Cancer Inst. 2003, 95, 906-913. [CrossRef] [PubMed]
121. Nagata, C.; Mizoue, T.; Tanaka, K.; Tsuji, I.; Tamakoshi, A.; Matsuo, K.; Wakai, K.; Inoue, M.; Tsugane, S.; Sasazuki, S. Soy intake and breast cancer risk: An evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn. J. Clin. Oncol. 2014, 44, 282-295. [CrossRef] [PubMed]
122. Chen, M.; Rao, Y.; Zheng, Y.; Wei, S.; Li, Y.; Guo, T.; Yin, P. Association between soy isoflavone intake and breast cancer risk for pre-and post-menopausal women: A meta-analysis of epidemiological studies. PLoS ONE 2014, 9, e89288. [CrossRef] [PubMed]
123. Mense, S. M.; Hei, T. K.; Ganju, R. K.; Bhat, H. K. Phytoestrogens and breast cancer prevention: Possible mechanisms of action. Environ. Health Perspect. 2008, 116, 426. [CrossRef] [PubMed]
124. Allred, C. D.; Allred, K. F.; Ju, Y. H.; Clausen, L. M.; Doerge, D. R.; Schantz, S. L.; Korol, D. L.; Wallig, M. A.; Helferich, W. G. Dietary genistein results in larger mnu-induced, estrogen-dependent mammary tumors following ovariectomy of sprague-dawley rats. Carcinogenesis 2004, 25, 211-218. [CrossRef] [PubMed]
125. Kijkuokool, P.; Parhar, I. S.; Malaivijitnond, S. Genistein enhances N-nitrosomethylurea-induced rat mammary tumorigenesis. Cancer Lett. 2006, 242, 53-59. [CrossRef] [PubMed]
126. Yang, Q.; Mas, A.; Elam, L.; Trevino, L.; Berry, T.; Walker, C.; Diamond, M.; Al-Hendy, A. Early life exposure to genistein permanently decreases myometrial DNA repair capacity, which may contribute to increased risk of uterine fibroid development. Fertil. Steril. 2015, 104, e30. [CrossRef]
127. Greathouse, K. L.; Bredfeldt, T.; Everitt, J. I.; Lin, K.; Berry, T.; Kannan, K.; Mittelstadt, M. L.; Ho, S.-M.; Walker, C. L. Environmental estrogens differentially engage the histone methyltransferase ezh2 to increase risk of uterine tumorigenesis. Mol. Cancer Res. 2012, 10, 546-557. [CrossRef] [PubMed]
128. Hsu, A.; Bray, T. M.; Helferich, W. G.; Doerge, D. R.; Ho, E. Differential effects of whole soy extract and soy isoflavones on apoptosis in prostate cancer cells. Exp. Biol. Med. 2010, 235, 90-97. [CrossRef] [PubMed]
129. Rietjens, I. M.; Sotoca, A. M.; Vervoort, J.; Louisse, J. Mechanisms underlying the dualistic mode of action of major soy isoflavones in relation to cell proliferation and cancer risks. Mol. Nutr. Food Res. 2013, 57, 100-113. [CrossRef] [PubMed]
130. Yellayi, S.; Naaz, A.; Szewczykowski, M. A.; Sato, T.; Woods, J. A.; Chang, J.; Segre, M.; Allred, C. D.; Helferich, W. G.; Cooke, P. S. The phytoestrogen genistein induces thymic and immune changes: A human health concern? Proc. Natl. Acad. Sci. USA 2002, 99, 7616-7621. [CrossRef] [PubMed]
131. Yellayi, S.; Zakroczymski, M. A.; Selvaraj, V.; Valli, V. E.; Ghanta, V.; Helferich, W. G.; Cooke, P. S. The phytoestrogen genistein suppresses cell-mediated immunity in mice. J. Endocrinol. 2003, 176, 267-274. [CrossRef] [PubMed]
132. Ebaid, H. M.; Elgawish, R. A. R.; Abdelrazek, H. M.; Gaffer, G.; Tag, H. M. Prenatal exposure to soy isoflavones altered the immunological parameters in female rats. Int. J. Toxicol. 2016. [CrossRef] [PubMed]
133. Portman, M. A. Kawasaki disease and soy: Potential role for isoflavone interaction with fcγ receptors. Pediatr. Res. 2012, 73, 130-134. [CrossRef] [PubMed]
134. Chen, A.; Rogan, W. J. Isoflavones in soy infant formula: A review of evidence for endocrine and other activity in infants. Annu. Rev. Nutr. 2004, 24, 33-54. [CrossRef] [PubMed]
135. Andrade, J. E.; Ju, Y. H.; Baker, C.; Doerge, D. R.; Helferich, W. G. Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (mcf-7) xenograft model. Mol. Nutr. Food Res. 2015, 59, 413-423. [CrossRef] [PubMed]
136. Woo, H. D.; Park, K.-S.; Ro, J.; Kim, J. Differential influence of dietary soy intake on the risk of breast cancer recurrence related to her2 status. Nutr. Cancer 2012, 64, 198-205. [CrossRef] [PubMed]
137. Lofamia, E. A. A.; Ramos, G. B.; Mamon, M. A. C.; Salido, F. M.; Su, G. S.; de Vera, M. P. Isoflavone maternal-supplementation during periconception period: Influence on the reproductive organs of the first generation (f1) murine weanling-stage offspring. Asian Pac. J. Reprod. 2014, 3, 268-274. [CrossRef]
138. Delclos, K. B.; Bucci, T. J.; Lomax, L. G.; Latendresse, J. R.; Warbritton, A.; Weis, C. C.; Newbold, R. R. Effects of dietary genistein exposure during development on male and female cd (sprague-dawley) rats. Reprod. Toxicol. 2001, 15, 647-663. [CrossRef]
139. Xiao, Y.; Mao, X.; Yu, B.; He, J.; Yu, J.; Zheng, P.; Huang, Z.; Chen, D. Potential risk of isoflavones: Toxicological study of daidzein supplementation in piglets. J. Agric. Food Chem. 2015, 63, 4228-4235. [CrossRef] [PubMed]
140. Ziberna, L.; Lunder, M.; Moze, S.; Vanzo, A.; Tramer, F.; Passamonti, S.; Drevensek, G. Acute cardioprotective and cardiotoxic effects of bilberry anthocyanins in ischemia-reperfusion injury: Beyond concentration-dependent antioxidant activity. Cardiovasc. Toxicol. 2010, 10, 283-294. [CrossRef] [PubMed]
141. Chen, W.; Lin, Y. C.; Ma, X. Y.; Jiang, Z. Y.; Lan, S. P. High concentrations of genistein exhibit pro-oxidant effects in primary muscle cells through mechanisms involving 5-lipoxygenase-mediated production of reactive oxygen species. Food Chem. Toxicol. 2014, 67, 72-79. [CrossRef] [PubMed]