Isoflavones: Anti-Inflammatory Benefit and Possible Caveats

Barton, 2008, A calculated response: Control of inflammation by the innate immune system, J. Clin. Investig., 118, 413, 10.1172/JCI34431

Guillamon, 2009, Flavonoids as anti-inflammatory agents: Implications in cancer and cardiovascular disease, Inflamm. Res., 58, 537, 10.1007/s00011-009-0037-3

Libby, 2002, Inflammation in atherosclerosis, Nature, 420, 868, 10.1038/nature01323

Samad, 2013, Inflammation, obesity, and thrombosis, Blood, 122, 3415, 10.1182/blood-2013-05-427708

Khandpur, 2013, Nets are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis, Sci. Transl. Med., 5, 178ra140, 10.1126/scitranslmed.3005580

Shay, 2015, Molecular mechanisms and therapeutic effects of (-)-epicatechin and other polyphenols in cancer, inflammation, diabetes, and neurodegeneration, Oxidative Med. Cell. Longev., 2015, 181260, 10.1155/2015/181260

Elinav, 2013, Inflammation-induced cancer: Crosstalk between tumours, immune cells and microorganisms, Nat. Rev. Cancer, 13, 759, 10.1038/nrc3611

Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala, N., Emberson, J., Merhi, A., Abramson, S., Arber, N., Baron, J.A., Bombardier, C., Cannon, C., and Farkouh, M.E. (2013). Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet, 382, 769–779.

Trichopoulou, 2009, Anatomy of health effects of mediterranean diet: Greek epic prospective cohort study, BMJ, 338, b2337, 10.1136/bmj.b2337

Ros, 2013, Consumption of plant seeds and cardiovascular health: Epidemiological and clinical trial evidence, Circulation, 128, 553, 10.1161/CIRCULATIONAHA.112.001119

Woo, 2014, Vegan diet, subnormal vitamin b-12 status and cardiovascular health, Nutrients, 6, 3259, 10.3390/nu6083259

Li, 2013, Traditional Chinese medicine network pharmacology: Theory, methodology and application, Chin. J. Nat. Med., 11, 110, 10.3724/SP.J.1009.2013.00110

Yin, 2015, Developing an activity and absorption-based quality control platform for chinese traditional medicine: Application to zeng-sheng-ping (antitumor b), J. Ethnopharmacol., 172, 195, 10.1016/j.jep.2015.06.019

Bo, 2012, 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., 64, 882, 10.1111/j.2042-7158.2012.01480.x

Dower, 2015, 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., 145, 1459, 10.3945/jn.115.211888

Dower, 2015, 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., 101, 914, 10.3945/ajcn.114.098590

Esposito, 2014, Inhibitory effects of wild blueberry anthocyanins and other flavonoids on biomarkers of acute and chronic inflammation in vitro, J. Agric. Food Chem., 62, 7022, 10.1021/jf4051599

Terashima, 2012, Antioxidant activity of flavonoids evaluated with myoglobin method, Plant Cell Rep., 31, 291, 10.1007/s00299-011-1163-2

Crozier, 2009, Dietary phenolics: Chemistry, bioavailability and effects on health, Nat. Prod. Rep., 26, 1001, 10.1039/b802662a

Sakai, 2008, Soy isoflavones and immunity, J. Med. Investig., 55, 167, 10.2152/jmi.55.167

Marzocchella, 2011, Dietary flavonoids: Molecular mechanisms of action as anti-inflammatory agents, Recent Pat. Inflamm. Allergy Drug Discov., 5, 200, 10.2174/187221311797264937

Cassidy, 2000, Isoflavones, lignans and stilbenes—Origins, metabolism and potential importance to human health, J. Sci. Food Agric., 80, 1044, 10.1002/(SICI)1097-0010(20000515)80:7<1044::AID-JSFA586>3.0.CO;2-N

Neveu, 2010, Systematic analysis of the content of 502 polyphenols in 452 foods and beverages: An application of the phenol-explorer database, J. Agric. Food Chem., 58, 4959, 10.1021/jf100128b

Setchell, 2013, Novel soy germ pasta enriched in isoflavones ameliorates gastroparesis in type 2 diabetes a pilot study, Diabetes Care, 36, 3495, 10.2337/dc12-1615

Barros, 2011, Estrogen receptors and the metabolic network, Cell Metab., 14, 289, 10.1016/j.cmet.2011.08.005

Vitale, 2013, Isoflavones: Estrogenic activity, biological effect and bioavailability, Eur. J. Drug Metab. Pharmacokinet., 38, 15, 10.1007/s13318-012-0112-y

Conklin, 2007, Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells, Carcinogenesis, 28, 93, 10.1093/carcin/bgl106

Dhayakaran, 2015, Characterization of antimicrobial efficacy of soy isoflavones against pathogenic biofilms, LWT Food Sci. Technol., 63, 859, 10.1016/j.lwt.2015.04.053

2013, Soymilk phenolic compounds, isoflavones and antioxidant activity as affected by in vitro gastrointestinal digestion, Food Chem., 136, 206, 10.1016/j.foodchem.2012.07.115

Chacko, 2007, Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell ppargamma, J. Nutr., 137, 351, 10.1093/jn/137.2.351

Kuiper, 1998, Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β, Endocrinology, 139, 4252, 10.1210/endo.139.10.6216

Phetnoo, 2013, Genistein could have a therapeutic potential for gastrointestinal diseases, Thai J. Gastroenterol. 2013, 14, 120

Marugame, 2006, International comparisons of cumulative risk of breast and prostate cancer, from cancer incidence in five continents vol. Viii, Jpn. J. Clin. Oncol., 36, 399, 10.1093/jjco/hyl049

Medjakovic, 2010, Potential health-modulating effects of isoflavones and metabolites via activation of ppar and ahr, Nutrients, 2, 241, 10.3390/nu2030241

Wu, 1998, Soy intake and risk of breast cancer in asians and asian americans, Am. J. Clin. Nutr., 68, 1437S, 10.1093/ajcn/68.6.1437S

Nielsen, 2007, Review of the factors affecting bioavailability of soy isoflavones in humans, Nutr. Cancer, 57, 1, 10.1080/01635580701267677

Vergne, 2007, Bioavailability and urinary excretion of isoflavones in humans: Effects of soy-based supplements formulation and equol production, J. Pharm. Biomed. Anal., 43, 1488, 10.1016/j.jpba.2006.10.006

Day, 1998, Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver β-glucosidase activity, FEBS Lett., 436, 71, 10.1016/S0014-5793(98)01101-6

Setchell, 2001, Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements, J. Nutr., 131, 1362S, 10.1093/jn/131.4.1362S

Barnes, 2010, The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products, Lymphat. Res. Biol., 8, 89, 10.1089/lrb.2009.0030

Manach, 2005, Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies, Am. J. Clin. Nutr., 81, 230S, 10.1093/ajcn/81.1.230S

Barnes, 1998, Evolution of the health benefits of soy isoflavones, Proc. Soc. Exp. Biol. Med., 217, 386, 10.3181/00379727-217-44249

Messina, 2014, Soy foods, isoflavones, and the health of postmenopausal women, Am. J. Clin. Nutr., 100, 423S, 10.3945/ajcn.113.071464

Verdrengh, 2003, Genistein as an anti-inflammatory agent, Inflamm. Res. Off. J. Eur. Histamine Res. Soc., 52, 341

Paradkar, 2004, Dietary isoflavones suppress endotoxin-induced inflammatory reaction in liver and intestine, Cancer Lett., 215, 21, 10.1016/j.canlet.2004.05.019

Kao, 2007, Anti-inflammatory effects of isoflavone powder produced from soybean cake, J. Agric. Food Chem., 55, 11068, 10.1021/jf071851u

Carrara, 2008, Anti-inflammatory activity of the soybean methanolic fraction containing isoflavones, Planta Medica, 74, 1179, 10.1055/s-0028-1084877

Lim, 2013, Anti-inflammatory effects of total isoflavones from pueraria lobata on cerebral ischemia in rats, Molecules, 18, 10404, 10.3390/molecules180910404

Ganai, 2015, 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., 283, 139, 10.1016/j.taap.2015.01.012

Duan, 2003, Antiinflammatory effects of genistein, a tyrosine kinase inhibitor, on a guinea pig model of asthma, Am. J. Respir. Crit. Care Med., 167, 185, 10.1164/rccm.200205-420OC

Hooshmand, 2007, Genistein reduces the production of proinflammatory molecules in human chondrocytes, J. Nutr. Biochem., 18, 609, 10.1016/j.jnutbio.2006.11.006

Li, 2014, Daidzein suppresses pro-inflammatory chemokine cxcl2 transcription in tnf-alpha-stimulated murine lung epithelial cells via depressing parp-1 activity, Acta Pharmacol. Sin., 35, 496, 10.1038/aps.2013.191

Tanaka, 2014, Anti-inflammatory effects of green soybean extract irradiated with visible light, Sci. Rep., 4, 4732, 10.1038/srep04732

Han, 2015, Protective effects of genistein in homocysteine-induced endothelial cell inflammatory injury, Mol. Cell. Biochem., 403, 43, 10.1007/s11010-015-2335-0

Azadbakht, 2007, Soy consumption, markers of inflammation, and endothelial function a cross-over study in postmenopausal women with the metabolic syndrome, Diabetes Care, 30, 967, 10.2337/dc06-2126

Nasca, 2008, Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women, Am. J. Cardiol., 102, 84, 10.1016/j.amjcard.2008.02.100

Fanti, 2006, 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., 21, 2239, 10.1093/ndt/gfl169

Ferguson, 2014, Dietary isoflavone intake is associated with evoked responses to inflammatory cardiometabolic stimuli and improved glucose homeostasis in healthy volunteers, Nutr. Metab. Cardiovasc. Dis., 24, 996, 10.1016/j.numecd.2014.03.010

Wu, 2012, Soy food intake and circulating levels of inflammatory markers in Chinese women, J. Acad. Nutr. Diet., 112, 996, 10.1016/j.jand.2012.04.001

Mangano, 2013, Soy proteins and isoflavones reduce interleukin-6 but not serum lipids in older women: A randomized controlled trial, Nutr. Res., 33, 1026, 10.1016/j.nutres.2013.08.009

Acharjee, 2015, Effect of soy nuts and equol status on blood pressure, lipids and inflammation in postmenopausal women stratified by metabolic syndrome status, Metabolism, 64, 236, 10.1016/j.metabol.2014.09.005

Lee, 2013, Reactive oxygen species and tumor metastasis, Mol. Cells, 35, 93, 10.1007/s10059-013-0034-9

Brown, 2014, Microglial phagocytosis of live neurons, Nat. Rev. Neurosci., 15, 209, 10.1038/nrn3710

Halliwell, B., and Gutteridge, J.M. (2015). Free Radicals in Biology and Medicine, Oxford University Press.

Niki, 2014, Role of vitamin E as a lipid-soluble peroxyl radical scavenger: In vitro and in vivo evidence, Free Radic. Biol. Med., 66, 3, 10.1016/j.freeradbiomed.2013.03.022

Lee, 2012, Role of nadph oxidase/ros in pro-inflammatory mediators-induced airway and pulmonary diseases, Biochem. Pharmacol., 84, 581, 10.1016/j.bcp.2012.05.005

Lengyel, 2013, On the radical scavenging activity of isoflavones: Thermodynamics of O-H bond cleavage, Phys. Chem. Chem. Phys., 15, 10895, 10.1039/c3cp00095h

Prasain, 2003, Polyphenols, inflammatory response, and cancer prevention: Chlorination of isoflavones by human neutrophils, J. Nutr., 133, 3773S, 10.1093/jn/133.11.3773S

Patel, 2001, Antioxidant mechanisms of isoflavones in lipid systems: Paradoxical effects of peroxyl radical scavenging, Free Radic. Biol. Med., 31, 1570, 10.1016/S0891-5849(01)00737-7

Boersma, 1999, Chlorination and nitration of soy isoflavones, Arch. Biochem. Biophys., 368, 265, 10.1006/abbi.1999.1330

Lai, 2002, Inhibitory effect of isoflavones on peroxynitrite-mediated low-density lipoprotein oxidation, Biosci. Biotechnol. Biochem., 66, 22, 10.1271/bbb.66.22

Tie, 2013, Genistein accelerates refractory wound healing by suppressing superoxide and foxo1/inos pathway in type 1 diabetes, J. Nutr. Biochem., 24, 88, 10.1016/j.jnutbio.2012.02.011

Wachowicz, 2013, Antioxidative effects of extracts from trifolium species on blood platelets exposed to oxidative stress, J. Physiol. Biochem., 69, 879, 10.1007/s13105-013-0264-5

Yen, 2003, Inhibition of reactive nitrogen species effects in vitro and in vivo by isoflavones and soy-based food extracts, J. Agric. Food Chem., 51, 7892, 10.1021/jf034876b

Ma, 2015, Isoflavone ameliorates H2O2 induced injury by activating the antioxidant system of sow mammary gland cell, Nat. Sci., 7, 571

Jin, 2015, Soy isoflavones protect against H2O2-induced injury in human umbilical vein endothelial cells, Mol. Med. Rep., 12, 4476, 10.3892/mmr.2015.3949

Mann, 2009, Targeting the redox sensitive nrf2–keap1 defense pathway in cardiovascular disease: Protection afforded by dietary isoflavones, Curr. Opin. Pharmacol., 9, 139, 10.1016/j.coph.2008.12.012

Zhai, 2013, 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., 57, 249, 10.1002/mnfr.201200536

Blay, 2010, Isoflavone effect on gene expression profile and biomarkers of inflammation, J. Pharm. Biomed. Anal., 51, 382, 10.1016/j.jpba.2009.03.028

Ji, G., Zhang, Y., Yang, Q., Cheng, S., Hao, J., Zhao, X., and Jiang, Z. (2012). Genistein suppresses lps-induced inflammatory response through inhibiting nf-κb following amp kinase activation in raw 264.7 macrophages. PLoS ONE, 7.

Gao, 2014, Suppressive effects of irisflorentin on lps-induced inflammatory responses in raw 264.7 macrophages, Exp. Biol. Med., 239, 1018, 10.1177/1535370214530081

Satsu, 2009, 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., 55, 442, 10.3177/jnsv.55.442

Morimoto, 2009, Isoflavones regulate innate immunity and inhibit experimental colitis, J. Gastroenterol. Hepatol., 24, 1123, 10.1111/j.1440-1746.2008.05714.x

Lesinski, 2015, Consumption of soy isoflavone enriched bread in men with prostate cancer is associated with reduced proinflammatory cytokines and immunosuppressive cells, Cancer Prev. Res., 8, 1036, 10.1158/1940-6207.CAPR-14-0464

Rodrigues, 2008, Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis, Int. Immunopharmacol., 8, 1291, 10.1016/j.intimp.2008.05.002

Yoo, 2015, Dietary supplementation of genistein alleviates liver inflammation and fibrosis mediated by a methionine-choline-deficient diet in db/db mice, J. Agric. Food Chem., 63, 4305, 10.1021/acs.jafc.5b00398

Langenbach, 1995, Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration, Cell, 83, 483, 10.1016/0092-8674(95)90126-4

Kuehl, 1980, Prostaglandins, arachidonic acid, and inflammation, Science, 210, 978, 10.1126/science.6254151

Vane, 1994, Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation, Proc. Natl. Acad. Sci. USA, 91, 2046, 10.1073/pnas.91.6.2046

Xiang, 2013, Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway, Nat. Commun., 4, 2657, 10.1038/ncomms3657

Middleton, 2000, The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer, Pharmacol. Rev., 52, 673

Dharmappa, 2010, Genistein, a potent inhibitor of secretory phospholipase a2: A new insight in down regulation of inflammation, Inflammopharmacology, 18, 25, 10.1007/s10787-009-0018-8

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., and Gaeta, H.H. (2012). 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.

Suleyman, 2007, Anti-inflammatory and side effects of cyclooxygenase inhibitors, Pharmacol. Rep., 59, 247

Vera, 2005, 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., 314, 1300, 10.1124/jpet.105.085530

Ahmad, 2014, 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., 65, 120, 10.1016/j.fct.2013.12.025

Lau, 2006, Soya isoflavones suppress phorbol 12-myristate 13-acetate-induced cox-2 expression in mcf-7 cells, Br. J. Nutr., 96, 169, 10.1079/BJN20061639

Li, 2011, 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., 39, 2141, 10.1177/147323001103900610

Mahesha, 2007, Inhibition of lipoxygenase by soy isoflavones: Evidence of isoflavones as redox inhibitors, Arch. Biochem. Biophys., 461, 176, 10.1016/j.abb.2007.02.013

Mascayano, 2015, Enzymatic studies of isoflavonoids as selective and potent inhibitors of human leukocyte 5-lipo-oxygenase, Chem. Biol. Drug Des., 86, 114, 10.1111/cbdd.12469

Mascayano, 2013, In vitro study of isoflavones and isoflavans as potent inhibitors of human 12-and 15-lipoxygenases, Chem. Biol. Drug Des., 82, 317, 10.1111/cbdd.12157

Moncada, 1991, Nitric oxide: Physiology, pathophysiology, and pharmacology, Pharmacol. Rev., 43, 109

Salvemini, 2013, Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: Relevance and clinical implications, Am. J. Physiol. Regul. Integr. Comp. Physiol., 304, R473, 10.1152/ajpregu.00355.2012

Sheu, 2001, Suppression effect of soy isoflavones on nitric oxide production in raw 264.7 macrophages, J. Agric. Food Chem., 49, 1767, 10.1021/jf001198+

Park, 2007, Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells, J. Pharmacol. Exp. Ther., 320, 1237, 10.1124/jpet.106.114322

Chinta, 2013, Anti-inflammatory role of the isoflavone diadzein in lipopolysaccharide-stimulated microglia: Implications for Parkinson’s disease, Neurotox. Res., 23, 145, 10.1007/s12640-012-9328-5

Nakaya, 2005, Isoflavone genistein and daidzein up-regulate lps-induced inducible nitric oxide synthase activity through estrogen receptor pathway in raw264. 7 cells, Biochem. Pharmacol., 71, 108, 10.1016/j.bcp.2005.10.002

Valachovicova, 2004, Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition of nf-κb/ap-1-dependent and-independent pathways, Int. J. Oncol., 25, 1389

Pereira, 2008, Nuclear factor-kappab1: Regulation and function, Int. J. Biochem. Cell Biol., 40, 1425, 10.1016/j.biocel.2007.05.004

Barnes, 1997, Nuclear factor-kappab: A pivotal transcription factor in chronic inflammatory diseases, N. Engl. J. Med., 336, 1066, 10.1056/NEJM199704103361506

Yang, 2003, Ikk beta plays an essential role in the phosphorylation of rela/p65 on serine 536 induced by lipopolysaccharide, J. Immunol., 170, 5630, 10.4049/jimmunol.170.11.5630

Chen, 2004, Inhibition of nf-kappab activity by ikappabbeta in association with kappab-ras, Mol. Cell. Biol., 24, 3048, 10.1128/MCB.24.7.3048-3056.2004

Davis, 2001, Soy isoflavone supplementation in healthy men prevents nf-κb activation by tnf-α in blood lymphocytes, Free Radic. Biol. Med., 30, 1293, 10.1016/S0891-5849(01)00535-4

Kim, 2009, Daidzein administration in vivo reduces myocardial injury in a rat ischemia/reperfusion model by inhibiting nf-kb activation, Life Sci., 84, 227, 10.1016/j.lfs.2008.12.005

Lu, 2009, Genistein, a soybean isoflavone, reduces the production of pro-inflammatory and adhesion molecules induced by hemolysate in brain microvascular endothelial cells, Acta Neurol. Belg., 109, 32

Eo, 2015, Dietary supplementation of genistein attenuates inflammatory responses and oxidative stress during cutaneous wound healing in diabetic mice, J. Agric. Sci., 7, 80

Andrade, 2010, Is soy consumption good or bad for the breast?, J. Nutr., 140, 2326S, 10.3945/jn.110.124230

Ravishankar, 2013, Flavonoids as prospective compounds for anti-cancer therapy, Int. J. Biochem. Cell Biol., 45, 2821, 10.1016/j.biocel.2013.10.004

Boucher, 2013, Use of isoflavone supplements is associated with reduced postmenopausal breast cancer risk, Int. J. Cancer, 132, 1439, 10.1002/ijc.27769

Yamamoto, 2003, Soy, isoflavones, and breast cancer risk in japan, J. Natl. Cancer Inst., 95, 906, 10.1093/jnci/95.12.906

Nagata, 2014, Soy intake and breast cancer risk: An evaluation based on a systematic review of epidemiologic evidence among the Japanese population, Jpn. J. Clin. Oncol., 44, 282, 10.1093/jjco/hyt203

Chen, M., Rao, Y., Zheng, Y., Wei, S., Li, Y., Guo, T., and Yin, P. (2014). Association between soy isoflavone intake and breast cancer risk for pre-and post-menopausal women: A meta-analysis of epidemiological studies. PLoS ONE, 9.

Mense, 2008, Phytoestrogens and breast cancer prevention: Possible mechanisms of action, Environ. Health Perspect., 116, 426, 10.1289/ehp.10538

Allred, 2004, Dietary genistein results in larger mnu-induced, estrogen-dependent mammary tumors following ovariectomy of sprague-dawley rats, Carcinogenesis, 25, 211, 10.1093/carcin/bgg198

Kijkuokool, 2006, Genistein enhances N-nitrosomethylurea-induced rat mammary tumorigenesis, Cancer Lett., 242, 53, 10.1016/j.canlet.2005.10.033

Yang, 2015, Early life exposure to genistein permanently decreases myometrial DNA repair capacity, which may contribute to increased risk of uterine fibroid development, Fertil. Steril., 104, e30, 10.1016/j.fertnstert.2015.07.092

Greathouse, 2012, Environmental estrogens differentially engage the histone methyltransferase ezh2 to increase risk of uterine tumorigenesis, Mol. Cancer Res., 10, 546, 10.1158/1541-7786.MCR-11-0605

Hsu, 2010, Differential effects of whole soy extract and soy isoflavones on apoptosis in prostate cancer cells, Exp. Biol. Med., 235, 90, 10.1258/ebm.2009.009128

Rietjens, 2013, Mechanisms underlying the dualistic mode of action of major soy isoflavones in relation to cell proliferation and cancer risks, Mol. Nutr. Food Res., 57, 100, 10.1002/mnfr.201200439

Yellayi, 2002, The phytoestrogen genistein induces thymic and immune changes: A human health concern?, Proc. Natl. Acad. Sci. USA, 99, 7616, 10.1073/pnas.102650199

Yellayi, 2003, The phytoestrogen genistein suppresses cell-mediated immunity in mice, J. Endocrinol., 176, 267, 10.1677/joe.0.1760267

Ebaid, H.M., Elgawish, R.A.R., Abdelrazek, H.M., Gaffer, G., and Tag, H.M. (2016). Prenatal exposure to soy isoflavones altered the immunological parameters in female rats. Int. J. Toxicol.

Portman, 2012, Kawasaki disease and soy: Potential role for isoflavone interaction with fcγ receptors, Pediatr. Res., 73, 130, 10.1038/pr.2012.168

Chen, 2004, Isoflavones in soy infant formula: A review of evidence for endocrine and other activity in infants, Annu. Rev. Nutr., 24, 33, 10.1146/annurev.nutr.24.101603.064950

Andrade, 2015, Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (mcf-7) xenograft model, Mol. Nutr. Food Res., 59, 413, 10.1002/mnfr.201300780

Woo, 2012, Differential influence of dietary soy intake on the risk of breast cancer recurrence related to her2 status, Nutr. Cancer, 64, 198, 10.1080/01635581.2012.635261

Lofamia, 2014, Isoflavone maternal-supplementation during periconception period: Influence on the reproductive organs of the first generation (f1) murine weanling-stage offspring, Asian Pac. J. Reprod., 3, 268, 10.1016/S2305-0500(14)60038-5

Delclos, 2001, Effects of dietary genistein exposure during development on male and female cd (sprague-dawley) rats, Reprod. Toxicol., 15, 647, 10.1016/S0890-6238(01)00177-0

Xiao, 2015, Potential risk of isoflavones: Toxicological study of daidzein supplementation in piglets, J. Agric. Food Chem., 63, 4228, 10.1021/acs.jafc.5b00677

Ziberna, 2010, Acute cardioprotective and cardiotoxic effects of bilberry anthocyanins in ischemia–reperfusion injury: Beyond concentration-dependent antioxidant activity, Cardiovasc. Toxicol., 10, 283, 10.1007/s12012-010-9091-x

Chen, 2014, 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., 67, 72, 10.1016/j.fct.2014.02.004