Advertisement

Therapeutic Potential of Phytoestrogens

  • Atiya Fatima
  • Asrar Alam
  • Ram Singh
Chapter

Abstract

Phytoestrogens are naturally occurring constituents of plants present in the significant proportion of our diet. They have been extensively studied due to their potential as pharmacological targets and nutraceutical benefits. The potential pharmacological applications of these molecules include cardioprotection, antimicrobial, anticancer, anti-obesity, antiosteoporosis, antidiabetic, and neuroprotection. Phytoestrogens are polyphenolic nonsteroidal compounds of plant origin with estrogen-like biological activity. They mimic estradiol-like effects in several tissue/tissues of the mammalian body. The health benefits accredited to them are due to their ability to mimic estrogenic actions. In this chapter, we aim to provide comprehensive coverage of the pharmacological aspects of the most pronounced phytoestrogens of our daily life. We will discuss different classes of phytoestrogens under the subcategory of flavonoids and non-flavonoids. Numerous plant-derived compounds like genistein, daidzein, 8-prenylnaringenin, equol, quercetin, coumestrol, isoliquiritigenin, and resveratrol belonging to different classes of phytoestrogens will be discussed with their therapeutic values and clinical applications in a broad range of health-related problems and disorders.

Keywords

Phytoestrogens Flavonoids Estrogenic activity RBA (Receptor binding affinity) Genistein Resveratrol 

Notes

Acknowledgments

AA is supported by a research fellowship from the Japan Society for the Promotion of Science.

References

  1. 1.
    Rietjens IM, Sotoca AM, Vervoort J, Louisse J (2013) Mechanisms underlying the dualistic mode of action of major soy isoflavones in relation to cell proliferation and cancer risks. Mol Nutr Food Res 57:100–113PubMedCrossRefGoogle Scholar
  2. 2.
    Knight DC, Eden JA (1996) A review of the clinical effects of phytoestrogens. Obstet Gynecol 87:897–904PubMedGoogle Scholar
  3. 3.
    Yildiz F (2005) Phytoestrogens in Functional Foods. Taylor & Francis Ltd, Boca Raton, pp 3–5:210–211Google Scholar
  4. 4.
    Paterni I., Granchi C., Katzenellenbogen J.A, Minutolo F. (2014) Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. Steroids 90 13–29 S0039-128X(14: 00151–00152PubMedCrossRefGoogle Scholar
  5. 5.
    Böttner M, Thelen P, Jarry H (2013) Estrogen receptor beta: Tissue distribution and the still largely enigmatic physiological function. J Steroid Biochem Mol Biol 139:245–251 pii: S0960-0760(13)00052-6PubMedCrossRefGoogle Scholar
  6. 6.
    Anderson JJB, Anthony M, Messina M, Garner SC (1999) Effects of phyto-oestrogens on tissues. Nutr Res Rev 12:75–116PubMedCrossRefGoogle Scholar
  7. 7.
    Messina MJ, Loprinzi CL (2001) Soy for breast cancer survivors: a critical review of the literature. J Nutr 131:3095S–3108SPubMedCrossRefGoogle Scholar
  8. 8.
    Adlercreutz H (1998b) Evolution, nutrition, intestinal microflora, and prevention of cancer: a hypothesis. Proc Soc Exp Biol Med 217:241–246PubMedCrossRefGoogle Scholar
  9. 9.
    Kurzer MS, Xu X (1997) Dietary phytoestrogens. Annu Rev Nutr 17:353–381PubMedCrossRefGoogle Scholar
  10. 10.
    Carlson S, Peng N, Prasain JK, Wyss JM (2008) Effects of botanical dietary supplements on cardiovascular, cognitive, and metabolic function in males and females. Gen Med 5:S76–S90CrossRefGoogle Scholar
  11. 11.
    Martin JHJ, Crotty S, Warren P, Nelson PN (2007) Does an apple a day keep the doctor away because a phytoestrogen a day keeps the virus at bay? A review of antiviral properties of phytoestrogen. Phytochemistry 68:266–274PubMedCrossRefGoogle Scholar
  12. 12.
    Januario AH, Lourenco MV, Domezio LA, Pietro R, Castilho MS, Tomazela DM, da Silva M, Vieira PC, Fernandes JB, Franca SD (2005) Isolation and structure determination of bioactive isoflavones from callus culture of Dipteryx odorata. Chem Pharm Bull 53:740PubMedCrossRefGoogle Scholar
  13. 13.
    Hu J-Y, Aizawa T (2003) Quantitative structure–activity relationships for estrogen receptor binding affinity of phenolic chemicals. Water Res 37:1213–1222PubMedCrossRefGoogle Scholar
  14. 14.
    Brzozowski AM, Pike ACW, Dauter Z et al (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758PubMedCrossRefGoogle Scholar
  15. 15.
    Vaya J, Tamir S (2004) The relation between the chemical structure of flavonoids and their estrogen-like activities. Curr Med Chem 11:1333–1343PubMedCrossRefGoogle Scholar
  16. 16.
    Cassidy A, Bingham S, Setchell K (1995) Biological effects of isoflavones in young women: importance of the chemical composition of soyabean products. Br J Nutr 74:587–601PubMedCrossRefGoogle Scholar
  17. 17.
    Fatima A, Singh R (2016) The chemistry and pharmacology of genistein. Nat Prod J 6:3–12Google Scholar
  18. 18.
    Makiewicz L, Garey J, Adlercreutz H, Gurpide E (1993) In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol 45:399–405CrossRefGoogle Scholar
  19. 19.
    Shutt DA, Cox RI (1972) Steroid and phyto-estrogen binding to sheep Uterine receptors in vitro. J Endocrinol 52:291–310CrossRefGoogle Scholar
  20. 20.
    Kuiper GGJM, Lemmen JG, Carlsson B et al (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen. Endocrinology 139:4252–4263PubMedCrossRefGoogle Scholar
  21. 21.
    Wang TT, Sathymoorthy N, Phang JM (1996) Molecular effects genistein on estrogen receptor mediated pathways. Carcinogenesis 17:271–275PubMedCrossRefGoogle Scholar
  22. 22.
    Agarwal R (2000) Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochem Pharmacol 60:1051–1059PubMedCrossRefGoogle Scholar
  23. 23.
    Lakshman M, Li X, Vijayalakshmi A, Joshua C, Takimoto Chris H, Irene H, Pelling Jill C, Bergan Raymond C (2008) Dietary Genistein inhibits metastasis of human prostate cancer in mice. Cancer Res 68:20–24CrossRefGoogle Scholar
  24. 24.
    Pavese JM, Krishn SN, Bergan RC (2014) Genistein inhibits human prostate cancer cell detachment, invasion, and metastasis. Am J Clin Nutr 100:431S–436SPubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Caruso MG, Notarnicola M, Cavallini A, Guerra V, Misciagna G, Di Leo A (1993) Demonstration of low density lipoprotein receptor in human colonic carcinoma and in surrounding mucosa by immunoenzymatic assay. Ital J Gastroenterol 25:361PubMedGoogle Scholar
  26. 26.
    Qi W, Weber CR, Wasland K, Savkovic SD (2011) Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC Cancer 11:219PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Kaushik S, Shyam H, Sharma R, Balapure AK (2016) Genistein synergizes centchroman action in human breast cancer cells. Indian J Pharm 48:637–642CrossRefGoogle Scholar
  28. 28.
    Sarkar FH, Li Y (2006) Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res 66:3347–3350PubMedCrossRefGoogle Scholar
  29. 29.
    Mohammad RM, Banerjee S, Li Y, Aboukameel A, Kucuk O, Sarkar FH (2006) Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts. Cancer 106:1260–1268PubMedCrossRefGoogle Scholar
  30. 30.
    Hwang JT, Park IJ, Shin JI, Lee YK, Lee SK, Baik HW, Ha J, Park OJ (2005) Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem Biophys Res Commun 338:694–699PubMedCrossRefGoogle Scholar
  31. 31.
    Aditya NP, Shim M, Yang H, Lee YJ, Ko S (2014) Antiangiogenic effect of combined treatment with curcumin and genistein on human prostate cancer cell line. J Funct Foods 8:204–213CrossRefGoogle Scholar
  32. 32.
    Chang KL, Cheng HL, Huang LW, Hsieh BS, Hu YC, Chi TT, Shyu HW, Su SJ (2009) Combined effects of terazosin and genistein on a metastatic, hormone-independent human prostate cancer cell line. Cancer Lett 276:14–20PubMedCrossRefGoogle Scholar
  33. 33.
    Park HJ, Della-Fera MA, Hausman DB, Rayalam S, Ambatia S, Baile CA (2009) Genistein inhibits differentiation of primary human adipocytes. J Nutr Biochem 20:140–148PubMedCrossRefGoogle Scholar
  34. 34.
    Aguero MF, Fachinetti MM, sheleg Z, Senderowicz AM (2005) phenoxodiol: a novel isoflavone, induces G1 arrest by specific loss in cyclin dependent kinase 2 activity by p- 53 independent induction of p21WAF1/CIP1. Cancer Res 65:3364–3373PubMedCrossRefGoogle Scholar
  35. 35.
    Choueiri TK, Mekhail T, Hutson TE, Ganapathi R, Kelly GE, Bukowsky RM (2006) Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer. Ann Oncol 17:860–865PubMedCrossRefGoogle Scholar
  36. 36.
    Rickard DJ, Monroe DG, Ruesink TJ, Khosla S, Riggs BL, Spelsberg TC (2003) Phytoestrogen genistein acts as an estrogen agonist on human osteoblastic cells through estrogen receptors alpha and beta. J Cell Biochem 89:633–646PubMedCrossRefGoogle Scholar
  37. 37.
    Yamagishi T, Otsuka E, Hagiwara H (2001) Reciprocal control of expression of mRNAs for osteoclast differentiation factor and OPG in osteogenic stromal cells by genistein: evidence for the involvement of topoisomerase II in osteoclas- togenesis. Endocrinology 142:3632–3637PubMedCrossRefGoogle Scholar
  38. 38.
    Atteritano M, Pernice F, Mazzaferro S, Mantuano S, Frisina A, D'Anna R, Cannata ML, Bitto A, Squadrito F, Frisina N, Buemi M (2008) Effects of phytoestrogen genistein on cytogenetic biomarkers in postmenopausal women: 1 year randomized, placebo-controlled study. Eur J Pharmacol 589:22–26PubMedCrossRefGoogle Scholar
  39. 39.
    Sehmisch S, Uffenorde J, Maehlmeyer S, Tezval M, Jarry H, Stuermer KM, Stuermer EK (2010) Evaluation of bone quality and quantity in osteoporotic mice–The effects of genistein and equol. Phytomedicine 17:424–430PubMedCrossRefGoogle Scholar
  40. 40.
    Choi EJ, Kim G (2008) Daidzein causes cell cycle arrest at the G1 and G2/M phases in human breast cancer MCF-7 and MDA-MB-453 cells. Phytomedicine 15:683–690PubMedCrossRefGoogle Scholar
  41. 41.
    Bhathena SJ, Velasquez MT (2002) Beneficial role of dietary phytoestrogens in obesity and diabetes. Am J Clin Nutr 76:1191–1201PubMedCrossRefGoogle Scholar
  42. 42.
    Hamideh S, Marcus BM, Antonio A, Marcelo HL (2011) The antioxidant effect of genistein on the in vitro metal -mediated formation of free radicals. Clin Biochem 44:S226–S226Google Scholar
  43. 43.
    Palanisamy N, Kannappan S, Anuradha CV (2011) Genistein modulates NF-kB-associated renal inflammation, fibrosis and podocyte abnormalities in fructose-fed rats. Eur J Pharmacol 667:355–364PubMedCrossRefGoogle Scholar
  44. 44.
    Gelinas S, Martinoli MG (2002) Neuroprotective effect of estradiol and phytoestrogens on MPP+-induced cytotoxicity in neuronal PC12 cells. J Neurosci Res 70:90–96PubMedCrossRefGoogle Scholar
  45. 45.
    Liu LX, Chen W, Xie J, Wong M (2008) Neuroprotective effects of genistein on dopaminergic neurons in the mice model of Parkinson’s disease. Neurosci Res 60:156–161PubMedCrossRefGoogle Scholar
  46. 46.
    Gao Q, Xie J, Wong M, Chen W (2012) IGF-I receptor signaling pathway is involved in the neuroprotective effect of genistein in the neuroblastoma SK-N-SH cells. Eur J Pharmacol 677:39–46PubMedCrossRefGoogle Scholar
  47. 47.
    Jakob-Roetne R, Jacobsen H (2009) Alzheimer’s disease: from pathology to therapeutic approaches. Angew Chem Int Ed Eng 48:3030–3059CrossRefGoogle Scholar
  48. 48.
    Bagheri M, Roghanid M, Joghataeib M, Mohsenia S (2012) Genistein inhibits aggregation of exogenous amyloid-beta1-40 and alleviates astrogliosis is in the hippocampus of rats. Brain Res 1429:145–154PubMedCrossRefGoogle Scholar
  49. 49.
    Alonso A, Gonzalez-Pardo H, Garrido P et al (2010) Acute effects of 17 beta-estradiol and genistein on insulin sensitivity and spatial memory in aged ovariectomized female rats. Age (Dordr) 32(4):421–434CrossRefGoogle Scholar
  50. 50.
    Bagheri M, Joghataei M-T, Mohsen S, Roghani M (2011) Genistein ameliorates learning and memory deficits in amyloid β(1-40) rat model of Alzheimer’s disease. Neurobiol Learn Mem 95:270–276PubMedCrossRefGoogle Scholar
  51. 51.
    ClinicalTrials.gov identifier: NCT01982578l Genistein as a Possible Treatment for Alzheimer's Disease. (GENISTEÍNA_2)l juy 2015).
  52. 52.
    Zhang X, Wang J, Hong C, Luon W, Wang C (2015) Design, synthesis and evaluation of genistein-polyamine conjugates as multi-functional anti-Alzheimer agents. Acta Pharm Sin B 5:67–73PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Sathyamoorthy N, Wang TT (1997) Differential effects of dietary phyto-oestrogens daidzein and equol on human breast cancer MCF-7 cells. Eur J Cancer 33:2384–2389PubMedCrossRefGoogle Scholar
  54. 54.
    Guo JM, Kang GZ, Xiao BX, Liu DH, Zhang S (2004) Effect of daidzein on cell growth, cell cycle, and telomerase activity of human cervical cancer in vitro. Int J Gynecol Cancer 14:882–888PubMedCrossRefGoogle Scholar
  55. 55.
    Lee JS, Son KH, Sung MK, Kim YK, Yu R, Kim JS (2003) Anticarcinogenic properties of a daidzein-rich fraction isolated from soybean. J Med Food 6:175–181PubMedCrossRefGoogle Scholar
  56. 56.
    Rabiau N, Kossaï M, Braud M, Chalabi N, Satih S, Bignon YJ, Bernard-Gallon DJ (2010) Genistein and daidzein act on a panel of genes implicated in cell cycle and angiogenesis by polymerase chain reaction arrays in human prostate cancer cell lines. Cancer Epidemiol 34:200–206PubMedCrossRefGoogle Scholar
  57. 57.
    Somjen D, Katzburg S, Nevo N, Gayera B, Hodged RP, Reneveyd MD, Kalchenko V, Meshorere A, Sternc N, Kohena F (2008) A daidzein–daunomycin conjugate improves the therapeutic response in an animal model of ovarian carcinoma. J Steroid Biochem Mol Biol 110:144–149PubMedCrossRefGoogle Scholar
  58. 58.
    Yamaguchi M, Sugimoto E (2000) Stimulatory effect of genistein and daidzein on protein synthesis in osteoblastic MC3T3-E1 cells: activation of aminoacyl-tRNA synthetase. Mol Cell Biochem 214:97PubMedCrossRefGoogle Scholar
  59. 59.
    Yadav DK, Gautam AK, Kureel J, Srivastava K, Sahai M, Singh D, Chattopadhyay N, Maurya R (2011) Synthetic analogs of daidzein, having more potent osteoblast stimulating effect. Bioorg Med Chem Lett 21:677–681PubMedCrossRefGoogle Scholar
  60. 60.
    Pagano L, Teofili L, Mele L, Piantelli M, Ranelletti FO et al (1999) Oral ipriflavone (7-isopropoxy-isoflavone) treatment for elderly patients with resistant acute leukemias. Ann Oncol 10:124–125PubMedCrossRefGoogle Scholar
  61. 61.
    Petilli M, Fiorolli G, Benvenuti S, Frediani U, Gorif BMLIBI, estrogen r (1995) Calcif Tissue Int 56:160–165PubMedCrossRefGoogle Scholar
  62. 62.
    Kampkötter A, Chovolou A, Kulawik A, Röhrdanz E, Weber N, Proksch P, Wätjen W (2008) Isoflavone daidzein possesses no antioxidant activities in cell-free assays but induces the antioxidant enzyme catalase. Nutr Res 28:620–628PubMedCrossRefGoogle Scholar
  63. 63.
    Gredel S, Grad C, Rechkemmer G, Watzl B (2008) Phytoestrogens and phytoestrogen metabolites differentially modulate immune parameters in human leukocytes. Food Chem Toxicol 46:3691–3696PubMedCrossRefGoogle Scholar
  64. 64.
    Yum MK, Jung MY, Cho D, Kim TS (2011) Suppression of dendritic cells’ maturation and functions by daidzein, a phytoestrogen. Toxicol Appl Pharmacol 257:174–181PubMedCrossRefGoogle Scholar
  65. 65.
    Xu SZ, Zhong W, Ghavideldarestani M, Saurabh S, Lindow SW, Atkin SL (2009) Multiple mechanisms of soy isoflavones against oxidative stress-induced endothelium injury. Free Radic Biol Med 47:167–175PubMedCrossRefGoogle Scholar
  66. 66.
    Hsieh H, Wua W, Hu M (2009) Soy isoflavones attenuate oxidative stress and improve parameters related to aging and Alzheimer’s disease in C57BL/6J mice treated with D-galactose. Food Chem Toxicol 47:625–632PubMedCrossRefGoogle Scholar
  67. 67.
    Borradaile NM, Dedreu LE, Wilcox LJ (2002) Soya phytoestrogens, genistein and daidzein, decrease apolipoprotein B secretion from HepG2 cells through multiple mechanisms. Biochem J 366:531–539PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    He Y, Niu W, Xia C, Cao B (2016) Daidzein reduces the proliferation and adiposeness of 3T3-L1 preadipocytes via regulating adipogenic gene expression. J Funct Foods 22:446–453CrossRefGoogle Scholar
  69. 69.
    Song TT, Hendrich S, Murphy PA (1999) Estrogenic activity of glycitein, a soy isoflavone. J Agric Food Chem 47:1607–1610PubMedCrossRefGoogle Scholar
  70. 70.
    Gutierrez-Zepeda A, Santell R, Wu Z, Brown M, Wu Y, Khan I, Link CD, Zhao B, Luo Y (2005) Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans. BMC Neurosci 6:54PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Chen ZY, Ma KY, Liang Y, Peng C, Zuo Y (2011) Role and classification of cholesterol-lowing functional foods. J Funct Foods 3:61–69CrossRefGoogle Scholar
  72. 72.
    Lin CC, Chen TS, Lin YM, Yeh YL, Li YH, Kuo WW, Tsai FJ, Tsai CH, Yen SK, Huang CY (2013) The p38 and NFjB signaling protein activation involved in glycitein protective effects on isoproterenol-treated H9c2 cardiomyoblast cells. J Funct Foods 5:460–465CrossRefGoogle Scholar
  73. 73.
    Mu H, Bai YH, Wang ST, Zhu ZM, Zhang YW (2008) Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine 16:314–319PubMedCrossRefGoogle Scholar
  74. 74.
    Wu J, Li Q, Wu M, Guo D, Chen H, Chen S, Seto S, Alice LSA, Poon CCW, Leung GPH, Lee SMY, Kwan Y, Chan S (2010) Formononetin, an isoflavone, relaxes rat isolated aorta through endothelium-dependent and endothelium-independent pathways. J Nutr Biochem 21:613–620PubMedCrossRefGoogle Scholar
  75. 75.
    Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, Kuwahara Y, Ohkawara T, Hagihara K, Yamadori T, Shima Y, Ogata A, Kawase I, Tanaka T (2007) Flavonoids and related compounds as anti-allergic substances. Allergol Int 56:113–123PubMedCrossRefGoogle Scholar
  76. 76.
    Theoharides TC, Alexandrakis M, Kempuraj D, Lytinas M (2001) Anti-inflammatory actions of flavonoids and structural requirements for new design. Int J Immunopathol Pharmacol 14:119–127PubMedGoogle Scholar
  77. 77.
    Arao T, Udayama M, Kinjo J, Nohara T, Funakoshi T, Kojima S (1997) Preventive effects of saponins from Puerariae radix (the root of Pueraria lobata Ohwi) on in vitro immunological injury of rat primary hepatocyte cultures. Biol Pharm Bull 20:988–991PubMedCrossRefGoogle Scholar
  78. 78.
    Wolfe K, Wu X, Liu RH (2003) Antioxidant activity of apple peels. J Agric Food Chem 51:609–614PubMedCrossRefGoogle Scholar
  79. 79.
    Joshi KS, Rathos MJ, Joshi RD, Sivakumar M, Mascarenhas M, Kamble S, Lal B, Sharma S (2007) In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor. P276-00. Mol Cancer Ther 6:918–925PubMedCrossRefGoogle Scholar
  80. 80.
    Formica JV, Regelson W (1995) Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol 33:1061–1080PubMedCrossRefGoogle Scholar
  81. 81.
    Middleton E Jr, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation. Heart disease and cancer. Pharmacol Rev 52:673–751PubMedGoogle Scholar
  82. 82.
    Wang L, Tu YC, Lian TW, Hung JT, Yen JH, Wu MJ (2006) Distinctive antioxidant and antiinflammatory effects of flavonols. J Agric Food Chem 54:9798–9804PubMedCrossRefGoogle Scholar
  83. 83.
    Khan TH, Jahangir T, Prasad L et al (2006) Inhibitory effect of apigenin on benzo(a)pyrene mediated genotoxicity in Swiss albino mice. J Pharm Pharmacol 58:1650–1655Google Scholar
  84. 84.
    Siddique YH, Afzal M (2009) Antigenotoxic effect of apigenin against mitomycin C induced genotoxic damage in mice bone marrow cells. Food Chem Toxicol 47:536–539PubMedCrossRefGoogle Scholar
  85. 85.
    King JC, Lu Q, Li G, Moro A, Takahashi H, Chen M, Go VLW, Reber HA, Eibl G, Hines OJ (2012) Evidence for activation of mutated p53 by apigenin in human pancreatic cancer. Biochim Biophys Acta 1823:593–604PubMedCrossRefGoogle Scholar
  86. 86.
    Strouch MJ, Milam BM, Melstrom LG, McGill JJ, Salabat MR, Ujiki MB, Ding XZ, Bentrem DJ (2009) The flavonoid apigenin potentiates the growth inhibitory effects of gemcitabine and abrogates gemcitabine resistance in human pancreatic cancer cells. Pancreas 38:409–415PubMedCrossRefGoogle Scholar
  87. 87.
    Han JY, Ahn SY, Kim CS, Yoo SK, Kim SK et al (2012) Protection of apigenin against kainate-induced excitotoxicity by anti-oxidative effects. Biol Pharm Bull 35:1440–1446CrossRefGoogle Scholar
  88. 88.
    Jagan K, Priya CS, Kalpana K, Vidhya R, Anuradha CV (2017) Apigenin attenuates hippocampal oxidative events, inflammation and pathological alterations in rats fed high fat, fructose diet. Biomed Pharmacother 89:323–331CrossRefGoogle Scholar
  89. 89.
    Erdogan S, Turkekul K, Serttas R, Erdogan Z (2017) The natural flavonoid apigenin sensitizes human CD44+ prostate cancer stem cells to cisplatin therapy. Biomed Pharmacother 88:210–217PubMedCrossRefGoogle Scholar
  90. 90.
    Paoletti T, Fallarini S, Gugliesi F, Minassi A, Appendino G, Lombardi G (2009) Anti-inflammatory and vascular protective properties of 8-prenylapigenin. Eur J Pharmacol 620:120–130PubMedCrossRefGoogle Scholar
  91. 91.
    Milligan SR, Kalita JC, Heyerick A, Rong H, Cooman L, Keukeleire D (1999) Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab 83:2249–2252CrossRefGoogle Scholar
  92. 92.
    Milligan SR, Kalita JC, Pocock V, Van De Kauter V, Stevens JF, Deinzer ML, Rong H, De Keukeleire D (2000) The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) flavonoids. J Clin Endocrinol Metab 85:4912–4915PubMedCrossRefGoogle Scholar
  93. 93.
    Matsumura A, Ghosh A, Pope GS, Darbre PD (2005) Comparative study of oestrogenic properties of eight phytoestrogens in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol 94:431–443PubMedCrossRefGoogle Scholar
  94. 94.
    Brunelli E, Minassi A, Appendino G, Moro L (2007) 8-Prenylnaringenin, inhibits estrogen receptor-a mediated cell growth and induces apoptosis in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 107:140–148PubMedCrossRefGoogle Scholar
  95. 95.
    Brunelli E, Pinton G, Chianale F, Graziani A, Appendino G, Moro L (2009) 8-Prenylnaringenin inhibits epidermal growth factor-induced MCF-7 breast cancer cell proliferation by targeting phosphatidylinositol-3-OH kinase activity. J Steroid Biochem Mol Biol 113:163–170PubMedCrossRefGoogle Scholar
  96. 96.
    Helle J, Kräker K, Bader MI, Keiler AM, Zierau O, Vollmer G, Welsh JE, Kretzschmar G (2014) Assessment of the proliferative capacity of the flavanones 8-prenylnaringenin, 6-(1.1-dimethylallyl)naringenin and naringenin in MCF-7 cells and the rat mammary gland. Mol Cell Endocrinol 392:125–135PubMedCrossRefGoogle Scholar
  97. 97.
    Vito CD, Bertoni A, Nalin M, Sampietro S, Zanfa M, Sinigaglia F (2012) The phytoestrogen 8-prenylnaringenin inhibits agonist-dependent activation of human platelets. Biochimica et Biophysica Acta (BBA) 1820:1724–1733CrossRefGoogle Scholar
  98. 98.
    Wang J, Fang F, Huang Z, Wang Y, Wong C (2009) Kaempferol is an estrogen-related receptor a and c inverse agonist. FEBS Lett 583:643–647PubMedCrossRefGoogle Scholar
  99. 99.
    Strauss L, Santti R, Saarinen N, Streng T, Joshi S, Mäkelä S (1998) Dietary phytoestrogens and their role in hormonally dependent disease. Toxicol Lett 102–103:349–354PubMedCrossRefGoogle Scholar
  100. 100.
    Sahu SC, Gray GC (1994) Kaempferol-induced nuclear DNA damage and lipid peroxidation. Cancer Lett 85:159–164PubMedCrossRefGoogle Scholar
  101. 101.
    Zhang Y, Chen AY, Li M, Chen C, Yao Q (2008) Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. J Surg Res 148:17–23PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Kim S-H, Choi K-C (2013) Anti-cancer effect and underlying mechanism(s) of kaempferol, a phytoestrogen, on the regulation of apoptosis in diverse cancer cell models. Toxicol Res 29:229–234PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Kashafi E, Moradzadeh M, Mohamadkhani A, Erfaniand S (2017) Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/AKT and telomerase pathways. Biomed Pharmacother 89:573–577PubMedCrossRefGoogle Scholar
  104. 104.
    Zhang R, Ai X, Duan Y, Xue M, He W, Wang C, Xu T, Xu M, Liu B, Li C, Wang Z, Zhang R, Wang G, Tian S, Liu H (2017) Kaempferol ameliorates H9N2 swine influenza virus-induced acute lung injury by inactivation of TLR4/MyD88-mediated NF-kB and MAPK signaling pathways. Biomed Pharmacother 89:660–672PubMedCrossRefGoogle Scholar
  105. 105.
    Wu J, Du J, Xu C, Le J, Liu B, Xu Y et al (2010) In vivo and in vitro anti-inflammatory effects of a novel derivative of icariin. Immunopharmacol Immunotoxicol 33:49–54PubMedCrossRefGoogle Scholar
  106. 106.
    Meng FH, Li YB, Xiong ZL, Jiang ZM, Li FM (2005) Osteoblastic proliferative activity of Epimedium brevicornum Maxim. Phytomedicine 12:189–193PubMedCrossRefGoogle Scholar
  107. 107.
    Sakai S, Tamura M, Mishima H, Kojima H, Uemura T (2008) Bone regeneration induced by adenoviral vectors carrying til-1/Cbfa1 genes implanted with biodegradable porous materials in animal models of osteonecrosis of the femoral head. J Tissue Eng Regen Med 2:164–167PubMedCrossRefGoogle Scholar
  108. 108.
    Hsieh T, Sheu S, Sun J, Chen M, Liu M (2010) Icariin isolated from Epimedium pubescens regulates osteoblasts anabolism through BMP-2, SMAD4, and Cbfa1 expression. Phytomedicine 17:414–423PubMedCrossRefGoogle Scholar
  109. 109.
    Qian ZQ, Wang YW, Li YL, Li YQ, Zhu L, Yanga DL (2017) Icariin prevents hypertension-induced cardiomyocyte apoptosis through the mitochondrial apoptotic pathway. Biomed Pharmacother 88:823–831PubMedCrossRefGoogle Scholar
  110. 110.
    Algandaby MM, Breikaa RM, Eid BG, Neamatallah TA, Abdel-Naim AB, Ashour OM (2017) Icariin protects against Thioacetamide-induced liver fibrosis in rats: implication of anti-angiogenic and anti-autophagic properties. Pharmacol Rep.  https://doi.org/10.1016/j.pharep.2017.02.016 PubMedCrossRefGoogle Scholar
  111. 111.
    Xiong D, Deng Y, Huang B, Yin C, Liu B, Shi J et al (2016) Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-κB, PPARα and PPARγ in rats. Int Immunopharmacol 30:157–162PubMedCrossRefGoogle Scholar
  112. 112.
    Wu JW, Lin LC, Tsai TH (2009) Drug–drug interactions of silymarin on the perspective of pharmacokinetics. J Ethnopharmacol 121:185–193PubMedCrossRefGoogle Scholar
  113. 113.
    Wellington K, Jarvis B (2001) Silymarin: a review of its clinical properties in the management of hepatic disorders. BioDrugs 15:465–489PubMedCrossRefGoogle Scholar
  114. 114.
    Sonnenbichler J, Zetl I, Cody V, Middleton E, Karbone JB, Berck A (eds) (1988) Specific binding of a flavonolignane derivative to an estradiol receptor. Prog Clin Biol Res 280:369–374Google Scholar
  115. 115.
    El-Shitany NA, Hegazy S, El-desoky K (2010) Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats. Phytomedicine 17:116–125PubMedCrossRefGoogle Scholar
  116. 116.
    Gharagozloo M, Velardi E, Bruscoli E, Agostini M, Di Sante M, Donato V, Amirghofran Z, Riccard C (2010) Silymarin suppress CD4+ T cell activation and proliferation: effects on NF-κB activity and IL-2 production. Pharmacol Res 61:405–409PubMedCrossRefGoogle Scholar
  117. 117.
    Wu T, Liu W, Guo W, Zhu X (2016) Silymarin suppressed lung cancer growth in mice via inhibiting myeloid-derived suppressor cells. Biomed Pharmacother 81:460–467PubMedCrossRefGoogle Scholar
  118. 118.
    Song JH, Choi HJ (2011) Silymarin efficacy against influenza A virus replication. Phytomedicine 18:832–835PubMedCrossRefGoogle Scholar
  119. 119.
    Srivastava S, Sammi SR, Laxman TS, Pant A, Nagar A, Trivedi S, Bhatta RS, Tandon S, Pandey R (2017) Silymarin promotes longevity and alleviates Parkinson’s associated pathologies in Caenorhabditis elegans. J Funct Foods 31:32–43CrossRefGoogle Scholar
  120. 120.
    Yun DG, Lee DG (2017) Silymarin exerts antifungal effects via membrane-targeted mode of action by increasing permeability and inducing oxidative stress. Biochim Biophys Acta 1859:467–474CrossRefGoogle Scholar
  121. 121.
    Kimata M, Inagaki N, Nagai H (2000) Effects of luteolin and other flavonoids on IgE-mediated allergic reactions. Planta Med 66:25–29PubMedCrossRefGoogle Scholar
  122. 122.
    Hong T, Jin GB, Cho S, Cyong JC (2002) Evaluation of the anti-inflammatory effect of baicalein on dextran sulfate sodium-induced colitis in mice. Planta Med 68:268–271PubMedCrossRefGoogle Scholar
  123. 123.
    Piao YS, Du YC, Oshima H, Jin JC, Nomura M, Yoshimoto T, Oshima M (2008) Platelet-type 12-lipoxygenase accelerates tumor promotion of mouse epidermal cells through enhancement of cloning efficiency. Carcinogenesis 29:440–447PubMedCrossRefGoogle Scholar
  124. 124.
    Kuntz S, Wenzel U, Daniel H (1999) Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines. Eur J Nutr 38:133–142PubMedCrossRefGoogle Scholar
  125. 125.
    Tong WG, Ding XZ, Adrian TE (2002a) The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. Biochem Biophys Res Commun 296:942–948PubMedCrossRefGoogle Scholar
  126. 126.
    Tong WG, Ding XZ, Witt RC, Adrian TE (2002b) Lipoxygenase inhibitors attenuate growth of human pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. Mol Cancer Ther 1:929–935PubMedGoogle Scholar
  127. 127.
    Chung H, Choi HS, Seo EK, Kang DK, Oh ES (2015) Baicalin and baicalein inhibit transforming growth factor-b1-mediated epithelial-mesenchymal transition in human breast epithelial cells. Biochem Biophys Res Commun 458:707–713PubMedCrossRefGoogle Scholar
  128. 128.
    Chen C, Huang T, Wong C, Hong C, Tsai Y, Liang C, Lu F, Chang W (2009) Synergistic anti-cancer effect of baicalein and silymarin on human hepatoma HepG2 Cells. Food Chem Toxicol 47:638–644PubMedCrossRefGoogle Scholar
  129. 129.
    Zhu M, Rajamani S, Kaylor J, Han S, Zhou F, Fink AL (2004) The flavonoid Baicalein inhibits fibrillation of Synuclein and disaggregates existing fibrils. J Biol Chem 279:26846–26857PubMedCrossRefGoogle Scholar
  130. 130.
    Kang TH, Hong BN, Park C, Kim SY, Park R (2010) Effect of baicalein from Scutellaria baicalensis on prevention of noise-induced hearing loss. Neurosci Lett 469:298–302PubMedCrossRefGoogle Scholar
  131. 131.
    Setchell KD, Brown NM, Lydeking-Olsen E (2002) The clinical importance of the metabolite equol—a clue to the effectiveness of soy and its isoflavones. J Nutr 132:3577PubMedCrossRefGoogle Scholar
  132. 132.
    Muthyala RS, Ju YH, Sheng S, Williams LD, Doerge DR, Katzenellenbogen BS, Helferich WG, Katzenellenbogen JA (2004) Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg. Med Chem 12:1559–1567CrossRefGoogle Scholar
  133. 133.
    Choi EJ, Ahn WS, Bae SM (2009) Equol induces apoptosis through cytochrome c-mediated caspases cascade in human breast cancer MDA-MB-453 cells. Chem Biol Interact 177:7–11PubMedCrossRefGoogle Scholar
  134. 134.
    Jackman A, Woodman OL, Chrissobolis S, Sobey CG (2007) Vasorelaxant and antioxidant activity of the isoflavone metabolite equol in carotid and cerebral arteries. Brain Res 1141:99–107PubMedCrossRefGoogle Scholar
  135. 135.
    Chung J, Kim SY, Jo HH, Hwang SJ, Chae B, Kwon DJ, Lew YO, Lim Y, Kim JH, Kim EJ, Kim J, Kim M (2008) Antioxidant effects of equol on bovine aortic endothelial cells. Biochem Biophys Res Commun 375:420–424PubMedCrossRefGoogle Scholar
  136. 136.
    Setchell KD, Lydeking-Olsen E (2003) Dietary phytoestrogens and their effect on bone: evidence from in vitro and in vivo, human observational, and dietary intervention studies. Am J Clin Nutr 78:593S–609SPubMedCrossRefGoogle Scholar
  137. 137.
    Lampe JW (2009) Is equol the key to the efficacy of soy foods? Am J Clin Nutr 89:1664S–1667SPubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Davinelli S, Scapagnini G, Marzatico F, Nobile V, Ferrara N, Corbi G (2017) Influence of equol and resveratrol supplementation on health-related quality of life in menopausal women: a randomized, placebo-controlled study. Maturitas 96:77–83PubMedCrossRefGoogle Scholar
  139. 139.
    Knekt P, Jarvinen R, Seppanen R, Hellovaara M, Teppo L, Pukkala E, Aroma A (1997) Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am J Epidemiol 146:223–230PubMedCrossRefGoogle Scholar
  140. 140.
    Geleijnse JM, Launer LJ, Van der Kuip DA, Hofman A, Witteman JC (2002) Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study. Am J Clin Nutr 75:880–886PubMedCrossRefGoogle Scholar
  141. 141.
    Rice-Evans CA, Miller NJ, Paganga G (1996) Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956PubMedCrossRefGoogle Scholar
  142. 142.
    Agullo G, Gamet-Payrastre L, Fernandez Y, Anciaux N, Demigne C, Remesy C (1996) Comparative effects of flavonoids on the growth, viability and metabolism of a colonic adenocarcinoma cell line (HT29 cells). Cancer Lett 105:61–70PubMedCrossRefGoogle Scholar
  143. 143.
    Russo M, Palumbo R, Tedesco I, Mazzarella G, Russo P, Iacomino G, Russo GL (1999) Quercetin and anti-CD95(Fas/ Apo1) enhance apoptosis in HPB-ALL cell line. FEBS Lett 462:322–328PubMedCrossRefGoogle Scholar
  144. 144.
    Sotocaa AM, Ratman D, Saag PV, Ström A, Gustafsson JA, Vervoort J, Rietjens IMCM, Murk AJ (2008) Phytoestrogen-mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ER_/ER_ ratio. J Steroid Biochem Mol Biol 112:171–178CrossRefGoogle Scholar
  145. 145.
    Bernad FX, Sable S, Cameron B (1997) glycosylated flavones as selective inhibitors of topoisomerases IV. Antimicrob Agents Chemother 41:992–998CrossRefGoogle Scholar
  146. 146.
    Kim MK, Choo H, Chong Y (2014) Water-soluble and cleavable Quercetin−amino acid conjugates as safe modulators for P-glycoprotein-based multidrug resistance. J Med Chem 57:7216−7233Google Scholar
  147. 147.
    Haleagrahara N, Miranda-Hernandez S, Alim MA, Hayesa L, Bird G, Ketheesan N (2017) Therapeutic effect of quercetin in collagen-induced arthritis. Biomed Pharmacother 90:38–46PubMedCrossRefGoogle Scholar
  148. 148.
    Whitten PL, Naftolin F (1998) Reproductive actions of phytoestrogens. Bailliere Clin Endocrinol Metab 12:667–690CrossRefGoogle Scholar
  149. 149.
    Saarinen NM, Penttinen PE, Smeds AI, Hurmerinta TT, Makela SI (2005) Structural determinants of plant lignans for growth of mammary tumors and hormonal responses in vivo. J Steroid Biochem Mol Biol 93:209–219PubMedCrossRefGoogle Scholar
  150. 150.
    Zafar A, Singh S, Naseem I (2016) Cytotoxic activity of soy phytoestrogen coumestrol against human breast cancer MCF-7 cells: insights into the molecular mechanism. Food Chem Toxicol.  https://doi.org/10.1016/j.fct.2016.11.034 PubMedCrossRefGoogle Scholar
  151. 151.
    Lim W, Jeong M, Bazer FW, Song G (2017) Coumestrol inhibits proliferation and migration of prostate cancer cells by regulating AKT, ERK1/2, and JNK MAPK cell signaling cascades. J Cell Physiol 232(4):862–871PubMedCrossRefGoogle Scholar
  152. 152.
    Tsutsumi N (1995) Effect of coumestrol on bone metabolism in organ culture. Biol Pharm Bull 18:1012–1015PubMedCrossRefGoogle Scholar
  153. 153.
    Wang H, Li H, Moore LB, Johnson MDL, Maglich JM, Goodwin B, Ittoop ORR, Wisely B, Creech K, Parks DJ, Collins JL, Willson TM, Kalpana GV, Venkatesh M, Xie W, Cho SY, Roboz J, Redinbo M, Moore JT, Mani S (2008) The phytoestrogen coumestrol is a naturally occurring antagonist of the human Pregnane X receptor. Mol Endocrinol 22:838–857PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Zhai Y, Li Y, Wang Y, Cui J, Feng K, Kong X, Chen L (2017) Psoralidin, a prenylated coumestan, as a novel anti-osteoporosis candidate to enhance bone formation of osteoblasts and decrease bone resorption of osteoclasts. Eur J Pharmacol Apr 15(801):62–71CrossRefGoogle Scholar
  155. 155.
    Hong Y, Cho M, Yuan Y, Chen S (2008) Molecular basis for the interaction of four different classes of substrates and inhibitors with human aromatase. Biochem Pharmacol 75:1161–1169PubMedCrossRefGoogle Scholar
  156. 156.
    Whitten PL, Patisaul HB, Younga LJ (2002) Neurobehavioral actions of coumestrol and related isoflavonoids in rodents. Neurotoxicol Teratol 24:47–54PubMedCrossRefGoogle Scholar
  157. 157.
    Canal Castro C, Pagnussat AS, Orlandi L, Worm P, Moura N, Etgen AM, Alexandre Netto C (2012) Coumestrol has neuroprotective effects before and after global cerebral ischemia in female rats. Brain Res 1474:82–90PubMedCrossRefGoogle Scholar
  158. 158.
    Dai Q, Franke AA, Jin F, Shu XO, Hebert JR et al (2002) Urinary excretion of phytoestrogens and risk of breast cancer among Chinese women in Shanghai. Cancer Epidemiol Biomark Prev 11:815–821Google Scholar
  159. 159.
    De Kleijn MJJ, Van der Schouw YT, Wilson PWF, Grobbee DE, Jacques PF (2002) Dietary intake of phytoestrogens is associated with a favorable metabolic cardiovascular risk profile in postmenopausal U.S. women: the Framingham study. J Nutr 132:276–282PubMedCrossRefGoogle Scholar
  160. 160.
    Aehle E, Müller U, Eklund PC, Willför SM, Sippl W, Dräger B (2011) Lignans as food constituents with estrogen and antiestrogen activity. Phytochemistry 72:2396–2405PubMedCrossRefGoogle Scholar
  161. 161.
    Adlercreutz H, Höckerstedt K, Bannwart C, Bloigu S, Hämäläinen E, Fotsis T, Ollus A (1987) Effect of dietary components, including lignans and phytoestrogens, on enterohepatic circulation and liver metabolism of estrogens and on sex hormone binding globulin (SHBG). Journal of Steroid Biochemistry 27:1135–1144PubMedCrossRefGoogle Scholar
  162. 162.
    Prasad K (2000) Antioxidant activity of secoisolariciresinol diglucoside- derived metabolites secoisolariciresinol. Enterodiol, and enterolactone. Int J Angiol 9:220–225PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Boccardo F, Lunardi G, Guglielmini P, Parodi M, Murialdo R, Schettini G, Rubagotti A (2004) Serum enterolactone levels and the risk of breast cancer in women with palpable cysts. Eur J Cancer 40:84–89PubMedCrossRefGoogle Scholar
  164. 164.
    Mousavi Y, Adlercreutz H (1992) Enterolactone and estradiol inhibit each other’s proliferative effect on MCF-7 breast cancer cells in culture. J Steroid Biochem Mol Biol 41:615–619PubMedCrossRefGoogle Scholar
  165. 165.
    Figueiredo MS, Maia LA, Guarda DS, Lisboa PC, Moura EG (2017) Flaxseed secoisolariciresinol diglucoside (SDG) during lactation improves bone metabolism in offspring at adulthood. J Funct Foods 29:161–171CrossRefGoogle Scholar
  166. 166.
    Ma X, Wang R, Zhao X, Zhang C, Sun J, Li J, Zhang L, Shao T, Ruan L, Chen L, Xu Y, Pan J (2013) Antidepressant-like effect of flaxseed secoisolariciresinol diglycoside in ovariectomized mice subjected to unpredictable chronic stress. Metab Brain Dis 28:77–84PubMedCrossRefGoogle Scholar
  167. 167.
    Hu P, Mei QY, Ma L, Cui WG, Zhou WH, Zhou DS, Zhao Q, Xu DY, Zhao X, Lu Q, Hu ZY (2015) Secoisolariciresinol diglycoside, a flaxseed lignan, exerts analgesic effects in a mouse model of type 1 diabetes: engagement of antioxidant mechanism. Eur J Pharmacol 767(15):183–192PubMedCrossRefGoogle Scholar
  168. 168.
    Stewart JR, Christman KL, O’Brian CA (2000) Effects of resveratrol on the autophosphorylation of phorbol ester-responsive protein kinases: inhibition of protein kinase D but not protein kinase C isozyme autophosphorylation. Biochem Pharmacol 60:1355–1359PubMedCrossRefGoogle Scholar
  169. 169.
    Bhat KPL, Lantvit D, Christov K, Mehta RC, Pezzuto JM (2001) Estrogenic and antiestrogenic properties of resveratrol in mammary tumour models. Cancer Res 61:7456–7463PubMedGoogle Scholar
  170. 170.
    Stojanovic S, Sprinz H, Brede O (2001) Efficiency and mechanism of the antioxidant action of trans-resveratrol and its analogues in the radical liposome oxidation. Arch Biochem Biophys 391:79–89PubMedCrossRefGoogle Scholar
  171. 171.
    Fontecave M, Lepoivre M, Elleingand E, Gerez C, Guittet O (1998) Resveratrol: a remarkable inhibitor of ribonucleotide reductase. FEBS Lett 421:277–279PubMedCrossRefGoogle Scholar
  172. 172.
    Locatelli GA, Savio M, Forti L, Shevelev I, Ramadan K, Stivala LA, Vannini V, Hubscher U, Spadari S, Maga G (2005) Inhibition of mammalian DNA polymerases by resveratrol: mechanism and structural determinants. Biochem J 389:259–268PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Bhat KPL, Lantvit D, Christov K, Mehta RC, Pezzuto JM (2001) Estrogenic and antiestrogenic properties of resveratrol in mammary tumour models. Cancer Res 61:7456–7463PubMedGoogle Scholar
  174. 174.
    Sakamoto T, Horiguchi H, Oguma E, Kayama F (2010) Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. J Nutr Biochem 21(9):856–864PubMedCrossRefGoogle Scholar
  175. 175.
    Wesierska-Gadek J, Kramer MP, Maurer M (2008) Resveratrol modulates roscovitine-mediated cell cycle arrest of human MCF-7 breast cancer cells. Food Chem Toxicol 46:1327–1333PubMedCrossRefGoogle Scholar
  176. 176.
    Zhu Y, Fu J, Shurlknight KL, Soroka DN, Hu Y, Chen X, Sang S (2015) Novel resveratrol-based aspirin prodrugs: synthesis, metabolism, and anticancer activity. J Med Chem 58(16):6494–6506PubMedCrossRefGoogle Scholar
  177. 177.
    Du C, Dong MH, Ren YJ, Jin L, Xu C (2016) Design, synthesis and antibreast cancer MCF-7 cells biological evaluation of heterocyclic analogs of resveratrol. J Asian Nat Prod Res 3:1–13Google Scholar
  178. 178.
    Alamolhodaei NS, Tsatsakis AM, Ramezani M, Hayes AW, Karimi G (2017) Resveratrol as MDR reversion molecule in breast cancer: an overview. Food Chem Toxicol 103:223–232PubMedCrossRefGoogle Scholar
  179. 179.
    Anekonda TS, Reddy PH (2006) Neuronal protection by sirtuins in Alzheimer’s disease. J Neurochem 96:305–313PubMedCrossRefGoogle Scholar
  180. 180.
    Karlsson J, Emgard M, Brundin P, Burkitt MJ (2000) trans-resveratrol protects embryonic mesencephalic cells from tert-butyl hydroperoxide: electron paramagnetic resonance spin trapping evidence for a radical scavenging mechanism. J Neurochem 75:141–150PubMedCrossRefGoogle Scholar
  181. 181.
    ClinicalTrials.gov Identifier: NCT01504854 Phase II Study to Evaluate the Impact on Biomarkers of Resveratrol Treatment in Patients With Mild to Moderate Alzheimer’s Disease April 2016Google Scholar
  182. 182.
    Wallerath T, Deckert G, Ternes T, Anderson H, Li H et al (2002) Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106:1652–1658PubMedCrossRefGoogle Scholar
  183. 183.
    Das S, Das DK (2007) Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Targets 6:168–173PubMedCrossRefGoogle Scholar
  184. 184.
    Stagos D, Portesis N, Spanou C, Mossialos D, Aligiannis N, Chaita E, Panagoulis C, Reri E, Skaltsounis L, Tsatsakis AM (2012b) Correlation of total polyphenolic content with antioxidant and antibacterial activity of 24 extracts from greek domestic Lamiaceae species. Food Chem Toxicol 50:4115–4124PubMedCrossRefGoogle Scholar
  185. 185.
    Mizutani K, Keda K, Kawai Y, Yamori Y (2001) Protective effect of resveratrol on oxidative damage in male and female stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 28:55–59PubMedCrossRefGoogle Scholar
  186. 186.
    Szkudelska K, Nogowski L, Szkudelski T (2009) Resveratrol, a naturally occurring diphenolic compound, affects lipogenesis, lipolysis and the antilipolytic action of insulin in isolated rat adipocytes. J Steroid Biochem Mol Biol 113:17–24PubMedCrossRefGoogle Scholar
  187. 187.
    Sanchez-Fidalgo S, Cardeno A, Villegas I, Talero E, Alarcon de la Lastra C (2010) Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice. Eur J Pharmacol 633:78–84PubMedCrossRefGoogle Scholar
  188. 188.
    De Vincenzo R, Scambia G, Panici PB, Ranelletti FO, Bonanno G, Ercoli A, Delle MF, Ferrari F, Piantelli M, Mancuso S (1995) Effect of synthetic and naturally occurring chalcones on ovarian cancer cell growth: structure–activity relationships. Anticancer Drug Des 10:481–490PubMedGoogle Scholar
  189. 189.
    Tamir S, Eizemberg M, Somjen D, Izrael S, Vaya J (2001) Estrogen-like activity of glabrene and other constituents isolated from licorice root. J Steroid Biochem Mol Biol 78:291–298PubMedCrossRefGoogle Scholar
  190. 190.
    Haraguchi H, Ishikawa H, Mizutani K, Tamura Y, Kinoshita T (1998) Antioxidative and superoxide scavenging activities of retrochalcones in Glycyrrhiza inflata. Bioorg Med Chem 6:339–347PubMedCrossRefGoogle Scholar
  191. 191.
    Tawata M, Aida K, Noguchi T, Ozaki Y, Kume S, Sasaki H, Chin M, Onaya T (1992) Anti-platelet action of isoliquiritigenin, an aldose reductase inhibitor in licorice. Eur J Pharmacol 212:87–92PubMedCrossRefGoogle Scholar
  192. 192.
    Chowdhury SA, Kishino K, Satoh R, Hashimoto K, Kikuchi H, Nishikawa H, Shirataki Y, Sakagami H (2005) Tumor-specificity and apoptosis-inducing activity of stilbenes and flavonoids. Anticancer Res 25:2055–2063PubMedGoogle Scholar
  193. 193.
    Takahashi T, Takasuka N, Iigo M, Baba M, Nishino H, Tsuda H, Okuyama T (2004) Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development. Cancer Sci 95:448–453PubMedCrossRefGoogle Scholar
  194. 194.
    Jung JI, Chung E, Seon MR, Shin HK, Kim EJ, Lim SS, Chung WY, Park KK, Park JH (2006) Isoliquiritigenin (ISL) inhibits ErbB3 signaling in prostate cancer cells. Biofactors 28:159–168PubMedCrossRefGoogle Scholar
  195. 195.
    Hsu YL, Kuo PL, Lin LT, Lin CC (2005) Isoliquiritigenin inhibits cell proliferation and induces apoptosis in human hepatoma cells. Planta Med 71:130–134PubMedCrossRefGoogle Scholar
  196. 196.
    Maggiolini M, Statti G, Vivacqua A, Gabriele S, Rago V, Loizzo M, Menichini F, Amdoc S (2002) Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. J Steroid Biochem Mol Biol 82:315–322PubMedCrossRefGoogle Scholar
  197. 197.
    Kanga S, Choi J, Choi Y, Bae J, Li J, Kim DS, Kim J, Shin S, Lee Y, Kwun I, Kang Y (2010) Licorice isoliquiritigenin dampens angiogenic activity via inhibition of MAPK-responsive signaling pathways leading to induction of matrix metalloproteinases. J Nutr Biochem 21:55–65CrossRefGoogle Scholar
  198. 198.
    Li D, Wang Z, Chen H, Wang J, Zheng Q, Shang J, Li J (2009) Isoliquiritigenin induces monocytic differentiation of HL-60 cells. Free Radic Biol Med 46:731–736PubMedCrossRefGoogle Scholar
  199. 199.
    Zhan C, Yang J (2006) Protective effects of isoliquiritigenin in transient middle cerebral artery occlusion-induced focal cerebral ischemia in rats. Pharmacol Res 53:303–309PubMedCrossRefGoogle Scholar
  200. 200.
    Chi JH, Seo GS, Cheon JH, Lee SH (2017) Isoliquiritigenin inhibits TNF-α-induced release of high-mobility group box 1 through activation of HDAC in human intestinal epithelial HT-29 cells. Eur J Pharmacol 796:101–109PubMedCrossRefGoogle Scholar
  201. 201.
    Liu S, Zhu L, Zhang J, Yu J, Cheng X, Peng B (2016) Anti-osteoclastogenic activity of isoliquiritigenin via inhibition of NF-κB-dependent autophagic pathway. Biochem Pharmacol 106:82–93PubMedCrossRefGoogle Scholar
  202. 202.
    Tsukiyama R, Katsura H, Tokuriki N, Kobayashi M (2002) Antibacterial activity of licochalcone A against spore-forming bacteria. Antimicrob Agents Chemother 46:1226–1230PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Chen M, Christensen SB, Blom J, Lemmich E, Nadelmann L, Fich K et al (1993) Licochalcone A, a novel antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania. Antimicrob Agents Chemother 37:2550–2556PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Iwata S, Nishino T, Nagata N, Satomi Y, Nishino H, Shibata S (1995) Antitumorigenic activities of chalcones I. Inhibitory effects of chalcone derivatives on 32P-Incorporation into phospholipids of Hela cells promoted by 12-O- tetradecanoyl-phorbol 13-acetate (TPA). Biol Pharm Bull 18:1710–1713PubMedCrossRefGoogle Scholar
  205. 205.
    Chen X, Liu Z, Meng R, Shi C, Guo N (2017) Antioxidative and anticancer properties of Licochalcone A from licorice. J Ethnopharmacol 198:331–337PubMedCrossRefGoogle Scholar
  206. 206.
    Rafi MM, Rosen RT, Vassil A, Ho CT, Zhang H, Ghai G, Lambert G, Di Paola RS (2000) Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res 20:2653–2658PubMedGoogle Scholar
  207. 207.
    Rafi M, Vastano BC, Zhu N, Ho CT, Ghai G, Rosen RT, Gallo MA, DiPaola RS (2002) Novel polyphenol molecule isolated from licorice root (Glycyrrhiza glabra) induces apoptosis, G2/M cell cycle arrest, and Bcl-2 phosphorylation in tumor cell lines. J Agric Food Chem 50:677–684PubMedCrossRefGoogle Scholar
  208. 208.
    Fu Y, Hsieha T, Guo J, Kunicki J, Lee MYWT, Darzynkiewicz Z, Wu JM (2004) Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells. Biochem Biophys Res Commun 322:263–270PubMedCrossRefGoogle Scholar
  209. 209.
    Xiao X, Hao M, Yang X, Ba Q, Li M, Ni S, Wang L, Du X (2011) Licochalcone A inhibits growth of gastric cancer cells by arresting cell cycle progression and inducing apoptosis. Cancer Lett 302:69–75PubMedCrossRefGoogle Scholar
  210. 210.
    Won S, Kim S, Kim Y, Lee P, Ryu J, Kim J, Rhee H (2007) Licochalcone A: a lipase inhibitor from the roots of Glycyrrhiza uralensis. Food Res Int 40:1046–1050CrossRefGoogle Scholar
  211. 211.
    Shang F, Ming L, Zhou Z, Yu Y, Sun J, Ding Y, Jin Y (2014) The effect of licochalcone A on cell-aggregates ECM secretion and osteogenic differentiation during bone formation in metaphyseal defects in ovariectomized rats. Biomaterials 35:2789–2797PubMedCrossRefGoogle Scholar
  212. 212.
    Oliveira PJ, Carvalho RA, Portincasa P, Bonfrate L, Sardao VA Fatty acid oxidation and cardiovascular risk during menopause: a mitochondrial connection? J Lipids 2012, 2012:365798CrossRefGoogle Scholar
  213. 213.
    Jenkins DJ, Mirrahimi A, Srichaikul K et al (2010) Soy protein reduces serum cholesterol by both intrinsic and food displacement mechanisms. J Nutr 140(12):2302S–2311SPubMedCrossRefGoogle Scholar
  214. 214.
    Rigallia JP, Tocchettib GN, Aranab MR, Villanueva SSM, Catania VA, Theile D, Ruiz ML, Weiss J (2016) The phytoestrogen genistein enhances multidrug resistance in breast cancer cell lines by translational regulation of ABC transporters. Cancer Lett 376-1:165–172CrossRefGoogle Scholar
  215. 215.
    Henderson BE, Bernstein L (1991) The international variation in breast cancer rates: an epidemiological assessment. Breast Cancer Res Treat 18(1): S11–S117PubMedCrossRefGoogle Scholar
  216. 216.
    Soni M, White LR, Kridawati A, Bandelow S, Hogervorst E (2016) Phytoestrogen consumption and risk for cognitive decline and dementia: with consideration of thyroid status and other possible mediators. J Steroid Biochem Mol Biol 160:67–77PubMedCrossRefGoogle Scholar
  217. 217.
    Gopaul R, Knaggs HE, Lephart ED (2012) Biochemical investigation and gene analysis of equol: a plant and soy-derived isoflavonoid with antiaging and antioxidant properties with potential human skin applications. Biofactors 38:44–52PubMedCrossRefGoogle Scholar
  218. 218.
    Crain DA, Janssen SJ, Edwards TM, Heindel J, Ho SM, Hunt P, Iguchi T, Juul A, McLachlan JA, Schwartz J, Skakkebaek N, Soto AM, Swan S, Walker C, Woodruff TK, Woodruff TJ, Giudice LC, Guillette LJ Jr (2008) Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril 90:911–940PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    This P, Cremoux PD, Leclercq G, Jacquot Y (2011) A critical view of the effects of phytoestrogens on hot flashes and breast cancer risk. Maturitas 70:222–226PubMedCrossRefGoogle Scholar
  220. 220.
    Glazier MG, Bowman MA (2001) A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy. Arch Intern Med 161:1161–1172PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Atiya Fatima
    • 1
  • Asrar Alam
    • 2
  • Ram Singh
    • 1
  1. 1.Department of Applied ChemistryDelhi Technological UniversityNew DelhiIndia
  2. 2.Laboratory of Vaccinology and Applied ImmunologyKanazawa University School of PharmacyKanazawaJapan

Personalised recommendations