Genistein modulates the estrogen receptor and suppresses angiogenesis and inflammation in the murine model of peritoneal endometriosis

10.1016/j.jtcme.2017.03.002

Sutrisno Sutrisno；Hardianti Aprina；Happy Marthalena Simanungkalit；Asti Andriyani；Wisnu Barlianto；Hidayat Sujuti；Sanarto Santoso；Pande Made Dwijayasa；Endang Sri Wahyuni；Edy Mustofa

Estrogen receptor ； Growth factor ； Inflammation ； Angiogenesis ； Peritoneum

Journal of Traditional and Complementary Medicine

8卷2期（2018 / 04 / 01）

278 - 281

英文

The purpose of this study was to investigate the effect of genistein administration on the modulation of the estrogen receptor, inhibition of inflammation and angiogenesis in the murine model of peritoneal endometriosis. A total of thirty-six mice (Mus musculus) were divided into six groups (n = 6), including the control group, endometriosis group, endometriosis group treated with various doses of genistein (0.78; 1.04; 1.3 mg/day), and endometriosis group treated with leuprolide acetate (0.00975 mg/day every 5 days for 15 days). Analysis of estrogen receptor-α, estrogen receptor-β, TNF-α, IL-6, VEGF, and HIF-1α were performed immunohistochemically. Expression of estrogen receptor-α, estrogen receptor-β, TNF-α, IL-6, VEGF and HIF-1α increased significantly compared with the control group (p ＜ 0.05). All doses of genistein decreased the expression of estrogen receptor-α, increased estrogen receptor-β, lowered VEGF and HIF-1α significantly compared with endometriosis group (p ＞ 0.05). Genistein also decreased the expression of TNF-α and IL-6 (1.04 and 1.3 mg/day) compared with the endometriosis group, reaching level comparable to that of the control group (p ＞ 0.05). It was concluded that genistein is able to modulate estrogen receptor-α and estrogen receptor-b and inhibit the development of inflammation and angiogenesis in the murine model of peritoneal endometriosis. Thus, genistein can be a candidate in the treatment of endometriosis.

1. Akiyama, T,Ishida, J,Nakagawa, S(1987).Genisteinspecific inhibitor of tyrosine-specific protein kinases.J Biol Chem,262,5592-5595.
2. Aref, S,El Sherbiny, M,Goda, T(2005).Soluble VEGF/sFLt1 ratio is an independent predictor of AML patient out come.Hematology,10,131-134.
3. Asahara, T,Takahashi, T,Masuda, H(1999).VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells.EMBO J.,18,3964-3972.
4. Badawy, SZ,Cuensa, V,Stitzel, A,Jacobs, RB,Tomar, RH(1984).Autoimmune phenomena in infertile patients with endometriosis.Obstet Gynecol,63,271-275.
5. Barnes, S,Peterson, TG,Coward, L(1995).Rationale for the use genistein-containing soy matrics in chemoprevention trials for breast and prostate cancer.J Cell Biocherm,59(22),181-187.
6. Bayoglu Tekin, Y,Guven, S,Kirbas, A,Kalkan, Y,Tumkaya, L,Guvendag Guven, ES(2015).Is resveratrol a potential substitute for leuprolide acetate in experimental endometriosis?.Eur J Obstet Gynecol Reprod Biol,184,1-6.
7. Benjamin, LE(2000).The controls of microvascular survival.Cancer Metastasis Rev.,19,75-81.
8. Bourlev, V,Iljasova, N,Adamyan, L(2010).Signs of reduced angiogenic activity after surgical removal of deeply infiltrating endometriosis.Fertil Steril,94,52-57.
9. Bourlev, V,Larsson, A,Olovsson, M(2006).Elevated levels of fibroblast growth factor-2 in serum from women with endometriosis.Am J Obstet Gynecol,194,755-759.
10. Brandenberger, AW,Lebovic, DI,Tee, MK(1999).Oestrogen receptor (ER)-alpha and ER-beta isoforms in normal endometrial and endometriosis-derived stromal cells.Mol Hum Reprod,5(7),651-655.
11. Bukulmez, O,Hardy, DB,Carr, BR,Word, RA,Mendelson, CR(2008).Inflammatory status influences aromatase and steroid expression in endometriosis.Endocrinology,149,1190-1204.
12. Cho, S,Choi, YS,Jeon, YE(2012).Expression of vascular endothelial growth factor (VEGF) and its soluble receptor-1 in endometriosis.Microvas Rese,83,237-242.
13. Dhananjaya, K,Sibi, G,Mallesha, H,Ravikumar, KR,Awasthi, S(2012).In silico studies of daidzein and genistein with human estrogen receptor-α.Asian Pac J Trop Biomed,2(3),S1747-S1753.
14. Eskenazi, B,Warner, ML(1997).Epidemiology of endometriosis.Obstet Gynecol Clin North Am,24(2),235-258.
15. Ferrara, N,Gerber, HP,LeCouter, J(2003).The biology of VEGF and its receptors.Nat Med.,9,669-676.
16. Fujimoto, J,Hirose, R,Sakaguchi, H(1999).Expression of oestrogen receptor-alpha and -beta in ovarian endometriomata.Mol Hum Reprod,5(8),742-747.
17. Gazvani, R,Templeton, A(2002).Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis.Reproduction,123,217-226.
18. Gossner, G,Choi, M,Tan, L(2007).Genistein-induced apoptosis and autophagocytosis in ovarian cancer cells.Gynecol Oncol,105(1),23-30.
19. Halnes, J,Becker, S,Wing, R(1984).Accentuated cyclic activation of peritoneal macrophages in patients with endometriosis.Am J Obstet Gynecol,148,85-90.
20. Hayashi, A,Tanabe, A,Kawabe, S(2012).Dienogest increases the progesterone receptor isoform B/A ratio in patients with ovarian endometriosis.J Ovarian Res,5,31.
21. Hudelist, G,Keckstein, J,Czerwenka, K(2005).Estrogen receptor beta and matrix metalloproteinase1 are coexpressed in uterine endometrium and endometriotic lesions of patients with endometriosis.Fertil Steril,84(suppl 2),1249-1256.
22. Hutchings, H,Ortega, N,Plouet, J(2003).Extracellular matrix-bound vascular endothelial growth factor promotes endothelial cell adhesion, migration and survival through integrin ligation.FASEB J.,17,1520-1522.
23. Jeong, JW,Lee, HH,Han, MH,Kim, GY,Kim, WJ,Choi, YH(2014).Anti-inflammatory effects of genistein via suppression of the toll like receptor 4-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglia.Chem Biol Interact
24. Ji, G,Yang, Q,Hao, J(2011).Anti-inflammatory effect of genistein on non-alcoholic steatohepatitis rats inducecd by high fat diet and its potential mechanisms.Int Immunopharmacol,11(6),762-768.
25. Koumantakis, E,Matalliotakis, I,Neonaki, M,Froudarakis, G,Georgoulias, V(1994).Soluble serum interleukin-2 receptor, interleukin-6 and interleukin-1a inpatients with endometriosis and in controls.Arch Gynecol Obstet,255,107-112.
26. Kyama, CM,Debrock, S,Mwenda, JM(2003).Potential involvement of the immune system in the development of endometriosis.Reprod Biol Endocrinol,1,123.
27. Liu, AJ,Guan, Z,Zhang, ZM,Wei, LX,Li, YL(2008).Study on expression of estrogen receptor isoforms in eutopic and ectopic endometrium of ovarian endometriosis.Zhonghua Bing Li Xue Za Zhi.,37,584-588.
28. Mahnke, JL,Dawood, MY,Huang, JC(2000).Vascular endothelial growth factor and interleukin-6 in peritoneal fluid of women with endometriosis.Fertil Steril,73,166-170.
29. Matalliotakis, I,Neonaki, M,Zolindaki, A,Hassan, E,Georgoulias, V,Koumantakis, E(1997).Changes in immunologic variables (TNF-α, sCD8 and sCD4) during danazol treatment in patients with endometriosis.Int J Fertil Women's Med.,42,211-214.
30. McLaren, J,Prentice, A,Charnock-Jones, DS(1996).Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids.J Clin Investig,98,482-489.
31. Novak, M,Madej, JA,Dziegeil, P(2007).Intensity of Cox 2 expression in cell of soft tissue fibrosarcomas in dog as related to grade of tumor malignation.Bull Vet Inst Pulawy,51,275-279.
32. Qian, Y,Guan, T,Huang, M(2012).Neuroprotection by the soy isoflavone, genistein, via inhibition of mitochondria-dependent apoptosis pathways and reactive oxygen induced-NF-kB activation in a cerebral ischemia mouse model.Neurochem Int,60(8),759-767.
33. Rigalli, JP,Tochhetti, GN,Arana, MR(2016).The phytoestrogen genistein enhances multidrug resistance in breast cancer cell lines by translational regulation of ABC transporters.Cancer Lett,376(1),165-172.
34. Ryan, IP,Tseng, JF,Schriock, ED,Khorram, O,Landers, DV,Taylor, RN(1995).Interleukin-8 concentrations are elevated in peritoneal fluid of women with endometriosis.Fertil Steril,63,929-932.
35. Shifren, JL,Tseng, JF,Zaloudek, CJ(1996).Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.J Clin Endocrinol Metab,81,3112-3118.
36. Su, SJ,Yeh, TM,Chuang, WJ(2005).The novel targets for anti-angiogenesis of genistein on human cancer cells.Biochem Pharmacol,69(2),307-318.
37. Sutrisno, S,Wulandari, RRCL,Sulistyowati, DWW(2015).Effect of genistein on proinflammatory cytokines and estrogen receptor-β in mice model of endometriosis.Asian Pac J Reprod,4(2),96-99.
38. Trukhacheva, E,Lin, Z,Reierstad, S(2009).Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis.J Clin Endocrinol Metab,94(2),615-622.
39. Vitale, DC,Piazza, C,Melilli, B,Drago, F,Salomone, S(2013).Isoflavones: estrogenic activity, biological effect and bioavailability.Eur J Drug Metab Pharmacokinet,38,15-25.
40. Wei, H,Bowen, R,Cai, Q,Barnes, S,Wang, Y(1995).Antioxidant and antipromotional effects of the soybean isoflavone genistein.Exp Biol Med,208,124-130.
41. Wise, LM,Veikkola, T,Mercer, AA(1999).The vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1.Proc Natl Acad Sci U. S. A.,96,3071-3076.
42. Xue, Q,Lin, Z,Cheng, YH(2007).Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis.Biol Reprod,77(4),681-687.
43. Yavuz, E,Oktem, M,Esinler, I(2007).Genistein causes regression of endometriotic implants in the rat model.Fertil Steril,88(4 suppl),1129-1134.
44. Zachary, I,Gliki, G.(2001).Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family.Cardiovasc Res,49,568-581.