Therapeutic Potential of Wenshen Xiaozheng Tang, a Traditional Chinese Medicine Prescription, for Treating Endometriosis

The objective of this study is to investigate the effect of Wenshen Xiaozheng Tang (WXT) on the development of endometriosis in a rat model. Sprague-Dawley rats in which endometriotic implants were induced were divided randomly into 3 groups. The rats in the low-dose and high-dose WXT groups were administered WXT 8.57 and 17.14 g/kg/d, respectively. The rats in the control groups received an equal volume of dissolvent, as did the sham-operated rats. After treatment for 4 weeks, WXT significantly decreased the mean lesion size as well as the peritoneal fluid and serum levels of tumor necrosis factor α and interleukin 1β. Cyclooxygenase-2, matrix metalloproteinase 9, plasminogen activator inhibitor 1, and intercellular adhesion molecule 1 messenger RNA (mRNA) levels were downregulated, and the mRNA expression of tissue inhibitor of metalloproteinase 1 was upregulated in the endometriotic lesions of WXT versus control group. Our data suggested that WXT may suppress the development of endometriosis by inhibiting the production of proinflammatory cytokines and regulating the expression of invasion-related genes in the endometriotic lesions. Similar content being viewed by others

Cosin R, Gilabert-Estelles J, Ramon LA, et al. Influence of peritoneal fluid on the expression of angiogenic and proteolytic factors in cultures of endometrial cells from women with endometriosis. Hum Reprod. 2010;25(2):398–405. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–2398. Celik O, Hascalik S, Elter K, Tagluk ME, Gurates B, Aydin NE. Combating endometriosis by blocking proteasome and nuclear factor-kappaB pathways. Hum Reprod. 2008;23(11):2458–2465. Augoulea A, Alexandrou A, Creatsa M, Vrachnis N, Lambrinoudaki I. Pathogenesis of endometriosis: the role of genetics, inflammation and oxidative stress. Arch Gynecol Obstet. 2012;286(1): 99–103. Pitsos M, Kanakas N. The role of matrix metalloproteinases in the pathogenesis of endometriosis. Reprod Sci. 2009;16(8):717–726. Bruse C, Radu D, Bergqvist A. In situ localization of mRNA for the fibrinolytic factors uPA, PAI-1 and uPAR in endometriotic and endometrial tissue. Mol Hum Reprod. 2004;10(3):159–166. Kyama CM, Debrock S, Mwenda JM, D’Hooghe TM. Potential involvement of the immune system in the development of endometriosis. Reprod Biol Endocrinol. 2003;1:123. Zhou WD, Yang HM, Wang Q, et al. SB203580, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis by down-regulating proinflammatory cytokines and proteolytic factors in a mouse model. Hum Reprod. 2010; 25(12):3110–3116. Chen Q, Zhou W, Pu D, Li Z, Huang Q, Chen Q. The inhibitory effect of 15-R-LXA4 on experimental endometriosis. Eur J Obstet Gynecol Reprod Biol. 2009;145(2):200–204. Zheng Y, Liu X, Guo SW. Therapeutic potential of andrographolide for treating endometriosis. Hum Reprod. 2012;27(5): 1300–1313. Ozawa Y, Murakami T, Tamura M, Terada Y, Yaegashi N, Okamura K. A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis xenografts via antiangiogenic activity in severe combined immunodeficiency mice. Fertil Steril. 2006;86(4 suppl 1):1146–1151. Banu SK, Lee J, Speights VO Jr, Starzinski-Powitz A, Arosh JA. Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms. Endocrinology. 2008;149(3):1180–1189. Kyama CM, Mihalyi A, Simsa P, et al. Role of cytokines in the endometrial-peritoneal cross-talk and development of endometriosis. Front Biosci. 2009; 1:444–454. Ueda M, Yamashita Y, Takehara M, et al. Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis. Gynecol Endocrinol. 2002;16(5):391–402. Collette T, Maheux R, Mailloux J, Akoum A. Increased expression of matrix metalloproteinase-9 in the eutopic endometrial tissue of women with endometriosis. Hum Reprod. 2006;21(12): 3059–3067. Bruse C, Bergqvist A, Carlstrom K, Fianu-Jonasson A, Lecander I, Astedt B. Fibrinolytic factors in endometriotic tissue, endometrium, peritoneal fluid, and plasma from women with endometriosis and in endometrium and peritoneal fluid from healthy women. Fertil Steril. 1998;70(5):821–826. Pino M, Galleguillos C, Torres M, et al. Association between MMP1 and MMP9 activities and ICAM1 cleavage induced by tumor necrosis factor in stromal cell cultures from eutopic endometria of women with endometriosis. Reproduction. 2009;138(5): 837–847. Domeij H, Modeer T, Quezada HC, Yucel-Lindberg T. Cell expression of MMP-1 and TIMP-1 in co-cultures of human gingival fibroblasts and monocytes: the involvement of ICAM-1. Biochem Biophys Res Commun. 2005;338(4):1825–1833. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005; 20(10):2698–2704. Rocha AL, Reis FM, Petraglia F. New trends for the medical treatment of endometriosis. Expert Opin Investig Drugs. 2012;21(7): 905–919. Flower A, Liu JP, Chen S, Lewith G, Little P. Chinese herbal medicine for endometriosis. Cochrane Database Syst Rev. 2009;(3):CD006568. Li SP, Zhao J, Yang B. Strategies for quality control of Chinese medicines. J Pharm Biomed Anal. 2011;55(4):802–809. Fan X, Cheng Y, Ye Z, Lin R, Qian Z. Multiple chromatographic fingerprinting and its application to the quality control of herbal medicines. Ana Chim Acta. 2006;555(12):217–224. National Research Council. Guide for the Care and Use of Laboratory Animals. Washington, DC: National Research Council, National Academy Press; 1996. Yavuz E, Oktem M, Esinler I, Toru SA, Zeyneloglu HB. Genistein causes regression of endometriotic implants in the rat model. Fertil Steril. 2007;88(4 suppl 1):1129–1134. Szymanowski K, Chmaj-Wierzchowska K, Yantczenko A, et al. Endometriosis prophylaxis and treatment with the newly developed xenogenic immunomodulator RESAN in an animal model. Eur J Obstet Gynecol Reprod Biol. 2009;142(2):145–148. Ji X, Gao J, Cai X, et al. Immunological regulation of Chinese herb Guizhi Fuling Capsule on rat endometriosis model. J Ethnopharmacol. 2011;134(3):624–629. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22(3):659–661. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–408. Xu H, Becker CM, Lui WT, et al. Green tea epigallocatechin-3-gallate inhibits angiogenesis and suppresses vascular endothelial growth factor C/vascular endothelial growth factor receptor 2 expression and signaling in experimental endometriosis in vivo. Fertil Steril. 2011;96(4):1021–1028. Jiang HQ, Li YL, Zou J. Effect of recombinant human endostatin on endometriosis in mice. Chin Med J. 2007;120(14): 1241–1246. Wieser F, Cohen M, Gaeddert A, et al. Evolution of medical treatment for endometriosis: back to the roots? Hum Reprod Update. 2007;13(5):487–499. Scholl B, Bersinger NA, Kuhn A, Mueller MD. Correlation between symptoms of pain and peritoneal fluid inflammatory cytokine concentrations in endometriosis. Gynecol Endocrinol. 2009;25(11):701–706. Wu MY, Ho HN. The role of cytokines in endometriosis. Am J Reprod Immunol. 2003;49(5):285–296. Bedaiwy MA, Falcone T. Peritoneal fluid environment in endometriosis. Clinicopathological implications. Minerva Ginecol. 2003;55(4):333–345. Gupta S, Agarwal A, Sekhon L, Krajcir N, Cocuzza M, Falcone T. Serum and peritoneal abnormalities in endometriosis: potential use as diagnostic markers. Minerva Ginecol. 2006;58(6):527–551. D’Hooghe TM, Bambra CS, Xiao L, Peixe K, Hill JA. Effect of menstruation and intrapelvic injection of endometrium on inflammatory parameters of peritoneal fluid in the baboon (Papio anubis and Papio cynocephalus). Am J Obstet Gynecol. 2001;184(5):917–925. Fruet AC, Seito LN, Rao VL, Di Stasi LC. Dietary intervention with narrow-leaved cattail rhizome flour (Typha angustifolia L.) prevents intestinal inflammation in the trinitrobenzenesulphonic acid model of rat colitis. BMC Complement Altern Med. 2012; 12:62. Qin Q, Niu J, Wang Z, Xu W, Qiao Z, Gu Y. Astragalus embranaceus extract activates immune response in macrophages via heparanase. Molecules. 2012;17(6):7232–7240. Rahimi R, Shams-Ardekani MR, Abdollahi M. A review of the efficacy of traditional Iranian medicine for inflammatory bowel disease. World J Gastroenterol. 2010;16(36):4504–4514. Cheng L, Lei Y, Liang YY, Tang DX, Huang L, Tan ZH. Compared studies on the effect and toxicity of extractions of Fructus Meliae Toosendan in mice [in Chinese]. Zhong Yao Cai. 2007; 30(10):1276–1279. Binder BR, Mihaly J, Prager GW. uPAR-uPA-PAI-1 interactions and signaling: a vascular biologist’s view. Thromb Haemost. 2007;97(3):336–342. Myers CL, Wertheimer SJ, Schembri-King J, Parks T, Wallace RW. Induction of ICAM-1 by TNF-alpha, IL-1 beta, and LPS in human endothelial cells after downregulation of PKC. Am J Physiol. 1992;263(4 pt 1):C767–C772. Park YG, Kang SK, Kim WJ, Lee YC, Kim CH. Effects of TGF-beta, TNF-alpha, IL-beta and IL-6 alone or in combination, and tyrosine kinase inhibitor on cyclooxygenase expression, prostaglandin E2 production and bone resorption in mouse calvarial bone cells. Int J Biochem Cell Biol. 2004;36(11):2270–2280. Chakrabarti S, Zee JM, Patel KD. Regulation of matrix metalloproteinase-9 (MMP-9) in TNF-stimulated neutrophils: novel pathways for tertiary granule release. J Leukoc Biol. 2006;79(1):214–222. Fontana VA, Sanchez M, Cebral E, Calvo JC. Interleukin-1 beta regulates metalloproteinase activity and leptin secretion in a cytotrophoblast model. Biocell. 2010;34(1):37–43. Nee LE, McMorrow T, Campbell E, Slattery C, Ryan MP. TNF-alpha and IL-1beta-mediated regulation of MMP-9 and TIMP-1 in renal proximal tubular cells. Kidney Int. 2004;66(4):1376–1386. Guo SW. Nuclear factor-kappab (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large? Gynecol Obstet Invest. 2007;63(2):71–97. Xue J, Thippegowda PB, Hu G, et al. NF-kappaB regulates thrombin-induced ICAM-1 gene expression in cooperation with NFAT by binding to the intronic NF-kappaB site in the ICAM-1 gene. Physiol Genomics. 2009;38(1):42–53. Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L. IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J. 2003;17(14):2115–2117. Chou YC, Sheu JR, Chung CL, et al. Nuclear-targeted inhibition of NF-kappaB on MMP-9 production by N-2-(4-bromophenyl) ethyl caffeamide in human monocytic cells. Chem Biol Interact. 2010;184(3):403–412. Bommarito A, Richiusa P, Carissimi E, et al. BRAFV600E mutation, TIMP-1 upregulation, and NF-kappaB activation: closing the loop on the papillary thyroid cancer trilogy. Endocr Relat Cancer. 2011;18(6):669–685. D’Hooghe TM, Kyama CM, Chai D, et al. Nonhuman primate models for translational research in endometriosis. Reprod Sci. 2009;16(2):152–161. Author information Authors and Affiliations Corresponding authors Rights and permissions About this article Cite this article Zhang, Z., Hu, C., Tang, W. et al. Therapeutic Potential of Wenshen Xiaozheng Tang, a Traditional Chinese Medicine Prescription, for Treating Endometriosis. Reprod. Sci. 20, 1215–1223 (2013). https://doi.org/10.1177/1933719113483008 Published: Issue date: DOI: https://doi.org/10.1177/1933719113483008