Moutan Cortex extract inhibited the proliferation and migration of endometrial stromal cells by inhibiting OPN-induced, MAPK-mediated MMP9 activation
Main Article Content
Keywords
endometriosis, Moutan Cortex extract, human endometrial stromal cells, osteopontin, MAPK, MMP9
Abstract
Endometriosis is frequent in women of childbearing age with a morbidity rate of approximately 10%. Its clinical features mainly manifest as dysmenorrhea, chronic pelvic pain, and infertility. However, effective treatments are still lacking; hence, it is necessary to identify an effective and safe treatment strategy on endometriosis. Moutan Cortex extract (MCE) was prepared by decoction. Then, cell proliferation and apoptosis in human endometrial stromal cells (HESCs) were detected by cell counting kit-8, EdU cell proliferation assay, and flow cytometry. Wound-healing assay and transwell migration assay were performed to explore cell migration or invasion. The expression of indicators of downstream signaling pathways was determined by Western blot analysis or enzyme-linked-immunosorbent serologic assay. MCE treatment inhibited cell viability and proliferation in HESCs while promoting cell apoptosis. MCE reduced migration and invasion of HESCs. Furthermore, MCE inhibited osteopontin-induced, mitogen-activated, protein kinase (MAPK)-mediated matrix metallopeptidase 9 (MMP9) activation, and upregulation of OPN reversed the effect of MCE on HESCs. In this study, MCE inhibited the proliferation and migration of endometrial stromal cells by inhibiting OPN induced, MAPK-mediated MMP9 activation. MCE might be a novel treatment strategy on endometriosis.
References
Altayyeb, A., Othman, E., Khashbah, M., Esmaeel, A., El-Mokhtar, M., Lambalk, C., Mijatovic, V. and Abdelgawad, M., 2020. Characterization of mechanical signature of eutopic endometrial stromal cells of endometriosis patients. Reproductive Sciences 27: 364–374. 10.1007/s43032-019-00042-3
Bai, M., Liu, H., Wang, S., Shu, Q., Xu, K., Zhou, J., Xiong, X., Huang, R., Deng, J., Yin, Y. and Liu, Z., 2021. Dietary Moutan Cortex Radicis improves serum antioxidant capacity and intestinal immunity and alters colonic microbiota in weaned piglets. Frontiers in Nutrition 8: 679129. 10.3389/fnut.2021.679129
Bakır, M.S., Birge, Ö., Karadag, C., Doğan, S., Tuncer, H.A. and Simsek, T., 2021. Clinicopathological risk factors and survival analysis of ovarian cancer with synchronous endometrial cancer diagnosed after surgery. European Journal of Gynaecological Oncology 42(3): 499–505.
Bozorgmehr, M., Gurung, S., Darzi, S., Nikoo, S., Kazemnejad, S., Zarnani, A.H. and Gargett, C.E., 2020. Endometrial and menstrual blood mesenchymal stem/stromal cells: biological properties and clinical application. Frontiers in Cell and Developmental Biology 8: 497. 10.3389/fcell.2020.00497
Cao, Y., Liu, X. and Guo, S.W., 2019. Plasma high mobility group Box 1 (HMGB1), osteopontin (OPN), and hyaluronic acid (HA) as admissible biomarkers for endometriosis. Scientific Reports 9: 9272. 10.1038/s41598-019-45785-w
Chen, Z.Z. and Gong, X., 2020. Tanshinone IIA contributes to the pathogenesis of endometriosis via renin angiotensin system by regulating the dorsal root ganglion axon sprouting. Life Sciences 240: 117085. 10.1016/j.lfs.2019.117085
Chen, G., Zhang, L. and Yang, P., 2005. Determination of three bioactive constituents in Moutan Cortex by capillary electrophoresis with electrochemical detection. Analytical Science 21: 1161–1165. 10.2116/analsci.21.1161
Cheng, J., Li, C., Ying, Y., Lv, J., Qu, X., McGowan, E., Lin, Y. and Zhu, X., 2022. Metformin alleviates endometriosis and potentiates endometrial receptivity via decreasing VEGF and MMP9 and increasing leukemia inhibitor factor and HOXA10. Frontiers in Pharmacology 13: 750208. 10.3389/fphar.2022.750208
Cho, S., Ahn, Y.S., Choi, Y.S., Seo, S.K., Nam, A., Kim, H.Y., Kim, J.H., Park, K.H., Cho, D.J. and Lee, B.S., 2009. Endometrial osteopontin mRNA expression and plasma osteopontin levels are increased in patients with endometriosis. American Journal of Reproductive Immunology 61: 286–293. 10.1111/j.1600-0897.2009.00692.x
Chun, S.C., Jee, S.Y., Lee, S.G., Park, S.J., Lee, J.R. and Kim, S.C., 2007. Anti-inflammatory activity of the methanol extract of Moutan Cortex in LPS-activated raw 264.7 cells. Evidence-Based Complementary and Alternative Medicine 4: 327–333. 10.1093/ecam/nel093
Dai, S., Zhu, M., Wu, R., Lin, D., Huang, Z., Ren, L., Huang, S., Cheng, L. and Chen, Q., 2019. Lipoxin A(4) suppresses IL-1β-induced cyclooxygenase-2 expression through inhibition of p38 MAPK activation in endometriosis. Reproductive Sciences 26: 1640–1649. 10.1177/1933719119828115
Dan, H., Zhang, L., Qin, X., Peng, X., Wong, M., Tan, X., Yu, S. and Fang, N., 2016. Moutan Cortex extract exerts protective effects in a rat model of cardiac ischemia/reperfusion. Canadian Journal of Physiology and Pharmacology 94: 245–250. 10.1139/cjpp-2015-0168
Delic, R., 2018. Ovarian endometrioid carcinoma associated with diffused pulmonary endometriosis: a case report. European Journal of Gynaecological Oncology 39(1): 143–145.
Fu, X., Yao, M., Ye, C., Fang, T. and Wu, R., 2021. Osteopontin regulates endometrial stromal cell migration in endometriosis through the PI3K Pathway: osteopontin regulates endometrial cell migration in endometriosis. Reproductive Sciences 28: 435–446. 10.1007/s43032-020-00301-8
Gu, Y. and Zhou, Z., 2021. Berberine inhibits the proliferation, invasion and migration of endometrial stromal cells by downregulating miR-429. Molecular Medicine Reports 23(6): 416. 10.3892/mmr.2021.12055
Huang, Z.X., Mao, X.M., Lin, D.C., Hong, Y.H., Liang, G.S., Chen, Q.X. and Chen, Q.H., 2020. Establishment and characterization of immortalized human eutopic endometrial stromal cells. American Journal of Reproductive Immunology 83: e13213. 10.1111/aji.13213
Ilhan, M., Ali, Z., Khan, I.A., Taştan, H. and Küpeli Akkol, E., 2019. Promising activity of anthemis austriaca Jacq. on the endometriosis rat model and isolation of its active constituents. Saudi Pharmaceutical Journal 27: 889–899. 10.1016/j.jsps.2019.06.002
Jang, M.H., Kim, K.Y., Song, P.H., Baek, S.Y., Seo, H.L., Lee, E.H., Lee, S.G., Park, K.I., Ahn, S.C., Kim, S.C. and Kim, Y.W., 2017. Moutan Cortex protects hepatocytes against oxidative injury through AMP-activated protein kinase pathway. Biological and Pharmaceutical Bulletin 40: 797–806. 10.1248/bpb.b16-00884
Kabukcuoglu, S. and Hayit, B., 2020. Histopathologic features of advanced stage endometrial carcinoma. Eur. J. Gynaecol. Oncol. 40(4): 614–618.
Lee, I.S., Kim, C.S., Kim, J., Jo, K., Hyun, S.W., Zhang, H., Noh, M., Kwon, Y.G., Kim, M. and Kim, J.S., 2022. Extract of moutan radicis cortex and cinnamomi ramulus ameliorates laser-induced choroidal neovascularization in Brown-Norway rats. Phytomedicine 94: 153794. 10.1016/j.phymed.2021.153794
Li, X., Xiong, W., Long, X., Dai, X., Peng, Y., Xu, Y., Zhang, Z., Zhang, L. and Liu, Y., 2021. Inhibition of METTL3/m6A/miR126 promotes the migration and invasion of endometrial stromal cells in endometriosis. Biology of Reproduction 105: 1221–1233. 10.1093/biolre/ioab152
Lin, M.Y., Lee, Y.R., Chiang, S.Y., Li, Y.Z., Chen, Y.S., Hsu, C.D. and Liu, Y.W., 2013. Cortex Moutan induces bladder cancer cell death via apoptosis and retards tumor growth in mouse bladders. Evidence-Based Complementary and Alternative Medicine 2013: 207279. 10.1155/2013/207279
Liu, Y., Ma, J., Cui, D., Fei, X., Lv, Y. and Lin, J., 2020. LncRNA MEG3-210 regulates endometrial stromal cells migration, invasion and apoptosis through p38 MAPK and PKA/SERCA2 signalling via interaction with Galectin-1 in endometriosis. Molecular and Cellular Endocrinology 513: 110870. 10.1016/j.mce.2020.110870
Lu, S., Guo, M., Fan, Z., Chen, Y., Shi, X., Gu, C. and Yang, Y., 2019. Elevated TRIP13 drives cell proliferation and drug resistance in bladder cancer. American Journal of Translational Research 11: 4397–4410.
Ma, L.Y., Liu, J.M., Du, G.L. and Dang, X.B., 2021. Irisin attenuates lipopolysaccharide-induced acute lung injury by downregulating inflammatory cytokine expression through miR-199a-mediated Rad23b overexpression. Experimental Cell Research 404: 112593. 10.1016/j.yexcr.2021.112593
Mc Cormack, B.A., Bilotas, M.A., Madanes, D., Ricci, A.G., Singla, J.J. and Barañao, R.I., 2020. Potential use of ellagic acid for endometriosis treatment: its effect on a human endometrial cell cycle, adhesion and migration. Food & Function 11: 4605–4614. 10.1039/d0fo00267d
Moradi, M., Parker, M., Sneddon, A., Lopez, V. and Ellwood, D., 2014. Impact of endometriosis on women’s lives: a qualitative study. BMC Womens Health 14: 123. 10.1186/1472-6874-14-123
Pang, C., Wu, Z., Xu, X., Yang, W., Wang, X. and Qi, Y., 2021. Paeonol alleviates migration and invasion of endometrial stromal cells by reducing HIF-1α-regulated autophagy in endometriosis. Frontiers in Bioscience (Landmark Edition) 26: 485–495. 10.52586/4961
Park, S., Lim, W., Bazer, F.W., Whang, K.Y. and Song, G., 2019. Quercetin inhibits proliferation of endometriosis regulating cyclin D1 and its target microRNAs in vitro and in vivo. Journal of Nutritional Biochemistry 63: 87–100. 10.1016/j.jnutbio.2018.09.024
Tang, W., Chen, O., Yao, F. and Cui, L., 2019. miR-455 targets FABP4 to protect human endometrial stromal cells from cytotoxicity induced by hydrogen peroxide. Molecular Medicine Reports 20: 4781–4790. 10.3892/mmr.2019.10727
Wang, Y., Nicholes, K. and Shih, I.M., 2020a. The origin and pathogenesis of endometriosis. Annual Review of Pathology 15: 71–95. 10.1146/annurev-pathmechdis-012419-032654
Wang, H., Wei, H., Wang, J., Li, L., Chen, A. and Li, Z., 2020b. MicroRNA-181d-5p-containing exosomes derived from CAFs promote EMT by regulating CDX2/HOXA5 in breast cancer. Molecular Therapy Nucleic Acids 19: 654–667. 10.1016/j.omtn.2019.11.024
Wang, H., Zhou, G., Zhuang, M., Wang, W. and Fu, X., 2021. Utilizing network pharmacology and molecular docking to explore the underlying mechanism of Guizhi Fuling Wan in treating endometriosis. PeerJ 9: e11087. 10.7717/peerj.11087
Yu, H., Zhong, H., Li, N., Chen, K., Chen, J., Sun, J., et al., 2021. Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma. Faseb J. 35(3):e21405. 10.1096/fj.202002218R
Bai, M., Liu, H., Wang, S., Shu, Q., Xu, K., Zhou, J., Xiong, X., Huang, R., Deng, J., Yin, Y. and Liu, Z., 2021. Dietary Moutan Cortex Radicis improves serum antioxidant capacity and intestinal immunity and alters colonic microbiota in weaned piglets. Frontiers in Nutrition 8: 679129. 10.3389/fnut.2021.679129
Bakır, M.S., Birge, Ö., Karadag, C., Doğan, S., Tuncer, H.A. and Simsek, T., 2021. Clinicopathological risk factors and survival analysis of ovarian cancer with synchronous endometrial cancer diagnosed after surgery. European Journal of Gynaecological Oncology 42(3): 499–505.
Bozorgmehr, M., Gurung, S., Darzi, S., Nikoo, S., Kazemnejad, S., Zarnani, A.H. and Gargett, C.E., 2020. Endometrial and menstrual blood mesenchymal stem/stromal cells: biological properties and clinical application. Frontiers in Cell and Developmental Biology 8: 497. 10.3389/fcell.2020.00497
Cao, Y., Liu, X. and Guo, S.W., 2019. Plasma high mobility group Box 1 (HMGB1), osteopontin (OPN), and hyaluronic acid (HA) as admissible biomarkers for endometriosis. Scientific Reports 9: 9272. 10.1038/s41598-019-45785-w
Chen, Z.Z. and Gong, X., 2020. Tanshinone IIA contributes to the pathogenesis of endometriosis via renin angiotensin system by regulating the dorsal root ganglion axon sprouting. Life Sciences 240: 117085. 10.1016/j.lfs.2019.117085
Chen, G., Zhang, L. and Yang, P., 2005. Determination of three bioactive constituents in Moutan Cortex by capillary electrophoresis with electrochemical detection. Analytical Science 21: 1161–1165. 10.2116/analsci.21.1161
Cheng, J., Li, C., Ying, Y., Lv, J., Qu, X., McGowan, E., Lin, Y. and Zhu, X., 2022. Metformin alleviates endometriosis and potentiates endometrial receptivity via decreasing VEGF and MMP9 and increasing leukemia inhibitor factor and HOXA10. Frontiers in Pharmacology 13: 750208. 10.3389/fphar.2022.750208
Cho, S., Ahn, Y.S., Choi, Y.S., Seo, S.K., Nam, A., Kim, H.Y., Kim, J.H., Park, K.H., Cho, D.J. and Lee, B.S., 2009. Endometrial osteopontin mRNA expression and plasma osteopontin levels are increased in patients with endometriosis. American Journal of Reproductive Immunology 61: 286–293. 10.1111/j.1600-0897.2009.00692.x
Chun, S.C., Jee, S.Y., Lee, S.G., Park, S.J., Lee, J.R. and Kim, S.C., 2007. Anti-inflammatory activity of the methanol extract of Moutan Cortex in LPS-activated raw 264.7 cells. Evidence-Based Complementary and Alternative Medicine 4: 327–333. 10.1093/ecam/nel093
Dai, S., Zhu, M., Wu, R., Lin, D., Huang, Z., Ren, L., Huang, S., Cheng, L. and Chen, Q., 2019. Lipoxin A(4) suppresses IL-1β-induced cyclooxygenase-2 expression through inhibition of p38 MAPK activation in endometriosis. Reproductive Sciences 26: 1640–1649. 10.1177/1933719119828115
Dan, H., Zhang, L., Qin, X., Peng, X., Wong, M., Tan, X., Yu, S. and Fang, N., 2016. Moutan Cortex extract exerts protective effects in a rat model of cardiac ischemia/reperfusion. Canadian Journal of Physiology and Pharmacology 94: 245–250. 10.1139/cjpp-2015-0168
Delic, R., 2018. Ovarian endometrioid carcinoma associated with diffused pulmonary endometriosis: a case report. European Journal of Gynaecological Oncology 39(1): 143–145.
Fu, X., Yao, M., Ye, C., Fang, T. and Wu, R., 2021. Osteopontin regulates endometrial stromal cell migration in endometriosis through the PI3K Pathway: osteopontin regulates endometrial cell migration in endometriosis. Reproductive Sciences 28: 435–446. 10.1007/s43032-020-00301-8
Gu, Y. and Zhou, Z., 2021. Berberine inhibits the proliferation, invasion and migration of endometrial stromal cells by downregulating miR-429. Molecular Medicine Reports 23(6): 416. 10.3892/mmr.2021.12055
Huang, Z.X., Mao, X.M., Lin, D.C., Hong, Y.H., Liang, G.S., Chen, Q.X. and Chen, Q.H., 2020. Establishment and characterization of immortalized human eutopic endometrial stromal cells. American Journal of Reproductive Immunology 83: e13213. 10.1111/aji.13213
Ilhan, M., Ali, Z., Khan, I.A., Taştan, H. and Küpeli Akkol, E., 2019. Promising activity of anthemis austriaca Jacq. on the endometriosis rat model and isolation of its active constituents. Saudi Pharmaceutical Journal 27: 889–899. 10.1016/j.jsps.2019.06.002
Jang, M.H., Kim, K.Y., Song, P.H., Baek, S.Y., Seo, H.L., Lee, E.H., Lee, S.G., Park, K.I., Ahn, S.C., Kim, S.C. and Kim, Y.W., 2017. Moutan Cortex protects hepatocytes against oxidative injury through AMP-activated protein kinase pathway. Biological and Pharmaceutical Bulletin 40: 797–806. 10.1248/bpb.b16-00884
Kabukcuoglu, S. and Hayit, B., 2020. Histopathologic features of advanced stage endometrial carcinoma. Eur. J. Gynaecol. Oncol. 40(4): 614–618.
Lee, I.S., Kim, C.S., Kim, J., Jo, K., Hyun, S.W., Zhang, H., Noh, M., Kwon, Y.G., Kim, M. and Kim, J.S., 2022. Extract of moutan radicis cortex and cinnamomi ramulus ameliorates laser-induced choroidal neovascularization in Brown-Norway rats. Phytomedicine 94: 153794. 10.1016/j.phymed.2021.153794
Li, X., Xiong, W., Long, X., Dai, X., Peng, Y., Xu, Y., Zhang, Z., Zhang, L. and Liu, Y., 2021. Inhibition of METTL3/m6A/miR126 promotes the migration and invasion of endometrial stromal cells in endometriosis. Biology of Reproduction 105: 1221–1233. 10.1093/biolre/ioab152
Lin, M.Y., Lee, Y.R., Chiang, S.Y., Li, Y.Z., Chen, Y.S., Hsu, C.D. and Liu, Y.W., 2013. Cortex Moutan induces bladder cancer cell death via apoptosis and retards tumor growth in mouse bladders. Evidence-Based Complementary and Alternative Medicine 2013: 207279. 10.1155/2013/207279
Liu, Y., Ma, J., Cui, D., Fei, X., Lv, Y. and Lin, J., 2020. LncRNA MEG3-210 regulates endometrial stromal cells migration, invasion and apoptosis through p38 MAPK and PKA/SERCA2 signalling via interaction with Galectin-1 in endometriosis. Molecular and Cellular Endocrinology 513: 110870. 10.1016/j.mce.2020.110870
Lu, S., Guo, M., Fan, Z., Chen, Y., Shi, X., Gu, C. and Yang, Y., 2019. Elevated TRIP13 drives cell proliferation and drug resistance in bladder cancer. American Journal of Translational Research 11: 4397–4410.
Ma, L.Y., Liu, J.M., Du, G.L. and Dang, X.B., 2021. Irisin attenuates lipopolysaccharide-induced acute lung injury by downregulating inflammatory cytokine expression through miR-199a-mediated Rad23b overexpression. Experimental Cell Research 404: 112593. 10.1016/j.yexcr.2021.112593
Mc Cormack, B.A., Bilotas, M.A., Madanes, D., Ricci, A.G., Singla, J.J. and Barañao, R.I., 2020. Potential use of ellagic acid for endometriosis treatment: its effect on a human endometrial cell cycle, adhesion and migration. Food & Function 11: 4605–4614. 10.1039/d0fo00267d
Moradi, M., Parker, M., Sneddon, A., Lopez, V. and Ellwood, D., 2014. Impact of endometriosis on women’s lives: a qualitative study. BMC Womens Health 14: 123. 10.1186/1472-6874-14-123
Pang, C., Wu, Z., Xu, X., Yang, W., Wang, X. and Qi, Y., 2021. Paeonol alleviates migration and invasion of endometrial stromal cells by reducing HIF-1α-regulated autophagy in endometriosis. Frontiers in Bioscience (Landmark Edition) 26: 485–495. 10.52586/4961
Park, S., Lim, W., Bazer, F.W., Whang, K.Y. and Song, G., 2019. Quercetin inhibits proliferation of endometriosis regulating cyclin D1 and its target microRNAs in vitro and in vivo. Journal of Nutritional Biochemistry 63: 87–100. 10.1016/j.jnutbio.2018.09.024
Tang, W., Chen, O., Yao, F. and Cui, L., 2019. miR-455 targets FABP4 to protect human endometrial stromal cells from cytotoxicity induced by hydrogen peroxide. Molecular Medicine Reports 20: 4781–4790. 10.3892/mmr.2019.10727
Wang, Y., Nicholes, K. and Shih, I.M., 2020a. The origin and pathogenesis of endometriosis. Annual Review of Pathology 15: 71–95. 10.1146/annurev-pathmechdis-012419-032654
Wang, H., Wei, H., Wang, J., Li, L., Chen, A. and Li, Z., 2020b. MicroRNA-181d-5p-containing exosomes derived from CAFs promote EMT by regulating CDX2/HOXA5 in breast cancer. Molecular Therapy Nucleic Acids 19: 654–667. 10.1016/j.omtn.2019.11.024
Wang, H., Zhou, G., Zhuang, M., Wang, W. and Fu, X., 2021. Utilizing network pharmacology and molecular docking to explore the underlying mechanism of Guizhi Fuling Wan in treating endometriosis. PeerJ 9: e11087. 10.7717/peerj.11087
Yu, H., Zhong, H., Li, N., Chen, K., Chen, J., Sun, J., et al., 2021. Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma. Faseb J. 35(3):e21405. 10.1096/fj.202002218R
Article Sidebar
Published
Jan 10, 2023
Article Details
Section
Original Article
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
