Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy.
Department of Biomedical, Dental and Morphological and Functional Imaging, University of Messina, Via Consolare Valeria, 98125 Messina, Italy.
Int J Mol Sci. 2021 Apr 13;22(8):3991. doi: 10.3390/ijms22083991.
Endometriosis is a common gynecological disease. Here, we aimed to investigate the anti-fibrotic, anti-inflammatory, and anti-oxidative role of the methyl ester of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) on endometriosis. An endometriosis rat model was constructed by intraperitoneally injecting recipient rats with an equivalent of tissue from the uterus of a donor animal. Endometriosis was allowed to develop for seven days. CDDO-Me was administered on the 7th day and for the next 7 days. On day 14, rats were sacrificed, and peritoneal fluid and endometriotic implants were collected. CDDO-Me displayed antioxidant activity by activating the Nfr2 pathway and the expression of antioxidant mediators such as NQO-1 and HO-1. Moreover, it reduced lipid peroxidation and increased glutathione (GSH) levels and superoxide dismutase (SOD) activity. CDDO-Me also showed anti-inflammatory activity by decreasing the expression of pro-inflammatory cytokines in peritoneal fluids and NFkB activation. It, in turn, reduced cyclooxygenase-2 (COX-2) expression in the endometriotic loci and prostaglandin E2 (PGE2) levels in the peritoneal fluids, leading to increased apoptosis and reduced angiogenesis. The reduced oxidative stress and pro-inflammatory microenvironment decreased implants diameter, area, and volume. In particular, CDDO-Me administration reduced the histopathological signs of endometriosis and inflammatory cells recruitment into the lesions, as shown by toluidine blue staining and myeloperoxidase (MPO) activity. CDDO-Me strongly suppressed α-SMA and fibronectin expression and collagen deposition, reducing endometriosis-associated fibrosis. In conclusion, CDDO-Me treatment resulted in a coordinated and effective suppression of endometriosis by modulating the Nrf2 and NFkB pathways.
子宫内膜异位症是一种常见的妇科疾病。在这里，我们旨在研究 2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸甲酯（CDDO-Me）对子宫内膜异位症的抗纤维化、抗炎和抗氧化作用。通过向受体大鼠腹腔内注射供体动物子宫组织的等效物构建子宫内膜异位症大鼠模型。允许子宫内膜异位症在 7 天内发展。在第 7 天和接下来的 7 天内给予 CDDO-Me。第 14 天，处死大鼠，收集腹腔液和子宫内膜异位症植入物。CDDO-Me 通过激活 Nfr2 途径和表达抗氧化介质如 NQO-1 和 HO-1 来发挥抗氧化作用。此外，它还降低了脂质过氧化作用，增加了谷胱甘肽（GSH）水平和超氧化物歧化酶（SOD）活性。CDDO-Me 还通过减少腹腔液中促炎细胞因子的表达和 NFkB 激活来发挥抗炎作用。它继而降低了子宫内膜异位症部位的环氧化酶-2（COX-2）表达和腹腔液中的前列腺素 E2（PGE2）水平，导致细胞凋亡增加和血管生成减少。氧化应激和促炎微环境的减少降低了植入物的直径、面积和体积。特别是，CDDO-Me 给药减少了子宫内膜异位症的组织病理学征象和炎症细胞浸润到病变中，如甲苯胺蓝染色和髓过氧化物酶（MPO）活性所示。CDDO-Me 强烈抑制α-SMA 和纤维连接蛋白的表达和胶原蛋白沉积，减少与子宫内膜异位症相关的纤维化。总之，CDDO-Me 治疗通过调节 Nrf2 和 NFkB 途径导致子宫内膜异位症的协调和有效抑制。
