Department of Obstetrics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, People's Republic of China.
Department of Gynecology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, People's Republic of China.
Acta Histochem. 2020 Dec;122(8):151620. doi: 10.1016/j.acthis.2020.151620. Epub 2020 Oct 14.
Preeclampsia is a pregnancy-specific syndrome and is one of the major causes of maternal mortality around the world. Cell apoptosis and oxidative stress are involved in development of preeclampsia. Silibinin has been known with anti-inflammatory, anti-oxidative and anti-tumor roles. In this study, hydrogen peroxide (HO) administration induced apoptosis in HTR-8/SVneo trophoblast cells, evidenced by decreased level of Bcl-2 and increased levels of Bax and cleaved caspase-3. Western blot and JC-1 staining revealed that HO led to decline of mitochondrial membrane potential (Δψm) and release of cytochrome C from mitochondria to cytoplasm. HO also resulted in reactive oxygen species production and oxidative stress response, evidenced by elevated levels of malondialdehyde, and reduced activity of superoxide dismutase and glutathione peroxidase. Silibinin suppressed HO-induced apoptosis, decrease of Δψm and oxidative stress response. In addition, immunofluorescent staining and electrophoretic mobility shift assay demonstrated that HO enhanced expression and nuclear translocation of nuclear factor-erythroid 2-like 2 (Nrf2), and the expression levels of heme oxygenases-1 and quinone oxidoreductase 1 were increased, suggesting the activation of Nrf2 signaling. The activity of Nrf2 signaling was further promoted by silibinin administration. Interestingly, the effect of silibinin on apoptosis and oxidative stress was abolished by interference RNA of Nrf2. In conclusion, we demonstrated that silibinin ameliorated HO-induced apoptosis and oxidative stress response by activating Nrf2 signaling in trophoblast cells. These findings may provide novel insights for treatment of preeclampsia.
子痫前期是一种妊娠特有的综合征，是全球孕产妇死亡的主要原因之一。细胞凋亡和氧化应激参与子痫前期的发生发展。水飞蓟素具有抗炎、抗氧化和抗肿瘤作用。在这项研究中，过氧化氢（HO）处理诱导 HTR-8/SVneo 滋养细胞凋亡，表现为 Bcl-2 水平降低，Bax 和 cleaved caspase-3 水平升高。Western blot 和 JC-1 染色显示，HO 导致线粒体膜电位（Δψm）下降和细胞色素 C 从线粒体释放到细胞质。HO 还导致活性氧（ROS）产生和氧化应激反应，表现为丙二醛水平升高，超氧化物歧化酶和谷胱甘肽过氧化物酶活性降低。水飞蓟素抑制 HO 诱导的凋亡、Δψm 下降和氧化应激反应。此外，免疫荧光染色和电泳迁移率变动分析显示，HO 增强了核因子红细胞 2 样 2（Nrf2）的表达和核转位，血红素加氧酶-1 和醌氧化还原酶 1 的表达水平增加，提示 Nrf2 信号通路的激活。水飞蓟素处理进一步促进了 Nrf2 信号通路的活性。有趣的是，Nrf2 的干扰 RNA 可消除水飞蓟素对凋亡和氧化应激的影响。总之，我们证明了水飞蓟素通过激活滋养细胞中的 Nrf2 信号通路改善了 HO 诱导的凋亡和氧化应激反应。这些发现可能为子痫前期的治疗提供新的思路。
