Curculigoside inhibits ferroptosis in ulcerative colitis through the induction of GPX4
Curculigoside inhibits ferroptosis in ulcerative colitis through the induction of GPX4
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DOI：
10.1016/j.lfs.2020.118356
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发表时间：
2020-10-15
期刊：
影响因子：
6.1
通讯作者：
Bai, Xia
中科院分区：
文献类型：
--
作者：
Wang, Shujun;Liu, Wei;Bai, Xia
兰花苷是从兰花中提取的具有多种生物活性的天然成分。然而，CUR是否保护溃疡性结肠炎（UC）和潜在的机制尚不清楚。在此，建立用葡聚糖硫酸钠（DSS）攻击的小鼠并施用CUR 7天。然后在体内测定组织病理学和铁凋亡调节剂。制备铁凋亡IEC-6细胞以研究CUR的潜在机制。结果表明，CUR可抑制小鼠结肠炎的疾病活动指数、组织损伤和细胞死亡。我们还发现，在患有结肠炎的小鼠中诱导了铁凋亡，如铁超负荷、GSH耗竭、ROS和MDA产生所证明的，伴随着SOD和GPX 4表达的降低。CUR治疗显着逆转DSS诱导的小鼠的这些变化的铁蛋白功能。此外，在H2 O2和六水合氯化铁联合作用下，CUR对IEC-6细胞的铁细胞凋亡也有类似的作用。有趣的是，我们发现CUR可以增加IEC-6细胞对硒的敏感性，并促进GPX 4的转录水平。GPX 4的敲除可显著阻断CUR对铁凋亡IEC-6细胞的保护作用，并阻断CUR对铁凋亡IEC-6细胞GSH、MDA含量和LDH活性的影响。综上所述，这些发现表明，CUR通过诱导GPX 4来防止UC中的铁凋亡，GPX 4是UC治疗的潜在药物。
Curculigoside (CUR) is natural ingredient from Curculigo orchioides Gaertn with multiple biological activities. However, whether CUR protects from ulcerative colitis (UC) and underlying mechanisms are unclear. Herein, mice challenged with dextran sulfate sodium (DSS) were established and administrated with CUR for 7 days. Then histological pathologies and ferroptosis regulators were determined in vivo. The ferroptotic IEC-6 cells were prepared to investigate the underlying mechanism of CUR. Results showed that CUR inhibited the disease ac-tivity index, histological damage and cell death in mice with colitis. We also found that ferroptosis was induced in mice with colitis, as evidenced by iron overload, GSH depletion, ROS and MDA production, accompanied by decreased expression of SOD and GPX4. CUR treatment significantly reversed these alterations of ferroptotic features in DSS-induced mice. Furthermore, similar effects of CUR on ferroptosis were observed in IEC-6 cells under the combined treatment of H2O2 and iron chloride hexahydrate. Interestingly, we found that CUR could increase the selenium sensitivity and promote GPX4 transcription level in IEC-6 cells. Knockdown of GPX4 significantly blocked the protective effects of CUR on cell death, GSH and MDA contents as well as LDH activity in ferroptotic IEC-6 cells. Taken together, these findings suggest that CUR protects against ferroptosis in UC by the induction of GPX4, which presents a potential agent for UC treatment.