Department of Rehabilitation Medicine, Shunde Hospital of Southern Medical University, Foshan 528000, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Biomed Pharmacother. 2023 Dec 31;169:115815. doi: 10.1016/j.biopha.2023.115815. Epub 2023 Nov 11.
Celastrol, a natural compound purified from the Chinese herb Tripterygium wilfordii Hook. f., has excellent pharmacological activity for the treatment of various diseases. Assessing the safety of its use is essential for its development into a clinical medicine. However, research assessing its toxicity on the female reproductive system has never been reported. In this study, the ovarian toxicity of celastrol and its underlying mechanism were investigated. We found that celastrol induced premature ovarian insufficiency and apoptosis in granulosa cells. Activity-based protein profiling results showed that high mobility group box 1 was a candidate target protein of celastrol. Celastrol directly bound to Cys106 of high mobility group box 1. Knocking down high mobility group box 1 induced apoptosis of granulosa cells, while overexpression of this gene reversed celastrol-induced apoptosis. Celastrol treatment upregulated p21 transcription, but overexpression of high mobility group box 1 reversed this upregulation. Thus, Celastrol induces premature ovarian insufficiency and apoptosis in granulosa cells by directly binding to high mobility group box 1 and interfering with its biological function to regulate p21 transcription. This study provides valuable information for assessing the safety of the clinical application of celastrol on female patients.
从中国草药雷公藤中提取的天然化合物雷公藤红素具有治疗多种疾病的极佳药理活性。评估其使用安全性对于将其开发为临床医学至关重要。然而，关于其对女性生殖系统毒性的研究从未有过报道。在这项研究中，研究了雷公藤红素对卵巢的毒性及其潜在机制。研究发现，雷公藤红素诱导颗粒细胞过早卵巢功能不全和细胞凋亡。基于活性的蛋白质谱结果表明，高迁移率族蛋白 1 是雷公藤红素的候选靶蛋白。雷公藤红素直接与高迁移率族蛋白 1 的 Cys106 结合。敲低高迁移率族蛋白 1 诱导颗粒细胞凋亡，而过表达该基因则逆转了雷公藤红素诱导的凋亡。雷公藤红素处理上调了 p21 转录，但高迁移率族蛋白 1 的过表达逆转了这种上调。因此，雷公藤红素通过直接与高迁移率族蛋白 1 结合并干扰其生物学功能来调节 p21 转录，从而诱导颗粒细胞过早卵巢功能不全和细胞凋亡。这项研究为评估雷公藤红素在女性患者中的临床应用的安全性提供了有价值的信息。
