Liu Wei, Sun Meng, Wang Wen-Ting, Song Jian, Wang Chun-Mei, Mou Neng-Yan, Shao Tian-Qi, Zhang Zhi-Hong, Wang Meng-Yang, Sun Hai-Ming
College of Pharmacy, Beihua University, Jilin 132013, P. R. China.
School of Life Science, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, P. R. China.
Am J Chin Med. 2024;52(7):2187-2209. doi: 10.1142/S0192415X24500848. Epub 2024 Nov 19.
Cisplatin-evoked profound gastrointestinal symptomatology is one of the most common side effects of chemotherapy drugs, causing further gastrointestinal cell and intestinal mucosal injury. Ginsenoside Rh4 (G-Rh4), an active component extracted from red ginseng, possesses beneficial anti-oxidative and anti-apoptosis effects. This study aimed to assess the effectiveness of pharmacological intervention with G-Rh4 mitigating intestinal toxicity evoked by cisplatin in a murine model and in IEC-6 cells . Following oral administration for 10 days, G-Rh4 (10[Formula: see text]mg/kg and 20[Formula: see text]mg/kg) significantly increased the indicators of diamine oxidase (DAO) affected by cisplatin (20[Formula: see text]mg/kg) in mice, and histopathological analysis further indicated that G-Rh4 could effectively improve intestinal tissue morphology, as well as the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 [Formula: see text] (PGC-1[Formula: see text] pathway and autophagy-related proteins. Moreover, experiments demonstrated that G-Rh4 exerted a concentration-dependent increase in cell viability, while also inhibiting cytotoxicity and abnormal rise of reactive oxygen species (ROS). Notably, ROS also activate PGC-1[Formula: see text] protein and mediate the occurrence of mitochondrial autophagy and apoptosis pathways. The molecular docking approach was employed to dock G-Rh4 with PGC-1[Formula: see text] and AMPK, revealing a binding energy of [Formula: see text]7.3[Formula: see text]kcal/mol and [Formula: see text]8.1[Formula: see text]kcal/mol and indicating a tight interaction between the components and the target. G-Rh4 could reduce the expression of autophagy-related protein p62/p53, reduce the accumulation of autophagy products, and promote the flow of autophagy. In conclusion, G-Rh4 exerted protective effects against cisplatin-induced intestinal toxicity, at least partially through PGC-1[Formula: see text]-mediated autophagy and apoptosis.
顺铂引起的严重胃肠道症状是化疗药物最常见的副作用之一，会导致进一步的胃肠道细胞和肠黏膜损伤。人参皂苷Rh4（G-Rh4）是从红参中提取的一种活性成分，具有有益的抗氧化和抗凋亡作用。本研究旨在评估G-Rh4药物干预减轻顺铂在小鼠模型和IEC-6细胞中引起的肠道毒性的有效性。口服给药10天后，G-Rh4（10[公式：见正文]mg/kg和20[公式：见正文]mg/kg）显著提高了受顺铂（2×0[公式：见正文]mg/kg）影响的小鼠二胺氧化酶（DAO）指标，组织病理学分析进一步表明，G-Rh4可有效改善肠道组织形态，以及过氧化物酶体增殖物激活受体γ共激活因子1[公式：见正文]（PGC-1[公式：见正文]）途径和自噬相关蛋白的表达。此外，实验表明，G-Rh4可使细胞活力呈浓度依赖性增加，同时还可抑制细胞毒性和活性氧（ROS）的异常升高。值得注意的是，ROS还可激活PGC-1[公式：见正文]蛋白，并介导线粒体自噬和凋亡途径的发生。采用分子对接方法将G-Rh4与PGC-1[公式：见正文]和AMPK进行对接，结合能分别为[公式：见正文]7.3[公式：见正文]kcal/mol和[公式：见正文]8.1[公式：见正文]kcal/mol，表明各成分与靶点之间存在紧密相互作用。G-Rh4可降低自噬相关蛋白p62/p53的表达，减少自噬产物的积累，并促进自噬流。总之，G-Rh4对顺铂诱导的肠道毒性具有保护作用，至少部分是通过PGC-1[公式：见正文]介导的自噬和凋亡实现的。
