Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Food Chem Toxicol. 2023 Nov;181:114050. doi: 10.1016/j.fct.2023.114050. Epub 2023 Sep 20.
Doxorubicin induced cardiotoxicity (DIC) arises from mitochondrial dysfunction and oxidative stress. Oridonin (Ori), a natural tetracycline diterpenoid, has shown cardiac protective effect; however, its role in DIC remains unclear. This study investigates the protective effect of Ori against DIC and elucidates its underlying molecular mechanisms. The results demonstrate that Ori significantly alleviated DIC by improving myocardial structure, reducing the proportion of apoptotic cells, and alleviating the myocardial oxidative damage and mitochondrial dysfunction both in vivo and in vitro. Doxorubicin significantly decreased Sirt6 and PGC1α levels in cardiac tissues, which was reversed by Ori. Furthermore, Sirt6 overexpression significantly improved myocardial structure and reduced the proportion of apoptotic cells by reducing oxidative stress and improving mitochondrial function. The protective effect of Ori is neutralized by the Sirt6 inhibitor OSS_128167, evidenced by downregulated mRNA and protein expression of PGC1α. The transcription factor E2F1 was upregulated by doxorubicin, leading to decreased Sirt6 expression-an effect mitigated by Ori. Molecular docking simulations indicate direct binding between Ori and specific amino acid residues on E2F1 through hydroxyl bonds. These findings uncover a novel mechanism whereby Ori attenuates DIC by modulating the E2F1/Sirt6/PGC1α pathway.
多柔比星诱导的心脏毒性（DIC）源于线粒体功能障碍和氧化应激。冬凌草甲素（Ori）是一种天然的四环二萜类化合物，具有心脏保护作用；然而，其在 DIC 中的作用尚不清楚。本研究探讨了 Ori 对 DIC 的保护作用，并阐明了其潜在的分子机制。结果表明，Ori 通过改善心肌结构、减少凋亡细胞比例以及减轻心肌氧化损伤和线粒体功能障碍，在体内和体外均显著缓解 DIC。多柔比星显著降低了心脏组织中的 Sirt6 和 PGC1α 水平，而 Ori 则逆转了这一现象。此外，Sirt6 过表达通过减少氧化应激和改善线粒体功能，显著改善心肌结构并减少凋亡细胞比例。Sirt6 抑制剂 OSS_128167 中和了 Ori 的保护作用，表现为 PGC1α 的 mRNA 和蛋白表达下调。多柔比星上调转录因子 E2F1，导致 Sirt6 表达减少，而 Ori 减轻了这种作用。分子对接模拟表明 Ori 通过氢键与 E2F1 上的特定氨基酸残基直接结合。这些发现揭示了 Ori 通过调节 E2F1/Sirt6/PGC1α 通路来减轻 DIC 的新机制。
