Oridonin ameliorates doxorubicin induced-cardiotoxicity via the E2F1/Sirt6/PGC1 α pathway in mice

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.PMID:37734463 | DOI:10.1016/j.fct.2023.114050
Source: Food and Chemical Toxicology - Category: Food Science Authors: Source Type: research