2. Academic Validation
  3. Oridonin ameliorates doxorubicin induced-cardiotoxicity via the E2F1/Sirt6/PGC1α pathway in mice

Oridonin ameliorates doxorubicin induced-cardiotoxicity via the E2F1/Sirt6/PGC1α pathway in mice

  • Food Chem Toxicol. 2023 Sep 19;114050. doi: 10.1016/j.fct.2023.114050.
Dongsheng Yu 1,  Jiye Li 2,  Yu Wang 1,  Danfeng Guo 3,  Chunsheng Zhu 1,  Bao Sun 4,  Zheng Zhou 5
Affiliations

Affiliations

  • 1 Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
  • 2 Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
  • 3 Henan Research Centre for Organ Transplantation, Zhengzhou, 450000, China; Henan Key Laboratory for Digestive Organ Transplantation, Zhengzhou, 450000, China.
  • 4 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China. Electronic address: [email protected].
  • 5 Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China. Electronic address: [email protected].
PMID: 37734463 DOI: 10.1016/j.fct.2023.114050
Abstract

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.

Keywords

Doxorubicin induced cardiotoxicity; Mitochondrial; Oridonin; PGC1α; Sirt6.

Figures
Products