Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside F1 attenuates pirarubicin-induced cardiotoxicity by modulating Nrf2 and AKT/Bcl-2 signaling pathways

  • Yang, Zhang (Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University) ;
  • Jiulong, Ma (Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University) ;
  • Shan, Liu (Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University) ;
  • Chen, Chen (Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University) ;
  • Qi, Li (Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University) ;
  • Meng, Qin (Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University) ;
  • Liqun, Ren (Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University)
  • Received : 2022.02.08
  • Accepted : 2022.06.28
  • Published : 2023.01.02
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Abstract

Background: Pirarubicin (THP) is an anthracycline antibiotic used to treat various malignancies in humans. The clinical usefulness of THP is unfortunately limited by its dose-related cardiotoxicity. Ginsenoside F1 (GF1) is a metabolite formed when the ginsenosides Re and Rg1 are hydrolyzed. However, the protective effects and underlying mechanisms of GF1 on THP-induced cardiotoxicity remain unclear. Methods: We investigated the anti-apoptotic and anti-oxidative stress effects of GF1 on an in vitro model, using H9c2 cells stimulated by THP, plus trigonelline or AKT inhibitor imidazoquinoxaline (IMQ), as well as an in vivo model using THP-induced cardiotoxicity in rats. Using an enzyme-linked immunosorbent test, the levels of malondialdehyde (MDA), brain natriuretic peptide (BNP), creatine kinase (CK-MB), cardiac troponin (c-TnT), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione (GSH) were determined. Nuclear factor (erythroid-derived2)-like 2 (Nrf2) and the expression of Nrf2 target genes, including heme oxygenase-1 (HO-1), glutathione-S-transferase (Gst), glutamate-cysteine ligase modifier subunit (GCLM), and expression levels of AKT/Bcl-2 signaling pathway proteins were detected using Western blot analysis. Results: THP-induced myocardial histopathological damage, electrocardiogram (ECG) abnormalities, and cardiac dysfunction were reduced in vivo by GF1. GF1 also decreased MDA, BNP, CK-MB, c-TnT, and LDH levels in the serum, while raising SOD and GSH levels. GF1 boosted Nrf2 nuclear translocation and Nrf2 target gene expression, including HO-1, Gst, and GCLM. Furthermore, GF1 regulated apoptosis by activating AKT/Bcl-2 signaling pathways. Employing Nrf2 inhibitor trigonelline and AKT inhibitor IMQ revealed that GF1 lacked antioxidant and anti-apoptotic effects. Conclusion: In conclusion, GF1 was found to alleviate THP-induced cardiotoxicity via modulating Nrf2 and AKT/Bcl-2 signaling pathways, ultimately alleviating myocardial oxidative stress and apoptosis.

Keywords

Acknowledgement

This work was supported by funding from the National Natural Science Foundation of China (No. 81773934).

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