Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3β Signaling

  • Molecules. 2018 Dec 29;24(1):110. doi: 10.3390/molecules24010110.
Huachao Li  1  2  3 ,  Yueming Chen  4  5  6 ,  Jiahao Zhang  7  8  9 ,  Xiangcui Chen  10  11  12 ,  Zheng Li  13  14 ,  Bing Liu  15  16  17 ,  Luyong Zhang  18  19  20
Affiliations
  • 1. Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 2. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 3. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 4. Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 5. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 6. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 7. Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 8. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 9. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 10. Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 11. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 12. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 13. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 14. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 15. Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 16. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 17. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 18. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 19. Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
  • 20. The Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China. [email protected].
PMID: 30597971 DOI: 10.3390/molecules24010110
Abstract

Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and Reactive Oxygen Species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice. SHK rescued the cell viability and GSH depletion, but neutralized oxidative stress in APAP-treated human normal liver L-02 cells. Mechanically, SHK increased Nrf2 expression in the exposure of APAP at the protein level but not at the mRNA level. Inhibition of Nrf2 blocked the SHK effect in APAP-treated hepatocytes. Furthermore, SHK improved Nrf2 stability through stimulating PI3K/Akt pathway, thus inhibiting GSK-3β. In vivo studies confirmed the close correlation of liver protection of SHK against APAP and Akt/GSK-3β/Nrf2 pathway. In conclusion, this study reveals that SHK prevents APAP hepatotoxicity by upregulation of Nrf2 via PI3K/Akt/GSK-3β pathway. Therefore, SHK may be a promising candidate against APAP-induced liver injury.

Keywords
GSK-3β; Nrf2; PI3K/Akt pathway; acetaminophen; hepatotoxicity; shikonin.
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