2. Academic Validation
  3. Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3β Signaling

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

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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