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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01334

Isoorientin ameliorates APAP-induced hepatotoxicity via activation Nrf2 antioxidative pathway: the involvement of AMPK/Akt/GSK3β

 Xinxin Ci1*, xiaoye fan2, 3, hongming lv3, lidong wang3 and xuming deng3
  • 1Institute of Translational Medicine, The First Hospital of Jilin University, China
  • 2Jilin University, China
  • 3First Hospital, Jilin University, China

Oxidative stress has been highlighted as therapeutic targets for acetaminophen (APAP)-induced hepatotoxicity. Isoorientin (ISO), the most important flavonoid-like compound, has been shown to have antioxidant potential. However, the effect of isoorientin on APAP-induced liver injury has not yet been elucidated. The present study investigated the hepatoprotective effect and mechanism of isoorientin. C57BL/6J mice were used to evaluate the hepatoprotective effect of isoorientin in vivo and HepG2 cells were utilized to further decipher the mechanisms of isoorientin -induced Nrf2 activation. We found that isoorientin treatment significantly reduced APAP-induced hepatotoxicity by alleviating the lethality, histopathological liver changes, alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in serum. These were accompanied by decreasing malondialdehyde (MDA) formation, myeloperoxidase level (MPO), and superoxide dismutase (SOD) and glutathione (GSH) depletion. Moreover, isoorientin induced Nrf2 activation and translocation, as well as its upstream AMPK/Akt/GSK3β activation. Furthermore, isoorientin efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, Bax mitochondrial translocation, as well as apoptosis-inducing factor and cytochrome c release. Further mechanistic investigations reveal that activation of Nrf2 via the AMPK/Akt/GSK3β pathway a by isoorientin contribute to its hepatoprotetive activity in vitro. In addition, isoorientin-inhibited APAP-induced the lethality, histopathological changes and mitochondrial dysfunction in WT mice were almost abolished in Nrf2 -/- mice. In summary, isoorientin ameliorate APAP-induced hepatotoxicity by activating Nrf2 via AMPK/Akt/GSK3β pathway.

Keywords: Isoorientin, Acetaminophen, Nrf2, liver injury, AMPK

Received: 25 Jul 2018; Accepted: 30 Oct 2018.

Edited by:

Jinyong Peng, Dalian Medical University, China

Reviewed by:

Guoxun Chen, University of Tennessee, Knoxville, United States
Xufeng Tao, Dalian Medical University, China
Shasha Song, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China  

Copyright: © 2018 Ci, fan, lv, wang and deng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Xinxin Ci, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China, cixinxin@jlu.edu.cn