Original Research ARTICLE
Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Protects Against Acetaminophen-Induced Hepatotoxicity
- 1Institute of Translational Medicine, The First Hospital of Jilin University, China
- 2Department of Nephrology, First Hospital of Jilin University, China
- 3Key Laboratory of Zoonosis, Ministry of Education, Jilin University, China
Acetaminophen (APAP) overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2) is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A) upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our ﬁndings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t-BHP)- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species (ROS) generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element (ARE) promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure (ALF) by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, malondialdehyde (MDA) formation, myeloperoxidase (MPO) level and superoxide dismutase (SOD) depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase (JNK) phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor (AIF) and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2 -/- mice. These investigations firstly implicated that Lico A has protective potential against APAP-induced hepatotoxicity which may be strongly associated with the Nrf2-mediated defense mechanisms.
Keywords: Licochalcone A;, Acetaminophen;, hepatotoxicity;, Nrf2;, Oxidative Stress;
Received: 08 Dec 2017;
Accepted: 12 Feb 2018.
Edited by:Jinyong Peng, Dalian Medical University, China
Reviewed by:Martin Roderfeld, Justus Liebig Universität Gießen, Germany
Xufeng Tao', Dalian Medical University, China
Copyright: © 2018 Ci, Lv, Xiao, Zhou, Feng and Liu. 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 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: Mrs. Xinxin Ci, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China, firstname.lastname@example.org