Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2017; 23(21): 3839-3849
Published online Jun 7, 2017. doi: 10.3748/wjg.v23.i21.3839
Inhibitory effect of oxymatrine on hepatocyte apoptosis via TLR4/PI3K/Akt/GSK-3β signaling pathway
Xian Zhang, Wei Jiang, Ai-Ling Zhou, Min Zhao, Dao-Rong Jiang
Xian Zhang, Dao-Rong Jiang, Department of Infectious Diseases, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
Wei Jiang, Department of Science Technology and Industry, Nantong University, Nantong 226019, Jiangsu Province, China
Ai-Ling Zhou, Department of Pathophysiology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
Min Zhao, Department of Pathology, Nantong Tumor Hospital, Nantong 226000, Jiangsu Province, China
Author contributions: Zhang X and Jiang W contributed equally to this work; Zhang X and Jiang W designed the study, performed the experiments and wrote the manuscript; Zhou AL and Zhao M analyzed the data; Jiang DR helped to review and edit the manuscript.
Supported by the Jiangsu Bureau of Traditional Chinese Medicine, No. YB2015177.
Institutional review board statement: The study was reviewed and approved by the Laboratory Animal Center of NTU.
Conflict-of-interest statement: We declare that there are no conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Dao-Rong Jiang, Department of Infectious Diseases, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Nantong 226001, Jiangsu Province, China. jdr@ntu.edu.cn
Telephone: +86-13606299378 Fax: +86-513-85052085
Received: December 1, 2016
Peer-review started: December 6, 2016
First decision: January 19, 2017
Revised: February 9, 2017
Accepted: March 2, 2017
Article in press: March 2, 2017
Published online: June 7, 2017
Processing time: 187 Days and 8.2 Hours
Abstract
AIM

To evaluate the effect of oxymatrine (OMT) on hepatocyte apoptosis in rats with lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver failure (ALF).

METHODS

LPS/D-GalN was used to establish a model of ALF in rats. To evaluate the effect of OMT, we assessed apoptosis by transmission electron microscopy, and the pathological changes in the liver by light microscopy with hematoxylin and eosin staining. An automated biochemical analyzer was used to measure serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Enzyme-linked immunosorbent assay was used to determine the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Western blotting was used to detect protein levels in liver tissues. Streptavidin peroxidase immunohistochemistry was used to observe expression of Toll-like receptor (TLR)4, active caspase-3, Bax and Bcl-2.

RESULTS

All rats in the normal control and OMT-pretreated groups survived. The mortality rate in the model group was 30%. OMT preconditioning down-regulated apoptosis of hepatocytes and ameliorated pathological changes in liver tissue. The levels of AST, ALT, TNF-α and IL-1β in the model group increased significantly, and were significantly reduced by OMT pretreatment. OMT pretreatment down-regulated expression of TLR4 and active caspase-3 and the Bax/Bcl-2 ratio, and up-regulated expression of P-AktSer473 (Akt phosphorylated at serine 473) and P-GSK3βSer9 (glycogen synthase kinase 3β phosphorylated at serine 9) induced by LPS/D-GalN.

CONCLUSION

OMT inhibits hepatocyte apoptosis by suppressing the TLR4/PI3K/Akt/GSK-3β signaling pathway, which suggests that OMT is an effective candidate for ameliorating acute liver failure.

Keywords: Oxymatrine; Acute liver failure; Toll-like receptor 4; Apoptosis

Core tip: The role of oxymatrine (OMT) in inhibiting apoptosis in acute liver failure (ALF) was investigated. OMT pretreatment protected liver cells by improving the liver pathological change and reducing serum aminotransferase in lipopolysaccharide/D-galactosamine-induced ALF in rats. OMT preconditioning down-regulated apoptosis of hepatocytes and ameliorated pathological changes in liver tissue. The levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-α and interleukin-1β in the model group increased significantly, and were significantly reduced by OMT pretreatment. OMT pretreatment down-regulated expression of Toll-like receptor (TLR)4 and active caspase-3 and the Bax/Bcl-2 ratio, and up-regulated expression of P-AKTSer473 and P-GSK3βSer9. OMT could inhibit hepatocyte apoptosis through the TLR4/PI3K/Akt/GSK-3β signaling pathway.