Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 7, 2020; 26(41): 6346-6360
Published online Nov 7, 2020. doi: 10.3748/wjg.v26.i41.6346
Dihydromyricetin ameliorates chronic liver injury by reducing pyroptosis
Quan-Cheng Cheng, Jing Fan, Xin-Wei Deng, Huai-Cun Liu, Hui-Ru Ding, Xuan Fang, Jian-Wei Wang, Chun-Hua Chen, Wei-Guang Zhang
Quan-Cheng Cheng, Xin-Wei Deng, Huai-Cun Liu, Hui-Ru Ding, Xuan Fang, Jian-Wei Wang, Chun-Hua Chen, Wei-Guang Zhang, Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
Jing Fan, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 202155, China
Author contributions: Cheng QC and Fan J performed the majority of experiments and analyzed the data; Fang X and Chen CH typeset the figures; Deng XW, Liu HC, Wang JW and Ding HR participated equally in treatment of the animals; Zhang WG designed and coordinated the research; Cheng QC wrote the paper.
Supported by National Natural Science Foundation of China, No. 81873769; and Beijing Municipal Natural Science Foundation, No. 7162098.
Institutional review board statement: The study was reviewed and approved by the Biomedical Ethics Committee of Peking University Institutional Review Board, No. LA2017100.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Peking University, No. SCXK 2016-0010.
Conflict-of-interest statement: There is no conflict of interest in this study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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/
Corresponding author: Wei-Guang Zhang, MD, PhD, Professor, Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, No. 38 Xueyuan Road, Haidian District, Beijing 100191, China. zhangwg@bjmu.edu.cn
Received: May 19, 2020
Peer-review started: May 19, 2020
First decision: July 29, 2020
Revised: July 30, 2020
Accepted: August 29, 2020
Article in press: August 29, 2020
Published online: November 7, 2020
Abstract
BACKGROUND

Chronic liver injury (CLI) is now a worldwide disease. However, there is no effective treatment. Pyroptosis plays an essential role in CLI. Dihydromyricetin (DHM) resists oxidation and protects the liver. We hypothesize that the beneficial effect of DHM on CLI is related to its effect on the expression of pyroptosis-related molecules. Therefore, we studied the influence of DHM on CLI and pyroptosis.

AIM

To study the role of pyroptosis in the pathogenesis of CLI and the therapeutic mechanism of DHM.

METHODS

Thirty-two mice were randomly divided into four groups: The control group was injected with olive oil, the carbon tetrachloride (CCl4) group was injected with CCl4, the vehicle group was injected with hydroxypropyl-β-cyclodextrin while injecting CCl4 and the DHM group was injected with DHM while injecting CCl4. After four weeks of treatment, liver tissues from the mice were stained with hematoxylin and eosin, and oil red O. Blood was collected from the angular vein for serological analysis. The severity of CLI was estimated. Some liver tissue was sampled for immunohistochemistry, Western blotting and quantitative reverse transcription PCR to observe the changes in pyroptosis-related molecules.

RESULTS

Serum total cholesterol, low density lipoprotein, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the CCl4 group were higher than those in the control group, and serum total cholesterol, low density lipoprotein, AST and ALT in the DHM group were lower than those in the vehicle group. Hematoxylin and eosin and oil red O staining showed that there were more lipid droplets in the CCl4 group than in the control group, and there were fewer lipid droplets in the DHM group than in the vehicle group. Western blotting showed that the expression of the pyroptosis-related molecules caspase-1, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and gasdermin D (GSDMD)-N in the CCl4 group was higher than that in the control group, while expression of these proteins in the DHM group was lower than that in the vehicle group. Quantitative reverse transcription PCR results showed that the expression of the pyroptosis-related genes caspase-1, NLRP3, GSDMD and interleukin-1β (IL-1β) in the CCl4 group was higher than that in the control group, while there was no significant change in NLRP3 and caspase-1 expression in the DHM group compared with that in the vehicle group, and the expression of GSDMD and IL-1β was decreased.

CONCLUSION

DHM improves CCl4-induced CLI and regulates the pyroptosis pathway in hepatocytes. DHM may be a potential therapeutic agent for CLI.

Keywords: Chronic liver injury, Dihydromyricetin, Pyroptosis, Carbon tetrachloride, Pathogenesis, Steatosis

Core Tip: We established a model of chronic liver injury (CLI) in mice by subcutaneous injection of CCL4 into the back. The effect of dihydromyricetin on improving CLI in terms of morphology and serum level was demonstrated, and the activation of pyroptosis in CLI and the regulation of pyroptosis by dihydromyricetin in terms of protein level and mRNA level were verified, respectively.