Gandouling inhibits hepatic fibrosis in Wilson's disease through Wnt-1/β-catenin signaling pathway

Chenglong Cheng; Qiang Wang; Yurong Huang; Qiuyun Xue; Yuting Wang; Peng Wu; Faxue Liao; Chenggui Miao

doi:10.1016/j.jep.2023.116445

Gandouling inhibits hepatic fibrosis in Wilson's disease through Wnt-1/β-catenin signaling pathway

J Ethnopharmacol. 2023 Jul 15:311:116445. doi: 10.1016/j.jep.2023.116445. Epub 2023 Apr 2.

Authors

Chenglong Cheng¹, Qiang Wang², Yurong Huang³, Qiuyun Xue⁴, Yuting Wang⁵, Peng Wu⁶, Faxue Liao⁷, Chenggui Miao⁸

Affiliations

¹ Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China. Electronic address: chenglongcheng2019@stu.ahtcm.edu.cn.
² Department of Pharmaceutical Preparation, School of Life and Health Sciences, Anhui University of Science and Technology, China. Electronic address: wangqiang@ahstu.edu.cn.
³ Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China. Electronic address: yuronghuang2019@stu.ahtcm.edu.cn.
⁴ Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China. Electronic address: xueqiuyun2019@stu.ahtcm.edu.cn.
⁵ Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China. Electronic address: yutingwang@stu.ahtcm.edu.cn.
⁶ Department of Anatomy, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China. Electronic address: azywupeng@ahtcm.edu.cn.
⁷ Department of Orthopaedics, The First Affiliated Hospital, Anhui Medical University, Hefei, China; Anhui Public Health Clinical Center, Hefei, China. Electronic address: liaofaxue@126.com.
⁸ Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China. Electronic address: miaocg@ahtcm.edu.cn.

PMID: 37015279
DOI: 10.1016/j.jep.2023.116445

Abstract

Ethnopharmacologic significance: Wilson's disease (WD) hepatic fibrosis is the result of chronic liver injury induced by Cu²⁺ deposition in the liver. Gandouling (GDL) is a hospital preparation of the First Affiliated Hospital of Anhui University of Chinese Medicine. Previous studies have found that GDL can play an anti-inflammatory, anti-oxidation, and promote Cu²⁺ excretion, which has a clear anti-WD effect.

Aim of the study: We found that Wnt-1 was significantly up-regulated in the liver tissue of toxic-milk (TX) mouse in the WD gene mutant model, and the monomer components of GDL could combine well with Wnt-1. Therefore, in this work, we used RT-qPCR, Western blot, immunofluorescence, network pharmacology, molecular docking, and related methods to study the effects of GDL on hepatic stellate cell (HSC) activation and Wnt-1/β-catenin pathway in TX mice to clarify the effect of GDL on WD hepatic fibrosis.

Results: GDL could alleviate hepatic fibrosis, improve liver function, and inhibit the activation of HSC in TX mice. Network pharmacology predicted that the Wnt-1/β-catenin was the target of GDL, and molecular dynamics further revealed that GDL has a good binding ability with Wnt-1 and inhibits the Wnt/β-catenin signaling pathway through Wnt-1. Furthermore, we found that GDL blocked the Wnt-1/β-catenin signaling pathway in the liver of TX mice in vivo. In vitro, serum containing GDL blocked the Cu²⁺ ion-induced Wnt-1/β-catenin signaling pathway in LX-2 cells. Therefore, GDL blocked the Wnt-1/β-catenin signaling pathway, inhibited HSC activation, and improved WD hepatic fibrosis by binding to Wnt-1.

Conclusion: GDL improves hepatic fibrosis in WD model mice by blocking the Wnt-1/β-catenin signaling pathway, and Wnt-1 may be a new target for the diagnosis and treatment of WD. This reveals a new mechanism of GDL against WD, and promotes the clinical promotion of GDL.

Keywords: Gandouling; Hepatic fibrosis; Hepatic stellate cells; Wilson's disease; Wnt-1/β-catenin signaling pathway.

MeSH terms

Animals
Cell Proliferation
Hepatic Stellate Cells
Hepatolenticular Degeneration* / drug therapy
Hepatolenticular Degeneration* / metabolism
Hepatolenticular Degeneration* / pathology
Liver Cirrhosis / metabolism
Mice
Molecular Docking Simulation
Wnt Signaling Pathway
beta Catenin / metabolism

Substances

beta Catenin