Gentiopicroside Ameliorated Ductular Reaction and Inflammatory Response in DDC-induced Murine Cholangiopathies Model

Juan Hao; Jian Wu; Quanjun Yang; Kan Lu; Yi Xu; Yiyue Chen; Jibo Liu; Xiaohong Shao; Chunling Zhu; Yaqin Ding; Xin Xie

doi:10.2174/0118761429251911231011092145

Gentiopicroside Ameliorated Ductular Reaction and Inflammatory Response in DDC-induced Murine Cholangiopathies Model

Curr Mol Pharmacol. 2023 Oct 19. doi: 10.2174/0118761429251911231011092145. Online ahead of print.

Authors

Juan Hao¹, Jian Wu¹, Quanjun Yang¹, Kan Lu¹, Yi Xu¹, Yiyue Chen¹, Jibo Liu¹, Xiaohong Shao¹, Chunling Zhu¹, Yaqin Ding¹, Xin Xie²

Affiliations

¹ Department of Endocrinology, Shanghai TCM-Integrated Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Department of Pharmacy, Shanghai Sixth People Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, China.

PMID: 37881074
DOI: 10.2174/0118761429251911231011092145

Abstract

Background: Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress.

Objective: The present study aims to investigate the effect of GPS on 3,5-diethoxycarbonyl-1,4dihydrocollidine (DDC)-induced cholangiopathy.

Methods: Two independent animal experiments were designed to evaluate the comprehensive effect of GPS on chronic DDC diet-induced cholangiopathy, including bile duct obliteration, ductular reaction, BA metabolism reprogramming, liver fibrosis, oxidative stress and inflammatory responses.

Results: In the first pharmacological experiment, three doses of GPS (5, 25 and 125 mg/kg) were injected intraperitoneally into mice fed a DDC diet for 14 days. DDC induced a typical ductular reaction, increased periductal fibrosis and mixed inflammatory cell infiltration in the portal areas. GPS treatment showed dose-dependent improvements in the ductular reaction, BA metabolism, fibrosis, oxidative stress and inflammatory response. In the second experiment, a high dose of GPS was injected intraperitoneally into control mice for 28 days, resulting in no obvious histologic changes and significant serologic abnormalities in liver function. However, GPS inhibited DDC-induced oxidative stress, serum and hepatic BA accumulation, proinflammatory cytokine production, and immunocyte infiltration. Specifically, the GPS-treated groups showed decreased infiltration of monocyte-derived macrophages and CD4+ and CD8+ T lymphocytes, as well as preserved Kupffer cells.

Conclusion: GPS alleviated chronic DDC diet-induced cholangiopathy disorder by improving the ductular reaction, periductal fibrosis, oxidative stress and inflammatory response. Its dosage-dependent pharmacological effects indicated that GPS warrants its further evaluation in clinical trials for cholangiopathy.

Keywords: Bile acids; Cholangiopathies; Ductular reaction; Gentiopicroside; Inflammatory; ductular reaction.