Luteolin-7-diglucuronide,a novel PTP1B inhibitor,ameliorates hepatic stellate cell activation and liver fibrosis in mice

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外文标题：Luteolin-7-diglucuronide,a novel PTP1B inhibitor,ameliorates hepatic stellate cell activation and liver fibrosis in mice

外文摘要：Liver fibrosis,one of the leading causes of morbidity and mortality worldwide,lacks effective therapy.The activation of hepatic stellate cells(HSCs)is the dominant event in hepatic fibrogenesis.Luteolin-7-diglucuronide(L7DG)is the major flavonoid extracted from Perilla frutescens and Verbena officinalis.Their beneficial effects in the treatment of liver diseases were well documented.In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms.We established TGF-β1-activated mouse primary hepatic stellate cells(pHSCs)and human HSC line LX-2 as in vitro liver fibrosis models.Co-treatment with L7DG(5,20,50 μM)dose-dependently decreased TGF-β1-induced expression of fibrotic markers collagen 1,α-SMA and fibronectin.In liver fibrosis mouse models induced by CCl4 challenge alone or in combination with HFHC diet,administration of L7DG(40,150 mg·kg-1·d-1,i.g.,for 4 or 8 weeks)dose-dependently attenuated hepatic histopathological injury and collagen accumulation,decreased expression of fibrogenic genes.By conducting target prediction,molecular docking and enzyme activity detection,we identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B(PTP1B)with an IC50 value of 2.10 μM.Further studies revealed that L7DG inhibited PTP1B activity,up-regulated AMPK phosphorylation and subsequently inhibited HSC activation.This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.

外文关键词：

liver fibrosisphytochemicalluteolin 7-diglucuronideHSC activationPTP1B

作者：

Bi-xi Tang、Yong Zhang、Dan-dan Sun、Qin-yi Liu、Cong Li、Pei-pei Wang、Li-xin Gao、Xue-mei Zhang、Jia Li、Wei-liang Zhu、Yi Zang

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作者单位：

Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 201203,China

Stake Key Laboratory of Chemical Biology,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

University of Chinese Academy of Sciences,100049 Beijing,China

Shandong Laboratory of Yantai Drug Discovery,Bohai Rim Advanced Research Institute for Drug Discovery,Yantai 264117,China

Lingang Laboratory,Shanghai 201203,China

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关键词：

liver fibrosis phytochemical luteolin 7-diglucuronide HSC activation PTP1B

出版年：

2025

DOI：

10.1038/s41401-024-01351-3

中国药理学报(英文版)

中科院上海药物研究所

中国药理学报(英文版)

影响因子：0.926

ISSN：1671-4083

年,卷(期)：2025.46(1)