Farnesoid X receptor modulator 12β-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid represses liver fibrosis by inhibiting ERK/p38 signaling pathways.

IF 3.2 4区医学 Q1 Pharmacology, Toxicology and Pharmaceutics Toxicology Mechanisms and Methods Pub Date : 2024-09-01 Epub Date: 2024-05-14 DOI:10.1080/15376516.2024.2349551

Yiming Li, Yunyang Bao, Simin Guo, Yang Li, Weishuo Fang, Na Zhang, Hongwei He

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Abstract

Liver fibrosis is a common pathological process in the progression of several chronic liver diseases to cirrhosis and hepatocellular carcinoma. Therefore, the development of medications that can repress the progress of liver fibrosis is essential. We discovered that initially, 12β-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid (12d-OA), a farnesoid X receptor (FXR) modulator, possessed potential anti-fibrotic properties. Through an in-depth study, we revealed that 12d-OA not only inhibited the expression of fibrogenic markers in the LX-2 cells and HSC-T6 cells but also exhibited significant protective effects against liver injury and liver fibrosis in bile duct ligation (BDL) rats. Further exploration of its molecular mechanism indicated that 12d-OA exerted antifibrotic activity by inhibiting the extracellular signal-regulated kinase (ERK)/stress-activated protein kinase (p38) signaling pathways. Consequently, the great effects of 12d-OA in vitro and in vivo suggest that it may be a good candidate for liver fibrosis.

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类arnesoid X受体调节剂12β-（甲基苯甲酰基）-11,12-二氢齐墩果酸通过抑制ERK/p38信号通路抑制肝纤维化

肝纤维化是多种慢性肝病发展为肝硬化和肝细胞癌的常见病理过程。因此，开发能够抑制肝纤维化进程的药物至关重要。我们最初发现，12β-（间甲基苯甲酰基）-11,12-二氢齐墩果酸（12d-OA）是一种法尼类固醇 X 受体（FXR）调节剂，具有潜在的抗肝纤维化特性。通过深入研究，我们发现 12d-OA 不仅能抑制 LX-2 细胞和 HSC-T6 细胞中纤维化标志物的表达，而且对胆管结扎（BDL）大鼠的肝损伤和肝纤维化具有显著的保护作用。对其分子机制的进一步研究表明，12d-OA是通过抑制细胞外信号调节激酶（ERK）/应激激活蛋白激酶（p38）信号通路来发挥抗肝纤维化活性的。因此，12d-OA在体外和体内的巨大作用表明，它可能是一种治疗肝纤维化的良好候选药物。

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来源期刊

Toxicology Mechanisms and Methods 医学-毒理学

CiteScore

6.60

自引率

3.10%

发文量

审稿时长

6-12 weeks

期刊介绍： Toxicology Mechanisms and Methods is a peer-reviewed journal whose aim is twofold. Firstly, the journal contains original research on subjects dealing with the mechanisms by which foreign chemicals cause toxic tissue injury. Chemical substances of interest include industrial compounds, environmental pollutants, hazardous wastes, drugs, pesticides, and chemical warfare agents. The scope of the journal spans from molecular and cellular mechanisms of action to the consideration of mechanistic evidence in establishing regulatory policy. Secondly, the journal addresses aspects of the development, validation, and application of new and existing laboratory methods, techniques, and equipment. A variety of research methods are discussed, including: In vivo studies with standard and alternative species In vitro studies and alternative methodologies Molecular, biochemical, and cellular techniques Pharmacokinetics and pharmacodynamics Mathematical modeling and computer programs Forensic analyses Risk assessment Data collection and analysis.