Co-treatment of trigonelline and everolimus synergistically prevented chronic steatohepatitis induced by fast food diet and thioacetamide in a novel murine nonalcoholic steatohepatitis model.

IF 1.5 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Indian Journal of Pharmacology Pub Date : 2025-07-01 Epub Date: 2025-07-21 DOI:10.4103/ijp.ijp_323_23
Raghu Rai Sharma, Love Sharma, Haroon Rashid, Aalim Maqsood Bhat, Divya Gupta, Sheikh Abdullah Tasduq
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引用次数: 0

Abstract

Objectives: Nonalcoholic steatohepatitis (NASH) is a strong risk factor for end-stage liver disease. Trigonelline (TG) is a plant alkaloid with anti-oxidant, anti-dyslipidemic, and anti-insulin resistance activities. Everolimus (EV), a conventional drug and an mTOR inhibitor, has been demonstrated to improve metabolic outcomes. The synergistic effect of the co-treatment of TG and EV against NASH conditions remains unknown.

Materials and methods: We have developed a fast food (FF)-diet and thioacetamide-induced chronic steatohepatitis in a C57BL/6J mice model of 24 weeks duration. We have evaluated the synergistic protective effect of TG and EV at reduced doses to avoid any undesired toxic manifestations of the FF and thioacetamide. The study was demonstrated by comparative analysis across different groups after 24 weeks.

Results: Co-exposure to FF diet and thioacetamide resulted in chronic steatohepatitis, evident by focal necrosis, bridging fibrosis, loss of liver architecture, and excessive collagen deposition. Protein and gene analysis revealed enhanced de novo lipogenesis (SREBP-1, PPAR-Ƴ, CD36), inflammation (interleukin-6, tumor necrosis factor, CYP2E1), fibrosis (transforming growth factor beta, alpha-smooth muscle actin, tissue inhibitors of metalloproteinases-1), and extracellular matrix deposition (MMP-1, Col1A1). TG + EV at reduced doses showed marked synergistic effects in preventing inflammation, fibrosis, and lipogenesis markers.

Conclusion: This study provides a novel 24-week FF diet and thioacetamide-induced murine NASH model for possible preclinical drug discovery studies. Furthermore, our treatment regimen discovered the synergistic effect of TG and EV at reduced doses in preventing chronic steatohepatitis.

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葫芦巴碱和依维莫司联合治疗可协同预防快餐饮食和硫代乙酰胺诱导的小鼠非酒精性脂肪性肝炎模型。
目的:非酒精性脂肪性肝炎(NASH)是终末期肝病的一个重要危险因素。葫芦巴碱(TG)是一种具有抗氧化、抗血脂异常和抗胰岛素抵抗活性的植物生物碱。依维莫司(evolimus, EV)是一种传统药物和mTOR抑制剂,已被证明可以改善代谢结果。甘油三酯和EV联合治疗NASH的协同效应尚不清楚。材料与方法:采用快餐饮食和硫代乙酰胺诱导的C57BL/6J小鼠慢性脂肪性肝炎模型,持续24周。我们已经评估了TG和EV在减少剂量时的协同保护作用,以避免FF和硫乙酰胺的任何不希望的毒性表现。24周后,通过不同组间的比较分析证明了该研究的有效性。结果:共同暴露于FF饮食和硫乙酰胺导致慢性脂肪性肝炎,表现为局灶性坏死、桥式纤维化、肝脏结构丧失和过多的胶原沉积。蛋白和基因分析显示,新生脂肪生成(SREBP-1、PPAR-Ƴ、CD36)、炎症(白细胞介素-6、肿瘤坏死因子、CYP2E1)、纤维化(转化生长因子β、α -平滑肌肌动蛋白、金属蛋白酶组织抑制剂-1)和细胞外基质沉积(MMP-1、Col1A1)增强。减少剂量的TG + EV在预防炎症、纤维化和脂肪生成标志物方面显示出显著的协同作用。结论:本研究为可能的临床前药物发现研究提供了一种新的24周FF饮食和硫代乙酰胺诱导的小鼠NASH模型。此外,我们的治疗方案发现减少剂量的TG和EV在预防慢性脂肪性肝炎方面具有协同作用。
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来源期刊
CiteScore
4.00
自引率
4.20%
发文量
53
审稿时长
4-8 weeks
期刊介绍: Indian Journal of Pharmacology accepts, in English, review articles, articles for educational forum, original research articles (full length and short communications), letter to editor, case reports and interesting fillers. Articles concerning all aspects of pharmacology will be considered. Articles of general interest (e.g. methods, therapeutics, medical education, interesting websites, new drug information and commentary on a recent topic) are also welcome.
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