Tohamy Mohamed A, Muhammed Hisham R, Mahmoud Mohamed O
Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Bioorg Chem. 2025 Aug;163:108755. doi: 10.1016/j.bioorg.2025.108755. Epub 2025 Jul 16.
Non-alcoholic steatohepatitis (NASH) is a progressive hepatic disease that can advance into hepatocellular fibrosis, cirrhosis, and carcinoma. This study evaluates the therapeutic potential of Nebivolol on a diet-induced NASH rat model. Out of 32 male Wistar albino rats, 24 rats were fed a NASH-inducing diet for 8 weeks. The remaining were kept on a normal diet as healthy controls. After the induction phase, the NASH group was divided into three equal subgroups: an untreated NASH group and two treatment groups receiving 5 or 10 mg/kg/day of Nebivolol orally for six weeks. The NASH model demonstrated significantly higher levels of lipid profile, glucose, hepatic enzymes, Interleukin-1 beta (IL-1β), and malondialdehyde. NASH group also showed downregulation of endothelial nitric oxide synthase (e-NOS), AMP-activated protein kinase (AMPK), Beclin-1, and Peroxisome proliferator-activated receptor alpha (PPAR-α) with upregulation of mammalian target of rapamycin (mTOR) and sterol regulatory element-binding proteins (SREBP). The liver histopathology showed hepatocellular steatosis, fibroblastic proliferation, and inflammation. Immunohistochemical analysis revealed elevated transforming growth factor beta (TGF-β1) and α-smooth muscle actin (α-SMA) compared to normal control. Nebivolol administration dose-dependently reduced oxidative stress, inflammation, lipid profile, glucose, and hepatic enzymes. Besides, nebivolol downregulated mTOR, SREBP, TGF-β1, and α-SMA while inducing e-NOS, AMPK, PPAR-α, and Beclin-1 signaling. The histopathology of Nebivolol-treated rats revealed a noticeable improvement in hepatic architecture, characterized by reduced steatosis, inflammation, and fibrosis. Nebivolol exerts a multi-targeted hepatoprotective effect against NASH, mainly mediated through the modulation of AMPK/mTOR and TGF-β1/α-SMA pathways, besides restoration of NO and eNOS signaling. These findings highlight Nebivolol as a promising candidate for the management of NASH and related liver disorders.
非酒精性脂肪性肝炎（NASH）是一种进行性肝病，可发展为肝细胞纤维化、肝硬化和肝癌。本研究评估了奈必洛尔对饮食诱导的NASH大鼠模型的治疗潜力。在32只雄性Wistar白化大鼠中，24只大鼠接受诱导NASH的饮食8周。其余大鼠保持正常饮食作为健康对照。诱导期结束后，NASH组被分为三个相等的亚组：未治疗的NASH组和两个治疗组，分别口服5或10mg/kg/天的奈必洛尔，持续六周。NASH模型显示血脂、血糖、肝酶、白细胞介素-1β（IL-1β）和丙二醛水平显著升高。NASH组还显示内皮型一氧化氮合酶（e-NOS）、AMP激活蛋白激酶（AMPK）、Beclin-1和过氧化物酶体增殖物激活受体α（PPAR-α）下调，而雷帕霉素哺乳动物靶点（mTOR）和固醇调节元件结合蛋白（SREBP）上调。肝脏组织病理学显示肝细胞脂肪变性、成纤维细胞增殖和炎症。免疫组织化学分析显示，与正常对照相比，转化生长因子β（TGF-β1）和α平滑肌肌动蛋白（α-SMA）升高。给予奈必洛尔剂量依赖性地降低氧化应激、炎症、血脂、血糖和肝酶。此外，奈必洛尔下调mTOR、SREBP、TGF-β1和α-SMA，同时诱导e-NOS、AMPK、PPAR-α和Beclin-1信号通路。奈必洛尔治疗大鼠的组织病理学显示肝脏结构有明显改善，其特征为脂肪变性、炎症和纤维化减轻。奈必洛尔对NASH具有多靶点肝保护作用，主要通过调节AMPK/mTOR和TGF-β1/α-SMA途径介导作用，此外还可恢复NO和eNOS信号通路。这些发现突出了奈必洛尔作为治疗NASH和相关肝脏疾病的有前景的候选药物。
