Department of Biochemistry, Faculty of Pharmacy, Tanta University, Postal code: 31527, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Menoufia University, Postal code: 32511, Egypt.
Cytokine. 2020 Dec;136:155250. doi: 10.1016/j.cyto.2020.155250. Epub 2020 Sep 1.
Liver fibrosis is a serious health problem which may lead to advanced liver cirrhosis and hepatocellular carcinoma.
The present study aimed to investigate the role of Wnt/β-catenin signaling pathway and glutamine aminohydrolase enzyme (l-glutaminase) in the pathogenesis of liver fibrosis and the potential benefits of niclosamide in treating liver fibrosis.
Ninety male Albino rats were divided into 6 equal groups (n = 15) as follows: a normal control group (NC), CCl-only treated group (Fib.) which received 1 mg/kg CCl two times weekly, niclosamide-treated group (Niclo.) which received 5 mg/kg of niclosamide one time daily, lithium chloride-treated group (LiCl) which received 100 mg/kg of LiCl one time daily, niclosamide-and-CCl-treated group (Niclo. + Fib.) which received same doses of niclosamide and CCl given to other groups, and finally lithium chloride-and-CCl-treated rat group (LiCl + Fib.) which received same doses of LiCl and CCl given to other groups. All treatments were administered orally for 8 weeks. Liver tissue was assessed for l-hydroxyproline, beta-catenin (β-catenin), l-glutaminase activity, as well as the gene expression of transforming growth factor beta-1 (TGF-β1) and Dishevelled-2 (Dvl2). Histopathological and immunohistochemical analyses of alpha smooth muscle actin α-SMA were performed. Serum alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin were measured.
The group of niclosamide-and-CCl-treated rats showed a significant decrease in total bilirubin, ALT and AST, β-catenin, l-hydroxyproline, l-glutaminase activity, and gene expression of TGF-β1 and Dvl2. Moreover, the liver tissue in this group of rats showed mild α-SMA reactivity compared with the rats treated with CCl only (fibrosis group). On the other hand, lithium chloride-and-CCl-treated rats showed a significant increase in liver indices, TGF-β1 expression, β-catenin, l-hydroxyproline, and l-glutaminase activity with severe α-SMA reactivity and apoptosis in the liver tissue.
Niclosamide protected rats against liver fibrosis by inhibiting the Wnt/β-catenin pathway and glutaminolysis.
肝纤维化是一种严重的健康问题，可能导致晚期肝硬化和肝细胞癌。
本研究旨在探讨 Wnt/β-catenin 信号通路和谷氨酰胺氨基水解酶（l-谷氨酰胺酶）在肝纤维化发病机制中的作用，以及尼氯酰胺治疗肝纤维化的潜在益处。
将 90 只雄性白化大鼠随机分为 6 组（每组 15 只）：正常对照组（NC）、仅给予 CCl 处理组（Fib.），每周两次给予 1mg/kg CCl；给予尼氯酰胺处理组（Niclo.），每日给予 5mg/kg 尼氯酰胺；给予氯化锂处理组（LiCl），每日给予 100mg/kg 氯化锂；给予尼氯酰胺和 CCl 处理组（Niclo. + Fib.），给予其他组相同剂量的尼氯酰胺和 CCl；最后给予氯化锂和 CCl 处理组（LiCl + Fib.），给予其他组相同剂量的氯化锂和 CCl。所有治疗均为口服，共 8 周。评估肝组织羟脯氨酸、β-catenin（β-catenin）、l-谷氨酰胺酶活性以及转化生长因子-β1（TGF-β1）和 Dishevelled-2（Dvl2）的基因表达。进行α平滑肌肌动蛋白α-SMA 的组织病理学和免疫组织化学分析。测定血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和总胆红素。
给予尼氯酰胺和 CCl 的大鼠组总胆红素、ALT 和 AST、β-catenin、羟脯氨酸、l-谷氨酰胺酶活性以及 TGF-β1 和 Dvl2 的基因表达均显著降低。此外，与仅给予 CCl 的大鼠（纤维化组）相比，该组大鼠的肝组织 α-SMA 反应性较弱。另一方面，给予氯化锂和 CCl 的大鼠肝指数、TGF-β1 表达、β-catenin、羟脯氨酸和 l-谷氨酰胺酶活性显著增加，肝组织 α-SMA 反应性严重，细胞凋亡增加。
尼氯酰胺通过抑制 Wnt/β-catenin 通路和谷氨酰胺分解代谢来保护大鼠免受肝纤维化的影响。
