Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
Department of Clinical pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
Toxicol Appl Pharmacol. 2020 Nov 15;407:115246. doi: 10.1016/j.taap.2020.115246. Epub 2020 Sep 19.
Mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-ĸB signaling have been recognized for their causal connection with liver fibrosis. Hence, it is encouraging to discover drugs that can modify the interactions between these signaling cascades. It has been suggested that glucagon-like peptide-1 receptors (GLP-1Rs) might have a role in the observed hepatoprotection of dipeptidyl peptidase-4 inhibitors other than vildagliptin (VLD). Consequently, we aimed to elucidate the mechanisms underlying its potential antifibrotic activity in a CCl-intoxicated mouse model. VLD increased the percentage of viable CCl-intoxicated primary rat hepatocytes in vitro. It also attenuated hepatic fibrosis, improved liver function, and prolonged survival of CCl-intoxicated mice in a dose-dependent manner. This hepatoprotection might be mediated mainly through interference with extracellular signal-regulated protein kinase 1/2 phosphorylation, the most downstream signal of the MAPK pathway. In addition, VLD hepatoprotective activity could be partially mediated through inhibition of p38α phosphorylation and phosphorylation-induced NF-ĸB activation. As a result, VLD downregulated profibrogenic mediators, such as tumor necrosis factor α, transforming growth factor β, tissue inhibitor of metalloproteinase 1 and platelet-derived growth factor BB. Consequently, decreased expression levels of fibrosis markers, such as hydroxyproline and α smooth muscle actin, were confirmed. VLD showed a strong trend toward increasing the antioxidant defense machinery of fibrotic tissue, and we confirmed that GLP-1Rs were not implicated in the observed hepatoprotection. Since VLD poses little risk of hypoglycemia and is a safe drug for patients with liver injury, it may be a hopeful candidate for adjuvant treatment of liver fibrosis in humans.
丝裂原活化蛋白激酶（MAPK）和核因子（NF）-κB 信号通路已被证实与肝纤维化的发生有因果关系。因此，发现能够改变这些信号级联相互作用的药物令人鼓舞。有人认为，胰高血糖素样肽-1 受体（GLP-1R）可能除维格列汀（VLD）外，在二肽基肽酶-4 抑制剂观察到的肝保护中发挥作用。因此，我们旨在阐明其在 CCl4 中毒的小鼠模型中潜在抗纤维化活性的机制。VLD 增加了体外 CCl4 中毒原代大鼠肝细胞的存活率。它还以剂量依赖的方式减轻肝纤维化、改善肝功能并延长 CCl4 中毒小鼠的存活时间。这种肝保护作用可能主要通过干扰细胞外信号调节蛋白激酶 1/2 磷酸化来介导，这是 MAPK 途径的最下游信号。此外，VLD 的肝保护活性部分可通过抑制 p38α 磷酸化和磷酸化诱导的 NF-κB 激活来介导。结果，VLD 下调了促纤维化介质，如肿瘤坏死因子α、转化生长因子β、金属蛋白酶组织抑制剂 1 和血小板衍生生长因子 BB。因此，纤维化标志物如羟脯氨酸和α平滑肌肌动蛋白的表达水平降低。VLD 表现出强烈的趋势，增加了纤维化组织的抗氧化防御机制，我们证实 GLP-1R 未参与观察到的肝保护作用。由于 VLD 低血糖风险低，并且是肝损伤患者的安全药物，因此它可能是人类肝纤维化辅助治疗的有希望的候选药物。
