Table1_Therapeutic Effects of an Inhibitor of Thioredoxin Reductase on Liver Fibrosis by Inhibiting the Transforming Growth Factor-β1/Smads Pathway.DOCX

Liver fibrosis is an important stage in the progression of liver injury into cirrhosis or even liver cancer. Hepatic stellate cells (HSCs) are induced by transforming growth factor-β1 (TGF-β1) to produce α-smooth muscle actin (α-SMA) and collagens in liver fibrosis. Butaselen (BS), which was previously synthesized by our group, is an organic selenium compound that exerts antioxidant and tumor cell apoptosis–promoting effects by inhibiting the thioredoxin (Trx)/thioredoxin reductase (TrxR) system. The aim of this study was to investigate the potential effects of BS on liver fibrosis and explore the underlying molecular mechanisms of its action. Liver fibrosis models were established using male BALB/c mice through intraperitoneal injection of CCl4. BS was administered orally once daily at a dose of 36, 90, or 180 mg/kg. Silymarin (Si), which is a drug used for patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, was administered at a dose of 30 mg/kg per day as a control. The action mechanisms of BS against liver fibrosis progression were examined in HSCs. The study revealed that the activity and expression levels of TrxR were elevated in the mouse liver and serum after CCl4-induced liver fibrosis. Oral administration of BS relieved the pathological state of mice with liver fibrosis, showing significant therapeutic effects against liver fibrosis. Moreover, BS not only induced HSC apoptosis but also inhibited the production of α-SMA and collagens by HSCs by downregulating the TGF-β1 expression and blocking the TGF-β1/Smads pathway. The results of the study indicated that BS inhibited liver fibrosis by regulating the TGF-β1/Smads pathway.

肝脏纤维化是肝脏损伤进展为肝硬化甚至肝癌的重要阶段。肝星状细胞（HSCs）在转化生长因子-β1（TGF-β1）的作用下，诱导生成α-平滑肌肌动蛋白（α-SMA）和胶原蛋白，从而引发肝脏纤维化。本课题组先前合成的有机硒化合物布他硒（BS），通过抑制硫氧还蛋白（Trx）/硫氧还蛋白还原酶（TrxR）系统，发挥抗氧化和促进肿瘤细胞凋亡的作用。本研究旨在探究BS对肝脏纤维化的潜在影响及其作用机制的分子基础。通过腹腔注射四氯化碳（CCl4）建立雄性BALB/c小鼠的肝脏纤维化模型。每日口服给予BS，剂量分别为36、90或180mg/kg。以30mg/kg/天的剂量给予非酒精性脂肪性肝病和非酒精性脂肪性肝炎患者使用的药物水飞蓟素（Si）作为对照。研究考察了BS对肝脏纤维化进展中HSCs作用机制的影响。研究发现，在CCl4诱导的肝脏纤维化后，小鼠肝脏和血清中TrxR的活性和表达水平升高。口服给予BS可缓解肝脏纤维化小鼠的病理状态，显示出显著的抗纤维化治疗效果。此外，BS不仅诱导HSC凋亡，还通过下调TGF-β1表达和阻断TGF-β1/Smads通路，抑制HSCs产生α-SMA和胶原蛋白。研究结果表明，BS通过调节TGF-β1/Smads通路抑制肝脏纤维化。