Table2_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.

肝纤维化是肝脏损伤进展至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，可诱导生成α-平滑肌肌动蛋白（α-SMA）和胶原蛋白，进而引发肝纤维化。由本课题组先前合成的有机硒化合物Butaselen（BS），通过抑制硫氧还原蛋白（Trx）/硫氧还原蛋白还原酶（TrxR）系统，发挥抗氧化和促进肿瘤细胞凋亡的效果。本研究旨在探讨BS对肝纤维化的潜在影响及其作用机制的分子基础。通过向雄性BALB/c小鼠腹腔注射四氯化碳（CCl4）建立肝纤维化模型。每日口服给予BS，剂量分别为36、90或180 mg/kg。作为对照，对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硅硫素（Si），每日给予30 mg/kg。本研究考察了BS对肝纤维化进展的拮抗作用机制。研究结果显示，在CCl4诱导的肝纤维化小鼠的肝脏和血清中，TrxR的活性和表达水平升高。口服给予BS可缓解肝纤维化小鼠的病理状态，显示出显著的抗肝纤维化治疗作用。此外，BS不仅诱导HSC凋亡，而且通过下调TGF-β1表达和阻断TGF-β1/Smads通路，抑制HSCs产生α-SMA和胶原蛋白。研究结果提示，BS通过调节TGF-β1/Smads通路抑制肝纤维化。