Zhang Jie, Fu Yiwei, Yang Bin, Xiang Xiaoxing
Department of Gastroenterology, Taizhou People's Hospital Affiliated to Medical College of Yangzhou University Taizhou 225300, Jiangsu, P. R. China.
Yangzhou University Medical College Yangzhou 225009, Jiangsu, P. R. China.
Am J Transl Res. 2022 Jun 15;14(6):4321-4336. eCollection 2022.
Total glucosides of paeony (TGP) has a myriad of hepatoprotective activities. However, its role in cirrhosis, a major risk factor for hepatocellular carcinoma, remains largely unexplored. Here, we determined the impact of TGP on liver fibrosis and inflammation in mice modeled by carbon tetrachloride with an aim to explore a possible molecular mechanism.
Liver fibrosis and inflammation in mice were evaluated using ELISA, hematoxylin-eosin, Masson's trichrome, immunohistochemical staining and TUNEL methods. The impact of TGP on gene expression in the liver tissues of the mice was investigated using microarray analysis, showing the most significant increase in expression of friend leukemia integration 1 transcription factor (FLI1). After loss-of-functions assays of FLI1, the downstream gene of FLI1 was searched by bioinformatics analysis and verified.
TGP reduced liver tissue damage, inhibited apoptosis, and alleviated liver fibrosis and inflammation in cirrhotic mice. FLI1 was downregulated in the liver of cirrhotic mice and lipopolysaccharide-treated hepatocytes, and TGP promoted the expression of FLI1. FLI1 depletion inhibited the effects of TGP on alleviating liver fibrosis and inflammatory responses in mice. FLI1 repressed Nod-like receptor protein 3 (NLRP3) transcription by binding to its promoter. Further silencing of NLRP3 in the presence of shFLI1 alleviated histopathological changes, inhibited apoptosis, and attenuated liver fibrosis and inflammatory responses in the liver of cirrhotic mice.
TGP promotes the expression of FLI1, which in turn inhibits NLRP3 expression, thereby reducing cirrhosis-induced liver fibrosis and inflammatory response in mice.
白芍总苷（TGP）具有多种肝脏保护活性。然而，其在肝硬化（肝细胞癌的主要危险因素）中的作用在很大程度上仍未得到探索。在此，我们确定了TGP对四氯化碳诱导的小鼠肝纤维化和炎症的影响，旨在探索可能的分子机制。
采用酶联免疫吸附测定（ELISA）、苏木精-伊红染色、Masson三色染色、免疫组织化学染色和TUNEL法评估小鼠的肝纤维化和炎症。使用微阵列分析研究TGP对小鼠肝组织基因表达的影响，结果显示Friend白血病整合1转录因子（FLI1）的表达显著增加。在对FLI1进行功能丧失实验后，通过生物信息学分析搜索并验证了FLI1的下游基因。
TGP减轻了肝硬化小鼠的肝组织损伤，抑制了细胞凋亡，并减轻了肝纤维化和炎症。FLI1在肝硬化小鼠肝脏和脂多糖处理的肝细胞中表达下调，而TGP促进了FLI1的表达。FLI1缺失抑制了TGP对减轻小鼠肝纤维化和炎症反应的作用。FLI1通过与其启动子结合抑制Nod样受体蛋白3（NLRP3）转录。在存在shFLI1的情况下进一步沉默NLRP3可减轻组织病理学变化，抑制细胞凋亡，并减轻肝硬化小鼠肝脏的肝纤维化和炎症反应。
TGP促进FLI1的表达，进而抑制NLRP3表达，从而减轻小鼠肝硬化诱导的肝纤维化和炎症反应。
