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Antcin A alleviates pyroptosis and inflammatory response in Kupffercells of non-alcoholic fatty liver disease by targeting NLRP3
International Immunopharmacology ( IF 4.8 ) Pub Date : 2021-09-04 , DOI: 10.1016/j.intimp.2021.108126
Shuiliang Ruan 1 , Chenyang Han 2 , Yongjia Sheng 2 , Jin Wang 2 , Xiaohong Zhou 2 , Qiaobing Guan 2 , Wenyan Li 2 , Caiqun Zhang 2 , Yi Yang 2
Affiliation  

Pyroptosis, a pattern of inflammatory death, is regulated by NLRP3-Caspase-1 inflammasome and GSDMD-FL protein. Antcin A is a small triterpenoid molecule. In this study, Kupffer cells (KC) were used for in vitro model, which were treated with LPS and Nigericin (L/N) to induce pyroptosis. ELISA was used to determine the influence of Antcin A on the expression of inflammatory factors, IF was utilized to investigate NLRP3 and Caspase-1, PI staining was used to detect the opening level of membrane pores in KCs, C57BL/6J wild-type mice were fed with high-fat diet to construct a NAFLD model, and were simultaneously treated with Antcin A. H&E staining was used to detect hepatic pathological changes in mice, oil red staining was utilized to detect hepatic fat deposits in mice, IHC was used to detect the expression of NLRP3 and Caspase-1, Western blot was used to detect the expression levels of NLRP3 inflammasome (including NLRP3, ASC, Caspase-1, GSDMD-FL and GSDMD-NT). Pull-down assay and immunoprecipitation assay were used to detect the binding between Antcin A and NLRP3. As a result, Antcin A could significantly inhibit the occurrence of pyrolysis, decrease the expression of inflammatory factors, inhibit the activation and assembly of NLRP3 inflammasome, and significantly down-regulate the expression of NLRP3, Caspase-1 and GSDMD-NT in KCs. In NAFLD mice, Antcin A could suppress the inflammatory response in liver tissues of mice, reduce lipid deposition, down-regulate the levels of ALT and AST, and improve liver function in mice. Antcin A could also inhibit the activation of NLRP3 inflammasome in liver tissue and decrease the level of inflammatory factors. In the study of mechanism, we revealed that Antcin A could inhibit the assembly and activation of NLRP3 inflammasome by binding with NLRP3.

In summary, in this study, we found that Antcin A could inhibit pyroptosis in KC and alleviate the inflammatory response of liver tissue in NAFLD by targeting NLRP3 inflammasome, which was one of the mechanisms of Anctin A in protecting liver.



中文翻译:

Antcin A 通过靶向 NLRP3 减轻非酒精性脂肪肝 Kupffer 细胞的焦亡和炎症反应

Pyroptosis 是一种炎症性死亡模式,由 NLRP3-Caspase-1 炎性体和 GSDMD-FL 蛋白调节。Antcin A 是一种小的三萜类分子。在本研究中,Kupffer 细胞 (KC) 用于体外模型,用 LPS 和 Nigericin (L/N) 处理诱导细胞焦亡。ELISA检测Antcin A对炎症因子表达的影响,IF检测NLRP3和Caspase-1,PI染色检测KCs、C57BL/6J野生型小鼠膜孔开放水平采用高脂饮食构建NAFLD模型,同时给予Antcin A处理。H&E染色检测小鼠肝脏病理变化,油红染色检测小鼠肝脏脂肪沉积,IHC检测小鼠肝脏脂肪沉积。检测NLRP3和Caspase-1的表达,Western blot检测NLRP3炎症小体(包括NLRP3、ASC、Caspase-1、GSDMD-FL和GSDMD-NT)的表达水平。采用下拉法和免疫沉淀法检测Antcin A与NLRP3的结合。因此,Antcin A 可显着抑制热解的发生,降低炎症因子的表达,抑制 NLRP3 炎性体的活化和组装,并显着下调 KCs 中 NLRP3、Caspase-1 和 GSDMD-NT 的表达。在NAFLD小鼠中,Antcin A可以抑制小鼠肝组织炎症反应,减少脂质沉积,下调ALT和AST水平,改善小鼠肝功能。Antcin A还可以抑制肝组织中NLRP3炎症小体的激活,降低炎症因子水平。

综上所述,本研究发现Antcin A可通过靶向NLRP3炎症小体抑制KC细胞焦亡,减轻NAFLD肝组织的炎症反应,这是Antcin A保护肝脏的机制之一。

更新日期:2021-09-04
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