Fisetin mitigates hepatic ischemia-reperfusion injury by regulating GSK3β/AMPK/NLRP3 inflammasome pathway

作     者：Jun-Liang Pu Zuo-Tian Huang Yun-Hai Luo Tong Mou Ting-Ting Li Zhong-Tang Li Xu-Fu Wei Zhong-Jun Wu Jun-Liang Pu;Zuo-Tian Huang;Yun-Hai Luo;Tong Mou;Ting-Ting Li;Zhong-Tang Li;Xu-Fu Wei;Zhong-Jun Wu

作者机构：Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of AnatomyBasic Medical CollegeChongqing Medical UniversityChongqing 400016China 

出 版 物：《Hepatobiliary & Pancreatic Diseases International》 (国际肝胆胰疾病杂志（英文版）)

年 卷 期：2021年第20卷第4期

页      面：352-360页

核心收录：

学科分类：1008[医学-中药学(可授医学、理学学位)] 1006[医学-中西医结合] 100602[医学-中西医结合临床] 10[医学] 

基　　金：This study was supported by grants from the National Natural Science Foundation of China(81672959,81873592 and 81703063) the Science and Technology Commission Foundation of Chongqing,China(cstc2019jscx-gksb X0005) the Natural Science Foundation of Chongqing,China(cstc2018jscx-msyb X0133) the graduate tu-tor team construction project of Chongqing Municipal Education Commission Foundation,China(dstd201801) 

主　　题：Fisetin Hepatic ischemia-reperfusion injury GSK3βAMPK NLRP3 

摘      要：Background: Hepatic ischemia-reperfusion(I/R) injury(IRI) represents a crucial challenge in liver transplantation. Fisetin has anti-inflammatory, anti-aging and anti-oxidative properties. This study aimed to examine whether fisetin mitigates hepatic IRI and examine its underlying mechanisms. Methods: Sham or warm hepatic I/R operated mice were pretreated with fisetin(5, 10 or 20 mg/kg). Hepatic histological assessments, TUNEL assays and serum aminotransferase measurements were performed. An in vitro hypoxia/reoxygenation(H/R) model using RAW264.7 macrophages pretreated with fisetin(2.5, 5 or 10 μmol/L) was also used. Serum and cell supernatant concentrations of interleukin-1 β(IL-1 β), IL-18 and tumor necrosis factor-α(TNF-α) were determined by enzyme-linked immunosorbent assay(ELISA). Protein levels of p-GSK3 β, p-AMPK and NLR family pyrin domain-containing 3(NLRP3)-associated proteins were detected by Western blotting. Results: Compared with the I/R group, fisetin pretreatment reduced pathological liver damage, serum aminotransferase levels, serum concentrations of IL-1 β, IL-18 and TNF-α in the murine IRI model. Fisetin also reduced the expression of NLRP3 inflammasome-associated proteins(NLRP3, cleaved caspase-1, IL-1 β and IL-18) in I/R-operated liver. The experiments in vitro showed that fisetin decreased the release of IL-1 β, IL-18 and TNF-α, and reduced the expression of NLRP3 inflammasome-associated proteins in H/R-treated RAW264.7 cells. Moreover, fisetin increased the expressions of p-GSK3 β and p-AMPK in both models, indicating that its anti-inflammatory effects were dependent on GSK3 β/AMPK signaling. The antiinflammatory effects of fisetin were partially inhibited by the AMPK specific inhibitor compound C. Conclusions: Fisetin showed protective effects against hepatic IRI, countering inflammatory responses through mediating the GSK3 β/AMPK/NLRP3 inflammasome pathway.