Abstract:

Objective To explore the effect and preliminary mechanism of plant extract ursolic acid（UA）inreducing hepatic ischemia/reperfusion injury（HIRI）. Methods C57 male mice were divided into sham operation group，sham operation +UA group，HIRI group，HIRI low-dose group and HIRI high-dose group. The analysis and validationwere carried out by methods such as animal experiments，network pharmacology and molecular biology. Results Animal experiments showed that UA significantly reduced the activities of AST and ALT in serum of HIRI mice. Target genescorresponding to HIRI and ursolic acid were obtained by TCMSP，Pharm Mapper，Swiss Target Prediction，GeneCards and other databases，and key target genes were obtained by DAVID，STRING and Cytoscape. They were PPARG （peroxisome proliferator-activated receptor gamma，PPARG），

MAPK3（mitogen-activated protein kinase 3，MAPK3） and PTGS2（prostaglandin G/H synthase 2，PTGS2）. Finally，PTGS2 was identified as the hub target gene in this study according to the molecular docking score and the number of hydrogen bonds binding between receptor and ligand. Compared with Sham operation group，PTGS2 was highly expressed in HIRI group（P ＜ 0.01）. Compared with HIRI group，the expression of PTGS2 in HIRI + LUA and HIRI + HUA groups was significantly decreased （P ＜ 0.01）. Conclusion UA can regulate the protective effect of PTGS2 on hepatic ischemia reperfusion injuryin mice. Thisstudy providesa reference for clinical development of new drugsto interveneHIRI.

Key words:

Ursolic acid , Hepatic ischemia/reperfusion injury , Prostaglandin G/H synthase 2 , Protective effect, Molecular docking

摘要：

目的 探索植物提取物熊果酸（ursolic acid，UA）减轻肝缺血 / 再灌注损伤（hepatic ischemia reperfusion injury，HIRI）的作用及初步作用机制。方法 C57 雄性小鼠分为假手术组、假手术组 +UA 组、HIRI 组、HIRI 低剂量组和 HIRI 高剂量组。通过动物实验、网络药理学和分子生物学等方法进行分析验证。 结果 动物实验显示 UA 显著降低 HIRI 小鼠血清中 AST、ALT 的活性。利用 TCMSP、Pharm Mapper、Swiss Target Prediction、GeneCards 等数据库获取熊果酸与 HIRI 对应的靶基因，再利用 DAVID、STRING 以及Cytoscape 得到初步关键靶基因，它们是 PPARG（peroxisome proliferator-activated receptor gamma，PPARG）、MAPK3（mitogen-activated protein kinase 3，MAPK3）及 PTGS2（prostaglandin G/H synthase 2，PTGS2）。最后，根据分子对接得分、受体与配体结合的氢键数目，确定 PTGS2 为本研究的 hub 靶基因。后经免疫组化实验验证，与假手术组比较，PTGS2 在 HIRI 组中高表达（P＜ 0.01）；与 HIRI 组比较，PTGS2 在 HIRI 低剂量组及HIRI高剂量组的表达明显降低（P＜0.01）。 结论 熊果酸通过调控PTGS2 对小鼠肝缺血/再灌注损伤的保护作用，该研究为临床研制干预 HIRI 的新药提供了参考。

关键词: 熊果酸 , 肝缺血 / 再灌注损伤 , PTGS2 , 保护作用 , 分子对接 ,