Abstract
Panax notoginseng mixture (PNM) has the characteristics of multicomponent, multitarget, and multieffect, which can cope with the multidirectional and multidimensional complex pathological process caused by hepatic ischemia/reperfusion injury (HIRI). Our animal experiments showed that PNM composed of notoginseng, dogwood, and white peony root could significantly reduce the level of aspartate transaminase and alanine aminotransferase in the blood of mice with HIRI, indicating that this preparation had a protective effect on HIRI in mice. Therefore, on this basis, the molecular mechanism of PNM intervention in HIRI was further explored by network pharmacology. First, target genes corresponding to active components and HIRI were obtained through databases such as TCMSP, Pharm Mapper, Swiss Target Prediction, GeneCards, and so on. All target genes were standardized by Uniprot database, and a total of 291 target genes with their intersection were obtained. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and biological processes (BPs) of 291 target genes were obtained through the online public platform of DAVID. A total of 177 KEGG pathways and 337 BPs were obtained by setting p < 0.01 and false discovery rate <0.05. The network mapping map of components and disease targets was drawn by Cytoscape, and the top 10 Hub target genes related to HIRI were obtained. At the same time, the String database was used to obtain the protein–protein interaction dataset, which was imported into Cytoscape, and the first 10 Hub target genes were obtained. The Hub target genes obtained by the above two methods were molecular docking with their corresponding small molecule compounds through DockThor online tool. The results showed that the docking of paeoniflorin with glyceraldehyde 3-phosphate dehydrogenase (GAPDH), paeoniflorin and loganin with SRC, ginsenoside Rb1 with NR3C2, ursolic acid and oleanolic acid with IL-6, paeoniflorin docking VEGFA, and MMP9. Finally, NR3C2, SRC, and GAPDH were identified as target genes in this study by referring to relevant literature reports. After verification by immunohistochemical experiments, compared with the sham group, the above three target genes were highly expressed in the HIRI group (p < 0.01). Compared with the HIRI group, the expression of three target genes in the PNM + HIRI group was significantly decreased (p < 0.01). The results showed that PNM could protect mouse HIRI by decreasing the expression of NR3C2, SRC, and GAPDH.
Highlights
Hepatic ischemia/reperfusion injury (HIRI) refers to the process of hepatic cells undergoing different degrees of apoptosis and necrosis during blood reperfusion after the temporary loss of blood supply, which aggravates hepatic function damage
For the HIRI and HIRI + Panax notoginseng mixture (PNM) groups, operation was performed for 1-h liver ischemia and 6-h reperfusion, whereas for the sham and sham + PNM group, only the hilum was dissociated without blocking the blood flow
Compared with the HIRI model group, the serum ALT and aspartate transaminase (AST) levels in the PNM group were significantly decreased (p < 0.01), indicating that PNM had a protective effect on HIRI mice
Summary
Hepatic ischemia/reperfusion injury (HIRI) refers to the process of hepatic cells undergoing different degrees of apoptosis and necrosis during blood reperfusion after the temporary loss of blood supply, which aggravates hepatic function damage. It is commonly seen in the process of hepatic transplantation, hepatic resection, hemorrhagic shock or trauma, and so on (Ito et al, 2019; Zhang et al, 2019). Intervention methods for HIRI mainly include ischemic preconditioning, drug intervention, monoclonal antibodies, signaling pathway inhibitors, cytokine antagonists, gene knockout and RNA interference, and so on (Peng et al, 2015). Most of these research ideas and methods are still in the stage of research and development, and there is still a long way to go before they can be really used in clinical practice to weaken or eliminate the efficacy of HIRI
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