Uncovering the multi-target pharmacological mechanism of Xuebijing injection against sepsis by a systems pharmacology approach

摘要

Sepsis is a life-threatening organ dysfunction that is associated with a high risk of death.Xuebijing(XBJ)injection,a Chinese herbal compound preparation,has been widely used for the treatment of sepsis in China.The purpose of this research is to decipher the underlying multi-target pharmacological mechanism of XBJ in the treatment of sepsis using a systems pharmacology approach.Compounds in XBJ were collected by literature retrieval.The corresponding putative targets of XBJ were screened from the Traditional Chinese Medicine Systems Pharmacology(TCMSP),Swiss Target Prediction(STP),and Search Tool for Interacting Chemicals(STITCH)databases.Sepsis-related targets were summarized using the Genecards,DrugBank,and Online Mendelian Inheritance in Man(OMIM)databases.The intersection targets were obtained with Venny 2.1.Subsequently,protein-protein interaction(PPI)networks were constructed with the STRING database and Cytoscape 3.7.1.Then,degree,betweenness,and closeness were calculated to recognize the core targets in the PPI network.Moreover,the pharmacological mechanism of XBJ against sepsis was predicted via gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.After the literature review,the 33 most commonly cited chemical ingredients,were screened out as major compounds.Bioinformatics analysis revealed that the major compounds of XBJ modulated 218 common targets associated with sepsis.Through PPI network analysis,41 genes,including IL-6,AKT1,STAT3,TP53,and MAPK1,were identified as core targets.The results of GO and KEGG enrichment revealed that the potential biological functions of XBJ against sepsis were mainly involved in cytokine receptor binding,cytokine activity,growth factor receptor binding,growth factor activity,and chemokine activity.The crucial pathways were closely associated with initial immune activation(CLR/TLR4-NF-κB/MAPK pathway),the acute inflammatory response(TNFMAPK/caspase and IL-MAPK/STAT pathways),and the late inflammation and coagulation process(HMGB1-RAGE and HIF-1 signaling pathways).This study revealed that the multiple components of XBJ exert multitarget effects against sepsis by regulating initial immune activation,the acute inflammatory response,and the late inflammation and coagulation process.