血清药物化学与网络药理学解析开心散"异病同治"作用机制OA

Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UHPLC/Q-TOF-MS),net-work pharmacology,and molecular docking approaches were integrated to investigate the potential molecular mechanism of Kaixin San in treating the comorbidity of depression and cognitive impairment.Firstly,UHPLC/Q-TOF-MS technology was employed to identify the chemical constituents of Kaixin San and its absorbed components in rat plasma.Active compounds were screened by combining these results with the Traditional Chinese Medicine Systems Pharmacology Database(TCMSP)and Analysis Platform,thereby constructing a potential active compound library for Kaixin San.Common targets for depression and cognitive dysfunction were obtained from databases such as GeneCards and DrugBank.A"compound-disease-target"regulatory network was constructed using Cytoscape 3.9.1.A protein-protein interaction(PPI)network was built using the search tool for the retrieval of interacting genes/proteins(STRING)database to screen for core targets.Gene Ontology(GO)functional enrichment analysis and Kyoto Ency-clopedia of Genes and Genomes(KEGG)pathway enrichment analysis of the core targets were performed using the Metascape plat-form.Finally,molecular docking validation was conducted using AutoDock Vina 1.2.2.A total of 81 chemical components were identified from Kaixin San,35 of which were absorbed into the bloodstream.From database screening,41 potential active com-pounds and their corresponding 178 targets were obtained.A total of 2 513 depression-related targets and 2 082 cognitive dysfunc-tion-related targets were retrieved.By intersecting these disease targets with the compound targets,56 common targets were identi-fied.GO enrichment analysis indicated that these targets are primarily involved in biological processes such as inflammatory re-sponse regulation,cell migration,apoptotic process,and glutamatergic synapse.KEGG pathway enrichment analysis suggested that the common targets are mainly enriched in signaling pathways including advanced glycation end products-receptor for advanced gly-cation end products,interleukin-17,tumor necrosis factor,and Alzheimer's disease.PPI network analysis screened out 21 core tar-gets,among which prostaglandin-endoperoxide synthase 2,sodium voltage-gated channel alpha subunit 5,and gamma-aminobutyric acid type A receptor subunit alpha1 were identified as key nodes.The top five active compounds ranked by node degree value in the"compound-disease-target"network were kaempferol,beta-sitosterol,stigmasterol,fumarine,and 8-isopentenyl-kaempferol,and 8-prenylkaempferol.By intersecting the core targets with the targets of these compounds,PTGS2 was identified as a key target.Molec-ular docking results showed that Prostaglandin-Endoperoxide Synthase 2(PTGS2)exhibited good binding affinity with each of these potential active compounds,suggesting that PTGS2 is a core target through which Kaixin San improves the comorbidity of de-pression and cognitive impairment,with compounds like kaempferol being its potential active constituents.This study preliminarily reveals that the mechanism underlying the"treating different diseases with the same method"effect of Kaixin San on depression and cognitive dysfunction may be associated with the regulation of inflammatory response,apoptosis,and glutamatergic synapse.