山东医药2023，Vol.63Issue(29)：1-6,6.DOI:10.3969/j.issn.1002-266X.2023.29.001
二肽激肽酶4抑制剂对帕金森病模型细胞形态和增殖的干预作用及其机制
Intervention effects of DPP-4 inhibitors on morphology and proliferation of model cells with Parkinson's disease and the mechanism
摘要
Abstract
Objective To investigate the protective effects of DPP-4 inhibitors against rotenone-induced neuronal Parkinson's disease and its associated mechanism based on in vitro experiments and network pharmacology.Methods The neural cell line PC-12 was divided into the control group,model group,model + sitagliptin group,model + linagliptin group,and model + vildagliptin group,respectively.After 16-18 h,the PD in vitro models were established using ROT in all groups except the control group.In the model + sitagliptin,model + linagliptin,and model + vildagliptin groups,ROT was added along with sitagliptin,linagliptin,and vildagliptin for intervention.The morphological changes of the cells in each group were observed using the inverted microscope,and the proliferative ability of the cells in each group was ob-served by CCK-8.The drug targets of DPP-4 inhibitors,sitagliptin,linagliptin,vildagliptin,saxagliptin and alogliptin,were obtained from Swiss Target Prediction,SEA,Super-Pred,and PharmMapper databases,respectively.PD-related dis-ease targets were obtained from DisGeNet,OMIM,and GeneCards databases.A visualization of the common targets of DPP-4 inhibitors acting on PD was obtained from the Venn diagram database.The protein-protein interaction(PPI)net-work was constructed through the String database,and the genes with degree values>the average were selected as the key targets of DPP-4 inhibitors on PD,and the key target genes were input into the DAVID database for the analysis of Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway.The key targets of DPP-4 inhibitors for PD treatment and KEGG signaling pathway were imported into Cytoscape 3.7.2 software to construct a drug-disease-target-pathway network,and the targets most closely related to PD-related signaling pathways were screened as the core targets of DPP-4 inhibitors for PD treatment.The CB-Dock 2 docking platform was used to validate the molecular docking of the core target.Results The cells in the control group were morphologically intact,with good growth status,and the cells were in a polygonal state,with synapse-like connections between the cells and long synapses.In the model group,cell density was reduced,cells became wrinkled,synapse-like connections between cells were broken,and more rounded damaged cells were observed.The cell morphology of the model + sitagliptin,model + linagliptin and model + vildagliptin groups was im-proved compared to the model group and returned to the elongated and polygonal morphology as in the normal state.The cell survival rate in the model group was lower than that in the control,model + sitagliptin,model + linagliptin,and model + vildagliptin groups(all P<0.05).We collected a total of 486 sitagliptin drug targets,665 linagliptin drug targets,524 vildagliptin drug targets,507 saxagliptin drug targets,408 alogliptin drug targets,and 1121 PD disease targets.We took the intersection of DPP-4 inhibitor targets with PD disease-related targets to obtain 36 DPP-4 inhibitor-associated targets acting in PD.The PPI network showed that DPP-4 inhibitors acted on a total of 16 key PD targets with greater degree val-ues than the average,namely ALB,IGF1,STAT3,CASP3,EGFR,ESR1,MAPK14,PPARG,MAPK1,HMOX1,NOS3,REN,MMP3,IL2,AR,and IGF1R.GO analysis showed that the biological processes involved in the key targets of DPP-4 inhibitors acting on PD mainly included signal transduction,positive regulation of cell migration and negative reg-ulation of apoptosis,etc.,the cellular components mainly included cytoplasm,cytoplasmic membrane and nucleus,etc.,and the molecular functions mainly included enzyme binding,protein binding,and protein serine/threonine/tyrosine ki-nase activity.KEGG pathway enrichment analysis resulted in a total of 20 signaling pathways,and the signaling pathways more relevant to PD were PI3K-Akt signaling pathway,the FoxO signaling pathway,and MAPK signaling pathway.The drug-disease-target-pathway network map showed that the targets enriched in the PI3K-Akt,FoxO,and MAPK signaling pathways were IGF1,EGFR,IGF1R,and MAPK1.The molecular docking results demonstrated that all five DPP-4 inhibi-tors bound well to the PD-associated core target proteins,and their binding energies were all less than-5.0 kcal/mol.Conclusion DPP-4 inhibitors were protective in the in vitro models of PD,possibly exerting their protective effects through core targets such as IGF1,EGFR,IGF1R,and MAPK1 acting on signaling pathways such as PI3K-Akt,FoxO,and MAPK,etc.关键词
二肽激肽酶4抑制剂/网络药理学/神经细胞/帕金森病Key words
dipeptidyl peptidase-4(DPP-4)inhibitor/network pharmacology/neurocytes/Parkinson's disease分类
药学引用本文复制引用
伊木然江·苏布哈提,艾尼瓦尔·吾买尔,木塔力甫·艾买提..二肽激肽酶4抑制剂对帕金森病模型细胞形态和增殖的干预作用及其机制[J].山东医药,2023,63(29):1-6,6.基金项目
新疆维吾尔自治区自然科学基金资助项目(2022D01C89). （2022D01C89）
