Abstract
BackgroundPanax notoginseng saponins (PNS) have been deemed effective herb compounds for treating ischaemic stroke (IS) and improving the quality of life of IS patients. This study aimed to investigate the underlying mechanisms of PNS in the treatment of IS based on network pharmacology. Methods PNS were identified from the Traditional Chinese Medicine System Pharmacology (TCMSP) database, and their possible targets were predicted using the PharmMapper database. IS-related targets were identified from the GeneCards database, OMIM database, and DisGeNET database. A herb-compound-target-disease network was constructed using Cytoscape, and protein-protein interaction (PPI) networks were established with STRING. GO enrichment and KEGG pathway analysis were performed using DAVID. The binding of the compounds and key targets was validated by molecular docking studies using AutoDock Vina. The neuroprotective effect of TFCJ was substantiated in terms of oxidative stress (superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde) and the levels of IGF1/PI3K/Akt pathway proteins. Results A total of 375 PNS targets and 5111 IS-related targets were identified. Among these targets, 241 were common to PNS, and IS network analysis showed that MAPK1, AKT1, PIK3R1, SRC, MAPK8, EGFR, IGF1, HRAS, RHOA, and HSP90AA1 are key targets of PNS against IS. Furthermore, GO and KEGG enrichment analysis indicated that PNS probably exert therapeutic effects against IS by regulating many pathways, such as the Ras, oestrogen, FoxO, prolactin, Rap1, PI3K-Akt, insulin, PPAR, and thyroid hormone signalling pathways. Molecular docking studies further corroborated the experimental results.The network pharmacology results were further verified by molecular docking and in vivo experiments. Conclusions The ameliorative effects of PNS against IS were predicted to be associated with the regulation of the IGF1-PI3K-Akt signalling pathway. Ginsenoside Re and ginsenoside Rb1 may play an important role in the treatment of IS.
Highlights
Stroke is a common disease worldwide, accounting for 11.59% of all deaths in 2019
Construction of the Protein-Protein Interaction (PPI) Network. e Panax notoginseng saponins (PNS) targets and ischaemic stroke (IS)-related targets that intersected were identified as common targets. e common PNS and IS-related targets were uploaded to the STRING 11.0 database [28], the type was set to “Homo sapiens,” the confidence level was set to > 0.700, the “hide disconnected nodes in the network” setting was simplified, the protein interaction information was obtained, the file was saved in the TSV format, and the data for node1, node2, and the combined score were imported into Cytoscape 3.7.2 [29] to establish a protein-protein interaction (PPI) network
For Gene Ontology (GO) enrichment analysis (Supplementary Tables S2, S3, S4), we filtered the top five cellular components (CC), biological process (BP), and molecular function (MF) categories based on the following criteria: p value < 0.01 and FDR < 0.05. e top 5 entries in the BP category were the steroid hormone-mediated compound disease e candidate targets of PNS anti IS Figure 4: Venn diagram and PPI network of target genes of PNS and IS
Summary
Stroke is a common disease worldwide, accounting for 11.59% of all deaths in 2019. Stroke, which accounts for more than 20% of China’s total deaths, is the most common cause of death in China [1]. e main categories of stroke are ischaemic stroke (IS), cerebral haemorrhage, and subarachnoid haemorrhage [2]. Stroke, which accounts for more than 20% of China’s total deaths, is the most common cause of death in China [1]. Is study aimed to investigate the underlying mechanisms of PNS in the treatment of IS based on network pharmacology. A total of 375 PNS targets and 5111 IS-related targets were identified Among these targets, 241 were common to PNS, and IS network analysis showed that MAPK1, AKT1, PIK3R1, SRC, MAPK8, EGFR, IGF1, HRAS, RHOA, and HSP90AA1 are key targets of PNS against IS. GO and KEGG enrichment analysis indicated that PNS probably exert therapeutic effects against IS by regulating many pathways, such as the Ras, oestrogen, FoxO, prolactin, Rap, PI3K-Akt, insulin, PPAR, and thyroid hormone signalling pathways. E ameliorative effects of PNS against IS were predicted to be associated with the regulation of the IGF1-PI3K-Akt signalling pathway. Ginsenoside Re and ginsenoside Rb1 may play an important role in the treatment of IS
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