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This study investigated the mechanism by which notoginsenoside R1 (NGR1) alleviates neuroinflammation by regulating metabolic disorders in microglia through network pharmacology, in vitro experiments, and untargeted metabolomics. Neuroinflammation-related disease targets and NGR1 targets were obtained through multi-database mining, overlapping targets were screened using Venny, and GO and KEGG enrichment analyses as well as protein-protein interaction network construction were performed to screen core targets. Molecular docking software was used to evaluate the binding ability between NGR1 and the core targets. An inflammatory model was established by lipopolysaccharide-induced BV2 microglial cells, and Western blot was used to detect the effects of different concentrations of NGR1 on the expression of inflammation-related proteins in microglia, and to determine the effective concentrations of NGR1 affecting the NF-κB signaling pathway. Untargeted metabolomic analysis was conducted within the effective concentration range of NGR1, and differential metabolites were screened by combining multivariate statistical analysis with metabolic pathway enrichment analysis. Cytoscape and MetaboAnalyst platforms were further used to screen key metabolites closely associated with the NF-κB signaling pathway. Exogenous metabolite supplementation experiments were conducted to verify whether NGR1 could inhibit the activation of the NF-κB signaling pathway by regulating the levels of related metabolites. The results showed that there were 43 overlapping genes between neuroinflammation-related disease targets and NGR1 targets, among which 16 were core targets. KEGG enrichment results indicated that the overlapping targets were significantly enriched in inflammatory signaling pathways such as NF-κB. Molecular docking results showed that NGR1 had high binding affinity with multiple NF-κB signaling pathway proteins. Western blot results demonstrated that NGR1 could significantly regulate the expression of NF-κB signaling pathway-related proteins and inflammatory factors, and 25 and 50 μmol·L-1 were the effective concentrations affecting the NF-κB signaling pathway. Metabolomic results showed that NGR1 could significantly affect multiple pathways such as glutathione metabolism. Metabolite-target association analysis results showed that NGR1 could reverse abnormal changes in metabolites closely related to NF-κB signaling pathway targets, including homocysteine, L-leucine, and prostaglandin E2 ethanolamide. Exogenous metabolite supplementation experiments showed that homocysteine could weaken the inhibitory effect of NGR1 on the NF-κB signaling pathway, suggesting that homocysteine may be involved in the NGR1-mediated NF-κB inhibitory process. In summary, NGR1 may inhibit the activation of the NF-κB signaling pathway through both direct inhibition and indirect regulation of homocysteine metabolism, thereby alleviating neuroinflammatory responses.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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