Network Pharmacology-Based Study of the Underlying Mechanisms of Huangqi Sijunzi Decoction for Alzheimer's Disease

Abstract

Background: Huangqi Sijunzi decoction (HQSJZD) is a commonly used conventional Chinese herbal medicine prescription for invigorating Qi, tonifying Yang, and removing dampness. Modern pharmacology and clinical applications of HQSJZD have shown that it has a certain curative effect on Alzheimer's disease (AD).

Methods: The active components and targets of HQSJZD were searched in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The genes corresponding to the targets were retrieved using UniProt and GeneCard database. The herb-compound-target network and protein-protein interaction (PPI) network were constructed by Cytoscape. The core targets of HQSJZD were analysed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HQSJZD were docked with acetylcholinesterase (AChE). In vitro experiments were conducted to detect the inhibitory and neuroprotective effects of AChE.

Results: Compound-target network mainly contained 132 compounds and 255 corresponding targets. The main compounds contained quercetin, kaempferol, formononetin, isorhamnetin, hederagenin, and calycosin. Key targets contained AChE, PTGS2, PPARG, IL-1B, GSK3B, etc. There were 1708 GO items in GO enrichment analysis and 310 signalling pathways in KEGG, mainly including the cAMP signalling pathway, the vascular endothelial growth factor (VEGF) signalling pathway, serotonergic synapses, the calcium signalling pathway, type II diabetes mellitus, arginine and proline metabolism, and the longevity regulating pathway. Molecular docking showed that hederagenin and formononetin were the top 2 compounds of HQSJZD, which had a high affinity with AChE. And formononetin has a good neuroprotective effect, which can improve the oxidative damage of nerve cells.

Conclusion: HQSJZD was found to have the potential to treat AD by targeting multiple AD-related targets. Formononetin and hederagenin in HQSJZD may regulate multiple signalling pathways through AChE, which might play a therapeutic role in AD.

Figure 1

Composition distribution of HQSJZD decoction.

Figure 2

Herb-compound-target network of HQSJZD. Blue nodes: protein targets; circular nodes: compounds; edges: interactions between compounds and proteins.

Figure 3

(a) Intersection of drug targets and AD disease targets; the number represents the number of targets. (b) Compound-target network of HQSJZD. Green nodes: protein targets; yellow nodes: key compounds; Orange pink: the ingredients of Chinese medicine; Edges: interactions between compounds and proteins.

Figure 4

GO enrichment analysis of the 60 targets of HQSJZD. The chart is arranged in order from high to low according to the number of target distributions.

Figure 5

KEGG enrichment analysis of the potential targets of HQSJZD. The larger rich factor stands for the higher level of enrichment. The size of the dot denotes the number of target genes in the pathway, and the color shade of the dot indicates the different P value range.

Figure 6

Protein-protein interaction network (network of the 16 key targets based on the STRING database. Large size represents higher degree value).

Figure 7

Results of docking 6 compounds with AChE. (a) Donepezil; (b) quercetin; (c) kaempferol; (d) formononetin; (e) isorhamnetin; (f) hederagenin; (g) calycosin. The yellow dotted line: hydrogen bond; the number: bond distance.

Figure 8

The inhibitory effect of donepezil (a), formononetin (b), and hederagenin (c) on AChE activity. Results are presented as means ± SEM, n = 3.

Figure 9

The protective effects of formononetin against cell injury induced by sodium nitroprusside (a) and potassium chloride (b) in SH-SY5Y cells. Results are presented as means ± SEM, n = 3. ^###P < 0.001 versus each control group. ^∗P < 0.05, ^∗∗P < 0.01, ^∗∗∗P < 0.001, versus group solely treated with sodium nitroprusside or potassium chloride, respectively.