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. 2020 Oct 15:13:487-502.
doi: 10.2147/PGPM.S269726. eCollection 2020.

Identifying the Mechanisms and Molecular Targets of Yizhiqingxin Formula on Alzheimer's Disease: Coupling Network Pharmacology with GEO Database

Tingting Zhang #  1   2 , Linlin Pan #  3 , Yu Cao  4 , Nanyang Liu  2 , Wei Wei  1   2 , Hao Li  2
Affiliations

Identifying the Mechanisms and Molecular Targets of Yizhiqingxin Formula on Alzheimer's Disease: Coupling Network Pharmacology with GEO Database

Tingting Zhang et al. Pharmgenomics Pers Med. .

Abstract

Background: Yizhiqingxin formula (YZQX) is a promising formula for the treatment of Alzheimer's disease (AD) with significant clinical effects. Here, we coupled a network pharmacology approach with the Gene Expression Omnibus (GEO) database to illustrate comprehensive mechanisms and screen for molecular targets of YZQX for AD treatment.

Methods: First, active ingredients of YZQX were screened for the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database with the absorption, distribution, metabolism, and excretion (ADME) parameters. Subsequently, putative targets of active ingredients were predicted using the DrugBank database. AD-related targets were retrieved by analyzing published microarray data (accession number GSE5281). Protein-protein interaction (PPI) networks of YZQX putative targets and AD-related targets were constructed visually and merged to identify candidate targets for YZQX against AD using Cytoscape 3.7.2 software. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to further clarify the biological functions of the candidate targets. The gene-pathway network was established to filter for key target genes.

Results: Forty-three active ingredients were identified, and 193 putative target genes were predicted. Seven hundred and ten targets related to AD were screened with |log2 FC| > 1 and P < 0.05. Based on the PPI network, 110 target genes of YZQX against AD were identified. Moreover, 32 related pathways including the PI3K-Akt signaling pathway, MAPK signaling pathway, ubiquitin-mediated proteolysis, apoptosis and the NF-kappa B signaling pathway were significantly enriched. In the gene-pathway network, MAPK1, AKT1, TP53, MDM2, EGFR, RELA, SRC, GRB2, CUL1, and MYC targets are putative core genes for YZQX in AD treatment.

Conclusion: YZQX against AD may exert its neuroprotective effect via the PI3K-Akt signaling pathway, MAPK signaling pathway, and ubiquitin-mediated proteolysis. YZQX may be a promising drug that can be used in the treatment of AD.

Keywords: Alzheimer’s disease; Yizhiqingxin formula; mechanism; molecular target; network pharmacology.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Workflow for Yizhiqingxin formula treatment of Alzheimer’s disease.
Figure 2
Figure 2
Volcano plot of differentially expressed genes. The red dots represent significantly up-regulated genes, the green dots represent significantly down-regulated genes.
Figure 3
Figure 3
Compound- target network of YZQX. Blue Diamonds represent targets contained in YZQX, yellow squares represent Chinese Herbs, purple vs represent ingredients of Chuanxiong, light red vs represent ingredients of Huanglian, and red vs represent ingredients of Renshen.
Figure 4
Figure 4
Identification of core targets of YZQX against AD. (A) YZQX putative targets PPI network. (B) AD-related targets PPI network. (C) The interactive PPI network of YZQX putative targets and AD-related targets. (D) PPI network of significant proteins extracted from C. (E) PPI network of candidate YZQX targets for AD treatment extracted from D.
Figure 5
Figure 5
Go analysis of core targets. (A) Biological process; (B) Cellular component; (C) Molecular function.
Figure 6
Figure 6
KEGG pathway enrichment of core targets of YZQX against AD. Pathways that had significant changes of p.adjust <0.05 were identified. The dot size represents number of genes and color represents p.adjust value.
Figure 7
Figure 7
Gene-Pathway Network. The topological analysis of 32 pathways and 70 genes was calculated with the degree. The yellow circles represent target genes and the red vs represent pathways. Big size represents the larger degree.
See this image and copyright information in PMC

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