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. 2023 Jun 27;9(7):e17603.
doi: 10.1016/j.heliyon.2023.e17603. eCollection 2023 Jul.

Repositioning of clinically approved drug Bazi Bushen capsule for treatment of Aizheimer's disease using network pharmacology approach and in vitro experimental validation

Tongxing Wang  1   2 , Meng Chen  1   2 , Huixin Li  1   2 , Guoyuan Ding  1   2 , Yanfei Song  1   2 , Bin Hou  1   2 , Bing Yao  1   2 , Zhixin Wang  1   2 , Yunlong Hou  1   2 , Junqing Liang  1   2 , Cong Wei  1   2   3 , Zhenhua Jia  1   2   3
Affiliations

Repositioning of clinically approved drug Bazi Bushen capsule for treatment of Aizheimer's disease using network pharmacology approach and in vitro experimental validation

Tongxing Wang et al. Heliyon. .

Abstract

Aims: To explore the new indications and key mechanism of Bazi Bushen capsule (BZBS) by network pharmacology and in vitro experiment.

Methods: The ingredients library of BZBS was constructed by retrieving multiple TCM databases. The potential target profiles of the components were predicted by target prediction algorithms based on different principles, and validated by using known activity data. The target spectrum of BZBS with high reliability was screened by considering the source of the targets and the node degree in compound-target (C-T) network. Subsequently, new indications for BZBS were predicted by disease ontology (DO) enrichment analysis and initially validated by GO and KEGG pathway enrichment analysis. Furthermore, the target sets of BZBS acting on AD signaling pathway were identified by intersection analysis. Based on STRING database, the PPI network of target was constructed and their node degree was calculated. Two Alzheimer's disease (AD) cell models, BV-2 and SH-SY5Y, were used to preliminarily verify the anti-AD efficacy and mechanism of BZBS in vitro.

Results: In total, 1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula, and 1320 BZBS targets with high confidence were predicted. Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treatment of AD. GO and KEGG enrichment results provide a preliminary verification of this point. Among them, 113 functional targets of BZBS belong to AD pathway. A PPI network containing 113 functional targets and 1051 edges for the treatment of AD was constructed. In vitro experiments showed that BZBS could significantly reduce the release of TNF-α and IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells, which may be related to the regulation of ERK1/2/NF-κB signaling pathway. BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells, significantly increased mitochondrial membrane potential, reduced the expression of Caspase3 active fragment and PSEN1, and increased the expression of IDE. This may be related to the regulation of GSK-3β/β-catenin signaling pathway.

Conclusions: BZBS formula has a potential use in the treatment of AD, which is achieved through regulation of ERK1/2, NF-κB signaling pathways, and GSK-3β/β-catenin signaling pathway. Furthermore, the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action. The study lays a foundation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.

Keywords: Aizheimer's disease; Bazi Bushen capsule; Drug repositioning; Mechanism of action; Network pharmacology; Network targets.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Schematic diagram describing the concept of enrichment-based drug repositioning of BZBS applied in this study.
Fig. 2
Fig. 2
Statistics of the target type and interaction type in compound-target network based on target data sources. (A) Types of interactions in compound-target network and (B) types of 1320 targets with high confidence; (C) Types of interactions in anti-AD compound-target network and (D) types of 113 anti-AD targets.
Fig. 3
Fig. 3
Enrichment analysis of 1320 BZBS targets. (A) Disease ontology (DO) enrichment analysis results; (B) KEGG pathway enrichment analysis results. Rich Factor refers to the ratio of the number of annotated GO entries in 1320 targets to the total number of genes in the GO entry. The greater the Rich Factor, the greater the degree of enrichment. The size of the dot is proportional to the number of genes enriched in the term; (C) Gene ontology (GO) enrichment analysis results. GO categories include “Molecular Function” and “Cellular Component”, “Biological Process” terms.
Fig. 4
Fig. 4
PPI network of 113 anti-AD functional targets of BZBS. PPI, Protein-protein interaction; AD, Alzheimer's disease; BZBS, Bazi Bushen capsule.
Fig. 5
Fig. 5
Regulatory mechanism of BZBS on Alzheimer disease pathway. Colored nodes are targets regulated by BZBS. Deep pink and green nodes are the key targets regulated by BZBS meeting one and two screening conditions, respectively. Blue nodes are the rest targets regulated by BZBS. The solid line represents the direct regulatory effect, and the dotted line indicates the indirect effect. The line with arrow indicates activation. The line with small line segments represents inhibition.
Fig. 6
Fig. 6
Effects of BZBS and DNPQ on cell viability. (A) Effects of BZBS and (B) DNPQ on BV-2 cell viability; (C) Effects of BZBS and (D) DNPQ on SH-SY5Y cell viability. The results represent the mean ± SD (n = 3). BZBS, Bazi Bushen; DNPQ, Donepezil; DMSO, Dimethyl sulfoxide.
Fig. 7
Fig. 7
In vitro validation of BZBS against AD. (A) Effects of BZBS on cell viability of Aβ25-35 induced BV-2 cells; (B–C) Inhibitory effects of BZBS on TNF-α and IL-6 in Aβ25-35 induced BV-2 cells; (D–E) Effects of BZBS on apoptosis rate and mitochondrial membrane potential of Aβ25-35 induced SH-SY5Y cells. The results represent the mean ± SD (n = 3), vs. Control, **p < 0.01, vs. Model #p < 0.05, ##p < 0.01. vs. DNPQ, && p < 0.01. BZBS, Bazi Bushen; AD, Alzheimer's disease; DNPQ, Donepezil; DMSO, Dimethyl sulfoxide; MMP, Mitochondrial membrane potential.
Fig. 8
Fig. 8
In vitro validation of BZBS anti-AD signaling pathway mechanism. (A) Effects of BZBS on the expression of COX-2, p-p65, p-ERK1/2, PSEN1 in BV-2 cells induced by Aβ25-35; (B–C) Effects of BZBS on the expression of IDE, PSEN1, p-Tau and active caspase3 in SH-SY5Y cells induced by Aβ25-35; (D) Effects of BZBS on the expression of β-catenin and p-GSK3β in SH-SY5Y cells induced by Aβ25-35. The results represent the mean ± SEM (n = 3). IDE, Insulin degrading enzyme; BZBS, Bazi Bushen; AD, Alzheimer's disease; DNPQ, Donepezil; DMSO, Dimethyl sulfoxide.
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