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Yuan-Zhi decoction in the treatment of Alzheimer's disease: An integrated approach based on chemical profiling, network pharmacology, molecular docking and experimental evaluation - PubMed

  • ️Sat Jan 01 2022

Yuan-Zhi decoction in the treatment of Alzheimer's disease: An integrated approach based on chemical profiling, network pharmacology, molecular docking and experimental evaluation

Qiong Wu et al. Front Pharmacol. 2022.

Abstract

Yuan-Zhi Decoction (YZD) is a traditional Chinese medical formulation with demonstrated clinical benefits in Alzheimer's disease (AD). We used liquid chromatography coupled with mass spectrometry to identify 27 unique chemical components of YZD. Analyzing these using network pharmacology and molecular docking models identified 34 potential interacting molecular targets involved in 26 biochemical pathways. When tested in an animal model of AD, the APP/PS1 transgenic mice showed measurable improvements in spatial orientation and memory after the administration of YZD. These improvements coincided with significantly reduced deposition of Aβ plaques and tau protein in the hippocampi in the treated animals. In addition, a decreased BACE1 and beta-amyloid levels, a downregulation of the p-GSK-3β/GSK-3β, and an upregulation of the PI3K and p-AKT/AKT pathway was seen in YZD treated animals. These in vivo changes validated the involvement of molecular targets and pathways predicted in silico analysis of the chemical components of YZD. This study provides scientific support for the clinical use of YZD and justifies further investigations into its effects in AD. Furthermore, it demonstrates the utility of network pharmacology in elucidating the biochemical mechanisms underlying the beneficial effects of traditional Chinese medicines (TCM).

Keywords: Alzheimer’s disease; Yuan-Zhi decoction; molecular docking; molecular mechanism; network pharmacology.

Copyright © 2022 Wu, Li, Jiang, Yao, Zhou, Xu, Wang, Zhao and Zhang.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

Flowchart of the steps taken during the system pharmacology analysis of the therapeutic mechanisms of action of Yuan-Zhi Decoction (YZD) in Alzheimer’s disease (AD).

FIGURE 2
FIGURE 2

Total ion chromatograms of the chemical constituents of YZD in positive (A) and negative (B) ion modes during UHPLC-Q Exactive HF analysis.

FIGURE 3
FIGURE 3

Analysis of proteins potentially affected by YZD treatment. (A) Venn diagram illustrating the overlap between proteins interacting with components of YZD and proteins know or predicted to be involved in the pathogenesis of AD. (B) PPI network of AD-related proteins that can interact with YZD components. (C) Analysis of the GO classification of the same set of proteins. (D) KEGG enrichment results of the interacting proteins represented as a bubble map. Red indicates greater, green a lesser enrichment of a given KEGG pathway, while the size of the bubbles corresponds to the number of proteins in each group.

FIGURE 4
FIGURE 4

Herb component—putative molecular target - major pathway network map. Pink nodes represent active ingredients of YZD, blue nodes represent potential targets, and the green nodes indicate the involved KEGG pathways.

FIGURE 5
FIGURE 5

Molecular docking models depicting interactions between YZD components and their putative molecular targets/receptors. (A) APP (Beta amyloid A4 protein Beta, PDB code: 6UWP) interacting with Paeoniflorin; (B) BACE (Beta-secretase 1, PDB code: 5CLM) interacting with Ginsenoside Rg3; (C) GSK3B (Glycogen synthase kinase-3 beta, PDB code: 1O6L) with Polygalaxanthone. Structures drawn entirely in black represent YZD components, the colored dots are amino acid residues from the interacting protein. Pink arrows represent hydrogen bonds while red lines indicate a P-π conjugate.

FIGURE 6
FIGURE 6

YZD administration ameliorated cognitive impairment in APP/PS1 mice. WT: wild-type mice; APP/PS1: APP/PS1 mice. (A) Swimming speed of mice in the Morris water maze. (B) Changes of escape latency of mice from the first day to the fifth day in different groups. (C) Changes in swimming distance from the first day to the fifth day in different groups. (D) The time that the indicated groups of mice spent at the target area that previously contained an escape platform in the Morris water maze. (E) The times of indicated groups of mice crossing the target area that previously contained an escape platform in the Morris water maze experiment. (F) Typical swimming trajectory maps of mice passing through the platform during the test period. *p < 0.05 compared to the WT group, #p < 0.05, ##p < 0.01 compared to the APP/PS1 group. All data are presented as mean ± SE (n = 6).

FIGURE 7
FIGURE 7

YZD treatment for 3 months reduces BACE1 and beta-amyloid protein abundance in the hippocampi of APP/PS1 transgenic mice. (A) Western blot analysis of APP, BACE1, beta-amyloid levels. Densitometry data of APP (B), BACE1 (C) and beta-amyloid (D). Values represented as the mean ± SE (n = 3), *p < 0.05, **p < 0.01, #p < 0.05 was considered statistically significant. Distinct symbols indicate differences in the level of significance between groups.

FIGURE 8
FIGURE 8

Effects of 3-months of YZD treatment on the expression of PI3K/AKT/GSK-3β pathway related proteins in the hippocampi of APP/PS1 mice. (A) Western blot analysis of PI3K, AKT, p-AKT, GSK-3β, p-GSK-3β. (B) Densitometry of PI3K, (C) Densitometry of p-AKT/AKT, (D) Densitometry of p-GSK-3β/GSK-3β. Values show the mean ± SE (n = 3), differences in the level of significance are: *p < 0.05, **p < 0.01, ##p < 0.01.

FIGURE 9
FIGURE 9

YZD inhibited Aβ and Tau deposition in the hippocampi of APP/PS1 mice. (A) Representative images of Aβ deposits (showing brown staining) in the hippocampi. Magnification: ×25, scale bar: 200 μm. (B) Images of Tau deposits in the hippocampi (appearing as brown deposits). Magnification: 400 × scale bar: 200 μm.

FIGURE 10
FIGURE 10

A schematic of proposed neuroprotective mechanism of YZD in AD.

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References

    1. Ahmad A., Ali T., Park H. Y., Badshah H., Rehman S. U., Kim M. O. (2017). Neuroprotective effect of fisetin against amyloid-beta-induced cognitive/synaptic dysfunction, neuroinflammation, and neurodegeneration in adult mice. Mol. Neurobiol. 54, 2269–2285. 10.1007/s12035-016-9795-4 PubMed Abstract | 10.1007/s12035-016-9795-4 | Google Scholar - DOI - DOI - PubMed
    1. Cai F. F., Zhou W. J., Wu R., Su S. B. (2018a). Systems biology approaches in the study of Chinese herbal formulae. Chin. Med. 13, 65. 10.1186/s13020-018-0221-x PubMed Abstract | 10.1186/s13020-018-0221-x | Google Scholar - DOI - DOI - PMC - PubMed
    1. Cai H., Luo Y., Yan X., Ding P., Huang Y., Fang S., et al. (2018b). The mechanisms of bushen-yizhi formula as a therapeutic agent against Alzheimer's disease. Sci. Rep. 8, 3104. 10.1038/s41598-018-21468-w PubMed Abstract | 10.1038/s41598-018-21468-w | Google Scholar - DOI - DOI - PMC - PubMed
    1. Chang W., Teng J. (2018). Combined application of tenuigenin and beta-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer's disease. Drug Des. devel. Ther. 12, 455–462. 10.2147/DDDT.S155567 PubMed Abstract | 10.2147/DDDT.S155567 | Google Scholar - DOI - DOI - PMC - PubMed
    1. Chen L., Du J., Dai Q., Zhang H., Pang W., Hu J. J. E. J. O. M. C. (2014). Prediction of anti-tumor chemical probes of a traditional Chinese medicine formula by HPLC fingerprinting combined with molecular docking. Eur. J. Med. Chem. 83, 294–306. 10.1016/j.ejmech.2014.06.037 PubMed Abstract | 10.1016/j.ejmech.2014.06.037 | Google Scholar - DOI - DOI - PubMed

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