基于网络药理学探讨桃红四物汤治疗阿尔茨海默症的主要有效成分及其作用机制

doi:10.5246/jcps.2024.06.039

中国药学(英文版) ›› 2024, Vol. 33 ›› Issue (6): 525-542.DOI: 10.5246/jcps.2024.06.039

基于网络药理学探讨桃红四物汤治疗阿尔茨海默症的主要有效成分及其作用机制

李双¹^,³^,^#, 孙璐瑶¹^,^#, 尤斯涵²^,⁴^,^#, 张佳燚¹, 殷宏艳²^,⁴, 曹津萌¹, 刘心星³, 郭春燕²^,³^,⁴^,^*(), 刘喜富¹^,^*()

^1. 河北师范大学生命科学学院, 河北石家庄 050024
^2. 河北北方学院药学院, 河北张家口 075000
^3. 张家口健垣精准医学有限公司, 河北张家口 075000
^4. 河北省神经药理学重点实验室, 河北张家口 075000

收稿日期:2023-12-10 修回日期:2024-01-02 接受日期:2024-02-23 出版日期:2024-06-30 发布日期:2024-06-30
通讯作者: 郭春燕, 刘喜富

Exploring the main active components and potential mechanisms of Taohong Siwu Decoction for the treatment of Alzheimer’s disease based on network pharmacology

Shuang Li¹^,³^,^#, Luyao Sun¹^,^#, Sihan You²^,⁴^,^#, Jiayi Zhang¹, Hongyan Yin²^,⁴, Jinmeng Cao¹, Xinxing Liu³, Chunyan Guo²^,³^,⁴^,^*(), Xifu Liu¹^,^*()

¹ Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Anti-Tumor Molecular Target Technology Innovation Center, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, China
² Department of Pharmacy, Hebei North University, Zhangjiakou 075000, Hebei, China
³ Jianyuan Precision Medicines (Zhangjiakou) Co., Ltd., Zhangjiakou 075000, Hebei, China
⁴ Hebei Key Laboratory of Neuropharmacology, Zhangjiakou 075000, Hebei, China

Received:2023-12-10 Revised:2024-01-02 Accepted:2024-02-23 Online:2024-06-30 Published:2024-06-30
Contact: Chunyan Guo, Xifu Liu
About author:
^# Shuang Li, Luyao Sun and Sihan You contributed equally to this work.
Supported by:
The Project of Hebei North University (Grant No. XJ2023041); the Natural Science Foundation of Hebei Province (Grant No. H2021405021); the S&T Program of Hebei (Grant No. V1623922326576).

摘要/Abstract

摘要：

桃红四物汤(TaohongSiwu Decoction, THSWD)是活血化瘀的经典中药方剂, 本研究利用网络药理学筛选THSWD潜在活性成分, 探讨其治疗阿尔茨海默症的核心作用靶点和信号通路。首先, 通过TCMSP和SEA数据库, 筛选THSWD的活性成分及其作用靶点, 共获得25个活性化合物(active compounds, ACs)和478个活性成分靶点; 通过TTD、DisGeNET、DrugBank、GAD和GeneCards数据库共获得阿尔茨海默症疾病靶点724个。寻找活性成分作用靶点和疾病相关靶点的交集, 共获得64个靶点(overlapping targets, OTs)。然后, 构建25个ACs和64个OTs相互关系网络, 获得21个一级关键化合物(first level key compound, FKCs)。通过对64个OTs进行PPI分析, 获得33个核心靶点(core targets, CTs), 并对这33个CTs进行KEGG聚类分析, 获得排名靠前73条通路。最后, 利用Cytoscape 3.7.2软件绘制"21个FKCs-33个CTs-73条通路"网络关系图, 根据拓扑参数进行选择, 进一步获得19个二级关键化合物(second key components, SKCs)。对"19个SKCs-33个CTs-73条通路"进行网络的分析与提取, 最终构建得到THSWD干预阿尔茨海默症"6种单味药-8种潜在活性成分-13个核心作用靶点-54条信号通路"的网络图谱。研究结果为阐明THSWD的药效物质基础和进一步研究THSWD治疗阿尔茨海默症的作用机制和临床应用提供了新思路。

关键词: 阿尔茨海默症, 网络药理学, 桃红四物汤, 中医药

Abstract:

Taohong Siwu Decoction (THSWD), a traditional Chinese prescription renowned for its efficacy in promoting blood circulation and alleviating blood stasis, was investigated in this study to delineate its potential active components and discern the core targets (CTs) and signaling pathways implicated in the treatment of Alzheimer’s disease (AD). Initially, 25 active compounds (ACs) and 478 corresponding active ingredient targets (AITs) of THSWD were meticulously identified by scrutinizing the active ingredients and their targets through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Similarity Ensemble Approach (SEA) databases. Subsequently, a comprehensive compilation of 724 AD-related targets was assembled from the Therapeutic Target Database (TTD), DisGeNET, DrugBank, Genetic Association Database (GAD), and GeneCards databases. Through a meticulous alignment of AITs with disease-related targets, 64 overlapping targets (OTs) emerged as critical intersections. To distill the key compounds, an intricate analysis of the interrelationships among the 25 ACs and 64 OTs resulted in the identification of 21 first-level key compounds (FKCs). Further scrutiny through protein-protein interaction (PPI) analysis of the 64 OTs revealed 33 CTs. KEGG cluster analysis of these CTs yielded the top 73 pathways, forming the basis for constructing a network diagram encompassing "21 FKCs-33 CTs-73 pathways" using Cytoscape 3.7.2 software. Refining the network through the selection of topological parameters led to the identification of 19 second key components (SKCs). This information was then employed to construct a refined network, "19 SKCs-33 CTs-73 pathways", providing deeper insights into the intricate connections within the system. Further analyses culminated in the creation of a comprehensive network map, encapsulating "6 single drugs-8 potential active ingredients-13 core targets-54 signaling pathways", elucidating the multifaceted intervention of THSWD in AD. These results offered a novel perspective for understanding the pharmacodynamic material basis of THSWD and paved the way for in-depth investigations into its mechanisms of action and clinical applications in the context of AD.

Key words: Alzheimer’s disease, Network pharmacology, Taohong Siwu Decoction, TCM

Supporting:

李双, 孙璐瑶, 尤斯涵, 张佳燚, 殷宏艳, 曹津萌, 刘心星, 郭春燕, 刘喜富. 基于网络药理学探讨桃红四物汤治疗阿尔茨海默症的主要有效成分及其作用机制[J]. 中国药学(英文版), 2024, 33(6): 525-542.

Shuang Li, Luyao Sun, Sihan You, Jiayi Zhang, Hongyan Yin, Jinmeng Cao, Xinxing Liu, Chunyan Guo, Xifu Liu. Exploring the main active components and potential mechanisms of Taohong Siwu Decoction for the treatment of Alzheimer’s disease based on network pharmacology[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(6): 525-542.

图/表 16

Figure 1. Flowchart of the analysis of the effect of THSWD against AD.

Table 1. Information on the ACs in the THSWD formula.

Figure 2. Venn diagram of AD-related targets.

Figure 3. Venn diagram of AITs and AD disease targets (ADTs).

Table 2. Information on disease targets of THSWD on AD predicted by network pharmacology.

Figure 4. "Component-target" intervention network. The diamond represents the active ingredient, and the oval represents the target.

Table 3. Information of the 21 FKCs of THSWD intervention in AD.

Figure 5. The PPI core network of the target of THSWD intervention in AD.

Table 4. Information on the 33 CTs of THSWD intervention in AD.

Figure 6. FKC-CT network.

Table 5. The 19 SKCs for THSWD to exert therapeutic effects against AD.

Figure 7. Gene ontology enrichment and KEGG pathway of the 33 CTs. (A) Histogram showing GO enrichment analysis of the CTs. The y-axis shows significantly enriched BP, CC, and MF categories, and the x-axis shows the enrichment numbers of these terms. BP: biological process; CC: cellular component; MF: molecular function. (B) The barplot of KEGG pathway analysis. The y-axis represents a significantly enriched pathway, and the x-axis shows the protein/gene numbers of the pathway (*P < 0.05).

Figure 8. In a "compound-target-pathway" network, each edge describes the interaction between them. The red rhombus represents the compounds (19 SKCs), the green circle represents targets (33 CTs), and the cyan diamond represents pathways (73 pathways).

Figure 10. Proposed mechanism of the main active ingredient of THSWD in treating AD. THSW1: Mairin; THSW5: Ferulic acid; THSW6: Kaempferol; THSW10: Amygdalin; THSW12: Mandenol; THSW20: Lignan; THSW25: Acteoside.

Figure 9. In a herbs-ingredients-targets-pathway network, each edge describes the interaction between them.

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基于网络药理学探讨桃红四物汤治疗阿尔茨海默症的主要有效成分及其作用机制

Exploring the main active components and potential mechanisms of Taohong Siwu Decoction for the treatment of Alzheimer’s disease based on network pharmacology

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