Computational systems pharmacology reveals an antiplatelet and neuroprotective mechanism of Deng-Zhan-Xi-Xin injection in the treatment of ischemic stroke. (September 2019)

• Record Type: Journal Article
• Authors: Zhao, Jing; Lv, Chao; Wu, Qiuling; Zeng, Huawu; Guo, Xin; Yang, Jian; Tian, Saisai; Zhang, Weidong
• Is Part Of: Pharmacological research. Volume 147(2019)
• Publication Date: 2019-09
• Subjects: AA Arachidonic acid -- ADME absorption distribution, metabolism, excretion -- CCA common carotid artery -- CETSA Cellular thermal shift assay -- DEG differentially expressed genes -- ECA external carotid artery -- CMAP connectivity map -- DAVID the Database for Annotation Visualization and Integrated Discovery -- DZXXI Deng-Zhan-Xi-Xin injection -- GEO Gene Expression Omnibus -- GSC giant strongly connected component -- IS ischemic stroke -- ICA internal carotid artery -- ITGA2B Integrin alpha-IIb -- ITGB3 Integrin beta-3 -- MCA middle cerebral artery -- MCAO Middle Cerebral Artery Occlusion -- NSAID non-steroidal anti-inflammatory drug -- PRP Platelet rich plasma -- PPI protein-protein interaction -- PPP platelet poor plasma -- PTGS1 Prostaglandin G/H synthase 1 -- PTGS2 Prostaglandin G/H synthase 2 -- SRWR signed random walk with restart -- STITCH Search Tool for Interactions of Chemicals -- TXA2 thromboxane A2 -- TXB2 thromboxane B2 -- TCM traditional Chinese medicine -- TCMSP Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform; Network pharmacology -- Traditional Chinese medicine -- Ischemic stroke -- Drug target -- Human signaling network -- Signed random walk with restart; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104365
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Herbs are typically prescribed in traditional Chinese medicine (TCM) to treat complex diseases. The multicomponent nature of herbal drug ingredients makes it difficult to readily understand their mode of action. To decipher their molecular mechanisms, here we proposed a novel computational systems pharmacology based approach, which consisted of transcriptome profiling, data collection, statistical analysis, network algorithm, bioinformatics analysis and pharmacological validation. The network algorithm called signed random walk with restart (SRWR) was used to simulate the propagation of drugs' effects on networks. This algorithm could identify proteins either positively or negatively regulated (activated or inhibited) by drugs on human signaling networks. To establish proof of principle, the herbal product Deng-Zhan-Xi-Xin injection (DZXXI), which exhibits pharmacological effects in ischemic stroke but its mechanism was unclear, was analyzed. Eighty-three targets were predicted with high confidence for DZXXI's active compounds in plasma, and 87 differentially expressed genes (DEGs) were identified in MCF7 cells treated with DZXXI. These target genes were further found to be associated with pathways involved in neuronal apoptosis in ischemic stroke, such as NF-κB signaling, TNF signaling, and PI3K-Akt signaling. Intersection analysis between DZXXI's putative targets with ischemic stroke-associated genes identified two important targets ( PTGS1, PTGS2 ) corresponding to four DZXXI compounds, which were further validated using in silico and in vitro/vivo models. The most inhibited genes identified by the SRWR algorithm were significantly enriched with ischemic stroke-associated disease genes, antiplatelet associated pathways, and their encoded proteins were enriched in brain, vascular endothelium and platelets. The CMAP analysis based on DEGs suggested that DZXXI could function as both an anti-inflammatory and anti-platelet agent. Taken together, the computational analysis suggested that DZXXI exhibited anti-platelet and neuroprotective effects in the treatment of ischemic stroke. These deductions were preliminarily confirmed by subsequent in vitro / vivo studies. This approach provides a systems perspective to study the relevance between herbal drugs and disease processes, and can reveal possible pharmacological effects of multiple ingredients within herbal product.