Abstract
Salvianolic acid C (SAC) is a major bioactive component of Salvia miltiorrhiza Bunge (Danshen), a Chinese herb for treating ischemic stroke (IS). However, the mechanism by which SAC affects the IS has not yet been evaluated, thus a network pharmacology integrated molecular docking strategy was performed to systematically evaluate its pharmacological mechanisms, which were further validated in rats with cerebral ischemia. A total of 361 potential SAC-related targets were predicted by SwissTargetPrediction and PharmMapper, and a total of 443 IS-related targets were obtained from DisGeNET, DrugBank, OMIM, and Therapeutic Target database (TTD) databases. SAC-related targets were hit by the 60 targets associated with IS. By Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment combined with the protein-protein interaction (PPI) network and cytoHubba plug-ins, nine related signaling pathways (proteoglycans in cancer, pathways in cancer, PI3K-Akt signaling pathway, Focal adhesion, etc.), and 20 hub genes were identified. Consequently, molecular docking indicated that SAC may interact with the nine targets (F2, MMP7, KDR, IGF1, REN, PPARG, PLG, ACE and MMP1). Four of the target proteins (VEGFR2, MMP1, PPARγ and IGF1) were verified using western blot. This study comprehensively analyzed pathways and targets related to the treatment of IS by SAC. The results of western blot also confirmed that the SAC against IS is mainly related to anti-inflammatory and angiogenesis, which provides a reference for us to find and explore the effective anti-IS drugs.
Highlights
Stroke is a severe disease caused by cerebral blood circulation disorders, which can lead to high disability rate and high mortality, and has become one of the three most prevalent and serious diseases in the world (Krishnamurthi et al, 2020; Ajoolabady et al, 2021)
A total of 361 potential Salvianolic acid C (SAC)-related targets were predicted for further verification by SwissTargetPrediction and PharmMapper, and a total of 443 ischemic stroke (IS)-related targets were obtained from DisGeNET, DrugBank, OMIM, and Target database (TTD) databases. 60 overlapping genes of targets were identified as co-expressed targets (Figure 2A)
Compared with the important targets enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, four targets (KDR, Insulin-like growth factor-1 (IGF1), PPARG, and Matrix metalloproteinase 1 (MMP1)) were selected and displayed in a 3D graph (Figure 7)
Summary
Stroke is a severe disease caused by cerebral blood circulation disorders, which can lead to high disability rate and high mortality, and has become one of the three most prevalent and serious diseases in the world (Krishnamurthi et al, 2020; Ajoolabady et al, 2021). The pathological process of IS is mainly manifested by focal cerebral ischemia, hypoxia and nerve necrosis The therapeutic effect of existing drugs is not ideal (Ciccone et al, 2013; Saver et al, 2015). More effective drugs and measures are urgently needed to prevent and treat this disease
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