A Study To Explore The Mechanism Of S Miltiorrhiza Depside Salt Combined With Aspirin For The Treatment Of Stable Angina Pectoris Based On Biological Molecules Network

1 BackgroundIn recent years, aspirin resistance problems attracted widely concern. Combination therapy of Chinese and Western medicine treatment for complex diseases such as coronary heart disease have achieved good effects in clinical. Through the analysis based on HIS database of 18 hospitals, we found that S miltiorrhiza depside salt and Aspirin commonly combined in treatment of coronary heart disease (CHD). Meta-analysis showed that the efficient of combination treatment for SAP patients is superior to pure western medicine treatment, and no significant adverse reactions. Most complex diseases are not caused by a single gene, but a result of multiple genes or imbalance of network. Molecular biology network analysis method provides a new way to study, which can build a "disease-gene-drug" network to reveal the molecules’mechanism of combination therapy.2 ObjectiveThrough molecular biology network analysis to compare S miltiorrhiza depside salt and Aspirin’s similarities and differences between biological function of molecular network, and predict the mechanism of combination Salvia miltiorrhiza Depside Salt with Aspirin for the treatment of SAP.3 Methods3.1 Gene Obtaining"MLB", "RA", "LA" (Active components of S miltiorrhiza depside salt) and "Aspirin" were entered into the integrated and searchable database of GeneCards and STITCH4.0 to search and export related genes in homo sapiens, respectively. "Angina, Stable "was entered into the DisGeNET database to explore related genes.3.2 Network ConstructionThe genes related with active components of S miltiorrhiza depside salt ("MLB", "RA" and "LA") and "Aspirin" were submitted to the Agilent Literature Search software, for associations among genes of interest and constructing a network. Identification of modules3.3 Identification of modulesThe modular structures exist in a complex biological systematic network, so we detect highly interconnected regions clusters in the network by AP^ MCODE and MCL three ways. Module’s stability is higher if entropy small. Results can be visualized by Cytoscape.3.4 GO Biological Process and KEGG Pathway EnrichmentEnrichment GO biological process and KEGG pathways of S miltiorrhiza depside salt and Aspirin by DAVID software. DAVID can display genes from a user’s list on pathway maps to facilitate biological interpretation in a network context by taking full advantage of the well-known KEGG pathways. The biological processes and KEGG pathway corresponding to the modules were identified, and ranked by the P values (P<0.05, reliability is higher).4 Result4.1 Network building and module partitionThrough database retrievaled 79 S miltiorrhiza depside salt related genes,498 aspirin related genes,75 SAP related genes. There were 715 nodes (genes) and 2310 edges (interactions) identified from the active components of S miltiorrhiza depside salt-related genes, and 2120 nodes (genes) and 9064 edges (interactions) from the Aspirin-related genes, and 630 nodes (genes) and 630 edges (interactions) from the SAP-related genes. There were 61,122,40 modules were identified from S miltiorrhiza depside salt, aspirin and SAP’s network.4.2 GO biological functions and KEGG signaling pathway enrichment755 GO biological functions and 61 KEGG pathways were found in modules of active components of S miltiorrhiza depside salt’s network, which includs immune system, signaling molecules and interaction, signal transduction, metabolic and endocrine system, nervous system related pathways.831 GO biological functions and 53 KEGG pathways in modules of aspirin’s network, which includes metabolism system, signaling molecules and interaction, immune system and cellular processes related pathways.1220 GO biological functions and 65 KEGG pathway in modules of SAP’s network, which includes immune system, metabolic system, cellular processes, related signaling pathways, endocrine system and nervous system related pathways.4.3 Combination effect of the network and important node for SAPS miltiorrhiza depside salt and aspirin for SAP molecular network coverage is 45.92% and 62.56%, respectively and combination of coverage is 71.64%. The important nodes’overlap rate in S miltiorrhiza depside salt, aspirin and SAP networks’ former 10 nodes is 60%, and combination of overlap at a rate of 80%. Two drugs together cover 209 SAP related nodes, important node including IL6, IL8, MAPK14 and MAPK8 inflammatory factor= S miltiorrhiza depside salt cover 56 SAP related genes, important node includs AKT1, IFNG associated with atherosclerosis and myocardial ischemia-reperfusion injury. Aspirin cover 177 SAP related genes, important nodes includs EPHB2 and TP53 associated with vascular smooth muscle cell proliferation.4.4 Combination effect of SAP related pathwaysS miltiorrhiza depside salt and aspirin were involved in the 64.62% and 56.92% of SAP related signaling pathways regulating, respectively. Combination therapy can cover 86.15% of SAP related signaling pathways, which includes immune function, cellular processes, metabolism system, signaling molecules and interaction. S miltiorrhiza depside salt and aspirin effect 16 SAP related signaling pathways, which includs immune function, signal transduction and signal molecule interactions, cell processes, metabolism and tumor related signaling pathway is given priority to, such as JAK-STAT signal pathway, MAPK signal pathways associated with inflammation and atherosclerosis development. S miltiorrhiza depside salt participate in 17 SAP related signaling pathways, in signal transduction, endocrine system, immune function and endocrine disease related signaling pathway is given priority to, such as VEGF signaling pathways, GnRH signaling pathways, and type 1 diabetes signaling pathway associated with regulating endothelial cell function and glucose metabolism. Aspirin participate 11 SAP related signaling pathways, in process of metabolism, cell, the immune system and nervous system disease related signaling pathway is given priority to, such as arachidonic acid metabolism pathway, linoleic acid metabolism, alzheimer’s disease associated with platelet aggregation and regulating lipid metabolism.5 Conclusion(1) S miltiorrhiza depside salt and aspirin combination may have an enhancement effect on treatment of SAP through anti-inflammatory reaction by inhibition of atherosclerosis development.(2) The combination may have an additive effect through the antiplatelet aggregation, protection of endothelial cells, regulating blood lipid, regulating glucose metabolism, and reduce blood sugar caused by aspirin resistance.(3) S miltiorrhiza depside salt can reduce the risk of bleeding by aspirin, which may be associated with the regulation of endothelial cell.