Research On The Network Biological Mechanism Of Syndrome Of Intermingled Phlegm And Blood-stasis Of Coronary Atherosclerotic Heart Disease Based On Effective Herbs

ObjectThe network biological mechanism on the syndrome of intermingled phlegm and blood stasis of coronary atherosclerotic heart diseaseMaterials and MethodsThe disease network of coronary atherosclerotic Heart Disease was constructed based on the seed genes and their modules. Against this background of the disease network, a blood stasis target set/a phlegm target set was constructed which composed of the active ingredients’targets of the herbs which could remove the blood stasis/eliminate sputum when treating the syndrome of intermingled phlegm and blood stasis of coronary atherosclerotic heart disease. At the same time, a western drugs’ target set was constructed as evidence of the ingredinets’targets. We analyzed the the shared enrichment functions of the seed gene set, the blood stasis target set and the phlegm target set and their modules. The shared genes/pathways/ modules might be the network biological mechanism of syndrome of intermingled phlegm and blood-stasis of Coronary Atherosclerotic Heart Disease. The steps are as follows.Step 1:Constructed the seed gene set which were from Pubmed literature review/CAD gene database/OMIM database/GWAS, analyed the funtion of the seed gene set and their modules.Step 2:Maked sure the herbs which could remove blood stasis and eliminate phlegm when treating the sydrome of intermingled phlegm and blood stasis of coronary atherosclerotic heart disease from the Chinese literature database including CNKI and WANGFANG and referring to the the previous knowledge/Chinese clinical expert’s experience.Step 3:Constrcuted the blood stasis target set which composed of the active ingredient’s targets of the herbs which could remove the blood stasis when treating the sydrome of intermingled phlegm and blood stasis of coronary atherosclerotic heart disease. constructed the phlegm target set which composed of the active ingredient’s targets of the herbs which could eliminate sputum when treating the sydrome of intermingled phlegm and blood stasis of coronary atherosclerotic heart disease. Analyed the funtion of the blood stasis/the phlegm set and their modules.Step 4:Integrated the data of target of western drugs which can treat Coronary Atherosclerotic Heart Disease (Therapeutic Target Database and Drugbank database) to validate the reliability of target of herbs.Step 5:Analyzed the the shared enrichment functions of the seed gene set/the blood stasis target set/the phlegm target set and their modules. The shared genes/pathways/modules might be the network biological mechanism of syndrome of intermingled phlegm and blood-stasis of Coronary Atherosclerotic Heart Disease.Results(1)The seed gene set was constructed which composed of 1086 seed genes and the main funciton of the seed gene set included wounding, inflammatory, oxidative, blood circulation and blood vasculature development, liqid,external stimulus, bacterial origin,response to lipopolysaccharide, regulation of inflammatory reponse, postive of cell migration. The significant pathway was Complement and coagulation cascades(hsa04610). The functions of the 10 highest ratio value modules in STRING 9.1 was egulation of transcription from RNA polymerase II promoter in response to hypoxia (GO:0061418), regulation of angiotensin levels in blood (GO:0002002), angiotensin maturation (GO:0002003), MLL5-L complex (GO:0070688). These results was corresponding to the recognize of the pathogenesis of the Coronary Atherosclerotic Heart Disease.(2)152 formulas were get from 188 public literature from the CNKI and WANGFANG. Fructus Trichosanthis(GuaLou), Allium macrostem(XieBai), Rhizoma Pinelliae(BanXia), Rhizoma Coptidis(HuangLian), Rubra Poria(FuLing), Pericarpium Citri Reticulatae (ChenPi), Fructus Aurantii Immaturus(ZhiShi), Bamboo Shavings(ZhuRu), Rhizoma Acori Talarinowii (ShiChangpu) was regarded as the herbs to remove the blood stasis when treating the intermingled phlegm and blood-stasis of Coronary Atherosclerotic Heart Disease. Radix Salviae liguliobae(DanShen), Lignum Santaii Albi(TanXiang), Fructus Amomi(ShaRen), Semen Persicae(TaoRen), Flos Carthami(HongHua), Radix Angelicae sinensis(DangGui), Radix Paeoniae Rubra(ChiShao), Rhizoma Chuanxiong(ChuanXiong), Radix Rehmanniae (ShengDihuang) were regarded as the herbs to eliminate the phlegm when treating the intermingled phlegm and blood-stasis of Coronary Atherosclerotic Heart Disease. The phlegm target set composed of 133 target and the blood Stasis target set composed of 152 target were constructed.The significant GO terms of the blood stasis set were reactive oxygen species biosynthetic process(GO:1903409), positive regulation of reactive oxygen species metabolic process(GO:2000379), vascular process in circulatory system(GO:0003018), response to lipopolysaccharide (GO:0032496), response to bacterium(GO:0009617), response to hypoxia (GO:0001666). The significant Pathway of the blood stasis set was Hepatitis B(Has:hsa05161). It was consistent with previous understanding partly.The significant GO terms of the phlegm target set were response to steroid hormone(GO:0048545), response to lipopolysaccharide (GO:0032496), Fc-epsilon receptor signaling pathway(GO:0038095), regulation of nitric oxide biosynthetic process(GO:0045428), and the signifcant pathwaye of the phlegm target set was Hepatitis B(Has:hsa05161). It was consistent with previous understanding partly.The shared enrichment GO terms of the seed gene set/the blood stasis target set/the eliminate phlegm were response to corticosteroid(GO:0031960), cellular response to lipopolysaccharide (GO:0071222). inflammatory response (GO:0006954)]、positive regulation of nitric oxide biosynthetic process (GO:0045429)]、cell-type specific apoptotic process (GO:0097285).The shared enrichment pathways of the seed gene set/the blood stasis target set/the eliminate phlegm were TNF signaling pathway, Apoptosis,HIF-1 signaling pathway,NF-kappa B signaling pathway. The main function of the four pathways was inflammatory response, immune reponse, apoptosis.There were 4 shared genes PTGS29(Gene ID:5743), NOS2(Gene ID:4843), MMP9(GeneID:4318,VEGFA(GeneID:7422).) in Module 95 (typical module related to the syndrome of intermingled phlegm and blood-stasis of Coronary Atherosclerotic Heart Disease which appeared in the seed gene set/the drug target set/the blood stasis target set/the phlegm target set at the same time). The function of the PTGS29 and NOS2 was related to the inflammatory response. The significant GO terms of module 95 were defense response,immune system process,immune response,response to stress, extracellular region part,extracellular space, inflammatory response, extracellular region,response to stimulus,response to other organism. The main function of Module 95 was inflammatory response and immune reponse.In all, The shared functions of 4 shared genes/GO terms/Pathway in which the seed gene set/the drug target set/the blood stasis target set/the phlegm target set appeared at the same time was inflammatory response.ConclusionsInflammatory response probably played a important role in the biological mechanism on the sydrome of intermingled phlegm and blood stasis of Coronary Atherosclerotic Heart Disease.