| Atherosclerosis(AS)is the pathological basis of a variety of cardiovascular and cerebrovascular diseases,abnormal lipid metabolism and the formation of lipid core in AS plaques are its pathological basis,and dyslipidemia is its most common risk factor.Academician Chen Keji and his team put forward the theory of "blood stasis and toxicity" based on long-term clinical and research,and applied the method of activating blood circulation and detoxicating to guide the treatment of AS with significant effect.Huanglian(Coptidis rhizoma)-Danshen(Salvia miltiorrhiza)are widely used in clinical treatment together.However,the exploration of their active ingredients against AS is mainly based on single drug,as well as the active ingredients and mechanisms of action of the combination of them are not clear yet.So,we conducted related studies to reveal the potentionl mechanism of effects of Huanglian and Danshen.Part 1:Net-work PharmacologyNet-work Pharmacology 1:Study on the mechanism of Huanglian and Danshen on atherosclerosis based on Net-work Pharmacology.Objective:To explore the mechanism of Huanglian and Danshen on atherosclerosis.Methods:The main chemical constituents and targets of Coptis chinensis and Salvia miltiorrhiza Bunge were obtained from TCMSP database,and the therapeutic targets of AS were collected by searching GeneCards,OMIM and DisGeNET databases.Obtain the intersection of drug target and disease target,and draw the drug-component-target network diagram through Cytoscape 3.9.1 software.The GO function and KEGG pathway enrichment analysis of intersection targets were performed using DAVID database.Results:A total of 68 effective chemical components of Huanglian and Danshen were selected.153 intersection targets of herbs and disease were obtained.It was found that the active components of Huanglian and Danshen may be luteolin,tanshinoneⅡ A(TSⅡA),quercetin and berberine(BBR).GO functional enrichment analysis showed they through biological processes such as positive regulation of gene expression,response to drugs,response to lipopolysaccharide,and protein binding to take effect.KEGG pathway enrichment analysis showed that the potential action pathways include lipids and atherosclerosis,AGE-RAGE signaling pathway in diabetic complications,TNF signaling pathway,IL-17 signaling pathway and PI3K-Akt signaling pathway.Conclusions:The active ingredients in Huanglian-Danshen can exert anti-atheroscl erotic effects through multiple targets and pathways,among which lipid and atheroscle rotic pathways have the greatest influence,so the active ingredients of berberine(BBR)-tanshinoneⅡA(TSⅡA)were screened for the next study.Net-work Pharmacology 2:Study on the mechanism of berberine(BBR)-tanshinoneⅡA(TSⅡA)on atherosclerosis based on Net-work Pharmacology.Objective:To explore the mechanism of BBR-TSⅡA on atherosclerosis.Methods:The same as Net-work Pharmacology 1.Results:A total of 95 intersection targets of BBR-TS ⅡA-AS were obtained,and the possible core targets of the active ingredient were mainly SRC,PIK3R1,PIK3CA,CDC42,LCK,JAK2,ABL1,RAC1,etc.by protein interaction analysis.Further GO functional analysis revealed that the main biological functions of BBR-TSIIA anti-AS include protein phosphorylation,signal transduction,and response to exogenous stimuli.The KEGG signaling pathway enrichment analysis revealed that the potential action pathways of BBR-TSⅡA also included AGE-RAGE signaling pathway in diabetic complications,lipid and atherosclerosis,PI3K-Akt signaling pathway and other signaling pathways,and its core targets mainly involved lipid and atherosclerosis pathways.Conclusions:BBR-TS ⅡA exerts anti-AS effects in possibly affecting lipid metabolism,based on which the next part of BBR-TSⅡA intervention in lipid metabolism in ApoE-/-mice atherosclerosis model was conducted.Part 2:Study on the lipid metabolism changes and potential mechanism of BBR-TSⅡA-treated high-fat fed ApoE-/-mice.Objective:Based on the results of Part 1,we select berberine(BBR)-tanshinonea ndⅡA(TSⅡA)and designed animal experiment to reveal the changes of lipid metabolit es and potentional mechanism of their therapeutic efficacy on high-fat fed ApoE-/-mice.Methods:ApoE-/-mice fed with high fat diet for 12 weeks were randomly divided into model group,BBR group(50 mg/kd/d),TSIIA group(30 mg/kg/d),atorvastatin group(10 mg/kg/d)and BBR(50 mg/kd/d)+TSIIA(30 mg/kg/d)groups.We mear sured serum total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholestero 1(LDL-C)and high-density lipoprotein cholesterol(HDL-C)in each group,and evaluated aortic plaque and hepatocyte appearance and hepatic lipid profiles and lipid metabolites.Results:Compared with the Control group,TC,LDL-C and TG levels were increased in the model group(P<0.05),and compared with the Model group,TC and LDL-C levels were significantly decreased(P<0.01)and HDL-C levels were increased(P<0.05)in the BBR+TSⅡA group;the single-agent BBR group could reduce TC and LDL-C levels(P<0.05),and the TSⅡA group could lowered TC levels(P<0.05).BBR+TSⅡA group could reduce aortic plaque,hepatic steatosis and lipid deposition to different extents.Examination of hepatic lipid metabolism revealed that a total of 43 differential metabolites were selected between control group and the model group,which may be the main lipid metabolites of hepatic lipid metabolism changes in AS mice and can be mainly divided into triglyceride(TG),phosphatidylcholine(PC),sphingomyelin(SM)and phosphatidylethanolamine(PE).The major impact metabolic pathywany of BBR-TSⅡA was Glycerophospholipid metabolism and Sphingolipid metabolism.Conclusion:BBR-TSⅡA can reduce the blood lipid level and hepatic lipid deposition in atherosclerotic mice.The major impact metabolic pathywany of BBR-TSⅡA was Glycerophospholipid metabolism and Sphingolipid metabolism. |
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