| Atherosclerosis(AS)is an important pathological basis of cardiovascular disease.Fragile plaque rupture and secondary thrombosis are the main causes of acute cardiovascular events.Vulnerable plaque has the characteristics of foam cell aggregation,lipid core enlargement and fibrous cap thinning.These characteristics are closely related to inflammation,oxidative stress and endothelial damage.In recent years,a large number of studies have shown that the PI3K/Akt/NF-?B signaling pathway is closely related to the pathophysiological process of AS,and is involved in the regulation of inflammation,oxidative stress and endothelial function.Regulating the PI3K/Akt/NF-?B pathway is expected to become a stable AS pathway.New strategies for plaque damage.The yiqi yangyin huoxue method is one of the basic therapies to prevent and treat atherosclerotic cardiovascular disease.Previous studies have found that replenishing qi,activating blood and nourishing yin can inhibit vascular inflammation,oxidative stress,and protect endothelial function to prevent AS.The role of American ginseng and Salvia miltiorrhiza is a commonly used pair of medicines for replenishing qi,activating blood and nourishing yin.Whether it can inhibit the progression of atherosclerosis and stabilize the vulnerable plaque of AS remains to be further explored and answered.This project explores the intervention effect of the compatibility of American ginseng and Salvia miltiorrhiza on AS vulnerable plaques through systematic reviews,network pharmacology,in vivo experiments and in vitro experiments,and explores the relationship between the intervention effect and the PI3K/Akt/NF-?B pathway.Evidence-based medicine,biological network,material basis,overall animal and cellular molecular level to elucidate the characteristics and mechanism of action of American ginseng and Salvia miltiorrhiza to stabilize AS vulnerable plaques.The research of this subject is divided into two parts:literature review and experimental research.1 Literature review:Review ?:Research progress of American ginseng and Salvia miltiorrhiza in the treatment of atherosclerosisReview ?:Research progress of PI3K/Akt/NF-?B signaling pathway in atherosclerosis2 Experimental research:including the following five parts.Study ?:A systematic review study on the treatment of angina pectoris with Yiqi Huoxue Yangyin RecipeObjective:Using meta-analysis method to explore the efficacy and safety of Yiqi Huoxue Yangyin Recipe in the treatment of coronary heart disease angina pectoris.Methods:Computer searched PubMed,EMbase,The Cochrane Library,CNKI,SinoMed,VIP and WanFang Data database,and included the relevant RCTs for the treatment of coronary heart disease and angina pectoris with the replenishing qi,activating blood and nourishing yin formula.The search time is from January 1,2010 to January 31,2021,Using RevMan5.3 software for Meta analysis.Results:Fifteen RCTs with a Jadad score>4 were finally included,and a total of 1388 patients with coronary heart disease and angina pectoris were included.Meta-analysis results showed that the efficacy of angina pectoris in the combination group[RR=1.22,95%CI(1.15,1.29),P<0.00001],the efficacy of TCM syndromes[RR=1.16 95%CI(1.08,1.25),P=0.0001],ECG curative effect[RR=1.27,95%CI(1.16,1.39),P<0.00001],HDL-C[MD=0.52,95%CI(0.26,0.78),P<0.0001]significantly higher than simple routine Western medicine treatment group,hs-CRP[SMD=-1.57,95%CI(-1.99,-1.14),P<0.00001],TC[MD=-1.05,95%CI(-1.57,-0.52),P<0.0001],TG[MD=-0.44,95%CI(-0.59,-0.29),P<0.00001],LDL-C[MD=-0.54,95%CI(-0.83,-0.24),P-0.0004],Plasma viscosity[MD=-0.38,95%CI(-0.57,-0.20),P<0.0001]and fibrinogen content[MD=-0.66,95%CI(-0.97,-0.36),P<0.0001]significant It is lower than the conventional western medicine treatment group alone,the difference is statistically significant;in terms of safety,the incidence of adverse reactions between the two groups[RR=1.57,95%Ci(0.63,3.91),P=0.33]has no statistical difference.Conclusion:Current evidence shows that compared with conventional western medicine treatment alone,the combination of Yiqi Huoxue Yangyin prescription combined with conventional western medicine treatment can effectively reduce inflammation,blood lipids and hemorheological index levels in patients with angina pectoris,improve myocardial ischemia,and relieve clinical symptoms.And has better safety.Limited by the quality and quantity of included studies,the above conclusions still need to be verified by more high-quality randomized controlled trials.Study ?:Based on network pharmacology to explore the mechanism of the combination of American ginseng and Danshen in the treatment of coronary heart diseaseObjective:To analyze the pharmacological mechanism of the combination of American ginseng and Salvia miltiorrhiza in the treatment of coronary heart disease by means of network pharmacology.Methods:Search the active ingredients and targets of American ginseng and Salvia miltiorrhiza through the TCMSP database,and standardize the target information in the Uniport database;obtain coronary heart disease-related target genes through the Gencards,OMIM,TTD,and DRUGBANK databases,and use the R language to screen drugs and diseases Intersection targets;analyze protein interactions through String platform to screen key target genes;use DAVID database to perform GO and KEGG pathway enrichment analysis on intersection targets.Results:The key targets of American ginseng and Salvia miltiorrhiza in the treatment of coronary heart disease were STAT3,AKT1,TP53,TNF,MAPK1,etc.The biological pathways mainly acted on the HIF-1 signaling pathway,PI3K/Akt signaling pathway and TNF signaling pathway.Conclusion:This study initially revealed the multi-component,multi-target,and multi-pathway mechanism of the combination of American ginseng and Salvia miltiorrhiza in the treatment of coronary heart disease,providing a theoretical basis and research direction for further development and utilization.Study ?:Preparation of effective parts of American ginseng and Salvia miltiorrhiza and determination of component content by HPLCObjective:To prepare the effective parts of American ginseng and Salvia miltiorrhiza on the basis of preliminary research,and to determine the content of key components in the effective parts by HPLC.Methods:In this part of the study,the three effective parts of American ginseng saponin,tanshinone and salvianolic acid were prepared by heating reflux method extraction,reduced pressure concentration,macroporous resin chromatography separation and purification,and vacuum drying and freezing.The effective parts were determined by high performance liquid chromatography.The content of the main components in the site.Results:The contents of ginsenosides Rbl,Rg1,and Re in American ginseng materials were 2.4%,0.13%,and 0.98%,respectively,totaling 3.51%;the contents of cryptotanshinone,tanshinone ?,and tanshinone ?A in salvia medicinal materials were 0.11%,0.05%,0.14,respectively%,a total of 0.30%,the salvianolic acid B content in the Salvia miltiorrhiza medicinal materials is 3.08%,which meets the national pharmacopoeia standards.The contents of the main components ginsenosides Rgl,Re,and Rb1 in the effective parts of American ginseng saponins were 1.24%,12.82%,and 42.49%,respectively,totaling 56.55%;the contents of the main components of the effective parts of tanshinone,cryptotanshinone,tanshinone ?,and tanshinone ?A,were 14.51%,respectively.4.72%,17.5%,a total of 36.73%;salvianolic acid B,the main ingredient in the effective part of salvianolic acid,is 40.67%.Conclusion:In this study,American ginseng and Salvia miltiorrhiza were extracted and purified to obtain three effective parts of American ginseng saponins,tanshinone and salvianolic acid.The effective parts of American ginseng and Salvia miltiorrhiza were mixed evenly according to the crude drug amount in a ratio of 1:3.The site is used for pharmacological experimental research of atherosclerosis.Study ?:Study on the mechanism of the compatibility of American ginseng and Salvia miltiorrhiza to intervene in ApoE-/-atherosclerotic vulnerable plaques in miceObjective:To observe the effects of compatibility of American ginseng and Salvia Miltiorrhiza on vulnerable plaques in ApoE-/-mice with AS,and to explore its mechanism from the perspectives of inflammation,endothelial damage and oxidative stress.Methods:Methods:After feeding 90 ApoE-/-mice with high-fat diet for 12 weeks,they were randomly divided into model group,simvastatin group(3.03mg/kg/d),low-dose group of effective parts of American ginseng and Salvia miltiorrhiza(calculated by crude drug amount,American ginseng 0.75g/kg/d+Salvia miltiorrhiza 2.25g/kg/d),middle-dose group of effective parts of American ginseng and Salvia miltiorrhiza(calculated by crude drug amount,American ginseng 1.5g/kg/d+Salvia miltiorrhiza 4.5g/kg/d),high-dose group of effective parts of American ginseng and Salvia miltiorrhiza(calculated by crude drug amount,American ginseng 3g/kg/d+Salvia miltiorrhiza 9g/kg/d)and American ginseng and Salvia miltiorrhiza decoction group(calculated by crude drug amount,American ginseng 1.5g/kg/d+Salvia miltiorrhiza 4.5g/kg/d),15 C57BL/6J mice were used as normal control group;the corresponding drugs were given by intragastric administration for 8 weeks;the aortic oil red O gross staining and the aortic root H&E staining were used to assess the degree of AS lesions and plaque stability;automatic biochemical analyzer was used Detect blood lipid index levels;use enzyme-linked immunosorbent assay to detect serum levels of IL-1?,TNF-?,ICAM-1 and ET-1;use biochemical methods to detect serum levels of MDA,SOD and NO;use Western blotting Method to detect the protein expression levels of MMP-9,p-PI3K,p-Akt and p-NF-?B.Results:?Pathological indicators:gross staining of aortic oil red O showed that compared with the normal group,the intima of the aorta in the model group showed lipid deposits,atherosclerotic plaque formation,and obvious red staining.Compared with the model group,lipid deposition in the simvastatin group,medium-dose group,high-dose group and water decoction group was significantly reduced,and the ratio of plaque area to aortic intima area was significantly reduced(P<0.05).Aortic H&E staining showed that plaques were seen in the model group The lumen is protruding,the lumen is narrowed,the fiber cap on the surface of the plaque is thin and uneven,the area of the lipid core can be seen in the plaque,and a large number of foam cells are gathered.Compared with the model group,the plaque narrowness of each drug intervention group was reduced,the number of foam cells was reduced,and the lipid core area was reduced.?Blood lipid index:Compared with the model group,the high-dose group of American ginseng and Salvia miltiorrhiza significantly reduced the levels of TG and TC(P<0.05),and the middle-dose group of American ginseng and Salvia miltiorrhiza significantly increased the level of HDL-C(P<0.05).?Inflammatory factor indicators:Compared with the model group,the levels of IL-1?and TNF-? in each drug intervention group were significantly reduced(P<0.05),and the levels of ICAM-1 in the middle-dose and high-dose groups of American ginseng and Salvia miltiorrhiza were significantly reduced(P<0.05).?Endothelial injury indicators:Compared with the model group,the NO content of simvastatin,medium and high dose and water decoction groups were significantly increased(P<0.05),ET-1 in simvastatin,medium and high dose and water decoction groups The content was significantly reduced(P<0.05).?Oxidative stress indicators:Compared with the model group,the SOD content of each drug intervention group was significantly increased(P<0.05),and the MDA content was significantly reduced(P<0.05).?MMP-9:Compared with the model group,the expression of MMP-9 protein in each drug intervention group was significantly reduced(P<0.05);there was no significant difference in the expression of MMP-9 between the effective part of American ginseng and salvia miltiorrhiza group and the water decoction group(P>0.05).?Pathway related indicators:Compared with the model group,the expression of p-PI3K protein in the simvastatin group,the low-dose and high-dose groups of American ginseng and Salvia miltiorrhiza was significantly reduced(P<0.05);the expression of p-Akt protein in each drug intervention group was significantly reduced(P<0.05);p-NF-?B protein expression in the medium-dose,high-dose and water decoction groups of simvastatin,American ginseng and Salvia miltiorrhiza was significantly reduced(P<0.05);The expressions of p-PI3K,p-Akt and p-NF-?B were not significantly different(P>0.05).Conclusion:The compatibility of American ginseng and Salvia miltiorrhiza can inhibit inflammatory response,improve oxidative stress,protect endothelial function and reduce aortic MMP-9 protein expression,reduce lipid deposition and plaque area,inhibit plaque progression,and stabilize atherosclerosis vulnerability Plaque,its mechanism of action may be related to inhibiting the activation of PI3K/Akt/NF-?B signaling pathway.Study ?:Study on the mechanism of compatibility of American ginseng and Salvia miltiorrhiza in intervention of ox-LDL-induced umbilical vein endothelial cell injuryObjective:To observe the effects of compatibility of American ginseng and salvia on endothelial cell injury and to explore its mechanism of action.Methods:According to the third experiment,the ratio of ginsenoside Rbl and salvianolic acid B in the effective part was obtained,and the monomers of the corresponding quality were weighed and mixed uniformly to be used as intervention drugs.Umbilical vein endothelial cells induced by ox-LDL were used to establish endothelial cell injury models,which were divided into normal control group,model group(ox-LDL 75?g/mL),and low-dose group(ox-LDL 75?g/mL+Chinese medicine monomer 5?g)./mL),high-dose group(ox-LDL 75?g/mL+Chinese medicine monomer 25?g/mL),high-dose group+740 YP group(ox-LDL 75?g/mL+Chinese medicine monomer 5?g/mL+740 YP 25 ?g/mL),given corresponding drug intervention for 24h;CTG was used to detect cell viability;ELISA method was used to detect ICAM-1 and MMP-9 content;biochemical method was used to detect MDA and SOD levels;Western blotting(WB)was used The protein expression levels of p-PI3K,p-Akt and p-NF-?B were detected.Results:?CTG indicators:Compared with the model group,the cell viability of the low-dose and high-dose groups was significantly increased(P<0.05);compared with the high-dose group,the cell viability of the 740YP group was significantly reduced(P<0.05).? Inflammatory factor indicators:Compared with the model group,ICAM-1 and MMP-9 in the low-dose and high-dose groups of American ginseng and Salvia miltiorrhiza were significantly reduced(P<0.05);compared with the high-dose group,the ICAM-1 and MMP-9 in the 740YP group were significantly lower Increase(P<0.05).?Oxidative stress indicators:Compared with the model group,the SOD of the high-dose group was significantly increased,and the MDA was significantly reduced(P<0.05);compared with the high-dose group,the SOD of the 740YP group was significantly reduced,and the MDA was significantly increased(P<0.05).?Pathway related indicators:Compared with the model group,p-PI3K,p-Akt and p-NF-?B in the low and high dose groups of American ginseng and Salvia miltiorrhiza were significantly reduced(P<0.05);compared with the high dose group,the 740YP group had p-PI3K,p-Akt and p-NF-?B were significantly increased(P<0.05).Conclusion:The compatibility of American ginseng and Salvia miltiorrhiza can increase cell activity,improve oxidative stress and inhibit inflammation by inhibiting PI3K/Akt/NF-?B pathway,reduce endothelial cell damage,and protect HUVEC cells. |
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