| Purpose:1.Based on the research method of bibliometrics,systematically sort out the pathogenesis,treatment ideas and prescriptions and medication rules of traditional Chinese medicine in the treatment of atherosclerosis(AS)in modern literature,so as to construct the theoretical system and treatment principles of traditional Chinese medicine for the treatment of AS.Provide documentary support for the formation of governance law.2.Based on the network pharmacology research,preliminarily predict the action targets of Yiqi Tongmai Jiangzhi Recipe to interfere with atherosclerosis,verify the predicted targets through animal experiments,and further verify the curative effect characteristics of Yiqi Tongmai Jiangzhi Recipe and mechanism of action.To compare and evaluate the curative effect characteristics of Yiqi Tongmai Jiangzhi Recipe with different efficacy modules of invigorating qi,promoting blood circulation and resolving phlegm in atherosclerosis in ApoE-/-mice,and verifying that Yiqi Tongmai Jiangzhi Recipe treats both the symptoms and the root cause,and the trinity of invigorating qi,activating blood and resolving phlegm The rationality of the construction of comprehensive governance law.3.Preliminarily evaluate the efficacy and safety of Yiqi Tongmai Jiangzhi Formula in improving atherosclerotic plaque and reducing blood lipids through clinical trials,and provide data support for further research.Method:1.Based on bibliometric analysis of the medication rules of traditional Chinese medicine in the treatment of AS in modern literature.The databases of China National Knowledge Infrastructure(CNKI)and Wan Fang Data Knowledge Platform(Wan Fang Data)were retrieved,and literatures related to traditional Chinese medicine for atherosclerosis in the past ten years were retrieved.The search strategy of CNKI is SU=’atherosclerosis’*(TCM’+’TCM’),and the search strategy of Wanfang database is the subject:("TCM" and "TCM")and atherosclerosis.To construct a modern literature database of atherosclerosis,summarize and analyze the syndromes of atherosclerosis,the distribution of syndrome elements,treatment ideas,and classification of drug efficacy.2.Prediction of anti-atherosclerosis targets of Yiqi Tongmai Jiangzhi Recipe based on network pharmacology.Log in to TCMSP,Pubchem,OMIM and other databases to obtain the chemical components and target proteins of Yiqi Tongmai Jiangzhi Formula,and obtain the disease targets of atherosclerosis.After obtaining the intersection genes of drugs and diseases,the STRING online database was used to construct the PPI protein network,and the R language program package was used to carry out the enrichment analysis of the GO biological process and KEGG pathway of the intersection genes to predict Yiqi Tongmai and lipid-lowering Mechanism of action in the treatment of atherosclerosis.3.An experimental study on the rationality and effectiveness of the prescription of Yiqi Tongmai Jiangzhi prescription for intervening in ApoE-/mice with atherosclerosis.140 healthy male SPF ApoE-/-mice were randomly divided into 7 groups,model group,atorvastatin control group,Chinese medicine Yiqi group,Chinese medicine activating blood group,Chinese medicine reducing phlegm group,Chinese medicine promoting blood circulation removing phlegm group,Chinese medicine whole group.There were 20 mice in each group,and the other 20 C57B1/6 male mice were used as blank control group.The blank control group was fed with normal chow,and 0.1 mL/10 g of normal saline was given by gavage,once a day,for 8 weeks..Model group,atorvastatin control group,Yiqi group,Huoxue group,Huatan group,Huoxue Huatan group and Quanfang group were all fed with high-fat diet,and at the same time given 0.1 mL/10 g of normal saline,Atorvastatin solution,Yiqi group solution,Huoxue group solution,Huatan group solution,Huoxue Huatan group solution and Complete prescription group solution were administered once a day for 12 weeks.Blood was collected by enucleation of the eyeball to detect blood lipid content;aortic root tissue was collected for HE staining and oil red staining for quantitative analysis of plaque;and pulse conduction velocity and carotid intima-media thickness were measured under ultrasound.4.Study on the mechanism of Yiqi Tongmai Jiangzhi Recipe interfering with atherosclerosis in ApoE-/-mice.The feeding process of the mice was the same as above.After the experiment,blood was collected by removing the eyeballs,and Luminex detection technology was used to detect TNF-α,IL-1β,IL-6,IL-4,VEGF,IL-10,CCL5,TNF-α,IL-1β,IL-6,IL-4,VEGF,Expression of IFN-γ,CRP and other factors,serum OX-LDL content of mice was measured by ELISA;PPARα,PPARγ,MMP9,IL-6,RAGE,SRC and PPARα,PPARγ,MMP9,IL-6,RAGE,SRC and ERK1/2 expression.5.Clinical study on the efficacy and safety of Yiqi Tongmai Jiangzhi Fang in anti-atherosclerosis and lipid-lowering effects.Patients diagnosed as carotid atherosclerotic plaque with hyperlipidemia from March 2021 to January 2022 were collected from the Comprehensive Department,Physical Examination Center and cardiovascular Clinic of Xiyuan Hospital,China Academy of Chinese Medical Sciences.The experimental group was given Yiqi Tongmai Lipid-lowering granules(if no lipid-lowering drugs were taken before treatment,only Yiqi Tongmai lipid-lowering granules were given;For those who have taken statins regularly,the original treatment plan of western medicine remains unchanged,and on this basis,yiqi Tongmai Jiangzhi granule should be added),1 dose per day,2 bags in total,1 bag each time,1 hour after breakfast and meal,and the intervention period is 24 weeks.The control group was blank control.Carotid intimedia thickness,blood lipid level,carotid ultrasound,blood pressure,fasting blood glucose,glycosylated hemoglobin,C-reactive protein,homocysteine,BAPWV and other indicators were detected before and after treatment.Result:1.Based on bibliometrics analysis of the medication rules of traditional Chinese medicine in the treatment of AS in modern literature After screening in the Chinese core database,1,270 literatures were finally included,involving 38 types of TCM syndrome types.Phlegm-turbidity block syndrome was the most common,followed by liver-kidney yin deficiency syndrome,blood stasis blockage syndrome,and phlegm and blood stasis syndrome.Syndrome,Qi deficiency and blood stasis syndrome;according to the frequency of TCM syndrome elements appearing in the literature,the top five are blood stasis,yin deficiency,phlegm turbidity,qi deficiency,yang deficiency;TCM treatment of atherosclerosis Oral administration of traditional Chinese medicine involves 17 categories and 169 kinds of drugs.The most used are tonic drugs,such as astragalus,angelica,licorice,etc.Coptis chinensis,etc.),and phlegm-relieving drugs(pinxia,melon,etc.)are also used more.The use of specific drugs also reflects the etiology and pathogenesis characteristics of "phlegm","stasis" and "deficiency" of atherosclerosis.2.Prediction of anti-atherosclerosis targets of Yiqi Tongmai Jiangzhi Recipe based on network pharmacology.Through the retrieval and screening of TCMSP and other databases,a total of 176 active ingredients and 173 action targets of 9 traditional Chinese medicines in Yiqi Tongmai Jiangzhi Fang for the treatment of atherosclerotic diseases were obtained.The main active ingredients of 9 traditional Chinese medicines in Yiqi Tongmai Jiangzhi Fang for the treatment of atherosclerosis are kaempferol,isorhamnetin,5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)Chrom-4-one,trans-9trans-12-linoleic acid,linolenic acid,caffeic acid dimethyl ether,naringenin,quercetin,3,7,11-trimethyl ether y1-1,7,10-dodecatrien-3-ol-9-one.The top 10 core targets include IL-6,AKT1,VEGFA,TNF,TP53,CXCL8,CASP3,EGFR,MMP9,PTGS2.The results of GO functional enrichment analysis and KEGG enrichment analysis showed that Yiqi Tongmai Jiangzhi Fang may participate in biological processes such as the response to lipopolysaccharide,lipid localization,regulation of reactive oxygen species metabolism,as well as adipocytokine signaling pathway,lipid Atherosclerosis is regulated by signaling pathways such as the Apelin signaling pathway,the serotonergic synapse,and the PI3K-Akt signaling pathway.3.An experimental study on the rationality and effectiveness of the prescription of Yiqi Tongmai Jiangzhi prescription for intervening in ApoE-/mice with atherosclerosis.After 12 weeks of administration,the weight of mice in the atorvastatin group and other groups of traditional Chinese medicine decreased compared with the model group.Compared with the model group,the weight of mice in the traditional Chinese medicine for promoting blood circulation and resolving phlegm increased.Compared with the blank group,the levels of TC,TG and LDL-C in the model group were significantly higher than those in the blank group;the levels of TC and LDL-C in the positive drug statin group were lower than those in the model group(p>0.05),and the levels of HDL-C were higher than those in the model group.Compared with the model group,the TC and TG levels in the Yiqi Tongmai Jiangzhi Fang group and the Yiqi group,as well as the LDL-C level in the Quanfang group had a decreasing trend,and the Quanfang group showed a trend of increasing(p>0.05).The reduction of TC and TG was statistically significant(p<0.01).HE staining of the aorta of the mice in the model group showed that the intima of the aorta was significantly thickened,and obvious AS plaques were seen in the aorta.A large number of foam cells were formed in the plaques,some fat vacuoles and necrotic lipid cores were formed,and the lumen was visible.Obvious stenosis;HE staining of the liver in the model group showed that the arrangement of hepatocytes was obviously disordered,with large balloon-like degeneration of hepatocytes,focal vesicular steatosis,spherical lipid droplets,and large areas of lipid droplet cavities;HE staining of the heart in the model group It showed that atherosclerosis was formed in some blood vessels of the heart,and the lumen of the blood vessels was obviously narrowed,indicating that the AS model of ApoE-/-mice was successfully established.HE staining of the aorta in the statin group showed that the endothelial cells were arranged in disorder,the intimal thickening was more obvious,the infiltration of inflammatory cells and the disorder of vascular elastic fibers were more common in the thickened part of the intima,and mild AS plaque formation and vascular stenosis were seen in the vascular lumen.A certain degree of foam cells were formed in the block,and a small amount of fat vacuoles and necrotic lipid nuclei were formed;HE staining of liver tissue in the statin group showed that the liver structure was normal,and the balloon-like degeneration of sheet hepatocytes was seen,and the degree and scope of the degeneration were higher than those in the model group.In the statin group,there was no significant difference in myocardial structure,and some blood vessels in the heart showed obvious plaque formation.The results of HE staining of the aorta in each Chinese medicine group showed that the intimal thickening,plaque number and the degree of vascular stenosis in Yiqi Tongmai Jiangzhi Fang group,Yiqi group,Huoxue group,Huatan group and Huoxue Huatan group Compared with the model group,there was significant improvement.Among them,there was no obvious AS plaque formation and vascular stenosis in the Yiqi Tongmai Jiangzhi Fang group,the Huoxue group and the Yiqi group,and a small amount of AS was seen in the Huatan group and the Huoxue Huatan group.Plaque formation and narrowing of blood vessels.At the same time,liver HE staining showed that the whole formula of Yiqi Tongmai Jiangzhi Prescription and the Huoxue Huatan group,Yiqi group,Huoxue group and Huatan group were significantly smaller than the model group.The reduction was more obvious in the Tongmai Jiangzhi Fang group and the blood-activating and phlegm-resolving group.HE staining of heart tissue showed that the number of plaques in Yiqi Tongmai Jiangzhi Fang group,Huatan group,Huoxue group,Yiqi group and Huoxue Huatan group were significantly reduced compared with the model group.No obvious plaques were found in the heart vessels of the Quanfang group and the Yiqi group.The results of aortic gross oil red O staining showed that there was no obvious red staining area in the blank group,indicating that the aorta of the mice in the blank group had no atherosclerotic plaque formation.Compared with the blank group,the red colored areas in the model group increased significantly(P<0.05),indicating that atherosclerotic plaques were formed in the aorta of the mice in the model group;The red colored areas were all reduced,and the reduction was more obvious in the Quanfang group and the Yiqi group,and the difference was statistically significant(P<0.05).Compared with the blank group,the PWV of the model group was significantly increased(p<0.01).Compared with the model group,the PWV of the atorvastatin group and each traditional Chinese medicine treatment group decreased,and the decrease of the whole prescription group was the most obvious,and the difference was statistically significant(p<0.01).Compared with the model group,the aortic intima-media thickness in the atorvastatin group and each Chinese medicine treatment group decreased,but there was no statistical significance(p>0.05).4.Study on the mechanism of Yiqi Tongmai Jiangzhi Recipe interfering with atherosclerosis in ApoE-/-mice.Compared with the blank group,the contents of TNF-α,IL-1β,VEGF,IFN-γ,IL4,IL-6,CRP and CCL5/RANTES in the model group were significantly increased,and the difference was statistically significant(p<0.05 or p<0.01).Compared with the model group,the atorvastatin group had different reductions in each index,among which the reductions of TNF-α,IL-6,CRP and CCL5/RANTES were statistically significant(p<0.05 or p<0.05).01);compared with the model group,the contents of TNF-α,L-4,IL-6,CRP and CCL5/RANTES in the whole prescription group were significantly decreased,and the difference was statistically significant(p<0.05 or p<0.01).);the contents of IFN-y,IL-4 and CRP in the Yiqi group were significantly decreased(p<0.05);the contents of CRP in the Huoxue group and the contents of IL6,CRP and CCL5/RANTES in the Huoxue Huatan group were significantly decreased(p<0.05).0.05 or p<0.01).Compared with the blank group,the level of OX-LDL in the model group was significantly increased,and the difference was statistically significant(p<0.01).Compared with the model group,the level of OX-LDL in the atorvastatin group decreased,but there was no statistical significance(p>0.05).The decrease in Qi group and Quanfang group was statistically significant(p<0.05 or p<0.01).Compared with the blank group,the expressions of PPARa and PPARy in the aortic tissue of the mice in the model group were significantly decreased,and the difference was statistically significant(P<0.01).The expressions of MMP9 and IL-6 were increased,and the increase of SRC and ERK1/2 was statistically significant(P<0.01).Compared with model group,statin group,Huatan group,Huoxue group,Yiqi group and Quanfang group could significantly increase the expression of PPARa in aortic tissue,and the difference was statistically significant(P<0.01).The levels of PPARy in the aorta of the sputum group,the Yiqi group and the Quanfang group were significantly increased(P<0.01),Compared with the model group,the expressions of MMP9 and IL-6 in the aorta tissue of the mice in each Chinese medicine administration group and the positive drug statin group showed a downward trend.Among them,the decrease of MMP9 in statin group,Yiqi group and Quanfang group was statistically significant(P<0.01);the decrease of IL-6 in statin group,Huoxue Huatan group,Yiqi group and Quanfang group was statistically significant(P<0.01).P<0.01).Compared with the model group,the expression of RAGE in the aorta tissue of the mice in the statin group,the Yiqi group and the Quanfang group and the expression of SRC and ERK1/2 in the aorta tissue of the mice in the statin group,the Huatan group,the Yiqi group and the Quanfang group.The expression decreased significantly(P<0.01).5.Clinical study on the efficacy and safety of Yiqi Tongmai Jiangzhi Fang in anti-atherosclerosis and lipid-lowering effects.After 6 months of treatment,compared with the control group,the plaque areas on both sides of the experimental group were significantly reduced,and the right plaque in the experimental group was significantly reduced compared with the control group,and the BAPWV(BAPWV-L and BAPWV)were significantly reduced.-R)significantly slowed down(P<0.05),but there was no significant change in IMT before and after treatment in the two groups of patients in this study.Compared with the control group,after treatment(3 months or 6 months of treatment),the levels of CHOL and LDL-C were significantly decreased,and the level of APOA1 was significantly increased(P<0.05).To a certain extent,it reduces the fasting blood glucose level and blood pressure level of the patient.Compared with the control group,there was no significant difference in the levels of ALT,Cr and uric acid between the experimental group and the control group,and there was no significant difference in the levels of ALT,Cr and uric acid in each group before and after treatment,indicating that Yiqi Tongmai Jiangzhi Recipe did not affect the liver and kidney function indexes of the patients.During the treatment period,neither the experimental group nor the control group had any adverse drug reactions,and no patients had acute cardiovascular and cerebrovascular events during the experimental period.In conclusion:1.The essence of atherosclerosis is due to the loss of righteousness,and disordered eating,gluttony,emotional disorders,and liking for leisure and dislike of work are all contributing to the disease.Its core pathogenesis is the loss of qi and stagnation of turbid pathogens;the core treatment is tonifying qi and resolving turbidity.Specifically,the three-in-one treatment of tonifying qi,promoting blood circulation and resolving phlegm can achieve the purpose of treating both the symptoms and the root causes.2.The results of animal experiments showed that the Yiqi Tongmai Jiangzhi Fang group was more effective than the statin group and each split prescription group in reducing the number of plaques in AS model mice,improving vascular stenosis and dyslipidemia.The rationality of the compatibility of Qitongmaijiangzhi recipes,and the scientificity and importance of traditional Chinese medicine for nourishing qi and removing turbidity and treating both symptoms and root causes in the treatment of atherosclerosis.Judging from the efficacy of each disassembled prescription group,the efficacy of Yiqi group is better than that of the phlegm-resolving group,the bloodactivating group and the blood-activating and phlegm-resolving group,indicating the important role of Yiqi in fighting AS.The medicine belongs to the attacking product,and most of them tend to be warm and dry.Long-term use is easy to damage the righteousness,and the deficiency of Qi will stop the blood and stop the phlegm,stagnate but not change,and greatly reduce its lipid-lowering and speckle-reducing effect.3.The results of animal experiments show that Yiqi Tongmai Jiangzhi Fang may reduce inflammatory response and lipid deposition by reducing the levels of serum inflammatory factors and Ox-LDL;reduce lipid deposition by increasing the expression of PPARα and PPARγ proteins,and inhibit RAGE/SRC/ERK1/2/MMP9/IL-6 signaling pathway reduces inflammatory response,restores vascular endothelial injury,and then achieves the purpose of treating atherosclerosis,reflecting the multi-component and multi-target effect of traditional Chinese medicine.4.Clinical research results suggest that Yiqi Tongmai Jiangzhi Fang can significantly reduce the plaque area in patients with AS,increase the arterial elasticity of patients,and be beneficial to the recovery of arterial blood vessel function.In addition,Yiqi Tongmai Jiangzhi Fang can also improve the patient’s hs-CRP and Hcy levels,thereby reducing or delaying the patient’s endothelial damage and the progression of chronic inflammation.In addition,Yiqi Tongmai Jiangzhi Recipe also has the effect of lowering blood pressure,CHOL,LDL-C,fasting blood glucose and glycosylated hemoglobin in patients with AS,and can regulate the state of hypertension,dyslipidemia and abnormal blood sugar metabolism in AS patients.Therefore,Yiqi Tongmai Jiangzhi Formula can play a role in treating AS or delaying disease progression through various synergistic effects,and it will not affect the liver and kidney function levels of patients such as ALT,Cr and uric acid during clinical use.Effectiveness and safety of Yiqi Tongmai Jiangzhi Formula based on the method of nourishing qi and removing turbidity and treating both symptoms and root causes.Therefore,from the construction of theoretical system,the formation of treatment principles and methods,the prediction of network pharmacology,and the integrated verification of animal experiments and clinical trials,this study overall evaluated the theory of Yiqi Tongmai Jiang based on the theory of TCM invigorating qi and removing turbidity and treating both symptoms and symptoms.The efficacy,safety and efficacy advantages of Zhifang in anti-atherosclerosis and lipid-lowering effects. |
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