| Objective1.The clinical randomized controlled trials of traditional Chinese medicine compound prescription in the treatment of CHF inflammation were systematically evaluated by meta analysis,and the clinical efficacy and safety of traditional Chinese medicine compound prescription in the treatment of CHF-related inflammation were discussed.2.Through data mining,the compatibility rule of traditional Chinese medicine compound prescription for the treatment of CHF qi-yin deficiency and blood stasis syndrome was studied,and the core drug composition was found.3.The main chemical components of Xinyin tablet were analyzed by network pharmacology technology,and the drug target genes were predicted and intersected with the target genes of CHF to find out their common targets and pathways,and to predict the possible molecular mechanism of Xinyin tablets in the treatment of CHF.4.To verify the mechanism of Xinyin tablet in regulating macrophage polarization and anti-myocardial fibrosis in patients with chronic heart failure through MLK3/JNK signal axis.Methods1.According to the characteristics of different databases,comprehensive retrieval is carried out by means of subject words,free words,keywords,full text,etc.,the retrieved documents are screened according to the Nanpai standard,the included documents are extracted,and the quality and system evaluation of the documents are carried out by using Rev Man5.3 software.2..After data extraction,processing and standardization,the retrieved documents are imported into the ancient and modern medical record cloud platform.Using the ancient and modern medical record cloud platform data mining module,the imported traditional Chinese medicine data are analyzed by frequency statistics,traditional Chinese medicine attribute meridian statistics,cluster analysis,association analysis and complex network analysis,so as to realize the discovery of the prescription rule of traditional Chinese medicine compound prescription in the treatment of CHF qi-yin deficiency and blood stasis syndrome.3.Through screening and predicting the effective chemical components and targets of Xinyin tablets,the drug targets and CHF targets were intersected to get potential therapeutic targets.The drug-effective compound-target-disease network diagram was constructed by Cytoscape3.7.2software,and the PPI network diagram was constructed by String database,and cluster analysis was carried out.The core targets were analyzed by GO functional enrichment analysis and KEGG pathway enrichment analysis.4.The mice were randomly divided into sham operation group(n=10),model group(n=20),low dose group(n=20),medium dose group(n=20),high dose group(n=20),perindopril group(n=20)and MLK3 inhibitor group(n=10).Low-dose traditional Chinese medicine group is given equivalent dose treatment,that is,0.34g/kg.The Chinese medicine middle-dose group was given 2 times the equivalent dose of treatment,namely 0.68g/kg.The Chinese medicine high-dose group was given 4 times the equivalent dose of treatment,namely 1.36g/kg.The positive control group was given the equivalent dose of perindopril,namely 0.607mg/kg.The sham operation group and the model group were given the same amount of normal saline.The MLK3 inhibitor group was intraperitoneally injected with URMC-099 at 10mg/kg twice a day.Drug intervention was started 1W before the model was made until the end of the sampling.The indexes of cardiac function were detected by ultrasound,the morphology of myocardial tissue was observed by HE staining,collagen deposition was observed by Masson staining,cardiomyocyte hypertrophy was observed by WGA staining,the expression of fibrosis-related proteins Collagen I,Collagen III,α-SMA and fibronectin was observed by immunohistochemistry,and the expression of MLK3,JNK,TGF-β and Arg1 was detected by WB.The expression of Col Ⅰ,Fibronectin,MMP2,MMP9,IL-10 and TGF-β m RNA in heart tissue was detected by RT-PCR,and the expression of M1 macrophage marker CCR7 and M2 macrophage marker CD-206 was observed by immunofluorescence.Results1.A total of 70 RCT literatures were included.The results of meta analysis showed that:(1)there were 60 articles comparing the total clinical effective rate of traditional Chinese medicine compound prescription in the treatment of CHF.The results showed that the total clinical effective rate of traditional Chinese medicine combined with conventional western medicine in the treatment of CHF was significantly higher than that of conventional western medicine alone(P<0.05).(2)there are 16 literatures comparing the 6min walking test before and after the treatment of CHF with traditional Chinese medicine.The results suggest that the treatment of traditional Chinese medicine combined with conventional western medicine can effectively improve the walking distance of 6min in patients with CHF,and the effect is better than that of conventional western medicine alone(P<0.05).(3)there are 50 literatures comparing the LVEF before and after the treatment of CHF with traditional Chinese medicine.The results suggest that compared with the control group,the treatment of CHF with traditional Chinese medicine combined with conventional western medicine can more effectively increase the level of left ventricular ejection fraction and improve cardiac function(P< 0.05).(4)there are 26 literatures to compare the serum hs-CRP of patients with CHF before and after the treatment of traditional Chinese medicine compound.The results suggest that compared with conventional western medicine treatment,traditional Chinese medicine compound prescription combined with conventional western medicine treatment can more effectively reduce the level of serum hs-CRP in patients with CHF(P<0.05).(5)there are 49 literatures comparing the level of serum TNF-α before and after the treatment of CHF with traditional Chinese medicine.The results suggest that the treatment of traditional Chinese medicine combined with conventional western medicine can significantly reduce the level of serum TNF-α in patients with CHF,and the effect is better than that of conventional western medicine alone(P<0.05).(6)there are 40 literatures comparing the level of serum IL-6 before and after the treatment of CHF with traditional Chinese medicine.The results suggest that the treatment of traditional Chinese medicine combined with conventional western medicine can significantly reduce the level of serum IL-6 in patients with CHF,and the effect is better than that of conventional western medicine alone(P<0.05).2.A total of 51 articles were included in the criteria.(1)Drug frequency analysis: 102 Chinese herbal medicines were used in 51 articles,with a total frequency of 603,and 20 herbs were used more than 8 times.the top 5 drugs with the highest frequency were Mai Dong,Wu Weizi,Huang Qi,Dan Shen and Chuan Xiong.(2)Meridian analysis of four qi and five flavors of drugs: the cumulative occurrence of medicinal properties was 595 times,of which the frequency of warm,slightly cold and flat traditional Chinese medicine was the most,accounting for 71% of the total frequency,and the cumulative occurrence of drug flavor was 875 times.Among them,the frequency of sweet taste is the most,accounting for about 60.53%.There were a total of 1534 meridians,of which lung meridian(313,51.91%),heart meridian(300,49.75%)and liver meridian(228,37.81%)accounted for the most.(3)Drug cluster analysis: they are divided into four groups:(1)Huang Qi,Dan Shen,Chuan Qiong,Mai Dong,Wu Weizi;(2)Dang Gui,Chi Shao,Di Huang,(3)Ren Shen,Hong Hua,Tao Ren;(4)The fourth group contains more drugs and is subdivided into two categories based on the distance≥4.7: a:Ze Xie,Tai Zishen,Ting Lizi,Che Qianzi;b: Dang Shen,Gui Zhi,Fu Ling,Gan Cao,Bai Zhu;(4)Drug correlation analysis: the effective strong correlation drug combinations with high frequency were as follows: 1.Mai Dong-Wu Weizi;2.Mai Dong-Dan Shen;3.Mai Dong-Chuan Xiong;4.Mai DongHuang Qi-Dan Shen;5.Mai Dong-Huang Qi-Wu Weizi.Mai Dong is strongly associated with many drugs,a total of 22 groups,followed by Wu Weizi.(5)Drug complex network analysis: the core drug combination network is composed of Mai Dong,Dan Shen,Huang Qi,Wu Weizi,Ren Shen,Fu Ling,Chi Shao,Ze Xie,Che Qianzi,Chuan Xiong,Gui Zhi,Hong Hua and Dang Gui.3.827 predicted targets of Xinyin tablet were obtained,1366 CHF related targets and 235 effective therapeutic targets were obtained.PPI network analysis showed that the potential therapeutic targets of Xinyin tablet on chronic heart failure were not only strongly related to MAPK signal pathways such as JNK,jun,IL-10,IL-6,STAT,TNF-α,but also closely related to fibrosis related targets such as MMP2 and MMP9.We speculate that the therapeutic effect of Xinyin tablet on chronic heart failure may be related to the regulation of MLK3/JNK signal axis affecting macrophage polarization and alleviating myocardial fibrosis,which will be verified by experiments.4.Ultrasonic detection showed that Xinyin tablet could effectively improve the cardiac function index of CHF mice;HE staining and Masson staining found that Xinyin tablet could effectively reduce the area of myocardial fibrosis and collagen deposition and improve myocardial remodeling in heart failure mice under pressure overload;by WGA staining,it was found that Xinyin tablet could effectively improve cardiomyocyte hypertrophy;WB test found that Xinyin tablet could significantly inhibit the increase of MLK3 and JNK in myocardial tissue.Immunohistochemistry showed that Xinyin tablet could effectively inhibit the expression of MMP2,MMP9 and Col I,Col III in myocardial tissue;WB detection showed that Xinyin tablet could significantly inhibit the expression of Arg1;immunofluorescence detection showed that Xinyin tablet could effectively reduce the expression of CD206 in myocardial tissue of mice with heart failure;RT-PCR and WB showed that Xinyin tablet could significantly reduce the expression of IL-10 and TGF-β in myocardial tissue.ConclusionChinese herbal compound can significantly reduce the level of inflammatory factors in the heart of CHF patients,improve clinical efficacy,and have fewer adverse reactions and higher safety.Yiqi Yangyin Huoxue Diuretic Medicine Xinyin Tablets can effectively improve the adverse cardiac remodeling in CHF mice.It may inhibit the polarization of macrophages to M2 type by regulating the MLK3/JNK signaling pathway,and reduce related anti-inflammatory cytokines and M2 type at the same time.The expression of macrophage-specific cytokines reduces the expression of fibrosis-related proteins and plays a role in the treatment of myocardial fibrosis in chronic heart failure. |
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