| Objective:diopathic membranous nephropathy(IMN)is a primary nephrotic syndrome characterized by a large amount of immune complex deposition on the epithelial side of the glomerular capillary loop.The clinical manifestations are mainly proteinuria,hematuria,edema and hypertension.,Partly manifested as progressive renal dysfunction.The rate of IMN in primary glomerular disease has risen to 30.2%,becoming the second largest primary glomerular disease after IgA nephropathy.Although there is a certain spontaneous remission rate,about 35%of patients will progress to end-stage renal disease within 10 years.At present,ACEI/ARB,hormones combined with immunosuppressive agents are mainly used clinically to reduce urine protein in patients and delay the progression of renal function.However,the adverse reactions are obvious and expensive.Traditional Chinese medicine treatment of IMN has gradually come into the sight of clinicians with its advantages of high safety and obvious effects.This article uses three parts:Meta-analysis,data analysis,and network pharmacology analysis to:1.Evaluate the efficacy of traditional Chinese medicine compound in the treatment of idiopathic membranous nephropathy through Meta-analysis,and explore its influence on different clinical indicators,so as to provide a reference for further research on the diagnosis and treatment of idiopathic membranous nephropathy in Chinese medicine.2.To understand the clinical treatment of idiopathic membranous nephropathy by Chinese medicine compound prescriptions through data analysis,and summarize the prescriptions and types of Chinese medicines included in the literature to provide references for clinical diagnosis and treatment.3.Carry out multi-level data screening and network construction through network pharmacology,visualize the data,visually display the connection between traditional Chinese medicine compounds and disease treatment,and explore the potential targets of different efficacy Chinese medicines in the treatment of idiopathic membranous nephropathy And the pathway of action to further clarify the mechanism of drug action.Methods:1.Through computer retrieval,we searched the database of Cochrane Central Register of Controlled Trials(CENTRAL),MEDLINE database,CNKI,Wanfang,Weipu and other databases published in the database as of June 1,2020 for the treatment of idiopathic membranous properties.A randomized controlled trial of kidney disease.Two independent investigators selected the literature according to the inclusion and exclusion criteria,and used Revman 5.3.3 and Stata14 as the tools of this Meta-analysis after the literature quality evaluation to analyze the difference in efficacy between the patients’ indicators.2.The two-person recording method was used to conduct statistics and regular analysis of the Chinese medicines included in the literature.The names of the medicinal materials were standardized with reference to the "Twelfth Five-Year"textbook "Chinese Materia Medica" of the national advanced Chinese medicine.The Apriori module in IBM SPSS Modeler 18.0 is used to analyze the association rules of the collected traditional Chinese medicine data.3.Perform active ingredient search and target screening through the TCMSP database,find the corresponding target of the active ingredient of the drug,and search for the corresponding gene of the target in the Uniprot database to match.Retrieve IMN-related genes through GeneCards,a human genome database,and compare the obtained target genes with the corresponding genes of candidate targets obtained by the aforementioned drugs to obtain an intersection.Upload the screened common target protein to STRING,and use the R software barplot script to calculate the number of interactions between each protein.Perform GO function and KEGG pathway enrichment analysis on the screened drug-disease common targets,combined with literature search,and further screen the pathways for the treatment of diseases in terms of gene function and signal pathways.Through network pharmacology,research and discussion of Professor Kong Wei’s experience formula-Yishen Qingli Recipe,to find its therapeutic targets and pathways,and to correspond to the drug targets and pathways found above,to further confirm the reliability of the research.It is the foundation for the study of the molecular mechanism of Yishen Qingli Recipe.Results:Finally,18 randomized controlled experimental literatures were included,and a total of 1275 patients were divided into a control group treated with western medicine alone and an experimental group treated with a combination of traditional Chinese medicine and western medicine.1.Meta analysis shows:(1)24h urinary protein quantification:6 of the 18 included literatures studied Chinese medicine compound+ACEI/ARB VS simple ACEI/ARB,and 12 items described Chinese medicine compound+immunosuppressive agent VS simple immunosuppressive agent.The results showed that:(MD=-0.76,95%Cl(-0.91--0.61)],P<0.00001),suggesting that the test group’s reduction of 24h urine protein is statistically significant compared with the control group.The combination of traditional Chinese medicine and western medicine treatment can reduce 24h urine protein Quantitatively superior to western medicine alone;(2)Serum albumin:A total of 18 studies compared the serum albumin of the test group and the control group,and the combined results showed:[MD=3.27,95%Cl(2.35-4.19)],P<0.05,suggesting that the test group is elevated The serum albumin level is better than that of the western medicine group alone;(3)Seram creatinine and urea nitrogen:A total of 9 studies included in the study compared the blood creatinine levels of the test group and the control group.The results showed:[MD=-4.02,95%Cl(-8.98-0.94)],P>0.05(P=0.11);A total of 4 included studies described the comparison of urea nitrogen levels between the experimental group and the control group.The results showed:[MD=-0.87,95%Cl(-3.68-1.93)],P>0.05(P=0.54),suggesting that there is no significant difference in the efficacy of creatinine and urea nitrogen in the treatment of idiopathic membranous nephropathy in the combination of traditional Chinese medicine and western medicine group and the western medicine group alone;(4)Cholesterol:A total of 13 RCTs included in the study compared the cholesterol levels of the experimental group and the control group,[MD=-0.59,95%Cl(-0.83-0.34)],P<0.05,suggesting that Chinese herbal compound can reduce IMN The patient’s cholesterol level;(5)Triglycerides:A total of 11 articles related to the comparison of triglycerides between the control group and the test group.The results showed:[MD=-0.20,95%Cl(-0.31-0.09)],P<0.05,showing Chinese medicine compound Can significantly reduce the level of triglycerides in patients with IMN;(6)PLA2,FIB:A total of 4 articles describe the comparison of PLA2 between the experimental group and the control group.The results show:[MD=-28.44,95%Cl(-50.32,-6.56)],P<0.05;4 articles in total The article describes the FIB(fibrinogen)comparison between the experimental group and the control group,[MD=-0.59,95%Cl(-0.77,-0.41)],P<0.05,the research shows that it is more important than Western medicine treatment,combined with traditional Chinese medicine Western medicine group can further reduce patients’ PLA2 and FIB;(7)Safety evaluation:Of the 18 included studies,13 studies mentioned safety evaluation.Comprehensive analysis showed that the adverse reaction rate of the control group was 16.9%,while the adverse reaction rate of the experimental group was 7.7%.It is suggested that traditional Chinese medicine can reduce the incidence of adverse reactions.2.Data analysis shows:In this study,a total of 18 traditional Chinese medicine compound prescriptions were counted,including 75 traditional Chinese medicines.Astragalus,Atractylodes,Poria,Angelica,Chuanxiong,etc.are commonly used medicines.There are 15 types of Chinese medicines involved.The first four commonly used medicines are tonic drugs,Activating blood and removing blood stasis medicine,heat-clearing medicine,diuretic and dampening medicine.Analyzing the association rules of the appeared drugs,38 association rules were obtained,including 15 second-order associations and 23 third-order associations.The analysis of the second-order correlation law shows that the commonly used drugs for the treatment of IMN are Astragalus with Atractylodes and Astragalus with Angelica,which shows the prominent position of the method of invigorating the spleen,nourishing blood and promoting blood circulation in the treatment of IMN.The analysis of the third-order correlation law shows that the commonly used compatibility methods include astragalus with Chinese angelica and Atractylodes macrocephala to invigorate the spleen and kidneys,Poria with Chinese yam and astragalus for diuresis and dampness,Chinese angelica with chuanxiong and safflower for promoting blood circulation and removing blood stasis,and Gorgon with golden cherry,Astragalus method of replenishing qi and collecting astringent.3.Network pharmacology shows:(1)Active ingredients of the drug and targets:Use TCMSP to screen the active ingredients of various traditional Chinese medicines.After screening,it is concluded that the main active ingredients of tonic drugs for treating IMN are digitonin,quercetin,and isoflavone;The main active ingredients of blood stasis drugs for the treatment of IMN include quercetin,digitoxin and β-sitosterol;the main active ingredients of heat-clearing drugs for the treatment of IMN are quercetin,β-sitosterol,and stigmasterol;the main use of diuretic and dampness drugs Active ingredients such as stigmasterol,β-carotene,and sitosterol exert their therapeutic effects on IMN.(2)Screening of IMN-related targets:Search for IMN-related genes through GeneCards,a human genome database,and enter venny to find the common targets of four types of Chinese medicines and IMN.(3)PPI target network construction:the common target proteins obtained from the screening are uploaded to the STRING platform,and the R software barplot script is used to calculate the number of interactions between the proteins.The results show that the main targets of the tonic drugs are JUN and TP53.,TNF,AKT1,MAPK1,the main targets of blood circulation and blood stasis drugs in the treatment of IMN are STAT3,JUN,AKT1,TP53 and TNF.The antipyretic drugs mainly act on JUN,AKT1,MAPK1,MAPK3,TNF and other targets.,The main targets of diuresis and dampness medicine treatment are CTNNB1,AKT1,CASP8,JUN,and CASP3.(4)Enrichment analysis:The main pathways of tonic drugs are PI3K-Akt pathway,fluid shear and arteriosclerosis pathways,TNF pathways,and MAPK pathways;the main pathways of blood-activating drugs arefluid shear and arteriosclerosis pathways,PI3K-Akt pathways,TNF pathways and hypoxia-inducible factors-1 pathway;the pathways of antipyretics mainly involve PI3K-Akt pathways,MAPK pathways,endocrine resistance,hypoxia-inducible factors-1 pathway;diuresis and dampness medicine mainly works through Kaposi’s sarcoma-associated herpes virus infection and human cytomegalovirus infection.4.The analysis result of Yishen Qingli Recipe shows:The main active ingredients of Yishen Qingli Recipe for treating IMN are 7-O-methyl isopropanolamine,β-sitosterol,β-carotene,formononetin,stigmasterol,and the main targets are AKT1.CTNNB1,JUN,VEGFA and ESR1,etc.,achieve the effect of treating IMN through the three pathways of P13K-AKT,MAPK,and TNF,which are basically consistent with the results of the network pharmacology study of Chinese medicine,further confirming the accuracy of the study.Conclusion:1.The traditional Chinese medicine compound can reduce the 24-hour urine protein quantification of IMN patients,reduce the triglycerides,cholesterol,PLA2 and fibrinogen of the patients,and increase the serum albumin of the patients,but compared with the control group in reducing the levels of creatinine and urea nitrogen of the patients There is no significant difference.It is considered that the included population is mostly IMN patients with normal renal function;the traditional Chinese medicine compound can reduce the adverse reaction rate of western medicine,and the treatment is relatively safe.2.Through the analysis of the law of traditional Chinese medicine,it is found that the four commonly used drugs mainly include tonic drugs(Astragalus,Atractylodes,Angelica,Codonopsis,Chinese yam),blood promoting and stasis removing drugs(Ligusticum chuanxiong,safflower,leech,Danshen,peach kernel),and heat-clearing drugs(Centella asiatica,Rehmannia glutinosa,Red peony root,Smilax glabra,Oldenlandia diffusa)and diuretic and dampening medicine(Poria cocos,Alisma,Coix seed,Polyporus umbellatus,Winter melon peel),suggesting that both tonic and blood circulation should be taken into account in the treatment.Clear heat and promote dampness.Analysis of association rules also found that commonly used medicines include the method of invigorating the spleen and kidney with the compatibility of Astragalus and Atractylodes macrocephala,the method of promoting blood circulation and removing blood stasis with astragalus combined with Ligusticum chuanxiong and safflower,and the method of invigorating the spleen and dampening dampness with Poria and Chinese yam It is based on the method of Gorgon and Golden Sakura seeds to reduce the protein bet with its solid intake.3.Network pharmacology analysis shows that the main active ingredients of four types of Chinese medicines for IMN are quercetin,β-sitosterol,and stigmasterol;the main targets are JUN,AKT1,TNF,etc.,and the main pathways for the treatment of IMN include P13K-AKT pathway,MAPK pathway and TNF pathway provide us with new ideas for future molecular research on traditional Chinese medicine.According to the different types of traditional Chinese medicine,it can be analyzed that the pathway of tonic drugs focuses on immune suppression and the elimination of inflammatory factors,which is in line with the concept of "strengthening the body to consolidate the roots" of traditional Chinese medicine.The medicine for promoting blood circulation and removing blood stasis mainly focuses on fluid shear pathway and HIF-1 pathway to improve the ischemic and hypoxic state,which can promote blood circulation and produce blood,promote blood flow without consuming qi,and replenish blood without leaving blood stasis.Heat-clearing drugs can act on the RAS pathway,reduce the hyperperfusion of the globules,reduce the permeability of the filtration membrane,and slow down proteinuria.The main action pathways of diuresis and dampness drugs are anti-infective pathways,and anti-infective pathways are used to cure evil.According to the analysis of the closeness of fit with the IMN treatment pathway,it can be concluded that traditional Chinese medicine should focus on invigorating deficiency in the treatment of IMN,with heat-clearing drugs and blood-activating drugs as the minister,and diuretic and dampening drugs as auxiliary treatment. |
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