The Effect Of Naoxintong Capsule On Diabetic Kidney Disease Based On Meta Analysis And Network Pharmacology

Background:The incidence rate of diabetes mellitus(DM)is about 9.4%Diabetic kidney disease(DKD)is a common microvascular complication and is the main cause of end-stage renal disease and DM death.The clinical manifestations of DKD include the initial increase of glomerular filtration,the increase of proteinuria and creatinine,and finally the decrease of glomerular filtration.The onset of DKD is insidious and has strong latency.If the treatment is not timely,the best treatment time will be missed.The prevention and treatment of DKD has become the focus and problem in the medical field.The treatment of DKD mainly includes changing bad life style,strengthening nutrition,controlling blood glucose and blood pressure,dialysis treatment and transplantation,correcting dyslipidemia,etc.In the case of DM with hypertension and UACR>300 mg/g or without hypertension but UACR≥30 mg/g,the treatment with ACE inhibitors(ACEI)or Angiotension receptor blocker(ARB)can effectively delay the progression of nephropathy.Renin-a-aldosterone system inhibitor can alleviate some symptoms of DKD,but can not prevent its development to end-stage renal disease.For a long time,traditional Chinese medicine has been widely used in the treatment of DM and its related complications due to its small side effects and unique advantages in the treatment of DKD.The results show that Naoxintong capsules(NXT)can inhibit DKD by inhibiting mesangial expansion,improving glucose/lipid metabolism,maintaining tissue integrity and correcting renal dysfunction caused by DM.Study one:Systematic evaluation of NXT in the treatment of DKDObjective:To evaluate the efficacy and safety of NXT in the treatment of DKDMethod:In this meta-analysis,seven databases at home and abroad were selected PubMed,EMBASE,Cochrane Library,China national knowledge infrastructure(CNKI),Wanfang database,China biology medicine database(CBM),and VIP database for Chinese technical periodicals(VIP).The retrieval task is jointly completed by two people.In case of disagreement,it can be solved through consultation with a third person.The retrieval time is March 2020.According to the standards of Cochrane manual,the two research institutes respectively studied the evaluation of the qualification,research selection,data extraction and research quality of the retrieval documents,and used Review Manager 5.3 software to conduct bias analysis and outcome analysis.Results:1 Included literature:171 studies were found through network and manual retrieval,and the last 7 studies met the inclusion requirements of Meta-analysis.The number of participants in each study ranged from 54 to 150 and included 610 patients(310 in the treatment group and 300 in the control group).2 The effect of NXT on UAER:five studies reported UAER in the experimental group and the control group,two of which were measured in different units,and one did not carry out DKD staging for the study subjects,so their studies could not be conducted meta analysis in a unified way.We conducted meta analysis on the other two items.The forest map showed no significant heterogeneity(P=0.24,I2=27%).We used FE model for data analysis.The results of meta-analysis showed that 95%CI was-22.57,-19.21;P<0.00001,there was significant difference in the treatment group of DKD stage Ⅲ.3 The effect of NXT on 24h UTP:NXT alone was better than irbesartan in reducing 24h DKD Ⅲ of UTP(P<0.01);NXT combined with irbesartan was better than irbesartan in the treatment of DKD Ⅳ(P<0.05).4 The effect of NXT on Scr:The three subjects were DKD Ⅱ,DKD Ⅲ and DKD Ⅳ,which could not be analyzed by meta analysis.The results showed that the effect of NXT combined with valsartan,irbesartan and Fosinopril was better than that of the control group.5 The effect of NXT on FBG:the forest map showed that the heterogeneity between the studies was not significant(P=0.99,I2=0%),so FE model was used for statistical analysis.There was no significant difference in FBG between the two groups(95%CI:-0.51,0.60;P=0.87).6 The effect of NXT on 2hPG:no heterogeneity was found in the forest map(P=0.97,I2=0%),so FE model was selected for data analysis.There was no significant difference in 2hPG between the two groups(95%CI:-0.44,0.32;P=0.74)7 The effect of NXT on HbAlc:the forest map shows that the heterogeneity of the study is small(P=0.95,I2=0%),so FE model is selected for data analysis.There was no significant difference in HbAlc between the two groups(95%CI:-0.32,0.25;P=0.81).8 The effect of NXT on blood pressure:NXT combined with valsartan was better than valsartan(P<0.05).9 The effect of NXT on TC:the forest map showed heterogeneity(P<0.00001,I2=92%).RE model was used for data analysis.Meta results showed that there was no significant difference in TC between the two groups(95%CI:-2.50,0.20;P=0.1 0).10 The effect of NXT on TG:the forest map showed that there was heterogeneity between the studies(P<0.00001,I2=92%).The treatment group had the advantage of reducing TG(95%CI:-1.04,-0.03;P=0.04)by re model.11 The effect of NXT on LDL:the forest map showed heterogeneity(P=0.05,I2=74%).RE model was used for data analysis,and NXT combined therapy had the advantage of reducing LDL(95%CI:-0.77,-0.03;P=0.03)12 The effect of NXT on HDL:no heterogeneity was found in the forest map(P=0.84,I2=0%),so FE model was selected for data analysis.There was no significa1t difference in HDL between the two groups(95%CI:-0.14,0.14;P=0.99).13 Adverse reactions:adverse reactions were reported in two trials.The incidence of adverse reactions was calculated according to the current sample size of randomized controlled trials,and there was no significant difference in the results.Conclusion1 In this meta-analysis,it was found that NXT combined with ACEI/ARB or Danhong injection can reduce the urinary microalbumin excretion rate of early DKD patients.2 The quality of 7 articles included in this analysis is not comprehensive and low.Only three studies specifically describe the random method,and only one study describes the incomplete result date.Assignment concealment is not discussed in all the studies,and few studies give detailed explanations for the evaluation of results.Secondly,the report of random method is relatively simple,and the implementation of blind method cannot be determined.Study two:The mechanism of NXT in the treatment of DKD based on network pharmacologyObjective:To analyze the effective components,targets and pathways of NXT in the treatment of DKD,so as to provide theoretical basis for further research and clinical use of NXT in the treatment of DKDMethod:1 Through the pharmacology database and analysis platform of traditional Chinese medicine system,and searching the literature in recent years,NXT was collected to make up the pharmaceutical chemical components.The effective components were selected as the following:oral bioavailability(OB)≥ 30%,drug-likeness(DL)≥0.18,half-life(HL)>4 hours,topological polar surface area(TPSA)<60,number of rotatable bonds(RBN)<10.and the targets were screened by the online screening tool of Swiss target prediction web server.2 Collection and integration of OMIM database,drugbank database,GAD database and TTD database DKD disease target data.3 The NXT effective component target and DKD related target are extracted for matching,and the overlapping target is selected as the related target of NXT treatment of DKD.The intersection between the two may be the effective target of NXT treatment of DKD.These targets are processed by merge in the Cytoscape software.4 The target of the interaction between NXT and DKD was analyzed by David database,and the enrichment of GO ontology and KEGG pathway was analyzedResults:1 NXT active ingredients and targets:145 NXT active ingredients were screened through tcmsp database and retrieval of related literature in recent years,and 258 related targets were predicted.2 Network map of DKD disease targets:118 human targets related to DKD were searched in OMIN,GAD,TTD and DrugBank databases.After the deletion,102 DKD related targets were reserved,and the relationship between the disease targets was drawn by the software of Cytoscape.3 Construct network target map:draw the relationship between NXT drug target and DKD target through Cytoscape.4 Target analysis of NXT in the treatment of DKD:in this study,effective chemical components of NXT were found,including oleic acid,alanine,glycine,L-histidine,L-glutamic acid,L-arginine,tyrosine,proline,L-aspartic acid,valine,L-isoleucine,succinic acid,niacin,betaine,cnidine,sitosterol,stigmasterol,etc.,mainly including amino acids Compounds,sterols.The topological analysis of NXT showed that the targets of CAT,NOS3,NOS2,PPARG,VEGFA,IL1B,JUN and MME were high,so these targets were considered as the key targets of NXT for DKD treatment.The GO and KEGG pathways closely related to NXT in the treatment of DKD include the regulation of insulin secretion,cGMP-PKG signaling pathway,estrogen signaling pathway,etc.ConclusionThis study constructed the network map of NXT drug composition target and DKD disease target,explained the mechanism of NXT treatment of DKD from the perspective of network pharmacology,found that NXT may mediate blood glucose concentration,reduce renal fibrosis and delay the progression of kidney disease through cGMP-PKG signaling pathway,estrogen signaling pathway,TGF-β receptor signaling pathway,and blocking VEGF-A pathway,providing mechanism prediction for clinical use of NXT in the treatment of DKD.