| Objectives: In this study,network meta-analysis combined with network pharmacology was employed to evaluate the efficacy of Chinese patent medicine with spleen deficiency and qi stagnation in the treatment of functional dyspepsia from the perspective of TCM syndrome differentiation.Focus on the analysis of effectiveness and safety for different interventions,and the interventions were prioritized according to the computational results.In addition,based on the outcomes of evidence-based research,the optimal therapeutic drugs were studied in combination with the network pharmacology method in order to further analyze the mechanisms of action related to the treatment of FD.Common drugs for the treatment of FD were analyzed through evidence-based and network pharmacology research methods,and from the macroscopic analysis of drugs and diseases to the analysis of protein targets and pathways,to provide evidence-based medical evidence for the rational use of FD.Methods:（1）Efficacy and safety of Chinese patent medicine with spleen deficiency and qi stagnation in the treatment of FD based on evidence-based methods:we preferred the reporting items for systematic reviews and meta-analyses（PRISMA）guidelines,“bailing jianpi granule”,“shenling baizhu granule”,“kaiwei lipi oral liquid”,“kaiwei lipi pill”,“liuwei anxiao capsule”,“muxiang shunqi pill”,“shenqu xiaoshi oral liquid”,“wei naian capsule”,“xiangsha liujun pill”,“xiangshang liujunzi pill”,“xiangsha pingwei granule”,“xiangsha pingwei pill”,“xiangsha zhizhu pill”,“zhishi xiaopi pill”,“zhizhu kuanzhong granule”,“functional dyspepsia” were used to search Medline,Embase,Cochrane library,Sion Med（CBM）,Chinese National Knowledge Infrastructure（CNKI）,Technology of Chongqing（VIP）,and Wan Fang Database from establishment until December 2020.Studies were screened according to inclusion and exclusion criteria,and basic information and related data were collected.Stata software（version 14.0）was used for NMA network plot,ranking graph,inconsistency test and cluster analysis plot,and Win BUGS software（version 1.4）was used to direct comparison and indirect comparison between interventions.Forest plots for comparison between individual interventions were calculated using R software（version4.1.1）,and results were expressed as odds ratios（OR）and 95% confidence interval（CI）.（2）Study on the relevant mechanism of optimal drug treatment for FD based on network pharmacology analysis methods: drug-related targets were acquired from TCMSP and Swiss Target Prediction databases,and Cytoscape software（version 3.8.2）was utilized to conduct the drug compound targets network graph after screening and correction.Related disease targets were obtained from Gene Cards,TTD,Drug Bank and OMIM databases,and then summarized,collated and corrected,after the intersection with drug targets,protein-protein interactions（PPI）network was constructed using STRING.R software（version 4.1.1）was used to perform the gene ontology（GO）enrichment and Kyoto Encyclopedia of Genes and Genomes（KEGG）pathway functional analyses.Results:（1）In terms of NMA,according to the inclusion and exclusion criteria,a total of 83 studies involving 8330 patients were included in this study,including 4223 FD patients and 4107 control patients.The top 3 interventions in respect of effectiveness for the 15 treatment measures included in the study on the surface under the cumulative ranking curves（SUCRA）were zhizhu kuanzhong capsule and prokinetics and antidepressants,zhizhu kuanzhong capsule and gastric motility drugs,zhizhu kuanzhong capsule and anti-depressants,SUCRA values were 91.3%,88.7% and86.5%.Compared with the gastrokinetic drugs with the largest sample size,the top 3interventions with ORs were zhizhu kuanzhong capsule and prokinetics and antidepressants [18（8.5,40）],zhizhu kuanzhong capsule and antidepressants [16（5.1,62）],zhizhu kuanzhong capsule and gastric motility drugs [15（4.4,56）].After compared zhizhu kuanzhong capsule and prokinetics and anti-depressants with other interventions,there was a statistical difference with 14 interventions,and the curative effect was better than 14 interventions,with zhizhu kuanzhong capsule and antidepressants,zhizhu kuanzhong capsule and improving digestion drugs being the second.In terms of safety,the top 3 interventions were zhizhu kuanzhong capsule and prokinetics and antidepressants,gastrokinetic drugs and antidepressants,liuwei anxiao capsule and antidepressants,with SUCRA values of 83.6%,80.2% and 65.8%.The results of comparison with the largest sample size of gastroprokinetic drugs showed that the interventions of liuwei anxiao capsule and gastroprokinetic drug [0.11（0.020,0.49）],zhizhu kuanzhong capsule and placebo [1.1e-16（2.1e-53,0.013）],xiangsha pingwei granule [8.3e-11（1.3e-43,0.24）] were superior to gastroprokinetic drugs in terms of safety.The interventions were zhizhu kuanzhong capsule and prokinetics and antidepressants with 9 interventions were statistically different,and the incidence of adverse reactions was greater than 9 interventions,with gastroprokinetic drugs and antidepressants,liuwei anxiao capsule and gastroprokinetic drug being the second.（2）Combined with the results of the NMA,the network pharmacological analysis was performed for zhizhu kuanzhong capsule for the treatment of FD: 43 active compounds,457 predicted active ingredient targets,2557 FD disease targets and 250drug-disease intersection targets were obtained from the 4 ingredients of zhizhu kuanzhong capsule,namely Atractylodes Macrocephalae,Citrus Aurantium,Radix Bupleuri and Fructus Crataegi.The key targets in the drug compound-target network were quercetin,luteolin,naringenin and kaempferol.The PPI network graph calculation results showed 8 targets（TP53,SRC,MAPK3,MAPK1,CDKN1 A,JUN,RELA,TNF）as core targets.GO functional enrichment results showed that targets are mainly enriched in biological processes such as response to drug,response to lipopolysaccharide and response to molecular of bacterial origin,cellular components such as membrane raft,membrane microdomain and apical part of cell,molecular functions such as DNA-binding transcription factor binding,endopeptidase activity and RNA polymerase II-specific DNA-binding transcription factor binding.The KEGG pathway analysis results indicated that targets were mainly enriched in PI3K-Akt signaling pathway,lipid and atherosclerosis,and hepatitis B and C pathways.Conclusions:（1）Zhizhu kuanzhong capsule combined with prokinetics and antidepressants were the best effect in the treatment of FD.Although the incidence of adverse reactions was high,the degree was mild and could be tolerated by patients.Consequently,it was recommended to use this treatment regimen for patients diagnosed with FD or with anxiety and depression symptoms.For patients diagnosed as individual FD,zhizhu kuanzhong capsule and gastric motility drugs could be used.The curative effect of shenling baizhu granule,liuwei anxiao capsule,xiangsha pingwei granule combined with Western medicine was better than alone,and the incidence of adverse reactions is lower,could be used as a secondary choice.There was a high incidence of adverse reactions with FD treated with combination antidepressants.（2）The key targets（TP53,SRC,MAPK3,MAPK1,CDKN1 A,JUN,RELA,TNF）of active components in zhizhu kuanzhong capsule and related pathways（PI3K-Akt signaling pathway,lipid and atherosclerosis,hepatitis B,hepatitis C）played critical roles in the treatment of FD. |
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