| BackgroundAcute cerebral infarction is the most common type of stroke,accounting for 69.6%to 70.8%of stroke in China.In China,the mortality of hospitalized patients with acute cerebral infarction within one month after onset is about 2.3%to 3.2%.The 3-month mortality and disability rates are 9%to 9.6%and 34.5%to 37.1%,respectively.1-year mortality and disability are 14.4%to 15.4%and 33.4%to 33.8%,respectively.High morbidity,high disability and high mortality make acute cerebral infarction a major public health problem,placeing a heavy burden on society and families.Currently,thrombolysis,anticoagulation,antiplatelet aggregation,lowering intracranial pressure,defibrillation,and stent placement are recommended by western medicine to treat acute cerebral infarction.In recent years,with the widespread application of medical technology in the field of traditional Chinese medicine preparations,traditional Chinese medicine injections,mainly for promoting blood circulation and removing blood stasis,have begun to be used in cerebral infarction and have achieved good curative effects.However,there are many kinds of traditional Chinese medicine injections for promoting blood circulation and removing blood stasis,each with its own advantages and disadvantages.However,most of the clinical researches are the comparison of the efficacy of traditional Chinese medicine injection and western medicine treatment.Therefore,it is not clear whether different traditional Chinese medicine injections for activating blood circulation and removing blood stasis are good or not,making it difficult for clinicians to choose due to lack of evidence.Therefore,it is necessary to compare the effects of different traditional Chinese medicine injections for acute cerebral infarction.ObjectivesTo evaluate the efficacy of different Chinese medicine injections for promoting blood circulation and removing blood stasis in the treatment of acute cerebral infarction and rank these drugs,and select two drugs with better efficacy ranking to explore the difference in the therapeutic mechanism of the two for the treatment of cerebral infarction.Outline of the current studyThis study has been conducted in two aspects.The first is to carry out a network meta-analysis of 16 kinds of traditional Chinese medicine injections for promoting blood circulation and removing blood stasis in the National Medical Insurance Catalog in 2019 for the treatment of acute cerebral infarction.The second is to study the mechanism of the top 5 Chinese medicine injections to treat cerebral infarction.According to the results of the network meta-analysis,two Chinese medicine injections ranked in the top 5 in both the total effective rate of neurological deficit score score and the NIHSS score were selected.Based on the network pharmacology research method,the effect of the two traditional Chinese medicine injections on the treatment of cerebral infarction was initially explored.Surface under the cumulative ranking was calculated and the numerical value was used to predict the curative effect of various treatment measures.Methods(1)Network meta-analysis research methodFirst,China National Knowledge Infrastructure(CNKI),Chongqing Weipu Chinese Science and Technology Journal Database(VIP),WanFang Database,China Biomedical Literature Service System(SinoMed),Pubmed,Embase,Cochrane Library and Web of Science was comprehensively searched.Randomized controlled trials of 16 kinds of traditional Chinese medicine injections for promoting blood circulation and removing blood stasis including Xiangdan injection,Danshen injection,Danhong injection,Mailuoning injection,Safflower injection,Kudiezi injection,Danshen polyphenolate for injection,Xuesaitong injection/Xuesaitong injection(lyophilized),Xueshuantong injection/Xueshuantong(lyophilized)for injection,breviscapine injection,breviscapine injection/breviscapine injection,Guanxinning injection,Shuxuetong injection,Shuxuening injection,astragalus injection,and melon peel injection in treating acute cerebral infarction were retrieved.Second,Cochrane Collaboration's tool for assessing risk of bias in randomized trials recommended by the Cochrane Handbook was used to evaluate the quality of the included studies.Finally,based on the statistical model of the frequency school,all data were analyzed using STATA 16 software.The specific contents include as follows.Network meta-analysis was conducted by using the mvMeta software package based on multiple regression model in STATA 16 software.The loop-specific method is used to evaluate the consistency between the direct comparison result and the indirect comparison result.(2)Network pharmacology research methodFirst,the active ingredients and targets of Danhong injection(Danshen,Honghua)and Mailuoning injection(Shihu,Niuxi,Jingyinhua,Xuanshen)were collected through the TCMSP platform and ETCM,and collected through the human phenotypic ontology(HPO)database,disease connect database,OMIM database and Genecard database were used to collect cerebral infarction-related genes,and the data background was set to human genes(Homo sapiens).Second,Excel 2010 was used to collate the collected and filtered results above and remove duplicate targets.The data was imported into the STRING tool to build the following network.?Protein-protein interaction network(PPI)of overlapping targets of Danhong injection and cerebral infarction.?PPI of overlapping targets of Mailuoning injection and cerebral infarction.The node of the network represents the target,and the edge represents the interaction between the target and the target.The Network Analyzer tool in Cytoscape software was used to calculate the important topological parameters of the network including degree and betweenness centrality and to screen the core targets of Danhong injection and Mailuoning injection overlapping with cerebral infarction.Finally,the DAVID database was used to perform the Gene Ontology function and the Kyoto Encyclopedia of Genes and Genomes on the targets of Danhong injection overlapping with cerebral infarction and targets of Mailuoning injection overlapping with cerebral infarction,and to understand the biological processes,molecular functions,cellular components,and KEGG signaling pathways involved in Danhong injection and Mailuoning injection in the treatment of cerebral infarction.The selected targets were introduced into the DAVID database,the species was limited to humans,the identification was officially-gene-symbol,and the threshold P<0.05 was set to screen statistically significant biological processes and signal pathways.Results(1)Results of network meta-analysisA total of 21,348 related studies were retrieved and imported into the literature management software NoteExpress.After reading the title and abstract,3,894 studies were initially selected for full-text evaluation.Further reading the full text,120 Chinese studies were finally included.The methodological quality of the included studies was generally low,mainly reflecting in the generation of random sequences,allocation hiding and blind methods.The related studies of Guanxinning injection,Guaguapi inj ection and Astragalus injection did not meet the criteria In addition to conventional treatment,the efficacy of 13 traditional Chinese medicine injections on the total effective index of neurological deficit scores was ranked from high to low as follows.Mailuoning injection+conventional treatment>Dengzhanxixin injection+conventional treatment>Danhong injection+conventional treatment>Danshen polyphenolic acid+conventional treatment>Xueshuantong injection+conventional treatment>Kudiezi injection+conventional treatment>Xiangdan injection+Conventional treatment>Xuesaitong injection+conventional treatment>Shuxuetong injection+conventional treatment>Dengzhanhuasu injection+conventional treatment>Shuxuening injection+conventional treatment>Honghua injection+conventional treatment>Danshen injection+conventional treatment.The efficacy of 13 traditional Chinese medicine injections on the NIHSS scores was ranked from high to low as follows.Xueshuantong injection+conventional treatment>Mailuoning injection+conventional treatment>Shuxuetong injection+conventional treatment>Kudiezi injection+conventional treatment>Danhong injection+conventional treatment>Shuxuening injection+conventional treatment>Dengzhanhuasu+conventional treatment>Salvia polyphenolic acid for injection+conventional treatment>Dengzhanxixin injection+conventional treatment>Xuesaitong injection+conventional treatment>Honghua injection+conventional treatment>Xiangdan injection+conventional treatment>Danshen injection+conventional treatment.The injections ranked in the top 5 in efficacy were Mailuoning injection,Danhong injection and Xueshuantong injection.It is not easy to distinguish Xueshuantong injection and Xuesaitong injection since they have same active chemical components.Therefore,this study selected Mailuoning injection and Danhong injection for mechanism research.(2)Results of network pharmacology339 active ingredients and 2479 gene targets of Danhong injection were obtained by searching TCMSP platform and ETCM platform.204 active ingredients and 1660 gene targets of Danhong injection were obtained by searching TCMSP platform and ETCM platform.650 genes of cerebral infarction were obtained by searching HPO database,Disease-connect database,OMIM database and Genecard database.Danhong injection had 13 overlapping target genes for cerebral infarction and Mailuoning injection had 38 overlapping target genes for cerebral infarction.Interaction network of Danhong injection and cerebral infarction overlapping targets included 12 nodes and 21 edges.Interaction network of Mailuoning injection and cerebral infarction overlapping targets included 34 nodes and 125 edges.Both above Chinese medicine injections treat cerebral infarction through core targets such as TP53 and NOS3 and enrichment pathways such as fbrinolysis,nitric oxide biosynthesis,nitric oxide-mediated signal transduction,negative regulation of endothelial cell apoptosis,negative regulation of apoptotic processes,PI3K-Akt signaling pathway,HIF-1 signaling pathway and apoptosis.Danhong injection treat cerebral infarction through core targets such as SERPINE1,IL4,APP,biological processes including stress-activated MAPK cascade,positive regulation of reactive oxygen metabolism,and negative regulation of exogenous apoptotic signaling pathways by death domain receptors and MAPK signaling pathway.Mailuoning injection treat cerebral infarction through core targets such as KDR?IL10?TLR4,biological processes including inflammatory response,hypoxic cellular response,and positive regulation of interleukin-10 production and enrichment pathways including platelet activation and VEGF signaling.Conclusion(1)The results of network-meta analysis show that Danhong injection and Mailuoning injection in the treatment of acute cerebral infarction are better than other traditional Chinese medicine injections for promoting blood circulation and stasis in improving the neurological deficit score total effectiveness and NIHSS score.(2)The results of network pharmacology research show that the overall situation of topological analysis of core targets of Mailuoning injection is better than Danhong injection.The active ingredients of Danhong injection focus on the treatment of cerebral infarction by regulating the coagulation process,regulating energy metabolism and protecting the blood-brain barrier,and focus on activating blood.The active ingredients of Mailuoning injection focus on the treatment of cerebral infarction by regulating platelet activation,thrombus formation,inflammatory response,and regulating vascular function to inhibit atherosclerotic damage,and focus on activating blood and clearing heat.(3)The results of pharmacological studies explain the difference in clinical efficacy to some extent.The evaluation of the efficacy of traditional Chinese medicine should insist on advocating research strategies based on curative effects.After the comparative evaluation of clinical efficacy is definite,based on the advantages of evaluation indicators,targeted mechanism research is carried out to better provide clinical reference and basis for the selection of similar competitive drugs for the same disease in the clinic. |
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