背景:脓毒性心肌病(SCM)的预后较差,死亡率高达70%。大多数现有的治疗方法都是无用的,并且在心肌功能减退的患者中没有发现特定的药物或治疗方法。
方法:我们基于高通量测序和生物信息学分析,探索了目标药物(Binimetinib)在SCM模型体内的疗效。首先,建立了稳定的SCM小鼠模型。其次,通过高通量测序和生物信息学分析明确了SCM的hub基因。通过京都基因和基因组百科全书(KEGG)和基因本体论(GO)富集分析揭示了相关途径和生物学过程。第三,通过网络药理学分析研究了hub基因的靶药物。第四,通过SCM小鼠模型证明了Binimetinib的疗效和hub基因调控作用。最后,通过分子对接分析了靶向药物对hub基因的调控机制。
结果:伤口涂抹109CFU/ml铜绿假单胞菌可以建立稳定的SCM小鼠模型。IL-6、IL-1β和Tnf是SCM的中心基因。免疫体系进程和炎症反响是主要的生物学进程。Binimetinib是IL-6、IL-1β和TNF-α的靶向药物。JUN和NFKB1是hub基因的转录因子(TFs),Binimetinib与NFKB1的结合能最低。
结论:通过伤口铜绿假单胞菌感染建立了稳定的SCM模型。Tnf,IL-1β,Il-6是SCM的关键基因。Binimetinib可能是一种通过下调hub基因来治疗SCM的药物。其作用机制可能与NFKB1有关。
BACKGROUND: Septic cardiomyopathy (SCM) has a worse prognosis with mortality rates of up to 70%. Most existing treatment is useless and no specific drug or treatment has been found in patients with myocardial hypofunction.
METHODS: We explored the efficacy of the target drugs (
Binimetinib) in SCM model in vivo based on high throughput sequencing and bioinformatics analysis. Firstly, a stable SCM mice model was constructed. Secondly, the hub genes of SCM were clarified by high throughput sequencing and bioinformatics analysis. The related pathways and biological process were revealed by Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) enrichment analysis. Thirdly, the target drugs of the hub genes were investigated by network pharmacology analysis. Fourthly, the curative effects and hub genes regulatory effects of
Binimetinib were demonstrated by SCM mice model. Finally, the regulatory mechanism of the target drugs on the hub genes were analyzed by molecular docking.
RESULTS: 109 CFU/ml P. aeruginosa daubed in wound could establish a stable SCM mice model. Il-6, Il-1β and Tnf were the hub genes of SCM. Immune system process and inflammatory response were the main biological process.
Binimetinib was the target drug of IL-6, IL-1β and TNF-α. JUN and NFKB1 were the transcription factor (TFs) of hub genes and
Binimetinib had the lowest binding energy with NFKB1.
CONCLUSIONS: A stable SCM model was established by wound P. aeruginosa infection. Tnf, Il-1β, Il-6 were the key genes of SCM.
Binimetinib might be a drug for the treatment of SCM by downregulating the hub genes. Its active mechanism might be related to NFKB1.