复方木芙蓉涂鼻软膏治疗变应性鼻炎的临床疗效及其网络药理学研究

Efficacy of Mufurong nasal ointment in treating allergic rhinitis and analysis of its mechanism based on network pharmacology

目的探讨复方木芙蓉涂鼻软膏治疗变应性鼻炎(AR)的临床疗效,并结合网络药理学探索其治疗AR的作用机制,明确其作用靶点及信号通路。方法选择重庆市妇幼保健院2019年10月至2020年12月确诊为AR的病人130例,使用随机数字表法分为对照组和观察组,每组均65例,对照组采用丙酸氟替卡松鼻喷雾剂常规治疗,观察组采用复方木芙蓉涂鼻软膏,均治疗4周。比较两组治疗前后尿中白三烯E(4 leukotriene E4,LTE4)水平、肿瘤坏死因子-α(TNF-α)、白细胞介素-4(IL-4)、白细胞介素-6(IL-6)、白细胞介素-12(IL-12)水平以及总有效率。同时通过中药系统药理学数据库和分析平台(TCMSP),以及多个数据库联合检索筛选复方木芙蓉涂鼻软膏活性成分-作用靶点,采用Rversion 3.6.2软件及Cytoscape 3.7.1软件构建复方木芙蓉涂鼻软膏治疗AR的成分-作用靶点-通路网络,最后利用R语言中Bioc Manager包进行基因本体功能注释及京都基因与基因组百科全书(KEGG)通路富集分析。结果观察组总有效率(89.23%)明显高于对照组总有效率(72.31%),经过4周治疗后,两组尿中LTE4水平均显著低于治疗前,且两组TNF-α、IL-4、IL-6、IL-12表达水平均出现显著下降,观察组下降程度较对照组较大,均差异有统计学意义(P<0.05)。经筛选得到槲皮素、山柰酚等9个主要活性成分,并得到复方木芙蓉涂鼻软膏治疗AR的关键靶点为IL-6、血管内皮生长因子A(VEGFA)、丝裂原活化蛋白激酶1(MAPK1)、蛋白激酶(AKT1)等,关键通路为低氧诱导因子-1(HIF-1)信号通路、TNF信号通路、磷脂酰肌醇3-激酶(PI3K)和AKT/蛋白激酶b(PI3K-Akt)信号通路以及晚期糖基化终末产物糖基化终末产物受体(AGE-RAGE)信号通路等。结论复方木芙蓉涂鼻软膏可作用于VEGFA、IL-6、AKT1、MAPK1等靶点,调控HIF-1、TNF、PI3K-Akt等信号通路,从而降低或抑制变应性鼻炎TNF-α、IL-4、IL-6、IL-12等炎性因子水平,达到治疗效果。

Objective To explore the therapeutic efficacy of compound Mufurong nasal ointment(MNO)in treating allergic rhinitis,and to study the mechanism in treating allergic rhinitis and explore the action target and signal pathway of MNO for allergic rhinitis by network pharmacology.Methods A total of 130 patients diagnosed with AR in Chongqing Health Center for Women and Children from October 2019 to December 2020 were included in the study and assigned into control group and observation group using random number table method;there were 65 cases in each group.The control group was treated with Fluticasone while the observation group was treated with MNO,both for 4 weeks.observe comparison was made of the levels of leukotriene E4(LTE_(4)),tumor necrosis factorα(TNF-α),interleukin-4(IL-4),interleukin-6(IL-6)and interleukin-12(IL-12)in urine and the total effective rate before and after treatment.At the same time,the study used Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and other databases to screen MNO active components and TCM targets,then the Rversion 3.6.2 software and Cytoscape 3.7.1 software were used to construct the network of component,action target and pathway for treating AR.Finally,gene ontology function annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed using bioc manager package in the R language.Results The total efficiency of the observation group(89.23%)was significantly higher than that of the control group(72.31%).After 4 weeks of treatment,the levels of LTE4 in urine of the two groups were significantly lower than those before treatment,and the expression levels of TNF-α,IL-4,IL-6,and IL-12 of the two groups decreased significantly;the decrease in the observation group was greater than that in the control group,and the difference was statistically significant(all P<0.05).Nine active ingredients,including quercetin and kaempferol,were obtained.The key targets were also identified,including IL6,vascular endothelial growth factor A(VEGFA),mitogen-activated protein kinase 1(MAPK1),and protein kinase 1(AKT1).The key pathways were hypoxic inducible factor-1(HIF-1)signaling pathway,TNF signaling pathway,Phosphatidylinositol 3-kinase and AKT/protein kinase b(PI3K-Akt)signaling pathway,and advanced glycosylation end products-receptor for advanced glycosylation end products(AGE-RAGE)signaling pathway.Conclusion Compound MNO can regulate the signaling pathways of HIF-1,TNF and PI3K-Akt by targeting VEGFA,IL-6,AKT1 and MAPK1,so as to reduce or inhibit the inflammatory factors of TNF-α,IL-4,IL-6,and IL-12 to achieve efficacy.