探索补肺益肾方Ⅲ号有效成分组合对气道上皮屏障损伤的干预机制：基于miRNA-mRNA调控网络的分析
Exploring the Intervention Mechanism of Effective-Component Combination of Bufei Yishen Formula III for Airway Epithelial Barrier Injury: A miRNA-mRNA Regulatory Network Analysis.
作者信息
Liu Chunlei, Yue Changyuan, Xing Xiaoxiang, Huang Lidong, Wei Yanxin, Zhao Peng, Li Jiansheng, Guan Qingzhou
机构信息
Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed by Henan Province and Education Ministry of People's Republic of China, Henan University of Chinese Medicine, Zhengzhou, 450046, People's Republic of China.
Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, People's Republic of China.
出版信息
J Inflamm Res. 2025 Sep 4;18:12145-12167. doi: 10.2147/JIR.S529587. eCollection 2025.
OBJECTIVE
To investigate the mechanism by which the effective-component combination of Bufei Yishen formula III (ECC-BYF III) ameliorates airway epithelial barrier injury in chronic obstructive pulmonary disease (COPD) through miRNA-mRNA regulatory networks.
METHODS
Differentially expressed mRNAs (DEmRNAs) and miRNAs (DEmiRNAs) were identified using the edgeR algorithm. The target genes of DEmiRNAs were predicted using four online databases. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis based on the hypergeometric distribution model was performed for DEmRNAs and the predicted target genes, respectively. DEmiRNAs and their corresponding target genes that were regulated by ECC-BYF III were subsequently identified. The reliability of these miRNAs and target genes was validated using independent datasets, qRT-PCR in human bronchial airway epithelial cells (BEAS-2B), COPD rat models, and molecular docking.
RESULTS
Compared with the control group, 2997 DEmRNAs and 4 DEmiRNAs were identified in the model group (edgeR, <0.05). A total of 2430 target genes of the DEmiRNAs were predicted, and the miRNA-mRNA regulatory network was constructed. Pathway enrichment analysis revealed that DEmRNAs were enriched in 96 pathways and target genes in 112 pathways, with 53 overlapping pathways (<0.05). ECC-BYF III treatment reversed the expression of 13 miRNA-mRNA pairs. Further screening and validation in COPD rat models and BEAS-2B cells identified two miRNAs and five regulated hub genes (ESM1, RNF44, BCL2L1, ADAM19, and SMYD5). The reliability of these hub genes was further confirmed by independent datasets (GSE173896 and GSE11906) and molecular docking.
CONCLUSION
ECC-BYF III may alleviate airway epithelial barrier injury in COPD by regulating the hsa-miR-3685-ESM1 and hsa-miR-3936-RNF44/BCL2L1/ADAM19/SMYD5 networks.
目的
通过微小RNA-信使核糖核酸（miRNA-mRNA）调控网络，研究补肺益肾方Ⅲ号有效成分组合（ECC-BYFⅢ）改善慢性阻塞性肺疾病（COPD）气道上皮屏障损伤的机制。
方法
使用edgeR算法鉴定差异表达的信使核糖核酸（DEmRNAs）和微小RNA（DEmiRNAs）。利用四个在线数据库预测DEmiRNAs的靶基因。分别基于超几何分布模型对DEmRNAs和预测的靶基因进行京都基因与基因组百科全书（KEGG）通路富集分析。随后鉴定受ECC-BYFⅢ调控的DEmiRNAs及其相应的靶基因。使用独立数据集、人支气管气道上皮细胞（BEAS-2B）中的定量逆转录聚合酶链反应（qRT-PCR）、COPD大鼠模型和分子对接验证这些miRNAs和靶基因的可靠性。
结果
与对照组相比，模型组鉴定出2997个DEmRNAs和4个DEmiRNAs（edgeR，<0.05）。共预测出DEmiRNAs的2430个靶基因，并构建了miRNA-mRNA调控网络。通路富集分析显示，DEmRNAs富集于96条通路，靶基因富集于112条通路，其中有53条重叠通路（<0.05）。ECC-BYFⅢ处理逆转了13对miRNA-mRNA的表达。在COPD大鼠模型和BEAS-2B细胞中进一步筛选和验证，鉴定出两个miRNAs和五个受调控的枢纽基因（内皮细胞特异性分子1（ESM1）、环指蛋白44（RNF44）、凋亡调节蛋白Bcl-2样蛋白1（BCL2L1）、解聚素和金属蛋白酶19（ADAM19）以及含SET和MYND结构域蛋白5（SMYD5））。独立数据集（GSE173896和GSE11906）和分子对接进一步证实了这些枢纽基因的可靠性。
结论
ECC-BYFⅢ可能通过调控hsa-miR-3685-ESM1和hsa-miR-3936-RNF44/BCL2L1/ADAM19/SMYD5网络减轻COPD中的气道上皮屏障损伤。
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