黄芪甲苷IV通过抑制STAT6/GATA3/IL-4和PI3K/AKT/NF-κB信号通路的激活改善过敏性鼻炎合并哮喘综合征

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中文摘要

黄芪甲苷IV（As-IV）已显示出对过敏性鼻炎和哮喘的治疗潜力。然而，尚缺乏系统性研究。本研究旨在通过网络药理学结合RNA测序分析，系统阐明As-IV治疗过敏性鼻炎合并哮喘综合征（CARAS）的分子机制。采用卵清蛋白建立BALB/c小鼠CARAS模型。记录鼻部和支气管肺过敏性症状。通过H&E、PAS和Masson染色评估呼吸道组织病理学变化。系统采用网络药理学和肺RNA测序预测潜在分子机制。使用WB、IF和IHC验证STAT6/GATA3/IL-4和PI3K/AKT/NF-κB信号通路的激活，以及上皮屏障和间充质成分的表达。最后，进行分子对接和分子动力学模拟以评估As-IV与关键靶蛋白的结合亲和力。As-IV减轻过敏症状，改善组织病理学形态，并减少嗜酸性粒细胞和Th2细胞浸润。此外，As-IV显著抑制STAT6/GATA3/IL-4和PI3K/AKT/NF-κB信号通路的激活，减轻上皮屏障损伤，并降低间充质成分表达。分子对接和分子动力学模拟证实As-IV可能潜在地与STAT6和AKT相互作用，提示其能够调节它们的构象和生物活性。As-IV通过抑制STAT6/GATA3/IL-4和PI3K/AKT/NF-κB信号通路，减轻呼吸道中的2型炎症和上皮屏障损伤。本研究首次通过整合网络药理学和RNA测序分析，系统揭示并验证了As-IV在CARAS中的分子机制，为其治疗应用提供了坚实的科学依据。

英文摘要

Astragaloside IV (As-IV) has demonstrated therapeutic potential for allergic rhinitis and asthma. However, a systematic investigation is lacking. This study was aimed at systematically elucidating the molecular mechanisms of As-IV in treating combined allergic rhinitis and asthma syndrome (CARAS) through network pharmacology combined with RNA sequencing analysis. A BALB/c mouse model of CARAS was established using ovalbumin. Nasal and bronchopulmonary allergic symptoms were recorded. Histopathological changes in the respiratory tract were assessed via H&E, PAS, and Masson staining. Network pharmacology and lung RNA sequencing were systematically employed to predict potential molecular mechanisms. WB, IF, and IHC were used to validate the activation of the STAT6/GATA3/IL-4 and PI3K/AKT/NF-κB signaling pathways, as well as the expression of epithelial barrier and mesenchymal components. Finally, molecular docking and molecular dynamics simulations were performed to evaluate the binding affinity of As-IV with key target proteins. As-IV alleviated allergic symptoms, improved histopathological morphology, and reduced eosinophil and Th2 cell infiltration. Furthermore, As-IV markedly suppressed the activation of STAT6/GATA3/IL-4 and PI3K/AKT/NF-κB signaling pathways, mitigated epithelial barrier damage, and decreased mesenchymal component expression. Molecular docking and molecular dynamics simulations confirmed that As-IV may potentially interact with STAT6 and AKT, suggesting its ability to modulate their conformations and biological activities. As-IV attenuates type 2 inflammation and epithelial barrier injury in the respiratory tract by inhibiting the STAT6/GATA3/IL-4 and PI3K/AKT/NF-κB signaling pathways. This study is the first to systematically unravel and validate the molecular mechanisms of As-IV in CARAS through integrated network pharmacology and RNA sequencing analysis, providing a robust scientific basis for its therapeutic application.