Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.
Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institutes of Integrative Medicine, Fudan University, Shanghai, China.
Phytomedicine. 2022 Sep;104:154252. doi: 10.1016/j.phymed.2022.154252. Epub 2022 Jun 8.
Despite the substantial amount of efforts made to reduce morbidity and improve respiratory management, asthma control remained a major challenge for severe patients. Plant isoflavones, one of the most estrogenic compounds, are considered a potential alternative therapy for asthma. Iristectorigenin A, a naturally occurring isoflavone, is extracted from a variety of medical plants and its biological activity has not been reported previously.
In present study, we aim to reveal the potential therapeutic role of Iristectorigenin A against acute asthmatic mice.
We established ovalbumin (OVA) induced asthmatic murine model and orally administrated Iristectorigenin A at concentration of 5 and 10 mg/kg and dexamethasone as a positive control substance.
Asthmatic murine model was established with OVA sensitization and challenge. Lung function was assessed with FinePoint Ventilation system recording lung resistance (RI) and lung compliance (Cydn). White cells were sorted and counted in BALF. Histopathological assessment was conducted by H&E, PAS, and Masson's trichrome staining on paraffin embedded lung tissues. BALF content of IL-4, IL-5, IL-33, IL-13, INF-γ, IL-9 and serum IgE, IgG1 were measured using ELISA kit. Expression levels of mRNAs associated with inflammatory cytokines and goblet cell metaplasia were evaluated via quantitative RT-PCR. Protein expression levels of FOXA3, MUC5AC, SPDEF were estimated by immunohistochemistry on lung tissue, while NOTCH1 and NOTCH2 expressions were evaluated by western blotting analysis.
Iristectorigenin A resulted in improved airway hyperresponsiveness (AHR) mirrored by decreased RI and increased Cydn. With Iristectorigenin A, we also observed reduced number of BALF leukocytes, improved inflammatory cell infiltration in lung tissue, decreased content of BALF IL-4, IL-5, IL-33, but not IL-13, INF-γ, IL-9, and their mRNA levels, along with decreased levels of OVA-specific IgE, IgG1 in asthmatic mice. Additionally, Iristectorigenin A exhibited significant therapeutic potential on attenuating mucus production reflected by mitigated FOXA3 and MUC5AC immunostaining on the airway epithelium, as well as decreased mRNAs associated with goblet cell metaplasia. At last, a decrease in elevated expression level of NOTCH2, but not NOTCH1, in asthmatic mice lung tissue was observed by western blotting analysis.
Our study provides strong evidence that Iristectorigenin A can be potential therapeutic agent ameliorating airway inflammation and mucus hypersecretion in allergic asthma. This is a first research reported the potential of Iristectorigenin A as an alternative therapeutic agent.
尽管为降低发病率和改善呼吸管理做出了大量努力，但哮喘控制仍然是重症患者面临的主要挑战。植物异黄酮是最具雌激素活性的化合物之一，被认为是哮喘的潜在替代疗法。鸢尾甲素 A 是一种天然异黄酮，从多种药用植物中提取得到，其生物活性尚未见报道。
本研究旨在揭示鸢尾甲素 A 对急性哮喘小鼠的潜在治疗作用。
我们建立了卵清蛋白（OVA）诱导的哮喘小鼠模型，并以 5 和 10mg/kg 的剂量口服给予鸢尾甲素 A，以地塞米松作为阳性对照药物。
通过 OVA 致敏和激发建立哮喘小鼠模型。使用 FinePoint 通气系统记录肺阻力（RI）和肺顺应性（Cydn）评估肺功能。对 BALF 中的白细胞进行分类和计数。通过 H&E、PAS 和 Masson 三色染色对石蜡包埋的肺组织进行组织病理学评估。通过 ELISA 试剂盒测定 BALF 中 IL-4、IL-5、IL-33、IL-13、INF-γ、IL-9 和血清 IgE、IgG1 的含量。通过定量 RT-PCR 评估与炎症细胞因子和杯状细胞化生相关的 mRNA 表达水平。通过免疫组织化学法评估肺组织中 FOXA3、MUC5AC、SPDEF 的蛋白表达水平，通过 Western blot 分析评估 NOTCH1 和 NOTCH2 的表达水平。
鸢尾甲素 A 可改善气道高反应性（AHR），表现为 RI 降低和 Cydn 增加。与鸢尾甲素 A 治疗组相比，BALF 白细胞数量减少，肺组织炎症细胞浸润改善，BALF 中 IL-4、IL-5、IL-33 含量降低，但 IL-13、INF-γ、IL-9 及其 mRNA 水平无明显变化，同时哮喘小鼠血清 OVA 特异性 IgE、IgG1 水平降低。此外，鸢尾甲素 A 还可显著减轻气道黏液分泌，表现在气道上皮的 FOXA3 和 MUC5AC 免疫染色减弱，与杯状细胞化生相关的 mRNAs 水平降低。最后，Western blot 分析显示，哮喘小鼠肺组织中 NOTCH2 的表达水平升高，但 NOTCH1 的表达水平无明显变化。
本研究提供了有力证据表明，鸢尾甲素 A 可作为一种潜在的治疗药物，改善变应性哮喘的气道炎症和黏液高分泌。这是首次报道鸢尾甲素 A 作为一种替代治疗药物的潜在作用。
