MiR-200a inversely correlates with Hedgehog and TGF-β canonical/non-canonical trajectories to orchestrate the anti-fibrotic effect of Tadalafil in a bleomycin-induced pulmonary fibrosis model.,Inflammopharmacology

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MiR-200a inversely correlates with Hedgehog and TGF-β canonical/non-canonical trajectories to orchestrate the anti-fibrotic effect of Tadalafil in a bleomycin-induced pulmonary fibrosis model.
Inflammopharmacology ( IF 4.6 ) Pub Date : 2020-09-10 , DOI: 10.1007/s10787-020-00748-w
Suzan M Mansour ₁ , Hanan S El-Abhar ₂ , Ayman A Soubh ₃

Affiliation

Abstract

Few reports have documented the ability of phosphodiesterase-5 inhibitors (PDE-5-Is) to ameliorate idiopathic pulmonary fibrosis (IPF) mainly by their anti-inflammatory/antioxidant capacities, without unveiling the possible molecular mechanisms involved. Because of the recent role of miR-200 family and Sonic Hedgehog (SHH) trajectory in IPF, we have studied their impact on the anti-fibrotic potential of tadalafil against bleomycin-induced pulmonary fibrosis. Animals were allocated into normal-control, bleomycin-fibrotic control, and bleomycin post-treated with tadalafil or dexamethasone, as the reference drug. On the molecular level, tadalafil has reverted the bleomycin effect on all the assessed parameters. Tadalafil upregulated the gene expression of miR-200a, but decreased the smoothened (SMO) and the transcription factors glioma-associated oncogene homolog (Gli-1, Gli-2), members of SHH pathway. Additionally, tadalafil ebbed transforming growth factor (TGF)-β, its canonical (SMAD-3/alpha smooth muscle actin [α-SMA] and Snail), and non-canonical (p-Akt/p-Forkhead box O3 (FOXO3) a) pathways. Besides, a strong negative correlation between miR-200a and the analyzed pathways was proved. The effect of tadalafil was further confirmed by the improved lung structure and the reduced Ashcroft score/collagen deposition. The results were comparable to that of dexamethasone. In conclusion, our study has highlighted the involvement of miR-200a in the anti-fibrotic effect of tadalafil with the inhibition of SHH hub and the pro-fibrotic pathways (TGF-β/ SMAD-3/α-SMA, Snail and p-AKT/p-FOXO3a).

Graphic abstract

Potential anti-fibrotic effect of tadalafil. Modulation of miR200a/SHH/canonical and non-canonical TGF-β trajectories. → : stimulatory effect; ┴: inhibitory effect

中文翻译：

MiR-200a 与 Hedgehog 和 TGF-β 经典/非经典轨迹呈负相关，以协调他达拉非在博莱霉素诱导的肺纤维化模型中的抗纤维化作用。

摘要

很少有报道记录磷酸二酯酶 5 抑制剂 (PDE-5-Is) 主要通过其抗炎/抗氧化能力改善特发性肺纤维化 (IPF) 的能力，而没有揭示所涉及的可能分子机制。由于最近 miR-200 家族和 Sonic Hedgehog (SHH) 轨迹在 IPF 中的作用，我们研究了它们对他达拉非对抗博来霉素诱导的肺纤维化的抗纤维化潜力的影响。将动物分为正常对照、博来霉素纤维化对照和用他达拉非或地塞米松作为参考药物后处理的博来霉素。在分子水平上，他达拉非已经恢复了对所有评估参数的博来霉素效应。他达拉非上调miR-200a的基因表达，但降低了SHH 通路的平滑 (SMO) 和转录因子胶质瘤相关癌基因同源物 ( Gli-1、Gli-2 )。此外，他达拉非减少了转化生长因子 (TGF)-β、其经典 (SMAD-3/α 平滑肌肌动蛋白 [α-SMA] 和Snail ) 和非经典 ( p -Akt/ p -Forkhead box O3 (FOXO3) a) 途径。此外，证实了miR-200a与所分析的通路之间存在强烈的负相关。他达拉非的作用通过改善的肺结构和减少的 Ashcroft 评分/胶原沉积得到进一步证实。结果与地塞米松的结果相当。总之，我们的研究强调了miR-200a在他达拉非的抗纤维化作用中具有抑制 SHH 中枢和促纤维化途径（TGF-β/SMAD-3/α-SMA、Snail和 p-AKT/p-FOXO3a）。