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NEDD4L-induced β-catenin ubiquitination suppresses the formation and progression of interstitial pulmonary fibrosis via inhibiting the CTHRC1/HIF-1α axis
International Journal of Biological Sciences ( IF 9.2 ) Pub Date : 2021-7-25 , DOI: 10.7150/ijbs.57247
Lin Chen 1 , Yang Yang 1 , Haiying Yan 1 , Xiaying Peng 1 , Jun Zou 1
Affiliation  

Interstitial pulmonary fibrosis (IPF) is a severe progressive lung disease with limited therapeutic options and poor prognosis. Initially, we found the downregulated level of neural precursor cell expressed developmentally down-regulated 4-like protein (NEDD4L) in IPF-related expression microarray dataset, and this study was thus performed to explore the molecular mechanism of NEDD4L in IPF. The expression of NEDD4L was subsequently validated in lung tissues of IPF patients and mouse models. Then, mouse primary lung fibroblasts (LFs) were collected for in vitro functional experiments, with CCK-8, Transwell, and immunofluorescence assays used to examine the viability, migration, and differentiation of LFs. The in vitro findings were further assessed using in vivo mouse models. The expression of NEDD4L was down-regulated in lung tissues of IPF patients and mouse models. Overexpression of NEDD4L restricted the formation and progression of IPF in mice and attenuated the proliferative, invasive and differentiative abilities of LFs. Further, NEDD4L halted LFs activity by enhancing β-catenin ubiquitination and down-regulating the CTHRC1/HIF-1α axis. Also, in vivo experiments then validated that NEDD4L silencing repressed β-catenin ubiquitination and activated the CTHRC1/HIF-1α axis, thereby aggravating IPF in mice. NEDD4L may suppress the formation and progression of IPF through augmenting β-catenin ubiquitination and inhibiting the CTHRC1/HIF-1α axis.

中文翻译:

NEDD4L诱导的β-catenin泛素化通过抑制CTHRC1/HIF-1α轴抑制间质性肺纤维化的形成和进展

间质性肺纤维化(IPF)是一种严重的进行性肺部疾病,治疗选择有限且预后不良。最初,我们在IPF相关表达微阵列数据集中发现神经前体细胞表达发育下调的4样蛋白(NEDD4L)的表达水平下调,因此本研究旨在探索NEDD4L在IPF中的分子机制。随后在 IPF 患者和小鼠模型的肺组织中验证了 NEDD4L 的表达。然后,收集小鼠原代肺成纤维细胞 (LF) 用于体外功能实验,使用 CCK-8、Transwell 和免疫荧光测定法检查 LF 的活力、迁移和分化。使用体内进一步评估了体外研究结果鼠标模型。NEDD4L的表达在IPF患者和小鼠模型的肺组织中下调。NEDD4L的过表达限制了小鼠IPF的形成和进展,并减弱了LFs的增殖、侵袭和分化能力。此外,NEDD4L 通过增强 β-catenin 泛素化和下调 CTHRC1/HIF-1α 轴来停止 LFs 活性。此外,体内实验随后验证了 NEDD4L 沉默抑制了 β-连环蛋白泛素化并激活了 CTHRC1/HIF-1α 轴,从而加重了小鼠的 IPF。NEDD4L 可能通过增强 β-catenin 泛素化和抑制 CTHRC1/HIF-1α 轴来抑制 IPF 的形成和进展。
更新日期:2021-09-08
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