Oxy210, a Semi-Synthetic Oxysterol, Inhibits Profibrotic Signaling in Cellular Models of Lung and Kidney Fibrosis.
Oxy210, a Semi-Synthetic Oxysterol, Inhibits Profibrotic Signaling in Cellular Models of Lung and Kidney Fibrosis.
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DOI：
10.3390/ph16010114
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发表时间：
2023-01-12
期刊：
影响因子：
--
通讯作者：
Parhami F
中科院分区：
文献类型：
--
作者：
Wang F;Stappenbeck F;Parhami F
Oxy210是一种半合成的氧固醇衍生物，在肝纤维化模型中显示出对上皮细胞、成纤维细胞和巨噬细胞中Hedgehog(HH)和转化生长因子β(β)信号的细胞选择性抑制以及抗纤维化和抗炎的作用。在本报告中，我们研究了Oxy210在肺和肾纤维化细胞模型中的作用，例如来自健康肺组织的人肺成纤维细胞系IMR-90和来自特发性肺纤维化(IPF)患者的LL97A。此外，我们研究了Oxy210对原代人肾成纤维细胞、周细胞、系膜细胞和肾小管上皮细胞的影响，这些细胞与慢性肾脏疾病(CKD)和肾脏纤维化有关。在成纤维细胞中，我们证明了几个促纤维化的转化生长因子-β靶基因的表达，包括纤维连接蛋白(FN)、胶原1A1(COL1A1)和结缔组织生长因子(CTGF)，在基础水平和转化生长因子-β刺激后都被Oxy210显著抑制。COL1A1基因表达的抑制直接转化为COL1A1蛋白表达的显著降低。在人原代小气道上皮细胞和肾小管上皮细胞中，Oxy210显著抑制与上皮-间充质转化相关的转化生长因子-β靶基因的表达。Oxy210对成纤维细胞、周细胞和系膜细胞的增殖也有抑制作用，且呈剂量依赖性和统计学意义。
Oxy210, a semi-synthetic oxysterol derivative, displays cell-selective inhibition of Hedgehog (Hh) and transforming growth factor beta (TGF-β) signaling in epithelial cells, fibroblasts, and macrophages as well as antifibrotic and anti-inflammatory efficacy in models of liver fibrosis. In the present report, we examine the effects of Oxy210 in cellular models of lung and kidney fibrosis, such as human lung fibroblast cell lines IMR-90, derived from healthy lung tissue, and LL97A, derived from an idiopathic pulmonary fibrosis (IPF) patient. In addition, we examine the effects of Oxy210 in primary human renal fibroblasts, pericytes, mesangial cells, and renal tubular epithelial cells, known for their involvement in chronic kidney disease (CKD) and kidney fibrosis. We demonstrate in fibroblasts that the expression of several profibrotic TGF-β target genes, including fibronectin (FN), collagen 1A1 (COL1A1), and connective tissue growth factor (CTGF) are inhibited by Oxy210, both at the basal level and following TGF-β stimulation in a statistically significant manner. The inhibition of COL1A1 gene expression translated directly to significantly reduced COL1A1 protein expression. In human primary small airway epithelial cells (HSAECs) and renal tubular epithelial cells, Oxy210 significantly inhibited TGF-β target gene expression associated with epithelial–mesenchymal transition (EMT). Oxy210 also inhibited the proliferation of fibroblasts, pericytes, and mesangial cells in a dose-dependent and statistically significant manner.
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影响因子：
5.6
作者：
Giroux-Leprieur E;Costantini A;Ding VW;He B
通讯作者：
He B
Hedgehog信号传导，控制肝细胞癌发生和进展的关键途径
影响因子：
6
作者：
Ding J;Li HY;Zhang L;Zhou Y;Wu J
通讯作者：
Wu J
DOI：
10.1038/nrneph.2016.54
发表时间：
2016-07
期刊：
Nature reviews. Nephrology
影响因子：
--
作者：
Edeling M;Ragi G;Huang S;Pavenstädt H;Susztak K
通讯作者：
Susztak K
影响因子：
13.8
作者：
Arensdorf AM;Marada S;Ogden SK
通讯作者：
Ogden SK
内皮 TGF-β 信号传导驱动血管炎症和动脉粥样硬化
影响因子：
20.8
作者：
Chen, Pei-Yu;Qin, Lingfeng;Simons, Michael
通讯作者：
Simons, Michael