关键词: Extracellular matrix Glaucoma Silibinin Trabecular meshwork cells Transforming growth factor-β2

Mesh : Humans Antioxidants / pharmacology Blotting, Western Cell Movement / drug effects Cell Proliferation / drug effects Cells, Cultured Fibrosis Glaucoma, Open-Angle / metabolism drug therapy pathology Janus Kinase 2 / metabolism Phosphatidylinositol 3-Kinases / metabolism Proto-Oncogene Proteins c-akt / metabolism Signal Transduction Silybin / pharmacology Silymarin / pharmacology STAT3 Transcription Factor / metabolism Trabecular Meshwork / drug effects metabolism pathology Transforming Growth Factor beta2 / pharmacology metabolism

来  源:   DOI:10.1016/j.exer.2024.109939

Abstract:
Transforming growth factor-β2 (TGF-β2) induced fibrogenic changes in human trabecular meshwork (HTM) cells have been implicated in trabecular meshwork (TM) damage and intraocular pressure (IOP) elevation in primary open-angle glaucoma (POAG) patients. Silibinin (SIL) exhibited anti-fibrotic properties in various organs and tissues. This study aimed to assess the effects of SIL on the TGF-β2-treated HTM cells and to elucidate the underlying mechanisms. Our study found that SIL effectively inhibited HTM cell proliferation, attenuated TGF-β2-induced cell migration, and mitigated TGF-β2-induced reorganization of both actin and vimentin filaments. Moreover, SIL suppressed the expressions of fibronectin (FN), collagen type I alpha 1 chain (COL1A1), and alpha-smooth muscle actin (α-SMA) in the TGF-β2-treated HTM cells. RNA sequencing indicated that SIL interfered with the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, also known as AKT) signaling pathway, extracellular matrix (ECM)-receptor interaction, and focal adhesion in the TGF-β2-treated HTM cells. Western blotting demonstrated SIL inhibited the activation of Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) and the downstream PI3K/AKT signaling pathways induced by TGF-β2, potentially contributing to its inhibitory effects on ECM protein production in the TGF-β2-treated HTM cells. Our study demonstrated the ability of SIL to inhibit TGF-β2-induced fibrogenic changes in HTM cells. SIL could be a potential IOP-lowering agent by reducing the fibrotic changes in the TM tissue of POAG patients, which warrants further investigation through additional animal and clinical studies.
摘要:
转化生长因子-β2(TGF-β2)诱导的人小梁网(HTM)细胞纤维化变化与原发性开角型青光眼(POAG)患者小梁网(TM)损伤和眼内压(IOP)升高有关。水飞蓟宾(SIL)在各种器官和组织中表现出抗纤维化特性。本研究旨在评估SIL对TGF-β2处理的HTM细胞的影响并阐明其潜在机制。我们的研究发现SIL能有效抑制HTM细胞的增殖,减弱TGF-β2诱导的细胞迁移,并减轻TGF-β2诱导的肌动蛋白和波形蛋白丝的重组。此外,SIL抑制纤维连接蛋白(FN)的表达,I型胶原α1链(COL1A1),TGF-β2处理的HTM细胞中的α-平滑肌肌动蛋白(α-SMA)。RNA测序表明SIL干扰了磷酸肌醇3-激酶(PI3K)/蛋白激酶B(PKB,也称为AKT)信号通路,细胞外基质(ECM)-受体相互作用,和在TGF-β2处理的HTM细胞中的局灶性粘附。Western印迹表明SIL抑制Janus激酶2(JAK2)/信号转导和转录激活因子3(STAT3)的激活以及TGF-β2诱导的下游PI3K/AKT信号通路,可能有助于其对ECM蛋白产生的抑制作用。TGF-β2处理的HTM细胞。我们的研究证明了SIL抑制TGF-β2诱导的HTM细胞纤维化变化的能力。SIL可以通过减少POAG患者TM组织的纤维化变化而成为潜在的降低IOP的药物。这需要通过其他动物和临床研究进行进一步调查。
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