ITF2357调节NF-κB信号通路,以保护视网膜色素上皮细胞中的屏障完整性
Rayne R Lim1, Binapani Mahaling1, Alison Tan2
1Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin Eye Institute, Milwaukee, Wisconsin, USA.
概括
ITF2357通过加强RPE完整性和紧密的接口来保护外部血视网膜屏障. 这种基因素脱乙酶抑制剂调节NF-κB信号传递,为视网膜血管疾病 (如糖尿病黄斑) 提供潜在的治疗.
科学领域:
- 眼科医生 眼科 眼科
- 细胞生物学 细胞生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 视网膜色素上皮质 (RPE) 形成外血液视网膜屏障 (oBRB),对视网膜健康至关重要.
- 在像糖尿病黄斑 (DME) 这样的视网膜疾病中,RPE完整性受到损害.
- 基因组脱乙酶抑制剂 (HDACi) 正在探索其治疗潜力.
研究的目的:
- 评估ITF2357的有效性,一个新的HDACi,在维护RPE完整性.
- 研究ITF2357保护oBRB免受炎症损伤的机制.
- 评估ITF2357在视网膜血管疾病中的潜在治疗作用.
主要方法:
- 使用了暴露于瘤死因子-α (TNFα) 的永生RPE细胞系 (ARPE-19).
- 评估了ITF2357的无毒性和保护作用,对紧密的结合和粘附.
- 研究了NF-κB信号通路组件 (IKK,IκBα,p65) 和炎症标记物 (IL-1β,IL-6,MCP-1) 的调节.
主要成果:
- ITF2357在预防TNFα诱导的RPE透性方面证明了安全性和有效性.
- ITF2357增强了紧结蛋白 (ZO-1,奥克卢丁,克劳丁) 和附着结蛋白 (E-cadherin,Nectin-1).
- ITF2357通过抑制IKK,IκBα和p65酸化来减弱NF-κB激活,并减少炎症性细胞因子表达.
结论:
- ITF2357通过调节节点蛋白循环和调节NF-κB信号来保护RPE的完整性.
- ITF2357显示出作为治疗视网膜血管疾病的治疗剂的承诺,其特点是oBRB分解.
- 需要进一步研究ITF2357在非正规NF-κB激活中的作用.
相关概念视频
NF-κB-dependent Signaling Pathway
7.4K
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
NF-κB-dependent Signaling Mechanism
The...
7.4K
TGF - β Signaling Pathway
7.4K
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.4K
Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
Receptor Downregulation in MVBs
2.1K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.1K
Regulation of Angiogenesis and Blood Supply
2.6K
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
2.6K
The Extrinsic Apoptotic Pathway
6.4K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
6.4K


