铁死亡在眼底疾病中的研究进展

铁死亡是一种独特的细胞死亡方式,是铁依赖性的新型细胞程序性死亡,以细胞内胞质和脂质的活性氧堆积为主要特征。铁死亡在很多眼底疾病的发病机制中发挥重要作用,如视网膜色素变性、年龄相关性黄斑变性、糖尿病视网膜病变、视网膜脱离、视网膜母细胞瘤等疾病,使用铁死亡相关抑制剂或激活剂可调节疾病进程,为眼科疾病的研究、预防及治疗提供新的思路。     

铁死亡与视网膜疾病的相关性研究进展

铁死亡是近些年来发现的一种新型细胞死亡方式,以铁依赖性脂质过氧化为特征,在形态和生物化学上不同于已知的细胞死亡方式,可能参与多种疾病的发生发展。本文就铁死亡的特征、分子机制、诱导剂/抑制剂及其在视网膜疾病中的研究进展进行综述,以期为视网膜疾病的防治提供新途径。     

铁死亡在眼科疾病中的应用研究进展

铁死亡是一种特殊类型的细胞死亡方式,其为依赖铁元素代谢紊乱,并以细胞内胞质和脂质的活性氧堆积为特征的调节性细胞死亡.本文综述了铁死亡概念的发展、铁死亡的机制及其在眼科疾病中的最新研究进展,包括角膜上皮、视网膜色素上皮细胞、糖尿病视网膜病变、视网膜缺血-再灌注损伤、青光眼、视网膜母细胞瘤、视网膜色素变性等,为临床上眼科医...     

铁死亡在年龄相关性黄斑变性中的调控机制研究进展

目的 铁死亡是一种以脂质过氧化为特征的调节性细胞死亡，在年龄相关性黄斑变性(AMD)中扮演重要角色。本文就AMD的病理机制、铁死亡过程及特征进行回顾，并从铁离子代谢途径、胱氨酸/谷氨酸逆向转运体途径、脂质代谢途径、核转录因子途径、自噬依赖性途径及免疫相关途径对铁死亡在AMD发生发展中的调控机制进行论述，最后归纳总结部分铁死亡抑制剂对视网膜色素上皮细胞的保护作用，为AMD的治疗提供新的思路。     

铁死亡在高糖诱导的视网膜色素上皮细胞损伤中的作用及机制

目的：观察铁死亡在高糖(HG)诱导的视网膜色素上皮(RPE)细胞损伤中的作用及机制,为糖尿病视网膜病变(DR)的治疗提供新思路。

方法：将体外培养的ARPE-19细胞分为正常对照组(NC组)、高糖组(HG组)、高糖+铁死亡抑制剂组(Fer-1组)。采用CCK-8法检测各组细胞活力; 使用ELISA试剂盒检测白细胞介素6(IL-6)、IL-1β及单核细胞趋化蛋白-1(MCP-1)的表达水平; 使用化验试剂盒检测丙二醛(MDA)、谷胱甘肽(GSH)、谷胱甘肽过氧化物酶4(GPX4)水平; 使用铁离子检测试剂盒检测细胞铁含量; 通过透射电子显微镜观察细胞线粒体变化; 通过Western blotting和免疫荧光染色技术检测铁死亡相关蛋白长链脂酰CoA合成酶4(ACSL4)、GPX4以及血管内皮生长因子(VEGF)蛋白的表达。

结果：与NC组相比,HG组细胞活力显著下降,细胞上清液中炎症因子表达水平升高,细胞中氧化应激指标MDA和铁含量显著升高,GSH含量和GPX4活性显著降低(均P<0.01),且线粒体皱缩,ACSL4及VEGF蛋白表达增加,GPX4蛋白表达降低(均P<0.01)。与HG组相比,Fer-1组细胞活力明显增加,细胞上清液中炎症因子表达水平下降,细胞中MDA和铁含量明显下降,GSH含量和GPX4活性显著提高(均P<0.05),且线粒体形态改善,ACSL4及VEGF蛋白表达减少,GPX4蛋白表达升高(均P<0.05)。

结论：铁死亡参与高糖诱导的RPE细胞损伤,抑制铁死亡能改善细胞活性,降低炎症及氧化应激水平,减轻高糖诱导的RPE细胞损伤。     

铁死亡机制在视网膜色素上皮细胞损伤相关眼病中的研究进展

铁死亡(ferroptosis)是一种新发现的以脂质过氧化和铁积累为特征的程序性细胞死亡。近年来,随着铁死亡概念的提出和其机制研究的不断深入,视网膜色素上皮细胞(retinal pigment epithelium cells, RPECs)功能下降相关眼病如年龄相关性黄斑变性(age-related macular degeneration, AMD)、视网膜色素变性(retinitis pigmentosa, RP)和糖尿病视网膜病变(diabetic retinopathy, DR)等疾病的发病机制的探索也取得了重大突破。本文将对铁死亡的基本概念、RPECs铁死亡的主要机制及调控铁死亡对RPECs相关眼病发生发展的作用研究进行综述,希望为RPECs相关眼病发病机制的研究提供参考。     

线粒体自噬在眼科相关疾病中的研究进展

线粒体自噬是一种选择性自噬,是指细胞通过自噬的机制选择性地清除线粒体的过程。线粒体自噬在清除功能失调的线粒体、降低线粒体数量及维持细胞稳态中起着重要的作用。它的分子机制涉及PINK1/Parkin、BNIP3、NIX和FUNDC1等多种蛋白。线粒体发生功能障碍或损坏都可能造成严重的后果,甚至导致细胞死亡。研究发现线粒体自噬紊乱与多种眼科疾病的发生有关,如白内障、青光眼、年龄相关性黄斑变性(age-related macular degenration, AMD)、糖尿病视网膜病变(diabetic retinopathy, DR)等。本文就线粒体自噬的发生机制和它在眼科相关疾病中的研究进行综述。     

调节性细胞死亡在糖尿病视网膜病变中的研究进展

调节性细胞死亡(RCD)是一种独特的细胞死亡方式,包括细胞凋亡等多种形式。RCD参与人类正常生理活动的诸多环节,更与多种疾病的发生发展密切相关。糖尿病视网膜病变(DR)是近年来发病率较高的一种致盲性眼病。研究表明,DR的发生与细胞凋亡、铁死亡、细胞焦亡、细胞自噬、依赖性细胞死亡等多种RCD的相关蛋白异常表达有关。本文将对DR发病过程中与RCD相关的机制作一综述,以期为DR的靶向治疗提供思路。     

PINK1/Parkin介导的线粒体自噬在眼科疾病中作用的研究进展

线粒体自噬作为一种选择性自噬过程,通过清除受损和多余线粒体来维持细胞正常生理功能。线粒体自噬与多种眼科疾病的发生发展有密切联系,而PINK1/Parkin信号通路作为线粒体自噬的主要通路之一,在白内障、青光眼、年龄相关性黄斑变性等多种眼科疾病中发挥了重要作用,靶向该通路的治疗手段也为多种眼科疾病的治疗提供了新思路。本文将对PINK1/Parkin介导的线粒体自噬通路在眼科疾病中的相关作用及机制进行综述,以期深入了解线粒体自噬在眼科相关疾病中的影响与价值。     

GSDMD介导的细胞焦亡在眼科疾病中的研究进展

细胞焦亡是一种新的细胞死亡形式。2015年,gasdermin家族成员gasdermin D（GSDMD）蛋白作为焦亡的关键效应蛋白被发现,并引起了广泛关注。细胞中的GSDMD被激活的caspase-1、caspase-4、caspase-5、caspase-11裂解后,氨基末端转移至细胞膜上寡聚并形成孔隙,允许水分子等物质进入细胞,导致细胞膨胀、破裂从而引发细胞焦亡。本文就GSDMD的结构、作用机制、其与焦亡之间的关系以及GSDMD在眼科疾病中最新的研究进展进行综述,为眼科疾病的治疗提供新思路。     

蓝光诱导视网膜色素上皮细胞铁死亡的机制研究

目的:探讨蓝光诱导人视网膜色素上皮(ARPE)细胞铁死亡的发生及可能机制。方法:体外培养的ARPE-19细胞接受405nm蓝光50mW/cm²辐照度照射不同时间,分为对照组、16.3J/cm²组、32.6J/cm²组和65.2J/cm²组;将65.2J/cm²组定为高能量蓝光照射组,进一步分为对照组、高能量蓝光照射组和高能量蓝光照射+铁死亡抑制剂组,CCK-8检测细胞活力,试剂盒检测细胞内谷胱甘肽(GSH)含量、二价铁离子浓度及丙二醛(MDA)含量,Western blot法检测细胞内GPX4和xCT蛋白相对表达量。结果:蓝光照射导致ARPE-19细胞活力下降呈剂量依赖性,高能量蓝光照射导致细胞内GSH含量下降,二价铁离子浓度和MDA含量上升(均P<0.05);加入铁死亡抑制剂可部分恢复蓝光照射组细胞活力和GSH含量,减少MDA含量,降低二价铁离子浓度(均P<0.05);蓝光照射组GPX4和xCT蛋白相对表达量显著下降,加入铁死亡抑制剂后蛋白表达量不同程度恢复(P&...     

Cold-induced injury to porcine corneal endothelial cells and its mediation by chelatable iron: implications for corneal preservation

PURPOSE: During hypothermic storage of the cornea, corneal endothelial damage restricts storage times. We previously reported a new, iron-dependent mechanism of cold-induced injury to cultured liver cells. In this study, we sought to evaluate whether corneal endothelial cells incur a similar kind of injury. METHODS: Cultured porcine corneal endothelial cells were exposed to 4 degrees C in either cell culture medium, Krebs-Henseleit buffer, Optisol-GS solution, or McCarey-Kaufman medium for 5 hours to 14 days and then rewarmed under cell culture conditions (3 hours). The cultures were assessed for lethal cell injury (LDH release); cellular, nuclear, and mitochondrial morphologic alterations; lipid peroxidation; and mitochondrial membrane potential. RESULTS: Corneal endothelial cells sustained substantial injury following cold storage and rewarming in cell culture medium (47% +/- 8% and 64% +/- 20% cell death after 2 and 5 days cold storage, respectively). The injury displayed some apoptotic features, and cells lost mitochondrial membrane potential before cell death occurred. The iron chelators deferoxamine, 1,10-phenanthroline, and 2,2'-dipyridyl and the antioxidant butylated hydroxytoluene completely inhibited this cell injury. Marked iron-dependent cell injury and lipid peroxidation also occurred during and after cold incubation in Krebs-Henseleit buffer and, most importantly, iron-dependent cell injury was also observed after cold incubation in Optisol solution and in McCarey-Kaufman medium. CONCLUSIONS: Cultured porcine corneal endothelial cells incur a strong iron-dependent injury elicited by hypothermia. This cold-induced injury might provide an explanation for the known corneal endothelial susceptibility to hypothermic preservation injury, which thus might be amenable to therapeutic interventions (ie, by iron chelators).     

Iron toxicity as a potential factor in AMD

While it has been known for years that iron overload is associated with retinal degeneration in the context of ocular siderosis, intraocular hemorrhage, and the hereditary diseases aceruloplasminemia and pantothenate kinase associated neurodegeneration, recent evidence suggests that age-related macular degeneration (AMD) may also be exacerbated by retinal iron overload. In the retina, iron is necessary for normal cellular function. Iron overload, however, can cause retinal toxicity through the generation of oxygen free radicals. Histopathology of eyes with macular degeneration has shown elevated levels of iron in the retinal pigment epithelium, Bruch membrane, and within drusen, some of which was chelatable in vitro with deferoxamine. In this review, the authors summarize the evidence that iron overload may contribute to AMD pathogenesis. It is hoped that continued investigation of the role of iron and iron associated proteins in the retina will uncover clues to AMD pathogenesis and lead to new preventative or therapeutic options.     

Iron induced oxidative damage as a potential factor in age-related macular degeneration: the Cogan Lecture

Iron is a potent generator of oxidative damage whose levels increase with age, potentially exacerbating age-related diseases. Several lines of evidence suggest that iron accumulation may be a factor in age-related macular degeneration (AMD). AMD retinas have more iron within the photoreceptors, RPE, and drusen than do age-matched control retinas. Accelerated AMD-like maculopathy develops in patients with retinal iron overload from the hereditary disease aceruloplasminemia. Mice with retinal iron overload resulting from knockout of ceruloplasmin and its homologue hephaestin exhibit retinal degeneration with some features of AMD, including subretinal neovascularization, accumulation of RPE lipofuscin and sub-RPE deposits, and RPE/photoreceptor death. Increased understanding of the mechanisms of retinal iron homeostasis may help in the development of therapies to prevent iron overload. For example, herein it is shown that one regulator of systemic iron homeostasis, HFE, is expressed in the RPE. Thus, patients with the common disease hereditary hemochromatosis, which is often caused by an HFE mutation, may have retinal iron overload predisposing to AMD. Preliminary data suggest that iron chelation can reduce RPE iron overload in mice and protect them from degeneration, suggesting that iron-binding drugs may one day prove useful in reducing RPE oxidative stress and decreasing the risk of AMD progression.     

Beyond the cherry-red spot: Ocular manifestations of sphingolipid-mediated neurodegenerative and inflammatory disorders

Sphingolipids are a ubiquitous membrane lipid present in every cell and found most abundantly in neural tissues. Disorders such as Tay-Sachs or Niemann-Pick disease are the most familiar examples of dysfunction in sphingolipid metabolism and are typically associated with neurodegeneration and ocular findings such as blindness. More recently, the role of bioactive sphingolipids has been established in a multitude of cellular events, including cell survival, growth, senescence and apoptosis, inflammation, and neovascularization. We discuss our current knowledge and understanding of sphingolipid metabolism and signaling in the pathogenesis of ocular diseases.     

长非编码RNA在视网膜发育和眼部病变中的作用

长非编码RNA(lncRNA)是一类长度大于200个核苷酸,不具有编码蛋白功能的转录本,在哺乳动物细胞转录本中占很大比例.近年来,旨在阐明lncRNA在发育和疾病中功能的研究急剧增加.已经证实这类非编码RNA可以在表观遗传、转录和转录后水平调控基因表达.视网膜的发育依赖于复杂而精确的转录作用和转录调控.在这些调节机制中,lncRNA起到了重要的作用.现已知或预测lncRNA参与视网膜细胞亚型的分化和发育,并与若干眼部疾病相关.虽然,大部分lncRNA的分子机制还不清楚,但是它们很可能是决定视网膜细胞命运的重要组成部分.在视网膜发育中,lncRNA可诱导细胞分化、影响细胞周期并调控X染色体失活.在无眼畸形、糖尿病视网膜病变和脊髓小脑运动失调7型等眼部疾病中,lncRNA也发挥了重要作用.本文综述lncRNA在视网膜发育及眼部疾病中作用的最新研究进展及存在的问题,对基础和临床研究及药物靶点开发具有重要意义.