视紫红质类及卷曲蛋白受体在糖尿病视网膜病变发生发展中的作用

        鸟苷酸结合蛋白偶联受体（GPCRs）是一类膜受体超家族,被视为最好的药物靶点。在糖尿病视网膜病变（DR）进程中有大量不同亚型GPCRs参与。其中,视紫红质类和卷曲蛋白（Frizzled）受体广受关注,研究方向主要为视网膜炎症反应、新生血管生成、神经元和神经胶质细胞损伤等。血管紧张素Ⅱ受体是最为熟知的视紫红质类受体亚家族。应用血管紧张素Ⅱ受体1拮抗剂可显著降低1型糖尿病患者发生DR的可能性,但无法减缓已并发DR患者的病变进展;可减缓并发轻中度DR的2型糖尿病患者的病变进展。其他的视紫红质类受体还有趋化因子受体、大麻素相关受体、GPR91、GPR109A、APJ受体等。Frizzled受体是Wnt信号通路重要的膜受体等。在DR动物模型中,使用Wnt通路阻断剂Dickkopf homolog 1能改善视网膜炎症、血管渗出、新生血管生成等。但Wnt通路参与DR进展的具体机制有待研究。随着对GPCRs与DR关系了解的加深,未来将有更多以GPCRs为治疗靶点的药物应用于临床,为DR患者带来福音。     

米诺环素对糖尿病大鼠视网膜内肿瘤坏死因子-α表达的干预作用

糖尿病视网膜病变（DR）发病机制复杂，现有观点认为，炎症与免疫反应贯穿DR的全过程。有人提出DR是一种炎症性疾病。肿瘤坏死因子-α（TNF-α）就是炎症反应中最具代表性的细胞因子之一。国外研究表明米诺环素（minocycline）的作用可减少炎症介质的表达及糖尿病时视网膜内细胞凋亡的发生率。我们观察了米诺环素对糖尿病大鼠视网膜内TNF-α表达的干预作用，现将结果报告如下。     

促红细胞生成素对早期糖尿病大鼠视网膜神经胶质细胞的影响

糖尿病是一组以长期高血糖为主要特征的代谢综合征。糖尿病视网膜病变（DR）是糖尿病的严重并发症之一。有学者认为糖尿病引起的视网膜神经元和（或）神经胶质细胞的改变早于糖尿病视网膜微血管病变Ⅲ。近年来研究表明，促红细胞生成素（EPO）也是一种参与中枢神经损伤反应包括保护视网膜缺血的重要介质。     

糖尿病视网膜神经变性机制的研究进展

糖尿病视网膜病变(diabetic retinopathy,DR)一直被认为是微血管病变。然而,大量的研究已经证实,DR不仅会引起视网膜的血管病变,也会引起视网膜神经退行性改变。越来越多的证据也表明,在DR早期未发生视网膜血管病变之前就已经出现了视网膜神经变性,且视网膜神经变性可能参与了微血管异常的发生发展。目前,糖尿病视网膜神经变性的机制尚不十分明确,现就近年来糖尿病视网膜神经变性机制的研究进展做一综述。     

单核细胞趋化蛋白-1在糖尿病视网膜病变中的作用研究进展

糖尿病视网膜病变（DR）是糖尿病最为常见和严重的并发症之一,是成年人视力丧失的主要原因。越来越多的证据表明,炎症在DR的发病机制中发挥关键作用,抗炎治疗或许能有效延缓DR的发生和发展。单核细胞趋化蛋白-1 （MCP-1）作为炎症反应过程中一种重要的趋化因子,通过趋化和激活因子、破坏血视网膜屏障、引起视网膜血管病变、激活...     

炎症和糖尿病视网膜病变

糖尿病可引起视网膜代谢和生理的异常,但目前还不太清楚哪些异常可导致糖尿病性视网膜病变.现已发现,在糖尿病性视网膜病变的发生发展中,许多分子和生理的异常与炎症息息相关.此外,在动物模型中还发现,一些抗炎疗法能显著抑制其发生发展.现就糖尿病性视网膜病变早期和后期中的炎性介质及其关系做一综述,并探讨抗炎疗法在抑制糖尿病视网膜病变不同阶段的发展前景.     

小胶质细胞在糖尿病视网膜病变视网膜神经血管单元中的作用

糖尿病视网膜病变(DR)是工作年龄人群主要致盲眼病,血-视网膜屏障破坏是关键环节。近年研究显示,DR不再是单纯微血管病变,而是视网膜胶质细胞与神经退行性变、微血管病变的共同发展结果。DR病程早期视网膜神经血管单元(RNVU)中神经元的损伤可能早于血管内皮的变化,胶质细胞的激活加重血管屏障功能障碍。视网膜小胶质细胞是常驻视网膜的局部免疫细胞,参与长期高糖诱导的慢性炎症反应、高糖诱导其分泌多种炎症因子,破坏血-视网膜屏障结构、增加神经元凋亡、改变Müller细胞胶质化等,影响视网膜局部稳态平衡。RNVU作为一个单元结构研究,近年来受到越来越多的关注,本文将针对小胶质细胞在RNVU中的作用机制、研究进展进行综述。     

炎症在糖尿病视网膜病变发病机制中的作用

糖尿病视网膜病变（DR）是糖尿病常见的严重并发症,也是主要的致盲疾病之一,其发病机制尚不清楚。近年的研究发现早期糖尿病视网膜中白细胞粘附增加,并与DR微血管损伤在时间和空间上一致。同时细胞内粘附分子-1（ICAM-1）及其基因表达上调,抗ICAM-1抗体及CD18抗体可抑制糖尿病引起的白细胞粘附和血管内皮损伤。血管内皮生长因子（VEGF）和糖基化终产物（AGEs）可引起DR中的炎症改变。增加视网膜内VEGF及AGEs可明显增加白细胞粘附和血-视网膜屏障的破坏。非甾体类抗炎药物可能参与抑制糖尿病视网膜炎症。     

糖尿病视网膜病变神经血管损伤发病机制的研究进展

糖尿病视网膜病变(diabetic retinopathy,DR)曾被认为是糖尿病微血管病变的并发症,如今已被广泛认为是神经血管单元（neurovascular unit,NVU）损伤引起的一类神经血管性疾病。研究表明,在出现临床可检测的微血管病变之前,视网膜神经损伤已经出现,并参与了微血管病变的进展。因此,微血管病变这一观点并没有揭示视网膜神经元、神经胶质细胞和血管间相互联系及影响的重要性。以NVU作为整体研究神经血管损伤及保护机制,寻找临床新的预防和干预DR的措施必定成为未来研究的热点。     

炎性细胞因子在糖尿病视网膜病变发病中的作用

血管内皮生长因子、白介素-1、白介素-8、肿瘤坏死因子等炎性细胞因子在糖尿病视网膜病变(diabetic retinopathy,DR)的发生发展中起着重要作用,可诱导白细胞活化和迁移,导致毛细血管阻塞、视网膜缺氧及内皮细胞损伤,进而血-视网膜屏障破坏,视网膜出现水肿、出血、渗出和微动脉瘤形成。视网膜在持续的炎性反应和细胞因子刺激下,局部病理性新生血管增生,加重了DR进展。玻璃体和房水中的炎性因子与DR的进展有关。在免疫病理学上,炎症过程诱导了一系列复杂的分子和细胞信号传导,改变了患眼组织的生理反应,产生炎症表型。这些炎性生物标志物可评估炎症过程,可靠、易获得的炎性生物标志物将为开发新的DR生物标志物及其治疗提供有价值的信息。     

Inflammatory mediators in diabetic retinopathy: Deriving clinicopathological correlations for potential targeted therapy

The role of inflammation in diabetic retinopathy (DR) is well-established and dysregulation of a large number of inflammatory mediators is known. These include cytokines, chemokines, growth factors, mediators of proteogenesis, and pro-apoptotic molecules. This para-inflammation as a response is not directed to a particular pathogen or antigen but is rather directed toward the by-products of the diabetic milieu. The inflammatory mediators take part in cascades that result in cellular level responses like neurodegeneration, pericyte loss, leakage, capillary drop out, neovascularization, etc. There are multiple overlaps between the inflammatory pathways occurring within the diabetic retina due to a large number of mediators, their varied sources, and cross-interactions. This makes understanding the role of inflammation in clinical manifestations of DR difficult. Currently, mediator-based therapy for DR is being evaluated for interventions that target a specific step of the inflammatory cascade. We reviewed the role of inflammation in DR and derived a simplified clinicopathological correlation between the sources and stimuli of inflammation, the inflammatory mediators and pathways, and the clinical manifestations of DR. By doing so, we deliberate mediator-specific therapy for DR. The cross-interactions between inflammatory mediators and the molecular cycles influencing the inflammatory cascades are crucial challenges to such an approach. Future research should be directed to assess the feasibility of the pathology-based therapy for DR.     

Bone marrow-CNS connections: implications in the pathogenesis of diabetic retinopathy

Diabetic retinopathy is the fourth most common cause of blindness in adults. Current therapies, including anti-VEGF therapy, have partial efficacy in arresting the progression of proliferative diabetic retinopathy and diabetic macular edema. This review provides an overview of a novel, innovative approach to viewing diabetic retinopathy as the result of an inflammatory cycle that affects the bone marrow (BM) and the central and sympathetic nervous systems. Diabetes associated inflammation may be the result of BM neuropathy which skews haematopoiesis towards generation of increased inflammatory cells but also reduces production of endothelial progenitor cells responsible for maintaining healthy endothelial function and renewal. The resulting systemic inflammation further impacts the hypothalamus, promoting insulin resistance and diabetes, and initiates an inflammatory cascade that adversely impacts both macrovascular and microvascular complications, including diabetic retinopathy (DR). This review examines the idea of using anti-inflammatory agents that cross not only the blood-retinal barrier to enter the retina but also have the capability to target the central nervous system and cross the blood-brain barrier to reduce neuroinflammation. This neuroinflammation in key sympathetic centers serves to not only perpetuate BM pathology but promote insulin resistance which is characteristic of type 2 diabetic patients (T2D) but is also seen in T1D. A case series of morbidly obese T2D patients with retinopathy and neuropathy treated with minocycline, a well-tolerated antibiotic that crosses both the blood-retina and blood-brain barrier is presented. Our results indicates that minocycine shows promise for improving visual acuity, reducing pain from peripheral neuropathy, promoting weight loss and improving blood pressure control and we postulate that these observed beneficial effects are due to a reduction of chronic inflammation.     

Inflammation in diabetic retinopathy

Diabetes causes a number of metabolic and physiologic abnormalities in the retina, but which of these abnormalities contribute to recognized features of diabetic retinopathy (DR) is less clear. Many of the molecular and physiologic abnormalities that have been found to develop in the retina in diabetes are consistent with inflammation. Moreover, a number of anti-inflammatory therapies have been found to significantly inhibit development of different aspects of DR in animal models. Herein, we review the inflammatory mediators and their relationship to early and late DR, and discuss the potential of anti-inflammatory approaches to inhibit development of different stages of the retinopathy. We focus primarily on information derived from in vivo studies, supplementing with information from in vitro studies were important.     

Role of inflammatory cells in pathophysiology and management of diabetic retinopathy

Diabetic retinopathy (DR) is a sight-threatening complication of diabetes mellitus. Several inflammatory cells and proteins, including macrophages and microglia, cytokines, and vascular endothelial growth factors, are found to play a significant role in the development and progression of DR. Inflammatory cells play a significant role in the earliest changes seen in DR including the breakdown of the blood retinal barrier leading to leakage of blood into the retina. They also have an important role in the pathogenesis of more advanced stage of proliferative diabetic retinopathy, leading to neovascularization, vitreous hemorrhage, and tractional retinal detachment. In this review, we examine the function of numerous inflammatory cells involved in the pathogenesis, progression, and role as a potential therapeutic target in DR. Additionally, we explore the role of inflammation following treatment of DR.     

Prevention of hypertension abrogates early inflammatory events in the retina of diabetic hypertensive rats

Hypertension is an important risk factor associated with development and progression of diabetic retinopathy (DR). The mechanisms by which hypertension increases the risk for DR are poorly understood. As the inflammatory mechanisms play a pivotal role in the pathogenesis of DR, in the present study, we investigated the effects of diabetes, hypertension, and combination of diabetes and hypertension on early inflammatory phenomena in the retina, and the effects of blood pressure control on retinal inflammation. Four-week-old spontaneously hypertensive rats (SHR) and their normotensive counterpart Wistar Kyoto (WKY) rats were rendered diabetic by intravenous injection of streptozotocin. Diabetic SHR rats were randomized to receive no antihypertensive drug (Sd), an antihypertensive drug that acts on renin-angiotensin system (losartan, Sd+Los), or antihypertensive drug that do not affect renin-angiotensin system (triple therapy, Sd+Tri). After 20 days, rats were sacrificed and the retinas were collected. The number of immunohistochemically detected ED1/microglial positive cells and the expression of ICAM-1 in the retina were significantly higher in diabetic SHR than in control SHR (p=0.003). The NF-kappaB p65 levels were higher in SHR compared with WKY groups (p=0.001) and its increment in diabetic SHR was not significant. These abnormalities in diabetic SHR rats were completely prevented by both types of antihypertensive drugs. The concomitance of diabetes and hypertension leads to exuberant inflammatory response in the retina, and the prevention of hypertension abrogates these abnormalities. It is suggested that the inflammatory events may be involved in the mechanism by which hypertension exacerbates retinopathy in patients with diabetes.     

ICAM-1和VCAM-1在糖尿病视网膜病变中的作用

糖尿病会造成视网膜很多异常改变,其中包括细胞间粘附分子-1(intercellular adhesion molecule-1,ICAM-1)和血管细胞粘附分子-1(vascular cell adhesion molecule-1,VCAM-1)的上调,这显示了炎症反应在糖尿病视网膜病变(diabetic retinopathy,DR)发展中发挥了一些作用。本文针对粘附分子ICAM-1和VCAM-1在DR的血管内皮细胞的损伤及其在炎症反应中发挥的重要作用进行了简要分析。     

糖尿病视网膜病变中视网膜小胶质细胞活化及干预机制研究进展

糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病(diabetes mellitus,DM)最常见的并发症,其发病率随DM病程的延长而增高.DR是一种高发病率和高致盲率的疾病,对DR的发病机制研究一直是国内外的热点之一.但是DR的发病机制尚未完全阐明,近年来,越来越多的学者认为DR可能是一种慢性、低度炎性反应.小胶质细胞(microglia,MG)是视网膜中的单核巨噬细胞,具有抗原呈递功能,DR中MG被活化,释放大量炎症因子,参与DR的炎症反应.了解DR中MG的活化机制,可更好地为DR的预防和治疗开辟新的视角.因此,本文就DR中视网膜MG活化及干预机制进行综述.     

微炎症在视网膜变性类疾病中的作用及其研究进展

视网膜变性类疾病是一组以光感受器细胞凋亡、视网膜神经元进行性退化为特征的严重致盲性眼病。研究发现炎症在此类疾病中发挥重要作用。视网膜神经炎症可能是导致光感受器细胞凋亡、视网膜神经元变性的共同因素; 此外,炎症反应不仅局限在视网膜,前房、玻璃体甚至外周血也表现为微炎症状态。本文就视网膜变性类疾病相关微炎症反应的产生、表现以及与疾病转归的关系的研究进展做一综述。     

长链非编码RNA 母系表达基因3调控miR-34a对糖尿病视网膜病变Müller细胞活化及炎症因子分泌的影响

目的　探讨母系表达基因3（maternally expressed gene 3,MEG3）对糖尿病视网膜病变（DR）Müller细胞的活化及炎症因子分泌的影响及机制。方法　高脂饮食联合链脲佐菌素腹腔注射构建小鼠DR体内模型。高糖刺激人视网膜Müller细胞株MIO-M1构建DR体外模型。免疫荧光化学染色及Western blot检测小鼠视网膜及Müller细胞中胶质纤维酸性蛋白（GFAP）的表达。Western blot及酶联免疫吸附实验（ELISA）检测小鼠视网膜及细胞培养基上清中血管内皮生长因子（VEGF）蛋白的表达。ELISA检测小鼠视网膜及细胞培养基上清中IL-1β蛋白的表达。分别或同时向Müller细胞中转染pcDNA-MEG3及miR-34a mimic对其表达进行干预。qRT-PCR检测MEG3 mRNA及miR-34a表达。结果　与正常对照组小鼠比较,DR组小鼠视网膜中GFAP、VEGF及IL-1β蛋白表达均增多（均为P<0.05）,MEG3 mRNA表达降低(P<0.01)。与对照组比较,高糖组Müller细胞中MEG3 mRNA表达降低(P<0.01),而GFAP、VEGF及IL-1β蛋白表达均升高（均为P<0.05）。与高糖组比较,高糖+pcDNA-MEG3组中GFAP、VEGF及IL-1β蛋白表达均降低（均为P<0.05）。与正常对照组比较,DR组小鼠视网膜及高糖刺激的Müller细胞中miR-34a表达均升高(均为P<0.05)。与pcDNA组比较,pcDNA-MEG3组中miR-34a表达减少(P<0.01)。与pcDNA+NC mimic组比较,pcDNA+miR-34a mimic组中GFAP、VEGF及IL-1β蛋白表达均升高（均为P<0.05）,而pcDNA-MEG3+NC mimic组中GFAP、VEGF及IL-1β蛋白表达均减少（均为P<0.05）。与pcDNA-MEG3+miR-34a mimic组比较,GFAP、VEGF及IL-1β蛋白表达水平均升高（均为P<0.05）。结论　MEG3在DR小鼠视网膜及高糖刺激的Müller细胞中表达均降低,其可通过负向调控miR-34a抑制Müller细胞活化及炎症因子的分泌。过表达MEG3可能成为DR治疗的新靶点。     

浅谈在糖尿病性视网膜病变中调节血管内皮生长因子产生的信号通路

糖尿病性视网膜病变(DR)作为糖尿病(DM)在眼部最严重的微血管并发症,已成为全球工作年龄人群首位的致盲性眼病。血管内皮生长因子(VEGF)已被证实在DR新生血管的形成中起着重要作用,VEGF的表达增加可导致新生血管形成、血管内皮细胞通透性增加、促凋亡蛋白抑制作用减弱以及各种其它炎症介质的激活等病理改变的发生。因此,探索各种调节VEGF产生的信号通路有助于更深层次的了解这些病理改变发展的关系。本文中笔者就DR中各种调节VEGF产生的信号通路以及其与DR的相关性进行综述。