色素上皮衍生因子与糖尿病肾病

色素上皮衍生因子(PEDF)是丝氨酸蛋白酶抑制剂超家族成员之一,其主要生物学作用是营养神经、神经元保护、抗氧化应激、抗炎性反应、抑制新生血管形成等.越来越多的研究显示,PEDF在糖尿病肾病中可发挥独特的保护作用,如减少肾小球细胞外基质生成、预防肾脏纤维化,并通过抑制肾脏炎性反应和氧化应激反应而抑制肾小球毛细血管内皮细胞增生、调节血管的渗透性,从而减少尿蛋白的生成.因此,PEDF有望成为糖尿病肾病的一个治疗靶点.     

色素上皮衍生因子与糖尿病肾病

色素上皮衍生因子(PEDF)是一种高效、天然的血管增生抑制剂,具有神经营养保护、调节血管通透性和高效抑制血管生成等作用.近年来有研究表明,PEDF的减少与糖尿病肾病(DN)有密切关系,PEDF可抑制转化生长因子-β1(TGF-β1)和结缔组织生长因子(CTGF)的表达,抑制细胞外基质(ECM)的聚积,提示其具有抗纤维化活性,同时可通过调节肾脏脉管系统发展和维持肾自身稳态来发挥对DN的保护作用.PEDF可抑制DN的发生、发展,可能成为DN治疗的一种新方向.     

色素上皮衍生因子与胰岛素抵抗及2型糖尿病的研究进展

色素上皮衍生因子(PEDF)首次从视网膜色素上皮细胞中被发现,其抑制新生血管生成、促进细胞凋亡生物特性在糖尿病微血管并发症中保护作用已得到肯定。近年发现,PEDF与IR、T2DM及其大血管病变关系密切,但机制尚未完全阐明。其在氧化应激中扮演的作用受到越来越多的重视,有望成为一个治疗糖尿病及并发症的靶点和疾病预测因子。     

色素上皮细胞衍生因子在氧诱导大鼠视网膜病变新生血管中的表达及意义

目的 观察氧诱导大鼠视网膜病变新生血管中色素上皮衍生因子（PEDF）的表达,并探讨其意义.方法 选择SD幼鼠120只,随机分为实验组90只、对照组30只.实验组按幼鼠处死时间不同分为12、17、24d三个亚组.实验组采用Smith等方法建立氧诱导视网膜病变（OIR）模型.利用SABC免疫组织化学法和RT-PCR法检测各组PEDF蛋白和mRNA表达.结果 对照组视网膜神经纤维层、神经节细胞层、内核层、感光细胞层及视网膜色素上皮细胞有PEDF蛋白阳性表达,呈黄色;与对照组相比,实验组各层PEDF蛋白表达逐渐减弱,由棕黄色变为淡黄色;新生血管生成后,PEDF蛋白表达增强,呈棕黄色.实验组各亚组PEDF蛋白和mRNA与对照组比较差异均有统计学意义（P均＜0.05）;实验组各亚组两两比较差异均有统计学意义（P均＜0.05）.结论 PEDF参与大鼠OIR新生血管的形成.     

不同分期糖尿病视网膜病变激光光凝效果分析

目的分析治疗不同分期糖尿病视网膜病变患者采用激光光凝的临床效果。方法选取该院2016年4月—2017年4月所收治的糖尿病视网膜疾病患者60例,通过糖尿病视网膜病变分级标准对该60例患者进行划分,其中增生性糖尿病性视网膜病变患者21例,重度非增生性糖尿病性视网膜病变患者19例,中度非增生性糖尿病性视网膜病变患者20例,按照糖尿病视网膜病变早期治疗标准,采用氪激光对中度患者进行全视网膜光凝,重度以及增生性糖尿病性视网膜病变患者采用标准全视网膜光凝,60例患者治疗后的最佳视力、眼底以及荧光眼底造影检查变化状态。对出现新生血管为消退的患者以及无灌注去残留的患者继续进行光凝治疗,根据标准时间以及荧光血管造影眼底检查结果进行评价,对患者视力以及视网膜病变情况进行对比。结果 60例患者其中增生性糖尿病性视网膜病变患者21例,重度非增生性糖尿病性视网膜病变患者19例,中度非增生性糖尿病性视网膜病变患者20例,不同分期糖尿病视网膜病变患者治疗后,增生性糖尿病视网膜病变患者治疗总有效率71.43%,中度非增生糖尿病视网膜病变患者治疗总有效率90.00%。重度非增生糖尿病视网膜病变患者治疗总有效率84.21%,总有效率为81.67%。结论不同分期糖尿病视网膜病变激光光凝治疗效果不同,根据患者实际情况选择有效的治疗方式,寻找适当的治疗时机,能够有效稳定糖尿病视网膜病变患者的视力以及改善患者眼底病变。     

新生血管动物模型的构建

新生血管是指从已有毛细血管发展形成新血管,该过程受血管生成因子和血管抑制因子双重调控,是一个动态平衡的过程。新生血管是多种疾病的病理性改变,包括肿瘤、早产儿视网膜病变和糖尿病视网膜病变等,是严重的致残性病变。建立新生血管动物模型是研究这些疾病发病机制的重要前提,本文主要对主动脉环血管生成模型、基质胶栓动物模型、氧诱导视网膜病变模型、激光诱导脉络膜新生血管动物模型4种建模方法进行了综述。     

血管生成素与糖尿病视网膜病变

血管生成素(Ang)家族是一类促血管生成因子,参与生理性及病理性的血管生成。糖尿病时,视网膜局部Ang表达发生变化。Ang-1可参与血管生成,维持血管稳定,抑制视网膜内皮细胞凋亡、炎症、渗出及白细胞黏附;Ang-2可促进血管出芽,导致周细胞丧失,增加血管通透性。Ang可能通过上述机制参与了糖尿病视网膜病变的发生、发展。     

糖尿病视网膜病变患病率及危险因素的研究

目的针对糖尿病视网膜病变在糖尿病患者中的患病率及危险因素进行初步探讨,为临床防治糖尿病视网膜病变提供重要参考依据。方法采取回顾性分析方法收集2014年9月—2015年9月期间收治的60例糖尿病视网膜病变患者有关资料,分析研究患者基本情况、既往病史、眼部及相关检查结果等,通过对糖尿病视网膜病变、糖尿病黄斑水肿及增生性糖尿病视网膜病变等眼科疾病发病率的比较,初步探讨了对产生糖尿病视网膜病变、病情发展产生影响的一些危险因素。结果在收集的患者中糖尿病视网膜病变患者有19例(占31.7%)、糖尿病黄斑水肿患者有5例(占8.3%)、增生性糖尿病视网膜病变患者有4例(占6.7%)。糖尿病病程、胆固醇、收缩压、肌酐、尿素氮、24 h尿蛋白量及其浓度、应用胰岛素等因素与产生糖尿病视网膜病变及其病情发展具有一定关系,糖尿病病程、周围神经病变、24 h尿蛋白量是产生糖尿病视网膜病变及其病情发展的独立危险因素。结论通过分析糖尿病视网膜病变在糖尿病患者中的患病率及危险因素,对于提高预防糖尿病视网膜病变具有一定的参考价值。     

糖尿病视网膜病变的筛查与治疗——2015年ADA诊疗指南解读

<正>糖尿病视网膜病变(DR)是糖尿病高度特异性微血管并发症,是导致成年人群失明的主要原因。在2型糖尿病成年患者中,大约有20%~40%出现视网膜病变,8%有严重视力丧失。2型糖尿病患者也是发生其他眼部疾病的高危人群,这些眼病包括白内障、青光眼、视网膜血管阻塞及缺血性视神经病变等。已有共识,糖尿病视网膜病变的主要危险因素包括     

miRNA-200b对糖尿病视网膜病变大鼠内皮细胞生长因子介导的相关改变的影响

糖尿病视网膜病变的最主要发病机制是过度表达的血管内皮生长因子引起新生血管增多及血管通透性增加。本研究着眼于miRNA-200b及其下游靶因子血管内皮生长因子，探讨miRNA改变在糖尿病视网膜病变发病中的作用。     

Pigment epithelium-derived factor inhibits leptin-induced angiogenesis by suppressing vascular endothelial growth factor gene expression through anti-oxidative properties

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. Recently, leptin was found to be an angiogenic factor, and its vitreous levels are associated with angiogenic eye diseases such as proliferative diabetic retinopathy. However, the molecular mechanism for leptin-elicited angiogenesis remains to be elucidated. Pigment epithelium-derived factor (PEDF) has been shown to be the most potent natural inhibitor of angiogenesis in the mammalian eye, and its levels in the vitreous were decreased in angiogenic eye diseases. In this study, we investigated whether and how PEDF could inhibit the leptin-induced DNA synthesis in microvascular endothelial cells (EC), a key step of angiogenesis. Leptin significantly increased intracellular reactive oxygen species (ROS) generation in microvascular EC. PEDF was found to inhibit the leptin-induced ROS generation in EC. An anti-oxidant, N-acetylcysteine, or PEDF completely prevented the leptin-induced upregulation of vascular endothelial growth factor (VEGF) mRNA levels as well as any increase in DNA synthesis in microvascular EC. Polyclonal antibodies against human VEGF were also found to completely inhibit DNA synthesis in leptin-exposed EC. The present study suggests that leptin could elicit angiogenesis through autocrine VEGF production via intracellular ROS generation. PEDF may block the angiogenic effects of leptin through its anti-oxidative properties.     

Antiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma

Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous antiangiogenic reagents discovered to date. Its antiangiogenic potential in neoplastic disease remains unclear. In this study, we investigated antiangiogenic property of PEDF in hepatocellular carcinoma (HCC), a typical hypervascular tumor. In HCC cell lines, constitutive messenger RNA and protein expression of PEDF varied. Genomic DNA encoding the PEDF gene was the same in the cell lines examined by Southern blotting. In chemically induced hypoxic conditions, secreted PEDF protein was suppressed in contrast to elevation of vascular endothelial growth factor protein. When PEDF was overexpressed by gene transfer, proliferation and migration of endothelial cells were inhibited in conditioned media derived from all HCC cell lines. However, the serum concentration of PEDF, as measured by enzyme-linked immunosorbent assay, was decreased in patients with cirrhosis or HCC complicated by cirrhosis compared to healthy volunteers and patients with chronic hepatitis. According to the endothelial cell proliferation assay, the serum PEDF of patients with HCC had antiangiogenic activity. Moreover, intratumoral injection of a PEDF-expressing plasmid in athymic mouse models caused significant inhibition of preestablished tumor growth. In conclusion, PEDF plays a role in the angiogenic properties of HCC. Reduction of serum PEDF concentration associated with the development of chronic liver diseases may contribute to the progression of HCC. In addition, gene therapy using PEDF may provide an efficient treatment for HCC.     

Adeno-associated virus type-2 expression of pigmented epithelium-derived factor or Kringles 1-3 of angiostatin reduce retinal neovascularization

Neovascular diseases of the retina include age-related macular degeneration and diabetic retinopathy, and together they comprise the leading causes of adult-onset blindness in developed countries. Current surgical, pharmaceutical, and laser therapies for age-related macular degeneration (AMD) rarely result in improved vision, do not significantly prevent neovascularization (NV), and often result in at least some vision loss. To address this therapeutic gap, we determined the efficacy of recombinant adeno-associated viral (rAAV) serotype-2-mediated expression of pigment epithelium-derived factor (PEDF) or Kringle domains 1-3 of angiostatin (K1K3) in reducing aberrant vessel formation in a mouse model of ischemia-induced retinal NV. Both PEDF and K1K3 are potent inhibitors of NV when injected directly, hence expression of these therapeutic factors from rAAV may provide long-term protection from neovascular eye disease. rAAV vectors expressing the therapeutic gene were injected into one eye of postnatal day 0 (P0) newborn mouse pups. Retinal NV was induced in P7 mice by exposure to elevated oxygen for 5 days followed by room air for another five days. Retinal NV was quantified by the number of vascular-endothelial-cell nuclei above the inner-limiting membrane in P17 eyes. The number of such vascular endothelial cell nuclei in eyes treated with rAAV-PEDF or rAAV-K1K3 was significantly reduced (both P < 0.0000002) compared with control eyes. Ocular protein levels detected by ELISA correlate well with the reduction in NV and confirm that expression of antineovascular agents from rAAV vectors may be a therapeutically useful treatment of retinal or choroidal neovascular disease.     

Down-regulation of angiogenic inhibitors: a potential pathogenic mechanism for diabetic complications

Diabetic retinopathy (DR) and diabetic nephropathy (DN) are the most common microvascular complications of diabetes. DR is a leading cause of blindness, and DN is a major cause of end-stage renal diseases. Diabetic macular edema (DME) resulting from increased vascular permeability in the retina and retinal neovascularization (NV) represent two major pathological changes in DR and are the primary causes of vision loss in diabetic patients. Previous studies have shown that angiogenic factors such as vascular endothelial growth factor (VEGF) play a key role in the development of DME and retinal NV. Studies in recent years have demonstrated that a number of endogenous angiogenic inhibitors are present in the normal retina and counter act the effect of VEGF in the regulation of angiogenesis and vascular permeability. Decreased levels of angiogenic inhibitors in the vitreous and retina have been found in diabetic patients and diabetic animal models. The decreased levels of angiogenic inhibitors shift the balance between angiogenic factors and angiogenic inhibitors and consequently, lead to the development of DME and retinal NV. Recently, we have found that these angiogenic inhibitors are expressed at high levels in the normal kidney and are down-regulated in diabetes. Moreover, these inhibitors inhibit the activity of VEGF and TGF-beta, two major pathogenic factors of DN. Therefore, decreased levels of these angiogenic inhibitors in diabetes may be associated with pathologies of DN. This review will summarize recent progress in these fields and therapeutic approaches to use angiogenic inhibitors for the treatment of diabetic complications.     

Pigment epithelium-derived factor (PEDF) prevents diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis

Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. Leukocyte adhesion to retinal capillary endothelium (leukostasis) is a critical event in early diabetic retinopathy, whose process is mainly mediated by intercellular adhesion molecule-1 (ICAM-1). We investigated here whether PEDF could prevent diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis by suppressing ICAM-1 expression. Immunohistochemistry of 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, showed intense staining in the nuclei of cells in the inner and outer plexiform layers of streptozotocin-induced diabetic rat retinas. Administration of PEDF or pyridoxal phosphate, an AGE inhibitor, decreased retinal levels of 8-OHdG and subsequently suppressed ICAM-1 gene expression and retinal leukostasis in diabetic rats. Further, intravenous administration of AGE to normal rats increased ICAM-1 gene expression and retinal leukostasis, which were blocked by PEDF. PEDF also inhibited the AGE-induced T cell adhesion to microvascular endothelial cells by suppressing ICAM-1 expression. These results demonstrated that PEDF inhibited diabetes- or AGE-elicited retinal leukostasis by suppressing ICAM-1. Our present study suggests that PEDF may play a protective role against early diabetic retinopathy by attenuating the deleterious effect of AGE.     

眼底荧光血管造影对早期诊断糖尿病性视网膜病变的意义

目的研究眼底荧光血管造影(FFA)对糖尿病性视网膜病变(DR)早期诊断的临床价值。方法选取2017年2月-2019年2月该院完成FFA检查的T2DM患者87例(174眼)临床资料进行回顾性研究,分析FFA图像特征并以临床诊断结果为金标准,探讨其诊断和分期准确性。结果 174眼中FFA检查诊断为DR者135眼(77.59%),其中非增生性DR 38眼(28.15%),增生前DR 41眼(30.37%),增生性DR 35眼(25.93%),糖尿病性黄斑病为16眼(11.85%),糖尿病性视神经乳头病变5眼(3.70%);与临床诊断结果相比,FFA检查诊断灵敏度为94.20%,特异度为86.11%,阳性预测值为96.30%,阴性预测值为79.49%,准确率为92.53%,一致性Kappa值为0.779;FFA检查和临床诊断对DR分期结果差异无统计学意义(P>0.05)。结论 FFA用于DR早期诊断不仅准确率较高,同时还有助于病情严重程度判断,为治疗方案选择提供参考信息。     

Vitreous biomarkers in diabetic retinopathy: A systematic review and meta-analysis

The aim of this study was to perform a systematic meta-analysis of biomarkers investigated with diabetic retinopathy (DR) in the vitreous, and to explore the molecular pathway interactions of these markers found to be consistently associated with DR. Relevant databases [PubMed and ISI web of science] were searched for all published articles investigating molecular biomarkers of the vitreous associated with DR. Based on set exclusion/inclusion criteria available data from studies with human vitreous samples were extracted and used for our meta-analysis. The interactions of significant biomarkers in DR were investigated via STRING and KEGG pathway analysis. Our meta-analysis of DR identifies eleven biomarkers as potential therapeutic candidates alternate to current anti-VEGF therapy. Four of these are deemed viable therapeutic targets for PDR; ET receptors (ET A and ET B), anti-PDGF-BB, blocking TGF-β using cell therapy and PEDF. The identification of supplementary or synergistic therapeutic candidates to anti VEGF in the treatment of DR may aid in the development of future treatment trials.     

Evaluation of protein pigment epithelium-derived factor (PEDF) and microvessel density (MVD) as prognostic indicators in breast cancer

Purpose  

Angiogenesis, which plays an important role in tumor growth and metastasis, is regulated by a balance between angiogenic stimulators and inhibitors. Pigment epithelium-derived factor (PEDF), a secreted glycoprotein is an important inhibitor of angiogenesis. Although the precise mechanisms by which PEDF exerts its actions remain poorly understood, there is growing evidence supporting the role of PEDF as a candidate antitumor agent. In this study, we investigated the role of PEDF in breast cancer.