内皮抑素对眼部新生血管抑制的研究进展

眼部新生血管存在于多种常见的眼病的发展过程中,对视功能危害大,是致盲的主要原因之一。包括糖尿病视网膜病变,视网膜栓塞,早产儿视网膜病变,老年性黄斑变性等眼病。由于其发病机制尚未完全清楚,因此目前仍无确切有效的药物治疗方法。内皮抑素（Endostatin,ES）是1997年首先从小鼠血管内皮瘤EOMA细胞培养上清中发现的,是胶原xⅧ的蛋白降解产物,分子质量约为20KD,为胶原xⅧc端非胶原区（NCl）内的184个氨基酸片段。ES是目前发现的最强的血管生成抑制因子,可抑制VEGF,bFGF,EGF等刺激的血管内皮细胞的增殖和迁移,诱导其凋亡,进而抑制新生血管的形成。通过抑制眼部新生血管的实验研究表明,ES是当前抗新生血管疗法中最有潜力的一种新药。本文就内皮抑素的结构特点及其对眼部新生血管的治疗研究进展作一综述。     

内皮抑素与肿瘤治疗

内皮抑素(endostatin)是近年来发现的,天然产生的新血管生成抑制因子。它在体内由胶原ⅩⅧ经酶解产生,可以抑制新血管生成,在肿瘤动物模型中显示出显著的抑瘤活动。通过抑制肿瘤相关的新血管的形成来治疗肿瘤,是目前出现的新疗法,内皮抑素是这种疗法中很有前景的侯选药物之一。在美国已经开始了用内皮抑素治疗肿瘤的Ⅰ期临床试验,关于它的临床前基础实验也在广泛开展。本文综述了内皮抑素在肿瘤治疗中的应用基础研究 。     

内皮抑素与肿瘤治疗

内皮抑素（endostatin）是近年来发现的,天然产生的新血管生成抑制因子。它在体内由胶原ⅩⅧ经酶解产生,可以抑制新血管生成,在肿瘤动物模型中显 同显著的抑瘤活动。通过抑制肿瘤相关的新血管的形成来治疗肿瘤,是目前出现的新疗法,内皮抑素是这种疗法中很有前景的侯选药物之一。在美国已经开始了用内皮抑素治疗肿瘤的Ⅰ期临床试验,关于它的临床前基础实验也在广泛开展。本文综述了内皮抑素在肿瘤治疗中的应用基础研究。     

内皮抑素研究进展

新生血管的生成 (Angiogenesis)与多种生理过程相关 ,受多种促进和抑制因子的调节 ,细胞外基质蛋白经酶解产生的小片段中很多都参与了这一过程的调节。内皮抑素 (Endostatin)是 1997年首先从小鼠血管内皮瘤EOMA细胞培养上清中发现的 ,是细胞外基质蛋白胶原XVⅢα1链NC1结构域C末端 184个Aa的片段。可抑制bFGF和VEGF刺激的血管内皮细胞的增殖和迁移 ,抑制新生血管的形成 ,抑制肿瘤的形成和转移。由于其作用对象是血管内皮细胞 ,而不是转化的肿瘤细胞本身 ,长期反复治疗中不会引起耐药性。它在肿瘤治疗中的应用前景引起多方关注 ,相关研究广泛开展起来。本文综述了近几年在其生物功能、作用机理及应用等方面的研究进展     

肿瘤生长抑制因子—血管抑素和内皮抑素

血管生成是肿瘤生长转移过程中的一个关键环节,因此控制血管生成成为抑制肿瘤生长的重要途径之一。目前已发现了许多血管生成抑制因子,尤以血管抑素和内皮抑素最为引人瞩目。综述了两种肿瘤生长抑制因子的发现、分子结构、生物学活性等,尤其侧重于它们抗肿瘤作用的实验研究。血管抑素与内皮抑素的发现与研究为恶性肿瘤的治疗开辟了新的道路。     

中药促缺血心肌血管新生机制研究进展

中药在缺血性心脏病的治疗方面具有重要作用,能够缓解症状并改善预后,促血管新生可能是其发挥作用的机制之一。已证实通过促进血管新生,可使心肌梗死面积缩小,减少细胞坏死和凋亡,改善心功能等,但其机制尚需进一步明确。目前中医药在促进梗死心肌血管新生研究方面已经取得了一定的成果,研究发现,大量中药单体、方剂及中成药具有促进血管新生作用。随着对中药促血管新生研究的不断深入,其机制的研究亦愈趋广泛,已深入到细胞及分子水平:涉及骨髓干细胞,促进血管生长的因子及其受体(血管内皮细胞生长因子、碱性成纤维细胞生长因子、胰岛素样生长因子等),抑制血管生长的因子(血管抑素、内皮抑素)及Akt/NOS/NO等通路。本文就相关研究回顾中药对缺血心肌血管新生影响并对机制进行探讨。     

白介素-18与新生血管性眼病

新生血管形成引起的眼病是眼科常见病和疑难病,常导致视功能严重障碍,由于对其发病机制研究有限,长期以来临床处理非常棘手,预后颇差.随着基础医学科学的发展,对眼内新生血管的形成有了重大发现,特别对某些促新生血管因子的研究,随之对抑制新生血管形成的研究也有了一些发展.目前,认为抑制新生血管生长是治疗这类疾病的关键,并且已有多种疗法问世.研究发现,白介素-18对新生血管有较强的抑制作用.本文从白介素-18的结构、功能、抑制新生血管的机制及其与眼部新生血管性疾病的关系等方面做一综述.     

人重组内皮抑素辅助化疗对食管癌疗效分析

目的:评估人重组内皮抑素(endostar,ES)辅助化疗药物治疗食管癌的临床效果。方法:研究共入组128例食管癌患者,根据化疗方案将患者分为试验组与对照组,试验组患者(n=60)进行5个疗程ES联合化疗,每个化疗疗程持续3周,静脉注射ES 15mg/d。对照组患者(n=68)未使用ES化疗。化疗2个疗程后,手术切除肿瘤,分析肿瘤对化疗的反应。检测血管内皮生长因子(vascular endothelial growth factor,VEGF)和血小板-内皮细胞粘附分子(Platelet endothelial cell adhesion molecule-1,CD31)的表达。结果:同治疗前比较,化疗明显促进了食管癌肿瘤组织中的VEGF的表达和组织中血管的再生。两组相比,试验组患者的生存率明显提高,转移率明显降低,通过重组内皮抑素治疗显著抑制了化疗引起的VEGF的表达和微血管的生成。结论:联合重组内皮抑素化疗能够显著改善食管癌患者的临床结局。     

内皮抑素在新生血管形成相关疾病中的作用机制研究进展

新血管形成是许多生理、病理过程的关键步骤,受血管形成促进因子和抑制因子的调节。内皮抑素是最重要的血管形成抑制因子之一,可在体外抑制血管内皮细胞的增殖、迁移和血管化,在动物模型中抑制新血管形成,对新生血管形成相关疾病,特别是肿瘤有治疗作用。关于内皮抑素抑制新血管形成的分子机制尚无定论,已有线索表明,它可通过与VEGF、MMP-2、整合素以及VEGF受体KDR等相互作用,从而抑制内皮细胞增殖、迁移或通过多种途径促进内皮细胞凋亡。本就内皮抑素作用的分子机制,及其作用于新血管形成相关疾病的最新研究成果进行综述。     

内抑素在肿瘤生长和动脉粥样硬化斑块形成中的作用

内抑素是新发现的很强的血管生成抑制剂。它是ⅩⅧ胶原的C末端片断 ,包含 1 84个氨基酸。内抑素能够特异地抑制内皮细胞增殖和迁移并抑制新生血管生成。内抑素能够有效地抑制肿瘤的生长和转移 ,为肿瘤的治疗提供了新的希望。内抑素还能够延缓动脉粥样硬化的发展。     

骨髓间充质干细胞外泌体中miRNA在视网膜新生血管形成中的作用及机制

视网膜血管疾病如早产儿视网膜病变、糖尿病视网膜病变和视网膜静脉阻塞等以异常增生的视网膜新生血管为主要病理表现。骨髓间充质干细胞来源外泌体通过旁分泌作用传递生物活性分子介导细胞间的物质与信息交换。其中,miRNA等内容物在传递信息中起关键作用,可调控缺血缺氧环境下内皮细胞的增殖、管腔形成和新生血管的形成。并且能够通过血视网膜屏障而不引起免疫、炎症反应,在眼科疾病治疗中极具潜力。本文总结骨髓间充质干细胞衍生外泌体中miRNA在视网膜新生血管形成中的作用和可能的作用机制,以期为外泌体在眼科疾病诊治中的应用拓宽新思路。     

葛根素对糖尿病视网膜细胞凋亡作用的研究进展

糖尿病的发病率逐年上升,其并发症的严重性日趋明显,特别是糖尿病视网膜病变导致视力下降和丧失已经引起了广泛关注,所以研究糖尿病视网膜病变的发病机制及其防治是必要的。糖尿病视网膜病变是一种多种机制共同作用的复杂性疾病,而细胞凋亡在糖尿病视网膜病变的发生和发展中起着重要的作用,所以研究细胞凋亡对糖尿病视网膜病变的治疗有着重要意义。由于细胞凋亡研究的深入,人们将注意力集中于糖尿病视网膜细胞凋亡能否得到抑制和逆转的问题上。研究发现,糖尿病视网膜病变细胞凋亡可能与视网膜新生血管形成、VEGF水平增高等因素有关。当前对葛根素的研究表明,葛根素能有效抑制视网膜新生血管形成,并且对于缺血、缺氧等因素引起的损害有很强的改善作用,葛根素还可以降低糖尿病糖基化终产物水平,甚至对视网膜超微结构的损害具有一定的保护作用,所以葛根素可能是治疗糖尿病性视网膜病变的新策略。本文就近期糖尿病视网膜病变中细胞凋亡的有关研究和葛根素的抗细胞凋亡作用做一综述,提示在糖尿病视网膜病变中葛根素的不可忽视的作用。     

抗血管生成药物Endostatin作用下实体肿瘤血管网络血液灌注数值模拟

目的研究抗血管生成治疗肿瘤主要药物之一的血管生成抑制素ES（Endostatin）对肿瘤血液灌注的影响。方法在数值生成ES作删下肿瘤血管的基础上．设血液为不可压缩牛顿流体,用扩展的Poiseuille定律和Starling定律分别计算管内流量和跨壁流量,肿瘤内间质流动遵循Darcy定律,肿瘤微血管渗透率受Endostatin的影响,用差分法数值模拟在ES作用下肿瘤血管网络的血液灌注。结果在ES作用下,肿瘤微血管生成减少,间质压力下降,压力梯度增大。结论ES药物在减少肿瘤血管生成数量的同时,改变肿瘤血管渗透性,改善肿瘤血液动力学环境,有利于其他治疗肿瘤药物的输运。     

Effects of intraocular or systemic administration of neutralizing antibody against vascular endothelial growth factor on the murine experimental model of retinopathy

Vascular endothelial growth factor (VEGF), the strongest known angiogenic cytokine and also a potent enhancer of vascular permeability, is closely associated with diabetic ocular complications and other intraocular neovascular diseases. The therapeutic effect of VEGF-neutralizing antibody on oxygen-induced retinopathy in an experimental murine model of proliferative retinopathy was investigated. Intraocular and systemic injection of the antibody resulted in 46% and 18% reductions in the number of nuclei of newly formed vessels of this model, respectively. The results demonstrated that a neutralizing antibody against VEGF was highly effective in the treatment of intraocular neovascularization and suggested possible modes of therapy in human intraocular neovascular diseases, including diabetic proliferative retinopathy.     

Anti-Angiogenic Effects of a Mutant Endostatin: A New Prospect for Treating Retinal and Choroidal Neovascularization

Purpose

Pathological fundus angiogenesis is a major cause of vision loss in retina diseases. Endostatin, a C-terminal fragment of collagen XVIII, is an endogenous anti-angiogenic protein. The present study aimed to investigate the in vitro and in vivo anti-angiogenic properties of two proteins: an N-terminal H1D/H3D mutant endostatin (M-ES) and a polyethylene glycol propionaldehyde (PEG) covalent M-ES (PEG-M-ES).

Methods

M-ES and PEG-M-ES properties were characterized in vitro using a zinc ion binding assay and a stability test. Activity assays, including migration, proliferation, and tube formation assays, were performed with human retinal microvascular endothelial cells (HRMECs) and human umbilical vein endothelial cells (HUVECs). Mouse oxygen-induced retinopathy (OIR) and choroidal neovascularization (CNV) models were used to evaluate in vivo anti-angiogenic effects. In addition, a rabbit model was used to study the retinal pharmacokinetic profile following an intravitreal injection.

Results

The results indicated that the H1D/H3D mutations of endostatin reduced the zinc binding capacity of M-ES and facilitated PEG covalent binding. PEG-M-ES was more stable and persisted longer in the retina compared with M-ES. The in vitro studies demonstrated that M-ES and PEG-M-ES inhibited HRMEC and HUVEC proliferation, migration, and tube formation more efficiently than ES. In vivo, a single intravitreal injection of M-ES and PEG-M-ES significantly decreased neovascularization in both the OIR and CNV animal models.

Conclusion

The present study demonstrated for the first time that PEG-M-ES exhibits a long-term inhibitory effect on neovascularization in vitro and in vivo. These data suggest that PEG-M-ES may represent an innovative therapeutic strategy to prevent fundus neovascularization.     

Intraocular neovascularization.

An important character of the eye is transparency, so intraocular neovascularization, which is fragile and likely to result in hemorrhage, would cause a functional disorder of the eye and contribute to loss of vision associated with such diseases as retinopathy of prematurity, diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration. Recently interest in the mechanisms of intraocular neovascularization has increased, and the mechanisms have been gradually elucidated using several in vitro and in vivo angiogenesis models. Blood vessels in the eye are composed of, and surrounded by, various types of cells that produce multiple factors. Neovascularization is regulated by complex interactions among these angiogenic factors, angiostatic factors, and adhesion molecules, and some of these angiogenesis-related molecules have also been suggested as new targets for novel therapeutic agents of intraocular neo-vascularization. This review focuses on in vivo representative angiogenesis models of the corneal pocket model and the model of oxygen-induced retinopathy, and discusses the role of some angiogenesis-related factors and adhesion molecules in intraocular neovascularization.     

Characterization and secondary structure analysis of endostatin covalently modified by polyethylene glycol and low molecular weight heparin

Endostatin (ES), as an angiogenesis inhibitor, has been approved by the State Food and Drug Administration (SFDA) in China for the treatment of patients with non-small-cell lung cancer. However, as a protein drug, there are a lot of obstacles on its clinical application, such as need of high dose to maintain its efficacy, expensive and poor stability, etc and limits its clinical use. In order to overcome these shortcomings, we chemically modified ES by polyethylene glycol and low molecular weight heparin (LMWH), respectively. The changes of the secondary structure of the modified products were studied by Fourier transform infrared spectroscopy and Circular dichroism spectra to obtain better ES derivatives. Our study demonstrated that the modified products have a better heat tolerance than ES towards. The result of secondary structure analysis suggests the percentage of beta-turn in whole protein is an important factor on the activity and heat stability and ES modified by LMWH can maintain higher activity and its secondary structure.     

Detection of Neovascularization Based on Fractal and Texture Analysis with Interaction Effects in Diabetic Retinopathy

Diabetic retinopathy is a major cause of blindness. Proliferative diabetic retinopathy is a result of severe vascular complication and is visible as neovascularization of the retina. Automatic detection of such new vessels would be useful for the severity grading of diabetic retinopathy, and it is an important part of screening process to identify those who may require immediate treatment for their diabetic retinopathy. We proposed a novel new vessels detection method including statistical texture analysis (STA), high order spectrum analysis (HOS), fractal analysis (FA), and most importantly we have shown that by incorporating their associated interactions the accuracy of new vessels detection can be greatly improved. To assess its performance, the sensitivity, specificity and accuracy (AUC) are obtained. They are 96.3%, 99.1% and 98.5% (99.3%), respectively. It is found that the proposed method can improve the accuracy of new vessels detection significantly over previous methods. The algorithm can be automated and is valuable to detect relatively severe cases of diabetic retinopathy among diabetes patients.     

Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor

Although insulin-like growth factor 1 (IGF-1) has been associated with retinopathy, proof of a direct relationship has been lacking. Here we show that an IGF-1 receptor antagonist suppresses retinal neovascularization in vivo, and infer that interactions between IGF-1 and the IGF-1 receptor are necessary for induction of maximal neovascularization by vascular endothelial growth factor (VEGF). IGF-1 receptor regulation of VEGF action is mediated at least in part through control of VEGF activation of p44/42 mitogen-activated protein kinase, establishing a hierarchical relationship between IGF-1 and VEGF receptors. These findings establish an essential role for IGF-1 in angiogenesis and demonstrate a new target for control of retinopathy. They also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with insulin therapy, permitting VEGF-induced retinopathy.