In vitro and in vivo biological activity of PEDF against a range of tumors

Background: Pigment epithelium-derived factor (PEDF) is an emerging anti-cancer agent that targets both tumor tissue and its supporting vasculature. These direct and indirect effects of PEDF have been examined in vitro and in vivo for a range of malignancies. Objective: This review seeks to present PEDF as a potential anti-cancer agent with applications across multiple malignancies. We refer closely to experimental methodology whilst still highlighting the clinical significance of PEDF in cancer, drawing on biological findings in vitro and in vivo. Methods: A Pubmed database search was performed limiting the scope of this discussion paper mainly to PEDF's biological role in cancer, specifically lung, breast, prostatic, ovarian and pancreatic carcinomas, melanoma, glioma and osteosarcoma. Conclusions: The biological roles of PEDF are diverse and multidimensional. As an anti-cancer agent, PEDF has great potential as a focused anti-neoplastic therapy against a variety of tumor types.     

Pigment epithelium-derived factor inhibits TNF-alpha-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation

Pigment epithelium-derived factor (PEDF) has recently been shown to be involved in the pathogenesis of proliferative diabetic retinopathy. Atherosclerosis is an inflammatory-fibroproliferative disease as well. Oxidative stress plays a major role in retinopathy and atherosclerosis. Accordingly, we investigated effects of PEDF on reactive oxygen species (ROS) generation, NF-kappaB activation and interleukin (IL)-6 expression in TNF-alpha-exposed HUVEC. TNF-alpha significantly increased intracellular ROS generation, which was completely blocked by PEDF or diphenylene iodonium, an inhibitor of NADPH oxidase. Further, PEDF completely prevented the TNF-alpha-induced increase in NADPH oxidase activity. PEDF or an antioxidant, N-acetylcysteine, significantly inhibited the TNF-alpha-induced NF-kappaB activation. PEDF inhibited TNF-alpha-induced expression of IL-6 at both mRNA and protein levels. Moreover, TNF-alpha downregulated PEDF mRNA levels. Ligand blot analysis revealed that HUVEC possessed a membrane protein with binding affinity for PEDF. The results demonstrated that PEDF inhibited TNF-alpha-induced NF-kappaB activation and subsequent IL-6 overexpression in HUVEC by suppressing NADPH oxidase-mediated ROS generation. Our present study suggests that PEDF may play an important role in the development and progression of atherosclerosis.     

增殖性糖尿病视网膜病变患者玻璃体液中PEDF与TAOC的关系研究

目的探讨增殖性糖尿病视网膜病变(proliferative diabetic retinopathy,PDR)患者玻璃体液中色素上皮衍生因子(pigment epithelium-derived factor,PEDF)与总抗氧化能力(total anti-oxidant capacity,TAOC)的关系。方法选择行玻璃体切割术的增殖性糖尿病视网膜病变患者20例(20眼),其中PDR合并玻璃体出血组12眼,PDR无玻璃体出血组8眼。非糖尿病患者18例(18眼)作为对照组。采用ELISA方法测定玻璃体液中PEDF和TAOC的水平,并行统计学分析。结果与对照组比较,PDR患者玻璃体液中的TAOC明显降低(P<0.01)。玻璃体液中PEDF水平与TAOC呈正相关(r=0.35,P<0.05),和对照组呈正相关(r=0.39,P<0.05)。无玻璃体出血组PDR患者玻璃体液中PEDF水平与对照组和合并玻璃体出血组比较明显降低(P<0.05)。结论玻璃体液中PEDF水平与TAOC密切相关。PEDF可作为眼内源性抗氧化物并对PDR起到保护作用。     

GM-CSF在兔动脉粥硬化非梗死模型颅内血管生成中的作用及其机制的探讨

目的观察预防性给予"兔动脉粥硬化非梗死模型"GM-CSF治疗诱导颅内血管生成后,是否可以改善全脑血液循环状态,同时对其可能的调节机制进行初步探讨。方法 40只雄性新西兰大白兔随机分为对照组(ctr)、动脉粥样硬化组(AS)、生理盐水治疗组(NS)、GM-CSF治疗组(GM-CSF),每组10只,各组均进行右侧锁骨下动脉椎动脉开口近端结扎手术。先检测脑血管血液动力学指标(CVHI)的变化。再利用Western Blot检测缺血敏感区域脑组织血管内皮生长因子(VEGF)及色素上皮衍生生长因子(PEDF)蛋白的表达情况。结果 CVHI检测显示,GM-CSF组较AS组及NS组颈动脉Vmin有所增快(P0.01),同时,GM-CSF组的Wv和Rv值较AS及NS组显著降低(P0.01)。AS和NS组的缺血敏感区域脑组织PEDF、VEGF蛋白的表达较ctr组均有所增加(P0.01);GM-CSF组PEDF表达较AS及NS组明显被抑制(P0.01),而GM-CSF组VEGF蛋白的表达则高于其他3组(P0.05)。结论预防性皮下注射GM-CSF,可以促进兔动脉粥样硬化非梗死模型颅内血管生成及侧枝循环的建立,进而改善全脑血液循环状态。另外,本研究发现,GM-CSF可能干预了血管平衡系统中关键因子PEDF及VEGF的表达。这可能是GM-CSF诱导颅内血管生成的重要的机制之一。     

Localization of Pigment Epithelium-Derived Factor in Growing Mouse Bone

Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor found in a wide range of fetal and adult tissues, where it is thought to play a role in the regulation of angiogenesis during development. The temporal expression of PEDF during endochondral bone formation has not previously been reported. In this study, we analysed the expression pattern of PEDF in growing mouse hindlimbs from newborn day one through to maturation at week 9, using immunohistochemistry and in situ hybridization. PEDF expression was demonstrated in chondrocytes within the resting, proliferative and upper hypertrophic zones of the epiphyseal growth plate. The pattern of expression was consistent throughout the developmental stages of the mouse. In addition, PEDF was expressed by osteoblasts lining the bone spicules in the ossification zone of metaphyseal bone, as well as by osteoblasts lining cortical periosteum. These novel results demonstrate that PEDF is developmentally expressed in both cartilage and bone cells during endochondral bone formation, and strongly suggest that it may play a regulatory role in the processes of chondrocyte and osteoblast differentiation, endochondral ossification, and bone remodelling during growth and development of long bones.     

人恶性黑素瘤细胞株A375中色素上皮衍生因子基因的突变

目的 探讨色素上皮衍生因子（PEDF）基因在恶性黑素瘤细胞系中的突变情况。方法 采用聚合酶链反应--单链构象多态性分析（PCR-SSCP）对人恶性黑素瘤细胞株A375和正常人黑素细胞中PEDF基因的所有8个外显子进行突变检测。对SSCP分析有异常泳动条带样本的PCR产物进行DNA 测序。结果 人恶性黑素瘤细胞株A375的第3到第7外显子都出现DNA泳动变位,其中以外显子5,6最为明显。PEDF基因第5,6外显子均存在突变。第5外显子的突变类型以单个碱基的缺失为主,第6外显子的突变类型则以单个碱基的置换为主。结论 PEDF基因的突变可能在恶性黑素瘤的发病中起一定作用。     

Pigment epithelium‐derived factor (PEDF) and PEDF‐receptor in the adult mouse brain: Differential spatial/temporal localization pattern

Pigment epithelium‐derived factor (PEDF) is a multifunctional protein which was initially described in the retina, although it is also present in other tissues. It functions as an antioxidant agent promoting neuronal survival. Recently, a PEDF receptor has shown an elevated binding affinity for PEDF. There are no relevant data regarding the distribution of both proteins in the brain, therefore the main goal of this work was to investigate the spatiotemporal presence of PEDF and PEDFR in the adult mouse brain, and to determine the PEDF blood level in mouse and human. The localization of both proteins was analyzed by different experimental methods such as immunohistochemistry, western‐blotting, and also by enzyme‐linked immunosorbent assay. Differential expression was found in some telencephalic structures and positive signals for both proteins were detected in the cerebellum. The magnitude of the PEDFR labeling pattern was higher than PEDF and included some cortical and subventricular areas. Age‐dependent changes in intensity of both protein immunoreactions were found in the cortical and hippocampal areas with greater reactivity between 4 and 8 months of age, whilst others, like the subventricular zones, these differences were more evident for PEDFR. Although ubiquitous presence was not found in the brain for these two proteins, their relevant functions must not be underestimated. It has been described that PEDF plays an important role in neuroprotection and data provided in the present work represents the first extensive study to understand the relevance of these two proteins in specific brain areas.