Current Molecular Medicine - Volume 10, Issue 3, 2010

Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. It was first purified from the conditioned media of human retinal pigment epithelial cells as a factor with potent neuronal differentiating activity. Recently, PEDF has been shown to be a highly effective inhibitor of angiogenesis in cell culture and animal models. Further, we, along with others, have found that PEDF is a multifunctional secreted protein; it possesses complex neuroprotective, anti-oxidative, anti-inflammatory, antithrombogenic, insulin-sensitizing properties, any of which could potentially be exploited as a therapeutic option for the treatment of a variety of disorders, including neurodegenerative disorder, angiogenic eye disease, neoplasms, hyperpermeable renal-retinal disorder, cardiometabolic disease, diabetes and its vascular complications and various bone diseases. However, as far as we know, there are few comprehensive reviews to summarize the pathophysiological role of PEDF in health and disease. I believe that this issue is helpful for most of the researchers in the field of biochemistry, molecular biology, tumor cell biology, vascular cell biology, endocrinology and cardiology who would like to understand the role of PEDF and its clinical implications in various devastating disorders. In this issue, I would like to reinforce the emerging knowledge regarding PEDF as a novel biomarker and therapeutic target in vivo.

Neuronal degeneration is closely associated with cognitive, motor and visual dysfunctions. Neuroprotective strategies have been investigated with the view to being employed as potential therapy for patients with these disabilities. Pigment epithelium-derived factor (PEDF) is a 50-kDa secreted glycoprotein and a non-inhibitory member of the serine protease inhibitor (SERPIN) gene family. PEDF is detected in a broad range of human tissues, including almost all brain areas, and has been shown to have strong neuroprotective properties for various types of neurons including cerebellar granule neurons, hippocampal neurons, striatal neurons, retinal neurons and spinal cord motor neurons. These observations raise the possibility that application of PEDF may be helpful in designing new therapeutic strategies for neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease and brain ischemia.

Most diseases that cause blindness do so as a result of neovascularization. Angiogenesis is a complex process regulated in adult tissues by a large interacting network of molecules. In pathological conditions the checks and balances of the angiogenesis system go awry and endothelial cells of the microvasculature, proliferate, migrate, and form new but leaky vessels that invade the tissue. Hemorrhaging vessels cause edema and damage to surrounding tissues, particularly the retina. Microvascular lesions often cause severe retinal detachment and loss of vision. In this review, the value of an important endogenous anti angiogenic molecule, PEDF, is discussed in relationship to its ability to prevent retinal cell death and counter the abnormal vessel growth induced by VEGF in the eye. Its control of a neuroprotective and an antineovascular regulatory axis that determines cell fate, and its possible use in combination therapeutic strategies for ocular neovascular diseases are also reviewed.

The vascular system has an important function of supplying tissues with oxygen and nutrients and clearing waste products. Therefore, the microvasculature must be sufficiently permeable to allow the free, bidirectional passage of small molecules and gases and, to a lesser extent, of plasma proteins. It is well recognized that vascular endothelial growth factor (VEGF) can increase vascular permeability, thus playing important roles in variety of disorders, including diabetic retinopathy, nephrotic syndrome, brain edema, acute respiratory distress syndrome, and sepsis-associated hypotension. However, how vascular permeability is controlled by anti-permeable factors is not fully understood. We have recently found that pigment epithelium-derived factor (PEDF), a 50kD glycoprotein, inhibits retinal, renal and brain hyperpermeability by counteracting the biological actions of VEGF. In this review, we discuss about the pathophysiological role of PEDF in vascular permeability, especially focusing on retinal- renal disorders.

Cardiovascular disease (CVD) such as myocardial infarction and stroke is a leading cause of death in developed countries. Atherothrombosis, characterized by atherosclerotic lesion disruption with superimposed thrombus formation, is thought to be the major cause of CVD. Although remarkable therapeutic advances in the treatment of atherothrombosis have been made with anti-platelet and anti-thrombotic therapy, these therapeutic options may be limited by considerable side effects. In addition, they may not protect the endothelium and thus could not stabilize culprit lesions. Therefore, to develop a novel therapeutic strategy is needed for the prevention of atherothrombosis in high-risk patients. Recently, we, along with others, have shown that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, exerts anti-oxidative and anti-inflammatory anti-thrombogenic and vasculoprotective properties in various cell types. In addition, PEDF not only suppresses neointimal hyperplasia after balloon angioplasty, but also blocks occlusive thrombus formation in a rat arterial thrombosis model. These observations suggest that substitution of PEDF may be a novel therapeutic strategy for atherothrombosis. This article summarizes the pathophysiological role of PEDF in atherothrombosis and its potential therapeutic implication in CVD. We also discuss here the kinetics and regulation of PEDF in high-risk patients for atherothrombosis.

Pigment epithelium-derived factor (PEDF), one of the non-inhibitory serpines, is widely expressed throughout the body. Although PEDF was initially identified as a neuronal differentiation factor, more attention has been paid to its anti-angiogenic activity. Additionally, recent researches have demonstrated that PEDF has an anti-tumor effect against several human neoplasms. This review focuses on the pathological role of PEDF in tumors, especially tumor growth and metastasis. PEDF is an endogenous anti-tumor factor and its clinical application seems quite promising, although there is much to be further investigated.

First discovered in 1991 as a factor secreted by retinal pigment epithelial cells, the potency of pigment epithelium derived factor (PEDF) as an anti-angiogenic has led to examination of its role in active bone growth, repair and remodelling. In the musculoskeletal system, PEDF expression occurs particularly at sites of active bone formation. Expression has been noted in osteoblasts and to a lesser degree osteoclasts, the major classes of bone cells. In fact, PEDF is capable of inducing differentiation of precursor cells into mature osteoblasts. Expression and localisation are closely linked with that of vascular endothelial growth factor (VEGF). Studies at the epiphyseal plate have revealed that PEDF expression plays a key role in endochondral ossification, and beyond this may account for the epiphyseal plate's innate ability to resist neoplastic cell invasion. Collagen-1, the major protein in bone, is avidly bound by PEDF, implicating an important role played by this protein on PEDF function, possibly through MMP-2 and -9 activity. Surprisingly, the role of PEDF has not been evaluated more widely in bone disorders, so the challenge ahead lies in a more diverse evaluation of PEDF in various osteologic pathologies including osteoarthritis and fracture healing.

Pigment epithelial-derived factor (PEDF) is a 50-kDa secreted glycoprotein that belongs to the non-inhibitory serpin. It has an α/β core serine-protease inhibitor domain, 3 major β-sheets, and 10 α-helices. Although PEDF does not inhibit either serine or cysteine proteinases, PEDF exerts diverse physiological activities including anti-angiogenesis, anti-vasopermeability, anti-tumor, and neurotrophic activities. Recent studies have shown that a variety of peptides derived from PEDF possess activities similar to those of the parent molecule through interactions with the extracellular matrix, binding to PEDF receptors, nuclear localization and phosphorylation. Thus, peptides derived from PEDF have therapeutic potential for various diseases and therefore, it is important to clarify the structure-function relationship of PEDF. In this review, we summarize structural features of PEDF that could affect various target organs such as blood vessels, tumors, and the central nervous system. In addition, since PEDF is recently identified as a regulator for glucose and lipid metabolism, we also discuss PEDF structures specially related to insulin-sensitizing and triglyceride-reducing properties.

Septic shock is one of the leading causes of morbidity and mortality. Endotoxin plays an important role in the pathogenesis of septic shock. Lack of clinical success with anti-endotoxin or anti-cytokine therapies has shifted interest to extracorporeal therapies to reduce circulating levels of various mediators for septic shock patients. Polymyxin B -immobilized polystyrene fiber (PMX-F) is a medical device that aims to remove circulating endotoxin by adsorption. Since 1994, PMX-F column has been available in Japan, and many investigators have reported that PMX-F treatment is safe and effective in patients with septic shock. Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. PEDF induces macrophages apoptosis and necrosis through the activation of peroxisome proliferator-activated receptor-gamma by which PEDF could modulate inflammatory reactions in septic shock. Further, given the fact that PEDF possesses anti-oxidative and anti-inflammatory properties in vivo, serum PEDF level may be a biomarker of septic shock. However, little is known about the relationship between serum level of PEDF and inflammatory biomarkers such as endotoxin and high mobility group box 1 (HMGB1) in septic shock and the effects of PMX-F treatment on these markers. This review aims to provide current knowledge about the pathogenesis of septic shock and the clinical utility of PMX-F treatment. We also discuss here the pathophysiological role of PEDF in this devastating disorder.

Pigment epithelium-derived factor (PEDF) is reported to play a protective role against diabetic vascular complications through its anti-oxidative properties. However, since a commercially available kit is not suitable for measurement of serum PEDF in humans, kinetics and regulation of serum PEDF are not known in these devastating disorders. Therefore, we developed a simple, specific and reliable method for measurement of serum PEDF in humans using a competitive enzyme-linked immunosorbent assay (ELISA) system. Assay linearity was shown intact with 50∼300-fold dilution of urea-pretreated serum by phosphate-buffered saline. The recovery ratio of added recombinant human PEDF in serum was 94.2 ± 1.7 %. Inter- and intra-assay coefficient of variations of the ELISA were 4.7 and 7.3 %, respectively. When we measured serum PEDF levels in a general population, PEDF levels were elevated in proportion to the accumulation of the number of the components of the metabolic syndrome. Further, the percent changes in serum levels of PEDF during 1-year observational periods were positively correlated with those of body mass index (BMI) in patients with type 2 diabetes. In addition, PEDF mRNA levels in cultured adipocytes were increased in parallel to the BMI values of subjects from which adipocytes were derived, especially in omental adipocytes. These observations suggest that PEDF is generated from adipose tissues and could be increased as a counter-system against vascular cell damage in humans. PEDF may be one of the useful biomarkers for vascular injury in high-risk patients.

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. DNA damage in response to genotoxic and oncogenic stresses activate the tumor suppressor pathways initiating DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence. On the other hand, DDR reasons in adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disrupt the existing cellular homeostasis. Significant metabolic changes occurred by the influence of the major tumor suppressor protein p53 and other related factors such as FOXO, AMPK, PARP, NF-κB and PGC-1 are discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that “metabolic syndrome” is a real disease.

The impact of selected antibiotics on combating malaria infections was discovered in the mid of last century. Only recently, studies on their modes of action in malaria parasites have been initiated, prompted by the discovery of a prokaryotic organelle, the apicoplast. This plastid-derived structure, which originates from a secondary endosymbiotic event, possesses important metabolic as well as housekeeping functions, including fatty acid and heme biosynthesis. Due to its indispensability for parasite survival it represents a promising target for the use of antibiotics in malaria therapy. Most antibiotics cause a delayed death phenotype, which manifests in the late onset of antimalarial activity during the second replication cycle of the pathogen. This review will describe the effect of classical antibacterial agents against malaria parasites and the use of some of these compounds in clinical settings. Firstly we discuss the current knowledge about the physiological and morphological effects of antibiotics on the parasite and the apicoplast in particular, with special focus on the delayed death effect. Secondly antimalarial antibiotics are specified and their effects in vitro are compared with available in vivo data and clinical studies. Major precautions and side effects are described.