Pigment Epithelium-derived Factor Levels Research Articles

The Dual Role of PEDF in the Pathogenesis of OHSS: Negating Both Angiogenic and Inflammatory Pathways.

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproductive technologies. This complex syndrome is known to involve massive angiogenesis and inflammation. We have previously established the anti-angiogenic involvement of pigment epithelium-derived factor (PEDF) in the pathophysiology and treatment of OHSS. Evaluate the anti-inflammatory role of PEDF in OHSS. In vivo mouse OHSS model and in vitro cultures of granulosa cells. Changes in the expression of PEDF, IL-6, IL-8, and vascular endothelial growth factor (VEGF) were measured by quantitative PCR and ELISA; OHSS symptoms were recorded (body and ovarian weight gain and peritoneal vascular leakage quantified by the modified Miles's assay). Rat granulosa cell-line stimulated with lysophosphatidic acid (LPA), exhibited a significant increase in IL-6 expression, concomitantly with a decrease in PEDF level (P < .01). Co-stimulation with recombinant PEDF (rPEDF) decreased the expression of IL-6 significantly (P < .05). Furthermore, the expression of IL-6 and IL-8 increased in LPA-stimulated human primary granulosa cells (P < .01). Co-stimulation with rPEDF decreased the expression of LPA-induced IL-6 and IL-8 mRNA and protein by 4- and 2- to 5-fold, respectively. IL-8-stimulated human primary granulosa cells exhibited increased expression of VEGF mRNA; co-stimulation with hCG induced a significantly higher increase in the expression of VEGF mRNA (P < .001), which was counteracted by rPEDF. Subcutaneous injection of 0.5 mg/kg rPEDF to OHSS-induced mice reduced the increased expression of IL-6 in the ovary (P < .01) and alleviated the severity of all OHSS parameters. Our findings provide a framework that correlates down-regulation of OHSS symptoms caused by PEDF with both angiogenic and inflammatory pathways.

Downregulation of pigment epithelium-derived factor is associated with increased epithelial-mesenchymal transition in bladder cancer.

Pigment epithelium-derived factor (PEDF) has been reported to inhibit angiogenesis in bladder cancer, but whether it modulates epithelial-mesenchymal transition (EMT) remains unknown. We have included 68 samples of non-muscle invasive bladder cancer in this study. Immunohistochemistry was performed in all sample sections for expressions of PEDF, SNAI2, Vimentin and E-cadherin, which were quantified and The EMT Index (EMTi) was calculated by Vimentin/E-cadherin. Levels of expression were studied for correlations with clinicopathological parameters. Patients were grouped with high (EMTi≤1) and low (EMTi>1) EMT level for comparisons of clinicopathological parameters. In the univariate analysis, EMT level was shown to be significantly associated with tumor onset and PEDF level, but not with gender, occurrence, stage, grade, or SNAI2 level. Further multivariate analysis revealed that PEDF level was significantly negatively correlated with EMTi independent of other clinicopathological parameters. Our results indicate that PEDF may serve as a promising novel modality for the treatment of bladder cancer, as it can inhibit not only angiogenesis but also EMT process of bladder cancer.

Нейротрофический фактор пигментного эпителия в стекловидном теле у больных пролиферативной диабетической ретинопатией

Нейротрофический фактор пигментного эпителия в стекловидном теле у больных пролиферативной диабетической ретинопатией

Association of the anti-angiogenic factor secreted protein and rich in cysteine (SPARC) with vascular complications among Chinese type 2 diabetic patients in Singapore

This study evaluated the association of the anti-angiogenic SPARC with known angiogenesis-associated factors and diabetes-related micro- and macro-vascular complications in a Singapore Chinese cohort with type 2 diabetes (T2DM). Plasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years). Higher SPARC levels in subjects stratified by SPARC tertiles displayed decreased pro-angiogenic adiponectin, osteopontin, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinase (MMP)-2 concentrations (all p<0.05). The anti-angiogenic pigment epithelium-derived factor (PEDF) level was not statistically different among the SPARC tertiles. Age-adjusted partial correlation revealed significant associations of SPARC with adiponectin, osteopontin, VCAM-1, MMP-2, and PEDF (all p<0.05). Lower SPARC was accompanied by less favorable estimated glomerular filtration rate (eGFR) and carotid-femoral pulse wave velocity (PWV) readings (all p<0.05). Conversely, ankle-brachial index (ABI) reduced with increasing SPARC (p=0.048). The eGFR (B=0.834, p=0.019), PWV (B=-7.925, p=0.009), and ABI (B=-142.160, p=0.010) remained as determinants of SPARC after confounder adjustment. Moreover, individuals in the lowest SPARC tertile had increased odds of aortic stiffness (OR=1.900, 95% CI=1.103-3.274) but reduced odds of peripheral arterial disease (OR=0.400, 95% CI=0.175-0.919). However, SPARC was not independently associated with chronic kidney disease. The anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications.

Pigment epithelial-derived factor gene loaded novel COOH-PEG-PLGA-COOH nanoparticles promoted tumor suppression by systemic administration.

Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D-NPs) were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W) solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%), probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide) terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on proliferation of human umbilical vein endothelial cells in vitro and inhibited the tumor-induced angiogenesis in vivo by an alginate-encapsulated tumor cell assay. Further in vivo antitumor investigation, carried out in a C26 subcutaneous tumor model by intravenous injection, demonstrated that D-NPs could achieve a significant antitumor activity with sharply reduced microvessel density and significantly promoted tumor cell apoptosis. Additionally, the in vitro hemolysis analysis and in vivo serological and biochemical analysis revealed that D-NPs had no obvious toxicity. All the data indicated that the novel CPPC nanoparticles were ideal vectors for the systemic delivery of PEDF gene and might be widely used as systemic gene vectors.

The changes of aqueous humor vascular endothelial growth factor and pigment epithelium-derived factor levels before and after intravitreal injection of ranibizumab in proliferative diabetic retinopathy

Background Intraocular neovascularization is a primary cause of visual reduce in proliferative diabetic retinopathy (PDR), and intravitreal injection of ranibizumab is one of treating approachs.Researching the mechanism of intravitreal injection of ranibizumab for PDR is a new target for the prevention and management of PDR. Objective This study was to determine the levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in aqueous humor of PDR eyes before and after intravitreal injection of ranibizumab. Methods Self-controlled observational study was designed.Fifteen eyes of 15 PDR patients with type 2 diabetes mellitus were included in Fuzhou General Hospital of Nanjing Military Command from January to August 2014, and 1 eye combined with neovascular glaucoma and iris rubeosis.Aqueous samples of 0.1 ml at each time were collected before and 7 days after the injection of ranibizumab from all patients under the informed consent.The changes of aqueous VEGF and PEDF concentrations were detected and analyzed by enzyme-linked immunosorbent assay.This study complied with Declaration of Helsinki and the protocol was approved by this hospital. Results The freeVEGF concentrations before and 7 days after intravitreal injection were (179.4±136.5) pg/ml and (27.1±23.5) pg/ml, respectively, showing a significant reduce after intravitreal injection of ranibizumab (t=4.172, P=0.001). PEDF concentrations before and 7 days after intravitreal injection were (394.0±237.2) pg/ml and (267.7±199.6) pg/ml, respectively, showing a significant reduce after intravitreal injection of ranibizumab (t=5.443, P=0.000). Intraocular neovascularization vanished after intravitreal injection of ranibizumab and vitrectomy was carried out at the seventh day after intravitreal injection. Conclusions Free VEGF and PEDF levels in aqueous humor appear to be significantly decreased after intravitreal injection of ranibizumab, and ocular neovascularization disappears at same time, which avoids intraoperative bleeding during vitrectomy. Key words: Angiogenic factor/aqueous humor; Angiostatic proteins/aqueous humor; Diabetic retinopathy; Neovascularization; Vascular endothelial growth factor; Pigment epithelium-derived factor; Enzyme-linked immunosorbent assay; Ranibizumab

各期糖尿病视网膜病变患者房水中PEDF与OPs的相关性分析

目的：探讨房水中色素上皮衍生因子(pigment epithelium derived factor, PEDF)与视网膜电图振荡电位(oscillatory potentials, OPs)在各期糖尿病性视网膜病变中的相关性研究分析，为糖尿病视网膜病变(diabetic retinopathy, DR)的早期诊断及病程进展预测提供客观的检测依据。方法：房水来自2型糖尿病患者40例40眼。单纯2型糖尿病患者组19例19只眼，非增殖期糖尿病性视网膜病变(non-proliferative diabetic retinopathy, NPDR)组患者11例11只眼，增殖期糖尿病视网膜病变(proliferative diabetic retinopathy, PDR)组患者10例10只眼，单纯老年性白内障患者20例20只眼作为对照组。用酶联免疫吸附法检測房水中PEDF的水平，用德国 ROLAND CONSULT公司生产的罗兰视觉电生理检查仪检测全视网膜电图中OPs的总振幅值。结果：单纯2型糖尿病患者组、NPDR组及PDR组的房水中PEDF的浓度分别为(9.13 ± 4.43) ng/ml、(7.00 ± 2.04) ng/ml、(6.39 ± 1.66) ng/ml与对照组(13.87 ± 0.36) ng/ml相比，房水中PEDF浓度均明显降低(P < 0.01)，单纯2型糖尿病患者组与NPDR组及PDR组相比，房水中PEDF浓度亦均明显降低(P = 0.04, P = 0.02)，而NPDR组与PDR组相比无明显差异(P = 0.34)；单纯2型糖尿病患者组、NPDR组及PDR组的OPs的总振幅值分别为(164.56 ± 37.41) μV、(79.80 ± 19.89) μV、(28.55 ± 17.47) μV与对照组(237.96 ± 35.96) μV相比，OPs的总振幅值均明显降低(P < 0.01)，而且组间两两比较亦有明显差异(P < 0.01)；各期糖尿病性视网膜病变房水中PEDF浓度变化与OPs的总振幅值呈典型的正相关(r = 0.905, P < 0.01)。结论：房水中PEDF的浓度与OPs总波幅在各期糖尿病性视网膜病变中呈正相关，可为糖尿病视网膜病变的早期诊断及病程进展预测提供客观的检测依据。 Objective: To investigate the relationship between pigment epithelium derived factor (PEDF) and oscillatory potentials (OPs) in various diabetic retinopathy and to provide an objective basis for the early diagnosis of diabetic retinopathy (diabetic retinopathy, DR) and the prediction of the progression of the disease. Methods: Aqueous humor samples were collected from 40 eyes of 40 type 2 diabetes patients, including 19 eyes without diabetic retinopathy and 21 eyes with diabetic (11 eyes with NPDR and 10 eyes with PDR), twenty aqueous samples from 20 cataract patients without other ocular or systemic diseases served as controls. The PEDF levels in aqueous humor were measured by enzyme-linked immunosorbent assay (ELISA). The total amplitude of OPs in the whole retina was detected by the Roland visual electrophysiological test instrument of the German CONSULT ROLAND company. Results: The PEDF and OPs level in eyes without diabetic retinopathy [(9.13 ± 4.43) ng/ml, 164.56 ± 37.41) μV, P < 0.01] was significantly lower than that in controls [(13.87 ± 0.36) ng/ml, (237.96 ± 35.96) μV]; the PEDF Ievel in eyes with NPDR [(7.00 ± 2.04) ng/ml, (79.80 ± 19.89) μV, P < 0.01] and PDR [(6.39 ± 1.66) ng/ml, (28.55 ± 17.47) μV, P < 0.01] was sig-nificantly lower than that in controls [(13.87 ± 0.36) ng/ml, (237.96 ± 35.96) μV]; the concentration of PEDF in the patients with type 2 diabetes mellitus was significantly lower than that in the NPDR and PDR group (P = 0.04, P = 0.02), while there was no significant difference between NPDR group and PDR group (P = 0.34). There were significant differences in different OPs group (P < 0.01). The PEDF concentration in the aqueous humor of the diabetic retinopathy was a typical positive correlation with the total amplitude of OPs (r = 0.905, P < 0.01). Conclusion: The concentration of PEDF in aqueous humor and the total amplitude of OPs were positively correlated with the diabetic retinopathy, which could provide an objective basis for the early diagnosis of diabetic retinopathy and the prediction of the progression of the disease.

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by beta cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in correlation with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600a) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nM. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas, and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.

Pigment epithelium-derived factor and matrix metalloproteinase-9 in liver cirrhosis.

Background/Aim:The aim of this study was to assess the role of serum pigment epithelium-derived factor (PEDF) and matrix metalloproteinase-9 (MMP-9) in progression of liver cirrhosis and development of hepatocellular carcinoma (HCC).Patients and Methods:Serum levels of PEDF and MMP-9 were tested in 212 patients with liver cirrhosis and in a control group of 30 healthy volunteers. HCC was diagnosed in 45 of the 212 patients studied (21%).Results:Serum PEDF and MMP-9 were higher in the study group than that in the control group (P < 0.001). In patients with alcoholic or mixed (alcoholic and viral hepatitis-related) cirrhosis, serum PEDF was higher than that in other patients (13970.2 ± 13406.9 ng/ml vs. 8563.5 ± 9602.7 ng/ml, P = 0.008). In patients with viral hepatitis-related cirrhosis, significantly higher PEDF levels were recorded in those with HCC (13429.1 ± 12045.8) than that in patients without HCC (6660.1 ± 7927.1; P = 0.04). There was a trend for higher serum MMP-9 in patients with HCC (5778.7 ± 12426.6 vs. 1389.8 ± 1944.7 in those without HCC; P = 0.07). Significant negative correlation between serum MMP-9 and serum alpha-fetoprotein in patients with HCC was observed (r = −0.54; P = 0.04).Conclusion:Serum PEDF and MMP-9 could be auxiliary markers in diagnosis of HCC, especially in patients with low alpha-fetoprotein level. Alcohol consumption can affect serum PEDF.

Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice.

Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by bone fragility and deformity. OI type VI is unique owing to the mineralization defects observed in patient biopsies. Furthermore, it has been reported to respond less well to standard therapy with bisphosphonates [1]. Others and we have previously identified SERPINF1 mutations in patients with OI type VI. SERPINF1 encodes pigment epithelium derived factor (PEDF), a secreted collagen-binding glycoprotein that is absent in the sera of patients with OI type VI. Serpinf1 null mice show increased osteoid and decreased bone mass, and thus recapitulate the OI type VI phenotype. We tested whether restoration of circulating PEDF in the blood could correct the phenotype of OI type VI in the context of protein replacement. To do so, we utilized a helper-dependent adenoviral vector (HDAd) to express human SERPINF1 in the mouse liver and assessed whether PEDF secreted from the liver was able to rescue the bone phenotype observed in Serpinf1(-/-) mice. We confirmed that expression of SERPINF1 in the liver restored the serum level of PEDF. We also demonstrated that PEDF secreted from the liver was biologically active by showing the expected metabolic effects of increased adiposity and impaired glucose tolerance in Serpinf1(-/-) mice. Interestingly, overexpression of PEDF in vitro increased mineralization with a concomitant increase in the expression of bone gamma-carboxyglutamate protein, alkaline phosphatase and collagen, type I, alpha I, but the increased serum PEDF level did not improve the bone phenotype of Serpinf1(-/-) mice. These results suggest that PEDF may function in a context-dependent and paracrine fashion in bone homeostasis.

Expression of pigment epithelium-derived factor is associated with a good prognosis and is correlated with epithelial-mesenchymal transition-related genes in infiltrating ductal breast carcinoma.

Epithelial-mesenchymal transition (EMT) is a pivotal event in the progression of cancer towards metastasis. Given that pigment epithelium-derived factor (PEDF) inhibits angiogenesis, the present study analyzed whether PEDF expression is associated with EMT and prognosis in invasive ductal breast cancer (IDC). Immunohistochemical analysis was used to examine the expression levels of PEDF, E-cadherin, vimentin, Snail and nuclear factor-κB (NF-κB) in 119 cases of IDC. Correlations between PEDF expression and EMT-related genes, and clinicopathological features and clinical prognosis were analyzed. E-cadherin, vimentin, Snail and NF-κB expression was correlated with tumor size, lymph node metastasis and clinicopathological stage. PEDF expression was closely associated with tumor size. Spearman's rank correlation analysis revealed a positive correlation between PEDF and E-cadherin, vimentin, Snail and NF-κB expression (P<0.05). Additionally, Kaplan-Meier survival analysis demonstrated that the five-year survival rate was higher for patients with PEDF- and E-cadherin-positive tumors, but was lower for those with vimentin-, Snail- and NF-κB-positive tumors. Vimentin, E-cadherin and NF-κB levels were dependent prognostic factors of favorable outcomes in IDC, as determined by Cox multivariate analysis. PEDF expression in breast cancer was significantly associated with EMT-related genes, suggesting that it may be an EMT suppressor. However, its potential as a prognostic indicator in breast cancer warrants further investigation.

Effect of dipeptidyl peptidase-4 inhibitors linagliptin on the expression of serum pigment epithelium-derived factor in type 2 diabetes patients

To investigate the difference in serum pigment epithelium-derived factor(PEDF)among type 2 diabetic patients before and after use of dipeptidyl peptidase-4 inhibitors linagliptin for treatment, and to explore the correlation of serum PEDF with lipids, body mass index, and HbA1C. 39 patients with recently diagnosed type 2 diabetes and 30 healthy individuals were enrolled. Baseline weight, waist circumference, body mass index, fasting plasma glucose, HbA1C, serum glutamic-pyruvic transaminase, glutamic oxaloacetic transaminase, total cholesterol, triglyceride, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol(LDL-C), and PEDF measured by enzyme linked immunosorbant assay were determined both in the diabetic and control subject. The treatment group was treated with oral linagliptin 5 mg/d for six month, serum PEDF and clinical parameters were determined in the diabetic group during 6 months of treatment.(1)PEDF levels were found to be comparable with the controls(P=0.584); LDL-C and waist circumference showed positive correlation with PEDF(P<0.05 or P<0.01). (2)PEDF level was significantly increased in patients with type 2 diabetes after linagliptin treatment [(3.21±1.91 vs 2.45±1.53)μg/ml, P<0.01]. Serum PEDF level in patients with type 2 diabetes was similar to that of healthy controls with associated LDL-C and waist circumference. After linagliptin treatment, serum PEDF level was raised, suggesting that it may have certain protective effect for diabetic vascular complications. (Chin J Endocrinol Metab, 2015, 31: 696-699) Key words: Diabetes mellitus, type 2; Pigment epithelium-derived factor; Dipeptidyl peptidase-4 inhibitors

Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver.

Background & AimsPigment epithelium-derived factor (PEDF) is a secretory protein that inhibits multiple tumor types. PEDF inhibits the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (LRP6), in the eye, but whether the tumor-suppressive properties of PEDF occur in organs such as the liver is unknown.MethodsWnt-dependent regulation of PEDF was assessed in the absence and presence of the Wnt coreceptor LRP6. Whole genome expression analysis was performed on PEDF knockout (KO) and control livers (7 months). Interrogation of Wnt/β-catenin signaling was performed in whole livers and human hepatocellular carcinoma (HCC) cell lines after RNA interference of PEDF and restoration of a PEDF-derived peptide. Western diet feeding for 6 to 8 months was used to evaluate whether the absence of PEDF was permissive for HCC formation (n = 12/group).ResultsPEDF levels increased in response to canonical Wnt3a in an LRP6-dependent manner but were suppressed by noncanonical Wnt5a protein in an LRP6-independent manner. Gene set enrichment analysis (GSEA) of PEDF KO livers revealed induction of pathways associated with experimental and human HCC and a transcriptional profile characterized by Wnt/β-catenin activation. Enhanced Wnt/β-catenin signaling occurred in KO livers, and PEDF delivery in vivo reduced LRP6 activation. In human HCC cells, RNA interference of PEDF led to increased levels of activated LRP6 and β-catenin, and a PEDF 34-mer peptide decreased LRP6 activation and β-catenin signaling, and reduced Wnt target genes. PEDF KO mice fed a Western diet developed sporadic well-differentiated HCC. Human HCC specimens demonstrated decreased PEDF staining compared with hepatocytes.ConclusionsPEDF is an endogenous inhibitor of Wnt/β-catenin signaling in the liver.

Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells.

Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.

Increased plasma level of pigment epithelium-derived factor is associated with diabetic neuropathy. (P5.077)

Increased plasma level of pigment epithelium-derived factor is associated with diabetic neuropathy. (P5.077)

Effect of intravitreal ranibizumab injections on aqueous humour concentrations of vascular endothelial growth factor and pigment epithelium-derived factor in patients with myopic choroidal neovascularisation

AimsTo investigate aqueous humour changes in vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) levels in patients with choroidal neovascularisation (CNV) secondary to pathological myopia (mCNV) before and...

Elevated plasma levels of pigment epithelium-derived factor correlated with inflammation and lung function in COPD patients.

RationalePigment epithelium-derived factor (PEDF) is a 50 kD small secreting glycoprotein that participates in multiple physiological and pathological processes. Recent studies have reported that PEDF plays an important role in inflammatory responses in several diseases. However, the role of PEDF in the pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear.ObjectiveThe aim of the present study is to explore the potential relationship between PEDF and COPD.MethodsWe used differential proteomics – stable isotope labeling with amino acids in cell culture – to investigate protein expression profile changes in cigarette smoke extract-treated pulmonary cells and found that the neurotrophic and antiangiogenic protein PEDF was abnormally expressed. Furthermore, Western blotting was used to detect the expression of PEDF in the lung tissue of rats that were exposed to cigarette smoke. Eighty subjects between the ages of 40–90 years, including 20 healthy nonsmokers, ten smoking volunteers, and 50 COPD patients, were recruited from September 2012 until August 2013 in Sichuan Province, People’s Republic of China. We measured the plasma PEDF concentration and classic proinflammatory cytokines by multiplex enzyme-linked immunosorbent assay. In addition, we performed a spirometry examination to diagnose COPD patients and we also analyzed the correlation between PEDF and lung function.ResultsFirst, we found that the expression of PEDF in cigarette smoke extract-treated cells increased 16.2-fold when compared with the control group. Next, we confirmed that 4 weeks’ exposure to cigarette smoke can upregulate PEDF levels in rat lung tissues. We also discovered that plasma PEDF in COPD patients was significantly increased when compared with either healthy nonsmoking or smoking subjects. Furthermore, circulating PEDF was correlated with inflammatory cytokine and blood neutrophil numbers, but it was reversely associated with a decline in forced expiratory volume in 1 second percent predicted.ConclusionOur findings provide a novel link between PEDF and COPD. Elevated PEDF levels may be involved in promoting the development of COPD by performing proinflamma-tory functions.

Pigment epithelium-derived factor is associated with necrotic core progression during statin therapy.

Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis and an important target molecule for preventing the progression of atherosclerosis. However, the relationship between PEDF and coronary atherosclerosis has not been fully examined. The aim of the present study is to evaluate the effects of statins on serum PEDF levels and the association between PEDF and coronary atherosclerosis. Coronary atherosclerosis in nonculprit lesions in the vessel of patients undergoing a percutaneous coronary intervention was evaluated using virtual histology intravascular ultrasound in 99 patients during percutaneous coronary intervention and after 8 months of statin therapy. Serum PEDF levels at baseline and at the 8-month follow-up did not differ. A significant decrease in the fibro-fatty component (-0.24 mm³/mm, P=0.0003) and increases in the necrotic core (0.13 mm³/mm, P=0.02) and dense calcium components (0.11 mm³/mm, P<0.0001) were observed during the 8-month statin therapy. On univariate regression analyses, serum PEDF levels (r=0.291, P=0.004) and unstable angina pectoris (r=0.203, P=0.04) showed significant positive correlations with the percentage change in necrotic core volume. Multivariate regression analysis showed that serum PEDF level was a significant independent predictor associated with necrotic core progression during statin therapy (β=0.218, P=0.04). Statin therapy had no effects on serum PEDF levels. Serum PEDF was a useful biomarker for predicting necrotic core progression during statin therapy, and its levels could be elevated as a counter-regulatory response mechanism to protect against necrotic core progression.

Clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues by FDG-PET/CT.

Body fat distribution and inflammation may play a role in metabolic derangements and cardiovascular disease in obesity. The aim of this study is to investigate clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues (VAT and SAT). (18)F-fluorodeoxyglucose-positron emission tomography and computed tomography imaging was performed in 251 consecutive subjects (62.6 ± 9.3 y) for risk screening. We examined which clinical, anthropometric, metabolic, and inflammatory variables including advanced glycation end products (AGEs) and pigment epithelium-derived factor (PEDF) were independently associated with area and metabolic activity in VAT and SAT. Adipose tissue area was determined with computed tomography, whereas metabolic activity was assessed by (18)F-fluorodeoxyglucose uptake expressed as a target to background ratio (TBR) of blood-normalized standardized uptake. Serum levels of AGEs and PEDF were 9.81 ± 3.21 U/mL and 14.0 (range 10.8-17.7) μg/mL, respectively. Although the area in VAT and SAT was associated with waist circumference and sex, each adipose tissue area and TBR had different metabolic risk profiles. The TBR value in VAT was higher than that in SAT. In a multiple stepwise regression analysis, AGEs and medication for hypertension were independently associated with VAT TBR (R(2) = 0.102), whereas medication for diabetes, mean intima-media thickness, AGEs, and PEDF were the independent correlates of SAT TBR (R(2) = 0.132). The present study demonstrated that area and metabolic activity in VAT and SAT could be differently regulated, suggesting the involvement of AGEs and PEDF in adipose tissue inflammation.

Biomarkers of progression in diabetic nephropathy: The past, present and future.

More than 380 million people are currently suffering from diabetes. The International Diabetes Federation estimated that this would rise to 592 million within a generation. Despite this relentless increase in the prevalence of type 2 diabetes worldwide, with the advent of potent statins, there has been a gradual decline in mortality from macrovascular complications, such as stroke and coronary heart disease. However, this is not the situation in diabetic nephropathy, which remains a leading cause of end-stage renal disease (ESRD) globally, with its incidence being still on a rising trend. Notably, once nephropathy develops, approximately 20–40% of patients inevitably progress to ESRD. Therefore, we need biomarkers that would enable early risk stratification in diabetic nephropathy (Figure​(Figure1),1), so that those at higher risk of progression to ESRD are identified at early stages of nephropathy development. Long-term follow up of interventional studies, such as STENO-2, have clearly shown that, even at the stage of microalbuminuria, intensive multifactorial management targeting blood pressure (particularly with blockade of the renin–angiotensin system), glucose, cholesterol and lifestyle issues could reduce the progression to ESRD as well as the associated cardiovascular mortality. The availability of sensitive and well-validated biomarkers for nephropathy progression would allow targeted intensive management to be provided to those who would derive the most cost-effective benefits from such intervention.