Pigment epithelium-derived factor may induce antidepressant phenotypes in mice by the prefrontal cortex.

Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein encoded by SERPINF1 and our previous study reported that PEDF may have antidepressant effects. As a key brain region regulating cognition, memory and emotion, the prefrontal cortex (PFC) has been studied extensively in major depressive disorder (MDD), but there are few reports on the relationship between PEDF and the PFC. In this study, enzyme-linked immunosorbent assay showed that the PEDF level was decreased in the plasma of MDD patients compared with that of healthy controls. Western blotting validated that the PEDF expression in the PFC was downregulated in the mouse chronic social defeat stress and rat chronic unpredictable mild stress models of depression. Correspondingly, normal mice overexpressing PEDF in the PFC showed depression-resistant phenotypes. We detected PFC metabolite levels by liquid chromatography-tandem mass spectrometry and found significant upregulation of 5-hydroxyindoleacetic acid, kynurenine, 5-hydroxytryptamine, ornithine and glutamine, and downregulation of 5-hydroxytryptophan, glutamic acid and aspartic acid in PEDF-overexpressing mice compared with control mice, in which no such changes were detected. Combined with the above findings, this provides an insight into a potential mechanism of the antidepressant effects of PEDF via the PFC, which may help to improve understanding of depression pathophysiology.

PEDF, a pleiotropic WTC-LI biomarker: Machine learning biomarker identification and validation.

Biomarkers predict World Trade Center-Lung Injury (WTC-LI); however, there remains unaddressed multicollinearity in our serum cytokines, chemokines, and high-throughput platform datasets used to phenotype WTC-disease. To address this concern, we used automated, machine-learning, high-dimensional data pruning, and validated identified biomarkers. The parent cohort consisted of male, never-smoking firefighters with WTC-LI (FEV1, %Pred< lower limit of normal (LLN); n = 100) and controls (n = 127) and had their biomarkers assessed. Cases and controls (n = 15/group) underwent untargeted metabolomics, then feature selection performed on metabolites, cytokines, chemokines, and clinical data. Cytokines, chemokines, and clinical biomarkers were validated in the non-overlapping parent-cohort via binary logistic regression with 5-fold cross validation. Random forests of metabolites (n = 580), clinical biomarkers (n = 5), and previously assayed cytokines, chemokines (n = 106) identified that the top 5% of biomarkers important to class separation included pigment epithelium-derived factor (PEDF), macrophage derived chemokine (MDC), systolic blood pressure, macrophage inflammatory protein-4 (MIP-4), growth-regulated oncogene protein (GRO), monocyte chemoattractant protein-1 (MCP-1), apolipoprotein-AII (Apo-AII), cell membrane metabolites (sphingolipids, phospholipids), and branched-chain amino acids. Validated models via confounder-adjusted (age on 9/11, BMI, exposure, and pre-9/11 FEV1, %Pred) binary logistic regression had AUCROC [0.90(0.84-0.96)]. Decreased PEDF and MIP-4, and increased Apo-AII were associated with increased odds of WTC-LI. Increased GRO, MCP-1, and simultaneously decreased MDC were associated with decreased odds of WTC-LI. In conclusion, automated data pruning identified novel WTC-LI biomarkers; performance was validated in an independent cohort. One biomarker-PEDF, an antiangiogenic agent-is a novel, predictive biomarker of particulate-matter-related lung disease. Other biomarkers-GRO, MCP-1, MDC, MIP-4-reveal immune cell involvement in WTC-LI pathogenesis. Findings of our automated biomarker identification warrant further investigation into these potential pharmacotherapy targets.

Association of overhydration and serum pigment epithelium-derived factor with CKD progression in diabetic kidney disease: A prospective cohort study.

AIM: Little is known about whether overhydration (OH), measured using bioimpedance assay (BIA), is associated with CKD progression in patients with type 2 diabetes mellitus (T2DM). We hypothesised that OH was a predictor, and pigment epithelium-derived factor (PEDF) was a modifiable risk factor of CKD progression. METHODS: We conducted a prospective cohort study of 1,065 patients with clinically euvolemic T2DM who attended the diabetes centre in a tertiary hospital or primary care clinic. CKD progression was defined as a combination of the worsening of the KDIGO defined CKD category by eGFR and a ≥25% decline in eGFR compared to baseline. RESULTS: Patients with T2DM in the highest tertile of OH and relative OH (OH/ extracellular water > 7%) were positively associated with CKD progression (hazard ratio [HR] 1.45 [95% confidence interval (CI) 1.14-1.85; p = 0.003 and HR 1.29 [95%CI 1.05-1.59; p = 0.017]). There were positive associations between PEDF and CKD progression (ß = 1.10; p = 0.001) and between OH and CKD progression (ß = 0.21; p = 0.036). OH remained positively associated with CKD progression mediated by PEDF. CONCLUSIONS: OH is an independent risk factor for CKD progression in patients with T2DM. Our study supports the novel definition of PEDF as a positive mediator between OH and CKD progression.

Systematic Quantification of Neurotrophic Adipokines RBP4, PEDF, and Clusterin in Human Cerebrospinal Fluid and Serum.

CONTEXT: Data on the presence/quantification of the neurotrophic adipokines retinol-binding protein-4 (RBP4), clusterin, and pigment epithelium-derived factor (PEDF) in human cerebrospinal fluid (CSF) are scarce and migration of these adipokines across of the blood-brain barrier (BBB) is uncertain. OBJECTIVE: This work aimed to quantify RBP4, PEDF, and clusterin in paired serum and CSF samples of patients undergoing neurological evaluation. METHODS: A total of 268 patients (109 male, 159 female) were included. Adipokine serum and CSF concentrations were measured by enzyme-linked immunosorbent assay in duplicate. RESULTS: RBP4 was abundant in serum (mean, 31.9 ±â€…24.2 µg/mL). The serum concentrations were approximately 145 times higher than in CSF (CSF to serum RBP4 ratio, 8.2 ±â€…4.3 × 10-3). PEDF was detectable in serum (mean, 30.2 ±â€…11.7 µg/mL) and concentrations were approximately 25 times higher than in CSF (CSF to serum PEDF ratio, 42.3 ±â€…15.6 × 10-3). Clusterin serum concentrations were abundant with mean levels of 346.0 ±â€…114.6 µg/mL, which were approximately 40 times higher than CSF levels (CSF to serum clusterin ratio, 29.6 ±â€…23.4 × 10-3). RBP4 and PEDF serum levels correlated positively with CSF levels, which were increased in overweight/obese patients and in type 2 diabetic patients. The CSF concentrations of all 3 adipokines increased with BBB dysfunction. RBP4 in CSF correlated positively with inflammatory parameters. In detail, only RBP4 showed the kinetics and associations that are mandatory for a putative mediator of the fat-brain axis. CONCLUSION: RBP4, PEDF, and clusterin are permeable to the BBB and increase with the measure of BBB dysfunction. RBP4 represents an inflammatory neurotrophic adipokine and is a promising mediator of the fat-brain axis.

Identification of Potential Biomarkers in Peripheral Blood Supernatants of South African Patients with Syphilitic and Herpetic Uveitis.

Purpose: To identify potential diagnostic biomarkers for herpetic and syphilitic uveitis.Methods: Blood samples were collected from 92 uveitis patients. Concentrations of 47 biomarkers were evaluated in unstimulated Quantiferon supernatants using the Luminex platform.Results: Results showed 11 patients (12%) had herpetic uveitis, 11 (12%) syphilis, 40 (43.5%) other infectious causes, 16 (17.4%) established noninfectious causes and 14 (15.2%) were idiopathic. Biomarker analysis revealed three proteins (Apo-A1, Apo-CIII, CRP) that differed between syphilis and other causes. A three-marker biosignature (CCL4/MIP-1ß, Apo-CIII and CRP) separated syphilis from other groups with AUC = 0.83 (95% CI: 0.68-0.98). Apo-CIII and CRP differed between herpetic cases and other groups (p < .05). A three-analyte biosignature (Apo-A1, SAP and CRP) separated the herpetic group from other groups with AUC = 0.79 (95% CI: 0.65-0.93).Conclusion: We have identified candidate biomarkers with potential to differentiate between herpetic, syphilitic and other causes of uveitis. These results warrant further investigation in larger future studies.

Plasma metabolites in treatment-requiring retinopathy of prematurity: Potential biomarkers identified by metabolomics.

Retinopathy of prematurity (ROP) is a potentially blinding condition caused by disruption of retinal vascularization and metabolism. This study aims to identify altered metabolites from plasma in patients with treatment-requiring ROP (TR-ROP) compared with controls. An untargeted metabolomics analysis was performed to reveal the metabolomic profiles of the plasma between TR-ROP patients (n = 38) and age-matched infants (n = 23). The Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore the potential signaling pathways of the changed metabolites. Under positive ion mode, a total of 29 metabolites were significantly altered in plasma between TR-ROP patients and controls, and 23 altered metabolites were identified under negative ion mode. KEGG analyses indicated that "protein digestion and absorption" and "aminoacyl-tRNA biosynthesis" were the most enriched pathways of the altered metabolites. These results demonstrated that metabolomic profiles changed in plasma of TR-ROP, and the altered metabolites could be served as potential biomarkers for the diagnosis and prognosis of TR-ROP patients. Besides, the metabolomic profiles might provide clues to discover novel therapeutic strategies in ROP treatment.

Plasma angiogenesis and oxidative stress markers in patients with diabetic retinopathy.

Background: Neovascularization in the retina and hyperglycaemia-induced oxidative stress are implicated in the pathogenesis of diabetic retinopathy (DR). In this study, we hypothesized that the plasma angiogenic and oxidative stress markers associated with these derangements could aid in the screening of diabetic patients who are at an increased risk of developing retinopathy.Methods: This study included normal (n = 148), type2 diabetes without retinopathy (DNR; n = 148), proliferative DR (PDR; n = 74) and non-PDR (NPDR; n = 148) subjects. Plasma concentrations of vascular endothelial growth factor-A (VEGF-A), hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), pigment epithelium-derived factor (PEDF), nitric oxide (NO), soluble receptors for advanced glycation end products (sRAGE), malondialdehyde (MDA) and protein thiols were estimated.Results: A statistically significant increase was observed in the plasma concentrations of pro-angiogenic factors and markers of oxidative stress in both retinopathy groups. By contrast, the concentrations of anti-angiogenic factors and antioxidants were decreased significantly in these groups. Receiver operating characteristic analysis indicated that the plasma thresholds of HIF-1α and PEDF can be suitable markers in case of NPDR. However, in PDR, HIF-1α, NO, MMP-9 and PEDF showed high sensitivity and specificity.Conclusions: The factors associated with hypoxia, matrix degradation and angiogenic inhibition play a crucial role in predicting DR.

[MeArg1, NLe10]-apelin-12: Optimization of solid-phase synthesis and evaluation of biological properties in vitro and in vivo.

Chemically modified peptide apelin-12 ([MeArg1, NLe10]-apelin12, peptide M) is able to reduce reactive oxygen species (ROS) formation, cell death, and metabolic and ionic homeostasis disorders in experimental myocardial ischemia-reperfusion injury. These beneficial effects indicate the therapeutic potential of this compound in cardiovascular diseases. The goals of this work were to optimize the synthesis of peptide M, and to study its proteolytic stability and effect on the heart function of rabbits with doxorubicin (Dox) cardiomyopathy. We have developed a rational method of solid-phase synthesis of peptide M using the Fmoc methodology in combination with the temporary protection of the guanidine function of arginine residues by protonation (salt formation) during the formation of the amide bond. It avoids the formation of by-products, and simplifies the post-synthetic procedures, providing an increase in the yield of the final product of higher purity. Comparative evaluation of the proteolytic stability of peptide M and apelin-12 in human blood plasma was carried out using 1H NMR spectroscopy. It was shown that the half-life of peptide M in plasma is approximately three times longer than that of apelin-12. Intravenous infusion of increasing doses of peptide M caused a gradual increase in left ventricular (LV) fractional shortening and ejection fraction in rabbits after 8 weeks of Dox administration (2 mg/kg weekly). The effect of the modified peptide on LV systolic dysfunction was significantly more pronounced than the effect of apelin-12, which suggests the promise of using this pharmacological agonist of the APJ receptor in patients with heart failure.

Clinical findings and RS1 genotype in 90 Chinese families with X-linked retinoschisis.

Purpose: X-linked retinoschisis (XLRS) is an early-onset retinal degenerative disorder caused by mutations in the RS1 gene. The objective of this study was to describe the clinical and genetic findings in 90 unrelated Chinese patients with XLRS. Methods: All patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, and spectral domain-optical coherence tomography (SD-OCT). A combination of molecular screening methods, including Sanger-DNA sequencing of RS1 and targeted next-generation sequencing (TES), were used to detect mutations. In silico programs were used to analyze the pathogenicity of all the variants. Long-range PCR with subsequent DNA sequencing was employed to find the breakpoints of large deletions. Results: The 90 probands (mean age 17.29±12.94 years; 3-52 years) showed a variety of clinical phenotypes, and their average best correct visual acuity was 0.81±0.48 (logarithm of the minimal angle of resolution, 0-3). Of the 175 eyes analyzed, 140 (80%) had macular retinoschisis, 84 (48%) had peripheral retinoschisis, 28 (16%) had macular atrophy, and five (3%) had a normal macular structure. We identified 68 mutations in this cohort of patients, including 15 novel mutations. Most mutations (65%) were missense; the remaining null mutations included nonsense, splicing effect, frameshift indel, and large genomic DNA deletions. The 62 patients with missense mutations seemed to have relatively milder visual defects than the 28 patients with null mutations. Conclusions: Patients with RS1 mutations present profound phenotypic variability and show no clear genotype-phenotype correlations. Patients with null mutations tend to have more severe XLRS-related visual defects.

Two-hour postload plasma glucose and pigment epithelium-derived factor levels are markers of coronary artery inflammation in type 2 diabetic patients.

BACKGROUND: We have previously found that pioglitazone attenuates inflammation in the left main trunk of coronary artery (LMT), evaluated as target-to-background ratio (TBR) by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with impaired glucose tolerance or type 2 diabetes. OBJECTIVES: We assessed which clinical variables could predict the change in TBR in the LMT after 4-month add-on therapy with oral hypoglycemic agents (OHAs). METHODS: A total of 38 type 2 diabetic patients with carotid atherosclerosis who had already received OHAs except for pioglitazone was enrolled. At baseline and 4 months after add-on therapy with pioglitazone or glimepiride, all patients underwent 75 g oral glucose tolerance test, blood chemistry analysis, and FDG-PET/CT. RESULTS: Fasting plasma glucose, 30-, 60-, 90-, 120-minutes postload plasma glucose, HbA1c, and LMT-TBR values were significantly decreased by add-on therapy, whereas high-density lipoprotein-cholesterol and adiponectin levels were increased. Increased serum levels of pigment epithelium-derived factor (PEDF), a marker of insulin resistance and non-use of aspirin at baseline could predict the favorable response of LMT-TBR to add-on therapy. Moreover, Δ120-minutes postload plasma glucose and ΔPEDF were independent correlates of ΔLMT-TBR. CONCLUSIONS: Our present study suggests that 120-minutes postload plasma glucose and PEDF values may be markers and potential therapeutic targets of coronary artery inflammation in type 2 diabetic patients. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov . Unique identifier: NCT00722631. New markers for diabetes and CAD is on the horizon! Two-hour postload plasma glucose and pigment epithelium derived factor are markers of coronary artery inflammation in type 2 diabetic patients.

Insulin resistance is associated with Sfrp5 in obstructive sleep apnea / Resistência à insulina está associada à Sfrp5 na apneia obstrutiva do sono

Abstract Introduction: Obstructive sleep apnea, a common disease, is usually complicated by insulin resistance and type 2 diabetes mellitus. Adipokine is considered to play an important role in the development of insulin resistance and type 2 diabetes mellitus in obstructive sleep apnea. Objective: To assess whether secreted frizzled-related protein 5, a new adipokine, is involved in untreated obstructive sleep apnea patients. Methods: Seventy-six subjects with obstructive sleep apnea and thirty-three control subjects without obstructive sleep apnea were recruited and matched in terms of body mass index and age. The fasting secreted frizzled-related protein 5 plasma concentration was tested using ELISA. In addition, the correlation between secreted frizzled-related protein 5 and the homeostasis model assessment of insulin resistance was obtained. Multiple linear regression analysis models with stepwise selection were performed to determine the independent associations between various factors and secreted frizzled-related protein 5. Results: Plasma secreted frizzled-related protein 5 levels were significantly lower in the obstructive sleep apnea group than in the control group (obstructive sleep apnea group: 28.44 ± 13.25 ng/L; control group: 34.16 ± 13.51 ng/L; p = 0.023). In addition, secreted frizzled-related protein 5 was negatively correlated with homeostasis model assessment of insulin resistance but positively correlated with the mean and lowest oxygen saturation with or without adjusting for age, gender, body mass index, neck circumference, waist circumference and waist-to-hip ratio. The multiple linear regression analysis showed there was an independent negative association between secreted frizzled-related protein 5 and homeostasis model assessment of insulin resistance. Conclusion: Secreted frizzled-related protein 5 was involved in obstructive sleep apnea and the decrease in secreted frizzled-related protein 5 was directly proportional to the severity of obstructive sleep apnea. There was an independent negative correlation between homeostasis model assessment of insulin resistance and secreted frizzled-related protein 5 in the obstructive sleep apnea group. Secreted frizzled-related protein 5 might be a therapeutic target for insulin resistance in obstructive sleep apnea.

Resumo Introdução: A apneia obstrutiva do sono, uma doença comum, é geralmente complicada com resistência à insulina e diabetes melito tipo 2. Acredita-se que a adipocina possa ter um papel importante no desenvolvimento de resistência à insulina e diabetes melito tipo 2 na apneia obstrutiva do sono. Objetivo: Avaliar se a proteína secretada relacionada ao receptor frizzled-5, uma nova adipocina, está envolvida em pacientes com apneia obstrutiva do sono não tratada. Método: Foram recrutados 76 indivíduos com apneia obstrutiva do sono e 33 indivíduos controle sem apneia obstrutiva do sono e pareados em relação a índice de massa corporal e idade. A concentração plasmática de proteína secretada relacionada ao receptor frizzled-5 foi testada em jejum com o teste Elisa. Além disso, obteve-se correlação entre a proteína secretada relacionada ao receptor frizzled-5 e o modelo de avaliação da homeostase de resistência à insulina. Modelos de análise de regressão linear múltipla com seleção stepwise foram feitos para determinar as associações independentes entre vários fatores e a proteína secretada relacionada ao receptor frizzled-5. Resultados: Os níveis plasmáticos de proteína secretada relacionada ao receptor frizzled-5 foram significativamente menores no grupo com apneia obstrutiva do sono do que no grupo controle (grupo com apneia obstrutiva do sono: 28,44 ± 13,25 ng/L; grupo controle: 34,16 ± 13,51 ng/L; p = 0,023). Além disso, a proteína secretada relacionada ao receptor frizzled-5 foi correlacionada negativamente com o modelo de avaliação da homeostase de resistência à insulina, mas se correlacionou positivamente com a média e a saturação mínima de oxigênio com ou sem ajuste para idade, gênero, índice de massa corporal, circunferência do pescoço, circunferência da cintura e relação cintura-quadril. A análise de regressão linear múltipla mostrou que houve uma associação negativa independente entre a proteína secretada relacionada ao receptor frizzled-5 e o modelo de avaliação da homeostase de resistência à insulina. Conclusões: A proteína secretada relacionada ao receptor frizzled-5 esteve envolvida na apneia obstrutiva do sono e sua diminuição foi diretamente proporcional à gravidade da apneia obstrutiva do sono. Houve uma correlação negativa independente entre o modelo de avaliação da homeostase de resistência à insulina e a proteína secretada relacionada ao receptor frizzled-5 no grupo da apneia obstrutiva do sono. A proteína secretada relacionada ao receptor frizzled-5 pode ser um alvo terapêutico para a resistência à insulina na apneia obstrutiva do sono.

Serum pigment epithelium-derived factor: Relationships with cardiovascular events, renal dysfunction, and mortality in the Veterans Affairs Diabetes Trial (VADT) cohort.

BACKGROUND: To determine if serum pigment epithelium-derived factor (PEDF) levels predict cardiovascular events, renal dysfunction and mortality in the Veterans Affairs Diabetes Study (VADT). METHODS: PEDF was evaluated in relation to subsequent cardiovascular outcomes, mortality, and renal dysfunction (defined as urinary albumin creatinine ratio (ACR) ≥300 mg/g), or chronic kidney disease (CKD) stages 3 (eGFR<60 ml/min) or 4 (eGFR<60 and <30 ml/min respectively). PEDF was measured by ELISA on sera from 881 participants collected a median (range) of 1.7 (0-5.0) years post-baseline, and later, from 832 participants 4.0 (1.5-6.9) years post-baseline. RESULTS: In 743 participants, PEDF was measured at both time-points. PEDF increased over time from (mean ±â€¯SD) 10.5 ±â€¯4.03 to 11.0 ±â€¯4.86 ng/ml (paired t-test p = 0.0092). Lower eGFR (p < 0.01), higher serum creatinine (p < 0.01) and urinary ACR (p < 0.01) were associated with increasing PEDF. Multivariate event time models included either one or two follow-up windows (i.e., between first and second PEDF measures; and, when available, from second PEDF measure until study-end). PEDF tertiles were not associated with cardiovascular events, but were significantly associated with all-cause mortality [HR = 2.00 (1.03, 3.89) comparing first to third tertile] in models adjusted for age, minority status, VADT treatment arm and prior cardiovascular event status. Higher PEDF levels also associated with development of kidney dysfunction with adjusted HRs (95% CI comparing third to first PEDF tertiles: 2.74 (1.71, 4.39) for stage 3 CKD; and 3.84 (95% CI: 1.17, 12.5) for stage 4 CKD. CONCLUSIONS: Over 2-years, higher serum PEDF levels predicted advanced nephropathy in patients with type 2 diabetes.

Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy.

The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.

Clinical Significance of Serum Vascular Endothelial Growth Factor, Pigment Epithelium-Derived Factor, Tumor Necrosis Factor Alpha, and Progranulin Levels in Patients with Gastric Cancer and Gastric Precancerous Lesions.

BACKGROUND: The purpose of this study is to evaluate serum levels of vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), tumor necrosis factor alpha (TNF-α), and progranulin in patients with gastric cancer (GC) and precancerous lesions (PCL) and to determine the usefulness of these markers as diagnostic biomarkers in these diseases. METHOD: A total of 32 GC patients, 35 PCL patients, and 23 healthy controls participated in the study. The serum levels of VEGF, PEDF, TNF-α, and progranulin were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean serum VEGF levels were 30.6 ± 12.98 pg/mL in GC, 18.2 ± 5.72 pg/mL in PCL, and 17.5 ± 5.59 pg/mL in controls. GC VEGF levels were significantly higher than both PCL and control groups (p < 0.001). The mean serum PEDF levels were 1516.1 ± 993.8 pg/mL in GC, 1039.1 ± 1002.3 pg/mL in PCL, and 767.5 ± 661.5 pg/mL in controls. The serum PEDF level in the GC group was significantly higher than that in both PCL and control groups (p = 0.004 and p = 0.038, respectively). The mean serum TNF-α levels were 46.7 ± 14.82 pg/mL in GC, 38.4 ± 11.89 pg/mL in PCL, and 33.8 ± 12.77 pg/mL in controls. There was a significant difference between GC and controls (p = 0.022) in TNF-α levels. The mean serum progranulin levels in GC were 2496.6 ± 737.8 pg/mL, 2332.0 ± 482.1 pg/mL in PCL, and 1288.7 ± 830.9 pg/mL in controls. Progranulin levels in both GC and PCL groups were significantly higher than that in the control group (p < 0.001 for both). CONCLUSION: There were significant differences among patients with GC and PCL and healthy controls in terms of serum VEGF, PEDF, TNF-α, and progranulin levels.

Association of pigment epithelium derived factor with von Willebrand factor and plasminogen activator inhibitor 1 in patients with type 2 diabetes.

To compare circulating pigment epithelium derived factor (PEDF) levels in type 2 diabetes patients (T2D) with and without metabolic syndrome (MetS+/-) to healthy controls and assess PEDF association with plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF) as markers of endothelial dysfunction. Fifty T2D individuals and forty healthy controls were included. PEDF, PAI-1, vWF, anthropological parameters, lipids, and markers of insulin resistance were investigated in all subjects. Compared to controls only MetS+ diabetics had higher PEDF levels [14.2 (10.2-16.0) mg/l vs. 11.1 (8.6-14.4) mg/l; p<0.05]. PEDF significantly correlated: positively with body mass index (rho=0.25), smoking (rho=0.21), C-reactive protein (rho=0.22), triglycerides (rho=0.38), non-HDL-cholesterol (rho=0.39), apolipoprotein B (rho=0.38), fasting glucose (rho=0.22), glycated hemoglobin (rho=0.24), C-peptide (rho=0.28), insulin (rho=0.26); and negatively with HDL-cholesterol (rho=-0.42) and apolipoprotein A1 (rho=-0.27). Independent association of PEDF with vWF in T2DMetS- subjects was found. Significantly elevated PEDF in T2DMet+ patients and its association with adverse metabolic profile confirmed PEDF as a marker of insulin resistance. Negative independent association of PEDF with vWF in T2DMetS- patients may reveal its angio-protective role.

Pigment Epithelium-Derived Factor Affects Angiogenesis in Celiac Disease.

OBJECTIVE: Recent studies have demonstrated that angiogenesis is impaired in patients with celiac disease (CD). In this study, we evaluated the levels of the novel antiangiogenic factor pigment epithelium-derived factor (PEDF) in CD patients. METHODS: Eighty-four patients were included in the study; 71 patients with CD and 13 healthy controls. In the CD patient cohort, there were 21 newly diagnosed patients, 19 with adherence to a gluten-free diet and 31 practicing no adherence to this diet. The PEDF levels were measured using enzyme-linked immunosorbent assays. RESULTS: The data revealed that celiac patients had higher levels of PEDF than did healthy controls. PEDF levels were not significantly different among the three CD groups. Additionally, the PEDF levels were not correlated with tissue transglutaminase IgA or IgG. CONCLUSIONS: Our data indicate that PEDF levels are significantly higher in CD patients than those in the healthy controls. This result suggests that PEDF negatively affects angiogenesis in CD. Although we did not observe any differences of PEDF levels among celiac patients, additional studies including more patients could clarify this issue.

Umbilical Cord SFRP5 Levels of Term Newborns in Relation to Normal and Excessive Gestational Weight Gain.

Among the new adipokines, secreted frizzled-related protein 5 (SFRP5) is considered to prevent obesity and insulin resistance. The umbilical cord SFRP5 levels have not yet been investigated. The main aim of the study was to investigate whether the umbilical cord SFRP5 concentrations are altered in term neonates born to mothers with excessive gestational weight gain (EGWG). Two groups of subjects were selected depending on their gestational weight gain, i.e. 28 controls and 38 patients with EGWG. Umbilical cord and maternal serum SFRP5 levels were lower in the EGWG group. Umbilical cord SFRP5 concentrations were directly associated with the maternal serum SFRP5, hemoglobin A1c and lean tissue index, umbilical cord leptin levels, as well as newborns' anthropometric measurements in the EGWG subjects. In multiple linear regression models performed in all the study participants, umbilical cord SFRP5 concentrations depended positively on the maternal serum SFRP5, ghrelin, and leptin levels and negatively on the umbilical cord ghrelin levels, low-density lipoprotein cholesterol, pre-pregnancy body mass index, and gestational weight gain. EGWG is associated with disturbances in SFRP5 concentrations. Obstetricians and midwives should pay attention to nutrition and weight management during pregnancy.

Insulin resistance is associated with Sfrp5 in obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea, a common disease, is usually complicated by insulin resistance and type 2 diabetes mellitus. Adipokine is considered to play an important role in the development of insulin resistance and type 2 diabetes mellitus in obstructive sleep apnea. OBJECTIVE: To assess whether secreted frizzled-related protein 5, a new adipokine, is involved in untreated obstructive sleep apnea patients. METHODS: Seventy-six subjects with obstructive sleep apnea and thirty-three control subjects without obstructive sleep apnea were recruited and matched in terms of body mass index and age. The fasting secreted frizzled-related protein 5 plasma concentration was tested using ELISA. In addition, the correlation between secreted frizzled-related protein 5 and the homeostasis model assessment of insulin resistance was obtained. Multiple linear regression analysis models with stepwise selection were performed to determine the independent associations between various factors and secreted frizzled-related protein 5. RESULTS: Plasma secreted frizzled-related protein 5 levels were significantly lower in the obstructive sleep apnea group than in the control group (obstructive sleep apnea group: 28.44±13.25ng/L; control group: 34.16±13.51ng/L; p=0.023). In addition, secreted frizzled-related protein 5 was negatively correlated with homeostasis model assessment of insulin resistance but positively correlated with the mean and lowest oxygen saturation with or without adjusting for age, gender, body mass index, neck circumference, waist circumference and waist-to-hip ratio. The multiple linear regression analysis showed there was an independent negative association between secreted frizzled-related protein 5 and homeostasis model assessment of insulin resistance. CONCLUSION: Secreted frizzled-related protein 5 was involved in obstructive sleep apnea and the decrease in secreted frizzled-related protein 5 was directly proportional to the severity of obstructive sleep apnea. There was an independent negative correlation between homeostasis model assessment of insulin resistance and secreted frizzled-related protein 5 in the obstructive sleep apnea group. Secreted frizzled-related protein 5 might be a therapeutic target for insulin resistance in obstructive sleep apnea.

Increased levels of serum pigment epithelium-derived factor aggravate proteinuria via induction of podocyte actin rearrangement.

PURPOSE: To assess the role of serum pigment epithelium-derived factor (PEDF) in the occurrence and development of proteinuria and renal dysfunction and determine its relevant signaling pathway. METHODS: We analyzed serum PEDF, creatinine, the urinary albumin-to-creatinine ratio, and renal morphology of normal or streptozotocin (STZ)-induced diabetic mice, before and after treatment with PEDF. In vitro, podocytes were stimulated with PEDF under normal or high-glucose conditions; permeability was measured by the transwell assay with fluorescein isothiocyanate (FITC)-dextran; and F-actin cytoskeleton was analyzed by phalloidin staining. Apoptosis was assessed by flow cytometry. RhoA activity and ROCK1, ZO-1, nephrin, and podocin levels were detected by Western blotting. RESULTS: Diabetic mice exhibited a high serum PEDF level. In vivo, elevated serum PEDF led to proteinuria, increased serum creatinine, and podocyte foot process fusion in normal or diabetic mice. In vitro, both high-glucose and PEDF stimulation activated the RhoA/ROCK1 pathway in podocytes and promoted cell permeability, F-actin rearrangement, and apoptosis. Inhibition of RhoA/ROCK1 alleviated the damage from these effects. CONCLUSIONS: Elevated serum PEDF aggravates the development of proteinuria and renal dysfunction by inducing F-actin arrangement, foot process fusion, and apoptosis of podocytes in both normal and diabetic mice, and this effect may be mediated by activation of the RhoA/ROCK1 pathway.

Type 2 diabetes with hypertensive patients results in changes to features of adipocytokines: Leptin, Irisin, LGR4, and Sfrp5.

The incidence of hypertension and diabetes is increasing, it is reported that adipocytokines might be involved in the pathogenesis of diabetes and hypertension. We aimed to investigate the features of adipocytokines, included of Leptin, Irisin, LGR4, and Sfrp5 in type 2 diabetes mellitus (T2DM) patients with hypertension, simultaneously analyzed the connection of the alteration of adipocytokines with blood pressure and glucose. 424 patients with T2DM and 90 healthy subjects were included in the study. The patients with T2DM were divided into 4 groups based on the blood pressure. The levels of adipocytokines (Leptin, Irisin, LGR4, and Sfrp5) were determined by enzyme-linked immunosorbent assay (ELISA). Significantly higher levels of Leptin and lower levels of Irisin, LGR4 and Sfrp5 were seen in patients with diabetes compared with non-diabetes (P < 0.05), the mean values of Leptin level was ascending and Irisin, LGR4, and Sfrp5 levels were declining with promoting of blood pressure in hypertension as compared to the non-hypertension with diabetic patients. Multiple stepwise linear regression analysis showed that the concentrations of Leptin, Irisin, Sfrp5, and LGR4 were found to be closely associated with the control of blood pressure and glucose. Conclusion: Four adipocytokines might play different roles and closely relate to the occurrence and development of diabetes and hypertension.