Serum Pigment Epithelium-derived Factor Levels Research Articles

Pigment epithelium-derived factor (PEDF) represses the glucose transporter 1 (GLUT1) mRNA expression and may be a potential therapeutic agent in psoriasis: a case–control and experimental study

We investigated the whole blood GLUT1 mRNA expression and serum pigment epithelium-derived factor (PEDF), interleukin-6 (IL-6), fetuin-A, and pentraxin-3 (PTX3) levels in psoriatic patients and tested their correlations with the severity of psoriasis using the psoriasis area and severity index (PASI) score. Also, we tested the GLUT1 mRNA expression after an in vitro treatment of human skin fibroblast (HSF) cell lines with PEDF. The case–control part of the study recruited 74 participants (44 psoriatic patients and 30 healthy volunteers). Whole blood GLUT1 mRNA fold changes were estimated by RT-PCR, and serum PEDF, IL-6, fetuin-A, and PTX3 levels were measured by ELISA kits. In the experimental part, the HSF cell lines were treated with different concentrations of PEDF for different times to test its effect on the GLUT1 mRNA expression. The whole blood GLUT 1 expression significantly increased in psoriatic patients and correlated positively with serum IL-6, fetuin-A, PTX3 levels and with the severity of psoriasis while negatively with serum PEDF levels. The PEDF-treated HSF cell lines showed a time- and dose-dependent decline in the GLUT 1 mRNA expression. The whole blood GLUT 1 mRNA is a non-invasive biomarker that is associated with the severity of psoriasis. PEDF represses GLUT 1 expression and may be a potential therapeutic agent in psoriasis.Trial registration: ClinicalTrials.gov Identifier: NCT04242082.

Sex differences in serum pigment epithelium-derived factor in healthy individuals.

To investigate sexual dimorphism of serum pigment epithelium-derived factor (PEDF) and its influencing factors in healthy individuals. A total of 162 healthy people (69 males, 93 females) who underwent health examinations in our department were selected. Serum PEDF, estradiol and other metabolic indices were measured, and homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were calculated to evaluate insulin resistance and β-cell function, respectively. Subjects were divided into < 50 years and ≥ 50 years groups to explore the sexual dimorphism of serum PEDF in different age groups. We found no statistically significant difference in serum PEDF levels between men and women in total. However, in the group of subjects under 50 years old, men had significantly higher PEDF levels than women (9.32 ± 2.07 μg/mL vs 8.24 ± 2.29 μg/mL, P < .05), and no sex difference was found in the ≥ 50 years group. In women, serum PEDF levels were significantly higher in subjects aged 50 years and over than in those younger than 50 years of age (9.56 ± 3.05 μg/mL vs 8.25 ± 2.30 μg/mL, P < .05). In men, there was no significant difference in serum PEDF levels between the 2 age groups. In women, correlation analysis showed that serum PEDF levels were significantly correlated with body mass index, waist circumference, diastolic blood pressure (DBP), 2-h postprandial glucose, fasting and 2-h postprandial insulin, HOMA-β, HOMA-IR, aminotransferase, triacylglycerol, and estradiol. Elevated triacylglycerol and aminotransferase and decreased estradiol were significant predictors of increased PEDF concentrations in women. There is sexual dimorphism in circulating PEDF levels, which may be related to estrogen status.

Circulating AFABP, FGF21, and PEDF Levels as Prognostic Biomarkers of Sight-threatening Diabetic Retinopathy.

Adipocyte fatty acid-binding protein (AFABP), fibroblast growth factor 21 (FGF21), and pigment epithelium-derived factor (PEDF) are 3 diabetes-related biomarkers whose circulating levels had been shown to associate with nephropathy progression in Chinese patients with type 2 diabetes. Here, we evaluated and compared their prospective associations with the development of sight-threatening DR (STDR), another important diabetic microvascular complication. Baseline serum AFABP, PEDF, and FGF21 levels were measured in 4760 Chinese individuals with type 2 diabetes and without STDR at baseline. The associations of these biomarkers with incident STDR were analyzed using Cox regression analysis. Among these 4760 participants (mean diabetes duration of 11 years and ≥ 50% with nonproliferative DR at baseline), 172 participants developed STDR over a median follow-up of 8.8 years. Participants with incident STDR had comparable baseline serum FGF21 levels but significantly higher baseline serum AFABP and PEDF levels (both P < .001) than those without. However, in multivariable Cox regression analysis, only serum AFABP remained independently associated with incident STDR (hazard ratio 1.28; 95% CI, 1.05-1.55; P = .013). The addition of serum AFABP to a clinical model of conventional STDR risk factors including diabetes duration, glycemic control, albuminuria, and baseline DR status significantly improved the c statistics (P < .001), net reclassification index (P = .0027), and integrated discrimination index (P = .033) in predicting incident STDR among participants without DR or with mild DR at baseline. Among the 3 diabetes-related biomarkers, serum AFABP level appeared to be a more clinically useful biomarker for predicting incident STDR in type 2 diabetes.

Changes in serum pigment epithelium-derived factor levels after kidney transplantation in patients with end-stage renal disease

Background Pigment epithelium-derived factor (PEDF) is a serin protease inhibitor and a potent inhibitor of angiogenesis. Its serum level has significant associations with metabolic parameters. However, little is known about the association between PEDF levels and lipid parameters in renal transplanted (TX) patients. Therefore, our aim was to investigate the relationship between PEDF level and lipid parameters in TX patients. Methods Seventy TX patients (47 males, 23 females, mean age 51.7 ± 12.4 years) and 34 healthy controls were enrolled. We examined the serum creatinine, C-reactive protein, fasting glucose and lipid parameters right before, then 1 and 6 months after TX. High-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) activities were measured spectrophotometrically. Lipoprotein subfractions were determined by Lipoprint. PEDF and oxidized low-density liporotein (oxLDL) levels were measured by ELISA. Results Before transplantation, patients had had a significantly higher PEDF level compared to control subjects (p < 0.001). One month after transplantation, their PEDF level decreased significantly reaching the healthy controls’ level, and this lower level was maintained during the 6 months follow-up period as well. The initial oxLDL level was significantly higher, while PON1 activities were significantly lower in the patient group compared to the control group. We found a significant positive correlation between PEDF and total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride, oxLDL and small HDL subfraction; while negative correlations were found between PEDF and mean LDL size and large HDL subfraction during the entire follow-up period. Conclusion PEDF may play an important role in the increased oxidative stress and enhanced atherogenesis in renal transplant patients.

Serum Pigment Epithelium-Derived Factor Levels are Associated with Estradiol and Decrease After Adjusting for Alanine Aminotransferase in Chinese Women Based on Multiple Linear Regression Analysis.

PurposeTo assess changes in pigment epithelium-derived factor (PEDF) levels in patients with metabolic syndrome (MetS) and to investigate sexual dimorphism in serum PEDF levels and their relationships with estradiol.MethodsA total of 318 individuals (145 men, 173 women) who underwent health examinations in our department were selected. Serum PEDF, estradiol and other metabolic parameters were determined. Homeostasis model assessment of insulin resistance (HOMA- IR) and homeostasis model assessment of β-cell function (HOMA-β) were calculated to evaluate insulin resistance and β-cell function, respectively. Multiple linear regression analysis was used to analyse the factors influencing serum PEDF.ResultsSerum PEDF levels were significantly higher in subjects with MetS in both men and women (12.09±2.75 vs 8.97±3.19 μg/mL in men and 11.31±2.79 vs 8.40±2.32 μg/mL in women, MetS vs non-MetS, P<0.001). Correlation analysis showed that serum PEDF levels were significantly correlated with body mass index (BMI), waist circumference, waist-to-hip ratio, diastolic blood pressure (DBP), fasting and 2-h postprandial glucose, fasting and 2-h postprandial insulin, HOMA-β, HOMA-IR, hemoglobin A1c (HbA1c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid (UA), triacylglycerol (TG) and high-density lipoprotein cholesterol (HDL-C). Elevated ALT, HOMA-IR and TG were significant predictors of increased PEDF concentrations. In women, estradiol was inversely correlated with PEDF levels (r=−0.25, P=0.011), and the association was no longer significant after adjustment for ALT.ConclusionPEDF could be used as a biomarker of MetS in both men and women. This study reported for the first time that circulating PEDF displays sexual dimorphism, which could be related to estrogen. The association between estrogen and circulating PEDF levels was attenuated after adjusting for ALT.

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

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. This work aimed to quantify RBP4, PEDF, and clusterin in paired serum and CSF samples of patients undergoing neurological evaluation. 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. RBP4 was abundant in serum (mean, 31.9 ± 24.2 μg/mL). The serum concentrations were approximately 145 times higher than in CSF (CSF to serum RBP4 ratio, 8.2 ± 4.3 × 10-3). PEDF was detectable in serum (mean, 30.2 ± 11.7 μg/mL) and concentrations were approximately 25 times higher than in CSF (CSF to serum PEDF ratio, 42.3 ± 15.6 × 10-3). Clusterin serum concentrations were abundant with mean levels of 346.0 ± 114.6 μg/mL, which were approximately 40 times higher than CSF levels (CSF to serum clusterin ratio, 29.6 ± 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. 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.

Changes of serum FGF19 and PEDF levels in patients with type 2 diabetic retinopathy

Objective To observe the expression of FGF19 ( fibroblast growth factor 19) and PEDF (pigment epithelium-derived factor) in the serum of type 2 diabetic retinopathy (DR) patients and discuss their significance. Methods Total 89 patients with type 2 diabetes were selected and divided into two groups according to whether they were combined with diabetic retinopathy: 45 patients with type 2 diabetes alone (DM group) and 44 patients with type 2 diabetes mellitus combined with retinopathy (DR group). At the same time, 40 healthy people were selected as the control group (NDM group). The serum levels of FGF19 and PEDF and their biochemical indexes were detected and compared in each group. The correlation between the indexes and the relationship between FGF19, PEDF and DR were analyzed. Results Compared with NDM group, serum FGF19 level in DM group and DR group decreased, while C-reactive protein (CRP) and PEDF level in DM group and DR group increased (P 0.05); the levels of Hcy, triacylglycerol (TG) and CRP in DR group were higher than those in DM and NDM group (P 12.76 mg/L, the sensitivity and specificity of PEDF dignosing DR were 80.9% and 56.7% respectively. Conclusions In patients with DR, serum FGF19 level decreased and serum PEDF levels increased. The level of both changes is closely related to DR and may be involved in the development of DR. Key words: Diabetic retinopathy; Diabetes mellitus, type 2; Fibroblast growth factor 19; Pigment epithelium derived factor

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

BackgroundTo determine if serum pigment epithelium-derived factor (PEDF) levels predict cardiovascular events, renal dysfunction and mortality in the Veterans Affairs Diabetes Study (VADT). MethodsPEDF 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. ResultsIn 743 participants, PEDF was measured at both time-points. PEDF increased over time from (mean ± SD) 10.5 ± 4.03 to 11.0 ± 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. ConclusionsOver 2-years, higher serum PEDF levels predicted advanced nephropathy in patients with type 2 diabetes.

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.

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. 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). The mean serum VEGF levels were 30.6 ± 12.98pg/mL in GC, 18.2 ± 5.72pg/mL in PCL, and 17.5 ± 5.59pg/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 ± 993.8pg/mL in GC, 1039.1 ± 1002.3pg/mL in PCL, and 767.5 ± 661.5pg/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 ± 14.82pg/mL in GC, 38.4 ± 11.89pg/mL in PCL, and 33.8 ± 12.77pg/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 ± 737.8pg/mL, 2332.0 ± 482.1pg/mL in PCL, and 1288.7 ± 830.9pg/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). There were significant differences among patients with GC and PCL and healthy controls in terms of serum VEGF, PEDF, TNF-α, and progranulin levels.

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

PurposeTo 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.MethodsWe 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.ResultsDiabetic 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.ConclusionsElevated 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.

Role of pigment epithelium-derived factor (PEDF) on arsenic-induced neuronal apoptosis

Chronic exposure to high levels of arsenic is closely associated with nervous system disorders that harm learning, memory, and intelligence. Studies have shown that the primary characteristic of brain damage is neuronal apoptosis. Arsenic induces apoptosis in a variety of nerve cells. Therefore, substance that inhibit apoptosis promise to mitigate arsenic toxicity. Pigment epithelium-derived factor (PEDF) is widely distributed in brain tissues and has various effects on neurons, including induction of apoptosis. Our previous study suggested that PEDF might augment arsenic-induced apoptosis in rat brains. In this study of 151 adults with normal, mild, moderate, and high exposure to arsenic, the measured serum PEDF levels were 15.46 ± 5.87 ng/mL, 17.33 ± 8.22 ng/mL, 19.43 ± 9.51 ng/mL and 21.65 ± 14.46 ng/mL, respectively. Multiple linear regression analysis revealed an independent positive correlation between serum PEDF levels and arsenic exposure in drinking water. To study the underlying mechanism of arsenic-induced apoptosis, we exposed PEDF-transfected PC12 cells to NaAsO2. We discovered that NaAsO2--induced mitochondrial apoptosis was enhanced in cells that over expressed PEDF. Moreover, p53 up regulated modulator of apoptosis (PUMA) gene and B-cell lymphoma 2 (Bcl-2) protein were primary factors in the progression of arsenic-induced apoptosis. Taken together, our results suggest that PEDF inhibition might mitigate arsenic toxicity to nerve cells.

Circulating Pigment Epithelium-Derived–Factor Levels—Hyperglycemia vs. Insulin Resistance

Serum pigment epithelium-derived factor (PEDF) levels are correlated with adiposity, dyslipidemia, and renal dysfunction in type 2 diabetes (T2D) men. Major sources of circulating PEDF include the liver and adipose tissue. Cross-sectional studies have reported higher serum PEDF levels in T2D vs. controls. Although studies have suggested PEDF’s role in mediating insulin resistance, its potential role with regard to glycemic control remains unclear. We examined the association of serum PEDF and glycemic control in individuals with T2D (n=50; 21 men/29 women; age=63±10 years; CKD&amp;lt;stage 3b). PEDF was higher for those in poor (HbA1c≥7%; n=26) glycemic control (12.8±3.3 vs. 11.2±2.2 µg/mL; p=0.047) and for those that were insulin resistant (HOMA-IR&amp;gt;1.8; n=23; p&amp;lt;0.05). Spearman rank correlations of PEDF included: HbA1c≥7% (r=0.27, p=0.059), HOMA-IR&amp;gt;1.8 (r=0.30, p=0.037), triglycerides (r=0.53, p&amp;lt;0.001), creatinine (r=0.51, p&amp;lt;0.001), and AST (r=0.33, p=0.02). Linear regression, with PEDF as the dependent variable, revealed that AST (p=0.003), creatinine (p=0.001), triglycerides (p&amp;lt;0.001), and poor glycemic control (HbA1c≥7%) (p=0.009) were significant correlates (model R2=0.63, p&amp;lt;0.001); whereas insulin resistance (HOMA-IR&amp;gt;1.8) was not (p=0.70). There was also a significant interaction of AST x creatinine (p=0.02). While some suggest that elevated PEDF levels are associated with insulin resistance, the lack of an association in our data is intriguing. It is possible that gluconeogenesis by the liver and kidney is associated with elevation in circulating PEDF and PEDF may be part of an incomplete self-defensive regulatory mechanism to limit hyperglycemia. The significant interaction suggests that the relationship between creatinine and PEDF depends on AST. Taken together, the association between PEDF and poor glycemic control in persons with T2D may suggest a preferentially protective compensatory response of PEDF against hyperglycemia but not insulin resistance. Disclosure R.E. Maser: None. J. Lenhard: Speaker's Bureau; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi. R. Pohlig: None. P. Balagopal: None.

Extremely low level of serum pigment epithelium-derived factor is a special biomarker of Chinese osteogenesis imperfecta patients with SERPINF1 mutations

BackgroundsSERPINF1 mutations caused deficiency of pigment epithelium-derived factor (PEDF) and would lead to osteogenesis imperfecta (OI) type VI. However, serum PEDF levels were unclear in Chinese OI patients who had clear molecular diagnosis. ObjectiveTo assess PEDF levels in different genotypes of OI, to evaluate the influencing factors of PEDF in Chinese OI patients with clear molecular diagnosis. MethodsKnown candidate genes of OI were examined by a targeted next generation sequence. Serum PEDF levels were measured by ELISA in 6 OI patients with SERPINF1 mutations, 6 carriers of one copy of the SERPINF1 mutation, 88 OI patients with COL1A1, CLO1A2, IFITM5 and other pathogenic mutations of OI and 24 healthy controls. We compared the differences in serum PEDF levels among different OI patients and normal controls. ResultsSerum PEDF levels were extremely low in OI patients with SERPINF1 mutations (0.66±1.60μg/ml) than in OI patients with other pathogenic mutations (4.88±1.43–7.07±2.43μg/ml), carriers of one copy of SERPINF1 mutation (4.94±2.35μg/ml), and normal controls (7.29±2.31μg/m) (P<0.001). No significant differences in serum PEDF concentrations were found among patients with OI type I, III or IV, and between patients with or without bisphosphonate treatment. Serum PEDF level was positively correlated with Z-score of weight (r=0.310, P=0.004), BMI (r=0.253, P=0.020) and alanine aminotransferase (r=0.291, P=0.007). ConclusionsExtremely low level of PEDF was demonstrated as a specific, convenient, and inexpensive diagnostic biomarker for OI patients with SERPINF1 mutations, but it could not provide information regarding the clinical severity of OI and the efficacy of bisphosphonates treatment.

Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI.

Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is known to cause a distinct, extremely rare autosomal recessive form of type VI OI. Here we report, for the first time, the detection of SERPINF1 mutations in Chinese OI patients. We designed a novel targeted next-generation sequencing panel of OI-related genes to identify pathogenic mutations, which were confirmed with Sanger sequencing and by co-segregation analysis. We also investigated the phenotypes of OI patients by evaluating bone mineral density, radiological fractures, serum bone turnover markers, and pigment epithelium-derived factor (PEDF) concentration. Six patients with moderate-to-severe bone fragility, significantly low bone mineral density, and severe deformities of the extremities were recruited from five unrelated families for this study. Six pathogenic mutations in SERPINF1 gene were identified, five of which were novel: (1) a homozygous in-frame insertion in exon 3 (c.271_279dup, p.Ala91_Ser93dup); (2) compound heterozygous mutations in intron 3 (c.283+1G>T, splicing site) and exon 5 (c.498_499delCA, p.Arg167SerfsX35, frameshift); (3) a homozygous frameshift mutation in exon 8 (c.1202_1203delCA, p.Thr401ArgfsX); (4) compound heterozygous missense mutation (c.184G>A, p.Gly62Ser) and in-frame insertion (c.271_279dup, p.Ala91_Ser93dup) in exon 3; and (5) a heterozygous nonsense mutation in exon 4 (c.397C>T+?, p.Gln133X+?). Serum PEDF levels were barely detectable in almost all subjects. We identified five novel mutations in SERPINF1 and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.

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.

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 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.

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.

Serum levels of pigment epithelium-derived factor (PEDF) are inversely associated with circulating levels of dipeptidyl peptidase-4 (DPP-4) in humans

BackgroundWe have previously found that advanced glycation end products (AGEs) stimulate the proteolytic cleavage of dipeptidyl peptidase-4 (DPP-4) from plasma membranes, and circulating AGE levels are independently correlated with serum DPP-4 values. Since pigment epithelium-derived factor (PEDF), one of the adipocytokines, inhibits the AGEs-induced insulin resistance and vascular damage, it is conceivable that besides AGEs, PEDF might also regulate soluble DPP-4 levels. In this study, we addressed the issue. Study design and methodsThe study involved 188 subjects (123 males and 65 females; mean age of 61.1±9.2) who visited our hospital for a risk-screening test or treatment for cardiovascular disease. They underwent complete history and physical examinations, and determination of blood chemistry and anthropometric variables, including visceral and subcutaneous fat areas. Serum levels of DPP-4 and PEDF levels were examined by enzyme-linked immunosorbent assay. ResultsMedian (interquartile range) serum levels of DPP-4 and PEDF were 466.6 (400.2–545.1) ng/mL and 14.0 (10.6–17.0) μg/mL, respectively. Multiple stepwise regression analysis revealed that female (p<0.001), aspartate aminotransferase (p<0.001), glycated hemoglobin (p<0.001) and PEDF (inversely, p=0.020) were independently associated with DPP-4 levels (R2=0.267). ConclusionWe found here for the first time that serum PEDF levels were one of the independent correlates of circulating DPP-4 levels in humans. Since DPP-4 could impair insulin action and evoke vascular damage, our present study suggests that insulin-sensitizing and atheroprotective properties of PEDF might be ascribed partly to its inhibitory actions on DPP-4.