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.

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.

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.

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.

Peptides of the variable IgG domain as potential biomarker candidates in primary open-angle glaucoma (POAG).

Autoantibody profiling has gained increasing interest in the research field of glaucoma promising the detection of highly specific and sensitive marker candidates for future diagnostic purposes. Recent studies demonstrated that immune responses are characterized by the expression of congruent or similar complementarity determining regions (CDR) in different individuals and could be used as molecular targets in biomarker discovery. Main objective of this study was to characterize glaucoma-specific peptides from the variable region of sera-derived immunoglobulins using liquid chromatography--mass spectrometry (LC-MS)-based quantitative proteomics. IgG was purified from sera of 13 primary open-angle glaucoma patients (POAG) and 15 controls (CTRL) and subsequently digested into Fab and Fc by papain. Fab was further purified, tryptic digested and measured by LC-MS/MS. Discovery proteomics revealed in total 75 peptides of the variable IgG domain showing significant glaucoma-related level changes (P < 0.05; log2 fold change ≥ 0.5): 6 peptides were high abundant in POAG sera, whereas 69 peptides were low abundant in comparison to CTRL group. Via accurate inclusion mass screening strategy 28 IgG V domain peptides were further validated showing significantly decreased expression levels in POAG sera. Amongst others 5 CDR1, 2 CDR2 and 1 CDR3 sequences. In addition, we observed significant shifts in the variable heavy chain family distribution and disturbed κ/λ ratios in POAG patients in contrast to CTRL. These findings strongly indicate that glaucoma is accompanied by systemic effects on antibody production and B cell maturation possibly offering new prospects for future diagnostic or therapy purposes.

Effect of SFRP5 (Secreted Frizzled-Related Protein 5) on the WNT5A (Wingless-Type Family Member 5A)-Induced Endothelial Dysfunction and Its Relevance With Arterial Stiffness in Human Subjects.

OBJECTIVE: SFRP5 (secreted frizzled-related protein 5) is an endogenous inhibitor of WNT5A (wingless-type family member 5a), which has been implicated in atherosclerosis. However, contradictory results have been reported about the role of SFRP5 in atherosclerosis. We aimed to investigate whether SFRP5 could restore WNT5A-induced endothelial dysfunction in vitro and ex vivo. In addition, we sought to determine whether the serum concentration of SFRP5 is associated with atherosclerosis in humans. APPROACH AND RESULTS: We measured endothelium-dependent vasorelaxation in the isolated thoracic aorta of Sprague-Dawley rats. In addition, we measured intracellular nitric oxide (NO) in human endothelial cells. The protein abundance of total and phosphorylated JNK (c-Jun N-terminal kinase), AKT (protein kinase B), and endothelial NO synthase was analyzed in human endothelial cells. Circulating SFRP5 and WNT5A levels and brachial-ankle pulse wave velocity were measured in 282 human subjects with type 2 diabetes mellitus. SFRP5 dose dependently restored Wnt5-induced impaired vasorelaxation in rat thoracic aorta by an endothelial NO synthase-dependent mechanism. SFRP5 treatment restored the WNT5A-induced reduction of NO production via endothelial NO synthase in human endothelial cells. WNT5A-induced changes in the phosphorylation of JNK, AKT, and endothelial NO synthase were ameliorated with SFRP5 administration. In humans with type 2 diabetes mellitus, the serum SFRP5 concentration positively correlated with brachial-ankle pulse wave velocity (r=0.146; P=0.024). Multivariate linear regression analysis demonstrated that the serum SFRP5 concentration was independently associated with brachial-ankle pulse wave velocity after adjustment for potential confounders [B (SE)=7.40 (3.35); P=0.028]. CONCLUSIONS: Our data suggest the possible compensatory action of SFRP5 against atherosclerosis under conditions of metabolic dysfunction.

Activation of Complement by Pigment Epithelium-Derived Factor in Rheumatoid Arthritis.

The aim of this study was to identify molecules that trigger complement activation in rheumatic joints. C4d, the final cleavage product of C4 activation, is found in the diseased joint and can bind covalently to complement-activating molecules. By using a highly specific Ab against a cleavage neoepitope in C4d, several molecules that were specifically bound to C4d were identified from pooled synovial fluid (SF) from four rheumatoid arthritis (RA) patients. One of these molecules, pigment epithelium-derived factor (PEDF), is a broadly expressed multifunctional member of the serine proteinase inhibitor family. Using ELISA, we confirmed the presence of various amounts of complexes between PEDF and C4d in the SF from 30 RA patients, whereas none were detected in SF from control subjects. Correlation analyses suggested that, in arthritis patients, C4d-PEDF complexes found in sera arise from the joints, as well as from other tissues, and levels of the complexes did not differ in sera of RA patients and healthy controls. When immobilized, recombinant PEDF expressed in eukaryotic cells activated the classical complement pathway but not the alternative or lectin pathways. C1q protein was demonstrated to bind immobilized PEDF, and PEDF was shown to bind to immobilized C1q, in particular its head regions, which are known to interact with other activators of the classical pathway. Our results call for further investigation into the role of PEDF in inflammatory processes in the joint, which, in combination with classical complement activation, appears to be part of a (patho-)physiologic response.

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.

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.

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.

Circulating secreted frizzled-related protein 5 and chronic kidney disease in patients with acute ST-segment elevation myocardial infarction.

Secreted frizzled-related protein-5 (Sfrp5) known as secreted antagonist binds to Wnt protein. It has been shown to be downregulated by histone acetylation and promoter methylation, and to function as a tumor suppressor gene by inducing apoptosis in renal cell cancer cells. However, its relationship with chronic kidney disease (CKD) has not been well studied. Our objective was to investigate the effect of plasma Sfrp5 levels in subjects with and without CKD. Plasma Sfrp5 levels were determined by enzyme-linked immunosorbent assays in 196 consecutive patients with acute ST-segment elevation myocardial infarction (STEMI). CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. For the purpose of this study, stage 1 or 2 CKD patients (eGFR ≥ 60 ml/min per 1.73 m2) were classified as not having CKD. With increasing Sfrp5 tertiles, the patients had higher frequencies of hypertension, stage 4 or 5 CKD, and waist-to-hip ratio, incrementally lower eGFRs and serum hemoglobin levels, and higher levels of blood urine nitrogen (BUN), creatinine, and adiponectin. Multivariate logistic regression analysis showed that an increased plasma Sfrp5 level was independently associated with CKD for all subjects (adjusted odds ratio (OR), 1.08; 95% confidence interval (CI), 1.02-1.14; p = 0.011). Sfrp5 was also significantly positively related to BUN, creatinine, and adiponectin, and significantly negatively related to eGFR and hemoglobin. When the patients were stratified by age, plasma Sfrp5 level was independently related to CKD for patients >65 years old (adjusted OR, 1.10; 95% CI, 1.00-1.20; p = 0.045), however, the association was not significant for those <65 years old. In addition, Sfrp5 was significantly positively related to BUN, creatinine, and adiponectin, and significantly negatively related to eGFR and hemoglobin in patients >65 years old. Our results suggest that Sfrp5 may play a role in the pathogenesis of CKD in acute STEMI patients who are older than 65 years.

Plasma levels of hypoxia-regulated factors in patients with age-related macular degeneration.

PURPOSE: Various hypoxia-related proteins are differentially expressed in the retina and secreted to the vitreous and/or aqueous humor of patients affected by dry or neovascular age-related macular degeneration (nAMD). To determine whether these conditions alter concentrations of cytokines also in the systemic circulation, we measured plasma levels of six hypoxia-related proteins. METHODS: Plasma was prepared from EDTA blood that was collected from patients affected by dry AMD (n = 5), nAMD (n = 11), proliferative diabetic retinopathy (PDR; n = 9), and patients with an epiretinal membrane (ERM; n = 11). ERM samples served as negative controls, PDR samples as positive controls. Protein concentrations of vascular endothelial growth factor (VEGF), erythropoietin (EPO), angiopoietin-like 4 (ANGPTL4), placental growth factor (PlGF), tumor necrosis factor alpha (TNF-α), and pigment epithelium-derived factor (PEDF) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The concentration of PlGF was significantly increased in plasma of patients affected by nAMD. Although no statistically significant differences were found for EPO, ANGPTL4, PlGF, TNF-α, and PEDF, the mean concentration of VEGF was lowest in the nAMD group. Plasma concentrations of the six factors did not correlate with gender or age of patients. CONCLUSIONS: nAMD may increase plasma concentrations of PlGF, making it a candidate as a biomarker for the neovascular form of AMD. Other factors, however, were not differentially regulated, suggesting that their systemic concentrations are not generally increased in hypoxia-related retinal diseases.

Correlation Between Pigment Epithelium-Derived Factor (PEDF) level and Degree of Coronary Angiography and Severity of Coronary Artery Disease in a Chinese Population.

BACKGROUND The role of pigment epithelium-derived factor (PEDF) in protection of coronary artery disease (CAD) remains controversial. The aim of this study was to reassess the value of PEDF in predicting the severity and prognosis of newly diagnosed stable CAD in a Chinese population. MATERIAL AND METHODS Plasma PEDF levels were measured in 259 stable CAD patients undergoing coronary angiography and 116 age- and sex-matched healthy controls. The severity of coronary atherosclerosis was assessed using Gensini score. RESULTS PEDF levels were significantly lower in CAD patients than in healthy subjects (5.856±0.790 vs. 6.658±1.070 µg/ml, respectively, p<0.01). Stepwise regression analysis showed a negative correlation between PEDF levels and severity of CAD as quantified by Gensini score value (ß=-0.626, p<0.01). CONCLUSIONS Our study showed that plasma PEDF levels were significantly lower in CAD patients than in controls, and the plasma PEDF levels may be used as a potential predicator for coronary severity.

Proteomics reveals the effects of sustained weight loss on the human plasma proteome.

Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individual's health state remain ill-defined. Here, we investigate the plasma proteomes of a cohort of 43 obese individuals that had undergone 8 weeks of 12% body weight loss followed by a year of weight maintenance. Using mass spectrometry-based plasma proteome profiling, we measured 1,294 plasma proteomes. Longitudinal monitoring of the cohort revealed individual-specific protein levels with wide-ranging effects of losing weight on the plasma proteome reflected in 93 significantly affected proteins. The adipocyte-secreted SERPINF1 and apolipoprotein APOF1 were most significantly regulated with fold changes of -16% and +37%, respectively (P < 10-13), and the entire apolipoprotein family showed characteristic differential regulation. Clinical laboratory parameters are reflected in the plasma proteome, and eight plasma proteins correlated better with insulin resistance than the known marker adiponectin. Nearly all study participants benefited from weight loss regarding a ten-protein inflammation panel defined from the proteomics data. We conclude that plasma proteome profiling broadly evaluates and monitors intervention in metabolic diseases.

Inverse associations between serum levels of secreted frizzled-related protein-5 (SFRP5) and multiple cardiometabolic risk factors: KORA F4 study.

AIMS: Secreted frizzled-related protein (Sfrp)5 has beneficial effects on insulin sensitivity, inflammation and cardiovascular risk in different mouse models, but its relevance for cardiometabolic diseases in humans is controversial. We aimed to characterise associations of circulating SFRP5 with cardiometabolic risk factors and prediabetes/type 2 diabetes in a large population-based cohort. METHODS: Cross-sectional associations between serum SFRP5 and cardiometabolic risk factors as well as prediabetes/type 2 diabetes were investigated in 1096 participants aged 62-81 years from the German KORA F4 study, of whom 666 had prediabetes or type 2 diabetes. Multivariable linear regression models were adjusted for potential confounders including age, sex, body mass index (BMI), lifestyle factors, lipids, hypertension, kidney function and myocardial infarction. RESULTS: Higher serum SFRP5 levels were associated with lower HbA1c, BMI, systolic blood pressure, estimated glomerular filtration rate and high-sensitivity C-reactive protein levels and with higher levels of high-density lipoprotein cholesterol and adiponectin in the fully adjusted model (all P < 0.009). In contrast, favourable associations between SFRP5 and glycaemia, insulin, insulin resistance and other cardiometabolic risk factors were attenuated after adjustment for BMI. Serum SFRP5 levels were lower in participants with prediabetes or type 2 diabetes [(median (25th; 75th percentile) 48.8 (35.5; 65.7) ng/ml] compared to participants with normal glucose tolerance [55.9 (42.6; 69.6) ng/ml] (P < 0.001). In the fully adjusted model, higher SFRP5 was associated with lower odds of prediabetes/type 2 diabetes [OR (95% CI) (0.72 (0.58; 0.89)) per doubling of SFRP5, P < 0.01]. CONCLUSIONS: Higher serum SFRP5 was inversely associated with multiple risk factors for type 2 diabetes and cardiovascular diseases. However, BMI represents a strong confounder of some of these associations. Higher circulating SFRP5 was also associated with lower odds of prediabetes/type 2 diabetes, and this association was independent of BMI. Thus, SFRP5 emerges as novel biomarker that merits further research in the context of prevention of cardiometabolic diseases.

Plasma Sfrp5 levels correlate with determinants of the metabolic syndrome in Chinese adults.

BACKGROUND: Secreted frizzled-related protein-5 (Sfrp5) is a novel adipokine, and it has been found to link insulin resistance with diabetes. Animal studies have revealed the role of Sfrp5 in regulating lipid and glucose metabolism. The objective of this study was to investigate the relationship between Sfrp5 and the metabolic syndrome (MetS) in a cross-sectional study. METHODS: We conducted a series of cross-sectional studies of Chinese population including 194 control participants and 90 MetS patients. Circulating Sfrp5 concentrations were determined by ELISA. The relationships between circulating Sfrp5 levels and MetS components were assessed. RESULTS: Circulating Sfrp5 was significantly lower in newly examined MetS patients than in control participants (49.1 ± 17.2 vs 61.6 ± 23.2 µg/L, P < .01). Circulating Sfrp5 correlated negatively with markers of adiposity (waist-to-hip ratio, body mass index, and free fatty acids, P < .001 or P < .05). Furthermore, Sfrp5 levels correlated with fasting insulin, 2 h-ins, fasting blood glucose, 2 h post-glucose load blood glucose, HbA1c , and homeostasis model assessment of insulin resistance. In addition, circulating Sfrp5 levels were closely associated with blood pressure, high-density lipoprotein cholesterol, triglycerides, and atherosclerotic index. Circulating concentrations of Sfrp5 decreased progressively with continued increases in the numbers of MetS components. The analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating Sfrp5 to predict MetS was 46.8 µg/L (sensitivity 70.1 %, specificity 47.8 %, and AUC 0.66). CONCLUSIONS: We conclude that Sfrp5 may be an adipokine that is associated with the pathogenesis of MetS in humans.

Diabetic nephropathy: serum miR-9 confers a poor prognosis in and is associated with level changes of vascular endothelial growth factor and pigment epithelium-derived factor.

OBJECTIVE: To investigate the relationship between the serum level of miR-9 and the progression of diabetic nephropathy (DN) and related molecular mechanisms. RESULTS: Thirty-five healthy subjects and 140 DN patients were divided into five groups: control, DN I-II, DN III, DN IV and DN V. Serum level of miR-9 was measured by real-time qPCR. Serum levels of vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF) lipids, fasting glucose, insulin, hemoglobin A1c (HBA1c), creatinine, fibrinogen and insulin resistance (HOMA-IR) were also measured. The results show that the levels of miR-9, PEDF and VEGF are increased with DN progression (P < 0.05). miR-9, VEGF and PEDF are independent risk factors of DN (R2 = 0.430). Spearman rank correlation analysis showed that miR-9 level is positively related to the levels of VEGF, PEDF, cholesterol, triglyceride, fasting glucose, fasting insulin, HBA1c, creatinine, fibrinogen and HOMA-IR (P < 0.05). CONCLUSIONS: Serum miR-9 is a potential marker for conferring a poor prognosis in DN and associated with the levels of VEGF, PEDF and biochemical indices.

Secreted Frizzled-Related Protein 5 (SFRP5) in Patients with Obstructive Sleep Apnea.

Objective Obstructive sleep apnea (OSA) is closely related to obesity, insulin resistance and inflammation. Secreted frizzled-related protein 5 (SFRP5) is a recently discovered adipokine. It is involved in insulin resistance and inflammation in obesity. This study aimed at evaluating the association between SFRP5 and sleeping characteristics as well as biochemical parameters of OSA patients. Methods This was a prospective case control study. Nondiabetic OSA patients and controls were consecutively recruited and divided into three groups: OSA group, apnea-hypopnea Index (AHI)≥5/h; healthy controls with normal body mass index (BMI); obese controls without OSA, and BMI > 24.0 kg/m2. All participants underwent polysomnography (PSG). Plasma SFRP5 was examined using enzyme-linked immunosorbent assay (ELISA). Blood biochemical examinations, including fasting blood glucose (FBG), lipid profile, hypersensitive C-reactive protein (hsCRP), were performed early in the morning after PSG. Patients with severe OSA were treated with nasal continuous positive airway pressure (nCPAP), and plasma SFRP5 was repeatedly measured for comparison. Results Sixty-eight subjects were enrolled in the study, including 38 patients of OSA, whose medium AHI was 58.70 /h (36.63, 71.15), 20 obese controls, and 10 healthy controls. The plasma SFRP5 level of OSA patients was not significantly different from that of healthy controls or obese controls. In OSA patients, SFRP5 level correlated positively with triglyceride level (r=0.447, P=0.005) and negatively with LDL-cholesterol level and HDL- cholesterol level (r=-0.472 and P=0.003; r=-0.478 and P=0.002; respectively). SFRP5 level was not found correlating with FBG, AHI, or any of nocturnal hypoxia parameters. After overnight nCPAP treatment, plasma SFRP5 levels of OSA patients did not change significantly (t=1.557, P = 0.148) compared to that of pretreatment. Conclusions In nondiabetic OSA patients, plasma SFRP5 is associated with the lipid profile. However, no correlation was observed between SFRP5 and FBG or sleep parameters. The SFRP5 level of OSA patients did not differ from that of non-OSA individuals in our study.

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.