METFORMIN MODULATED ADIPOKINES BIOCHEMICAL MARKERS IN TYPE-2 DIABETES PATIENTS.

Type 2 diabetes mellitus is the most widespread type of diabetes, mainly affecting adults. Long-term complications are related to the progression of type 2 diabetes mellitus. Metformin is a key treatment option for type 2 diabetes. OBJECTIVES: To evaluate serum irisin, visfatin, and RBP4 levels and to determine the effects of metformin treatment on irisin, visfatin, and RBP4 levels in patients with type 2 diabetes mellitus (Type 2 DM). MATERIAL AND METHODS: A total of 70 patients with type 2 diabetes mellitus, aged between 48 and 82 years were enrolled in the current study. Serum collected and irisin, visfatin, and RBP4 levels were measured, in Type 2 DM patients and control, using the ELISA Kit. RESULTS: The findings observed that there were significantly increased levels of irisin, visfatin, and RBP4 in patients with T2DM when compared with control groups. After 3 months of metformin treatment, irisin levels significantly decreased irisin, visfatin, and RBP4 in patients with T2DM when compared before treatment. Receiver operator characteristic curve investigation shows the levels of visfatin, and irisin are the best biomarkers differentiating subjects with T2DM. CONCLUSION: In patients with type 2 diabetes, 3 months of treatment with metformin reduces levels of Irisin, Visfatin, and RBP4.The clinical significance of these findings remains to be investigated.

Association of selected adipokines with vitamin D deficiency in children with inflammatory bowel disease.

BACKGROUND: Adipose tissue is significantly involved in inflammatory bowel disease (IBD). Vitamin D can affect both adipogenesis and inflammation. The aim of this study was to compare the production of selected adipokines, potentially involved in the pathogenesis of IBD - adiponectin, resistin, retinol binding protein 4 (RBP-4), adipocyte fatty acid binding protein and nesfatin-1 in children with IBD according to the presence of 25-hydroxyvitamin D (25(OH)D) deficiency. METHODS: The study was conducted as a case-control study in pediatric patients with IBD and healthy children of the same sex and age. In addition to adipokines and 25(OH)D, anthropometric parameters, markers of inflammation and disease activity were assessed in all participants. RESULTS: Children with IBD had significantly higher resistin levels regardless of 25(OH)D levels. IBD patients with 25(OH)D deficiency only had significantly lower RBP-4 compared to healthy controls and also compared to IBD patients without 25(OH)D deficiency. No other significant differences in adipokines were found in children with IBD with or without 25(OH)D deficiency. 25(OH)D levels in IBD patients corelated with RBP-4 only, and did not correlate with other adipokines. CONCLUSIONS: Whether the lower RBP-4 levels in the 25(OH)D-deficient group of IBD patients directly reflect vitamin D deficiency remains uncertain. The production of other adipokines does not appear to be directly related to vitamin D deficiency.

Diagnostic value of retinol-binding protein 4 in diabetic nephropathy: a systematic review and meta-analysis.

Objective: Diabetic nephropathy (DN) is a major microvascular complication of diabetes and the leading cause of end-stage renal disease. Early detection and prevention of DN are important. Retinol-binding protein 4 (RBP4) has been considered as a single diagnostic marker for the detection of renal impairment. However, the results have been inconsistent. The present meta-analysis aimed to determine the diagnostic potential of RBP4 in patients in type 2 diabetes mellitus (T2DM) with DN. Methods: We searched PubMed, Web of Science, Embase, Wanfang and CNKI databases from inception until January 2024. The meta-analysis was performed by Stata version 15.0, and sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR) and area under the curve (AUC) were pooled. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was utilized to assess the quality of each included study. In addition, heterogeneity and publication bias were evaluated. Results: Twenty-nine studies were included in the meta-analysis. The pooled sensitivity and specificity were 0.76 [95% confidence interval (CI), 0.71-0.80] and 0.81 (95% CI, 0.76-0.85), respectively. The results showed a pooled PLR of 4.06 (95% CI, 3.16-5.21), NLR of 0.29 (95% CI, 0.24-0.36) and DOR of 13.76 (95% CI, 9.29-20.37). The area under the summarized receiver operating characteristic curve was given a value of 0.85 (95% CI, 0.82-0.88). No obvious publication bias existed in the Deeks' funnel plot asymmetry test. Conclusion: Our findings suggest that RBP4 has a promising diagnostic value with good sensitivity and specificity for patients with T2DM with DN.

iTRAQ-based mass spectrometry screen to identify serum biomarkers in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disorder with no reliable serum biomarkers currently available other than autoantibodies. METHODS: In the present study, isobaric tags for relative and absolute quantitation-based mass spectrometry was used to screen the sera of patients with SLE to uncover potential disease biomarkers. RESULTS: 85 common proteins were identified, with 16 being elevated (≥1.3) and 23 being decreased (≤0.7) in SLE. Of the 16 elevated proteins, serum alpha-1-microglobulin/bikunin precursor (AMBP), zinc alpha-2 glycoprotein (AZGP) and retinol-binding protein 4 (RBP4) were validated in independent cross-sectional cohorts (Cohort I, N=52; Cohort II, N=117) using an orthogonal platform, ELISA. Serum AMBP, AZGP and RBP4 were validated to be significantly elevated in both patients with inactive SLE and patients with active SLE compared with healthy controls (HCs) (p<0.05, fold change >2.5) in Cohort I. All three proteins exhibited good discriminatory power for distinguishing active SLE and inactive SLE (area under the curve=0.82-0.96), from HCs. Serum AMBP exhibited the largest fold change in active SLE (5.96) compared with HCs and correlated with renal disease activity. The elevation in serum AMBP was validated in a second cohort of patients with SLE of different ethnic origins, correlating with serum creatinine (r=0.60, p<0.001). CONCLUSION: Since serum AMBP is validated to be elevated in SLE and correlated with renal disease, the clinical utility of this novel biomarker warrants further analysis in longitudinal cohorts of patients with lupus and lupus nephritis.

One Novel Urinary Biomarkers of Acute Kidney Injury in Patients After Allogeneic Hematopoetic Stem Cell Transplantation.

Hematopoietic stem cell transplantation could be complicated by acute kidney injury and chronic kidney disease. It may be due to either previous chemotherapy or exposure to a variety of nephrotoxic drug or other causes. The aim of the study was to assess biomarkers of kidney injury in patients at least 3 months after hematopoetic stem cell transplantation (HSCT) under ambulatory care of the Hematology, Transplantation and Internal Medicine Department. We studied 80 prevalent patients after allogeneic HSCT and 32 healthy volunteers to obtain normal ranges of biomarkers. In this cross-sectional study we assessed retinol-binding protein 4 (RBP4), a biomarker of kidney injury in urine using commercially available assays. It was significantly higher in patients after HSCT when compared to healthy volunteers. When we divided patients according to kidney function (below and over 60 mL/min/1.72 m2), we found that the concentration of RBP4 was significantly higher in 23 patients with chronic kidney disease stage 3 compared to patients with estimated glomerular filtration (eGFR) over 60 mL/min/1.72 m2. In univariate correlations RBP4 was positively related to serum creatinine (r = 0.34, P < .01) and inversely to eGFR (r = -0.20, P < .05). Patients after allogeneic HSCT despite normal or near normal kidney function show evidence of kidney injury.

Does Retinol-Binding Protein 4 (holo- and apo-RBP4) Increase or Remain Constant in Sera from Patients with Hypothyroidism?

Retinol-binding protein 4 (RBP4) is a retinol transporter in the blood plasma. Many diseases alter the plasma or serum levels of RBP4. Since serum RBP4 concentrations have been reported to decrease in hyperthyroidism, this study investigated whether serum RBP4 concentrations increased or remained constant in hypothyroidism. In sera from patients with hypothyroidism (n=71), hyperthyroidism (n=30), and healthy subjects (n=20), serum concentrations of RBP4 (sum of holo- and apo-RBP4), retinol, albumin, creatinine, and related constituents were measured, and RBP4/retinol molar ratio (as an index of apo-RBP4) and estimated glomerular filtration rate (eGFR) were calculated. The results showed that serum RBP4 concentrations tended to increase with decreasing free thyroxine concentrations, but there were no significant differences among patients with hypothyroidism, hyperthyroidism, and healthy subjects. When patients with hypothyroidism were subdivided by serum RBP4 level using 2.1 µmol/L cut-off value, patients with >2.1 µmol/L were revealed to be patients with older age having lower tri-iodothyronine, higher holo-RBP4, higher apo-RBP4, higher retinol, higher RBP4/retinol molar ratio, and lower eGFR than those in patients with <2.1 µmol/L. Multiple regression analysis showed significant associations between serum RBP4 levels and explanatory variables (retinol and eGFR). Although serum levels of RBP4 prior to the onset of renal dysfunction may affect the present concentrations, we conclude that the increase of serum RBP4 (both holo- and apo-RBP4) in patients with hypothyroidism was attributed to the decline in eGFR. In contrast, serum RBP4 concentration remained constant without renal dysfunction.

ALB, HP, OAF and RBP4 as novel protein biomarkers for identifying cured patients with pulmonary tuberculosis by DIA.

BACKGROUND: Pulmonary tuberculosis (TB) is a serious infectious disease that lacks robust blood-based biomarkers to identify cured TB. Some discharged patients are not fully cured and may relapse or even develop multidrug-resistant TB. This study is committed to finding proteomic-based plasma biomarkers to support establishing laboratory standards for clinical TB cure. METHODS: Data-independent acquisition (DIA) was used to obtain the plasma protein expression profiles of TB patients at different treatment stages compared with healthy controls. Multivariate statistical methods and bioinformatics were used to analyze the data. RESULTS: Bioinformatic analysis suggests coagulation dysfunction and vitamin and lipid metabolism disturbances in TB. Albumin (ALB), haptoglobin (HP), out at first protein homolog (OAF), and retinol-binding protein 4 (RBP4) can be used to establish a diagnostic model for the efficacy evaluation of TB with an area under the curve of 0.963, which could effectively distinguish untreated TB patients from cured patients. CONCLUSIONS: Our research demonstrated that ALB, HP, OAF and RBP4 can be potential biomarkers for evaluating the efficacy of TB. These findings may provide experimental data for establishing the laboratory indicators of clinical TB cure and providing clinicians with new targets for exploring the underlying mechanisms of TB pathogenesis.

Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patients.

The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, or in the transcriptionally active form as retinoic acid. The main function of retinol binding protein 4 (RBP4), synthesized in the liver, is to transport hydrophobic vitamin A to various tissues. Vitamin A has an important role in the innate and acquired immune system. In particular, it is involved in the repair of lung tissue after infections. In viral respiratory diseases such as influenza pneumonia, vitamin A supplementation has been shown to reduce mortality in animal models. In critically ill COVID-19 patients, a significant decrease in plasma vitamin A levels and an association with increased mortality have been observed. However, there is no evidence on RBP4 in relation to COVID-19. This prospective, multicenter, observational, cross-sectional study examined RBP4 (enzyme-linked immunosorbent assay) and vitamin A plasma levels (high-performance liquid chromatography) in COVID-19 patients, including 59 hospitalized patients. Of these, 19 developed critical illness (ARDS/ECMO), 20 developed severe illness (oxygenation disorder), and 20 developed moderate illness (no oxygenation disorder). Twenty age-matched convalescent patients following SARS-CoV-2 infection, were used as a control group. Reduced RBP4 plasma levels significantly correlated with impaired liver function and elevated inflammatory markers (CRP, lymphocytopenia). RBP4 levels were decreased in hospitalized patients with critical illness compared to nonpatients (p < 0.01). In comparison, significantly lower vitamin A levels were detected in hospitalized patients regardless of disease severity. Overall, we conclude that RBP4 plasma levels are significantly reduced in critically ill COVID-19 patients during acute inflammation, and vitamin A levels are significantly reduced in patients with moderate/severe/critical illness during the acute phase of illness.

Baseline Levels of Retinol-Binding Protein 4 and Vitamin A in Healthy Subjects, Stargardt Disease, and Geographic Atrophy Patients.

INTRODUCTION: The accumulation of lipofuscin is a hallmark in the pathogenesis of Stargardt disease type 1 (STGD1) and geographic atrophy (GA) secondary to age-related macular degeneration. Limiting lipofuscin accumulation by inhibiting the retinol-binding protein 4 (RBP4) is being explored as a potential treatment target for those diseases. In this study, we aimed to establish the concentration of RBP4 in the systemic circulation in different age cohorts of healthy individuals and to check if patients with STGD1 or GA may show abnormal RBP4 levels. METHODS: Forty healthy subjects of various age-groups, 15 Stargardt patients, and 15 GA patients were included in the study. We measured RBP4 levels, serum retinol (SR) levels, complete blood count, and blood chemistry including liver function tests. RESULTS: Mean RBP4 for all cohorts was 26,911.40 ± 6,198.61 ng/mL, and mean SR 1.75 ± 0.36 µmol/L. Age was not found to significantly impact levels neither of RBP4 and SR nor of the RBP4-to-SR ratio. Also, the 2 patient groups showed similar blood levels to their age-matched controls. CONCLUSION: Serum RBP4 and SR do not appear to be affected by age in healthy individuals and remain within normal limits in both STGD1 and GA.

Transthyretin and retinol-binding protein as discriminators of diabetic retinopathy in type 1 diabetes mellitus.

PURPOSE: Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM), which is still a major reason for blindness. Transthyretin (TTR) and retinol-binding protein (RBP) are thought to be related to the pathogenesis both in T2DM and T1DM. We aimed to investigate the association between serum levels of TTR, RBP, RBP/TTR ratio, and DR. METHODS: This retrospective study involved 188 T1DM inpatients divided into two groups: patients with DR (n = 95) and patients without DR (n = 93). Data of serum levels on lipids and inflammation were collected. Multiple logistic regression analysis was performed to research the association between TTR, RBP, RBP/TTR, and diabetic retinopathy in T1DM. RESULTS: Compared with patients without DR, those with DR have a higher level of TTR (207 versus 195 mg/L, p = 0.034) and RBP4 (36.85 versus 25.68 mg/L, p < 0.001). Significant differences were also observed between two groups with respect to body mass index (BMI), blood pressure (BP), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), homocysteine, apolipoprotein B (APOB), leucocyte, monocyte, neutrophil, and uric acid (p < 0.05 for all). TTR, RBP, and RBP/TTR were positively correlated with BP, BMI, TG, LDL, homocysteine, APOB, and uric acid. A multivariate logistic regression model revealed individuals with RBP4 level in the highest quartile had 58.95 times higher risk of developing diabetic retinopathy than those in the lowest quartile. CONCLUSIONS: In conclusion, TTR, RBP, and RBP/TTR ratio are risk factors of DR in T1DM. They are potential markers and targets for diagnosis and treatment of DR.

Plasma Retinol Binding Protein 4 as a Biomarker for Detecting Progressive Stroke and Prediction of Early Prognosis in Patients with Acute Ischemic Stroke.

Aim and Purpose: Progressive Stroke (PS) lacks effective treatment measures and leads to serious disability or death. Retinol binding protein 4 (RBP4) could be closely associated with acute ischemic stroke (AIS). We aimed to explore plasma RBP4 as a biomarker for detecting the progression in patients with AIS. METHODS: Participants of this retrospective study were 234 patients with AIS within the 48 h onset of disease. The primary endpoint was to ascertain if there was PS through the National Institute of Health stroke scale (NIHSS); the early prognosis was confirmed through the modified Rankin scale score (mRS) at discharge or 14 days after the onset of stroke, and the significance of demographic characteristics and clinical data was determined. RESULTS: In this study, 43 of 234 patients demonstrated PS. The level of plasma RBP4 in patients with progressive stroke was significantly lower (29 mg/L, 22.60-40.38 mg/L) than that without progression (38.70 mg/L, 27.28-46.40 mg/L, P = 0.003). In patients with lower plasma RBP4, the proportion of patients with progression (χ2 = 9.63, P = 0.008) and with mRS scores ≥2 (χ2 = 6.73, P = 0.035) was significantly higher. Multivariate logistic regression analysis showed that a lower RBP4 level on admission was an independent risk factor for progressive stroke during hospitalization with an OR value of 2.70 (P = 0.03, 95% CI: 1.12-6.52). CONCLUSION: A low plasma RBP4 level on admission could be an independent risk factor of PS during hospitalization.

The prognostic role of RBP-4 and adiponectin in patients with peripheral arterial disease undergoing lower limb endovascular revascularization.

BACKGROUND: RBP4 is an adipokine with an established role in atherosclerosis, while adiponectin has unique anti-inflammatory properties. We investigated the association of RBP4 and adiponectin with the presence of symptomatic peripheral artery disease (PAD) and their possible prognostic role in major adverse cardiovascular events (MACE). METHODS: We enrolled 168 consecutive patients with symptomatic, established PAD, requiring revascularization by endovascular means of any or both of their lower limbs. 88 age- and sex-matched subjects with less than 2 classical cardiovascular risk factors served as controls. Clinical parameters, glycemic and lipid profile, RBP4 and adiponectin levels were assayed. The occurrence of MACE was recorded during the 6-month follow-up and patients were assigned to MACE and non-MACE subgroups. RESULTS: The presence of symptomatic PAD was significantly correlated with age, diabetes, hsCRP, RBP4 and low adiponectin levels (p < 0.05). After adjustment for age, RBP4 (ß = 0.498, p < 0.001), and adiponectin (ß = -0.288, p < 0.001) levels remained as independent predictors of PAD presence in the whole study cohort. At baseline, MACE subgroup appeared with higher RBP-4 and hsCRP serum levels than non-MACE subgroup (p < 0.001), but no differences were detected for adiponectin (p = 0.758). Serum RBP4 levels remained independent predictor of MACE (ß = 0.455, p < 0.001) after adjustment for traditional cardiovascular risk factors. CONCLUSIONS: High RBP4 and low adiponectin serum levels are independently associated with PAD presence. In addition, RBP4 is an independent predictor of MACE incidence in symptomatic PAD patients.

A dual-quenched ECL immunosensor for ultrasensitive detection of retinol binding protein 4 based on luminol@AuPt/ZIF-67 and MnO2@CNTs.

BACKGROUND: Retinol binding protein 4 (RBP4) has been regarded as an important serological biomarker for type 2 diabetes mellitus (T2DM). Hence, the construction of a highly sensitive detection method for RBP4 is the key to early prevention and multidisciplinary intervention of T2DM. In this work, a dual-quenched electrochemiluminescence (ECL) immunosensor has been fabricated for ultrasensitive detection of RBP4 by combining zeolitic imidazolate framework-67/AuPt-supported luminol (luminol@AuPt/ZIF-67) with MnO2 nanosheets-grown on carbon nanotubes (MnO2@CNTs). RESULTS: AuPt/ZIF-67 hybrids with high-efficiency peroxidase-like activity could provide multipoint binding sites for luminol and antibodies and significantly boost the amplified initial signal of the ECL immunosensor. Upon glutathione/H2O2 coreactants system, MnO2@CNTs composites could quench the initial signal by inhibiting mimic peroxidase activity of luminol@AuPt/ZIF-67. Moreover, the absorption spectrum of the MnO2@CNTs composites completely overlaps with the emission spectrum of luminol, which can further reduce initial signal by ECL resonance energy transfer (ECL-RET). CONCLUSIONS: Benefiting from the above-mentioned properties, the designed immunoassay sensitivity exhibited excellent sensitivity and relative stability for RBP4 detection range from 0.0001 to 100 ng mL-1 with a low detection limit of 43 fg mL-1. Therefore, our ECL immunosensor provides an alternative assaying strategy for early diagnosis of T2DM.

Circulating retinol binding protein 4 levels in coronary artery disease: a systematic review and meta-analysis.

BACKGROUND: Retinol binding protein 4 (RBP4) has been proposed to play a role in the pathophysiology of coronary artery disease (CAD), but previous findings on the association of RBP4 levels with CAD are inconsistent. METHODS: A meta-analysis based on observational studies was conducted to evaluate the association between circulating RBP4 levels and CAD. Databases including PubMed, Web of Science, Embase, Google Scholar and ClinicalTrials.gov database were searched for eligible studies published up to 12 July 2021. Standard mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using the inverse variance heterogeneity (IVhet) and random-effects model for data with moderate and high heterogeneity (I2 > 30%) and data with low heterogeneity were analysed using a fixed-effects model (I2 ≤ 30%). Moreover, a bias-adjusted quality-effects model was generated, and the prediction interval was also calculated under the random-effects model. RESULTS: Two nested case-control studies, one cohort study and twelve case-control studies with a total of 7111 participants were included. Circulating RBP4 levels in patients with CAD were comparable to those in the controls under the IVhet model (SMD: 0.25, 95% CI: - 0.29-0.79, I2: 96.00%). The quality-effects model produced consistent results. However, the association turned to be significant under the random-effect model (SMD: 0.46, 95% CI: 0.17-0.75, I2: 96.00%), whereas the 95% predictive interval (PI) included null values (95% PI: - 0.82-1.74). Subgroup analyses illustrated a positive relationship between CAD and RBP4 levels in patients with complications (SMD: 1.34, 95% CI: 0.38-2.29, I2: 96.00%). The meta-regression analysis revealed that the mean BMI of patients (P = 0.03) and complication status (P = 0.01) influenced the variation in SMD. CONCLUSIONS: There was low-quality evidence that patients with CAD exhibited similar circulating RBP4 levels compared with controls, and high inter-study heterogeneity was also observed. Thus, RBP4 might not be a potential risk factor for CAD. Comparisons among different subtypes of RBP4 with larger sample size are needed in the future.

Retinol-binding protein 4 in combination with lipids to predict the regression phenomenon of autism spectrum disorders.

BACKGROUND: About 20-40 % of autistic people experience a phenomenon of regression. Retinol binding protein 4 (RBP4) plays an important role as an inflammatory neurotrophic adipokine and is a promising mediator of the fat-brain axis. Abnormal fatty acid metabolism and lipid mediators have been reported to be related to the etiological mechanism in autism, and amelioration of impaired lipid metabolism can be recognized as a treatment strategy for autism. The purpose of this study is to explore the relationship between RBP4, lipids, and the autistic regression phenomenon, and to discuss their potentials as biomarkers for the autistic regression phenomenon. METHODS: A total of 60 autistic individuals (18 with regression phenomenon, 42 without regression phenomenon) (ASD group) and 36 healthy controls were enrolled in this case-control study. The levels of RBP4, total cholesterol (TC), high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglyceride (TG) were measured. Childhood Autism Rating Scale (CARS) is used to assess the severity of autism. Ethical measures were performed in compliance with the current Declaration of Helsinki and written informed consent was obtained from the parents before enrollment of the children and adolescents. RESULTS: Compared with control subjects, autistic individuals had lower levels of TC (P = 0.007), RBP4 (P = 0.001), and HDLC (P = 0.027). The levels of RBP4 in ASD group were positively correlated with TG (r = 0.355, P = 0.005), HDLC (r = 0.257, P = 0.047), TG/TC (r = 0.376, P = 0.003) and TG/LDLC (r = 0.363, P = 0.004), and were negatively correlated with CARS (r=-0.296, P = 0.003). Further logistic regression demonstrated that decreased RBP4 concentration was associated with the presentation of the autistic regression phenomenon even after the adjustment of the potential confounding factors. CONCLUSIONS: Serum RBP4 is associated with the autistic regression phenomenon and the severity of ASD. Further studies are needed to expound whether decreased RBP4 participates in the development of the autistic regression phenomenon.

Retinol-binding protein 4 and plasminogen activator inhibitor-1 as potential prognostic biomarkers of non-allergic asthma caused by obesity in adolescents.

BACKGROUND: Non-allergic asthma caused by obesity is a complication of the low-grade chronic inflammation inherent in obesity. Consequently, the serum concentrations of adipokines such as retinol-binding protein 4 (RBP4) and plasminogen activator inhibitor-1 (PAI-1) increase. No gold standard molecule for the prediction of non-allergic asthma among obese patients has been identified. OBJECTIVE: To evaluate RBP4 and PAI-1 as prognostic biomarkers of non-allergic asthma caused by obesity. METHODS: A cross-sectional study between four groups of adolescents: (1) healthy (n = 35), (2) allergic asthma without obesity (n = 28), (3) obesity without asthma (n = 33), and (4) non-allergic asthma with obesity (n = 18). RESULTS: RBP4 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (39.2 ng/mL [95% confidence interval (CI): 23.8-76.0] vs. 23.5 ng/mL [95% CI: 3.2-33.5], p < 0.01), and PAI-1 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (21.9 ng/mL [95% CI: 15.7-26.5] vs. 15.9 ng/mL [95% CI: 9.4-18.2], p < 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated that the serum RBP4 cut-off value was >42.78 ng/mL, with an area under the ROC curve (AUC) of 0.741 (95% CI: 0.599-0.853, p = 0.001), considered acceptable. The PAI-1 cut-off value was >12.0 ng/mL, with an AUC of 0.699 (95% CI: 0.554-0.819, p = 0.008), considered fair. CONCLUSIONS: RBP4 may be useful to predict non-allergic asthma among obese adolescents in clinical practice.

Associations of dietary fats intake and adipokines levels in obese women.

AIM: RBP4, Vaspin and omentin-1 are adipokines, which play an important role in the development of obesity-related complications. The main aim of this study was to investigate the effects of different kinds of fat intake on adipokine levels in obese women. METHODS: A total of 272 obese women (BMI ≥ 30) were included in the current cross-sectional study, according to the inclusion and exclusion criteria. Body composition was measured using a body composition analyzer. For the measurement of retinol binding protein 4 (RBP4), vaspin and omentin-1 serum concentrations, an enzyme-linked immunosorbent assay (ELISA) method was used. Dietary intake was assessed using a 3-day 24-h dietary recall. RESULTS: Statistically significant differences were found between polyunsaturated fatty acid (PUFAs) and linoleic acid intake and vaspin and omentin-1 levels. In addition, there were found statistically significant relationships between cholesterol, monounsaturated fatty acid (MUFAs) and total fat intakes with omentin-1 levels. Also, RBP4 and vaspin levels were different significant with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake. Moreover, the results revealed that there were statistically significant differences between RBP4 levels and α-linolenic acid and oleic acid intake. CONCLUSION: This study revealed that by examining RBP4, vaspin and omentin-1 as adipokines, a novel link between fat intakes and adipokine levels was found.

Association of Retinol-Binding Protein 4 with Arteriovenous Fistula Dysfunction in Hemodialysis Patients.

BACKGROUND: Arteriovenous fistula (AVF) is the most common vascular access for patients undergoing hemodialysis (HD). Neointimal hyperplasia (NIH) might be a potential mechanism of AVF dysfunction. Retinol-binding protein 4 (RBP4) may play an important role in the pathogenesis of NIH. The aim of this study was to investigate whether AVF dysfunction is associated with serum concentrations of RBP4 in HD subjects. METHODS: A cohort of 65 Chinese patients undergoing maintenance HD was recruited between November 2017 and June 2019. The serum concentrations of RBP4 of each patient were measured with the ELISA method. Multivariate logistic regression was used to analyze data on demographics, biochemical parameters, and serum RBP4 level to predict AVF dysfunction events. The cutoff for serum RBP4 level was derived from the highest score obtained on the Youden index. Survival data were analyzed with the Cox proportional hazards regression analysis and Kaplan-Meier method. RESULTS: Higher serum RBP4 level was observed in patients with AVF dysfunction compared to those without AVF dysfunction events (174.3 vs. 168.4 mg/L, p = 0.001). The prevalence of AVF dysfunction events was greatly higher among the high RBP4 group (37.5 vs. 4.88%, p = 0.001). In univariate analysis, serum RBP4 level was statistically significantly associated with the risk of AVF dysfunction (OR = 1.015, 95% CI 1.002-1.030, p = 0.030). In multivariate analysis, each 1.0 mg/L increase in RBP4 level was associated with a 1.023-fold-increased risk of AVF dysfunction (95% CI for OR: 1.002-1.045; p = 0.032). The Kaplan-Meier survival analysis indicated that the incidence of AVF dysfunction events in the high RBP4 group was significantly higher than that in the low-RBP4 group (p = 0.0007). Multivariate Cox regressions demonstrated that RBP4 was an independent risk factor for AVF dysfunction events in HD patients (HR = 1.015, 95% CI 1.001-1.028, p = 0.033). CONCLUSIONS: HD patients with higher serum RBP4 concentrations had a relevant higher incidence of arteriovenous dysfunction events. Serum RBP4 level was an independent risk factor for AVF dysfunction events in HD patients.

Impaired Hepatic Vitamin A Metabolism in NAFLD Mice Leading to Vitamin A Accumulation in Hepatocytes.

BACKGROUND & AIMS: Systemic retinol (vitamin A) homeostasis is controlled by the liver, involving close collaboration between hepatocytes and hepatic stellate cells (HSCs). Genetic variants in retinol metabolism (PNPLA3 and HSD17B13) are associated with non-alcoholic fatty liver disease (NAFLD) and disease progression. Still, little mechanistic details are known about hepatic vitamin A metabolism in NAFLD, which may affect carbohydrate and lipid metabolism, inflammation, oxidative stress and the development of fibrosis and cancer, e.g. all risk factors of NAFLD. METHODS: Here, we analyzed vitamin A metabolism in 2 mouse models of NAFLD; mice fed a high-fat, high-cholesterol (HFC) diet and Leptinob mutant (ob/ob) mice. RESULTS: Hepatic retinol and retinol binding protein 4 (RBP4) levels were significantly reduced in both mouse models of NAFLD. In contrast, hepatic retinyl palmitate levels (the vitamin A storage form) were significantly elevated in these mice. Transcriptome analysis revealed a hyperdynamic state of hepatic vitamin A metabolism, with enhanced retinol storage and metabolism (upregulated Lrat, Dgat1, Pnpla3, Raldh's and RAR/RXR-target genes) in fatty livers, in conjunction with induced hepatic inflammation (upregulated Cd68, Tnfα, Nos2, Il1ß, Il-6) and fibrosis (upregulated Col1a1, Acta2, Tgfß, Timp1). Autofluorescence analyses revealed prominent vitamin A accumulation in hepatocytes rather than HSC in HFC-fed mice. Palmitic acid exposure increased Lrat mRNA levels in primary rat hepatocytes and promoted retinyl palmitate accumulation when co-treated with retinol, which was not detected for similarly-treated primary rat HSCs. CONCLUSION: NAFLD leads to cell type-specific rearrangements in retinol metabolism leading to vitamin A accumulation in hepatocytes. This may promote disease progression and/or affect therapeutic approaches targeting nuclear receptors.