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.

Pre-treatment plasma retinol binding protein 4 level and its change after treatments predict systemic treatment response in psoriasis patients.

BACKGROUND: Retinol binding protein 4 (RBP4) is a mediator of inflammation and related to skin lesion formation, which suggests its engagement in psoriasis pathology and progression. This study intended to explore the change in RBP4 after systemic treatments, and its ability to predict treatment response in psoriasis patients. METHODS: This prospective study enrolled 85 psoriasis patients and 20 healthy subjects. Plasma RBP4 was detected by enzyme-linked immunosorbent assay at baseline and 12th week (W12) after systemic treatments in psoriasis patients, as well as after enrollment in healthy subjects. Psoriasis Area and Severity Index (PASI) 75 and PASI 90 were evaluated at W12 in psoriasis patients. RESULTS: RBP4 at baseline was higher in psoriasis patients than in healthy subjects [median (interquartile range): 13.39 (9.71-22.92) versus 9.59 (6.57-13.72) µg/mL] (P = 0.003). In psoriasis patients, 50 (58.8%) patients achieved PASI 75 at W12, and 25 (29.4%) patients achieved PASI 90 at W12. RBP4 was decreased at W12 compared to its level at baseline (P < 0.001). Lower RBP4 at baseline predicted achieving PASI 75 at W12 (P = 0.038). Greater RBP4 change (baseline-W12) precited achieving PASI 75 (P = 0.036) and PASI 90 (P = 0.045) at W12. Receiver operating characteristic curves suggested that after adjustment for all clinical features, RBP4 at baseline and RBP4 change (baseline-W12) had an acceptable ability to predict PASI 75 and PASI 90 at W12 with all area under curve values > 0.7. CONCLUSION: Plasma RBP4 is decreased after systemic treatments, and its low baseline level and greater decline after treatments predict good treatment response in psoriasis patients.

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.

Exploratory Mass Spectrometry of Cerebrospinal Fluid from Persons with Autopsy-Confirmed LATE-NC.

Common neuropathologies associated with dementia include Alzheimer's disease neuropathologic change (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Biofluid proteomics provides a window into the pathobiology of dementia and the information from biofluid tests may help guide clinical management. Participants (n = 29) had been autopsied and had antemortem CSF draws in a longitudinal cohort of older adults at the University of Kentucky AD Research Center. Cases were designated as LATE-NC + if they had LATE-NC stage > 1 (n = 9); the remaining 20 cases were designated LATE-NC-. This convenience sample of CSF specimens was analyzed in two separate processes: From one group, aliquots were depleted of highly abundant proteins using affinity spin columns. Tryptic digests of sample proteins were subjected to liquid chromatographic separation and mass spectrometry. Relative quantification was performed using Sciex software. Peptides referent to a total of 949 proteins were identified in the samples depleted of abundant proteins, and 820 different proteins were identified in the non-depleted samples. When the Bonferroni/false-discovery statistical correction was applied to account for having made multiple comparison tests, only 4 proteins showed differential expression (LATE-NC + vs LATE-NC-) in the non-depleted samples (RBP4, MIF, IGHG3, and ITM2B). Post hoc western blots confirmed that RBP4 expression was higher in the LATE-NC + cases at the group level. In summary, an exploratory assessment of proteomes of autopsy-confirmed LATE-NC and non-LATE-NC CSF did not demonstrate a clear-cut proteomic fingerprint that distinguished the two groups. There was, however, an increase in RBP4 protein levels in CSF from LATE-NC cases.

Concussion-Related Biomarker Variations in Retired Rugby Players and Implications for Neurodegenerative Disease Risk: The UK Rugby Health Study.

The health and well-being of retired rugby union and league players, particularly regarding the long-term effects of concussions, are of major concern. Concussion has been identified as a major risk factor for neurodegenerative diseases, such as Alzheimer's and Amyotrophic Lateral Sclerosis (ALS), in athletes engaged in contact sports. This study aimed to assess differences in specific biomarkers between UK-based retired rugby players with a history of concussion and a non-contact sports group, focusing on biomarkers associated with Alzheimer's, ALS, and CTE. We randomly selected a sample of male retired rugby or non-contact sport athletes (n = 56). The mean age was 41.84 ± 6.44, and the mean years since retirement from the sport was 7.76 ± 6.69 for participants with a history of substantial concussions (>5 concussions in their career) (n = 30). The mean age was 45.75 ± 11.52, and the mean years since retirement was 6.75 ± 4.64 for the healthy controls (n = 26). Serum biomarkers (t-tau, RBP-4, SAA, Nf-L, and retinol), plasma cytokines, and biomarkers associated with serum-derived exosomes (Aß42, p-tau181, p-tau217, and p-tau231) were analyzed using validated commercial ELISA assays. The results of the selected biomarkers were compared between the two groups. Biomarkers including t-tau and p-tau181 were significantly elevated in the history of the substantial concussion group compared to the non-contact sports group (t-tau: p < 0.01; p-tau181: p < 0.05). Although between-group differences in p-tau217, p-tau231, SAA, Nf-L, retinol, and Aß42 were not significantly different, there was a trend for higher levels of Aß42, p-tau217, and p-tau231 in the concussed group. Interestingly, the serum-derived exosome sizes were significantly larger (p < 0.01), and serum RBP-4 levels were significantly reduced (p < 0.05) in the highly concussed group. These findings indicate that retired athletes with a history of multiple concussions during their careers have altered serum measurements of exosome size, t-tau, p-tau181, and RBP-4. These biomarkers should be explored further for the prediction of future neurodegenerative outcomes, including ALS, in those with a history of concussion.

RBP4 promotes denervation-induced muscle atrophy through STRA6-dependent pathway.

BACKGROUNDS: Fat infiltration of skeletal muscle has been recognized as a common feature of many degenerative muscle disorders. Retinol binding protein 4 (RBP4) is an adipokine that has been demonstrated to be correlated with the presence and severity of sarcopenia in the elderly. However, the exact role and the underlying mechanism of RBP4 in muscle atrophy remains unclear. METHODS: Denervation-induced muscle atrophy model was constructed in wild-type and RBP4 knockout mice. To modify the expression of RBP4, mice were received intramuscular injection of retinol-free RBP4 (apo-RBP4), retinol-bound RBP4 (holo-RBP4) or oral gavage of RBP4 inhibitor A1120. Holo-RBP4-stimulated C2C12 myotubes were treated with siRNAs or specific inhibitors targeting signalling receptor and transporter of retinol 6 (STRA6)/Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) pathway. Fat accumulation, myofibre cross-sectional area, myotube diameter and the expression of muscle atrophy markers and myogenesis markers were analysed. RESULTS: The expression levels of RBP4 in skeletal muscles were significantly up-regulated more than 2-fold from 7 days and sustained for 28 days after denervation. Immunofluorescence analysis indicated that increased RBP4 was localized in the infiltrated fatty region in denervated skeletal muscles. Knockout of RBP4 alleviated denervation-induced fatty infiltration and muscle atrophy together with decreased expression of atrophy marker Atrogin-1 and MuRF1 as well as increased expression of myogenesis regulators MyoD and MyoG. By contrast, injection of retinol-bound holo-RBP4 aggregated denervation-induced ectopic fat accumulation and muscle atrophy. Consistently, holo-RBP4 stimulation also had a dose-dependent effect on the reduction of C2C12 myotube diameter and myofibre cross-sectional area, as well as on the increase of Atrogin-1and MuRF1 expression and decrease of MyoD and MyoG expression. Mechanistically, holo-RBP4 treatment increased the expression of its membrane receptor STRA6 (>3-fold) and promoted the phosphorylation of downstream JAK2 and STAT3. Inhibition of STRA6/JAK2/STAT3 pathway either by specific siRNAs or inhibitors could decrease the expression of Atrogin-1 and MuRF1 (>50%) and decrease the expression of MyoD and MyoG (>3-fold) in holo-RBP4-treated C2C12 myotube. RBP4 specific pharmacological antagonist A1120 significantly inhibited the activation of STRA6/JAK2/STAT3 pathway, ameliorated ectopic fat infiltration and protected against denervation-induced muscle atrophy (30% increased myofibre cross-sectional area) in mice. CONCLUSIONS: In conclusion, our data reveal that RBP4 promotes fat infiltration and muscle atrophy through a STRA6-dependent and JAK2/STAT3 pathway-mediated mechanism in denervated skeletal muscle. Our results suggest that lowering RBP4 levels might serve as a promising therapeutic approach for prevention and treatment of muscle atrophy.

Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting.

Vitamin A (retinol) is distributed via the blood bound to its specific carrier protein, retinol-binding protein 4 (RBP4). Retinol-loaded RBP4 is secreted into the circulation exclusively from hepatocytes, thereby mobilizing hepatic retinoid stores that represent the major vitamin A reserves in the body. The relevance of extrahepatic retinoid stores for circulating retinol and RBP4 levels that are usually kept within narrow physiological limits is unknown. Here, we show that fasting affects retinoid mobilization in a tissue-specific manner, and that hormone-sensitive lipase (HSL) in adipose tissue is required to maintain serum concentrations of retinol and RBP4 during fasting in mice. We found that extracellular retinol-free apo-RBP4 induces retinol release by adipocytes in an HSL-dependent manner. Consistently, global or adipocyte-specific HSL deficiency leads to an accumulation of retinoids in adipose tissue and a drop of serum retinol and RBP4 during fasting, which affects retinoid-responsive gene expression in eye and kidney and lowers renal retinoid content. These findings establish a novel crosstalk between liver and adipose tissue retinoid stores for the maintenance of systemic vitamin A homeostasis during fasting.

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.

A candidate panel of eight urinary proteins shows potential of early diagnosis and risk assessment for diabetic kidney disease in type 1 diabetes.

Diabetic kidney disease (DKD) poses a significant health challenge for individuals with diabetes. At its initial stages, DKD often presents asymptomatically, and the standard for non-invasive diagnosis, the albumin-creatinine ratio (ACR), employs discrete categorizations (normal, microalbuminuria, macroalbuminuria) with limitations in sensitivity and specificity across diverse population cohorts. Single biomarker reliance further restricts the predictive value in clinical settings. Given the escalating prevalence of diabetes, our study uses proteomic technologies to identify novel urinary proteins as supplementary DKD biomarkers. A total of 158 T1D subjects provided urine samples, with 28 (15 DKD; 13 non-DKD) used in the discovery stage and 131 (45 DKD; 40 pDKD; 46 non-DKD) used in the confirmation. We identified eight proteins (A1BG, AMBP, AZGP1, BTD, RBP4, ORM2, GM2A, and PGCP), all of which demonstrated excellent area-under-the-curve (AUC) values (0.959 to 0.995) in distinguishing DKD from non-DKD. Furthermore, this multi-marker panel successfully segregated the most ambiguous group (microalbuminuria) into three distinct clusters, with 80% of subjects aligning either as DKD or non-DKD. The remaining 20% exhibited continued uncertainty. Overall, the use of these candidate urinary proteins allowed for the better classification of DKD and offered potential for significant improvements in the early identification of DKD in T1D populations.

Retinol and retinol binding protein 4 levels and COVID-19: a Mendelian randomization study.

BACKGROUND: The Corona Virus Disease 2019 (COVID-19) pandemic has struck globally. Whether the related proteins of retinoic acid (RA) signaling pathway are causally associated with the risk of COVID-19 remains unestablished. We conducted a two-sample Mendelian randomization (MR) study to assess the associations of retinol, retinol binding protein 4 (RBP4), retinol dehydrogenase 16 (RDH16) and cellular retinoic acid binding protein 1 (CRABP1) with COVID-19 in European population. METHODS: The outcome utilized the summary statistics of COVID-19 from the COVID-19 Host Genetics Initiative. The exposure data were obtained from public genome wide association study (GWAS) database. We extracted SNPs from exposure data and outcome data. The inverse variance weighted (IVW), MR-Egger and Wald ratio methods were employed to assess the causal relationship between exposure and outcome. Sensitivity analyses were performed to ensure the validity of the results. RESULTS: The MR estimates showed that retinol was associated with lower COVID-19 susceptibility using IVW (OR: 0.69, 95% CI: 0.53-0.90, P: 0.0065), whereas the associations between retinol and COVID-19 hospitalization or severity were not significant. RBP4 was associated with lower COVID-19 susceptibility using the Wald ratio (OR: 0.83, 95% CI: 0.72-0.95, P: 0.0072). IVW analysis showed RDH16 was associated with increased COVID-19 hospitalization (OR: 1.10, 95% CI: 1.01-1.18, P: 0.0199). CRABP1 was association with lower COVID-19 susceptibility (OR: 0.95, 95% CI: 0.91-0.99, P: 0.0290) using the IVW. CONCLUSIONS: We found evidence of possible causal association of retinol, RBP4, RDH16 and CRABP1 with the susceptibility, hospitalization and severity of COVID-19. Our study defines that retinol is significantly associated with lower COVID-19 susceptibility, which provides a reference for the prevention of COVID-19 with vitamin A supplementation.

Retinol binding protein 4 and type 2 diabetes: from insulin resistance to pancreatic ß-cell function.

BACKGROUND AND AIM: Retinol binding protein 4 (RBP4) is an adipokine that has been explored as a key biomarker of type 2 diabetes mellitus (T2DM) in recent years. Researchers have conducted a series of experiments to understand the interplay between RBP4 and T2DM, including its role in insulin resistance and pancreatic ß-cell function. The results of these studies indicate that RBP4 has a significant influence on T2DM and is considered a potential biomarker of T2DM. However, there have also been some controversies about the relationship between RBP4 levels and T2DM. In this review, we update and summarize recent studies focused on the relationship between RBP4 and T2DM and its role in insulin resistance and pancreatic ß-cell function to clarify the existing controversy and provide evidence for future studies. We also assessed the potential therapeutic applications of RBP4 in treating T2DM. METHODS: A narrative review. RESULTS: Overall, there were significant associations between RBP4 levels, insulin resistance, pancreatic ß-cell function, and T2DM. CONCLUSIONS: More mechanistic studies are needed to determine the role of RBP4 in the onset of T2DM, especially in terms of pancreatic ß-cell function. In addition, further studies are required to evaluate the effects of drug intervention, lifestyle intervention, and bariatric surgery on RBP4 levels to control T2DM and the role of reducing RBP4 levels in improving insulin sensitivity and pancreatic ß-cell function.

Circulating transthyretin and retinol binding protein 4 levels among middle-age V122I TTR carriers in the general population.

BACKGROUND: Hereditary transthyretin cardiac amyloidosis (ATTRv-CA) has a long latency phase before clinical onset, creating a need to identify subclinical disease. We hypothesized circulating transthyretin (TTR) and retinol binding protein 4 (RBP4) levels would be associated with TTR carrier status and correlated with possible evidence of subclinical ATTRv-CA. METHODS: TTR and RBP4 were measured in blood samples from V122I TTR carriers and age-, sex- and race-matched non-carrier controls (1:2 matching) among Dallas Heart Study participants (phases 1 (DHS-1) and 2 (DHS-2)). Multivariable linear regression models determined factors associated with TTR and RBP4. RESULTS: There were 40 V122I TTR carriers in DHS-1 and 54 V122I TTR carriers in DHS-2. In DHS-1 and DHS-2, TTR was lower in V122I TTR carriers (p < .001 for both), and RBP4 in DHS-2 was lower in V122I TTR carriers than non-carriers (p = .002). Among V122I TTR carriers, TTR was negatively correlated with markers of kidney function, and limb lead voltage (p < .05 for both) and TTR and RBP4 were correlated with atrial volume in DHS-2 (p < .05). CONCLUSIONS: V122I TTR carrier status is independently associated with lower TTR and RBP4 in comparison with non-carriers. These findings support the hypothesis that TTR and RBP4 may correlate with evidence of subclinical ATTRv-CA.

Adipose Signals Regulating Distal Organ Health and Disease.

Excessive adiposity in obesity is a significant risk factor for development of type 2 diabetes (T2D), nonalcoholic fatty liver disease, and other cardiometabolic diseases. An unhealthy expansion of adipose tissue (AT) results in reduced adipogenesis, increased adipocyte hypertrophy, adipocyte hypoxia, chronic low-grade inflammation, increased macrophage infiltration, and insulin resistance. This ultimately culminates in AT dysfunction characterized by decreased secretion of antidiabetic adipokines such as adiponectin and adipsin and increased secretion of proinflammatory prodiabetic adipokines including RBP4 and resistin. This imbalance in adipokine secretion alters the physiological state of AT communication with target organs including pancreatic ß-cells, heart, and liver. In the pancreatic ß-cells, adipokines are known to have a direct effect on insulin secretion, gene expression, cell death, and/or dedifferentiation. For instance, impaired secretion of adipsin, which promotes insulin secretion and ß-cell identity, results in ß-cell failure and T2D, thus presenting a potential druggable target to improve and/or preserve ß-cell function. The cardiac tissue is affected by both the classic white AT-secreted adipokines and the newly recognized brown AT (BAT)-secreted BATokines or lipokines that alter lipid deposition and ventricular function. In the liver, adipokines affect hepatic gluconeogenesis, lipid accumulation, and insulin sensitivity, underscoring the importance of adipose-liver communication in the pathogenesis of nonalcoholic fatty liver disease. In this perspective, we outline what is currently known about the effects of individual adipokines on pancreatic ß-cells, liver, and the heart.

Succinate-induced macrophage polarization and RBP4 secretion promote vascular sprouting in ocular neovascularization.

Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), in which macrophages (Mφs) play a key role. Tip cell specialization is critical in angiogenesis; however, its interconnection with the surrounding immune environment remains unclear. Succinate is an intermediate in the tricarboxylic acid (TCA) cycle and was significantly elevated in patients with wet AMD by metabolomics. Advanced experiments revealed that SUCNR1 expression in Mφ and M2 polarization was detected in abnormal vessels of choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) models. Succinate-induced M2 polarization via SUCNR1, which facilitated vascular endothelial cell (EC) migration, invasion, and tubulation, thus promoting angiogenesis in pathological neovascularization. Furthermore, evidence indicated that succinate triggered the release of RBP4 from Mφs into the surroundings to regulate endothelial sprouting and pathological angiogenesis via VEGFR2, a marker of tip cell formation. In conclusion, our results suggest that succinate represents a novel class of vasculature-inducing factors that modulate Mφ polarization and the RBP4/VEGFR2 pathway to induce pathological angiogenic signaling through tip cell specialization.

Effect of non-surgical periodontal treatment on cytokines/adipocytokines levels among periodontitis patients with or without obesity: a systematic review and meta-analysis.

BACKGROUND: The objective of this systematic review and meta-analysis was to evaluate the effects of non-surgical periodontal therapy (NSPT) on inflammatory-related cytokines/adipocytokines in periodontitis patients with or without obesity. METHODS: We followed the preferred reporting items for systematic reviews and meta-analyses statement and registered the study (CRD42022375331) in the Prospective International Register of Systematic Reviews. We screened randomized-controlled trials and controlled clinical trials from six databases up to December 2022. Quality assessment was performed with RoB-2 and ROBINS-I tools for randomized trials and non-randomized trials, respectively. Meta-analysis was carried out using a random-effect model. RESULTS: We included seventeen references in the systematic analysis, and sixteen in the meta-analysis. Baseline results of pro-inflammatory biomarkers, including serum interleukin (IL)-6, serum and gingival crevicular fluid (GCF), tumor necrosis factor (TNF)-a, serum C-reactive protein (CRP)/hs-CRP, and serum and GCF resistin, were higher in obesity subjects than in normal weight subjects. The effect of NSPT with respect to levels of cytokines/adipocytokines, including IL-6, TNF-a, CRP/hs-CRP, resistin, adiponectin, leptin and retinol binding protein 4 (RBP4), were then analyzed in the systematic and meta-analysis. After three months of NSPT, serum (MD = -0.54, CI = -0.62 - -0.46), and GCF (MD = -2.70, CI = -4.77 - -0.63) levels of IL-6, along with the serum RBP4 (MD = -0.39, CI = -0.68-0.10) decreased in periodontitis individuals with obesity. NSPT also improved GCF adiponectin levels after three months (MD = 2.37, CI = 0.29 - 4.45) in periodontitis individuals without obesity. CONCLUSIONS: Obese status altered the baseline levels of cytokines/adipocytokines (serum IL-6, serum and GCF TNF-a, serum CRP/hs-CRP, and serum and GCF resistin). Then NSPT can shift the levels of specific pro-inflammatory mediators and anti-inflammatory mediators in biological fluids, both in obesity and non-obesity individuals. NSPT can reduce serum and GCF IL-6 levels together with serum RBP4 level in individuals with obesity after 3 months, besides, there is no sufficient evidence to prove that obese patients have a statistically significant decrease in the levels of other cytokines compared to patients with normal weight. NSPT can also increase GCF adiponectin level in normal weight individuals after 3 months. Our findings imply the potential ideal follow-up intervals and sensitive biomarkers for clinical bioanalysis in personalized decision-making of effect of NSPT due to patients' BMI value.

Clinical, genetic and biochemical signatures of RBP4-related ocular malformations.

BACKGROUND: The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with monoallelic and biallelic pathogenic variants in retinol-binding protein 4 (RBP4), encoding a serum retinol-specific transporter, display variable ocular phenotypes. Although few families have been reported worldwide, recessive inherited variants appear to be associated with retinal degeneration, while individuals with dominantly inherited variants manifest ocular development anomalies, mainly microphthalmia, anophthalmia and coloboma (MAC). METHODS: We report here seven new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, of whom we performed biochemical analyses. RESULTS: For the first time, malformations that overlap the clinical spectrum of vitamin A deficiency are reported, providing a link with other RA disorders. Our data support two distinct phenotypes, depending on the nature and mode of inheritance of the variants: dominantly inherited, almost exclusively missense, associated with ocular malformations, in contrast to recessive, mainly truncating, associated with retinal degeneration. Moreover, we also confirm the skewed inheritance and impact of maternal RBP4 genotypes on phenotypical expression in dominant forms, suggesting that maternal RBP4 genetic status and content of diet during pregnancy may modify MAC occurrence and severity. Furthermore, we demonstrate that retinol-binding protein blood dosage in patients could provide a biological signature crucial for classifying RBP4 variants. Finally, we propose a novel hypothesis to explain the mechanisms underlying the observed genotype-phenotype correlations in RBP4 mutational spectrum. CONCLUSION: Dominant missense variants in RBP4 are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism.

A computational approach for the identification of key genes and biological pathways of chronic lung diseases: a systems biology approach.

BACKGROUND: Chronic lung diseases are characterized by impaired lung function. Given that many diseases have shared clinical symptoms and pathogenesis, identifying shared pathogenesis can help the design of preventive and therapeutic strategies. This study aimed to evaluate the proteins and pathways of chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and mustard lung disease (MLD). METHODS AND RESULTS: After collecting the data and determining the gene list of each disease, gene expression changes were examined in comparison to healthy individuals. Protein-protein interaction (PPI) and pathway enrichment analysis were used to evaluate genes and shared pathways of the four diseases. There were 22 shared genes, including ACTB, AHSG, ALB, APO, A1, APO C3, FTH1, GAPDH, GC, GSTP1, HP, HSPB1, IGKC, KRT10, KRT9, LCN1, PSMA2, RBP4, 100A8, S100A9, TF, and UBE2N. The major biological pathways in which these genes are involved are inflammatory pathways. Some of these genes activate different pathways in each disease, leading to the induction or inhibition of inflammation. CONCLUSION: Identification of the genes and shared pathways of diseases can contribute to identifying pathogenesis pathways and designing preventive and therapeutic strategies.

RBP4-based Multimarker Score: A Prognostic Tool for Adverse Cardiovascular Events in Acute Coronary Syndrome Patients.

CONTEXT: Retinol binding protein 4 (RBP4) has been implicated in the progression of cardiovascular diseases. However, its association with major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) remains obscure. OBJECTIVE: Here, we examined the prognostic value of baseline RBP4 and its derived multimarker score for MACEs in ACS patients. METHODS: A total of 826 patients with ACS were consecutively recruited from the department of cardiology and prospectively followed up for a median of 1.95 years (interquartile range, 1.02-3.25 years). Plasma RBP4 was measured using enzyme-linked immunosorbent assay. Adjusted associations between RBP4 and its derived multimarker score (1 point was assigned when RBP4 ≥ 38.18µg/mL, left ventricular ejection fraction [LVEF] ≤ 55%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥ 450 ng/L, estimated glomerular filtration rate [eGFR] ≤ 90 mL/min/1.73 m2, and age ≥60) with MACEs were analyzed. RESULTS: In total, 269 ACS patients (32.57%) experienced MACEs. When patients were grouped by multimarker score (0-1, n = 315; 2-3, n = 406; 4-5, n = 105), there was a significant graded association between RBP4-based multimarker score and risk of MACEs (intermediate score (2-3): HRadj: 1.80; 95% CI, 1.34-2.41; high score (4-5): HRadj: 3.26; 95% CI, 2.21-4.81) and its components (P < .05 for each). Moreover, the prognostic and discriminative value of the RBP4-derived multimarker score remained robust in ACS patients with various high-risk anatomical or clinical characteristics. CONCLUSION: The RBP4-derived 5-item score serves as a useful risk stratification and decision support for secondary prevention in patients with ACS.

Factors and Molecular Mechanisms of Vitamin A and Childhood Obesity Relationship: A Review.

Childhood obesity has become a public health concern. As the importance of vitamin A (VA) in the body has become increasingly acknowledged, there is limited clinical trial evidence to substantiate the association between VA and childhood obesity. Vitamin A deficiency (VAD) increases the risk of childhood obesity, a finding consistently reported in pregnant women. VA could regulate the adipogenic process, inflammation, oxidative stress and metabolism-related gene expression in mature adipocytes. VAD disrupts the balance of obesity-related metabolism, thus affecting lipid metabolism and insulin regulation. Conversely, VA supplementation has a major impact on efficacy in obesity, and obese individuals typically have a lower VA status than normal-weight individuals. Several studies have attempted to identify the genetic and molecular mechanisms underlying the association between VA and obesity. In this review, we summarize and discuss recent new developments focusing on retinol, retinoic acid, and RBP4 and elucidate and provide an overview of the complex interrelationships between these critical components of VA and childhood obesity. However, the causal relationship between VA status and childhood obesity remains unclear. It is also unknown whether VA supplementation improves the overall obesogenic metabolic profile.

The inverse association between fasting blood glucose and the occurrence of gallbladder cancer in type 2 diabetes mellitus patients: a case-control study.

OBJECTIVE: This study aimed to explore the correlation between diabetes mellitus (DM) and gallbladder cancer (GBC) in an epidemiological setting. METHODS: The study summarized the clinical and laboratory data of 2210 GBC Chinese patients in the authors' hospital. A total of 17 influencing factors for GBC, including gender, body mass index (BMI), fasting blood glucose (FBG), fasting insulin (FINS), the homeostasis model assessment of insulin resistance (HOMA-IR), retinol-binding protein 4 (RBP4), and lipid indexes were analyzed using unconditional logistic regression analysis. RESULTS: Based on the results of univariate logistic regression, the risk of GBC was significantly and positively correlated with serum triglyceride, low-density lipoprotein, FINS, HOMA-IR, being female, BMI, DM, non-alcoholic fatty liver disease, and gallbladder stone disease (GSD), and significantly negatively correlated with high-density lipoprotein and FBG concentrations in serum, as well as hypertension. According to multivariate analysis, FINS was significantly positively associated with GBC risk, while DM showed an insignificant negative association; FBG was also not important. The most significant independent factor of GBC risk in patients with DM was HOMA-IR. Fasting blood glucose levels showed a significant negative relationship with GBC in patients with DM. In addition, this study indicated a significantly negative association between serum RBP levels and GBC. CONCLUSIONS: The findings of the current study revealed that the efficient treatment of insulin resistance is an important approach for decreasing GBC risk, as opposed to lowering blood sugar only, particularly in patients with DM. Interestingly, FBG may have had an inverse association with the development of GBC in patients with type 2 DM. Of note, the study found that a dramatic initial drop in RBP may help predict the occurrence of GBC.