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Autophagy is a highly conserved degradative process that has been linked to various functions, including defending host cells against pathogens. Although the involvement of autophagy in porcine circovirus 2 (PCV2) infection has become apparent, it remains unclear whether selective autophagy plays a critical role in PCV2 restriction. Here we show that retinol-binding protein 4 (RBP4), an adipokine for retinol carrier, initiates the autophagic degradation of PCV2 ORF1 protein. PCV2 infection increases RBP4 protein levels through MAPK-eIF4E axis in living cells. Ectopic expression of RBP4 or recombinant RBP4 treatment promotes the degradation of ORF1 protein. Mechanistically, RBP4 activates TRAF6 to induce K63-linked ubiquitination of ORF1, leading to SQSTM1/p62-mediated selective autophagy for degradation. Consequently, RBP4 deficiency increases viral loads and exacerbates the pathogenicity of PCV2 in vivo. Collectively, these results identify RBP4 as a key host restriction factor of PCV2 and reveal a previously undescribed antiviral mechanism against PCV2 in infected cells., (© 2024. The Author(s).)

Identifying biomarkers can help in the early detection of muscle loss and drive the development of new therapies. Research suggests a potential link between retinol-binding protein 4 (RBP4) and muscle mass, particularly in postmenopausal women. This study aimed to examine the association between baseline RBP4 levels and changes in appendicular lean mass (ALM), an indicator of muscle mass, in postmenopausal women. A 12-month follow-up period ( n =  153) included baseline and 12-month ALM assessments using DXA. ALM was normalized to squared height (ALMI). Baseline evaluations encompassed insulin resistance via HOMA-IR and immunoassay magnetic bead panel measurements of RPB4, IL-6, TNF-α, and IL-10. Postmenopausal women were categorized into higher ( n =  77) and lower ( n =  76) RPB4 groups based on baseline RPB4 values. Their changes in ALMI were compared using Mann-Whitney tests. General linear model was employed to evaluate the predictive power of baseline RBP4 for ALMI changes, adjusting for confounding variables: age, physical activity, smoking status, body fat, HOMA-IR, inflammatory markers (TNF-α and IL-6), and anti-inflammatory factor (IL-10). The higher RBP4 group exhibited a more pronounced reduction in ALMI compared to the lower RBP4 group (Higher RBP4 = -0.39 kg/m 2 , 95% CI: -0.48 to -0.31 kg/m 2 vs. Lower RBP4 = -0.24 kg/m 2 , 95% CI: -0.32 to -0.15 kg/m 2 , P =  0.011). After adjusting for confounding factors, the association between baseline RBP4 changes and ALMI remained ( b = -0.008, SE = 0.002, P <  0.001), indicating higher baseline RBP4 values linked to greater ALMI reduction. Our findings support RBP4 as a potential biomarker for changes in muscle mass in postmenopausal women.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide, with high incidence and poor survival rates. RBP1 is highly expressed in several kinds of cancer and plays a potential prognostic factor. However, the relationship between RBP1 and HNSCC were analyzed based on The Cancer Genome Atlas (TCGA) database., Materials and Methods: RBP1 expression and clinical information were obtained from the Cancer Genome Atlas (TCGA) database. Tumor tissue and adjacent normal tissue of 6 HNSCC patients were collected to analyze the RBP1 mRNA expression level by quantitative PCR. Cox regression analysis was used to evaluate the prognostic values of RBP1 and clinical data in HNSCC. A nomogram was also established to predict the impact of RBP1 on prognosis based on Cox multivariate results. The methylation level of RBP1 in HNSC and its prognosis were analyzed in UALACN and MethSurv. Finally, the potential biological functions of RBP1 were investigated using gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA)., Results: The mRNA expression levels of RBP1 were highly expressed in HNSCC tissue. The Cox analyses demonstrate that highly-expressed RBP1 is an independent prognosis marker(P < 0.05). ROC curve analysis showed that performances of RBP1 (area under the ROC curve: 0.887, sensitivity: 84.1%, specificity: 79.9%). The methylation was increased in HNSCC patients compared with normal subjects(P < 0.05) and was associated with better prognosis at sites cg06208339, cg12298268, cg12497564, cg15288618, cg20532370, cg23448348. Additionally, RBP1 expression is mildly associated with immune cell infiltration and immunological checkpoints., Conclusion: RBP1 is overexpressed and associated with poor patient prognosis in head and neck squamous cell carcinoma., (© 2024. The Author(s).)

Distribution of dietary vitamin A/all-trans retinol (ROL) throughout the body is critical for maintaining retinoid function in peripheral tissues and generating the retinylidene protein for visual function. RBP4-ROL is the complex of ROL with retinol-binding protein 4 (RBP4), which is present in the blood. Two membrane receptors, Retinol Binding Protein 4 Receptor 2 (RBPR2) in the liver and STimulated by Retinoic Acid 6 Retinol (STRA6) in the eye, bind circulatory RBP4 and this mechanism is critical for internalizing ROL into cells. Establishing methods to investigate receptor-ligand kinetics is essential in understanding the physiological function of vitamin A receptors for retinoid homeostasis. Using Surface Plasmon Resonance (SPR) assays, we can analyze the binding affinities and kinetic parameters of vitamin A membrane receptors with its physiological ligand RBP4. These methodologies can reveal new structural and biochemical information of RBP4-binding motifs in RBPR2 and STRA6, which are critical for understanding pathological states of vitamin A deficiency. In the eye, internalized ROL is metabolized to 11-cis retinal, the visual chromophore that binds to opsin in photoreceptors to form the retinylidene protein, rhodopsin. The absorbance of light causes the cis-to-trans isomerization of 11-cis retinal, inducing conformational changes in rhodopsin and the subsequent activation of the phototransduction cascade. Decreased concentrations of serum and ocular ROL can impact retinylidene protein formation, which in turn can cause rhodopsin mislocalization, apoprotein opsin accumulation, night blindness, and photoreceptor outer segment degeneration, leading to Retinitis Pigmentosa or Leber Congenital Amaurosis. Therefore, spectrophotometric methodologies to quantify the G protein-coupled receptor opsin-11-cis retinal complex in the retina are critical for understanding mechanisms of retinal cell degeneration in the above-mentioned pathological states. With these comprehensive methodologies, investigators will be able to better assess dietary vitamin A supply in maintaining systemic and ocular retinoid homeostasis, which is critical for generating and maintaining retinylidene protein concentrations in photoreceptors, which is critical for sustaining visual function in humans.

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 β-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 β-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 β-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 β-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 β-cell function., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

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 (Aβ42, 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 Aβ42 were not significantly different, there was a trend for higher levels of Aβ42, 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.

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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.

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., Competing Interests: Declaration of competing interest J-X.S. is CEO of Jinfiniti Precision medicine. However, the individual declares there are no competing interest or benefit received to them or the company in relation to this project. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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.

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., (© 2024. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cao, Zhong, Jin, Hu, Wang, Shi and Wei.)

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 β-cells, heart, and liver. In the pancreatic β-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 β-cell identity, results in β-cell failure and T2D, thus presenting a potential druggable target to improve and/or preserve β-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 β-cells, liver, and the heart., (© 2024 by the American Diabetes Association.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2023. The Author(s).)

Objective: The aim of this study is to investigate whether Serpin clade C (SERPINC1), E-selectin, P-selectin, Placental protein 13 (PP13), and Retinol-binding protein-4 (RBP4) levels in maternal serum were associated with the presence of preeclampsia and to compare them with uncomplicated pregnancies., Methods: This prospective study included 40 women with preeclampsia and 40 healthy pregnant women. An enzyme-linked immunosorbent assay kit was used to measure serum SERPINC1, E-selectin, P-selectin, PP13, and RBP4 levels., Results: The preeclampsia group had significantly higher E-selectin and P-selectin levels than the control group. PP13 and SERPINC1 levels were also significantly lower than the control group. There was no significant difference in RBP4 levels. The receiver operating characteristic curve revealed the best cutoff values for the following: E-selectin >19.2 ng/mL, with 87.5% sensitivity and 95% specificity; P-selectin >5.1 ng/mL, with 97.5% sensitivity and 100% specificity; PP13 ≤ 107.03 pg/mL, with 72.5% sensitivity and 77.5% specificity; and SERPINC1 ≤ 87.76 ng/mL, with 100% sensitivity and 97.5% specificity., Conclusion: In this study, the endothelial dysfunction parameters SERPINC1, PP13, E-selectin, and P-selectin were found to be associated with preeclampsia. Endothelial dysfunction biomarkers in maternal non-serum body fluids may differ. More research is needed, especially to determine the relationship between SERPINC1 and preeclampsia.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Exercise and dietary interventions have been described to positively affect metabolic syndrome (MetS) via molecular-induced changes. The purpose of this study was to investigate the effects of dietary carbohydrate restriction and aerobic exercise (AE) on retinol binding protein 4 (RBP4) and fatty acid binding protein 5 (FABP5) in middle-aged men with MetS. The study had a randomised, double-blinded, parallel-controlled design. Forty middle-aged men with MetS (age: 53·97 ± 2·85 years, BMI = 31·09 ± 1·04 kg/m 2 ) were randomly assigned to four groups, AE ( n 10), ketogenic diet (KD; n 10), AE combined with KD (AE + KD; n 10) or control (C; n 10). RBP4, FABP5, body composition (body mass, BMI and body fat), insulin resistance, insulin sensitivity and MetS factors were evaluated prior to and after the 12-week intervention. AE + KD significantly decreased the body fat percentage ( P = 0·006), BMI ( P = 0·001), Zmets ( P = 0·017), RBP4 ( P = 0·017) and the homeostasis model of insulin resistance (HOMA-IR) ( P = 0·001) as compared with control group and marginally significantly decreased the Zmets as compared with exercise group ( P = 0·086). KD significantly decreased RBP4 levels as compared with control group ( P = 0·041). Only the AE intervention ( P = 0·045) significantly decreased FABP5 levels. Combining intervention of carbohydrate restriction with AE compared with carbohydrate restriction and AE alone improved RBP4, HOMA-IR as well as different body composition and MetS factors in middle-aged men with MetS.

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., (© 2023. The Author(s).)

Purpose: Adipokines produced by adipose tissue have been found to be involved in the pathophysiology of metabolic and cardiovascular diseases. We aimed to investigate the relationships of resistin, retinol-binding protein 4 (RBP4) and adiponectin produced by epicardial adipose tissue with coronary artery disease (CAD) and cardiac structure and function., Methods: Forty-one non-diabetic males scheduled for cardiothoracic surgery were examined. Anthropometric measurements, echocardiography, coronary angiography, and blood analysis were performed preoperatively. We measured the serum levels of resistin, RBP4, and adiponectin and their mRNA expression in thoracic subcutaneous adipose tissue and two epicardial adipose tissue samples, one close to left anterior descending artery (LAD) (resistin-LAD, RBP4-LAD, adiponectin-LAD), and another close to the right coronary artery (RCA) (resistin-RCA, RBP4-RCA, adiponectin-RCA)., Results: Left ventricular (LV) ejection fraction correlated negatively with adiponectin-LAD (rho =  - 0.390, p = 0.025). The ratio of early to late diastolic transmitral flow velocity, as an index of LV diastolic function, correlated negatively with resistin-LAD (rho =  - 0.529, p = 0.024) and RBP4-LAD (rho =  - 0.458, p = 0.049). There was no difference in epicardial adipose tissue mRNA expression of resistin, RBP4, and adiponectin between individuals with CAD and those without CAD. When we compared the individuals with CAD in the LAD with those without CAD in the LAD, there was no difference in resistin-LAD, RBP4-LAD, and adiponectin-LAD. There was no difference in resistin-RCA, RBP4-RCA, and adiponectin-RCA between the individuals with CAD in the RCA and those without CAD in the RCA., Conclusion: Elevation of epicardial adipose tissue mRNA expression of adiponectin was associated with LV systolic dysfunction, while that of both resistin and RBP4 was linked to LV diastolic dysfunction., (© 2023. The Author(s).)

Objective: Adipose tissue remodeling is a dynamic process that is pathologically expedited in the obese state and is closely related to obesity-associated disease progression. This study aimed to explore the effects of human kallistatin (HKS) on adipose tissue remodeling and obesity-related metabolic disorders in mice fed with a high-fat diet (HFD)., Methods: Adenovirus-mediated HKS cDNA (Ad.HKS) and a blank adenovirus (Ad.Null) were constructed and injected into the epididymal white adipose tissue (eWAT) of 8-weeks-old male C57B/L mice. The mice were fed normal or HFD for 28 days. The body weight and circulating lipids levels were assessed. Intraperitoneal glucose tolerance test (IGTT) and insulin tolerance test (ITT) were also performed. Oil-red O staining was used to assess the extent of lipid deposition in the liver. Immunohistochemistry and HE staining were used to measure HKS expression, adipose tissue morphology, and macrophage infiltration. Western blot and qRT-PCR were used to evaluate the expression of adipose function-related factors., Results: At the end of the experiment, the expression of HKS in the serum and eWAT of the Ad.HKS group was higher than in the Ad.Null group. Furthermore, Ad.HKS mice had lower body weight and decreased serum and liver lipid levels after four weeks of HFD feeding. IGTT and ITT showed that HKS treatment maintained balanced glucose homeostasis. Additionally, inguinal white adipose tissue (iWAT) and eWAT in Ad.HKS mice had a higher number of smaller-size adipocytes and had less macrophage infiltration than Ad.Null group. HKS significantly increased the mRNA levels of adiponectin, vaspin, and eNOS. In contrast, HKS decreased RBP4 and TNFα levels in the adipose tissues. Western blot results showed that local injection of HKS significantly upregulated the protein expressions of SIRT1, p-AMPK, IRS1, p-AKT, and GLUT4 in eWAT., Conclusions: HKS injection in eWAT improves HFD-induced adipose tissue remodeling and function, thus significantly improving weight gain and dysregulation of glucose and lipid homeostasis in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Endometrial receptivity plays a vital role in the success of embryo implantation. However, the temporal proteomic profile of porcine endometrium during embryo implantation is still unclear., Results: In this study, the abundance of proteins in endometrium on days 9, 10, 11, 12, 13, 14, 15 and 18 of pregnancy (D9, 10, 11, 12, 13, 14, 15 and 18) was profiled via iTRAQ technology. The results showed that 25, 55, 103, 91, 100, 120, 149 proteins were up-regulated, and 24, 70, 169, 159, 164, 161, 198 proteins were down-regulated in porcine endometrium on D10, 11, 12, 13, 14, 15 and 18 compared with that on D9, respectively. Among these differentially abundance proteins (DAPs), Multiple Reaction Monitoring (MRM) results indicated that S100A9, S100A12, HRG and IFI6 were differentially abundance in endometrial during embryo implantation period. Bioinformatics analysis showed that the proteins differentially expressed in the 7 comparisons were involved in important processes and pathways related to immunization, endometrial remodeling, which have a vital effect on embryonic implantation., Conclusion: Our results reveal that retinol binding protein 4 (RBP4) could regulate the cell proliferation, migration and apoptosis of endometrial epithelial cells and endometrial stromal cells to affect embryo implantation. This research also provides resources for studies of proteins in endometrium during early pregnancy., (© 2023. The Author(s).)

Background: There is a sex-dependent difference in blood retinol and RBP concentrations, and plasma RBP is associated with insulin resistance., Objectives: We aimed to clarify sex-dependent variations in body concentrations of retinol and RBPs and their association with sex hormones in rats., Methods: Plasma and liver retinol concentrations and hepatic mRNA and plasma concentrations of RBP4 were analyzed in 3- and 8-wk-old male and female Wistar rats before and after sexual maturity (experiment 1) and in orchiectomized male Wistar rats (experiment 2) and ovariectomized female Wistar rats (experiment 3). Furthermore, the mRNA and protein concentrations of RBP4 in adipose tissue were measured in ovariectomized female rats (experiment 3)., Results: There were no sex-dependent differences in liver retinyl palmitate and retinol concentrations; however, the plasma retinol concentration was significantly higher in male rats than that in female rats after sexual maturity. Furthermore, the plasma retinol concentrations did not differ between the ovariectomized or orchiectomized rats and the control rats. Plasma Rbp4 mRNA concentrations were higher in male rats than those in female rats but not in castrated and control rats, a change consistent with plasma retinol concentration. Plasma RBP4 concentrations were also higher in male rats than those in female rats; however, unlike liver Rbp4 gene expression, plasma RBP4 concentrations were 7-fold higher in the ovariectomized rats than those in the control rats. Moreover, the Rbp4 mRNA concentrations in inguinal white adipose tissue was significantly higher in the ovariectomized rats than those in the control rats and correlated with plasma RBP4 concentrations., Conclusions: Hepatic Rbp4 mRNA is higher in male rats through a sex hormone-independent mechanism, which may contribute to sex differences in blood retinol concentrations. Furthermore, ovariectomy leads to an increase in adipose tissue Rbp4 mRNA and blood RBP4 concentrations, which may contribute to insulin resistance in ovariectomized rats and postmenopausal women., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

The lipocalin (LCN) family members, a group of small extracellular proteins with 160-180 amino acids in length, can be detected in all kingdoms of life from bacteria to human beings. They are characterized by low similarity of amino acid sequence but highly conserved tertiary structures with an eight-stranded antiparallel β-barrel which forms a cup-shaped ligand binding pocket. In addition to bind small hydrophobic ligands (i.e., fatty acids, odorants, retinoids, and steroids) and transport them to specific cells, lipocalins (LCNs) can interact with specific cell membrane receptors to activate their downstream signaling pathways, and with soluble macromolecules to form the complex. Consequently, LCNs exhibit great functional diversity. Accumulating evidence has demonstrated that LCN family proteins exert multiple layers of function in the regulation of many physiological processes and human diseases (i.e., cancers, immune disorders, metabolic disease, neurological/psychiatric disorders, and cardiovascular disease). In this review, we firstly introduce the structural and sequence properties of LCNs. Next, six LCNs including apolipoprotein D (ApoD), ApoM, lipocalin 2 (LCN2), LCN10, retinol-binding protein 4 (RBP4), and Lipocalin-type prostaglandin D synthase (L-PGDS) which have been characterized so far are highlighted for their diagnostic/prognostic values and their potential effects on coronary artery disease and myocardial infarction injury. The roles of these 6 LCNs in cardiac hypertrophy, heart failure, diabetes-induced cardiac disorder, and septic cardiomyopathy are also summarized. Finally, their therapeutic potential for cardiovascular disease is discussed in each section., Competing Interests: Declaration of Competing Interest All authors including H.-H. Yang, X. Wang, S. Li, Y. Liu, R. Akbar, and G.-C. Fan confirm that this article content has no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Exosomes containing various biological cargoes have potential to be novel diagnostic biomarkers for metabolic diseases. In this study, retinol-binding protein 4 (RBP4) was found to be enriched in serum exosomes, and its increased levels could be considered as an independent risk factor for the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Exosomal RBP4 (exo-RBP4), primarily derived from hepatocytes, significantly enhanced the M1-like polarization of Kupffer cells (KCs) via promoting the activation of NOX2 and NF-κB and reactive oxygen species (ROS) accumulation, resulting in the over-production of inflammatory cytokines including TNF-α. Subsequently, those excess cytokines remarkably increased the levels of intracellular free fatty acid uptake and lipogenesis-related genes (FAS and SREBP-1c) but decreased fatty acid degradation-related genes (CPT-1 and PPARα) in palmitic acid-treated LO2 cells. More notably, TNF-α significantly elevated RBP4 transcription by activating STAT3 in hepatocytes, playing a positive role in NAFLD development. Intravenous injection with RBP4 (50 μg/kg) potentiated hepatic lipid accumulation, M1-type KC proportion, and serum pro-inflammatory cytokine levels in the hepatic tissues of high-fat-diet-fed mice. Collectively, these data indicated that exo-RBP4 converted KCs to M1 subtype by mediating the NOX2/ROS/NF-κB pathway, subsequently promoting de novo lipogenesis in hepatocytes by TNF-α secretion to activate the JAK2/STAT3 signaling pathway. Therefore, this study uncovered a novel intercellular communication between the inflammatory microenvironment and lipid metabolism for fostering NAFLD progression and found the potential of exo-RBP4 as a novel diagnostic biomarker and therapeutic target for NAFLD., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.

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.

Backgrounds: Retinol-binding protein 4 (RBP4) is a monomeric-binding protein belonging to the lipocalin protein family, which has been reported to be dysregulated in several malignancies such as breast cancer and lung cancer. However, the expression and function of RBP4 in glioblastoma (GBM) are completely unknown., Materials and Methods: TCGA datasets were used for analyzing the mRNA level of RBP4 in GBM and its clinical relevance. A retrospective GBM cohort ( n  = 73) was enrolled from our hospital to test the protein expression profile of RBP4 in GBM tissues as well as its correlation with patients' prognoses. Two human GBM cell lines, LN229 and U251, were collected to conduct overexpression and knockdown experiments targeting RBP4. The tumor-related effects of RBP4 in GBM were finally evaluated by proliferation and invasion assays., Results: Both the higher mRNA level and protein level of RBP4 in GBM tissues were significantly correlated with poorer patients' overall survival. Multivariate analysis identified RBP4 as a novel independent prognostic predictor in GBM patients. Overexpression of RBP4 resulted in enhanced GBM proliferation capacity, which was consistent with clinical findings on the positive correlation between RBP4 level and tumor size. Meanwhile, overexpressing RBP4 promoted GBM cell migration and invasion, while silencing RBP4 led to the opposite results., Conclusions: RBP4 overexpression in tumor tissues is correlated with poorer prognosis of GBM patients, which functions by promoting GBM proliferation and invasion, thus, may serve as an invaluable predictive biomarker and therapeutic target., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Xinqing Deng et al.)

Retinol-binding protein 4 (RBP4) is claimed to be associated with the development of preeclampsia, yet the reports are inconclusive. This systematic review and meta-analysis aimed to assess the association between RBP4 levels and preeclampsia. The PubMed, Google Scholar and ScienceDirect databases were searched for studies that investigated RBP4 levels in preeclampsia patients and compared them with normal controls. The meta-analysis was conducted by calculating the standardized mean difference (SMD) of RBP4 between cases and controls. The meta package with the R software was used to perform all statistical analysis. A total of 13 studies, comprising 569 cases and 1411 controls, met the inclusion criteria and were thus included in the meta-analysis. According to the random effect model, the SMD of RBP4 was significantly higher in women with preeclampsia compared with normal controls [SMD of RBP4: 0.55 ng/mL; 95% CI (0.06; 1.05); p = 0.028; I 2 = 89%]. Likewise, the stratified meta-analysis showed the same pattern in the studies which measured RBP4 levels in the third trimester, as well as in the studies that investigated severe preeclampsia. Meta-regression did not identify any factor that significantly affected the overall estimate. There was no evidence of reporting bias (Egger's test; t = 0.43; p = 0.587). This meta-analysis with high heterogeneity showed that higher levels of RBP4 were associated with preeclampsia risk. More longitudinal studies spanning the three trimester periods are needed to clarify the association of RBP4 and its dynamics in preeclampsia cases throughout pregnancy.

Background: Non-alcoholic fatty liver disease (NAFLD) development is linked to insulin resistance and influenced by environmental factors, but it also underlined a genetic predisposition. The aim of this research was to build a predictive model based on genetic and hepatic health information, deeming insulin resistance markers in order to personalize dietary treatment in overweight/obese subjects with NAFLD., Methods: A 6-month nutritional intervention was conducted in 86 overweight/obese volunteers with NAFLD randomly assigned to 2 energy-restricted diets: the American Heart Association (AHA) diet and the Fatty Liver in Obesity (FLiO) diet. Individuals were genotyped using a predesigned panel of 95 genetic variants. A Genetic Risk Score (GRS) for each diet was computed using statistically relevant SNPs for the change on Fatty Liver Index (FLI) after 6-months of nutritional intervention. Body composition, liver injury and insulin resistance markers, as well as physical activity and dietary intake were also assessed., Results: Under energy restriction, both the AHA and FLiO diets induced similar significant improvements on body composition, insulin resistance markers, hepatic health and dietary and lifestyle outcomes. The calculated score included in the linear mixed regression model was able to predict the change of FLI adjusted by diet, age and sex. This model allowed to personalize the most suitable diet for 72% of the volunteers. Similar models were also able to predict the changes on Triglycerides and Glucose (TyG) Index and retinol-binding protein 4 (RBP4) levels depending on diet., Conclusions: Models integrating genetic screening and insulin resistance markers can be useful for the personalization of NAFLD weight loss treatments.

Intravitreal injection of anti-VEGF antibodies has been widely used in the treatment of proliferative diabetic retinopathy (PDR). However, anti-VEGF drugs can exacerbate fibrosis and eventually lead to retinal detachment. To explore proteins closely related to fibrosis, we conducted proteomic analysis of human vitreous humour collected from PDR patients who have or have not intravitreal Conbercept (IVC) injection. Sixteen vitreous humour samples from PDR patients with preoperative IVC and 20 samples from those without preoperative IVC were examined. An immunodepletion kit was used to remove high-abundance vitreous proteins. Conbercept-induced changes were determined using a tandem mass tag-based quantitative proteomic strategy. Enzyme-linked immunosorbent assays were performed to confirm the concentrations of selected proteins and validate the proteomic results. Based on a false discovery rate between 0.05% and -0.05% and a fold-change > 1.5, 97 proteins were altered (49 higher levels and 48 lower levels) in response to IVC. Differentially expressed proteins were found in the extracellular and intracellular regions and were found to be involved in VEGF binding and VEGF-activated receptor activity. Protein-protein interactions indicated associations with fibrosis, neovascularisation and inflammatory signalling pathways. We found the low levels of RBP4 in the vitreous humour of PDR patients with IVC injection, as revealed by ELISA and proteomic profiling. Moreover, RBP4 significantly restored the mitochondrial function of HRMECs induced by AGEs and down regulated the level of glycolysis. Our study is the first to report that RBP4 decreases in the vitreous humour of PDR patients who underwent Conbercept treatment, thereby verifying the role of RBP4 in glucose metabolism. Results provide evidence for the potential mechanism underlying Conbercept-related fibrosis., (Copyright © 2022. Published by Elsevier Ltd.)

Efficient delivery of vitamin A to the retinal pigment epithelium is vital to the production of the light-sensitive visual chromophore 11-cis-retinal. Nevertheless, retinol binding protein 4 (RBP4) is the only known carrier of vitamin A in plasma. Here, we present new findings that further characterize the visual cycle in the presence of Rbp4 deficiency. In the face of impaired delivery of retinol in Rbp4 -/- mice, we determined that 11-cis-retinaldehyde reached levels that were ∼60% of WT at 4 months of age and all-trans-retinyl ester was 18% of normal yet photoreceptor cell loss was apparent by 8 months of age. The lack of Rbp4 appeared to have a greater impact on scotopic rod-mediated responses than on cone function at early ages. Also, despite severely impaired delivery of retinol, bisretinoid lipofuscin that forms as a byproduct of the visual cycle was measurable by HPLC and by quantitative fundus autofluorescence. In mice carrying an Rpe65 amino acid variant that slows visual cycle kinetics, Rbp4 deficiency had a less pronounced effect on 11-cis-retinal levels. Finally, we found that ocular retinoids were not altered in mice expressing elevated adipose-derived total Rbp4 protein (hRBP4 +/+ AdiCre +/- ). In conclusion, our findings are consistent with a model in which vitamin A can be delivered to the retina by Rbp4-independent pathways., Competing Interests: Conflicts of interest The authors declare that there are no conflicts of interest related to the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The main pathophysiological abnormalities in type 2 diabetes (T2D) include pancreatic β -cell dysfunction and insulin resistance. Due to hyperglycemia, patients receive long-term treatment. However, side effects and drug tolerance usually lead to treatment failure. GuaLouQuMaiWan (GLQMW), a common traditional Chinese medicine (TCM) prescription, has positive effects on controlling blood sugar and improving quality of life, but the mechanism is still unclear. To decipher their molecular mechanisms, we used a novel computational systems pharmacology-based approach consisting of bioinformatics analysis, network pharmacology, and drug similarity comparison. We divided the participants into nondisease (ND), impaired glucose tolerance (IGT), and type 2 diabetes groups according to the WHO's recommendations for diabetes. By analyzing the gene expression profile of the ND-IGT-T2D (ND to IGT to T2D) process, we found that the function of downregulated genes in the whole process was mainly related to insulin secretion, while the upregulated genes were related to inflammation. Furthermore, other genes in the ND-IGT (ND to IGT) process are mainly related to inflammation and lipid metabolic disorders. We speculate that 17 genes with a consistent trend may play a key role in the process of ND-IGT-T2D. We further performed target prediction for 50 compounds in GLQMW that met the screening criteria and intersected the differentially expressed genes of the T2D process with the compounds of GLQMW; a total of 18 proteins proved potential targets for GLQMW. Among these, RBP4 is considerably related to insulin resistance. GO/KEGG enrichment analyses of the target genes of GLQMW showed enrichment in inflammation- and T2D therapy-related pathways. Based on the RDKit tool and the DrugBank database, we speculate that (-)-taxifolin, dialoside A&#95;qt, spinasterol, isofucosterol, and 11,14-eicosadienoic acid can be used as potential drugs for T2D via molecular docking and drug similarity comparison., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2022 Jiahao Feng et al.)

Preeclampsia (PE) is a pregnancy-related disease and is the leading cause of overall maternal mortality and morbidity. Our previous studies have shown that the serum and placental levels of retinol-binding protein 4 (RBP4) in PE are reduced. Our previous bioinformatics analysis predicted that RBP4 is a target of the microRNA miRNA-24-3p. In this study, our database analysis also indicated that RBP4 is a miR-24-3p target. Compared with that of the normal placenta, the expression level of RBP4 in human PE placenta was significantly reduced, and miR-24-3p was highly expressed. In HTR-8/SVneo cells, transfection of exogenous miR-24-3p reduced RBP4 expression. A dual-luciferase reporter assay validated RBP4 as a direct target of miR-24-3p, indicating that it directly binds to the 3'-untranslated region of RBP4. This binding was reversed by a mutation in the microRNA-binding site. Transwell invasion experiments and CCK8 assay showed that inhibitory effect of miR-24-3p reduced RBP4 mediated HTR-8/SVneo cell invasion and proliferation. These data provide a new overarching perspective on the physiological role played by miR-24-3p in regulating RBP4 during trophoblast dysfunction and PE development., (© 2022 Wiley Periodicals LLC.)

Chronic low-grade inflammation in adipose tissue (AT) is a hallmark of obesity and contributes to various metabolic disorders, such as type 2 diabetes and cardiovascular diseases. Inflammation in ATs is characterized by macrophage infiltration and the activation of inflammatory pathways mediated by NF-κB, JNK, and NLRP3 inflammasomes. Adipokines, hepatokines and myokines - proteins secreted from AT, the liver and skeletal muscle play regulatory roles in AT inflammation via endocrine, paracrine, and autocrine pathways. For example, obesity is associated with elevated levels of pro-inflammatory adipokines (e.g., leptin, resistin, chemerin, progranulin, RBP4, WISP1, FABP4, PAI-1, Follistatin-like1, MCP-1, SPARC, SPARCL1, and SAA) and reduced levels of anti-inflammatory adipokines such as adiponectin, omentin, ZAG, SFRP5, CTRP3, vaspin, and IL-10. Moreover, some hepatokines (Fetuin A, DPP4, FGF21, GDF15, and MANF) and myokines (irisin, IL-6, and DEL-1) also play pro- or anti-inflammatory roles in AT inflammation. This review aims to provide an updated understanding of these organokines and their role in AT inflammation and related metabolic abnormalities. It serves to highlight the molecular mechanisms underlying the effects of these organokines and their clinical significance. Insights into the roles and mechanisms of these organokines could provide novel and potential therapeutic targets for obesity-induced inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ren, Zhao, Yin, Lan, Wu, Du, Griffiths and Gao.)

Objective: Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged., Methods: 9-week-old C57BL/6 J female mice were subjected to ovariectomy (OVX) or SHAM surgery (n = 10 per group), fed a standard diet and sacrificed 6- & 12 weeks post-surgery., Results: Increased weight gain, hepatic triglyceride content and changes in hepatic gene expression of Cyp17a1, Rgs16, Fitm1 as well as Il18, Rares2, Retn, Rbp4 in mesenteric visceral adipose tissue (VAT) were observed in OVX vs. SHAM. Liver RNA-sequencing 6-weeks post-surgery revealed changes in genes and microRNAs involved in fat metabolism in OVX vs. SHAM mice. Energy Homeostasis Associated gene (Enho) coding for the hepatokine adropin was significantly reduced in OVX mice livers and strongly inversely correlated with weight gain (r = -0.7 p < 0.001) and liver triglyceride content (r = -0.4, p = 0.04), with a similar trend for serum adropin. In vitro, Enho expression was tripled by 17β-estradiol in BNL 1 ME liver cells with increased adropin in supernatant. Analysis of open-access datasets revealed increased hepatic Enho expression in estrogen treated OVX mice and estrogen dependent ERα binding to Enho. Treatment of 5-month-old OVX mice with Adropin (i.p. 450 nmol/kg/twice daily, n = 4,5 per group) for 6-weeks reversed adverse adipokine gene expression signature in VAT, with a trended increase in lean body mass and decreased liver TG content with upregulation of Rgs16., Conclusions: OVX is sufficient to induce deranged metabolism in adult female mice. Hepatic adropin is regulated by estrogen, negatively correlated with adverse OVX-induced metabolic phenotypes, which were partially reversed with adropin treatment. Adropin should be further explored as a potential therapeutic target and biomarker for menopause-related metabolic derangement., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Vitamin A is vital to maternal-fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women ( n = 23) during two stages of pregnancy (25-28 weeks gestation and 28-32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25-28 weeks gestation, plasma retinol (-27%), 4-oxo-13- cis -retinoic acid (-34%), and albumin (-22%) concentrations were significantly lower, and all-trans -retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28-32 weeks gestation, plasma retinol (-41%), retinol binding protein 4 (RBP4; -17%), transthyretin (TTR; -21%), albumin (-26%), 13- cis -retinoic acid (-23%) and 4-oxo-13- cis -retinoic acid (-48%) concentrations were significantly lower, whereas plasma all-trans -retinoic acid concentrations (+30%) were significantly higher than ≥3 months postpartum. Collectively, the data demonstrates that in healthy pregnancies, retinol plasma concentrations are lower, but all-trans -retinoic acid concentrations are higher than postpartum.

Anti-VEGF-based treatment have been regularly used in recent years in proliferative diabetic retinopathy (PDR) patients. However, some of these patients fail to respond effectively to anti-VEGF. Given that VEGF is not the sole factor influencing PDR pathogenesis and that different anti-VEGF pharmaceuticals are likely to differentially impact these underlying pathophysiological processes, we performed a prospective analysis of the protein profiles of the aqueous humor (AH) in PDR patients before and after treatment with three intravitreal anti-VEGF drugs (ranibizumab, aflibercept, and conbercept) to assess and compare the short-term impacts of these agents. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic methods were used to evaluate the AH protein profiles of PDR patients using paired pre- and 7 days post-anti-VEGF treatment samples (ranibizumab [IVR]: n = 10; conbercept [IVC]: n = 10; aflibercept [IVA]: n = 5). Gene ontology (GO) annotation, KEGG pathway analyses, and protein-protein interaction (PPI) networks were then used to explore the functional relevance of proteins that were differentially expressed between groups. Here, a total of 874 proteins from 25 patients (50 AH samples) were identified in the three patient groups. Different and common clusters of regulated proteins for each group were identified. We identified RARRES1, ALDH3A1, and RBP4 as being specifically regulated following treatment with all three tested anti-VEGF agents. We further found that VEGFR1, VEGFR2, APOM, hornerin, and HSP90B1 were differentially expressed in different anti-VEGF agent groups. In summary, we discovered that ALDH3A1 was a previously unreported protein that was related to angiogenesis and was differentially expressed in the three anti-VEGF treatment groups, suggesting that it may be a new target for PDR therapy. The described proteomic changes in the AH of PDR patients treated with different anti-VEGF agents provide novel targets which may explain the heterogeneity of anti-VEGF treatment responses in these patients, providing a robust foundation for future studies of PDR pathogenesis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Minimally invasive skin sampling is used in various fields. In this study, we examined whether it was possible to obtain skin specimens using biocompatible microneedles composed of sodium hyaluronate and performed transcriptome analysis., Materials and Methods: Thirty-three subjects with different skin conditions, such as skin aging, skin hydration, skin pigmentation, oily skin and sensitive skin, were recruited. Skin types were evaluated based on age, non-invasive measurement devices, 10% lactic acid stinging test and visual assessment; the skin specimens were sampled from the face using microneedles. Total RNA was extracted, and microarray was performed. Correlations between various biomarkers and skin condition parameters were analysed., Results: Several skin-type biomarkers are correlated with age, non-invasive device measurements, LAST score and visual assessment of acne lesions. Representatively, COL1A1 (Collagen type 1 alpha 1 chain), FN1 (Fibronectin 1) and PINK1 (PTEN-induced putative kinase protein 1) for skin aging, FLG (Filaggrin), KLF4 (Kruppel-like factor 4) and LOR (Loricrin) for skin hydration, GPNMB (Glycoprotein non-metastatic melanoma protein B), MLANA (Melan-A) and TYR (Tyrosinase) for skin pigmentation, IGF1 (insulin-like growth factor-1), MPZL3 (Myelin protein zero like 3) and AQP3 (Aquaporin 3) for oily skin and PGF (placental growth factor), CYR61 (cysteine-rich angiogenic inducer 61), RBP4 (retinol-binding protein 4), TAC1 (Tachykinin precursor 1), CAMP (Cathelicidin antimicrobial peptide), MMP9 (Matrix metallopeptidase 9), MMP3, MMP12 and CCR1 (C-C motif chemokine receptor 1) for sensitive skin., Conclusion: Microneedle skin sampling is a new and minimally invasive option for transcriptome analysis of human skin and can be applied for diagnosis and treatment efficacy evaluation, as well as skin type classification., (© 2022 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4 + T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4 + T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4 + T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders ( p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits ( p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels ( p < 0.01), and low circulating RBP4 concentrations were related to a low CD4 + T-cell gain ( p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4 + T cells at 144 weeks ( p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response.

Context: Retinol-binding protein 4 ( RBP4) is associated with visceral fat and insulin resistance (IR) in obesity, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), but some of these data remain controversial., Objective: This study evaluated the relationship between serum RBP4 levels and prediabetes in obese patients with NAFLD., Methods: A total of 79 obese NAFLD patients without ( n  = 41) and with prediabetes ( n  = 38) were included. Serum RBP4 was measured using ELISA method., Results: Higher RBP4 serum levels were observed in patients with prediabetes, metabolic syndrome (MetS), or dyslipidaemia. There was correlation between RBP4 levels and visceral adiposity index (VAI), glucose, insulin, HOMA-IR, and Quicki index. RBP4 ≥ 61 mcg/ml have about 3.5-fold higher risk of prediabetes (OR 3.544, 95% CI 1.385-9.072, p =.008), and RBP4 ≥ 55 mcg/ml increased the risk for MetS approximately 3.1 times., Conclusions: RBP4 is associated with increased risk for prediabetes and MetS in obese patients with NAFLD.

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of β-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed β-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in β-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal β-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1 -/- and Bco2 -/- mice we also show that fenretinide regulates intestinal carotenoid and vitamin E uptake by activating vitamin A signaling during short-term vitamin A deficiency. This study provides a deeper understanding of the impact of fenretinide on vitamin A, carotenoid, and vitamin E homeostasis, which is crucial for the pharmacological utilization of this retinoid., (Copyright © 2021 Elsevier B.V. All rights reserved.)