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BackgroundThe 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).MethodsWe report here seven new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, of whom we performed biochemical analyses.ResultsFor 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.ConclusionDominant missense variants in RBP4 are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism.

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/m2) 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.

Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.

In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4-/-) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4-/- mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.

Parasitic nematodes are major pathogens of humans, animals, and plants, contributing to global health challenges and substantial agricultural losses. Fatty acid- and retinol-binding proteins (FARs), secreted by parasitic nematodes, are believed to play key roles in host–pathogen interactions, including immune modulation and nutrient acquisition. In this study, we characterize a FAR protein from the gastrointestinal nematode Heligmosomoides polygyrus , Hp-FAR-2. Hp-FAR-2, unlike FARs from Caenorhabditis elegans , Steinernema carpocapsae , and Ancylostoma ceylanicum , did not influence immunity or survival in a Drosophila melanogaster infection model, suggesting functional divergence within the FAR family. Competitive lipid-binding assays revealed a preference for omega-3 and omega-6 polyunsaturated fatty acids, indicating selective binding to bioactive lipids that may modulate immunity. Using RAW 264.7 macrophages, we found that Hp-FAR-2 suppresses the expression of both M1-associated (TNF-α, IL-6) and M2-associated (Chil3) markers during polarization, implicating it as a broad immunomodulator that may inhibit inflammatory responses and tissue repair mechanisms to promote chronic infection. Our findings support a model in which Hp-FAR-2 disrupts host lipid signaling and immune function to favor parasite persistence, suggesting its potential role in the excretory/secretory products of H. polygyrus . These findings enhance our understanding of FAR-mediated host manipulation and may inform the development of novel anthelmintic or immunoregulatory therapies.

Background: Childhood vitamin A deficiency leads to increased morbidity and mortality. Human milk is the only source of vitamin A for exclusively breastfed infants. Dried Moringa oleifera leaf powder (moringa) is a good food source of provitamin A and other carotenoids. Its effect during lactation on human milk vitamin A and carotenoid content is unclear. Objectives: Our objective was to investigate the effect of maternal moringa consumption on human milk retinol and carotenoid concentrations and maternal and infant vitamin A status. Methods: We conducted a 3-month pilot single-blinded cluster-randomized controlled trial in breastfeeding mother–infant pairs (n = 50) in Kenya. Mothers received corn porridge with (20 g/d) or without moringa with complete breast expressions and maternal and infant serum collected at enrollment (infant <30 days old) and 3 months. Milk was analyzed for retinol and selected carotenoids; maternal/infant serum was analyzed for retinol binding protein (RBP). Results: 88% (n = 44) pairs completed milk and serum samples. Four mothers (9%) had vitamin A deficiency (RBP <0.07 µmol/L); 11 (25%) were vitamin A insufficient (VAI; RBP <1.05 µmol/L). Alpha-carotene concentration in milk was higher in the moringa than the control group at baseline (p = 0.024) and at exit (least squares means, LSM, 95%CI µg/mL 0.003, 0.003–0.004 moringa vs. 0.002, 0.001–0.003 control, n = 22/cluster; p = 0.014). In mothers with VAI, alpha-carotene was higher in the moringa group than controls at exit (LSM, 95%CI µg/mL 0.005, 0.003–0.009 moringa, n = 3, vs. 0.002, 0.000–0.004 control, n = 8, p = 0.027) with no difference at baseline. Milk carotenoids did not correlate with vitamin A status (serum RBP) in infants or mothers. Conclusions: Maternal moringa consumption did not impact concentration of milk vitamin A and resulted in limited increase in milk carotenoids in this cohort.

Gestational diabetes mellitus (GDM) is a condition that affects increasing number of pregnant women worldwide. Sitagliptin was reported to alleviate symptoms of type 2 diabetes mellitus by reducing serum levels of retinol-binding protein 4 (RBP-4). We investigated the effectiveness of sitagliptin on insulin sensitivity parameters in GDM patients. Pregnant GDM women in the 2nd trimester were recruited for this study. Participants were then assigned randomly to sitagliptin treatment group or placebo treatment group, and administered sitagliptin or placebo daily for 16 weeks. Glucose and insulin profiles, as well as serum RBP-4 level, were measured at both baseline and end of the study. After 16 weeks of treatment, participants in the STL group exhibited significantly improved levels of fasting plasma glucose and serum insulin, homeostasis model of assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR), compared with those in the placebo group. Serum levels of RBP-4 were also markedly decreased in the sitagliptin treatment group, and more importantly it was positively correlated with improved insulin resistance parameters. Our study supports a potentially promising role of sitagliptin in improving insulin resistance by decreasing RBP-4 in GDM-affected women.

The protein therapeutics market, including antibody and fusion proteins, has experienced steady growth over the past decade, underscoring the importance of optimizing amino acid sequences. In our previous study, we developed a fusion protein, R31, which combines retinol-binding protein (RBP) with albumin domains IIIA and IB, linked by a sequence (AAAA), and includes an additional disulfide bond (N227C-V254C) in IIIA. This fusion protein effectively inhibited hepatic stellate cell activation. In this study, we further optimized the sequence. The G176K mutation at the C-terminus of RBP altered the initiation site of the first α-helix in domain IIIA, shifting it from P182 to K176, and promoted polar interactions between K176 and adjacent residues, enhancing the rigidity of the RBP/IIIA interface. The introduction of an additional disulfide bond (V231C/Y250C) connecting helices 3 and 4 in IIIA resulted in a three-fold increase in productivity and a 2 °C improvement in thermal stability compared to R31. Furthermore, combining the G176K mutation with V231C/Y250C further enhanced both productivity and anti-fibrotic activity. These findings suggest that the enhanced stability of domain IIIA, conferred by V231C/Y250C, along with the increased rigidity of the RBP/IIIA interface, optimizes interdomain distance and alignment, facilitating proper protein folding.

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.

In recent years, the awareness that pesticides can have other effects apart from generic toxicity is growing. In particular, several pieces of evidence highlight their influence on human fertility. In this study, we investigated, by a virtual screening approach, the binding between pesticides and proteins present in human gametes or associated with reproduction, in order to identify new interactions that could affect human fertility. To this aim, we prepared ligand (pesticides) and receptor (proteins) 3D structure datasets from online structural databases (such as PubChem and RCSB), and performed a virtual screening analysis using Autodock Vina. In the comparison of the predicted interactions, we found that famoxadone was predicted to bind Cellular Retinol Binding Protein-III in the retinol-binding site with a better minimum energy value of −10.4 Kcal/mol and an RMSD of 3.77 with respect to retinol (−7.1 Kcal/mol). In addition to a similar network of interactions, famoxadone binding is more stabilized by additional hydrophobic patches including L20, V29, A33, F57, L117, and L118 amino acid residues and hydrogen bonds with Y19 and K40. These results support a possible competitive effect of famoxadone on retinol binding with impacts on the ability of developing the cardiac tissue, in accordance with the literature data on zebrafish embryos. Moreover, famoxadone binds, with a minimum energy value between −8.3 and −8.0 Kcal/mol, to the IZUMO Sperm–Egg Fusion Protein, interacting with a network of polar and hydrophobic amino acid residues in the cavity between the 4HB and Ig-like domains. This binding is more stabilized by a predicted hydrogen bond with the N185 residue of the protein. A hindrance in this position can probably affect the conformational change for JUNO binding, avoiding the gamete membrane fusion to form the zygote. This work opens new interesting perspectives of study on the effects of pesticides on fertility, extending the knowledge to other typologies of interaction which can affect different steps of the reproductive process.