Search Results (80)

Transthyretin (TTR) amyloidosis is a systemic, progressive, and fatal disease. TTR is integral in vitamin A (retinol) transport via its binding to retinol binding protein 4 (RBP4). Current and emerging therapies for TTR amyloid cardiomyopathy (ATTR-CM), including RNAi therapies and potentially CRISPR-based therapies, reduce hepatic transthyretin production and hence decrease serum RBP4, which decreases circulating vitamin A levels. However, despite these reductions in circulating vitamin A, hepatic reserves and alternative delivery mechanisms may prevent clinical manifestations of vitamin A deficiency. Vitamin A functions as a key regulator of immunity, antioxidant function, cell growth and differentiation and vision. This paper aims to serve as a comprehensive review of vitamin A and its metabolites, their transport, and their function in human health and disease. Additionally, we seek to synthesize the relevant outcomes and safety data of TTR silencing therapies and how they relate to circulating vitamin A levels and vitamin A-related clinical outcomes in a manner that is relevant to the cardiac amyloidosis specialist. Full article

Background: Vitamin A is an essential micronutrient critical for vision, immune function, cellular differentiation, and metabolic homeostasis. The liver serves as the primary site of vitamin A storage and systemic distribution, delivering all-trans-retinol (ROL) to peripheral tissues, including the retina, via retinol-binding protein 4 (RBP4). Tight regulation of retinoid delivery to peripheral tissues is crucial for metabolic function and photoreceptor integrity. Objectives: This review provides a current understanding of intestinal absorption, hepatic storage, systemic transport, and ocular utilization of vitamin A, with a focus on the role of retinol-binding protein 4 receptor 2 (RBPR2) in mediating liver–eye communication. Results: Studies using Rbpr2 knockout mice show that loss of RBPR2 impairs hepatic ROL-bound RBP4 uptake and retinyl ester concentrations, alters circulating holo-RBP4 levels, and reduces ocular retinoid content, leading to visual dysfunction and photoreceptor structural abnormalities. These effects are amplified under dietary vitamin A-deficient conditions, highlighting its unique sensitivity to tightly regulated serum RBP4-ROL transport. In mouse models of Stargardt disease, dietary modulation of RBPR2 mRNA expression and serum RBP4-ROL levels protects against lipofuscin accumulation and attenuates retinal cell degeneration, suggesting translational relevance. Conclusions: This review article explores the liver–eye axis by focusing on the regulation of retinoid homeostasis in the liver and other systemic organs through the non-ocular RBP4 receptor protein, RBPR2, and how RBPR2 expression may influence liver and serum retinoid homeostasis, which can impact visual function. Disruption of RBPR2 markedly compromises systemic and retinal retinoid supply, emphasizing its potential as a therapeutic target for metabolic and retinal disorders. Full article

Background: The protein that binds to retinol 4 (RBP4), is a lipocalin-family protein, secreted primarily by the adipose tissue and the liver, and has also been reported to be produced by other tissues, including the kidney. This protein mediates the transport of vitamin A (retinol) in the circulation, bound to a transporter protein, transthyretin. In recent years, RBP4 has been shown to contribute to the development of insulin resistance and a range of metabolic disorders such as type 2 diabetes mellitus, gestational diabetes, obesity, metabolic syndrome, hyperuricaemia, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiorenal diseases. Objectives: The objective was to analyse the role of RBP4 in ageing, as well as its mechanisms and effects across organs and systems. Results: Circulating RBP4 levels increase with age and have been related to the onset of various processes like sarcopenia, elevated neurodegenerative markers in the brain, and an increase in TSH levels. Furthermore, it appears that in ageing, the rise in RBP4 is related to the development of atherogenesis, chronic kidney disease, and osteoarthritis. These effects appear to be mediated by chronic inflammation along with the development of insulin resistance, increased oxidative stress and mitochondrial dysfunction, inhibition of autophagy, and intestinal dysbiosis. Conclusions: RBP4 is a factor to be taken into account in the ageing process, as it has been shown that elevated circulating serum levels in older individuals lead to and accelerate deterioration across different organs or systems. Full article

Retinol-binding protein 4 (RBP4), an adipokine secreted by adipose tissues, has been implicated in metabolic inflammation and insulin resistance. Type 2 diabetes (T2D) is a recognized risk factor for osteoarthritis, with both conditions characterized by chronic low-grade inflammation, suggesting potential links between metabolic disorder and joint degeneration. This study aimed to investigate whether inflammatory and metabolic stresses regulate RBP4 expression and function in joint-related cells. Murine immature chondrocyte cells (iMACs) and the mouse AT805 teratocarcinoma cell line, clone 5, that differentiates into chondrogenic cells (ATDC5), were used as in vitro models for chondrocyte cells. Rbp4 mRNA expression increased during differentiation of iMACs, with 3.6- and 2.2-fold elevations observed on days 7 and 14, respectively (p < 0.01 vs. undifferentiated controls). Inflammatory stimulation with interleukin-6 (IL-6) significantly increased Rbp4 mRNA expression in ATDC5 cells (p < 0.05 vs. vehicle), along with elevated expression of catabolic and inflammatory mediators, including monocyte chemoattractant protein-1 (Mcp1), cyclooxygenase-2 (Cox2), and matrix metalloproteinase-3 (Mmp3) (p < 0.05 vs. vehicle). Pharmacological inhibition of RBP4 using fenretinide (FEN) attenuated chondrogenic differentiation marker expression, reduced glycosaminoglycan synthesis during chondrogenic differentiation, and mitigated high-glucose-induced catabolic responses, as indicated by reduced Mcp2 (p = 0.04) and Mmp13 (p = 0.01) expression in ATDC5 cells treated with FEN compared with cells treated with the vehicle under high-glucose conditions. Furthermore, in RAW 264.7 cells, a murine macrophage cell line commonly used as an in vitro model for osteoclastogenesis, FEN significantly reduced the expression of osteoclast differentiation markers, dendritic cell-specific transmembrane protein (DC-Stamp), nuclear factor of activated T-cells, cytoplasmic 1 (Nf-atc1), cathepsin k (Cath.k), and tartrate-resistant acid phosphatase (Trap) under osteoclastogenic conditions (p < 0.01 vs. vehicle). Collectively, these findings suggest that RBP4 functions as a metabolic–inflammatory mediator influencing both cartilage and bone-remodeling processes. This study reveals a previously unrecognized role of RBP4 in regulating osteoclast-associated pathways. Targeting RBP4 may, therefore, represent a promising therapeutic strategy for delaying or preventing osteoarthritis progression, particularly in metabolically compromised conditions. Full article

Cardio-kidney-metabolic (CKM) syndrome represents an integrated clinical and molecular continuum encompassing metabolic dysfunction, cardiovascular disease and chronic kidney disease. This multidimensional disorder arises from interdependent biological pathways that extend beyond conventional risk factors. Emerging evidence highlights a group of adipokines and vascular modulators—including retinol-binding protein 4 (RBP4), lipocalin 2 (LCN2), apolipoprotein M (ApoM), Klotho and matrix Gla protein (MGP)—emerging molecular modulators with potential involvement in CKM pathophysiology. Pro-inflammatory adipokines such as RBP4 and LCN2 contribute to insulin resistance, oxidative stress and endothelial dysfunction. In contrast, protective molecules including ApoM and Klotho preserve nitric oxide bioavailability, lipid metabolism and antioxidant defense. MGP modulates vascular calcification and adipose remodeling, with its inactive form (dp-ucMGP) linked to vascular stiffness and renal decline. The combined dysregulation of these molecules sustains cycles of inflammation, oxidative stress and tissue remodeling that drive CKM progression. Collectively, current data support their dual role as biomarkers and therapeutic targets. Nonetheless, clinical translation remains limited, emphasizing the need for standardized assays, longitudinal validation, and integrative multimarker approaches within precision medicine frameworks for CKM syndrome. Full article

Introduction: Polycystic ovary syndrome (PCOS) is associated with obesity, numerous metabolic complications, and an increased risk of cardiovascular disease. Adipokines, secreted by adipose tissue, may contribute to the development of these cardiometabolic disturbances. The aim of this study was to investigate the adipokine levels and their relationship with metabolic status in adolescent girls with PCOS. Patients and Methods: This cross-sectional study included 66 adolescent girls with PCOS (mean age: 16.5 ± 1.08 years; study group, SG) and 30 regularly menstruating girls (mean age: 16.2 ± 1.37 years; control group, CG) recruited between 2012 and 2017. All participants underwent physical examination, body composition assessment, liver ultrasonography, and biochemical and hormonal evaluations. Fasting venous blood samples were collected to determine the adipokine profile, and the leptin-to-adiponectin ratio (L/A) was calculated. Results: Compared with the control group, the PCOS group demonstrated significantly lower adiponectin (p = 0.019) and vaspin (p = 0.037) concentrations, and higher RBP-4 levels (p = 0.048). Positive correlations were observed between adiponectin, apelin, and omentin, while negative correlations were found between leptin and L/A and HDL cholesterol levels in the SG. Omentin showed a negative association, and leptin and L/A a positive association, with triglyceride concentration. In the SG, resistin and visfatin levels were negatively correlated with total cholesterol, and resistin also showed a negative correlation with LDL cholesterol. In patients with PCOS, adverse associations were observed between carbohydrate metabolism parameters and insulin resistance indices, while insulin sensitivity indices correlated positively with adiponectin and omentin concentrations. Visfatin levels in the SG correlated negatively with QUICKI. Conclusions: The adipokine profile of adolescent girls with PCOS differs from that of regularly menstruating peers, particularly in adiponectin, RBP-4, and vaspin concentrations. However, the absence of significant correlations between RBP-4 and vaspin and lipid or carbohydrate metabolism parameters suggests that these adipokines are not reliable markers of metabolic disturbances in adolescent girls with PCOS. Full article

Obesity is characterized by chronic low-grade inflammation, largely driven by macrophage infiltration into adipose tissue, which contributes to the development of insulin resistance. All-trans retinoic acid (ATRA), a biologically active metabolite of vitamin A, has demonstrated anti-inflammatory properties. This study examined the effects of ATRA on inflammation and insulin resistance using a coculture model comprising hypertrophied 3T3-L1 adipocytes and RAW264.7 macrophages. Coculture markedly elevated the production of pro-inflammatory mediators—including nitric oxide, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interleukin-6—and increased free fatty acid release while suppressing the secretion of anti-inflammatory adiponectin. Treatment with ATRA (0.1, 1, and 10 μM) significantly reversed these coculture-induced alterations (p < 0.001). ATRA also inhibited the nuclear translocation of NF-κB and downregulated the expression of retinol-binding protein 4 (RBP4). Moreover, ATRA improved insulin-stimulated glucose uptake in adipocytes rendered insulin-resistant by coculture (p < 0.01), an effect associated with the restoration of glucose transporter 4 (GLUT4) and insulin receptor substrate-2 (IRS-2) expression. These findings suggest that ATRA effectively mitigates inflammation and insulin resistance arising from adipocyte–macrophage interactions, highlighting its potential as a therapeutic agent for obesity-related metabolic disorders. Full article

Chronic kidney disease (CKD) poses a global burden affecting over 10% of the adult population worldwide. Acute kidney injury (AKI) is an important cause of CKD, especially following severe and repeated episodes. However, the processes underpinning progressive and chronic renal deterioration after AKI are only incompletely understood. Thus, models reproducing this scenario are needed to study the pathophysiological mechanisms involved and identify biomarkers and molecular targets for diagnostic and therapeutic purposes. In this study, we developed a rat model of 3 serial AKIs leading to CKD, in which renal function, kidney structure and fibrosis, and urinary injury biomarkers were studied over a period of 9 months, alongside a traditional model of CKD caused by renal mass reduction. Our results show that consecutive AKIs eventually develop key features of CKD including progressive fibrosis and albuminuria. Renal injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and retinol binding protein 4 (RBP4) show distinct evolution patterns suggestive of specific but undetermined damages with different time courses. The chronic evolution of renal tissue degeneration and dysfunction following serial AKIs closely resembles those observed after extensive renal mass reduction, which indicates chronic degeneration. Finally, a clear dissociation in the evolution of interstitial fibrosis (progressively increasing) and of glomerular filtration (mainly stable) was observed in both models. This questions the consuetudinary paradigm ascribing an etiological role to fibrosis in progressive renal dysfunction. Full article

Background/Objectives: Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Inflammation and metabolic dysregulation, particularly those related to obesity, have emerged as critical contributors to CRC progression. Interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4), an adipokine involved in metabolic regulation, may be key mediators of these processes. This study aimed to evaluate the expression levels of IL-6 and RBP4 in CRC tissues and their associations with clinicopathological features and overall survival. Furthermore, in silico analyses were performed to explore the molecular networks and signaling pathways related to both biomarkers. Methods: Immunohistochemical staining of IL-6 and RBP4 was conducted in 118 CRC and matched adjacent normal tissues. Expression levels were assessed using the H-score system and correlated with clinical parameters. Survival analysis was performed using Kaplan–Meier curves. In silico analyses were based on RNA-seq data from TCGA and included pathway enrichment, gene co-expression, and protein–protein interaction networks. Results: IL-6 and RBP4 expression were significantly elevated in tumor tissue compared to adjacent normal mucosa. High IL-6 expression correlated with age and obesity measures, while RBP4 expression showed significant associations with pT stage, lymph node involvement, TNM stage, and obesity-related parameters. Kaplan–Meier analyses indicated shorter overall survival in patients with high IL-6 or RBP4 expression. In silico analysis confirmed upregulation of IL6 and RBP4 in CRC and highlighted immune-related pathways for IL-6 and developmental signaling for RBP4. Conclusions: Elevated expression of IL-6 and RBP4 in CRC tissue is associated with adverse clinical features and reduced survival, underscoring their potential role as prognostic biomarkers. These findings support the involvement of inflammation and metabolic dysfunction in CRC progression and suggest IL-6 and RBP4 as candidates for future targeted therapeutic approaches. Full article

Previous studies have suggested that T14, a 14-amino-acid peptide derived from acetylcholinesterase (AChE), functions as an activity-dependent signalling molecule with key roles in brain development, and its dysregulation has been linked to neurodegeneration in Alzheimer’s disease. In this study, we examined the distribution of T14 under normal developmental conditions in the mouse forebrain, motor cortex (M1), striatum (STR), and substantia nigra (SN). T14 immunoreactivity declined from E16 to E17 and further decreased by P0, then peaked at P7 during early postnatal development before declining again by adulthood at P70. Lower T14 immunoreactivity in samples processed without Triton indicated that T14 is primarily localised intracellularly. To explore the relationship between T14 expression and neuronal activity, we used mouse models with chronic silencing (Rbp4Cre-Snap25), acute silencing (Rbp4Cre-hM4Di), and acute activation (Rbp4Cre-hM3D1). Chronic silencing altered the location and size of intracellular T14-immunoreactive particles in adult brains, while acute silencing had no observable effect. In contrast, acute activation increased T14+ density in the STR, modified T14 puncta size near Rbp4Cre cell bodies in M1 layer 5 and their projections to the STR, and enhanced co-localisation of T14 with presynaptic terminals in the SN. Full article

The increasing number of individuals with chronic kidney disease (CKD), mainly due to lifestyle changes—such as increased consumption of processed foods, physical inactivity, obesity, and smoking habits—and population aging, highlights the need to identify new biomarkers to facilitate monitoring of CKD progression and, consequently, predict end-stage renal disease (ESRD). This study aimed to analyze the proteomic profile of urine samples from healthy individuals and those with ESRD to identify potential biomarkers for this advanced stage of CKD. Urine samples were collected from 20 participants, comprising 10 healthy individuals and 10 patients with ESRD, and analyzed via liquid chromatography coupled with a tandem mass spectrometer. Bioinformatics analyses, including gene ontology and protein interaction, were subsequently conducted. A total of 416 proteins were identified in the proteomic profiles of the groups, and 19 proteins showed statistically significant differences between them. Of these, five proteins—hemopexin, beta-2-microglobulin, retinol-binding protein 4, transthyretin, and factor D—emerged as potential biomarkers for ESRD. The proteins identified were able to characterize and differentiate the urinary proteomic profiles of the two groups. The five selected proteins represent promising candidates for ESRD biomarkers. Full article

Background: This prospective study aimed to evaluate renal function using retinol binding protein 4 (RBP4), cystatin C, and glomerular filtration rate (GFR) in relation to physical activity and lesion level in children with neurogenic bladder (NB) post-myelomeningocele. Methods: Two groups were studied: 33 children with NB and 20 healthy controls. Data collected included demographic details, physical activity levels, uroflowmetry, urodynamic diagnosis, and renal function parameters. Urinary RBP4 and serum cystatin C were measured using ELISA, and GFR was calculated using the Schwartz formula. Results: The NB group had higher median serum cystatin C and urinary RBP4/creatinine ratios compared to the control group (0.28 vs. 0.22; 18.6 vs. 3.2, respectively). The participants were categorized based on activity levels, lesion levels, catheterization status, and urodynamic diagnosis. No differences in RBP4, cystatin C, or urodynamic diagnosis were observed according to activity and lesion levels. Significant differences in GFR were found based on activity and lesion levels, with higher median GFR in NB children (182.7 vs. 147.3). No differences were found between catheterized and non-catheterized children in the studied parameters. Conclusions: Elevated urinary RBP4 in NB patients suggests possible proximal renal tubule dysfunction. Higher serum cystatin C despite lower creatinine levels indicates altered renal function in NB children. Urinary RBP4 correlates positively with bladder pressure at maximum cystometric capacity, suggesting potential utility in therapy monitoring and modification. Full article

Background: Retinol-binding protein 4 (RBP4) is primarily recognized for its role in retinoid transport, but has recently been implicated in cancer progression and prognosis. However, a comprehensive pan-cancer analysis of RBP4’s expression, prognostic significance, and functional associations across various cancers is lacking. Methods: We conducted a pan-cancer analysis of RBP4 using data from public databases. RBP4 expression levels were examined in 33 tumor types, and correlations with clinical outcomes, immune cell infiltration, DNA methylation, and gene mutations were assessed. Enrichment analyses of RBP4 and its co-expressed genes were performed to explore associated biological pathways. Additionally, in vitro experiments were conducted to assess the effects of RBP4 on cell migration and proliferation. Results: RBP4 showed differential expression between tumor and normal tissues, with downregulation in 21 cancer types and upregulation in 6. High expression levels of RBP4 were associated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in specific cancers, notably in BRCA, HNSC, and STAD, whereas it was a favorable prognostic factor in cancers such as KIRP and MESO. RBP4 expression was also associated with immune cell infiltration, particularly with CD4+ Th2 cells and immune checkpoint genes. DNA methylation analysis suggested that the methylation of RBP4 may play a role in its regulatory mechanisms across cancer types. Enrichment analyses revealed that RBP4 and its co-expressed genes are involved in metabolism-related pathways and immune regulation. Functional assays indicated that RBP4 knockdown promoted tumor cell migration and proliferation. Conclusions: This study provides a comprehensive pan-cancer analysis of RBP4, identifying its prognostic potential and possible involvement in tumor immunity and metabolism. Our findings suggest that RBP4 could serve as a novel biomarker and therapeutic target in cancer, although further experimental studies are required to elucidate its precise mechanisms in specific cancer types. Full article

Parathyroid hormone-related protein (PTHrP) and retinol-binding protein 4 (RBP4) have been associated with a worse prognosis of kidney disease. Recently, the direct interconnection between PTHrP and the peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor whose activation is nephroprotective, has been discovered. The aim of this study was to analyze the relationship between PTHrP, PPARγ, and RBP4. For this purpose, we analyzed the levels of these proteins, which were studied in the kidneys of five experimental groups of mice at 6 weeks of age: controls, diabetics, insulin-treated diabetics, transgenic mice overexpressing PTHrP at the renal level, and the latter mice that were also induced with diabetes. In addition, we also analyzed the expression levels of these molecules in two mouse podocyte cell lines, controls and PPARγKO, subjected to a lipotoxic insult by palmitic acid. We found that RBP4 and PTHrP are increased in the kidney in pathological conditions and that insulin and PPARγ act regulating PTHrP and RBP4 expression, suggesting that the regulation of this system is critical for the maintenance of renal homeostasis and how it becomes imbalanced in different pathophysiological conditions. Full article

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. Full article