Fatty Acid Binding Protein Research Articles

Longitudinal analysis of urinary I-FABP in extremely preterm infants that develop necrotizing enterocolitis.

Intestinal fatty acid binding protein (I-FABP) is an intestinal epithelial protein detectable in infants with necrotizing enterocolitis (NEC). The longitudinal behavior of I-FABP following NEC or its association with gastrointestinal or neurodevelopmental outcomes is unknown. In this secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, we compared infants with and without NEC. Urine I-FABP concentrations in matched infants (n = 70) were measured serially using ELISA and compared using paired analysis. In infants with NEC, the associations of I-FABP levels with short-term outcomes and neurodevelopmental outcomes at 22-26 months corrected age were determined using non-parametric analysis. Infants with NEC were more likely to have cholestasis, death or severe neurodevelopmental impairment, cerebral palsy, and lower Bayley-III motor scores. Baseline urinary I-FABP levels were similar between groups. When compared to controls, infants with NEC had urinary I-FABP concentrations that were higher at diagnosis (median 11 vs 2.6 ng/ml, p = 0.006) and lower post-NEC (median 1 vs 5 ng/ml, p = 0.002). Diagnosis I-FABP levels were not associated with gastrointestinal or neurodevelopmental outcomes at 22-26 months corrected age. In extremely preterm infants, urinary I-FABP was elevated at NEC diagnosis and lower post-NEC compared to matched controls. I-FABP levels were not associated with adverse gastrointestinal or neurodevelopmental outcomes. Urinary intestinal fatty acid binding protein (I-FABP) levels are increased at diagnosis of NEC and fall to below baseline after NEC in extremely preterm infants. Urine I-FABP levels at NEC diagnosis are not associated with cholestasis, intestinal stricture or obstruction, need for additional intestinal surgery after NEC, or neurodevelopmental outcomes at 22-26 months corrected age. Urine I-FABP levels may be useful in the diagnosis of NEC. Diagnostic I-FABP levels do not predict short-term gastrointestinal or neurodevelopmental outcomes after NEC.

Late-gestation maternal undernutrition induces circulatory redistribution while preserving uteroplacental function independent of fetal glycaemic state.

Programming effects of maternal undernutrition on fetal metabolic and cardiovascular systems are well elucidated, yet a detailed characterization of maternal haemodynamics is not available. This study used comprehensive cardiovascular magnetic resonance (CMR) imaging to quantify maternal haemodynamics after 29days (111-140 days) of late-gestation undernutrition (LGUN) in pregnant sheep. Control ewes received 100% of metabolizable energy requirements (MERs, n=15), whereas LGUN ewes were globally nutrient restricted to 50% MER (n=18), with a subset of fetuses undergoing continuous glucose infusion (LGUN+G, n=6/18). Ewes underwent CMR (138-140 days' gestation), and placental tissue was collected the next day. Ewes in both LGUN groups had reduced body weight and mean blood glucose concentration across gestation. Ventricular dimensions were lower in both LGUN groups. Uterine artery blood flow (QUtA) was elevated in the LGUN group compared with controls, whereas peripheral blood flow was reduced and further diminished in LGUN+G. Maternal weight change correlated with all haemodynamic parameters across all groups. Uteroplacental oxygen and glucose delivery were increased in LGUN compared to control ewes, whereas uteroplacental oxygen consumption was preserved. LGUN did not impact placental or fetal weight, and markers of brain-sparing physiology were absent. Placental expression of insulin-like growth factors (IGF-1 and IGF-2) and their receptors, glucose, fatty acid (FA) or amino acid transporters and markers of angiogenesis was not impacted. FA transporter expression was positively correlated with QUtA, and FA binding protein correlated negatively with maternal weight change. Maternal cardiovascular adaptations in response to LGUN manifest as preservation of placental growth and function, thereby preserving fetal growth. KEY POINTS: Maternal undernutrition during pregnancy alters fetal metabolic and cardiovascular physiology, but little is known about alterations in maternal haemodynamics. Late-gestation undernutrition (LGUN) and LGUN+G redirected maternal blood flow from the periphery to the uteroplacental unit, concomitantly increasing the delivery of glucose and oxygen to the uteroplacental unit. Substrate transporter expression and uteroplacental oxygen consumption were preserved in LGUN and LGUN+G, suggesting prioritization of the placenta. This study is the first to report detailed maternal haemodynamics in the setting of maternal undernutrition, where placental growth and function were maintained, ultimately preserving fetal oxygen metabolism and growth.

Transportery kwasów tłuszczowych jako potencjalne markery diagnostyczne raka jelita grubego

Colorectal cancer (RJG) is one of the most frequently diagnosed malignant neoplasms: approximately 1.9 million new cases are reported annually. Notwithstanding the advent of techniques for the early detection of RJG and the introduction of novel therapeutic modalities, this disease remains the second leading cause of cancer-related mortality. The results of recent studies highlight the role of fatty acid transporters, including fatty acid translocase/cluster of differentiation 36 (FAT/CD36), fatty acid transport proteins (FATPs), and fatty acid-binding proteins (FABPs), in the pathogenesis of RJG. Changes in serum concentrations and in expression levels in tumor tissue may serve as promising biomarkers for the early diagnosis of the disease and/or the monitoring of its progression and the efficacy of its treatment. Moreover, the fatty acid carriers present a promising avenue for the development of efficacious therapies against RJG.

Light up heart-type fatty acid binding protein (FABP3) with a novel fluorine-18 labelled selective FABP3 ligand.

Heart-type fatty acid binding proteins (FABP3) constitute a family of lipid chaperone proteins. They are found in the cytosol and enhance cellular fatty acid solubilisation, transport, and metabolism. FABP3 is highly expressed in the myocardium and is released from myocytes during myocardial damage. As FABP3 content in the myocardium is closely related to the metabolic state of fatty acids, we hypothesised that targeting of FABP3 with a radiolabelled small organic compound would visualise myocardium. The selective FABP3 inhibitor, 4-(4-fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid (LUF), was radiolabelled via a two-step reaction comprising copper-mediated 18F-fluorination of an arylboronic precursor followed by alkaline hydrolysis of the ethoxy protecting group. [18F]LUF was successfully synthesised by automated synthesiser with sufficient activity yields (14.0 ± 1.8 GBq) and high quality (molar activity, > 250 GBq/µmol and radiochemical purity, > 99.6%). Biological assessment of [18F]LUF as an in vivo myocardial imaging agent included evaluations of biodistribution, metabolite analysis, and positron emission tomography (PET) imaging of small animals. [18F]LUF clearly visualised the myocardium with high contrast against background tissues such as the lung and liver. [18F]LUF also showed a high absolute myocardial uptake equivalent to that of the promising myocardial perfusion tracer [18F]flurpiridaz and excellent metabolic stability in the body. These properties are ideal for stable and noise-less imaging of the heart. PET imaging of rat surgical permanent myocardial infarction (MI) and experimental autoimmune myocarditis (EAM) was also performed. [18F]LUF successfully visualised lesions of permanent MI and EAM. Our results showed for the first time that the 18F-labelled FABP3 selective small organic compound clearly visualised myocardium with good quality. To determine the clinical utility of [18F]LUF for cardiovascular disease in clinical practice, it will be necessary to evaluate a greater variety of cardiovascular disease models and elucidate the accumulation mechanism, particularly in relation to fatty acid metabolism in the myocardium.

Gene Expression Study in Gilthead Seabream (Sparus aurata): Effects of Dietary Supplementation with Olive Oil Polyphenols on Immunity, Metabolic, and Oxidative Stress Pathways

In an era with an ever-growing population, sustainability and green transition are the main milestones to be considered within the current European Green Deal program, and the recovery of by-products for the integration of feed with bioactive molecules, that are sustainable and with high nutritional value, is an ambitious mission to be explored also in aquaculture. Olive oil extraction produces a range of solid and liquid by-products, in varying proportions depending on the utilized production techniques, all of which are considered as possible pollutants. However, these products are also rich of polyphenols, bioactive molecules with several and well-known beneficial properties (antimicrobic, anti-inflammatory, antioxidant, and immune-modulating). On this basis, this work aimed at evaluating the effects of dietary supplementation with polyphenols derived from olive mill wastewater on growth performance and on gene expression modulation, by means of RT-qPCR assays, in farmed Sparus aurata. Particularly, some target genes of metabolic, immunity, and oxidative stress pathways have been investigated in breeding gilthead seabream. Differential gene expression analysis was carried out, and differences between the control group (n = 9) and the treated one (n = 9) were computed with Student’s t test. The results have highlighted that supplemented feed enhanced fish growth, with a significant feed conversion ratio between the two groups. Furthermore, the polyphenol diet had a beneficial impact on gene expression fold with a level of significance for fatty acid binding protein 2, superoxide dismutase 1, and interleukin-12 genes at hepatic or intestinal district. These significant and promising preliminary findings promote, in the future, other investigations on polyphenolic by-products and on their putative or possible re-utilization in fish feeding.

Abstract 4145829: Fatty Acid Binding Protein 4 as Potential Indicator for Gestational Diabetes Mellitus-Induced Fetal Endothelial Dysfunction

Introduction/Background: Gestational diabetes mellitus (GDM) is the most common complication during pregnancy. GDM is leading to an elevated risk for the development of cardiovascular diseases both in the mother and the child in later life. Previous studies have identified fatty acid-binding protein 4 (FABP4) as a prime candidate involved in the pathophysiology of GDM. Indeed, women with GDM exhibit elevated blood levels of FABP4, suggesting its potential role as a biomarker for endothelial dysfunction and cardiovascular risk assessment in GDM. Research Question/Hypothesis: Does FABP4 affect the function of human endothelial cells from patients with GDM? Goals/Aim: Our aim is a better understanding of the role of FABP4 in fetal endothelial dysfunction of patients with GDM and the development of potential therapeutic strategies. Methods/Approach: Primary human umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords obtained from normoglycemic and GDM pregnancies. Total mRNA from HUVECs was used for bulk RNA sequencing to compare gene expression pattern. HUVECs were subjected to functional analyses assessing proliferation, migration, NO and insulin signaling. Finally, human endothelial cells were exposed to high laminar flow (30 dyn/cm 2 ) or simvastatin (10 nM) treatment to investigate their impact on FABP4 expression and endothelial function. Results/Data: Bulk RNA sequencing data analysis revealed FABP4 as a gene overexpressed in GDM HUVECs compared to normoglycemic controls. Gene set enrichment analysis showed in addition an enrichment of genes involved in angiogenesis and Notch signaling pathways in human endothelial cells from GDM patients. GDM HUVECs had a significantly higher wound healing capacity compared to normoglycemic controls. The PI3K/AKT/mTOR pathway was enriched in GDM HUVECs. GDM HUVECs displayed impaired activation of AKT and eNOS (expression and phosphorylation) after stimulation with insulin, suggesting a possible insulin resistance. Finally, subjecting HUVECs to high laminar shear stress or simvastatin treatment caused a reduction of FABP4 mRNA expression and an increase of eNOS expression, indicating potential therapeutic strategies to improve endothelial function. Conclusions: We provided evidence that FABP4 could be involved in fetal GDM-induced endothelial dysfunction. High laminar shear stress and medications activating eNOS signaling could protect the endothelium against the negative impact of FABP4 in GDM.

Abstract 4115669: Single-cell and Spatial Transcriptomics Identified Fatty Acid-binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension

We are seeking to elucidate the endothelial fatty acid metabolism role for obstructive vascular remodeling in the pathogenesis of PAH. In this study, we bred a severe mouse model of PH Egln1 Tie2Cre mice with Fabp45 -/- mice to generate Egln1 Tie2Cre / Fabp45 -/- mice. We applied single-cell RNA sequencing (scRNA-seq) to profile the pulmonary cells in Egln1 Tie2Cre mice and Egln1 Tie2Cre / Fabp45 -/- mice. Human hPAEC from idiopathic PAH patients and healthy donors were used to measure fatty acid-binding protein 4 and 5 (FABP4 and FABP5) expression via sc-RNA seq and spatial transcriptomics. siRNA-mediated knockdown of FABP4 and FABP5 and lentivirus-mediated FABP4 and 5 overexpression were performed to study cell proliferation, apoptosis, and glycolysis. Our scRNA-seq analysis demonstrated that both FABP4 and 5 were highly induced in the ECs of Egln1 Tie2Cre mice. PAECs from IPAH patients also showed higher expression of FABP4 and 5. Knockdown of FABP4-5 reduced EC proliferation, starvation-induced Caspase 3/7 activity, and glycolysis. Overexpression of FABP4-5 promoted EC glycolysis and proliferation. Genetic deletion of Fabp4 and 5 in Egln1 Tie2Cre mice exhibited a reduction of RVSP, RV hypertrophy, and reduction of EC glycolysis gene programming compared to Egln1 Tie2Cre mice. In conclusion, we found that FABP4 and 5 control EC glycolysis and contribute to the development of PAH.

Precision medicine in intestinal ischemia: the emerging role of biomarkers.

Intestinal ischemia (IIs) is a significant gastrointestinal condition characterized by reduced blood flow to the bowel, leading to inflammation and injury. Early diagnosis and management are crucial for preventing severe complications. Under this point of view, circulating biomarkers can enhance patient stratification and guide therapeutic decisions. Fatty acid-binding proteins (FABPs), specifically I-FABP and L-FABP, are small cytosolic proteins released upon enterocyte membrane integrity loss, with elevated plasma levels indicating early intestinal ischemia. Stromal Cell-Derived Factor-1 (SDF-1) regulates stem cell function and shows significantly higher levels in patients with IIs and cardiovascular disease compared to controls. D-Lactate, a bacterial fermentation byproduct, is another significant marker, with higher serum levels observed in intestinal ischemia cases. Alpha-glutathione S-transferase combats intracellular oxidative stress, with significantly elevated levels in acute mesenteric ischemia patients. Additionally, SM22, a small smooth muscle protein, shows higher plasma levels in patients with transmural ischemia compared to those with mucosal ischemic lesions and healthy controls. These biomarkers are promising for their roles in early detection and differentiation of IIs from other gastrointestinal conditions. Therapeutic strategies, including anti-inflammatory therapies, have shown efficacy in managing IIs symptoms and preventing recurrence. This review aims to inform clinicians and researchers about the current advancements in biomarker research and therapeutic approaches for IIs, emphasizing the importance of integrating these biomarkers and treatments into clinical practice to improve the management and prognosis of the disease.

Association of urinary EGF, FABP3, and VCAM1 levels with the progression of early diabetic kidney disease.

Introduction Diabetic kidney disease (DKD) is a common cause of chronic kidney disease with around 25-40% of patients with diabetes being affected. The course of DKD is variable and estimated glomerular filtration rate (eGFR) and albuminuria, the currently used clinical markers, are not able to accurately predict the individual disease trajectory, in particular in early stages of the disease. The aim of this study was to assess the association of urine levels of selected protein biomarkers with the progression of DKD at an early stage of disease. Methods We measured 22 protein biomarkers using the Mesoscale Discovery platform in 461 urine samples of the PROVALID cohort, an observational study of patients with type 2 diabetes mellitus followed at the primary health care level for a minimum of four years. Odds ratios (OR) were estimated for the effect of marker values above median on fast progression using unadjusted and adjusted logistic regression models. RNA expression at the single cell level in kidney biopsy samples obtained from a cohort of young persons with type 2 diabetes mellitus was in addition determined for markers showing significant associations with disease progression. Results Increased urinary levels of epidermal growth factor (EGF) were linked to lower odds of fast progression (defined as annual eGFR decline greater than 2.58 ml/min per 1.73 m2) with an odds ratio (OR) of 0.60 (95% CI 0.46, 0.78). The association with outcome was even stronger when adjusting for a set of 14 baseline clinical parameters including age, biological sex, eGFR, body mass index, albuminuria, and HbA1c. Elevated urinary levels of fatty acid binding protein 3 (FABP3) and vascular cell adhesion molecule 1 (VCAM1) were each significantly associated with fast progression with an OR of 1.44 (95% CI 1.11, 1.87) and an OR of 1.41 (95% CI 1.08, 1.83), respectively. Enriched expression of EGF and FABP3 was observed in distal convoluted tubular cells and VCAM1 in parietal epithelial cells at single cell level from biopsies of patients with early DKD. Conclusion In summary we show that lower urinary levels of EGF and higher urinary levels of FABP3 and VCAM1 are significantly associated with DKD progression in early-stage disease.

Association Between FABP7-5-HT Pattern and Anxiety or Depression in Patients With Psoriasis: A Cross-Sectional Study.

Psoriasis exhibits a higher incidence of anxiety and depression. However, the diagnostic process heavily relies on subjective evaluation. Fatty acid-binding protein 7 (FABP7) and serotonin (5-HT) are considered as potential plasma biomarkers. We aimed to investigate the potentiality of plasma FABP7 and 5-HT as biomarkers for predicting anxiety and depression in psoriasis. Data were analysed from 140 patients with psoriasis in the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH). Unsupervised clustering was employed to group patients based on their FABP7 and 5-HT profiles. Subsequently, patients were categorised into Group 1 (lower FABP7 and higher 5-HT) or Group 2. Multivariate logistic regression was employed to investigate the correlation between the FABP7-5-HT pattern and anxiety or depression in psoriasis patients. Patients with psoriasis have a higher incidence of anxiety or depression, as well as higher levels of FABP7 and lower levels of 5-HT. After clustering patients using K-means clustering, Group 2 showed a higher body mass index, a higher incidence of hypertension, more severe psoriasis, and more significant anxiety and depression compared to Group 1. Multivariate logistic regression shows that adjusting for covariates except PASI, duration of psoriasis, and psoriatic arthritis, Group 2 had a higher risk of anxiety and depression compared to Group 1. Further adjustment for covariates yielded similar results. Pattern of FABP7-5-HT that may indicate an association with psoriasis accompanied by anxiety or depression.

Daphnetin ameliorates hepatic steatosis by suppressing peroxisome proliferator-activated receptor gamma (PPARG) in ob/ob mice

Non-alcoholic fatty liver disease (NAFLD) is the predominant metabolic liver disorder and currently lacks effective and safe pharmaceutical interventions. Daphnetin (DA), a natural coumarin derivative with anti-inflammatory and antioxidant activities, is a promising agent for NAFLD treatment. In this study, we evaluated the effects and mechanisms of DA on hepatic lipid metabolism in ob/ob mice. Our results showed that DA effectively ameliorates glucose metabolism and hepatic lipid accumulation in ob/ob mice. Metabolomics and RNA sequencing (RNA-seq), combined with GEO data analysis, suggest that DA primarily modulates the peroxisome proliferator-activated receptor gamma (PPARG) pathway, as validated in vivo in ob/ob mice. Mechanistically, DA selectively targets PPARG in hepatic cells by inhibiting PPARG promoter activity and downregulating its expression, resulting in decreased transcription of downstream lipid metabolism-related genes, including fatty acid binding protein 4 (Fabp4), cluster of differentiation 36 (Cd36), and fatty acid synthase (Fasn). This effect was abolished in PPARG-deficient HepG2 cells subjected to palmitic acid (PA) insult. Our findings provide evidence that DA acts as a selective suppressor of hepatic PPARG, suggesting an attractive strategy by targeting PPARG for the prevention of hepatic steatosis.

Fatty acid-binding protein 7 gene deletion promotes decreases in brain cannabinoid type 1 receptor binding.

Fatty acid-binding protein 7 (FABP7) aids in the intracellular transport of endogenous cannabinoids and is involved in regulating the stress response system. This study examined the role of FABP7 in chronic stress exposure through the binding of CB1 receptors. Adult male FABP7+/+ and FABP7-/- mice were treated with the unpredictable chronic mild stress (UCMS) procedure. After 28 days of treatment, mice were euthanized, and CB1 was measured with in vitro autoradiography using [3H] SR141716A. FABP7-/- mice, irrespective of stress treatment, showed reduced [3H] SR141716A binding in the amygdala, secondary somatosensory cortex, and ventral caudate putamen compared with the FABP7+/+ mice. Additionally, FABP7-/- mice treated with UCMS exhibited a reduction in CB1 binding in the globus pallidus and ventral caudate putamen compared with UCMS-treated FABP7+/+ mice. Genetic deletion of FABP7 can decrease CB1 expression in various brain regions; however, the underlying mechanism remains unclear.

Pd@PtCu Core–Shell Nanocrystal-Assisted Signal Amplification for Label-Free Electrochemical Immunoanalysis of the Human Fatty Acid Binding Protein Biomarker

Pd@PtCu Core–Shell Nanocrystal-Assisted Signal Amplification for Label-Free Electrochemical Immunoanalysis of the Human Fatty Acid Binding Protein Biomarker

Natural Honey Proteins Prevent Diet-Induced Obesity and Metabolic Disorders in Rats.

Previous studies have shown that oral whole honey reduces weight gain in rats on a normal diet (ND) or high-fat diet (HFD) and suppresses inflammation by modulating immunological cytokines in human neutrophils and macrophages. We hypothesize that the honey proteins (HP) are responsible for the reduced weight gain in rats on ND and HFD and that HP would alleviate obesity parameters. To test this, proteins were isolated from acacia honey through the salting-out method. Wistar rats (N = 24) were randomized to get ND or HFD for 4 weeks, then further randomized to four groups and treated with HP or saline for another 4 weeks. Energy intake (EI), body weight gain, EI per gram body weight gain, serum glucose, and lipids were measured. Expression of adipose tissue genes fatty acid binding protein (FABP), lipase C (LIPC), and apolipoprotein A-1 (APOA1) was evaluated through the quantitative polymerase chain reaction. HFD increased the body weight versus ND in weeks 1-4. HP for the next 4 weeks reduced weight gain in ND-HP and HFD-HP groups versus saline controls (P < .01). EI was not significantly different among groups. However, EI per gram body weight gain among groups was markedly different (P < .01), demonstrating reduced weight gain efficiency by HP (P < .01). HP reduced glucose in ND but not in HFD groups. Triglycerides were lower in both HP groups. The expressions of FABP, LIPC, and APOA1 genes were significantly increased (P < .05) in HP-treated HFD rats. Collectively, weight gain efficiency was remarkably reduced without altering EI in rats following the HP treatment, suggesting HP increased metabolic rate or substrate partitioning. Studies of HP are suggested in humans.

Severe Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Patients on Chronic Hemodialysis-Reconsidering the Relationship with Thrombo-Inflammation and Oxidative Stress.

Besides a multitude of consequences patients on chronic renal replacement therapy have, anemia is one of the most prominent factors making a significant number of patients dependent on erythropoiesis-stimulating agent (ESA) therapy. The aim of this study was to examine the relationship between the levels of a broad spectrum of thrombo-inflammatory and oxidative stress-related biomarkers and the presence and level of ESA hyporesponsiveness in patients undergoing regular chronic hemodialysis. This cross-sectional study included 96 patients treated with chronic hemodialysis. Levels of several thrombo-inflammatory and oxidative stress-related biomarkers, as well as demographic, clinical, and laboratory analyses, were collected and analyzed based on the calculated value of the ESA-hyporesponsiveness index (EHRI). In the analyzed sample, 58 patients received ESAs. Of all the investigated parameters, only body mass index (BMI), level of plasminogen activator inhibitor-1, and level of L-type fatty acid binding protein (L-FABP) were observed as significant predictors of EHRI. A significant diagnostic potential for ESA resistance has been observed in BMI and L-FABP between ESA-resistant and ESA-non-resistant groups of patients (p = 0.004, area under the curve 0.763 and p = 0.014, area under the curve 0.712, respectively) with the cut-off values of 25.46 kg/m2 and 5355.24 ng/mL, respectively. Having a BMI of 25.46 kg/m2 or less and an L-FABP level higher than 5355.24 ng/mL were observed as significant predictors of ESA resistance (odds ratio 9.857 and 6.125, respectively). EHRI was positively predicted by low BMI and high levels of plasminogen activator inhibitor-1 and L-FABP. High levels of L-FABP and low BMI have been observed as strong predictors of ESA resistance.

FABP7: A Potential Diagnostic and Prognostic Biomarker for Clear Cell Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is highly heterogeneous, with distinct patient management between clear cell RCC (ccRCC) and non-ccRCC groups. Previous bioinformatics and machine learning techniques identified fatty acid binding protein 7 (FABP7) as a potential ccRCC biomarker. However, FABP7 expression studies between ccRCC and non-ccRCC were incomplete. This study aimed to assess FABP7 as a biomarker for distinguishing between ccRCC and non-ccRCC tissue samples. FABP7 expression was evaluated via immunohistochemical staining in 58 RCC cases, including 43 ccRCC and 15 non-ccRCC cases. Staining results were interpreted using H-scores; scores above the cut-off were deemed positive. The correlation between FABP7 expression and clinicopathological RCC features was investigated. FABP7 positivity was 48.8% in ccRCC and only 13.3% in non-ccRCC cases, with weak positivity in non-ccRCC tissues. FABP7 expression significantly differed between ccRCC and non-ccRCC (p<0.05). This finding was confirmed in a TCGA dataset. However, FABP7 expression was not correlated with other RCC clinicopathological features in our dataset. TCGA results linked FABP7 expression to tumor stage and disease-free survival in patients with ccRCC. This study preliminarily evaluated FABP7 as a differential diagnostic biomarker in RCC subtyping, showing higher expression in ccRCC than non-ccRCC. FABP7 may serve as a potential diagnostic and prognostic biomarker for ccRCC.

Semaglutide modulates adipogenic differentiation and extracellular acidification in epicardial (EAT) and subcutaneous (SAT) adipose tissue stromal cells from patients with cardiovascular disease

Abstract Backround Cardiovascular disease (CVD) is the main cause of death in the world. One of the known risk factors is the epicardial fat (EAT) accumulation, which is around the myocardium and coronaries playing a paracrine role over them. Although mature and functional adipocytes are involved in energy balance and glucose metabolism, the hypertrophic state increases the production of fatty acid binding protein 4 (FABP4), which is a pro-inflammatory adipokine, with consequences on extracellular acidification. Recent data shows that glucagon-like peptide receptor agonists 1 (GLP1ra) drug improves the insulin response and reduces EAT thickness. Although GLP1ra has a direct effect on hypothalamus for reducing food intake, this drug might play a direct role on adipogenesis process in this fat stromal cells. Purpose Our study aims to demonstrate the effect of semaglutide on adipogenesis and metabolism in epicardial and subcutaneous stromal cells from patients with cardiovascular disease. Methods The study was approved by the Galician Research Ethics Committee, and subcutaneous adipose tissue (SAT) and EAT samples from 17 patients were obtained undergoing open-heart surgery with informed consent. Stromal cells from biopsies were isolated and cultured. Adipogenesis was induced for 15 days with or without 1 nM semaglutide, given by Novo-Nordisk (Bagsværd, Denmark), using an adipogenesis cocktail. Cells were lysed and RNA was isolated for RT-qPCR. Target genes were amplified for Glucagon like peptide 1- receptor (GLP1R), differentiation, adipogenesis, glucose metabolism and cellular markers. Extracellular acidification rate was measured with glycolytic rate assay on Seahorse. Lipids accumulation was tested by AdipoRed staining. Results Stromal cells from both tissues express GLP1R but higher differentiation factor (PGC1α) was detected in SAT compared to EAT (p=0.02), as well as adipogenesis induction. After semaglutide treatment, we observed a downregulation of FABP4 and GLUT1 in EAT (p=0.01 and p=0.02, respectively). Despite FABP4 was not modulated on SAT, there was a reduction of PGC1α levels. (p=0.02). Since glitazones upregulate PGC1α, which is used for adipogenesis induction, these results might suggest the counteract mechanism of semaglutide. The metabolism assay showed that semaglutide reduces extracellular acidification rate in EAT cells (p=0.04) and oxidative glycolysis with semaglutide treatment (p=0.003) but not in SAT cells. Conclusions Semaglutide reduces adipogenesis, through modulation of PGC1α transcription factor in EAT from patients with cardiovascular disease and extracellular acidification and oxidative glycolysis. These results might help to understand one of the mechanisms associated with EAT reduction in patients with semaglutide treatment.

Comparing de novo heart failure and acute decompensated heart failure using a proteomic approach

Abstract Background Acute heart failure (HF) is defined as new or worsening symptoms of HF and stands as the most common cause of unscheduled hospital admission in patients above the age of 65. Acute HF can be classified into de novo HF (DNHF), defined as no previous history of HF, and acutely decompensated HF (ADHF), defined as worsening symptoms of HF in individuals with a prior diagnosis of HF. Clinically, it is relevant to distinguish ADHF from DNHF as they differ regarding aetiology, comorbidities, mortality, and morbidity. The aim of this study was to compare DNHF and ADHF using a proteomic approach. Method Using a proximity extension assay in a Swedish HF cohort, a total of 324 individuals hospitalized for acute HF underwent proteomic analysis of 92 proteins. The population was categorized into DNHF and ADHF, subsequently comparing normally distributed proteins using an independent samples t-test. Non-normally distributed proteins were compared using the Mann-Whitey U-test. To adjust for multiple testing, Benjamini Hochberg method was applied with a false discovery rate of 5%. Fold change was calculated by subtracting the mean or median protein concentration in ADHF from DNHF. As protein concentrations are expressed on a log2-scale, the difference between the groups equals the fold change. Proteins were considered differentially expressed at a fold change threshold of 1.15. The proteins that met a cut-off, were thereafter analysed with a pathway enrichment analysis using Reactome (only a corrected p-value ≤0.05 was considered significant). Results Complete data was available for n=317 (30.3% women; mean age 74.6) individuals (Table 1). After FDR adjustment, differential protein expression analysis yielded 56 differentially expressed proteins. After applying the fold change threshold, 51 proteins were significantly up regulated in ADHF compared to DNHF and one (Paraoxonase 3) was significantly downregulated. The most prominently up-regulated protein was fatty acid binding protein-4 (FABP4) (fold change 1.68, p &amp;lt;0.001). The largest number of proteins were related to neutrophil degranulation (Figure 1). Conclusion In patients hospitalized for acute HF, we identified several common pathways of the proteins differentially expressed in DNHF compared with ADHF. Neutrophil degranulation was related to the largest number of proteins. The most prominently up regulated protein was FABP4. These findings may inspire future investigation into the different underlying molecular mechanisms in ADHF and DNHF and reveal potentially different targets of treatment between the two conditions.Figure 1.Pathway enrichment analysis

An Elevated FIB-4 Score is associated with the severity of heart failure

Abstract Background Liver disease and heart failure (HF) are known to be closely associated. Non-invasive tests (NIT), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced liver fibrosis and to stratify the risk of liver-related outcomes in patients with chronic liver diseases. Purpose Thus, our goal was to evaluate the connection between the FIB-4 index, heart failure, associated comorbidities, and cardiological biomarkers that predict the risk of liver fibrosis in patients with heart failure. Methods HF patients hospitalized in the cardiology department were divided into a group with an FIB-4 index &amp;lt;1.3 (indicating a low risk of liver fibrosis) (n=53) and a group with an FIB-4 index ≥1.3 (indicating intermediate and high risk of fibrosis) (n=59). Clinical examinations, laboratory results, echocardiography with Vivid E95-GE Healthcare, non-invasive body mass analysis with Body Composition Analyzer (Tanita Pro), and measurements of NT-proBNP, growth differentiation factor 15 (GDF-15), galectin-3, fatty acid-binding protein (FABP), copeptin, and vascular endothelial growth factor (VEGF) concentrations were performed. Results The patients with an FIB-4 index ≥1.3 had significantly higher: left ventricular volume index (LAVI) (p=0.004), E/E’ ratio (p=0.004) and lower left ventricular ejection fraction (p=0.003) compared to group with low risk of liver fibrosis. There were no differences in body mass compartments between groups except for ECW/TBW (%) - an index of body water distribution, which was lower in low-risk liver fibrosis group (p=0.0002). Patients with an FIB-4 index ≥1.3 had also lower: GFR MDRD (median 59.95 vs 85.1 mL/min/1.73 m²; p&amp;lt;0.001), total cholesterol (116.5 vs 15 mg/dL; p=0.002), LDL cholesterol (median 56 vs 93 mg/dL; p&amp;lt;0.0001) and HDL cholesterol (median 39 vs 47 mg/dL; p=0.03). Regarding heart failure biochemical biomarkers, patients with low risk of liver fibrosis had significantly lower level of NT-proBNP (median 37 vs 161 pg/ml; p&amp;lt;0.0001), GDF-15 (median 399.6 vs 898.9 pg/ml; p&amp;lt;0.0001) and FABP (median 101 vs 264,7 pg/ml; p=0.04). In a multiple logistic regression model the factors that were independently associated with the risk of liver fibrosis in HF patients based on an FIB-4 index were GDF-15 &amp;gt;724 pg/ml (OR 33.7, 95%CI: 6.5-174.2; p=0.0001), and NT-proBNP &amp;gt;129 pg/ml (OR 19.9, 95% CI: 3.8-103; p=0.0001) (Figure 1) Conclusion Our study suggests association between an elevated FIB-4 score and heart functions, and kidney impairment with fluid overload but not with higher total and low density cholesterols fractions or percentage of fat. Higher GDF-15 and NT-proBNP levels are independently associated with the risk of liver fibrosis based on an FIB-4 index. FIB-4 index in HF patients is an easy method to monitor the risk of liver fibrosis and might help to predict the HF progression and CVD complications.

CSTB, FABP4, IBP-1 and ST2 are strong predictors of mortality after transcatheter edge-to-edge mitral valve repair

Abstract Introduction Various clinical characteristics have emerged as prognostic factors in patients undergoing transcatheter edge-to-edge mitral valve repair (M-TEER). The use of biomarkers for outcome prediction has enormous potential. The goal of this study was to identify novel biomarkers linked with adverse events after M-TEER. Methods We prospectively included 242 patients undergoing M-TEER at our center and obtained pre-procedural blood samples for biomarker analysis. Additionally, 94 follow-up samples were taken three months after M-TEER. A commercial multiplex protein assay (Cardiovascular III, Olink, Uppsala, Sweden) was used to quantify expression levels of 92 defined biomarkers. We analyzed differences in biomarker expression levels between patients that had died within one year after M-TEER and patients that had survived. Results 39 patients (16.3%) had died within one year after M-TEER. In these patients the most significantly upregulated biomarkers were NT-proBNP (expression 3.0-fold compared to survivors, p &amp;lt; 0.001), Cystatin B (CSTB; 2.0-fold, p &amp;lt; 0.001), fatty acid binding protein 4 (FABP4; 2.0-fold, p &amp;lt; 0.001), insulin-like growth factor-binding protein 1 (IBP-1; 1.9-fold, p &amp;lt; 0.001) and suppression of tumourigenicity 2 (ST2; 1.7-fold, p &amp;lt; 0.001). In non-survivors, expression levels of NT-proBNP (6.1-fold, p = 0.036), CSTB (3.2-fold, p = 0.050), FABP4 (3.7-fold, p = 0.037) and ST2 (2.1-fold, p = 0.017) were persistently elevated at the time of follow-up. Since its prognostic impact has already been described elsewhere, NT-proBNP was excluded from further analysis. Kaplan Meier analysis for 1-year mortality was carried out using tertiles of the respective biomarker expression levels. Mortality risk increased significantly with rising expression levels (CSTB: 3.4% in tertile 1, 12.2% in tertile 2, 37.9% in tertile 3; FABP4: 5.1%, 14.2% and 31.7%; IBP-1: 3.3%, 13.2% and 36.2%; ST2: 4.9%, 11.9% and 36.7%; p by log-rank-test &amp;lt; 0.001 for all biomarkers). Patients in which all 4 biomarkers were elevated to the highest tertile had an excessively high mortality risk of 52.9 vs. 13.5% (p by log-rank-test &amp;lt; 0.001). Receiver operating characteristic (ROC) analysis suggested higher predictive performances for mortality of all 4 biomarkers as compared to the EuroSCORE II (CSTB: area under the curve (AUC) 78.1%, 95% CI 70.7 – 85.5%; FABP4: AUC 71.6%, 95% CI 63.1 – 80.0%; IBP-1: AUC 73.9%, 95% CI 65.7 – 82.1%; ST2: AUC 76.2%, 95% CI 68.5 – 84.0%; EuroSCORE II: AUC 68.4%, 95% CI 59.3 – 77.5%). Conclusion This analysis has revealed novel biomarkers (CSTB, FABP4, IBP-1, ST2), which so far have not been characterized in M-TEER and suggests significant prognostic implications. Predictive performance of each of the respective biomarkers was superior to the most commonly used pre-operative risk stratification tool: the surgical EuroSCORE II. This hypothesis-generating study warrants further examination of these promising biomarkers.