👤 Dénes Tóth

“Surrogate” definitions of intrinsic subtypes, which imply the Ki67 proliferation marker, help to clinically distinguish luminal breast carcinomas (Lum BC). Here, mass spectrometry–based proteomics can help analyse the protein content of malignant and normal cells and eventually distinguish patient samples from healthy controls at the molecular level. In this work, peripheral blood CD14 + monocyte proteomes of the LumA, LumB-HER2 − and LumB-HER2 + subtypes and those with benign disease were compared to healthy controls (HCs). Among differentially expressed proteins (DEPs), The online version contains supplementary material available at 10.1038/s41598-026-39686-y. Show less

Obesity is a global health challenge that can lead to various complications, such as metabolic syndrome, diabetes mellitus, and cardiovascular diseases. Heat shock proteins are evolutionarily conserved chaperones that help maintain cellular protein homeostasis. Their expression is dysregulated in various chronic diseases, including diabetes mellitus and hyperlipidemia, and they also regulate inflammatory processes. Therefore, the present study aimed to investigate the effects of a small heat shock protein, HSPB1, on the comorbidities and complications of obesity in a transgenic mouse model. Male and female human apolipoprotein B-100 (APOB) transgenic mice fed with a high-fat diet (HFD) from months 3-10 of age were used as a model of metabolic syndrome (MetS). To study whether HSPB1 influences the development of MetS, APOB animals were crossed with HSPB1-overexpressing mice. Age and sex-matched wild-type and human HSPB1-overexpressing mice were used as controls. Changes in cardiac morphology and function were assessed by transthoracic echocardiography at month 9. At month 10, serum triglyceride and cholesterol concentrations were determined by enzymatic colorimetric assays. Pathological changes in the liver were studied on hematoxylin-eosin-stained sections. Expression levels of genes involved in inflammation and metabolism were measured by quantitative real-time polymerase chain reaction in the liver, left ventricle, and visceral white adipose tissue (vWAT). The body weight and serum LDL-cholesterol levels were significantly higher in the APOB animals than in the wild-type mice in both sexes. Notably, HSPB1 overexpression further increased weight gain in female APOB animals. Conversely, in APOB males, HSPB1 overexpression decreased LDL-cholesterol levels without significantly affecting body weight. Furthermore, in APOB females, HSPB1 overexpression elevated Fgf-21 expression in the vWAT, restored Lpl levels, and reduced the expression of several cytokines in the liver. APOB males developed left ventricular hypertrophy (LVH) with diastolic dysfunction. HSPB1 overexpression induced LVH without cardiac dysfunction in the wild-type animals. Both sexes of APOB animals developed MetS. APOB males presented LVH with preserved ejection fraction (EF); however, APOB females showed enlarged left ventricular end-systolic volume (LVESV). In APOB animals, HSPB1 overexpression exerted a sex-dependent influence on obesity-related alterations, including weight gain, hypercholesterolemia, and hepatic and vWAT gene expression. Show less

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4R Show less

In this study we tested whether a protein corona is formed around extracellular vesicles (EVs) in blood plasma. We isolated medium-sized nascent EVs of THP1 cells as well as of Optiprep-purified platelets, and incubated them in EV-depleted blood plasma from healthy subjects and from patients with rheumatoid arthritis. EVs were subjected to differential centrifugation, size exclusion chromatography, or density gradient ultracentrifugation followed by mass spectrometry. Plasma protein-coated EVs had a higher density compared to the nascent ones and carried numerous newly associated proteins. Interactions between plasma proteins and EVs were confirmed by confocal microscopy, capillary Western immunoassay, immune electron microscopy and flow cytometry. We identified nine shared EV corona proteins (ApoA1, ApoB, ApoC3, ApoE, complement factors 3 and 4B, fibrinogen α-chain, immunoglobulin heavy constant γ2 and γ4 chains), which appear to be common corona proteins among EVs, viruses and artificial nanoparticles in blood plasma. An unexpected finding of this study was the high overlap of the composition of the protein corona with blood plasma protein aggregates. This is explained by our finding that besides a diffuse, patchy protein corona, large protein aggregates also associate with the surface of EVs. However, while EVs with an external plasma protein cargo induced an increased expression of TNF-α, IL-6, CD83, CD86 and HLA-DR of human monocyte-derived dendritic cells, EV-free protein aggregates had no effect. In conclusion, our data may shed new light on the origin of the commonly reported plasma protein 'contamination' of EV preparations and may add a new perspective to EV research. Show less

Activation of the type I angiotensin receptor (AT1-R) in vascular smooth muscle cells (VSMCs) plays a crucial role in the regulation of blood pressure; however, it is also responsible for the development of pathological conditions such as vascular remodeling, hypertension and atherosclerosis. Stimulation of the VSMC by angiotensin II (AngII) promotes a broad variety of biological effects, including gene expression changes. In this paper, we have taken an integrated approach in which an analysis of AngII-induced gene expression changes has been combined with the use of small-molecule inhibitors and lentiviral-based gene silencing, to characterize the mechanism of signal transduction in response to AngII stimulation in primary rat VSMCs. We carried out Affymetrix GeneChip experiments to analyze the effects of AngII stimulation on gene expression; several genes, including Show less

Apolipoprotein A5 (APOA5) gene variants have been shown to be associated with elevated TG levels; the T-1131C (rs662799) variant has been reported to confer risk for the metabolic syndrome in adult populations. Little is known about the APOA5 variants in pediatric population, no such information is available for pediatric obesity at all. Here we examined four haplotype-tagging polymorphisms (T-1131C, IVS3 + G476A [rs2072560], T1259C [rs2266788] and C56G [rs3135506]) and studied also the frequency of major naturally occurring haplotypes of APOA5 in obese children. The polymorphisms were analyzed in 232 obese children, and in 137 healthy, normal weight controls, using PCR-RFLP methods. In the pediatric patients we could confirm the already known adult subjects based association of -1131C, IVS3 + 476A and 1259C variants with elevated triglyceride concentrations, both in obese patients and in the controls. The prevalence of the APOA5*2 haplotype (containing the minor allele of T-1131C, IVS3 + G476A and T1259C SNPs together) was 15.5% in obese children, and 5.80% in the controls (p<0.001); multiple logistic regression analysis revealed that this haplotype confers susceptibility for development of obesity (OR=2.87; 95% CI: 1.29-6.37; p≤0.01). By contrast, the APOA5*4 haplotype (with -1131C alone) did not show similar associations. Our findings also suggest that the APOA5*5 haplotype (1259C alone) can be protective against obesity (OR=0.25; 95% CI: 0.07-0.80; p<0.05). While previous studies in adults demonstrated, that the APOA5 -1131C minor allele confers risk for adult metabolic syndrome, here we show, that the susceptibility nature of this SNP restricted to the APOA5*2 haplotype in pediatric obese subjects. Show less