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The goal of this study was to evaluate the intensity of autophagy and ubiquitin-dependent proteolysis processes occurring in myocardium of left ventricle (LV) in subsequent stages of pulmonary arterial hypertension (PAH) to determine mechanisms responsible for LV mass loss in a monocrotaline-induced PAH rat model. LV myocardium samples collected from 32 Wistar rats were analyzed in an early PAH group (n = 8), controls time-paired (n = 8), an end-stage PAH group (n = 8), and their controls (n = 8). Samples were subjected to histological analyses with immunofluorescence staining, autophagy assessment by western blotting, and evaluation of ubiquitin-dependent proteolysis in the LV by immunoprecipitation of ubiquitinated proteins. Echocardiographic, hemodynamic, and heart morphometric parameters were assessed regularly throughout the experiment. Considerable morphological and hemodynamic remodeling of the LV was observed over the course of PAH. The end-stage PAH was associated with significantly impaired LV systolic function and a decrease in LV mass. The LC3B-II expression in the LV was significantly higher in the end-stage PAH group compared to the early PAH group (p = 0.040). The measured LC3B-II/LC3B-I ratios in the end-stage PAH group were significantly elevated compared to the controls (p = 0.039). Immunofluorescence staining showed a significant increase in the abundance of LC3 puncta in the end-stage PAH group compared to the matched controls. There were no statistically significant differences in the levels of expression of all ubiquitinated proteins when comparing both PAH groups and matched controls. Autophagy may be considered as the mechanism behind the LV mass loss at the end stage of PAH., (© 2024. The Author(s).)

Barth syndrome is a rare disease affecting mitochondria structure and function in males. In our previous study, we have shown a new mutation (c.83T>A, p.Val28Glu) in the TAZ gene in two affected patients with congenital cardiomyopathy. Furthermore, women in this family had no mutations in their blood cells, whereas they only had mutations in the oral epithelial cells. The objective of the project was to evaluate the effect of intertissue mosaicisms on the Barth syndrome phenotypes, searching for another disease-related loci on chromosome X and finally to assess the consequences of the mutation. We conducted the advanced genetic study including cytogenetic research (constitutional karyotyping in blood and fibroblasts), NGS sequencing (with custom chromosome X sequencing together with the evaluation of loss of heterozygosity (LOH) and aberrations (CNV) in the whole genome) in four different tissues and sequencing of tafazzin and deoxyribonuclease 1 like 1 transcripts. The presence of deletions within the 5'untranslated region of the TAZ gene and/or the noncoding regions of the DNASE1L1 gene were detected in several tissues. Whereas, there is no intertissue mosaicism regarding point mutation in TAZ gene in all investigated tissues in female carriers. Only the male patient presented biochemical markers and neurological symptoms of Barth syndrome. All the female carriers are healthy and have normal tafazzin and deoxyribonuclease 1 like 1 transcripts in 2 analyzed tissues. The conclusion of this study is that we cannot rule out or confirm mosaicism in the noncoding regions of TAZ or DNASE1L1 genes, but this is not clinically relevant in female carriers because they are healthy. Finally, it has been proven that mutation (c.83T>A, p.Val28Glu) is responsible for disease in males in this family., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The proper functioning of adipose tissue is one of the factors in maintaining energy homeostasis. Adipocytes not only store lipids but also produce active molecules such as adipokines and adipocytokines, which are involved in many functions of adipose tissue, including the secretion of hormones that regulate energy and lipid metabolism. Inflammation has been shown to underlie the deregulation of adipose tissue function. Bradykinin belongs to a family of pro-inflammatory kinin peptides that are abundant in most tissues and biological fluids. This study aimed to determine the ability to produce kinin peptides and characterize the effect of bradykinin on pro-inflammatory responses in adipocytes. The Chub-S7 human preadipocyte line was differentiated to show specific properties for adipose tissue cells. The differentiated cells expressed genes that encode proteins such as kininogen, kallikrein, and prolylcarboxypeptidase that are involved in the production of kinins and also showed the expression of kinin receptors. The response of adipocytes to bradykinin was examined in relation to kinin concentration and the presence of kininase inhibitors. The high concentration of bradykinin induced a moderate increase in lipid accumulation, increased release of pro-inflammatory cytokines, and altered gene expression of molecules involved in adipocyte function, such as adiponectin, lipoprotein lipase, and other transcription factors. This study suggests an important role for kinin peptides in inducing inflammatory responses in adipocytes, which can modify the function of adipose tissue and ultimately lead to diseases related to disturbance of energy homeostasis. The results obtained may enrich our understanding of the mechanisms underlying obesity-related disorders.

Gaucher disease (GD) caused by mutation in the GBA gene has a wide spectrum of phenotypes. Besides the storage disorder, secondary alteration of various pathways occurs with modification of the expression of many genes. In our work we analysed the expression profile of genes in adult patients with type 1 GD., Methods: This study was an observational, cross-sectional analysis of a group of twenty patients with type 1 GD and ten healthy volunteers as a control group. First, on the group of ten persons, microarray gene analysis was performed. Afterwards, significantly regulated genes were selected, and the microarray results were confirmed by real-time PCR on the whole study group., Results: Based on the microarray results in the pathway analysis, we focused on genes related to chemokines, inflammatory processes, endocytosis, autophagy, and apoptosis. Patients with GD demonstrated up-regulation of genes related to NFkB pathway (NFkB, NKkBR SQSTM1), inflammation (IL-1b), endocytosis and autophagy (BCN1, SMAD), genes coding proteins involved in apoptosis (CASP, NFkB, BCL2) as well as genes related to proteasome degradation (PSMD2, PSMB9) and SNARE complex (SNAP, STX). Simultaneously, we showed down-regulation of genes coding proteins of chemokines and their receptors (GNB4, CCL5). The qRT-PCR results confirmed changes in expression of selected genes. Parallel microarray results showed inhibition of genes related to neurones development and survival (NTRK1) and stimulation of gene expression related to neurodegeneration and apoptosis (BCN1, IL1B)., Conclusions: The work revealed different pathway activation, especially inflammatory processes followed by autophagy and apoptosis. Our results also pay attention to new pathways leading to disorders of the functioning of the nervous tissue in patients with type 1 GD, which may lead to the development of polyneuropathy and chronic pain. These are clinical symptoms that severely decrease the quality of life in GD patients., (Copyright © 2021. Published by Elsevier Inc.)

Aims: The aim of the work was to establish potential biomarkers or drug targets by analysing changes in miRNA concentration among patients with Gaucher disease (GD) compared to in healthy subjects., Methods: This study was an observational, cross-sectional analysis of 30 adult participants: 10 controls and 20 adults with GD type 1. Patients with GD type 1 were treated with enzyme replacement therapy (ERT) for at least two years. The control group was composed of healthy volunteers, unrelated to the patients, adjusted with age, sex and body mass index (BMI). The miRNA alteration between these groups was examined. After obtaining preliminary results on a group of six GD patients by the high-output method (TaqMan low-density array (TLDA)), potential miRNAs were selected for confirming the results by using the qRT-PCR method. With Diane Tools, we analysed miRNAs of which differential expression is most significant and their potential role in GD pathophysiology. We also determined the essential pathways these miRNAs are involved in., Results: 266 dysregulated miRNAs were found among 753 tested. Seventy-eight miRNAs were downregulated, and 188 were upregulated. Thirty miRNAs were significantly altered; all of them were upregulated. The analysis of pathways regulated by the selected miRNAs showed an effect on bone development, inflammation or regulation of axonal transmission in association with Parkinson's disease., Conclusions: We revealed few miRNAs, like miR-26-5p, which are highly altered and fit the GD pathophysiological model, might be considered as novel biomarkers of disease progression but need further evaluation.