Stroke is the second-most common cause of death worldwide. The pathophysiology of ischemic stroke (IS) is related to inflammation, atherosclerosis, blood coagulation, and platelet activation. MicroRNAs (miRNAs) play important roles in physiological and pathological processes of neurodegenerative diseases and progression of certain neurological diseases, such as IS. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of IS. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique value as diagnostic and prognostic markers in IS. In this review, we focus on the role of miRNAs as diagnostic and prognostic biomarkers in IS. We discuss the most common and reliable detection methods available and promising tests currently under development. We also present original results from bioinformatic analyses of published results, identifying the ten most significant genes (HMGB1, YWHAZ, PIK3R1, STAT3, MAPK1, CBX5, CAPZB, THBS1, TNFRSF10B, RCOR1) associated with inflammation, blood coagulation, and platelet activation and targeted by miRNAs in IS. Additionally, we created miRNA-gene target interaction networks based on Gene Ontology (GO) information derived from publicly available databases. Among our most interesting findings, miR-19a-3p is the most widely modulated miRNA across all selected ontologies and might be proposed as novel biomarker in IS to be tested in future studies.

In the light of growing global epidemic of type 2 diabetes mellitus (T2DM), significant efforts are made to discover next-generation biomarkers for early detection of the disease. Multiple mechanisms including inflammatory response, abnormal insulin secretion and glucose metabolism contribute to the development of T2DM. Platelet activation, on the other hand, is known to be one of the underlying mechanisms of atherosclerosis, which is a common T2DM complication that frequently results in ischemic events at later stages of the disease. Available data suggest that platelets contain large amounts of microRNAs (miRNAs) that are found in circulating body fluids, including the blood. Since miRNAs have been illustrated to play an important role in metabolic homeostasis through regulation of multiple genes, they attracted substantial scientific interest as diagnostic and prognostic biomarkers in T2DM. Various miRNAs, as well as their target genes are implicated in the complex pathophysiology of T2DM. This article will first review the different miRNAs studied in the context of T2DM and platelet reactivity, and subsequently present original results from bioinformatic analyses of published reports, identifying a common gene (PRKAR1A) linked to glucose metabolism, blood coagulation and insulin signalling and targeted by miRNAs in T2DM. Moreover, miRNA–target gene interaction networks built upon Gene Ontology information from electronic databases were developed. According to our results, miR-30a-5p, miR-30d-5p and miR-30c-5p are the most widely regulated miRNAs across all specified ontologies, hence they are the most promising biomarkers of T2DM to be investigated in future clinical studies.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that plays a crucial role in the development of the nervous system while supporting the survival of existing neurons and instigating neurogenesis. Altered levels of BDNF, both in the circulation and in the central nervous system (CNS), have been reported to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), multiple sclerosis (MS), and ischemic stroke. MicroRNAs (miRNAs) are a class of non-coding RNAs found in body fluids such as peripheral blood and cerebrospinal fluid. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of neurodegenerative and neurovascular diseases. Thus, they present as promising biomarkers and a novel treatment approach for CNS disorders. Currently, limited studies provide viable evidence of miRNA-mediated post-transcriptional regulation of BDNF. The aim of this review is to provide a comprehensive assessment of the current knowledge regarding the potential diagnostic and prognostic values of miRNAs affecting BDNF expression and its role as a CNS disorders and neurovascular disease biomarker. Moreover, a novel therapeutic approach in neurodegenerative diseases and ischemic stroke targeting miRNAs associated with BDNF will be discussed.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; COVID-19) is associated with adverse outcomes in patients with cardiovascular disease (CVD). The aim of the study was to characterize the interaction between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) functional networks with a focus on CVD. Methods: Using the network medicine approach and publicly available datasets, we investigated ACE2 tissue expression and described ACE2 interaction networks that could be affected by SARS-CoV-2 infection in the heart, lungs and nervous system. We compared them with changes in ACE-2 networks following SARS-CoV-2 infection by analyzing public data of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This analysis was performed using the Network by Relative Importance (NERI) algorithm, which integrates protein-protein interaction with co-expression networks. We also performed miRNA-target predictions to identify which miRNAs regulate ACE2-related networks and could play a role in the COVID19 outcome. Finally, we performed enrichment analysis for identifying the main COVID-19 risk groups. Results: We found similar ACE2 expression confidence levels in respiratory and cardiovascular systems, supporting that heart tissue is a potential target of SARS-CoV-2. Analysis of ACE2 interaction networks in infected hiPSC-CMs identified multiple hub genes with corrupted signaling which can be responsible for cardiovascular symptoms. The most affected genes were EGFR (Epidermal Growth Factor Receptor), FN1 (Fibronectin 1), TP53, HSP90AA1, and APP (Amyloid Beta Precursor Protein), while the most affected interactions were associated with MAST2 and CALM1 (Calmodulin 1). Enrichment analysis revealed multiple diseases associated with the interaction networks of ACE2, especially cancerous diseases, obesity, hypertensive disease, Alzheimer’s disease, non-insulin-dependent diabetes mellitus, and congestive heart failure. Among affected ACE2-network components connected with the SARS-Cov-2 interactome, we identified AGT (Angiotensinogen), CAT (Catalase), DPP4 (Dipeptidyl Peptidase 4), CCL2 (C-C Motif Chemokine Ligand 2), TFRC (Transferrin Receptor) and CAV1 (Caveolin-1), associated with cardiovascular risk factors. We described for the first time miRNAs which were common regulators of ACE2 networks and virus-related proteins in all analyzed datasets. The top miRNAs regulating ACE2 networks were miR-27a-3p, miR-26b-5p, miR-10b-5p, miR-302c-5p, hsa-miR-587, hsa-miR-1305, hsa-miR-200b-3p, hsa-miR-124-3p, and hsa-miR-16-5p. Conclusion: Our study provides a complete mechanistic framework for investigating the ACE2 network which was validated by expression data. This framework predicted risk groups, including the established ones, thus providing reliable novel information regarding the complexity of signaling pathways affected by SARS-CoV-2. It also identified miRNAs that could be used in personalized diagnosis in COVID-19.

Impaired thermogenesis can promote obesity. Therefore, the aim of this study was to investigate whether the expression of thermogenesis-related genes is altered in adipose tissues of obese individuals and whether excessive methylation of their promoters is involved in this phenomenon. The expression of genes encoding β adrenergic receptors (ADRBs), thyroid hormone receptors (THRs), 5’-iodothyronine deiodinases (DIOs), and uncoupling proteins (UCPs) was measured by real-time PCR in visceral and in subcutaneous adipose tissues of 58 obese (BMI >40 kg/m2) and 50 slim (BMI 20-24.9 kg/m2) individuals. The methylation status of these genes was studied by the methylation-sensitive digestion/real-time PCR method. The expression of ADRB2, ADRB3, THRA, THRB, DIO2, UCP2 was significantly lower in the adipose tissues of obese patients than in tissues of normal-weight individuals (P < 0.00001). In the obese, the expression of ADRB2, ADRB3, DIO2 was lower in visceral adipose tissue than in subcutaneous adipose tissue (P = 0.008, P = 0.002, P = 0.001, respectively). However, the mean methylation of CpG islands of these genes was similar in tissues with their high and low expression, and there was no correlation between the level of expression and the level of methylation. Decreased expression of thermogenesis-related genes in adipose tissues of obese patients might result in the reduced reactivity to both hormonal and adrenergic stimuli and therefore in a lower potential to activate thermogenesis.