Biology subjects

Belogurov, A.

Publications and source records attributed to Belogurov, A..

3 recordsLinked to original sources

bioRxiv2026

Loss of tissue specificity and recurrent pan-cancer activation define a conserved oncogenic microRNA class

MicroRNAs are frequently dysregulated in cancer, yet how their tissue-specificity is remodeled during malignant transformation remains poorly characterized. Here we systematically quantified the tissue-specificity of miRNAs across normal (GTEx) and tumor (TCGA) tissues using the Tau index, and compared its distribution between healthy and cancerous states. To robustly define dysregulation, we combined two independent analyses: a binomial test over per-project differential expression across 17 matched normal tissues within TCGA cohort, and a TCGA-GTEx pan-tissue comparison of mean expression. The change in specificity ({Delta}Tau) separated up- from down-regulated miRNAs, showing moderate agreement with the binomial signal and a strong correlation with the expression-based contrast. Finally, we identified 6 miRNAs that lose tissue-specificity upon transformation while remaining consistently upregulated (miR-519a-5p, miR-512-3p, miR-522-3p, miR-105-5p, miR-935, miR-1269a). Functional analysis of experimentally validated targets showed significant enrichment for converging on core oncogenic programs for miR-512-3p, miR-105-5p and miR-935, such as apoptosis and cellular-stress regulation, TP53, FoxO, PI3K-Akt/mTOR signaling, immune modulation. Collectively, integrating specificity dynamics with dysregulation evidence pinpoints candidate miRNAs with coordinated, cancer-relevant regulatory roles and highlights those with favorable tissue specificity profiles for therapeutic targeting.

bioinformatics↗

bioRxiv2024

COMPARATIVE CHARACTERISTICS OF THE ACCUMULATION OF DIFFERENT VARIANTS OF THE SARS-COV-2 VIRUS (WUHAN, DELTA, OMICRON) IN THE ORGANS OF MODEL ANIMALS

BackgroundThe genotypic variability of the SARS-CoV-2 virus has proven to be extremely high, and the emergence of new strains raises concerns about their possible high virulence, transmissibility, and ability to bypass responses of the bodys immune system induced by previous infection or vaccination. Therefore, one of the main tasks is to study the pathogenesis of various variants of the virus using experimental animal biomodels of SARS-CoV-2 to quickly find methods and approaches to fighting new viruses. Methods60 humanized mice of the C57BL/6-Tgtn (CAG-human AEC2-IRES-Luciferase-WPRE-polyA) line (hACE2) were used. Mice were infected intranasally at different doses with three variants of the SARS-CoV-2 virus: Wuhan, Delta and Omicron. ResultsWe showed that humanized hACE2 mice, when infected with all three variants of the SARS-CoV-2 virus, showed typical pathological changes in lung consistency comparable to those found in COVID-19 in humans. All mice developed interstitial pneumonia, characterized by inflammatory cell infiltration and thickening of the alveolar septa, characteristic of vascular damage. ConclusionsAt a dose of 4 lg plaque-forming unit (PFU), all variants showed 100% mortality. A dose-dependent effect was established only for the Wuhan and Delta variants. In a comparative assessment of different variants of the SARS-CoV-2 virus in a humanized mouse model of hACE2, it was found that the Delta variant leads to more severe damage compared to Wuhan or Omicron.

pathology↗

bioRxiv2023

CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in murine model of the SARS-CoV-2-related acute respiratory distress syndrome

The acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis is one of the main causes of high mortality in patients with COVID-19 (novel coronavirus disease 2019) - ongoing SARS-CoV-2 infection, reached more than 0.7 billion registered cases. Recently we elaborated non- surgical and reproducible method of unilateral total diffuse alveolar damage (DAD) of the left lung in ICR mice - a publicly available imitation of the ARDS caused by SARS-CoV-2. Our data reads that two C-C chemokine receptor 5 (CCR5) ligands - macrophage inflammatory proteins (MIP) - (MIP-1/CCL3) and (MIP-1{beta}/CCL4) are upregulated in this DAD model up to three orders of magnitude compared to the background level. Here we showed that a nonpeptide compound TAK- 779, antagonist of CCR5/CXCR3, readily prevents DAD of the lung with a single injection of 2.5 mg/kg. Histological analysis revealed reduced peribronchial and perivascular mononuclear infiltration in the lung, and mononuclear infiltration of the wall and lumen of the alveoli in the TAK- 779-treated animals. Administration of the TAK-779 decreased 3-5-fold level of serum cytokines and chemokines in animals with DAD, including CCR5 ligands MIP-1/{beta}, MCP-1 and CCL5. Computed tomography revealed rapid recovery of the density and volume of the affected lung in TAK-779- treated animals. Our pre-clinical data suggest that TAK-779 is more effective than administration of dexamethasone or anti-IL6R therapeutic antibody tocilizumab, which brings novel therapeutic modality to TAK-779 and other CCR5 inhibitors recruited in ongoing clinical studies as a potential drugs for treatment of COVID19 and similar virus-induced inflammation syndromes. Abstract summaryThe pathogenesis of the SARS-CoV-2 infection is tightly linked with the cytokine storm resulting in the enormous release of cytokines and chemokines. Its clinical manifestation - the acute respiratory distress syndrome (ARDS), may be caused by self-sustaining hypersensitivity reactions leading to lung collapse even after virus clearance. Here we report that two macrophage inflammatory proteins, MIP-1/CCL3 and MIP-1{beta}/CCL4, seem to orchestrate mononuclear infiltration into the lungs during diffuse alveolar damage (DAD) in ICR mice - our murine model of ARDS caused by SARS-CoV-2. Inhibition of the C-C chemokine receptor 5 (CCR5) - parental receptor for MIP-1 and MIP-1{beta}, by nonpeptide antagonist TAK-779 results in significant amelioration of DAD in terms of reduced mononuclear infiltration into the lung, suppressed cytokine storm and restored physiology of affected lung according to computed tomography data. We suggest that targeted inhibition of CCR5 should be further elucidated as safe and effective approach to overcome severe viral pneumonia in humans.

pathology↗