Biology subjects

Litvinov, S.

Publications and source records attributed to Litvinov, S..

2 recordsLinked to original sources

bioRxiv2024

Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone

A hallmark of Alzheimers disease (AD) is the extracellular aggregation of toxic amyloid-beta (A{beta}) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an A{beta} aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of A{beta} plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy. Significance statementAlzheimers disease (AD) is the most prevalent neurodegenerative disease. Its primary symptom is progressive cognitive decline, which impairs executive brain functions and deprives patients of their autonomy in life. Experimental and clinical evidence points to the critical pathophysiological role of the amyloid-beta (A{beta}) peptide. Despite some limited successes in AD immunotherapy targeting A{beta}, AD is still incurable. Here, we use an innovative pipeline for accurate whole-brain measurements of A{beta} load to test the efficacy of the antidiabetic compound, netoglitazone. We found that netoglitazone decreases A{beta} burden in certain brain areas but not in others. Region-specific assessment of anti-A{beta} efficacy may be useful in the development of effective drugs against Alzheimers disease.

neuroscience↗

bioRxiv2020

Structural variability, expression profile and pharmacogenetics properties of TMPRSS2 gene as a potential target for COVID-19 therapy

The human serine protease TMPRSS2 gene is involved in the priming of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins being one of the possible targets for COVID-19 therapy. TMPRSS2 gene is possibly co-expressed with SARS-CoV-2 cell receptor genes ACE2 and BSG, but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data of 76 human populations demonstrates that functionally significant missense mutation in exon 6/7 in TMPRSS2 gene, was found in many human populations in relatively high frequency, featuring region-specific distribution patterns. The frequency of the missense mutation encoded by the rs12329760, which previously was found to be associated with prostate cancer, is ranged between 10% and 63% being significantly higher in populations of Asian origin compared to European populations. In addition to SNPs, two copy numbers variants (CNV) were detected in the TMPRSS2 gene. Number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well studied drugs can downregulate the expression of TMPRSS2 in human cells, including Acetaminophen (Paracetamol) and Curcumin. Thus TMPRSS2 interaction with the SARS-CoV-2, its structural variability, gene-gene interactions, and expression regulation profiles, and pharmacogenomics properties characterize this gene as a potential target for COVID-19 therapy.

genomics↗