Arginase Inhibitor in the Pharmacological Correction of Endothelial Dysfunction

This paper is about a way of correction of endothelial dysfunction with the inhibitor of arginase: L-norvaline. There is an imbalance between vasoconstriction and vasodilatation factors of endothelium on the basis of endothelial dysfunction. Among vasodilatation agents, nitrogen oxide plays the basic role. Amino acid L-arginine serves as a source of molecules of nitrogen oxide in an organism. Because of the high activity of arginase enzyme which catalyzes the hydrolysis of L-arginine into ornithine and urea, the bioavailability of nitrogen oxide decreases. The inhibitors of arginase suppress the activity of the given enzyme, raising and production of nitrogen oxide, preventing the development of endothelial dysfunction

Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase

The anticancer effect of L-asparaginases (L-ASNases) is attributable to their ability to hydrolyze L-asparagine in the bloodstream and cancer cell microenvironment. Rhodospirillum rubrum (RrA) has dual mechanism of action and plays a role in the suppression of telomerase activity. The aim of this work was to investigate the possible mechanism of RrA penetration into human cancer cells. Labeling of widely used L-ASNases by fluorescein isothiocyanate followed by flow cytometry and fluorescent microscopy demonstrated that only RrA can interact with cell membranes. The screening of inhibitors of receptor-mediated endocytosis demonstrated the involvement of clathrin receptors in RrA penetration into cells. Confocal microscopy confirmed the cytoplasmic and nuclear localization of RrA in human breast cancer SKBR3 cells. Two predicted nuclear localization motifs allow RrA to penetrate into the cell nucleus and inhibit telomerase. Chromatin relaxation promoted by different agents can increase the ability of RrA to suppress the expression of telomerase main catalytic subunit. Our study demonstrated for the first time the ability of RrA to penetrate into human cancer cells and the involvement of clathrin receptors in this process

A Data-Driven Approach to Carrier Screening for Common Recessive Diseases

Genetic screening is an advanced tool for reducing recessive disease burden. Nowadays, it is still unclear as to the number of genes or their variants that are necessary for effective screening. This paper describes the development of a carrier screening custom panel for cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss consisting of 116 variants in the CFTR, PAH, SERPINA1, and GJB2 genes. The approach is based on the cheapest and fastest method, on using a small number of genes, and on the estimation of the effectiveness of carriers’ detection. The custom panel was tested on a population-based cohort that included 1244 participants. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The frequency of heterozygotes in the Russian population was 16.87% or 1:6 (CI95%: 14.76–19.00% by Clopper-Pearson exact method): in CFTR—2.81% (1:36), PAH—2.33% (1:43), SERPINA1—4.90% (1:20), and GJB2—6.83% (1:15). The data on allele frequencies were obtained for the first time on a Russian population. The panel allows us to identify the vast majority of carriers of recessive diseases in the population. It is an effective approach to carrier screening for common recessive diseases