Synthesis of acyclic nucleoside analogues by one-step Vorbrüggen glyco-sylation of 1,2,4-triazolo[1,5-a]pyrimidine-7-ones

New analogues of acyclovir have been prepared by reacting 1,2,4 -triazolo[1,5-a]pyrimidin-7-ones 1а-i and (2-acetoxyethoxy)methyl acetate 2 in the presence of trimethylsilyl trifluoromethanesulfonate as a catalyst. The interaction between the compounds 1а-е and 2 has led to a mixture of N3 and N4 isomers. In contrast, the reaction of compounds 1g-i and 2 proceeded selectively to form N3 isomers. In the case of compounds 1a-c the predominant product is the one with the acyclic moiety in azine ring (N4 isomer). Interaction between 1d-f and 2 has led to mixtures comprising mainly N3 isomer. It has been found that the ratio of glycosylation products 1 and 2 are thermodynamically controlled. The structure of the obtained compounds has been proved by 1Н, 13С, two-dimensional 1Н-13С NMR spectroscopy and X-ray analysis

Long-range 1H-15N J couplings providing a method for direct studies of the structure and azide-tetrazole equilibrium in a series of azido-1,2,4-triazines and azidopyrimidines

The selectively 15N labeled azido-1,2,4-triazine 2*A and azidopyrimidine 4*A were synthesized by treating hydrazinoazines with 15N-labeled nitrous acid. The synthesized compounds were studied by 1H, 13C, and 15N NMR spectroscopy in DMSO, TFA, and DMSO/TFA solutions, where the azide-tetrazole equilibrium could lead to the formation of two tetrazoles (T, T′) and one azide (A) isomer for each compound. The incorporation of the 15N label led to the appearance of long-range 1H-15N coupling constants (JHN), which can be measured easily by using amplitude-modulated 1D 1H spin-echo experiments with selective inversion of the 15N nuclei. The observed JHN patterns enable the unambiguous determination of the mode of fusion between the azole and azine rings in the two groups of tetrazole isomers (2*T′, 4*T′ and 2*T, 4*T), even for minor isoforms with a low concentration in solution. However, the azide isomers (2*A and 4*A) are characterized by the absence of detectable J HN coupling. The analysis of the JHN couplings in 15N-labeled compounds provides a simple and efficient method for direct NMR studies of the azide-tetrazole equilibrium in solution. © 2013 American Chemical Society

Spin-spin coupling constants 13C-15N and 1H-15N in the investigation of azido-tetrazole tautomerism in a series of 2-azidopyrimidines

A new method was developed for the investigation of an azido-tetrazole equilibrium based on using a complex analysis of 13C-15N and 1H-15N spin-spin coupling constants. The use of this approach became possible due to the selective inclusion of 15N isotopes into the structures of 2-azidopyrimidines and their cyclic analogs tetrazolo[1,5-a]pyrimidines. © 2013 Springer Science+Business Media New York

Serum Cytokine Profile in a Patient Diagnosed with Dysferlinopathy

© 2017 Svetlana F. Khaiboullina et al. Limb-girdle muscular dystrophy type 2 (LGMD2B) is a mild form of dysferlinopathy, characterized by limb weakness and wasting. It is an autosomal recessive disease, with currently 140 mutations in the LGMD2B gene identified. Lack of functional dysferlin inhibits muscle fiber regeneration in voluntary muscles, the main pathological finding in LGMD2B patients. However, the immune system has been suggested to contribute to muscle cell death and tissue regeneration. Serum levels of 27 cytokines wer e evaluated in a dysferlinopathy patient. Levels of 8 cytokines differed in patient serum compared to controls. Five cytokines (IL-10, IL-17, CCL2, CXCL10, and G-CSF) were higher while 3 were lower in the patient than in controls (IL-2, IL-8, and CCL11). Together, these data on serum cytokine profile of this dysferlinopathy patient suggest immune response activation, which could explain leukocyte infiltration in the muscle tissue

Cardiopulmonary factors associated with atrial fibrillation in patients with chronic obstructive pulmonary disease

Aim. To study the relationships between clinical and functional features of chronic obstructive pulmonary disease (COPD) and status of cardiovascular system with focus on identifying factors associated with the atrial fibrillation (AF) in patients with COPD.Material and methods. Patients (n=94) with COPD out of exacerbation and airways obstruction of 2-4 degree (GOLD 2013) were examined. The spirometry, daily pulse oximetry, 24-hour ECG and blood pressure monitoring with vascular wall stiffness estimation, echocardiography were performed. Levels of high-sensitivity C-reactive protein (CRP) werealso assessed.Results. AF paroxysms were found in 46 patients, including newly diagnosed ones in 22 patients. According to the results of multiple correlation analysis, the frequency of AF paroxysms correlated with forced expiratory volume in 1 sec (FEV1) (R=-0.348; p=0.013), minimum oxygen saturation of the blood (min%SpO2) (R=-0.356; p=0.011), CRP level (R=0.442; p=0.001), the sizes of both atria (p<0.001), isovolumic relaxation time (IVRT) of left ventricle (LV) (R=0.350; p=0.022), the right ventricle (RV) size (R=0.478; p<0.001), systolic blood pressure level in the pulmonary artery (PASP) (р<0.001), vascular stiffness - pulse wave velocity in aorta (PWao) (p=0.001). The influence of FEV1 on the left atrium volume index (χ2=7.0; p=0.008) and IVRT LV (χ2=7.9; p=0.005) was revealed. Correlations between min%SpO2 and IVRT and PWao were observed.Conclusion. Severe bronchial obstruction, hypoxemia, systemic inflammation with increase in vascular stiffness (PWao) and myocardium remodeling (increase in the sizes of both atria, PASP, RV size and diastolic dysfunction of LV) are the factors that associated with the occurrence of AF in patients with COPD

Hemolysis and ATP release from human and rat erythrocytes under conditions of hypoxia: a comparative study

Red blood cells are involved not only in transportation of oxygen and carbon dioxide but also in autoregulation of vascular tone by ATP release in hypoxic conditions. Molecular mechanisms of the ATP release from red blood cells in response to a decrease in partial oxygen pressure still remain to be elucidated. In this work we have studied effects of hypoxia on red blood cell hemolysis in humans and rats and compared the effects of inhibitors of ecto-ATPase and pannexin on the release of ATP and hemoglobin from rat erythrocytes. The 20-min hypoxia at 37°C increased hemolysis of red blood cells in humans and rats 1.5- and 2.5-fold, respectively. In rat erythrocytes a significant increase in hypoxia-induced extracellular ATP level was found only in the presence of ecto-ATPase inhibitor ARL 67156. In these conditions we observed a positive correlation (R2 = 0.5003) between the increase in free hemoglobin concentration and the ATP release. Neither carbenoxolon nor probenecid, the inhibitors of low-selectivity pannexin channels, altered the hypoxia-induced ATP release from rat erythrocytes. The obtained results indicate a key role of hemolysis in the ATP release from red blood cells

Modern (rational) methods for detecting genetic features of athletes

Molecular genetic methods are an integral part of recent medicine. Polymerase chain reaction, Sanger sequencing, next-generation sequencing are widely used in many areas: diagnostics of infectious, inherited, oncological diseases, prenatal screening, study of polymorphisms that increase the risk of developing multifactorial diseases or promoting development physical qualities necessary to achieve success in sports and competitive activity. The growing demand for genotyping raises a number of ethical and social issues affecting the degree of usefulness of genotyping a healthy person and the scientific reliability of the data obtained using direct-to-consumer genetic testing.The review presents and systematizes the laboratory diagnostic methods used today to study nucleic acids that carry important information about human health and physical qualities

Phenotypic heterogeneity and diagnostic features of transthyretin amyloidosis with polyneuropathy

Transthyretin amyloidosis (ATTR-amyloidosis) is a systemic progressive fatal disease, for which a modifying therapy has recently been proposed that delays the progression of the disease and improves the patient’s quality of life. The delay in the diagnosis of ATTR-amyloidosis is associated with the heterogeneity of the manifestations of the disease, as well as insufficient awareness of doctors of different specialties about the disease. A review of recent studies on the symptomatology, diagnosis, molecular genetic characteristics of ATTR-amyloidosis and the most common forms of the disease with the predominant involvement of peripheral nerves and the heart, as well as the kidneys, gastrointestinal tract, and eyes is presented. The international consensus recommendations for the diagnosis of suspected ATTR-amyloidosis using modern methods that facilitate early and accurate diagnosis are discussed. The reasons and the most frequent misdiagnoses of ATTR-amyloidosis, which also lead to a delay in the timely appointment of therapy, are considered. Molecular genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy and cardiomyopathy. A diagnostic algorithm based on the initial symptoms and manifestations of the cardiovascular and nervous systems facilitates the identification of a patient with clinical suspicion of ATTR-amyloidosis by the general practitioner. Early diagnosis is critically important for patients with ATTR polyneuropathy, since the early prescription of Vyndaqel (tafamidis), registered in the Russian Federation in 2017, allows a significant clinical effect to be obtained. Timely administration of Vyndaqel significantly slows down the progression of the disease, improves the prognosis and quality of life in patients with ATTR polyneuropathy

Biological activity comparative evaluation of the gene-Activated bone substitutes made of octacalcium phosphate and plasmid DNA carrying VEGF and SDF genes: Part 1 - in vitro

High need for effective bone substitutes and drawbacks of the materials approved for clinical use determine the increasing activity of biomedical research in this area. We have developed gene-Activated bone substitutes consisting of a scaffold based on octacalcium phosphate (OCP) and one of the two variants of plasmid DNA carrying either a gene for vascular endothelial growth factor (VEGF) or two genes encoding VEGF and stromal derived factor- 1α (SDF-1α). The aim of the study was to evaluate the cytotoxicity of the gene-Activated materials and their components, as well as biological activity in vitro. We found that both OCP and gene-Activated bone substitutes did not have any cytotoxicity, but reduced the proliferative activity of human bone marrow-derived multipotent mesenchymal stromal cells: material with doublegene construct decreased cell culture doubling rate of 24.3% more compared with the material carrying plasmid DNA encoding only VEGF. Both gene-Activated materials led to an increase in therapeutic genes mRNA levels, but the material with double-gene system enhanced VEGF protein production greater. Thus, the gene-Activated bone substitutes characterized by the absence of cytotoxic properties and possessed a specific activity increasing expression of the therapeutic genes. However, further studies are needed to detail the identified characteristics and assess the feasibility of the defined biological action in vivo