Репозиторий Университета

Background Cytochrome P450s (CYPs, EC 1.14.14.1) are the main enzymes of drug metabolism. The functional significance of CYPs also includes the metabolism of foreign chemicals and endogenic biologically active compounds. The CYP3A4 isoform contributes to the metabolism of about half of all marketed medicinal preparations. The aim of this study was to investigate the effects of two biologically active compounds: 2-aminoethane-sulfonic acid (taurine) and 3-hydroxy-4-trimethylaminobutyrate (L-carnitine) on urinary 6β-hydroxycortisol/cortisol (6β-OHC/cortisol) metabolic ratio as a biomarker of the CYP3A4 activity of healthy volunteers. Taurine is used for the treatment of chronic heart failure and liver disease. Cardiologists, nephrologists, neurologists, gerontologists in addition to the main etiopathogenetic therapies, use L-carnitine. The quantification of the 6β-OHC/cortisol metabolic ratio as a biomarker of CYP3A4 activity in human urine was used for the assessment of CYP3A4 catalytic activity as a non-invasive test. Methods The study included 18 healthy male volunteers (aged from 18 to 35 years old). The volunteers took taurine in a dose of 500 mg twice a day or L-carnitine in a dose of 2.5 mL 3 times a day for 14 consecutive days. The test drug was given 20 min before meals. The collection of urine samples was performed before and after 3, 7, 10, and 14 days after taurine intake. The metabolic ratio of 6β-OHC/cortisol in morning spot urine samples was studied by the liquid chromatography/mass spectroscopy (LC/MS) method. Results The ratio of 6-6β-OHC/cortisol was used as a biomarker to study the taurine and L-carnitine influence on CYP3A4 metabolism of cortisol. The ratio of urinary 6β-OCH/cortisol in the morning urine samples of volunteers before the beginning of taurine therapy (baseline ratio) was 2.71 ± 0.2. Seven days after the administration of taurine in a dose of 500 mg twice a day, the 6β-OCH/cortisol ratio was 3.3 ± 0.2, which indicated the increased catalytic activity of CYP3A4 towards cortisol. As for the L-carnitine supplementation, analysis of the 6β-OCH/cortisol ratio in the urine for 14 days did not show any significant changes in this baseline ratio, indicating the lack of L-carnitine influence on the catalytic activity of CYP3A4 to cortisol. Conclusions The results obtained demonstrated the influence of taurine on 6β-OCH/cortisol metabolic ratio as a biomarker of CYP3A4 catalytic activity to cortisol. L-carnitine did not affect the activity of CYP3A4. The lack of a clinically meaningful effect of L-carnitine was established.

© Copyright © 2019 Veremeyko, Yung, Dukhinova, Strekalova and Ponomarev. Twenty years ago, the scientific community exhibited relatively little interest in the study of microglial cells. However, recent technical and conceptual advances in this field have greatly increased interest in the basic biology of these cells within various neurodegenerative diseases, including multiple sclerosis, Alzheimer’s disease, and traumatic brain/spinal cord injuries. The main functions of these cells in the normal central nervous system (CNS) remain poorly understood, despite considerable elucidation of their roles in pathological conditions. Microglia populate the brain before birth and remain in close lifelong contact with CNS-resident cells under the influence of the local microenvironment. Within the CNS parenchyma, microglia actively interact with two main cell types, astrocytes and neurons, which produce many factors that affect microglia phenotypes in the normal CNS and during neuroinflammation. These factors include interleukin (IL)-34, macrophage colony-stimulating factor, transforming growth factor-β, and IL-4, which promote microglial expansion, survival, and differentiation to an anti-inflammatory phenotype in the normal CNS. Under inflammatory conditions, however, astrocytes produce several pro-inflammatory factors that contribute to microglial activation. The interactions of microglia with neurons in the normal and diseased CNS are especially intriguing. Microglia are known to interact actively with neurons by facilitating axonal pruning during development, while neurons provide specific factors that alter microglial phenotypes and functions. This review focuses mainly on the roles of soluble neuronal factors that affect microglial phenotypes and functions and the possible involvement of these factors in the pathology of neurodegenerative diseases.

© 2019 The Author(s). Background: Trypanosomatids of the genus Leishmania are parasites of mammals or reptiles transmitted by bloodsucking dipterans. Many species of these flagellates cause important human diseases with clinical symptoms ranging from skin sores to life-threatening damage of visceral organs. The genus Leishmania contains four subgenera: Leishmania, Sauroleishmania, Viannia, and Mundinia. The last subgenus has been established recently and remains understudied, although Mundinia contains human-infecting species. In addition, it is interesting from the evolutionary viewpoint, representing the earliest branch within the genus and possibly with a different type of vector. Here we analyzed the genomes of L. (M.) martiniquensis, L. (M.) enriettii and L. (M.) macropodum to better understand the biology and evolution of these parasites. Results: All three genomes analyzed were approximately of the same size (~ 30 Mb) and similar to that of L. (Sauroleishmania) tarentolae, but smaller than those of the members of subgenera Leishmania and Viannia, or the genus Endotrypanum (~ 32 Mb). This difference was explained by domination of gene losses over gains and contractions over expansions at the Mundinia node, although only a few of these genes could be identified. The analysis predicts significant changes in the Mundinia cell surface architecture, with the most important ones relating to losses of LPG-modifying side chain galactosyltransferases and arabinosyltransferases, as well as β-amastins. Among other important changes were gene family contractions for the oxygen-sensing adenylate cyclases and FYVE zinc finger-containing proteins. Conclusions: We suggest that adaptation of Mundinia to different vectors and hosts has led to alternative host-parasite relationships and, thereby, made some proteins redundant. Thus, the evolution of genomes in the genus Leishmania and, in particular, in the subgenus Mundinia was mainly shaped by host (or vector) switches.

© 2019 Elsevier B.V. While research into the role of cathepsins has been progressing at an exponential pace over the years, research into their respective isoform proteins has been less frenetic. In view of the functional and biological potential of such protein isoforms in model systems for cancer during their initial discovery, much later they have offered a new direction in the field of cathepsin basic and applied research. Consequently, the analysis of such isoforms has laid strong foundations in revealing other important regulatory aspects of the cathepsin proteins in general. In this review article, we address these key aspects of cathepsin isoform proteins, with particular emphasis on how they have shaped what is now known in the context of nuclear cathepsin localization and what potential these hold as nuclear-based therapeutic targets in cancer.

© 2019 by the authors. Oligonucleotides with an antiproliferative activity for human cancer cells have attracted attention over the past decades; many of them have a G-quadruplex structure (GQ), and a cryptic target. In particular, DNA oligonucleotide HD1, a minimal GQ, could inhibit proliferation of some cancer cell lines. The HD1 is a 15-nucleotide DNA oligonucleotide that folds into a minimal chair-like monomolecular antiparallel GQ structure. In this study, for eight human cancer cell lines, we have analyzed the antiproliferative activities of minimal bimodular DNA oligonucleotide, biHD1, which has two HD1 modules covalently linked via single T-nucleotide residue. Oligonucleotide biHD1 exhibits a dose-dependent antiproliferative activity for lung cancer cell line RL-67 and cell line of central nervous system cancer U87 by MTT-test and Ki-67 immunoassay. The study of derivatives of biHD1 for the RL-67 and U87 cell lines revealed a structure-activity correlation of GQ folding and antiproliferative activity. Therefore, a covalent joining of two putative GQ modules within biHD1 molecule provides the antiproliferative activity of initial HD1, opening a possibility to design further GQ multimodular nanoconstructs with antiproliferative activity—either as themselves or as carriers.

© 2019 Elsevier B.V. The stratum corneum is the main barrier to transdermal drug delivery which has previously resulted in mathematical modelling of solute transport in the skin being primarily directed at this skin layer. However, for topical treatment and skin toxicity studies, the concentration in the epidermis and dermis is important and needs to be modelled mathematically. Hitherto, mathematical models for viable skin layers typically simplified the clearance of solute by blood, either assuming sink condition at the top of the skin capillary loops or assuming a distributed clearance in the dermis. This paper is an attempt to develop a physiologically based mathematical model of drug transport in the viable skin. It incorporates explicit modelling of the capillary loops within the dermis and employs COMSOL Multiphysics® software to model the transport in three dimensions. Previously derived simplified models were compared to the results from this new numerical model. The results of this comparison showed that the simplified model reasonably described the average concentration in the viable skin layers when parameters of the models were chosen appropriately. When the recruitment of the capillary loops in the dermis was full and the top of capillary loops was at a depth of 100μm, the effective depth to place a sink condition in the simpler models was found to be at 150μm. However, when there was only partial recruitment of the capillaries, the effective depth increased to 180μm. The presented modelling is also essential for determining a transdermal flux when the stratum corneum barrier is compromised by such methods as microporation, application of chemical enhancers or microneedles.

© 2019 American Physical Society. In this paper, we present a detailed study of the oscillating magnetic relaxation in the synthetic antiferromagnet (SAF) with two ferromagnetic Co layers of different thicknesses separated by an Ir spacer. The four stable magnetic states of the SAF are determined by the mutual alignment of magnetic moments in the layers and are controlled by both the magnetic interlayer exchange interaction and the Zeeman energy. The specific variations in the thicknesses of the layers and/or temperature allow the existence of a "triple point," which corresponds to a coincidence of the critical switching fields for two or three interstate transitions. In this case, two or even three different types of magnetization reversals occur simultaneously and competitively. A nonmonotonic dependence of the domain-wall speed vDW on magnetic field H and an oscillating time dependence of magnetic moment M in a constant magnetic field were observed in a Pt/Co/Ir/Co/Pt synthetic antiferromagnet with perpendicular anisotropy due to interplay between the magnetic nuclei produced by Dzyaloshinskii-Moriya interaction. The proximity of two or three (triple-point) critical fields of SAF switching is the necessary condition for both a nonmonotonic magnetic relaxation and the oscillating time variations of the magnetic moment. The dynamical model describing the interaction and subsequent evolution of the magnetic nuclei demonstrates that this nontrivial magnetic relaxation obeys a simple Schrödinger equation.

© Mattioli 1885. Background and aim: The studies of Nobel laureate Robert Geoffrey Edwards led to the first in vitro fertilization and embryo transfer in 1978. Since then, reproductive medicine has made huge advances. Methods available to sterile couples now include: purchasing oocytes and sperm, uterus surrogacy, pre-implantation or pre-natal diagnosis, embryo/fetal selection. Here we highlight the fact that combinations of existing technologies could threaten the non-marketability of human life. Methods: We searched PubMed and websites to find articles regarding assisted reproduction techniques. Results: These methods, taken separately, provide support for natural fertilization, but when used together, they may lead to genuine “baby factories”. In poor countries, such “factories” exist and often act illegally. Conclusions: We highlight the need for deeper bioethical studies and better legislation regarding the combined use of medically-assisted reproductive techniques.

© BEIESP. Based on the issue of the genesis of subjectivity, the authors of the article turn to the Hegelian model, which captures the two-sided and fundamentally changeable nature of the relationship between subject and object. The article substantiates the idea that imagination, being considered outside of the context of psychologization or reduction of it only to the reproductive aspect, is a source of binary differences fundamental to philosophical thought. Following Hegel’s dialectical method, the authors note that the presence of the image already indicates the difference between the two dimensions of consciousness and knowledge. The image expresses the primary truth of substance and, at the same time, the way it is subjectively given. There is a differentiation of the subjective moment of Being with the realization of fantasy. All formations of Spirit are interpretations of the figurative series, primal scenes, the analog of which was studied by classical psychoanalysis. From this perspective, the genesis of such subjective modes as consciousness, self-consciousness and mind inevitably includes symbolization, interpretation of the "Self" images, cognizing, willing and acting in various situations and contexts. The study of the concepts developed by Hegel, Kennouche, Verene and Merleau-Ponty allows concluding about two arguments in favor of the fundamentality of imagination. This refers, on the one hand, to subjective imagination that generates meanings and the need for their interpretation and, on the other hand, to the initial form of synthesis, on the basis of which, the subject and object of cognition, formations of consciousness and types of knowledge characteristic of them are further distinguished. The image, being the first meeting of the concrete and universal, is capable of setting the plot of one or another form of subjectivity.

© 2019, Italian Society of Hypertension. Introduction: Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis. Aim: Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery. Methods: The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated. Results: The study revealed the following haplotypes: (1) ABCB1 rs1045642—CYP3A4 rs35599367 and (2) ABCB1 rs4148738—CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001). Conclusion: No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.

© 2019 The Author(s) The article highlights the experimental results on calf demand provision by mammary gland secretion during the first days of post-natal development. Changes in mammary gland secretion content during the transition process from colostrum to natural milk were showed. Lactoferrin level changes were demonstrated. Population-based composition of colostrum somatic cells was determined. A hypothesis concerning apoptosis role of the somatic cells and neutrophils’ burst was presented. The present study highlights calf provision with mammary gland secretion during the first 10 days of the postnatal development. Analytical chemistry; Food science; Animal science; Animal nutrition; Ruminant; Colostrum; Immunoglobulins; Lactoferrin; Somatic cells; Minor nutrient elements

© 2019 by the authors. This paper reveals the mechanism of nanowelding a branched network of single-walled carbon nanotubes (SWCNTs) used as a framework for the formation of protein-polymer matrices with albumin, collagen, and chitosan. It is shown that the introduction of certain point defects into the structure of SWCNTs (single vacancy, double vacancy, Stone-Wales defect, and a mixed defect) allows us to obtain strong heating in defective regions as compared to ideal SWCNTs. The wavelengths at which absorption reaches 50% are determined. Non-uniform absorption of laser radiation along with inefficient heat removal in defective regions determines the formation of hot spots, in which nanowelding of SWCNTs is observed even at 0.36 nm between contacting surfaces. The regularities of formation of layered protein-polymer matrices and the features of their interaction with cell membrane are revealed. All studies are carried out in silico using high-precision quantum approaches.

© 2019, Spandidos Publications. All rights reserved. Adiponectin, endothelin and nitric oxide (NO) are major regulators of vascular function. An imbal-ance of vasoactive factors contributes to the onset and progression of atherosclerosis. Various single nucleotide polymorphisms (SNPs) are considered to be risk factors for coronary heart disease. However, the molecular mechanisms of their associations with the components of endothelial dysfunction are poorly understood. In the present study, rs17366743, rs17300539, rs266729, rs182052 and rs2241766 SNPs of the adiponectin (ADIPOQ) gene and rs2070699, rs1800542 and rs1800543 SNPs of the endothelin-1 (EDN1) gene were genotyped in 477 patients with coronary heart disease who were subjected to coronary angiography, in order to determine the presence or absence of coronary atherosclerosis. The serum levels of adiponectin, endothelin and stable metabolites of NO, (nitrate and nitrite NOx), were assayed and their associations with the SNP genotypes and coronary lesions were calculated. The results indicated that rs17366743 of the ADIPOQ gene and rs2070699 and rs1800543 of the EDN1 gene were associated with the levels of NOx in women, which in turn was associated with cardiovascular mortality. In men, rs182052 and rs266729 of the ADIPOQ gene were associated with adiponectin levels, whereas rs17366743 of the ADIPOQ gene was associated with endothelin levels. Additionally, these SNPs were indirectly associated with the prevalence of coronary lesions in men. Therefore, the tested SNPs can be considered potential risk factors that lead to imbalance of vasoactive mediators in a gender-specific manner and contribute to the development of clinical manifestations of atherosclerosis.

© 2019 Journal of Advanced Pharmaceutical Technology  &  Research Published by Wolters Kluwer - Medknow. Species, known as mixture herbal products, are compositions of several types of crushed, sometimes whole, medicinal plant materials with additives; they are a widely used dosage form in the Russian Federation. A large range of species are produced at the pharmaceutical companies. In pharmacopoeial analysis, the most popular and widely used method for the determination of flavonoids, suitable for the standardization of species, is the method of differential spectrophotometry, based on the complexation of flavonoids with aluminum chloride. In accordance with modern requirements for the drugs production, the validation of analytical methods is a prerequisite for the creation of pharmacopoeial monographs projects regulating the quality of pharmaceutical substances of plant origin. Therefore, it is necessary to validate analytical methods for their intended use in evaluating the drug quality. This article discusses/presents the main stages of development and validation (by parameters: accuracy, precision, specificity, linearity) of the methodology for determining total flavonoid content using original species 'Fitourol' as a model.