Molekulyarnaya Meditsina (Molecular medicine)

The computational study of 3D-model hyaluronidase interaction with shortchain glycosaminoglycan ligands had performed demonstrating the diversity and significance of their reaction on enzyme structure. The purpose of this review was evolution of limiting enzyme functioning interactions (impact on stability, biocatalyst activity) with grounding of recommendations for experimental modification of hyaluronidase for obtaining of its derivative of medicine destination (according the results of theoretical researches). The analysis was performed on databases of PubMed, Web of Science, MedLine, E-library in frames last 15 years. The binding of chondroitin trimers (on centers cn6, cn3, cn1) to hyaluronidase molecular surface increased the enzyme stability, binding of chondroitin sulfate trimers (on centers cs2, cs4, cs7, cs8 or cs1, cs2, cs4, cs7, cs8) decreased the inhibition of enzyme by tetramer heparin. It should be noted the importance of ligand binding for regulation of enzyme functioning and existence of multiform and multicomponent microenvironment of enzyme. The sequence of preferable coupling of ligands with hyaluronidase is elicited in our study and with its help was evaluate reality of experimental selective modification of enzyme (possibly noncovalent or covalently, for instance, with chondroitin sulfate trimers on centers cs7, cs1, cs5) for experimental obtaining of stabilized enzyme forms. The perspective approaches for this aim may be the noncovalent reaction on hyaluronidase by chondroitin or chondroitin sulfate trimers as well covalent modification of biocatalyst by chondroitin sulfate trimers.

Introduction. Despite numerous studies in the field of neurodegenerative diseases, the exact mechanisms of these processes have not yet been identified.

The purpose of this review is to analyze the methodological approaches necessary to revise the traditional and create new reliable prognostic and diagnostic algorithms that reflect pathogenetic features at different stages of neurodegeneration and atypical course of the disease.

Material and methods. The review highlights the results of clinical and experimental studies obtained using a complex of clinical, laboratory and instrumental methods with an emphasis on markers of oxidative stress and proteopathy. In preparing the materials, sources from international and domestic databases were used: Scopus, Web of Science, Pub Medline, RSCI mainly for the last 15 years.

Results. An idea has been formed about the molecular mechanisms of neural tissue regression in a number of neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s disease. The relationship between the parameters of the oxidative process and the features of metal-energy shifts in organs and organ systems is demonstrated. The role of markers of oxidative stress in the early stages, when the process of inflammation prevails and in the atypical course of the disease, is shown. Valuable biochemical markers are cytokines, glutathione levels, myeloperoxidase activation, and isoprostanes. The review points to the prospect of including in screening indicators of iron and other metals such as Zn, Mg, affecting the clinic accumulation of β-amyloid, in connection with which they can be considered as the basis for the progression of neurodegeneration. New data on the contribution of halogenating stress to the pathogenesis of neuroinflammation are presented. An aspect requiring development in the field of biomarkers for assessing the duration of the disease and prognostic prospects is the data on the correlation of metabolic shifts in the intestinal microbiota with the duration of the disease and the inflammatory process. Essential for the creation of express diagnostic methods is the determination of redox balance as an integral marker in saliva, which has obvious advantages over the use of biological fluids, such as liquor and serum.

Conclusion. The prospects of creating new prognostic and diagnostic schemes are associated with complexes, including laboratory and instrumental methods, in blood, liquor and saliva. Evaluation of the sensitivity and specificity of new markers depending on the clinical diagnosis allows the selection of pathogenetically significant markers in the early stages of the disease, with atypical neurodegeneration, to establish subtypes of the disease, to carry out their differential diagnosis.

Introduction. Lung cancer occupies a leading position in the structure of mortality from cancer. Chronic inflammation characteristic of tuberculosis increases the risk of lung cancer. Currently, more and more information is emerging confirming the cause-and-effect relationship between tuberculosis and cancer. The need to develop recommendations for public health regarding screening and treatment of tuberculosis in the tumor process determines the relevance of experimental studies on biological models of the combination of cancer and tuberculosis.

Aim. Creation а biological model of the combination of lung cancer and tuberculosis for preclinical study of rational combinations of antitumor and antituberculosis therapy.

Material and methods: The biological model was implemented on C57BL/6 mice at the age of two months. Lewis epidermoid lung carcinoma was used to reproduce the tumor process. Modeling of tuberculosis was carried out using the reference strain Mycobacterium Tuberculosis H37RV. During the study, the following groups were formed: “intact mice” (healthy, uninfected with the Mycobacterium Tuberculosis (MBT) H37Rv strain without tumor cell transplantation); “control of MBT infection” (animals infected with Mycobacterium Tuberculosis strain H37Rv), “tumor control” (animals that were transplanted with epidermoid Lewis lung carcinoma) and “main group” (animals that were transplanted with epidermoid Lewis lung carcinoma simultaneously with MBT infection).

Results. During the experiment, several models for creating the combined pathology of lung cancer and tuberculosis were identified. In the first (simultaneous infection and tumor inoculation), carcinoma developed more slowly in infected animals than in the tumor control group, and lung damage occurred with a predominance of the tuberculous process over the tumor process. The second (staged infection) also showed minimal metastatic manifestations with pronounced secondary changes in the primary tumor node. Analysis of the choice of model showed that the model with simultaneous infection and tumor inoculation most adequately ensures the development of the tumor process and tuberculosis infection, which allows maintaining the viability of the animal, fully developing the tumor process with metastasis to the lungs and obtaining the development of morphologically verified pulmonary tuberculosis.

Aim of the study was to establish the significance of TR-receptor, P2X₁-receptor and P2Y-receptor synergism for the efficiency of TC aggregation in patients with different sensitivity to non-selective NSAIDs, which will allow us to approach an understanding the causes of the variability of hematuria associated with NLT.

Material and methods. The study was prospective and included 60 patients with nephrolithiasis who were treated with high doses of NSAIDs for analgesia. The cohort of patients was divided into two groups: with effective (group 1. n=30) and ineffective (group 2. n=30) COX inhibition. The severity of hematuria was assessed during 7 days of drug therapy. The activity of TR receptors, purine P2X₁- and P2Y- receptors of platelets (Tc) was analysed by turbidimetric method on ChronoLog analyser (USA). Agonists (ATP, ADP and Arachidonic acid) were used at EC₅₀ and EC₁₀ concentrations.

Results. In the 1 group of patients, hyporeactivity of the TP receptor was established within 72 hours, which was restored to the level of normoreactivity on the 5^th day of therapy. Optimal modulation of the compensatory reaction of Pl in response to hematuria was provided through the synergism of purine P2X₁ and P2Y receptors. Optimal modulation of the compensatory reaction of Tc in response to hematuria was provided through the synergism of purine P2X₁ and P2Y receptors. On the 7^th day, a residual level of COX activity was reached, while intracellular signaling associated with stimulation of the TP receptor and purine P2 receptors did not provide the limitation of hematuria. In the 2 group, when patients were prescribed NSAIDs for 7 days, hyperreactivity of the TP receptor, P2 receptors and a stable level of microhematuria remained. In the case of COX resistance and increased production of TxA2, the maximum increase in proaggregant Tc activity was ensured through the stereotypical mechanism of intracellular signaling associated with stimulation of P2Y receptors (through Gi- and Gq- proteins) and the TP receptor (through Gq- and Gq_12/13- proteins).

Conclusion. Further study of the mechanisms of crosstalk signaling pathways with different COX activity will allow us to establish promising directions for pharmacological correction aimed at preventing hematuria and ensuring hemostasis in nephrolithiasis.

Introduction. Paratraumatic eczema (PTE), being a type of microbial eczema, occurs after surgical interventions, chronic wound healing, accompanied by pronounced inflammatory changes with hyperemia, edema, exudation, soreness and itching. Genetic polymorphisms of cytokines and Toll-like receptors (TLRs) may be pathogenetic factors in the development of PTE, causing the penetration of microorganisms and violation of the protective properties of the skin barrier.

Goal. To study the relationship of polymorphisms rs1800629 of the TNFα gene, rs5743708 of the TLR2 gene, rs3775291 of the TLR3 gene, rs4986790 of the TLR4 gene with the development of paratraumatic eczema in combat trauma victims. Material and methods. The study included 162 patients, of whom 82 showed signs of PTE (comparison group), 80 people had no signs of PTE (control group). Genotyping of polymorphisms was carried out using the polymerase chain reaction method with electrophoretic detection using test systems of NPF Litech (Russia). The Statistica 10 program (StatSoft, Inc., USA) was used for statistical data processing.

Results. A connection with the development of PTE with variants of genotypes and alleles of polymorphisms was established: rs1800629 of the TNFα gene (χ²=6.9; p=0.033 and χ²=8.12; p=0.005); rs3775291 of the TLR3 gene (χ²=6.9; p=0.039 and χ²=5.74; p=0.018); rs4986790 of the TLR4 gene (χ²=8.17; p=0.018 and χ²=7.85; p=0.005). The increase in the chances of developing PTE was influenced by: genotypes GA (OR=1.64; 95% CI 0.83–3.24) and AA (OR=2.94; 95% CI 0.9–9.67), allele A (OR=2.13; 95% CI 1.26–3.6) rs1800629 TNFα gene; genotypes CT (OR=1.58; 74% CI 0.93–3.24) and TT (OR=1.79; 95% CI 0.67–4.8), allele T (OR=1.76; 95% CI 1.1–2.8) rs3775291 TLR3 gene; genotypes AG (OR=2.58; 95% CI 1.24–5.37) and GG (OR=3.0; 95% CI 0.31–29.47), allele G (OR=2.44; 95% CI 1.29–4.62) rs4986790 of the TLR4 gene.

Conclusions. Polymorphisms rs1800629 of the TNFα gene, rs3775291 of the TLR3 gene, rs4986790 of the TLR4 gene are associated with the development of paratraumatic eczema in combat trauma victims.

Introduction. Thyroid disease is currently the most common among endocrine pathology. Hyperproduction of thyroid hormones is accompanied by stimulation of humoral reactions, contributing to the development of immune-mediated pathology under certain conditions, which actualizes the need to develop means for correcting neuroimmunoendocrine processes. Gliproline compounds analogous to neuropeptide protein molecules, among which are Thr-Lys-Pro-Arg-Pro-Gly-Pro and Pro-Gly-Pro, can be considered as such agents.

The aim of the study. The aim of the study was to study the immunotropic properties of gliproline compounds Thr-Lys-Pro-Arg-Pro-Gly-Pro and Pro-Gly-Pro under experimental hyperthyroidism.

Material and methods. The immunotropic properties of the gliproline compounds Thr-Lys-Pro-Arg-Pro-Gly-Pro and Pro-Gly-Pro were studied in white nonlinear male rats. Hyperthyroid status in animals was modeled by intragastric administration of L-thyroxine sodium salt pentahydrate («Sigma»; USA) at 150 μg/kg for 21 days. Laboratory animals were divided into groups (n=10): control group – intact animals (control); animals treated with L-thyroxine sodium salt pentahydrate (hyperthyroidism); rats receiving Thr-Lys-Pro-Arg-Pro-Gly-Pro (selanc) and rats receiving Pro-Gly-Pro intraperitoneally daily for 21 days at doses of 87 and 33 μg/kg/day.

Results. The obtained results indicate the presence in gliproline compounds Thr-Lys-Pro-Arg-Pro-Gly-Pro and Pro-Gly-Pro of immune correcting activity manifested under the conditions of experimental hyperthyroidism, with the greatest impact on the humoral unit of immunity, which is confirmed by the presence of statistically significant changes in the cellular parameters of the spleen and titer antierythrocytic antibodies in a direct hemagglutination reaction.

Conclusion. Thus, the study of the immunotropic properties of gliproline peptide compounds under experimental hyperthyroidism established the presence of immune-correcting activity in Thr-Lys-Pro-Arg-Pro-Gly-Pro and Pro-Gly-Pro substances.