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Vol 20, No 2 (2022)

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Articles

Cytokines for allergic diseases

Morozova O.V., Ospelnikova T.P.

Abstract

Introduction. In allergic diseases a T-helper (Th) type 2 immune response with activation of B-lymphocytes secreting IgE immunoglobulins is prevalent. The majority of IgE binds with Fcε mast cells receptors. Repeated contacts between allergen and specific IgE on the surface of mast cells result in Fcε-receptors cross-linking, degranulation and release of inflammation mediators such as histamine, proteases, cytokines and chemokines. The aim of the study: analysis of general properties and specific features of cytokine profiles for immediate hypersensitivity reactions including bronchial asthma (BA), atopic dermatitis (AD) and urticarial (U). Results. During the sensitizing stage the induction of interleukin (IL)-4, IL-5, IL-6 gene expression activates the B-cells production of specific antibodies of class IgE. The subsequent cascade enhancement results from IL-4, IL-6 and granulocyte-macrophage colony-stimulatingfactor (GM-CSF) action. Additionally, IL-17 stimulates Th2 cytokines and eosinophilia development. Besides common cytokines for all allergic diseases, BA has increased levels of pro-inflammatory IL-6, IL-8, IL-22, IFNγ and TNFα as well as anti-inflammatory IL-37. AD increases the production of Th22, some Th17 cytokines and IL-37. Specific features of U include production of IL-9, IL-10, IL-22, IL-25, IL-33 and thymic stromal lymphopoetin. Conclusion. Identification of cytokines responsible for development of allergic diseases, mainly IL-4, IL-5, IL-13 permits to design new therapy approaches targeted at inhibiting of those ILs by using specific recombinant receptors or humanized monoclonal antibodies as well as by inactivating the corresponding mRNAs with antisense oligonucleotides, ribozymes and DNA enzymes, short interfering RNA, decoys and aptamers. For supression of Th2 cytokines interferon-γ, IL-12 and IL-37 can be used.

Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):3-10
pages 3-10 views

Intestinal microbiota in the pathogenesis of chronic heart failure

Fadeeva M.V., Skhirtladze M.R., Zolnikova O.Y., Ivashkin V.T.

Abstract

It is currently being discussed that the microbiota of the gastrointestinal tract and its metabolites affect the course of chronic heart failure (CHF). The purpose to summarize the available data on the role of the intestinal microbiota in the pathogenesis of CHF. Material and methods. A analysis of the main foreign and domestic sources on PubMed, MedLine, eLIBRARY databases over the last 20 years has been carried out. Results. In the course of the analysis of published works, the key links in the pathogenesis of CHF (imbalance of neurohumoral systems, inflammatory theory, metabolic disorders) and changes arising from disturbance of intestinal microbiota composition were compared. The results of studies where microbiota correction by prescribing antibiotics, probiotics and prebiotics resulted in positive effects on the course and prognosis in CHF are presented. Conclusion: Commonality in CHF pathogenesis (imbalance of neurohumoral systems, inflammatory theory and metabolic disorders) and changes in microbiota disturbances (including those mediated by microbial metabolites and inflammatory cytokines), the positive effects of pro- and prebiotics both on the microbial composition of the intestine and on course and prognosis in CHF, allow the consideration of microbiome as a marker and a possible target in CHF therapy. All of the above necessitates for further research in this area.

Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):11-18
pages 11-18 views

Compensatory mutations as a mechanism for preserving virulence and viability of drug-resistant forms of Mycobacterium tuberculosis

Vishnevsky B.I.

Abstract

Tuberculosis remains one of the leading causes of death from infectious diseases in the world. According to WHO data, tuberculosis is diagnosed annually in more than 100 million people and causes 4.5 thousand deaths. Despite a steady decline in the main epidemiological indicators for tuberculosis, the drug resistance of Mycobacterium tuberculosis (MBT) continues to increase steadily, and according to the Saint-Petersburg Research Institute for Phthisiopulmonology data that occures in all its localizations. There is a dangerous spread of multiple and broad drug resistance of MBT, and, most alarmingly, total resistance of MBT to all anti-tuberculosis drugs. The purpose of the review is to summarize current data on compensatory mutations that pose a serious threat, allowing to preserve the viability and virulence of drug-resistant forms of M. tuberculosis. Material and methods. The literature search was carried out using databases eLIBRARY.RU, MedLine, PubMed for 2000 - 2021. Results. MBT drug resistance, unlike other infections, results from accumulation of chromosomal mutations, rather than from plasmids and mobile genetic elements. Currently, mutations in genes associated with resistance to almost all anti-tuberculosis drugs are known. Drug resistance acquisition has pleiotropic effects, i.e. it is associated with known biological costs, often reducing the viability and virulence of MBT. But numerous studies have established that in the course of MBT evolution, so-called compensatory mutations are acquired in other genes, that can interact epistatically with resistance mutations, thereby reducing the «cost» of adaptiveness while maintaining the viability and virulence of the pathogen. Conclusion. The current crisis of classical antibacterial therapy necessitates further in-depth study of compensatory mutations, mainly to find «antimutators» as an alternative therapy to improve the effectiveness of tuberculosis treatment.

Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):19-25
pages 19-25 views

Soluble forms of programmable cell death receptor sPD-L and ligand sPD-L1, as well as some biochemical and hematological indicators in the blood of COVID-19 diseased

Kushlinskii N.E., Babkina I.V., Gerstein E.S., Lyubimova N.V., Timofeev Y.S., Korotkova E.A., Zubrikhina G.N., Davydova T.V., Somonova O.V., Stilidi I.S.

Abstract

Introduction. The main reason for the severity of COVID-19 and the death of patients is the «cytokine storm» - a strong inflammatory response caused by SARS-CoV-2. Macrophages, immune cells that help eliminate pathogens and repair damaged tissues, play a key role in the expression of inflammatory mediators. In addition to known cytokines, macrophages express the PD-L1 protein, a ligand of the PD1 apoptosis receptor. The aim of the study was to comparatively analyze the levels of soluble forms of the programmed cell death receptor (sPD-1) and its ligand (sPD-L1), as well as biochemical and hematological parameters in the blood of patients who underwent COVID-19. Material and methods. We carried out sPD-1 and sPD-L1 enzyme immunoassay and biochemical studies in 72 employees of the N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation who have undergone COVID-19. The control group consisted of 57 healthy donors. The fact of the disease was confirmed by the presence of antibodies to class G immunoglobulins (SARS-Cov-2 IgG) in the blood serum using the ELISA test system Antigma-G (Generium, Russia). The concentrations of sPD-1 and sPD-L1 in blood serum were studied using the Human sPD-L1 ELISA kit and Human sPD-1 ELISA kit (Affimetrix, eBioscience, USA). The levels of iron, transferrin and ferritin were determined on an automatic analyzer Cobas (Roche). Complete blood count was performed on an automatic Sysmex XE-2100 analyzer (Japan). Results. In the serum of those who underwent COVID-19 (30-50 days after the onset of the first symptoms), there was a significant decrease in sPD-L1 levels and a change in the correlation between the components of the sPD-1 / sPD-L1 system. A statistically significant direct relationship was found between the concentrations of soluble forms of the sPD-1 receptor and its ligand sPD-L1 with the levels of iron, hemoglobin and the number of erythrocytes, as well as between sPD-L1 and ferritin. No relationship was found between sPD-1 and sPD-L1 levels and erythrocyte counts (MCV, MCH, RDW-SD). Conclusion. The results obtained expand the understanding of the role of sPD-1 and sPD-L1 in persons who have undergone COVID-19, demonstrate the relationship between the processes of apoptosis, some biochemical and hematological parameters of blood serum, and are the basis for further research.

Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):26-31
pages 26-31 views

AED peptide activates gene expression and differentiation proteins synthesis of human skin fibroblasts during replicative aging

Gutop E.O., Linkova N.S., Fridman N.V., Kozhevnikova E.O., Polyakova V.O., Khavinson V.K.

Abstract

Skin fibroblasts aging is caused by genetic features and the environmental factors influence. One of the physiological aspects of skin aging is a decrease of regenerative capacity of dermis fibroblasts, including their ability to differentiate. The aim of this work is to study the effect of the AED peptide on fibroblast differentiation of human skin when aging in vitro. Methods. The study was conducted on DF-1 cell line (human dermal fibroblasts (mesenchymalstem cells)) isolated from the skin of the eyelids of a 37-year-old female donor). Cells were cultured till 25 passages for achieving the replicative aging. The effects of the AED peptide on gene expression and protein synthesis of early (Engrailed 1, PDGFRa) and late (Spry4, Twist2) fibroblast differentiation were assessed by polymerase chain reaction and immunocytochemistry. Results. The expression of the ENGRAILED1, PDGFRA, SPRY4, TWIST2 genes decreased by 1,7; 1.6; 1.5; 4.5 times respectively with aging of dermal fibroblasts. The addition of the AED peptide increased the expression of the ENGRAILED1, PDGFRA, SPRY4, TWIST2 genes in «old» skin fibroblasts by 1,9; 2,1; 2,3; 3,4 times, respectively. Expression of Engrailed 1, PDGFRa, Spry4, Twist2 proteins in fibroblasts decreased by 1,9; 2,3; 5,1; 4,3 times respectively with aging. The AED peptide increased the synthesis of Engrailed 1, PDGFRa, Spry4, Twist2 proteins in «old» fibroblasts by 3.3; 2.0; 2.5; 3.9 times respectively. Conclusion. Thus, the AED peptide increases the functional activity of skin fibroblasts during aging by increasing gene expression and synthesizing differentiation proteins in dermal fibroblast. This geroprotective effect of the AED peptide can accelerate the skin regeneration, stimulate chemotaxis and mitosis of fibroblasts, the synthesis of collagen in them, and activate the remodeling of the extracellular matrix.

Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):32-38
pages 32-38 views

Studying of P-, E-selectins and glycoprotein ligand PSGL-1 level in blood serum of patients with atherosclerosis of the arteries of lower limb

Korotkova N.V., Kalinin R.E., Suchkov I.A., Nikiforova L.V., Ryabkov A.N.

Abstract

Introduction. The study of intermoleculars interactions can contribute to the development of ideas about the violation of the endothelium,s adhesive function as one of the pathogenetic links in the development of peripheral artery diseases of atherosclerotic etiology. The aim of the study. To study the content of P- and E-selectins, a high-affinity glycoprotein ligand PSGL-1; to identify correlations between the represented values in the blood serum of patients with atherosclerosis of the lower extremities arteries. Methods. Quantitative determination of selectins P., E and glycoprotein ligand PSGL-1 by the sandwich method of ELISA in blood serum. Results. A decrease in the concentrations of selectins P and E, an increase in the concentration of the glycoprotein ligand of selectins PSGL-1 was revealed; a moderate negative correlation (r = -0,48) between the concentration of selectin P and the concentration of PSGL-1 in the blood serum of patients with atherosclerosis of the arteries of the lower extremities was detected. The findings of the study are as follows: • a statistically significant decrease in the concentration of selectin P in the blood serum of patients with atherosclerosis of the arteries of the lower extremities was revealed; • a statistically insignificant decrease in the concentration of selectin E in the blood serum of patients with atherosclerosis of the arteries of the lower extremities was detected; • a statistically significant increase in the concentration of glycoprotein ligand selectins PSGL-1 in the blood serum of patients with atherosclerosis of the arteries of the lower extremities was detected; • a moderate negative relationship was found between the concentration of selectin P and PSGL-1 (r = -0.48) in the blood serum of patients with atherosclerosis of the arteries of the lower extremities. All of the above changes can be related to the death of endotheliocytes and their reduction in synthesis of intercellular adhesion molecules, which is reflected in the disruption of the adhesive function, which is a component of endothelial dysfunction.

Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):39-45
pages 39-45 views

Рurinergic regulation of stones elimination from the upper part of the ureter during lithokinetic therapy

Barinov E.F., Malinin Y.Y., Grigoryan K.V.

Abstract

The reasons for the low efficiency of the α1A-blockers using in the scheme of lithokinetic therapy (LCT) remain unclear. The aim of the study was to evaluate the activity of the purinergic P2X1 receptor in the blockade of the α1A-adrenergic receptor during LCT in patients with calculi localization in the upper third of the ureter. Material and methods. The study was prospective and included 61 patients with calculi in the upper third of the ureter. For 7 days, patients underwent standard LBT, including an α1A-blocker, non-steroidal anti-inflammatory drugs (NSAIDs), and antibiotics. According to the imaging control of calculus traffic, the cohort of patients was divided into two groups: with effective (group 1) and ineffective (group 2) elimination of calculus. The activity of the P2X1 receptor was studied in vitro on a suspension of platelets. Platelet aggregation was assessed by the turbidimetric method using a ChronoLog analyzer (USA). Results. During hospitalization of patients, the P2X1-receptor hyperreactivity was revealed. When the standard LCT was prescribed after 7 days in the 1st group, the elimination of calculi from the upper third of the ureter was observed; the effect was reproduced in case of P2X1 receptor hyporeactivity. Fast and slow elimination of calculi. was determined by the kinetics of inhibition of ATP-induced intracellular signaling. In group 2, this phenomenon was not reproduced, while the P2X1 receptor hyperreactivity persisted for 7 days. According to the results of modeling the risk of ineffective elimination of calculi 72 h after the onset of LCT, the critical threshold of P2X1 receptor activity (P2X-R crit) was >58%. Conclusion. The effectiveness of LCT, associated, among other things, with the appointment of blockers of α1A-adrenergic receptors, is dependent of the activity P2X1 receptor, which modulates the contraction of the muscular layer of the ureter.

Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):46-52
pages 46-52 views

Decrease in ANG and VEGF mRNA levels during progressive angiogenesis of the liver venous system of Wistar rats in experimental cirrhosis

Lebedeva E.I., Shchastny A.T., Babenko A.S.

Abstract

Introduction. Currently, understanding the molecular mechanisms of pathological angiogenesis remains a fundamental problem in hepatology. The aim of this work was to find a relationship between the level of mRNA expression of the ang, vegf genes and angiogenesis in the liver of Wistar rats in experimental cirrhosis. Methods. The experiment used 117 sexually mature male Wistar rats weighing from 190-210g. Liver cirrhosis in animals was induced with a solution of thioacetamide, which was introduced into the stomach using a probe at a dose of 200 mg/kg of animal body weight 2 times a week. The dynamics of the process was studied at nine time points (over 17 weeks). The level of mRNA expression of the ang and vegf genes in the liver was studied by real-time polymerase chain reaction. To obtain overview histological preparations, liver sections were stained with hematoxylin and eosin, and to identify connective tissue - by the Mallory method. Microscopic analysis was performed using an OLYMPUS BX51 microscope and ImageScope Color and cellSens Standard image analysis programs. The degree offlbrosis was assessed using the Ishak K.G. Conclusion. A statistically significant relationship was established between the level of expression of the total mRNA of target genes, angiogenesis of the venous system, and fibrogenesis. No pronounced morphological changes were observed on the part of the liver arterial system throughout the experiment; arterial angiogenesis was not identified. Probably, the spliced forms of mRNA of the ang and vegf genes estimated by us are more important factors in the pathological angiogenesis of the venous system. Significant correlations were found between target genes r=0.65-0.84 (splice variants that were investigated). The joint study of genes with respect to each other is a necessary additional parameter when conducting basic and preclinical research.

Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):53-62
pages 53-62 views

Pravila dlya avtorov

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Molekulyarnaya Meditsina (Molecular medicine). 2022;20(2):63-63
pages 63-63 views

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