Vol 16, No 3 (2021)

Full Issue


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Transposon hypothesis of carcinogenesis

Mustafin R.N.


The hypothesis is presented according to which the key drivers of carcinogenesis are transposons causing genomic instability, activation of oncogenes and inactivation of oncosuppressor genes. Expression of retroelements is under the negative regulatory control of proteins p53, RB1, VHL, BRCA1, ATM. It is assumed that most oncosuppressors have this property, since their genes are characterized by the presence in their composition of mobile elements (causing recombinations upon their activation) and hot spots of insertional mutagenesis. Accordingly, suppression of the expression of transposons as an adaptive process is necessary to ensure the stability of these genes. Therefore, the development of neoplasms in hereditary tumor syndromes may be due to pathological activation of transposons, which cause mutation of the second allele and other oncosuppressor genes due to congenital deficiency of oncosuppressor. Identical mechanisms are likely for sporadic carcinogenesis, when an activated transposon moves to new loci, causes complex genomic rearrangements specific to neoplasms, and inactivates oncosuppressors. Since the sequences of the transposable elements serve as alternative promoters for many genes, their activation causes enhanced expression of oncogenes in carcinogenesis. The transposons located in introns facilitate the transcription of chimeric molecules that have a pronounced oncogenic activity. In addition, mobile elements are sources of oncogenic microRNAs and long noncoding RNAs. The same microRNAs affect both neoplasms and aging, which confirms the hypothesis put forward, since dysregulation of mobile elements occurs with age, and aging is associated with an increased risk of cancer developing.
Genes & Cells. 2021;16(3):8-15
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Next-generation immunotherapy: regulatory T-cells

Churov A.V., Novitskaya A.V., Zhulai G.A.


Regulatory T lymphocytes (Treg) control the activity of immune cells and suppress the development of inflammation, maintaining the immune balance necessary for the body. Dysfunctions of Tregs are associated with the pathogenesis of autoimmune and oncological diseases. With systemic and organ-specific autoimmune reactions, as well as organ transplantation, a decrease in the function of Tregs is observed. While in the course of oncogenesis, the activity of Tregs prevents the development of an adequate immune response to tumor antigens, promotes the processes of angiogenesis and uncontrolled growth of transformed cells. Taking into account the important function of Tregs in the control of autoimmunity and oncogenesis, approaches to immunotherapy of inflammatory pathologies based on autologous and donor Tregs, as well as methods of activating an antitumor immune response as a result of selective blockade of the functional activity of Tregs, are being actively developed. The review provides an overview of technologies for modulating the activity of Tregs for the treatment of cancer, autoimmunity and adverse reactions after transplantation.
Genes & Cells. 2021;16(3):16-32
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Biogenesis and secretory pathways of mast cell chymase: structural and functional aspects

Atiakshin D.A., Klochkova S.V., Shishkina V.V., Nikityuk D.B., Alekseeva N.T., Kostin A.A.


Chymase is a specific protease of mast cells (MC) with variable expression and is one of the preformed components of the secre-tome. Chymase biogenesis begins with the processes of transcription in the nucleus, continuing in the cytoplasm of MC on ribosomes and in the cisterna of the endoplasmic reticulum. Entering the Golgi complex, molecules of the prochymase undergo post-translational modifications, this continuing in the vesicles detached from trans Golgi network. During further processing under granules maturation, chymase becomes an active enzyme and undergoes in-tragranular accumulation with typical topographic regularities, determining the features of the cytological and ultrastructural phenotype of MC. Various secretory mechanisms of chymase excretion into the extracellular matrix result in the development of diverse biological effects due to high selectivity of the protease to the molecular targets of cellular and extracellular components of the specific tissue microenvironment. Since chymase is an important enzyme in the formation of the state of the integrative-buffer metabolic environment of connective tissue, it is advisable to consider it as a diagnostic marker and a probable pharmacological target in the treatment of a number of pathological conditions. The involvement of chymase in the mechanisms of inflammation and allergy, angiogenesis and oncogenesis, remodeling of the extracellular matrix of connective tissue and changes in the histoarchitectonics of organs is also known. The technology of immunohistochemical staining using chro-mogenic or fluorescence detection allows objectively determining the number of chymase-positive MCs in the intraorgan population, the mechanisms of biogenesis and processing, cyto- and histoto-pographic characteristics with visualization of secretory pathways. Thus, the morphological identification of chymase significantly expands the interpretation of the data obtained in the study of adaptive and pathological states of internal organs, claiming not only diagnostic value, but also an assessment of the therapy performed.
Genes & Cells. 2021;16(3):33-43
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Cryopreservation of gametes: history and current state of a question

Odintsova I.A., Rusakova S.E., Schmidt A.A., Timoshkova Y.L.


Development of reproductive medicine, namely, extracorporal fertilization, set the task of preservation and preserving of biological suitability of female and men's gametes for scientific community. Opening of a method of a vitrification showed its benefit before other methods of a cryopreservation and became the encouraging event in development of cryobank of gametes. In this work the history of emergence of a method of a cryopreservation is described; modern aspects of a cryopreservation of gametes; shortcomings and benefits of various techniques of selection of full-fledged gametes are reflected; some protocols of carrying out a cryo-preservation are provided; short characteristic of separately used cryoprotectors and their various combinations capable more effectively to protect the freezing objects from damage, than, each of cryoprotectors separately is given. It is noted that in modern literature special attention is paid to consideration of mechanisms of cryodamages and cryoprotection during the freezing and a vitrification. Characteristics of the changes happening in gametes after the procedure of freezing and thawing are discussed. Modern techniques of assessment of viability of gametes before and after a cryopreservation are given. It is shown that violation of compaction of chromatin and fragmentation of DNA in morphologically not changed spermiya has negative impact and on quality of embryos. The benefit of a structurally functional condition of oocytes of mammals at a cryopreservation of oocytes in structure is emphasized an oocyte-kumulyusnykh of complexes in comparison with the oocytes which ripened in the kultivatsionny environment.
Genes & Cells. 2021;16(3):44-51
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Allele expression of Peroxisome-gamma2 proliferation activator receptor gene in overweight eldery patients with ischemic heart disease

Folomeeva L.I., Filippov E.V.


It is known that about a third of the world's population suffers from obesity. Peroxisome activation receptors, namely, the γ2 promoter, is abundantly locatein adipose tissue, regulating adipogenesis, lipid accumulation, and glucose homeostasis. The aim of this investigations was to study the expression features of the PPARγ2 gene alleles in elderly patients with comorbid conditions such as obesity and ischemic heart disease. From 2017 to 2019 in "Clinical Hospital № 29 named. N.E. Bauman” (Moscow) 140 patients of both sexes (54.3% men and 45.7% women) aged 60-89 years were examined by us. The main group included 70 pts with ischemic heart disease, and the control group included 70 pts without it. Pro12 allele carriage in the main group had 85%, and the Ala12 allele - 15%. Pro12Ala and Ala12Ala genotypes, Ala12 allele were detected more often in patients with ischemic heart disease than in the control group (p=0.0008 and p=0.0003, respectively). Pro12Ala genotypes carriage (OR=2.02, CI = 1.28-3.19, p=0.003) and Ala12Ala (OR=2.002, CI = 1.32-3.04, p=0.0006) of the Ala12 gene PPARγ2 increases the risk of developing ischemic heart disease by 2 times. The revealed features of the expression of PPARγ2 gene alleles in elderly patients with obesity and ischemic heart disease e confirm the ability of nuclear PPARs to control development, differentiation, metabolic homeostasis and reproduction. To clarify the role of various genotypes of the PPARy2 gene in the regulation of lipid metabolism and angiogenesis in the discussed comorbid conditions in elderly patients may help to identify new methods of it treatment.
Genes & Cells. 2021;16(3):52-55
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Analysis of the features of neurofibromatosis type 1 in the Republic of Bashkortostan

Mustafin R.N., Valiev R.R., Bermisheva M.A., Khusnutdinova E.K.


Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome that occurs on average with a frequency of 1: 3000 people. Clinical features of NF1 include cafe-au-lait macules on the skin, multiple cutaneous, subcutaneous, and plexi-form neurofibromas, Lisch nodules, and optic gliomas. The disease is also characterized by damage to the musculoskeletal system, impaired intelligence and behavior. The cause of the disease is germinal mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. NF1 is characterized by pronounced polymorphism of clinical manifestations, from erased to severe, without geno-phenotypic correlations. Therefore, the role of modifier genes in the pathogenesis of NF1 is assumed. We carried out a clinical-epidemiological and molecular-genetic study of patients with NF1 from the Republic of Bashkortostan (RB). We searched for intragenic mutations by sequencing 57 exons of the NF1 gene, and identified deletions of the entire gene using microsatellite analysis. The prevalence of NF1 in RB is 10 per 100 000. We identified 14 intragenic mutations in the NF1 gene in 20 patients with NF1 and 2 extended deletion of NF1 gene in 3 patients from 2 unrelated families. We did not find a correlation between the type of mutation and the characteristics of the clinical manifestations of the disease. To determine the possible influence of modifier genes on pathogenesis of NF1, we carried out a comparative analysis of the clinical manifestations of NF1 depending on inheritance, ethnicity and association of systemic manifestations. Among the clinical manifestations of NF1 in RB, there was a low frequency of optic nerve gliomas (5,25%) and plexiform neurofibromas (5%). The incidence of brain cysts was 4,25% among patients with NF1. We identified 9 mutations for the first time in the world, 5 out of 14 identified mutations are known (c.2806A>T, c.2991-1G>C, c.3158C>G, c.4537C>T, c.6792C>A). The distribution of mutation types turned out to be random. We identified a protective role of crossbreeding for the development of severe manifestations of NF1. We determined a high incidence of scoliosis, short stature, facial dysmorphism and chest deformity in the inheritance of NF1 from the mother, which suggests the influence of modifier genes on the pathogenesis of NF1.
Genes & Cells. 2021;16(3):56-62
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Distribution of cytokeratins and vimentin in rats liver at various stages of ontogenesis

Dvoryashina I.A., Velikorodnaya Y.I., Terent'ev A.V., Zagrebin V.L.


In recent years, there has been increasing understanding that the molecular mechanisms of liver morphogenesis are also involved in the mechanisms of regeneration and pathogenesis of some organ diseases. Epithelial-mesenchymal and mesenichymal-epithelial transitions play a significant role in embryogenesis, morphogenesis and regeneration. The aim of the study was to characterize the localization and ratio of epithelial and mesenchymal cells in the liver tissue during embryonic and postnatal development of rat liver as a possible criterion for mesenchymal-epithelial transition. We have analyzed immunohistochemically the production and distribution of vimen-tin (mesenchymal marker) and cytokeratin 18 (epithelial marker) in the liver tissue of rats from day 1 0 of embryonic development to adults. The relative area of hybrid cells has determined by double immunofluorescence followed by morphometry. The study showed that as the liver develops, the content of the epithelial marker (cy-tokeratin 18) increases, while the production of the mesenchymal marker (vimentin) decreases, with the exception of the period from 1 to 17 days after birth, when the amount of vimentin increases. In addition, hybrid cells were found in the liver of embryos on days 10 and 17 of gestation, which synthesized both intermediate microfilaments - vimentin and cytokeratin 1 8. Thus, based on the ratio of vimentin and cytokeratin 18 in the process of embryonic and postnatal liver morphogenesis and the presence of hybrid cells allow make an assumption about the origin of a part of hepatocytes by mesenchymal-epithelial transition.
Genes & Cells. 2021;16(3):63-68
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Some features of reproductive health in male patients in Samara

Pervova Y.V., Starikova T.V.


In the past few decades, there has been a decline in male fertility worldwide. The article is devoted to the study of the reproductive health of subfertile men. Purpose of the work: analysis of the biochemical composition of sperm plasma, spermogram and sperm morphology in subfertile men of reproductive age. The study included 85 patients aged 25 to 45 years, who were under observation in the clinic of Professor M.A. Florova (Samara): 60 patients seeking help to optimize reproductive health and procreation planning (a group of subfertile men, spermogram indices have deviations) and 25 clinically healthy men - a comparison group (control, spermogram indices are within the WHO norm). In subfertile men, morphological abnormalities of spermatozoa and changes in the biochemical composition of sperm plasma (increased concentration of transamination enzymes) were established. Spermatozoa with immature chromatin were identified. Electron microscopic analysis revealed fragmentation of sperm DNA: the highest percentage of spermatozoa with fragmented DNA was found in subfertile men (more than 22%).
Genes & Cells. 2021;16(3):69-71
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The effect of the cell-free matrix of the human umbilical cord on the growth dynamics and viability of cultured human and animal cells ex vivo

Kalyuzhnaya L.I., Sokolova M.O., Chernov V.E., Zemlyanoy D.A., Chebotarev S.V., Chalisova N.I., Kondratenko A.A., Grechanaya Y.S., Edomenko N.V., Alexander-Sinclair E.I.


Due to its extraembryonic origin, the umbilical cord retains regenerative molecules of the fetal phenotype The cell-free matrix of the human umbilical cord as the basis of various tissue-engineering structures (TES) for regenerative medicine can contribute to the repopulation of transplanted matrices by patient-specific cells. The aim of the work was to study in vitro the cytotoxic properties of a tissue-engineered lyophilized cell-free matrix made by the detergent method from the human umbilical cord Warton jelly with respect to human skin fibroblasts, as well as the effect of this matrix on the viability and growth of cells of the cerebral cortex, liver, spleen, articular cartilage, heart and skin of various laboratory animals during organotypic cultivation. Using the MTT test, it was revealed that the tissue-engineered acellular lyophilized matrix of the human umbilical cord does not show a toxic effect on human dermal fibroblast. When using the method of organ cultures, differences were revealed in the influence of the tissue-engineered matrix on the migration of cells from explants of tissues of different organs of various laboratory animals, their growth dynamics and viability, which may be due to species specificity, which must be taken into account when choosing test systems. The most noticeable positive effect of the matrix on the growth dynamics and viability of articular cartilage explant cells was found. Adhesion to the matrix of cells of the cerebral cortex of the Vietnamese lop-bellied pig as well as cells of the spleen of a guinea pig was revealed. The cell-free human umbilical cord matrix can be used in the creation of acellular matrices for the treatment of deep dermal and articular cartilage damages.
Genes & Cells. 2021;16(3):72-79
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Comparative characterization of cell products derived from adipose tissue using different systems for the isolation of cellular fractions

Gilmutdinova I.R., Kostromina E.Y., Veremeev A.V., Putova M.V., Markov P.A., Kudryashova I.S., Eremin P.S.


The use of autologous adipose tissue-derived cell products to restore the morphology and function of organs and tissues affected by the disease have become widespread in regenerative medicine. For the wide application of cell-based products in clinical practice, it is important to develop and implement new devices to automate and standardize the isolation of stromal vascular fraction cells. This work aimed to compare cell products obtained from human adipose tissue using two systems, both registered in the Russian Federation and based on enzymatic and mechanical methods of cell fractions isolation. As clinical material, we used samples of adipose tissue in the form of lipoaspirate obtained from healthy patients. The isolation of cell products was performed according to the instructions for the use of these systems. A comparative analysis of the effectiveness of these systems for the isolation of cell fractions was carried out by evaluating several parameters determined for obtained cell products. The cell product obtained by the enzymatic method is characterized by a high yield of nucleated cells, as well as a high proliferative potential of stem cells isolated from adipose tissue. The cellular product obtained from adipose tissue using the mechanical method is characterized by a low yield of nucleated cells, the presence of a large volume of residual oil, and destroyed connective tissue in the final product. The work shows that the method of adipose tissue processing (enzymatic or mechanical) has a significant effect on the characteristics of the products obtained.
Genes & Cells. 2021;16(3):80-85
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Investigation of HLA-DRB1 and IL28 gene polymorphism in patients with varying severity of COVID-19 infection

Kolyubaeva S.N., Kondratenko A.A., Alkhazhe K., Kryukov E.V., Чирский В.С., Kachnov V.A., Glushakov R.I., Sveklina T.S., Myakoshina L.A., Tyuryupov M.S., Neronova E.G., Eliseeva M.I.


The work analyzed the polymorphisms of the HLA-DRB1 and IL28 genes in 100 patients who underwent COVID-19 with the development of infection with varying degrees of severity. To a mild degree of severity were patients without complications in the form of infectious pneumonate, to moderate and severe degrees - with the development of pneumonate with varying degrees of lung damage. In general, the distribution of alleles in patients with COVID-19 did not differ from the distribution of average values in Russia. However, the HLA-DRB1 *01 и *07 alleles were more common. Comparison of the frequency of HLA-DRB1 alleles in patients with COVID-19 with varying severity revealed more common alleles of *13 and *07 in the severety severe group. However, with OR of 3.2 and 1.8, their confidence intervals (CL) were in the range of 0.9-9.8 and 0.7-4.5 respectively. At severe severity, the presence of homozigotic variants of allele *07 is noted. (Fisher exact test, r.0.04). As for the IL28B gene, no statistically significant differences from the control group were found.
Genes & Cells. 2021;16(3):86-90
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Non-viral gene transfer in hydrogel matrices with octacalcium phosphate microgranules in optimization of reparative osteogenesis

Bozo I.Y., Presnyakov E.V., Rochev E.S., Tserceil V.V., Podluzny P.S., Mavlikeev M.O., Fedotov A.Y., Baranov O.V., Eremin I.I., Pulin A.A., Chauzova T.S., Petrikina A.P., Bilyalov A.I., Titova A.A., Isaev A.A., Komlev V.S., Deev R.V.


There is a strong unmet need for bone grafts and substitutes combining osteoinductive capacities and biophysical properties for using them in minimally invasive surgical interventions. We have developed three variants of injectable gene-activated bone substitutes containing three components: octacalcium phosphate microgranules (OCP), plasmid DNA delivering the gene of vascular endothelial growth factor, and one of the hydrogels based on sodium alginate, type I collagen, and hyaluronic acid. The molecules of the gene constructs were contained both in the hydrogel and on the surface of the OCP microgranules. In the model of a critical-sized bone defect in rabbit parietal bone, we found that all the gene-activated hydrogels contributed to bone tissue regeneration, however, the largest amount of newly formed bone, including those in the central part of the defect, was detected in the groups with gene-activated materials based on hyaluronic acid and collagen. Thus, the developed materials can be considered as candidates for medical devices, but additional studies are required to assess the dose-depended effect and optimize the materials composition.
Genes & Cells. 2021;16(3):91-96
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Legal problems in the protection of human rights in the russian federation in the use of molecular genetic technologies in medicine

Khusainova R.I., Minniakhmetov I.R., Yalaev B.I., Akhtyamova E.V., Alsynbaeva E.M.


The article analyses possible human rights violations that occur in the application of molecular genetic technologies in medical practice. A brief description of the problem of the regulation of human rights in the implementation of genomic research at the international level, the provisions of which affect the protection of individual rights. Particular attention is paid to the current legislation of the Russian Federation, which concerns the protection of individual rights in the collection, storage and processing of genomic information during genetic testing, counseling, treatment of patients and other genomic studies in medicine. General recommendations are given for improving legislation in the field of human rights protection when using modern molecular genetic technologies in medicine. In order to overcome the problems associated with the protection of human rights in the use of modern molecular genetic technologies in medicine, an effective system of legal guarantees should be developed, taking into account international principles aimed at ensuring respect for human dignity, protecting the rights and interests of the individual.
Genes & Cells. 2021;16(3):97-103
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Genes & Cells. 2021;16(3):104-106
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