Vol 16, No 2 (2021)

The review article is devoted to the history of the discovery of genes that regulate iron metabolism. The natural model that became the basis for the study of genes was hemochromatosis (HC). HC is a hereditary disease caused by excess iron in tissues. The first to be discovered was the HFE gene, whose physiological role is to prevent iron overload in cells by decreasing the binding of transferrin receptor-1 (TFR-1) to metal-saturated transferrin. This happened in 1996; the gene was mapped to chromosome 6p.23.3. In the European population, mutations in the HFE gene were detected in 80-100% of patients with HC. This variant of the disease is classified as type 1 He in OMIM. In 1999, the HJV gene on chromosome 1q21 was discovered, the product of which, hemouvelin, was later found to modulate the expression of hepcidin, and the SLC40A1 gene on chromosome 2q32, which encodes ferroportin, an iron transporter from enterocytes, macrophages, hepatocytes and placental cells into blood plasma. HC associated with mutations in these genes is represented by types 2A and 4 in the OMIM classification. In 2000, the HAMP gene on chromosome 19q13.1 was discovered, encoding the main iron regulatory hormone hepcidin, which blocks ferroportin, and the TFR-2 gene on chromosome 7q22. controlling the capture of iron by hepato-cytes and bone marrow cells, as well as the level of metal in the blood plasma. HC associated with mutations in these genes is represented by types 2B and 3 in the OMIM classification.

We presented evidence of the role of transposons in the occurrence of centromeric repeats in plants and animals. During evolution, transposable elements are retained as part of centromeres and participate in interaction with kinetochore. Moreover, the centromere protein CENP-B, telomerase and telomeres were derived from transposons. For the functioning of centromeres, the necessary role of RNA interference was proved. Non-coding RNAs that are processed from centromere transcripts are involved in this process. We assume that this property was acquired due to the protective mechanisms of the hosts against transposons, which have been successfully used for the regulation of genomes. As a result, the universal mechanism of chromosomes during mitosis was formed for all eukaryotes, since transposons play a global role in the structural and functional regulation of genomes. Evolutionary kinship of transposons with viruses, which are characterized by interactions with microtubule tubulin, is proved. Moreover, bacteriophages encode tubulin-like PhuZ protein. In evolution, spliceosomal introns, epigenetic and transcription factors and their binding sites, non-coding RNAs and many protein-coding genes have evolved from transposons. These facts indicate the evolutionary formation of a complex system of regulation of cell functions involving transposons and the role of transposons in the structural evolution of genomes.

Telocytes (TCs) are a recently described population of cells. Their histogenesis, phytophysiology, function and role in the development of pathological conditions are discussed by many researchers. In particular, the pathophysiological role of TCs in the fallopian tubes affected by inflammation remains unexplored. Objective: to study ultrastructural changes in the TC and their diagnostic significance in the distal fallopian tubes in acute and chronic salpingitis. Histological, immunohistochemical (IHC) and electron microscopic (EM) examination of fragments of the distal fallopian tubes of 10 women (age 37.8 ± 7.1 years) with acute and chronic inflammation, as well as without disease were carried out. IHC study was carried out with antibodies characteristic of stem cells (CD34, CD117) and Cajal cells (CD117, DOG1). We believe that immunophenotyping with well-known markers is not specific and is not suitable for the identification of TCs in the fallopian tubes. An EM study revealed multiple destructive changes in the TC. In acute salpingitis - loss of organelles, cytoplasmic vacuolization, dilatation of the granular endoplasmic reticulum, loss of intercellular contacts, shortening of telopodia, local loss of plasma membrane integrity. In chronic salpingitis, there is an increase in destructive changes and a further decrease in the number of TCs. Changes in TC and a decrease in their number alter the three-dimensional organization of the extracellular matrix in the stromal compartment of the fallopian tube, weaken intercellular signaling and contractility of the fallopian tube, which contributes to impaired organ motility.

The emergence and progression of a tumor (relapses, metastasis) is largely due to the presence and nature of inflammatory processes. It is promising to clarify the pathogenetic role and prognostic value of cytokines involved in the inflammation. The basal cell hyperplasia in the bronchial epithelium adjacent to the tumor may be associated with inflammation in the tumor microenvironment. Objective: to study the production of inflammatory cytokines in the tumor, taking into account basal cell hyperplasia in the bronchial epithelium adjacent to the tumor in the patients with nonsmall cell lung cancer. 35 patients with non-small cell lung cancer (T1-3N0-2M0) were included in the study. Neoadjuvant chemotherapy was administered in 17 cases. The production of TGF-β, TNF-α, SDF-1, VEGFA was determined by immunohistochemistry in tumor cells and alveolar macrophages. Basal cell hyperplasia in the bronchi adjacent to the tumor was morphologically diagnosed. The absence of SDF-1 in the nuclei of tumor cells was associated with the hematogenous metastases in patients with BCH of the bronchi adjacent to the tumor. Basal cell hyperplasia is correlated with an increased TGF-β production in alveolar macrophages and a decreased of SDF-1 in the cytoplasm of tumor cells. The frequency of case TNF-α in alveolar macrophages is reduced in patients with hematogenous metastases who received neoadjuvant chemotherapy. Cytokine production in the tumor cells and leukocytes was associated with the hematogenous metastases, taking into account the basal cell hyperplasia, which is associated with the pro-inflammatory cytokines in the tumor. The effects of neoadjuvant chemotherapy differ depending hematogenous metastasis.

The most common reason for patients with endometriosis seeking medical help is infertility, which affects 25-50% of patients with this disease. One of the essential factors of infertility in deep infiltrative endometriosis is the depletion of the ovarian reserve. To study the effect of deep infiltrative endometriosis on the state of the ovarian reserve in patients of reproductive age, as well as to assess the range of mutations in the PIK3CA gene among patients with infiltrative endometriosis. The main group consisted of 50 patients of reproductive age with deep infiltrative endometriosis, 18 of whom with ovarian endometriomas. The comparison group included 25 patients of reproductive age with inconsistency of the uterine scar after cesarean section. The level of anti-Mullerian hormone, follicle-stimulating hormone and estradiol in the blood was determined, as well as the number of antral follicles in the ovaries was counted during trans-vaginal ultrasound. The search for activating mutations of the PIK3CA gene was carried out by the method of new generation DNA sequencing in tissue samples of ovarian endometriomas and in biopsies of healthy ovarian tissue. The anti-Mullerian hormones level was lower in patients with infiltrative endometriosis than in patients in the comparison group by 1.0 ng/ml (2.6 ± 2.2 ng/ml in the main group, 3.6 ± 3.5 ng/ ml in the comparison group), however, the difference did not reach statistical significance, p>0.05. The number of antral follicles according to ultrasound data was significantly lower in the main group (8.5 ± 4.5) than in the comparison group (12.2 ± 4.1), p=0.001. This difference was statistically significant both for patients with ovarian endometriomas (6.0 ± 4.2, p<0.001) and for patients without ovarian involvement (9.8 ± 4.2, p=0.04). Our study did not reveal PIK3CA gene mutations in any of the ovarian endometrioma tissue samples and healthy ovarian tissue biopsies in patients of both groups. The presence of deep infiltrative endometriosis is associated with a decrease in ovarian reserve in patients of reproductive age, regardless of the presence of endometrioid ovarian lesions. Population studies are needed to identify mutations of this gene in endometriosis, as well as to study mutations of other genes encoding proteins regulating the antiapoptic signaling pathway PI3K/ AKT/mTOR, to identify the mechanism of depletion of the ovarian reserve in infiltrative form of external genital endometriosis.

Earlier, in mice after a 30-day space flight on the Bion-M1 biosatellite, we found signs of a negative effect of weightlessness on the structure of myelinated fibers of the spinal cord tracts; these findings indicate their involvement in the pathogenesis of hypogravitational motor syndrome (HMS). In the present study, under conditions of hypogravity modeling by the hindlimb unloading, we obtained data on destructive changes in the myelinated fibers of the motor posterior corticospinal tract (tractus corticospinalis posterior), sensitive anterior spinocerebellar tract (tractus spino-cerebellaris anterior), and the gracile fascicle (fasciculus gracilis), as well as in the tibial fascicle (fasciculus tibialis) of the sciatic nerve of mice 30 days after unloading. The obtained data confirm our hypothesis on the role of disturbance in the processes of myelination of nerve fibers during the development of HMS, both during space flight and under conditions of simulating hypogravity on Earth. Morphometric analysis after a 7-day period of readaptation did not reveal signs of restoration of pathological changes in myelinated fibers that arose after 30 days of hanging. However, preventive gene therapy (administration of a gene construct providing the synthesis of recombinant vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and neural cell adhesion molecule, prior to hindlimb unloading) has been shown to be effective in the preservation of myelinated fibers in projection anterior spininocerebellar tract, compared with control animals that did not receive gene therapy. The research carried out at this stage gives ground to make a preliminary conclusion about the advisability of developing methods of preventive gene therapy to prevent the development of GDS during long-term space flights.