Molekulyarnaya Meditsina (Molecular medicine)

Background. Hypoxic training are actively used in both professional and amateur sports. Hypoxia triggers a number of adaptive mechanisms aimed at improving stamina. However, these compensatory and adaptive pathways can be activated through rational pharmacological exposure, inducing pseudohypoxia.

The aim of the study was to compare the molecular mechanisms of performance enhancement in short-term hypobaric hypoxia and pharmacological pseudohypoxia.

Material and methods. Hypobaric hypoxia was simulated in male C57BL/6 mice by placing the animals in a pressure chamber with 14% oxygen content and reduced atmospheric pressure (equivalent to 4000 m above sea level). Pseudohypoxia was reproduced by a course of administration of a succinate dehydrogenase inhibitor – sodium polydihydroxyphenylene thiosulfonate, orally at a dose of 2.1 mg/kg. A combined exposure option was also simulated in animals: hypoxia + pseudohypoxia. After 21 days, the level of physical activity of the animals was recorded in the forced swimming test. Next, the concentrations of Hif-1α, AMP-activated protein kinase, and insulin receptors in muscle tissue, as well as erythropoietin, insulin-like growth factor-1, and cortisol in blood serum were evaluated.

Results. It has been shown that both in conditions of hypobaric hypoxia and pharmacological pseudohypoxia, as well as their combined variants, there is an increase in the concentration of Hif-1α, AMP-activated protein kinase and insulin receptors in muscle tissue. An increase in serum erythropoietin concentration of 51.8% (p < 0.05) was noted in hypobaric hypoxia, which was not observed in the case of pseudohypoxia and combined exposure. It is also worth noting that the physical performance of the animals to which the combined treatment option was applied was significantly higher than in mice that were simulated hypoxia (by 41.8%; p < 0.05) and pseudohypoxia (by 64.1%; p < 0.05). Cortisol concentration are not change in all groups.

Conclusion. In order to increase the level of physical activity through the activation of Hif-1α and insulin-dependent cellular signaling mechanisms, it is advisable to combine hypobaric hypoxic effects and pharmacological pseudohypoxia.

Introduction. Metabolic syndrome is a cluster of interrelated disorders of carbohydrate and lipid metabolism and requires reproducible experimental models suitable for pharmacological screening. Long-term exposure of laboratory animals to high-calorie diets can reproduce individual features of metabolic syndrome but substantially limits the rapid search for potential pharmacological correctors.

Objective. To model metabolic syndrome in female and male CBA/lac mice using a high-calorie diet combined with repeated tyloxapol administration and to perform a screening evaluation of the ability of the nerve growth factor mimetic GK-2 to correct carbohydrate and lipid metabolism disorders in comparison with the reference drugs metformin and glimepiride.

Material and methods. The study was performed in male and female CBA/lac mice aged 8–9 weeks. Metabolic syndrome was modeled by maintaining the animals on a high-calorie diet for 2 months and 3 weeks; from the beginning of the third month, tyloxapol was administered intraperitoneally at a dose of 200 mg/kg once every 3 days for 3 weeks. Pharmacological correction consisted of daily oral administration of metformin at 250 mg/kg, glimepiride at 4 mg/kg, or GK-2 at 10 mg/kg. Body weight, fasting blood glucose, glucose tolerance, insulin concentration, the HOMA-IR insulin resistance index, total cholesterol, triacylglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were assessed.

Results. The combination of a high-calorie diet and repeated tyloxapol administration reproduced a cluster of metabolic syndrome-related abnormalities in mice of both sexes, including increased body weight, elevated fasting glucose, impaired glucose tolerance, and increased total and low-density lipoprotein cholesterol levels. Glimepiride predominantly corrected carbohydrate metabolism abnormalities. The effects of metformin depended on animal sex and the parameter assessed. GK-2 at a dose of 10 mg/kg reduced blood glucose levels in mice of both sexes, decreased HOMA-IR in females and males, and exerted favorable effects on lipid metabolism parameters. Among the pharmacological interventions studied, a statistically significant reduction in low-density lipoprotein cholesterol in male mice with metabolic syndrome was observed with GK-2 treatment.

Conclusion. A combination of a high-calorie diet and fractional tyloxapol administration reproduces, within a relatively short period, a cluster of abnormalities characteristic of metabolic syndrome in male and female CBA/lac mice and may be suitable for pharmacological screening. GK-2 at a dose of 10 mg/kg demonstrated an ability to correct carbohydrate metabolism disorders comparable to that of glimepiride and showed a potentially relevant effect on selected lipid profile parameters, supporting its further investigation as a possible pharmacological corrector of metabolic disorders.

Introduction. The Gly-His-Lys (GHK) peptide, which is a fragment of type I collagen, has a wide range of biological effects, including neurotropic ones, and has an anxiolytic and analgesic effect. However, GHK is susceptible to proteases and various proline-containing amino acid sequences were added to the C-terminus to increase the duration of its effects.

Purpose of the study. Study of the behavior of rats in the forced swimming test using the GHK-PGP peptide and its structural analogs.

Material and methods. The experiments were performed on 200 male Wistar rats weighing 170–190 g. The work used peptides synthesized in the Laboratory of Molecular Pharmacology of Peptides of the National Research Center “Kurchatov Institute” (GHK, Pro-Gly-Pro (PGP), Gly-His-Lys-Pro-Gly-Pro (GHK-PGP), Gly-His-Lys-Gly-Pro (GHK-GP), Gly-His-Lys-Pro (GHK-P), Gly-His-Lys-Val-Glu-Pro (GHK-VEP)), which were administered intraperitoneally 15 min before the experiment at doses of 0,5; 5,0 and 50,0 μg/kg. Animal behavior was assessed using a forced swim test.

Results. GHK at a dose of 5,0 μg / kg caused a decrease in motor activity, and the PGP peptide at doses of 0,5 and 50,0 μg/kg had a pronounced antidepressant effect. GHK-PGP had an antidepressant effect only at a dose of 5,0 μg / kg. Thus, in the total GHK-PGP molecule, the PGP peptide neutralized the effect of GHK and was its structural part, determining this type of biological activity. GHK-GP had no effects at all doses. The GHK-VEP peptide had an antidepressant effect at a dose of 0,5 μg / kg.

Conclusion. GHK-PGP and its structural modifications using proline-containing amino acid sequences affect behavior in the forced swim test in rats, while the anxiolytic effect of GHK is neutralized with the appearance of an antidepressant effect.

Introduction. Plant biologically active compounds are considered as potential means of correcting reproductive function in obesity, but the molecular and cellular mechanisms of their action remain poorly understood.

The purpose of the study. To study the effect of a phytocomposition (PC) based on extracts of bergamot fruit (Citrus Bergamia), dioscorea rhizome (wild yam, Dioscorea Villosa), barberry fruit (Berberis Vulgaris) and Peruvian maca root (Lepidium Meyenii) on the state of the germinal epithelium of rats kept on a standard diet (SD) or a high-fat diet (HFD).

Material and methods. Male Wistar rats (n=63) were divided into 8 groups (Gr). During 4 and 7 weeks, animals Gr1 and G5, respectively, received SD (the proportion of fat in total calories was 11%), Gr2 and Gr6 – SD + PC, Gr3 and G7 – HFD (the proportion of fat in total calories was 36%), Gr4 and Gr8 – HFD + PC. After removing the animals from the experiment, histological sections were stained with hematoxylin and eosin to study the morphology of the testes. An indirect streptavidin peroxidase method was used for the immunohistochemical study.

Results. After 4 weeks of keeping rats on HFD, a decrease in Ki-67 and vimentin expression, a 60% increase in caspase 3 expression, a 22% decrease in the number of Leydig cells were found in the testes; after 7 weeks, the revealed shifts were joined by a decrease in tubule diameter by 18% and a decrease in the height of the germinal epithelium by 25%. Simultaneous administration of PC partially compensated for the revealed disorders in HFD, the most pronounced effect on the increase in expression was found for vimentin.

Conclusion. HFD causes degeneration of the testes, disrupting the balance of proliferation and apoptosis, FC has a protective effect, increasing proliferation and reducing apoptosis, preserving the structure of tubules and cellular composition.

Objective. To systematically categorize contemporary approaches and technologies for visualizing structural components of the tissue microenvironment (TME), with a focus on the advantages, limitations, and data analysis strategies of multiplex immunohistochemistry.

Material and Methods. A comprehensive literature analysis was conducted using the PubMed, Scopus, and Web of Science databases. The search was restricted to publications from the last 5–7 years.

Results. The integration of multidimensional histology with spatial context and AI-driven analysis establishes a new paradigm of informativeness in functional morphology. Current spatial profiling techniques – including macro- and microdissection, barcoding, optical imaging, and mass spectrometry imaging - differ substantially in resolution, multiplexing capacity, and the types of molecular markers they can analyze. Among optical imaging methods, multiplex immunofluorescence (mIF) offers distinct advantages: high sensitivity, preservation of tissue structural and biological integrity, reliable objectivity in cell detection within the histoarchitectural context, and robust validation of results through accessible quality control of immunolabeling at each stage of the staining design. mIF-based spatial proteomics is technologically accessible and cost-effective compared to other omics technologies, positioning it as a promising tool of choice for functional morphology in both normal and pathological states. The integration of artificial intelligence into whole-slide image analysis enables automated cell segmentation, classification, and subsequent statistical evaluation.

Conclusion. The convergence of visualization technologies and spatial analysis of the tissue microenvironment provides unprecedented opportunities to uncover fundamental principles of biological organization at the tissue, cellular, and molecular levels. This creates a novel informational framework for the development of translational biomarkers, enhances the informativeness of diagnostic and prognostic algorithms, and improves therapeutic efficacy within the paradigm of personalized medicine.

The review aims at analyzing the present-day knowledge of iron-regulating molecules in microorganisms: their synthesis, secretion, the transport systems that facilitate iron uptake into the cell, the role of these molecules in the development of pathological processes in the human body, and the prospects for their use in developing a new generation of antimicrobial agents.

Material and Methods. The authors analyzed full-text articles published in PubMed/Medline from 2021 to 2026. The analysis included full-length articles only. A search for the term “iron-regulating molecules of microorganisms” yielded 78 articles for the specified period. 43 articles that did not correspond to the target topic were excluded from the total list. In total, the analysis included 34 publications found through electronic searching and 16 manually-retrieved articles.

Results. Iron is a mineral essential for the normal functioning of almost all forms of life, and pathogenic microorganisms are no exception. Acting as a cofactor, iron ions are involved in various biochemical processes: the synthesis of nucleic acids and proteins, the regulation of virulence factor expression, the metabolism of reactive oxygen species; therefore, its bioavailability is crucial for the metabolism of bacteria and fungi. In the human body, the level of free iron ions is extremely low, since most of it is either in a stored state or bound to metabolic and transport molecules. Thus, despite the abundance of iron in the human body, the amount available to potential pathogens is negligible. To address this deficiency, many microorganisms have developed systems that allow them to thrive under the deficiency of this chemical element in the host organism. Conclusion. The main functions of iron-regulating molecules consist in converting iron bound to proteins or water-soluble compounds into an ionic form accessible to microorganisms. The loss of the ability to synthesize these molecules correlates with a loss of virulence in microorganisms.

Introduction. Spiral artery transformation is a key physiological process of pregnancy that establishes low-resistance uteroplacental blood flow. It involves trophoblast invasion of the vascular wall, replacement of the endothelium, and disruption of the smooth muscle layer, resulting in dilated vessels that lose vasomotor control. Abnormalities of this process have traditionally been associated with preeclampsia; however, current evidence indicates a more complex and heterogeneous pathogenesis. Altered pathways of trophoblast invasion and its interactions with vessels of the uteroplacental region are also of major importance in placenta accreta spectrum (PAS).

Objective. To analyze and compare current evidence on the mechanisms of spiral artery transformation, patterns of trophoblast invasion, and shared pathogenetic pathways in preeclampsia and PAS.

Material and methods. An analytical review of published scientific data on physiological and pathological spiral artery remodeling, molecular mechanisms of trophoblast invasion, angiogenic imbalance, hypoxia, inflammatory responses, matrix metalloproteinase expression, and cell adhesion molecules in preeclampsia and PAS was performed. Morphological, molecular, and pathogenetic findings were comparatively synthesized.

Results. Impaired spiral artery transformation is an important but non-universal mechanism of preeclampsia and appears to be predominantly associated with specific disease phenotypes. In PAS, the absence or deficiency of decidual cells plays a key role, disrupting the physiological regulation of trophoblast invasion and altering the direction of trophoblast cell spread. Under these conditions, trophoblast cells may spread through the myometrium and invade the vascular wall from the adventitial side. Preeclampsia and PAS share several pathogenetic pathways, including hypoxia, disturbances in angiogenic balance, altered expression of matrix metalloproteinases and cell adhesion molecules, and activation of proinflammatory responses. However, trophoblast functional status differs between these conditions: preeclampsia is associated with trophoblast dysfunction, injury, and shedding, whereas in PAS a relatively preserved trophoblast, in the setting of absent or deficient decidual cells, may spread in an unregulated manner into the myometrium.

Conclusion. Preeclampsia and PAS represent distinct clinical and morphological patterns of disturbed interactions among trophoblast, decidual cells, and vessels of the uteroplacental region. Despite differences in the direction and morphological manifestations of invasion, shared molecular and pathogenetic mechanisms support consideration of these conditions within a broader concept of abnormal trophoblast invasion. Further investigation of spiral artery transformation and trophoblast phenotypic plasticity may improve understanding of disease mechanisms and contribute to more accurate diagnosis of placenta-associated pregnancy complications.

Introduction. Immunomodulatory complexes based on yeast RNA and ascorbic acid are regarded as a natural multitarget platform capable of affecting innate immune receptors, interferon signaling and cellular redox balance. However, variability of the interferon response to such compositions and the reasons for differences between experimental models, batches and potential patient groups remain insufficiently understood.

Objective. To systematize current concepts of the interferon signature as a tool for assessing and stratifying response to yeast RNA and ascorbic acid complexes, to identify key molecular markers of efficacy and to propose a conceptual framework for their application.

Material and methods. An analytical review of Russian and international publications devoted to innate immunity, receptors recognizing exogenous RNA, interferon response, interferon-stimulated genes, redox regulation, immunomodulatory effects of ascorbic acid and critical quality attributes of RNA-containing compositions was performed.

Basic provisions. The interferon signature may be considered an integrated molecular profile reflecting interactions between the characteristics of the complex, the baseline state of target cells and parameters of innate immune response. The most promising components of this signature include TLR3, TLR7, TLR8, DDX58, IFIH1, MAVS, IRF3, IRF7, IFN-α/β, ISG15, MX1, OAS1, IFIT1 and CXCL10. Cellular redox status represents an important modifying contour.

Conclusion. The interferon signature is the most promising tool for the molecular stratification of the effectiveness of immunomodulatory complexes of yeast RNA and ascorbic acid. Its use makes it possible to move from a general description of immunotropic activity to a predictive assessment of response and to the development of personalized application schemes. The most promising area of further research is the integration of quality control of RNA compositions with a panel of laboratory markers that characterize the readiness of cells for an interferon response and its early implementation.