Bulletin of RSMU

ISSN Print 2500–1094 ISSN Online 2542–1204

Bulletin of RSMU

BIOMEDICAL JOURNAL OF PIROGOV UNIVERSITY (MOSCOW, RUSSIA)

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Shagina IA, Turchaninova MA, Golovina OA, Bufeeva LS, Zhurina TI, Saifullin RF, Myshkin MYu, Mutovina ZYu, Britanova OV

Systemic scleroderma (SS) remains a disease with a high mortality rate; validated biomarkers for stratification and disease monitoring are still lacking. The study aimed to assess the expression of the developed panel of IFN-I-induced genes (IFI27, IFI44, IFIT3, ISG15, XAF1) in peripheral blood and affected skin of patients with SS. We tested samples of 48 SS patients and 31 healthy donors. Gene expression was analyzed using RT-qPCR (ΔΔCt) method (with normalization to the reference housekeeping gene TBP). The SFRP4 gene expression was used as a marker of skin fibrosis. Expression values of the IFN-I-induced genes were significantly (p < 0.1) increased in both blood and skin of SS patients compared to healthy donors. Comparison between compartments revealed that the expression levels of XAF1, IFI44, IFIT3, ISG15 in the patients’ blood are higher (p < 0.01), than those in skin samples. The IFI27 gene expression, in contrast, is higher in the skin (p < 0.01). The findings show that the test system developed for interferon signature assessment can potentially be used as a noninvasive tool for stratifying SS patients by analysis of RNA from peripheral blood samples, to substantiate the prescription of therapy with the IFN-I receptor blockers.

Received: 2025-09-06

Published online: 2025-10-21

DOI: 10.24075/brsmu.2025.047

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VIEWS 215

Shatalova RO, Sheverev DV

Cellular senescence is associated with the accumulation of senescent cells characterized by functional alterations, telomere shortening, cell cycle arrest, resistance to apoptosis, and metabolic dysregulation. In recent years, senescence has been extensively investigated not only in the context of aging but also in relation to cancer therapy, as senescence induction in various tumor cell types may differentially influence disease progression. The aim of this study was to comparatively evaluate commonly used chemotherapeutic agents with respect to their ability to induce senescence and their effects on mitochondrial and lysosomal compartments in primary dermal fibroblasts isolated from C57BL/6 mice. Cellular senescence was assessed using both chromogenic and fluorescent assays for β-galactosidase (β-Gal) activity. Mitochondria were labeled with the potential-sensitive dye MitoTracker® Orange, and lysosomes were stained with LysoTracker® Red. Flow cytometry analysis was performed using a BD LSRFortessa cytometer. Our results revealed a significant decrease in mitochondrial membrane potential and an increase in lysosomal fluorescence intensity in cells undergoing chemotherapy-induced senescence. Using an integrative senescence induction index developed in our laboratory, we demonstrated that doxorubicin exerts a more pronounced effect on senescence induction and on mitochondrial and lysosomal compartments compared to cisplatin, bleomycin, and etoposide.

Received: 2025-09-06

Published online: 2025-10-19

DOI: 10.24075/brsmu.2025.045

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VIEWS 275

Kalinchuk AYu, Patskan IA, Stadelman MM, Grigoryeva ES, Tashireva LA

Understanding subtype-specific variability of functional programs in FAP+ tumor-associated fibroblasts (TAFs) is fundamental for developing effective therapeutic strategies targeting stromal components. The aim of this study was to identify subtype-specific signaling pathways, markers, and molecular features of FAP+ TAFs. Using spatial transcriptomic analysis, we demonstrated that FAP+ TAFs in luminal breast cancer exhibit a phenotype characterized by extracellular matrix organization (GO:0030198, FDR q-value = 0.0307) and expression of genes associated with metastasis (COL10A1, MMP13, CXCL14, TSPAN8). In contrast, FAP+ TAFs in triple-negative breast cancer display a pronounced immunomodulatory phenotype with overexpression of immunosuppressive genes (CD36, PLA2G2A, CHI3L1) and enrichment of immune response-related pathways (immune response (GO:0006955, FDR q-value = 7.85e-17), inflammatory response (GO:0006954, FDR q-value = 2.79e-11), regulation of cytokine production (GO:0001817, FDR q-value = 3.39e-10)). We also identified subtype-specific gene signatures related to radioresistance: luminal A and B subtypes showed activation of DNA repair pathways (IGF1R, ERBB3, CRIP1), while triple-negative tumors demonstrated enrichment of epithelial-mesenchymal transition and stemness markers (ZEB2, NOTCH4, FOXM1). These findings emphasize that FAP+ fibroblasts are not a homogeneous population but functionally specialize depending on tumor subtype — acting as stromal architects in luminal breast cancer and as regulators of immune response in triple-negative breast cancer.

Received: 2025-09-10

Published online: 2025-10-16

DOI: 10.24075/brsmu.2025.046

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VIEWS 254

Chepeleva EV, Kozyr KV, Vaver AA, Khakhalkin VV

The materials used to restore bone defets have a number of systemic limitations. The metal implants showing high mechanical strength have an insufficient osseointegration capability, while ceramic and polymer materials have better biocompatibility, but do not meet the requirements of mechanical reliability in the zones of considerable load. In this regard, the study of new classes of materials combining the strength characteristics with the osseogenic potential seems to be a promising area. The study aimed to assess cytocompatibility of the boron carbide (B4C)-based porous ceramic material to confirm the possibility of its use for bone defect replacement. The B4C semi-finished products were manufactured by pressureless sintering at 1900–2100 °C; ultrastructure of the resulting sample surface was examined by atomic force and scanning electron microscopy. Citotoxicity of the B4C samples was estimated by an indirect method relative to human mesenchymal stem cells. The following cell survival rates were reported: 102.1% (24 h) and 99.1% (72 h) for the samples autoclaved; 110.0% (24 h) and 94.4% (72 h) for those treated with ethylene oxide. No significant intergroup differences were revealed (Mann–Whitney U-test). The findings allow us to consider B4C ceramics as a promising solution for bone grafting. However, further research is required to assess its clinical potential, including the development of sterilization protocols for larger and complex-shaped samples.

Received: 2025-09-10

Published online: 2025-10-12

DOI: 10.24075/brsmu.2025.044

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VIEWS 222

Matveeva KS, Sheverev DV

Accumulation of senescent cells in the tissues is associated with functional impairment and the development of age-related disorders. The key role in this process is played by the senescence-associated secretory phenotype (SASP) contributing to chronic systemic inflammation, which is associated with the increased risk of autoimmune disorders and cancer, as well as the decreased resistance to infections. Normally, the immune system eliminates senescent cells, but the effectiveness of this process decreases with age, including due to the immune system aging. The study aimed to assess age-related alterations in the main lymphocyte and myelocyte populations in the spleen and bone marrow samples of senile mice. The study involved groups of young (n = 8) and elderly (n = 4) С57BL/6 mice. Populations were tested by flow cytometry using the fluorescence-labeled antibodies. The aging phenotype was assessed based on the β-Gal enzyme activity with pre-treatment with bafilomycin А1, ensuring lysosomal alkalinization and allowing one to detect the increased enzyme activity typical for the aging cells (SA-β-Gal). As a result, the significantly increased levels of myeloid populations, CD11c+ B cells, double-negative T cells, along with the decreased levels of the CD8α+ dendritic cells, were reported in elderly mice. Furthermore, aging was associated with the significant increase in the levels of SA-β-Gal-positive cells, especially in the populations of myeloid cells. The data obtained suggest that the age-related alterations are of systemic nature and reflect the so-called myeloid shift, as well as accumulation of pro-inflammatory populations in the myeloid and lymphoid compartments.

Received: 2025-08-27

Published online: 2025-09-30

DOI: 10.24075/brsmu.2025.043

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VIEWS 279

Makhachev DR, Bulanov DV, Shovkhalov MM, Bekmurziev BZ, Geroev IA, Netsvetova AM, Zhusupova AR, Gubich DS, Manovski AM

High-grade non-anaplastic (HGFC-NA) thyroid tumors belong to a rare and aggressive category of neoplasms that occupy an intermediate position between differentiated and anaplastic carcinomas. There are high mortality rate and limited standard treatment options, which usually include surgical tumor removal with subsequent radioiodine treatment and levothyroxine suppression therapy. Targeted tyrosine kinase inhibitors are additionally considered in radioiodineresistant forms, but the efficacy of those is limited. A clinical case of differentiated high-grade thyroid carcinoma (DHGTC) in a 62-year-old female patient post hemithyroidectomy is presented. Histological assessment, immunohistochemistry (TTF-1, PAX8, CK19, p53, Ki-67), and the key marker (TERT, TP53, BRAF) molecular testing methods were used. The tumor size was 3.4 × 2.8 × 2.5 cm; the tumor showed pronounced architectonic heterogeneity, focal necrosis, high mitotic activity — 8–10 mitoses per 10 fields of view at ×400 (corresponding to ≥ 5 per 2 mm2), and the Ki-67 proliferation index reached 35%. IHC was used to detect the TTF-1 and PAX8 expression, mutational p53 pattern of expression, suggesting the TP53 mutation. Molecular testing revealed no alteration of the TERT and BRAF genes. These characteristics made it possible to verify the diagnosis of DHGTC. A conclusion was drawn about the need for comprehensive morphological and molecular diagnosis of HGFC-NA tumors, since the mitotic activity quantitative parameters, Ki-67, and TERT/TP53 status determine the prognosis and the personalized therapy selection.

Received: 2025-09-02

Published online: 2025-09-24

DOI: 10.24075/brsmu.2025.042

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VIEWS 390

Grechenko VV, Gromova TV, Ogurtsova AD, Muradyan TG, Zhuravleva ER, Gankovskaya LV

During the aging the immune system alterations are accompanied by developing the systemic, sterile inflammation: inflammaging. Successful and pathological aging phenotypes are distinguished. Inflammaging severity depends largely on the ratio of pro- and anti-inflammatory mediators, especially IL6 and IL10. The study aimed to conduct the analysis of IL6 and IL10 production in the cultures of the patients’ peripheral blood mononuclear cells (MNCs) as a possible approach to determining the aging phenotype. The data of elderly patients (n = 80), senile patients (n = 100), and centenarians (n = 30) were included in the study. Among those the groups were allocated with the successful and pathological phenotypes, along with the comparison group (young adults). The stimulation coefficient (SC) was assessed based on the ratio of the levels of stimulated and induced cytokine production. For the successful phenotype in elderly and senile individuals, as well as centenarians, a decrease in the IL6 SC to 5.3 [2.2–14.3] (p < 0.01), 5.3 [3.01–7.8] (p < 0.01), 6.5 [5.2–14.1], respectively, was reported, against the comparison group, where the value was 17.6 [13.7–31.1] (p < 0.05). With the pathological phenotype, the IL6 SC values of the studied age group showed no significant differences from that of the comparison group. For the successful phenotype in senile individuals, the increase in the IL10 SC to 6.9 [3.8–13.8] relative to the values of the group with the pathological phenotype — 3.3 [2.0–5.9] (p < 0.01) and the comparison group — 2.0 [1.9–2.2] (p < 0.001) was reported. In the group of centenarians with the pathological phenotype, there was a significant increase in the IL10 SC (11.2 [5.4–18.1] vs 2.7 [2.3–6.5] p < 0.001) in the group with successful aging, which can indicate the pronounced compensatory anti-inflammatory reserve being a factor of survival and long life in the context of the presence of a large number of age-related disorders in this group.

Received: 2025-08-03

Published online: 2025-08-30

DOI: 10.24075/brsmu.2025.041

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VIEWS 431

Kirshina AS, Shepelkova GS, Khlebnikova AS, Maslov AA, Kozlova AV, Kunyk DA, Yeremeev VV, Ivanov RA, Reshetnikov VV

The success of mRNA-based vaccine formulations against viral infections motivated many researchers to develop mRNA vaccines against bacterial infections. The development of new anti-tuberculosis vaccine is an urgent task since the only approved BCG vaccine is not effective enough in terms of infection prevention, despite the fact that it reduces the risk of severe disease. The study aimed to compare two anti-tuberculosis mRNA vaccines based on the classic linear mRNA (mRNA-MTBmEp-5-1) and circular RNA (circRNA-MTB-mEp-5-1) by immunogenicity and the capability of protecting I/St mice against M. tuberculosis infection. The efficacy of mRNA vaccines in the formulations with lipid nanoparticles was compared with the BCG efficacy. The findings suggest that immunization with the mRNA vaccine based on the linear mRNA resulted in the cell-based and humoral immune response (OD IgG = 0.36 ± 0.12) that was less pronounced than after BCG vaccination (OD IgG = 0.54 ± 0.14). At the same time, immunization with the mRNA vaccine and BCG ensured comparable reduction of bacterial load in the lung and spleen of experimental mice (CFU in lung tissue for BCG: 4.00 × 105 ± 2.13 × 105, p = 0.0068; mRNA: 4.72 × 105 ± 3.44 × 105, p = 0.0059; LNP: 4.91 × 106 ± 3.89 × 106, ns; PBS: 4.01 × 106 ± 1.69 × 106) and increased survival of mice after getting infected with M. tuberculosis. Immunization with the vaccine based on the circular RNA resulted in developing humoral mmunity only (OD IgG = 0.52 ± 0.13) and did not ensure protection after getting infected with M. tuberculosis (CFU in the lung for circRNA: 2.12 × 106 ± 5.30 × 105, p = 0.85). Thus, in our studies, anti-tuberculosis vaccines based on circular RNAs are inferior in effectiveness to formulations based on linear RNAs.

Received: 2025-07-22

Published online: 2025-08-26

DOI: 10.24075/brsmu.2025.040

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VIEWS 561