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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Kubekina MV, Kalinina AA, Korshunova DS, Bruter AV, Silaeva YY

Mitochondrial dysfunctions, which underlie many systemic diseases in animals and humans, may arise from accumulation of mutations in the mitochondrial genome. PolG-alpha enzyme encoded by Polg gene is crucial for replication and repair of the mitochondrial genome. The aim of this study was to assess the possible role of Polg mutations in mitochondrial dysfunctions using in vitro and in vivo animal models. The experiments involved transgenic mice with inducible expression of Polg mutant variant; the methods included cell culture, real time PCR assay, fluorescence flow cytometry, and skeletal muscle functional tests. The results indicate that mouse embryonic fibroblasts (MEFs) expressing Polg pathogenic mutant variant have decreased mitochondrial membrane potential and increased expression of mitophagy markers compared with control cultures. Transgenic animals with systemic expression of the pathogenic variant develop mitochondrial dysfunction which significantly affects muscular performance. In addition, systemic expression of mutated Polg in transgenic animals significantly inhibits expression of TCR subunit α and CD3 coreceptor complex subunits δ and ε in total splenocyte populations and significantly affects cellularity of the thymus without altering its CD4/CD8 subpopulation ratio. Thus, inducible expression of mutated Polg in transgenic animals provides a relevant model for studying mitochondrial dysfunction and its treatment in vitro and in vivo.

Received: 2022-04-14

Published online: 2022-04-27

DOI: 10.24075/brsmu.2022.021

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VIEWS 3049

Balanovska EV, Gorin IO, Ponomarev GYu, Pylev VYu, Petrushenko VS, Markina NV, Mamaeva AD, Larin AK, Agdzhoyan AT

Genetic contribution of pre-Slavic populations to gene pools of modern Russia is increasingly relevant, along with genetic footprints of the Golden Horde invasion. The novel genome-wide approaches enable advanced solutions in this field. The study aimed at searching for the footprints of genetic interaction among Finnicspeaking, Slavic and Turkic-speaking populations of Central Russia and Volga Region and their reflection in pharmacogenetic landscape. Modeling ancestral components by ADMIXTURE software and their mapping involved genome-wide genotyping data for 248 individual genomes representing 47 populations of 9 ethnic groups. Of specific ancestral components identified in each of the Finnic-speaking peoples, only Mordovian ancestral components are common for all populations within the studied geographic area, regardless of their linguistic affiliation. Gene pools of Russian populations include 80% of intrinsic component, 19% contribution from Finnic-speaking peoples, and 1% of Central Asian influence. The Tatar gene pool combines all identified ancestral components, including 81% contribution from Finnic-speaking peoples and only 12% of Central Asian influence, which prevents using it as a reference for the assessment of Golden Horde footprints in Russian gene pools. A map of genetic distances from Ryazan Russians based on a panel of 42 pharmacogenetic markers reveals a landscape strikingly independent from the selectively neutral ancestral genomic patterns. For instance, populations of Mordovia, Kaluga, Smolensk, and Kostroma regions are the closest to Ryazan Russians in pharmacogenetic status, whereas populations of Ryazan and Nizhny Novgorod regions have strikingly divergent pharmacogenetic status despite the similarity of the selectively neutral ancestral genomic patterns. These findings confirm the relevance of targeted pharmacogenetic characterization for gene pools of Russia.

Received: 2022-04-01

Published online: 2022-04-26

DOI: 10.24075/brsmu.2022.019

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VIEWS 3982

Milushkina OYu, Popov VI, Skoblina NA, Bokareva NA, Astashkevich EV, Zakharova AA, Skoblina EV

The problems of migration are becoming increasingly important and have primary impact on women’s and children’s health. The aim of the study was to evaluate the influence of migration factor on the establishment of menstrual function in girls. The study enrolled 1,222 female undergraduate students of Moscow universities, born in 1995–2000, of diverse ethnicity. The data were collected in 2015–2020 by questionnaire method. The main group included 322 students classified as migrants and the comparison group included 900 students of local origin (Muscovites). Statistical processing of the data was carried out using Statistica 10.0 package (StatSoft; USA). Mean age at menarche constituted 151.35 ± 1.20 months in migrants and 150.88 ± 1.06 months in Muscovites (p > 0.05). For all participants, menarcheal age fell within the range of 11–15 years (normal). Other parameters of menstrual function were also similar between the groups and comparable to corresponding data collected in other countries.

Received: 2022-03-24

Published online: 2022-04-24

DOI: 10.24075/brsmu.2022.017

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VIEWS 2990

Dovgan AA, Drapkina YuS, Dolgushina NV, Menzhinskaya IV, Krechetova LV, Sukhikh GT

Autoimmune mechanisms have been implicated in the negative effects of vaccines on female reproductive health. This study evaluates the endogenous levels of self-reactive antibodies and ovarian reserve-associated hormones before and after immunization with the domestically developed Gam-COVID-Vac combined vector vaccine to check for possible reproductive sequelae. The prospective study enrolled 120 women aged 18–49, subject to vaccination with Gam-COVID-Vac. Ovarian reserve was assessed prior to vaccination and 90 days after the first component injection. Profiles of specific antibodies to self-antigens, including phospholipids, nuclear antigens, FSH, progesterone, and also thyroid, ovarian, trophoblast, and zona pellucida antigens, were assessed at the same time points by enzyme immunoassay. Overall, the vaccination had no effect on the levels of ovarian reserve-associated hormones and autoantibodies, apart from a transient increase in positivity for antiphosphatidylethanolamine IgM and anti-dsDNA IgG. Seroprevalence of elevated serum autoantibodies constituted 70.8% before and 75% after vaccination. According to the results, immunization with Gam-COVID-Vac does not affect ovarian reserve or autoimmune status, thus being safe for the female reproductive potential.

Received: 2022-03-30

Published online: 2022-04-21

DOI: 10.24075/brsmu.2022.016

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VIEWS 3189

Burgasova OA, Dolinniy SV, Tetova VB, Ogarkova DA, Odnoralov MA, Bakalin VV, Smetanina SV, Antipyat NA, Taranova MV

Severe form of COVID 19 has been linked to the phenomenon of dysregulated inflammation with excessive cytokine release and elevated interleukin 6 (IL6) levels. Suppressive agents enabling specific inhibition of cytokines, notably monoclonal antibodies to IL6 and its receptors, have been applied as a rescue therapy in COVID 19 despite the underexplored clinical scope for these biologic medications. This study aimed to evaluate the clinical utility of IL6 receptor antagonist tocilizumab in moderate symptomatic COVID 19 prone to aggravation. The retrospective cohort study enrolled two groups of hospitalized patients (a total of n = 72) diagnosed with moderate COVID-19. The main group received a single 400 mg dose of tocilizumab (TCZ) on top of standard therapy. The comparative analysis included statistical evaluation for a number of clinical and laboratory parameters at reference time points and disease outcomes with regard to treatment strategy. Overall, TCZ administration provided no advantages in terms of oxygen supplementation status, disease progression, or survival. Lethal cases constituted 19.2% (10 pts) and 5% (1 pt) in TCZ and comparison groups, respectively. The results indicate that administration of monoclonal antibody drugs in hospital patients with COVID-19 must follow differential schemes with regard to the disease severity and comorbidities, as well as proper commencement schedules.

Received: 2022-03-10

Published online: 2022-04-15

DOI: 10.24075/brsmu.2022.015

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VIEWS 2929

Rakhmetova KK, Mishina ES, Vorvul AO, Bobyntsev II, Dolgintsev ME, Bezhin AI

Skin wound healing mechanisms and new ways of improving their efficiency represent an important focus in medicine. In this regard, regulatory peptides, which exhibit physiological polyfunctionality and modulate cell growth and differentiation, are of special interest. This study evaluates the effects of Gly-His-Lys (GHK) and Gly-His-Lys-D-Ala (GHK-D-Ala) peptides in the infected skin wound healing. The wounds were modeled in rats (n=150) by full-thickness dorsal skin defects. The peptides were administered intracutaneously at daily doses of 0.5 or 1.5 µg/kg. The healing was assessed on days 3, 7, and 10 by histomorphometric examination of the wounds with adjacent intact skin. GHK-D-Ala administered at daily doses of 0.5 µg/kg had pronounced positive effect on regeneration processes in the wound, as indicated by significantly reduced numbers of granulocytes and lymphocytes with increased representation of fibroblastic lineages and macrophages, and the resulting higher cellular index (p < 0.05–0.001). At higher doses of GHK-D-Ala (1.5 µg/kg), the beneficial effects were less pronounced. According to the comparative morphological examination, the highest positive effect was achieved with 0.5 µg/kg of GHK-D-Ala. Thus, local administration of the GHK peptide with extra D-alanine at carboxy-terminus significantly mitigated the inflammatory reaction and facilitated the healing of infected skin wounds in rat model.

Received: 2022-02-10

Published online: 2022-04-13

DOI: 10.24075/brsmu.2022.014

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VIEWS 3234

Vorobyeva IV, Bulava EV, Moshetova LK, Pinchuk AV

Simultaneous pancreas and kidney transplantation (SPK) provides effective treatment in patients with type 1 diabetes mellitus (T1DM) and end-stage renal failure (ESRF), mitigating the hyperglycemia and uremic syndrome. The study aimed at the assessment of morphofunctional status of the macula and macular hemodynamics in patients with T1DM after SPK. The study enrolled 45 patients subdivided into three groups: Group A — patients with T1DM after SPK; Group B — patients with T1DM and ESRF, maintained on programmed hemodialysis (PH), on waiting list for SPK; and Group C — individuals without ophthalmic or systemic pathologies. All patients were subject to the standard ophthalmological examination complemented by measurements of the central retinal thickness (CRT) and the average perfusion density (PD) in four vascular layers: superficial capillary plexus of the retina (SCP), deep capillary plexus of the retina (DCP), choriocapillaris, and choroid. The patients after SPK had significantly lower CRT (241 ± 33 µm in Group A, 309±10 µm in Group B; p < 0.05) and significantly higher PD of the macular region in both the retina (Group A: SCP — 19.0 ± 1.6%, DCP — 10.7 ± 1.3%; Group B: SCP — 11.7 ± 0.8%, DCP — 4.8 ± 0.8%; p < 0.05) and the choroid (Group A: choriocapillaris — 28.1 ± 1.8%, choroid — 31.3 ± 1.6%; Group B: choriocapillaris — 20.4 ± 1.6%, choroid — 21.8 ± 1.3%; p < 0.05), as well as significantly higher visual acuity (Group A: 0.7 ± 0.1; Group B: 0.5 ± 0.1; p < 0.05) and macular light threshold (Group A: 25.9 ± 1.4 dB; Group B: 22.3 ± 1.1 dB; p < 0.05) compared with the patients on PH. Thus, the normalization of carbohydrate metabolism and the mitigation of uremic syndrome in patients with T1DM and ESRF after SPK favorably affect the functional condition of the macular area, as indicated by the improvement in macular blood flow and visual functions.

Received: 2022-02-22

Published online: 2022-04-05

DOI: 10.24075/brsmu.2022.013

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VIEWS 2866

Kuptsova DG, Petrichuk SV, Murashkin NN, Kurbatova OV, Radygina TV, Khotko AA, Ivanov RA

Alterations in intracellular signaling pathways affecting immune cell activation, proliferation and differentiation of keratinocytes in psoriasis could explain the complex pathogenesis of the disease. NF-κB is one of the intracellular signaling pathways, which is involved in regulation of numerous pro-inflammatory genes, and affects the synthesis of pro-inflammatory cytokines directly involved in the development of psoriasis. The study was aimed to assess the number of cells with NF-κB translocation in lymphocyte populations of children with psoriasis depending in the disease severity and therapy. A total of 130 children with psoriasis vulgaris were examined. The comparison group included 30 healthy children. The study was conducted using the imaging flow cytometry Amnis ImageStreamX system. It was found that there were significant differences in the number of cells with NF-κB translocation in the lymphocyte populations of both children with psoriasis and comparison group. Children with psoriasis had a higher number of cells with NF-κB translocation in the populations of T helper cells, Tact, Treg, and Th17 compared to healthy children (p < 0.05). The number of cells with NF-κB translocation in children with psoriasis correlated with the disease severity PASI (Rmul = 0.32) and BSA (Rmul = 0.31) scores, as well as with the disease duration (p < 0.05). NF-κB determination could be considered an additional criterion for the disease severity assessment in children with psoriasis. The differences in the degree of reduction of the number of cells with NF-κB translocation 24 h after administration of biologics (adalimumab, etanercept, ustekinumab) have been shown. Studying NF-κB in cell populations offers the prospect of understanding pathogenetic mechanisms of inflammation and developing new therapeutic methods for psoriasis.

Received: 2022-02-11

Published online: 2022-03-20

DOI: 10.24075/brsmu.2022.012

Comments 0

VIEWS 3137