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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Maltseva DV, Poloznikov AA, Artyushenko VG

Intestinal epithelial cells are constantly exposed to physiologically hypoxic environment. The further reduction of tissue oxygen delivery may result in the intestinal epithelial cells function impairment, being a sign of active inflammation. The cultivation conditions are important when performing in vitro studies, since those may affect the cells’ properties. The study was aimed to assess the integrin receptor expression in the human colon adenocarcinoma Caco-2 cell line when simulating both hypoxic condition using the cobalt chloride and microcirculation. Transcriptome analysis revealed the significantly increased expression of the integrin receptors ITGA2 and ITGA5 α2- and α5-subunit genes under hypoxic conditions, as well as the reduction of ITGA5 during incubation in the microfluidic chip. The expression of β-subunits did not change. Analysis of microRNA transcriptomes revealed the decreased expression of hsa-miR-766-3p and hsa-miR-23b-5p microRNA. One of the validated targets for both microRNAs is mRNA of gene ITGA5. It has been shown that microcirculation makes it possible to bring the intestinal epithelial cells cultivation conditions closer to physiological conditions. The possible biological significance of the detected integrin expression profile alterations and the role of microcirculation have been discussed.

Received: 2020-11-09

Published online: 2020-12-17

DOI: 10.24075/brsmu.2020.078

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Nikulin SV, Poloznikov AA, Sakharov DA

To increase the efficiency of drug development process, it is important to improve performance of preclinical experiments. A major drawback of the currently used in vitro intestinal barrier models is that it takes a significant time to obtain functional enterocyte monolayers with formed tight junctions. In this work, we have optimized various parameters such as cell density and different coatings, for a more rapid and efficient producing Caco-2 cell monolayers suitable for further experiments. In vivo microscopy and impedance spectroscopy were used to monitor cells state under various conditions. To determine possible biological mechanisms affected by exposure to various protein substrates, the transcriptomic analysis was applied. It was shown that collagen IV coating of the cell growth substrate significantly increased the rate of proliferation and migration of Caco-2 cells. This effect allows forming a functional monolayer of epithelial cells with tight junctions within 24 hours. Optimally, the initial cell density should be 90,000 to 200,000 cells/cm2. It was observed that collagen IV was poorly expressed by Caco-2 cells while the collagen IV receptor was expressed at a relatively high level in these cells. Laminin-332, another basement membrane component, was found to have no significant effect on times of formation of functional epithelial monolayers. Thus, using the optimal parameters determined in this study allows to significantly improve efficiency of using the in vitro intestinal barrier models.

Received: 2020-11-09

Published online: 2020-12-15

DOI: 10.24075/brsmu.2020.077

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VIEWS 3153

Kovtun AS, Averina OV, Poluektova EU, Kostyuk GP, Danilenko VN

Recently much attention is paid to investigation of the gut microbiome impact on children's mental health. The study was aimed to detect alterations in the taxonomic composition and content of bacterial genes encoding key enzymes involved in the metabolism of neuroactive compounds in the metagenomes of healthy young children and adolescents. The whole metagenome sequencing was used to obtain the metagenomic data of the faecal specimens. The bioinformatics algorithm developed and the catalogue of homologs created were used to identify the changes in abundance of bacterial genes and metagenomic signatures in the studied metagenomes. The core neurometabolic signature of the healthy children gut microbiota included the Bacteroides uniformis, Faecalibacterium prausnitzii and Lachnospiraceae bacterium species, as well as genes involved in production of acetic, propionic and butyric acids, glutamate and enzymes possessing antioxidant activity. Comparison of metagenomes in children of different age groups revealed significant (p < 0.1) changes in the average abundance for 3 bacterial genera and 18 species. The higher alpha diversity of the adolescents’ microbiota was observed both at the genus and species level. Furthermore, in the adolescents’ microbiota metagenomes the increased average relative abundances for the genes encoding enzymes involved in production of SCFAs, glutamate, tryptophan and compounds with antioxidant properties, histidine degradation and linoleic acid conjugation were observed (p < 0.1). The study results support the evidence that healthy gut microbial communities become more diverse and functional as their human hosts become older.

Received: 2020-11-13

Published online: 2020-12-11

DOI: 10.24075/brsmu.2020.076

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Akhmadullina DR, Konovalov RN, Shpilyukova YuA, Grishina DA, Berdnikovich ES, Fomenko SS, Fedotova EYu, Illarioshkin SN

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by language and behaviour deficits, which is considered the second most common cause of early-onset dementia. Detection of brain atrophy patterns is important for FTD diagnosis. However, the visual assessment of magnetic resonance imaging data may not be sensitive enough requiring the use of objective gray matter (GM) volume determination method. The study was aimed to assess the GM atrophy pattern in patients with FTD compared to control group patients using voxel-based morphometry (VBM). The study included 16 patients with FTD (12 patients with nonfluent agrammatic variant primary progressive aphasia (nfvPPA), three patients with behavioral variant of FTD, and one patient with logopenic variant PPA) and 10 healthy volunteers. VBM of patients with FTD and healthy controls revealed three significant (pFWE-corr < 0.05) atrophy areas in the left inferior frontal, left fusiform, and left supramarginal gyri. Taking into account the predominance of patients with nfvPPA in the group of FTD patients, the additional VBM of this group and control group was carried out, which revealed a distinct atrophy pattern: the reduced GM volume was detected in the left inferior frontal and left middle frontal gyri (pFWE-corr < 0.05). The results obtained indicate that regardless of the clinical variant, there is a certain atrophy pattern characteristic of FTD, which involves both frontotemporal areas and parietal lobe. The example of nfvPPA shows that each variant of the disease is associated with distinct localization of atrophy.

Received: 2020-10-21

Published online: 2020-12-08

DOI: 10.24075/brsmu.2020.075

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VIEWS 3329

Nersisyan SA, Galatenko AV, Maltseva DV, Ushkaryov YuA, Tonevitsky AG

Hypoxia accompanies various pathophysiological processes, including progression of tumors and metastasis. One of the mechanisms of molecular response of cells to hypoxia implies recruitment of specific miRNAs that regulate the expression of their target genes. This study aimed to evaluate the hypoxia-induced change in expression of miRNAs and their target genes in the HT-29 human colorectal adenocarcinoma cell line with the help of integrated miRNA and mRNA sequencing. To simulate hypoxia, the cells were treated with cobalt (II) chloride. We registered a significant change in expression of sixteen human miRNAs. Six of them (hsa-miR-18a-5p, hsa-miR-22-3p, hsa-miR-27a-5p, hsa-miR-182-5p, hsa-miR-215 -5p, hsa-miR-425-5p) had a significant proportion of target genes that had the expression changing in the opposite direction. Based on the bioinformatic analysis of interactions between differentially expressed transcription factors and miRNAs, we built a possible regulatory network with its main hubs being HIF-1α, p65, с-Myc, and Egr1 (encoded by the HIF1A, RELA, MYC and EGR1 genes).

Received: 2020-10-26

Published online: 2020-12-07

DOI: 10.24075/brsmu.2020.074

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VIEWS 3185

Molchanova EE, Polunina VV, Polyaev BA, Plotnikov VP, Lobov AN, Parastaev SA

Stroke remains one of the leading causes of disability; therefore, it is important to investigate factors that might affect the quality of life of stroke patients and refine rehabilitation technologies for better functional gains. The aim of this paper was to study possible factors that determine the quality of life in the residual ischemic stroke period. The MOS SF-36 health survey was completed by 210 patients undergoing early rehabilitation at a stroke care unit. The study revealed a significant decline in some quality of life indicators correlated with advancing age and severity of the condition (correlation coefficient –0.5; р < 0.01). Both physical and mental component summary scores were lower in women than in men (p < 0.01 and p < 0.001, respectively). High scores on the majority of the applied subscales were observed in the patients with a vertebrobasilar stroke, as compared with those who had suffered a carotid stroke (p < 0.05). The early rehabilitation regimen complemented with acupuncture in the acute stroke period and the subsequent rehabilitation program at the Rehabilitation Hospital significantly contributed (р < 0.05) to improving the quality of life of stroke patients in the residual stroke period.

Received: 2020-10-20

Published online: 2020-12-05

DOI: 10.24075/brsmu.2020.073

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VIEWS 3414

Balanovsky OP, Gorin IO, Zapisetskaya YuS, Golubeva AA, Kostryukova ES, Balanovska EV

This study explored the gene pools of Russian and Karelian populations of Tver region. Forty-one samples representing Tver Karels (n = 11) and Russians residing in the Western, Central and Eastern districts of Tver region (n = 30) were genotyped using a genome-wide panel of 4,559,465 SNPs. In order to investigate the phenomenon of genetic admixture between Slavic and Finnish-speaking populations, the obtained results were compared to the data on the Russian populations inhabiting the neighboring territories, Karels from Karelia and other North Eastern Europeans. Studying the gene pools of Russian populations with a genome-wide SNP panel is essential for cataloging their genetic diversity and identifying the distinct features of regional gene pools; in addition, it provides valuable data for practical pharmacogenomics and forensics. Using the principal component analysis, the ADMIXTURE method and D- and f3-statistics, we demonstrated that the gene pool of Tver Karels is closest to the gene pool of Karelian Karels, despite a long (300 to 500 years) history of living among the larger Russian population and the twentyfold population decline during the 20th century. At the same time, the gene pool of Tver Karels exhibits more pronounced similarity to the gene pool of the studied Russian populations than does any other Karelian population. The genetic admixture between Tver Russians and Tver Karels occurred due to a more intense gene flow from Russians to Karels whereas the gene flow from Karels to Russians was much weaker: Tver Russians turned out to be as genetically different from Karels as Pskov Russians. The genetic similarity of Tver Karels to Karelian Karels assessed with the autosomal SNP panel exhibits a slight shift towards the Russian gene pool and is consistent with the previously published analysis of Y-chromosome lineages in these populations that detected no admixture between Tver Karels and Russians.

Received: 2020-10-10

Published online: 2020-11-26

DOI: 10.24075/brsmu.2020.072

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VIEWS 4698

Elezarov AA, Kucheryavyy AS, Gumenyuk LN, Sorokina LE, Arifdzhanova SR, Gerbali OYu

Dyssomnic disorders (DD) associated with juvenile rheumatoid arthritis (JRA) are some of the most common conditions that are difficult to endure and that lead to deconditioning. This study aimed to assess prevalence and structure of DD, their relationship with clinical picture peculiarities and contribution to deterioration of the quality of lives of JRA patients. At the 1st stage, we assessed prevalence of DD in a continuous sample of JRA patients and healthy children aged 8–16 years. At the 2nd stage, we assessed DD structure, features associated with gender and age, connections to the key clinical characteristics of JRA and quality of life of the patients. In the context of the study, we used the SDSC sleep quality scale, the PedsQL 4.0 quality of life model, and the Ritchie index. DD develop in JRA patients 3.3 times more often than in healthy children (in 178 (72.3%) and 93 (22.2%) children, respectively). The DD registered were sleep initiation and maintenance disorders (54 cases, 22.0%), respiratory disorders (32 cases, 13.0%), sleep-to-wakefulness transition disorders (31 cases, 12.6%), excessive sleepiness disorders (38 cases, 15.4%), combinations thereof (23, 9.3%). Girls had sleep initiation and maintenance disorders more pronounced (p = 0.003), boys were more prone to excessive sleepiness (p = 0.008). The severity of DD increases with patients' age (r = 0.69; p = 0.001) and JRA onset age (r = 0.71; p = 0.001); they are also more severe in polyarticular JRA patients (r = 0.32; p = 0.048). We have clarified the relationship between DD and indicators of inflammatory (r = 0.56; p = 0.001) and Ritchie indices (r = 0.44; p = 0.005), duration of morning stiffness (r = 0.49; p = 0.029). The proven connection between DD and JRA entails the need for routine checks for DD in such patients, and, when discovered, DD should call for personalized therapeutic and diagnostic approach rather than be regarded as one of the JRA syndromes.

Received: 2020-10-05

Published online: 2020-11-14

DOI: 10.24075/brsmu.2020.071

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VIEWS 3347