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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Gusar VA, Timofeeva AV, Fedorov IS, Tarasova AM, Suhova YuV, Ivanets TYu

The cellular response to various types of stress underlying placental vascular dysfunction is under the sumoylation control. Consequently, SUMO homeostasis is closely related to the maintenance of angiogenic balance, the disruption of which is a feature of preeclampsia (PE). The goal of the research is to search for exosomal markers of such a disorder. The expression and prognostic potential of exosomal SUMO 1–4, UBC9 and hnRNPA2/B1 were evalueted in 39 pregnant women (cohort I) in the first trimester using Western blotting technology. The expression of these proteins in the placenta (cohort II, 27 pregnant women) at the time of delivery was also assessed. The expression of their conjugated forms was significantly changed in pregnant women with early-onset (SUMO 1, p = 0.03; SUMO 2/3/4, p = 0.03) and late-onset PE (SUMO 1, p = 0.03; SUMO 2/3/4, p = 0.04; UBC9 and hnRNPA2/B1, p < 0.0001, respectively). This change may be due to the functional specificity of SUMO isoforms in the context of their subcellular targets upon exposure to stressful stimuli. Significant changes in the expression of these proteins were also found in the placenta. Significant correlations were established between the expression of exosomal SUMO 2/3/4 (r = –0.59; p = 0.01) and UBC9 (r = –0.88; p = 0.0001) with PlGF in early-onset PE. In late-onset PE, hnRNPA2/B1 (r = –0.48; p = 0.03) and UBC9 (r = –0.48; p = 0.03) was correlated with β-hCG, and SUMO 2/3/4 with PAPP-A (r = –0.60; p = 0.006) in the blood serum of pregnant women. The analyzed proteins also significantly correlated with uterine artery pulsation index (SUMO 1 (r = 0.59; p = 0.01), SUMO 2/3/4 (r = 0.54; p = 0.02), hnRNPA2/B1 (r = 0.75; p = 0.0001)) and mean arterial pressure (UBC9 (r = 0.53; p = 0.03)). Based on the data the logistic models have been created to predict the risk of developing early-onset (UBC9 (AUC = 0.88; Se-0.72; Sp-1)) and late-onset PE (SUMO 1 (AUC = 0.79; Se-0.8; Sp-0.77)) at 11–14 weeks of pregnancy.

Received: 2024-01-29

Published online: 2024-02-29

DOI: 10.24075/brsmu.2024.010

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VIEWS 743

Aznabaev BM, Mukhamadeev TR, Ismagilov TN, Dibaev TI

Reduction of the adverse effects of intraoperative intraocular pressure fluctuation referred to as post-occlusion surge on the intraocular structures is an important task for ensuring phacoemulsification safety. In this regard, the method to control infusion during phacoemulsification based on controlling the infusion and aspiration flow rates in combination with monitoring of vacuum parameters was developed. The study was aimed to provide comparative assessment of clinical and functional characteristics of the eye in patients after phacoemulsification using the new and already existing adaptive infusion control methods. A total of 38 patients aged 66.4 ± 7.8 years (15 males and 23 females) in the index group (Optimed Profi system with the use of new method) and 35 patients aged 68.7 ± 7.5 years (16 males and 19 females) in the control group (Centurion Vision System with Active Fluidics) underwent surgery due to cataract. The patients underwent comprehensive eye examination before surgery and on days 1, 7, 30, months 3, 6 after surgery. The smaller loss of corneal endothelial cells on months 3 and 6 after surgery was observed in patients of the index group with grade III and IV cataract (p < 0.05). Comparison of macular microcirculation parameters revealed the reduced FAZ area by month 6 of postoperative follow-up in the index group, along with the increased total vascular density of the deep vasculature (p < 0.001). A significant decrease in the total density of the superficial and deep vascular plexuses by month 6 of postoperative follow-up was observed in the control group (p < 0.05). The use of new adaptive infusion control method contributes to effective phacoemulsification of cataracts of varying density with the lower percentage of the corneal endothelial cells lost in the late postoperative period.

Received: 2024-01-19

Published online: 2024-02-28

DOI: 10.24075/brsmu.2024.009

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VIEWS 797

Tolstova TV, Pureczcky VK, Kozhin PM, Luzgina NG, Rusanov AL

Toxicity testing, including testing for skin toxicity, is essential for certification of novel pharmaceutical, chemical, and skincare products. The in vitro assessment models are considered to be the most promising; a number of such tests have been introduced into practice of approval testing. The new possibilities of detecting the early cellular response to damage can be provided by the cell-based sensors built upon visual quantification of the changes in activity of the signaling pathways involved in realization of such response. NF-κB and AP-1 represent two important protein transcription factors, the increase in activity of which in the cell is associated with damage, inflammation or redox balance alteration. The study was aimed to develop the cell-based sensors built upon the HaCaT immortalized human keratinocyte cell line that express green fluorescent protein (GFP) when the NF-κB (HaCaT/NF-κB) or AP-1 (HaCaT/AP-1) signaling pathway is activated, as well as to assess their information capacity when recording the dose-dependent response to the exposure to inducers of appropriate signaling pathways. The findings showed that the HaCaT/NF-κB cell fluorescence levels changed by 6.05 ± 0.51 and 5.53 ± 0.52 times upon exposure to TNFα or LPS (at a concentration of 0–80 ng/mL) in a dose dependent manner. The HaCaT/AP-1 biosensor also responded to the exposure to Cd (NO3)2 (at a concentration of 0–40 µМ) and ultraviolet A (UVA) (0–40 J/cm2), however, it enabled qualitative, but not quantitative detection. The censor cell fluorescence increased by 1.51 ± 0.24 and 1.66 ± 0.43 times, respectively. The cell-based sensors developed can be used to assess cytotoxic effects of the test substances on the human skin cells in vitro and study the cytotoxicity mechanisms.

Received: 2023-12-11

Published online: 2024-02-27

DOI: 10.24075/brsmu.2024.007

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VIEWS 742

Babkina II, Mazeeva VV, Morozova MP, Gorbacheva LR

Both acute brain injuries and neurodegenerative diseases are accompanied by neuroinflammation. The outcome of neuroinflammation and the prognosis of brain functional status depend on the balance of pro-inflammatory and anti-inflammatory factors. Many studies are aimed at finding possible therapeutic targets allowing to shift inflammatory response processes towards anti-inflammatory mechanisms. It has been shown that channels formed by pannexin proteins are expressed in all brain cells including astrocytes. However, their role in the processes of neuroinflammation is still unclear. Channels formed by pannexin 1 (Panx1) may be involved in proinflammatory activation of astrocytes induced by thrombin and/or lipopolysaccharide (LPS). The aim of this study was to assess thrombin- and LPS-induced activation of primary mouse cortical astrocytes under Panx1 blockade by probenecid. Functional profile of astrocytes, their proliferation and secretory activity changed both in case of thrombin application (50 nM and 100 nM) and in case of incubating cells with LPS. The observed increasing of nitric oxide (NO), β-hexosaminidase HEX and IL6 secretion stopped after the cells were treated with probenecid. Based on the obtained results, probenecid can be considered as a potential agent influencing the inflammatory process in brain tissue by stabilizing astrocytes through inactivation of Panx1 and reduction of astrogliosis.

Received: 2023-12-13

Published online: 2024-02-26

DOI: 10.24075/brsmu.2024.005

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VIEWS 750

Verbenko DA, Karamova AE, Chickin VV, Kozlova IV, Aulova KM, Kubanov AA, Gorodnichev PV

Atopic dermatitis (AD) is a widespread multifactorial genetically determined inflammatory skin disease caused by, among other causes, impaired functions of the epidermal barrier. Loss-of-function mutations of the filaggrin gene (important component of the natural moisturizing factor system) that arrest production of the full-fledged precursor protein are associated with AD. This work investigated the frequency of the 2282delACTG (rs558269137), R501X (rs61816761), S3247X (rs150597413), R2447X (rs138726443) loss-of-function mutations of the filaggrin gene in adult European patients with moderate to severe AD. The study involved 99 adult patients of both sexes aged 18-68 years. The mutations were identified with the help of the purpose-developed method of multiplex analysis of four single nucleotide polymorphisms that relies on the SNaPshot technique (minisequencing). The incidence of loss-of-function mutation of filaggrin 2282delACTG was 5.3%, that of R501X - 0.5%, R2447X - 1%. No S3247X mutation was detected in the sample. Collation of the results with Russian and European samples revealed a comparable level of the analyzed filaggrin gene mutations in adult patients with AD from different regions of the Russian Federation.

Received: 2024-01-12

Published online: 2024-02-25

DOI: 10.24075/brsmu.2024.006

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VIEWS 849

Pekov SI, Bocharov KV, Bormotov DS, Eliferov VA, Parochkina EV, Sorokin AA, Nikolaev EN, Popov IA

The use of ambient ionization mass spectrometry methods is one of the promising approaches to the impovement of glial tumor resection completeness by using an additional method to improve the tumor margin identification accuracy during the neurosurgical intervention itself. The amounts of data accumulated when testing such techniques can be also used in fundamental research to identify metabolic alterations associated with the tumor growth. The study was aimed to assess changes in the cell membrane lipid composition of diffuse and anaplastic astrocytomas based on the data acquired by ambient ionization mass spectrometry profiling of the tissues excised during the elective neurosurgical intervention. The lipid profiles obtained when assessing the tumor tissue samples (n = 43) by flow microextraction in a cartridge were subjected to shrinkage linear discriminant analysis enabling extraction of a number of lipids, the levels of which changed with increasing tumor grade. The lipid diversity decreased with increasing grade. Thus, the levels of 13 phospholipids belonging to six different subclasses turned out to be decreased in anaplastic tumors compared to diffuse ones. Both average size of the polar lipid fatty acid residues and their degree of unsaturation decrease with increasing tumor grade. The findings agree well with the data of the earlier study of high-grade glial tumors and confirm the biochemical view of metabolic reprogramming associated with malignant transformation of neuroglia.

Received: 2024-01-11

Published online: 2024-02-24

DOI: 10.24075/brsmu.2024.008

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VIEWS 711

Gumenyuk LN, Bordyugov MD, Sarchuk EV, Knyazeva SV, Zastavskii VA, Krickaya DV, Saitibragimova SE, Kurtvelieva AI

Currently, researchers show considerable interest in the link between gut microbiota and idiopathic recurrent miscarriage (IRM). This study aimed to analyze taxonomic changes of gut microbiota and assess its relationship with plasma levels of cortisol, melatonin, TNFa and IL17 in women with IRM. We invited 55 women with IRM and 60 women with normal pregnancy, studied their gut microbiota, and registered serum concentrations of cortisol, melatonin, TNFa and IL17. Women with IRM had changed gut microbiota: significantly decreased — diversity (Chao1 p = 0.014), significantly decreased abundance of Bifidobacterium (p < 0.001), Lachnospira (p = 0.032), Roseburia (p = 0.003), Coprococcus (p = 0.012), and significantly increased abundance of Ruminococcus (p < 0.001) and Klebsiella (p = 0.002). We have shown a statistically significant relationship between cortisol level and abundance of Lachnospira (r = –0.51; p = 0.002), melatonin level and abundance of Coprococcus (r = –0.49; p = 0.012), and identified connections between TNF and IL17 concentrations and Chao1 index (r = –0.51; p = 0.002, r = –0.54; p = 0.001, respectively), TNF concentration and abundance of Ruminococcus (r = 0.51; p = 0.002), IL17 concentration and abundance of Bifidobacterium (r = –0.52; p = 0.001). Modulation of gut microbiota may have preventive and therapeutic effects in women with IRM.

Received: 2024-01-04

Published online: 2024-02-21

DOI: 10.24075/brsmu.2024.004

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VIEWS 783

Mamedov IS, Zolkina IV, Sukhorukov VS, Krapivkin AI

Thorough investigation of metabolome by mass spectrometry is of great importance for personalized and preventive medicine. It is only timely laboratory diagnosis involving the use of high-tech chromatographic analysis methods that can help identify the patients with disorders of amino acid and acylcarnitine metabolism. The study was aimed to determine the efficacy of conventional and additional markers of metabolic disorders of amino acids and acylcarnitines detected by chromatography–mass spectrometry for the diagnosis of congenital metabolic disorders in children, as well as to create specific panels of the most effective indicators and determine the potential diagnostic efficacy of indentification of the relationships between the levels of amino acids and acylcarnitines in pediatric patients with congenital metabolic disorders. We assessed amino acid and acylcarnitine profiles in blood spots by high-performance liquid chromatography–tandem mass spectrometry in patients aged 6 months to 16 years (48 boys and 32 girls) with suspected aminoacidopathy and organic aciduria/acidemia. The comparison group consisted of 35 children with suspected peroxisomal metabolic disorders, the control group included 40 generally healthy children of various age groups. The data obtained were used to conduct the analysis of correlations between the groups of markers. Strong correlation was revealed for the levels of metabolically most closely related compounds (r < 0.8, р < 0.001). However, a similar relationship between metabolically not closely related compounds (correlation coefficient 0.45–0.73 (р < 0.001)) was revealed for some groups of compounds. Thus, the acylcarnitine profile can be proposed as an additional potential marker to be used in cases of borderline phenylalanine levels, and the sum of normalized acylcarnitine levels (С12+С16) can be a potential secondary marker of phenylketonuria.

Received: 2024-01-11

Published online: 2024-02-15

DOI: 10.24075/brsmu.2024.003

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VIEWS 902