The physiological role of melatonin in oxidative stress during the embryonic period of development

Introduction. Melatonin, being a powerful endogenous antioxidant, provides healthy course of pregnancy and childbirth. Decrease of melatonin levels in blood correlates with severity of preeclampsia. Currently, melatonin is viewed as a perspective antioxidant, able to improve mother’s condition during preeclampsia and protect fetus from unfavorable intrauterine environment.The objective was to study melatonin effects on remodeling of chicken embryo heart tissue under normal conditions and under oxidative stress model.Materials and methods. The study was performed using organotypic culture of heart tissue of 10–12-day-old chicken embryos. Oxidative stress was modeled by adding epinephrine 10–4 М or homocysteine thiolactone 10–3 М to culture medium.Results. The trophotropic effects of melatonin was detected at a concentration of 10–6 M. Drug stimulated heart tissue explants’ growth on 20 %. Epinephrine showed cardiotoxic effects at concentrations of 10–4 and 10–6 М. Melatonin (10–6 М) neutralized cardiotoxic effects of epinephrine (10–4 M). Cardiotoxic effects of homocysteine thiolactone (10–3 М) preserved in presence of melatonin (10–6 М).Conclusion. During embryonic period, melatonin neutralizes cardiotoxic effects of oxidative stress caused by a high concentration of epinephrine, but not by homocysteine thiolactone

Научно-информационное обеспечение исследований и разработок в области медицины: подходы и решения

The authors discuss intellectualization of information analytics; in particular, they analyze the experience of medicine information support through the established system of databases and services of the Coсkrane Collaboration (Cockrane academic network). The authors reconstruct and explore the Cockrane method (model) of information analysis within the subject field of bibliography and informatics based on one of the authors’ personal experience of building systematic reviews of clinical trial results. The goal of the study is to reveal the potential and quality of the information analysis tools within the field of medicine, as well as to explore the feasibility and possibility of their adaptation and limitations in other fields. The study is based on the subject approach in bibliography and information analytics, informological approach, and theoretical tools of applied informatics. The structural functional and iterative methods were applied to study Cockrane through the prism of information analytics, professional user orientation, and knowledge management. The factors of user quality and performance of meta-analytical products for the purposes of evidence medicine are revealed; among them, source selection methods, data processing, procedural and organizational models, critical reviewing, and user differentiation in presenting information search findings. The analysis of meta-analytical information product building in evidence medicine enables to identify the range of methodological problems and promising vectors in the information studies.Статья посвящена проблемам интеллектуализации информационно-аналитической деятельности. Анализируется опыт научно-информационного обеспечения медицины, сформированный системой баз данных и сервисов академической сети «Кокрейновское сотрудничество» (Кокран). Методология (модель) информационного анализа Кокран реконструирована и изучена в предметном поле библиографоведения и информатики на основе личного участия одного из авторов в создании систематических обзоров результатов клинических испытаний методов лечения и диагностики. Цель проведённого изучения этой методологии – выявление потенциала и качества отраслевых инструментов информационного анализа, рассмотрение целесообразности и возможности их адаптации и границ применения в других отраслях. Исследование базируется на отраслевом подходе в библиографоведении и информационно-аналитической деятельности, информологическом подходе, теоретических инструментах прикладной информатики. Применены структурно-функциональный и итерационный методы в изучении Кокран в проекции информационной аналитики, ориентации на пользователя-специалиста, механизмы управления знаниями. Раскрыты факторы пользовательского качества и эффективности метааналитических продуктов для целей доказательной медицины: методы отбора источников, методы работы с данными, процедурные и организационные модели, критическое резюмирование, пользовательская дифференциация в представлении информационно-аналитического результата. Разбор модели создания метааналитических информационных продуктов в доказательной медицине позволил очертить круг методологических задач и перспективных направлений разработок в информационных науках

Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

Background Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. Main body The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Conclusion Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.info:eu-repo/semantics/publishedVersio

Физиологическая роль мелатонина при оксидативном стрессе в эмбриональный период развития

Introduction. Melatonin, being a powerful endogenous antioxidant, provides healthy course of pregnancy and childbirth. Decrease of melatonin levels in blood correlates with severity of preeclampsia. Currently, melatonin is viewed as a perspective antioxidant, able to improve mother’s condition during preeclampsia and protect fetus from unfavorable intrauterine environment.The objective was to study melatonin effects on remodeling of chicken embryo heart tissue under normal conditions and under oxidative stress model.Materials and methods. The study was performed using organotypic culture of heart tissue of 10–12-day-old chicken embryos. Oxidative stress was modeled by adding epinephrine 10–4 М or homocysteine thiolactone 10–3 М to culture medium.Results. The trophotropic effects of melatonin was detected at a concentration of 10–6 M. Drug stimulated heart tissue explants’ growth on 20 %. Epinephrine showed cardiotoxic effects at concentrations of 10–4 and 10–6 М. Melatonin (10–6 М) neutralized cardiotoxic effects of epinephrine (10–4 M). Cardiotoxic effects of homocysteine thiolactone (10–3 М) preserved in presence of melatonin (10–6 М).Conclusion. During embryonic period, melatonin neutralizes cardiotoxic effects of oxidative stress caused by a high concentration of epinephrine, but not by homocysteine thiolactone. Введение. Мелатонин является мощным эндогенным антиоксидантом, обеспечивает нормальное течение беременности и рождение здорового ребенка. Снижение концентрации гормона в крови коррелирует с тяжестью преэклампсии. В настоящее время мелатонин рассматривают как перспективный антиоксидант, который может улучшить состояние матери при преэклампсии, одновременно защищая плод от неблагоприятной внутриутробной среды.Цель – изучить прямое влияние мелатонина на ремоделирование ткани сердца куриного эмбриона в норме и при моделировании оксидативного стресса.Методы и материалы. В работе использован метод органотипической культуры ткани сердца 10–12-дневных куриных эмбрионов. Оксидативный стресс моделировали введением в питательную среду адреналина в дозе 10–4 М или гомоцистеин тиолактона в концентрации 10–3 М.Результаты. Обнаружен трофотропный эффект мелатонина в концентрации 10–6 М. Препарат стимулировал рост эксплантатов ткани сердца на 20 %. Адреналин проявил кардиотоксическое действие в концентрациях 10–4 и 10–6 М. Мелатонин (10–6 М) нивелировал кардиотоксический эффект адреналина (10–4 М). Кардиотоксический эффект гомоцистеин тиолактона (10–3 М) в присутствии мелатонина (10–6 М) сохранялся.Заключение. В эмбриональный периодмелатонин устраняет кардиотоксическое влияние окислительного стресса, вызванного высокой концентрацией адреналина, но не гомоцистеин тиолактона.

Аберрантный ангиогенез в ткани головного мозга при экспериментальной болезни Альцгеймера

The aim was to study the molecular mechanisms of the violation of the structural and functional integrity ofthe blood-brain barrier in chronic neurodegeneration of the Alzheimer’s type associated with the development of cerebral angiopathy.Materials and methods. The transgenic model of Alzheimer’s disease is the B6SLJ-Tg line mice (APPSwFlLon,PSEN1 * M146L * L286V) 6799Vas group which includes 9 months aged males. The control group included C57BL / 6 x SJL mice, males aged 9 months.Results. The total length of the vessels in the area of the dentate gyrus is 2.5 times greater in transgenic animal models of Alzheimer’s disease than in animals of the control group (p < 0.01). The average diameter of blood vessels in all areas of the hippocampus is smaller compared with the control (p < 0.05). Transgenic modeling of neurodegeneration in the CA2 zone of the hippocampus increases the relative area of tissue with increased permeability of blood-brain barrier (BBB) (17.80 [9.15; 36.75]) compared to control (1.38 [0.04; 7.60]) at p < 0.05. A similar difference (p < 0.05) is also observed in the hippocampal area CA1. A tendency (p > 0.05) to decrease the number of CD31+ endothelial cells in the dentate gyrus of the hippocampus (21.52 [17.56; 24.50]) in animals of the experimental group compared with the control group (23.08[21.18; 29.84]) was detected. A similar situation is observed in the CA2 and CA3 areas of the hippocampus.Conclusion. Neurodegenerative changes in the hippocampus of animals with a transgenic AD model are associated with impaired microcirculation in the brain tissue as a result of a reduction in the diameter and branching of blood vessels, and damage and increased permeability of BBB.Цель – изучение молекулярных механизмов нарушения структурно-функциональной целостности гематоэнцефалического барьера (ГЭБ) при хронической нейродегенерации  альцгеймеровского типа, ассоциированной с развитием церебральной ангипопатии. Материалы и методы. Опытная группа – генетическая модель болезни Альцгеймера (БА) – мыши линии B6SLJ -Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas, самцы в возрасте 9 мес. Контрольная группа – мыши линии C57BL/6 x SJL, самцы в возрасте 9 мес.Результаты. У животных с генетической моделью БА в зубчатой извилине гиппокампа  общая длина сосудов в 2,5 раза больше, чем у контрольной группы (p < 0,01), при этом  средний диаметр сосудов во всех областях гиппокампа меньше по сравнению с контролем (p < 0,05). Выявлено, что при генетическом моделировании  нейродегенерации в СА2 зоне гиппокампа наблюдается увеличение относительной  площади ткани с повышенной проницаемостью ГЭБ (17,80 [9,15;36,75]) по сравнению с контролем (1,38 [0,04;7,60]) при p < 0,05. Подобное различие (p < 0,05) наблюдается и в зоне СА1 гиппокампа. У животных опытной группы выявлена тенденция (p > 0,05) к снижению количества CD31+ эндотелиальных клеток в зубчатой извилине гиппокампа (21,52 [17,56; 24,50]) по сравнению с контролем (23,08 [21,18; 29,84]). Аналогичная ситуация наблюдается в зонах СА2 и СА3 гиппокампа.Заключение. Нейродегенеративные изменения в гиппокампе животных с генетической  моделью БА ассоциированы с нарушением микроциркуляции в ткани головного мозга в  результате сокращения диаметра и разветвленности сосудов, повреждения и повышения проницаемости ГЭБ

Analysis of the quality of life in patients with multiple sclerosis within 3 years after high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation

Introduction. To date, data have been accumulated indicating the high effectiveness of the HDIT-AHSCT and the possibility of preserving and improving the quality of life of patients after its application.The objective was to analyze the dynamics of quality of life using standardized assessment tools in patients with MS for 3 years after the use of HDIT-AHSCT, who participated in the program of clinical approbation of the method.Methods and materials. The single-center observational study included 21 patients (10 women, 11 men) with a reliable diagnosis of MS, who underwent HDIT-AHSCT at the Pavlov First Saint Petersburg State Medical Universityin accordance with the protocol of clinical approbation. Distribution by type of MS course: remitting (RMS) 16 (76.2 %), secondary progressive (SPMS) 4 (19 %), primary progressive (PPMS) 1 patient (4.8 %). The assessment of quality of life (SF-36, FAMS, CSP-MS42, HADS) and severity of disability (EDSS) in all patients was performed before, 12 and 36 months after HDIT-AHSCT.Results. Three years after the HDIT-AHSCT, a significant decrease in weakness, feelings of constant fatigue and rapid fatigue during exertion was recorded. The level of anxiety decreased in more than 50 % of patients. A direct relationship between the dynamics of clinical characteristics and the data of the scales of the SF-36 questionnaire was revealed; at the same time, after 36 months, an improvement in all parameters of the scale was noted.Conclusion. The assessment of the indicators of the quality of life questionnaires allows us to confirm the effectiveness and significance of therapy not only from the point of view of objective clinical and radiation parameters necessary for the evidence base of the treatment method, but also from the patient’s position, which in conditions of a chronic progressive process is an integral factor for the appointment of therapeutic intervention

Investigation the structure and properties of deformed semi-finished products produced from chips of Al–Mg alloys system alloyed with scandium

The article presents the results of studies that make it possible to solve the problem of processing secondary waste from expensive aluminum alloys without irretrievable loss of metal. For this purpose, tasks were set and solved for the development of technological schemes for obtaining longish deformed semi-finished products from chip waste of Al–Mg alloys 01570 and 1580 alloyed with scandium using methods of powder metallurgy and metal forming. For their experimental verification, the operations of chip briquetting, combined rolling-extrusion (continuous extrusion), sectional rolling, hot extrusion and drawing in combination with heat treatment were applied. According to these schemes, semi-finished products in the form of rods and wires were obtained. Structure and mechanical properties were investigated. It has been revealed that when hot-extruded rods are obtained from chip briquettes of alloy 01570 on a vertical hydraulic press, even with significant degrees of deformation during extrusion, the margin of plastic properties is small and makes it possible to obtain a wire with a diameter of only 4.2 mm after drawing. The processing of briquettes from 1580 alloy chips using the combined rolling-extrusion method makes it possible to obtain after cold deformation a wire with a diameter of up to 3 mm. At the same time, the influence of the annealing process on the structure and properties of deformed semi-finished products from the investigated alloys was studied. It is shown that due to the low plasticity of the investigated material cold working of the rods must be carried out with small degrees of deformation, alternating it with intermediate annealing according to the proposed regime. An analysis of the physical and mechanical properties of the wire obtained using combined processing showed that its strength and plastic properties are comparable to the properties of the wire obtained from a cast billet, and the structure is characterized by a high degree of elaboration and compactness. Thus, as a result of the research, technological schemes have been developed and processing parameters have been determined for the production of rods and wire from graded chip waste of alloys 01570 and 1580 using compaction, discrete and continuous extrusion, as well as cold drawing. © 2022 The AuthorsMinistry of Education and Science of the Russian Federation, Minobrnauka: FSRZ-2020-0013The research was carried out within the framework of the state assignment of the Ministry of Science and Higher Education of the Russian Federation (scientific theme code FSRZ-2020-0013)

ПРОГНОЗИРОВАНИЕ СВОЙСТВ МЕТАЛЛА ПРИ СОВМЕЩЕННОЙ ОБРАБОТКЕ СПЛАВОВ СИСТЕМЫ Al–РЗМ НА ОСНОВЕ ПОЭТАПНОЙ ОЦЕНКИ ИХ МЕХАНИЧЕСКИХ ХАРАКТЕРИСТИК

The data of experimental studies on determining the mechanical properties of long-length deformed semifinished products in a form of bars and wire made of alloys of aluminum with rare-earth metals, which are fabricated using the combined treatment methods, are presented. The application of the combined technology of casting, rolling, and pressing makes it possible to increase the strength of hot-extruded rod by 15–20 % on average compared with combined rolling–extruding the cast billet formed in an electromagnetic crystallizer. It is also shown that a decrease in the REM content in the alloy leads to the strength reduction and an increase in plastic characteristics. Herewith, it is possible to control the level of physicomechanical characteristics of the final product varying the summary deformation ratio during drawing and applying annealing.Приведены данные экспериментальных исследований по определению механических свойств длинномерных деформируемых полуфабрикатов в виде прутков и проволоки из сплавов алюминия с редкоземельными металлами, полученных с использованием методов совмещенной обработки. Применение совмещенной технологии литья, прокатки и прессования дает возможность увеличить прочность горячепрессованных прутков в среднем на 15–20 % по сравнению с совмещенными процессами прокатки и прессования литой заготовки, полученной в электромагнитном кристаллизаторе. Показано также, что уменьшение содержания РЗМ в сплаве приводит к снижению прочностных и повышению пластических характеристик. При этом, варьируя величиной суммарной степени деформации при волочении и применяя отжиги, можноуправлять уровнем физико-механических характеристик конечной продукции

DNA Methyltransferase Controls Stem Cell Aging by Regulating BMI1 and EZH2 through MicroRNAs

Epigenetic regulation of gene expression is well known mechanism that regulates cellular senescence of cancer cells. Here we show that inhibition of DNA methyltransferases (DNMTs) with 5-azacytidine (5-AzaC) or with specific small interfering RNA (siRNA) against DNMT1 and 3b induced the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) and increased p16INK4A and p21CIP1/WAF1 expression. DNMT inhibition changed histone marks into the active forms and decreased the methylation of CpG islands in the p16INK4A and p21CIP1/WAF1 promoter regions. Enrichment of EZH2, the key factor that methylates histone H3 lysine 9 and 27 residues, was decreased on the p16INK4A and p21CIP1/WAF1 promoter regions. We found that DNMT inhibition decreased expression levels of Polycomb-group (PcG) proteins and increased expression of microRNAs (miRNAs), which target PcG proteins. Decreased CpG island methylation and increased levels of active histone marks at genomic regions encoding miRNAs were observed after 5-AzaC treatment. Taken together, DNMTs have a critical role in regulating the cellular senescence of hUCB-MSCs through controlling not only the DNA methylation status but also active/inactive histone marks at genomic regions of PcG-targeting miRNAs and p16INK4A and p21CIP1/WAF1 promoter regions