Репозиторий Университета

Studies on the methods of nanoparticle (NP) synthesis, analysis of their characteristics, and exploration of new fields of their applications are at the forefront of modern nanotechnology. The possibility of engineering water-soluble NPs has paved the way to their use in various basic and applied biomedical researches. At present, NPs are used in diagnosis for imaging of numerous molecular markers of genetic and autoimmune diseases, malignant tumors, and many other disorders. NPs are also used for targeted delivery of drugs to tissues and organs, with controllable parameters of drug release and accumulation. In addition, there are examples of the use of NPs as active components, e.g., photosensitizers in photodynamic therapy and in hyperthermic tumor destruction through NP incorporation and heating. However, a high toxicity of NPs for living organisms is a strong limiting factor that hinders their use in vivo. Current studies on toxic effects of NPs aimed at identifying the targets and mechanisms of their harmful effects are carried out in cell culture models; studies on the patterns of NP transport, accumulation, degradation, and elimination, in animal models. This review systematizes and summarizes available data on how the mechanisms of NP toxicity for living systems are related to their physical and chemical properties.

Biological effects of hormones in both plants and animals are based on high-affinity interaction with cognate receptors resulting in their activation. The signal of cytokinins, classical plant hormones, is perceived in Arabidopsis by three homologous membrane receptors: AHK2, AHK3, and CRE1/AHK4. To study the cytokinin-receptor interaction, we used 25 derivatives of potent cytokinin N6-benzyladenine (BA) with substituents in the purine heterocycle and/or in the side chain. The study was focused primarily on individual cytokinin receptors from Arabidopsis. The main in planta assay system was based on Arabidopsis double mutants retaining only one isoform of cytokinin receptors and harboring cytokinin-sensitive reporter gene. Classical cytokinin biotest with Amaranthus seedlings was used as an additional biotest. In parallel, the binding of ligands to individual cytokinin receptors was assessed in the in vitro test system. Quantitative comparison of results of different assays confirmed the partial similarity of ligand-binding properties of receptor isoforms. Substituents at positions 8 and 9 of adenine moiety, elongated linker up to 4 methylene units, and replacement of N6 by sulfur or oxygen have resulted in the suppression of cytokinin activity of the derivative toward all receptors. Introduction of a halogen into position 2 of adenine moiety, on the contrary, often increased the ligand activity, especially toward AHK3. Features both common and distinctive of cytokinin receptors in Arabidopsis and Amaranthus were revealed, highlighting species specificity of the cytokinin perception apparatus. Correlations between the extent to which a compound binds to a receptor in vitro and its ability to activate the same receptor in planta were evaluated for each AHK protein. Interaction patterns between individual receptors and ligands were rationalized by structure analysis and molecular docking in sensory modules of AHK receptors. The best correlation between docking scores and specific binding was observed for AHK3. In addition, receptor-specific ligands have been discovered with unique properties to predominantly activate or block distinct cytokinin receptors. These ligands are promising for practical application and as molecular tools in the study of the cytokinin perception by plant cells.

BACKGROUND:

The 2013 International Classification of Headache Disorders-3 (ICHD-3) was published in a beta version to allow the clinicians to confirm the validity of the criteria or to suggest improvements based on field studies. The aim of this work was to review the Primary Headache Disorders Section of ICHD-3 beta data on children and adolescents (age 0-18 years), and to suggest changes, additions, and amendments.

METHODS:

Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the literature available on pediatric headache, they made observations and proposed suggestions for the primary headache disorders section of ICHD-3 beta data on children and adolescents.

RESULTS:

Some headache disorders in children have specific features which are different from those seen in adults and which should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psycho-social basis in children and adolescents making primary headache disorders in children distinct from those in adults.

CONCLUSIONS:

Several recommendations are presented in order to make ICHD-3 more appropriate for use with children.

Acetylcholinesterase inhibitors are widely used for a variety of medical, agricultural and public health purposes. Consequently, exposure is highly possible during lifetime. However, their systematic use raises concerns for the potential impact on the fetus and newborn since these substances may affect angiogenesis, the neonatal and maternal intensive care, neuroimmune function and response, mammary growth/lactation via cholinergic/non-cholinergic central and peripheral neuroendocrine pathways. New methodologies, neuroscientific technologies and research studies are needed to harness existing knowledge along with the proper management, availability for new acetylcholinesterase inhibitors, with stable pharmacodynamics and clinical outcomes.

Ischemic Heart Disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect and manipulating their cardiomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June 2018.

Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come. View Full-Text

The heme in the active center of peroxidases reacts with hydrogen peroxide to form highly reactive intermediates, which then oxidize simple substances called peroxidase substrates. Human peroxidases can be divided into two groups: (1) True peroxidases are enzymes whose main function is to generate free radicals in the peroxidase cycle and (pseudo)hypohalous acids in the halogenation cycle. The major true peroxidases are myeloperoxidase, eosinophil peroxidase and lactoperoxidase. (2) Pseudo-peroxidases perform various important functions in the body, but under the influence of external conditions they can display peroxidase-like activity. As oxidative intermediates, these peroxidases produce not only active heme compounds, but also protein-based tyrosyl radicals. Hemoglobin, myoglobin, cytochrome c/cardiolipin complexes and cytoglobin are considered as pseudo-peroxidases. Рeroxidases play an important role in innate immunity and in a number of physiologically important processes like apoptosis and cell signaling. Unfavorable excessive peroxidase activity is implicated in oxidative damage of cells and tissues, thereby initiating the variety of human diseases. Hence, regulation of peroxidase activity is of considerable importance. Since peroxidases differ in structure, properties and location, the mechanisms controlling peroxidase activity and the biological effects of peroxidase products are specific for each hemoprotein. This review summarizes the knowledge about the properties, activities, regulations and biological effects of true and pseudo-peroxidases in order to better understand the mechanisms underlying beneficial and adverse effects of this class of enzymes. View Full-Text

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

Osteoarthritis (OA), the most common form of arthritis, is characterized by inflammation of joints and cartilage degradation leading to disability, discomfort, severe pain, inflammation, and stiffness of the joint. It has been shown that adenosine, a purine nucleoside composed of adenine attached to ribofuranose, is enzymatically produced by the human synovium. However, the functional significance of adenosine signaling in homeostasis and pathology of synovial joints remains unclear. Adenosine acts through four cell surface receptors, i.e., A1, A2A, A2B, and A3, and here, we have systematically analyzed mice with a deficiency for A3 receptor as well as pharmacological modulations of this receptor with specific analogs. The data show that adenosine receptor signaling plays an essential role in downregulating catabolic mechanisms resulting in prevention of cartilage degeneration. Ablation of A3 resulted in development of OA in aged mice. Mechanistically, A3 signaling inhibited cellular catabolic processes in chondrocytes including downregulation of Ca2+/calmodulin-dependent protein kinase (CaMKII), an enzyme that promotes matrix degradation and inflammation, as well as Runt-related transcription factor 2 (RUNX2). Additionally, selective A3 agonists protected chondrocytes from cell apoptosis caused by pro-inflammatory cytokines or hypo-osmotic stress. These novel data illuminate the protective role of A3, which is mediated via inhibition of intracellular CaMKII kinase and RUNX2 transcription factor, the two major pro-catabolic regulators in articular cartilage.

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs. View Full-Text

Autophagy is an evolutionary conserved intracellular catabolic process of vital importance to cell and tissue homeostasis. Autophagy is implicated in the pathogenesis of atherosclerosis but participating cells, molecular mechanisms and functional outcomes have not been fully elucidated. T-cadherin, an atypical glycosylphosphatidylinositol-anchored member of the cadherin superfamily of adhesion molecules, is upregulated on smooth muscle cells (SMCs)¹ in atherosclerotic lesions. Here, using rat and murine aortic SMCs as experimental models, we surveyed the ability of T-cadherin to regulate autophagy in SMCs during serum-starvation stress. Ectopic upregulation of T-cadherin in SMCs resulted in augmented autophagy characterized by increased autophagic flux, LC3-II abundance and autophagosome formation. Analysis of signal transduction pathway effectors and use of specific pharmacological inhibitors demonstrated that T-cadherin-associated enhancement of the autophagic response to serum-deprivation was dependent on MEK1/2/Erk1/2 activation and independent of PI3K/Akt/mTORC1, reactive oxygen species or endoplasmic reticulum stress. T-cadherin upregulation on SMCs conferred a survival advantage during prolonged serum-starvation which was sensitive to inhibition of MEK1/2/Erk1/2 by PD98059 or UO126 and to blockade of autophagy by chloroquine. Loss of T-cadherin expression in SMCs diminished autophagy responsiveness and compromised survival under conditions of serum-starvation. Overall our findings have identified T-cadherin as a novel positive regulator of autophagy and survival in SMCs.

Цель исследования. Изучение связи между генами иммунной системы и депрессией, а также ее эндофенотипами (невротизм и личностная тревожность) при ишемической болезни сердца (ИБС). Материал и методы. Исследование проведено в группе мужчин с ИБС с депрессией (78 человек) и без нее (91 человек), а также у здоровых добровольцев мужского пола (127 человек). Изучены полиморфизмы генов интерлейкина-4 (IL-4 –589C/T), интерлейкина-6 (IL-6 –174G/C), фактора некроза опухолей-α (TNF-α –308G/A) и С-реактивного белка (CRP –717A/G). Результаты. Обнаружена ассоциация полиморфизма IL-6 –174 G/C с депрессией, коморбидной ИБС (р=0,01; ОШ=2,3 ДИ 95% 1,2—4,3), которая выражалась в повышении частоты высокоэкспрессивного аллеля G в группе больных с депрессией. Полиморфизм IL-4 –589C/T был ассоциирован с ИБС: частота генотипа СС IL-4 –589C/T была выше в группе больных по сравнению с контрольной группой независимо от наличия депрессии (р=0,007; ОШ=2,1 ДИ 95% 1,2—3,4). Полиморфизмы TNF-α –308G/A и CRP –717A/G не были ассоциированы с депрессией при ИБС. Значимых различий в выраженности невротизма и личностной тревожности у носителей различных генотипов по локусам IL-4 –589 C/T, IL-6 –174 G/C, TNF-α –308 G/A, CRP –717A/G выявлено не было. Заключение. Ассоциация полиморфизма IL-6 –174G/C с депрессией, коморбидной ИБС, согласуется с данными литературы о роли IL-6 в развитии депрессии у кардиологических больных.

The present study investigates the hepatoprotective effect of a novel zinc-containing drug acyzol in comparison with silymarin, a medicinal extract of milk thistle (Silybum marianum). The hepatoprotective effect was studied in 40 albino nonlinear male rats in a model of toxic liver injury induced by intragastric administration of carbon tetrachloride. Both drugs were diluted in water and administered intragastrically at doses 10 mg/kg (acyzol) and 100 mg/kg (silymarin) for 10 days twice daily, after development of clinical toxic hepatitis. Biochemical and functional indicators of the liver parenchyma demonstrated that both drugs reduced mortality, normalized the body and relative liver weight, reduced intensity of cytolytic, cholestatic, and mesenchymal inflammatory syndromes, and restored liver function. The study demonstrates that acyzol and silymarin have comparable hepatoprotective effect, thus, providing a rationale for the use of acyzol in complex therapy of toxic hepatitis and hepatosis.

One the current challenges of modern hepatology is to find new approaches to stimulate liver regeneration and to find new methods for liver disease treatment. Cell therapies, which are based on using regional stem cells for disease treatment, are under active development. However, studies, devoted to their transplantation, are currently scarce. In recent years, hepatic stellate cells are considered to be hepatic stem cells. It is known that activated hepatic stellate cells can transdifferentiate into myofibroblasts and lead to liver fibrosis. The aim of our work was to study the influence of native and activated hepatic stellate cells in vivo by lead nitrate injection after transplantation into partial hepatectomized rats, which is considered to be a classical model to study liver regeneration. Injection of 2-acetylaminofluorene (AAF), which selectively eliminates hepatocyte proliferation, was used to understand the hepatic stellate cells role in liver regeneration process better. Our results suggest that transplanted native and activated hepatic stellate cells can differentiate into hepatocyte-like cells and positively influence liver regeneration without inducing liver fibrosis.

Изучено влияние лектинов растительного происхождения на цитотоксическую активность мононуклеаров периферической крови (МНПК) здоровых доноров. Установлено, что лектин гороха вызывает статистически значимый цитотоксический эффект МНПК по отношению к клеткам колоректального рака.

Авторами рассмотрены современные аспекты лечения неспецифического аортоартериита (НАА) у детей. Освещены вопросы патогенеза, клинической картины, основных принципов лечения болезни Такаясу в детском возрасте, подходы к оценке эффективности и безопасности проводимой базисной терапии. Представлены алгоритм базисной терапии детей с НАА и проблемы хирургического лечения. Наиболее эффективным является комплексный подход к лечению, подразумевающий назначение в активной фазе заболевания противоспалительной иммуносупрессивной терапии глюкокортикостероидами и цитостатиками, а при неэффективности - использование генно-инженерной биологической терапии.

Повышение активности ренин-ангиотензин-альдостероновой системы - один из важнейших механизмов реализации сердечно-сосудистого континуума. Рассматривается роль, которую блокаторы рецепторов ангиотензина играют в достижении целевых цифр артериального давления и снижении сердечно-сосудистого риска. Освещается значение плейотропных свойств блокаторов рецепторов ангиотензина (в частности, активации гамма рецепторов, активируемых пероксисомными пролифераторами - PPAR-y) в ведении больных с инсулинорезистентностью, ожирением, дислипидемией. Обсуждается доказательная база применения телмисартана как препарата, обладающего плейотропным действием, у больных с артериальной гипертензией и сочетанными заболеваниями (сахарный диабет, ожирение, нарушение функции почек).

C целью повышения эффективности хирургического лечения больных с травматическими стенозами гортани разработан алгоритм выбора оперативной тактики, который включает антропометрию пациента — определение варианта шеи и телосложения, построение регрессионных моделей значимых ларингометрических параметров, выбор оптимальной технологии ларингопластики в зависимости от клинических данных — размеров голосовой щели и положения голосовых складок пациента; расчет размеров аутотрансплантата и длины Т-образной трубки, основанный на математическом анализе антропо- и органометрических характеристик пациента; ларинготрахеопластику и протезирование сформированного гортанно-трахеального просвета. Проведено обследование 71 пациента от 23 до 68 лет с хроническими паралитическими (31%) и сочетанными (69%) стенозами гортани с применением компьютерной томографии гортани и трахеи, антропометрического, эндоскопического и спирометрического методов. Больным проведено лечение по следующим методикам: экстраларингеальная латерофиксация голосовой складки (n=22); экстраларингеальная латерофиксация голосовой складки со стентированием Т-образной силиконовой трубкой (n=43); рассечение рубцов после предыдущих ларингопластик с редрессацией перстневидного хряща и стентированием гортани (n=6). В результате хирургического лечения по разработаному алгоритму с учетом варианта шеи и телосложения реабилитированы 68 (95,8%) пациентов с хроническими паралитическими и сочетанными стенозами гортани.

Цель работы — совершенствование диагностики и лечения односторонних параличей возвратных гортанных нервов с преходящим рефлекторным спазмом функционирующей голосовой складки. Проведено обследование и лечение 49 больных (46 женщин и 3 мужчин) в возрасте от 21 года до 75 лет с односторонним параличом возвратного гортанного нерва и преходящим рефлекторным спазмом функционирующей голосовой складки, возникшим вследствие операции на щитовидной железе. Для диагностики и объективизации результатов лечения проводились электромиографический тест на скрытую тетанию, исследование уровня ионизированного кальция крови и видеоларингостробоскопия. Лечение включало дыхательную гимнастику, рефлексотерапию (новокаиновые блокады зон Захарьина—Геда для гортани, аурикулотерапию), медикаментозную терапию (витаминно-кальциевая терапия, миорелаксанты и седативные препараты), фонопедию. У всех 49 больных был восстановлен достаточно громкий и звучный голос, а также нормализовано дыхание и прекращены или минимизированы приступы рефлекторного кашля и ларингоспазмы. Ни одному больному в дальнейшем не потребовалось проведение трахеотомии.