Mononuclear phagocyte system. Development and activation of macrophages

Traditionally mononuclear phagocyte system was considered as a system that provides mostly the reactions of immune response, but more recently with enough data been accumulated, the understanding of its functions extended greatly. With the new experimental data, the change in ideas about the origin and even the composition of the cells in the system was occurred. The review is devoted to actual topic—the formation of mononuclear phagocyte system. Special attention is given to monocytes and macrophage's activation as the modulator of their future functions. The review article is based on the data from contemporary works.Традиционно система фагоцитирующих мононуклеаров рассматривается как система, обеспечивающая, прежде всего, реакции иммунного ответа, однако в последнее время накопилось достаточное количество данных, расширяющих представления о ее функциях. С появлением нового экспериментального материала, меняются и представления о происхождении и даже составе клеток, входящих в систему. Данный обзор посвящен основным особенностям образования клеток системы. Особое внимание уделяется свойствам и направлению развития моноцитов крови и системе активации макрофагов, как основному процессу, модулирующей их функции. Обзор базируется на данных экспериментальных и клинических работ

Effects of 1,3,4-thiadiazine compound with antidepressant properties in ligation model of acute pancreatitis

Based on hypotheses concerning the role of stress in acute pancreatitis development, the experimental approach for the decrease stress damage via the use the compound with proven antistress/neuroleptic action was conducted. The study was aimed to discover 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrobromide (compound L-17) therapeutic action in experimental acute pancreatitis. The experimental model used was the ligation model. The trial was carried out on 50 male Wistar rats with average body weight 180-240g. Histological picture of the pancreas was studied and biochemical and enzyme-immunoassays were carried out on the first and seventh days. The significant reduction in mortality on the background of L-17 compound administration was observed. While levels of all cytokines increased in induced experimental acute pancreatitis groups, the cytokine level rise was decreased when compound L-17 was administered. On the cellular level, the study revealed L-17’s ability to prevent granulocytosis and decrease granulocytes infiltration to inflammatory foci. The decrease in inflammatory reaction magnitude and prevention of abscess formation in experimental acute pancreatitis accompanied by sistemic inflamamtion was due to L-17’s ability to reduce neutrophilia and neutrophil entry into the injury zone. © 2018, Slovak Academy of Sciences. All rights reserved.Government Council on Grants, Russian FederationMinistry of Education and Science of the Russian Federation, Minobrnauka: 17.7255.2017/8.9AAAA-A18-118020690020-1Funding information. Partly the study was supported by the Act 211 of the Government of Russian Federation, contract No 02.A03.21.0006; Government contract of Russian Federation with Institute of Immunology and Physiology (AAAA-A18-118020690020-1) and the Ministry of Education and Science of the Russian Federation (# 17.7255.2017/8.9)

Pharmacologic Evaluation of Antidepressant Activity and Synthesis of 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine Hydrobromide

Substituted thiadiazines exert a reliable therapeutic effect in treating stress, and a schematic description of their ability to influence all aspects of a stress response has been depicted. This study was conducted to pharmacologically evaluate compound L-17, a substituted thiadiazine, (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide) for possible anti-psychotic/antidepressant activity. Compound L-17 was synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide. Pharmacologic evaluations were conducted using methods described by E.F. Lavretskaya (1985), and in accordance with published guidelines for studying drugs for neuroleptic activity. Compound L-17 was evaluated for various possible mechanisms of action, including its effects on cholinergic system agonists/antagonists, dopaminergic neurotransmission, the adrenergic system, and 5-HT3 serotonin receptors. One or more of these mechanisms may be responsible for the beneficial effects shown by thiadiazine compounds in experiments conducted to evaluate their activity in models of acute stress and acute myocardial infarction

Immunomodulatory Action of Substituted 1,3,4-Thiadiazines on the Course of Myocardial Infarction

This review focuses on the biological action of the compounds from the group of substituted 1,3,4-thiadiazines on stress response and myocardial infarction. The aim of this review is to propose the possible mechanisms of action of 1,3,4-thiadiazines and offer prospectives in the development of new derivatives as therapeutic agents. It is known, that compounds that have biological effects similar to those used as antidepressants can down-regulate the secretion of proinflammatory cytokines, up-regulate the release of anti-inflammatory ones and affect cell recruitment, which allows them to be considered immunomodulators as well. The results of pharmacological evaluation, in silico studies, and in vivo experiments of several compounds from the group of substituted 1,3,4-thiadiazines with antidepressant properties are presented. It is proposed that the cardioprotective effects of substituted 1,3,4-thiadiazines might be explained by the peculiarities of their multi-target action: the ability of the compounds to interact with various types of receptors and transporters of dopaminergic, serotonergic and acetylcholinergic systems and to block the kinase signal pathway PI3K-AKT. The described effects of substituted 1,3,4-thiadiazines suggest that it is necessary to search for a new agents for limiting the peripheral inflammatory/ischemic damage through the entral mechanisms of stress reaction and modifying pro-inflammatory cytokine signaling pathways in the brain

Combined in Silico, Ex Vivo, and in Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro-and Cardioprotective and Antidepressant Effects

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepres-sants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobro-mide (L-17), a recently designed thiadiazine derivative with putative neuro-and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreac-tivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro-and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Funding: The work of the authors of this study was supported by the Slovak Research and Development Agency (contract APVV-19-0435), Scientific Grant Agency of the Ministry of Education of the Slovak Republic, the Slovak Academy of Sciences (grant VEGA 2/0046/18), and a Government Contract of the Russian Federation with the Institute of Immunology and Physiology (AAAA-A18-118020690020-1)

Correction of hemocoagulation abnormalities in experimental pancreatic necrosis

The goal of the study lies in researching the possibility of influence of compound “L-17", from the group of substituted 5R1,6H2-1,3,4-thiadiazine-2-amines, on the process of acute inflammation reaction in experimental pancreatic necrosis on the indices of hemocoagulation. An experimental model of pancreatic necrosis has been reproduced on rats. The results let us assert that the compound “L-17” has high efficiency when curing an experimental pancreatic necrosis. It has been proved by prevention of the progression of Disseminated Intravascular Coagulation syndrome.Цель работы заключалась в изучении воздействия соединения « И 7» из группы замещённых 5R116Н2-1,3,4-тиадиазин2-аминов на течение острой воспалительной реакции при экспериментальном панкреонекрозе по пока-зателям гемокоагуляции. Экспериментальная модель панкреонекроза воспроизведена на крысах. Полученные результаты позволяют судить о высокой эффективности соединения «L-17» при лечении экспериментального панкреонекроза, что подтверждается предупреждением развития ДВС-синдрома

Post-COVID immunopatology syndrome: characteristics of phenotypical changes in the immune system in post-COVID patients

This study examines the long-term effects of SARS-CoV-2 infection on immune status. Given the prolonged and profound immune dysregulation observed during acute SARS-CoV-2 infection, it remains to be determined whether these changes translate into subsequent immune system dysfunction in recovering individuals. In this sense, the aim of the study was to study the parameters of the immune system in patients who had undergone SARS-CoV-2 infection. 150 patients who underwent SARS-CoV-2 infection were examined according to 96 parameters using flow cytometry. A complete blood count was performed using a Medonic device (Sweden); ELISA method determined the levels of general and specific IgM, IgG, IgA, compliment fragments (JSC Vector-Best, Russia). The activity of the phagocytes was studied according to the generally accepted method. The study found that at least four phenotypes of immune system disorders are detected in patients. The first two phenotypes are related to the impairment of innate immune system factors and are associated with a decrease in the number of CD46+ and NK cells. It has been observed that a decrease in CD46+ persists for a long time in a significant number of recovered patients, highlighted by the impaired expression of this marker in various subpopulations of lymphocytes. The decrease in the level of natural killers was accompanied by a compensatory increase in the number of T lymphocytes, mainly due to T helpers and TNK lymphocytes, and the growth of total memory B cells. Two other identified phenotypes are characterized by damage to acquired immune response factors and are associated with damage to B cells and T cytotoxic cells. The relationship of such disorders with damage to hematopoiesis erythrocyte and platelet sprouts, which contribute to the appearance of hypoxia and possible violation of the blood coagulation system, has been shown. Therefore, the results obtained indicate a long-term pronounced damage to the immune system in postCOVID patients that requires immunocorrection of these disorders

Way of decreasing the level of endogenous intoxication syndrome in experimental pancreatonecrosis

The goal of the study lies in researching the possibility of influence of compound “L-17”, from the group of substituted 5R1,6H2-1,3,4-thiadiazine-2-amines, on the process of acute inflammation reaction in experimental pancreatic necrosis on the intensity of endogenous intoxication syndrome. An experimental model of pancreatic necrosis has been reproduced on rats. The results let us assert that the compound “L-17" has high efficiency when curing an experimental pancreatic necrosis. It has been proved by reduction of endointoxication.Цель работы заключалась в оценке возможности воздействия соединением «L-17» из группы замещённых 5R1, 6Н2-1,3,4-тиадиазин-2-аминов на выраженность синдрома эндогенной интоксикации при экспериментальном панкреонекрозе, воспроизведенном на крысах. Оценку уровня выраженности синдрома эндогенной интоксикации проводили на основе определения связывающей способности альбумина и концентрации веществ низкой и средней молекулярной массы в динамике эксперимента. Полученные в эксперименте результаты позволяют судить о высокой эффективности воздействия соединением «L-17» на снижение уровня эндогенной интоксикации