Репозиторий Университета

© 2019 The Authors Emerging evidence indicates that dietary nitrate can reverse several features of the metabolic syndrome, but the underlying molecular mechanisms still remain elusive. The aim of the present study was to explore mechanisms involved in the effects of dietary nitrate on the metabolic dysfunctions induced by high-fat diet (HFD) in mice. Four weeks old C57BL/6 male mice, exposed to HFD for ten weeks, were characterised by increased body weight, fat content, increased fasting glucose and impaired glucose clearance. All these metabolic abnormalities were significantly attenuated by dietary nitrate. Mechanistically, subcutaneous primary mouse adipocytes exposed to palmitate (PA) and treated with nitrite exhibited higher mitochondrial respiration, increased protein expression of total mitochondrial complexes and elevated gene expression of the thermogenesis gene UCP-1, as well as of the creatine transporter SLC6A8. Finally, dietary nitrate increased the expression of anti-inflammatory markers in visceral fat, plasma and bone marrow-derived macrophages (Arginase-1, Egr-2, IL-10), which was associated with reduction of NADPH oxidase-derived superoxide production in macrophages. In conclusion, dietary nitrate may have therapeutic utility against obesity and associated metabolic complications possibly by increasing adipocyte mitochondrial respiration and by dampening inflammation and oxidative stress.

© Copyright © 2019 Veremeyko, Yung, Dukhinova, Strekalova and Ponomarev. Twenty years ago, the scientific community exhibited relatively little interest in the study of microglial cells. However, recent technical and conceptual advances in this field have greatly increased interest in the basic biology of these cells within various neurodegenerative diseases, including multiple sclerosis, Alzheimer’s disease, and traumatic brain/spinal cord injuries. The main functions of these cells in the normal central nervous system (CNS) remain poorly understood, despite considerable elucidation of their roles in pathological conditions. Microglia populate the brain before birth and remain in close lifelong contact with CNS-resident cells under the influence of the local microenvironment. Within the CNS parenchyma, microglia actively interact with two main cell types, astrocytes and neurons, which produce many factors that affect microglia phenotypes in the normal CNS and during neuroinflammation. These factors include interleukin (IL)-34, macrophage colony-stimulating factor, transforming growth factor-β, and IL-4, which promote microglial expansion, survival, and differentiation to an anti-inflammatory phenotype in the normal CNS. Under inflammatory conditions, however, astrocytes produce several pro-inflammatory factors that contribute to microglial activation. The interactions of microglia with neurons in the normal and diseased CNS are especially intriguing. Microglia are known to interact actively with neurons by facilitating axonal pruning during development, while neurons provide specific factors that alter microglial phenotypes and functions. This review focuses mainly on the roles of soluble neuronal factors that affect microglial phenotypes and functions and the possible involvement of these factors in the pathology of neurodegenerative diseases.

© 2019 by the authors. Acid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium's acidification, and it plays an important role in the excitation of neurons in the central nervous system. Ligands of the ASIC1a channel are of great interest, both fundamentally and pharmaceutically. Using a two-electrode voltage-clamp electrophysiological approach, we characterized lindoldhamine (a bisbenzylisoquinoline alkaloid extracted from the leaves of Laurus nobilis L.) as a novel inhibitor of the ASIC1a channel. Lindoldhamine significantly inhibited the ASIC1a channel's response to physiologically-relevant stimuli of pH 6.5-6.85 with IC50 range 150-9 μM, but produced only partial inhibition of that response to more acidic stimuli. In mice, the intravenous administration of lindoldhamine at a dose of 1 mg/kg significantly reversed complete Freund's adjuvant-induced thermal hyperalgesia and inflammation; however, this administration did not affect the pain response to an intraperitoneal injection of acetic acid (which correlated well with the function of ASIC1a in the peripheral nervous system). Thus, we describe lindoldhamine as a novel antagonist of the ASIC1a channel that could provide new approaches to drug design and structural studies regarding the determinants of ASIC1a activation.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Objectives. To study the relationship between the immune system and depression, as well as its endophenotypes (neuroticism and trait anxiety), in patients with ischemic heart disease (IHD). Materials and methods. Studies were performed in a group of men with IHD and depression (78 patients) and without depression (91 patients), as well as in healthy male volunteers (127 subjects). Polymorphisms of the interleukin-4 (IL-4 –589C/T), interleukin-6 (IL-6 –174G/C), tumor necrosis factor α (TNF-α –308G/A), and C-reactive protein (CRP –717A/G) genes were studied. Results. An association between the IL-6 –174G/C polymorphism with depression comorbid with IHD was found (p = 0.01, OR = 2.3, 95% CI = 1.2–4.3), which was apparent as an increase in the frequency of the highly expressed G allele in the group of patients with depression. The IL-4 –589C/T polymorphism was associated with IHD: the frequency of the CC IL-4 –589C/T genotype was greater in this group of patients than in the control group regardless of the presence of depression (p = 0.007, OR = 2.1, 95% CI = 1.2–3.4). The TNF-α –308G/A and CRP –717A/G polymorphisms were not associated with depression in IHD. There were no signifi cant differences in the expression of neuroticism or trait anxiety in carriers of different genotypes at the IL-4 –589C/T, IL-6 –174G/C, TNF-α –308G/A, or CRP –717A/G loci. Conclusions. The association between the IL-6 –174G/C polymorphism with depression comorbid with IHD is consistent with published data on the role of IL-6 in the depression of depression in cardiology patients.

© 2018 Elsevier Inc. Oxidative stress is a major contributor to secondary injury signaling cascades following traumatic brain injury (TBI). The role of lipid peroxidation in the pathophysiology of a traumatic insult to neural tissue is increasingly recognized. As the methods to quantify lipid peroxidation have gradually improved, so has the understanding of mechanistic details of lipid peroxidation and related signaling events in the injury pathogenesis. While free-radical mediated, non-enzymatic lipid peroxidation has long been studied, recent advances in redox lipidomics have demonstrated the significant contribution of enzymatic lipid peroxidation to TBI pathogenesis. Complex interactions between inflammation, phospholipid peroxidation, and hydrolysis define the engagement of different cell death programs and the severity of injury and outcome. This review focuses on enzymatic phospholipid peroxidation after TBI, including the mechanism of production, signaling roles in secondary injury pathology, and temporal course of production with respect to inflammatory response. In light of the newly identified phospholipid oxidation mechanisms, we also discuss possible therapeutic targets to improve neurocognitive outcome after TBI. Finally, we discuss current limitations in identifying oxidized phospholipids and possible methodologic improvements that can offer a deeper insight into the region-specific distribution and subcellular localization of phospholipid oxidation after TBI.

© Kolosova et al. P62/SQSTM1, a multi-domain protein that regulates inflammation, apoptosis, and autophagy, has been linked to age-related pathologies. For example, previously we demonstrated that administration of p62/SQSTM1- encoding plasmid reduced chronic inflammation and alleviated osteoporosis and metabolic syndrome in animal models. Herein, we built upon these findings to investigate effect of the p62-encoding plasmid on an agerelated macular degeneration (AMD), a progressive neurodegenerative ocular disease, using spontaneous retinopathy in senescence-accelerated OXYS rats, as a model. Overall, the p62DNA decreased the incidence and severity of retinopathy. In retinal pigment epithelium (RPE), p62DNA administration slowed down development of the destructive alterations of RPE cells, including loss of regular hexagonal shape, hypertrophy, and multinucleation. In neuroretina, p62DNA prevented gliosis, retinal thinning, and significantly inhibited microglia/macrophages migration to the outer retina, prohibiting their subretinal accumulation. Taken together, our results suggest that the p62DNA has a strong retinoprotective effect in AMD.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Objective. To study the association between the kynurenine-3-monooxygenase (KMO) gene and depression. Materials and methods. Polymorphic loci rs2275163 (C/T) and rs1053230 (A/G) of the KMO gene were studied in patients with depression (study group) and mentally healthy subjects of comparable gender and age (control group). Results and conclusions. The rs2275163 polymorphism was not associated with depression. An association between the rs1053230 polymorphism and depression was found. The frequency of the GG genotype, linked with lower KMO activity and increased kynurenic acid levels in patients with endogenous psychoses, was greater in the study group than the control group (p = 0.001, OR 2.8 (95% CI 1.73–4.24). thus, the GG genotype can be regarded as a risk allele for developing depression.

© 2018, Pediatria Ltd. All rights reserved. The article presents results of conjugated pneumococcal vaccine use in combination with basic therapy in 64 children with chronic compensated tonsillitis. The study showed that vaccination assists activation of T-lymphocytes subpopulation, increases sensitization to bacterial antigens, normalization of proinflammatory cytokines content, which is clinically manifested in a significant decrease in acute respiratory infections incidences and antibacterial therapy courses for 2 years after vaccination compared to patients receiving a traditional therapy course.

© 2018 Veremeyko, Yung, Dukhinova, Kuznetsova, Pomytkin, Lyundup, Strekalova, Barteneva and Ponomarev. Although it has been demonstrated that cAMP pathway affect both adaptive and innate cell functions, the role of this pathway in the regulation of T-cell-mediated central nervous system (CNS) autoimmune inflammation, such as in experimental autoimmune encephalomyelitis (EAE), remains unclear. It is also unclear how cAMP pathway affects the function of CD4 T cells in vivo at the site of inflammation. We found that adenylyl cyclase activator Forskolin besides inhibition of functions autoimmune CD4 T cells also upregulated microRNA (miR)-124 in the CNS during EAE, which is associated with M2 phenotype of microglia/macrophages. Our study further established that in addition to direct influence of cAMP pathway on CD4 T cells, stimulation of this pathway promoted macrophage polarization toward M2 leading to indirect inhibition of function of T cells in the CNS. We demonstrated that Forskolin together with IL-4 or with Forskolin together with IL-4 and IFNγ effectively stimulated M2 phenotype of macrophages indicating high potency of this pathway in reprogramming of macrophage polarization in Th2-and even in Th1/Th2-mixed inflammatory conditions such as EAE. Mechanistically, Forskolin and/or IL-4 activated ERK pathway in macrophages resulting in the upregulation of M2-associated molecules miR-124, arginase (Arg)1, and Mannose receptor C-type 1 (Mrc1), which was reversed by ERK inhibitors. Administration of Forskolin after the onset of EAE substantially upregulated M2 markers Arg1, Mrc1, Fizz1, and Ym1 and inhibited M1 markers nitric oxide synthetase 2 and CD86 in the CNS during EAE resulting in decrease in macrophage/microglia activation, lymphocyte and CD4 T cell infiltration, and the recovery from the disease. Forskolin inhibited proliferation and IFNγ production by CD4 T cells in the CNS but had rather weak direct effect on proliferation of autoimmune T cells in the periphery and in vitro, suggesting prevalence of indirect effect of Forskolin on differentiation and functions of autoimmune CD4 T cells in vivo. Thus, our data indicate that Forskolin has potency to skew balance toward M2 affecting ERK pathway in macrophages and indirectly inhibit pathogenic CD4 T cells in the CNS leading to the suppression of autoimmune inflammation. These data may have also implications for future therapeutic approaches to inhibit autoimmune Th1 cells at the site of tissue inflammation.

© 2018 Tuberculosis and Lung Diseases. All rights reserved. The article presents the review of latest studies devoted to assessment of the eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) and opportunities for differential therapy of stable COPD and COPD therapy during exacerbation. Currently, there is no final definition what threshold blood level of eosinophils can be used for decision making in clinical practice. The only thing found out was that the high blood level of eosinophils could be a predictor of the risk of frequent exacerbations and the effectiveness of treatment with glucocorticosteroids.

© 2018, Media Sphera Publishing Group. All rights reserved. Objective. To study the association between proinflammatory cytokine genes and depression. Material and methods. IL-1B С-511T and TNF-a G-308A gene polymorphisms were studied in patients diagnosed with depression and age and sex-matched healthy controls. Results and conclusion. The IL-1B С-511T and TNF-a G-308A polymorphisms were associated with depression; CC genotype (р=0,001, OR=1.9 CI 1,3—2,7) and GG genotype (р=0,001, OR=3,0 CI 1,8—4,9) were the risk factors. The results suggest that immune factors may play a role in the development of depression. The authors highlight the role of clinical polymorphism of depression that makes it difficult to form homogenous groups of patients and to select phenotypes for biological studies.

© 2018 Vitebsk State Medical University. All rights reserved. Objective: To study the ultrastructural changes in the liver mitochondria in experimental diffuse purulent peritonitis against the background of the metabolic support. Methods: The morphometric evaluation of the rabbit liver mitochondria electron microscopic images (n=55) was performed in experimental diffuse purulent peritonitis. The obtained electron diffraction patterns were estimated using the ImageJ 1.45s program, in which the number of mitochondria sections, the number of intermithochondrial contacts and the number of damaged and intact mitochondria were counted. The average area, perimeter, and specific volume (measured in %) were calculated for the undamaged mitochondrial profiles. Metabolic agents with energotropic properties, phosphocreatine preparations containing creatine phosphate and preparations containing the succinic acid, niacinamide, inosine diphosphate and riboflavin were used. Results: Electron microscopic analysis of mitochondria of hepatocytes made it possible to reveal significant changes in their structure, caused by the development of purulent peritonitis. Morphometric evaluation of electron diffraction patterns showed changes in the quantitative and qualitative characteristics of mitochondria: the ratio of the damaged and intact mitochondria, their size, perimeter and specific volume of all groups. The use of metabolic support permitted to reduce the negative effect of purulent peritonitis in the postoperative period, which is exerted on the liver mitochondria, in comparison with the control group of animals that did not receive any metabolic support. Conducting a comparative analysis revealed a higher efficacy of the metabolic agent containing the succinic acid, niacinamide, inosine diphosphate and riboflavin, which resulted in more intensive restoration of the mitochondrial membrane structure. Conclusions: The development of purulent peritonitis is accompanied by a violation of the ultrastructural organization of the liver mitochondria in all studied groups. Metabolic correction allows restoring the membrane structure of mitochondria, and as the result improving the energy supply of cells to combat the negative consequences of endotoxicosis in peritonitis.

© 2018, Dynasty Publishing House. All rights reserved. We analysed the association between levels of various cytokines and specificities of the clinical course and severity of toxic syndrome in pregnant women with influenza А(H1N1)pdm09, complicated by pneumonia. Cytokines reduce the sensitivity of the warm receptors and increase that of the cold receptors, which is regarded by patients as episodes of chills. According to correlation analysis data, IL-6 has the largest direct correlation with the persistence of fever, whereas interrelations between other cytokines and persistence of higher temperature proved to be less significant. It is noteworthy that elevated IL-6 levels lead to impairment of sleep architecture, which contributes to increased and persistent weakness, drowsiness. As has been shown, persistence of cough is to a significant degree determined by correlations between the levels of such cytokines, as TNF-α, IL-4 and IL-8. We assessed correlations between individual signs of systemic inflammatory response syndrome (SIRS) and cytokine levels. In diagnosing SIRS according to procalcitonin levels in viral-bacterial pneumonia 3 significant correlations were found (association with IL-8 – 0.72, TNF-α – 0.76 and IL-6 – 0.66). In pregnant women with pneumonia, generalised inflammatory process and a subsequent development of SIRS lower levels of the anti-inflammatory cytokine IL-4 have been found. A quantitative correlational approach to assessment of cytokine interrelationships has been proposed, permitting to differentiate between uncomplicated and complicated forms of influenza.

[This corrects the article DOI: 10.3389/fimmu.2018.02515.].

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.

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.