Research Center for Childrens Health

Moscow, Russia

Research Center for Childrens Health

Moscow, Russia
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Chistiakov D.A.,Mount Sinai Comprehensive Cancer Center | Chistiakov D.A.,Research Center for Childrens Health | Orekhov A.N.,Russian Academy of Sciences | Bobryshev Y.V.,University of New South Wales | Bobryshev Y.V.,University of Western Sydney
Current Pharmaceutical Design | Year: 2016

Multiple pathogenic mechanisms contribute to the development of colorectal cancer. This tumor is characterized by high chemoresistance and low immunogenicity due to the effective mechanisms of immunosuppression. Dendritic cells (DCs) play a key role in recognition of tumor antigens and induction of T-cell-primed anticancer response. However, in cancer microenvironment, the function of tumor-infiltrating DCs becomes impaired and switched from the immunostimulation to the immunosuppression. Colorectal cancer cells express anti-inflammatory cytokines such as IL-10 and TGF-β that could affect DC phenotype and support tumor escape from the immune surveillance. As a result, tumor-associated DCs display numerous defects in antigen-presenting capacity and have an altered pattern of expression of immune costimulatory molecules towards the immunoregulatory phenotype. Indeed, understanding of mechanisms, such as how tumor could impair activity of DCs, would help in the development of new DC-based vaccines against colorectal cancer. © 2016 Bentham Science Publishers.


Chistiakov D.A.,Mount Sinai Comprehensive Cancer Center | Chistiakov D.A.,Research Center for Childrens Health | Orekhov A.N.,Russian Academy of Sciences | Bobryshev Y.V.,University of New South Wales | Bobryshev Y.V.,University of Western Sydney
Cellular and Molecular Life Sciences | Year: 2015

Circulating extracellular vesicles (EVs) comprise a heterogeneous population of vesicular structures. According to the current paradigm, there are three types of EVs, including exosomes, microvesicles and apoptotic bodies, that are differentiated in their size, formation, and release mechanisms. EVs were shown to act as a 'post service' that serves a long-distance delivery of complex cellular messages. The cargo of EVs consists of a variety of biomolecules including proteins, DNA, mRNA, and non-coding RNA. In normal or pathological conditions, EVs deliver various molecules to the recipient cells. Those molecules greatly vary depending on the microenvironmental stimuli. In proinflammatory conditions such as atherosclerosis and other cardiovascular diseases, EVs derived from vascular endothelial cells, vascular smooth muscle cells, macrophages, and other circulating immune cells mainly possess proinflammatory properties. However, the capacity of circulating EVs to stably maintain and deliver a variety of biomolecules makes these microparticles to be a promising therapeutic tool for treatment of cardiovascular pathology. To date, circulating EVs were evaluated to be as a source of valuable diagnostic and prognostic biomarkers such as microRNA. Circulating EVs keep a great therapeutic potential to serve as vehicles for targeted therapy of cardiovascular diseases. © 2015 Springer Basel.


Chistiakov D.A.,Moscow State University | Chistiakov D.A.,Research Center for Childrens Health | Sobenin I.A.,Russian Academy of Medical Sciences | Orekhov A.N.,Russian Academy of Medical Sciences | And 2 more authors.
Immunobiology | Year: 2015

Myeloid dendritic cells (mDCs) comprise a heterogeneous population of professional antigen-presenting cells, which are responsible for capture, processing, and presentation of antigens on their surface to T cells. mDCs serve as a bridge linking adaptive and innate immune responses. To date, the development of DC lineage in bone marrow is better characterized in mice than in humans. DCs and macrophages share the common myeloid progenitor called macrophage-dendritic cell progenitor (MDP) that gives rise to monocytoid lineage and common DC progenitors (CDPs). CDP in turn gives rise to plasmacytoid DCs and predendritic cells (pre-mDCs) that are common precursor of myeloid CD11b+ and CD8α+ DCs. The development and commitment of mDCs is regulated by several transcription and hematopoietic growth factors of which CCr7, Zbtb46, and Flt3 represent 'core' genes responsible for development and functional and phenotypic maintenance of mDCs. mDCs were shown to be involved in the pathogenesis of many autoimmune and inflammatory diseases including atherosclerosis. In atherogenesis, different subsets of mDCs could possess both proatherogenic (e.g. proinflammatory) and atheroprotective (e.g. anti-inflammatory and tolerogenic) activities. The proinflammatory role of mDCs is consisted in production of inflammatory molecules and priming proinflammatory subsets of effector T cells. In contrast, tolerogenic mDCs fight against inflammation through arrest of activity of proinflammatory T cells and macrophages and induction of immunosuppressive regulatory T cells. Microenvironmental conditions trigger differentiation of mDCs to acquire proinflammatory or regulatory properties. © 2015 Elsevier GmbH.


Chistiakov D.A.,Moscow State University | Chistiakov D.A.,Research Center for Childrens Health | Bobryshev Y.V.,University of New South Wales | Bobryshev Y.V.,University of Western Sydney | And 4 more authors.
Frontiers in Microbiology | Year: 2014

The mucosal barriers are very sensitive to pathogenic infection, thereby assuming the capacity of the mucosal immune system to induce protective immunity to harmful antigens and tolerance against harmless substances. This review provides current information about mechanisms of induction of mucosal tolerance and about impact of gut microbiota to mucosal tolerance. © 2014 Chistiakov, Bobryshev, Kozarov, Sobenin and Orekhov.


Chistiakov D.A.,Moscow State University | Chistiakov D.A.,Research Center for Childrens Health | Orekhov A.N.,Russian Academy of Sciences | Bobryshev Y.V.,University of New South Wales | Bobryshev Y.V.,University of Western Sydney
Acta Physiologica | Year: 2015

Atherosclerosis is a continuous pathological process that starts early in life and progresses frequently to unstable plaques. Plaque rupture leads to deleterious consequences such as acute coronary syndrome, stroke and atherothrombosis. The vulnerable lesion has several structural and functional hallmarks that distinguish it from the stable plaque. The unstable plaque has large necrotic core (over 40% plaque volume) composed of cholesterol crystals, cholesterol esters, oxidized lipids, fibrin, erythrocytes and their remnants (haeme, iron, haemoglobin), and dying macrophages. The fibrous cap is thin, depleted of smooth muscle cells and collagen, and is infiltrated with proinflammatory cells. In unstable lesion, formation of neomicrovessels is increased. These neovessels have weak integrity and leak thereby leading to recurrent haemorrhages. Haemorrhages deliver erythrocytes to the necrotic core where they degrade promoting inflammation and oxidative stress. Inflammatory cells mostly presented by monocytes/macrophages, neutrophils and mast cells extravagate from bleeding neovessels and infiltrate adventitia where they support chronic inflammation. Plaque destabilization is an evolutionary process that could start at early atherosclerotic stages and whose progression is influenced by many factors including neovascularization, intraplaque haemorrhages, formation of cholesterol crystals, inflammation, oxidative stress and intraplaque protease activity. © 2015 Scandinavian Physiological Society.


Chistiakov D.A.,Research Center for Childrens Health | Orekhov A.N.,Russian Academy of Sciences | Bobryshev Y.V.,University of New South Wales | Bobryshev Y.V.,University of Western Sydney
Acta Physiologica | Year: 2015

Vascular smooth muscle cells (VSMCs) exhibit phenotypic and functional plasticity in order to respond to vascular injury. In case of the vessel damage, VSMCs are able to switch from the quiescent 'contractile' phenotype to the 'proinflammatory' phenotype. This change is accompanied by decrease in expression of smooth muscle (SM)-specific markers responsible for SM contraction and production of proinflammatory mediators that modulate induction of proliferation and chemotaxis. Indeed, activated VSMCs could efficiently proliferate and migrate contributing to the vascular wall repair. However, in chronic inflammation that occurs in atherosclerosis, arterial VSMCs become aberrantly regulated and this leads to increased VSMC dedifferentiation and extracellular matrix formation in plaque areas. Proatherosclerotic switch in VSMC phenotype is a complex and multistep mechanism that may be induced by a variety of proinflammatory stimuli and hemodynamic alterations. Disturbances in hemodynamic forces could initiate the proinflammatory switch in VSMC phenotype even in pre-clinical stages of atherosclerosis. Proinflammatory signals play a crucial role in further dedifferentiation of VSMCs in affected vessels and propagation of pathological vascular remodelling. © 2015 Scandinavian Physiological Society.


Chistiakov D.A.,Research Center for Childrens Health | Bobryshev Y.V.,University of New South Wales | Bobryshev Y.V.,University of Western Sydney | Orekhov A.N.,Russian Academy of Sciences
Molecular Immunology | Year: 2015

The importance of immune inflammation in the development and progression of atherosclerotic lesions is well recognized. Accumulated evidence shows striking features of heterogeneity of regulatory T cells (Tregs) and the importance of the IL-12 cytokine family in regulation of Tregs in atherogenesis. The present review briefly summarized the current knowledge about the impact of the IL-12 cytokine family in regulation of immune processes in atherogenesis. © 2015 Elsevier Ltd.


Chistiakov D.A.,Research Center for Childrens Health | Ashwell K.W.,University of New South Wales | Orekhov A.N.,Russian Academy of Sciences | Bobryshev Y.V.,University of New South Wales | Bobryshev Y.V.,Russian Academy of Sciences
Autonomic Neuroscience: Basic and Clinical | Year: 2015

The autonomic nervous system (ANS) plays an essential role in the regulation of vascular tone. Sympathetic neurotransmitters epinephrine and norepinephrine are released from the terminals of perivascular nerves and suppress endothelial production of nitric oxide (NO), an important vasodilator. Sympathetic nerves also release neuropeptide Y, a co-transmitter that stimulates vasoconstriction and proliferation of vascular smooth muscle cells. Parasympathetic nerves release acetylcholine, which leads to vascular contraction when NO production is inhibited. The ANS produces a variety of other vasoactive substances including ATP, calcitonin gene-related peptide, dopamine, and serotonin. On the other hand, the vascular system can reciprocally influence ANS activity through the release of NO, reactive oxygen species (ROS), angiotensin II, and other mechanisms. In pathological conditions such as atherosclerosis, hyperactivation of sympathetic neural activity has pro-atherogenic effects on the vascular function by increasing vasoconstriction, accumulation of modified lipoproteins in the vascular wall, induction of endothelial dysfunction, and stimulation of oxidative stress and vascular remodeling. Indeed, suppression of the sympathetic ANS should be beneficial for the treatment of cardiovascular diseases. © 2015 Elsevier B.V..


Chistiakov D.A.,Moscow State University | Savost'Anov K.V.,Research Center for Childrens Health | Baranov A.A.,Research Center for Childrens Health
Autoimmunity | Year: 2014

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatologic disease in children. JIA is a group of disorders that share the clinical manifestation of chronic joint inflammation. The human leukocyte antigen region (HLA) seems to be a major susceptibility locus for JIA that is estimated to account for 17% of familial segregation of the disease. To date, around 20 non-HLA loci conferring susceptibility to JIA were found. At least a half of those are shared between JIA and rheumatoid arthritis (RA), an adult rheumatic disease, thereby suggesting for similarity of pathogenic mechanisms of both diseases. New findings also suggest for a likely role of epigenetic alterations in the pathogenesis of JIA that should be investigated in the future. © 2014 Informa UK Ltd.


PubMed | Research Center for Childrens Health
Type: Journal Article | Journal: Acta physiologica (Oxford, England) | Year: 2015

Vascular smooth muscle cells (VSMCs) exhibit phenotypic and functional plasticity in order to respond to vascular injury. In case of the vessel damage, VSMCs are able to switch from the quiescent contractile phenotype to the proinflammatory phenotype. This change is accompanied by decrease in expression of smooth muscle (SM)-specific markers responsible for SM contraction and production of proinflammatory mediators that modulate induction of proliferation and chemotaxis. Indeed, activated VSMCs could efficiently proliferate and migrate contributing to the vascular wall repair. However, in chronic inflammation that occurs in atherosclerosis, arterial VSMCs become aberrantly regulated and this leads to increased VSMC dedifferentiation and extracellular matrix formation in plaque areas. Proatherosclerotic switch in VSMC phenotype is a complex and multistep mechanism that may be induced by a variety of proinflammatory stimuli and hemodynamic alterations. Disturbances in hemodynamic forces could initiate the proinflammatory switch in VSMC phenotype even in pre-clinical stages of atherosclerosis. Proinflammatory signals play a crucial role in further dedifferentiation of VSMCs in affected vessels and propagation of pathological vascular remodelling.

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