55 results on '"Nikiforov NG"'
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2. Features of Gene Regulation in Violation of the Inflammatory Response of Monocyte-like Cells Bearing Mitochondrial Mutations Associated with Atherosclerosis.
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Orekhov AN, Nikiforov NG, Zhuravlev AD, Verkhova SS, Omelchenko AV, Borodko DD, Sukhorukov VN, Sinyov VV, and Sobenin IA
- Abstract
Аims: This research aimed to study the features of gene regulation of the inflammatory response in cells carrying mitochondrial mutations associated with atherosclerosis., Background: Inflammation plays an important, if not decisive, role in the occurrence of atherosclerotic lesions and then accompanies it throughout its further development. Thus, atherogenesis is a chronic inflammatory process. Chronification of inflammation is a consequence of disruption of the normal inflammatory response at the cell level of the vascular wall., Objectives: In this study, we used cytoplasmic hybrids or cybrids carrying atherosclerosis-associated mitochondrial mutations to study gene regulation of inflammatory response. The main goal of the study was to identify the key genes responsible for the impaired inflammatory response revealed for some cybrids., Methods: Inflammatory stimulation of cybrids was induced with bacterial lipopolysaccharide, and assessed through secretion of pro-inflammatory cytokines CCL2, IL8, IL6, IL1b. A transcriptome analysis was performed to identify the key genes (master regulators) in the normal (tolerant) and intolerant response of cybrid cells., Results: Normal inflammatory response after re-stimulation elicited a much smaller secretion of pro-inflammatory cytokines. In an intolerant response, the level of secretion upon re-stimulation was the same or even higher than after the first stimulation. Normal and intolerant responses differed significantly both in terms of the number of signaling pathways involved and qualitatively, since the signaling pathways for normal and intolerant responses are completely different. Master regulators controlling normal and intolerant inflammatory response were identified. For a normal response to the first inflammatory stimulation, no common master up-regulators and 3 master down-regulators were identified. The reverse situation was observed with the intolerant inflammatory response: 6 master up-regulators, and no master down regulators were identified. After the second inflammatory stimulation, no master regulator common to all studied cytokines was found. Thus, key genes involved in the development of intolerant inflammatory response have been identified. In addition, other key genes were identified that were initially associated with an intolerant inflammatory response and thus determine disorders of the inflammatory reaction leading to chronification of inflammation., Conclusion: We identified disturbances in gene associated with the development of intolerant immune response that may be relevant to atherosclerosis. Key genes responsible for the chronification of inflammation were discovered., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2024
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3. Variability of Mitochondrial DNA Heteroplasmy: Association with Asymptomatic Carotid Atherosclerosis.
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Sazonova MA, Kirichenko TV, Ryzhkova AI, Sazonova MD, Doroschuk NA, Omelchenko AV, Nikiforov NG, Ragino YI, and Postnov AY
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Background and Objectives: Atherosclerosis is one of the main reasons for cardiovascular disease development. This study aimed to analyze the association of mtDNA mutations and atherosclerotic plaques in carotid arteries of patients with atherosclerosis and conditionally healthy study participants from the Novosibirsk region. Methods: PCR fragments of DNA containing the regions of 10 investigated mtDNA mutations were pyrosequenced. The heteroplasmy levels of mtDNA mutations were analyzed using a quantitative method based on pyrosequencing technology developed by M. A. Sazonova and colleagues. Results: In the analysis of samples of patients with atherosclerotic plaques of the carotid arteries and conditionally healthy study participants from the Novosibirsk region, four proatherogenic mutations in the mitochondrial genome (m.5178C>A, m.652delG, m.12315G>A and m.3256C>T) and three antiatherogenic mutations in mtDNA (m.13513G>A, m.652insG, and m.14846G>A) were detected. A west-east gradient was found in the distribution of the mtDNA mutations m.5178C>A, m.3256C>T, m.652insG, and m.13513G>A. Conclusions: Therefore, four proatherogenic mutations in the mitochondrial genome (m.5178C>A, m.652delG, m.12315G>A, and m.3256C>T) and three antiatherogenic mutations in mtDNA (m.13513G>A, m.652insG, and m.14846G>A) were detected in patients with atherosclerotic plaques in their carotid arteries from the Novosibirsk region.
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- 2024
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4. Target Role of Monocytes as Key Cells of Innate Immunity in Rheumatoid Arthritis.
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Salnikova DI, Nikiforov NG, Postnov AY, and Orekhov AN
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Rheumatoid arthritis (RA) is a chronic, systemic, and inflammatory autoimmune condition characterized by synovitis, pannus formation (with adjacent bone erosion), and joint destruction. In the perpetuation of RA, fibroblast-like synoviocytes (FLSs), macrophages, B cells, and CD4
+ T-cells-specifically Th1 and Th17 cells-play crucial roles. Additionally, dendritic cells, neutrophils, mast cells, and monocytes contribute to the disease progression. Monocytes, circulating cells primarily derived from the bone marrow, participate in RA pathogenesis. Notably, CCR2 interacts with CCL2, and CX3CR1 (expressed by monocytes) cooperates with CX3CL1 (produced by FLSs), facilitating the migration involved in RA. Canonical "classical" monocytes predominantly acquire the phenotype of an "intermediate" subset, which differentially expresses proinflammatory cytokines (IL-1β, IL-6, and TNF) and surface markers (CD14, CD16, HLA-DR, TLRs, and β1- and β2-integrins). However, classical monocytes have greater potential to differentiate into osteoclasts, which contribute to bone resorption in the inflammatory milieu; in RA, Th17 cells stimulate FLSs to produce RANKL, triggering osteoclastogenesis. This review aims to explore the monocyte heterogeneity, plasticity, antigenic expression, and their differentiation into macrophages and osteoclasts. Additionally, we investigate the monocyte migration into the synovium and the role of their cytokines in RA.- Published
- 2024
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5. Defective Mitophagy Impairs Response to Inflammatory Activation of Macrophage-Like Cells.
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Orekhov AN, Zhuravlev AD, Vinokurov AY, Nikiforov NG, Omelchenko AV, Sukhorukov VN, Sinyov VV, and Sobenin IA
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Background and Aims: The role of mitophagy in atherosclerosis has been extensively studied during the last few years. It was shown that mitophagy is involved in the regulation of macrophages, which are important players as immune cells in atherosclerosis development. In this study, we investigated the relationship between mitophagy and response to inflammatory stimulation of macrophage-like cells. Six cybrid cell lines with normal mitophagy, that is, increasing in response to stimulation, and 7 lines with defective mitophagy not responding to stimulation were obtained. The objective of the study was to compare the nature of the inflammatory response in normal and defective mitophagy in order to elucidate the role of mitophagy defects in inflammation., Methods: We used cytoplasmic hybrids (cybrids) as cellular models, created using mitochondrial DNA from different atherosclerosis patients. Mitophagy was stimulated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and assessed as the degree of colocalization of mitochondria with lysosomes using confocal microscopy. Western blotting methods were used for the determination of proteins involved in the exact mechanism of mitophagy. Experiments with stimulation of mitophagy show a high correlation between these two approaches (microscopy and blotting). The pro-inflammatory response of cybrids was stimulated with bacterial lipopolysaccharide (LPS). The extent of the inflammatory response was assessed by the secretion of cytokines CCL2, IL8, IL6, IL1β, and TNF measured by ELISA., Results: Basal level of secretion of cytokines CCL2, IL8 and TNF was 1.5-2 times higher in cultures of cybrids with defective mitophagy compared to cells with normal mitophagy. This suggests a persistently elevated inflammatory response in cells with defective mitophagy, even in the absence of an inflammatory stimulus. Such cells in the tissue will constantly recruit other immune cells, which is characteristic of macrophages derived from monocytes circulating in the blood of patients with atherosclerosis. We observed significant differences in the degree and type of response to inflammatory activation in cybrids with defective mitophagy. These differences were not so much quantitative as they were dramatically qualitative. Compared with cells with normal mitophagy, in cells with defective mitophagy, the relative (to basal) secretion of IL8, IL6 and IL1b increased after the second LPS activation. This indicates a possible lack of tolerance to inflammatory activation in cells with defective mitophagy, since typically, re-activation reveals a smaller pro-inflammatory cytokine response, allowing the inflammatory process to resolve. In cells with normal mitophagy, exactly this normal (tolerant) inflammatory reaction was observed., Conclusion: Data on the involvement of mitophagy, including defective mitophagy, in disturbances of the inflammatory response in sepsis, viral infections, autoimmune diseases and other pathologies have previously been reported. In this work, we studied the role of defective mitophagy in non-infectious chronic inflammatory diseases using the example of atherosclerosis. We showed a dramatic disruption of the inflammatory response associated with defective mitophagy. Compared with cybrids with normal mitophagy, in cybrids with defective mitophagy, the secretion of all studied cytokines changed significantly both quantitatively and qualitatively. In particular, the secretion of 3 of 5 cytokines demonstrated an intolerant inflammatory response manifested by increased secretion after repeated inflammatory stimulation. Such an intolerant reaction likely indicates a significant disruption of the pro-inflammatory response of macrophages, which can contribute to the chronification of inflammation. Elucidating the mechanisms of chronification of inflammation is extremely important for the search for fundamentally new pharmacological targets and the development of drugs for the prevention and treatment of chronic inflammatory diseases, including atherosclerosis and diseases characteristic of inflammation. Such diseases account for up to 80% of morbidity and mortality., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
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- 2024
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6. Evidence for the Involvement of Gene Regulation of Inflammatory Molecules in the Accumulation of Intracellular Cholesterol: The Mechanism of Foam Cell Formation in Atherosclerosis.
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Sukhorukov VN, Khotina VA, Borodko DD, Ekta MB, Oishi Y, Omelchenko AV, Kolmychkova KI, Nikiforov NG, Sobenin IA, and Orekhov AN
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Background: The relationship between the cellular pro-inflammatory response and intracellular lipid accumulation in atherosclerosis is not sufficiently studied. Transcriptomic analysis is one way to establish such a relationship. Previously, we identified 10 potential key genes (IL-15, CXCL8, PERK, IL-7, IL-7R, DUSP1, TIGIT, F2RL1, TSPYL2, and ANXA1) involved in cholesterol accumulation in macrophages. It should be noted that all these genes do not directly participate in cholesterol metabolism, but encode molecules related to inflammation., Methods: In this study, we conducted a knock-down of the 10 identified key genes using siRNA to determine their possible role in cholesterol accumulation in macrophages. To assess cholesterol accumulation, human monocyte-derived macrophages (MDM) were incubated with atherogenic LDL from patients with atherosclerosis. Cholesterol content was assessed by the enzymatic method. Differentially expressed genes were identified with DESeq2 analysis. Master genes were determined by the functional analysis., Results: We found that only 5 out of 10 genes (IL-15, PERK, IL-7, IL-7R, ANXA1) can affect intracellular lipid accumulation. Knock-down of the IL-15, PERK, and ANXA1 genes prevented lipid accumulation, while knock-down of the IL-7 and IL-7R genes led to increased intracellular lipid accumulation during incubation of MDM with atherogenic LDL. Seventeen overexpressed genes and 189 underexpressed genes were obtained in the DGE analysis, which allowed us to discover 20 upregulated and 86 downregulated metabolic pathways, a number of which are associated with chronic inflammation and insulin signaling. We also elucidated 13 master regulators of cholesterol accumulation that are immune response-associated genes., Conclusion: Thus, it was discovered that 5 inflammation-related master regulators may be involved in lipid accumulation in macrophages. Therefore, the pro-inflammatory response of macrophages may trigger foam cell formation rather than the other way around, where intracellular lipid accumulation causes an inflammatory response, as previously assumed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
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- 2024
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7. Macrophages derived from LPS-stimulated monocytes from individuals with subclinical atherosclerosis were characterized by increased pro-inflammatory activity.
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Nikiforov NG, Kirichenko TV, Kubekina MV, Chegodaev YS, Zhuravlev AD, Ilchuk LA, Nikolaeva MA, Arefieva AS, Popov MA, Verkhova SS, Bagheri Ekta M, and Orekhov AN
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- Humans, Monocytes, Lipopolysaccharides pharmacology, Interleukin-10, Interleukin-6, Carotid Intima-Media Thickness, Macrophages, Cytokines, Inflammation, Plaque, Atherosclerotic, Atherosclerosis
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Objective: Atherosclerosis is characterized by chronic inflammation in the vascular wall. Currently the violation of immune tolerance of innate immune cells is considered as a possible mechanism of chronification of inflammation. The aim of this study is to assess the inflammatory activity and tolerance of monocytes and macrophages in subclinical atherosclerosis., Methods: A total of 55 individuals free from clinical manifestations of atherosclerosis-associated cardiovascular disease with a presence or absence of atherosclerotic plaques in the carotid arteries were included in this study. CD14+ monocytes were isolated from individuals' blood and stimulated with a single dose of lipopolysaccharide (LPS) on day 1 or with double doses of LPS on day 1 and day 6. The secretion of cytokines TNF, IL-1β, IL-6, IL-8, IL-10 and CCL2 were evaluated using ELISA., Results: Our findings demonstrate that macrophages derived from LPS-stimulated monocytes in individuals with subclinical atherosclerosis exhibited increased secretion of IL-6, IL-10 and CCL2, which was associated with intima-media thickness, body mass index, but not with individuals' age. Moreover, macrophages from individuals with atherosclerotic plaques exhibited impaired tolerance towards the second LPS stimulation manifested by elevated secretion of the chemoattractant CCL2., Conclusion: Increased secretion of these cytokines by macrophages may contribute to chronic local inflammation in the vascular wall by recruiting other immune cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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8. Therapeutic Role of Curcumin in Diabetes: An Analysis Based on Bioinformatic Findings.
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Mahmoudi A, Atkin SL, Nikiforov NG, and Sahebkar A
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- Computational Biology, Cytokines, Humans, Phosphatidylinositol 3-Kinases, Antioxidants pharmacology, Antioxidants therapeutic use, Curcumin pharmacology, Curcumin therapeutic use, Diabetes Mellitus drug therapy, Diabetes Mellitus genetics, Insulins therapeutic use
- Abstract
Background: Diabetes is an increasingly prevalent global disease caused by the impairment in insulin production or insulin function. Diabetes in the long term causes both microvascular and macrovascular complications that may result in retinopathy, nephropathy, neuropathy, peripheral arterial disease, atherosclerotic cardiovascular disease, and cerebrovascular disease. Considerable effort has been expended looking at the numerous genes and pathways to explain the mechanisms leading to diabetes-related complications. Curcumin is a traditional medicine with several properties such as being antioxidant, anti-inflammatory, anti-cancer, and anti-microbial, which may have utility for treating diabetes complications. This study, based on the system biology approach, aimed to investigate the effect of curcumin on critical genes and pathways related to diabetes., Methods: We first searched interactions of curcumin in three different databases, including STITCH, TTD, and DGIdb. Subsequently, we investigated the critical curated protein targets for diabetes on the OMIM and DisGeNET databases. To find important clustering groups (MCODE) and critical hub genes in the network of diseases, we created a PPI network for all proteins obtained for diabetes with the aid of a string database and Cytoscape software. Next, we investigated the possible interactions of curcumin on diabetes-related genes using Venn diagrams. Furthermore, the impact of curcumin on the top scores of modular clusters was analysed. Finally, we conducted biological process and pathway enrichment analysis using Gene Ontology (GO) and KEGG based on the enrichR web server., Results: We acquired 417 genes associated with diabetes, and their constructed PPI network contained 298 nodes and 1651 edges. Next, the analysis of centralities in the PPI network indicated 15 genes with the highest centralities. Additionally, MCODE analysis identified three modular clusters, which highest score cluster (MCODE 1) comprises 19 nodes and 92 edges with 10.22 scores. Screening curcumin interactions in the databases identified 158 protein targets. A Venn diagram of genes related to diabetes and the protein targets of curcumin showed 35 shared proteins, which observed that curcumin could strongly interact with ten of the hub genes. Moreover, we demonstrated that curcumin has the highest interaction with MCODE1 among all MCODs. Several significant biological pathways in KEGG enrichment associated with 35 shared included the AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, PI3K-Akt signaling pathway, TNF signaling, and JAK-STAT signaling pathway. The biological processes of GO analysis were involved with the cellular response to cytokine stimulus, the cytokine-mediated signaling pathway, positive regulation of intracellular signal transduction and cytokine production in the inflammatory response., Conclusion: Curcumin targeted several important genes involved in diabetes, supporting the previous research suggesting that it may have utility as a therapeutic agent in diabetes.
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- 2022
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9. The Role of Mitochondrial Mutations in Chronification of Inflammation: Hypothesis and Overview of Own Data.
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Orekhov AN, Nikiforov NG, Omelchenko AV, Sinyov VV, Sobenin IA, Vinokurov AY, and Orekhova VA
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Chronic human diseases, especially age-related disorders, are often associated with chronic inflammation. It is currently not entirely clear what factors are responsible for the sterile inflammatory process becoming chronic in affected tissues. This process implies impairment of the normal resolution of the inflammatory response, when pro-inflammatory cytokine production ceases and tissue repair process begins. The important role of the mitochondria in the correct functioning of innate immune cells is currently well recognized, with mitochondrial signals being an important component of the inflammatory response regulation. In this work, we propose a hypothesis according to which mitochondrial DNA (mtDNA) mutations may play a key role in rendering certain cells prone to prolonged pro-inflammatory activation, therefore contributing to chronification of inflammation. The affected cells become sites of constant pro-inflammatory stimulation. The study of the distribution of atherosclerotic lesions on the surface of the arterial wall samples obtained from deceased patients revealed a focal distribution of lesions corresponding to the distribution of cells with altered morphology that are affected by mtDNA mutations. These observations support the proposed hypothesis and encourage further studies.
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- 2022
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10. Phenotype Diversity of Macrophages in Osteoarthritis: Implications for Development of Macrophage Modulating Therapies.
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Mushenkova NV, Nikiforov NG, Shakhpazyan NK, Orekhova VA, Sadykhov NK, and Orekhov AN
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- Humans, Inflammation pathology, Macrophages pathology, Phenotype, Synovial Membrane pathology, Osteoarthritis pathology
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Chronic inflammation is implicated in numerous human pathologies. In particular, low-grade inflammation is currently recognized as an important mechanism of osteoarthritis (OA), at least in some patients. Among the signs of the inflammatory process are elevated macrophage numbers detected in the OA synovium compared to healthy controls. High macrophage counts also correlate with clinical symptoms of the disease. Macrophages are central players in the development of chronic inflammation, pain, cartilage destruction, and bone remodeling. However, macrophages are also involved in tissue repair and remodeling, including cartilage. Therefore, reduction of macrophage content in the joints correlates with deleterious effects in OA models. Macrophage population is heterogeneous and dynamic, with phenotype transitions being induced by a variety of stimuli. In order to effectively use the macrophage inflammatory circuit for treatment of OA, it is important to understand macrophage heterogeneity and interactions with surrounding cells and tissues in the joint. In this review, we discuss functional phenotypes of macrophages and specific targeting approaches relevant for OA treatment development.
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- 2022
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11. Effects of Metabolic Disorders in Immune Cells and Synoviocytes on the Development of Rheumatoid Arthritis.
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Blagov AV, Grechko AV, Nikiforov NG, Zhuravlev AD, Sadykhov NK, and Orekhov AN
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Rheumatoid arthritis (RA) is a progressive autoimmune disease that affects the joints. It has been proven that, with the development of RA, there are changes in the metabolism of cells located in the focus of inflammation. In this article, we describe the connection between metabolism and inflammation in the context of rheumatoid arthritis. We consider in detail the changes in metabolic processes and their subsequent immunomodulatory effects. In particular, we consider how changes in mitochondrial functioning lead to the modulation of metabolism in rheumatoid arthritis. We also describe the main features of the metabolism in cells present in the synovial membrane during inflammation, and we discuss possible targets for the therapy of rheumatoid arthritis.
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- 2022
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12. Role of Impaired Mitochondrial Dynamics Processes in the Pathogenesis of Alzheimer's Disease.
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Blagov AV, Grechko AV, Nikiforov NG, Borisov EE, Sadykhov NK, and Orekhov AN
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- Humans, Mitochondria metabolism, Neurons metabolism, Alzheimer Disease metabolism, Mitochondrial Dynamics
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Mitochondrial dysfunction is now recognized as a contributing factor to neurodegenerative diseases, including Alzheimer's disease (AD). Mitochondria are signaling organelles with a variety of functions ranging from energy production to the regulation of cellular metabolism, energy homeostasis, and response to stress. The successful functioning of these complex processes is critically dependent on the accuracy of mitochondrial dynamics, which includes the ability of mitochondria to change shape and position in the cell, which is necessary to maintain proper function and quality control, especially in polarized cells such as neurons. There has been much evidence to suggest that the disruption of mitochondrial dynamics may play a critical role in the pathogenesis of AD. This review highlights aspects of altered mitochondrial dynamics in AD that may contribute to the etiology of this debilitating condition. We also discuss therapeutic strategies to improve mitochondrial dynamics and function that may provide an alternative treatment approach.
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- 2022
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13. Somatic Mutations of Hematopoietic Cells Are an Additional Mechanism of Body Aging, Conducive to Comorbidity and Increasing Chronification of Inflammation.
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Yegorov YE, Poznyak AV, Bezsonov EE, Zhuravlev AD, Nikiforov NG, Vishnyakova KS, and Orekhov AN
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It is known that the development of foci of chronic inflammation usually accompanies body aging. In these foci, senescent cells appear with a pro-inflammatory phenotype that helps maintain inflammation. Their removal with the help of senolytics significantly improves the general condition of the body and, according to many indicators, contributes to rejuvenation. The cells of the immune system participate in the initiation, development, and resolution of inflammation. With age, the human body accumulates mutations, including the cells of the bone marrow, giving rise to the cells of the immune system. We assume that a number of such mutations formed with age can lead to the appearance of "naive" cells with an initially pro-inflammatory phenotype, the migration of which to preexisting foci of inflammation contributes not to the resolution of inflammation but its chronicity. One of such cell variants are monocytes carrying mitochondrial mutations, which may be responsible for comorbidity and deterioration in the prognosis of the course of pathologies associated with aging, such as atherosclerosis, arthritis, osteoporosis, and neurodegenerative diseases.
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- 2022
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14. Functional Phenotypes of Intraplaque Macrophages and Their Distinct Roles in Atherosclerosis Development and Atheroinflammation.
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Mushenkova NV, Nikiforov NG, Melnichenko AA, Kalmykov V, Shakhpazyan NK, Orekhova VA, and Orekhov AN
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Macrophages are the key inflammatory cell type involved in all stages of atherosclerosis development and progression, as demonstrated by numerous studies. Correspondingly, macrophages are currently regarded as a promising therapeutic target for the development of new treatment approaches. The macrophage population is heterogeneous and dynamic, as these cells can switch between a number of distinct functional states with pro- and anti-atherogenic activity in response to various stimuli. An atherosclerotic plaque microenvironment defined by cytokine levels, cell-to-cell interactions, lipid accumulation, hypoxia, neoangiogenesis, and intraplaque haemorrhage may guide local macrophage polarization processes within the lesion. In this review, we discuss known functional phenotypes of intraplaque macrophages and their distinct contribution to ahteroinflammation.
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- 2022
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15. Role of the mtDNA Mutations and Mitophagy in Inflammaging.
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Dabravolski SA, Nikiforov NG, Zhuravlev AD, Orekhov NA, Grechko AV, and Orekhov AN
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- Animals, Humans, Reactive Oxygen Species metabolism, DNA, Mitochondrial genetics, Inflammation genetics, Mitochondria genetics, Mitophagy genetics, Mutation genetics
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Ageing is an unavoidable multi-factorial process, characterised by a gradual decrease in physiological functionality and increasing vulnerability of the organism to environmental factors and pathogens, ending, eventually, in death. One of the most elaborated ageing theories implies a direct connection between ROS-mediated mtDNA damage and mutations. In this review, we focus on the role of mitochondrial metabolism, mitochondria generated ROS, mitochondrial dynamics and mitophagy in normal ageing and pathological conditions, such as inflammation. Also, a chronic form of inflammation, which could change the long-term status of the immune system in an age-dependent way, is discussed. Finally, the role of inflammaging in the most common neurodegenerative diseases, such as Alzheimer's and Parkinson's, is also discussed.
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- 2022
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16. Local Accumulation of Lymphocytes in the Intima of Human Aorta Is Associated with Giant Multinucleated Endothelial Cells: Possible Explanation for Mosaicism of Atherosclerosis.
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Nikiforov NG, Zlenko DV, Orekhova VA, Melnichenko AA, and Orekhov AN
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- Adult, Aorta pathology, Endothelium, Vascular pathology, Humans, Lipoproteins, LDL, Lymphocytes pathology, Middle Aged, Mosaicism, Young Adult, Atherosclerosis pathology, Endothelial Cells pathology
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Distribution of different types of atherosclerotic lesions in the arterial wall is not diffuse, but is characterized by mosaicism. The causes of such distribution remain to be established. At the early stages of atherogenesis, low-density lipoprotein (LDL) particles and immune cells penetrate into the intimal layer of the arterial wall through the endothelium. In adult humans, the luminal surface of the arterial wall is a heterogeneous monolayer of cells with varying morphology including typical endothelial cells (ECs) and multinucleated variant endothelial cells (MVECs). We hypothesized that distribution of MVECs in the endothelial monolayer can be related to the distribution pattern of early atherosclerotic lesions. We obtained en face preparations of intact adult (22-59 years old) aortic wall sections that allowed us to study the endothelial monolayer and the subendothelial layer. We compared the distribution of MVECs in the endothelial monolayer with the localization of early atherosclerotic lesions in the subendothelial layer, which were characterized by lipid accumulation and immune cell recruitment. In primary culture, MVECs demonstrated increased phagocytic activity compared to mononuclear ECs. Moreover, we have shown that unaffected aortic intima contained associates formed as a result of aggregation and/or fusion of LDL particles that are non-randomly distributed. This indicated that MVECs may be involved in the accumulation of LDL in the subendothelial layer through increased transcytosis. Interaction of LDL with subendothelial cells of human aorta in primary culture increased their adhesive properties toward circulating immune cells. Study of unaffected aortic intima revealed non-random distribution of leukocytes in the subendothelial layer and increased localization of CD45+ leukocytes in the subendothelial layer adjacent to MVECs. Together, our observations indicate that MVECs may be responsible for the distribution of atherosclerotic lesions in the arterial wall by participating in LDL internalization and immune cell recruitment.
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- 2022
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17. The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment.
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Dabravolski SA, Nikiforov NG, Zhuravlev AD, Orekhov NA, Mikhaleva LM, and Orekhov AN
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- Apoptosis, Humans, Reactive Oxygen Species, Carcinogenesis metabolism, Mitochondria drug effects, Mitochondria metabolism, Mitophagy drug effects, Thyroid Neoplasms drug therapy, Thyroid Neoplasms metabolism
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Thyroid cancer (TC) is the most common type of endocrine malignancy. Tumour formation, progression, and metastasis greatly depend on the efficacy of mitochondria-primarily, the regulation of mitochondria-mediated apoptosis, Ca
2+ homeostasis, dynamics, energy production, and associated reactive oxygen species generation. Recent studies have successfully confirmed the mitochondrial aetiology of thyroid carcinogenesis. In this review, we focus on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism. We also discuss the repurposing of known drugs and the induction of mitochondria-mediated apoptosis as a new trend in the development of anti-TC therapy.- Published
- 2021
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18. New Drug Targets to Prevent Death Due to Stroke: A Review Based on Results of Protein-Protein Interaction Network, Enrichment, and Annotation Analyses.
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Maes M, Nikiforov NG, Plaimas K, Suratanee A, Alfieri DF, and Vissoci Reiche EM
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- Gene Regulatory Networks genetics, Humans, Ischemic Stroke mortality, MicroRNAs genetics, Biomarkers, Computational Biology, Ischemic Stroke genetics, Protein Interaction Maps genetics
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This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6 , ALB , TNF , SERPINE1 , VWF , VCAM1 , TGFB1 , and SELE . Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF . Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4 , TNF , JAK-STAT , NOD , IL10 , IL13 , IL4 , and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due to IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell-surface interactions, and the proteoglycan-integrin extracellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: (a) that NFKB1 , RELA and SP1 were the major regulating actors of the PPI network; and (b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, the proteoglycan-integrin-ECM complex, TGF-β1/SMAD, NF-κB/RELA and SP1.
- Published
- 2021
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19. Macrophages and Foam Cells: Brief Overview of Their Role, Linkage, and Targeting Potential in Atherosclerosis.
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Poznyak AV, Nikiforov NG, Starodubova AV, Popkova TV, and Orekhov AN
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Atherosclerosis is still one of the main causes of death around the globe. This condition leads to various life-threatening cardiovascular complications. However, no effective preventive measures are known apart from lifestyle corrections, and no cure has been developed. Despite numerous studies in the field of atherogenesis, there are still huge gaps in already poor understanding of mechanisms that underlie the disease. Inflammation and lipid metabolism violations are undoubtedly the key players, but many other factors, such as oxidative stress, endothelial dysfunction, contribute to the pathogenesis of atherosclerosis. This overview is focusing on the role of macrophages in atherogenesis, which are at the same time a part of the inflammatory response, and also tightly linked to the foam cell formation, thus taking part in both crucial for atherogenesis processes. Being essentially involved in atherosclerosis development, macrophages and foam cells have attracted attention as a promising target for therapeutic approaches.
- Published
- 2021
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20. The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets.
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Dabravolski SA, Nikiforov NG, Starodubova AV, Popkova TV, and Orekhov AN
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- Animals, Cardiovascular Diseases metabolism, Cardiovascular Diseases pathology, Humans, Cardiovascular Diseases drug therapy, Mitochondria metabolism, Mitochondrial Proteins metabolism, Peptide Fragments pharmacology
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Mitochondria-derived peptides (MDPs) are small peptides hidden in the mitochondrial DNA, maintaining mitochondrial function and protecting cells under different stresses. Currently, three types of MDPs have been identified: Humanin, MOTS-c and SHLP1-6. MDPs have demonstrated anti-apoptotic and anti-inflammatory activities, reactive oxygen species and oxidative stress-protecting properties both in vitro and in vivo. Recent research suggests that MDPs have a significant cardioprotective role, affecting CVDs (cardiovascular diseases) development and progression. CVDs are the leading cause of death globally; this term combines disorders of the blood vessels and heart. In this review, we focus on the recent progress in understanding the relationships between MDPs and the main cardiovascular risk factors (atherosclerosis, insulin resistance, hyperlipidaemia and ageing). We also will discuss the therapeutic application of MDPs, modified and synthetic MDPs, and their potential as novel biomarkers and therapeutic targets.
- Published
- 2021
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21. CD47 in the Brain and Neurodegeneration: An Update on the Role in Neuroinflammatory Pathways.
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Gheibihayat SM, Cabezas R, Nikiforov NG, Jamialahmadi T, Johnston TP, and Sahebkar A
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- Animals, Humans, Inflammation metabolism, Brain metabolism, CD47 Antigen metabolism, Gaucher Disease metabolism, Multiple Sclerosis metabolism, Stroke metabolism
- Abstract
CD47 is a receptor belonging to the immunoglobulin (Ig) superfamily and broadly expressed on cell membranes. Through interactions with ligands such as SIRPα, TSP-1, integrins, and SH2-domain bearing protein tyrosine phosphatase substrate-1 (SHPS-1), CD47 regulates numerous functions like cell adhesion, proliferation, apoptosis, migration, homeostasis, and the immune system. In this aspect, previous research has shown that CD47 modulates phagocytosis via macrophages, the transmigration of neutrophils, and the activation of T-cells, dendritic cells, and B-cells. Moreover, several studies have reported the increased expression of the CD47 receptor in a variety of diseases, including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), bladder cancer, acute myeloid leukemia (AML), Gaucher disease, Multiple Sclerosis and stroke among others. The ubiquitous expression of the CD47 cell receptor on most resident cells of the CNS has previously been established through different methodologies. However, there is little information concerning its precise functions in the development of different neurodegenerative pathologies in the CNS. Consequently, further research pertaining to the specific functions and roles of CD47 and SIRP is required prior to its exploitation as a druggable approach for the targeting of various neurodegenerative diseases that affect the human population. The present review attempts to summarize the role of both CD47 and SIRP and their therapeutic potential in neurodegenerative disorders.
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- 2021
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22. The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes.
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Zhunina OA, Yabbarov NG, Grechko AV, Starodubova AV, Ivanova E, Nikiforov NG, and Orekhov AN
- Abstract
Mitochondrial dysfunction is known to be associated with a wide range of human pathologies, such as cancer, metabolic, and cardiovascular diseases. One of the possible ways of mitochondrial involvement in the cellular damage is excessive production of reactive oxygen and nitrogen species (ROS and RNS) that cannot be effectively neutralized by existing antioxidant systems. In mitochondria, ROS and RNS can contribute to protein and mitochondrial DNA (mtDNA) damage causing failure of enzymatic chains and mutations that can impair mitochondrial function. These processes further lead to abnormal cell signaling, premature cell senescence, initiation of inflammation, and apoptosis. Recent studies have identified numerous mtDNA mutations associated with different human pathologies. Some of them result in imbalanced oxidative phosphorylation, while others affect mitochondrial protein synthesis. In this review, we discuss the role of mtDNA mutations in cancer, diabetes, cardiovascular diseases, and atherosclerosis. We provide a list of currently described mtDNA mutations associated with each pathology and discuss the possible future perspective of the research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhunina, Yabbarov, Grechko, Starodubova, Ivanova, Nikiforov and Orekhov.)
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- 2021
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23. Associations between Pre-Bariatric High-Sensitivity C-Reactive Protein and Post-Surgery Outcomes.
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Jamialahmadi T, Nematy M, Bo S, Ponzo V, Jangjoo A, Goshayeshi L, Tasbandi A, Nikiforov NG, and Sahebkar A
- Abstract
Background: Obesity is a chronic inflammatory condition associated with increased circulating levels of C-reactive protein (CRP). Bariatric surgery has been reported to be effective in improving both inflammatory and liver status. Our aims were to elucidate the relationships between pre-surgery high sensitivity-CRP (hs-CRP) values and post-surgery weight loss and liver steatosis and fibrosis in patients with severe obesity undergoing Roux-en-Y gastric bypass., Methods: We conducted an observational prospective study on 90 individuals with morbid obesity, who underwent gastric bypass. Anthropometric indices, laboratory assessment (lipid panel, glycemic status, liver enzymes, and hs-CRP), liver stiffness and steatosis were evaluated at baseline and 6-months after surgery., Results: There was a significant post-surgery reduction in all the anthropometric variables, with an average weight loss of 33.93 ± 11.79 kg; the mean percentage of total weight loss (TWL) was 27.96 ± 6.43%. Liver elasticity was significantly reduced (from 6.1 ± 1.25 to 5.42 ± 1.52 kPa; p = 0.002), as well as liver aminotransferases, nonalcoholic fatty liver disease fibrosis score (NFS) and the grade of steatosis. Serum hs-CRP levels significantly reduced (from 9.26 ± 8.45 to 3.29 ± 4.41 mg/L; p < 0.001). The correlations between hs-CRP levels and liver fibrosis (elastography), steatosis (ultrasonography), fibrosis-4 index, NFS, and surgery success rate were not significant. Regression analyses showed that serum hs-CRP levels were not predictive of liver status and success rate after surgery in both unadjusted and adjusted models., Conclusions: In patients with morbid obesity, bariatric surgery caused a significant decrease in hs-CRP levels, liver stiffness and steatosis. Baseline hs-CRP values did not predict the weight-loss success rate and post-surgery liver status.
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- 2021
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24. Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome.
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Dabravolski SA, Nikiforov NG, Eid AH, Nedosugova LV, Starodubova AV, Popkova TV, Bezsonov EE, and Orekhov AN
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- Female, Humans, Inflammation diagnosis, Inflammation pathology, Mitochondria pathology, Mutation genetics, Oxidative Stress genetics, Polycystic Ovary Syndrome diagnosis, Polycystic Ovary Syndrome pathology, DNA, Mitochondrial genetics, Inflammation genetics, Mitochondria genetics, Polycystic Ovary Syndrome genetics
- Abstract
Polycystic ovarian syndrome (PCOS) is the most common endocrine-metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial dysfunctions and hormonal disbalance. Mutations in mtDNA have been identified in PCOS patients and likely play an important role in PCOS aetiology and pathogenesis; however, their causative role in PCOS development requires further investigation. As a low-grade chronic inflammation disease, PCOS patients have permanently elevated levels of inflammatory markers (TNF-α, CRP, IL-6, IL-8, IL-18). In this review, we summarise recent data regarding the role of mtDNA mutations and mitochondrial malfunctions in PCOS pathogenesis. Furthermore, we discuss recent papers dedicated to the identification of novel biomarkers for early PCOS diagnosis. Finally, traditional and new mitochondria-targeted treatments are discussed. This review intends to emphasise the key role of oxidative stress and chronic inflammation in PCOS pathogenesis; however, the exact molecular mechanism is mostly unknown and requires further investigation.
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- 2021
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25. Disturbance of Mitochondrial Dynamics and Mitochondrial Therapies in Atherosclerosis.
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Markin AM, Khotina VA, Zabudskaya XG, Bogatyreva AI, Starodubova AV, Ivanova E, Nikiforov NG, and Orekhov AN
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Mitochondrial dysfunction is associated with a wide range of chronic human disorders, including atherosclerosis and diabetes mellitus. Mitochondria are dynamic organelles that undergo constant turnover in living cells. Through the processes of mitochondrial fission and fusion, a functional population of mitochondria is maintained, that responds to the energy needs of the cell. Damaged or excessive mitochondria are degraded by mitophagy, a specialized type of autophagy. These processes are orchestrated by a number of proteins and genes, and are tightly regulated. When one or several of these processes are affected, it can lead to the accumulation of dysfunctional mitochondria, deficient energy production, increased oxidative stress and cell death-features that are described in many human disorders. While severe mitochondrial dysfunction is known to cause specific and mitochondrial disorders in humans, progressing damage of the mitochondria is also observed in a wide range of other chronic diseases, including cancer and atherosclerosis, and appears to play an important role in disease development. Therefore, correction of mitochondrial dynamics can help in developing new therapies for the treatment of these conditions. In this review, we summarize the recent knowledge on the processes of mitochondrial turnover and the proteins and genes involved in it. We provide a list of known mutations that affect mitochondrial function, and discuss the emerging therapeutic approaches.
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- 2021
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26. Autophagy and Mitophagy as Essential Components of Atherosclerosis.
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Poznyak AV, Nikiforov NG, Wu WK, Kirichenko TV, and Orekhov AN
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- Humans, Atherosclerosis genetics, Autophagy genetics, Cardiovascular Diseases genetics, Mitophagy genetics
- Abstract
Cardiovascular disease (CVD) is one of the greatest health problems affecting people worldwide. Atherosclerosis, in turn, is one of the most common causes of cardiovascular disease. Due to the high mortality rate from cardiovascular diseases, prevention and treatment at the earliest stages become especially important. This requires developing a deep understanding of the mechanisms underlying the development of atherosclerosis. It is well-known that atherogenesis is a complex multi-component process that includes lipid metabolism disorders, inflammation, oxidative stress, autophagy disorders and mitochondrial dysfunction. Autophagy is a cellular control mechanism that is critical to maintaining health and survival. One of the specific forms of autophagy is mitophagy, which aims to control and remove defective mitochondria from the cell. Particularly defective mitophagy has been shown to be associated with atherogenesis. In this review, we consider the role of autophagy, focusing on a special type of it-mitophagy-in the context of its role in the development of atherosclerosis.
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- 2021
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27. Retraction notice to Macrophage phenotypic plasticity in atherosclerosis: The associated features and the peculiarities of the expression of inflammatory genes, International Journal of Cardiology, Volume 184, 1 April 2015, Pages 436-445.
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Chistiakov DA, Bobryshev YV, Nikiforov NG, Elizova NV, Sobenin IA, and Orekhov AN
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- 2021
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28. Role of Telomeres Shortening in Atherogenesis: An Overview.
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Yegorov YE, Poznyak AV, Nikiforov NG, Starodubova AV, and Orekhov AN
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- Endothelial Cells metabolism, Endothelium, Vascular metabolism, Humans, Atherosclerosis genetics, Telomerase metabolism, Telomere metabolism, Telomere Shortening genetics
- Abstract
It is known that the shortening of the telomeres leads to cell senescence, accompanied by acquiring of pro-inflammatory phenotype. The expression of telomerase can elongate telomeres and resist the onset of senescence. The initiation of atherosclerosis is believed to be associated with local senescence of the endothelial cells of the arteries in places with either low or multidirectional oscillatory wall shear stress. The process of regeneration of the artery surface that has begun does not lead to success for several reasons. Atherosclerotic plaques are formed, which, when developed, lead to fatal consequences, which are the leading causes of death in the modern world. The pronounced age dependence of the manifestations of atherosclerosis pushes scientists to try to link the development of atherosclerosis with telomere length. The study of the role of telomere shortening in atherosclerosis is mainly limited to measuring the telomeres of blood cells, and only in rare cases (surgery or post-mortem examination) are the telomeres of local cells available for measurement. The review discusses the basic issues of cellular aging and the interpretation of telomere measurement data in atherosclerosis, as well as the prospects for the prevention and possible treatment of atherosclerosis.
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- 2021
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29. Two Subpopulations of Human Monocytes That Differ by Mitochondrial Membrane Potential.
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Nikiforov NG, Ryabova A, Kubekina MV, Romanishkin ID, Trofimov KA, Chegodaev YS, Ivanova E, and Orekhov AN
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Atherosclerosis is associated with a chronic local inflammatory process in the arterial wall. Our previous studies have demonstrated the altered proinflammatory activity of circulating monocytes in patients with atherosclerosis. Moreover, atherosclerosis progression and monocyte proinflammatory activity were associated with mitochondrial DNA (mtDNA) mutations in circulating monocytes. The role of mitochondria in the immune system cells is currently well recognized. They can act as immunomodulators by releasing molecules associated with bacterial infection. We hypothesized that atherosclerosis can be associated with changes in the mitochondrial function of circulating monocytes. To test this hypothesis, we performed live staining of the mitochondria of CD14+ monocytes from healthy donors and atherosclerosis patients with MitoTracker Orange CMTMRos dye, which is sensitive to mitochondrial membrane potential. The intensity of such staining reflects mitochondrial functional activity. We found that parts of monocytes in the primary culture were characterized by low MitoTracker staining (MitoTracker-low monocytes). Such cells were morphologically similar to cells with normal staining and able to metabolize 5-aminolevulinic acid and accumulate the heme precursor protoporphyrin IX (PplX), indicative of partially preserved mitochondrial function. We assessed the proportion of MitoTracker-low monocytes in the primary culture for each study subject and compared the results with other parameters, such as monocyte ability to lipopolysaccharide (LPS)-induced proinflammatory activation and the intima-media thickness of carotid arteries. We found that the proportion of MitoTracker-low monocytes was associated with the presence of atherosclerotic plaques. An increased number of such monocytes in the primary culture was associated with a reduced proinflammatory activation ability of cells. The obtained results indicate the presence of circulating monocytes with mitochondrial dysfunction and the association of such cells with chronic inflammation and atherosclerosis development.
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- 2021
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30. Overview of OxLDL and Its Impact on Cardiovascular Health: Focus on Atherosclerosis.
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Poznyak AV, Nikiforov NG, Markin AM, Kashirskikh DA, Myasoedova VA, Gerasimova EV, and Orekhov AN
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Cardiovascular pathologies maintain the leading position in mortality worldwide. Atherosclerosis is a chronic disease that can result in a variety of serious complications, such as myocardial infarction, stroke, and cardiovascular disease. Inflammation and lipid metabolism alterations play a crucial role in atherogenesis, but the details of relationships and causality of these fundamental processes remain not clear. The oxidation of LDL was considered the main atherogenic modification of LDL within the vascular wall for decades. However, recent investigations provided a growing body of evidence in support of the multiple LDL modification theory. It suggests that LDL particles undergo numerous modifications that change their size, density, and chemical properties within the blood flow and vascular wall. Oxidation is the last stage in this cascade resulting in the atherogenic properties. Moreover, recent investigations have discovered that oxLDL may have both anti-inflammatory and pro-inflammatory properties. Oxidized LDL can trigger inflammation through the activation of macrophages and other cells. After all, oxidized LDL is still a promising object for further investigations that have the potential to clarify the unknown parts of the atherogenic process. In this review, we discuss the role of oxLDL in atherosclerosis development on different levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Poznyak, Nikiforov, Markin, Kashirskikh, Myasoedova, Gerasimova and Orekhov.)
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- 2021
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31. Do Mitochondrial DNA Mutations Play a Key Role in the Chronification of Sterile Inflammation? Special Focus on Atherosclerosis.
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Orekhov AN, Gerasimova EV, Sukhorukov VN, Poznyak AV, and Nikiforov NG
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- Humans, Inflammation genetics, Mitochondria genetics, Mutation, Atherosclerosis genetics, DNA, Mitochondrial genetics
- Abstract
Background: The aim of the elucidation of mechanisms implicated in the chronification of inflammation is to shed light on the pathogenesis of disorders that are responsible for the majority of the incidences of diseases and deaths, and also causes of ageing. Atherosclerosis is an example of the most significant inflammatory pathology. The inflammatory response of innate immunity is implicated in the development of atherosclerosis arising locally or focally. Modified low-density lipoprotein (LDL) was regarded as the trigger for this response. No atherosclerotic changes in the arterial wall occur due to the quick decrease in inflammation rate. Nonetheless, the atherosclerotic lesion formation can be a result of the chronification of local inflammation, which, in turn, is caused by alteration of the response of innate immunity., Objective: In this review, we discussed potential mechanisms of the altered response of the immunity in atherosclerosis with a particular emphasis on mitochondrial dysfunctions., Conclusion: A few mitochondrial dysfunctions can be caused by the mitochondrial DNA (mtDNA) mutations. Moreover, mtDNA mutations were found to affect the development of defective mitophagy. Modern investigations have demonstrated the controlling mitophagy function in response to the immune system. Therefore, we hypothesized that impaired mitophagy, as a consequence of mutations in mtDNA, can raise a disturbed innate immunity response, resulting in the chronification of inflammation in atherosclerosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
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- 2021
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32. Genetics of Arterial-Wall-Specific Mechanisms in Atherosclerosis: Focus on Mitochondrial Mutations.
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Orekhov AN, Ivanova EA, Markin AM, Nikiforov NG, and Sobenin IA
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- Animals, Arteries metabolism, Arteries pathology, Atherosclerosis metabolism, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Genome, Mitochondrial, Humans, Phenotype, Polymorphism, Single Nucleotide, Atherosclerosis genetics, Mitochondria genetics, Mutation
- Abstract
Purpose of Review: Mutations in both nuclear and mitochondrial genes are associated with the development of atherosclerotic lesions in arteries and may provide a partial explanation to the focal nature of lesion distribution in the arterial wall. This review is aimed to discuss the genetic aspects of atherogenesis with a special focus on possible pro-atherogenic variants (mutations) of the nuclear and mitochondrial genomes that may be implicated in atherosclerosis development and progression., Recent Findings: Mutations in the nuclear genes generally do not cause a phenotype restricted to a specific vascular wall cell and manifest themselves mostly at the organism level. Such mutations can act as important contributors to changes in lipid metabolism and modulate other risk factors of atherosclerosis. By contrast, mitochondrial DNA (mtDNA) mutations occurring locally in the arterial wall cells or in circulating immune cells may play a site-specific role in atherogenesis. The mosaic distribution of heteroplasmic mtDNA mutations in the arterial wall tissue may explain, at least to some extent, the locality and focality of atherosclerotic lesions distribution. The genetic mechanisms of atherogenesis include alterations of both nuclear and mitochondrial genomes. Altered lipid metabolism and inflammatory response of resident arterial wall and circulating immune cells may be related to mtDNA damage and defective mitophagy, which hinders clearance of dysfunctional mitochondria. Mutations of mtDNA can have mosaic distribution and locally affect functionality of endothelial and subendothelial intimal cells in the arterial wall contributing to atherosclerotic lesion development.
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- 2020
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33. The Link between Chronic Stress and Accelerated Aging.
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Yegorov YE, Poznyak AV, Nikiforov NG, Sobenin IA, and Orekhov AN
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People exposed to chronic stress age rapidly. The telomeres in their cells of all types shorten faster. Inflammation is another important feature of stress that, along with aging, accounts for the phenomenon of inflammaging. In addition to aging itself, inflammaging can contribute to the development of several pathologies, including atherosclerosis, diabetes, hypertension, and others. Oxidative stress is one of the main mechanisms related to stress. Oxidative stress is caused by the over-production of reactive oxygen species (ROS) that can damage various tissues. The main source of ROS is mitochondria. Being suppressed by mitochondrial mutations, mitophagy can aggravate the situation. In this case, the aging-specific pro-inflammatory changes are amplified. It happens because of the inability of cells to maintain the normal state of mitochondria. Macrophages are the crucial element of the innate immunity associated with the chronic inflammation and, subsequently, with the inflammaging. In this review, we focus on the therapy approaches potentially reducing the deleterious effects of oxidative stress. These include stimulation of mitophagy, activation of mitochondrial uncoupling, induction of the expression of the telomerase catalytic component gene, and use of antioxidants. Any method reducing oxidative stress should improve post-traumatic stress disorder.
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- 2020
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34. Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response-What is First?
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Orekhov AN, Sukhorukov VN, Nikiforov NG, Kubekina MV, Sobenin IA, Foxx KK, Pintus S, Stegmaier P, Stelmashenko D, Kel A, Poznyak AV, Wu WK, Kasianov AS, Makeev VY, Manabe I, and Oishi Y
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- Biomarkers, Disease Susceptibility, Foam Cells pathology, Gene Expression Profiling, Humans, Inflammation etiology, Inflammation metabolism, Inflammation pathology, Inflammation Mediators metabolism, Macrophages metabolism, Macrophages pathology, Models, Biological, Cholesterol metabolism, Foam Cells metabolism, Lipid Metabolism, Signal Transduction
- Abstract
Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes ( F2RL1 , EIF2AK3 , and IL15 ) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15 , completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.
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- 2020
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35. Medicinal Plants as a Potential and Successful Treatment Option in the Context of Atherosclerosis.
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Kirichenko TV, Sukhorukov VN, Markin AM, Nikiforov NG, Liu PY, Sobenin IA, Tarasov VV, Orekhov AN, and Aliev G
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Atherosclerosis is a chronic multifactorial disease characterized by mainly changes of blood lipids profile and inflammation in vessel wall. The cardiovascular disease based on atherosclerosis is currently the leading cause of mortality in developed countries. Therefore, timely prevention and therapy of atherosclerosis are able to reduce the risk of the development of its clinical manifestations. Anti-atherosclerotic activity of medicinal plants mainly appears in their multiple effects such as anti-inflammatory, antioxidant, anti-atherogenic, hypotensive, lipid-lowering, anti-thrombotic. Moreover, most of medicinal plants are characterized by their pleiotropic anti-atherosclerotic action. In addition, the medicinal plants-derived pharmacological substances and/or compounds are characterized by relative safety and fewer side effects that allows considering them as one of potential anti-atherosclerotic effective agents. The direct anti-atherosclerotic effect of some medicinal plants was confirmed in clinical trials of carotid Intima-media thickness (IMT) progression during long-term medication with medicinal plants. This review attempted to determine the current status of the databases PubMed and Scopus (until November, 2019) to investigate the medicinal plants possessing anti-atherosclerotic activity in experimental and clinical studies., (Copyright © 2020 Kirichenko, Sukhorukov, Markin, Nikiforov, Liu, Sobenin, Tarasov, Orekhov and Aliev.)
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- 2020
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36. Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis.
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Orekhov AN, Nikiforov NG, Sukhorukov VN, Kubekina MV, Sobenin IA, Wu WK, Foxx KK, Pintus S, Stegmaier P, Stelmashenko D, Kel A, Gratchev AN, Melnichenko AA, Wetzker R, Summerhill VI, Manabe I, and Oishi Y
- Subjects
- Biomarkers, Foam Cells immunology, Gene Expression Profiling, Gene Knockdown Techniques, Humans, Immunity, Innate, Lipid Metabolism, Macrophages immunology, Macrophages metabolism, Monocytes immunology, Monocytes metabolism, Oxidation-Reduction, Signal Transduction, Transcriptome, Foam Cells metabolism, Foam Cells pathology, Lipoproteins, LDL metabolism, Phagocytosis genetics, Phagocytosis immunology
- Abstract
Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2 , and ANXA1 , on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response., Competing Interests: The authors declare no conflict of interest.
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- 2020
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37. Modification of Tumor Necrosis Factor-α and C-C Motif Chemokine Ligand 18 Secretion by Monocytes Derived from Patients with Diabetic Foot Syndrome.
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Galstyan KO, Nedosugova LV, Martirosian NS, Nikiforov NG, Elizova NV, Kolmychkova KI, Sobenin IA, and Orekhov AN
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Background: This study involves the investigation of spontaneous and induced secretion of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and the anti-inflammatory chemokine C-C motif chemokine ligand 18 (CCL18) by monocytes isolated from blood of patients with long-term type 2 diabetes mellitus (T2DM), both with or without foot ulcers. Methods: A total of 121 patients with T2DM (79 without diabetic foot syndrome (DFS) and 42 patients with DFS) were included. Cluster of Differentiation 14 (CD14+) monocytes were isolated from patients' blood and stimulated by interferon-γ (IFN-γ) and interleukin-4 (IL-4) for induction of pro- and anti-inflammatory monocyte activation, respectively. The concentrations of TNF-α and CCL18 in the culture medium were measured using ELISA on day 1 and day 6 after cell stimulation. Results: We found a correlation between glycated hemoglobin (HbA1c) and stimulated secretion levels of TNF-α ( r = 0.726, p = 0.027) and CCL18 ( r = -0.949, p = 0.051) in patients with DFS. There was an increase of pro- and anti-inflammatory activation of monocytes in all patients with different durations of DFS ( p < 0.05). However, no stimulation of anti-inflammatory activation was detected in patients with DFS lasting more than 6 months ( p = 0.033). Conclusions: Our study showed an increase in pro-inflammatory secretion and a decrease in anti-inflammatory secretion by monocytes isolated from blood of patients with T2DM depending on HbA1c levels and duration of the inflammatory process. These findings allow us to assume that monocytes isolated from T2DM patients are characterized by a biased ability to respond towards pro-inflammatory stimulation, contributing to the chronic wound process.
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- 2019
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38. Trained Circulating Monocytes in Atherosclerosis: Ex Vivo Model Approach.
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Nikiforov NG, Wetzker R, Kubekina MV, Petukhova AV, Kirichenko TV, and Orekhov AN
- Abstract
Inflammation is one of the key processes in the pathogenesis of atherosclerosis. Numerous studies are focused on the local inflammatory processes associated with atherosclerotic plaque initiation and progression. However, changes in the activation state of circulating monocytes, the main components of the innate immunity, may precede the local events. In this article, we discuss tolerance, which results in decreased ability of monocytes to be activated by pathogens and other stimuli, and training, the ability of monocyte to potentiate the response to pathological stimuli, and their relation to atherosclerosis. We also present previously unpublished results of the experiments that our group performed with monocytes/macrophages isolated from atherosclerosis patients. Our data allow assuming the existence of relationship between the formation of monocyte training and the degree of atherosclerosis progression. The suppression of trained immunity ex vivo seems to be a perspective model for searching anti-atherogenic drugs.
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- 2019
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39. HDL activates expression of genes stimulating cholesterol efflux in human monocyte-derived macrophages.
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Orekhov AN, Pushkarsky T, Oishi Y, Nikiforov NG, Zhelankin AV, Dubrovsky L, Makeev VJ, Foxx K, Jin X, Kruth HS, Sobenin IA, Sukhorukov VN, Zakiev ER, Kontush A, Le Goff W, and Bukrinsky M
- Subjects
- ATP Binding Cassette Transporter 1 genetics, Atherosclerosis physiopathology, Biological Transport, Cholesterol, Cholesterol, HDL metabolism, Delta-5 Fatty Acid Desaturase, Fatty Acid Desaturases genetics, Fatty Acid Desaturases metabolism, Foam Cells, Gene Expression Profiling, Gene Expression Regulation genetics, Gene Silencing, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Lipoproteins, HDL genetics, Lipoproteins, HDL metabolism, Macrophages metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, RNA, Messenger, RNA, Small Interfering, Receptors, LDL genetics, Receptors, LDL metabolism, THP-1 Cells, Up-Regulation, Cholesterol, HDL genetics, Macrophages physiology
- Abstract
High density lipoproteins (HDL) are key components of reverse cholesterol transport pathway. HDL removes excessive cholesterol from peripheral cells, including macrophages, providing protection from cholesterol accumulation and conversion into foam cells, which is a key event in pathogenesis of atherosclerosis. The mechanism of cellular cholesterol efflux stimulation by HDL involves interaction with the ABCA1 lipid transporter and ensuing transfer of cholesterol to HDL particles. In this study, we looked for additional proteins contributing to HDL-dependent cholesterol efflux. Using RNAseq, we analyzed mRNAs induced by HDL in human monocyte-derived macrophages and identified three genes, fatty acid desaturase 1 (FADS1), insulin induced gene 1 (INSIG1), and the low-density lipoprotein receptor (LDLR), expression of which was significantly upregulated by HDL. We individually knocked down these genes in THP-1 cells using gene silencing by siRNA, and measured cellular cholesterol efflux to HDL. Knock down of FADS1 did not significantly change cholesterol efflux (p = 0.70), but knockdown of INSIG1 and LDLR resulted in highly significant reduction of the efflux to HDL (67% and 75% of control, respectively, p < 0.001). Importantly, the suppression of cholesterol efflux was independent of known effects of these genes on cellular cholesterol content, as cells were loaded with cholesterol using acetylated LDL. These results indicate that HDL particles stimulate expression of genes that enhance cellular cholesterol transfer to HDL., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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40. Modified LDL Particles Activate Inflammatory Pathways in Monocyte-derived Macrophages: Transcriptome Analysis.
- Author
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Orekhov AN, Oishi Y, Nikiforov NG, Zhelankin AV, Dubrovsky L, Sobenin IA, Kel A, Stelmashenko D, Makeev VJ, Foxx K, Jin X, Kruth HS, and Bukrinsky M
- Subjects
- Healthy Volunteers, Humans, Lipoproteins, LDL chemistry, Gene Expression Profiling, Inflammation genetics, Inflammation metabolism, Lipoproteins, LDL genetics, Lipoproteins, LDL metabolism, Macrophages metabolism, Macrophages pathology
- Abstract
Background: A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation., Methods: We attempted to identify the main mater regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach., Results: We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL- 15 and CXCL8., Conclusion: Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)
- Published
- 2018
- Full Text
- View/download PDF
41. Tumor Necrosis Factor-α and C-C Motif Chemokine Ligand 18 Associate with Atherosclerotic Lipid Accumulation In situ and In vitro .
- Author
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Orekhov AN, Nikiforov NG, Elizova NV, Korobov GA, Aladinskaya AV, Sobenin IA, and Bobryshev YV
- Subjects
- Adult, Chemokines, CC analysis, Chemokines, CC genetics, Cholesterol analysis, Cholesterol metabolism, Female, Humans, Macrophages metabolism, Male, Middle Aged, Plaque, Atherosclerotic diagnosis, Plaque, Atherosclerotic genetics, Tumor Necrosis Factor-alpha analysis, Tumor Necrosis Factor-alpha genetics, Tunica Intima metabolism, Tunica Intima pathology, Chemokines, CC metabolism, Plaque, Atherosclerotic metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Atherosclerosis is regarded as a chronic inflammatory disease associated with changes in the innate immune system functioning and cytokine disturbances. Local inflammation in the arterial wall is an important component in the development and growth of atherosclerotic plaques. Inside the lesions, both pro- and antiinflammatory cytokines were detected, highlighting the complexity of the atherosclerotic process. However, little is known about the expression of these signaling molecules in early human atherosclerotic lesions. In this study, we explored localization of a pro-inflammatory cytokine, tumor necrosis factor-α (TNFα), and anti-inflammatory chemokine, C-C motif chemokine ligand 18 (CCL18), in the arterial wall of human aorta. We noticed differences in the intensity of staining for TNFα and CCL18 in atherosclerotic lesions and grossly normal areas, as well as differences in their localization. While CCL18 prevailed in the areas close to the aortic lumen, TNFα was localized in deeper layers of the intima. We next studied the expression of TNFα and CCL18 mRNA in lesions corresponding to different stages of atherosclerosis progression and found that it was maximal in lipofibrous plaques that are most enriched in lipids. To test the hypothesis that cytokine expression can be associated with lipid accumulation, we studied the TNFα and CCL18 expression profiles in primary human monocyte-derived macrophages after inducing lipid accumulation by incubating cultured cells with atherogenic LDL. We found that intracellular cholesterol accumulation was associated with upregulation of both TNFα and CCL18, confirming our hypothesis. These results encourage further investigation of cytokine expression in human atherosclerotic lesions and its role in the atherosclerosis progression., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)
- Published
- 2018
- Full Text
- View/download PDF
42. Multiple-modified Low-Density Lipoprotein as Atherogenic Factor of Patients' Blood: Development of Therapeutic Approaches to Reduce Blood Atherogenicity.
- Author
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Nikiforov NG, Zakiev ER, Elizova NV, Sukhorukov VN, and Orekhov AN
- Subjects
- Humans, Atherosclerosis blood, Atherosclerosis drug therapy, Lipoproteins, LDL blood
- Abstract
Generally, atherosclerosis first occurs by the way of accumulation of intracellular and extracellular lipids in the arterial intima. Foam cells, overloaded by lipids, are the essential harbinger of the coronary artery disease. It should be noted that lipids that are usually composed of bulk of the intracellular lipids found in human arterial cells originate from low-density lipoprotein (LDL) circulating in human blood. Nonetheless, many efforts to force cells to accumulate cholesteryl esters under the influence of native LDL have been unsuccessful. Whilst LDL modified in vitro (exposed to malondialdehyde, oxidized with ions of transition metals, acetylated, etc.) promoted accumulation of lipids in cells, all the attempts made for the sake of hunting down such LDLs in the bloodstream still do not provide confident conclusions. Therefore, a controversy arose: firstly, lipids from the cells of vascular wall have proved to be descending from LDL; secondly, foam cells do not form under the influence of native LDL in vitro (i.e. no visible intracellular lipid deposition observed); thirdly, chemically manipulated LDL seems to possess atherogenic properties. Acetylated LDL was not found in the bloodstream; similarly, the existence of oxidized LDL in the circulation remains controversial. Such a conundrum sparked a thorough investigation, leading to some interesting results. Modified desialylated LDL in human blood stream has been identified, which was able to promote lipid deposition in cultured cells. Such an LDL has been isolated, displaying atherogenic properties. The atherogenic LDL seems to deviate in multiple features from its non-atherogenic counterparts: carbohydrate, protein, and lipid moieties which were mangled. Such multiple LDL transformations take place in human blood stream and seem to denote a succession of events forcing the particle to become atherogenic: desialylation, lipid loss, shrinkage, rising of surface electronegative charge, etc. On top of the fat deposition in cells, multiple modifications of LDL as well as some other deleterious effects, like cell proliferation and fibrosis, seem to be part of the chain of events finally unfolding into a full-scale atherosclerotic lesion., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)
- Published
- 2017
- Full Text
- View/download PDF
43. Cell-Based Models for Development of Antiatherosclerotic Therapies.
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Zakiev ER, Nikiforov NG, and Orekhov AN
- Subjects
- Animals, Atherosclerosis pathology, Humans, Plaque, Atherosclerotic pathology, Atherosclerosis metabolism, Atherosclerosis therapy, Models, Biological, Plaque, Atherosclerotic metabolism, Plaque, Atherosclerotic therapy
- Abstract
The leading cause of death worldwide is cardiovascular disease. Among the conditions related to the term, the most prominent one is the development of atherosclerotic plaques in the walls of arteries. The situation gets even worse with the fact that the plaque development may stay asymptomatic for a prolonged period of time. When it manifests as a cardiovascular disorder, it is already too late: the unfortunate individual is prescribed with a plethora of synthetic drugs, which are of debatable efficacy in the prevention of atherosclerotic lesions and safety. Cell models could be useful for the purpose of screening substances potentially effective against atherosclerosis progression and effective in reduction of already present plaques. In this overview, we present studies making use of in vitro and ex vivo models of atherosclerosis development that can prove valuable for clinical applications., Competing Interests: The authors declare that there are no competing interests.
- Published
- 2017
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- View/download PDF
44. [Peculiarities of secretion of cytokines and chemokines by human blood monocytes in atherosclerosis].
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Nikiforov NG, Karagodin VP, Elizova NV, and Orekhov AN
- Subjects
- Asymptomatic Diseases, Cells, Cultured, Chemokines analysis, Cytokines analysis, Humans, Immunization, Immunoenzyme Techniques methods, Interferon-gamma immunology, Interleukin-4 immunology, Atherosclerosis immunology, Atherosclerosis pathology, Chemokines biosynthesis, Cytokines biosynthesis, Inflammation immunology, Inflammation pathology, Monocytes immunology, Monocytes pathology
- Abstract
The study included apparently healthy people, conventionally healthy people predisposed to atherosclerosis, and as well as people with preclinical atherosclerosis (50 subjects in each group). Monocytes were isolated from whole blood and transferred to culture followed by studying pro- and anti-inflammatory activation of monocytes in response to stimulation by interferon-gamma and interleukin-4, respectively. As a marker of pro-inflammatory activation was the level of secretion of tumour necrosis factor-α (TNF-α) in the culture medium measured by means of immunoenzymatic assay. Chemokine CCL18 served as a marker of anti-inflammatory activation. We also examined secretion of a series of other chemokines and cytokines: MCO-1, IL-6, IL-1β, IL-8, GM-CFS, and others. Pronounced individual differences of cytokines and chemokines secretion were revealed in all groups. We carried out assessment the degree of altering secretion of cytokines and chemokines by stimulated monocytes compared with unstimulated culture. This approach may serve as an effective tool for assessment an individual reaction of congenital immunity.
- Published
- 2017
45. Macrophages and Their Contribution to the Development of Atherosclerosis.
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Bobryshev YV, Nikiforov NG, Elizova NV, and Orekhov AN
- Subjects
- Animals, Humans, Inflammation immunology, Inflammation pathology, Macrophages cytology, Atherosclerosis immunology, Atherosclerosis pathology, Macrophages immunology
- Abstract
Atherosclerosis can be regarded as chronic inflammatory disease driven by lipid accumulation in the arterial wall. Macrophages play a key role in the development of local inflammatory response and atherosclerotic lesion growth. Atherosclerotic plaque is a complex microenvironment, in which different subsets of macrophages coexist executing distinct, although in some cases overlapping functions. According to the classical simplified nomenclature, lesion macrophages can belong to pro-inflammatory or anti-inflammatory or alternatively activated types. While the former promote the inflammatory response and participate in lipid accumulation, the latter are responsible for the inflammation resolution and plaque stabilisation. Atherosclerotic lesion dynamics depends therefore on the balance between these macrophages populations. The diverse functions of macrophages make them an attractive therapeutic target for the development of novel anti-atherosclerotic treatments. In this chapter, we discuss different types of macrophages and their roles in atherosclerotic lesion dynamics and describe the results of several experiments studying macrophage polarisation in atherosclerosis.
- Published
- 2017
- Full Text
- View/download PDF
46. Use of Primary Macrophages for Searching Novel Immunocorrectors.
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Nikiforov NG, Elizova NV, Bukrinsky M, Dubrovsky L, Makeev VJ, Wakabayashi Y, Liu P, Foxx KK, Kruth HS, Jin X, Zakiev ER, and Orekhov AN
- Subjects
- Animals, Humans, Adjuvants, Immunologic pharmacology, Anticholesteremic Agents pharmacology, Atherosclerosis drug therapy, Atherosclerosis immunology, Macrophages drug effects, Macrophages immunology
- Abstract
In this mini-review, the role of macrophage phenotypes in atherogenesis is considered. Recent studies on distribution of M1 and M2 macrophages in different types of atherosclerotic lesions indicate that macrophages exhibit a high degree of plasticity of phenotype in response to various conditions in microenvironment. The effect of the accumulation of cholesterol, a key event in atherogenesis, on the macrophage phenotype is also discussed. The article presents the results of transcriptome analysis of cholesterol-loaded macrophages revealing genes involved in immune response whose expression rate has changed the most. It turned out that the interaction of macrophages with modified LDL leads to higher expression levels of pro-inflammatory marker TNF-α and antiinflammatory marker CCL18. Phenotypic profile of macrophage activation could be a good target for testing of novel anti-atherogenic immunocorrectors. A number of anti-atherogenic drugs were tested as potential immunocorrectors using primary macrophage-based model., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)
- Published
- 2017
- Full Text
- View/download PDF
47. Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis.
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Bobryshev YV, Ivanova EA, Chistiakov DA, Nikiforov NG, and Orekhov AN
- Subjects
- Animals, Cytokines immunology, Humans, Atherosclerosis immunology, Inflammasomes immunology, Macrophage Activation immunology, Macrophages immunology, Models, Immunological, Transcriptome immunology
- Abstract
Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances.
- Published
- 2016
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- View/download PDF
48. [Macrophage activation in atherosclerosis. Message 2. Effects of factors on macrophage activation].
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Nikiforov NG, Elizova NV, Nikitina NA, Karagodin VP, and Orekhov AN
- Subjects
- Animals, Atherosclerosis pathology, Humans, Macrophages pathology, Atherosclerosis metabolism, Macrophage Activation, Macrophages metabolism
- Abstract
In atherosclerosis, macrophages demonstrate phenotypic plasticity to rapidly adjust to changing microenvironmental conditions. In the plaque, serum lipids, serum lipoproteins and various pro- or anti-inflammatory stimuli such as cytokines, chemokines and small bioactive molecules could greatly influence the macrophage phenotype inducing switch towards more proinflammatory or anti-inflammatory properties. Dynamic plasticity of macrophages is achieved by up-regulation and down-regulation of overlapping set of transcription factors that drive macrophage polarization. Understanding of mechanisms of macrophage plasticity and resolving functional characteristics of distinct macrophage phenotypes should help in the development of new strategies for treatment of chronic inflammation in cardiovascular disease.
- Published
- 2016
49. Phenomenon of individual difference in human monocyte activation.
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Orekhov AN, Nikiforov NG, Elizova NV, Ivanova EA, and Makeev VJ
- Subjects
- CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Carotid Artery Diseases pathology, Carotid Intima-Media Thickness, Chemokines, CC genetics, Chemokines, CC metabolism, Cross-Sectional Studies, Disease Progression, Humans, Immunity, Innate immunology, Macrophages, Monocytes metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Carotid Artery Diseases immunology, Monocytes cytology, Monocytes immunology
- Abstract
Macrophages play an important role in the pathogenesis of atherosclerosis, including the early pre-clinical stages of the disease development. We have explored the possibility that the disease onset could be associated with altered monocyte/macrophage response to activating pro- and anti-inflammatory stimuli. We evaluated the susceptibility of circulating monocytes from healthy individuals and patients with asymptomatic carotid atherosclerosis to M1 and M2 activation. The obtained data indicated the existence of a remarkable individual difference in susceptibility to activation among monocytes isolated from the blood of different subjects, regardless of the presence or absence of atherosclerosis. The identified differences in susceptibility to activation between monocytes may explain the individual peculiarities of the immune response in different subjects., (Copyright © 2015. Published by Elsevier Inc.)
- Published
- 2015
- Full Text
- View/download PDF
50. [Macrophage activation in atherosclerosis. Message 1: Activation of macrophages normally and in atherosclerotic lesions].
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Nikiforov NG, Kornienko VY, Karagodin VP, and Orekhov AN
- Subjects
- Animals, Atherosclerosis metabolism, Atherosclerosis pathology, Humans, Macrophages metabolism, Macrophages pathology, Plaque, Atherosclerotic metabolism, Plaque, Atherosclerotic pathology, Atherosclerosis immunology, Macrophage Activation, Macrophages immunology, Plaque, Atherosclerotic immunology
- Abstract
Macrophages play important role in initiation and progression of inflammation in atherosclerosis. Plaque macrophages were shown to exhibit a phenotypic range that is intermediate between two extremes, M1 (proinflammatory) and M2 (anti-inflammatory). Indeed, in atherosclerosis, macrophages demonstrate phenotypic plasticity to rapidly adjust to changing microenvironmental conditions. In plaque macrophages demonstrate different phenotypes, and besides macrophage phenotypes could be changed. Phenotypes M1, M2, M4, Mhem, HA-mac, M(Hb) u Mox are described in the article. Ability of macrophages change their phenotype also considered.
- Published
- 2015
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