Search

• Healthy and cancerous cells were subjected to the action of the magnetic nanoparticles and fields. • The new approach of magnetically activated antileukemia therapy was suggested. • Magnetic field enhances cytotoxicity of iron oxide magnetic nanoparticles. • Cancerous cells are more affected by combining the action of magnetic nanoparticles and fields. This paper describes proof-of-concept for antileukemia treatment based on the reactive oxygen species (ROS) induction supplemented with magnetic nanoparticles in the presence of moderate-intensity magnetic fields. The T-lymphoblastic leukemia cell line (Jurkat) was chosen as an in vitro model of acute lymphoblastic leukemia. The elevated ROS levels were generated by iron oxide magnetic nanoparticles. We found an enhanced cytotoxic effect of magnetic nanoparticles in the presence of a magnetic field on cancerous Jurkat cell line due to induced oxidative stress after cultivation in magnetic fields with an average strength of 0.26–0.36 T and the field spatial gradient up to 100 T/m. At the same conditions of nanoparticles intake, the viability of human peripheral blood mononuclear cells (model of healthy cells) was not inhibited. Thus, we demonstrated the feasibility of antileukemia treatment by magnetic nanoparticles controlled by a magnetic field. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a complex of serious pathologies with a high prevalence worldwide. Disruption of mitochondrial biogenesis and its interaction with other cell organelles plays an important role in the development of MetS. Studies have revealed the phenotypic and functional heterogeneity of mitochondria that exist within a single cell and can regulate metabolic signaling pathways, influencing the development of metabolic diseases. Excessive intake of fatty acids leads to changes in fatty acid metabolism that affect the biology of important cell organelles - the lipid droplets, whose specific biology is not fully understood. Perhaps targeted molecular genetic stimulation aimed at regulating the contact between mitochondria and lipids can break the vicious cycle of inflammation in MetS and restore normal cell function, reducing the risk of developing concomitant pathologies. The review describes potential (promising) therapeutic molecular targets associated with mitochondria and lipid droplets, focusing on the proteins involved in their contact and emphasizing their role in the pathogenesis of MetS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Prohibitins are the central regulatory element of cellular homeostasis, especially by modulating the response at different levels: Nucleus, mitochondria and membranes. Their localization and interaction with various proteins, homons, transcription and nuclear factors, and mtDNA indicate the globality and complexity of their pleiotropic properties, which remain to be investigated. A more detailed deciphering of cellular metabolism in relation to prohibitins under normal conditions and in various metabolic diseases will allow us to understand the precise role of prohibitins in the signaling cascades of PI3K/Akt, Raf/MAP/ERK, STAT3, p53, and others and to fathom their mutual influence. A valuable research perspective is to investigate the role of prohibitins in the molecular and cellular interactions between the two major players in the pathogenesis of obesity-adipocytes and macrophages - that form the basis of the meta-inflammatory response. Investigating the subtle intercellular communication and molecular cascades triggered in these cells will allow us to propose new therapeutic strategies to eliminate persistent inflammation, taking into account novel molecular genetic approaches to activate/inactivate prohibitins., 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 © 2024 Todosenko, Yurova, Vulf, Khaziakhmatova and Litvinova.)

We studied the effect of the HSP27 inhibitor, 5-(5-ethyl-2-hydroxy-4-methoxyphenyl)-4-(4-methoxyphenyl)-isoxazole, at a final concentration of 0.1 μM and/or the apoptosis inducer dexamethasone at a final concentration of 10 μM on the content of hydroxyl radical, reduced and oxidized glutathione, HSP27, activity of glutathione reductase, glutathione peroxidase, caspase-3, and the number of Annexin + Jurkat tumor cells. The involvement of HSP27 in apoptosis of Jurkat tumor cells was demonstrated. Simultaneous exposure to the HSP27 inhibitor and dexamethasone resulted in an increase in the level of HSP27 against the background of developing oxidative stress (increase in the concentration of hydroxyl radicals and changes in the state of the glutathione system)., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Monocytes play a key role in the development of metabolic syndrome, and especially obesity. Given the complex features of their development from progenitor cells, whose regulation is mediated by their interactions with bone marrow adipocytes, the importance of a detailed study of the heterogeneous composition of monocytes at the molecular and systemic levels becomes clear. Research argues for monocytes as indicators of changes in the body's metabolism and the possibility of developing therapeutic strategies to combat obesity and components of metabolic syndrome based on manipulations of the monocyte compound of the immune response. An in-depth study of the heterogeneity of bone-marrow-derived monocytes and adipocytes could provide answers to many questions about the pathogenesis of obesity and reveal their therapeutic potential.

Metabolic syndrome (MetS) is a precursor to the major health diseases associated with high mortality in industrialized countries: cardiovascular disease and diabetes. An important component of the pathogenesis of the metabolic syndrome is mitochondrial dysfunction, which is associated with tissue hypoxia, disruption of mitochondrial integrity, increased production of reactive oxygen species, and a decrease in ATP, leading to a chronic inflammatory state that affects tissues and organ systems. The mitochondrial AAA + protease Lon (Lonp1) has a broad spectrum of activities. In addition to its classical function (degradation of misfolded or damaged proteins), enzymatic activity (proteolysis, chaperone activity, mitochondrial DNA (mtDNA)binding) has been demonstrated. At the same time, the spectrum of Lonp1 activity extends to the regulation of cellular processes inside mitochondria, as well as outside mitochondria (nuclear localization). This mitochondrial protease with enzymatic activity may be a promising molecular target for the development of targeted therapy for MetS and its components. The aim of this review is to elucidate the role of mtDNA in the pathogenesis of metabolic syndrome and its components as a key component of mitochondrial dysfunction and to describe the promising and little-studied AAA + LonP1 protease as a potential target in metabolic disorders.

Obese individuals are at high risk for developing type 2 diabetes mellitus, cardiovascular diseases, and nonalcoholic fatty liver disease. The aim of this review was to analyze the scientific literature and databases to reveal the fundamental role of neuregulin 4 (NRG4) and its receptors in the development of obesity-associated metabolic disorders. This review demonstrates that NRG4 and its receptors are promising therapeutic targets for the treatment of socially significant obesity-associated pathologies. The review contains nine chapters. Information on the structure of ERBB4 and NRG4 splice isoforms and subsequent activation of downstream targets is presented. The tissue-specific features of the NRG4 and ERBB4 genes and protein production are also highlighted. The role of NRG4 and ERBB3/4 in the pathophysiological mechanisms of the development of metabolic disorders in obesity is discussed in detail. The final chapter of the review is devoted to the miRNA-dependent regulation of NRG4 and ERBB4. Recent studies have shown that several miRNAs regulate ERBB4 expression, but no information was found on the interaction of NRG4 with miRNAs. We now demonstrate the putative relationships between NRG4 and let-7a-5p, let-7c-5p, miR-423-5p, miR-93-5p, miR-23a-3p, and miR-15b-5p for the first time. In addition, we found SNP mutations affecting the interaction of NRG4 and ERBB4 with miRNA in these genes as well as in miRNAs. In summary, this review provides a detailed and comprehensive overview of the role of NRG4 in obesity-associated metabolic disorders. The review summarizes all current studies on this topic and opens perspectives for future research., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

The major challenges in Osteosarcoma (OS) therapy are its heterogeneity and drug resistance. The development of new therapeutic approaches to overcome the major growth mechanisms of OS is urgently needed. The search for specific molecular targets and promising innovative approaches in OS therapy, including drug delivery methods, is an urgent problem. Modern regenerative medicine focuses on harnessing the potential of mesenchymal stem cells (MSCs) because they have low immunogenicity. MSCs are important cells that have received considerable attention in cancer research. Currently, new cell-based methods for using MSCs in medicine are being actively investigated and tested, especially as carriers for chemotherapeutics, nanoparticles, and photosensitizers. However, despite the inexhaustible regenerative potential and known anticancer properties of MSCs, they may trigger the development and progression of bone tumors. A better understanding of the complex cellular and molecular mechanisms of OS pathogenesis is essential to identify novel molecular effectors involved in oncogenesis. The current review focuses on signaling pathways and miRNAs involved in the development of OS and describes the role of MSCs in oncogenesis and their potential for antitumor cell-based therapy.

Graphene oxide is a promising nanomaterial with many potential applications. However, before it can be widely used in areas such as drug delivery and medical diagnostics, its influence on various cell populations in the human body must be studied to ensure its safety. We investigated the interaction of graphene oxide (GO) nanoparticles with human mesenchymal stem cells (hMSCs) in the Cell-IQ system, evaluating cell viability, mobility, and growth rate. GO nanoparticles of different sizes coated with linear or branched polyethylene glycol (P or bP, respectively) were used at concentrations of 5 and 25 μg/mL. Designations were the following: P-GOs (Ø 184 ± 73 nm), bP-GOs (Ø 287 ± 52 nm), P-GOb (Ø 569 ± 14 nm), and bP-GOb (Ø 1376 ± 48 nm). After incubating the cells with all types of nanoparticles for 24 h, the internalization of the nanoparticles by the cells was observed. We found that all GO nanoparticles used in this study exerted a cytotoxic effect on hMSCs when used at a high concentration (25 μg/mL), whereas at a low concentration (5 μg/mL) a cytotoxic effect was observed only for bP-GOb particles. We also found that P-GOs particles decreased cell mobility at a concentration of 25 μg/mL, whereas bP-GOb particles increased it. Larger particles (P-GOb and bP-GOb) increased the rate of movement of hMSCs regardless of concentration. There were no statistically significant differences in the growth rate of cells compared with the control group.

Obesity is the main cause of metabolic complications. Fatty liver infiltration is a companion of obesity. NAFLD is associated with impaired energy metabolism with an excess of nutrients. Mitochondrial dynamics are important for the regulation of energy balance, which regulates mitochondrial function, apoptosis, and mitophagy. The aim of this study was to investigate the effect of gp130 on the components of mitochondrial dynamics in a cellular model of steatohepatitis. Addition of IL-6/gp130 contributed to an increase in the percentage of live cells and a decrease in the percentage of dead and apoptotic cells. Addition of IL-6/gp130 increased the expression of NF-kB1 gene and mitochondrial dynamics markers (MFN2 and TFAM) in HepG2 with tBHP/Oleic. Addition of IL-6 or gp130 reduced the expression of cytoprotector genes (HSF1 and HSP70) in HepG2 cell cultures with tBHP/Oleic. Increased mitochondrial dynamics gene activity protected against HepG2 cell death in the steatohepatitis model. Trans-signaling resulted in increased TFAM and MAPLC3B, and decreased DNM1L gene expression in HepG2 with tBHP/Oleic.

The prospect of continued manned space missions warrants an in-depth understanding of how prolonged microgravity affects the human brain. Functional magnetic resonance imaging (fMRI) can pinpoint changes reflecting adaptive neuroplasticity across time. We acquired resting-state fMRI data of cosmonauts before, shortly after, and eight months after spaceflight as a follow-up to assess global connectivity changes over time. Our results show persisting connectivity decreases in posterior cingulate cortex and thalamus and persisting increases in the right angular gyrus. Connectivity in the bilateral insular cortex decreased after spaceflight, which reversed at follow-up. No significant connectivity changes across eight months were found in a matched control group. Overall, we show that altered gravitational environments influence functional connectivity longitudinally in multimodal brain hubs, reflecting adaptations to unfamiliar and conflicting sensory input in microgravity. These results provide insights into brain functional modifications occurring during spaceflight, and their further development when back on Earth., (© 2023. The Author(s).)

The development of “biohybrid” drug delivery systems (DDS) based on mesenchymal stem/stromal cells (MSCs) is an important focus of current biotechnology research, particularly in the areas of oncotheranostics, regenerative medicine, and tissue bioengineering. However, the behavior of MSCs at sites of inflammation and tumor growth is relevant to potential tumor transformation, immunosuppression, the inhibition or stimulation of tumor growth, metastasis, and angiogenesis. Therefore, the concept was formulated to control the lifespan of MSCs for a specific time sufficient for drug delivery to the target tissue by varying the number of internalized microcontainers. The current study addressed the time-dependent in vitro assessment of the viability, migration, and division of human adipose-derived MSCs (hAMSCs) as a function of the dose of internalized polyelectrolyte microcapsules prepared using a layer-by-layer technique. Polystyrene sulfonate (PSS)—poly(allylamine hydrochloride) (PAH)-coated spherical micrometer-sized (diameter ~2−3 µm) vaterite (CaCO3) microcapsules (PAH-PSS)6 with the capping PSS layer were prepared after dissolution of the CaCO3 core template. The Cell-IQ phase contrast imaging results showed that hAMSCs internalized all (PAH-PSS)6 microcapsules saturating the intercellular medium (5−90 particles per cell). A strong (r > 0.7) linear dose-dependent and time-dependent (up to 8 days) regression was observed between the in vitro decrease in cell viability and the number of internalized microvesicles. The approximate time-to-complete-death of hAMSCs at different concentrations of microcapsules in culture was 428 h (1:5 ratio), 339 h (1:10), 252 h (1:20), 247 h (1:45), and 170 h (1:90 ratio). By varying the number of microcontainers loaded into the cells (from 1:10 to 1:90), a dose-dependent exponential decrease in both the movement rate and division rate of hAMSCs was observed. A real-time cell analysis (RTCA) of the effect of (PAH-PSS)6 microcapsules (from 1:5 to 1:20) on hAMSCs also showed a dose- and time-dependent decrease in cell longevity after a 50h study at ratios of 1:10 and 1:20. The incorporation of microcapsules (1:5, 1:20, and 1:45) resulted in a dose-dependent increase in 24−48 h secretion of GRO-α (CXCL1), MIF, and SDF-1α (CXCL12) chemokines in hAMSC culture. In turn, the normalization or inhibition of chemokine secretion occurred after 72 h, except for MIF levels below 5−20 microcapsules, which were internalized by MSCs. Thus, the proposed concept of controlling the lifespan of MSC-based DDS using a dose of internalized PAH-PSS microcapsules could be useful for biomedical applications. (PAH-PSS)6 microcapsule ratios of 1:5 and 1:10 have little effect on the lifespan of hAMSCs for a long time (up to 14−18 days), which can be recommended for regenerative therapy and tissue bioengineering associated with low oncological risk. The microcapsule ratios of 1:20 and 1:45 did not significantly restrict the migratory activity of hAMSCs-based DDS during the time interval required for tissue delivery (up to 4−5 days), followed by cell death after 10 days. Therefore, such doses of microcapsules can be used for hAMSC-based DDS in oncotheranostics.

Bacterial extracellular membrane nanovesicles (EMNs) are attracting the attention of scientists more and more every year. These formations are involved in the pathogenesis of numerous diseases, among which, of course, the leading role is occupied by infectious diseases, the causative agents of which are a range of Gram-positive and Gram-negative bacteria. A separate field for the study of the role of EMN is cancer. Extracellular membrane nanovesicles nowadays have a practical application as vaccine carriers for immunization against many infectious diseases. At present, the most essential point is their role in stimulating immune response to bacterial infections and tumor cells. The possibility of nanovesicles' practical use in several disease treatments is being evaluated. In our review, we listed diseases, focusing on their multitude and diversity, for which EMNs are essential, and also considered in detail the possibilities of using EMNs in the therapy and prevention of various pathologies.

Lipid metabolism alterations are an important component of the pathogenesis of atherosclerosis. However, it is now clear that the atherogenesis process involves more than one mechanism, and more than one condition can predispose this condition. Multiple risk factors contribute to the atherosclerosis initiation and define its course. Familial hypercholesterolaemia is a disorder of lipid metabolism that often leads to atherosclerosis development. As is clear from the disease name, the hallmark is the increased levels of low-density lipoprotein cholesterol (LDL-C) in blood. This creates favourable conditions for atherogenesis. In this review, we briefly described the familial hypercholesterolaemia and summarized data on the relationship between familial hypercholesterolaemia and atherosclerosis.

One of the main problems of modern health care is the growing number of oncological diseases both in the elderly and young population. Inadequately effective chemotherapy, which remains the main method of cancer control, is largely associated with the emergence of multidrug resistance in tumor cells. The search for new solutions to overcome the resistance of malignant cells to pharmacological agents is being actively pursued. Another serious problem is immunosuppression caused both by the tumor cells themselves and by antitumor drugs. Of great interest in this context is heparin, a biomolecule belonging to the class of glycosaminoglycans and possessing a broad spectrum of biological activity, including immunomodulatory and antitumor properties. In the context of the rapid development of the new field of "osteoimmunology," which focuses on the collaboration of bone and immune cells, heparin and delivery systems based on it may be of intriguing importance for the oncotherapy of malignant bone tumors. Osteosarcoma is a rare but highly aggressive, chemoresistant malignant tumor that affects young adults and is characterized by constant recurrence and metastasis. This review describes the direct and immune-mediated regulatory effects of heparin and drug delivery systems based on it on the molecular mechanisms of (multiple) drug resistance in (onco) pathological conditions of bone tissue, especially osteosarcoma.

Cardiovascular diseases remain the leading cause of death and disability. The development of cardiovascular diseases is traditionally associated with various risk factors, most of which are somehow related to an unhealthy lifestyle (smoking, obesity, lack of physical activity, etc.). There are also risk factors associated with genetic predisposition, as well as the presence of concomitant diseases, especially chronic ones. One of the most striking examples is, of course, type 2 diabetes. This metabolic disorder is associated with impaired carbohydrate metabolism. The main clinical manifestation of type 2 diabetes is elevated blood glucose levels. The link between diabetes and CVD is well known, so it is logical to assume that elevated glucose levels may be important, to some extent, in the context of heart and vascular disease. In this review, we tried to summarize data on the possible role of blood glucose as a risk factor for the development of CVD.

Atherosclerosis is a common cause of cardiovascular disease, which, in turn, is often fatal. Today, we know a lot about the pathogenesis of atherosclerosis. However, the main knowledge is that the disease is extremely complicated. The development of atherosclerosis is associated with more than one molecular mechanism, each making a significant contribution. These mechanisms include endothelial dysfunction, inflammation, mitochondrial dysfunction, oxidative stress, and lipid metabolism disorders. This complexity inevitably leads to difficulties in treatment and prevention. One of the possible therapeutic options for atherosclerosis and its consequences may be metformin, which has already proven itself in the treatment of diabetes. Both diabetes and atherosclerosis are complex metabolic diseases, the pathogenesis of which involves many different mechanisms, including those common to both diseases. This makes metformin a suitable candidate for investigating its efficacy in cardiovascular disease. In this review, we highlight aspects such as the mechanisms of action and targets of metformin, in addition to summarizing the available data from clinical trials on the effective reduction of cardiovascular risks.

Obesity and osteoporosis are global health problems characterized by high rates of prevalence and mortality due to complications. As people with visceral obesity age, the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) increases, and adipocytes become the predominant stromal cells in the bone marrow microenvironment, which hinders the physiological regeneration and mineralization of bone tissue. Primary and secondary osteoporosis remain severe progressive diseases. Both osteoporosis and obesity are associated with microRNAs (miRNAs) that induce adipogenesis and osteoresorption. This review presents analyses of the roles and clinical potential of miRNAs in the epigenetic control of BMSC differentiation and the formation and function of osteoclasts in osteoporosis with and without obesity. Understanding the fine-tuned regulation of the expression of genes critical for the balance of osteogenesis/osteolysis processes may provide hope for the development of effective and safe osteoporosis therapies in the future., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

This paper focuses mainly on the in vitro study of a five-week biodegradation of a-C:H:SiO x films of different thickness, obtained by plasma-assisted chemical vapor deposition onto Ti-6Al-4V alloy substrate using its pulsed bipolar biasing. In vitro immersion of a-C:H:SiO x films in a solution of 0.9% NaCl was used. It is shown how the a-C:H:SiO x film thickness (0.5-3 µm) affects the surface morphology, adhesive strength, and Na + and Cl - precipitation on the film surface from the NaCl solution. With increasing film thickness, the roughness indices are reducing a little. The adhesive strength of the a-C:H:SiO x films to metal substrate corresponds to quality HF1 (0.5 µm in thickness) and HF2-HF3 (1.5-3 µm in thickness) of the Rockwell hardness test (VDI 3198) that defines strong interfacial adhesion and is usually applied in practice. The morphometric analysis of the film surface shows that on a-C:H:SiO x -coated Ti-6Al-4V alloy surface, the area occupied by the grains of sodium chloride is lower than on the uncoated surface. The reduction in the ion precipitation from 0.9% NaCl onto the film surface depended on the elemental composition of the surface layer conditioned by the thickness growth of the a-C:H:SiO x film. Based on the results of energy dispersive X-ray spectroscopy, the multiple regression equations are suggested to explain the effect of the elemental composition of the a-C:H:SiO x film on the decreased Na + and Cl - precipitation. As a result, the a-C:H:SiO x films successfully combine good adhesion strength and rare ion precipitation and thus are rather promising for medical applications on cardiovascular stents and/or friction parts of heart pumps.

Long-duration spaceflight induces changes to the brain and cerebrospinal fluid compartments and visual acuity problems known as spaceflight-associated neuro-ocular syndrome (SANS). The clinical relevance of these changes and whether they equally affect crews of different space agencies remain unknown. We used MRI to analyze the alterations occurring in the perivascular spaces (PVS) in NASA and European Space Agency astronauts and Roscosmos cosmonauts after a 6-mo spaceflight on the International Space Station (ISS). We found increased volume of basal ganglia PVS and white matter PVS (WM-PVS) after spaceflight, which was more prominent in the NASA crew than the Roscosmos crew. Moreover, both crews demonstrated a similar degree of lateral ventricle enlargement and decreased subarachnoid space at the vertex, which was correlated with WM-PVS enlargement. As all crews experienced the same environment aboard the ISS, the differences in WM-PVS enlargement may have been due to, among other factors, differences in the use of countermeasures and high-resistive exercise regimes, which can influence brain fluid redistribution. Moreover, NASA astronauts who developed SANS had greater pre- and postflight WM-PVS volumes than those unaffected. These results provide evidence for a potential link between WM-PVS fluid and SANS.

A number of preclinical and clinical studies have demonstrated the efficiency of mesenchymal stromal cells to serve as an excellent base for a cell-mediated drug delivery system. Cell-based targeted drug delivery has received much attention as a system to facilitate the uptake a nd transfer of active substances to specific organs and tissues with high efficiency. Human mesenchymal stem cells (MSCs) are attracting increased interest as a promising tool for cell-based therapy due to their high proliferative capacity, multi-potency, and anti-inflammatory and immunomodulatory properties. In particular, these cells are potentially suitable for use as encapsulated drug transporters to sites of inflammation. Here, we studied the in vitro effects of incorporating synthetic polymer microcapsules at various microcapsule-to-cell ratios on the morphology, ultrastructure, cytokine profile, and migration ability of human adipose-derived MSCs at various time points post-phagocytosis. The data show that under appropriate conditions, human MSCs can be efficiently loaded with synthesized microcapsules without damaging the cell's structural integrity with unexpressed cytokine secretion, retained motility, and ability to migrate through 8 μm pores. Thus, the strategy of using human MSCs as a delivery vehicle for transferring microcapsules, containing bioactive material, across the tissue-blood or tumor-blood barriers to facilitate the treatment of stroke, cancer, or inflammatory diseases may open a new therapeutic perspective., 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 © 2022 Litvinova, Shupletsova, Khaziakhmatova, Daminova, Kudryavtseva, Yurova, Malashchenko, Todosenko, Popova, Litvinov, Korotkova, Sukhorukov, Gow, Weissman, Atochina-Vasserman and Khlusov.)

Humans undergo extreme physiological changes when subjected to long periods of weightlessness, and as we continue to become a space-faring species, it is imperative that we fully understand the physiological changes that occur in the human body, including the brain. In this study, we present findings of brain structural changes associated with long-duration spaceflight based on diffusion magnetic resonance imaging (dMRI) data. Twelve cosmonauts who spent an average of six months aboard the International Space Station (ISS) were scanned in an MRI scanner pre-flight, ten days after flight, and at a follow-up time point seven months after flight. We performed differential tractography, a technique that confines white matter fiber tracking to voxels showing microstructural changes. We found significant microstructural changes in several large white matter tracts, such as the corpus callosum, arcuate fasciculus, corticospinal, corticostriatal, and cerebellar tracts. This is the first paper to use fiber tractography to investigate which specific tracts exhibit structural changes after long-duration spaceflight and may direct future research to investigate brain functional and behavioral changes associated with these white matter pathways., 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 © 2022 Doroshin, Jillings, Jeurissen, Tomilovskaya, Pechenkova, Nosikova, Rumshiskaya, Litvinova, Rukavishnikov, De Laet, Schoenmaekers, Sijbers, Laureys, Petrovichev, Van Ombergen, Annen, Sunaert, Parizel, Sinitsyn, zu Eulenburg, Osipowicz and Wuyts.)

Background: First reported case of Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in Kazakhstan was identified in March 2020. Many specialized tertiary hospitals in Kazakhstan including National Research Cardiac Surgery Center (NRCSC) were re-organized to accept coronavirus disease 2019 (COVID-19) infected patients during summer months of 2020. Although many studies from worldwide reported their experience in treating patients with COVID-19, there are limited data available from the Central Asia countries. The aim of this study is to identify predictors of mortality associated with COVID-19 in NRCSC tertiary hospital in Nur-Sultan, Kazakhstan., Methods: This is a retrospective cohort study of patients admitted to the NRCSC between June 1st-August 31st 2020 with COVID-19. Demographic, clinical and laboratory data were collected from electronic records. In-hospital mortality was assessed as an outcome. Patients were followed-up until in-hospital death or discharge from the hospital. Descriptive statistics and factors associated with mortality were assessed using univariate and multivariate logistic regression models., Results: Two hundred thirty-nine admissions were recorded during the follow-up period. Mean age was 57 years and 61% were males. Median duration of stay at the hospital was 8 days and 34 (14%) patients died during the hospitalization. Non-survivors were more likely to be admitted later from the disease onset, with higher fever, lower oxygen saturation and increased respiratory rate compared to survivors. Leukocytosis, lymphopenia, anemia, elevated liver and kidney function tests, hypoproteinemia, elevated inflammatory markers (C-reactive protein (CRP), ferritin, and lactate dehydrogenase (LDH)) and coagulation tests (fibrinogen, D-dimer, international normalized ratio (INR), and activated partial thromboplastin time (aPTT)) at admission were associated with mortality. Age (OR 1.2, CI:1.01-1.43), respiratory rate (OR 1.38, CI: 1.07-1.77), and CRP (OR 1.39, CI: 1.04-1.87) were determined to be independent predictors of mortality., Conclusion: This study describes 14% mortality rate from COVID-19 in the tertiary hospital. Many abnormal clinical and laboratory variables at admission were associated with poor outcome. Age, respiratory rate and CRP were found to be independent predictors of mortality. Our finding would help healthcare providers to predict the risk factors associated with high risk of mortality. Further investigations involving large cohorts should be provided to support our findings., Competing Interests: The authors have declared that no competing interests exist.

Novel polyfluorene polymer brushes with polymethacrylic acid side chains were obtained by atom transfer radical polymerization (ATRP) and activator generated by electron transfer (AGET) ATRP of tert-butyl methacrylate on polyfluorene multifunctional macroinitiator, followed by protonolysis of the tert-butyl groups of the side chains. Kinetics of polymerization and molecular weights were fully characterized. These polymer brushes luminesce in the blue region of the spectrum with high quantum yields (0.64-0.77). It was shown that the luminescence intensity of polymer brushes is higher than the luminescence intensity of the macroinitiator (0.61). Moreover, due to their amphiphilic nature, they can form unimolecular micelles when an alcohol solution of the polymer brush is injected into water. These properties can potentially be used in drug delivery and bioimaging.

We studied the effects of pregnancy-specific β1-glycoprotein (PSG) on the replicative potential of naïve T cells (CD45RA + ) and immune memory T cells (CD45R0 + ) in vitro by evaluating the expression of the hTERT gene in combination with the proliferative activity of cells. Human PSG was obtained by the author's patented method of immunopurification using a biospecific sorbent with subsequent removal of immunoglobulin contamination on a HiTrap Protein G HP column. We used monocultures of CD45RA + and CD45R0 + lymphocytes isolated from peripheral blood mononuclear cells of reproductive-age women. It was found that PSG in physiological concentrations inhibited the expression of the hTERT gene mRNA in naïve T cells and immune memory T cells and simultaneously reduced the number of proliferating T cells estimated by the differential gating method. At the same time, PSG reduced CD71 expression only on naïve T cells without affecting this molecule on immune memory T cells. Thus, PSG decreased the replication potential and suppressed the proliferation of T cells and immune memory T cells, which in the context of pregnancy can contribute to the formation of immune tolerance to the semi-allogeneic embryo., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Subclinical inflammation in morbid obesity is associated with immune activation and the development of concomitant diseases. Impaired immune homeostasis and immune cell dysregulation in adipose tissue are associated with phenotypic and functional changes in the pool of T lymphocytes and the development of chronic hypovitaminosis D. Low vitamin D levels in obesity lead to the activation, proliferation and production of pro-inflammatory mediators by T cells. Hypovitaminosis D is the cause of a decrease in the functional potential of regulatory and anti-inflammatory lymphocytes and the maintenance of the inflammatory response. The exact molecular genetic mechanisms of the effect of vitamin D on T lymphocytes have not been fully elucidated. Therefore, uncovering the functional role of T cells and their relationship to vitamin D homeostasis in the context of obesity development may contribute to the development of new pathogenetic methods for clinical prediction of the risk of metabolic, oncologic, autoimmune and infectious complications. The review presents the molecular genetic mechanisms of the effect of vitamin D on adipose tissue resident T lymphocytes and the characteristics of vitamin D receptor expression, and analyzes the phenotypic and functional characteristics of potentially pathogenic T lymphocytes in relation to the development of obesity and its associated complications.

Interactions between receptors and ligands of the tumor necrosis factor superfamily (TNFSF) provide costimulatory signals that control the survival, proliferation, differentiation, and effector function of immune cells. All components of the TNF superfamily are associated with NF-kB functions that are not limited to cell death and may promote survival in the face of adipose tissue inflammation in obesity. Inflammation dysfunction of mitochondria is a key factor associated with insulin resistance in obesity. The aim of the study was to analyze the relationship of soluble forms of receptors and ligands of the TNF superfamily in blood plasma with mitochondrial dynamics in adipose tissue (greater omentum (GO) and subcutaneous adipose tissue (Sat)) of obese patients with and without type 2 diabetes mellitus (T2DM). Increased plasma sTNF-R1, sTNF-R2, sTNFRSF8 receptors, and ligands TNFSF12, TNFSF13, TNFSF13B are characteristic of obese patients without T2DM. The TNF-a levels in blood plasma were associated with a decrease in MFN2 gene expression in GO and IL-10 in blood plasma. The TNFSF12 levels contributed to a decrease in glucose levels, a decrease in BMI, and an increase in IL-10 levels by influencing the MFN2 gene expression in GO, which supports mitochondrial fusion.

Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases worldwide, affecting 25% of the world population. In recent years, there has been increasing evidence for the involvement of microRNAs in the epigenetic regulation of genes taking part in the development of steatosis and steatohepatitis-two main stages of NAFLD pathogenesis. In the present study, miRNA profiles were studied in groups of patients with steatosis and steatohepatitis to compare the characteristics of RNA-dependent epigenetic regulation of the stages of NAFLD development. According to the results of miRNA screening, 23 miRNAs were differentially expressed serum in a group of patients with steatohepatitis and 2 in a group of patients with steatosis. MiR-195-5p and miR-16-5p are common differentially expressed miRNAs for both steatosis and steatohepatitis. We analyzed the obtained results: the search for target genes for the differentially expressed miRNAs in our study and the subsequent gene set enrichment analysis performed on KEGG and REACTOME databases revealed which metabolic pathways undergo changes in RNA-dependent epigenetic regulation in steatosis and steatohepatitis. New findings within the framework of this study are the dysregulation of neurohumoral pathways in the pathogenesis of NAFLD as an object of changes in RNA-dependent epigenetic regulation. The miRNAs differentially expressed in our study were found to target 7% of genes in the classic pathogenesis of NAFLD in the group of patients with steatosis and 50% in the group of patients with steatohepatitis. The effects of these microRNAs on genes for the pathogenesis of NAFLD were analyzed in detail. MiR-374a-5p, miR-1-3p and miR-23a-3p do not target genes directly involved in the pathogenesis of NAFLD. The differentially expressed miRNAs found in this study target genes largely responsible for mitochondrial function. The role of miR-423-5p, miR-143-5p and miR-200c-3 in regulating apoptotic processes in the liver and hepatocarcinogenesis is of interest for future experimental studies. These miR-374a, miR-143, miR-1, miR-23a, and miR-423 have potential for steatohepatitis diagnosis and are poorly studied in the context of NAFLD. Thus, this work opens up prospects for further studies of microRNAs as diagnostic and therapeutic biomarkers for NAFLD., 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 Vulf, Shunkina, Komar, Bograya, Zatolokin, Kirienkova, Gazatova, Kozlov and Litvinova.)

Calcium chelidonate [Ca(ChA)(H 2 O) 3 ] n was obtained by semi-synthesis using natural chelidonic acid. The structure of the molecular complex was determined by X-ray diffraction analysis. The asymmetric unit of [Ca(ChA)(H 2 O) 3 ] n includes chelidonic acid coordinated through three oxygen atoms, and three water ligands. The oxygen atoms of acid and oxygen atoms of water from each asymmetric unit are also coordinated to the calcium of another one, forming an infinite linear complex. Calcium geometry is close to the trigonal dodecahedron (D2d). The intra-complex hydrogen bonds additionally stabilize the linear species, which are parallel to the axis. In turn the linear species are packed into the 3D structure through mutual intercomplex hydrogen bonds. The osteogenic activity of the semi-synthetic CaChA was studied in vitro on 21-day hAMMSC culture and in vivo in mice using ectopic (subcutaneous) implantation of CaP-coated Ti plates saturated in vitro with syngeneic bone marrow. The enhanced extracellular matrix ECM mineralization in vitro and ectopic bone tissue formation in situ occurred while a water solution of calcium chelidonate at a dose of 10 mg/kg was used. The test substance promotes human adipose-derived multipotent mesenchymal stromal/stem cells (hAMMSCs), as well as mouse MSCs to differentiate into osteoblasts in vitro and in vivo, respectively. Calcium chelidonate is non-toxic and can stimulate osteoinductive processes.

Type 2 diabetes mellitus (T2DM) is one of the most prominent and socially significant problems. The present study aimed to identify the mechanisms of interaction of critical regulators of carbohydrate metabolism using bioinformatics and experimental methods and to assess their influence on the development of T2DM. We conducted an in silico search for the relationship of hormones and adipokines and performed functional annotation of the receptors for ghrelin and incretins. Hormones and adipokines were assessed in the plasma of obese patients with and without T2DM as well as after laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB) surgeries. Incretin- and ghrelin-associated functions and metabolic processes were discovered. Low ghrelin levels were observed in obese patients without T2DM compared with healthy volunteers and the other groups. The highest ghrelin levels were observed in obese patients with T2DM. This defense mechanism against insulin resistance could be realized through the receptors G-protein-coupled receptor (GPCR), growth hormone secretagogue receptor (GHSR), and growth hormone-releasing hormone receptor (GHRHR). These receptors are associated with proliferative, inflammatory, and neurohumoral signaling pathways and regulate responses to nutrient intake. Signaling through the GPCR class unites ghrelin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide (GLP)-1. Ghrelin impairs carbohydrate and lipid metabolism in obese patients. Ghrelin is associated with elevated plasma levels of insulin, glucagon, and leptin. Specific activation of receptors and modulation by posttranslational modifications of ghrelin can control IR's development in obesity, which is a promising area for 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 Skuratovskaia, Vulf, Chasovskikh, Komar, Kirienkova, Shunkin, Zatolokin and Litvinova.)

Aims: To identify an imbalance of cardiac remodeling mediators and monocytes subpopulation in blood, distribution of myocardium macrophages in patients with ischemic cardiomyopathy (ICMP)., Methods: The study engaged 30 patients with ICMP, 26 patients with coronary heart disease (CHD) without ICMP, 15 healthy donors. Concentrations of TGFβ, MMP-9, MCP-1, galectin-3 were measured in plasma of blood from the coronary sinus and peripheral blood in CHD patients, as well as in peripheral blood in healthy donors, by enzyme immunoassay method. The ration of classical, intermediate, non-classical, transitional monocytes in peripheral blood of patients and healthy donors was assessed by flow cytometry (expression CD14, CD16); the content of CD68+ macrophages in myocardium - by immunohistochemistry method., Results: In both samples of blood, the content of galectin-3 in patients with ICMP was higher than in CHD patients without ICMP and the level of TGFβ was comparable between the groups. At ICMP, the concentration of MMP-9 in sinus blood was higher than that in CHD patients without ICMP in whom an excess of MCP-1 in the general blood flow was determined. The density of distribution of CD68+ cells in the myocardium in patients with ICMP was higher in the perianeurysmal zone than in the right atrium appendage. ICMP was characterized by a deficiency of non-classical monocytes, and CHD without ICMP - by an excess of intermediate cells in peripheral blood., Conclusion: Myocardium remodeling at ICMP is mediated by not so much TGFβ but intracardiac galectin-3, which determines the subpopulation composition of blood monocytes., Competing Interests: 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., (© 2021 The Authors.)

The paper focuses on the SiO x -doped amorphous hydrocarbon (a-C:H:SiO x ) coating on the titanium (Ti-6Al-4V) alloy substrate obtained by plasma-assisted chemical vapor deposition (PACVD) in a mixture of argon gas and polyphenylmethylsiloxane vapor using a bipolar substrate bias. It is shown that the a-C:H:SiO x coating deposition results in the formation of a negative surface potential important for application of this coating for medical implants. The a-C:H:SiO x coatings improve the corrosion resistance of Ti alloy to 0.5 M NaCl solution and phosphate-buffered saline. In particular, the corrosion current density of the a-C:H:SiO x -coated sample in a 0.5 M NaCl solution at 22 °C decreases from 1∙10 -8 to 1.7∙10 -10 A/cm 2 , that reduces the corrosion rate from 9∙10 -5 to 15∙10 -7  mm/year. The a-C:H:SiO x coating facilitates the surface endothelization of an implant located in the thoracic aorta of a mini pig, and reduces the risk of thrombosis and implant failure. This effect can be explained by the ability of the a-C:H:SiO x coating ability to reduce in vitro a 24-hour secretion of pro-inflammatory interleukins (IL-6, IL-12(p70), IL-15, and IL-17) and cytokines (IFN-g and TNF-a) by blood mononuclear cells (MNCs) and elevates the concentration of anti-inflammatory interleukin IL-1Ra. In vitro analysis shows no cytotoxicity of the a-C:H:SiO x coating for the human blood MNCs, suggesting a promising PACVD on Ti alloys for cardiovascular implants, including pumps for mechanical heart support systems., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The Scythians are frequently presented, in popular and academic thought alike, as highly mobile warrior nomads who posed a great economic risk to growing Mediterranean empires from the Iron Age into the Classical period. Archaeological studies provide evidence of first millennium BCE urbanism in the steppe while historical texts reference steppe agriculture, challenging traditional characterizations of Scythians as nomads. However, there have been few direct studies of the diet and mobility of populations living in the Pontic steppe and forest-steppe during the Scythian era. Here, we analyse strontium, oxygen, and carbon isotope data from human tooth enamel samples, as well as nitrogen and carbon isotope data of bone collagen, at several Iron Age sites across Ukraine commonly associated with 'Scythian' era communities. Our multi-isotopic approach demonstrates generally low levels of human mobility in the vicinity of urban locales, where populations engaged in agro-pastoralism focused primarily on millet agriculture. Some individuals show evidence for long-distance mobility, likely associated with significant inter-regional connections. We argue that this pattern supports economic diversity of urban locales and complex trading networks, rather than a homogeneous nomadic population., Competing Interests: The authors have declared that no competing interests exist.

Thin calcium phosphate (CaP) coatings were deposited on titanium substrates by radio frequency magnetron sputtering of hydroxyapatite target in neon (Ne), argon (Ar), krypton (Kr) and xenon (Xe). The influence of the working gas (Ne, Ar, Kr and Xe) on the wettability and biodegradation in the RPMI 1640 synthetic culture medium of the CaP coatings was investigated. This paper is the first comprehensive study of working gas effect on properties of the CaP coatings. There was an increase in the polar component of surface free energy (SFE) and a decrease in the dispersion component of SFE with an increase in the atomic mass of the working gas. All CaP coatings had a pronounced protective effect, reducing double the number of dead cells in culture compared to the Ti control. The most soluble CaP coatings formed in the atmosphere of Xe stimulated the hAMMSCs division, which led to an increase in the total number of cells (208% of the initial culture). Samples with CaP coatings formed in an inert gas atmosphere increased the gene expression (ALPL, BMP6, BMP2) in vitro . The most biocompatible coatings were those formed in the atmosphere of Xe and Ar., (© 2021 IOP Publishing Ltd.)

Interleukin (IL)-6 family cytokines act through a receptor complex with gp130 subunits. IL-6 is a pleiotropic cytokine that regulates inflammation and liver regeneration. Mitochondria are the first to respond to stress and adapt their dynamics in conditions of damage. In this regard, the study aimed to investigate the role of the IL-6 cytokine family (sIL-6Ra, gp130/sIL-6Rb, and IL-11) in the regulation of mitochondrial dynamics in the liver in obese patients and to assess the contribution of these cytokines to the pathogenesis of type 2 diabetes mellitus (T2DM). We studied 134 obese patients with and without T2DM and 41 healthy donors. We found that increasing the concentration of sIL-6Ra and gp130/sIL-6Rb protected against carbohydrate disorders in obese patients and prevented non-alcoholic fatty liver disease (NAFLD) progression in obese patients. An increase in plasma IL-6 levels is associated with decreased, mitochondrial transcription factor A (TFAM) protein production in liver biopsies in obese patients with and without T2DM. Replication, transcription, and division processes in liver biopsy were reduced in patients with T2DM. Inflammatory processes stimulate liver cell apoptosis in obese patients with T2DM. The increase in IL-11 levels is associated with decreased pro-apoptotic Bcl-2-associated X protein (BAX) protein production in obese patients with and without T2DM., Competing Interests: The authors declare no conflict of interest.

The review considers complex, controversial, and individual effects of heparin and its derivatives on the bone and circulatory systems in dependence of the dose, the state of the cells and tissues of the recipient. General data on the anticoagulant activity of heparin and its derivatives are presented; special attention is paid to the effect of heparin on mesenchymal cells and tissues and its role in angiogenesis. We also discuss the ability of heparin to bind osteogenic and angiogenic biomolecules in the context of the development of systems for their delivery and sustained controlled release and propose a schematic representation of the positive and side effects of heparin as a delivery system for biomolecules in tissue engineering., Competing Interests: CONFLICT OF INTERESTSThe authors declare that they have no conflicts of interest., (© Pleiades Publishing, Ltd. 2021, ISSN 1990-7508, Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry, 2021, Vol. 15, No. 2, pp. 147–152. © Pleiades Publishing, Ltd., 2021.Russian Text © The Author(s), 2020, published in Biomeditsinskaya Khimiya.)

Background: Despite the great interest and numerous studies, there is currently no unified standard describing the sequential manipulation with cells to obtain exosomes for clinical use.The use of exosomes has become an attractive alternative to cell therapy, since the flexible nature of these biological vesicles allows scientists to manipulate their composition to produce the desired exosomes carrying specific drugs, RNA and proteins. This study aimed to analyse scientific literature on the changes in the functional characteristics of exosomes, depending on the method of manipulation, potentially contributing to the development of negative effects in the treatment of diseases of inflammatory genesis., Results: The choice of isolation method affects the expressed sets of protein markers, nucleic acids and receptors on microparticles. Various surface receptors present on the exosome membrane can be engineered to target lesions. Exosomes from healthy patients help to reduce inflammation, normalize intercellular communication and have anti-fibrotic, antioxidant, and cytoprotective effects. Exosomes can change the microenvironment, but the microenvironment can also change the composition of exosomes., Conclusion: Exosomes obtained from sick patients carry markers characteristic of the corresponding disease. Such exosomes can have pro-inflammatory, pro-fibrotic, cytotoxic, and oncogenic properties, and disrupt cellular cooperation. Until now, questions regarding the dose, reactions to repeated administration, and dosage regimes have not been completely resolved., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Obesity is a metabolic disease characterized by a chronic subclinical inflammatory response associated with an imbalance/dysregulation of cellular homeostasis in response to excessive nutrient intake and accumulation. CD4+ T-lymphocytes form different populations, Th1, Th2, Th9, Th17, Th22, and Treg cells, which have phenotypic and functional differences. Despite the active study of Th17 cells in severe disorders, their role in metabolic disorders, particularly in obesity, is not well understood. Th17 lymphocytes, depending on the microenvironment, can form pathogenic and nonpathogenic subpopulations. Systemic inflammation induces the reprogramming of the transcriptome of normal Th17 cells formed in epithelial tissues, which acquire new properties. A zone of overlapping states exists between IL-17A-producing cells, which does not allow a clear boundary between non-pathogenic Th17 and pathogenic Th17 lymphocytes. We assume that in obesity, the pool of inflammatory pathogenic Th17 cells with cytotoxic potential is a fraction of terminally differentiated memory lymphocytes which is responsible for developing autoimmune reactions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The review discusses the complex, ambiguous and individual effects of heparin and its derivatives on the bone and circulatory systems, in dependence of the dosage, the state of the cells and tissues of recipients. General data on the anticoagulant activity of heparin and its derivatives are presented; aspects of the effect of heparin on mesenchymal cells and tissues and its role in angiogenesis are considered in details. Particular attention is paid to the ability of heparin to bind osteogenic and angiogenic biomolecules: thus us especially important for the development of systems for their delivery and sustained controlled release. A schematic representation of the positive and side effects of heparin as a delivery system for biomolecules in tissue engineering is proposed.

The manufacture of biomaterial surfaces with desired physical and chemical properties that can directly induce osteogenic differentiation without the need for biochemical additives is an excellent strategy for controlling the behavior of mesenchymal stem cells (MSCs) in vivo. We studied the cellular and molecular reactions of MSCs to samples with a double-sided calcium phosphate (CaP) coating and an average roughness index (Ra) of 2.4-4.6 µm. The study aimed to evaluate the effect of a three-dimensional matrix on the relative mRNA expression levels of genes associated with the differentiation and maturation of MSCs toward osteogenesis ( RUNX2 , BMP2 , BMP6 , BGLAP , and ALPL ) under conditions of distant interaction in vitro. Correlations were revealed between the mRNA expression of some osteogenic and cytokine/chemokine genes and the secretion of cytokines and chemokines that may potentiate the differentiation of cells into osteoblasts, which indicates the formation of humoral components of the extracellular matrix and the creation of conditions supporting the establishment of hematopoietic niches.

Chronic inflammation may not begin with local tissue disorders, such as hypoxia, but with the accumulation of critically activated macrophages in one site. The purpose of this review is to analyze the data reported in the scientific literature on the features of the functions of macrophages and their contributions to the development of pathology in various tissues during aseptic inflammation in obese subjects. In individuals with obesity, increased migration of monocytes from the peripheral blood to various tissues, the proliferation of resident macrophages and a change in the balance between alternatively activated anti-inflammatory macrophages (M2) and pro-inflammatory classically activated macrophages (M1) towards the latter have been observed. The primary cause of some metabolic pathologies has been precisely identified as the recruitment of macrophages with an altered phenotype, which is probably typical for many other pathologies. Recent studies have identified phenotypes, such as metabolically activated M (MMe), oxidized (Mox), hemoglobin-related macrophages (Mhem and MHb), M4 and neuroimmunological macrophages (NAM, SAM), which directly and indirectly affect energy metabolism. The high heterogeneity of macrophages in tissues contributes to the involvement of these cells in the development of a wide range of immune responses, including pathological ones. The replenishment of tissue-specific macrophages occurs at the expense of infiltrating monocyte-derived macrophages (MoMFs) in the pathological process. The origin of MoMFs from a general precursor retains their common regulatory mechanisms and similar sensitivity to regulatory stimuli. This makes it possible to find universal approaches to the effect on these cells and, as a consequence, universal approaches for the treatment of various pathological conditions.

Long-duration spaceflight causes widespread physiological changes, although its effect on brain structure remains poorly understood. In this work, we acquired diffusion magnetic resonance imaging to investigate alterations of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) compositions in each voxel, before, shortly after, and 7 months after long-duration spaceflight. We found increased WM in the cerebellum after spaceflight, providing the first clear evidence of sensorimotor neuroplasticity. At the region of interest level, this increase persisted 7 months after return to Earth. We also observe a widespread redistribution of CSF, with concomitant changes in the voxel fractions of adjacent GM. We show that these GM changes are the result of morphological changes rather than net tissue loss, which remained unclear from previous studies. Our study provides evidence of spaceflight-induced neuroplasticity to adapt motor strategies in space and evidence of fluid shift-induced mechanical changes in the brain., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: One reason for the development of insulin resistance is the chronic inflammation in obesity., Materials & Methods: Scientific articles in the field of knowledge on the involvement of mitochondria and mitochondrial DNA (mtDNA) in obesity and type 2 diabetes were analyzed., Results: Oxidative stress developed during obesity contributes to the formation of peroxynitrite, which causes cytochrome C-related damage in the mitochondrial electron transfer chain and increases the production of reactive oxygen species (ROS), which is associated with the development of type 2 diabetes. Oxidative stress contributes to the nuclease activity of the mitochondrial matrix, which leads to the accumulation of cleaved fragments and an increase in heteroplasmy. Mitochondrial dysfunction and mtDNA variations during insulin resistance may be connected with a change in ATP levels, generation of ROS, mitochondrial division/fusion and mitophagy. This review discusses the main role of mitochondria in the development of insulin resistance, which leads to pathological processes in insulin-dependent tissues, and considers potential therapeutic directions based on the modulation of mitochondrial biogenesis. In this regard, the development of drugs aimed at the regulation of these processes is gaining attention., Conclusion: Changes in the mtDNA copy number can help to protect mitochondria from severe damage during conditions of increased oxidative stress. Mitochondrial proteome studies are conducted to search for potential therapeutic targets. The use of mitochondrial peptides encoded by mtDNA also represents a promising new approach to therapy., Competing Interests: The authors declare there are no competing interests., (©2020 Skuratovskaia et al.)

The actual conditions of "physician-patient" interaction in hospital department presents high requirements to quality and rate of provided services. The development of conflicts because of misunderstanding of behavior motivation of physician and patient in hospital department determined purpose of actual study. The standardized psychological questionnaire "Big Five" and Myers-Briggs questionnaire were used to obtain needed data. The study results were statistically processed using Student's test. The statistical analysis established in physicians and patients' reliable difference in indices of "attachment - isolation" (p=0.035), prevalence in physicians of mental processes (p=0.001) and sensuous component in social interaction of patients (p=0.025). The physician of orthopedic department seeks to keep exact logical sequence of actions. The patients fully rely on their feelings in their decision making. The established hypersensitivity of patients and inner strive to move "not according plan" results in disagreements concerning therapeutic strategy and failure in strict applications of all physician recommendations that frequently becomes a cause of uncoordinated actions and conflict situations.

The osteogenic, cytotoxic, and antibacterial activities of polysaccharide (PS-SC) and flavonoid (F-SC) fractions isolated from the leaves extract of Saussurea controversa were studied in vitro. F-SC consists of the five quercetin glycosides in the ratio 2:8:10:1:4, which were isolated from the leaves extract of S. controversa and have been characterized previously. PS-SC was first isolated from the leaves extract of S. controversa and has been described. PS-SC consists in 30 compounds is characterized by a high degree of heterogeneity with a heterogeneity index of 19.74. The Mw and Mn of PS-SC were 108.6 and 5.5 kDa, respectively. Structural fragments are represented by galactose, arabinose, xylose, glucose, uronic acids, mannose, and rhamnose in a 10.1:3.3:2.2:2.1:1.7:0.9:0.5 molar ratio. F-SC as compared with PS-SC showed in vitro microbicidal (50 g/L) and better bacteriostatic (6.25 g/L versus 25 g/L of PS-SC) effects against the 24-h growth of Staphylococcus aureus strain 209 P and a 21-day absence of cytotoxicity on human adipose-derived multipotent mesenchymal stromal cells (hAMMSCs). Both fractions (PS-SC>F-SC) at doses of 10-50 mg/L stimulated differentiation of hAMMSCs into secreting osteoblasts accompanied by local mineralization of extracellular matrix. These fractions of S. controversa and especially F-SC, might be promising peroral drugs in the complex treatment of bone fractures and for prophylaxis of their infectious complications., Competing Interests: The authors declare no conflict of interest.

We studied the role of native α-fetoprotein preparation in the regulation of proliferation and functional activity of naïve T cells and immune memory T cells in vitro. The study was carried out on separated fractions of naïve T cells (CD45RA + ) and immune memory T cells (CD45R0 + ) incubated with α-fetoprotein under conditions of TCR activation. At the level of naïve T cells, α-fetoprotein in a concentration of 100 U/ml reduced the expression of CD28, but increased the expression of CD25, while at the level of immune memory T cells α-fetoprotein (50 and 100 U/ml) only suppressed the expression of CD25. No effects of α-fetoprotein on the proliferative status of the studied lymphocyte subpopulations and on the expression of CD71 (proliferation marker) by these cells were detected. Addition of α-fetoprotein in a concentration of 100 U/ml increased the level of IL-2 in naïve T cell culture supernatants, while production of IL-2 by memory T cells remained unchanged. These data demonstrated the priority aspects of regulation of the functional activities of naïve T cells and immune memory T cells.

The present study reports alterations of task-based functional brain connectivity in a group of 11 cosmonauts after a long-duration spaceflight, compared to a healthy control group not involved in the space program. To elicit the postural and locomotor sensorimotor mechanisms that are usually most significantly impaired when space travelers return to Earth, a plantar stimulation paradigm was used in a block design fMRI study. The motor control system activated by the plantar stimulation involved the pre-central and post-central gyri, SMA, SII/operculum, and, to a lesser degree, the insular cortex and cerebellum. While no post-flight alterations were observed in terms of activation, the network-based statistics approach revealed task-specific functional connectivity modifications within a broader set of regions involving the activation sites along with other parts of the sensorimotor neural network and the visual, proprioceptive, and vestibular systems. The most notable findings included a post-flight increase in the stimulation-specific connectivity of the right posterior supramarginal gyrus with the rest of the brain; a strengthening of connections between the left and right insulae; decreased connectivity of the vestibular nuclei, right inferior parietal cortex (BA40) and cerebellum with areas associated with motor, visual, vestibular, and proprioception functions; and decreased coupling of the cerebellum with the visual cortex and the right inferior parietal cortex. The severity of space motion sickness symptoms was found to correlate with a post- to pre-flight difference in connectivity between the right supramarginal gyrus and the left anterior insula. Due to the complex nature and rapid dynamics of adaptation to gravity alterations, the post-flight findings might be attributed to both the long-term microgravity exposure and to the readaptation to Earth's gravity that took place between the landing and post-flight MRI session. Nevertheless, the results have implications for the multisensory reweighting and gravitational motor system theories, generating hypotheses to be tested in future research.

Atherosclerosis is one of the leading causes of mortality from cardiovascular disease (CVD) and is a chronic inflammatory disease of the middle and large arteries caused by a disruption of lipid metabolism. Noncoding RNA (ncRNA), including microRNA (miRNA), small interfering RNA (siRNA) and long noncoding RNA (lncRNA), was investigated for the treatment of atherosclerosis. Regulation of the expression of noncoding RNA targets the constituent element of the pathogenesis of atherosclerosis. Currently, miRNA therapy commonly employs miRNA antagonists and mimic compounds. In this review, attention is focused on approaches to correcting molecular disorders based on the genetic regulation of the transcription of key genes responsible for the development of atherosclerosis. Promising technologies were considered for the treatment of atherosclerosis, and examples are given for technologies that have been shown to be effective in clinical trials.

Secretion of 21 cytokines, chemokines and growth factors (LIF, SCF, SDF-1a, SCGF-b, M-CSF, MCP-3, MIF, MIG, TRAIL, GRO-a; IL-1a, IL-2ra, IL-3, IL-12(p40), IL-16, IL-18, HGF, TNF-b, b-NGF, IFN-a2, CTACK) has been studied in vitro in the culture of human adipose-derived multipotent mesenchymal stromal cells (hAMMSCs) in conditions of its osteogenic differentiation caused by 14-day contact with calcium phosphate (CP) surface with different roughness. Bilateral X-ray amorphous CP coatings were prepared on the samples of commercially pure titanium in the anodal regime using a micro-arc method. An aqueous solution prepared from 20 wt% phosphoric acid, 6 wt% dissolved hydrohyapatite nanopowder (particle diameter 10-30 nm with single agglomerates up to 100 nm), and 9 wt% dissolved calcium carbonate was used to obtain CP coating. hAMMSCs isolated from lipoaspirate were co-cultured after 4 passages with the CP-coated samples at final concentration of 1.5´105 viable karyocytes per 1.5 mL of standard nutrition medium (without osteogenic stimulators) for 14 days (a determination of [CD45,34,14,20], CD73, CD90 и CD105 cell immunophenotype; an analysis of secretory activity) and 21 days (alizarin red S staining of culture) with medium replacement every 3-4 days. Under conditions of in vitro contact with rough CP coating hAMMSCs differentiated into osteoblasts synthesizing the mineralized bone matrix; this was accompanied by 2-3-fold increasing ratio of [CD45,34,14,20]+ hemopoietic cells. The following humoral factors of hemopoietic niches acted as the signal molecules escalating in vitro the hemopoietic base in 14 days of differentiating three-dimensional culture of hAMMSCs: either leukemia inhibitory factor (LIF) and stem cell factor (SCF) cytokines under mean index of CP roughness Ra=2.4-2.6 mm or stromal derived factor-1 (SDF-1a, CXCL12 chemokine) under Ra=3.1-4.4 mm.

We studied the effect of the native (non-recombinant) alpha-fetoprotein (AFP) on differentiation, proliferation, and cytokine profile of activated helper T cells 17 (Th17). The object of the study was a culture of isolated by immunomagnetic separation helper T cells (CD4+), induced into the Th17 phenotype by using TCR-activator and proinflammatory cytokines (IL-1β and IL-6). AFP had not significant effect on the frequency of Th17 cells (ROR-γτ+) in the helper T cell culture, and did not affect proliferation of these cells, as measured by Ki-67 expression. Evaluation of the cytokine profile of culture supernatants by using the Luminex xMAP technology, revealed that AFP did not affect the levels of IL-4, IL-5, IL-7, IL-8, IL-10, IL-17, IFN-γ and TNF-α, but at concentrations of 50 IU/ml and 100 IU/ml it increased IL-2 production by activated helper T cells. At the same time, AFP suppressed the synthesis of G-CSF and GM-CSF (10 IU/ml), but stimulated the production of CCL4/MIP-1β (100 IU/ml) and CCL2/MCP-1 chemokines (10 IU/ml and 50 IU/ml).