Mitochondrial calcium uniporter structure and function in different types of muscle tissues in health and disease

Calcium ions (Ca2+) influx to mitochondrial matrix is crucial for the life of a cell. Mitochondrial calcium uniporter (mtCU) is a protein complex which consists of the pore-forming subunit (MCU) and several regulatory subunits. MtCU is the main contributor to inward Ca2+ currents through the inner mitochondrial membrane. Extensive investigations of mtCU involvement into normal and pathological molecular pathways started from the moment of discovery of its molecular components. A crucial role of mtCU in the control of these pathways is now recognized in both health and disease. In particular, impairments of mtCU function have been demonstrated for cardiovascular and skeletal muscle-associated pathologies. This review summarizes the current state of knowledge on mtCU structure, regulation, and function in different types of muscle tissues in health and disease. © 2019 by the authors. Licensee MDPI, Basel, Switzerland

Macrophage Modification Strategies for Efficient Cell Therapy

Macrophages, important cells of innate immunity, are known for their phagocytic activity, capability for antigen presentation, and flexible phenotypes. Macrophages are found in all tissues and therefore represent an attractive therapeutic target for the treatment of diseases of various etiology. Genetic programming of macrophages is an important issue of modern molecular and cellular medicine. The controllable activation of macrophages towards desirable phenotypes in vivo and in vitro will provide effective treatments for a number of inflammatory and proliferative diseases. This review is focused on the methods for specific alteration of gene expression in macrophages, including the controllable promotion of the desired M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes in certain pathologies or model systems. Here we review the strategies of target selection, the methods of vector delivery, and the gene editing approaches used for modification of macrophages

Phenotypical and Functional Polymorphism of Liver Resident Macrophages

Liver diseases are one of the main causes of mortality. In this regard, the development of new ways of reparative processes stimulation is relevant. Macrophages play a leading role in the regulation of liver homeostasis in physiological conditions and in pathology. In this regard, the development of new liver treatment methods is impossible without taking into account this cell population. Resident macrophages of the liver, Kupffer cells, represent a unique cell population, first of all, due to their development. Most of the liver macrophages belong to the self-sustaining macrophage cell population, whose origin is not bone marrow. In addition, Kupffer cells are involved in such processes as regulation of hepatocyte proliferation and apoptosis, remodeling of the intercellular matrix, lipid metabolism, protective function, etc. Such a broad spectrum of liver macrophage functions indicates their high functional plasticity. The review summarizes recent data on the development, phenotypic and functional plasticity, and participation in the reparative processes of liver macrophages: resident macrophages (Kupffer cells) and bone marrow-derived macrophages

Application of machine learning algorithms in morphopathology and in assisted reproductive technologies

Machine learning models are used everywhere to analyze images, signals, and videos. At first glance, this is a well-designed process that involves the stages of data collection, mark-up, and training a model, and, as a result, its application in a particular field (recognition of vehicle plate numbers, smartphone faces, etc.). However, everything is much more complicated in the field of medicine: the use of artificial intelligence models is a serious challenge. Machine learning methods are becoming more and more used in morphological sciences and biomedical studies. The introduction of artificial intelligence for image analysis can lower the burden on an operator (a pathologist, a histologist), eliminate the factor of subjective assessment, and reduce the likelihood of an error. This review provides a brief excursion into the history of machine learning methods, considers the examples of their use in two areas where they are most widespread: morphopathology and assisted reproductive technologies, and also indicates the limitations and difficulties that developers face when training neural networks. Conclusion: The authors also propose solutions to overcome the difficulties associated with the collection and joint marking of data, and model training: creation of a high-quality infrastructure, attraction of highly qualified specialists who mark data, an advanced scientific approach to artificial intelligence technologies; cloud platforms are offered to be used as a basis for the scalable storage and analysis of biomedical data. © 2021, Bionika Media Ltd.. All rights reserved

THE ROLE OF PLACENTAL MACROPHAGES IN PHYSIOLOGICAL PREGNANCY AND PREECLAMPSIA

Preeclampsia (PE) is a multisystem pregnancy complication that is the leading cause of maternal and perinatal morbidity and mortality. Today, a large body of data has been accumulated, suggesting that an abnormal maternal immune response in PE is manifested, among other things, as a change in the functional activity of the monocyte-macrophage system, the most important unit of innate immunity. The cause of abnormal placentation underlying PE, especially early PE, may be dysfunction of placental immune cells, namely macrophages. The macrophages are one of the main cellular constituents of the decidua, the maternal component of the placenta, and also play an important role in the development of the fetal part of the placenta, per se being one of the first immune cells of a baby. Depending on their functional state, the macrophages can either stimulate or suppress inflammation, angiogenesis, and the proliferation of neighboring cells. According to the concept of binary polarization, there are two states of macrophages: classically activated macrophages (M1) produce proinflammatory cytokines and reactive oxygen/nitrogen species. The other type of macrophages (M2) produces anti-inflammatory cytokines and is involved in the elimination of inflammation. Conclusion: Turning to the key differential markers of macrophages, this review attempts to summarize the current data on the functioning of the monocyte-macrophage system in physiological pregnancy and PE. © A group of authors, 2022

Фенотипический полиморфизм клеток Купфера печени крыс в норме

The aim of study was to evaluate the immunophenotype of resident macrophages of the liver, Kupffer cells, in rats in the norm. Material and methods. The study included male Wistar rats’ samples (n=6) that presented fragments of the middle lobe of the liver taken under ether anesthesia. The obtained samples were fixed in liquid nitrogen, after that cryosections 5-7 μm thick were prepared. Histological slides were used to detect the expression of a number of macrophage markers with an antibody kit: CD68, CD206, CD 163, CD86. After the first antibodies, sections were stained with antibodies conjugated to FITC, cell nuclei were detected using DAPI, the obtained preparations were studied using a fluorescence microscope. Results. When analyzing the expression of CD68 in the rat liver, it was found that normally about 20% of the cells in the field of vision appeared to be CD68+ cells, which was consistent with the earlier study results of the authors. The number of CD163+ and CD206+ cells coincided with the number of CD68+ macrophages, while CD86+ macrophages were significantly less. Conclusions. Under normal conditions, the population of resident macrophages of the rat liver is represented by cells with pronounced expression of CD68, CD163 and CD206. A large number of CD163+ and CD206+ macrophages allows concluding that Kupffer cells are close to the M2 pro-regenerative phenotype. However, the detection of CD86+ resident macrophages indicates the presence of M1 macrophages, or the presence of normal macrophages with an intermediate M1 and M2 phenotype, in the rat liver. The revealed high content of macrophages expressing CD163 and CD206 in the liver evidences not only pro-regenerative properties of Kupffer cells, but also the close connection of macrophages with liver functions, since these receptors are involved in the utilization of hemoglobin and a number of hormones.Цель исследования - оценить иммунофенотип резидентных макрофагов печени, клеток Купфера, у крыс в норме. Материал и методы. В работе использовали самцов крыс Вистар (n=6), у которых под эфирным наркозом забирали фрагмент срединной доли печени. Полученный материал фиксировали в жидком азоте, после чего готовили криосрезы толщиной 5-7 мкм. На гистологических препаратах с помощью набора антителами выявляли экспрессию ряда маркеров макрофагов: CD68, CD206, CD 163, CD86 после первых антител срезы докрашивали антителами, конъюгированными с FITC, ядра клеток выявляли с помощью DAPI, полученные препараты изучали с помощью флуоресцентного микроскопа. Результаты. При анализе экспрессии CD68 в печени крыс, установлено, что в норме примерно 20% клеток в поле зрения приходится на CD68+ клетки, что согласуется с нашими более ранними исследованиями. Количество CD163+ и CD206+ клеток совпадало с количеством CD68+ макрофагов, в то время как CD86+ макрофагов было значительно меньше. Выводы. В нормальных условиях популяция резидентных макрофагов печени крыс представлена клетками с выраженной экспрессией CD68, CD163 и CD206. Большое количество CD163+ и CD206+ макрофагов позволяет заключить, что клетки Купфера близки к М2-прорегенераторным фенотипу. Однако выявление CD86+ резидентных макрофагов свидетельствует о наличии М1-макрофагов, или о присутствии в печени крыс в норме макрофагов с промежуточным между М1- и М2-фенотипом. Выявленное высокое содержание в печени макрофагов, экспрессирующих CD163 и CD206, свидетельствует не только о прорегенераторных свойствах клеток Купфера, но также о тесной связи макрофагов с функциями печени, поскольку указанные рецепторы участвует в утилизации гемоглобина и ряда гормонов

Molecular mechanisms of splenectomy-induced hepatocyte proliferation

Functional and anatomical connection between the liver and the spleen is most clearly manifested in various pathological conditions of the liver (cirrhosis, hepatitis). The mechanisms of the interaction between the two organs are still poorly understood, as there have been practically no studies on the influence exerted by the spleen on the normal liver. Mature male Sprague-Dawley rats of 250-260 g body weight, 3 months old, were splenectomized. The highest numbers of Ki67+ hepatocytes in the liver of splenectomized rats were observed at 24 h after the surgery, simultaneously with the highest index of Ki67-positive hepatocytes. After surgical removal of the spleen, expression of certain genes in the liver tissues increased. A number of genes were upregulated in the liver at a single time point of 24 h, including Ccne1, Egf, Tnfa, Il6, Hgf, Met, Tgfb1r2 and Nos2. The expression of Ccnd1, Tgfb1, Tgfb1r1 and Il10 in the liver was upregulated over the course of 3 days after splenectomy. Monitoring of the liver macrophage populations in splenectomized animals revealed a statistically significant increase in the proportion of CD68-positive cells in the liver (as compared with sham-operated controls) detectable at 24 h and 48 h after the surgery. The difference in the liver content of CD68-positive cells between splenectomized and sham-operated animals evened out by day 3 after the surgery. No alterations in the liver content of CD163-positive cells were observed in the experiments. A decrease in the proportion of CD206-positive liver macrophages was observed at 48 h after splenectomy. The splenectomy-induced hepatocyte proliferation is described by us for the first time. Mechanistically, the effect is apparently induced by the removal of spleen as a major source of Tgfb1 (hepatocyte growth inhibitor) and subsequently supported by activation of proliferation factor-encoding genes in the liver. Copyright: © 2020 Elchaninov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Congenital deficiency of surfactant protein c: Literature review and first clinical observations in the russian federation

Surfactant is a complex mixture of phospholipids, neutral lipids and specific surfactant-associated proteins. Genetic diseases associated with gene mutations of surfactant proteins are rare, and treatment options for these children are currently limited. The article presents modern information on congenital deficiency of surfactant protein C, its genetics, pathogenesis, histological patterns, clinical and radiological manifestations in children and adults, outcomes and therapy. It also provides clinical observations of first three pediatric patients in the Russian Federation with this disease, including a rare manifestation in the form of primary pulmonary alveolar proteinosis. © 2018, Pediatria Ltd. All rights reserved