Revisiting the multiple roles of T-cadherin in health and disease.

As a non-canonical member of cadherin superfamily, T-cadherin was initially described as a molecule involved in homophilic recognition in the nervous and vascular systems. The ensuing decades clearly demonstrated that T-cadherin is a remarkably multifunctional molecule. It was validated as a bona fide receptor for both: LDL exerting adverse atherogenic action and adiponectin mediating many protective metabolic and cardiovascular effects. Motivated by the latest progress and accumulated data unmasking important roles of T-cadherin in blood vessel function and tissue regeneration, here we revisit the original function of T-cadherin as a guidance receptor for the growing axons and blood vessels, consider the recent data on T-cadherin-induced exosomes' biogenesis and their role in myocardial regeneration and revascularization. The review expands upon T-cadherin contribution to mesenchymal stem/stromal cell compartment in adipose tissue. We also dwell upon T-cadherin polymorphisms (SNP) and their possible therapeutic applications. Furthermore, we scrutinize the molecular hub of insulin and adiponectin receptors (AdipoR1 and AdipoR2) conveying signals to their downstream targets in quest for defining a putative place of T-cadherin in this molecular circuitry.

[Unipolar depression: a gender-based comparative analysis]. / Depressivnye rasstroistva s monopolyarnym techeniem: sravnitel'nyi analiz po gendernomu priznaku.

OBJECTIVE: To compare socio-demographic and clinical characteristics in men and women with depression. MATERIAL AND METHODS: We studied 388 patients with unipolar depression, 74 men and 314 women. The survey was carried out using the clinical-psychopathological method and psychometric scales for depression. RESULTS AND CONCLUSION: Gender differences are identified for several parameters. Women are older, more often had comorbid somatic and organic disorders; men have personality disorders and chronic depression. The severity of depression in women was higher due to symptoms such as reported sadness, anxiety, reduced sleep and appetite, concentration difficulties, and suicidal thoughts. Apparent sadness did not significantly differ in men and women. Anhedonia was more pronounced in men.

Secretome of Multipotent Mesenchymal Stromal Cells as a Promising Treatment and for Rehabilitation of Patients with the Novel Coronaviral Infection.

As a rule, coronavirus infections are mild in healthy adults and do not require special approaches to treatment. However, highly pathogenic strains, particularly the recently isolated SARS-CoV2, which causes COVID-19 infection, in about 15% of cases lead to severe complications, including acute respiratory distress syndrome, which causes high patient mortality. In addition, a common complication of COVID-19 is the development of pulmonary fibrosis. Why is the novel coronavirus so pathogenic? What new treatments can be proposed to speed up the recovery and subsequent rehabilitation of the organism? In 2020, over 34 000 scientific articles were published on the structure, distribution, pathogenesis, and possible approaches to the treatment of infection caused by the novel SARS-CoV2 coronavirus. However, there are still no definitive answers to these questions, while the number of the diseased is increasing daily. One of the comprehensive approaches to the treatment of the consequences of the infection is the use of multipotent human mesenchymal stromal cells and products of their secretion (secretome). Acting at several stages of the development of the infection, the components of the secretome can suppress the interaction of the virus with endothelial cells, regulate inflammation, and stimulate lung tissue regeneration, preventing the development of fibrosis. The results of basic and clinical research on this topic are summarized, including our own experimental data, indicating that cell therapy approaches can be successfully applied to treat patients with COVID-19.

Urokinase receptor regulates nerve regeneration through its interaction with α5ß1-integrin.

PURPOSE: Urokinase receptor (uPAR) promotes extracellular matrix proteolysis, regulates adhesion and cell migration, transduces intracellular signals through interactions with the lateral partners. The expression of uPAR and urokinase (uPA) is significantly upregulated in peripheral nerves after injury, however, little is known about uPAR function in nerve regeneration or the molecular mechanisms involved. The purpose of this study is to investigate the role of uPAR in nerve regeneration after traumatic injury of n. Peroneus communis in uPA-/-, uPAR-/- or control mice (WT) and in neuritogenesis in an in vitro Neuro 2A cell model. RESULTS: Electrophysiological analysis indicates that nerve recovery is significantly impaired in uPAR-/- mice, but not in uPA-/- mice. These data correlate with the reduced amount of NF200-positive axons in regenerating nerves from uPAR-/- mice compared to uPA-/- or control mice. There is an increase in uPAR expression and remarkable colocalization of uPAR with α5 and ß1 integrin in uPA-/- mice in recovering nerves, pointing to a potential link between uPAR and its lateral partner α5ß1-integrin. Using an in vitro model of neuritogenesis and α325 blocking peptide, which abrogates uPAR-α5ß1 interaction in Neuro 2A cells but has no effect on their function, we have further confirmed the significance of uPAR-α5ß1 interaction. CONCLUSION: Taken together, we report evidence pointing to an important role of uPAR, rather than uPA, in peripheral nerve recovery and neuritogenesis.

Plasticity of Human THP-1 Cell Phagocytic Activity during Macrophagic Differentiation.

Studies of the role of macrophages in phagocytosis are of great theoretical and practical importance for understanding how these cells are involved in the organism's defense response and in the development of various pathologies. Here we investigated phagocytic plasticity of THP-1 (acute monocytic human leukemia) cells at different stages (days 1, 3, and 7) of phorbol ester (PMA)-induced macrophage differentiation. Analysis of cytokine profiles showed that PMA at a concentration of 100 nM induced development of the proinflammatory macrophage population. The functional activity of macrophages was assessed on days 3 and 7 of differentiation using unlabeled latex beads and latex beads conjugated with ligands (gelatin, mannan, and IgG Fc fragment) that bind to the corresponding specific receptors. The general phagocytic activity increased significantly (1.5-2.0-fold) in the course of differentiation; phagocytosis occurred mostly through the Fc receptors, as shown previously for M1 macrophages. On day 7, the levels of phagocytosis of gelatin- and Fc-covered beads were high; however, the intensity of ingestion of mannan-conjugated beads via mannose receptors increased 2.5-3.0-fold as well, which indicated formation of cells with an alternative phenotype similar to that of M2 macrophages. Thus, the type and the plasticity of phagocytic activity at certain stages of macrophage differentiation can be associated with the formation of functionally mature morphological phenotype. This allows macrophages to exhibit their phagocytic potential in response to specific ligands. These data are of fundamental importance and can be used to develop therapeutic methods for correcting the M1/M2 macrophage ratio in an organism.

Increased expression of uPA, uPAR, and PAI-1 in psoriatic skin and in basal cell carcinomas.

There is substantial evidence implicating the urokinase system in tissue remodeling during neo-vascularization, inflammation, tumor invasion, and metastasis. Regulated degradation of the extracellular matrix at the leading edge of migrating cells, mediated by uPA and uPAR, is required for tissue remodeling, invasiveness, and angiogenesis. Psoriasis and basal cell carcinoma (BCC) are the most common skin diseases. Pathogenesis of both of them is associated with keratinocyte hyperproliferation, inflammatory cell migration, and angiogenesis-processes in which the plasminogen system (uPA, uPAR, tPA, and PAI-1) plays a crucial role. In the present study, the comparative analysis of uPA, uPAR, tPA, and PAI-1 expression in the normal skin, in the biopsies of patients with psoriasis vulgaris, and BCC was carried out. uPA, uPAR, and PAI-1 expression was up-regulated in the epidermis of psoriatic skin and in tumor cells in BCC. Increased uPAR expression was detected in the derma of psoriatic lesions and in the stroma surrounding tumor cells in BCC. Increased expression of uPA in epidermal cells in psoriasis and in tumor cells in BCC suggests an important role of the uPA system for aggressively proliferating and invading cells of epidermal origin. A possible activation of the stroma, as a result of uPA-uPAR interaction between tumor cells and the surrounding stroma, is suggested.

Collagen-1 Membrane for Replacing the Bladder Wall.

We studied the possibility of using membrane fabricated from type 1 collagen isolated from cattle tissues (group 1) or porcine tissues (group 2) for replacement of the resected bladder wall defect in rabbits in order to retain functional volume of the organ. Satisfactory take of both types of collagen membranes with formation of competent anastomosis was observed. Histological studies revealed inflammatory process in the bladder wall at the site of contact with the implanted membrane (more pronounced in case of membranes from cattle tissues) that decreased by day 21 of the experiment. Bladder tissue ingrowth into the implant from was observed starting from day 14. The bladder capacity decreased in 7 days after surgery in both groups, presumably because of increasing tone of the organ wall resulting from surgical trauma and inflammation. In group 2, the bladder volume increased by day 14 after surgery and returned to normal by day 21, whereas in group 1 it remained below the control despite a trend to increase. These findings confirm good prospects of using collagen-1 membranes for plastic repair of the urinary bladder, the membranes from porcine collagen being more preferable.

[The possibility of using standardized self-report anxiety and depression scales in elderly patients: anxiety scales/questionnaires]. / Izuchenie vozmozhnosti primeneniya standartizirovannykh shkal samootsenki trevogi i depressii pri obsledovanii bol'nykh pozhilogo vozrasta: shkaly-oprosniki trevogi.

AIM: To describe the specifics of using self-report anxiety scales in elderly patients, determine the parameters of their reliability and validity and develop recommendations on the use of these scales. MATERIAL AND METHODS: The study included 234 patients, aged over 50 years, with non-psychotic anxiety disorders. The following scales/questionnaires BAI, GAI, STAI, ZAS, HADS were used at baseline and 12 weeks after treatment. Conditions of testing, form and content of instructions were similar. Data analysis included the estimation of reliability and validity of these scales. Assessment made by the physician on the Hamilton anxiety scale (HAМ-А) was used as «validity standard¼. RESULTS AND CONCLUSION: All scales (BAI, GAI, STAI, ZAS, HADS-А) can be used for screening diagnosis of anxiety in elderly people. The diagnostic sensitivity and specificity of the scales for subjective assessment of anxiety slightly decrease in advanced age and is sufficient for screening purposes. Based on the analysis, the authors have developed recommendations (common and specific for each scale) on the optimization of using self-report anxiety scales in advanced age.

ISOLATION AND CHARACTERIZATION OF CARDIAC PROGENITOR CELLS OBTAINING FROM MYOCARDIAL RIGHT ATRIAL APPENDAGE TISSUE.

Resident stem cells of the heart are denoted as heterogeneous population of immature cells, which reside in the myocardium and characterized by their ability to self-renewal and are multipotent differentiation capacity into cardiomyocyte-like and vascular like cells. CSCs were originally isolated directly by long enzymatic digestion of heart tissue and selection using stem cell markers. However, long exposure to enzymatic digestion and small myocardial sample size can affect the possibility of obtaining a significant amount of viable cells. To avoid these problems, we developed a method consisting of growing of the CPC in explant culture and subsequent immunomagnetic selection.

[Therapeutic potential of human mesenchymal stromal cells secreted components: a problem with standartization].

Regenerative medicine approaches, such as replacement of damaged tissue by ex vivo manufactured constructions or stimulation of endogenous reparative and regenerative processes to treat different diseases, are actively developing. One of the major tools for regenerative medicine are stem and progenitor cells, including multipotent mesenchymal stem/stromal cells (MSC). Because the paracrine action of bioactive factors secreted by MSC is considered as a main mechanism underlying MSC regenerative effects, application of MSC extracellular secreted products could be a promising approach to stimulate tissue regeneration; it also has some advantages compared to the injection of the cells themselves. However, because of the complexity of composition and multiplicity of mechanisms of action distinguished the medicinal products based on bioactive factors secreted by human MSC from the most of pharmaceuticals, it is important to develop the approaches to their standardization and quality control. In the current study, based on the literature data and guidelines as well as on our own experimental results, we provided rationalization for nomenclature and methods of quality control for the complex of extracellular products secreted by human adipose-derived MSC on key indicators, such as "Identification", "Specific activity" and "Biological safety". Developed approaches were tested on the samples of conditioned media contained products secreted by MSC isolated from subcutaneous adipose tissue of 30 donors. This strategy for the standardization of innovative medicinal products and biomaterials based on the bioactive extracellular factors secreted by human MSC could be applicable for a wide range of bioactive complex products, produced using the different types of stem and progenitor cells.

Detection of T-Cadherin Expression in Mouse Embryos.

The aim of the present study was to evaluate T-cadherin expression at the early developmental stages of the mouse embryo. Using in situ hybridization and immunofluorescent staining of whole embryos in combination with confocal microscopy, we found that T-cadherin expression is detected in the developing brain, starting with the E8.75 stage, and in the heart, starting with the E11.5 stage. These data suggest a possible involvement of T-cadherin in the formation of blood vessels during embryogenesis.

[UROKINASE SYSTEM INVOLVES IN VASCULAR CELLS MIGRATION AND REGULATES THE GROWTH AND BRANCHING OF CAPILLARIES].

Urokinase system representing urokinase-type plasminogen activator (urokinase, uPA) and urokinase re- ceptor (uPAR) plays an important regulatory role in the vascular wall and has the ability to run a proteolytic cascade, degradation of extracellular matrix and activate intracellular signaling in vascular cells. In this work, we have firstly shown a fundamental mechanism of urokinase system-dependent regulation of the trajectory of growth and branching of blood vessels what may be of particular importance in the growth of blood vessels in early embryogenesis and in adults during the repair/regeneration of tissues.

[Remote consequences of the long-term uncontrolled use of anxiolytic and hypnotic drugs by elderly patients: cognitive disorders].

OBJECTIVE: Frequents cases (10-30% of the elderly population) of regular long-term use of anxiolytic and hypnotic drugs, in particular, benzodiazepines, without control of the physician is an urgent problem of medicine worldwide. Severe and irreversible cognitive impairment is a frequent and severe consequence of this use. Authors studied cognitive impairment in these cases. MATERIAL AND METHODS: Patients were enrolled in the study from a psychiatric hospital. The study included 56 women, aged over 50 years, admitted to the hospital with the diagnosis of a mental disorder. Before admission, the patients regularly used benzodiazepines without a prescription for more than 2 months. Later on, anxiolytics were withdrawn during 1-5 days. The patients were studied during 4 weeks in the hospital. To assess the severity and dynamics of their condition, authors used MADRS, HAM-A, MMSE. RESULTS AND CONCLUSION: Severe cognitive impairment, achieving the level of dementia, was found in 57.2% of the patients, mild or moderate of cognitive impairment was in 32.1% and only 10.7% had normal level of cognitive functioning. After 4 weeks of benzodiazepine withdrawal, the percentage of patients with dementia reduced to 21.4%, the severity of cognitive impairment was estimated as mild or moderate. A number of patients without cognitive impairment increased to 37.5%. The old age of patients was a significant negative predictor of the dynamics. An impact of the high anxiolytic dose was shown on trend level. The duration of a mental disorder and duration of uncontrollable consumption of anxiolytics and hypnotics did not exert an effect on the development and reversibility of cognitive impairment. A combination of anxiolytics with alcohol increased the risk of dementia and did not reverse the cognitive pathology.

[Characteristics of migration of adipose tissue derived mesenchymal stromal cells after co-cultivation with activated monocytes in vitro].

Mesenchymal stromal cells (MSC) are considered to be promising tool of regenerative medicine. Migration of MSC toward damaged inflammatory site is essential for physiological tissue reparation. Therefore we studied modifications of migratory features of adipose tissue derived MSC (AT-MSC) after co-cultivation with activated monocytes derived from THP-1 cell line. As a result, we have observed an increased migration rate of AT-MSC in vitro in the absence of chemoattractant gradient as well as toward the gradient of PDGF BB (platelet-derived growth factor BB), which is well known chemoattractant for the cells of mesenchymal origin. Furthermore, the rate of directional AT-MSC migration through fibronectin was also increased. We have established that signaling from PDGFRß which is activated through binding of integrin receptors with extracellular matrix may be possible way to stimulate cellular migration under simulated inflammatory conditions.

[Anxiety disorders in elderly patients: psychopathological characteristics, diagnosis, similarities and differences with anxious depression].

OBJECTIVE: There are two points of view on the relation between anxiety and depression: they are comorbid diseases or they are symptoms of the same disease. This inconsistency complicates the diagnosis of anxiety and depressive disorders in clinical practice, in particular in elderly patients. We attempted to study the nosological structure of anxiety states in elderly patients and work out recommendations on differential diagnosis of anxiety disorders and depressions. MATERIAL AND METHODS: A main group included 80 elderly patients with anxiety disorders, 80 patients with anxious depression were enrolled in comparison group. These groups were selected on the basis of the primary diagnosis made before enrollment patients into the study. RESULTS: After the detailed examination of patients with anxiety disorders, the diagnosis has been changed in 67.5% of patients. Symptoms of all patients with hypochondriac, somatisized and somatoform pain disorders were corresponded to atypical anxious depression. Duration and severity of psychogenic disorders of adaptation and acute reactions to stress were also corresponded to the diagnosis of depression. All patients with obsessive-compulsive disorders had typical symptoms of neurosis-like schizophrenia, these patients were excluded from the study. After the revision of diagnoses, the group with anxiety disorders comprised 26 patients and the group with depression increased up to 131 patients. A between-group comparison of clinical/anamnesis data showed that mean age of patients with depression (59.7 years) was significantly higher than that of patients with anxiety disorders (56 years). Levels of anxiety measured with the Hamilton scale (HAM-A) were similar in both groups. MADRS scores were significantly higher in the depression group (27.9) compared to patients with anxiety disorders (16.5). CONCLUSION: The most frequent diagnoses that mask depression in elderly people are hypochondriac, somatisized and somatoform pain disorders as well as acute reactions to stress and disorders of adaptation. Somatoform autonomic dysfunction and agoraphobia are less frequent diagnoses. Clinical-psychopathological examination of elderly patients with these disorders requires a careful search for symptoms of a possible atypical depression. Definite diagnosis is necessary for adequate treatment.

[Clinical characteristics of patients and number of stem cells in the myocardium of right atrial appendage in patients with ischemic heart disease].

In the last years stem cells (SC) have been identified in rodent and human hearts. These cells have ability to multilineage differentiation in vitro and in vivo and improve cardiac function. The development of new methods of isolation SC offers new approaches to cardiac regeneration. However, the question of how individual patient characteristics influence the number of SC remains unclear. In our study we aimed to define the correlation between patient characteristics and SC number. Our findings suggest that clinical characteristics and severity of the disease may affect the yield of SC in heart tissue. Our data contribute to the development of efficient methods for SC isolation for stem cell therapy.

Regulation of Immunity via Multipotent Mesenchymal Stromal Cells.

Immune cells responsible for inflammation development are involved in tissue damage caused by wounding and various pathologies. Control of immune cell activation could be of significant benefit for regenerative medicine and the treatment of patients with autoimmune and degenerative diseases. It is a proven fact that MCSs (multipotent mesenchymal stromal cells) are capable of suppressing immune responses via the inhibition of dendritic cell maturation and via the restraining of the T, B, and NK cell function in the course of autoimmune diseases and various forms of inflammation. MSCs can be isolated easily from almost every type of tissue or organ and subsequently expandedin vitro. These cells are self-renewable and can be differentiated into various cell types of mesenchymal lineage. The current review contains a collection and critical analysis of data regarding the molecular mechanisms responsible for cross-talk between immune cells and MSCs. Some of these mechanisms can be used for the development of new practical approaches for the treatment of autoimmune diseases.