[Predictive role of erythrocytes in assessment of COVID-19 outcomes].

INTRODUCTION: The search for affordable and accurate predictors of the outcome of COVID-19 is extremely important, as it provides the possibility to effectively correct the patient treatment tactics. AIM OF THE STUDY: To develop simple and accurate criteria based on the dynamics of red blood counts that predict the outcome of COVID-19. MATERIALS AND METHODS: Observations were carried out in 125 patients with severe and extremely severe COVID-19, in whom indicators characterizing the state of red blood were determined in dynamics on days 1, 5, 7, 10, 14 and 21 after the hospitalization. ROC analysis was performed to calculate the threshold predictive values for survival and mortality. RESULTS: The total number of erythrocytes and the level of hemoglobin in severe and extremely severe patients did not go beyond the acceptable limits, although showed a tendency to decrease in the group of fatal cases. On the 1st and 21st days, the number of MacroR in the deceased patients was reduced compared to those in group of survivors. It has been established that the RDW-CV test can predict the outcome of the COVID-19 with a high degree of probability at a relatively early stage of disease. RDW-SD test can be an additional predictive criterion of COVID-19 outcome. CONCLUSION: The RDW-CV test can be used as an effective predictor of disease outcome in patients with severe COVID-19.

[Morphological compound and indicators of the blood clotting system in severe COVID-19 patients of middle aged and elderly during treatment of Tocilizumab and Thymalin.]

The aim of the work was a comparative study of Tocilizumab and Thymalin effects on the morphological composition and indicators of the blood clotting system in COVID-19 of middle aged and elderly patients. Severe COVID-19 patients were divided into 3 groups: 1st - control (basic therapy), 2nd - basic therapy +Tocilizumab, 3rd - basic therapy +Thymalin. Hospital mortality in COVID-19 patients after standard therapy, Tocilizumab and Thymalin application was 40,9; 28,4 and 20,6% accordingly. The number of platelets increased by 1,5 times, the concentration of fibrinogen in blood decreased by 78% and activated partial thromboplastin time decreased by 9,3% in patients taking Tocilizumab. Under the influence of Tocilizumab, the platelet/white blood cell and platelet/lymphocyte ratios increased by 1,6 and 1,4 times, which may be a predictor of an unfavorable outcome of COVID-19. Thymalin increased the number of lymphocytes and monocytes by 2 times, the number of leukocytes - by 1,3 times, the number of platelets in the blood - by 1,5 times. Thymain decreased the platelet/lymphocyte and neutrophil/lymphocyte ratios by 1,4 times and 2 times. The use of Thymalin decreased the level of fibrinogen, lactate dehydrogenase and D-dimer in the blood by 1,2; 1,8 and 1,7 times, respectively. Thymalin, compared with Tocilizumab, meets the principles of pathogenic therapy for severe COVID-19 of middle aged and elderly patients to a greater extent, having a normalizing effect on the morphological composition and indicators of the blood clotting system.

The State of Microcirculatory Hemodynamics in Patients with Moderate and Severe COVID-19.

Microcirculatory hemodynamic indexes (HI) were assessed in patients with moderate and severe COVID-19. In both groups, a significant increase in the absolute spectral indexes (HI1, HI2, and HI3) and the ratio of low-frequency to high-frequency component (HI1/HI3) was revealed. In the group of severe infection, only the "slow" index (low-frequency HI1) of microcirculatory hemodynamics was significantly lower. The oscillatory indices MAYER1-3 and RESP1-3 were reduced in patients of both groups. The aggravation of the disease course was accompanied by depression of the low-frequency index HI1. Regulatory shifts compensate for disturbances in microcirculatory processes in moderate COVID-19, but severe course was associated with their decompensation.

Results and Prospects of Using Activator of Hematopoietic Stem Cell Differentiation in Complex Therapy for Patients with COVID-19.

The paper presents the results of a standard and complex treatment method using the peptide drug thymus thymalin in patients with COVID-19. One of the mechanisms of the immunomodulatory effect of thymalin is considered to be the ability of this peptide drug to influence the differentiation of human hematopoietic stem cells (HSCs). It was found that, as a result of standard treatment, patients in the control group showed a decrease in the concentration of the pro-inflammatory cytokine IL-6, C-reactive protein, D-dimer. The addition of thymalin to standard therapy accelerated the decline in both these indicators and the indicators of the T cell system. This has helped reduce the risk of blood clots in COVID-19 patients. The revealed properties of the thymus peptide preparation are the rationale for its inclusion in the complex treatment of coronavirus infection. Peptideswith potential biological activity against SARS-CoV-2 virus [29]. Note: Nitrogen atoms are shown in blue, oxygen atoms - in red, carbon atoms - in gray, hydrogen atoms - in white, and phosphorus atoms - in yellow.

Integrative Approach to Assessing the Complex of Correlations between Indicators of Physiological Functions.

We present the results of application of the combined correlation matrix method in some clinical studies. A practical algorithm is proposed for constructing a correlation matrix that compactly reflects a large number of interconnections for the situations when several diagnostic methods are used in an experimental clinical or preclinical trial. Several approaches to assessing and displaying the relationships are demonstrated for comparison.

[Age features of bioregulatory therapy of dental diseases.]

The article presents data on the use of peptide bioregulators of cell homeostasis and the protective functions of the body in various dental diseases and pathology of organs and tissues of the maxillofacial region. Issues related to the immunopharmacological effect and clinical use of natural and synthetic peptide thymomimetics (thymalin, thymogen, vilon, epithalamin, cortexin) and peptide bioregulators from cartilaginous (sigumir, chondrolux) and other tissues in case of trauma, as well as inflammatory, inflammatory and other pathological processes of tissues of the oral cavity and maxillofacial region. Particular attention is paid to their use in the complex treatment of dental diseases in the elderly.

[The influence of polypeptide liver complex and tetrapeptide KEDA on organism physiological function in norm and age-related pathology.]

The applying of many drugs in elderly and old people often is the reason of liver dysfunction. Thereat, the risk of liver fibroid induration, acute and chronic hepatitis increases during aging. It is the reason to find new, effective and harmless hepatoprotectors. In the review is shown the data of hepatoprotective, immunoprotective and antiageing properties of liver polypeptide complex (Ventvil) and KEDA tetrapeptide (Lys-Glu-Asp-Ala, Livagen). In liver pathology experimental models (liver fibroid induration, acute and chronic hepatitis) in amimals and in vitro was shown high efficiency of Ventvil and KEDA peptide. Ventvil and KEDA peptide had concordant effects - normalized immune and antioxidant status, restored liver function during hepatitis. It was demonstrated, that maximal hepato- and immunoprotective effect of peptides verified in aging.

Peptide KE in Human Proteome.

Peptide KE exhibits immunoprotective, geroprotective, and oncostatic activities and stimulates functional activity of fibroblasts. The KE motif is present in amino acid sequences of some cytokines and peptide hormones functionally similar to KE peptide. However, the relationship between the presence of KE motif and protein functions on the scale of known human proteome has not yet received sufficient attention. The incidence of bioregulatory peptide KE in proteins of various functional groups constituting human proteome is studied. The study is carried out with the use of the available data on the human proteome (UniProt portal) comprising 20,417 proteins. The levels of KE motifs were maximum in cytoplasmic and nuclear proteins, while the presence of KE in the membrane and all other proteins was the minimum. KE peptide molecules released from nuclear proteins during limited proteolysis can bind to DNA and regulate gene expression.

Method for Determining Microcirculatory Hemodynamics by Laser Speckle Interferometry in Small Animals.

We performed experimental evaluation of various positions (ear, paw, and tail) of the of dynamic light scattering sensor of near-infrared laser radiation (840 nm) using speckle interferometry in rats. Dynamic monitoring of the reactions to prolonged ultrasound exposure (7 days) showed that the base of the tail is most suitable for this purpose. Additionally, analysis of microcirculation parameters on the surface of skin autograft was performed. The method of analysis of hemodynamics in humans was adapted for animals.

[Features of pathogenesis and COVID-19 course for the elderly and old age.]

The causative agents of coronavirus infection have long been considered the cause of benign respiratory diseases «common colds¼ until their pathogenic types appeared on the epidemic arena: SARS-CoV-1, MERS and finally, SARS-CoV-2. Diseases caused by the listed viruses characterized by moderate invasiveness and noticeable mortality compared to other respiratory viruses. The pathogenesis of these infections is based on a wide range of innate immunity dysfunctions, manifested in the direct suppression of anti-inflammatory functions and, on the contrary, the activation of pro-inflammatory functions, such as the assembly and activation of NLRP3 inflammasome, as well as the synthesis and secretion of pro-inflammatory cytokines and chemokines. Excessive secretion of pro-inflammatory factors is accompanied by a disturbance in the balance of cytokines, leading to the development of a cytokine storm. When the body manages to cope with these disorders, a stable adaptive immunity develops, which is a harmonious combination of cellular and humoral mechanisms of resistance. Particularly difficult COVID-19 occurs in elderly and senile people. It has been shown that the main tests for the risk of multiple organ failure and death in COVID-19 in this category of patients are concomitant diseases, lymphocytopenia, increased transferases, D-dimer and other metabolic disorders. It has been established that critically ill COVID-19 patients develop endothelial dysfunction, thrombotic microangiopathy, immunothrombosis and disseminated intravascular coagulation, which are the basis of multiple organ failure. Pneumonia, as a complication of COVID-19, accompanied by the development of acute respiratory respiratory syndrome, ultimately leads to pulmonary fibrosis, which is often fatal. There is no specific therapy for COVID-19. Recently, immunomodulatory drugs have been widely introduced in the treatment of this infection, including remdesivir, synthetic quinine derivatives and neutralize antibodies.

[Polypeptide vessel complex and its role in physiology function regulation in aging pathology.]

In review it is shown data about polypeptide vessel complex, extracted from calf vessel and named Slavinorm® (Vasolin). Slavinorm® had therapeutic effects in cardio-vascular age related pathology in animal models. Slavinorm® prevents atherosclerosis, normalizes lipid metabolism, lipid peroxidation parameters, station of congenital and adaptive immunity, callicrein-kinins system, vessel and trombocitary hemostasis, blood coagulability, fibrinolysis, activates vessel wall reparation. Slavinorm® has positive effects in other age-related diseases (arthritis, pancreatitis, respiratory distress).

[Epigenetic Mechanisms of Peptide-Driven Regulation and Neuroprotective Protein FKBP1b].

Cortexin is a clinically approved cerebral cortex polypeptide complex in calves. The mechanism of cortexin action is not understood well. Two cortexin derivatives, short peptides EDR and DS with neuroprotective activity, were synthesized. According to the data of molecular modeling, these peptides are able to bind to the histone H1.3 protein. This can affect the conformation of histone H1.3, which leads to a change in the chromatin structure in the loci of some genes, in particular Fkbp1b encoding the FK506-binding protein. Electrophysiological processes associated with the Ca^(2+) exchange are disturbed in the pyramidal neurons of the hippocampus during aging of the brain. The Fkbp1b gene encodes peptidyl-prolyl cis-trans isomerase, regulating the release of calcium ions from the sarcoplasmic and endoplasmic reticulum of neurons. The activation of the Fkbp1b gene transcription under treatment with short peptides can promote the synthesis of its protein product and the activation of the Ca^(2+) release from organelles of the sarcoplasmic and endoplasmic reticulum of neurons, which, in turn, can lead to an increase in the functional activity of neurons.

[The role of «Youth and aging proteins¼ in essential hypertension pathogenesis.]

Essential hypertension (EG) is an age-associated disease. Often EG of elderly patients haven't good way of treatment. Thus, the search of new target molecules for EG therapy is an actual goal of gerontology and molecular medicine. It was shown, that during EG concentrations of GDF11 «youth protein¼ decreased in 3,3 times and GDF15, JAM-A/1, CCL11 «aging proteins¼ increased in 1,4-2,4 times. EG patients have abnormal microcirculation processes. It was shown as decreasing in 1,3 and 1,7 times of hemodynamic HI1 and H1-H3 indexes. EG patients have negative correlation of GDF15 concentration with arterial pressure. EG patients have no correlation of JAM-A/1 concentration with arterial pressure. Normal is positive correlation with GDF15, JAM-A/1 concentration with arterial pressure. GDF15 blood level during EG have positive correlation with HI1-HI3 and negative correlation with NEUR_HI2 and MAYER_HI3 indexes. It can show on pathogenesis mechanisms of endothelial and smooth muscles function of vessels tissues. We suppose, that the regulation of GDF11, GDF15, JAM-A/1, CCL11 «youth and aging proteins¼ can be target object of EG therapy.

Impact of Fitness Status on the Optically Measured Hemodynamic Indexes.

The physiological characteristics of skin blood flow can be described in terms of the hemodynamic indices (HI). The HI is derived from the laser speckle characteristics, which are governed by the cutaneous blood flow. A miniaturized dynamic light-scattering sensor was used to measure the speckle pattern from the finger root. Three groups of subjects from 15 to 25 years of age were tested. The first group included subjects who are actively engaged in sport activities; the second group included subjects with low level of physical activity; and the third group included healthy controls with moderate physical activity. The HI parameters were measured prior to and after the performance of a determined physical load. As a marker of cardiovascular fitness (CVF), we used the postload decay rate of HI. We found that the hemodynamic response to the physical load provides a statistically significant correlation with the postload heart rate decay. It was also found that postocclusion increase of the arterial HI is more prominent in the group with higher physical activity. These results indicate that hemodynamic indices can be used as an additional marker for cardiovascular fitness level.

Short Peptides and Telomere Length Regulator Hormone Irisin.

Irisin produced by muscles during exercise and promoting fat burning also exhibits geroprotective effect and induces telomere elongation in normal somatic cells. Special attention is paid to studies of the role of peptides Lys-Glu, Glu-Asp-Arg, and Ala-Glu-Asp-Gly in epigenetic regulation of irisin content. The data suggest that the immunomodulatory peptide Lys-Glu and neuroprotective peptide Glu-Asp-Arg modulate the life span by modulating irisin gene expression.

[The methods of evaluation of aggregative activity of blood corpuscles in norm and in patients with ischemic stroke.]

The article presents comparative evaluation of aggregative activity of blood corpuscles in norm and in patients with ischemic stroke derived using flow cytofluorometry and light microscopy. It is noted that in patients with stroke in peripheral blood absolute content of leukocyte thrombocyte and erythrocyte thrombocyte aggregates is drastically increased as compared with healthy examined persons. Besides, more the number of aggregates is formed during the first day of onset of disease more the severe cerebral stroke progresses.

["Protein of senility" CCL11, "protein of juvenility" GDF11 and their role in age-related pathology].

The paper presents the latest literature data on the structure and functions of «protein of juvenility¼ - CCL11 and «protein of senility¼ - GDF11. Chemokine CCL11 injected to young animals has been shown to lead to degenerative changes in the central nervous system (CNS), disturb cognitive functions and impede tissue regeneration. CCL11 concentration increases dramatically in schizophrenia, Alzheimer's disease, neuro-inflammatory disorders, cerebral malaria, drug addiction, as well as in atherosclerosis, periodontal disease, macular degeneration, cancer and other pathologies. In contrast to CCL11, differentiation growth factor 11 (GDF11), being administered to old mice, eliminates age-associated hypertrophy of the heart, improves muscle tone and prevents degenerative changes in the CNS, improves cognitive functions and enhances tissue regeneration. Its concentration decreases in cardiovascular disease, osteoporosis, and other «diseases of old age¼. At the same time, the higher the GDF11 level in the blood, the milder myocardial infarction, stroke and other age-related diseases of the cardiovascular system.

The Effect of Kinesitherapy Exercises on the Level of Irisin among Females with Cardio-vascular diseases depending on the body mass and hormonal status.

The observation was conducted on 41 female subjects age 32 to 69 with compensated cardio-vascular diseases. 23 of the subjects had an increased body mass index (BMI). It was established that the older the females the less of the irisin muscle hormone is found in the blood. In the subjects with a higher BMI the level of irisin in the blood is also higher. Direct correlations were found between the level of irisin and the level of female sex hormones - estrogen and progesterone. Under the effect of kinesitherapy exercises the level of irisin in females with normal BMI increases; whereas in the females with a higher BMI it generally stays the same or is decreased. The characteristics of irisin's response to the kinesitherapy exercises depends on its original level, the intensity of physical exercise and the subject's physique.

The JAM Family of Molecules and Their Role in the Regulation of Physiological and Pathological Processes.

The review covers the main functions of the family of adhesion molecules JAMs (Junctional adhesion molecules). This review provides information about the role of the molecules JAM-AH, JAM-BH and JAM-CF in the occurrence of pathological conditions, including diseases of the nervous and cardiovascular systems, atherosclerosis, thrombosis and malignant growth. A molecule JAM-C and JAM-C directly affect platelet's adhesion to endothelial and dendritic cells, neutrophils, and other types of leukocytes, which makes their involvement in the regulation of hemostasis, and migration processes. JAM-A has an effect on the inflammatory response, leading to impaired cognitive function in HIV infection. JAM-B is involved in suppression of tumor growth in patients with Down syndrome. It is described the role of molecule JAM-A and JAM-C in the pathogenesis of hypertension, hypertensive crisis, atherosclerosis, cardiac abnormalities in the syndrome of Jacobson. Molecules JAM-B and JAM-C reduce the growth and invasion of human gliomas, and JAM-A has static effect against breast cancer. JAM-A molecule, JAM-B and JAM-C are involved in the development of inflammatory reactions and pathological neoangiogenesis in the cornea. The molecule JAM-C is involved in differentiation and polarization photoreceptors of the retina. The review provides own data of the authors, suggests the presence of epigenetic mechanisms of regulation of expression of the family of molecules JAMs, carried out with the direct participation of peptide geroprotectors.