The global pandemic of a new coronavirus disease (COVID-19) has posed challenges to public health specialists around the world associated with diagnosis, intensive study of epidemiological and clinical features of the coronavirus infection, development of preventive approaches, therapeutic strategies and rehabilitation measures. However, despite the successes achieved in the study of COVID-19 pathogenesis, many aspects that aggravate the severity of the disease and cause high mortality of patients remain unclear. The main clinical manifestation of the new variant of SARS-CoV-2 virus infection is pneumonia with massive parenchymal lesions of lung tissue, diffuse alveolar damage, thrombotic manifestations, disruption of ventilation-perfusion relationships, etc. However, symptoms in patients hospitalized with COVID pneumonia show a broad diversity: the majority has minimal manifestations, others develop severe respiratory failure complicated by acute respiratory distress syndrome (ARDS) with rapidly progressing hypoxemia that leads to high mortality. Numerous clinical data publications report that some COVID pneumonia patients without subjective signs of severe respiratory failure (dyspnea, "air hunger") have an extremely low saturation level. As a result, there arises a paradoxical condition (called "silent hypoxia" or even "happy hypoxia") contradicting the very basics of physiology, as it essentially represents a severe life-incompatible hypoxemia which lacks respiratory discomfort. All this raises numerous questions among professionals and has already ignited a discussion in scientific publications concerned with the pathogenesis of COVID-19. Respiratory failure is a complex clinical problem, many aspects of which remain controversial. However, according to the majority of authors, one of the first objective indicators of the clinical sign of respiratory failure are hypoxemia-associated changes in external respiration. This review addresses some possible causes of hypoxemia in COVID-19.

The development of drugs for the therapy of COVID-19 is one of the main problems of modern physiology, biochemistry and pharmacology. Taking into account the available information on the participation of mast cells and the role of histamine in the pathogenesis of COVID-19, as well as information on the positive role of famotidine in the prevention and treatment of coronavirus infection, an experiment was carried out using famotidine in a mouse model. We used a type A/PR/8/34 (H1N1) virus adapted to mice. The antiviral drug oseltamivir (Tamiflu), which belongs to the group of neuraminidase inhibitors, was used as a reference drug. The use of famotidine in combination with oseltamivir can increase survival, improve the dynamics of animal weight, reduce the level of NKT cells and increase the level of naive T-helpers. Further studies of famotidine in vivo should be aimed at optimizing the regimen of drug use at a higher viral load, as well as with a longer use of famotidine.

The effect of moderate neonatal stress induced by inflammatory pain in rat pups of both sexes on the hormonal response and cognitive processes in adult animals was studied in the Morris water maze. No significant differences in spatial learning and memory were found in experimental rats exposed to neonatal inflammatory pain vs. control animals. However, experimental rats exhibited sex differences in long-term spatial memory whose efficiency was higher in males vs. females. After long-term memory testing, stress responsiveness of the hypothalamic-pituitary-adrenocortical axis, as assessed by the plasma corticosterone level in the formalin test, was higher in experimental males vs. females. Only experimental females exhibited differences between short-term and long-term memory, with the efficiency being higher in the former. Thus, sexual dimorphism was found in the effect of neonatal nociceptive stress on long-term spatial memory in adult rats: experimental males vs. females demonstrated more effective long-term memory combined with a higher stress reactivity of the hormonal response.

The disease caused by the coronavirus SARS-CoV-2, named COVID-19, has been spread around the world at a high transmission rate. It was initially considered to be an acute respiratory distress syndrome. Recent clinical data has highlighted that COVID-19 is characterized by a vascular dysfunction and thrombosis, which are not typical for many other acute respiratory diseases. Thrombotic complications are markers of severe COVID-19 and are associated with multiple organ failure and increased mortality. The application of unfractionated and/or low-molecular-weight heparins as anticoagulant medications, significantly reduced the severity of the disease and COVID-19-induced mortality, since heparin is a multifunctional agent. The goal of this review is to summarize the literature data on the pathogenic mechanisms of SARS-CoV-2 and to characterize the properties of heparin, which allow inhibiting these mechanisms at any stage of pathogenesis. We proposed a vicious circle hypothesis of SARS-CoV-2 pathogenesis, as well as an original approach to low-dose heparin therapy beyond its anticoagulant properties. The analysis of a wide range of effects and mechanisms of action of heparin will help create an idea of current possibilities and future potential of applying this drug.

A pressing issue of the day is the identification of therapeutic targets to suppress the "cytokine storm" in COVID-19 complicated by acute respiratory distress syndrome (ARDS) with concomitant hypoxemia. However, the key cytokine and its relative contribution to the pathogenesis of ARDS, which leads to high mortality, are unknown. A comparative assessment of the effect of elevated systemic levels of pro-inflammatory cytokines IL-1β, TNF-1α and IL-6 on the respiratory patterns and survival rate in rats was carried out under progressively increasing acute hypoxia. Increasing hypoxia was simulated by a rebreathing method (from normoxia to apnea). The recorded parameters were the breathing pattern components (tidal volume and respiratory rate), minute ventilation (MV), oxygen saturation, apnea onset time, and posthypoxic survival rate. A comparative analysis was carried out under mild, moderate and severe hypoxia (at FO = 15, 12 and 8%, respectively). It was shown that increasing hypoxia was accompanied by an acute suppression of the compensatory elevation of MV in rats with increased systemic levels of IL-1β and TNF-1α. By contrast, IL-6 caused an intensive elevation of MV with increasing hypoxia. Acute hypoxia (FO < 8%), in all experimental series, was accompanied by an impairment of the respiratory rhythm up to the development of apnea. Posthypoxic breathing restoration (survival rate) was 50% with IL-1β and TNF-1α and only 10% with IL-6. The obtained results indicate that the elevated IL-6 level, despite the absence of respiratory disorders at the initial stage of the developing pathologic process, leads to a higher mortality in rats compared to IL-1β and TNF-1α. This allows considering IL-6 as an early prognostic biomarker of a high risk of mortality under severe hypoxemia.

Numerous experimental and clinical studies have shown the effectiveness of various probiotic strains in metabolic disorders, gastrointestinal and liver diseases, immune system pathology. The effects of probiotics on cardiovascular dysfunction are less well known. The development and validation of a new experimental model in rats, including obesity, acute colon inflammation and antibiotic-induced dysbiosis, with common characteristics of systemic inflammatory response syndrome (SIRS), became the basis for investigating the effects of probiotic drugs on myocardial resistance to ischemic-reperfusion injury (IRI) using an in vivo model of infarction after coronary occlusion. A 24% increase in myocardial infarction compared to intact animals ( < 0.05) and significant changes in leukogram, biochemical and immunological parameters were found in Wistar rats with SIRS modelling. Introduction of a mixture of strains of (LA-5) and subsp. (BB-12) to animals with SIRS reduced infarct size to a value close to the control. Rats treated with LA-5 and BB-12 also showed normalization of the leukocyte count, bile acids, transforming growth factor-β, interleukins: IL-1α, IL-2, IL-6, IL-8, tumor necrosis factor-α, lipopolysaccharide and monocyte chemoattractant protein-1 in blood in comparison with the SIRS group and with the groups treated with other probiotic strains. The obtained data convincingly show the prospects for further study of the cardiotropic potential of probiotic microorganisms in translational studies.

[This corrects the article DOI: 10.1134/S0022093022020119.].

Although hypoxia tolerance is mainly determined genetically, it is important to study individual variability of animal organisms in order to identify the factors that underlie their tolerance to hypoxic exposure. We investigated blood cell counts and coagulograms in Wistar rats as predictors allowing the animal population to be split into hypoxia-tolerant and hypoxia-intolerant individuals. The validity of the specific predictors' choice was proved by a coincidence between the population split in accordance with the detected individual parameters and the results of testing animals in a decompression chamber at a rarefaction corresponding to the "rise to an altitude" of 11500 m above sea level. Circulating blood cells were quantitatively assessed by eighteen indicators before and after hypoxic exposure. The differences between animals low-tolerant (LT), high-tolerant (HT), and medium-tolerant (MT) to hypoxia were determined by five indicators: white blood cell count (WBC), granulocyte count (Gran#), red blood cell count (RBC), reticulocyte count/percent (RTC), and mean corpuscular hemoglobin (MCH). The RBC, RTC, and MCH values in HT rats were significantly higher than in LT animals (by 1.4, 1.9, and 1.1 times, respectively). The WBC and Gran# values in HT rats were lower than in LT individuals. The hypoxia tolerance indices (HTI) were calculated using the original formula. It was established that in LT rats, the HTI ≤ 0.203, in HT rats ≥ 0.335, and in MT rats < 0.335 but > 0.203. After testing in a decompression chamber, the activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT) decreased, but the fibrinogen level increased. LT rats were characterized by the lowest APTT, TT, and PT values and the highest values of the fibrinogen level. Our results indicate that one of the most important mechanisms underlying a high hypoxia tolerance in rats consists in sustaining reciprocal relationships between the complex of RBC indicators, which tend to increase under hypoxia, and Gran# indicators, which tend to decrease after hypoxic exposure.

The extraordinary situation of the 2019-2022 pandemic caused a dramatic jump in the incidence of post-traumatic stress disorder (PTSD). PTSD is currently regarded not only as a neuropsychiatric disorder, but also as a comorbidity accompanied by cardiovascular diseases, circulatory disorders, liver dysfunction, etc. The relationship between behavioral disorders and the degree of morphofunctional changes in the liver remains obscure. In this study, PTSD was modeled in sexually mature male Wistar rats using predatory stress induced by a prey's fear for a predator. Testing in an elevated plus maze allowed the rat population to be divided into animals with low-anxiety (LAP) and high-anxiety (HAP) phenotypes. It was found that morphofunctional analysis of the liver, in contrast to its biochemical profiling, provides a clearer evidence that predatory stress induces liver dysfunction in rats of both phenotypes. This may indicate a decrease in the range of compensatory adaptive reactions in stressed animals. However, in HAP rats, the level of morphofunctional abnormalities in the mechanisms responsible for carbohydrate-fat, water-electrolyte and protein metabolism in the liver testified the prenosological state of the organ, while further functional loading and resulting tension of the regulatory systems could lead to homeostatic downregulation. Meanwhile, the liver of LAP animals was only characterized by insignificant diffuse changes. Thus, we demonstrate here a link between behavioral changes and the degree of morphofunctional transformation of the liver.

Here, we discuss pathophysiological approaches to the defining of endothelial dysfunction criteria (i.e., endothelial activation, impaired endothelial mechanotransduction, endothelial-to-mesenchymal transition, reduced nitric oxide release, compromised endothelial integrity, and loss of anti-thrombogenic properties) in different in vitro and in vivo models. The canonical definition of endothelial dysfunction includes insufficient production of vasodilators, pro-thrombotic and pro-inflammatory activation of endothelial cells, and pathologically increased endothelial permeability. Among the clinical consequences of endothelial dysfunction are arterial hypertension, macro- and microangiopathy, and microalbuminuria. We propose to extend the definition of endothelial dysfunction by adding altered endothelial mechanotransduction and endothelial-to-mesenchymal transition to its criteria. Albeit interleukin-6, interleukin-8, and MCP-1/CCL2 dictate the pathogenic paracrine effects of dysfunctional endothelial cells and are therefore reliable endothelial dysfunction biomarkers in vitro, they are non-specific for endothelial cells and cannot be used for the diagnostics of endothelial dysfunction in vivo. Conceptual improvements in the existing methods to model endothelial dysfunction, specifically, in relation to the blood-brain barrier, include endothelial cell culturing under pulsatile flow, collagen IV coating of flow chambers, and endothelial lysate collection from the blood vessels of laboratory animals in situ for the subsequent gene and protein expression profiling. Combined with the simulation of paracrine effects by using conditioned medium from dysfunctional endothelial cells, these flow-sensitive models have a high physiological relevance, bringing the experimental conditions to the physiological scenario.

The last decade has been marked by an exponential increase in the number of publications on the physiological role of the normal human gut microbiota. The idea of a symbiotic relationship between the human organism and normal microbiota of its gastrointestinal tract has been firmly established as an integral part of the current biomedical paradigm. However, the type of this symbiosis varies from mutualism to parasitism and depends on the functional state of the host organism. Damage caused to the organism by external agents can lead to the emergence of conditionally pathogenic properties in the normal gut microbiota, mediated by humoral factors and affecting the outcome of exogenous exposure. Among the substances produced by symbiotic microbiota, there are an indefinite number of compounds with systemic toxicity. Some occur in the intestinal chyme in potentially lethal amounts in the case they enter the bloodstream quickly. The quick entry of potential toxicants is prevented by the intestinal barrier (IB), a set of structural elements separating the intestinal chyme from the blood. Hypothetically, severe damage to the IB caused by exogenous toxicants can trigger a leakage and subsequent systemic redistribution of toxic substances of bacterial origin. Until recently, the impact of such a redistribution on the outcome of acute exogenous poisoning remained outside the view of toxicology. The present review addresses causal relationships between the secondary dysfunction of the IB and complications of acute poisoning. We characterize acute systemic toxicity of such waste products of the normal gut microflora as ammonia and endotoxins, and demonstrate their involvement in the formation of such complications of acute poisoning as shock, sepsis, cerebral insufficiency and secondary lung injuries. The principles of assessing the functional state of the IB and the approaches to its protection in acute poisoning are briefly considered.

The review addresses modern methods of electrical stimulation used to regulate the function of external respiration in humans. The methods include abdominal functional stimulation of respiratory muscles, diaphragmatic stimulation, phrenic nerve stimulation, epidural and transcutaneous spinal cord stimulation. The physiological rationale of their application is described along with the examples of their use in clinical practice, including stimulation parameters and electrode placement diagrams for each of the methods. We analyze the effectiveness of each of the methods in patients with respiratory muscle paresis and the features of their use depending on the level of spinal cord injury. Special attention is paid to the method of epidural spinal cord stimulation because this technique is widely used in electrophysiological studies on animal models, providing deeper insight into the spinal levels of the functional control of external respiration. The review substantiates the great potential of using the method of transcutaneous electrical spinal cord stimulation both in fundamental studies of external respiration and in clinical practice.

Currently, there is a new surge of interest in the problem of hypoxia, almost lost in recent decades. Due to the fact that the circle of competent specialists in this field has significantly narrowed, it is necessary to carry out an intensive exchange of knowledge. In order to inform a wide range of interested researchers and doctors, this review summarizes the current understanding of hypoxia, its pathogenic and adaptogenic consequences, as well as key physiological and molecular mechanisms that implement the response to hypoxia at various levels-from cellular to organismic. The review presents a modern classification of forms of hypoxia, the understanding of which is necessary for the formation of a scientifically based approach to experimental modeling of hypoxic states. An analysis of the literature covering the history and current level of hypoxia modeling in mammals and human experiments, including methods for creating moderate hypoxia used to increase the resistance of the nervous system to severe forms of hypoxia and other extreme factors, is carried out. Special attention is paid to the discussion of the features and limitations of various approaches to the creation of hypoxia, as well as the disclosure of the potential for the practical application of moderate hypoxic effects in medicine.

Being one of the main proteins in the human body and many animal species, albumin plays a crucial role in the transport of various ions, electrically neutral molecules and in maintaining the colloidal osmotic pressure of the blood. Albumin is able to bind almost all known drugs, many nutraceuticals and toxic substances, determining their pharmaco- and toxicokinetics. However, albumin is not only the passive but also the active participant of the pharmacokinetic and toxicokinetic processes possessing a number of enzymatic activities. Due to the thiol group of Cys34, albumin can serve as a trap for reactive oxygen and nitrogen species, thus participating in redox processes. The interaction of the protein with blood cells, blood vessels, and also with tissue cells outside the vascular bed is of great importance. The interaction of albumin with endothelial glycocalyx and vascular endothelial cells largely determines its integrative role. This review provides information of a historical nature, information on evolutionary changes, inflammatory and antioxidant properties of albumin, on its structural and functional modifications and their significance in the pathogenesis of some diseases.

The obesity problem requires a study of its pathophysiological consequences affecting hormonal regulation and organism's reactivity to extreme exposures. The study was aimed first to examine the effect of a high-calorie diet and social isolation, as well as their combination for 4 months, on the development of obesity, its metabolic and behavioral sequelae, features of the thyroid status, while at the second stage, to assess the reaction of hormonal indices of the thyroid status to short-term stress in rats. The experiments were carried out on male Wistar rats and at the first stage focused on the effects of a high-calorie diet and social isolation, as well as their combinations for 4 months. At the end of the experiment, behavioral reactions, metabolic syndrome indices, thyroid status, and cortisol levels were evaluated. At the second stage, the animals were exposed to short-term acute stress, and the shifts in the hormonal indices were recorded one hour later versus the initial background. A high-calorie diet led to the development of metabolic syndrome, signs of depression, increased thyroid-stimulating hormone (TSH), thyroxine and triiodothyronine serum levels, as well as iodothyronine deiodinase type 1 (D1) activity, in the rat liver. At the same time, there was a decrease in thyroperoxidase activity and an increase in thyroid levels of triglycerides and malondialdehyde. The physiological response to stress in the control rat group included an increase in cortisol and TSH serum levels, however, against the background of a high-calorie diet, no cortisol release into the bloodstream was recorded. Social isolation did not alter normal reactivity of the adrenal cortex, but reduced TSH release in response to acute stress, since the initial level of this hormone was slightly elevated against the background of chronic social isolation stress. Thus, excessive nutrition and the deficit of social activities in male Wistar rats led to significant changes in the organism's reactivity to acute stress.

The aim of the work was to conduct a retrospective analysis of the clinical data of patients with pneumonia caused by the SARS-CoV-2 virus, and to determine via mathematical methods the significance of some physiological and biochemical indices as predictive markers of an unfavorable outcome of the disease. A random cohort of patients with COVID-19 pneumonia numbered 209 people. Mathematical analysis addressed the physiological characteristics of patients recorded at the time of hospital admission, as well as blood coagulation parameters and those reflecting the development of an inflammatory reaction. The analyzed parameters were categorized relative to the reference ranges of physiologically normal values. Correlation analysis was carried out using categorical data on the disease outcome. The algorithms for calculating statistical characteristics, as well as results visualization, were programmed in Python. When comparing patient groups, the significance of differences between the determined parameters was assessed using the Pearson's χ test with Yates' correction. The study showed that the age over 50 and male sex can be considered risk factors for patients with COVID-19 pneumonia ( < 0.05). The disease outcome was found to be significantly affected by cardiovascular pathologies ( < 0.01) and to a lesser extent by diabetes mellitus ( < 0.10). There were revealed maximal correlation coefficients between the oxygen saturation level (-0.43), as well as the breathing rate (0.43), and a fatal outcome of the disease. For patients over 50 years of age, oxygen saturation below 80% at the time of hospital admission turned out to be a marker of mortality. It was shown that D-dimer blood levels above 625 ng/mL in patients over 80 years of age correlated with mortal outcomes. No correlation was found between the C-reactive protein (CRP) level and the disease outcome. The effect of corticosteroids on the disease outcome was analyzed in patients with different CRP levels. It was found that, while using corticosteroids, the mortality rate in patients with CRP ≤ 12.5 mg/L is 2.7 times higher than in those with CRP > 12.5 mg/L ( < 0.01). Thus, the use of adequate mathematical methods made it possible to define more precisely some mortality-associated physiological and biochemical indices in patients with COVID-19 pneumonia.

Favipiravir and Vitamin C (Vit C) were used together in the treatment of the COVID-19 pandemic. However, the effects of favipiravir on the periodontium are still unknown. Therefore, the aim of this study was to investigate the effects of Favipiravir and Vit C treatment on alveolar bone metabolism. Fifty healthy adult male Sprague-Dawley rats (2-3 months old) were randomly divided into five equal groups ( = 10): Control, Favi 20, Favi 100, Favi 20+Vit C, Favi 100+Vit C. Favipiravir (20 mg/kg and 100 mg/kg, ) and Vit C (150 mg/kg/day, oral) were administered to the rats for 14 days. Alveolar bone loss (ABL) and histopathological changes were examined using a light microscope. Immunohistochemistry was used to determine levels of receptor activator of nuclear factor kappa-B ligand (RANKL), caspase-3, bone morphogenic protein 2 (BMP-2) and alkaline phosphatase (ALP) in the bone tissues. Favipiravir increased the levels of RANKL and caspase-3 expression but decreased BMP-2 and ALP levels in a dose-dependent manner. Favi 20+Vit C and Favi 100 +Vit C groups showed decreased RANKL and caspase-3 levels in addition to increased BMP-2 and ALP levels. Favipiravir can cause histopathological damage to the periodontium, but administration of favipiravir combined with Vit C can provide a protective effect against this damage.

The stress-inducible 70 kDa heat shock protein (Hsp70) can exert a protective effect on endotoxemia and sepsis due to its ability to interact with immune cells and modulate the immune response. However, it remains unknown whether Hsp70 is able to relieve endotoxemia-induced fever. We carried out a comparative study of the effects of preventive administration of the human recombinant Hsp70 (HSPA1A) on lipopolysaccharide (LPS)-induced endotoxemia in pigeons and rats with preimplanted electrodes and thermistors for recording the thermoregulation parameters (brain temperature, peripheral vasomotor reaction, muscular contractile activity). Additionally, we analyzed the dynamics of the white blood cell (WBC) count in rats under the same conditions. It was found that preventive administration of Hsp70 relieves the LPS-induced febrile reaction in pigeons and rats and accelerates the restoration of the WBC count in rats. The data obtained suggest that these warm-blooded animals share a common physiological mechanism that underlies the protective effect of Hsp70.

[This corrects the article DOI: 10.1134/S0022093022010203.].

Neutrophils are one of the main cells of innate immunity that perform a key effector and regulatory function in the development of the human inflammatory response. Apoptotic forms of neutrophils are important for regulating the intensity of inflammation and restoring tissue homeostasis. This review summarizes current data on the molecular mechanisms of modulation of neutrophil apoptosis by the main regulatory factors of the inflammatory response-cytokines, integrins, and structural components of bacteria. Disturbances in neutrophil apoptosis under stress are also considered, molecular markers of changes in neutrophil lifespan associated with various diseases and pathological conditions are presented, and data on pharmacological agents for modulating apoptosis as potential therapeutics are also discussed.

Stress plays an important role in the pathogenesis of anxiety and depressive disorders. Neuroinflammation is considered as one of the mechanisms by which stress alters the molecular and cellular plasticity in the nervous tissue and thus entails CNS dysfunction. The contribution of genetically determined features of the nervous system to the development of post-stress neuroinflammation has not been sufficiently studied. In this study, the dynamics of post-stress changes in mRNA levels of the β and genes encoding proinflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor (TNF) were evaluated in the blood and brain of two rat strains with high and low excitability thresholds of the nervous system (HT and LT, respectively). Changes in IL-1β and TNF mRNA levels were assessed by real-time PCR 24 h, 7, 24 and 60 days after long-term long-term emotional and painful stress in the blood and three brain structures involved in the development of post-stress pathology (prefrontal cortex, hippocampus, amygdala). In highly excitable LT rats, IL-1β mRNA level in the hippocampus and amygdala increased compared to the control 24 days after stress termination, while in low-excitable HT animals, an increase in the level of IL-1β mRNA was only detected in the hippocampus at the same time point. TNF mRNA level did not change in any of the rat strains at any of the post-stress time points. Genetically determined excitability of the nervous system is a promising marker of individual stress vulnerability, as manifested in post-stress disorders associated with developmental and time-course features of neuroinflammation.