We have previously proposed a unified mechanism for the formation of contrasted representations of multimodal sensory stimuli in the activity of neocortical neurons. Contrasting is based on the opposite sign of modification of the efficacy of strong and weak excitatory inputs to the spiny cells of the striatum (the input structure of the basal ganglia) and the subsequent dopamine-dependent activity reorganizations in parallel cortico – basal ganglia – thalamocortical loops. Oxytocin and dopamine (through D1 receptors) can improve the contrast of these representations, contributing to the induction of LTP of the efficacy of excitation of cortical, thalamic, and hippocampal neurons innervating spiny cells. In addition, oxytocin and dopamine can improve contrasting enhancement by increasing the signal-to-noise ratio in the neocortex, hippocampus, and striatum. A proposed mechanism for increasing the signal-to-noise ratio is based on the opposite sign of a long-term modification of the efficacy of monosynaptic excitatory and disynaptic inhibitory inputs, simultaneously affecting the postsynaptic neuron. The proposed mechanisms may underlie the contribution of oxytocin and dopamine to improving the formation and long-term maintenance of activity in neuronal groups with similar receptive fields that form columns in the primary visual cortex, a tonotopic map in the primary auditory cortex, a somatotopic map in the sensorimotor cortex, and distributed clusters in the olfactory piriform cortex. These mechanisms differ from the commonly accepted mechanisms of the formation of neuronal clusters in the neocortex with similar RPs, that are based on afferent and lateral excitation and inhibition, which does not allow providing the specificity and duration of effects. Understanding the mechanisms of involvement of oxytocin and dopamine in the processing of multimodal sensory information may be useful for developing treatments for some disorders of social behavior.
The review is devoted to the analysis of the relationship between dynamic changes in patterns of electrical activity of the brain during the occurrence of mental disorders in the form of paranoid schizophrenia and depression and in patterns of brain activity in cardiovascular pathology associated with permanent atrial fibrillation, as well as indicators of multifractality of the studied patterns. To assess these indicators of electroencephalographic patterns, we describe a method of multifractal analysis based on the search for maxima of wavelet coefficient modules, and to isolate the fractal component of the signal in the power spectrum we describe a method of autospectral analysis with irregular resampling. It has been shown that the main differences between the multifractal properties of the electrical activity of the brain in health and in pathology are the different widths of the multifractality spectrum and its location, associated with different types of sequential pattern values. In this regard, the multifractality indicators can serve as informative markers of neuronal disorders and can be included in a set of tests for studying various pathologies.
Extracellular matrix (ECM) is a dynamic three-dimensional network of macromolecules that provides structural support to cells and tissues. Over the last decades, a significant body of evidence has accumulated showing that ECM also plays a key regulatory role. The structural components of the ECM (proteins, glycoproteins, proteoglycans, glycosaminoglycans), the complex of remodeling molecules (proteases / antiproteases), and deposited/released bioactive mediators form an integrated functional system, which provides physiological homeostasis in the tissue. ECM can continuously adopt under the influence of mechanical, biochemical, physical signals, providing the ability to configure various tissues to meet the demands of their functions. The review briefly presents the current data on the structural components of the ECM. Special attention is paid to ECM as depo, as well as the source of biologically active products resulting from the physiological remodelling of the ECM. The role of the most important physical factor of the microenvironment, the tissue oxygen level, in the physiology of the ECM of stromal lineage cells is discussed.
Social and demographic changes in the recent decades have led to an increase in the prevalence of social isolation and loneliness in modern society. Social isolation and loneliness are common but underrated factors that determine health, especially cardiovascular health. In addition, the results of various studies have shown that the negative impact of loneliness and social isolation leads to dysfunction of other systems. Social isolation and loneliness are accompanied by the development of oxidative stress in brain structures. This stress activates neurons in the prefrontal cortex and limbic areas, which is accompanied by prolonged increased production of glucocorticoid hormones, eventually leading to resistance to glucocorticoids. At the same time, the sympathetic nervous system is also activated, which, against the backdrop of resistance to glucocorticoids, causes a persistent increase in blood pressure and the development of a pro-inflammatory state. As a result, lonely people experience increased peripheral vascular resistance and increased blood pressure. In addition, the atherosclerotic changes in the arteries develop faster. Although the molecular mechanisms responsible for increased cardiovascular risk in lonely and socially isolated people are not well studied, these changes have been proven to contribute to an increased risk of developing cardiovascular disease. Current measures to fight against loneliness and social isolation have the potential to reduce their negative impact on health. However, given their limited use, their effectiveness for society as a whole is insufficient. In order to better understand the mechanisms of the negative impact of loneliness and social isolation on cardiovascular health, more in-depth research and the development of more effective interventions are needed.
The study of connections between the action of genes and the implementation of behavior involves analyzing their influence on the structure and functions of the nervous system at different levels of its organization, among which special importance is given to the basic properties of nervous processes, the excitatory process and the excitability of the nervous system. The review is devoted to a historical examination of studies devoted to elucidating the role of hereditarily determined excitability in determining the functional characteristics of the nervous system, its influence on the brain and behavior, and revealing the physiological and genetic mechanisms of their interaction using animal models of different phylogenetic levels.
The article presents a review of literary sources dedicated to the physiological role and functions of certain proteins of the TGFβ superfamily, specifically GDF11 and GDF8, as well as their place in the pathogenesis of several diseases whose risk increases with age. Possible therapeutic applications of these proteins are described. It is shown that the role of GDF11 in the pathogenesis of the described diseases is ambiguous. GDF11 is a previously unrecognized regulator of bone remodeling, prevents myocardial hypertrophy, and improves the condition of animals with experimental diabetes or neurodegeneration. The anti-proliferative action of GDF11 is also observed in many oncological diseases. However, GDF11 may have a negative impact on the metabolism of muscle and bone tissue, which may limit its use in certain conditions. Due to differences in the expression and function of GDF11 in cardiac, nervous, muscular, and other tissues, its divergent actions, and the narrow therapeutic range of recombinant GDF11, further research is needed to determine the optimal range of indications and limitations, dosages, and methods to reduce side effects.
In the review, a generalized analysis of current scientific data explaining the physiological mechanisms of the influence of obesity on respiratory system is carried out. The multifactorial nature of the respiratory effect of obesity, including mechanical and inflammatory effects, is emphasized. The consequences of restrictive and obstructive changes in the biomechanics of respiration, changes in the topographic distribution of lung ventilation, mismatch of ventilation and perfusion, and a decrease in the efficiency of the respiratory muscles are considered. Elucidation of the central mechanisms of the respiratory action of proinflammatory mediators expressed by adipose tissue cells is recognized as a promising area of research. Special attention is paid to the action of leptin, which is the main regulator of metabolism and respiratory control in obesity. Its ability to modulate the central respiratory chemosensitive is discussed. It is assumed that an increase in pulmonary ventilation due to an increase in leptin production in obesity has a compensatory character and allows obese patients to maintain normocapnia despite an increase in mechanical load on respiration system. Whereas leptin resistance and suppressed hypercapnic ventilation response play a key role in the development of obesity–hypoventilation syndrome. It is concluded that it is necessary to further study the physiological mechanisms of the influence of obesity on the respiratory function in order to find new effective therapeutic methods for the treatment of diseases associated with obesity, which is the main factor in the development of metabolic syndrome.
Long-term studies (1987–2023) have shown that the model of chronic social conflict with the original name «sensory contact model» can be used to model various pathological conditions that develop in mice under the influence of chronic social stress, which makes it possible to study neurophysiological and neuromolecular mechanisms at different stages of disease development, in particular, increased anxiety, depression-like and psychosis-like states in mice of the C57BL/6 strain under repeated agonistic interactions. In pharmacological experiments in mice with different pathological symptoms, it becomes possible to study: the therapeutic and protective effects of drugs at different stages of disease development, the effectiveness of treatment, and methods for prevention of relapses of the disease. The model makes it possible to develop approaches to pharmacogenomic therapy, as well as search for peripheral markers of pathological conditions.
The membrane T1R taste receptor family interacts with sweet substances – carbohydrates, artificial sweeteners and some amino acids. An important result of research in the 21st century was the discovery of abundant expression of these receptors outside of the oral cavity, mainly in cells actively involved in metabolic processes: enteroendocrine cells of the intestine, pancreatic β-cells, adipose and bone tissue, etc. This review integrates and analyzes current data on the role of extraoral T1R receptors in the regulation of metabolism, cell growth and differentiation, which is achieved through modulation of hormone secretion (insulin, GLP-1, GIP), activity of membrane transporters and cell growth and proliferation factors. T1R mediated cellular responses to nutrients, mechanisms of signal transduction, effects on inositol triphosphate, cAMP and intracellular Ca2+ levels, stimulatory effects on glucose transporters SGLT1 and GLUT2, effects on mTOR and hormone secretion are described. The interaction of membrane receptor mechanisms and metabolic detection of glucose by the ATP/ADP ratio in the cell cytoplasm is also discussed. Putative evolutionary adaptation of metabolic processes related to nutrition and manifested in polymorphism of genes encoding T1R proteins is presented. It is suggested that extraoral taste receptors for sweet substances and amino acids may be a target for therapeutic interventions in obesity, hyperglycemia, insulin resistance, and hepatosteatosis.
Post-traumatic stress disorder is a mental disorder that is closely associated with dysfunction of the hypothalamic-pituitary-adrenal axis, and for its development is required the experience of a traumatic event that causes negative emotions and memories that persist for quite a long time. The likelihood of development of post-traumatic stress disorder is influenced both environmental factors, and genetic and epigenetic characteristics of the body. In this case epigenetic modifications act as dynamic biomarkers (“nanotags”) of the impact of the environment on the genome (epigenome), which can, under certain conditions, disappear or remain not only in an individual directly exposed to psychogenic trauma, but also transmitted over a number of generations. Review focuses on the possible mechanisms of intergenerational and transgenerational inheritance of the biological effects of post-traumatic and stress-related disorders.
The regulatory effects of luteinizing hormone (LH) and chorionic gonadotropin (CG) are realized through the activation of the G-protein coupled LH/CG receptor (LH/CG-R). The result of this is the activation of various types of G proteins, which leads to stimulation (Gs) or inhibition (Gi) of the cAMP-dependent pathway and stimulation of calcium signaling (Gq/11, Gi), and the recruitment of β-arrestins, which prevent G protein signaling through receptor internalization and downregulation, but can also activate the mitogen-activated protein kinase cascade. Despite a certain similarity in the effects of LH and CG, there are differences between them both in efficiency and in the pattern of regulation of LH/CG-R. This is a consequence of differences in the affinity of LH and CG to the orthosteric site of the receptor, as well as differences at the level of allosteric regulation of the receptor, which is due to the presence of a C-terminal extension in the β-subunit of CG, including sites for O-glycosylation, and the variability of N-glycosylation of α- and β-subunits of gonadotropins. Moreover, the number of N-glycans, the degree of their branching and charge differ, which leads to different efficiency of activation of intracellular cascades, affecting the physiological response of the reproductive system to gonadotropins. Of great importance is the formation of homodi(oligo)meric complexes of LH/CG-R and its heterocomplexes with the follicle-stimulating hormone receptor, where protomers allosterically influence the efficiency of LH/CG-R activation and the bias of signal transduction. Taking into account the large number of allosteric sites in LH/CG-R, the development of low-molecular allosteric regulators is underway, including agonists based on thieno[2,3-d]-pyrimidine and peptides derived from the cytoplasmic loops of LH/CG-R. These regulators can become prototypes of drugs for correcting the functions of the reproductive system. This review is devoted to the analysis of data on the similarities and differences in the signaling and physiological effects of gonadotropins with LH activity, the role of allosteric mechanisms in this, and the prospects for creating allosteric regulators of LH/CG-R.
Chlorine anions have a significant influence on the electrophysiological properties of excitable tissues, including myocardium. Chlorine anions and transmembrane chloride currents (ICl) determine the configuration of action potentials (AP) in various regions of hearts. Disruption of transmembrane chloride transport leads to alterations in normal electrical activity, resulting in cardiac pathologies and arrhythmias. Currently, chloride conductivity and expression in the heart and a functional role have been confirmed for several types of macromolecules. These channels include CFTR, ClC-2, CaCC (TMEM16), and VRAC (LRRC8x). Additionally, chloride cotransporters (KCC, NKCC) and chloride-bicarbonate exchangers make a significant contribution to the regulation of intracellular chlorid ion concentration ([Cl-]i) and, consequently, the equilibrium potential for chloride ions (ECl). The review covers the mechanisms by which chloride transmembrane transport influences the bioelectrical activity of cardiomyocytes and the potential functions of chloride and chloride currents in specialized regions of the heart.
Lung cancer and pulmonary tuberculosis have long been significant problems for global health, occupying leading positions in terms of morbidity and mortality in both developed and developing countries. Numerous clinical and experimental studies have allowed to get knowledge of the mechanisms of development of these pathological processes individually, the impact of diseases on the macroorganism, and various options of treatment. According to population studies, the interaction between these two processes is undeniable – both active tuberculosis and post-tuberculosis changes are equally risk factors for the development of neoplastic processes, and malignant tumors create favorable conditions and predispositions for the development of mycobacterial infection. However, the mechanisms of interaction between these two diseases in concomitant cases remain opened and insufficiently studied. This literature review provides a detailed description of the variants of lung cancer and pulmonary tuberculosis combinations, the pathophysiological basis of the interaction between infectious and neoplastic processes: modulation of the immune response by M. tuberculosis and lung tumor; oncogenic signaling pathways activated by tuberculosis infection; mechanisms of epithelial-mesenchymal transition in post-tuberculosis scar changes and its role in the formation of so-called "scarcinoma"; the relationship between tumor-mediated and tuberculosis-associated immunosuppression; the role of the PD-1: PD-L signaling pathway, and the influence of modern types of anti-tumor immunotherapy on the course of these pathological processes. The final part of the review presents our own data from experimental studies on the combination of cancer and tuberculosis in a laboratory model, identifying promising directions for further research on this issue.
The article presents an overview of the modern literature on the structure, distribution, biological and physiological role of xanthine oxidoreductase (XOR). XOR has been identified in all living organisms, from bacteria to humans. However, only in mammals it is presented in two forms, other species contain exclusively the XDH form. The enzyme is a homodimer with independent electron transfer in each monomer. XOR catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid in the final stage of purine metabolism and is widely distributed enzyme. The review highlights the forms of XOR and their role in the generation of reactive oxygen species (ROS), reactive nitrogen species (RNS) and synthesis of uric acid which are involved in many physiological processes. Uric acid shows antioxidant activity, and ROS and RNS play a role in innate immunity, in signaling, metabolism of xenobiotics, regulation of cellular redox potential and are also involved in mammogenesis and lactogenesis. Thus, in recent years significant progress has been made in understanding the biochemical and physiological nature of this enzyme system.
Autophagy is an intracellular mechanism for the isolation, transport and degradation of macromolecules and organelles. The physiological significance of autophagy lies, firstly, in maintaining the constancy of the intracellular environment through the timely disposal of proteins with a disrupted structure and damaged organelles. Secondly, due to the selective degradation of macromolecules, autophagy supplies the cell with monomers, which are then used by it to synthesize new compounds, which serves to ensure the rearrangement of cellular metabolism in the processes of cell differentiation, ontogenesis and adaptation to environmental challenges. Autophagy is an extremely important mechanism for maintaining normal functioning of postmitotic and differentiated cells, including neurons. Impaired neuronal autophagy leads to the formation of aggregated protein plaques, the accumulation of damaged cellular organelles, defects in the structure of processes and neuronal degeneration, which often accompanies to the progression of some forms of neurodegenerative diseases. In addition, the role of autophagy in synaptic plasticity and memory mechanisms has been established. Since autophagy has a significant impact on cellular metabolism, the study of the regulation and main pathways of this mechanism may be crucial in the elaboration of means and approaches to the treatment and prevention of many pathologies that progress with age. This review describes the basic concepts of the autophagy process, summarizes the key functions of autophagy in cells, and also presents current data on its role in ensuring the normal metabolism and implementation of specific functions of neurons.
Abstract – Different types of headaches, including migraine, may have a causal relationship with cold exposure, and this relationship can be either positive or negative, i.e. cold can both provoke and alleviate cephalalgia. Various representatives of the transient receptor potential ion channel superfamily, in particular TRPM8, act as molecular thermoreceptors that provide signal transduction in the response to low temperatures. These channels, which are known to mediate the normal cold sensation and play a role in both cold-induced pain and cryoanalgesia, are often considered as a promising target for the development of principally new anti-migraine drugs. This review summarizes recently obtained data on the TRPM8 structure and function, and their role in the pathogenesis of migraine, as well as discusses the intriguingly inconsistent results of studying TRPM8 agonists and antagonists in experimental headache models and clinical trials. Analyzing data from various studies allows to conclude that TRPM8 activation can be both pro- and antinociceptive; this correlates with the reported dual effect of cold exposure on the induction and resolution of headaches, leaving open the question on the vector of the TRPM8 pharmacological modulation required to produce anticephalgic effect.
Spinal cord injuries and strokes are the main causes of complete or partial loss of movement. Advances in minimizing motor dysfunction using spinal electrical stimulation in spinal cord injuries have contributed to increasing interest in the use of this type of neuromodulation for motor disorders of other pathologies. The review presents the results of recent studies on the use of various types of spinal electrical stimulation to minimize motor dysfunctions associated with cerebral blood flow disorders, and discusses the history of the use of spinal stimulation in this area.
This review comprehensively examines the features of the motion-specific brain response produced by human hearing system, the so-called motion-onset response (MOR). We discuss the interpretations of this component of auditory evoked potentials, its dependence on velocity and direction of sound motion and on various spatial characteristics of sound stimuli. We review the studies of event-related oscillations underlying the MOR which have shown that gradual sound motion causes the phase alignment of the delta-alpha range to the motion onset. We also consider the influence of audio-visual integration on motion processing. The MOR component as a correlate of the processes of spatial integration can provide new information about an early pre-conscious activation of brain structures that facilitates orientation and adaptation of a person to a changing acoustic environment.
A review of the results of half a century of research into the visual system as a hierarchical structure is presented: a multichannel, multilayer “pyramid”, each layer of which has a different spatiotemporal resolution, but together provides an invariant description of images for their classification, decision making, organization of eye movements and target search. An analysis of the multichannel organization of the human visual system was carried out, as the most effective and most economical. The “periscope and telescopic vision” systems, unique in their morphological and functional characteristics, are identified, providing gaze translation and recognition when searching and achieving a goal. Models of the pyramidal organization of the visual system have justified their existence by having an exceptional influence on the development of engineering solutions for the design of recognition systems operating in real time and the creation of artificial neural networks.
The formation and evolution of cell physiology in USSR was associated with the academician Platon Kostuk, an outstanding world-renowned scientist. His scientific activity occurred in the second half of 20th century, the period of burst-like progress in electrophysiology that provided a number of remarkable results rewarded with three Novel prizes. In biology of that time, electrophysiology was the only field, wherein methods and approaches were developed for the on-line analysis of physiological processes in cells and tissues. The goal of the given essay is to highlight retrospective aspects of the bioelectricity concept and to characterize the related contribution of the electrophysiological school of P.G. Kostuk to the field.
