Vol 111, No 7 (2025)
REVIEW
Modern concepts of endoneurial fibroblasts
Abstract
The purpose of this review was to summarize modern concepts of endoneurial fibroblasts of peripheral nerves and their role in reparative nerve regeneration. Along with Schwann cells and macrophages, fibroblasts are the main functionally significant cells of the endoneurium. There is little information in the literature on the characteristics of fibroblasts and their role in the regeneration of damaged nerves. Recent data on the morphofunctional features of endoneurial fibroblasts, their origin in ontogenesis and their functions are presented in the review. The characteristics of immunohistochemical markers used for their identification are presented. The necessity of studying the interactions of fibroblasts with other nerve cells is emphasized to clarify their role in nerve regeneration after injury.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):995-1017
995-1017
Cellular senescence in skeletal muscle: age, sarcopenia, therapy
Abstract
Progressive age-related decline in skeletal muscle mass, strength, and function results in muscle fiber loss and atrophy, with associated replacement by adipose and fibrous tissue, or sarcopenia. Muscles are subject to multiple forms of molecular and cellular damage, including impaired regenerative capacity, protein turnover, mitochondrial dysfunction, and cellular senescence, which manifests as cell cycle arrest. With age, these cells accumulate and acquire distinctive properties characterized by chromatin changes and the emergence of a specific secretory senescence-associated phenotype (SAS phenotype), which exerts local and/or systemic negative effects on organism tissues. The aim of this review is to present the cellular senescence landscape in the skeletal muscle based on the evidence for their role in age-related changes in muscle mass, strength, function, and clinical consequences of this phenomenon, denoting key directions for the development of new senescence-based therapies for sarcopenia. Methods: Inclusion criteria: randomized or non-randomized controlled trials investigating the role of cellular senescence in age-related changes and pathophysiology of skeletal muscles. Data were searched in the electronic scientific databases Google Scholar, Medline, PubMed, Scopus, Web of Science and Cochrane Library by keywords and their combinations using the AMSTAR 2 program. The selection of publications (82 included out of 430) was randomly performed, after which their methodological quality was independently assessed by the authors. The crucial role of cellular senescence with the formation of the secretory phenotype associated with aging (SAS phenotype) in the age-related pathophysiology of skeletal muscles has been proven. These phenomena alter muscle tissue homeostasis and contribute to the occurrence and progression of sarcopenia. The impact on senescent cells and their secretory profiles can contribute to the development of complex strategies, including the use of senolytics and senomorphs to improve the quality of life of older adults. On the other hand, currently, there is a lack of data on the vulnerability to aging of terminally differentiated skeletal muscle fibers and resident mononuclear cells of the interstitial microenvironment. There are different opinions on the contribution of this event to the onset and progression of age-related skeletal muscle mass loss and dysfunction, as well as the initiation of sarcopenia. Scientific advances in the study of cellular senescence will allow us to identify new therapeutic approaches to optimize muscle health in old age.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1018-1041
1018-1041
EXPERIMENTAL ARTICLES
Behavioral profile and gut microbiota composition in rats with different nervous system excitability
Abstract
Previous studies have shown that two rat strains selected by the excitability threshold of the nervous system exhibit differences in response to prolonged emotional-pain stress at behavioral, neurobiological, and molecular-genetic levels, as well as specific changes in gut microbiota composition. This suggests a potential link between genetic factors, microbiota, and behavioral disturbances. The aim of this study is to analyze the gut microbiota and behavioral profiles of intact rats with high (HT) and low (LT) excitability thresholds to identify key differences driven by their genetic characteristics. The behavior of intact rats from two strains was analyzed in the Open Field and Elevated Plus Maze, and microbiota analysis in stool samples was conducted using 16S rRNA gene amplicon sequencing. Behavioral analysis revealed that high-excitable (LT) rats exhibited higher activity and less freezing in the Elevated Plus Maze compared to low-excitable (HT) rats. Alpha-diversity indices showed no significant differences between the strains, but beta-diversity analysis revealed significant differences in microbial profiles between HT and LT rats. LT rats had significantly higher abundances of Lactobacillus and Faecalibacterium genera, whereas HT rats showed a higher relative abundance of Romboutsia, Eubacterium, and Turicibacter genera. The integration of behavioral and microbiota data highlights a potential relationship between genetic factors, gut microbiota profiles, and the unique physiological and behavioral traits of rat strains selected based on the excitability threshold of the nervous system.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1042-1065
1042-1065
Restoration of spike-wave discharges after their suppression with ethosuximide in WAG/Rij rats with genetic absence epilepsy
Abstract
WAG/Rij rats are a genetic model of absence epilepsy, in which generalized spike-wave discharges (SWDs) are registered on EEG. SWDs are generated in the hyperexcited somatosensory cortex of the brain. The antiabsence drug ethosuximide (ETX) reduces the excitability of the cortex and, as a result, suppresses SWDs. The work aims to discover the recovery features of discharges after their complete suppression by ETX. To do this, we compared the dynamics of SWD recovery after cancellation of 14-day ETX administration to 7–8-month-old WAG/Rij rats and the age-dependent maturation of SWDs. Earlier, we showed that the age-dependent maturation of discharges goes through 3 stages: 1 – immature discharges resembling spindle-like oscillations, 2 – immature discharges in which fragments of oscillating activity alternate with fragments of spike-wave complexes, and 3 – mature SWDs. During age-dependent maturation of SWDs, mature discharges gradually replace immature ones and, at the same time, spike-wave complexes replace oscillations. After the cancellation of ETX, only immature discharges were present on EEG, among which oscillations prevailed, which corresponds to the 1st stage of age-dependent development of discharges. On the 3rd day after drug cancellation, on EEG immature discharges prevailed, in which oscillations alternate with spike-wave complexes, which corresponds to the 2nd stage of age-dependent development of discharges. On day 7, mature SWDs prevailed, which corresponds to the 3rd stage. Thus, the 3 stages of discharge recovery after ETX cancellation are similar to the stages of age-dependent evolution of SWDs. In the process of discharge restoration, oscillations first appeared, and then waves. Mature discharges replaced immature ones, and spike-wave complexes replaced oscillations. We assume that the restoration of discharges is the result of increased excitability of the somatosensory cortex of the brain after ETX cancellation. Different points of view are discussed regarding the commonality of mechanisms or the independence of the origin of the wave and spike as indispensable attributes of a mature SWD. The results can be used to determine the early stages of spike-wave discharges development for the diagnostics and treatment of patients with absence epilepsy.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1066-1083
1066-1083
Effect of four-week semaglutide therapy and its combination with intranasal insulin on thyroid and gonadal status in male rats with type 2 diabetes
Abstract
Currently, semaglutide, glucagon-like peptide-1 (GLP-1) receptor agonist, is widely used to treat type 2 diabetes mellitus (T2DM) and obesity, but its effect on the endocrine system functions disrupted in the diseases remains poorly understood. There are no data on the possible enhancement of the effect of semaglutide in the presence of intranasal administered insulin (IAI). The aim of the work was to study the effect of a four-week treatment of adult male rats with T2DM with semaglutide (50 μg/kg/day, subcutaneously) and its combination with IAI (2 IU/rat/day) on the hormonal parameters of the thyroid and gonadal systems. T2DM was induced by a high-fat diet and a low-dose streptozotocin. Along with glucose homeostasis parameters and insulin levels, the levels of thyroid hormones (fT4, tT4, fT3, and tT3), thyroid-stimulating hormone (TSH), testosterone and luteinizing hormone (LH) were assessed in the blood of animals. In rats with T2DM, semaglutide was shown to reduce body weight and fat mass, improve glucose tolerance and insulin sensitivity, and restore triiodothyronine levels and peripheral thyroid hormone conversion. Combined use with IAI enhanced the stimulating effects of semaglutide on the decreased levels of thyroid hormones in T2DM and normalized the increased level of TSH in T2DM and the sensitivity of the thyroid gland to TSH, assessed by the integral thyroid index. Both monotherapy with semaglutide and its combination with IAI partially restored testosterone levels decreased in T2DM, preventing androgen deficiency. Thus, semaglutide and its combination with IAI can be used to correct endocrine disorders in T2DM, which is important for clinical endocrinology and reproductive medicine.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1084-1100
1084-1100
Immunological effect of moderately hypoxic mesenchymal stromal cell culture conditions on uterine healing in rats
Abstract
The aim is to determine the influence of conditioned medium of autologous bone marrow stromal cells (CMSC) cultured at 10% O2, on the healing of the rat uterus after a thorough surgical incision. Methods: In the treated group of animals (n = 14), the edges of the uterine wound were processed with a conditioned medium prior to suturing, in the control group of animals (n = 14), the incision was not processed. Results: On the 5th and 15th days after the operation, morphological studies of the healing zone were carried out. The number of macrophages CD68, FABP4+ cells and the level of mRNA expression of inflammatory cytokine IL-1b, IL-6 and anti-inflammatory IL-4, IL-10 were assessed. The healing area in the treated group was lower than the reference area in all monitoring periods (p < 0.05). From the 5th to the 15th day, the expression of IL-1b, IL-4, IL-6 and IL-10 in the control group decreased (p < 0.05), in the processed group no valid differences were found (p < 0.05). On the 5th day in the treatment group, the expression of IL-4 and IL-10 was lower than in the control, and on the 15th day the expression of IL-1b was lower in the control group. The number of macrophages of CD68 decreased by 15th day in the treated group compared to 5th day and was lower than in the control group. The FABP4 cell clusters in the area of damaged myometrium at 15 days in both groups were almost eliminated except for 2 animals in the control group. In the area of damaged perimetrium, FABP4 clusters increased in the control group by 15th day, and in the treated group decreased and was reliably lower than in the control group. Thus, the application of CMSC has resulted in a reduction of the damage area, reduced inflammatory response and accelerated recovery of the uterine wall.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1101-1116
1101-1116
Biochemical indicators of blood serum of male American minks (Neogale vison) involved in selection for tame and aggressive behavior
Abstract
Artificial selection of animals aimed at strengthening or weakening the defensive reaction to humans affects the variability of the functional state of regulatory systems, physiological functions of the body and the seasonality of biological cycles of reproduction and metabolism. The model object in the study of the influence of selection on the physiological functions of mammals is the seasonally breeding predator of the Mustelidae family, the American mink Neogale vison. In the course of many years of selection for a defensive reaction to humans, two lines of mink with pronounced aggressive and tame types of behavior, not typical for animals of industrial populations, were created over 27 generations. Studies of the biochemical picture of the blood serum of mammals to assess the state of metabolic processes in the body, under conditions of selection for behavior, have not been previously conducted. The aim of the work is to analyze the biochemical parameters of the blood serum of tame and aggressive American mink of cage breeding in the summer and autumn periods of the year. It is shown that both the season of the year and the type of animal behavior affect the biochemical parameters of the blood. Thus, the content of total protein, bilirubin, glucose and uric acid were higher, and the activity of alkaline phosphatase (ALP) was lower in the blood serum of animals in the autumn period compared to the summer, regardless of the type of behavior. In addition, aggressive animals had higher amylase activity, triglyceride levels, but lower lipase activity in the autumn compared to the summer period. In tame mink, the activity of aspartate aminotransferase (AST) and cholesterol levels were higher in the autumn period compared to the summer. Aggressive animals, compared to tame ones, were characterized by higher levels of albumin, glucose and cholesterol, as well as the activity of AST, lactate dehydrogenase (LDH), lipase in the summer and higher levels of glucose and LDH, but lower levels of urea and ALP in the fall. Thus, in the course of many years of selection of American mink for behavior, metabolic rates change while seasonal fluctuations in individual biochemical parameters of the blood are maintained, which reflects the evolutionary adaptive feature of mink to cyclic changes in environmental conditions.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1117-1133
1117-1133
Transcriptional activity of genes regulating neurogliogenesis and apoptosis in rats trained in morris water maze: the influence of stress and spatial memory formation
Abstract
The formation of new neural networks and the modification of pre-existing synaptic contacts, which underlie learning and memory, largely depend on the activity of genes involved in the regulation of the associated processes of neurogliogenesis and apoptosis. At the same time, the identification of changes in the functioning of the genome specific to cognitive functions requires a simultaneous assessment of the influence of stressful factors as a persistent component of all models of laboratory animal learning. The aim of this study was to compare the expression of genes regulating neurogliogenesis (S100А6, Ascl1), and apoptosis (Apaf1, Bax, Casp3, Bcl2) in animals trained in spatial Morris maze and those subjected to forced swimming in accordance with the training regime. The experiments were conducted on young adult male Wistar rats, distributed into the following groups: Training (trained to find a hidden platform in a water maze for 4 days), Control (swimming in a maze without a platform for 4 days) and Intact (staying in home cages). In tissue samples of the hippocampus, prefrontal cortex, and cerebellum obtained immediately after the end of experiments in the maze, the expression of target genes was determined by real-time polymerase chain reaction. It was found that cognitive activity reduces the expression of pro-apoptotic genes, which increases under stress conditions, and, on the contrary, stimulates the activity of genes regulating neurogliogenesis and synaptogenesis in structures relevant for various stages of memory trace formation. The results obtained, are of interest for understanding molecular mechanisms of stress and cognition as well as for determining the targets of therapy for cognitive disorders.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1134-1152
1134-1152
Peculiarities of Afferent Innervation of Antagonist Muscles of the Bilateral Lower Legs During High-Speed Locomotor Movements
Abstract
The article presents the specifics of intra-, intermuscular, and cross-manifestations of impulse activity of various groups of afferents (Ia, Ib, and II) of the antagonist muscles of the bilateral lower legs when performing high-speed locomotor movements. The study involved 9 male athletes specializing in short-distance running who performed a locomotor test – pushing a passive treadmill belt for 10 seconds at the fastest possible speed. Electromyograms of the antagonist muscles lower legs (m. tibialis anterior, m. gastrocnemius med.) were recorded during running, followed by its processing in the MatLab program and calculation of the impulse activity of primary and secondary afferents using mathematical model based on the prediction of the triggering of muscle spindles. It has been established that high-speed running is a cross intramuscular EMG pattern of tension of the antagonist muscles of the bilateral lower legs with a transition to their relaxation, which depends on the phase of movement. Such muscle innervation in the individual phases of a high-speed running step was manifested by effective intermuscular coordination of the flexor and extensor in the phases of stance and swing of the right leg, pronounced reciprocal relations of homonymous antagonistic muscles of the lower leg in the phases of swing of the right and stance of the left legs. Intramuscular proprioceptive afferentation of the antagonist muscles lower legs of high-speed movement is characterized by the manifestation of strong impulse activity of afferents Ib, moderate afferents II and weak Ia afferents of flexors and extensors of the of symmetrical legs. A phase-dependent modulation of the intermuscular afferentation of the primary and secondary fibers of the flexors and extensors of the bilateral lower legs in the phases of stance and swing of a high-speed running step is shown. The cross-interactions of afferent activity of homologous muscles of the bilateral lower legs in different phases of movement, characteristic of a high-speed running step, have been established. The identified features of intramuscular, intermuscular, and cross-limb afferent activity during running reflect their key role in regulating the inhibitory interneuron network of the spinal cord, which maintains targeted muscle contraction and modulates motor output parameters as a whole. The supposed reflex mechanisms of high-speed locomotor movements are discussed on the basis of well-known phenomena associated with the interaction of various afferent inputs to the spinal cord neuronal apparatus in the system of lower leg antagonist muscles.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1153-1167
1153-1167
Sex and age affect food choice and metabolic adaptation to short-term high-calorie palatable food eating in mice
Abstract
Incidence of obesity increases among young peoples, but influence of age and sex on adaptation to obesogenic diets in youth is little studied. We aimed to examine the influence of sex and age on short-term adaptation to palatable diet (PD: standard chow, lard and sweet cookies) from youth to adulthood in mice. Male and female C57Bl/6J mice consumed PD for 2 weeks at the age of 7 (young), 17 (early adult) and 27 (adult) weeks. Energy intake, food choice, morphometric and biochemical parameters were assessed. Sex and age influenced food choice and all parameters studied. From young to early adult age, blood Fibroblast Growth Factor 21 (FGF21) levels decreased, and consuming cookies increased. PD increased white fat mass, glucose levels, and decreased glucose tolerance in young females more than in young males. In early adult male and female mice, PD had no effect on glucose tolerance and blood glucose levels. In adult mice, body weight increased, hyperleptinemia, hyperglycemia, hyperinsulinemia developed and glucose tolerance decreased only in males. Thus, response to high-calorie diet varies with age, and males show greater resistance to PD than females in youth, and less resistance in adulthood. In obesity pathophysiology, both sex and age of diet initiation are important variables.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1168-1184
1168-1184
The Peculiarities of Neutrophils Migration Processes in the Flow System
Abstract
A flow system model simulating the hemodynamic process in capillaries was created to study neutrophil migration. It was found that the general patterns of neutrophil behavior (aggregate formation, formation of neutrophil tethers and migration of neutrophils along intercellular contacts of endothelial cells) are reproduced both in the control (system without chemoattractants) and in the experiment (system with low-molecular chemoattractants of bacteria), however, in the case of S. aureus and P. mirabilis using as a chemoattractant, the number of aggregates and neutrophil tethers increases statistically significantly (p < 0.05). Aggregates correspond to the swarming phenomenon in the transendothelial migration system and help limit the zone of bacterial damage. And neutrophil tethers cause a stop in hemodynamic movement and can cause either a transition to migration or be precursors to the formation of elongated neutrophil-derived structures with high antibacterial potential. Thus, all the observed phenomena contribute to the implementation of the protective function in case of bacteremia.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1185-1197
1185-1197
The effect of chronic stress and TAAR1 knockout on behavior characteristics of mice in tests assessing depressive-like behavior
Abstract
The aim of the study was to study the functional role of the TAAR1 receptor in the formation of the behavioral component of the stress response. The behavior of TAAR1–KO knockout mice and wild type (WT) mice was studied in tests reflecting a depressive-like state before and after the end of chronic stress (predator stress model), as well as delayed behavioral changes after 6 weeks. In the "hanging by the tail" test and the forced swimming Porsolt test, there were no differences between the TAAR1–KO and WT groups in terms of depressive-like behavior both during normal and after chronic stress exposure. However, TAAR1–KO mice, when placed in a stressful situation at the beginning of testing, demonstrate motor hyperactivity, which leads to a sharp increase in the latency periods of the first immobilization in both tests. Knockout of the TAAR1 receptor does not affect the signs of depressive-like behavior; however, it leads to a characteristic increase in the level of motor activity.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1198-1210
1198-1210
Vitamin D deficiency leads to deterioration of post-infarction remodeling of the left ventricle in rats
Abstract
Coronary heart disease (CHD) is a multifactorial pathology, the progression of which is associated with the development of chronic heart failure (CHF) after a myocardial infarction (MI). Recent studies have shown that vitamin D deficiency is an independent risk factor for coronary heart disease and the severity of its course. Due to the lack of a unified understanding of the pathogenetic role of vitamin D deficiency, it is relevant to study the relationship of vitamin D deficiency with myocardial remodeling after myocardial infarction in rats. The purpose of the study. To study echocardiographic and morphological parameters of postinfarction myocardial remodeling in rats with vitamin D deficiency. Vitamin D deficiency was modeled in male Wistar stock rats (n = 41) by feeding them for two months with Delta Feeds with zero vitamin D content, followed by IM modeling. The animals were divided into 3 groups: 1st – the comparison group, 2nd – rats that did not receive cholecalciferol after MI, 3rd – those who received cholecalciferol after MI. Echocardiography was performed on a high-resolution ultrasound machine MyLabTouchSL 3116 on the 30th and 60th days of the experiment after IM modeling. Content 25(ОН)D in blood serum D was determined in 5 individuals from each group by the enzyme immunoassay (ELISA). Histological examination determined the size of the scar and assessed the severity of myocardial remodeling. Level of 25(OH)D in rats from group 3 was higher than in animals from comparison group 1 and group 2 (59.70 (50.50–64.80) nmol/L, 9.00 (8.12–9.54) nmol/l and 8.20 (7.60–8.31) nmol/l, respectively; p = 0.04). Cholecalciferol therapy was accompanied by a decrease in heart rate in group 3 compared with this indicator in group 2 (p = 0.0004) on day 30 after MI. Compared with group 3, animals from group 2 had a higher end diastolic size (EDS) (p = 0.002), end systolic size (ESS) (p = 0.002) and lower left ventricular shortness fraction (SF) (p = 0.002) and ejection fraction (EF) (p = 0.002) on days 30 and 60 after ischemic myocardial injury. The scar area as a percentage of the LV wall area, LV wall thickness in the area of the scar and interventricular septum (IVS), hypertrophy and dilation indices, taking into account the thickness of the LV walls, were higher in group 2 than in group 3 (p < 0.05). In an experimental MI model in rats with vitamin D deficiency, those who did not receive cholecalciferol therapy after MI had a significant development of myocardial hypertrophy, decreased left ventricular function, and a larger postinfarction scar area than those who received cholecalciferol.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1211-1224
1211-1224
Metabolic alterations in mice bearing hepatoma 22A: focus on ceruloplasmin
Abstract
Ceruloplasmin (Cp), plays a key role in metabolism of two vital trace elements – iron and copper, whose metabolic pathways are closely related to each other as well as to zinc uptake. Increased concentration of Cp usually follows tumor growth, but its role in tumor progression is not clear. The aim of the study was to compare the changes of Cp concentration in blood serum with iron and zinc content as well as with concentrations of proinflammatory cytokines and lipids in the dynamics of tumor growth. Additionally, Cp concentration was studied in mice supplemented with zinc sulphate in drinking water. The study was performed in C3HA mice, which were subcutaneously inoculated with hepatoma 22a cells. Serum Cp increased from 14th day after tumor inoculation simultaneously with the appearence of central necrosis in the tumor and elevation of serum triglycerides. The growth of blood IL-6 concentration began from 7th day and could possibly trigger the acute phase reaction expressed in increase in Cp synthesis and the development of hypoferremia, hypozincemia and hypertriglyceridemia. The content of non-heme iron in blood and liver decreased later than Cp up-regulation. This indicates that iron deficiency was not the cause of Cp increase on 14th day, but could support it at later stages of tumor growth. Zinc sulphate supplementation returned non-heme iron content and partly returned zinc concentration in the blood of mice on 21st day, but did not influence the concentration of Cp. It is discussed that the possible protumoral role of Cp is related not as much to iron metabolism as to its ability to transport copper to tissues. We hypothesize that serum Cp is an important pathogenetic factor that participates in supplementation of tumors with necessary lipid metabolites since Cp, together with IL-6, can possibly support lipolysis in adipose tissue, delivering copper ions there.
Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(7):1225-1242
1225-1242