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Volume 111, Nº 2 (2025)

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REVIEW

Hypothermia and Reproductive Function of Male Mammals

Kuznetsova E., Tikhonova N., Ponomarenko E., Kuznetsov V., Nizyaeva N.

Resumo

The human and animal reproductive systems are sensitive to temperature, but there are very few studies on the effects of hypothermia. The widespread application of therapeutic hypothermia requires a comprehensive study of the time-delayed effects of low temperature on a variety of physiological systems. Hibernating mammals have a significant potential for reactivation of the reproductive system after prolonged hypothermia and can serve as an important experimental model for the development of new methods of treatment and prevention of human reproductive diseases. This review presents an analysis of currently available data on disorders in the mammalian reproductive system under hypothermia, and also discusses the mechanisms of natural protection of reproductive function in hibernating mammals.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):195-209
pages 195-209 views

Ultraslow Signals in the Diagnostics of a Stroke

Vinokurova D.

Resumo

The acute phase of ischemic stroke is accompanied by changes in the electrical activity of the cerebral cortex, reflecting the dynamics of pathophysiological processes in the damaged tissue. The first manifestation of ischemia is early depression of activity associated with a sharp suppression of synaptic transmission and an increase in the threshold of action potential generation. Further deterioration of the metabolic crisis in the tissue is marked by the emergence of waves of spreading depolarization (SD) – slow waves of mass depolarization of neurons and glial cells initiating in the area of the greatest deficit and spreading to the surrounding tissues. It has been shown that SDs are the main pathological mechanism causing growth of the ischemic focus, which makes them the most important target for therapeutic effects. In addition to SD, the development of a negative ultraslow potential (NUP) is observed, which is a high-amplitude (up to –100 mV) extracellular potential shift with extremely slow dynamics. It has been shown that the NUP occurs only in the area of developing damage, and its amplitude correlates with the size of the future ischemic damage. The mechanisms of NUP have not been fully studied to date. Both SD and NUP are highly informative markers of ischemic damage, but have extremely slow dynamics (frequency < 0.01 Hz), as a result they are not detectable when recorded in the classical EEG range (0.5–45 Hz). This review discusses the mechanisms underlying early depression of activity, and ultraslow SD and NUP signals in focal stroke, their importance for diagnostics and monitoring of the ischemic process, as well as modern therapeutic approaches to stroke management.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):210-232
pages 210-232 views

EXPERIMENTAL ARTICLES

Evaluation of Platelet Functional Activity in Healthy BALB/c Mice and in EMT-6 Breast Cancer Orthotopic Model

Mishukov A., Gaur S., Adamanskaya E., Panteleev M., Sveshnikova A.

Resumo

Platelets, anuclear cell fragments circulating in the blood, can be considered as vascular wall and latent thrombosis sensors. However, the heterogeneity of normal platelet indicators is too large for the correct «reading» of information from these sensors. Therefore, it is necessary to fine-tune methods for assessing the functional state of mouse platelets in order to then check under controlled conditions how various pathological processes change the state of platelets. In this work, we adapted previously developed flow cytometry platelet functional activity tests for use in blood samples from BALB/c mice and evaluated changes in platelet status in an in vivo model of spontaneous metastatic breast cancer EMT-6. Continuous and endpoint flow cytometry were used. Platelet shape change, decreased GPIb antibody binding, P-selectin exposure, integrin activation, calcium mobilization, and phosphatidylserine exposure were observed. Several functional activity differences between human and murine platelets were obtained. First, according to all observed parameters, activation of mouse platelets in response to 2.5 µm of ADP was significantly weaker than activation in response to 200 µm of AYPGKF (PAR4 thrombin receptor agonist). Second, reversible activation of integrins and shape change were observed in response to ADP. The main difference between platelets of mice with a tumor was a significant decrease in their number when isolated from the blood. Additionally, some responses were diminished: binding of antibodies to GPIb, shape change, activation of integrins, and procoagulant response. The results indicate that a tumor in the terminal stage probably reduces the number of circulating platelets and causes their damage.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):233-248
pages 233-248 views

Alterations of Neurohumoral Response to Acute Stress in Spontaneously Hypertensive Rats Subjected to Long-Term Isolation

Tretyakova L., Kvichansky A., Moiseeva Y., Ovchinnikova V., Mamedova D., Nedogreeva O., Lazareva N., Onufriev M., Gulyaeva N., Stepanichev M.

Resumo

Hypertension is a serious disease characterized by a sustained or recurrent increase in blood pressure, which can lead to various complications. Here, we studied the effect of genetically determined arterial hypertension in rats on their adaptation to long-term isolation and subsequent response to acute restraint stress. Male SHR rats with spontaneous hypertension were maintained in individual cages for 14 weeks. The serum levels of corticosterone, glucose, and pro- and anti-inflammatory cytokines and salivary α-amylase activity were studied, and the expression of genes associated with the regulation of steroidogenesis in the adrenal glands was evaluated. There were no significant changes in the parameters of the hypothalamic-pituitary-adrenocortical and sympatho-adrenal systems after isolation. Nevertheless, the preliminary isolation significantly affected the response to moderate restraint stress, including the expression of the regulatory genes Fkbp5 and Star in the adrenal glands and the content of proinflammatory cytokines IL-1β and IL-6 in the blood, although the changes in these indices were relatively subtle. This may reflect the predisposition of animals in isolation to develop quite specific stress-related changes.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):249-265
pages 249-265 views

Ex vivo Murine Thromboinflammation Model with Validation on EMT-6 Breast Cancer

Korobkina J., Mishukov A., Osidak E., Sveshnikova A.

Resumo

Thromboinflammation is a complex interaction between the hemostasis system and the immune system associated with the participation of neutrophils in the process of thrombosis. An imbalance in the mutual activation of platelets and neutrophils in various pathologies leads to thrombosis or bleeding. Previously, we developed a technique for ex vivo observation of the process of thrombosis and chemotaxis of neutrophils in parallel-plate flow chambers coated with fibrillar collagen. The aim of this work was to develop a technique for ex vivo observation of the thromboinflammation process in mice, which allows analyzing the interaction of polymorphonuclear leukocytes (PMN) with growing blood clots. To validate the technique, a breast cancer model was used in BALB/c mice (7 days after orthotopic inoculation with EMT-6 tumor cell culture). In the blood samples of healthy mice, blood clots formed on fibrillar collagen, however, nuclear cells were not observed. The use of a combination of fibronectin and collagen as a substrate made it possible to induce thrombosis and monitor the movement and behavior of PMNs in the vicinity of blood clots. Using the developed model, it was shown that in breast cancer, the growth of blood clots is slowed down – the relative size of blood clots in breast cancer is 21 ± 11% of the field of view compared with 39 ± 10% in healthy mice. At the same time, the number of PMNs adhering to blood clots and the speed of their movement on the substrate do not differ in healthy mice and mice with tumors. However, the number of PMNs leaving the thrombus and sliding onto the fibronectin-collagen matrix was significantly increased in mice with a tumor (39 ± 23 versus 15 ± 8 in healthy controls). Thus, using the developed thromboinflammation model, it is shown that already at the early stages of tumor development, violations of the thromboinflammation process are observed.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):266-277
pages 266-277 views

Effect of Empagliflozin on the Reactivity of Mesenteric Arteries and Skin Microvessels in Rats Treated with Doxorubicin

Ivanova G., Beresneva O., Okovity S., Kulikov A.

Resumo

The study assessed the potential protective effect of empagliflozin (EMPA) on the functional state of various types of vessels in Wistar rats that received a single injection of the anthracycline antibiotic doxorubicin (DOX), used clinically as a chemotherapeutic agent for cancer. The rats were divided into 3 groups, 15 animals in each group. Rats in the DOX group were administered DOX (4 mg/kg) once, while animals in the DOX+EMPA group after a single administration of DOX (4 mg/kg) received EMPA (1 mg/kg) daily through a tube for 5 weeks. The control group consisted of intact animals. After 4 weeks of the experiment, the rats were examined for the initial skin microcirculation indices and their changes after iontophoresis of acetylcholine (ACh) and sodium nitroprusside (NP) using Laser Doppler Flowmetry (LDF). One week after LDF, the mesenteric artery dilation value was analyzed by assessing the changes in vessel diameter before and after the action of ACh and NP, without blockers and under conditions of preliminary incubation of vessels with the NO synthase blocker L-NAME. In the control group rats, ACh iontophoresis caused an increase in perfusion intensity by 78.5%, in the DOX group the change was less pronounced (by 55.2%). EMPA prevented a decrease in the skin microvessel response to ACh, the perfusion index in rats of the DOX+EMPA group increased by 82.8%. The increase in the microcirculation index after NP iontophoresis in the DOX+EMPA group did not differ from the control, and in the DOX group it was significantly lower. ACh-induced dilation of the mesenteric arteries of the DOX group was 24.3% lower than in the control rats. The use of EMPA in rats that received DOX improved arterial reactivity. Compared with the reactivity of vessels without blockers, incubation of vessels with L-NAME reduced the amplitude of dilation under the action of ACh in all groups, but a less pronounced change was observed in the DOX group (45.6%). When using EMPA, the differences in the relaxation amplitude before and after NO synthase blockade increased (54.4%), but did not reach the control (64.1%). Conclusion. DOX leads to a decrease in the reactivity of various types of vessels to the action of vasodilators, in particular, ACh and NP. The use of EMPA has a protective effect in animals after the introduction of DOX, improving the dilation of the mesenteric arteries and vessels of the skin microcirculatory bed. It is possible that the effect of EMPA is associated with an improvement in the efficiency of NO-dependent vasorelaxation pathways, the disruption of which is observed upon the introduction of DOX.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):291-305
pages 291-305 views

The Contribution of BK Channels to Ischemic Reperfusion Changes in Cerebral Blood Flow

Gorshkova O.

Resumo

Ischemic/reperfusion (I/R) damage of cerebral vessels is a complex dynamic process leading to hypoxic brain damage. To improve the outcome and treatment of the effects of I/R, an understanding of the molecular mechanisms of changes occurring in the cerebral vascular bed after recovery of blood flow is required in order to identify therapeutic intracellular targets. High-conductivity calcium-dependent potassium channels (BK) involved in the vasodilator reaction of cerebral vessels and highly sensitive to changes in oxygen levels can be considered as such targets. The work investigated the change in the contribution of BK channels to the rats pial arteries dilation after I/R. Using the method of in vivo vascular imaging in I/R and sham-operated rats, the number and degree of dilatation reactions in response to acetylcholine chloride (ACh, 10-7 M, 8 min) and exogenous hydrogen sulfide (H2S) donor sodium hydrosulfide (30 µM, 2 min) were compared before and after the use of the BK channel blocker tetraethylammonium chloride (2 mM, 5 min). It was found that I/R inhibit the dilatatory reaction. Changes in ACh-induced vasodilation persist for 21 days after I/R. Changes of H2S-mediated processes are noted only in the first 14 days and depend on the vessel size. These changes may be based on a gradually developing decrease in the contribution of BK channels to vasodilation, mainly expressed in large pial arteries. The decrease in the contribution of BK channels to dilation is most pronounced after 14 days and persists for 21 days after I/R.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):278-290
pages 278-290 views

Electrical Activity of the Uterus in Rats at Different Stages of the Estrous Cycle

Rutkevich S., Pihul P., Panimatska Y., Kazakevich V., Veres I., Sidorov A., Chumak A.

Resumo

Experiments were performed under urethane anesthesia on sexually mature non-pregnant female rats (n = 36). Pattern of electrical activity of the uterus in different phases of the estrous cycle, determined by the vaginal cytology (staining by Romanovsky dye), was studied. Electrohysterograms from the middle third of the left horn of the uterus were recorded using pressure bipolar electrodes. Increased excitability and conductivity of the uterus smooth myocytes occur during the stages of proestrus, estrus and metestrus, and their suppression is observed in diestrus. The maximum amplitude of motor potentials, compared to diestrus, was detected at the pro- (174 ± 17 μV) and metestrus (202 ± 20 μV) stages, while their mean frequency was high at the metestrus [4.4 (4.0; 5.0) Hz] and estrus [4.0 (4.0; 5.0) Hz)], exceeding those indicators for diestrus (86 ± 9 μV and 1.9 (1.3; 3.2) Hz approximately twice. Burst phase duration [40 (32; 50) and 36 (28; 47) s] of uterus periodic electrical activity had it maximum while rest period had it minimum [46 (40; 55) and 42 (26; 84) s] at proestrus and estrus stages which is also reflected in the high values of duty cycle – 0.46 (0.43; 0.50) and 0.45 (0.26; 0.63), respectively. Similar indicators for the diestrus stage were 27 (22; 32) and 80 (58; 124) s, 0.27 (0.18; 0.34). It is assumed that the highest excitability of the myometrium and its rhythmogenic areas during the metestrus stage, an increase in myometrium’s excitation conduction rate during proestrus and estrus, are due to an increase of electrical coupling between uterus smooth muscle cells.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):306-319
pages 306-319 views

A 15-Minute Abdominal Breathing Exercise Promotes Nap in Undergraduates: Instrumental Study Findings

Khuurak A., Shumov D., Sveshnikov D., Bakaeva Z., Yakunina E., Torshin V., Dementienko V., Dorokhov V.

Resumo

The study purpose – to validate by polysomnography (PSG) tools the efficacy of deep abdominal breathing (AB) as a technique improving daytime nap in healthy subjects. Materials and methods: 43 healthy subjects participated in the study, of whom 22 were included into intervention group and 21 into control group. In the intervention group, nap PSGs were recorded for 30 min after performing AB for 15 minutes. In the control group, a similar PSGs were recorded after 15 min of wakefulness. To assess the nap quality, standard sleep characteristics (latency, etc.) were determined from the subjects' hypnograms. In the intervention group total sleep time was significantly longer and activation index was significantly lower than in control group, while sleep latency did not differ significantly. In addition, the electroencephalogram (EEG) spectrum power ratio in alpha (8–13 Hz) and theta (4–8 Hz) frequency bands was analyzed. Linear regression model of alpha/theta power ratio time series was constructed within the framework of statistical analysis. It was concluded based on comparison of coefficients of this model along with the time domain sleep characteristics, that AB exercise preceding daytime nap activates physiological mechanisms accelerating fall-asleep process and making sleep more stable. This finding may be useful in the development of non-invasive approaches to insomnia treatment.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):320-332
pages 320-332 views

Neurophysiological Correlates of the Aesthetic Judgment Formation in Conditions of Joint Paintings Perception

Nagornova Z., Shemyakina N.

Resumo

The article is devoted to the study of neurophysiological correlates of art work (paintings) perception under the conditions of conscious (implicit) formation of the evaluative opinion about them. Participants (24 subjects, 18–60 years old, median 22.5 years, 6 male, 18 female) visited the exhibition of modern artists and in pairs viewed the paintings selected by each other and shared their opinions on the selected paintings. For each participant, the spectral powers of the EEG were compared in the states of «viewing your own choice» and «viewing the painting selected by the partner in the pair».

According to the EEG spectral analysis, a group of subjects can be divided into 2 subgroups, between which there were no differences when viewing a self-selected painting, but there were different reactions when viewing paintings that were chosen by a partner. In the first subgroup (14 people), lower power values (theta (4–8 Hz), alpha-1(8–10 Hz) and alpha-2 EEG bands) were obtained during perception of the own chosen painting while in the second subgroup (9 people), lower power values (in delta (1.6–4 Hz), theta (4–8 Hz), beta-1 (13.7–18 Hz) and beta-2 (13–30 Hz) EEG bands) were observed when viewing the paintings chosen by the partner. We can assume a difference in the strategies for evaluating a painting chosen by another person.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):333-348
pages 333-348 views

Effect of Chloroquine on Expression of Apoptosis and Autophagy Genes in MOLT-3 and IMR-32 Cells

Prokopenko E., Sokolova T., Nadey O., Trubnikova A., Agalakova N.

Resumo

The goal of the study was to compare an influence of chloroquine (CQ) on expression of apoptosis and autophagy genes in the cells of two tumor cells – leukemia MOLT-3 and neuroblastoma IMR-32 cultured in complete growth and serum-free RPMI-1640 and DMEM media, respectively, for 24 and 48 hours. The viability of cells was evaluated by MTT method, gene expression – by real time PCR. For MTT test, the cells were incubated with 10–100 µМ CQ. The expression of apoptosis (CASP3, BAX, BCL2) and autophagy (ULK1, BECN1, MAP1LC3B) genes was studied using 30 and 50 µМ CQ, which exerted considerable inhibitory effect on viability of cells of both lines, but did not promote their complete death. The sensitivity of both cell lines to CQ was higher in serum-free medium, however, the expression of apoptosis and autophagy genes substantially differed between them. In MOLT-3 cells, mRNA levels of pro-apoptotic genes CASP3 and BAX increased after 24-h incubation in serum-free medium, whereas in IMR-32 cells the expression of these genes increased only after 48-h in the presence of higher CQ concentration. In the cells of both lines 24-h CQ treatment resulted in enhanced expression of anti-apoptotic gene BCL2. In MOLT-3 cells, the absence of nutrients different combinations stimulated the genes of all three autophagy stages ULK1, BECN1 и MAP1LC3B, but none of applied treatment schemes did not affect the expression of ULK1 and MAP1LC3B genes in IMR-32 cells. Overall, 24-h culture with CQ under conditions of serum starvation appears to be more optimal for modulation of autophagy in MOLT-3 cells. In IMR-32 cells, CQ does not exert considerable influence on expression of autophagy genes, and their decreased viability is associated with activation of other mechanisms.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):349-364
pages 349-364 views

Search for Inhibitors of Ionotropic Glutamate Receptors in a Series of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole Derivatives

Dron M., Maltsev D., Spasov A., Divaeva L., Sochnev V., Morkovnik A., Barygin O.

Resumo

In the present work, 14 new diazepinebenzimidazole derivatives (DAB series) were screened for inhibitory activity against NMDA- and Ca2+-impermeable (CI) AMPA-receptors. Experiments were conducted on isolated Wistar rat neurons; pyramidal neurons of the CA1 zone of the hippocampus were used to study NMDA- and CI-AMPA-receptors. Cell isolation was performed by vibrodissociation, and currents were recorded by whole-cell patch-clamp method. All the studied compounds at a concentration of 100 μM inhibited NMDA-receptors (≥30%), while CI-AMPA receptors currents were inhibited by only four compounds: DAB-8, DAB-12, DAB-19, and DAB-32. DAB-8, DAB-12 and DAB-32 have a 4-substituted phenacyl group at the nitrogen atom N11 with an electronegative fluorine atom in the para position (DAB-8 and DAB-32) or without it (DAB-12), whereas the most active compound DAB-19 has a 4-tert-butyl-benzyl group at atom N11 with a bulky tert-butyl substituent in the para position. The most active of them were DAB-12, DAB-19, and DAB-32, which were studied further for their IC50 values. Compound DAB-19 demonstrated the most pronounced activity against both NMDA- and CI-AMPA-receptors: IC50 values were 11,0 ± 1,6 µM and 15,4 ± 1,4 µM, respectively. Such an ability to inhibit both NMDA- and CI-AMPA-receptors at such concentrations is quite remarkable. Based on previous data on the neuropsychotropic effects of DAB-19, we put forward hypothesis about its possible anticonvulsant activity, which was confirmed in the "Pentylenetetrazol Seizure" test. The identification of DAB-19 as a combined antagonist of NMDA- and CI-AMPA-receptors is an important achievement for the further development of effective anticonvulsants.

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova. 2025;111(2):365-376
pages 365-376 views