Том 109, № 10 (2023)

Hemostasis and immune responses are evolutionarily and functionally related systems on the coordinated work of which vital processes – protection from blood loss and pathogens, depend. Thrombin is the central enzyme of the coagulation system, which has pronounced pro–inflammatory activity and plays an important role in the pathogenesis of a wide range of infectious and non-infectious diseases. Many humoral immune factors regulating inflammation (IL-1α, C3 and C5 complement components) and cell migration to the lesion site (osteopontin, chimerin) are thrombin targets and become activated by proteolytic cleavage. The main thrombin receptors – protease-activating receptors (PARs), are expressed on many cells of the immune system and are considered as non–classical pattern-recognizing receptors (PRRs). The effect of thrombin on innate immune cells may not be related to its enzymatic effects. Thrombin action on adaptive immunity is just beginning to be studied. Recent studies show that thrombin can act as an alarmin, stimulate the maturation of dendritic cells and adaptive immune responses. The production of this factor also affects Th cell polarization, which determines immune response strategy. The study of the immune functions of the components of the coagulation system reveals new pathogenetic mechanisms of the development of sterile inflammation and expands existing possibilities of allergic, autoimmune and neuroinflammatory disease therapy.

Organophosphates (OP) are one of the most common neurotoxic xenobiotics. In acute OP poisoning, as a result of suppression of synaptic acetylcholinesterase (AChE) activity, a cholinergic syndrome develops, which can transform into status epilepticus. Within a few days after acute poisoning, the so-called an intermediate syndrome can develop, which is associated with prolonged inhibition of AChE, desensitization of nicotinic receptors, and functional degradation of synapses and muscle fibers. In 10–20 days after a single acute or repeated subacute poisoning, OP-induced delayed polyneuropathy (OPIDN) can develop – a neurodegenerative disease, the signs of which are ataxia, loss of function of the distal sensory and motor axons of peripheral nerves. The occurrence of a neuropsychiatric disorder (NPD) caused by chronic exposure to relatively low-toxicity organophosphorus compounds is usually not associated with acute poisoning; symptoms include cognitive impairment, chronic fatigue, and extrapyramidal symptoms. The list of possible diseases or pathological conditions (syndromes) that develop as a result of acute, subacute or chronic effects of OP on the human body has expanded in recent years due a number of known neurodegenerative diseases (Alzheimer’s, Parkinson’s, multiple sclerosis, etc.). The aging of the body in general and the aging of the brain in particular are considered in the review from the point of view of the consequences of OP poisoning, which can serve as a nonspecific trigger of aging and related neurodegenerative diseases. Gulf syndrome is not a consequence of OP intoxication, but is also of interest and is considered in the context of OP-induced pathology, since its etiology and pathogenesis are associated with the exposure to cholinesterase inhibitors. The review presents data indicating the important role of the vascular endothelium in the development of OP-induced pathology; The first suggestions were made by clinicians in the late 1980s, and the first experimental data were obtained in the early 2000s. The principles of therapy for acute poisoning are outlined, taking into account experimental data from recent years. Some methods for studying OP in experiments in vitro, ex vivo and in vivo with laboratory animals, including the use of carboxylesterase inhibitors, are presented. The most important part of in vivo investigations has been and remains the search for new biomarkers to assess the effectiveness of adjuvant and regenerative therapies.

The key factor in maintaining the integrity of the gastric mucosa is its normal blood supply, respectively, the use of drugs that improve it, including through a positive effect on the rheological properties of blood, is in demand for the treatment of gastric ulcer. These drugs include the anticoagulant heparin. The aim of the work is to study the effect of heparin on the formation and healing of gastric ulcers induced by the application of 60% acetic acid to the gastric mucosa in rats, while assessing the possible risk of bleeding. After application of acetic acid (day 0), the area of gastric ulcers was assessed on the 4th day (formation of the ulcers) and the 7th day (healing of the ulcers). To assess the effect on ulcer formation, heparin (1000 IU/kg/day, subcutaneously) was administered from days 0 to 3, and on the healing from days 4 to 6 after acid application. To check for possible bleeding under the influence of heparin, the level of hemoglobin in the blood was tested before acid application (basal), on the 4th and 7th days after application. The degree of bleeding was assessed based on the relative decrease in hemoglobin levels. The administration of heparin led to a decrease in the average area of ulcers both on the 4th and on the 7th day compared with that in control rats (heparin vehicle). In control rats, both on the 4th and on the 7th day, the hemoglobin level was reduced compared to the corresponding basal level. Heparin had no effect on the hemoglobin level at day 4, but potentiated the decrease in mean hemoglobin level at day 7, increasing the number of animals having a greater relative decrease in hemoglobin level compared to the corresponding control group. Thus, heparin may have a gastroprotective effect, manifested both in the weakening of the formation of an ulcer and in the acceleration of its healing, however, there is a risk of bleeding when the ulcer heals.

It is well known that the inactivity of mammalian skeletal muscles leads to the cessation of their electrical activity and is accompanied by atrophic changes in muscle fibers. However, it has been repeatedly noted that starting from the 3rd day of functional unloading, spontaneous rhythmic neuromuscular activity appears, which is the result of a decrease in the expression of the potassium chloride co-transporter KCC-2 in neurons of the lumbar spinal cord. A decrease in the expression of KCC-2 and the onset of autonomous electrical activity of the unloaded muscle can be prevented by the administration of the neuroleptic prochlorperazine. Thus, the aim of this study was to evaluate the structural and signaling effects of the reduced spontaneous activity of the unloaded m.soleus. It was found that daily administration of prochlorperazine to rats under conditions of 7-day simulated gravitational unloading prevented a decrease in the content of the main markers of ribosome biogenesis (c-Myc, 18S rRNA and 28S rRNA), and also partially prevented a decrease in the cross-sectional area of fast and slow muscle fibers in the m.soleus. Morphofunctional changes caused by a decrease of spontaneous activity of the unloaded muscle were accompanied by complete or partial prevention of activation of key proteolytic markers expression (MuRF-1, MAFbx/atrogin-1, ubiquitin). Thus, we assume that spontaneous neuromuscular activity may be a factor that augments muscle atrophy during the first week of functional unloading.

Hypoxia can correct the development of diabetes and its complications in animals and humans, and diabetes exacerbates the gastric ulceration. However, the effect of hypoxia on the gastric ulceration in diabetes remains unknown. The task of the work was to compare the effect of keeping rats in the mountains under moderate natural hypoxia and on the plains on the development of type 1 diabetes and the gastric ulceration. Two weeks after the rats acclimatized to hypoxia (Elbrus region, 2125 m above sea level), they were injected with streptozotocin (STR, 50 or 70 mg/kg) or its vehicle. Simultaneously, rats on the plains were injected with STR (or its vehicle) at the same doses. Indomethacin (IM, 35 mg/kg) was administered two weeks after STR or its vehicle injection in rats after 24 h of fasting, both in the mountains and on the plains, which led to the gastric erosion formation 4 h later. The injection of STR (50 and 70 mg/kg) caused a dose-dependent increase in blood glucose levels in rats both in the mountains and on the plains, which indicates the development of diabetes of varying severity. In rats on the plains the administration of STR (50 and 70 mg/kg) led to a dose-dependent increase in the area of erosions induced by IM compared with those in control animals (STR vehicle). In rats in the mountains, an aggravation of gastric mucosal injury caused by IM was observed, both in control rats (STR vehicle) and in animals with STR-induced diabetes, compared with the gastric injury in rats of the corresponding groups on the plains. The greatest increase in the proulcerogenic effect of STR in the mountains was observed when it was administered at a dose of 70 mg/kg. Thus, persistent moderate hypoxia may lead to an increase in IM-induced gastric ulceration in rats with type 1 diabetes, and, in addition, by itself exacerbate the ulcerogenic effect of IM.

The rate and depth of myocardial relaxation determine left ventricular (LV) filling in early diastole. To analyze the relaxation phase, the method of logarithm of LV pressure fall in rats was used. A gradual acceleration of relaxation was found during the transition from the isovolumic phase to the auxovolumic phase, immediately before the opening of the atrioventricular valves. The relaxation rate constant in this phase has been inversely correlated with the values of the minimum LV diastolic pressure and LV endsystolic volume. The results suggest that the gradual acceleration of relaxation is due to the straightening of the spring-like structure of connectin (titin), which is compressed during contraction.