Xenon Antiaggregant Effects.

In in vitro model of short-term therapeutic inhalation of Xe/O2 mixture, xenon in millimolar concentrations led to a pronounced decrease in induced platelet aggregation in the platelet-enriched blood plasma. The maximum and statistically significant decrease occurred in response to induction by collagen (by ≈30%, p≤0.01) and ADP (by ≈25%, p≤0.01). A slightly weaker but statistically significant reduction in aggregation appeared in response to ristocetin (by ≈12%, p≤0.01) and epinephrine (by ≈9%, p≤0.01). It should be noted that the spontaneous aggregation exceeded the reference values in the control group. Nevertheless, even at minimal absolute values, spontaneous platelet aggregation decreased by 2 times in response to xenon (p≤0.01). The reasons for the decrease of spontaneous and induced aggregation are xenon accumulation in the lipid bilayer of the membrane with subsequent nonspecific (mechanical) disassociation of membrane platelet structures and specific block of its distinct from neuronal NMDA receptor.

Effect of Xe/O2 Inhalation on Hemostasis in Experimental Thromboplastin Pneumonitis.

We studied the effectiveness of Xe/O2 mixture inhalation (30% Xe and 70% O2, 20 min for 5 days) in a model of experimental thromboplastin pneumonitis. Inhalation of the studied mixture decreased the intensity of the inflammatory process in the lung tissue assessed by the temperature response of animals, changed lung weight and lung weight coefficient. At acute stage of pneumonitis, an increase in xenon consumption was recorded due to its retention in the gas exchange zone and a natural decrease in oxygen consumption due to partial alveolar/capillary block. The formation of pneumonitis was accompanied by a pronounced procoagulant shift in the regulation system of the aggregate state of blood. The Xe/O2 inhalations ensured physiologically optimal levels of prothrombin and activated partial thromboplastin time against the background of a moderate decrease in fibrinogen level throughout the experiment. At the same time, the activity of the natural anticoagulant antithrombin III increased from day 5 to day 14.

[Expression of immune checkpoints PD-L1, CTLA4, LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status]. / Ekspressiya immunnykh kontrol'nykh tochek PD-L1, CTLA4, LAG3 v mikrookruzhenii adenokartsinomy tolstoi kishki v zavisimosti ot MMR-statusa.

OBJECTIVE: Study of the features of expression of immune checkpoint proteins PD-L1, CTLA4 and LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status. MATERIAL AND METHODS: The study group consisted of 32 patients with a morphologically confirmed diagnosis of colon cancer; all of them underwent surgical treatment in the form of hemicolonectomy or resection. The work assessed samples of tumor tissue obtained as a result of surgery, the study was carried out in 3 stages: morphological examination of histological slides of colon tumors at the light-optical level, immunohistochemistry examination of tumor samples to determine the dMMR/pMMR status of carcinoma using a panel of antibodies to proteins of the unpaired nucleotide repair system MLH1, MSH2, MSH6 and PMS2, multiplex analysis of PD-L1, CTLA4, LAG3, CD3+, CD8+, CD163+ markers using the Vectra 3.0.3 tissue scanning system (Perkin Elmer, USA). RESULTS: Significant differences in the expression of PD-L1, CTLA4, LAG3 in the area of the invasive tumor margin were revealed between the dMMR and pMMR groups of colon adenocarcinomas in patients comparable in clinical and morphological characteristics and treatment. In the group of tumors with dMMR status, an increase in the expression of all studied markers was noted. The number of CD3+ TILs was also significantly higher in the invasive margin of tumors with dMMR status. Similarly, in this group of colon carcinomas, a large number of CD163+ macrophages were noted both in the center and in the invasive margin zone. No statistically significant differences were found in the expression of immune checkpoints and the composition of TILs in the central zone of tumors with different MMR status. CONCLUSION: A study using multiplex immunohistochemical analysis showed that MMR-deficient colon adenocarcinomas are characterized by more pronounced immune infiltration and increased expression of immune checkpoints in microenvironmental cells, mainly in the area of invasive tumor growth. The data obtained may be important for understanding the mechanisms of immune-mediated control of tumor growth and the choice of immunotherapy tactics depending on MMR status.

Xenon-Induced Effects in Relieving Experimental Acute Respiratory Distress Syndrome.

The effects of inhalations of an oxygen-xenon (70%/30%) mixture were studied in two models of acute respiratory distress syndrome caused by intratracheal administration of 0.5 mg/kg LPS or 0.04 ml acidin-pepsin (pH 1.2). Inhalation of the oxygen-xenon mixture inhibited the development and reduced the intensity of the inflammatory process in the lung tissue, which was assessed by the dynamics of lung weight and body weight of animals: the therapeutic exposure decreased both parameters. It was found that the thrombogenic stimulus, pathognomonic for the development of acute respiratory distress syndrome, decreased under the effect of oxygen-xenon inhalations, while the level of natural anticoagulant antithrombin III increased.

Xenon-Induced Recovery of Functional Activity of Pulmonary Surfactant (In Silico Study).

To understand the nature of xenon-induced recovery of the functional activity of pulmonary surfactant during inhalation of a gas mixture of Xe/O2, the mechanisms of the ongoing processes were studied in silico. Impaired ability of pulmonary surfactant to maintain low surface tension preventing alveolar atelectasis occurs due to formation of aggregates of its phospholipids and a decrease in their lateral mobility. Aggregated lipid systems, whose structure can explain the loss of lateral mobility of surfactant phospholipids, were modeled in silico at the molecular level. Changes in the Gibbs energy and enthalpy in the reactions of the formation and decomposition of xenon intermediates with model systems of various compositions/structures were calculated. The simulation was carried out for atomic xenon and for xenon polarized by molecular oxygen in the gas phase and taking into account solvation with water. The loss of lateral mobility of phospholipids can be explained by specific features of electronic structure of hydrophobic hydrocarbon molecules (acyl chains), which, under certain conditions, are capable of forming structured common regions of the electrostatic potential, to which xenon has an affinity. In this case, inclusion coordination compounds of the "guest-host" type are formed, which subsequently decompose due to the nature of the polarization of the Xe atoms. The formation and decomposition of xenon intermediates in these systems lead to recovery of the lateral mobility (fluidity) of phospholipids, which restores functional activity of surfactant films.

Mechanisms of the Effects of Short-Term Inhalations of Xe and O2 Gas Mixture in the Rehabilitation of Post-COVID Ventilation Failure.

The article presents a theoretical rationale and a clinical case of relief of post-COVID ventilation failure by inhalation of Xe and O2 gas mixture. Pneumonitis of coronavirus etiology transforms saturated phospholipids of surfactant into a solid-ordered phase, which disrupts surface tension, alveolar pneumatization, and alveolar-capillary gas exchange. Using molecular modeling (B3LYP/lanl2dz; GAUSSIAN09), we demonstrated that Xe atom due to the van der Waals dispersion interaction increases the distance between the phospholipid acyl chains providing a phase transition from the solid-ordered to liquid phase and restored the surface-active monolayer surfactant film. A clinical case confirmed that short-term inhalations of the Xe and O2 gas mixture relieved manifestations of ventilation insufficiency and increased SpO2 and pneumatization of the terminal parts of the lungs.

[PSYCHOPHARMACOLOGY OF ANTIPARKINSONIAN DRUGS].

Parkinson's disease as an extrapyramidal pathology is accompanied by some non-motor symptoms (depression, cognitive disorders, and sleep disturbance), which are based on disturbances of nigrostriatal dopaminergic neurotransmission supplemented by disorganization of other neuromediator systems. Traditional antiparkinsonian drugs with different cellular mechanism of action are capable of restricting these symptoms in patients and on animal models, while exhibiting their own psychotropic activity. This circumstance should be taken into account in assessing the pharmacological activity profiles of drugs.

[PROTECTIVE ROLE OF MELATONIN IN ETIOLOGY AND COURSE OF PARKINSON'S DISEASE: EXPERIMENTAL EVIDENCE.]

Literature data about participation of melatonin - the main hormone of pineal gland - in the origin and course of Parkinson's disease are reviewed. On the cellular level, melatonin demonstrates neuroprotective activity based on the limitation of oxidative stress, inflammation, and degradation of dopamine in nervous tissue, the attenuation of mitochondrial dysfunction, and the accumulation of alpha-synuclein, which are observed in parkinsonian animals and human patients. Moreover, melatonin is capable of inducing some systemic changes that limit disorganization of circadian rhythm and insomnia. It is suggested that, after extensive placebo controlled and randomized examinations in clinical practice, melatonin may be recommended for complex therapy of Parkinson's disease with obligatory taking into consideration some variable factors.

[Influence of melatonin and diclofenac on circadian rhythm of locomotor activity in rats with local inflammatory arthritis].

Inflammatory arthritis is accompanied by disorganization of the circadian rhythm of locomotion in rats. Control saline injections increased the rhythm disturbances. Chronic administration of melatonin (5 mg/kg) attenuated these chronopathological shifts. Diclofenac demonstrated much lower positive chronopharmacological activity than did melatonin.

[Comparative study of the influence of melatonin and diclofenac on some hematologic indices of experimental rheumatoid arthritis in rats].

Pineal hormone melatonin (1 and 5 mg/kg) and diclofenac (8 mg/kg) significantly limited hematologic indices of inflammation and immunologic reactivity in rats with experimental adjuvant arthritis. The effect of melatonin was more pronounced than that of diclofenac.

[Anti-inflammatory potential of melatonin].

The summary of anti-inflammatory properties, cellular and systemic mechanisms of action of epiphyseal melatonin is presented. Dual effect of interaction between melatonin and non-steroidal anti-inflammatory agents is discussed with reference to enhancement of their specific activity and prevention of side effects.

[Complex estimation of the psychotropic activity spectrum of pineal hormone melatonin in young healthy humans].

Effects of the pineal hormone melatonin (melaxen, 1.5 mg, 2 weeks) on a complex of psychophysiological indices have been studied on a group of healthy human volunteers in comparison to placebo. The drug improved the concentration of attention, improved its stability in the presence of visual hindrances, and increased the critical frequency of merging light flashes. The administration of melatonin also significantly increased the transient memory volume and reduced the levels of depression and anxiety. Shifts in the psychoemotional state were more pronounced than changes in the cognitive functions.

[Influence of pineal hormone melatonin on behavioral disturbances and neurological status of animals after hemorrhagic stroke].

Experimental hemorrhagic stroke causes behavior and locomotor activity with memory impairment and neurological disturbances in rats. These shifts are weaker in the evening hours than after morning testing. The repeated administration of the pineal gland hormone melatonin (melaxen) during one week significantly decreases behavior and neurological deficits as well as pathomorphological signs in the lesion focus. The normalizing effect of the hormone is more distinct in the evening.

[Comparative experimental study of the psychotropic and chronotropic activity of adaptogenic phytopreparations and melaxen].

Adaptogenic drugs of plant origin (complex phytopreparation tonizid, Ginkgo biloba extract bilobil) and hormonal origin (melaxen or melatonin) exhibit similar spectra ofpsychotropic activity in rats, which are manifested by improved memory, increased locomotion and investigation activity, and decreased anxiety. At the same time, these drugs had different chronotropic properties, depending on the schedule (acute vs. repeated) and daytime (morning vs. evening) of administration.

[Protective effect of melatonin on behavioral and morphological disturbances induced by cerebrocranial trauma in different daytime in rats].

Chronic administration of the pineal hormone melatonin improves the cognitive activity and stimulates locomotion in rats, the effect being more pronounced in evening hours. On the background of melatonin action, local cerebrocranial trauma produces less pronounced behavioral and morphological disturbances, which more rapidly disappear after brain injury in the evening. The protective effect of the hormone is less pronounced in the morning hours.

[Stroke and epiphysis].

The data on the role of epiphysis and its key hormone melatonin in the natural mechanisms of brain protection from stroke are reviewed. The authors consider chronobiological features of stroke with regard to the fact that epiphysis, which produces melatonin, is involved in the formation of oscillatory processes. Experimental evidences that cerebral ischemia depends on epiphysis activity and injection of exogenic melatonin are presented. Based on experimental data, the authors reveal the protective effect of epiphysis activity in stroke by means of the systemic and direct neuroprotective action of melatonin. It has been suggested that nontoxic preparations of melatonin may be needed in the complex prevention and treatment of stroke, especially in elderly patients with the natural involution of the pineal gland.

[Ambulatory surgery of inguinal hernias].

415 patients with inguinal hernia were operated on in the period of 1996-2005yy. In 87 cases the abdominal wall reconstruction was performed using local tissues, Lichtenstein's method was employed in 139 patients and in 189 cases we performed the modificated combined reconstruction. The latter constitutes of the posterior inguinal wall reconstruction, using local tissues and mesh implantation to the medial part of the inguinal space. Postoperative complications after the combined reconstruction were registered in 12,7%, whereas after Lichtenstein and autoplasty 23 and 30% of patients, respectively, suffered from complications. The low seroma and genital edema incidence in patients where the combined inguinal reconstruction was used, are obviously due to the smaller size of the mesh, low traumatism of the operation and absence of tissue strain and spermatic cord compression. Follow-up results are better in the third group. Pain and <> are registered half more rare then in other groups. There were no hernia recurrence registered in the third group during the 6 years follow-up period.