卷 110, 编号 1 (2024)

The blood coagulation system is actively involved in the development of cancer. It is known that many solid tumors express tissue factor, a “trigger” of the cascade of plasma coagulation reactions, which leads to an increased risk of cancer-associated thrombosis and venous thrombosis in cancer patients. It has also long been known that platelets - small cellular fragments that are the basis of blood clots - play a critical role in metastasis by binding to the tumor cell after it enters the blood vessel, “shielding” it from the immune system and promoting the adhesion and extravasation of the tumor cell into tissues and the formation metastasis. In addition, platelets, being mobile “storehouses” of growth factors, are actively attracted and, in some cases, consumed by the tumor, which contributes to its development and vascularization. Platelet attraction occurs both through activation of the blood coagulation system in the tumor area and through exposure of the adhesive surface by the tumor. Activated in the tumor vicinity, platelets attract and induce neutrophil activation and the formation of neutrophil extracellular traps (NETs), thereby modulating the tumor microenvironment. When activated, platelets are known to secrete a variety of growth factors that promote both tumor development and vascularization. In addition to direct interaction, platelets and tumor cells exchange mRNA, micro-RNA and other regulatory molecules through microvesicles, while platelets are containers for the spread of tumor genetic material (circulating nucleic acids) throughout the body. In this review, we consider the molecular mechanisms of platelet participation in the development and metastasis of solid tumors, and also discuss possible options for pharmacological interruption of this interaction.

The activity of many proteins and, as a result, of the mechanisms of vascular tone regulation depends on pH. A decrease of pH (uncompensated acidosis), usually causes relaxation of blood vessels, which has been studied in sufficient detail for an adult, matured organism. However, the effect of acidosis on the mechanisms of vascular tone regulation in the early postnatal period remains almost completely unexplored. The aim of this work was to study the effect of extracellular metabolic acidosis on the functional contribution of K_ATP and TASK-1 potassium channels to the regulation of vascular tone in early postnatal period. We modeled extracellular metabolic acidosis (pH 6.8, equimolar replacement of NaHCO₃ with NaCl in solution) and studied isometric contractile responses of the saphenous artery in rats aged 3–4 months and rat pups aged 12–15 days. Arterial contraction to the α₁-adrenergic agonist methoxamine at pH 6.8 was reduced compared to normal pH 7.4 in both 3–4-month-old and 12–15-day-old rats. The K_ATP channel blocker glibenclamide did not change the arterial responses to methoxamine, neither at pH 7.4 nor at pH 6.8 in any of the age groups. The TASK-1 channel blocker AVE1231 did not alter arterial contractile responses at any pH in 3–4-month-old rats. However, in 12–15-day-old rat pups, the increase in contractile responses to methoxamine under the influence of AVE1231 was less at pH 6.8 than at pH 7.4. Thus, the results of this work demonstrate that acidosis reduces the contractile activity of the arteries of 3–4-month-old animals and animals during early postnatal ontogenesis, while in the latter, the anticontractile role of TASK-1 channels decreases, and K_ATP channels do not affect the regulation of vascular tone, either under normal, or at acidic pH in any of the age groups.

The ratio of low-frequency (LF, ~0.1 Hz) waves of RR interval duration (RRI) and systolic blood pressure (SAP) reflects the cardiac baroreflex sensitivity (BRS). Gravitational unloading (GU) may alter BRS during the passive orthostatic test (HUT) and lower body negative pressure (LBNP) test. Both effects cause blood redistribution to the lower body, but HUT is accompanied by greater unloading of sinocarotid baroreceptors than LBNP and activation of the vestibulosympathetic reflex but GU effects on BRS in these tests have not been directly compared previously. In this study we tested the hypothesis that the effect of “dry” immersion (DI, on-ground model of GU) on BRS in the same subjects will be more pronounced during HUT than during LBNP, which causes a comparable decrease in stroke volume. Nine healthy men participated in two test sessions (before and after 7-day DI) consisting of five 3-min HUT (65°) and five 3-min LBNP (–35 mmHg) with averaging the parameters in each test. Wavelet analysis was used to determine the amplitude of the RRI and SAP waves in the range of 0.05–0.13 Hz. The amplitude of LF waves of SAP increased in both tests, after DI - more significantly in HUT. The amplitude of LF RRI waves decreased in the two tests; the degree of decrease did not differ between tests and did not change under the influence of DI. The α-coefficient (the ratio of the amplitudes of RRI and SAP LF waves) decreased equally in the two tests before DI, but after DI, the degree of α-coefficient reduction increased in HUT test but did not change in LBNP test. Thus, the effect of DI on BRS is evident in HUT, but not in LBNP, which may be explained by the more pronounced influence of HUT on the mechanisms of neural control of heart rhythm.

Autoimmune hyperthyroidism (Graves’ disease), which is caused by stimulating autoantibodies to the thyroid-stimulating hormone (TSH) receptor, and thyroid gland (TG) tumors, caused by constitutively increased activity of this receptor, are widespread and have a poor prognosis. The drugs used to treat them are not very effective and have many side effects. One of the approaches for the treatment of these thyroid diseases may be the use of allosteric regulators of the TSH receptor with the activity of inverse agonists. The purpose of the work was to study the effects of our previously developed compound TP48 and the new compound TPY5, belonging to the class of thieno[2,3-d]-pyrimidines, on the basal and thyrotropin-releasing hormone (TRH)-stimulated levels of thyroid hormones (THs) in the blood of rats and on the expression of genes responsible for the synthesis of THs in the TG. The effectiveness of TP48 and TPY5 was studied both with intraperitoneal (i.p., 20 mg/kg) and oral (40 mg/kg) administration. Using ELISA, the levels of free (fT4) and total (tT4) thyroxine and free (fT3) and total (tT3) triiodothyronine in the blood were assessed, including during TRH stimulation (intranasally, 300 μg/kg). The gene expression for thyroid peroxidase (Tpo), thyroglobulin (Tg), Na⁺/I^–-symporter (Nis), type 2 deiodinase (Dio2) and TSH receptor (Tshr) in the TG was assessed using PCR. TPY5, with both routes of administration, reduced both basal and TRH-stimulated TH levels, while TP48 suppressed TH production only with i.p. administration. Orally administered TPY5 significantly reduced basal Tpo gene expression and TRH-stimulated Tg and Dio2 gene expression. I.p. administered TP48 reduced only TRH-stimulated expression of the Tg and Dio2 genes. Quite surprisingly, TPY5 (oral) and TP48 (i.p.) reduced basal Tshr gene expression and did not prevent its inhibition by TRH. Thus, the TPY5 compound we developed has the activity of an inverse agonist of the TSH receptor, is effective when administered orally, which is more in demand in medicine, and can be considered as a prototype of drugs to treat autoimmune hyperthyroidism and thyroid tumors.

Epilepsy is a severe neuropsychological disease accompanied by the development of spontaneous recurrent seizures (SRS) and associated behavioral disorders that are difficult to treat. In recent years, the neuroprotective properties of agonists of peroxisome proliferator-activated receptors (PPAR α, β/δ, γ), nuclear transcription factors involved in the regulation of lipid and carbohydrate metabolism, as well as inflammatory signaling pathways involved in the pathogenesis of epilepsy, have been actively investigated. The neuroprotective properties of PPARγ agonists have been repeatedly described in models of epilepsy; the effects of PPARβ/δ agonists in these models have not been sufficiently investigated. The aim of this work was to study the effects of administering the PPARβ/δ agonist cardarin on the formation of histopathological and behavioral abnormalities in the lithium-pilocarpine model of temporal lobe epilepsy (TLE). The lithium-pilocarpine model is one of the best experimental models of chronic temporal lobe epilepsy. In this study, epilepsy was induced by administration of pilocarpine to male Wistar rats at the age of 7 weeks one day after LiCl injection. Cardarin (2.5 mg/kg) was administered daily for 7 days after pilocarpine, with the first injection one day after pilocarpine injection. Behavioral testing was performed 2‒3 months after induction of the model in the following tests: Open Field, Resident Stranger, New Object Exploration, Y Maze Spontaneous Alternation and Morris Water Maze. Brain sampling for histological studies (assessment of neuronal death, Nissl staining) was performed after the end of behavioral experiments, 95 days after TLE induction. It was shown that untreated rats with TLE exhibited significant hippocampal neuron death and behavioral disorders: increased motor activity, anxiety, memory disorders, research and communicative behavior. Caradrin did not affect the survival rate of hippocampal neurons, but reduced the manifestation of almost all the above-mentioned behavioral disorders, except for hyperactivity. Thus, this study demonstrated the promising use of PPARβ/δ agonists to attenuate the development of behavioral disorders characteristic of epilepsy.