Search

В развитии рака предстательной железы (РПЖ) макрофаги играют важную роль. Многие опухоли выделяют противовоспалительные цитокины, которые перепрограммируют М1 фенотип макрофагов на проопухолевый М2 фенотип. М2 макрофаги подавляют противоопухолевый иммунитет, способствуют делению и метастазированию опухолевых клеток. Предыдущие исследования позволили нам обосновать предположение, что деление опухолевых клеток РПЖ человека может быть ограничено особым М3 фенотипом макрофагов. Фенотип М3, в отличие от М1 фенотипа, реагирует на противовоспалительные цитокины увеличением продукции провоспалительных противоопухолевых цитокинов, что способствует сохранению их противоопухолевых свойств в зоне опухоли. Цель исследования - проверка гипотезы о способности М3 макрофагов останавливать деление клеток предстательной железы больного РПЖ. Методика. В работе использовали макрофаги мышей, выделенные из перитонеального лаважа и макрофаги человека, полученные из моноцитов крови больных РПЖ. Фенотип М3 макрофагов получали добавлением в среду культивирования IFN-γ, ингибиторов STAT3, STAT6 и SMAD3 с последующей стимуляцией липополисахаридом. Результаты. Показано, что М3 макрофаги мышей и человека ограничивали деление клеток предстательной железы больных РПЖ в условиях 2D (на плоскости) культивирования на 43% и 93%, соответственно. При 3D (в объеме) культивировании М3 макрофаги мышей не ограничивали, а М3 макрофаги человека лишь незначительно ограничивали деление клеток предстательной железы у больных РПЖ. Заключение. Результаты работы делают обоснованными дальнейшие исследования и разработку клинической версии биотехнологии лечения рака предстательной железы с использованием М3 макрофагов.Macrophages play an important role in the development of prostate cancer (PCa). Many tumors, including PCa, secrete anti-inflammatory cytokines that reprogram the M1 macrophage phenotype into the pro-tumor M2 phenotype. M2 macrophages suppress antitumor immunity and promote division and metastasis of tumor cells. We hypothesized that the division of human PCa cells may be restricted by a specific M3 macrophage phenotype. The M3 phenotype, in contrast to the M1 phenotype, responds to anti-inflammatory cytokines by increasing the production of inflammatory anti-tumor cytokines and retains its anti-tumor properties in the tumor area. The aim of the study was to test the hypothesis on the ability of M3 macrophages to stop division of prostate cells from patients with PCa. Methods. This study used murine macrophages isolated from the peritoneal lavage and human macrophages obtained from blood monocytes of patients with PCa. The M3 macrophage phenotype was obtained by adding IFN-γ, STAT3, STAT6, and SMAD3 inhibitors to the cultural medium followed by lipopolysaccharide (LPS) stimulation. Results. Murine and human M3 macrophages restricted the division of patients’ PCa cells in the conditions of 2D cultivation by 43% and 93%, respectively. In 3D cultivation, murine M3 macrophages did not restrict whereas human M3 macrophages only slightly limited the division of prostate cells from PCa patients. The results of the study warrant further research and development of a clinical biotechnology for PCa treatment with reprogrammed M3 macrophages.

Oxidation of magnesium and thallium with bis(η5-cyclopentadienyltricarbonylmolybdenum) in dimethyl sulfoxide and of indium with octacarbonyldicobalt in tetrahydrofuran was studied. The formal-kinetics relationships of the processes were revealed, and the intermediate and final products were identified. The apparent equilibrium constants, enthalpies and entropies of adsorption of reactants on the metal surface, and rate constants and activation energies of the reactions were determined. The reaction scheme was suggested.

Here we summarized the results of our studies and the data on the role and protective effects of heat-shock proteins, mechanisms of activation of their synthesis, and the role of nitric oxide in this process. The role of heat-shock proteins in preconditioned and adaptive cardioprotection and the possibility of their use as prognostic criteria in cardiology are discussed

We studied the role of nitric oxide in the stress response and apoptosis. Intracellular nitric oxide potentiated the stress response. However, intracellular nitric oxide suppressed the stress response in macrophages of proinflammatory and antiinflammatory phenotypes. Intracellular nitric oxide promoted apoptosis in macrophages of the proinflammatory phenotype, but inhibited this process in cells of the antiinflammatory phenotype. Exogenous nitric oxide synthesized by macrophages protected them from lipopolysaccharide-induced apoptosis. Our results indicate that nitric oxide produces various effects on the stress response and apoptosis in macrophages, which depends on modus operandi.

The content of NO in the kidneys, heart, and spleen of intact August rats surpasses that of Wistar rats. After heat shock the content of NO rises: in the kidneys 15.5-fold, in the liver 3.2-fold, in the heart 10-fold, in the spleen 6.4-fold, in the intestine 2.8-fold, and in the brain 1.9-fold. Thus, August rats, which are less resistant to heat shock than Wistar rats, are characterized by a more pronounced activation of NO synthesis in response to heat shock.

Polynuclear organometallic compounds [CpMo(CO)3]2BiCl and [CpMo(CO)3]BiCl2 were prepared by reaction of bismuth with tricarbonylcyclopentadienylmolybdenum chloride in dimethyl sulfoxide (DMSO). [CpMo(CO)3]2BiCl is reduced with magnesium or indium in tetrahydrofuran to give bismuth, [CpMo(CO)3]3Bi, and magnesium or indium chloride. In the presence of DMSO, the reaction of [CpMo(CO)3]2BiCl with magnesium or indium yields bismuth and the organomolybdenum derivative of magnesium or lithium, respectively.

The reactions of some organobimetallic chlorides [CpMo(CO)3]2BiCl, [CpM(CO)3]2SnCl2 , [CpMo(CO)3]2InCl (Ср = η5-C5H5; M = Mo, W) with sodium 3,6-di-tert-butyl-ortho-benzosemiquinolate in toluene were studied using the EPR spectroscopy. The possibility of formation of organoheterometallic complexes containing о-semiquinone ligand was shown.

We studied the role of extracellular and intracellular NO in the regulation of the stress response and apoptosis in macrophages of proinflammatory and antiinflammatory phenotypes under the influence of S. aureus and heat shock. Blockade of extracellular nitric oxide synthesis in cells with antiinflammatory phenotype inhibited the stress response induced by S. aureus and heat shock. The decrease in extracellular nitric oxide concentration around antiinflammatory macrophages potentiated the stress response induced by S. aureus, but had no effect on the stress response induced by heat shock. Hence, intracellular NO mediates the stress response induced by S. aureus and heat shock, while extracellular NO inhibits the stress response induced by S. aureus, but has no effect on the stress response induced by heat shock. In cells with antiinflammatory phenotype, intracellular NO plays an antiapoptotic role. S. aureus and heat shock did not cause apoptosis in macrophages with proinflammatory phenotype, while intracellular NO did not play a role in antiapoptotic activity of the proinflammatory phenotype. Extracellular NO synthesized by macrophages protects these cells from apoptosis induced by S. aureus and heat shock.

Caspase inhibitor Z-VAD-FMK potentiated heat shock-induced apoptosis in macrophages. Z-VAD-FMK did not activate HSP70 synthesis, but significantly increased the intensity of this process during heat shock. It cannot be excluded that caspases abolish HSP70 accumulation under these conditions. The HSP70 synthesis inhibitor quercetin potentiated DNA fragmentation in macrophages cocultured with Z-VAD-FMK after heat shock. HSP70 play an important role in the protection of macrophages from caspase-independent apoptosis.

In response to heat shock five isoforms of hsp 70 are accumulated in the myocardium of Wistar rats highly resistant to stress in comparison with only 3 isoforms of hsp 70 in August rats with a lower resistance to stress. This suggests that genetic mechanisms which determine the stress resistance of a particular strain are probably related to transcription of hsp 70 genes.

Oxidation of magnesium and tin with bis(η5-cyclopentadienyltricarbonylmolybdenum)indium and -bismuth chlorides in polar solvents yielded no organic heteropolymetallic complexes; instead, metallic indium and bismuth were isolated from the reaction mixture.

Control and acutely stressed August rats have corticosterone levels 62% and 15% higher, respectively, than their Wistar counterparts, indicating that the activity of stress-mediating hypothalamic-pituitary-adrenal system in August rats is higher. On the other hand, the intensity of stress reactions and, consequently, the degree of activation of this system in August rats are 40–50% lower, as is the blood level of creatine phosphokinase. During adaptation to stress, August and Wistar rats show a similar decrease in the stress reaction and in its damaging effects. However, judging from the blood corticosterone/insulin ratio, adaptation to stress in August rats coincides with intensification of catabolic processes and a reduction in the efficiency of energy production.