RESUMO
The features of the participation of Smad3 in the functioning of neural stem cells (NSC), neuronal committed precursors (NCP), and neuroglial elements were studied in vitro. It was found that this intracellular signaling molecule enhances the clonogenic and proliferative activities of NCP and inhibits specialization of neuronal precursors. At the same time, Smad3 does not participate in the realization of the growth potential of NSC. With regard to the secretory function (production of neurotrophic growth factors) of neuroglial cells, the stimulating role of Smad3-mediated signaling was shown. These results indicate the promise of studying the possibility of using Smad3 as a fundamentally new target for neuroregenerative agents.
Assuntos
Proliferação de Células , Células-Tronco Neurais , Neuroglia , Proteína Smad3 , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Proteína Smad3/metabolismo , Proteína Smad3/genética , Animais , Neuroglia/metabolismo , Neuroglia/citologia , Proliferação de Células/fisiologia , Transdução de Sinais , Diferenciação Celular/fisiologia , Células Cultivadas , Ratos , Neurônios/metabolismo , Neurônios/citologia , CamundongosRESUMO
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.
Assuntos
Agregação Plaquetária , Xenônio , Xenônio/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Humanos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Difosfato de Adenosina/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Plasma Rico em Plaquetas/metabolismo , Epinefrina/farmacologia , Epinefrina/sangue , Colágeno/metabolismoRESUMO
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.
Assuntos
Oxigênio , Pneumonia , Xenônio , Animais , Pneumonia/sangue , Pneumonia/patologia , Masculino , Oxigênio/metabolismo , Xenônio/administração & dosagem , Xenônio/farmacologia , Hemostasia/efeitos dos fármacos , Administração por Inalação , Fibrinogênio/metabolismo , Tempo de Tromboplastina Parcial , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Antitrombina III/metabolismo , Ratos , Tromboplastina/metabolismo , Protrombina/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Coagulação Sanguínea/efeitos dos fármacosRESUMO
Type 1 diabetes mellitus was modeled in Wistar rats by intraperitoneal injection of streptozotocin (25 mg/kg for 5 days), which led to the appearance of the main symptoms of insulin-dependent diabetes. In peripheral blood mononuclear cells isolated by centrifugation on a Ficoll density gradient, the production of ROS and the level of intracellular lipids were evaluated by flow cytofluorimetry. In rats with type 1 diabetes mellitus, an increase in ROS levels in isolated peripheral blood monocytes, but not in the lymphocytic fraction was revealed. Incubation of isolated monocytes in a medium containing 1 mM oleic acid led to a 1.5-fold increase of intracellular lipid levels. After incubation of the lymphocyte fraction in this medium, no differences from the control were revealed. Disorders of carbohydrate and lipid metabolism in type 1 diabetes mellitus leading to an increase of free fatty acids and ROS levels can be detected ex vivo in isolated peripheral blood mononuclear cells.
Assuntos
Diabetes Mellitus Tipo 1 , Ratos , Animais , Diabetes Mellitus Tipo 1/metabolismo , Leucócitos Mononucleares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ratos Wistar , Estresse Oxidativo , Ácidos Graxos não Esterificados/metabolismoRESUMO
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.
Assuntos
Síndrome do Desconforto Respiratório , Humanos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Pulmão , Oxigênio/farmacologia , Administração por InalaçãoRESUMO
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.
Assuntos
Surfactantes Pulmonares , Xenônio , Xenônio/farmacologia , Fosfolipídeos/química , Gases , Tensoativos/farmacologiaRESUMO
Experimental type 1 diabetes mellitus (T1DM) was induced in rats by daily intraperitoneal injections of alloxan in a dose of 90 mg/kg for 4 days. For verification of insulin resistance, insulin tolerance test was performed in 2 weeks and the glucose utilization rate constant (KITT) was calculated. The rats demonstrated the main symptoms of T1DM: hypoinsulinemia, hyperglycemia, ketonemia, glucosuria, ketonuria, polydipsia, polyphagia, weight loss, and insulin resistance, as evidenced by a decrease in KITT. The serum content of free fatty acids and triacylglycerols significantly increased. The content of triacylglycerols increased in skeletal muscles and decreased in the liver. A negative linear correlation was found between KITT and triacylglycerol content in muscles. Thus, the development of insulin resistance in experimental T1DM in rats is associated with accumulation of triacylglycerols in skeletal muscles.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Resistência à Insulina , Animais , Glicemia , Diabetes Mellitus Tipo 1/induzido quimicamente , Insulina , Resistência à Insulina/fisiologia , Ratos , TriglicerídeosRESUMO
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.
Assuntos
COVID-19/complicações , Oxigênio/administração & dosagem , Insuficiência Respiratória/terapia , Terapia Respiratória/métodos , Xenônio/administração & dosagem , Administração por Inalação , Anestésicos Inalatórios/administração & dosagem , COVID-19/etiologia , COVID-19/reabilitação , COVID-19/terapia , Combinação de Medicamentos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Respiração/efeitos dos fármacos , Insuficiência Respiratória/etiologia , Federação Russa , SARS-CoV-2 , Síndrome de COVID-19 Pós-AgudaRESUMO
The aim of the study was to develop composite film materials derived from modified sodium carboxymethyl cellulose and to evaluate their anti-adhesive effects. Materials and Methods: The modified film materials were obtained by dissolving sodium carboxymethyl cellulose (Na-CMC) in an aqueous solution of a modifier (glycoluril) with subsequent homogenization and drying in a vacuum drying oven at room temperature. Physicomechanical parameters of the obtained films were determined using the Instron 3369 universal electromechanical testing machine (Great Britain) equipped with a climatic chamber (300-523 K), improved video extensometer, and the MKC-25 micrometer (Russia). Cytotoxicity of glycoluril-modified film materials derived from Na-CMC was studied by incubating cell cultures of 3T3-L1 mouse fibroblasts directly with extracts from films under study using a colorimetric test. Their anti-adhesion effect was investigated on 40 female Wistar rats by modeling a flat adhesion by inducing abrasion of the cecum and suturing the deserosed surface of the abdominal wall anatomically opposite the abrasion area. The presence of adhesions was assessed on day 8 after the operation. Commercial membrane Seprafilm (USA) was used as a reference sample. Results: It was found that extracts obtained from film materials derived from Na-CMC modified with glycoluril at a concentration of 0.01 and 0.05 wt. % had no cytotoxic effect on the cell culture of mouse fibroblasts 3T3-L1. Flat adhesions were not detected when using Seprafilm. When film materials under study were placed in the abdominal cavity between the injured areas, formation of flat adhesions was not observed or observed in one case out of ten. Conclusion: The obtained films are promising for preventing adhesions as a barrier-type agent. Modifying Na-CMC with glycoluril made it possible to create films that prevent formation of flat adhesions, have improved physical and mechanical properties and no cytotoxic effect.
Assuntos
Carboximetilcelulose Sódica , Sódio , Animais , Feminino , Imidazóis , Camundongos , Ratos , Ratos Wistar , Aderências Teciduais/prevenção & controleRESUMO
Under conditions of steady-state hemopoiesis, nuclear factor NF-κB, in contrast to MAP kinase p38, plays an important role in the maintenance of the initial level of secretory activity of monocytes. The increase in the production of G-CSF under stress conditions (10-h immobilization) is mainly regulated by the alternative p38MARK signaling pathway via activation of p38 synthesis. It was shown that under conditions of cytostatic-induced myelosuppression, the production of protein kinase p38 in cells decreases, and it, like NF-κB, is not the main one in the production of hemopoietin by mononuclear phagocytes.
Assuntos
Diferenciação Celular , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Fagócitos/fisiologia , Animais , Células da Medula Óssea/fisiologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/fisiologia , NF-kappa B/metabolismo , Fagócitos/metabolismo , Transdução de Sinais/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Suppression of the production of granulocytic CSF under the effect of 5-fluorouracyl is related to disorders in the NF-κB-, cAMP-dependent signaling pathways and MAPK cascade. These secondary messengers are involved in the regulation of functional activity of nonadherent myelokaryocytes starting from day 10 of the experiment (initial period of the hemopoietic granulocytic stem regeneration after antimetabolite challenge). Granulocytic CSF does not play essential role in the formation of colony-stimulating activity of cells of the adherent and nonadherent fractions of the bone marrow. Only cAMP-dependent pathway is involved in the regulation of the realization of the granulocytic precursor growth potential in response to the challenge.
Assuntos
Citostáticos/farmacologia , Fluoruracila/farmacologia , Fator Estimulador de Colônias de Granulócitos/genética , Granulócitos/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , NF-kappa B/genética , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Adesão Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Didesoxiadenosina/análogos & derivados , Didesoxiadenosina/farmacologia , Regulação da Expressão Gênica , Tiomalato Sódico de Ouro/farmacologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Granulócitos/citologia , Granulócitos/metabolismo , Hematopoese/genética , Imidazóis/farmacologia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Piridinas/farmacologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Theoretic and experimental study of viscoelastic properties of the whole blood exposed to shear stress was carried out with acoustic resonance method based on the measurement of gain-frequency characteristics of resonating needle in an ARP-01M piezoelectric thromboelastograph (Mednord). The study revealed regularities in the changes of viscoelastic parameters of the whole blood within 0-80 kHz frequency range of shear vibrations. In this frequency range, the elastic (storage) modulus G' reflecting blood elasticity increased with frequency and significantly contributed to the complex viscosity coefficient. The revealed gain-frequency regularities open the vista to employ the acoustic resonance method to determine the viscoelastic parameters of the whole blood and their coagulation-induced changes in the wide frequency range of shear vibrations.
Assuntos
Modelos Teóricos , Animais , Módulo de Elasticidade , Elasticidade , Humanos , Resistência ao Cisalhamento/fisiologia , Estresse Mecânico , ViscosidadeRESUMO
Cytochrome p450-mediated metabolism of GRS (indolinone antiaggregant) and its effects on activities of cytochrome p450 isoenzymes were studied. Inhibition of 6 isomers of cytochrome p450 in human liver microsomes was studied with the use of specific substrates. It was found that human liver cytochrome p450 enzymes could not induce degradation of GRS and that GRS was not an inductor or inhibitor of cytochrome p450 family members 1A2, 2C9, 2C19, 2D6, 2C8, and 3A4. Hence, clinical use of the prospective antiaggregant would not involve the risk of uncontrolled fluctuations in GRS concentrations in the organism because of interactions between the drugs.
Assuntos
Microssomos Hepáticos/efeitos dos fármacos , Oxindóis/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Animais , Biotransformação/efeitos dos fármacos , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Ensaios Enzimáticos , Expressão Gênica , Humanos , Cinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , NADP/metabolismo , Ratos , Verapamil/farmacologiaRESUMO
Ethanol-induced neurodegeneration was modeled in vitro to study the roles of ERK1/2 and p38 in realization of the growth potential of neural progenitor cells and secretion of neurotrophic growth factors by glial elements. Addition of the neurotoxic dose of C2H5OH (65 mM) to the culture medium abolished the effects of specific ERK1/2 and p38 inhibitors on the formation of colonies (neurospheres) and proliferative activity of neural CFU in cultured cells derived from paraventricular region of the mouse brain. The study established that these protein kinases are not implicated in ethanol-induced stimulation of the formation of neural CFU, differentiation of neural progenitors, and synthesis of humoral functional regulators of neural CFU by glial cells.
Assuntos
Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Células-Tronco Neurais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Etanol/farmacologia , Flavonoides/farmacologia , Imidazóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
The role of NF-κB, cAMP/PKA, JAKs/STAT3, ERK1/2, p38, JNK, and p53 signaling pathways in the realization of growth potential of mesenchymal, neural, erythroid, and granulomonocytic progenitor cells were examined in vitro. Using selective blockers of signaling molecules, we revealed some principal distinctions of their involvement in determination of proliferation-differentiation status of the progenitor cells of different functional classes. The most salient peculiarities were observed in the roles of cAMP/PKA, JNK, and JAKs/STAT3 signaling pathways in the control of functions of various types of the regeneration-competent elements. The specific features of intracellular signaling revealed in histogenetically and functionally different progenitor cells attest to visibility of differentiated pharmacological stimulation of regeneration in individual tissues and prospectiveness in the development of targeted remedies for regenerative medicine based on modifiers of activity of the intracellular signaling molecules.
Assuntos
Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Neurais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antracenos/farmacologia , Antraquinonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Didesoxiadenosina/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Flavonoides/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Janus Quinases/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno , NF-kappa B/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Nitrilas , Fosforilação/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas , Medicina Regenerativa , Fator de Transcrição STAT3/metabolismo , Sulfonamidas/farmacologiaRESUMO
The study focuses on the development of principally novel priority-oriented healthcare strategy - targeted therapy in regenerative medicine known as Strategy of Pharmacological Control over Intracellular Signal Transduction in Regeneration-Competent Cells. It implies selective action of promising drugs on specific key elements in the signaling cascade responsible for functional activity of various progenitor cells (including stem cells) and elements of tissue microenvironment. The results of pioneer studies are described that were aimed on revealing the peculiarities in signal transduction and the role of distinct signaling molecules (the potential targets) in the control of cell cycle and other functions of progenitor elements and regulatory cells of different types. The models of some pathological states were employed to demonstrate the possibility of effective implementation of the advanced pharmacotherapeutic concept. The developed theoretical and applied platform can be used to launch synthesis of principally novel preparations with regenerative activity.
Assuntos
Medicina Regenerativa/métodos , Células-Tronco/citologia , Animais , Ciclo Celular/fisiologia , Humanos , Transdução de Sinais/fisiologia , Células-Tronco/fisiologiaRESUMO
The in vitro and in vivo models of ethanol-induced neurodegeneration were used to evaluate the content and functional activity of various types of regeneration-competent cells in subventricular zone of the cerebral hemispheres in C57Bl/6JY mice. In nervous tissue culture, ethanol (65 mM) produced no effect on formation of neurospheres. When administered per os in a daily dose of 3 g/kg for 8 weeks, ethanol produced no effect on the number of neural CFU in situ. In both cases, ethanol reduced proliferative activity of neural CFU. Long-term administration of ethanol in vivo suppressed differentiation of neural stem cells and decreased the number of committed precursors (neural cluster-forming units) in the subventricular zone of cerebral hemispheres. In vitro application of ethanol stimulated secretion of humoral growth factors by the cluster-forming neural glial cells. In contrast, in vivo administration of ethanol suppressed this secretion.
Assuntos
Alcoolismo/patologia , Cérebro/efeitos dos fármacos , Etanol/farmacologia , Ventrículos Laterais/efeitos dos fármacos , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Alcoolismo/metabolismo , Animais , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Cérebro/fisiopatologia , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Ventrículos Laterais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/patologia , Cultura Primária de Células , Esferoides Celulares/efeitos dos fármacosRESUMO
The role of signaling molecules in synthesis of humoral regulators of granulocytopoiesis by the hematopoietic microenvironmental cells during stress was analyzed using specific inhibitors. The major role in stimulation of the synthesis of granulocytic CSF during stressful stimulation is played by PI3K/Akt signaling cascade. Nuclear transcription factor NF-κB plays an auxiliary role in the regulation of functional activity of the bone marrow mononuclears. However, this factor affects the synthesis of granulocytic CSF by CD4+ cells of the bone marrow in response to stressful stimulation. Different degree and specific character of involvement of the signaling proteins in the regulation of the production of humoral factors determining colony-stimulating activity are explained by changes in functional state of monocyte-derived macrophages in different periods of stress response.
Assuntos
Fator Estimulador de Colônias de Granulócitos/genética , Granulócitos/imunologia , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/imunologia , Estresse Psicológico/genética , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Cromonas/farmacologia , Flavonoides/farmacologia , Regulação da Expressão Gênica , Tiomalato Sódico de Ouro/farmacologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Granulócitos/efeitos dos fármacos , Granulócitos/patologia , Imidazóis/farmacologia , Imobilização/métodos , Leucopoese/efeitos dos fármacos , Leucopoese/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Morfolinas/farmacologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Inibidores de Fosfoinositídeo-3 Quinase , Piridinas/farmacologia , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologiaRESUMO
We studied myelotoxicity of modern schemes of chemotherapy for breast cancer (docetaxel/doxorubicin and cyclophosphamide/doxorubicin/5-fluorouracil) towards granulocytopoiesis, the mechanisms determining the differences of hematological effects of these schemes, and the efficiency of correction of the observed changes with granulocyte CSF (filgrastim). Granulocytopoiesis stimulation with filgrastim during the treatment with docetaxel/doxorubicin combination was more pronounced than during cyclophosphamide/doxorubicin/5-fluorouracil therapy. The observed differences were found at all levels of granulocyte lineage organization (central and peripheral), which is related to different effects of the cytostatic substances used in the proposed protocols on the structures controlling hemopoiesis.