RESUMO
A model for accelerated aging in mice was developed: CB6F2 mice aged 39-45 days were exposed to fractionated 4-fold relatively uniform γ-radiation (137Cs, 0.98 Gy/min) at a total dose of 6.8 Gy. Radiation exposure led to delayed active growth, leukopenia, and lymphopenia for over 1 year during the post-radiation period. The death of irradiated males and females occurred significantly earlier than in control group animals. Median lifespans in the experimental group were 35-38% lower than in the control group (p<0.001). Ionizing radiation exposure led to the early development of hair depigmentation, cachexia, and the development of aging-associated diseases. In irradiated mice, oncological pathology constituted 30-35% in the mortality structure, which is twice as often as in the control group. The developed model can be used to study the pathogenesis of accelerated aging under radiation exposure and the search for means of its prevention and treatment.
Assuntos
Senilidade Prematura , Raios gama , Animais , Camundongos , Masculino , Feminino , Raios gama/efeitos adversos , Senilidade Prematura/patologia , Senilidade Prematura/genética , Senilidade Prematura/etiologia , Longevidade/efeitos da radiação , Radiação Ionizante , Envelhecimento/efeitos da radiação , Caquexia/patologia , Caquexia/etiologia , Radioisótopos de CésioRESUMO
A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice.
Assuntos
Analgésicos , Animais , Camundongos , Ratos , Masculino , Analgésicos/farmacologia , Diclofenaco/farmacologia , Tramadol/farmacologia , Psicotrópicos/farmacologia , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Ansiolíticos/farmacologia , Antagonistas de Receptor B1 da Bradicinina/farmacologia , Ratos Wistar , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodosRESUMO
We studied the action of a new indolinone derivative GRS, acetylsalicylic acid (ASA), and their combination on platelet aggregation, vasodilatory endothelial function, neurological status, and cerebral infarction area in experimental focal cerebral ischemia/reperfusion in rats. GRS compound (10 mg/kg), ASA (10 mg/kg), and their combination in the same doses were administered orally once a day as a suspension in 1% starch solution over 5 days after pathology modeling. Sham-operated and control animals were administered 1% starch solution. On day 5 after pathology modeling, platelet aggregation and brain damage area were studied in a half of rats in each group, and the vasodilatory function of the endothelium was studied in the other half. Neurological deficit was assessed 4 h and 1, 3, and 5 days after pathology modeling. GRS compound and ASA equally effectively prevent platelet aggregation and the development of neurological deficit in rats. GRS compound restores the vasodilatory effects of the endothelium, but only ASA contributes to reduction of the cerebral infarction area. In case of combined administration, GRS and ASA do not exhibit synergy in their antiaggregant effect.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Animais , Inibidores da Agregação Plaquetária/farmacologia , Guanilil Ciclase Solúvel , Aspirina/farmacologia , Agregação Plaquetária , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Vasodilatadores/farmacologia , Infarto Cerebral , Amido , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
We studied the effect of a new indolinone derivative GRS on animal survival and on functioning and histological structure of the lungs in rats with experimental pneumonitis. The rats of experimental groups were intratracheally administered 0.5% aqueous solution of carrageenan under intramuscular anesthesia. Compound GRS (10 mg/kg; a suspension in 0.5% aqueous solution of carboxymethyl cellulose) was orally administered for 4 days starting from the day of carrageenan administration; another rat group received the aqueous solution of carboxymethyl cellulose alone. Control rats received intratracheally isotonic solution of sodium chloride. Animal mortality was registered over 5 days; on day 5, the respiratory parameters were measured, the lungs were weighed, pulmonary edema was evaluated, and histological structure of the lungs was studied. GRS compound improved survival of animals with modeled pneumonitis, restored the respiratory parameters to the level of control animals, and reduced pulmonary edema by 35% and the severity of histological damage score in the lungs by 17% (p<0.05).
RESUMO
We studied the effect of an indolinone derivative GRS on the development of experimental atherosclerosis in C57BL/6 mice. Atherosclerosis was modeled by intraperitoneal administration of endothelial lipoprotein lipase inhibitor Kolliphor P 407 micro Geismar over 5 months. GRS was administered orally in a dose of 10 mg/kg once a day throughout the experiment. In 5 months, the levels of total cholesterol, LDL, and triglycerides in blood serum, as well as histological composition of the ascending aorta were studied. In mice with experimental atherosclerosis, we observed pronounced dyslipidemia with an increase in serum cholesterol, LDL, and triglycerides and accumulation of xanthoma cells in the aorta wall. Repeat administration of GRS did not eliminate dyslipidemia, but prevented an increase in the number of xanthoma cells in the aorta wall (p<0.05). The stimulator of soluble guanylate cyclase GRS did not exhibit hypolipidemic activity, but restored impaired endothelial function in the atherosclerosis model and prevented atherosclerotic damage to blood vessels and vascular wall remodeling.
Assuntos
Aterosclerose , Dislipidemias , Xantomatose , Camundongos , Animais , Guanilil Ciclase Solúvel , LDL-Colesterol , Camundongos Endogâmicos C57BL , Aterosclerose/tratamento farmacológico , Triglicerídeos , Dislipidemias/tratamento farmacológico , Guanilato CiclaseRESUMO
We studied antihypertensive activity of an indolinone derivative (compound GRS), a soluble guanylate cyclase stimulator and a drug with previously proven antiaggregant effects. Contraction activity of isolated aorta segments of Wistar-Kyoto (WKY) rats was assessed in vitro using a mechanographic method. Addition of GRS (0.1-100 µÐ) resulted in dose-dependent relaxation of endothelium-denuded aorta segments. Pretreatment of aorta smooth muscle segments with a specific inhibitor of soluble guanylate cyclase (ODQ, 1 µM) weakened the vasodilatory effect of GRS. Antihypertensive activity of the indolinone derivative GRS was studied in spontaneously hypertensive SHR rats. Single oral administration of 5 and 10 mg/kg GRS was followed by a significant dose-dependent reduction of systolic and diastolic BP in SHR rats. Antihypertensive effect of GRS in a dose of 5 mg/kg was more potent than that of the reference drug isosorbide dinitrate. GRS in a dose of 10 mg/kg did not affect systolic and diastolic BP in normotensive WKY rats.
Assuntos
Anti-Hipertensivos , Pressão Sanguínea , Oxindóis , Guanilil Ciclase Solúvel , Vasodilatadores , Animais , Ratos , Anti-Hipertensivos/farmacologia , Oxindóis/farmacologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores/farmacologia , Vasodilatação , Pressão Sanguínea/efeitos dos fármacosRESUMO
A kinetic study of the effect of thermoheliox (inhalation of a helium and oxygen mixture, 70 °C) on the functional hemodynamics of the human brain by functional magnetic resonance imaging was carried out. The dynamic responses of the BOLD signal were found to be biphasic. An empirical equation describing the first phase of the hemodynamic response to visual stimulus was proposed. It was shown that preliminary inhalation of thermoheliox stimulates the hemodynamic responses by slowing down the vasoconstriction.
RESUMO
New antithrombotic drug GRS, a soluble guanylate cyclase stimulator, after repeated administration in a dose of 10 mg/kg alleviates the symptoms of endothelial dysfunction in rats with myocardial infarction; it restores antiplatelet activity of the blood vessel wall and vasodilatory function of the endothelium without producing significant effect on endothelium-independent vasodilation. GRS also has direct antiaggregant and antihypertensive effects in therapeutic doses. The obtained data suggest that GRS can be therapeutically useful in patients with cardiovascular diseases accompanied by endothelial dysfunction.
Assuntos
Guanilato Ciclase , Infarto do Miocárdio , Animais , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Humanos , Infarto do Miocárdio/tratamento farmacológico , Óxido Nítrico , Ratos , Guanilil Ciclase Solúvel , Vasodilatadores/farmacologiaRESUMO
The anti-inflammatory effect of the ester derivative of indomethacin (IML) in doses of 6.25, 12.5, and 25 mg/kg was studied in rats with modeled rheumatoid arthritis (adjuvant arthritis) and compared to the effects of the reference drug indomethacin in a dose of 1 mg/kg. IML in doses of 12.5 and 25 mg/kg reduced joint inflammation and promoted recovery of the microstructure of the synovial membrane and articular cartilage better than indomethacin. IML produced no ulcerogenic effect, while indomethacin concentration in the stomach wall after administration of IML was 1.8-3.4 times lower than after administration of the reference drug (p<0.05).
Assuntos
Artrite Experimental/tratamento farmacológico , Indometacina/farmacologia , Indometacina/uso terapêutico , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/metabolismo , Inflamação/metabolismo , Masculino , Ratos , Ratos Wistar , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismoRESUMO
The high efficiency of using thermoheliox (inhalation with a high-temperature mixture of helium and oxygen) in the treatment of patients affected by COVID-19 was shown. The dynamics of accumulation of IgG, IgM, and C-reactive protein (CRP) in patients with coronavirus infection in the "working" and control groups was studied experimentally. It was shown that thermoheliox intensifies the synthesis of IgG, IgM, and CRP antibodies, while eliminating the induction period on the kinetic curves of the synthesis of specific antibodies in the IgG form and transfers the synthesis of CRP to a fast phase. The results of experiments confirm the previously obtained data based on the analysis of the kinetic model of the development of coronaviral infection in the human body.
Assuntos
Anticorpos Antivirais/imunologia , Proteína C-Reativa/biossíntese , COVID-19/metabolismo , COVID-19/prevenção & controle , Imunidade/imunologia , Vacinação/métodos , COVID-19/imunologia , Humanos , Cinética , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
The genotoxic and antigenotoxic potential of BP-C2, a novel lignin-derived polyphenolic composition with ammonium molybdate, was investigated as a radioprotector/radiomitigator for civil applications and as a medical countermeasure for radiation emergencies. Using the alkaline comet assay and methyl methanesulfonate (MMS, 40 mg/kg) as the DNA-damaging agent, these effects of BP-C2 on liver, bone marrow cells and blood leukocytes in rats were studied. The DNA damage was estimated by the DNA content in the comet tail (TDNA, %) 1, 6 and 18 h post exposure to MMS. BP-C2 at doses of 20, 200 and 2000 mg/kg did not exert genotoxic activity in the tested tissues in rats. BP-C2 administered at doses of 20, 100 and 200 mg/kg 1 h before MMS significantly (p < 0.01) mitigated MMS-induced DNA damage, showing a strong genoprotective effect in the liver. In blood leukocytes and bone marrow samples of animals treated with BP-C2, the TDNA % was slightly higher than in the negative control (vehicle) but significantly lower than in the positive control (MMS). Thus, BP-C2 exerted a genoprotective effect against MMS-induced DNA damage to a greater extent towards liver cells, requiring further evaluation of this substance as a genoprotective agent.
Assuntos
Dano ao DNA , Lignina , Animais , Ensaio Cometa , Metanossulfonato de Metila/toxicidade , Mutagênicos/toxicidade , Substâncias Protetoras , RatosRESUMO
Radiation-protective and anti-aging properties are often combined. Combination of this properties is linked to the common mechanisms of action such as direct and indirect antioxidant activities, inhibition of free radicals formation, increase resistance to stress impacts at the cellular level, acceleration of DNA reparation, prevention of chronic diseases linked to abnormalities in regeneration processes, activation of immune inflammatory processes and carcinogenesis. Regulation of cell cycle and apoptosis can often be considered as an implementing driver of radiation-protective and anti-aging activities. On the one hand, against the background of stopping the cell cycle and blockade of apoptosis increases the time required to repair the defects of a DNA. Antiapoptotic effects enhances survival chances at the early stage after irradiation in a particular range of doses. On the other hand, activation of apoptosis of altered cells can be seen as one of the mechanisms to delay aging processes and prevention of isolated effects of exposure to ionizing radiation. Formation of radiation-induced and age-related alterations are characterized by multiple factors and a variety of manifestations. Nevertheless, similarity of individual links of the pathogenesis of disease related to radiation exposure and aging of the body is striking. It could be stated that radiation-protective property defines an increase in life expectancy by short-term exposure in sub-lethal and lethal doses. However anti-aging activities prevent the development of remote effects of ionizing radiation by prolonged low doses or fractionated exposure to radiation.
Assuntos
Protetores contra Radiação , Apoptose , Dano ao DNA , Relação Dose-Resposta à Radiação , Radiação Ionizante , Protetores contra Radiação/farmacologiaRESUMO
OBJECTIVE: To establish the indications for optimal open lung surgery in patients with severe blunt chest injury. MATERIAL AND METHODS: Hematomas, lung wounds and purulent pulmonary complications were studied in four groups of victims. Causes of injuries included road accidents (n=426), falling and beating (n=387), catatrauma (n=217), squeezing the body with a massive weight (n=46). Majority of victims (n=731, 67.9%) were transferred to the hospital within 1-5 hours after injury; 345 (32.1%) patients were transferred from other hospitals to treat combined injuries of head, chest, abdomen and complications within 1-49 days after injury. RESULTS: Lung surgery was applied in 48 patients. Typical resections and pneumonectomies made up 77.1%. Indications for surgery included lung wounds complicated by pulmonary hemorrhage grade IIa and severe hemothorax, intrapulmonary hematoma ≥6 cm with high risk of bleeding and suppuration, gangrene, gangrenous and purulent abscesses of aspiration genesis, lung cancer first diagnosed in victims. Postoperative mortality was 14.6%. Twelve victims with unrecognized deep lung wounds and pulmonary root rupture were not operated. Thus, 5.6% of victims with severe blunt chest trauma need for open lung surgery.
Assuntos
Lesão Pulmonar , Traumatismos Torácicos , Ferimentos não Penetrantes , Hemotórax/etiologia , Hemotórax/cirurgia , Humanos , Pulmão/cirurgia , Pneumopatias/diagnóstico , Pneumopatias/etiologia , Pneumopatias/cirurgia , Lesão Pulmonar/etiologia , Lesão Pulmonar/cirurgia , Estudos Retrospectivos , Traumatismos Torácicos/complicações , Traumatismos Torácicos/cirurgia , Ferimentos não Penetrantes/complicações , Ferimentos não Penetrantes/cirurgiaRESUMO
A kinetic model is proposed to describe the key features of development of an acute viral infection, accumulation of antibodies, and immune response in the human body. The general features of immune system stimulation by thermoheliox are described. The model can be used for developing the basis for the application of thermoheliox in the treatment of patients affected by coronavirus.
RESUMO
Many natural substances exhibit anti-inflammatory activity and considerable potential in prophylaxis and treatment of allergies. Knowing exact molecular targets, which is required for developing these as medicinal products, is often challenging for multicomponent compositions. In the present study we examined novel polyphenolic substance, a water-soluble fraction of wood lignin (laboratory code BP-Cx-1). In our previous study, a number of polyphenolic components of BP-Cx-1 (flavonoids, sapogenins, phenanthrenes etc.) were identified as the major carriers of biological activity of BP-Cx drug family, and several molecular targets involved in cancer and/or inflammation signaling pathways were proposed based on the results of the in vitro and in silico screening studies. In the present study, half maximal inhibitory concentration (IC50) of BP-Cx-1 was established with a radioligand method and a range of IC50 values between 22.8 and 40.3 µg/ml were obtained for adenosine receptors A1, A2A and prostaglandin receptors EP2, IP (PGI2). IC50 for serotonin 5-HT1 and for glucocorticoid GR receptors were 3.0 µg/ml and 12.6 µg/ml, respectively, both being within the range of BP-Cx-1 concentrations achievable in in vivo models. Further, distribution of [3H] labelled BP-Cx-1 in NIH3T3 murine fibroblasts and MCF7/R carcinoma cells was studied with autoradiography. [3H]-BP-Cx-1 (visualized as silver grains produced by tritium beta particles) was mainly localized along the cell membrane, in the perinuclear region and in the nucleus, suggesting ability of BP-Cx-1 to enter cells and bind to membrane or cytosol receptors. In our experiment, we observed the effect of BP-Cx-1 on maturation of dendritic cells (DCs): downregulation of expression of the lipid-presentation molecule CD1a, co-stimulatory molecules CD80, CD83 and CD 40, decreased production of pro-inflammatory cytokines IL-4 and TNF-α and increased production of anti-inflammatory cytokine IL-10. It is hypothesized that [3H]-BP-Cx-1 detectable in the nucleus is part of the activated GR complex, known to be involved in regulation of transcription of genes responsible for the anti-inflammatory response. Based on IC50, cell distribution data and results of the experiment with DCs it is suggested that the in vivo effects of BP-Cx-1 are mediated via GR and 5-HT1 receptors thus promoting development of tolerogenic effector function in dendritic cells.
Assuntos
Células Dendríticas , Lignina , Animais , Citocinas , Camundongos , Células NIH 3T3 , ÁguaRESUMO
A kinetic model of the development of acute viral infection is proposed and the dynamic behavior of key variables, including the concentrations of viral particles, infected cells, and pathogenic microorganisms, is described. The change in the hydrogen ion concentration in the lungs and pH dependence of the activity of carbonic anhydrase, a key respiration enzyme, are critical factors. An acute bifurcation transition determining either the life or collapse of the system is demonstrated. The transition is associated with exponential increase in the concentrations of participants in the process and with functioning of the key enzyme, carbonic anhydrase. A physicochemical interpretation is given for the therapeutic effect of temperature rise and potential therapeutic effect of "thermoheliox", that is, breathing by heated helium-oxygen mixture.
RESUMO
In the framework of the kinetic model, the functioning of the cholinergic synapse is considered. The results of mathematical modeling of changes in the level of acetylcholine, induced pH impulse, the influence of the frequency of impulse transmission and inhibition of acetylcholinesterase are presented. Physicochemical explanation for a number of important physiological phenomena, such as neuromuscular paralysis, the molecular mechanism of neurological memory, and actions of nerve poisons and toxins, is given.
Assuntos
Acetilcolina/química , Acetilcolinesterase/metabolismo , Encéfalo/fisiologia , Colinérgicos/química , Junção Neuromuscular/metabolismo , Sinapses/fisiologia , Acetilcolina/metabolismo , Colinérgicos/metabolismo , Humanos , Cinética , Modelos Teóricos , Toxinas Biológicas/metabolismoRESUMO
A kinetic model describing the dynamics of synaptic "discharge" taking into account the kinetics of the injection of the neurotransmitter into the synaptic cleft, the pH-dependence of the catalytic activity of the enzyme, and diffusion withdrawal of protons is proposed. The model provides a physicochemical explanation for a number of important physiological phenomena, such as the neuromuscular paralysis, the molecular mechanism of neurological memory, and the effect of some neurotoxins and drugs.
Assuntos
Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Receptores Colinérgicos/metabolismo , Sinapses/metabolismo , Ácido Acético/química , Acetilcolina/metabolismo , Acetilcolinesterase/metabolismo , Encéfalo/efeitos dos fármacos , Colina/química , Colinérgicos/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Cinética , Junção Neuromuscular , Neurônios/metabolismo , Neurotoxinas/metabolismo , Neurotransmissores/farmacologia , Praguicidas , Prótons , Receptores Colinérgicos/efeitos dos fármacos , Sinapses/efeitos dos fármacosRESUMO
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
We studied the dynamics of respiratory function in rats during intratracheal poisoning with diisopropyl fluorophosphate and pentylenetetrazole in doses corresponding to the LD50 in humans. The maximum of external respiration impairment was recorded in 30 min after poisoning. Administration of diazepam and atropine both separately and in combination during the development of the first signs of poisoning did not significantly affect the respiration parameters, but reduced the incidence of seizures and contributed to a decrease in the rate of animal death. Intratracheal administration of cholinolytic, ß2-adrenomimetic, or glutamate receptors antagonist promoted correction of the respiratory function. It was found that the maximum therapeutic effect in case of diisopropyl fluorophosphates poisoning was achieved after intratracheal administration of ipratropium bromide (0.086 mg/kg), salbutamol (0.086 mg/kg), and MK-801 (0.1 mg/kg), while in case of pentylenetetrazole poisoning, intratracheal administration of ipratropium bromide (0.086 mg/kg) was most effective.