RESUMO
The effect of a new pyridoxine derivative B6NO on doxorubicin cytotoxicity and Nrf2-dependent cellular processes in vitro was studied. Antioxidant B6NO enhances the cytotoxic effect of doxorubicin on tumor cells, which is associated with G2/M cell division arrest and an increase in activity of proapoptotic enzyme caspase-3. The antioxidant promotes intracellular accumulation and nuclear translocation of Nrf2 transcription factor in non-tumor and tumor cells. In non-tumor cells, B6NO increases the expression of antioxidant system proteins and reduces ROS generation in the presence of doxorubicin. In tumor cells, no activation of Nrf2-dependent processes occurs under the action of the antioxidant. Our findings demonstrate the prospect of further studies of pyridoxine derivatives as antioxidants to reduce adverse reactions during chemotherapy.
Assuntos
Antioxidantes , Apoptose , Caspase 3 , Doxorrubicina , Fator 2 Relacionado a NF-E2 , Piridoxina , Espécies Reativas de Oxigênio , Doxorrubicina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Humanos , Piridoxina/farmacologia , Piridoxina/análogos & derivados , Caspase 3/metabolismo , Caspase 3/genética , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacosRESUMO
Antioxidant activity of a pharmaceutical substance hypocard was compared with activity of nitromalic acid and well-known agents nicorandil and Mexidol. The ability of these substances to inhibit spontaneous and oxidant-induced LPO process in rat brain homogenate was analyzed. The mechanisms of these effects were studied. The antioxidant properties of hypocard manifested in the inhibition of Fe(II)-induced LPO were significantly more pronounced in comparison with Mexidol and nicorandil.
Assuntos
Antioxidantes/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Nicorandil/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Picolinas/farmacologia , RatosRESUMO
Iron-chelating activity of synthesized spirocyclic hydroxamic acids, their toxicity, and effects on mitochondrial function were studied using primary culture of cerebral cortical neurons from newborn rats. All tested compounds effectively chelated Fe(II) ions. Activity of spirocyclic hydroxamic acids more strictly depended on the structure their piperidine, but not imidazolidine fragment. All compounds were non-toxic for normal neuronal culture.
Assuntos
Ácidos Hidroxâmicos/farmacologia , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Animais Recém-Nascidos , Animais não Endogâmicos , Cátions Bivalentes , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ferrozina/química , Ácidos Hidroxâmicos/síntese química , Quelantes de Ferro/síntese química , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Neurônios/metabolismo , Cultura Primária de Células , Ratos , Compostos de Espiro/síntese química , Relação Estrutura-AtividadeRESUMO
In experimental animals with tumors it was studied antitumor activity of spirocyclic hydroxamic acids which could be classified as targeted agents as their target was enzyme histonedeacetylase, which was involved in the neoplastic process. The results showed that the hydroxamic acids were chemosensitizers for anticancer agents increasing their efficacy and enabling the researchers to reduce significantly the therapeutic dose. Also it was showed that hydroxamic acid, containing nitrogen mustard, was effective in the action on tumors with phenotype and genotype of multidrug resistance.
Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Ciclofosfamida/administração & dosagem , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/uso terapêutico , Leucemia P388/tratamento farmacológico , Metotrexato/administração & dosagemRESUMO
The neuroprotective action of hybrid structures based on fullerene C60 with attached proline amino acid has been studied. Hybrid structures contained natural antioxidant carnosine or addends with one or two nitrate groups. It has been shown that all studied compounds had antioxidant activity and decreased the concentration of malondialdehyde in homogenates of the rat brain. Compound 1, which contained the antioxidant carnosine, has been found to be the most effective antioxidant. All compounds except IV and V inhibited the activity of monoamine oxidase B, while compounds I-IV increased the activity of monoamine oxidase A. All investigated compounds inhibited glutamate-induced Ca2+ uptake into synaptosomes of the rat brain cortex. Compound III, containing two nitrate groups, has been found to be the most effective inhibitor. This compound caused a significant increase of the currents of AMPA receptors (AMPA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid).
Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Fulerenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/química , Encéfalo/citologia , Encéfalo/enzimologia , Encéfalo/metabolismo , Cálcio/metabolismo , Fulerenos/química , Técnicas In Vitro , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Estrutura Molecular , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/química , Ratos , Receptores de AMPA/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
The action of heterocyclic amides series (ethosuximide, phenytoin, primidone) on lipid peroxidation and membrane bound monoamine oxidases A and B under stress condition has been studied. The intraperitoneal injection of the drugs resulted in enhancement of SOD, decrease of brain malondialdehyde content and mitochondrial activity of monoamine oxidases A and B.
Assuntos
Anticonvulsivantes/farmacologia , Antioxidantes/farmacologia , Estresse Psicológico/metabolismo , Animais , Encéfalo/metabolismo , Etossuximida/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos de Membrana/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Monoaminoxidase/metabolismo , Fenitoína/farmacologia , Primidona/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
The dynamics of total protein biosynthesis and procollagen biosynthesis in skeletal muscle of injury tissues with the antioxidant BHT (dibunol) treatment and with common healing were studied. The obtained date indicate that the AO treatment reduce the rate of biosynthesis both the total proteins and procollagen at the 3th day of healing. Dibunol also considerably reduce the protein biosynthesis in adrenals and brake of corticosteroids biogenesis as measured by ESR-signals intensity of reduced adrenodoxine. AO treatment also reduce the protein biosynthesis in thymus, spleen and bone marrow. The lowering of functional activity of endocrine and immune systems indicate that the AO significantly inhibit the systemic reactions of organism induced by acute wound affect. It was suggested that as "primary mediator" of stress-reaction may be considered lipoperoxide radicals and decay products of lipohydroperoide.