RESUMEN
Nitric oxide (NO) mediates diverse physiological processes in living organisms. Small molecular NO donors usually lack stability and have a short half-life in human tissues, limiting the therapeutic application. The anionic tetranitrosyl iron complex with thiosulfate ligands (TNIC) is one of the most promising NO donors. This study shows that bovine serum albumin (BSA) can effectively stabilize the TNIC complex under aerobic (physiological) conditions, which contributes to its prolonged action as NO donor. Our results demonstrated that TNIC-BSA inhibits formation of TBARS - standard biomarker for the lipid peroxidation induced oxidative stress. Also, it was found that TNIC-BSA inhibits the catalytic activity of mitochondrial membrane-bound enzymes: cytochrome c oxidase and monoamine oxidase A. Together, these results demonstrate that, stabilization of TNIC with BSA opens up the possibility of its practical application in chemotherapy of socially significant diseases.
Asunto(s)
Hierro , Peroxidación de Lípido/efectos de los fármacos , Mitocondrias , Óxidos de Nitrógeno , Albúmina Sérica Bovina , Tiosulfatos , Animales , Encéfalo/citología , Hierro/química , Hierro/farmacología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Mitocondrias/metabolismo , Monoaminooxidasa/metabolismo , Óxidos de Nitrógeno/química , Óxidos de Nitrógeno/farmacología , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/farmacología , Tiosulfatos/química , Tiosulfatos/farmacologíaRESUMEN
It was shown for the first time that pentaamino acid derivative of fullerene C60 (potassium salt of fullerenylpenta-N-dihydroxytyrosine) affects three targets of type 2 diabetes mellitus. It competitively inhibits the enzymes aldose reductase and sorbitol dehydrogenase and also has an antiglycation effect on bovine serum albumin. The inhibition constants for these enzymes were calculated.
Asunto(s)
Aldehído Reductasa/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/química , L-Iditol 2-Deshidrogenasa/química , Aldehído Reductasa/metabolismo , Animales , Evaluación Preclínica de Medicamentos , L-Iditol 2-Deshidrogenasa/metabolismo , RatonesRESUMEN
The antioxidant and antiradical properties of the tetra nitrosyl iron complex with thiosulfate ligands (TNIC) were studied in vitro in mouse brain homogenates. It was found for the first time that TNIC is an effective antioxidant. The effect of TNIC on the catalytic activity of mitochondrial enzymes cytochrome c oxidase and monoamine oxidase A was studied. It was shown for the first time that TNIC is an inhibitor of the catalytic activity of cytochrome c oxidase and monoamine oxidase A in animal brain mitochondria in vitro.
Asunto(s)
Encéfalo/enzimología , Complejo IV de Transporte de Electrones , Hierro , Mitocondrias/enzimología , Proteínas Mitocondriales , Inhibidores de la Monoaminooxidasa , Óxidos de Nitrógeno , Tiosulfatos , Animales , Complejo IV de Transporte de Electrones/antagonistas & inhibidores , Complejo IV de Transporte de Electrones/metabolismo , Hierro/química , Hierro/farmacología , Ratones , Proteínas Mitocondriales/antagonistas & inhibidores , Proteínas Mitocondriales/metabolismo , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Óxidos de Nitrógeno/síntesis química , Óxidos de Nitrógeno/química , Óxidos de Nitrógeno/farmacología , Tiosulfatos/síntesis química , Tiosulfatos/química , Tiosulfatos/farmacologíaRESUMEN
We studied membranotropic properties of NO donor 2-nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine and its structural analog succinate 3-hydroxy-6-methyl-2-ethylpyridine (Mexidol). It was shown that the compounds under study are incorporated into modeled membranes and form long-living complexes with pyrene in the region of fatty acid tails of phospholipids. Luminol-amplified chemiluminescence analysis showed that both compounds exhibited antiradical activity and in a concentration of 0.1 mM reduced chemiluminescence intensity by more than 70%. 2-Nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine inhibited catalytic activity of monoamine oxidase A more efficiently than its structural analogue Mexidol.
Asunto(s)
Antioxidantes/farmacología , Membrana Celular/efectos de los fármacos , Radicales Libres/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Animales , Membrana Celular/enzimología , Membrana Celular/metabolismo , Corazón , Liposomas/química , Mediciones Luminiscentes , Masculino , Ratones , Ratones Endogámicos C57BL , Monoaminooxidasa/efectos de los fármacos , Monoaminooxidasa/metabolismo , Miocardio/química , Miocardio/metabolismo , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Picolinas/química , Picolinas/farmacologíaRESUMEN
Exogenous NO donor 3,3-bis-(nitroxymethyl)oxetane (NMO) was synthesized at the Institute for Problems of Chemical Physics (Russian Academy of Sciences). This compound was shown to inhibit Ca2+-ATPase isolated from normal muscular cells and tumor cells. Both hydrolytic and transport functions of the enzyme were inhibited under these conditions. These changes were probably related to changes in membrane structure caused by NO donor. Our results suggest that changes in intracellular Ca2+ concentration can modulate the formation of tumor drug resistance.
Asunto(s)
ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Retículo Endoplásmico/efectos de los fármacos , Éteres Cíclicos/farmacología , Éteres Cíclicos/farmacocinética , Donantes de Óxido Nítrico/farmacología , Retículo Sarcoplasmático/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Calcio/metabolismo , ATPasas Transportadoras de Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Retículo Endoplásmico/enzimología , Éteres Cíclicos/síntesis química , Hidrólisis/efectos de los fármacos , Leucemia P388/enzimología , Leucemia P388/patología , Ratones , Músculos/efectos de los fármacos , Músculos/enzimología , Pirenos , Conejos , Retículo Sarcoplasmático/enzimología , Espectrometría de FluorescenciaRESUMEN
A triazole group radiosensitizer AK-2123 is shown to inhibit considerably the growth of hepatic metastases induced by the intrasplenic injection of colon adenocarcinoma cells in syngenic mice. Even an extremely low dose of the drug exhibits the antimetastatic effect. It is shown that AK-2123 injected at therapeutic dose inhibits active transport of calcium ions by the (Ca2+-Mg2+)-dependent ATP-ase. The antimetastatic effect of AK-2123 is suggested to be related, at least partially, to the inhibition of the active calcium transport.
Asunto(s)
Adenocarcinoma/secundario , Calcio/metabolismo , Neoplasias Hepáticas/secundario , Metástasis de la Neoplasia/prevención & control , Fármacos Sensibilizantes a Radiaciones/farmacología , Triazoles/farmacología , Adenocarcinoma/patología , Animales , Transporte Biológico Activo , ATPasa de Ca(2+) y Mg(2+)/metabolismo , Neoplasias del Colon/patología , Femenino , Neoplasias Hepáticas/prevención & control , Ratones , Ratones Endogámicos BALB C , Trasplante de NeoplasiasRESUMEN
The modifying effects of the products of the equimolar addition Of DL-alanine and DL-alanyl-DL-alanine to fullerene C60 on the structure and permeability of the lipid bilayer of phosphatidylcholine liposomes has been studied using the luminescence probe technique. It is shown that these water soluble amino acid and dipeptide derivatives of fullerene (C60-AD) are quenchers of pyrene fluorescence and erythrosine phosphorescence of in both a water solution and liposomes. To study the permeability of the lipid bilayer a procedure based on the triplet probe technique has been developed. It has been found that the C60-AD derivatives under study are able to localize inside the artificial membrane, to penetrate into the liposomes through the lipid bilayer and to perform activated transmembrane transport of bivalent metal ions.