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1.
Apoptosis ; 17(11): 1182-96, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22960730

RESUMEN

The potential for 60 Hz magnetic field (MF) preconditioning to protect heart-derived, H9c2 cultures from damage by simulated ischemia and reperfusion (I-R) was examined. The most effective MF exposure conditions (120 µT, 4-8 h) increased cell survival by 40-50 % over that seen with I-R alone. Potential targets of MF preconditioning were assessed by investigating the apoptosis-related drop in Bcl-2 levels and elevation of the specific activities of caspases 3, 8 and 9 produced by I-R. In response to MF exposure Bcl-2 levels rose 2 to 2.6-fold, and caspase specific activities fell 51-72 % from the values seen after I-R alone. Levels of Hsp's 25, 32 and 72 were examined in response to the MF, but showed little-to-no elevation beyond that produced by I-R. However, MF preconditioning produced a 77 % decrease in the I-R-induced translocation of phosphorylated Hsp25 (Hsp25-P) from the cytosolic to the nuclear-cytoskeletal cell fraction. This might protect by maintaining active Hsp25-P in the cytosol to function as a chaperone or to bind cytochrome c. Blocking Hsp25 phosphorylation with SB203580, an inhibitor of p38 MAPK, resulted in increases of 64 and 80 % in the respective specific activities of caspases 3 and 9 in cells subjected to I-R, and eliminated the MF-induced reduction in caspase 3 activity.


Asunto(s)
Apoptosis , Precondicionamiento Isquémico , Campos Magnéticos , Daño por Reperfusión Miocárdica/patología , Animales , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Citosol/metabolismo , Técnica del Anticuerpo Fluorescente , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas del Choque Térmico HSP72/metabolismo , Hemo Oxigenasa (Desciclizante)/metabolismo , Imidazoles/farmacología , Daño por Reperfusión Miocárdica/enzimología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Piridinas/farmacología , Ratas , Estrés Fisiológico/efectos de los fármacos
2.
Biochemistry ; 44(28): 9703-13, 2005 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-16008355

RESUMEN

The yeast ABC (ATP-binding cassette protein) multidrug transporter Pdr5p transports a broad spectrum of xenobiotic compounds, including antifungal and antitumor agents. Previously, we demonstrated that substrate size is an important factor in substrate-transporter interaction and that Pdr5p has at least three substrate-binding sites. In this study, we use a combination of whole cell transport assays and photoaffinity labeling of Pdr5p with [(125)I]iodoarylazidoprazosin in purified plasma membrane vesicles to study the behavior of two series of novel substrates: trityl (triphenylmethyl) and carbazole derivatives. The results indicate that site 2, defined initially by tritylimidazole efflux, requires at least a single hydrogen bond acceptor group (electron pair donor). In contrast, complete inhibition of rhodamine 6G efflux and [(125)I]iodoarylazidoprazosin binding at site 1 requires substrates with three electronegative groups. Carbazole and trityl substrates with two groups show saturating, incomplete inhibition at this site. This type of inhibition is frequently observed in bacterial multidrug-binding proteins that use a pocket with multiple binding sites. The presence of multiple sites with different requirements for substrate-Pdr5p interaction may explain the broad specificity of xenobiotic compounds transported by this protein.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/química , Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Xenobióticos/metabolismo , Antifúngicos/metabolismo , Antineoplásicos/metabolismo , Azidas/metabolismo , Sitios de Unión/efectos de los fármacos , Transporte Biológico/efectos de los fármacos , Carbazoles/química , Carbazoles/metabolismo , Clotrimazol/análogos & derivados , Clotrimazol/antagonistas & inhibidores , Clotrimazol/metabolismo , Reactivos de Enlaces Cruzados/metabolismo , Elipticinas/química , Elipticinas/metabolismo , Enlace de Hidrógeno/efectos de los fármacos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/química , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Prazosina/análogos & derivados , Prazosina/metabolismo , Rodaminas/antagonistas & inhibidores , Rodaminas/metabolismo , Especificidad por Sustrato/efectos de los fármacos , Tritio , Compuestos de Tritilo/química , Compuestos de Tritilo/metabolismo , Xenobióticos/química
3.
Curr Genet ; 41(1): 11-9, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12073095

RESUMEN

The yeast YRR1 gene was identified as a sequence encoding a protein that is related in structure to the Pdr1 and Pdr3 zinc cluster transcription factors. Dominant gain-of-function mutations were recovered that cause a multidrug resistance to inhibitors transported by the SNQ2 and YOR1 proteins. It was previously reported by others that null mutations in YRR1 cause hypersensitivity to these agents. In this study, evidence is presented for allelism between YRR1 and a previously identified locus: PDR2. Further characterization of hyperresistant PDR2 alleles and the initial characterization of a loss-of-function mutation created by a Tn3 insertion are described. Surprisingly, the PDR2-2-mediated hyperresistance to chloramphenicol, anisomycin, and cycloheximide requires the function of the UBP6 gene and at least one other gene product. The PDR2-2 allele eliminates the requirement for Pdr1 although, in our genetic backgrounds, elimination of Pdr2 function has little or no phenotypic effect.


Asunto(s)
Proteínas de Unión al ADN/genética , Farmacorresistencia Fúngica Múltiple/genética , Endopeptidasas/genética , Proteínas Fúngicas/genética , Proteínas de Saccharomyces cerevisiae , Transactivadores/genética , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Anisomicina/farmacología , Antifúngicos/farmacología , Secuencia de Bases , Cloranfenicol/farmacología , ADN de Hongos , Proteínas de Unión al ADN/metabolismo , Endopeptidasas/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fenotipo , Inhibidores de la Síntesis de la Proteína/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Transactivadores/metabolismo , Factores de Transcripción
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