Estudio de los mecanismos de muerte celular y de protección endógena inducidos por la toxicidad aguda del cobre
Copper (Cu) accumulation results toxic for cells, as observed in Wilson?s Disease. Nonetheless, the molecular mechanisms driving cell death upon intracellular Cu overload remain yet unveiled. Objective: to determine whether oxidative stress constitutes the driving force of Cu induced cell death, to...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2018
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2097 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2097.dir/2097.PDF |
| Aporte de: |
| Sumario: | Copper (Cu) accumulation results toxic for cells, as observed in Wilson?s Disease. Nonetheless, the molecular mechanisms driving cell death upon intracellular Cu overload remain yet unveiled. Objective: to determine whether oxidative stress constitutes the driving force of Cu induced cell death, to identify additional processes which may be involved and to comprehend the endogenous protection mechanism. Results: whereas Cu overload generates oxidative stress in rats and cultured cells, this held no correlation with cell sensitivity to the metal and the treatment with N-acetylcysteine did not protect the cells. The cell transcriptome showed an intense heat shock response in absence of an antioxidant response. The Cu2+/Cu1+ ions induced protein aggregation in a direct manner and metal toxicity is potentiated by pro-aggregating stimuli, but not by pro-oxidant stimuli. Meanwhile, glutathione resulted to be an endogenous protective molecule capable of inactivating Cu and preventing a broad spectrum of biochemical reactions, independently of its antioxidant features. Conclusion: Cu induced cell death is driven by altered proteostasis, whereas glutathione prevents this interaction. |
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