Oxidatív stressz hatása a poli(ADP-ribóz) metabolizmusra és a kalcium homeosztázisra humán keratinocita és egér makrofág sejtvonalakban

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dc.contributor.advisorVirág, László
dc.contributor.authorBakondi, Edina
dc.contributor.departmentDE -- Orvos- és Egészségtudományi Centrum -- Általános Orvostudományi Kar -- Orvosi Vegytani Intézeten
dc.contributor.departmentElméleti orvostudományok doktori iskola
dc.date.accessioned2006-12-19T10:29:14Z
dc.date.available2006-12-19T10:29:14Z
dc.date.created2003
dc.date.defended2003-11-05
dc.description.abstractVarious diseases are characterized by oxidative stress, when overproduction of reactive oxygen- and nitrogen-centered intermediates (ROI, RNI) occurs. Reactive species such as peroxynitrite and hydrogen peroxide are capable of causing DNA breakage triggering the activation of the DNA nick sensor enzyme poly(ADP-ribose) polymerase (PARP-1). Activated PARP-1 cleaves NAD+ into nicotinamide and (ADP-ribose), then attaches ADP-ribose residues onto nuclear acceptor proteins, and synthesizes branching polymer chains. PARP-1 fulfills a great number of biological functions ranging from the regulation of DNA repair, chromatin structure, replication, transcription to facilitating telomere elongation. However, overactivation of PARP by ROI and RNI in inflammation, shock and reperfusion injury, leads to necrotic cell death mainly due to depletion of NAD+ and ATP. We have developed three applications: enzyme cytochemistry, enzyme histochemistry and cellular ELISA to detect the activation of poly(ADP-ribose) polymerase in oxidatively stressed cells. and tissues The assays are based on the use of biotinylated NAD+ as PARP substrate. Furthermore, we have investigated the role of poly(ADP-ribose) glycohydrolase (PARG), the main poly(ADP-ribose) catabolyzing enzyme in oxidative stress-induced cytotoxicity. We have found that inhibition of PARG by gallotannin (GT) provided significant cytoprotection to peroxynitrite/hydrogen peroxide treated HaCaT cells (decrease in LDH release, propidium iodide uptake and caspase-3 activation), inhibited depletion of cellular NAD+ pools and caused the accumulation of poly(ADP-ribose) and inhibition of cellular PARP activity. Moreover, we have investigated the possible role of intracellular Ca2+ mobilization and high cell density, in the regulation of sensitivity of HaCaT keratinocytes to oxidative stress-induced cytotoxicity. First we have demonstrated that peroxynitrite triggered an elevation in intracellular calcium levels. Treatment of cells with the cell permeable calcium chelator BAPTA-AM provided significant cytoprotection against peroxynitrite/hydrogen peroxide–induced cytotoxicity. We have also observed that differentiating confluent keratinocytes were highly resistant to oxidative stress. Our results support a crucial role of Ca2+ homeostasis, cell density and poly(ADP-ribose) metabolism in the regulation of oxidative stress-induced cytotoxicity.en
dc.description.degreePhDen
dc.format.extent64 pen
dc.format.extent250563 bytes
dc.format.extent146763 bytes
dc.format.extent2017138 bytes
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.identifier.opachttp://webpac.lib.unideb.hu:8082/WebPac/CorvinaWeb?action=cclfind&resultview=longlong&ccltext=idno+bibKLT00360993
dc.identifier.urihttp://hdl.handle.net/2437/445
dc.languagehunhu
dc.language.isohuen
dc.language.isoenen
dc.rightsno_restrictionen
dc.subject.disciplineElméleti orvostudományok
dc.subject.dspaceDEENK Témalista::Orvostudomány::Orvosi vegytanhu
dc.subject.meshOxidative Stressen
dc.subject.meshPoly Adenosine Diphosphate Ribose -- metabolismen
dc.subject.meshPoly(ADP-ribose)Polymerasesen
dc.subject.meshCell Deathen
dc.subject.meshCalciumen
dc.subject.sciencefieldOrvostudományok
dc.titleOxidatív stressz hatása a poli(ADP-ribóz) metabolizmusra és a kalcium homeosztázisra humán keratinocita és egér makrofág sejtvonalakbanen
dc.title.subtitlePh.D. értekezésen
dc.title.translatedAlterations in Poly(ADP-Ribose) Metabolism and Calcium Homeostasis in Oxidatively Stressed HaCaT and Mouse Macrophage Cell Linesen
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