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Oxidative stress and alterations in the mammalian iron metabolism: A study on iron, inflammation, oxidative stress and neurodegeneration
Stockholm University, Faculty of Science, Department of Neurochemistry.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Iron is essential for all living organisms, from bacteria to man for a broad variety of biological functions, including oxygen transport and DNA synthesis. However, iron can also be toxic, due to its involvement in the formation of highly reactive oxygen species through Fenton chemistry. Iron has been suggested to be involved in the pathology of several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease as well as prion diseases, such as Creutzfeldt-Jakob’s disease and scrapie. The work presented in this thesis is linked to the intracellular iron metabolism, oxidative stress and inflammation.

Studies of iron metabolism in scrapie infected neuroblastoma N2a cells indicate that the scrapie infection is lowering the levels of both total iron and the labile iron pool. We also detected variations in the activities of iron regulatory protein 1 and 2 in the scrapie infected cells as compared to control cells. In addition, we have used DNA microarrays to compare the expression levels of mRNAs corresponding to several genes important for the antioxidative defense such as glutathione peroxidase and glutathione transferases between scrapie infected N2a and control cells. Our results suggest that the scrapie infected cells show differences in the expression of important genes involved in the cellular defense against oxidative stress as compared to control cells.

We have also studied alterations in the iron metabolism as a response to the bacterial toxin lipopolysaccharide (LPS). LPS treatment leads to a decrease of transferrin receptor protein (TfR) and to an increase of ferritin mRNA levels in N2a and BV-2 cells. The decrease of TfR expression is dependent on reactive oxygen species (ROS) and nitric oxide (NO) species, whereas the increase of ferritin mRNA is independent of both ROS and NO formation.

Finally, we have studied the effect of sulfide on iron regulation in RD4 cells. We detected a substantial sulfide-induced increase in the labile iron pool. We also measured markedly elevated levels of ferritin protein and a decrease in IRP2 protein, indicating that the released iron was made bioavailable.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi , 2007.
National Category
Neurosciences
Research subject
Neurochemistry and Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-7037ISBN: 978-91-7155-452-9 (print)OAI: oai:DiVA.org:su-7037DiVA: diva2:197515
Public defence
2007-09-21, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Opponent
Supervisors
Available from: 2007-08-30 Created: 2007-08-28Bibliographically approved
List of papers
1. Changed iron regulation in scrapie-infected neuroblastoma cells
Open this publication in new window or tab >>Changed iron regulation in scrapie-infected neuroblastoma cells
2005 In: Molecular brain research, ISSN 0169-328X, Vol. 133, no 2, 266-273 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24426 (URN)
Note
Part of urn:nbn:se:su:diva-7037Available from: 2007-08-30 Created: 2007-08-28Bibliographically approved
2. Microarray analysis of gene expression in scrapie-infected neuroblastoma cells: Implication of oxidative stress
Open this publication in new window or tab >>Microarray analysis of gene expression in scrapie-infected neuroblastoma cells: Implication of oxidative stress
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-24427 (URN)
Note
Part of urn:nbn:se:su:diva-7037Available from: 2007-08-30 Created: 2007-08-28 Last updated: 2010-01-13Bibliographically approved
3. NADPH oxidase inhibitor diphenyliodonium abolishes lipopolysacharide-induced down-regulation of transferrin receptor expression in N2a and BV-2 cells
Open this publication in new window or tab >>NADPH oxidase inhibitor diphenyliodonium abolishes lipopolysacharide-induced down-regulation of transferrin receptor expression in N2a and BV-2 cells
Show others...
2006 In: Journal of neuroscience research, ISSN 0360-4012, Vol. 84, no 5, 1047-1052 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24428 (URN)
Note
Part of urn:nbn:se:su:diva-7037Available from: 2007-08-30 Created: 2007-08-28Bibliographically approved
4. Sulfide increases labile iron pool in RD4 cells
Open this publication in new window or tab >>Sulfide increases labile iron pool in RD4 cells
2008 (English)In: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 21, no 2, 127-131 p.Article in journal (Refereed) Published
Abstract [en]

A linkage between sulfur and iron metabolism has been suggested since sulfide has the ability to release iron from ferritin in the presence of iron acceptors in vitro. Nevertheless, this linkage is still lacking evidence in vivo as well as in cellular models. In this study we have treated human RD4 skeletal muscle cells with sodium sulfide and measured the level of the labile iron pool (LIP) as well as the intracellular sulfide concentration. We have also detected the amounts of L-ferritin protein as well as the iron regulatory protein 2 (IRP2). The sulfide treatment resulted in a 100% increase in the amount of LIP after 1 and 2 h. We also found that the raise of the LIP levels was coupled to an elevation of the amounts of intracellular sulfide that increased by 60%. The bioavailability of the released iron was confirmed by a 100% increase in L-ferritin protein as well as a 60% decrease of the IRP2 protein levels. These results suggest that there is a linkage between sulfur metabolism and intracellular iron regulation in mammalian cells.

Place, publisher, year, edition, pages
Springer, 2008
Keyword
Sulfide - Ferritin - Labile iron pool - Iron regulation
National Category
Neurosciences
Identifiers
urn:nbn:se:su:diva-24429 (URN)10.1007/s10534-007-9099-2 (DOI)000254087000003 ()
Note
Part of urn:nbn:se:su:diva-7037Available from: 2007-08-30 Created: 2007-08-28 Last updated: 2011-01-18Bibliographically approved

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