| Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples. | |
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MedLine Citation:
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PMID: 20967426 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions. |
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Authors:
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Douglas B Kell |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Review Date: 2010-08-17 |
Journal Detail:
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Title: Archives of toxicology Volume: 84 ISSN: 1432-0738 ISO Abbreviation: Arch. Toxicol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2011-01-28 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0417615 Medline TA: Arch Toxicol Country: Germany |
Other Details:
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Languages: eng Pagination: 825-89 Citation Subset: IM |
Affiliation:
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School of Chemistry and the Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester M1 7DN, UK. dbk@manchester.ac.uk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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metabolism* Anti-Bacterial Agents / antagonists & inhibitors Apoptosis / drug effects Humans Huntington Disease / metabolism* Hydrogen Peroxide / metabolism Hydroxyl Radical / metabolism Iron / metabolism*, toxicity Iron Chelating Agents / therapeutic use Ligands Oxidative Stress / drug effects Parkinson Disease / metabolism* Prion Diseases / metabolism Systems Biology |
| Grant Support | |
ID/Acronym/Agency:
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//Biotechnology and Biological Sciences Research Council; //Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Fenton's reagent; 0/Iron Chelating Agents; 0/Ligands; 3352-57-6/Hydroxyl Radical; 7439-89-6/Iron; 7722-84-1/Hydrogen Peroxide |
| Comments/Corrections | |
Comment In:
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Arch Toxicol. 2010 Nov;84(11):823-4
[PMID:
20941480
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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