| Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity. | |
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MedLine Citation:
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PMID: 20811657 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP. We also investigated in fasted mice the critical role played by inhibition of caspase-dependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology. |
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Authors:
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Daniel James Antoine; Dominic P Williams; Anja Kipar; Hugh Laverty; B Kevin Park |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-27 |
Journal Detail:
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Title: Molecular medicine (Cambridge, Mass.) Volume: 16 ISSN: 1528-3658 ISO Abbreviation: Mol. Med. Publication Date: 2010 Nov-Dec |
Date Detail:
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Created Date: 2010-11-05 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9501023 Medline TA: Mol Med Country: United States |
Other Details:
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Languages: eng Pagination: 479-90 Citation Subset: IM |
Affiliation:
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Medical Research Council Centre for Drug Safety Science Department of Pharmacology and Therapeutics, Institute for Translational Medicine, University of Liverpool, Liverpool, UK. d.antoine@liv.ac.uk. |
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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G0700654//Medical Research Council |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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