| Poly(ADP-ribose) polymerase-1: a novel therapeutic target in necrotizing enterocolitis. | |
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MedLine Citation:
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PMID: 21399558 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of infancy, afflicting 11% of infants born 22-28 wk GA. Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production, protein oxidation, and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide (NAD+) as a substrate. However, in the presence of severe oxidative stress and DNA damage, PARP-1 overactivation may ensue, depleting cells of NAD+ and ATP, killing them by metabolic catastrophe. Here, we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked PARP-1 expression and that administration of a PARP-1 inhibitor (nicotinamide) attenuates intestinal injury in a newborn rat model of NEC. In this model, 56% of control pups developed NEC (any stage) versus 14% of pups receiving nicotinamide. Forty-four percent of control pups developed high-grade NEC (grades 3-4), whereas only 7% of pups receiving nicotinamide developed high-grade NEC. Nicotinamide treatment protects pups against intestinal injury incurred in the newborn rat NEC model. We speculate that PARP-1 overactivation in NEC may drive mucosal cell death in this disease and that PARP-1 may be a novel therapeutic target in NEC. |
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Authors:
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Peter J Giannone; Alicia A Alcamo; Brandon L Schanbacher; Craig A Nankervis; Gail E Besner; John A Bauer |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Pediatric research Volume: 70 ISSN: 1530-0447 ISO Abbreviation: Pediatr. Res. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-09 Completed Date: 2011-10-07 Revised Date: 2012-09-19 |
Medline Journal Info:
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Nlm Unique ID: 0100714 Medline TA: Pediatr Res Country: United States |
Other Details:
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Languages: eng Pagination: 67-71 Citation Subset: IM |
Affiliation:
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Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA. peter.giannone@nationwidechildrens.org |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Analysis of Variance Animals Animals, Newborn Cell Death / drug effects Disease Models, Animal Enterocolitis, Necrotizing / drug therapy*, enzymology, pathology Enzyme Activation Enzyme Inhibitors / pharmacology* Humans Infant, Newborn Intestinal Mucosa / drug effects*, enzymology, pathology Intestines / drug effects*, enzymology, pathology Niacinamide / pharmacology* Nitric Oxide / metabolism Nitric Oxide Synthase Type II / antagonists & inhibitors, metabolism Poly(ADP-ribose) Polymerases / antagonists & inhibitors*, metabolism Rats Rats, Sprague-Dawley Tyrosine / analogs & derivatives, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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1K23DK078909/DK/NIDDK NIH HHS; K23 DK078909/DK/NIDDK NIH HHS; K23 DK078909-01A1/DK/NIDDK NIH HHS; K23 DK078909-01A1S1/DK/NIDDK NIH HHS; K23 DK078909-02/DK/NIDDK NIH HHS; K23 DK078909-03/DK/NIDDK NIH HHS; K23 DK078909-05/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 10102-43-9/Nitric Oxide; 3604-79-3/3-nitrotyrosine; 55520-40-6/Tyrosine; 98-92-0/Niacinamide; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nos2 protein, rat; EC 2.4.2.30/Adprt protein, rat; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases |
| Comments/Corrections | |
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