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Titolo:
PROTECTION AGAINST PEROXYNITRITE-INDUCED FIBROBLAST INJURY AND ARTHRITIS DEVELOPMENT BY INHIBITION OF POLY(ADP-RIBOSE) SYNTHASE
Autore:
SZABO C; VIRAG L; CUZZOCREA S; SCOTT GS; HAKE P; OCONNOR MP; ZINGARELLI B; SALZMAN A; KUN E;
Indirizzi:
CHILDRENS HOSP,MED CTR,DIV CRIT CARE,3333 BURNET AVE CINCINNATI OH 45229 SAN FRANCISCO STATE UNIV,ROMBERG TIBURON CTR,OCTAMER RES FDN,LAB ENVIRONM TOXICOL & CHEM TIBURON CA 94920
Titolo Testata:
Proceedings of the National Academy of Sciences of the United Statesof America
fascicolo: 7, volume: 95, anno: 1998,
pagine: 3867 - 3872
SICI:
0027-8424(1998)95:7<3867:PAPFIA>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
DNA STRAND BREAKAGE; POLY-ADP RIBOSYLTRANSFERASE; ISCHEMIA-REPERFUSION INJURY; CELLULAR-ENERGY DEPLETION; NITRIC-OXIDE; CELLS; ACTIVATION; MECHANISMS; INFLAMMATION; TRANSFERASE;
Keywords:
NITRIC OXIDE; SUPEROXIDE; INFLAMMATION; INDUCIBLE NITRIC-OXIDE SYNTHASE; DNA SINGLE-STRAND BREAK;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
35
Recensione:
Indirizzi per estratti:
Citazione:
C. Szabo et al., "PROTECTION AGAINST PEROXYNITRITE-INDUCED FIBROBLAST INJURY AND ARTHRITIS DEVELOPMENT BY INHIBITION OF POLY(ADP-RIBOSE) SYNTHASE", Proceedings of the National Academy of Sciences of the United Statesof America, 95(7), 1998, pp. 3867-3872

Abstract

Peroxynitrite, a cytotoxic oxidant formed from nitric oxide (NO) and superoxide, induces DNA strand breakage, which activates the nuclear enzyme poly(ADP-ribose) synthase (PARS; EC 2.4.2.30), The cellular function of PARS was determined in fibroblast lines from PARS knock; out animals (PARS(-/-)) and corresponding wild type animals (PARS(+/+)), with the aid of the lipophilic PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP). We investigated the role of PARS in peroxynitrite-induced fibroblast injury in vitro and also in the development of arthritisin vivo. Exposure of embryonic fibroblasts from the PARS(+/+) animalsto peroxynitrite caused DNA single-stand breakage and PARS activationand caused an acute suppression of mitochondrial respiration, INH2BP protected the PARS(+/+) cells against the suppression of mitochondrialrespiration in response to peroxynitrite (50-100 mu M). Similarly to PARS inhibition with INH2BP, the PARS(-/-) cells were protected against peroxynitrite-induced injury, The protection against cellular injuryby PARS(-/-) phenotype or INH2BP waned when cells were challenged with higher concentrations of the oxidant, Inhibition of PARS by INH2BP or by PARS(-/-) phenotype reduced inducible nitric-oxide synthase (iNOS; EC 1.14.13.39) mRNA levels and inhibited production of NO in immunostimulated cells, INH2BP had no peroxynitrite scavenging or hydroxyl radical scavenging effects, and it exerted no additional (nonspecific) effects in the PARS(-/-) cells, In collagen-induced arthritis, significant staining for nitrotyrosine, a marker of peroxynitrite formation, was found in the inflamed joints, Oral treat ment with INH2BP (0.5 g/kg, daily), starting at the onset of arthritis (day 25), delayed the development of the clinical signs at days 26-35 and improved histologicalstatus in the knee and paw, Our data demonstrate that deletion of PARS by genetic manipulation or pharmacological inhibition of PARS protects against oxidant-induced cellular injury in vitro and exhibits anti-inflammatory effects in vivo.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 14:49:08