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001-es BibID:	BIBFORM028538
Első szerző:	Gilad, Eli
Cím:	Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages : role of inhibition of NFkappaB activation / Eli Gilad, Hector R. Wong, Basilia Zingarelli, László Virág, Michael O'Connor, Andrew L. Salzman, Csaba Szabó
Dátum:	1998
ISSN:	0892-6638
Megjegyzések:	The role of melatonin as an immunomodulator is well established. Recent reports showed that melatonin exerts protective effects in septic and hemorrhagic shock and in inflammation. The expression of the inducible isoform of nitric oxide synthase (iNOS) makes an important contribution to the pathophysiology of shock and inflammation. We studied, in cultured murine macrophages, the role of melatonin in the regulation of the expression of iNOS and defined the mode of melatonin's action. Our results show that melatonin, at 1 microM-1 mM, decreased the production of nitrite/nitrate (the breakdown products of NO) as well as the production of 6-keto-prostaglandin F1alpha (the major stable breakdown product of prostacyclin) in macrophages stimulated with bacterial lipopolysaccharide (10 microg/ml). We observed that melatonin reduces iNOS steady-state mRNA levels and iNOS protein expression in the same concentration range (1 microM-1 mM). Melatonin, up to 10 mM, exerted only a slight direct inhibitory effect on iNOS activity. Using iNOS promoter-luciferase constructs, we found that melatonin inhibits iNOS promoter activation. Inhibition of iNOS expression was associated with inhibition of activation of the transcription factor nuclear factor kappa B (NFkappaB). We conclude that melatonin inhibits NO production in immunostimulated macrophages mainly by inhibiting the expression of iNOS. This is due to inhibition of iNOS transcription, in part through inhibition of NFkappaB activation. Inhibition of iNOS-derived NO production by melatonin may contribute to the anti-inflammatory effects of this pineal secretory product.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban antioxidants scavengers inflammation gene expression LPS mesangial cells külföldön készült közlemény
Megjelenés:	Faseb Journal 12 : 9 (1998), p. 685-693. -
További szerzők:	Wong, Hector R. Zingarelli, Basilia Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) O'Connor, Michael Salzman, Andrew L. Szabó Csaba (1967-) (orvos)
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM030075
Első szerző:	Szabó Csaba (orvos)
Cím:	Role of poly(ADP-ribose) synthetase in the peroxynitrite- and nitric oxide-induced cytoxicity : studies in a PARS knockout fibroblast cell line / Szabo C., Virág L., Zingarelli B., Scott G. S., Cuzzocrea S., O'Connor M., Salzman A. L.
Dátum:	1998
Tárgyszavak:	Orvostudományok Elméleti orvostudományok könyvfejezet
Megjelenés:	The biology of nitric oxide. Vol. 6. / eds. Moncada S., Toda N., Maeda H., Higgs E. A. - p. 279
További szerzők:	Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Zingarelli, Basilia Scott, Gwen S. Cuzzocrea, Salvatore O'Connor, Michael Salzman, Andrew L.
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001-es BibID:	BIBFORM028456
Első szerző:	Szabó Csaba (orvos)
Cím:	Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase / Csaba Szabó, László Virág, Salvatore Cuzzocrea, Gwen S. Scott, Paul Hake, Michael P. O'Connor, Basilia Zingarelli, Andrew Salzman, Ernest Kun
Dátum:	1998
ISSN:	0027-8424
Megjegyzések:	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 knockout 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 arthritis in vivo. Exposure of embryonic fibroblasts from the PARS+/+ animals to peroxynitrite caused DNA single-stand breakage and PARS activation and caused an acute suppression of mitochondrial respiration. INH2BP protected the PARS+/+ cells against the suppression of mitochondrial respiration in response to peroxynitrite (50-100 microM). Similarly to PARS inhibition with INH2BP, the PARS-/- cells were protected against peroxynitrite-induced injury. The protection against cellular injury by 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 treatment 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 histological status 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.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban nitric oxide superoxide inflammation DNA single-strand break inducible nitric-oxide synthase külföldön készült közlemény
Megjelenés:	Proceedings of The National Academy Of Sciences of The United States Of America 95 : 7 (1998), p. 3867-3872. -
További szerzők:	Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Cuzzocrea, Salvatore Scott, Gwen S. Hake, Paul O'Connor, Michael Zingarelli, Basilia Salzman, Andrew L. Kun, Ernest
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM028415
Első szerző:	Virág László (biokémikus, sejtbiológus, farmakológus)
Cím:	Requirement of intracellular calcium mobilization for peroxynitrite-induced poly(ADP-ribose) synthetase activation and cytotoxicity / László Virág, Gwen S. Scott, Péter Antal-Szalmás, Michael O'Connor, Hiroshi Ohshima, Csaba Szabó
Dátum:	1999
ISSN:	0026-895X
Megjegyzések:	Peroxynitrite is a cytotoxic oxidant produced during shock, ischemia reperfusion, and inflammation. The cellular events mediating the cytotoxic effect of peroxynitrite include activation of poly(ADP-ribose) synthetase, inhibition of mitochondrial respiration, and activation of caspase-3. The aim of the present study was to investigate the role of intracellular calcium mobilization in the necrotic and apoptotic cell death induced by peroxynitrite. Peroxynitrite, in a low, pathophysiologically relevant concentration (20 microM), induces rapid (1 to 3 min) Ca(2+) mobilization in thymocytes. Inhibition of this early calcium signaling by cell-permeable Ca(2+) chelators [EGTA-acetoxymethyl ester (AM), 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM (BAPTA-AM), 8-amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N , N',N'-tetraacetic acid-tetra-AM] abolished cytotoxicity as measured by propidium iodide uptake. Intracellular Ca(2+) chelators also inhibited DNA single-strand breakage and activation of poly(ADP-ribose) synthase (PARS), which is a major mediator of cell necrosis in the current model. Intracellular Ca(2+) chelators also protected PARS-deficient thymocytes from peroxynitrite cytotoxicity, providing evidence for a PARS-independent, Ca(2+)-dependent cytotoxic pathway. Chelation of intracellular Ca(2+) blocked the peroxynitrite-induced decrease of mitochondrial membrane potential, secondary superoxide production, and mitochondrial membrane damage. Peroxynitrite-induced internucleosomal DNA cleavage was increased on BAPTA-AM pretreatment in the wild-type cells but decreased in the PARS-deficient cells. Two other apoptotic parameters (phosphatidylserine exposure and caspase 3 activation) were inhibited by BAPTA-AM in both the wild-type and the PARS-deficient thymocytes. Our findings provide evidence for the pivotal role of an early Ca(2+) signaling in peroxynitrite cytotoxicity.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban egyetemen (Magyarországon) készült közlemény
Megjelenés:	Molecular Pharmacology. - 56 : 4 (1999), p. 824-833. -
További szerzők:	Scott, Gwen S. Antal-Szalmás Péter (1968-) (laboratóriumi szakorvos) O'Connor, Michael Ohshima, Hiroshi Szabó Csaba (1967-) (orvos)
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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