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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:	BIBFORM028440
Első szerző:	Virág László (biokémikus, sejtbiológus, farmakológus)
Cím:	Peroxynitrite-induced thymocyte apoptosis : the role of caspases and poly (ADP-ribose) synthetase (PARS) activation / L. Virág, G. S. Scott, S. Cuzzocrea, D. Marmer, A. L. Salzman, Cs. Szabó
Dátum:	1998
ISSN:	0019-2805
Megjegyzések:	The mechanisms by which immature thymocyte apoptosis is induced during negative selection are poorly defined. Reports demonstrated that cross-linking of T-cell receptor leads to stromal cell activation, expression of inducible nitric oxide synthase (iNOS) and, subsequently, to thymocyte apoptosis. Therefore we examined, whether NO directly or indirectly, through peroxynitrite formation, causes thymocyte apoptosis. Immuno-histochemical detection of nitrotyrosine revealed in vivo peroxynitrite formation in the thymi of naive mice. Nitrotyrosine, the footprint of peroxynitrite, was predominantly found in the corticomedullary junction and the medulla of naive mice. In the thymi of mice deficient in the inducible isoform of nitric oxide synthase, considerably less nitrotyrosine was found. Exposure of thymocytes in vitro to low concentrations (10 microM) of peroxynitrite led to apoptosis, whereas higher concentrations (50 microM) resulted in intense cell death with the characteristics of necrosis. We also investigated the effect of poly (ADP-ribose) synthetase (PARS) inhibition on thymocyte apoptosis. Using the PARS inhibitor 3-aminobenzamide (3-AB), or thymocytes from PARS-deficient animals, we established that PARS determines the fate of thymocyte death. Suppression of cellular ATP levels, and the cellular necrosis in response to peroxynitrite were prevented by PARS inhibition. Therefore, in the absence of PARS, cells are diverted towards the pathway of apoptotic cell death. Similar results were obtained with H2O2 treatment, while apoptosis induced by non-oxidative stimuli such as dexamethasone or anti-FAS antibody was unaffected by PARS inhibition. In conclusion, we propose that peroxynitrite-induced apoptosis may play a role in the process of thymocyte negative selection. Furthermore, we propose that the physiological role of PARS cleavage by apopain during apoptosis may serve as an energy-conserving step, enabling the cell to complete the process of apoptosis.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban külföldön készült közlemény
Megjelenés:	Immunology. - 94 : 3 (1998), p. 345-355. -
További szerzők:	Scott, Gwen S. Cuzzocrea, Salvatore Marmer, Daniel J. Salzman, Andrew L. Szabó Csaba (1967-) (orvos)
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM028438
Első szerző:	Zingarelli, Basilia
Cím:	Oxidation, tyrosine nitration and cytostasis induction in the absence of inducible nitric oxide synthase / Zingarelli B., Virág L., Szabó A., Cuzzocrea S., Salzman A. L., Szabó Cs.
Dátum:	1998
ISSN:	1107-3756
Megjegyzések:	In the present study, we evaluated the impact of the lack of the gene for inducible nitric oxide synthase (iNOS) on oxidation, tyrosine nitration and cytotoxicity reactions triggered by immunostimulation. In mice injected with E. coli endotoxin (bacterial lipopolysaccharide, LPS, 50 mg/kg i.p.), there was a significant increase in the degree of oxidation of dihydrorhodamine 123 to rhodamine 123. This response was attenuated by inhibition of NO biosynthesis with NG-methyl-L-arginine (L-NMA, 30 mg/kg i.p.). In mice lacking functional iNOS gene (iNOS knock-out mice), the degree of the LPS-induced, L-NMA inhibitable increase in dihydrorhodamine oxidation was decreased, but not completely abolished. LPS stimulation induced a marked increase in the immunoreactivity for nitrotyrosine (an indicator of peroxynitrite formation), as measured in the aorta and lung. An L-NMA inhibitable increase in nitrotyrosine staining induced by LPS was also observed in the tissues of the iNOS knockout animals. LPS treatment induced the appearance of DNA single strand breakage and a suppression of mitochondrial respiration in peritoneal macrophages ex vivo. A significant degree of LPS-induced DNA single strand breakage and suppression of mitochondrial respiration was still observed in the peritoneal macrophages obtained from the iNOS knockout animals. Macrophages from wild-type mice stimulated with LPS and interferon-gamma suppressed the proliferation of various target cells (P815 mastocytoma, L929 fibrosarcoma and embryonic lung fibroblast cell line): this effect was abolished by in vitro treatment with L-NMA (1 mM). Macrophages from the iNOS knockout animals exhibited a reduced degree of target cell cytostatic activity. The remainder of the cytostasis in iNOS knockout macrophages was abolished by preventing cell contact and neutralizing tumor necrosis factor á. The present results demonstrate that the lack of iNOS gene does not fully abolish oxidation, tyrosine nitration and cytostatic activity in response to immunostimulation. The current findings may have implications for the development of NO-based approaches for the experimental therapy of inflammation.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban egyetemen (Magyarországon) készült közlemény
Megjelenés:	International Journal Of Molecular Medicine 1 : 5 (1998), p. 787-795. -
További szerzők:	Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Szabó A. Cuzzocrea, Salvatore Salzman, Andrew L. Szabó Csaba (1967-) (orvos)
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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