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1.

001-es BibID:BIBFORM028393
Első szerző:Scott, Gwen S.
Cím:Role of poly(ADP-ribose) synthetase activation in the development of experimental allergic encephalomyelitis / G. S. Scott, P. Hake, R. B. Kean, L. Virág, Cs. Szabó, D. C. Hooper
Dátum:2001
ISSN:0165-5728
Megjegyzések:Peroxynitrite formation has been demonstrated during experimental allergic encephalomyelitis (EAE). Furthermore, peroxynitrite has been identified as an activator of poly(ADP-ribose) synthetase (PARS), an enzyme implicated in neurotoxicity. In the current study, we examined the role of PARS activation in the development of EAE. Administration of the PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) delayed the onset of EAE and reduced the incidence and severity of disease signs. Moreover, drug treatment lowered iNOS activity and decreased cell infiltration in cervical spinal tissues from EAE-sensitized animals. To conclude, the results of the present investigation suggest that PARS activity may contribute to the pathogenesis of EAE.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
experimental allergic encephalomyelitis
poly(ADP-ribose) synthase
peroxynitrite
inflammation
blood-brain barrier
külföldön készült közlemény
Megjelenés:Journal of Neuroimmunology 117 : 1-2 (2001), p. 78-86. -
További szerzők:Hake, Paul Kean, R. B. Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Szabó Csaba (1967-) (orvos) Hooper, D. Craig
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2.

001-es BibID:BIBFORM028374
Első szerző:Scott, Gwen S.
Cím:Peroxynitrite-induced oligodendrocyte toxicity is not dependent on poly(ADP-ribose) polymerase activation / Gwen S. Scott, Laszlo Virág, Csaba Szabó, D. Craig Hooper
Dátum:2003
ISSN:0894-1491
Megjegyzések:Oligodendrocyte loss is a characteristic feature of several CNS disorders, including multiple sclerosis (MS) and spinal cord injury. However, the mechanisms responsible for oligodendrocyte destruction remain undefined. As recent studies have implicated peroxynitrite in the pathogenesis of both spinal cord injury and MS, we have examined whether peroxynitrite may mediate at least some of the oligodendrocyte damage and demyelination observed in these conditions. Primary rat oligodendrocytes were exposed to authentic peroxynitrite in vitro and assessed for cytotoxicity. Mitochondrial function, measured by the reduction of MTT to formazan, and mitochondrial membrane potential were used as indicators of cell viability. Cell death was quantitated by measuring either the release of lactate dehydrogenase from, or the uptake of propidium iodide into, damaged and dying cells. Peroxynitrite dose-dependently reduced the viability of primary oligodendrocytes and induced cell death. Furthermore, peroxynitrite significantly increased DNA strand breakage and the activity of poly(ADP-ribose) polymerase (PARP) in oligodendrocyte cultures. To identify whether PARP activation plays a role in peroxynitrite-induced oligodendrocyte toxicity, we examined the effects of the PARP inhibitors 3-aminobenzamide (3AB) and 5-iodo-6-amino-1,2-benzopyrone (INH(2)BP) on mitochondrial function and cell death in oligodendrocytes. The presence of 3AB and INH(2)BP did not protect oligodendrocytes from peroxynitrite-induced cytotoxicity. However, both compounds significantly reduced PARP activity in these cells. Primary oligodendrocytes generated from PARP-deficient mice were also highly susceptible to peroxynitrite-induced cell death. Therefore, our results show that peroxynitrite exerts cytotoxic effects on oligodendrocytes in vitro independently of PARP activation.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
free radicals
necrosis
demyelination
multiple sclerosis
spinal cord injury
egyetemen (Magyarországon) készült közlemény
Megjelenés:Glia 41 : 2 (2003), p. 105-116. -
További szerzők:Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Szabó Csaba (1967-) (orvos) Hooper, D. Craig
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DOI
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3.

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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4.

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
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5.

001-es BibID:BIBFORM028455
Első szerző:Szabó Csaba (orvos)
Cím:Suppression of macrophage inflammatory protein (MIP)-1alpha production and collagen-induced arthritis by adenosine receptor agonists / Csaba Szabó, Gwen S. Scott, László Virág, Greg Egnaczyk, Andrew L. Salzman, Thomas P. Shanley, György Haskó
Dátum:1998
ISSN:0007-1188
Megjegyzések:1. Ligands of the various adenosine receptor subtypes modulate the production of pro-and anti-inflammatory cytokines. Here we evaluated the effect of adenosine and various ligands of the adenosine receptor subtypes (A1, A2, A3) on the chemokine macrophage inflammatory protein (MIP) 1alpha production in immunostimulated RAW macrophages in vitro. Furthermore, we studied whether a selected A3 adenosine receptor agonist inhibits MIP-1alpha production and affects the course of inflammation in collagen-induced arthritis. 2. In the cultured macrophages, the A3 receptor agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA), and, less potently, the A2 receptor agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethyl-carboxamidoadenosine (CGS; 1-200 micro) dose-dependently suppressed the production of MIP-1alpha. The selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 1-200 microM) was ineffective, and adenosine was a weak inhibitor. The inhibition of MIP-1alpha production by the A3 and A2 agonist was associated with suppression of its steady-state mRNA levels. 3. Based on the in vitro data, we concluded that activation of A3, and to a lesser extent A2 adenosine receptors suppresses MIP-1alpha expression. Since IB-MECA was the most potent inhibitor of MIP-1alpha expression, we next investigated whether it affects the production of other pro-inflammatory mediators. We observed that IB-MECA (1-300 microM) inhibited, in a dose-dependent manner, the production of IL-12, IL-6, and, to a lesser extent, nitric oxide in the immunostimulated cultured macrophages. 4. Since MIP-alpha is a chemokine which enhances neutrophil recruitment into inflammatory sites, we investigated whether the A3 agonist IB-MECA affects the course of inflammation, MIP-alpha production and the degree of neutrophil recruitment in arthritis. In a model of collagen-induced arthritis in mice, IB-MECA (0.5 mg/kg/day) reduced the severity of joint inflammation. IB-MECA inhibited the formation of MIP-1alpha, IL-12 and nitrotyrosine (an indicator of reactive nitrogen species) in the paws, and suppressed neutrophil infiltration. 5. We conclude that adenosine receptor agonists, most notably the A3 agonist IB-MECA suppress the production of MIP-alpha, and exert anti-inflammatory effects. Therefore, stimulation of adenosine receptor subtypes A3 and A2 may be a strategy worthy of further evaluation for the abrogation of acute or chronic inflammatory disorders.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
cytokines
arthritis
Xanthine
inflammation
külföldön készült közlemény
Megjelenés:British Journal Of Pharmacology 125 : 2 (1998), p. 379-387. -
További szerzők:Scott, Gwen S. Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Egnaczyk, Greg Salzman, Andrew L. Shanley, Thomas P. Haskó György (1967-) (biokémikus)
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6.

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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7.

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)
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