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001-es BibID:BIBFORM040005
Első szerző:Liaudet, Lucas
Cím:Suppression of poly (ADP-ribose) polymerase activation by 3-aminobenzamide in a rat model of myocardial infarction : long term morphological and functional consequences / Liaudet, L., Szabó, É., Timashpolsky, L., Virág, L., Cziráki, A., Szabó, C.
Dátum:2001
ISSN:0007-1188
Megjegyzések:1. Recent studies demonstrated that inhibition or genetic inactivation of the enzyme poly (ADP-ribose) polymerase (PARP) is beneficial in myocardial reperfusion injury. PARP activation in the reperfused myocardium has been assumed, but not directly demonstrated. Furthermore, the issue whether pharmacological PARP inhibition affords long-term functional benefit in the reperfused myocardium has not been explored. These questions were addressed in the present study. 2. In a rat model of myocardial ischemia (1 h) and reperfusion (up to 24 h), there was a marked and significant activation of PARP in the ischemic borderzone, as determined by poly(ADP-ribose) (PAR) immunohistochemistry. PAR localized to the nuclei of myocytes and infiltrating mononuclear cells. In the core of the infarction, necrotic tissues and diffuse PAR staining were observed. PARP activation remained markedly detectable 24 h after reperfusion. The PARP inhibitor 3-aminobenzamide (20 mg kg(-1) intraperitoneally 10 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced the activation of the enzyme in myocytes. 3. 3-aminobenzamide significantly protected against myocardial morphological and functional alterations at 24 h post-reperfusion. Notably, infarct size was reduced, circulating creatine kinase activity was attenuated, and myocardial contractility (dP dt(-1)) was restored by 3-aminobenzamide. 4. Our results demonstrate a significant and prolonged activation of PARP in the reperfused myocardium, localizing to the necrotic area and the ischaemic borderzone. Furthermore, the studies demonstrate that PARP inhibition affords long-term beneficial morphological and functional effects in the reperfused myocardium. These data strengthen the notion that pharmacological PARP inhibition is a viable novel experimental approach for protection against myocardial reperfusion injury.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:British Journal Of Pharmacology. - 133 : 8 (2001), p. 1424-1430. -
További szerzők:Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Timashpolsky, Leonid Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Cziráki Attila Szabó Csaba
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2.

001-es BibID:BIBFORM090173
035-os BibID:(WoS)000611866700001 (Scopus)85099753663
Első szerző:Regdon Zsolt (biokémikus, molekuláris biológus)
Cím:High-Content Screening identifies inhibitors of oxidative stress-induced parthanatos : cytoprotective and anti-inflammatory effects of ciclopirox / Regdon Zsolt, Demény Máté A., Kovács Katalin, Hajnády Zoltán, Nagy-Pénzes Máté, Bakondi Edina, Kiss Alexandra, Hegedűs Csaba, Virág László
Dátum:2021
ISSN:0007-1188
Megjegyzések:Background and purpose: Excessive oxidative stress can induce poly (ADP-ribose) polymerase-1 (PARP1)-mediated, programmed necrotic cell death, termed parthanatos. Inhibition of parthanatos may be therapeutically beneficial in a wide array of diseases associated with tissue injury and inflammation. Our goal was to identify novel molecules inhibiting parthanatos. Experimental approach: A small library of 774 pharmacologically active compounds was screened in a Sytox green uptake assay which identified 20 hits that reduced hydrogen peroxide-induced parthanatos with an efficiency comparable to the benchmark PARP inhibitor, PJ34. Key results: Of these hits, two compounds, antifungal ciclopirox (CIP) and dopaminergic agonist apomorphine (AMO) inhibited PAR polymer synthesis. These two compounds prevented the binding of PARP1 to oxidatively damaged DNA but did not directly interfere with the interaction between DNA and PARP1. Both compounds inhibited mitochondrial superoxide and H2 O2 production and suppressed DNA breakage. Since H2 O2 -induced damage is dependent on Fe2+ -catalysed hydroxyl radical production (Fenton chemistry), we determined the iron chelation activity of the two test compounds and found that CIP and, to a lesser extent, AMO act as iron chelators. We also show that the Fe2+ chelation and indirect PARP inhibitory effects of CIP translate to anti-inflammatory actions as demonstrated in a mouse dermatitis model, where CIP reduced ear swelling, inflammatory cell recruitment, and poly (ADP-ribosyl)ation. Conclusion and implications: Our findings indicate that the antimycotic drug, CIP, acts as an iron chelator and thus targets an early event in hydrogen-peroxide-induced parthanatos. CIP has the potential to be repurposed as a cytoprotective and anti-inflammatory agent.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
cell death
cytoprotection
inflammation
oxidative stress
poly (ADP-ribose) polymerase 1
regulated necrosis
Megjelenés:British Journal Of Pharmacology. - 178 : 5 (2021), p. 1095-1113. -
További szerzők:Demény Máté Ágoston (1976-) (molekuláris biológus) Kovács Katalin (1978-) (biokémikus) Hajnády Zoltán (1991-) (biomérnök, biokémikus) Nagy-Pénzes Máté (1988-) (biokémikus) Bakondi Edina (1975-) (biokémikus, vegyész) Kiss Alexandra (1991-) (klinikai laboratóriumi kutató) Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
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3.

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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4.

001-es BibID:BIBFORM028422
Első szerző:Virág László (biokémikus, sejtbiológus, farmakológus)
Cím:Inhibition of poly(ADP-ribose) synthetase (PARS) and protection against peroxynitrite-induced cytotoxicity by zinc chelation / László Virág, Csaba Szabó
Dátum:1999
ISSN:0007-1188
Megjegyzések:Peroxynitrite, a potent oxidant formed by the reaction of nitric oxide and superoxide causes thymocyte necrosis, in part, via activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS). The cytotoxic PARS pathway initiated by DNA strand breaks and excessive PARS activation has been shown to deplete cellular energy pools, leading to cell necrosis. Here we have investigated the effect of tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) a heavy metal chelator on peroxynitrite-induced cytotoxicity. TPEN (10 microM) abolished cell death induced by authentic peroxynitrite (25 microM) and the peroxynitrite generating agent 3-morpholinosidnonimine (SIN-1, 250 microM). Preincubation of TPEN with equimolar Zn2+ but not Ca2+ or Mg2+ blocked the cytoprotective effect of the chelator. TPEN (10 microM) markedly reduced the peroxynitrite-induced decrease of mitochondrial transmembrane potential, secondary superoxide production and mitochondrial membrane damage, indicating that it acts proximal to mitochondrial alterations. Although TPEN (1 - 300 microM) did not scavenge peroxynitrite, it inhibited PARS activation in a dose-dependent manner. The cytoprotective effect of TPEN is only partly mediated via PARS inhibition, as the chelator also protected PARS-deficient thymocytes from peroxynitrite-induced death. While being cytoprotective against peroxynitrite-induced necrotic death, TPEN (10 microM), similar to other agents that inhibit PARS, enhanced apoptosis (at 5-6 h after exposure), as characterized by phosphatydilserine exposure, caspase activation and DNA fragmentation. In conclusion, the current data demonstrate that TPEN, most likely by zinc chelation, exerts protective effects against peroxynitrite-induced necrosis. Its effects are, in part, mediated by inhibition of PARS.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
peroxynitrite
TPEN
cytotoxicity
poly (ADP-ribose) synthetase
egyetemen (Magyarországon) készült közlemény
Megjelenés:British Journal Of Pharmacology. - 126 : 3 (1999), p. 769-777. -
További szerzők:Szabó Csaba (1967-) (orvos)
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