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1.

001-es BibID:BIBFORM014259
Első szerző:Jagtap, Prakash
Cím:Novel phenanthridinone inhibitors of poly (adenosine 5'-diphosphate-ribose) synthetase: potent cytoprotective and antishock agents / Jagtap, P., Soriano, F. G., Virag, L., Liaudet, L., Mabley, J., Szabo, E., Hasko, G., Marton, A., Lorigados, C. B., Gallyas, F., Jr., Sumegi, B., Hoyt, D. G., Baloglu, E., VanDuzer, J., Salzman, A. L., Southan, G. J., Szabo, C.
Dátum:2002
ISSN:0090-3493 (Print)
Megjegyzések:To synthesize novel inhibitors of the nuclear enzyme poly(adenosine 5'-diphosphate [ADP]-ribose) synthetase (PARS), also known as poly(ADP-ribose) polymerase (PARP), and to test them in in vitro models of oxidant-induced cytotoxicity and in endotoxin and splanchnic occlusion-reperfusion-induced shock. DESIGN: Randomized, prospective laboratory study. SETTING: Research laboratory. SUBJECTS: Murine macrophages, thymocytes, and endothelial cells; Balb/c mice and Wistar rats. INTERVENTIONS: Macrophages and endothelial cells were treated with peroxynitrite and bleomycin to induce PARS activation, and thymocytes were treated with peroxynitrite to induce cell necrosis. Novel PARS inhibitors were synthesized and used to reduce PARS activation and to reverse cytotoxicity. Balb/c mice were subjected to splanchnic occlusion and reperfusion and were pretreated with various doses (1-10 mg/kg intraperitoneally) of PJ34, a selected, potent, water-soluble PARS inhibitor. The passage of fluorescein isothiocyanate-conjugated dextran (4 kDa) was analyzed in everted gut ileal sacs incubated ex vivo as an index of gut permeability. Wistar rats were subjected to Escherichia coli bacterial lipopolysaccharide (40 mg/kg intraperitoneally). PJ34 was also used at 10 mg/kg intraperitoneally, 1 hr before lipopolysaccharide or at 25 mg/kg intraperitoneally 1 hr after lipopolysaccharide treatment. Serum concentrations of indicators or multiple organ injury, concentrations of various proinflammatory mediators, and tissue concentrations of myeloperoxidase and malondialdehyde were measured. In addition, survival rates and vascular contractile and relaxant responses were recorded. MEASUREMENTS AND MAIN RESULTS: Appropriate modifications of the phenanthridinone core structure yielded significant increases in the potency of the compounds, both as PARS inhibitors and as cytoprotective agents. The compound N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) -N,N-dimethylacetamide (designated as PJ34) was one of the potent PARS inhibitors of the series, and it dose-dependently protected against thymocyte necrosis, with a half-maximal restoration of cell viability of 35 nM and complete protection at 200 nM. PARS activation also was visualized by immunohistochemistry and was dose-dependently suppressed by PJ34. The effect of PJ34 was dose-dependently reversed by excess nicotinamide adenine dinucleotide (oxidized). The PARS inhibitors dose-dependently suppressed proinflammatory cytokine and chemokine production and restored viability in immunostimulated macrophages. PJ34 was selected for the subsequent in vivo studies. PJ34 significantly protected against splanchnic reperfusion-induced intestinal hyperpermeability in the mouse. PJ34 reduced peak plasma concentrations of tumor necrosis factor-alpha, interleukin-1beta, and nitrite/nitrate in the plasma of lipopolysaccharide-treated rats. PJ34 ameliorated the lipopolysaccharide-induced increases in indexes of liver and kidney failure and concentrations of myeloperoxidase and malondialdehyde in the lung and gut. Lipopolysaccharide elicited vascular dysfunction, which was normalized by PJ34. Lipopolysaccharide-induced mortality was reduced by PJ34 (both pre- and posttreatment). CONCLUSIONS: The novel series of phenanthridinone PARS inhibitors have potent cytoprotective effects in vitro and significant protective effects in shock and reperfusion injury in rodent models in vivo.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Animals
Bleomycin/pharmacology
Cells, Cultured
*Cytoprotection
Dose-Response Relationship, Drug
Enzyme Activation
Enzyme Inhibitors/*pharmacology
külföldön készült közlemény
Interleukin-1/blood
Kidney/chemistry
Lipopolysaccharides/pharmacology
Lung/chemistry
Malondialdehyde/analysis
Mice
Mice, Inbred BALB C
Nitrates/blood
Nitrites/blood
Peroxidase/analysis
Peroxynitrous Acid/pharmacology
Phenanthrenes/*pharmacology
Poly(ADP-ribose) Polymerases/*antagonists & inhibitors
Rats
Rats, Wistar
Shock/*prevention & control
Tumor Necrosis Factor-alpha/analysis
Megjelenés:Critical Care Medicine. - 30 : 5 (2002), p. 1071-1082. -
További szerzők:Soriano, Francisco Garcia Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Liaudet, Lucas Mabley, Jon G. Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Haskó György (1967-) (biokémikus) Marton, A. Lorigados, Clara Batista Gallyas Ferenc Jr Sümegi Balázs Hoyt, Dale G. Baloglu, Erkan VanDuzer, John Salzman, Andrew L. Southan, Garry J. Szabó Csaba
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2.

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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3.

001-es BibID:BIBFORM014260
Első szerző:Liaudet, Lucas
Cím:Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase / Liaudet, L., Soriano, F. G., Szabo, E., Virag, L., Mabley, J. G., Salzman, A. L., Szabo, C.
Dátum:2000
ISSN:0027-8424 (Print)
Megjegyzések:Hemorrhagic shock (HS) and resuscitation leads to widespread production of oxidant species. Activation of the enzyme poly(ADP-ribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various disease conditions associated with oxidative stress. We tested the hypothesis whether PARP activation plays a role in the multiple organ dysfunction complicating HS and resuscitation in a murine model of HS and resuscitation by using mice genetically deficient in PARP (PARP(-/-)) and their wild-type littermates (PARP(+/+)). Animals were bled to a mean blood pressure of 45 mmHg (1 mmHg = 133 Pa) and resuscitated after 45 min with isotonic saline (2x volume of shed blood). There was a massive activation of PARP, detected by poly(ADP-ribose) immunohistochemistry, which localized to the areas of the most severe intestinal injury, i.e., the necrotic epithelial cells at the tip of the intestinal villi, and colocalized with tyrosine nitration, an index of peroxynitrite generation. Intestinal PARP activation resulted in gut hyperpermeability, which developed in PARP(+/+) but not PARP(-/-) mice. PARP(-/-) mice were also protected from the rapid decrease in blood pressure after resuscitation and showed an increased survival time, as well as reduced lung neutrophil sequestration. The beneficial effects of PARP suppression were not related to a modulation of the NO pathway nor to a modulation of signaling through IL-6, which similarly increased in both PARP(+/+) and PARP(-/-) mice exposed to HS. We propose that PARP activation and associated cell injury (necrosis) plays a crucial role in the intestinal injury, cardiovascular failure, and multiple organ damage associated with resuscitated HS.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Acetylcholine/pharmacology
külföldön készült közlemény
Animals
Aorta, Thoracic/drug effects/physiology/physiopathology
Blood Pressure
Blood Volume
Dinoprost/pharmacology
Enzyme Activation
*Hemodynamics
Intestinal Mucosa/enzymology/*pathology
Liver/enzymology/pathology
Male
Mice
Mice, Knockout
Muscle Contraction/drug effects
Muscle Relaxation/drug effects
Muscle, Smooth, Vascular/drug effects/physiology/*physiopathology
Peroxidase/metabolism
Poly(ADP-ribose) Polymerases/deficiency/genetics/*metabolism
Resuscitation
Shock, Hemorrhagic/*genetics/physiopathology/therapy
Sodium Chloride/therapeutic use
Tyrosine/analogs & derivatives/metabolism
Megjelenés:Proceedings of the National Academy of Sciences of the United States of America. - 97 : 18 (2000), p. 10203-10208. -
További szerzők:Soriano, Francisco Garcia Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Mabley, Jon G. Salzman, Andrew L. Szabó Csaba
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4.

001-es BibID:BIBFORM040009
Első szerző:Mabley, Jon G.
Cím:Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase / Mabley, J. G., Jagtap, P., Perretti, M., Getting, S. J., Salzman, A. L., Virág, L., Szabó, É., Soriano, F. G., Liaudet, L., Abdelkarim, G. E., Haskó, G., Marton, A., Southan, G. J., Szabó, C.
Dátum:2001
ISSN:1023-3830
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Inflammation Research. - 50 : 11 (2001), p. 561-569. -
További szerzők:Jagtap, Prakash Perretti, Mauro Getting, S. J. Salzman, Andrew L. Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Soriano, Francisco Garcia Liaudet, Lucas Abdelkarim, G. Haskó György (1967-) (biokémikus) Marton, A. Southan, Garry J. Szabó Csaba
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5.

001-es BibID:BIBFORM014262
Első szerző:Pacher Pál
Cím:The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes / Pacher, P., Liaudet, L., Soriano, F. G., Mabley, J. G., Szabo, E., Szabo, C.
Dátum:2002
ISSN:0012-1797 (Print)
Megjegyzések:Patients with diabetes exhibit a high incidence of diabetic cardiomyopathy and vascular complications, which underlie the development of retinopathy, nephropathy, and neuropathy and increase the risk of hypertension, stroke, and myocardial infarction. There is emerging evidence that the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) importantly contributes to the development of endothelial dysfunction in a streptozotocin-induced model of diabetes. We investigated the role of PARP activation in the pathogenesis of cardiac dysfunction in streptozotocin-induced and genetic (nonobese diabetic) models of diabetes in rats and mice. Development of diabetes was accompanied by hyperglycemia, cardiac PARP activation, a selective loss of endothelium-dependent vasodilation in the thoracic aorta, and an early diastolic dysfunction of the heart. Treatment with a novel potent phenanthridinone-based PARP inhibitor, PJ34, starting 1 week after the onset of diabetes, restored normal vascular responsiveness and significantly improved cardiac dysfunction, despite the persistence of severe hyperglycemia. The beneficial effect of PARP inhibition persisted even after several weeks of discontinuation of the treatment. Thus, PARP activation plays a central role in the pathogenesis of diabetic cardiovascular (cardiac as well as endothelial) dysfunction. PARP inhibitors may exert beneficial effects against the development of cardiovascular complications in diabetes.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Animals
külföldön készült közlemény
Diabetes Mellitus/genetics/*physiopathology
Diabetes Mellitus, Experimental/physiopathology
Endothelium, Vascular/*physiopathology
Enzyme Activation/physiology
Female
Heart/*physiopathology
Male
Mice
Mice, Inbred NOD
Myocardium/enzymology
Poly(ADP-ribose) Polymerases/*metabolism/physiology
Rats
Rats, Wistar
Ventricular Function
Megjelenés:Diabetes. - 51 : 2 (2002), p. 514-521. -
További szerzők:Liaudet, Lucas Soriano, Francisco Garcia Mabley, Jon G. Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Szabó Csaba
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6.

001-es BibID:BIBFORM014261
Első szerző:Pacher Pál
Cím:Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction / Pacher, P., Liaudet, L., Bai, P., Mabley, J. G., Kaminski, P. M., Virag, L., Deb, A., Szabo, E., Ungvari, Z., Wolin, M. S., Groves, J. T., Szabo, C.
Dátum:2003
ISSN:1524-4539 (Electronic)
Megjegyzések:Increased oxidative stress and dysregulation of nitric oxide have been implicated in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide in various forms of cardiac injury. Using a novel metalloporphyrinic peroxynitrite decomposition catalyst, FP15, and nitric oxide synthase inhibitors or knockout mice, we now delineate the pathogenetic role of peroxynitrite in rodent models of DOX-induced cardiac dysfunction. METHODS AND RESULTS: Mice received a single injection of DOX (25 mg/kg IP). Five days after DOX administration, left ventricular performance was significantly depressed, and high mortality was noted. Treatment with FP15 and an inducible nitric oxide synthase inhibitor, aminoguanidine, reduced DOX-induced mortality and improved cardiac function. Genetic deletion of the inducible nitric oxide synthase gene was also accompanied by better preservation of cardiac performance. In contrast, inhibition of the endothelial isoform of nitric oxide synthase with N-nitro-L-arginine methyl ester increased DOX-induced mortality. FP15 reduced the DOX-induced increase in serum LDH and creatine kinase activities. Furthermore, FP15 prevented the DOX-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart but not NAD(P)H-driven superoxide generation. Peroxynitrite neutralization did not interfere with the antitumor effect of DOX. FP15 also decreased ischemic injury in rats and improved cardiac function and survival of mice in a chronic model of DOX-induced cardiotoxicity. CONCLUSIONS: Thus, peroxynitrite plays a key role in the pathogenesis of DOX-induced cardiac failure. Targeting peroxynitrite formation may represent a new cardioprotective strategy after DOX exposure or in other conditions associated with peroxynitrite formation, including myocardial ischemia/reperfusion injury.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Acute Disease
Animals
Catalysis/drug effects
külföldön készült közlemény
Chronic Disease
Creatine Kinase/blood
Disease Models, Animal
Doxorubicin/*toxicity
Enzyme Inhibitors/pharmacology
Heart/*drug effects/physiopathology
Heart Failure/*chemically induced/physiopathology/prevention & control
L-Lactate Dehydrogenase/blood
Male
Metalloporphyrins/*pharmacology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide Synthase/antagonists & inhibitors/genetics/metabolism
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Oxidative Stress/drug effects/genetics
Peroxynitrous Acid/*metabolism
Survival Rate
Megjelenés:Circulation. - 107 : 6 (2003), p. 896-904. -
További szerzők:Liaudet, Lucas Bai Péter (1976-) (biokémikus) Mabley, Jon G. Kaminski, Pawel M. Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Deb, Amitabha Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Ungvári Zoltán Wolin, Michael S. Groves, John T. Szabó Csaba
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DOI
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7.

001-es BibID:BIBFORM040071
Első szerző:Soriano, Francisco Garcia
Cím:Diabetic endothelial dysfunction : the role of poly(ADP-ribose) polymerase activation / Soriano G. F., Virág L., Jagtap P., Szabó E., Mabley J. G., Liaudet L., Marton A., Hoyt D. G., Murthy K. G., Salzman A. L., Southan G. J., Szabó C.
Dátum:2001
ISSN:1078-8956
Megjegyzések:Diabetic patients frequently suffer from retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. The loss of endothelial function precedes these vascular alterations. Here we report that activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of endothelial dysfunction in diabetes. Destruction of islet cells with streptozotocin in mice induced hyperglycemia, intravascular oxidant production, DNA strand breakage, PARP activation and a selective loss of endothelium-dependent vasodilation. Treatment with a novel potent PARP inhibitor, starting after the time of islet destruction, maintained normal vascular responsiveness, despite the persistence of severe hyperglycemia. Endothelial cells incubated in high glucose exhibited production of reactive nitrogen and oxygen species, consequent single-strand DNA breakage, PARP activation and associated metabolic and functional impairment. Basal and high-glucose-induced nuclear factor-kappaB activation were suppressed in the PARP-deficient cells. Our results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Nature Medicine. - 7 : 1 (2001), p. 108-113. -
További szerzők:Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Jagtap, Prakash Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Mabley, Jon G. Liaudet, Lucas Marton Anita Hoyt, Dale G. Murthy, Kanneganti G. Salzman, Andrew L. Southan, Garry J. Szabó Csaba
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8.

001-es BibID:BIBFORM014263
Első szerző:Soriano, Francisco Garcia
Cím:Resistance to acute septic peritonitis in poly(ADP-ribose) polymerase-1-deficient mice / Soriano, F. G., Liaudet, L., Szabo, E., Virag, L., Mabley, J. G., Pacher, P., Szabo, C.
Dátum:2002
ISSN:1073-2322 (Print)
Megjegyzések:Sepsis is associated with a widespread production of proinflammatory cytokines and various oxidant species. Activation of the enzyme poly(ADP-ribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various diseases associated with inflammation and reperfusion injury. The aim of the current study was to elucidate the role of PARP activation in the multiple organ dysfunction complicating sepsis in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice genetically deficient in PARP (PARP-/-) and their wild-type littermates (PARP+/+) were subjected to CLP. After 12 and 24 h, the proinflammatory cytokines TNF-alpha and IL-6, as well as the anti-inflammatory cytokine IL-10, and nitrite/nitrate were measured in plasma samples. Organs were harvested for the measurement of myeloperoxidase (MPO) and malondialdehyde (MDA) levels, and immunohistochemical staining for nitrotyrosine and poly(ADP ribose) was performed in gut sections. PARP-/- mice, and their wild-type littermate showed a similar time-dependent increase in plasma nitrite/nitrate and in gut and lung MDA content, as well as the presence of nitrotyrosine in the gut. In contrast to wild-type mice showing a PARP activation in the gut, PARP-/- mice had no staining for poly(ADP ribose). PARP-/- mice had significantly lower plasma levels of TNF-alpha, IL-6, and IL-10, and they exhibited a reduced degree of organ inflammation, indicated by decreased MPO activity in the gut and lung. These effects were associated with a significant improvement in the survival of CLP in PARP-/- mice. Thus, PARP activation has an important role in systemic inflammation and organ damage in the present model of polymicrobial septic shock.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Acute Disease
egyetemen (Magyarországon) készült közlemény
Animals
Cytokines
Enzyme Activation
Inflammation Mediators
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiple Organ Failure
Peritonitis
Peroxidase/metabolism
Poly(ADP-ribose) Polymerases
Sepsis
Megjelenés:Shock. - 17 : 4 (2002), p. 286-292. -
További szerzők:Liaudet, Lucas Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Mabley, Jon G. Pacher Pál Szabó Csaba
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DOI
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