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1.

001-es BibID:BIBFORM014284
Első szerző:Bai Péter (biokémikus)
Cím:Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity / Péter Bai, Jon G. Mabley, Lucas Liaudet, László Virág, Csaba Szabó, Pál Pacher
Dátum:2004
ISSN:0891-5849 (Print)
Megjegyzések:Matrix metalloproteinase (MMP) activation contributes to the development of various pathophysiological conditions, including dilated cardiomyopathy, congestive heart failure, and reperfusion injury. Increased oxidative and nitrosative stress have been implicated in the activation of MMPs and also in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Thus, we hypothesized that MMP activation occurs in DOX-induced cardiotoxicity. Male Balb/c mice received a single injection of DOX (25 mg/kg i.p.) and were sacrificed 12 h, 1, 2, 3 and 4 days later. Hearts and aortae were harvested for MMP zymography. DOX induced time-dependent activation of MMPs both in the heart and in the aortic tissue with an earlier onset in the latter. These results demonstrate that MMP activation is an early event in DOX-induced cardiotoxicity and raises the possibility that MMP inhibitors may influence the outcome of this severe complication.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Animals
Antineoplastic Agents/toxicity
Biological Markers/analysis
Cardiomyopathy, Dilated/chemically induced/enzymology
Doxorubicin/ toxicity
Enzyme Activation
Heart/ drug effects
Heart Failure/chemically induced
Male
Matrix Metalloproteinases/ metabolism0891-5849
Mice
Mice, Inbred BALB C
Models, Animal
Myocardium/enzymology/ pathology
Reperfusion Injury/chemically induced/enzymology
Acute Disease
Catalysis/drug effects
Chronic Disease
Creatine Kinase/blood
Disease Models, Animal
Enzyme Inhibitors/pharmacology
Heart/ drug effects/physiopathology
Heart Failure/ chemically induced/physiopathology/prevention & control
L-Lactate Dehydrogenase/blood
Metalloporphyrins/ pharmacology
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
Antibiotics, Antineoplastic
Creatine Kinase/metabolism
Doxorubicin
Enzyme Activation/drug effects
Heart Failure/ chemically induced/pathology/physiopathology
Hemodynamics/drug effects
L-Lactate Dehydrogenase/metabolism
Metalloendopeptidases/metabolism
Poly(ADP-ribose) Polymerases/ genetics/ metabolism
Survival Analysis
Ventricular Function, Left/genetics
Apoptosis
Benzamides/ pharmacology
Caspases/metabolism
Cells, Cultured
DNA Damage/drug effects
DNA Fragmentation/drug effects
Enzyme Activation/drug effects/physiology
Enzyme Inhibitors/ pharmacology
Mitochondria/ drug effects
Nitrates
Nitrites/toxicity
Nitrogen Oxides/ toxicity
Poly(ADP-ribose) Polymerases/ antagonists & inhibitors/metabolism
Protective Agents/ pharmacology
Thymus Gland/cytology/ drug effects
Tyrosine
Megjelenés:Oncology reports. - 11 : 2 (2004), p. 505-508. -
További szerzők:Mabley, Jon G. Liaudet, Lucas Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Szabó Csaba Pacher Pál
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
Borító:

2.

001-es BibID:BIBFORM015736
Első szerző:Mabley, Jon G.
Cím:Suppression of intestinal polyposis in Apcmin/+ mice by targeting the nitric oxide or poly(ADP-ribose) pathways / Mabley, J. G., Pacher, P., Bai, P., Wallace, R., Goonesekera, S., Virag, L., Southan, G. J., Szabo, C.
Dátum:2004
ISSN:0027-5107 (Print)
Megjegyzések:Min mice have a germ-line nonsense mutation at codon 850 of the adenomatous polyposis coli (Apc) gene. These mice spontaneously develop multiple polyps in the small and large intestine at the age of 10-12 weeks. The aim of this study was to assess the role of reactive nitrogen species and poly(ADP-ribose) synthetase in tumorogenesis. Oxidative stress was found to be increased in the mucosa of the small intestine of Apc(min/+) mice with a concomitant increase in intestinal polyposis over control mice. Pharmacological inhibition of inducible nitric oxide synthase (NOS) with guanidinoethyldisulfide (GED) or stimulation of the breakdown of the nitrogen reactive species peroxynitrite using a potent decomposition catalyst, FP 15, reduced both the intestinal tumor load and the oxidative stress associated with intestinal polyposis in Apc(min/+) mice. Surprisingly, pharmacological inhibition of poly(ADP-ribose) synthetase by the phenanthridinone derivative PJ 34 also reduced the intestinal polyposis and oxidative stress in these mice, possibly through the inhibition of induction of nitric oxide synthase. These results suggest that reactive nitrogen species particularly peroxynitrite play a pivotal role in development of intestinal polyposis and that strategies to reduce both the oxidative stress and the formation of these radical species may be potential chemopreventive approaches for colorectal cancers.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Animals
Colon/enzymology
Enzyme Inhibitors/pharmacology
Genes, APC/ physiology
Guanidines/pharmacology
Intestinal Mucosa/enzymology
Intestinal Polyps/genetics/ metabolism/therapy
Male
Malondialdehyde/metabolism
Metalloproteases/metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide/ metabolism
Nitric Oxide Synthase/antagonists & inhibitors
Nitric Oxide Synthase Type II
Oxidative Stress
Peroxynitrous Acid/metabolism
Phenanthrenes/pharmacology
Poly Adenosine Diphosphate Ribose/ metabolism
Poly(ADP-ribose) Polymerases/antagonists & inhibitors/metabolism
Signal Transduction
Megjelenés:Mutation Research. - 548 : 1-2 (2004), p. 107-116. -
További szerzők:Pacher Pál Bai Péter (1976-) (biokémikus) Wallace, R. Goonesekera, S. Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Southan, Garry J. Szabó Csaba
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
DOI
Borító:

3.

001-es BibID:BIBFORM014288
Első szerző:Pacher Pál
Cím:Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure / Pacher P., Liaudet L., Bai P., Virag L., Mabley J. G., Haskó G., Szabó C.
Dátum:2002
ISSN:0891-5849 (Print)
Megjegyzések:Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury in conditions associated with oxidative stress. Increased oxidative stress is a major factor implicated in the cardiotoxicity of doxorubicin (DOX), a widely used antitumor anthracycline antibiotic. Thus, we hypothesized that the activation of PARP may contribute to the DOX-induced cardiotoxicity. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ34, we now demonstrate the role of PARP in the development of cardiac dysfunction induced by DOX. PARP-1+/+ and PARP-1-/- mice received a single injection of DOX (25 mg/kg i.p). Five days after DOX administration, left ventricular performance was significantly depressed in PARP-1+/+ mice, but only to a smaller extent in PARP-1-/- ones. Similar experiments were conducted in BALB/c mice treated with PJ34 or vehicle. Treatment with a PJ34 significantly improved cardiac dysfunction and increased the survival of the animals. In addition PJ34 significantly reduced the DOX-induced increase in the serum lactate dehydrogenase and creatine kinase activities but not metalloproteinase activation in the heart. Thus, PARP activation contributes to the cardiotoxicity of DOX. PARP inhibitors may exert protective effects against the development of severe cardiac complications associated with the DOX treatment.Nitroxyl (NO(-)/HNO), has been proposed to be one of the NO(*)-derived cytotoxic species. Although the biological effect of nitroxyl is largely unknown, it has been reported to cause DNA breakage and cytotoxicity. We have therefore investigated whether NO(-)/HNO-induced DNA single-strand breakage activates the nuclear nick sensor enzyme poly(ADP-ribose) polymerase (PARP) and whether PARP activation affects the mode of NO(-)/HNO- induced cell death. NO(-)/HNO generated from Angeli's salt (AS, sodium trioxodinitrate) (0-300 microM) induced DNA single-strand breakage, PARP activation, and a concentration-dependent cytotoxicity in murine thymocytes. AS-induced cell death was also accompanied by decreased mitochondrial membrane potential and increased secondary superoxide production. The cytotoxicity of AS, as measured by propidium iodide uptake, was abolished by electron acceptors potassium ferricyanide, TEMPOL, the intracellular calcium chelator BAPTA-AM, and by PARP inhibitors 3-aminobenzamide (3-AB) and PJ-34. The cytoprotective effect of 3-AB was paralleled by increased output of AS-induced apoptotic parameters such as phosphatidylserine exposure, caspase activation, and DNA fragmentation. No significant increase in tyrosine nitration could be observed in AS-treated thymocytes as opposed to peroxynitrite-treated cells, indicating that tyrosine nitration is not likely to contribute to NO(-)/HNO-induced cytotoxicity. Our results demonstrate that NO(-)/HNO-induced PARP activation shifts the default apoptotic cell death toward necrosis in thymocytes. However, as total PARP inhibition resulted only in 30% cytoprotection, PARP-independent mechanisms dominate NO(-)/HNO-induced cytotoxicity in thymocytes.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Acute Disease
Animals
Antibiotics, Antineoplastic
Creatine Kinase/metabolism
Doxorubicin
Enzyme Activation/drug effects
Heart Failure/ chemically induced/pathology/physiopathology
Hemodynamics/drug effects
L-Lactate Dehydrogenase/metabolism
Male
Metalloendopeptidases/metabolism
Mice
Mice, Inbred BALB C
Mice, Knockout
Poly(ADP-ribose) Polymerases/ genetics/ metabolism
Survival Analysis
Ventricular Function, Left/genetics
Apoptosis
Benzamides/ pharmacology
Caspases/metabolism
Cells, Cultured
DNA Damage/drug effects
DNA Fragmentation/drug effects
Enzyme Activation/drug effects/physiology
Enzyme Inhibitors/ pharmacology
Mice, Inbred C57BL
Mitochondria/ drug effects
Nitrates
Nitrites/toxicity
Nitrogen Oxides/ toxicity
Poly(ADP-ribose) Polymerases/ antagonists & inhibitors/metabolism
Protective Agents/ pharmacology
Thymus Gland/cytology/ drug effects
Tyrosine
Megjelenés:The Journal of Pharmacology and Experimental Therapeutics. - 300 : 3 (2002), p. 862-867. -
További szerzők:Liaudet, Lucas Bai Péter (1976-) (biokémikus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Mabley, Jon G. Haskó György (1967-) (biokémikus) Szabó Csaba
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
DOI
Borító:

4.

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
Internet cím:elektronikus változat
Intézményi repozitóriumban (DEA) tárolt változat
DOI
Borító:

5.

001-es BibID:BIBFORM014289
Első szerző:Virág László (biokémikus, sejtbiológus, farmakológus)
Cím:Effects of poly(ADP-ribose) polymerase inhibition on inflammatory cell migration in a murine model of asthma / Virag, L., Bai, P., Bak, I., Pacher, P., Mabley, J. G., Liaudet, L., Bakondi, E., Gergely, P., Kollai, M., Szabo, C.
Dátum:2004
ISSN:0891-5849 (Print)
Megjegyzések:Poly(ADP-ribose) polymerase-1 (PARP-1), a monomeric nuclear enzyme present in eukaryotes, plays a role in cell death, inflammatory mediator expression, and mononuclear cell recruitment in various experimental models of inflammation and reperfusion injury. Part of the molecular mechanism of this function involves the regulation of cytokine and chemokine production. Since chemokines are principal regulators of mononuclear and polymorphonuclear cell trafficking in asthma, we investigated the possibility whether PARP modulates chemokine production and cell recruitment in a murine model of asthma. MATERIAL/METHODS: We studied ovalbumin-sensitized mice challenged with a single dose of ovalbumin. RESULTS: PARP inhibition with the phenanthridinone-based PARP inhibitor PJ34 suppressed inflammatory cell migration. These effects were associated with downregulation of the CC chemokine MIP-1alpha, but not the CXC chemokine MIP-2. The production of TNF- alpha and IL-12, but not IL-5 or IL-13, was also suppressed by PARP inhibition. CONCLUSIONS: Our results demonstrate the pathogenetic role of PARP activation in a murine model of asthma. PARP selectively regulates the production of certain chemokines and cytokines in this experimental model, which may be responsible for some of the observed protective effects seen in the current murine asthma model.Matrix metalloproteinase (MMP) activation contributes to the development of various pathophysiological conditions, including dilated cardiomyopathy, congestive heart failure, and reperfusion injury. Increased oxidative and nitrosative stress have been implicated in the activation of MMPs and also in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Thus, we hypothesized that MMP activation occurs in DOX-induced cardiotoxicity. Male Balb/c mice received a single injection of DOX (25 mg/kg i.p.) and were sacrificed 12 h, 1, 2, 3 and 4 days later. Hearts and aortae were harvested for MMP zymography. DOX induced time-dependent activation of MMPs both in the heart and in the aortic tissue with an earlier onset in the latter. These results demonstrate that MMP activation is an early event in DOX-induced cardiotoxicity and raises the possibility that MMP inhibitors may influence the outcome of this severe complication.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Animals
Asthma/ drug therapy
Bronchoalveolar Lavage
Catalysis
Cell Death
Cell Movement
Chemokine CXCL2
Chemokines/metabolism
Cytokines/metabolism
Disease Models, Animal
Down-Regulation
Enzyme Inhibitors/ pharmacology
Interleukin-10/metabolism
Interleukin-12/metabolism
Interleukin-13/metabolism
Interleukin-5/metabolism
Leukocytes, Mononuclear/metabolism
Lung/pathology
Male
Mice
Mice, Inbred BALB C
Ovalbumin/metabolism/pharmacology
Peroxidase/metabolism
Poly(ADP-ribose) Polymerases/ antagonists & inhibitors
Time Factors
Tumor Necrosis Factor-alpha/metabolism
Antineoplastic Agents/toxicity
Biological Markers/analysis
Cardiomyopathy, Dilated/chemically induced/enzymology
Doxorubicin/ toxicity
Enzyme Activation
Heart/ drug effects
Heart Failure/chemically induced
Matrix Metalloproteinases/ metabolism
Models, Animal
Myocardium/enzymology/ pathology
Reperfusion Injury/chemically induced/enzymology
Acute Disease
Catalysis/drug effects
Chronic Disease
Creatine Kinase/blood
Enzyme Inhibitors/pharmacology
Heart/ drug effects/physiopathology
Heart Failure/ chemically induced/physiopathology/prevention & control
L-Lactate Dehydrogenase/blood
Metalloporphyrins/ pharmacology
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
Antibiotics, Antineoplastic
Creatine Kinase/metabolism
Doxorubicin
Enzyme Activation/drug effects
Heart Failure/ chemically induced/pathology/physiopathology
Hemodynamics/drug effects
L-Lactate Dehydrogenase/metabolism
Metalloendopeptidases/metabolism
Poly(ADP-ribose) Polymerases/ genetics/ metabolism
Survival Analysis
Ventricular Function, Left/genetics
Apoptosis
Benzamides/ pharmacology
Caspases/metabolism
Cells, Cultured
DNA Damage/drug effects
DNA Fragmentation/drug effects
Enzyme Activation/drug effects/physiology
Mitochondria/ drug effects
Nitrates
Nitrites/toxicity
Nitrogen Oxides/ toxicity
Poly(ADP-ribose) Polymerases/ antagonists & inhibitors/metabolism
Protective Agents/ pharmacology
Thymus Gland/cytology/ drug effects
Tyrosine
külföldön készült közlemény
Megjelenés:Medical Science Monitor. - 10 : 3 (2004), p. BR77-83. -
További szerzők:Bai Péter (1976-) (biokémikus) Bak István (1975-) (vegyész, analitikus, farmakológus) Pacher Pál Mabley, Jon G. Liaudet, Lucas Bakondi Edina (1975-) (biokémikus, vegyész) Gergely Pál (1947-) (biokémikus) Kollai, M. Szabó Csaba
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
Borító:
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