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1.

001-es BibID:BIBFORM043662
Első szerző:Hegedűs Csaba (biokémikus, molekuláris biológus)
Cím:Cytoprotective dibenzoylmethane derivatives protect cells from oxidative stress-induced necrotic cell death / Csaba Hegedűs, Petra Lakatos, Attila Kiss-Szikszai, Tamás Patonay, Szabolcs Gergely, Andrea Gregus, Péter Bai, György Haskó, Éva Szabó, László Virág
Dátum:2013
ISSN:1043-6618
Megjegyzések:Screening of a small in-house library of 1863 compounds identified 29 compounds that protected Jurkatcells from hydrogen peroxide-induced cytotoxicity. From the cytoprotective compounds eleven provedto possess antioxidant activity (ABTS radical scavenger effect) and two were found to inhibit poly(ADP-ribosyl)ation (PARylation), a cytotoxic pathway operating in severely injured cells. Four cytoprotectivedibenzoylmethane (DBM) derivatives were investigated in more detail as they did not scavenge hydro-gen peroxide nor did they inhibit PARylation. These compounds protected cells from necrotic cell deathwhile caspase activation, a parameter of apoptotic cell death was not affected. Hydrogen peroxide acti-vated extracellular signal regulated kinase (ERK1/2) and p38 MAP kinases but not c-Jun N-terminal kinase(JNK). The cytoprotective DBMs suppressed the activation of Erk1/2 but not that of p38. Cytoprotectionwas confirmed in another cell type (A549 lung epithelial cells), indicating that the cytoprotective effectis not cell type specific. In conclusion we identified DBM analogs as a novel class of cytoprotective com-pounds inhibiting ERK1/2 kinase and protecting from necrotic cell death by a mechanism independentof poly(ADP-ribose) polymerase inhibition.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Dibenzoylmethane
Hydrogen peroxide
Apoptosis
Necrosis
Poly(ADP-ribosyl)ation
Extracellular signal regulated kinase
Molekulatudomány
Doktori iskola
Megjelenés:Pharmacological Research. - 72 (2013), p. 25-34. -
További szerzők:Lakatos Petra (1985-) (Molekuláris biológus) Kiss-Szikszai Attila (1975-) (vegyész) Patonay Tamás (1951-2015) (vegyész) Gergely Szabolcs (1977-) (kardiológus) Gregus Andrea (1980-) (biológus) Bai Péter (1976-) (biokémikus) Haskó György (1967-) (biokémikus) Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
Pályázati támogatás:K73003
OTKA
K60780
OTKA
K82009
OTKA
PD83473
OTKA
TÁMOP-4.2.2-08/1-2008-0019
TÁMOP
TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
Molekulakönyvtárak fejlesztése
TÁMOP-4.2.2.A-111/1/KONV-2012-0025
TÁMOP
TÁMOP-4.2.2/B-10/1-2010-0024
TÁMOP
Kémiai Tudományok Doktori Iskola
TéT_09-2010-0023
Egyéb
Mec-8/2011
Egyéb
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2.

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
Internet cím:elektronikus változat
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3.

001-es BibID:BIBFORM037716
Első szerző:Kovács Katalin (biokémikus)
Cím:Poly(ADP-ribosyl)ation is a survival mechanism in cigarette smoke-induced and hydrogen peroxide-mediated cell death / Kovács Katalin, Erdélyi Katalin, Hegedűs Csaba, Lakatos Petra, Regdon Zsolt, Bai Péter, Haskó György, Szabó Éva, Virág László
Dátum:2012
ISSN:0891-5849
Megjegyzések:Cigarette smoking can contribute to the development of many human diseases such as cardiovascular disease, lung cancer, asthma, and chronic obstructive pulmonary disease. Thousands of compounds are present in cigarette smoke, including a large number of reactive oxygen species that can cause DNA damage, leading to the activation of poly(ADP-ribose) polymerase (PARP) enzymes. The PAR polymer is degraded by poly(ADP-ribose) glycohydrolase (PARG). Here we have investigated the effects of cigarette smoke extract (CSE) on A549 human lung epithelial cells. CSE induced DNA damage (comet assay), PAR accumulation (immunofluorescence and immunoblotting), impaired proliferation (clonogenic survival assay and electric cell-substrate impedance sensing measurement), and cell death (MTT reduction, propidium iodide uptake, lactate dehydrogenase release). CSE-induced cell death was also characterized by mitochondrial depolarization but massive translocation of apoptosis-inducing factor could not be observed. To investigate the role of PARylation in CSE-induced oxidative stress, PARP-1- and PARG-silenced A549 cells were used. Silencing of both PARP-1 and PARG sensitized cells to CSE-induced toxicity: PARP-1- and PARG-silenced cell lines exhibited reduced clonogenic survival, displayed a delayed repair of DNA breaks, and showed higher levels of cytotoxicity. CSE triggered the production of mitochondrial superoxide and hydrogen peroxide. Addition of superoxide dismutase increased, whereas catalase abolished, CSE-induced PAR formation. In summary, our data show that the superoxide-hydrogen peroxide-DNA breakage pathway activates the PAR cycle by PARP-1 and PARG, which serves as a survival mechanism in CSE-exposed cells. Our data also raise the possibility that the PARP-1/PARG status of smokers may be an important determinant of the efficiency of DNA repair in their lungs and of their susceptibility to CS-induced carcinogenesis.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Molekuláris Medicina
Megjelenés:Free Radical Biology And Medicine. - 53 : 9 (2012), p. 1680-1688. -
További szerzők:Erdélyi Katalin (1978-) (molekuláris biológus, biokémikus) Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus) Lakatos Petra (1985-) (Molekuláris biológus) Regdon Zsolt (1988-) (biokémikus, molekuláris biológus) Bai Péter (1976-) (biokémikus) Haskó György (1967-) (biokémikus) Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
Pályázati támogatás:TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
Oxidatív stressz és ADP-riboziláció kapcsolatának vizsgálata
TÁMOP-4.2.2.A-11/1/KONV-2012-0025
TÁMOP
TÁMOP-4.2.2/B-10/1-2010-0024
TÁMOP
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4.

001-es BibID:BIBFORM040381
Első szerző:Lakatos Petra (Molekuláris biológus)
Cím:3-Aminobenzamide protects primary human keratinocytes from UV-induced cell death by a poly(ADP-ribosyl)ation independent mechanism / Petra Lakatos, Éva Szabó, Csaba Hegedűs, György Haskó, Pál Gergely, Péter Bai, László Virág
Dátum:2013
ISSN:0167-4889
Megjegyzések:Poly(ADP-ribosyl)ation (PARylation) is a NAD(+)-dependent protein modification carried out by PARP [poly(ADP-ribose) polymerase] enzymes. Here we set out to investigate whether PARylation regulates UVB-induced cell death in primary human keratinocytes. We used the benchmark PARP inhibitor 3-aminobenzamide (3AB) and a more potent and specific inhibitor PJ34 and found that UVB (0.05-0.2J/cm(2)) induced a dose dependent loss of viability that was prevented by 3AB but not by PJ34. Similarly to PJ34, two other new generation PARP inhibitors also failed to protect keratinocytes from UVB-induced loss of viability. Moreover, silencing PARP-1 in HaCaT human keratinocytes sensitized cells to UVB toxicity but 3AB provided protection to both control HaCaT cells and to PARP-1 silenced cells indicating that the photoprotective effect of 3AB is independent of PARP inhibition. Lower UVB doses (0.0125-0.05J/cm(2)) caused inhibition of proliferation of keratinocytes which was prevented by 3AB but augmented by PJ34. UVB-induced keratinocyte death displayed the characteristics of both apoptosis (morphology, caspase activity, DNA fragmentation) and necrosis (morphology, LDH release) with all of these parameters being inhibited by 3AB and apoptotic parameters slightly enhanced by PJ34. UVA also caused apoptotic and necrotic cell death in keratinocytes with 3AB protecting and PJ34 sensitizing cells to UVA-induced toxicity. 3AB prevented UVB-induced mitochondrial membrane depolarization and generation of hydrogen peroxide. In summary, PARylation is a survival mechanism in UV-treated keratinocytes. Moreover, 3-aminobenzamide is photoprotective and acts by a PARP-independent mechanism at a premitochondrial step of phototoxicity.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Molekuláris Medicina
Ultraviolet radiation
Poly(ADP-ribose) polymerase
3-Aminobenzamide
Cell death
Apoptosis
Megjelenés:Biochimica et Biophysica Acta (BBA). Molecular Cell Research. - 1833 : 3 (2013), p. 743-751. -
További szerzők:Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus) Haskó György (1967-) (biokémikus) Gergely Pál (1947-) (biokémikus) Bai Péter (1976-) (biokémikus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
Pályázati támogatás:TÁMOP-4.2.2-08/1-2008-0019
TÁMOP
TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
Oxidatív stressz és ADP-riboziláció kapcsolatának vizsgálata
TÁMOP-4.2.2.A-111/1/KONV-2012-0025
TÁMOP
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5.

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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6.

001-es BibID:BIBFORM028552
Első szerző:Szabó Éva (bőrgyógyász, kozmetológus)
Cím:Peroxynitrite production, DNA breakage, and poly(ADP-ribose) polymerase activation in a mouse model of oxazolone-induced contact hypersensitivity / Éva Szabó, László Virág, Edina Bakondi, László Gyüre, György Haskó, Péter Bai, János Hunyadi, Pál Gergely, Csaba Szabó
Dátum:2001
Megjegyzések:Peroxynitrite-induced poly(ADP-ribose) polymerase activation has been implicated in the pathogenesis of various inflammatory conditions. Here we have investigated whether peroxynitrite and poly(ADP-ribose) polymerase may play a role in the pathophysiology of the elicitation phase of contact hypersensitivity. We have detected nitrotyrosine, DNA breakage, and poly(ADP-ribose) polymerase activation in the epidermis of mice in an oxazolone-induced contact hypersensitivity model. As tyrosine nitration is mostly mediated by peroxynitrite, a nitric-oxide-derived cytotoxic oxidant capable of causing DNA breakage, we have applied peroxynitrite directly on mouse skin and showed poly(ADP-ribose) polymerase activation in keratinocytes and in some scattered dermal cells. We have also investigated the cellular effects of peroxynitrite in HaCaT cells, a human keratinocyte cell line. We found that peroxynitrite inhibited cell proliferation and at higher concentrations also caused cytotoxicity. Peroxynitrite activates poly(ADP-ribose) polymerase in HaCaT cells and poly(ADP-ribose) polymerase activation contributes to peroxynitrite-induced cytotoxicity, as indicated by the cytoprotective effect of the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide. The cytoprotective effect of 3-aminobenzamide cannot be attributed to inhibition of apoptosis, as apoptotic parameters (caspase activation and DNA fragmentation) were not reduced in the presence of 3-aminobenzamide in peroxynitrite-treated cells. Moreover, poly(ADP-ribose) polymerase inhibition by 3-aminobenzamide dose-dependently reduced interferon-induced intercellular adhesion molecule 1 expression as well as interleukin-1beta-induced interleukin-8 expression. Our results indicate that peroxynitrite and poly(ADP-ribose) polymerase regulate keratinocyte function and death in contact hypersensitivity.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Jounal of Investigative Dermatoloty. - 117 : 1 (2001), p. 74-80. -
További szerzők:Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Bakondi Edina (1975-) (biokémikus, vegyész) Gyüre László Haskó György (1967-) (biokémikus) Bai Péter (1976-) (biokémikus) Hunyadi János (1943-) (bőrgyógyász, kozmetológus, allergológus) Gergely Pál (1947-) (biokémikus) Szabó Csaba (1967-) (orvos)
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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