@article{MTMT:1071566, title = {Preventing apoptotic cell death by a novel small heat-shock protein}, url = {https://m2.mtmt.hu/api/publication/1071566}, author = {Bellyei, Szabolcs and Szigeti, András and Pozsgai, Éva and Boronkai, Árpád and Gömöri, Éva and Hocsák, Enikő and Farkas, Róbert and Sümegi, Balázs and Gallyas, Ferenc}, doi = {10.1016/j.ejcb.2006.12.004}, journal-iso = {EUR J CELL BIOL}, journal = {EUROPEAN JOURNAL OF CELL BIOLOGY}, volume = {86}, unique-id = {1071566}, issn = {0171-9335}, abstract = {NCBI database analysis indicated that the human C1orf41 protein (small heat shock-like protein—Hsp16.2) has sequence similarity with small heat shock proteins (sHsps). Since sHsps have chaperone function, and so prevent aggregation of denatured proteins, we determined whether Hsp16.2 could prevent the heat-induced aggregation of denatured proteins. Under our experimental conditions, recombinant Hsp16.2 prevented aggregation of aldolase and glyceraldehyde-3-phosphate dehydrogenase, and protected Escherichia coli cells from heat stress indicating its chaperone function. Hsp16.2 also formed oligomeric complexes in aqueous solution. Hsp16.2 was found to be expressed at different levels in cell lines and tissues, and was mainly localized to the nucleus and the cytosol, but to a smaller extent, it could be also found in mitochondria. Hsp16.2 could be modified covalently by poly(ADP ribosylation) and acetylation. Hsp16.2 over-expression prevented etoposide-induced cell death as well as the release of mitochondrial cytochrome c and caspase activation. These data suggest that Hsp16.2 can prevent the destabilization of mitochondrial membrane systems and could represent a suitable target for modulating cell death pathways.}, year = {2007}, eissn = {1618-1298}, pages = {161-171}, orcid-numbers = {Gallyas, Ferenc/0000-0002-1906-4333} } @article{MTMT:1071479, title = {Inhibition of cell death by a novel 16.2 kD heat shock protein predominantly via Hsp90 mediated lipid rafts stabilization and Akt activation pathway.}, url = {https://m2.mtmt.hu/api/publication/1071479}, author = {Bellyei, Szabolcs and Szigeti, András and Boronkai, Árpád and Pozsgai, Éva and Gömöri, Éva and Melegh, Béla and Janáky, Tamás and Bognár, Zita and Hocsák, Enikő and Sümegi, Balázs and Gallyas, Ferenc}, doi = {10.1007/s10495-006-0486-x}, journal-iso = {APOPTOSIS}, journal = {APOPTOSIS}, volume = {12}, unique-id = {1071479}, issn = {1360-8185}, abstract = {AlphaB-crystallin homology, heat stress induction and chaperone activity suggested that a previously encloned gene product is a novel small heat shock protein (Hsp16.2). Suppression of Hsp16.2 by siRNA sensitized cells to hydrogen peroxide or taxol induced cell-death. Over-expressing of Hsp16.2 protected cells against stress stimuli by inhibiting cytochrome c release from the mitochondria, nuclear translocation of AIF and endonuclease G, and caspase 3 activation. Recombinant Hsp16.2 protected mitochondrial membrane potential against calcium induced collapse in vitro indicating that Hsp16.2 stabilizes mitochondrial membrane systems. Hsp16.2 formed self-aggregates and bound to Hsp90. Inhibition of Hsp90 by geldanamycin diminished the cytoprotective effect of Hsp16.2 indicating that this effect was Hsp90-mediated. Hsp16.2 over-expression increased lipid rafts formation as demonstrated by increased cell surface labeling with fluorescent cholera toxin B, and increased Akt phosphorylation. The inhibition of PI-3-kinase-Akt pathway by LY-294002 or wortmannin significantly decreased the protective effect of the Hsp16.2. These data indicate that the over-expression of Hsp16.2 inhibits cell death via the stabilization of mitochondrial membrane system, activation of Hsp90, stabilization of lipid rafts and by the activation of PI-3-kinase-Akt cytoprotective pathway.}, year = {2007}, eissn = {1573-675X}, pages = {97-112}, orcid-numbers = {Janáky, Tamás/0000-0002-6466-8283; Gallyas, Ferenc/0000-0002-1906-4333} } @article{MTMT:1197995, title = {A novel SOD-mimetic permeability transition inhibitor agent protects ischemic heart by inhibiting both apoptotic and necrotic cell death.}, url = {https://m2.mtmt.hu/api/publication/1197995}, author = {Bognár, Zita and Kálai, Tamás and Pálfi, Anita and Hanto, K and Bognár, Balázs and Márk, László and Szabó, Zoltán and Tapodi, Antal and Radnai, Balázs and Sárszegi, Zsolt and Szántó, Árpád László and Gallyas, Ferenc and Hideg, Kálmán and Sümegi, Balázs and Varbiro, G}, doi = {10.1016/j.freeradbiomed.2006.06.004}, journal-iso = {FREE RADICAL BIO MED}, journal = {FREE RADICAL BIOLOGY AND MEDICINE}, volume = {41}, unique-id = {1197995}, issn = {0891-5849}, abstract = {In ischemia-reperfusion injuries, elevated calcium and reactive oxygen species (ROS) induce mitochondrial permeability transition (mPT), which plays a pivotal role in mediating damages and cell death. Inhibition of mPT decreases necrotic cell death; however, during reperfusion, the continuous production of ROS may contribute to the temporary opening of the pore and thus the onset of the delayed apoptotic cell death. Based on amiodarone structure, we developed the first SOD-mimetic mPT inhibitor (HO-3538) that can eliminate ROS in the microenvironment of the permeability pore. In isolated mitochondria, HO-3538 inhibited mPT and the release of proapoptotic mitochondrial proteins. It had a ROS scavenging effect and antiapoptotic effect in a cardiomyocyte line and it diminished release of mitochondrial proapoptotic proteins. Furthermore, HO-3538 significantly enhanced the recovery of mitochondrial energy metabolism and functional cardiac parameters; decreased infarct size, lipid peroxidation, and protein oxidation; and suppressed necrotic as well as apoptotic cell death pathways in Langendorff-perfused hearts. In these respects it was somewhat superior to its two constituents, amiodarone and a pyrrol-derivative free radical scavenger. These data suggest that the SOD-mimetic mPT inhibitors are ideal candidates for drug development for the alleviation of postinfarct myocardial injuries. (c) 2006 Elsevier Inc. All rights reserved.}, year = {2006}, eissn = {1873-4596}, pages = {835-848}, orcid-numbers = {Márk, László/0000-0002-9301-8159; Gallyas, Ferenc/0000-0002-1906-4333} } @article{MTMT:1071561, title = {Induction of necrotic cell death and mitochondrial permeabilization by heme binding protein 2/SOUL.}, url = {https://m2.mtmt.hu/api/publication/1071561}, author = {Szigeti, András and Bellyei, Szabolcs and Gasz, Balázs and Boronkai, Árpád and Hocsák, Enikő and Minik, O and Bognár, Zita and Varbiro, G and Sümegi, Balázs and Gallyas, Ferenc}, doi = {10.1016/j.febslet.2006.10.067}, journal-iso = {FEBS LETT}, journal = {FEBS LETTERS}, volume = {580}, unique-id = {1071561}, issn = {0014-5793}, abstract = {We found that heme-binding protein 2/SOUL sensifised NIH3T3 cells to cell death induced by A23187 and etoposide, but it did not affect reactive oxygen species formation. In the presence of sub-threshold calcium, recombinant SOUL provoked mitochondrial permeability transition (mPT) in vitro that was inhibited by cyclosporine A (CsA). This effect was verified in vivo by monitoring the dissipation of mitochondrial membrane potential. Flow cytometry analysis showed that SOUL promoted necrotic death in A23187 and etoposide treated cells, which effect was prevented by CsA. These data suggest that besides its heme-binding properties SOUL promotes necrotic cell death by inducing mPT. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.}, year = {2006}, eissn = {1873-3468}, pages = {6447-6454}, orcid-numbers = {Gallyas, Ferenc/0000-0002-1906-4333} } @article{MTMT:1060890, title = {Critical role of PI3-kinase/Akt activation in the PARP inhibitor induced heart function recovery during ischemia-reperfusion}, url = {https://m2.mtmt.hu/api/publication/1060890}, author = {Kovács, Krisztina and Toth, A and Deres, P and Kálai, Tamás and Hideg, Kálmán and Gallyas, Ferenc and Sümegi, Balázs}, doi = {10.1016/j.bcp.2005.05.036}, journal-iso = {BIOCHEMIC PHARMACOL}, journal = {BIOCHEMICAL PHARMACOLOGY}, volume = {71}, unique-id = {1060890}, issn = {0006-2952}, abstract = {Poly(ADP-ribose) polymerase (PARP) inhibitors protect hearts from ischemia-reperfusion (IR)-induced damages by limiting nicotinamide adenine dinucleotide (NAD(+)) and ATP depletion, and by other, not yet elucidated mechanisms. Our preliminary data suggested that PARP catalyzed ADP-ribosylations may affect signaling pathways in cardiomyocytes. To clarify this possibility, we studied the effect of a well-characterized (4-hydroxyquinazoline) and a novel (carboxaminobenzimidazol- derivative) PARP inhibitor on the activation of phosphatidylinositol-3-kinase (PI3-kinase)/Akt pathway in Langendorff-perfused hearts. PARP inhibitors promoted the restoration of myocardial energy metabolism (assessed by P-31 nuclear magnetic resonance spectroscopy) and cardiac function compared to untreated hearts. PARP inhibitors also attenuated the infarct size and reduced the IR-induced lipid peroxidation, protein oxidation and total peroxide concentration. Moreover, PARP inhibitors facilitated Akt phosphorylation and activation, as well as the phosphorylation of its downstream target glycogen synthase kinase-3 beta (GSK-3 beta) in normoxia and, more robustly, during IR. Blocking PI3-kinase by wortmannin or LY294002 reduced the PARP inhibitor-elicited robust Akt and GSK-3 beta phosphorylation upon ischemia-reperfusion, and significantly diminished the recovery of ATP and creatine phosphate showing the importance of Akt activation in the recovery of energy metabolism. In addition, inhibition of PI3-kinase/Akt pathway decreased the protective effect of PARP inhibitors on infarct size and the recovery of heart functions. All these data suggest that contrary to the original view, which considered preservation of NAD(+) and consequently ATP pools as the exclusive underlying mechanism for the cytoprotective effect of PARP inhibitors, the activation of PI3-kinase/Akt pathway and related processes are at least equally important in the cardioprotective effects of PARP inhibitors during ischemia-reperfusion. (c) 2005 Elsevier Inc. All rights reserved.}, year = {2006}, eissn = {1873-2968}, pages = {441-452}, orcid-numbers = {Gallyas, Ferenc/0000-0002-1906-4333} } @article{MTMT:1060889, title = {PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3 beta pathway}, url = {https://m2.mtmt.hu/api/publication/1060889}, author = {Pálfi, Anita and Toth, A and Hanto, K and Deres, P and Szabados, Eszter and Szereday, Z and Kulcsár, Győző and Kálai, Tamás and Hideg, Kálmán and Gallyas, Ferenc and Sümegi, Balázs and Tóth, Kálmán and Halmosi, Róbert}, doi = {10.1016/j.yjmcc.2006.03.427}, journal-iso = {J MOL CELL CARDIOL}, journal = {JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY}, volume = {41}, unique-id = {1060889}, issn = {0022-2828}, abstract = {The inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3 beta, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC alpha/beta II, PKC delta and PKC epsilon, which could be responsible for the activation of the antihypertrophic GSK-3 beta. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3 beta intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure. (c) 2006 Elsevier Inc. All rights reserved.}, year = {2006}, eissn = {1095-8584}, pages = {149-159}, orcid-numbers = {Szabados, Eszter/0000-0002-9809-699X; Kulcsár, Győző/0000-0002-4098-1072; Gallyas, Ferenc/0000-0002-1906-4333} } @article{MTMT:1060909, title = {Prevention of doxorubicin-induced acute cardiotoxicity by an experimental antioxidant compound}, url = {https://m2.mtmt.hu/api/publication/1060909}, author = {Deres, P and Halmosi, Róbert and Toth, A and Kovács, Krisztina and Pálfi, Anita and Habon, Tamás and Czopf, László and Kálai, Tamás and Hideg, Kálmán and Sümegi, Balázs and Tóth, Kálmán}, doi = {10.1097/00005344-200501000-00007}, journal-iso = {J CARDIOVASC PHARM}, journal = {JOURNAL OF CARDIOVASCULAR PHARMACOLOGY}, volume = {45}, unique-id = {1060909}, issn = {0160-2446}, year = {2005}, eissn = {1533-4023}, pages = {36-43}, orcid-numbers = {Habon, Tamás/0000-0002-4816-857X; Czopf, László/0000-0001-9565-0732} } @article{MTMT:1060906, title = {Synthesis and evaluation of the permeability transition inhibitory characteristics of paramagnetic and diamagnetic amiodarone derivatives}, url = {https://m2.mtmt.hu/api/publication/1060906}, author = {Kálai, Tamás and Varbiro, G and Bognár, Zita and Pálfi, Anita and Hanto, K and Bognár, Balázs and Osz, E and Sümegi, Balázs and Hideg, Kálmán}, doi = {10.1016/j.bmc.2005.01.028}, journal-iso = {BIOORGAN MED CHEM}, journal = {BIOORGANIC & MEDICINAL CHEMISTRY}, volume = {13}, unique-id = {1060906}, issn = {0968-0896}, year = {2005}, eissn = {1464-3391}, pages = {2629-2636} } @article{MTMT:1060902, title = {The role of Akt and mitogen-activated protein kinase systems in the protective effect of poly(ADP-ribose) polymerase inhibition in Langendorff perfused and in isoproterenol-damaged rat hearts}, url = {https://m2.mtmt.hu/api/publication/1060902}, author = {Pálfi, Anita and Tóth, A and Kulcsár, Győző and Hantó, K and Deres, P and Bartha, Éva and Halmosi, Róbert and Szabados, Eszter and Czopf, László and Kálai, Tamás and Hideg, Kálmán and Sümegi, Balázs and Tóth, Kálmán}, doi = {10.1124/jpet.105.088336}, journal-iso = {J PHARMACOL EXP THER}, journal = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS}, volume = {315}, unique-id = {1060902}, issn = {0022-3565}, year = {2005}, eissn = {1521-0103}, pages = {273-282}, orcid-numbers = {Kulcsár, Győző/0000-0002-4098-1072; Bartha, Éva/0000-0003-4318-9459; Szabados, Eszter/0000-0002-9809-699X; Czopf, László/0000-0001-9565-0732} } @article{MTMT:1060901, title = {Pivotal role of Akt activation in mitochondrial protection and cell survival by poly(ADP-ribose) polymerase-1 inhibition in oxidative stress}, url = {https://m2.mtmt.hu/api/publication/1060901}, author = {Tapodi, Antal and Debreceni, Balázs and Hanto, K and Bognár, Zita and Wittmann, István and Gallyas, Ferenc and Varbiro, G and Sümegi, Balázs}, doi = {10.1074/jbc.M507075200}, journal-iso = {J BIOL CHEM}, journal = {JOURNAL OF BIOLOGICAL CHEMISTRY}, volume = {280}, unique-id = {1060901}, issn = {0021-9258}, abstract = {According to the classical view, the cytoprotective effect of inhibitors of poly( ADP- ribose) polymerase ( PARP) in oxidative stress was based on the prevention of NAD(+) and ATP depletion, thus the attenuation of necrosis. Our previous data on PARP inhibitors in an inflammatory model suggested that PARP- catalyzed ADP- ribosylations may affect signaling pathways, which can play a significant role in cell survival. To clarify the molecular mechanism of cytoprotection, PARP activity was inhibited pharmacologically by suppressing PARP- 1 expression by a small interfering RNA ( siRNA) technique or by transdominantly expressing the N- terminal DNA-binding domain of PARP- 1 ( PARP- DBD) in cultured cells. Cell survival, activation of the phosphatidylinositol 3- kinase ( PI3- kinase)/ Akt system, and the preservation of mitochondrial membrane potential were studied in hydrogen peroxide- treated WRL- 68 cells. Our data showed that suppression of the single- stranded DNA break- induced PARP- 1 activation by pharmacological inhibitor, siRNA, or by the transdominant expression of PARP- DBD protected cells from oxidative stress and induced the phosphorylation and activation of Akt. Furthermore, prevention of Akt activation by inhibiting PI3- kinase counteracted the cytoprotective effect of PARP inhibition. Microscopy data showed that PARP inhibition-induced Akt activation was responsible for protection of mitochondria in oxidative stress because PI3- kinase inhibitors diminished the protective effect of PARP inhibition. Similarly, Src kinase inhibitors, which decrease Akt phosphorylation, also counteracted the protection of mitochondrial membrane potential supporting the pivotal role of Akt in cytoprotection. These data together with the finding that PARP inhibition in the absence of oxidative stress induced the phosphorylation and activation of Akt indicate that PARP inhibition- induced Akt activation is dominantly responsible for the cytoprotection in oxidative stress.}, year = {2005}, eissn = {1083-351X}, pages = {35767-35775}, orcid-numbers = {Gallyas, Ferenc/0000-0002-1906-4333} }