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1.

001-es BibID:BIBFORM050047
Első szerző:Király Anna
Cím:Hypoxia reduces the efficiency of elisidepsin by inhibiting hydroxylation and altering the structure of lipid rafts / Anna Király, Tímea Váradi, Tímea Hajdu, Ralph Rühl, Carlos M. Galmarini, János Szöllősi, Peter Nagy
Dátum:2013
Megjegyzések:The mechanism of action of elisidepsin (PM02734, Irvalec(R)) is assumed to involve membrane permeabilization via attacking lipid rafts and hydroxylated lipids. Here we investigate the role of hypoxia in the mechanism of action of elisidepsin. Culturing under hypoxic conditions increased the half-maximal inhibitory concentration and decreased the drug's binding to almost all cell lines which was reversed by incubation of cells with 2-hydroxy palmitic acid. The expression of fatty acid 2-hydroxylase was strongly correlated with the efficiency of the drug and inversely correlated with the effect of hypoxia. Number and brightness analysis and fluorescence anisotropy experiments showed that hypoxia decreased the clustering of lipid rafts and altered the structure of the plasma membrane. Although the binding of elisidepsin to the membrane is non-cooperative, its membrane permeabilizing effect is characterized by a Hill coefficient of ~3.3. The latter finding is in agreement with elisidepsin-induced clusters of lipid raft-anchored GFP visualized by confocal microscopy. We propose that the concentration of elisidepsin needs to reach a critical level in the membrane above which elisidepsin induces the disruption of the cell membrane. Testing for tumor hypoxia or the density of hydroxylated lipids could be an interesting strategy to increase the efficiency of elisidepsin
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
analysis
Anisotropy
article
Biophysics
cell biology
Cell Line
Cell Membrane
Cells
Confocal
Confocal microscopy
EXPRESSION
Fluorescence
FLUORESCENCE ANISOTROPY
Hungary
lipid raft
LIPID RAFTS
Lipids
Microscopy
Research
Research Support
Support
Megjelenés:Marine Drugs. - 11 : 12 (2013), p. 4858-4875. -
További szerzők:Váradi Tímea (1982-) (okleveles vegyész) Hajdu Tímea (1991-) (biomérnök) Rühl, Ralph (1969-) (vegyész) Galmarini, Carlos M. Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
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2.

001-es BibID:BIBFORM066288
035-os BibID:(Cikkazonosító)35850 (WOS)000385927600001 (Scopus)84992409144
Első szerző:Kovács Tamás (általános orvos)
Cím:The Dipole Potential Modifies the Clustering and Ligand Binding Affinity of ErbB Proteins and Their Signaling Efficiency / Tamás Kovács, Gyula Batta, Tímea Hajdu, Ágnes Szabó, Tímea Váradi, Florina Zákány, István Csomós, János Szöllősi, Peter Nagy
Dátum:2016
ISSN:2045-2322
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Scientific Reports. - 6 (2016), p. 35850. -
További szerzők:Batta Gyula (1979-) (biológus) Hajdu Tímea (1991-) (biomérnök) Nagyné Szabó Ágnes Timea (1982-) (vegyész) Váradi Tímea (1982-) (okleveles vegyész) Zákány Florina (1989-) (általános orvos) Csomós István (1983-) (molekuláris biológus) Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
Pályázati támogatás:K103906
OTKA
NK101337
OTKA
GINOP-2.3.2-15-2016-00020
GINOP
TÁMOP-4.2.2.A-11/1/KONV-2012-0025
GINOP
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3.

001-es BibID:BIBFORM057539
035-os BibID:(scopus)84896847673 (wos)000332354700009
Első szerző:Mocanu, Maria-Magdalena
Cím:Epigallocatechin 3-O-gallate induces 67 kDa laminin receptor-mediated cell death accompanied by downregulation of ErbB proteins and altered lipid raft clustering in mammary and epidermoid carcinoma cells / Maria-Magdalena Mocanu, Constanta Ganea, Laura Georgescu, Tímea Váradi, Dilip Shrestha, Irina Baran, Eva Katona, Peter Nagy, János Szöllősi
Dátum:2014
ISSN:0163-3864
Megjegyzések:Since the administration of synthetic medicines is associated with drug resistance and undesired side effects, utilization of natural compounds could be an alternative and complementary modality to inhibit or prevent the development of tumors. Epigallocatechin 3-O-gallate (EGCG, 1), the major flavan component of green tea, and genistein (2), a soy isoflavonoid, are known to have chemopreventive and chemotherapeutic effects against cancer. This study demonstrated that both flavonoids inhibit cell proliferation, an effect enhanced under serum-free conditions. Compound 1, but not 2, induced downregulation of ErbB1 and ErbB2 in mammary and epidermoid carcinoma cells, and its inhibitory effect on cell viability was mediated by the 67 kDa laminin receptor (67LR). While 1 was superior in inducing cell death, 2 was more efficient in arresting the tumor cells in the G2/M phase. Furthermore, number and brightness analysis revealed that 1 decreased the homoclustering of a lipid raft marker, glycosylphosphatidylinositol-anchored GFP, and it also reduced the co-localization between lipid rafts and 67LR. The main conclusion made is that the primary target of 1 may be the lipid raft component of the plasma membrane followed by secondary changes in the expression of ErbB proteins. Compound 2, on the other hand, must have other unidentified targets.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Epigallocatechin
Molekuláris Medicina
Megjelenés:Journal Of Natural Products. - 77 : 2 (2014), p. 250-257. -
További szerzők:Ganea, Constanta Georgescu, Laura Váradi Tímea (1982-) (okleveles vegyész) Shrestha, Dilip (1980-) (biológus) Baran, Irina Katona Éva (1961-) (klinikai biokémikus) Nagy Péter (1971-) (biofizikus) Szöllősi János (1953-) (biofizikus)
Pályázati támogatás:TÁMOP-4.2.2-08/1-2008-0019
TÁMOP
TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
Receptor tirozin kinázok mint terápiás célpontok: működésük szabályozásának, és a közöttük fellépő molekuláris kölcsönhatások vizsgálata
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4.

001-es BibID:BIBFORM022767
Első szerző:Mocanu, Maria-Magdalena
Cím:Comparative analysis of fluorescence resonance energy transfer (FRET) and proximity ligation assay (PLA) / Mocanu M. M., Váradi T., Szöllosi J., Nagy P.
Dátum:2011
ISSN:1615-9853
Megjegyzések:Both fluorescence resonance energy transfer (FRET) and proximity ligation assay (PLA) are techniques used in the investigation of protein interactions but the latter has not been evaluated in a systematic way, prompting us to compare their performance quantitatively. Proteins were labeled with oligonucleotide- or fluorophore-conjugated antibodies and their proximity was analyzed by flow cytometry in order to obtain statistically robust data. Both intermolecular and intramolecular PLA signals reached saturation at high expression levels. At the same time, the FRET efficiency was independent of, while the FRET signal exhibited a strict linear correlation with the expression levels of proteins. When the density of oligonucleotide- and fluorophore-conjugated antibodies was systematically changed by competition with unlabeled antibodies the FRET signal was linearly proportional to the amount of bound fluorophore-tagged antibodies, whereas the PLA signal was again saturated. The saturation phenomenon in PLA could not be eliminated by decreasing the duration of the rolling circle amplification reaction. Our data imply that PLA is a semiquantitative measure of protein colocalizations due to non-linear effects in the reaction and that caution should be exercised when interpreting PLA data in a quantitative way.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Cell biology
Fluorescence resonance energy transfer
Flow cytometry
Protein associations
Proximity ligation assay
Megjelenés:Proteomics. - 11 : 10 (2011), p. 2063-2070. -
További szerzők:Váradi Tímea (1982-) (okleveles vegyész) Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
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5.

001-es BibID:BIBFORM071351
035-os BibID:(scopus)84963800113 (wos)000374730400007
Első szerző:Nagy Péter (biofizikus)
Cím:rFRET : a comprehensive, Matlab-based program for analyzing intensity-based ratiometric microscopic FRET experiments / Nagy Peter, Szabó Ágnes, Váradi Tímea, Kovács Tamás, Batta Gyula, Szöllősi János
Dátum:2016
ISSN:1552-4922 1552-4930
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Cytometry Part A. - 89 : 4 (2016), p. 376-384. -
További szerzők:Nagyné Szabó Ágnes Timea (1982-) (vegyész) Váradi Tímea (1982-) (okleveles vegyész) Kovács Tamás (1985-) (általános orvos) Batta Gyula (1979-) (biológus) Szöllősi János (1953-) (biofizikus)
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6.

001-es BibID:BIBFORM057540
035-os BibID:(scopus)84911424770 (wos)000344166300007
Első szerző:Nagy Péter (biofizikus)
Cím:Maximum likelihood estimation of FRET efficiency and its implications for distortions in pixelwise calculation of FRET in microscopy / Peter Nagy, Ágnes Szabó, Tímea Váradi, Tamás Kovács, Gyula Batta, János Szöllősi
Dátum:2014
ISSN:1552-4922 1552-4930
Megjegyzések:Ratiometric determination of the efficiency of fluorescence or Forster resonance energy € transfer (FRET) is one of the most widespread methods for the characterization of protein clustering and conformation. Low photon numbers, often present in pixel-by-pixel determination of FRET efficiency in digital microscopy, result in large uncertainties in the derived FRET parameter. Here, we propose a method based on maximum likelihood estimation (MLE) of FRET efficiency using photon counting detectors to overcome this limitation. Intensities measured in the donor, FRET, and acceptor channels were all assumed to follow Poisson statistics as a result of detector shot noise. The joint probability of photon numbers detected in the donor, FRET, and acceptor channels was derived using an equation describing the relationship between the three measured intensities. The FRET efficiency generating the measured photon numbers with the largest likelihood was determined iteratively providing a single FRET value for all pixels in the calculation. Since as few as 100 pixels are sufficient to provide a maximum likelihood estimate for FRET, biological variability in FRET values can be revealed by performing the analysis for regions of interests in an image. Since the algorithm provides the probability of a combination of donor, FRET, and acceptor intensities observed in each individual pixel given a certain FRET efficiency, outlier pixels with low probabilities could be excluded from the analysis. Simulations carried out with low photon numbers in the presence and absence of outlier pixels revealed that the proposed approach can reliably and reproducibly estimate FRET efficiency. In addition, systematic evaluation of the simulation results showed that the distribution of pixel-by-pixel FRET efficiencies is skewed, and the mean of these FRET values is a biased and unreliable estimate of the FRET efficiency. In the absence of outlier pixels, FRET calculated from summed donor, FRET, and acceptor intensities proved to be as reliable as MLE. We conclude that MLE of FRET outperforms calculations using summed and pixel-bypixel intensities in biologically relevant situations involving low photon numbers and outlier pixels.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
FRET
maximum likelihood estimation (MLE)
microscopy
Poisson statistics
error propagation
Megjelenés:Cytometry Part A. - 85 : 11 (2014), p. 942-952. -
További szerzők:Nagyné Szabó Ágnes Timea (1982-) (vegyész) Váradi Tímea (1982-) (okleveles vegyész) Kovács Tamás (1985-) (általános orvos) Batta Gyula (1979-) (biológus) Szöllősi János (1953-) (biofizikus)
Pályázati támogatás:TAMOP-4.2.2.A-11/1/KONV-2012-0025
TÁMOP
OTKA-K103906
OTKA
OTKA-NK101337
OTKA
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7.

001-es BibID:BIBFORM082149
035-os BibID:(WoS)000497815800015 (Scopus)85073927406
Első szerző:Váradi Tímea (okleveles vegyész)
Cím:Homo- and Heteroassociations Drive Activation of ErbB3 / Váradi Tímea, Schneider Magdalena, Sevcsik Eva, Kiesenhofer Dominik, Baumgart Florian, Batta Gyula, Kovács Tamás, Platzer René, Huppa Johannes B., Szöllősi János, Schütz Gerhard J., Brameshuber Mario, Nagy Peter
Dátum:2019
ISSN:0006-3495
Megjegyzések:Dimerization or the formation of higher-order oligomers is required for the activation of ErbB receptor tyrosine kinases. The heregulin receptor, ErbB3, must heterodimerize with other members of the family, preferentially ErbB2, to form a functional signal transducing complex. Here, we applied single molecule imaging capable of detecting long-lived and mobile associations to measure their stoichiometry and mobility, and analyzed data from experiments globally taking the different lateral mobility of monomeric and dimeric molecular species into account. Although ErbB3 was largely monomeric in the absence of stimulation and ErbB2 coexpression, a small fraction was present as constitutive homodimers exhibiting a ?40% lower mobility than monomers. Heregulin-stimulation increased the homodimeric fraction of ErbB3 significantly and reduced the mobility of homodimers 4-fold compared to constitutive homodimers. Expression of ErbB2 elevated the homodimeric fraction of ErbB3 even in unstimulated cells and induced a ~2-fold reduction in the lateral mobility of ErbB3 homodimers. The mobility of ErbB2 was significantly lower than that of ErbB3, and heregulin induced a less pronounced decrease in the diffusion coefficient of all ErbB2 molecules as well as its heterodimers with ErbB3. The slower diffusion of ErbB2 compared to ErbB3 was abolished by depolymerizing actin filaments, while ErbB2-expression induced a substantial rearrangement of microfilaments implying a bidirectional interaction between ErbB2 and actin. Heregulin stimulation of cells coexpressing ErbB3 and ErbB2 led to the formation of ErbB3 homodimers and ErbB3/ErbB2 heterodimers in a competitive fashion. While pertuzumab, an antibody binding to the dimerization arm of ErbB2, completely abolished the formation of constitutive and heregulin-induced ErbB3/ErbB2 heterodimers, it only slightly blocked ErbB3 homodimerization. The results imply that a dynamic equilibrium exists between constitutive and ligand-induced homo- and heterodimers capable of shaping transmembrane signaling.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Biophysical Journal. - 117 : 10 (2019), p. 1935-1947. -
További szerzők:Schneider, Magdalena Sevcsik Éva Kiesenhofer, Dominik Baumgart, Florian Batta Gyula (1979-) (biológus) Kovács Tamás (1985-) (általános orvos) Platzer, René Huppa, Johannes B. Szöllősi János (1953-) (biofizikus) Schütz, Gerhard Brameshuber, Mario Nagy Péter (1971-) (biofizikus)
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8.

001-es BibID:BIBFORM036695
Első szerző:Váradi Tímea (okleveles vegyész)
Cím:Binding of Trastuzumab to ErbB2 Is Inhibited by a High Pericellular Density of Hyaluronan / Tímea Váradi, Tamás Mersich, Päivi Auvinen, Raija Tammi, Markku Tammi, Ferenc Salamon, István Besznyák, Ferenc Jakab, Zsolt Baranyai, János Szöllősi, Peter Nagy
Dátum:2012
Megjegyzések:Although trastuzumab is an efficient drug, primary and acquired resistance is a challenging problem. The authors have previously shown in mouse xenograft experiments that masking ErbB2 by hyaluronan leads to diminished binding ofthe antibody and consequent resistance. In the current work, they correlated trastuzumab binding with the pericellular density of hyaluronan in ErbB2-overexpressing human breast cancer samples. A method for quantifying the relative binding of trastuzumab was developed involving constant and low-frequency background subtraction, segmenting the image to membrane and background pixels followed by evaluation of trastuzumab fluorescence, normalized with the expression level of ErbB2, only in the membrane. The normalized binding of trastuzumab showed a negative correlation with the pericellular density of hyaluronan (r = ?0.52) with the effect being the most pronounced in the extreme cases (i.e., low and high hyaluronan densities predicted strong and weak binding of trastuzumab, respectively). Removal of hyaluronan by hyaluronidase digestion unmasked the trastuzumab binding epitope of ErbB2 demonstrated by a significantly increasednormalized binding of the antibody. The results show that the accumulation of pericellular hyaluronan plays a rucial role in masking ErbB2.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
breast cancer
ErbB2
trastuzumab resistance
hyaluronan
epitope masking
Molekuláris Medicina
Megjelenés:Journal of Histochemistry & Cytochemistry 60 : 8 (2012), p. 567-575. -
További szerzők:Mersich Tamás (sebész) Auvinen, Paivi (kutatóorvos) Tammi, Raija (kutatóorvos) Tammi, Markku (kutatóorvos) Salamon Ferenc (1965-) Besznyák István (1980-) (sebész) Jr. Jakab Ferenc Baranyai Zsolt (sebész) Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
Pályázati támogatás:TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
Sejt biofizika
TÁMOP-4.2.2-08/1-2008-0019
TÁMOP
TÁMOP-4.2.2/B-10/1-2010-0024
TÁMOP
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9.

001-es BibID:BIBFORM022510
Első szerző:Váradi Tímea (okleveles vegyész)
Cím:ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment / Váradi T., Roszik J., Lisboa D., Vereb G., Molina-Guijarro J. M., Galmarini C. M., Szöllosi J., Nagy P.
Dátum:2011
Megjegyzések:Elisidepsin is a marine-derived anti-tumor agent with unique mechanism of action. It has been suggested to induce necrosis associated with severe membrane damage. Since indirect evidence points to the involvement of ErbB receptor tyrosine kinases and lipid rafts in the mechanism of action of elisidepsin, we investigated the effect of the drug on the distribution of ErbB proteins and systematically compared the elisidepsin sensitivity of cell lines overexpressing ErbB receptors. Stable expression of a single member of the ErbB family (ErbB1-3) or co-transfection of ErbB2 and ErbB3 did not modify the elisidepsin sensitivity of CHO and A431 cells. However, elisidepsin induced the redistribution of ErbB3 and two GPI-anchored proteins (transfected GPI-anchored eGFP and placental alkaline phosphatase) from the plasma membrane to intracellular vesicles without comparable effects on ErbB1 and ErbB2. Elisidepsin increased the binding of a conformational sensitive anti-ErbB3 antibody without modifying the binding of other ErbB2 or ErbB3 antibodies, and it decreased the homoassociation of both ErbB2 and ErbB3. We also found that elisidepsin decreased the fluorescence anisotropy of a membrane specific fluorescent probe and induced a blue shift in the emission spectrum of Laurdan pointing to significant changes in the order of the plasma membrane possibly associated with the formation of liquid ordered domains. Although the distribution of ErbB proteins is preferentially altered by elisidepsin, our data question their role in determining sensitivity to the drug. We assume that induction of liquid ordered domains is the primary action of elisidepsin leading to all the other observed changes.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Elisidepsin
ErbB proteins
Liquid ordered domain
FRET
Megjelenés:European Journal of Pharmacology 667 : 1-3 (2011), p. 91-99. -
További szerzők:Roszik János (1979-) (biofizikus) Lisboa, Duarte (1982-) (biotechnológus) Vereb György (1965-) (biofizikus, orvos) Molina-Guijarro, J. M. Galmarini, Carlos M. Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
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