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1.

001-es BibID:BIBFORM046090
Első szerző:Bacsó Zsolt (biofizikus)
Cím:Raft and cytoskeleton associations of an ABC transporter : P-glycoprotein / Zsolt Bacso, Henrietta Nagy, Katalin Goda, László Bene, Ferenc Fenyvesi, János Matkó, Gábor Szabó
Dátum:2004
ISSN:0196-4763
Megjegyzések:A novel flow cytometric assay has been described in an accompanying report (Gombos et al., METHODS: The kinetics of the decrease in immunofluorescence intensity was analyzed after the addition of the raft-preserving Triton X-100 or Nonidet P-40, both of which disrupt the entire membrane. Mild treatments by both detergents leave cells attached to only those proteins that are anchored to the cytoskeleton by rafts or independent of rafts. Agents that affect microfilaments and modulate membrane levels of cholesterol by cyclodextrin were used to distinguish between the raft-mediated and non-raft-related associations of the Pgp. Confocal microscopy and flow cytometric fluorescence energy transfer measurements were used to confirm colocalization of Pgp with raft constituents. RESULTS: The assay was proved to be sensitive enough to resolve differences between the resistance of UIC2-labeled cell-surface Pgps to Triton X-100 versus Nonidet P-40. Approximately 34% of the UIC2 Fab-labeled Pgp molecules were associated with the cytoskeleton through detergent-resistant, cholesterol-sensitive microdomains or directly, whereas approximately 15% were found to be directly linked to the cytoskeleton. Accordingly, confocal microscopy showed that Pgps colocalize with raft markers, mainly in microvilli. Fluorescence resonance energy transfer efficiency data indicating molecular proximity between Pgp and the raft markers CD44, CD59, and G(M1)-gangliosides also suggested that a significant fraction of Pgps resides in raft microdomains. Raft association of Pgp appears to be of functional significance because its modulation markedly affected drug pumping. CONCLUSIONS: By using the flow cytometric detergent resistance assay in kinetic mode, we were able to assess the extent of raft association and actin cytoskeleton anchorage of Pgp expressed at physiologically relevant levels. We demonstrated that a significant fraction of Pgp is raft associated on LS-174-T human colon carcinoma cells and that this localization may influence its transporter function. The kinetic flow cytometric detergent resistance assay presented in this report is considered to be generally applicable for the analysis of molecular interactions of membrane proteins expressed at low levelsújratöltve - BIBFORM004828
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Cytometry. - 61 : 2 (2004), p. 105-116. -
További szerzők:Nagy Henrietta Goda Katalin (1969-) (biofizikus) Bene László (1963-) (biofizikus) Fenyvesi Ferenc (1977-) (gyógyszerész, gyógyszertechnológus) Matkó János (1952-) (biológus) Szabó Gábor (1953-) (biofizikus)
Pályázati támogatás:T032563
OTKA
034393
OTKA
T046945
OTKA
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DOI
Intézményi repozitóriumban (DEA) tárolt változat
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2.

001-es BibID:BIBFORM067229
Első szerző:Goda Katalin (biofizikus)
Cím:Flow cytometric functional assays for the detection of p-glycoprotein and multidrug resistance-associated protein / Goda Katalin, Szakács Gergely, Nagy Henrietta, Szabó Gábor, Sarkadi Balázs
Dátum:1998
ISBN:9639070319
Tárgyszavak:Orvostudományok Elméleti orvostudományok könyvfejezet
flow cytometry
Megjelenés:Practical guide to physical analysis of cell surface receptors / Szerk. Krasznai Zoltán, Mátyus László. - p. 110-126. -
További szerzők:Szakács Gergely Nagy Henrietta Szabó Gábor (1953-) (biofizikus) Sarkadi Balázs
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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3.

001-es BibID:BIBFORM039166
035-os BibID:(scopus)0036272752 (wos)000175906900005
Első szerző:Goda Katalin (biofizikus)
Cím:Effects of ATP depletion and phosphate analogues on P-glycoprotein conformation in live cells / Goda, K., Nagy, H., Mechetner, E., Cianfriglia, M., Szabo, G.
Dátum:2002
ISSN:0014-2956
Megjegyzések:P-glycoprotein (Pgp), a membrane pump often responsible for the multidrug resistance of cancer cells, undergoes conformational changes in the presence of substrates/modulators, or upon ATP depletion, reflected by its enhanced reactivity with the UIC2 monoclonal antibody. When the UIC2-shift was elicited by certain modulators (e.g. cyclosporin A or vinblastine, but not with verapamil or Tween 80), the subsequent binding of other monoclonal anti-Pgp Ig sharing epitopes with UIC2 (e.g. MM12.10) was abolished [Nagy, H., Goda, K., Arceci, R., Cianfriglia, M., Mechetner, E. & Szabó Jr, G. (2001) Eur. J. Biochem.268, 2416?2420]. To further study the relationship between UIC2-shift and the suppression of MM12.10 binding, we compared, on live cells, how ATP depletion and treatment of cells with phosphate analogues (sodium orthovanadate, beryllium fluoride and fluoro-aluminate) that trap nucleotides at the catalytic site, affect the two phenomena. Similarly to modulators or ATP depleting agents, all the phosphate analogues increased daunorubicin accumulation in Pgp-expressing cells. Prelabeling of ATP depleted cells with UIC2 completely abolished the subsequent binding of MM12.10, in accordance with the enhanced binding of the first mAb. Vanadate and beryllium fluoride, but not fluoro-aluminate, reversed the effect of cyclosporin A, preventing UIC2 binding and allowing for labeling of cells with MM12.10. Thus, changes in UIC2 reactivity are accompanied by complementary changes in MM12.10 binding also in response to direct modulation of the ATP-binding site, confirming that conformational changes intrinsic to the catalytic cycle are reflected by both UIC2-related phenomena. These data also fit a model where the UIC2 epitope is available for antibody binding throughout the catalytic cycle including the step of ATP binding, to become unavailable only in the catalytic transition state.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:European Journal Of Biochemistry. - 269 : 11 (2002), p. 2672-2677. -
További szerzők:Nagy Henrietta Mechetner, Eugene Cianfriglia, Maurizio Szabó Gábor (1953-) (biofizikus)
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Intézményi repozitóriumban (DEA) tárolt változat
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4.

001-es BibID:BIBFORM002233
035-os BibID:WOS:000242995600010
Első szerző:Goda Katalin (biofizikus)
Cím:Complete inhibition of P-glycoprotein by simultaneous treatment with a distinct class of modulators and the UIC2 monoclonal antibody / Katalin Goda, Ferenc Fenyvesi, Zsolt Bacsó, Henrietta Nagy, Teréz Márián, Attila Megyeri, Zoltán Krasznai, István Juhász, Miklós Vecsernyés, Gábor Szabó
Dátum:2007
Megjegyzések:P-glycoprotein (Pgp) is one of the active efflux pumps that are able to extrude a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance. The conformation-sensitive UIC2 monoclonal antibody potentially inhibits Pgp-mediated substrate transport. However, this inhibition is usually partial, and its extent is variable because UIC2 binds only to 10 to 40% Pgp present in the cell membrane. The rest of the Pgp molecules become recognized by this antibody only in the presence of certain substrates or modulators, including vinblastine, cyclosporine A (CsA), and SDZ PSC 833 (valspodar). Simultaneous application of any of these modulators and UIC2, followed by the removal of the modulator, results in a completely restored steady-state accumulation of various Pgp substrates (calcein-AM, daunorubicin, and 99mTc-hexakis-2- methoxybutylisonitrile), indicating near 100% inhibition of pump activity. Remarkably, the inhibitory binding of the antibody is brought about by coincubation with concentrations of CsA or SDZ PSC 833 20 times lower than what is necessary for Pgp inhibition when the modulators are applied alone. The feasibility of such a combinative treatment for in vivo multidrug resistance reversal was substantiated by the dramatic increase of daunorubicin accumulation in xenotransplanted Pgp tumors in response to a combined treatment with UIC2 and CsA, both administered at doses ineffective when applied alone. These observations establish the combined application of a class of modulators used at low concentrations and of the UIC2 antibody as a novel, specific, and effective way of blocking Pgp function in vivo.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
UIC2 monoclonal antibody
P-glycoprotein
Megjelenés:The Journal of Pharmacology and Experimental Therapeutics 320 : 1 (2007), p. 81-88. -
További szerzők:Fenyvesi Ferenc (1977-) (gyógyszerész, gyógyszertechnológus) Bacsó Zsolt (1963-) (biofizikus) Nagy Henrietta Márián Teréz (1950-) (radiobiológus) Megyeri Attila (1968-) (orvos) Krasznai Zoltán (1950-) (biofizikus) Juhász István (1956-) (bőrgyógyász, bőrsebész, kozmetológus, klinikai onkológus) Vecsernyés Miklós (1959-) (gyógyszertechnológus, endokrinológus) Szabó Gábor (1980-) (orvos) jr
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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5.

001-es BibID:BIBFORM046091
Első szerző:Gombos Imre
Cím:Cholesterol sensitivity of detergent resistance : a rapid flow cytometric test for detecting constitutive or induced raft association of membrane proteins / Imre Gombos, Zsolt Bacsó, Cynthia Detre, Henrietta Nagy, Katalin Goda, Márton Andrásfalvy, Gábor Szabó, János Matkó
Dátum:2004
ISSN:0196-4763
Megjegyzések:Lipid rafts are cholesterol- and glycosphingolipid-rich microdomains in the cellular plasma membranes that play critical roles in compartmentalization (concentration, coupling, and isolation) of receptors and signal molecules. Therefore, detecting constitutive or induced raft associations of such proteins is of central interest in cell biology. This has mostly been done with time- and cell-consuming immunobiochemical techniques affected by several sources of artifacts. A flow cytometric analysis of immunocytochemical staining under differential circumstances of detergent treatment offers a new alternative to this method. METHODS: Membrane microdomains are resistant to nonionic detergents due to extensive, strong interactions between their molecular constituents. We used this feature to develop a rapid flow cytometric assay of differential detergent resistance based on immunocytochemical labeling of extracellular domain epitopes in membrane proteins. Data evaluation is based on comparative detection of their detergent solubility without and with cholesterol depletion of cell membranes, resolved by moderate concentrations of nonionic detergents. RESULTS: Nonionic detergents Triton X-100 and Nonidet-40 (0.05-0.1%) in cold or Brij-98 (0.1-0.5%) at 37 degrees C efficiently resolved detergent solubility or resistance of many lymphocyte cell surface proteins. Kinetic data revealed that a short (5-10 min) detergent treatment is sufficient for this assay. Comparison of detergent solubility in untreated and cholesterol-depleted cells differentiated membrane proteins associated with or excluded from raft microdomains, respectively. Confocal microscopy showed that this mild detergent treatment leaves the cytoskeleton of the cells intact, with a detectable expression of raft marker detergent-resistant proteins attached to it. An induced association with rafts of immunoglobulin E receptors upon antigen cross-linking was also easily detectable in rat mast cells by this approach. CONCLUSIONS: A protocol is proposed for a rapid (5-10 min) test of detergent resistance of membrane proteins in cells. The approach requires only a small amount of cells (10(4)/sample) and offers a good resolution of detergent solubility or resistance of membrane proteins, also in terms of the underlying mechanisms, with an advantage of applicability for all conventional bench-top flow cytometers.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Cytometry. Part A. - 61A : 2 (2004), p. 117-126. -
További szerzők:Bacsó Zsolt (1963-) (biofizikus) Detre, Cynthia Nagy Henrietta Goda Katalin (1969-) (biofizikus) Andrásfalvy Márton Szabó Gábor (1953-) (biofizikus) Matkó János (1952-) (biológus)
Pályázati támogatás:T034393
OTKA
TS044711
OTKA
T032563
OTKA
T046945
OTKA
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
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6.

001-es BibID:BIBFORM045960
035-os BibID:PMID:12830325
Első szerző:Márián Teréz (radiobiológus)
Cím:In vivo and in vitro multitracer analyses of P-glycoprotein expression-related multidrug resistance / Teréz Márián, Gábor Szabó, Katalin Goda, Henrietta Nagy, Nóra Szincsák, István Juhász, László Galuska, László Balkay, Pál Mikecz, Lajos Trón, Zoltán Krasznai
Dátum:2003
ISSN:1619-7070
Megjegyzések:P-glycoprotein (Pgp) is an ABC (ATP binding cassette) transporter that is often overexpressed in tumours, contributing significantly to their multidrug resistance. In this study, we explored whether the radiotracers used in tumour diagnostics can be used for in vivo visualisation of Pgp-related multidrug resistance. We also examined the effects of different Pgp modulators on the accumulation of these radioligands in tumours with or without Pgp expression. In a SCID BC-17 mouse model, cells of the drug-sensitive KB-3-1 (MDR(-)) and the KB-V1 Pgp-expressing (MDR(+)) human epidermoid carcinoma cell lines were inoculated to yield tumours in opposite flanks. For in vivo scintigraphic (biodistribution) and positron emission tomography (PET) examinations, the mice were injected with technetium-99m hexakis-2-methoxybutylisonitrile ((99m)Tc-MIBI), carbon-11 labelled methionine and fluorine-18 fluoro-2-deoxy- d-glucose ((18)FDG). For validation, in vitro cell studies with (99m)Tc-MIBI,( 99m)Tc-tetrofosmin, [(11)C]methionine and (18)FDG were carried out using a gamma counter. The expression and function of the MDR product were proved by immunohistochemistry and spectrofluorimetry. (99m)Tc-MIBI uptake was significantly lower in KB-V1 cells as compared with KB-3-1-derived tumours in vivo (Pgp(+)/Pgp(-) =0.61+/-0.13; P<0.01) and cells in vitro (Pgp(+)/Pgp(-) =0.08+/-0.01; P<0.001).()Cyclosporin A reversed (99m)Tc-MIBI uptake in the Pgp+ cells, while verapamil failed to modify it. (18)FDG uptake was significantly higher in KB-V1 tumours (Pgp(+)/Pgp(-) =1.36+/-0.05; P<0.01) and cells (Pgp(+)/Pgp(- )=1.52+/-0.12; P<0.001). Whereas cyclosporin A eliminated the difference between FDG uptake in MDR(+) and MDR(-) cell lines, verapamil significantly increased it. When the animals were treated with verapamil, the ratio of (99m)Tc-MIBI uptake in the MDR(+) tumours to that in the MDR(-) tumours decreased to 0.38+/-0.05 ( P<0.01), while the ratio of (18)FDG uptake increased to 2.1+/-0.3 ( P<0.001). There were no significant differences in the [(11)C]methionine uptake in the MDR(+) and MDR(-) tumours and cell lines, nor was [(11)C]methionine accumulation modified by cyclosporin A. Parallel administration of (18)FDG and (99m)Tc-MIBI combined with verapamil treatment seems to be a good candidate as a non-invasive marker for the diagnosis of MDR-related Pgp expression in tumours.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:European Journal of Nuclear Medicine and Molecular Imaging 30 : 8 (2003), p. 1147-1154. -
További szerzők:Szabó Gábor (1953-) (biofizikus) Goda Katalin (1969-) (biofizikus) Nagy Henrietta Szincsák Nóra Juhász István (1956-) (bőrgyógyász, bőrsebész, kozmetológus, klinikai onkológus) Galuska László (1946-) (belgyógyász, izotópdiagnoszta) Balkay László (1963-) (biofizikus) Mikecz Pál (1956-) (vegyész) Trón Lajos (1941-) (biofizikus) Krasznai Zoltán (1950-) (biofizikus)
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Intézményi repozitóriumban (DEA) tárolt változat
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7.

001-es BibID:BIBFORM040018
Első szerző:Nagy Henrietta
Cím:P-Glycoprotein conformational changes detected by antibody competition / Nagy Henrietta, Goda Katalin, Arceci Robert, Cianfriglia Maurizio, Mechetner Eugene, Szabó Gábor jr.
Dátum:2001
ISSN:0014-2956
Megjegyzések:Conformational changes accompanying P-glycoprotein (Pgp) mediated drug transport are reflected by changes in the avidity of certain monoclonal antibodies (mAbs). More of the UIC2 mAb binds to Pgp-expressing cells in the presence of substrates or modulators [Mechetner, E.B., Schott, B., Morse, S.B., Stein, W., Druley, T., Dvis, K.A., Tsuruo, T. & Roninson, I.B. (1997) Proc. Natl Acad. Sci. USA 94, 12908-12913], while the binding of other mAbs (e.g. MM12.10, MRK16, 4E3) is not conformation sensitive. Pre-staining of Pgp+ cells with UIC2 decreased the subsequent binding of MM12.10 mAb by about 30-40%, suggesting that there are Pgp molecules available for both UIC2 and MM12.10, and others accessible only for MM12.10. In the presence of certain substrates/modulators such as vinblastin, cyclosporin A or valinomycin, the MM12.10 reactivity was completely abolished by preincubation with UIC2. However, verapamil, Tween-80 and nifedipine did not influence the ratio of bound mAbs significantly. This is the first assay to our knowledge, sharply distinguishing two classes of modulators. The conformational changes accompanying the mAb competition phenomenon appear to be closely related, though not identical to those accompanying the UIC2-shift, as suggested by the simultaneous assessment of the two phenomena.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
3T3 Cells
Animal
Antibiotics
Antibiotics,Peptide
Antibodies
Antibodies,Monoclonal
Antineoplastic Agents
Antineoplastic Agents,Phytogenic
Binding,Competitive
Biophysics
Calcium
Calcium Channel Blockers
Cells
chemistry
Cyclosporine
Drug Resistance,Neoplasm
Enzyme Inhibitors
Flow Cytometry
Human
Hungary
metabolism
Mice
Nifedipine
P-Glycoprotein
pharmacology
Polysorbates
Protein Binding
Protein Conformation
Substrate Specificity
Support,Non-U.S.Gov't
Tumor Cells,Cultured
Valinomycin
Verapamil
Vinblastine
Megjelenés:European Journal Of Biochemistry. - 268 : 8 (2001), p. 2416-2420. -
További szerzők:Goda Katalin (1969-) (biofizikus) Arceci, Robert Cianfriglia, Maurizio Mechetner, Eugene Szabó Gábor (1980-) (orvos) jr
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Intézményi repozitóriumban (DEA) tárolt változat
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8.

001-es BibID:BIBFORM004839
035-os BibID:(WOS)000220105600025 (scopus)1342345242
Első szerző:Nagy Henrietta
Cím:Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies / Nagy, H., Goda, K., Fenyvesi, F., Bacso, Z., Szilasi, M., Kappelmayer, J., Lustyik, G., Cianfriglia, M., Szabo, G.
Dátum:2004
Megjegyzések:P-glycoprotein (Pgp) is one of the ABC transporters responsible for the multidrug resistance of cancer cells. The conformational changes of Pgp that occur in the presence of substrates/modulators or ATP depletion are accompanied by the up-shift of UIC2 monoclonal antibody (mAb) binding. In the case of cyclosporin A, vinblastine or valinomycin, this up-shift was found to be concomitant with the near-complete suppression of labeling with other mAbs specific for Pgp epitopes overlapping with UIC2, while pre-treatment with verapamil or Tween 80 brings about a modest suppression. Here we have extended these observations to 44 Pgp interacting agents, and found that only 8 fall into the cyclosporin-like category, inducing a conformational state characterized by the complete UIC2 dominance. The rest of the drugs either did not affect antibody competition or had a modest effect. Thus, Pgp substrates/modulators can be classified into distinct modalities based on the conformational change they elicit.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Adenosine
Adenosine Triphosphatases
Animals
Anti-Bacterial Agents
Antibodies
Antibodies,Monoclonal
Antineoplastic Agents
Binding,Competitive
Biophysics
Calcium
Calcium Channel Blockers
Cells
Cyclosporine
Detergents
Drug Resistance,Multiple
Drug Resistance,Neoplasm
Epitopes
Flow Cytometry
Fluorescein
Fluoresceins
genetics
Humans
Hungary
immunology
Ivermectin
metabolism
Mice
Nih 3T3 Cells
P-Glycoprotein
pharmacology
physiology
Research
Substrate Specificity
Support
Valinomycin
Verapamil
Vinblastine
egyetemen (Magyarországon) készült közlemény
Megjelenés:Biochemical and Biophysical Research Communications. - 315 : 4 (2004), p. 942-949. -
További szerzők:Goda Katalin (1969-) (biofizikus) Fenyvesi Ferenc (1977-) (gyógyszerész, gyógyszertechnológus) Bacsó Zsolt (1963-) (biofizikus) Szilasi Mária (1953-) (tüdőgyógyász, klinikai immunológus, allergológus, belgyógyász) Kappelmayer János (1960-) (laboratóriumi szakorvos) Lustyik György Cianfriglia, Maurizio Szabó Gábor (1953-) (biofizikus)
Internet cím:elektronikus változat
DOI
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