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A Csordas

Publications and source records attributed to A Csordas.

At least 19 recordsLinked to original sources
PubMed2001

Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts.

We recently reported that butyrate, an inhibitor of histone deacetylases, is capable of inducing Fas-independent apoptosis in the acute lymphoblastic leukemia cell line CCRF-CEM. Here we demonstrate that butyrate enhances Fas-induced apoptosis in this cell line. The application of different histone deacetylase inhibitors revealed that tetra-acetylated histone H4 is associated with the amplifying effect of butyrate on Fas-induced cell death. FasL, Fas, FADD, RIP, caspase-8, caspase-3, Bid, FLIP(S+L), FLASH and FAP-1, proteins known to act within the Fas-apoptosis cascade, showed no changes in their expression levels in cells treated with butyrate compared with untreated cells. Analyses of Fas-oligomerization and Western blotting as well as enzyme activity assays of caspase-2, caspase-3 and caspase-8 suggest that butyrate enhances Fas-induced apoptosis downstream of Fas but upstream of caspase-8 activation. In immunoprecipitation experiments a 37 kD butyrate-regulated protein was detected which specifically interacts with caspase-8.

Apoptosis↗
PubMed2000

Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), in the concentration range of 20 microM and above, induced arrest in the S-phase and apoptosis in the T cell-derived T-ALL lymphocytic leukemia cell line CEM-C7H2 which is deficient in functional p53 and p16. Expression of transgenic p16/INK4A, which causes arrest in G0/G1, markedly reduced the percentage of apoptotic cells. Antagonist antibodies to Fas or FasL, or constitutive expression of crmA did not diminish the extent of resveratrol-induced apoptosis. Furthermore, a caspase-8-negative, Fas-resistant Jurkat cell line was sensitive to resveratrol-induced apoptosis which could be strongly inhibited in the Jurkat as well as in the CEM cell line by z-VAD-fmk and z-IETD-fmk. The almost complete inhibition by z-IETD-fmk and the lack of inhibition by crmA suggested caspase-6 to be the essential initiator caspase. Western blots revealed the massive conversion of procaspase-6 to its active form, while caspase-3 and caspase-2 were proteolytically activated to a much lesser extent.

Anti-Bacterial Agents↗
PubMed1999

Interaction between dexamethasone and butyrate in apoptosis induction: non-additive in thymocytes and synergistic in a T cell-derived leukemia cell line.

In thymocytes butyrate and trichostatin A are unable to augment dexamethasone-induced apoptosis. In cultured rat thymocytes the extent of apoptosis induced by dexamethasone alone did not increase by addition of 0.1 - 10 mM butyrate. Even more pronounced was the non-additive interrelationship between dexamethasone and trichostatin A, as trichostatin A-induced apoptosis was not only blocked by the presence of dexamethasone but dexamethasone-induced apoptosis was also partially inhibited in the presence of 0.1 - 0.5 microM trichostatin A. The fact that the non-additive relationship with dexamethasone for apoptosis induction was observed with both histone deacetylase inhibitors suggests that in thymocytes this phenomenon is related to histone acetylation. In contrast to this, in the human T cell-derived leukemia cell line CEM-C7H2, dexamethasone did not block butyrate- or trichostatin A-induced apoptosis; moreover, butyrate, in the concentration range of 0.1 - 1 mM, had a marked synergistic effect on dexamethasone-induced apoptosis. This synergism, however, was not mimicked by trichostatin A, indicating that the effect is not related to histone acetylation but rather due to a pleiotropic effect of butyrate. Furthermore, in CEM-C7H2 cells, at higher concentrations of butyrate (5 - 10 mM) or trichostatin A (0.4 - 0.8 microM), there was a minor but reproducible antagonistic effect of dexamethasone on apoptosis induced by each of the two histone deacetylase inhibitors, suggesting that this antagonistic effect too, is related to histone hyperacetylation.

Animals↗
PubMed1999

Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts.

The histone deacetylase inhibitor and potential anti-cancer drug sodium butyrate is a general inducer of growth arrest, differentiation, and in certain cell types, apoptosis. In human CCRF-CEM, acute T lymphoblastic leukemia cells, butyrate, and other histone deacetylase inhibitors caused G2/M cell cycle arrest as well as apoptotic cell death. Forced G0/G1 arrest by tetracycline-regulated expression of transgenic p16/INK4A protected the cells from butyrate-induced cell death without affecting the extent of histone hyperacetylation, suggesting that the latter may be necessary, but not sufficient, for cell death induction. Nuclear apoptosis, but not G2/M arrest, was delayed but not prevented by the tripeptide broad-range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (zVAD) and, to a lesser extent, by the tetrapeptide 'effector caspase' inhibitors benzyloxycarbonyl-Asp-Glu-Val-Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Glu-Ile-Asp.fluoromethyl-ketone (VEID); however, the viral protein inhibitor of 'inducer caspases', crmA, had no effect. Bcl-2 overexpression partially protected stably transfected CCRF-CEM sublines from butyrate-induced apoptosis, but showed no effect on butyrate-induced growth inhibition, further distinguishing these two butyrate effects. c-myc, constitutively expressed in CCRF-CEM cells, was down-regulated by butyrate, but this was not causative for cell death. On the contrary, tetracycline-induced transgenic c-myc sensitized stably transfected CCRF-CEM derivatives to butyrate-induced cell death.

Apoptosis↗
PubMed1996

Butyrate, aspirin and colorectal cancer.

In vitro, for animal cells generally, butyrate at millimolar concentrations is an inhibitor of growth. In vivo, however, colonocytes are able to grow in the environment of about 20 mM butyrate produced by bacterial fermentation on the luminal side of the colonic epithelium. An in vivo increase of the butyrate supply results in growth stimulation of cells in the colonic crypts. This discrepancy, namely, that in cell cultures butyrate is an inhibitor of growth, whereas in vivo it has a trophic effect, is the so called in vivo paradox of butyrate. In the present review it is pointed out that butyrate is an inhibitor of histone deacetylases and there is sufficient evidence for hyperacetylation being the mechanism of the in vitro growth-inhibiting effect of butyrate. As within animal cells hyperacetylation has to occur at a certain butyrate concentration (1-10 mM), it is postulated that the in vivo lack of inhibition and 'paradoxical' stimulation of growth is a result of a low intracellular steady state concentration of butyrate in the lower layers of the crypt in spite of the much higher butyrate concentration on the luminal side. As butyrate is the preferential source of energy for colonocytes, the in vivo trophic effect is not paradoxical, when in spite of an increase of the butyrate concentration in stool, the intracellular butyrate concentration of intestinal epithelial cells still remains below the inhibiting level. For mature non-dividing colonocytes which are programmed for apoptosis, there is no difference between the observations made in vitro or in vivo. Furthermore, recent developments are discussed which suggest that cyclo-oxygenase-2 may play an essential role in colonic carcinogenesis. Cyclo-oxygenase-2 is found to be expressed in most colorectal carcinomas, but not in normal non-transformed intestinal epithelial cells (DeWitt and Smith, 1995). Cyclo-oxygenase-2 overexpression makes intestinal epithelial cells resistant to butyrate-induced apoptosis (Tsujii and DuBois, 1995). This escape from butyrate-induced apoptosis appears to be an essential prerequisite for the development of colorectal cancer and suggests a functional role of butyrate in growth, differentiation and programmed cell death of colonic epithelial cells.

Acetylation↗
PubMed1992

Tissue-specific pattern of nonhistone high mobility group proteins in various organs of the chicken.

Electrophoretic analysis of tissue-specific differences of nonhistone high mobility group (HMG) proteins from nuclei of various organs of the chicken revealed that in organs with a higher proportion of replicating cells (thymus, Bursa Fabricii, spleen) the relative amount of HMG-17 is considerably higher than that of HMG-14; however, in transcriptionally active organs with a very small proportion of replicating cells (glandular stomach, liver) HMG-14 and HMG-17 are present at roughly equal and low amounts. In glandular stomach, liver and spleen, the relative contents of both HMG-1 and HMG-2 are markedly lower than in thymus and Bursa Fabricii. Moreover, the total amount of HMG proteins is higher in those organs which contain replicating lymphocytes.

Animals↗
PubMed1991

In-vivo treatment with 5-azacytidine causes degeneration of central lymphatic organs and induces autoimmune disease in the chicken.

In-vitro evidence suggests that DNA methylation may be involved in the development of forbidden immune responses that can result in autoimmune disease. In the present study we examined in-vivo effects of 5-azacytidine (5-azaC), a substance that inhibits DNA methylation, on the immune system and the occurrence of a spontaneous autoimmune disease in the chicken model. We found that (1) treatment of young normal chickens with 1.0 mg/kg 5-azaC on 7 consecutive days caused a rapid degeneration of the central lymphoid organs thymus and bursa; (2) this regimen with 5-azaC apparently inhibited B cell maturation, as the frequency of cytoplasmic Ig+ plasma cells in the bone marrow was found to be significantly reduced, whereas the total number of bone marrow cells was unchanged; and (3) a chronic low-dose (0.5 and 1.0 mg/kg) application of 5-azaC through 6 weeks was found to significantly enhance the spontaneous autoimmune thyroiditis in newly hatched chickens of the Cornell C strain, as determined by anti-thyroglobulin autoantibody titres and histological analysis of thyroid gland infiltration. The possible implications of these data for the generation of pathogenic autoimmune responses are discussed.

Animals↗
PubMed1990

Suitability of staining techniques for the detection and quantitation of nonhistone high mobility group proteins.

Three different staining techniques were compared for the detection of nonhistone high mobility group (HMG) proteins after acidic urea-polyacrylamide gel electrophoresis. Silver staining after glutaraldehyde fixation provides the highest detection sensitivity. Because of the acid solubility of HMG proteins special care has to be taken concerning fixation. Staining with colloidal CBB G-250 according to Neuhoff et al. is superior in sensitivity and reliability of quantitation when compared with noncolloidal Coomassie Brilliant Blue R-250. High detection sensitivity and reproducibility of quantitation are prerequisites for studying the tissue-specific expression of HMG proteins. In the present study tissue-specific differences in the molar amounts of various HMG proteins in thymus and erythrocytes of the chicken are documented by application of the methods tested.

Animals↗
PubMed1990

Interaction of free fatty acids with the erythrocyte membrane as affected by hyperthermia and ionizing radiation.

The interference of hyperthermia and ionizing radiation, respectively, with the effects of capric (10:0), lauric (12:0), myristic (14:0), oleic (cis-18:1) and elaidic (trans-18:1) acids on the osmotic resistance of human erythrocytes was investigated. The results are summarized as follows: (A) not only at 37 degrees, but also at 42 degrees and 47 degrees C lauric acid (12:0) represents the minimum chain length for the biphasic behaviour of protecting against hypotonic hemolysis at a certain lower concentration range and hemolysis promotion at subsequent higher concentrations; (B) with increasing temperatures the protecting as well as the hemolytic effects occur at lower concentrations of the fatty acids; (C) the increase of temperature promotes the extent of hemolysis and reduces the extent of protection against hypotonic hemolysis; (D) Gamma-irradiation of erythrocytes selectively affects the concentration of oleic acid at which maximum protection against hypotonic hemolysis occurs, without altering the minimum concentration for 100% hemolysis.

Decanoic Acids↗
PubMed1989

A proposal for a possible role of nucleosome positioning in the evolutionary adjustment of introns.

1. Prokaryotes and yeast have mostly intronless genes, whereas the presence of a large number of extended introns are characteristic of the genes of of multicellular eukaryotic organisms which, however, as an exception also have a few intronless genes. 2. According to the current view, the lack of introns in prokaryotic organisms and yeast is due to the selective pressure of a short cell division time. On the other hand, the presence of introns in multicellular eukaryotic organisms is explained by the lack of selective forces against them. 3. In the present hypothesis it is proposed that introns were used as tools in the course of evolution for the organization of eukaryotic genes within the repeating units of nucleosomes, since the distinct DNA conformations of the nucleosome core particle and of the linker region, respectively, represent a constraint for the positioning of genes. 4. Recently it was shown that initiation of transcription is inhibited when the promoter sequence is within a nucleosome. 5. Since the nucleosomal organization of DNA leads to a severely deformed DNA helix and recognition of sequences by regulatory proteins is likely to depend on the conformation of the double helix, it is postulated that for the different sizes of eukaryotic genes which have to be organized within repeating units of nucleosomes, introns provided the flexibility of adjustment for the positioning of regulatory sequences, by drifting in length, sequence and position.

Biological Evolution↗
PubMed1989

Chain length-dependent interaction of free fatty acids with the erythrocyte membrane.

Free fatty acids protect erythrocytes against hypotonic haemolysis in a certain low concentration range and become haemolytic at higher concentrations. The chain length dependence of this biphasic behaviour was investigated using human erythrocytes. The results can be summarized as follows: (i) A critical minimum chain length is required for both effects. Octanoic acid (C8) and fatty acids with a shorter chain length do not have any effect on the osmotic resistance of erythrocytes. (ii) Decanoic acid (C10) decreases the extent of hypo-osmotic haemolysis and does not become haemolytic at higher concentrations. (iii) Dodecanoic acid (C12) represents the minimum chain length for the typical concentration-dependent biphasic behaviour with protection against hypo-osmotic haemolysis at a certain low concentration range and subsequent haemolysis at higher concentrations. (iv) Tetradecanoic acid (C14) exhibits two concentration ranges of protection against hypo-osmotic haemolysis, each followed by haemolytic concentrations. (v) The observed effects are not correlated with the critical micellar concentrations of the investigated fatty acids.

Dose-Response Relationship, Drug↗
PubMed1988

Critical temperatures for the interaction of free fatty acids with the erythrocyte membrane.

Non-esterified long-chain fatty acids reduce the extent of hypotonic hemolysis at a certain low concentration range but cause hemolysis at higher concentrations. This biphasic behavior was investigated at different temperatures (0-37 degrees C) for lauric (12:0), myristic (14:0), palmitoleic (16:1), oleic (cis-18:1) and elaidic (trans-18:1) acids. The results are summarized as follows: (A) the fatty acids examined exhibit a high degree of specificity in their thermotropic behavior; (B) oleic acid protects against hypotonic hemolysis even at the highest concentrations, up to 15 degrees C, when it becomes hemolytic, but only in a limited concentration range; (C) elaidic acid does not affect the osmotic stability of erythrocytes up to 20 degrees C, when it starts protecting: above 30 degrees C, it becomes hemolytic at the highest concentrations; (D) palmitoleic acid is an excellent protecting agent at all temperatures in a certain concentration range, becoming hemolytic at higher concentrations; (E) lauric acid protects up to 30 degrees C and becomes hemolytic only above this temperature; (F) myristic acid exhibits an extremely unusual behavior at 30 and 37 degrees C by having alternating concentration ranges of protecting and hemolytic effects; (G) there is a common critical temperature for hemolysis at 30 degrees C for saturated and trans-unsaturated fatty acids; (H) the initial slope of Arrhenius plots of percent hemolysis at the concentration of maximum protection is negative for cis-unsaturated fatty acids and positive for saturated and trans-unsaturated fatty acids.

Erythrocyte Membrane↗
PubMed1988

Differential inhibition of mitogen induced T cell proliferation by 5-azacytidine and cytosine-arabinoside.

The cytotoxic drugs 5-azacytidine and cytosine-arabinoside influence the enzymatic methylation of DNA in opposite ways (1,2). The in vitro effects of these two drugs on Con A induced proliferation of thymic and splenic rat lymphocytes were investigated. Cytosine-arabinoside was found to inhibit mitogen induced proliferation already at a concentration of 0.001 microM, whereas 5-azacytidine was inhibitory only above concentrations of 1 microM. A stimulation of mitogen induced T cell proliferation was consistently seen with 5-azacytidine, but not with cytosine-arabinoside, at concentrations lower than the cytotoxic concentration. The results show that 5-azacytidine and cytosine-arabinoside interfere with mitogen stimulated lymphocyte proliferation by different mechanisms and suggest that hypomethylated DNA plays a role in the proliferation of T cells.

Animals↗
PubMed1987

Biphasic interaction of Triton detergents with the erythrocyte membrane.

Octylphenoxy polyoxyethylene ethers (Triton detergents) interact with the erythrocyte membrane in a biphasic manner, i.e. they stabilize erythrocytes against hypo-osmotic haemolysis at low concentrations (0.0001-0.01%, v/v), but become haemolytic at higher concentrations. This biphasic behaviour was demonstrated with Triton X-114, Triton X-100 and Triton X-102. However, a critical chain length is a prerequisite for the haemolytic effect, because Triton X-45, which differs from the other Tritons only by the shorter chain of the polyoxyethylene residue, does not exhibit this biphasic behaviour, but goes on protecting against osmotic rupture up to saturating concentrations. Even a 1% solution of Triton X-45 does not cause haemolysis. This structural specificity of Triton X-45, namely the lack of haemolysis and efficient stabilization against osmolysis even at higher concentrations of the detergent, is exhibited at 0 degree and 37 degrees C as well as at room temperature. Three conclusions are reached: (i) a critical chain length of the octylphenoxy polyoxyethylene ethers is required for the haemolytic effect; (ii) the different structural requirements would suggest that different mechanisms are responsible for the haemolytic and the stabilizing effect of amphiphilic substances; (iii) the results suggest that haemolysis is not caused simply by dissolution of the membrane by the detergent but is a rather more specific process.

Erythrocyte Membrane↗
PubMed1986

Temperature-dependent specificity of cis-trans isomeric fatty acid interaction with the erythrocyte membrane.

Stabilization of red cells against hypotonic haemolysis by cis-trans isomeric free C18 fatty acids occurs with pronounced specificity which is strongly temperature-dependent, but in a distinctly different manner for the two configurational isomers. Oleic acid (cis-18:1) stabilizes very efficiently at 0 degrees C, even at the highest concentrations. Elaidic acid (trans-18:1) causes neither stabilization nor haemolysis at this temperature. At room temperature (23 degrees C), elaidic acid acquires the ability to protect, without turning haemolytic at high concentrations. At 37 degrees C elaidic acid also becomes haemolytic. The protecting effect of oleic acid at 0 degrees C is the result of a rapid reaction. The characteristic, temperature-dependent specificity of cis-trans isomeric C18 fatty acid interaction with the red cell membrane appears to be a general phenomenon, since it was observed alike with erythrocytes of different species.

Animals↗
PubMed1986

Thymus involution induced by 5-azacytidine.

Hypomethylation of DNA, which can be achieved by incorporation of 5-azacytidine, has been correlated with derepression of genes. In order to examine the in vivo effects of 5-azacytidine on organ development and differentiation, young rats were treated with the drug. There was an almost complete reduction of thymus and a marked reduction of spleen weight, while other organs, including testes were only marginally affected. Control experiments with cytosine-arabinoside suggest that treatment with an inhibitor of DNA replication per se is not responsible for the very rapid thymus involution triggered by 5-azacytidine in rats. In spite of the drastic reduction of thymus and spleen weight, lymphocytes of these organs were not impaired in their response to the T cell mitogen Concanavalin A.

Animals↗