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  • 1
    Publication Date: 2012-02-22
    Description: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from alpha-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478770/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478770/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Chao -- Ward, Patrick S -- Kapoor, Gurpreet S -- Rohle, Dan -- Turcan, Sevin -- Abdel-Wahab, Omar -- Edwards, Christopher R -- Khanin, Raya -- Figueroa, Maria E -- Melnick, Ari -- Wellen, Kathryn E -- O'Rourke, Donald M -- Berger, Shelley L -- Chan, Timothy A -- Levine, Ross L -- Mellinghoff, Ingo K -- Thompson, Craig B -- R01 CA078831/CA/NCI NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 15;483(7390):474-8. doi: 10.1038/nature10860.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343901" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/cytology/drug effects/metabolism ; Animals ; Astrocytes/cytology/drug effects ; Cell Differentiation/drug effects/*genetics ; Cell Line, Tumor ; Cell Lineage/genetics ; DNA Methylation/drug effects ; Enzyme Induction/drug effects ; Gene Expression Regulation/drug effects ; Glioma/enzymology/genetics/pathology ; Glutarates/metabolism/pharmacology ; HEK293 Cells ; Histones/*metabolism ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors/*genetics/metabolism ; Jumonji Domain-Containing Histone Demethylases/antagonists & ; inhibitors/deficiency/genetics/metabolism ; Methylation/drug effects ; Mice ; Mutation/*genetics ; Neural Stem Cells/metabolism ; Promoter Regions, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 234 (1971), S. 352-354 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] It is possible that the high estimates from bioassays in the human are due to non-specific factors, and preliminary data using a specific radioimmunoassay have shown that oxytocin in the maternal circulation does not usually exceed 1 µU/ml. (ref. 6). By contrast, oxytocin levels in foetal ...
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1041
    Keywords: ACE inhibitors ; Posture ; diuretics ; cardiac failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The diuretic and natriuretic response to an intravenous dose of frusemide 40 mg was assessed in the erect and supine positions in 10 patients with cardiac failure who were being treated with enalapril 10 mg twice daily in addition to diuretics (Enalapril group) and in 10 patients with cardiac failure taking diuretics alone (Control group). Total 4 h diuresis in the erect position was 728 ml and in the supine position was 824 ml in the patients taking enalapril compared to 655 ml in the erect position and 1166 ml in the supine position in those patients taking diuretics alone. Total 4 h natriuresis in the erect positions was 78 mmol and in the supine position was 85 mmol in patients taking enalapril 10 mg twice daily but in those patients taking diuretics alone total 4 h natriuresis in the erect position was 67 mmol increasing to 120 mmol in the supine position. Measurements of plasma renin activity and plasma angiotensin II concentration confirmed effective converting enzyme inhibition, in the group of patients taking enalapril, but in those patients taking diuretics alone the erect position was associated with an increase in plasma renin activity, and plasma concentrations of angiotensin II and aldsterone. We conclude that the renin angiotensin system is a major factor in mediating the effect of posture on loop diuretic drugs.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1041
    Keywords: Haemodynamic responses ; Captopril ; Cardiac failure ; plasma renin activity ; angiotensin II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have given a series of incremental intravenous injections of captopril to ten patients with chronic cardiac failure. Small doses of captopril produced significant changes in pulmonary artery end-diastolic pressure and right atrial pressure, up to a total cumulative dose of captopril of 2.5 mg, after which further injections had no significant effect. There were large changes in systemic vascular resistance and blood pressure up to a cumulative dose of captopril of 5.0 mg, after which the injection of larger doses caused no further significant changes. Small doses of intravenous captopril produced large increases in plasma renin activity and plasma angiotensin I concentrations up to a total cumulative dose of captopril of 1.25 mg, after which there were no significant further changes in either plasma renin activity or plasma angiotensin I concentration. However the plasma concentration of angiotensin II fell more slowly, no further change being recorded after a total cumulative dose of captopril of 10 mg. These results suggest that plasma renin activity is not the only determinant of plasma angiotensin II concentrations.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1041
    Keywords: Platelet aggregation, Ketanserin ; sodium diet, pharma renin activity, platelet 5-HT2 receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have investigated the effect of varying sodium intake on the renin-angiotensin system, ADP-induced patelet aggregationin vitro, and blood 5-HT concentrations in 9 male volunteers. Systolic blood pressure was slightly reduced during a low sodium diet, whereas the diastolic pressure remained unchanged. Plasma renin activity and aldosterone concentration both fell significantly when sodium intake was increased; plasma angiotensin lI concentraion also fell, but not significantly. There was a significant fall in haematocrit after an increased sodium intake, but there was no change in the whole-blood platelet count after correcting for this. There were no significant changes in either total (i. e. PRP) or platelet 5-HT concentrations. The extent of platelet aggregation induced by 5 and 20 μmol · 1−1 of ADP increased significantly when dietary sodium intake was increased. When compared with low or normal sodium intakes, lower concentrations of ADP were required to produce 50% of maximum aggregation after a high sodium intake. The 5-HT2, receptor antagonist ketanserin (1 μmol · 1−1 in vitro) reduced the extent of aggregation induced by 5 μmol · 1−1 ADP after the volunteers had taken a high sodium diet, whereas the angiotensin 11 receptor anatgonist saralasin (1 nmol-1−1) increased the rate of aggregation after the low sodium diet. Thus, during a high sodium intake, human platelets become more sensitive to the aggregating agent ADP It is possible that this effect is mediatedvia platelet 5-HT2 receptors, since ketanserin abolished the increase in salt-induced aggregation seen with 5 μmol · 1−1 ADP.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1041
    Keywords: Captopril ; Blood platelets ; angiotensin II ; 5-hydroxytryptamine ; platelet aggregation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the acute and chronic effects of an ACE inhibitor (captopril) on platelet function and the renin-angiotensin system in patients with congestive heart failure. Plasma concentrations of angiotensin II fell significantly after a single dose of captopril (25 mg) and during long-term treatment with captopril (2 weeks, 75 mg/day). Plasma renin activity increased significantly after both the single and repeated doses. Captopril did not affect ADP-induced platelet aggregation or concentrations. It seems unlikely that circulating angiotensin II affects ADP-induced platelet aggregation in patients with congestive heart failure.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2018-07-20
    Description: Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of β-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase domain–focused CRISPR-Cas9–based genetic screen with a newly optimized single-guide RNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.
    Keywords: Medicine, Diseases, Molecular Biology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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