排序方式: 共有22条查询结果,搜索用时 31 毫秒
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AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias 总被引:2,自引:0,他引:2
Sykes SM Lane SW Bullinger L Kalaitzidis D Yusuf R Saez B Ferraro F Mercier F Singh H Brumme KM Acharya SS Scholl C Schöll C Tothova Z Attar EC Fröhling S DePinho RA Armstrong SA Gilliland DG Scadden DT 《Cell》2011,146(5):697-708
AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors. We show a converse role for AKT/FOXOs in acute myeloid leukemia (AML). Rather than decreased FOXO activity, we observed that FOXOs are active in ~40% of AML patient samples regardless of genetic subtype. We also observe this activity in human MLL-AF9 leukemia allele-induced AML in mice, where either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth, with the latter markedly diminishing leukemia-initiating cell (LIC) function in vivo and improving animal survival. FOXO inhibition resulted in myeloid maturation and subsequent AML cell death. FOXO activation inversely correlated with JNK/c-JUN signaling, and leukemic cells resistant to FOXO inhibition responded to JNK inhibition. These data reveal a molecular role for AKT/FOXO and JNK/c-JUN in maintaining a differentiation blockade that can be targeted to inhibit leukemias with a range of genetic lesions. 相似文献
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Tarova ET Polakova H Kayserova H Celec P Zuzulova M Kadasi L 《General physiology and biophysics》2011,30(4):373-378
Lung infections are the leading cause of morbidity and mortality in cystic fibrosis (CF). Mannose-binding lectin (MBL) is a key factor in innate immunity. We therefore investigated whether MBL2 gene variants are associated with pulmonary function or susceptibility to Pseudomonas aeruginosa and Burkholderia cepacia infection in Slovak patients affected with CF. DNA polymorphisms in exon 1 and the promoter region were typed by single base primer extension assay in 91 patients and 100 healthy controls. The concentrations of MBL protein were determined in 34 patients by a sandwich enzyme-linked immunosorbent assay, and spirometric and microbiological data were collected from medical records. In this study we found that MBL2 genotypes were associated neither with earlier acquisition of P. aeruginosa or B. cepacia nor with reduced pulmonary function among patients. Although MBL2 genotypes were associated with the MBL2 protein serum level, results were statistically significant only for polymorphisms in exon 1, with p = 0.0008. The role of the MBL2 gene in lung disease severity in CF patients represents a very complex phenomenon where both genetic and environmental factors play an important role in addition to that of the MBL2 gene. Understanding this complexity requires further studies based on a broader scale of genetic factors involving both a whole-genome approach and a larger patient cohort. 相似文献
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Maria Kovalska Barbara Tothova Libusa Kovalska Zuzana Tatarkova Dagmar Kalenska Anna Tomascova Marian Adamkov Jan Lehotsky 《Neurochemical research》2018,43(9):1766-1778
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder that results in massive hippocampal and neocortical neuronal loss leading to dementia and eventual death. The exact cause of Alzheimer’s disease is not fully explored, although a number of risk factors have been recognized, including high plasma concentration of homocysteine (Hcy). Hyperhomocysteinemia (hHcy) is considered a strong, independent risk factor for stroke and dementia. However, the molecular background underlying these mechanisms linked with hHcy and ischemic stroke is not fully understood. Paper describes rat model of global forebrain ischemia combined with the experimentally induced hHcy. Global ischemia-reperfusion injury (IRI) was developed by 4-vessels occlusion lasting for 15 min followed by reperfusion period of 72 h. hHcy was induced by subcutaneous injection of 0.45 µmol/g of Hcy in duration of 14 days. The results showed remarkable neural cell death induced by hHcy in the brain cortex and neurodegeneration is further aggravated by global IRI. We demonstrated degeneration of cortical neurons, alterations in number and morphology of tissue astrocytes and dysregulation of oxidative balance with increased membrane protein oxidation. Complementary to, an immunohistochemical analysis of tau protein and β-amyloid peptide showed that combination of hHcy with the IRI might lead to the progression of AD-like pathological features. Conclusively, these findings suggest that combination of risk factor hHcy with IRI aggravates neurodegeneration processes and leads to development of AD-like pathology in cerebral cortex. 相似文献
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Claudio Gatto Luca Dainese Marina Buzzi Adriana Terzi Anna Guarino Pasquale Paolo Pagliaro Gianluca Polvani Jana D’Amato Tothova 《Cell and tissue banking》2013,14(2):205-212
The success of allotransplants is critically dependent on both tissue viability and efficient removal of potentially toxic cryopreservants. In this study we analysed the dimethyl sulphoxide (Me2SO) content of cardiovascular tissue samples stored in tissue banks and optimized a washing protocol to be used before surgical implant. We compared the Me2SO content of heart valves, arteries and veins and quantitatively determined by HPLC the washing kinetics of each group of tissue samples under strictly controlled conditions using an industrial washing medium (BASE). Our results showed that heart valves and arteries have significantly slower Me2SO release kinetics than veins. Approximately 20 % of the initial content of cryopreservant could still be detected in the valves and arterial tissue after 15 min of continuous washing. Conversely, veins were almost completely cleared of the cryoprotectant under the same conditions. We propose a washing protocol consisting of two sequential washing with BASE for a total of 25 min for valves and arteries and 15 min for veins. In our hands, this protocol reliably ensures the removal of more than 95 % of the initial Me2SO content. 相似文献
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Timea Tothova Anna Sobekova Katarina Holovska Jaroslav Legath Peter Pristas Peter Javorsky 《Central European Journal of Biology》2010,5(5):656-663
Bacteria and fungi from pristine soil, never exposed to glufosinate herbicide, were isolated and analyzed for glufosinate
tolerance. Seven of the 15 tested isolates were sensitive to 1 mM glufosinate (an active ingredient of many nonselective contact
herbicides), 5 were resistant to 4 mM glufosinate and 3 even to 8 mM glufosinate in liquid medium. None of the isolated microorganisms
carried the gene for glufosinate resistance bar (bialaphos resistance) in its genome and at least in some of glufosinate-resistant isolates the increased glutamine synthetase
level was detected as a possible resistance mechanism. The transfer of the bar glufosinate resistance gene from transgenic maize Bt 176 into glufosinate-sensitive soil bacterium Bacillus pumilus S1 was not detected under the laboratory conditions by a classical plate count method and PCR. The ecological risk of potential
bar gene transfer from genetically modified plants into soil microcosms under natural circumstances is discussed. 相似文献