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991.
Claudia St?ubert Hasanuzzaman Bhuiyan Anna Lindahl Oliver Jay Broom Yafeng Zhu Saiful Islam Sten Linnarsson Janne Lehti? Anders Nordstr?m 《The Journal of biological chemistry》2015,290(13):8348-8359
Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid β-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies. 相似文献
992.
J?rg Willenborg Claudia Huber Anna Koczula Birgit Lange Wolfgang Eisenreich Peter Valentin-Weigand Ralph Goethe 《The Journal of biological chemistry》2015,290(9):5840-5854
Streptococcus suis is a neglected zoonotic pathogen that has to adapt to the nutritional requirements in the different host niches encountered during infection and establishment of invasive diseases. To dissect the central metabolic activity of S. suis under different conditions of nutrient availability, we performed labeling experiments starting from [13C]glucose specimens and analyzed the resulting isotopologue patterns in amino acids of S. suis grown under in vitro and ex vivo conditions. In combination with classical growth experiments, we found that S. suis is auxotrophic for Arg, Gln/Glu, His, Leu, and Trp in chemically defined medium. De novo biosynthesis was shown for Ala, Asp, Ser, and Thr at high rates and for Gly, Lys, Phe, Tyr, and Val at moderate or low rates, respectively. Glucose degradation occurred mainly by glycolysis and to a minor extent by the pentose phosphate pathway. Furthermore, the exclusive formation of oxaloacetate by phosphoenolpyruvate (PEP) carboxylation became evident from the patterns in de novo synthesized amino acids. Labeling experiments with S. suis grown ex vivo in blood or cerebrospinal fluid reflected the metabolic adaptation to these host niches with different nutrient availability; however, similar key metabolic activities were identified under these conditions. This points at the robustness of the core metabolic pathways in S. suis during the infection process. The crucial role of PEP carboxylation for growth of S. suis in the host was supported by experiments with a PEP carboxylase-deficient mutant strain in blood and cerebrospinal fluid. 相似文献
993.
N. Helge Meyer Hubert Mayerhofer Konstantinos Tripsianes Silke Blindow Daniela Barths Astrid Mewes Thomas Weimar Thies K?hli Steffen Bade Tobias Madl Andreas Frey Helmut Haas Jochen Mueller-Dieckmann Michael Sattler Gabriele Schramm 《The Journal of biological chemistry》2015,290(36):22111-22126
The IL-4-inducing principle from Schistosoma mansoni eggs (IPSE/α-1), the major secretory product of eggs from the parasitic worm S. mansoni, efficiently triggers basophils to release the immunomodulatory key cytokine interleukin-4. Activation by IPSE/α-1 requires the presence of IgE on the basophils, but the detailed molecular mechanism underlying activation is unknown. NMR and crystallographic analysis of IPSEΔNLS, a monomeric IPSE/α-1 mutant, revealed that IPSE/α-1 is a new member of the βγ-crystallin superfamily. We demonstrate that this molecule is a general immunoglobulin-binding factor with highest affinity for IgE. NMR binding studies of IPSEΔNLS with the 180-kDa molecule IgE identified a large positively charged binding surface that includes a flexible loop, which is unique to the IPSE/α-1 crystallin fold. Mutational analysis of amino acids in the binding interface showed that residues contributing to IgE binding are important for IgE-dependent activation of basophils. As IPSE/α-1 is unable to cross-link IgE, we propose that this molecule, by taking advantage of its unique IgE-binding crystallin fold, activates basophils by a novel, cross-linking-independent mechanism. 相似文献
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996.
Francesco Fazio Stefania Casella Claudia Giannetto Elisabetta Giudice Giuseppe Piccione 《Experimental Animals》2015,64(1):19-24
Haptoglobin (Hp), serum amyloid A (SAA), C-reactive protein (CRP), white blood cells
(WBC), reactive oxygen metabolites (ROMs), the antioxidant barrier (Oxy-adsorbent) and
thiol groups of plasma compounds (SHp) were measured in ten dogs that had been transported
a distance of about 230 km within 2 h (experimental group) and in ten dogs that had not
been subjected to road transportation (control group). Blood was collected via cephalic
venipuncture before road transportation (T0), after road transportation (T1), and more
than 6 (T6) and 24 (T24) hours after road transportation in the experimental group (Group
A) and at the same time points in the control group (Group B). The GLM (general linear
model) Repeated Measures procedure showed a significant difference between the two groups
(P<0.0001) and a significant rise (P<0.0001) in
the concentrations of Hp, SAA, CRP, WBC, ROMs, Oxy-adsorbent and SHp after road
transportation in Group A, underlining that physiological and homeostatic mechanisms are
modified differently at various sampling times. 相似文献
997.
David J. Aceti Craig A. Bingman Russell L. Wrobel Ronnie O. Frederick Shin-ichi Makino Karl W. Nichols Sarata C. Sahu Lai F. Bergeman Paul G. Blommel Claudia C. Cornilescu Katarzyna A. Gromek Kory D. Seder Soyoon Hwang John G. Primm Grzegorz Sabat Frank C. Vojtik Brian F. Volkman Zsolt Zolnai George N. Phillips Jr. John L. Markley Brian G. Fox 《Journal of structural and functional genomics》2015,16(2):67-80
998.
James J. Gilroy Graham W. Prescott Johann S. Cardenas Pamela González del Pliego Castañeda Andrés Sánchez Luis E. Rojas‐Murcia Claudia A. Medina Uribe Torbjørn Haugaasen David P. Edwards 《Global Change Biology》2015,21(4):1531-1540
Oil palm agriculture is rapidly expanding in the Neotropics, at the expense of a range of natural and seminatural habitats. A key question is how this expansion should be managed to reduce negative impacts on biodiversity. Focusing on the Llanos of Colombia, a mixed grassland–forest system identified as a priority zone for future oil palm development, we survey communities of ants, dung beetles, birds and herpetofauna occurring in oil palm plantations and the other principal form of agriculture in the region – improved cattle pasture – together with those of surrounding natural forests. We show that oil palm plantations have similar or higher species richness across all four taxonomic groups than improved pasture. For dung beetles, species richness in oil palm was equal to that of forest, whereas the other three taxa had highest species richness in forests. Hierarchical modelling of species occupancy probabilities indicated that oil palm plantations supported a higher proportion of species characteristic of forests than did cattle pastures. Across the bird community, occupancy probabilities within oil palm were positively influenced by increasing forest cover in a surrounding 250 m radius, whereas surrounding forest cover did not strongly influence the occurrence of other taxonomic groups in oil palm. Overall, our results suggest that the conversion of existing improved pastures to oil palm has limited negative impacts on biodiversity. As such, existing cattle pastures of the Colombian Llanos could offer a key opportunity to meet governmental targets for oil palm development without incurring significant biodiversity costs. Our results also highlight the value of preserving remnant forests within these agricultural landscapes, protecting high biodiversity and exporting avian ‘spill‐over’ effects into oil palm plantations. 相似文献
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1000.