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41.
ObjectiveWe investigated whether glutamate, NMDA receptors, and eukaryote elongation factor-2 kinase (eEF-2K)/eEF-2 regulate P-glycoprotein expression, and the effects of the eEF-2K inhibitor NH125 on the expression of P-glycoprotein in rat brain microvessel endothelial cells (RBMECs).MethodsCortex was obtained from newborn Wistar rat brains. After surface vessels and meninges were removed, the pellet containing microvessels was resuspended and incubated at 37°C in culture medium. Cell viability was assessed by the MTT assay. RBMECs were identified by immunohistochemistry with anti-vWF. P-glycoprotein, phospho-eEF-2, and eEF-2 expression were determined by western blot analysis. Mdr1a gene expression was analyzed by RT-PCR.ResultsMdr1a mRNA, P-glycoprotein and phospho-eEF-2 expression increased in L-glutamate stimulated RBMECs. P-glycoprotein and phospho-eEF-2 expression were down-regulated after NH125 treatment in L-glutamate stimulated RBMECs.ConclusionseEF-2K/eEF-2 should have played an important role in the regulation of P-glycoprotein expression in RBMECs. eEF-2K inhibitor NH125 could serve as an efficacious anti-multidrug resistant agent. 相似文献
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Yao Shen Yueyang Tian Xiaojie Shi Jianbo Yang Li Ouyang Jieqiong Gao Jianxin Lu 《Cell biochemistry and function》2014,32(6):530-537
Astrocytes play a key role in removing the synaptically released glutamate from the extracellular space and maintaining the glutamate below neurotoxic level in the brain. However, high concentration of glutamate leads to toxicity in astrocytes, and the underlying mechanisms are unclear. The purpose of this study was to investigate whether energy metabolism disorder, especially impairment of mitochondrial respiration, is involved in the glutamate‐induced gliotoxicity. Exposure to 10‐mM glutamate for 48 h stimulated glycolysis and respiration in astrocytes. However, the increased oxygen consumption was used for proton leak and non‐mitochondrial respiration, but not for oxidative phosphorylation and ATP generation. When the exposure time extended to 72 h, glycolysis was still activated for ATP generation, but the mitochondrial ATP‐linked respiration of astrocytes was reduced. The glutamate‐induced astrocyte damage can be mimicked by the non‐metabolized substrate d ‐aspartate but reversed by the non‐selective glutamate transporter inhibitor TBOA. In addition, the glutamate toxicity can be partially reversed by vitamin E. These findings demonstrate that changes of bioenergetic profile occur in cultured cortical astrocytes exposed to high concentration of glutamate and highlight the role of mitochondria respiration in glutamate‐induced gliotoxicity in cortical astrocytes. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
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J Gomez-Cambronero E Wang G Johnson C K Huang R I Sha'afi 《The Journal of biological chemistry》1991,266(10):6240-6245
The addition of platelet-activating factor (PAF) to human neutrophils increases the levels of the tyrosine phosphorylation in several proteins. These proteins have molecular weights of 41 (pp41), 54 (pp54), 66 (pp66), 104 (pp104), and 116 (pp116) kDa. The effect of PAF was dose-dependent and could be seen at concentrations as low as 1 nM. The nonmetabolizable bioactive PAF analog, C-PAF, caused an increase in the level of phosphorylation of the same proteins in a time- and dose-dependent manner. On the contrary, lyso-PAF, enantio-PAF, and L-beta,gamma-dihexadecyl-alpha-lecithin failed to stimulate the phosphorylation of any of the aforementioned proteins. The response to PAF was prevented by the PAF antagonist BN-52021. The PAF-induced increases in tyrosine phosphorylation in pp66, pp116, and pp104 were selectively inhibited by pertussis toxin. In contrast, the level of pp41 phosphorylation remained unchanged after the pertussis toxin treatment. The calcium chelator EGTA significantly inhibited the PAF-produced phosphorylation of the pp41 protein. The intracellular calcium chelator 1,2-bis-(O-aminophenoxil)ethane-N,N,N',N'-tetraacetic acid (BAPTA) potentiated the PAF-enhanced levels of tyrosine phosphorylation on the pp41 protein. On the other hand, the PAF-induced phosphorylations of pp66, pp104, and pp116 were inhibited in BAPTA-treated cells. The calcium ionophore A23187 selectively potentiated the phosphorylation of the pp41 protein and reduced the phosphorylation in the pp54 protein. This phosphorylation was dependent on the extracellular calcium and was inhibited in toxin-treated cells. The results suggest that PAF is able to affect either directly or indirectly tyrosine kinase and/or phosphotyrosine phosphatase activities. The phosphorylation of the high and low molecular weight proteins are mediated by two different sets of kinases and/or phosphatases. 相似文献
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Fatty acids and monoglycerides were evaluated in brain heart infusion broth and in milk for antimicrobial activity against the Scott A strain of Listeria monocytogenes. C12:0, C18:3, and glyceryl monolaurate (monolaurin) had the strongest activity in brain heart infusion broth and were bactericidal at 10 to 20 micrograms/ml, whereas potassium (K)-conjugated linoleic acids and C18:2 were bactericidal at 50 to 200 micrograms/ml. C14:0, C16:0, C18:0, C18:1, glyceryl monomyristate, and glyceryl monopalmitate were not inhibitory at 200 micrograms/ml. The bactericidal activity in brain heart infusion broth was higher at pH 5 than at pH 6. In whole milk and skim milk, K-conjugated linoleic acid was bacteriostatic and prolonged the lag phase especially at 4 degrees C. Monolaurin inactivated L. monocytogenes in skim milk at 4 degrees C, but was less inhibitory at 23 degrees C. Monolaurin did not inhibit L. monocytogenes in whole milk because of the higher fat content. Other fatty acids tested were not effective in whole or skim milk. Our results suggest that K-conjugated linoleic acids or monolaurin could be used as an inhibitory agent against L. monocytogenes in dairy foods. 相似文献
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Wang Ting-Ting Zhu Chen-Ye Zheng Shuang Meng Cai-Cai Wang Tian-Tian Meng Dan-Hua Li Yi-Jun Zhu Hao-Miao Wang Feng-Shan Sheng Ju-Zheng 《Applied microbiology and biotechnology》2018,102(11):4785-4797
Applied Microbiology and Biotechnology - Avibacterium paragallinarum is a Gram-negative bacterium that causes infectious coryza in chicken. It was reported that the capsule polysaccharides... 相似文献
50.
Improved two‐stage group sequential procedures for testing a secondary endpoint after the primary endpoint achieves significance 下载免费PDF全文
Huiling Li Jianming Wang Xiaolong Luo Janis Grechko Christopher Jennison 《Biometrical journal. Biometrische Zeitschrift》2018,60(5):893-902
In two‐stage group sequential trials with a primary and a secondary endpoint, the overall type I error rate for the primary endpoint is often controlled by an α‐level boundary, such as an O'Brien‐Fleming or Pocock boundary. Following a hierarchical testing sequence, the secondary endpoint is tested only if the primary endpoint achieves statistical significance either at an interim analysis or at the final analysis. To control the type I error rate for the secondary endpoint, this is tested using a Bonferroni procedure or any α‐level group sequential method. In comparison with marginal testing, there is an overall power loss for the test of the secondary endpoint since a claim of a positive result depends on the significance of the primary endpoint in the hierarchical testing sequence. We propose two group sequential testing procedures with improved secondary power: the improved Bonferroni procedure and the improved Pocock procedure. The proposed procedures use the correlation between the interim and final statistics for the secondary endpoint while applying graphical approaches to transfer the significance level from the primary endpoint to the secondary endpoint. The procedures control the familywise error rate (FWER) strongly by construction and this is confirmed via simulation. We also compare the proposed procedures with other commonly used group sequential procedures in terms of control of the FWER and the power of rejecting the secondary hypothesis. An example is provided to illustrate the procedures. 相似文献