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151.
Sandoval R González A Caviedes A Pancetti F Smalla KH Kaehne T Michea L Gundelfinger ED Wyneken U 《Journal of neurochemistry》2011,118(5):760-772
Nitric oxide (NO) has been proposed to down-regulate NMDA receptors (NMDA-Rs) in a homeostatic manner. However, NMDA-R-dependent NO synthesis also can cause excitotoxic cell death. Using bicuculline-stimulated hippocampal and cortical cell cultures, we have addressed the role of the brain-derived neurotrophic factor-NO pathway in NMDA-R down-regulation. This pathway protected cortical cells from NMDA-induced death and led to NMDA-R inhibition. In contrast, no evidence was gained for the presence of this protective pathway in hippocampal neurons, in which NMDA-induced NO synthesis was confirmed to be toxic. Therefore, opposing effects of NO depended on the activation of different signalling pathways. The pathophysiological relevance of this observation was investigated in synaptosomes and post-synaptic densities isolated from rat hippocampi and cerebral cortices following kainic acid-induced status epilepticus. In cortical, but not in hippocampal synaptosomes, brain-derived neurotrophic factor induced NO synthesis and inhibited NMDA-R currents present in isolated post-synaptic densities. In conclusion, we identified a NO-dependent homeostatic response in the rat cerebral cortex induced by elevated activity. A low performance of this pathway in brain areas including the hippocampus may be related to their selective vulnerability in pathologies such as temporal lobe epilepsy. 相似文献
152.
Waters LC Strong SL Ferlemann E Oka O Muskett FW Veverka V Banerjee S Schmedt T Henry AJ Klempnauer KH Carr MD 《The Journal of biological chemistry》2011,286(19):17270-17280
One of the key regulatory points of translation initiation is recruitment of the 43S preinitation complex to the 5' mRNA cap by the eIF4F complex (eIF4A, eIF4E, and eIF4G). The tumor suppressor protein Pdcd4 has been shown to inhibit cap-dependent translation by interacting tightly with the RNA helicase eIF4A via its tandem MA-3 domains. The NMR studies reported here reveal a fairly extensive and well defined interface between the two MA-3 domains in solution, which appears to be stabilized by a network of interdomain salt bridges and hydrogen bonds, and reveals a unique orientation of the two domains. Characterization of the stoichiometry of the Pdcd4-eIF4A complex suggests that under physiological conditions Pdcd4 binds to a single molecule of eIF4A, which involves contacts with both Pdcd4 MA-3 domains. We also show that contacts mediated by a conserved acidic patch on the middle MA-3 domain of Pdcd4 are essential for forming a tight complex with eIF4A in vivo, whereas the equivalent region of the C-terminal MA-3 domain appears to have no role in complex formation in vivo. The formation of a 1:1 eIF4A-Pdcd4 complex in solution is consistent with the reported presence in vivo of only one molecule of eIF4A in the eIF4F complex. Pdcd4 has also been reported to interact directly with the middle region of eIF4G, however, we were unable to obtain any evidence for even a weak, transient direct interaction. 相似文献
153.
154.
Furet P Bold G Hofmann F Manley P Meyer T Altmann KH 《Bioorganic & medicinal chemistry letters》2003,13(18):2967-2971
The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue. 相似文献
155.
156.
Effects of Diets High in Unsaturated Fatty Acids on Socially Induced Stress Responses in Guinea Pigs
Unsaturated fatty acids (UFAs), such as omega-3 and omega-6 poly- and omega-9 monounsaturated fatty acids are important nutrients and major components of neuronal cell membranes. They play a major role in modulating brain functions and physiology and may therefore diminish behavioral and physiological stress reactions in corroboration with decreased cortisol concentrations. Functionally, cortisol itself can modulate several behaviors and also the fatty acid metabolism in the long term. But only little is known about the behavioral and physiological influences of dietary UFAs in a social group, where individuals are regularly exposed to stressful situations. Therefore, the aim of this study was to determine the effects of dietary UFAs on saliva cortisol concentrations and behavioral responses in socially confronted guinea pigs. Three groups of animals were additionally supplemented with 500 mg chia seeds (high in omega-3), walnuts (high in omega-6), or peanuts (high in omega-9) per kg bodyweight each day and compared to a control group. During social confrontation saliva cortisol concentrations significantly increased in all groups, which was accompanied by a loss in bodyweight. However, cortisol levels remained lower in the chia and walnut groups compared to controls. Additionally, the walnut group displayed significantly increased locomotion, while no differences between groups were detected in socio-positive, sexual, or aggressive behaviors. Total plasma omega-3, omega-6, and omega-9 fatty acids were significantly increased in the corresponding groups, due to the dietary supplementations. However, a significant decrease in plasma omega-3 and an increase in plasma n-6 fatty acids were detected in the chia group when comparing the measurements before and after social confrontation. We conclude that both omega-3 and omega-6 polyunsaturated fatty acids can diminish behavioral and physiological stress responses to the social environment, enabling individuals to cope with social stressors, but at the expense of plasma derived omega-3 fatty acids. 相似文献
157.
Heidi Hintsala Tuomas V. Kentt? Mikko Tulppo Antti Kiviniemi Heikki V. Huikuri Matti M?ntysaari Sirkka Kein?nen-Kiukaannemi Risto Bloigu Karl-Heinz Herzig Riitta Antikainen Hannu Rintam?ki Jouni J. K. Jaakkola Tiina M. Ik?heimo 《PloS one》2014,9(7)
Objectives
The aim of our study was to assess the effect of short-term cold exposure, typical in subarctic climate, on cardiac electrical function among untreated middle-aged hypertensive men.Methods
We conducted a population-based recruitment of 51 hypertensive men and a control group of 32 men without hypertension (age 55–65 years) who underwent whole-body cold exposure (15 min exposure to temperature −10°C, wind 3 m/s, winter clothes). Conduction times and amplitudes, vectorcardiography, arrhythmias, and heart rate variability (autonomic nervous function) were assessed.Results
Short-term cold exposure increased T-peak to T-end interval from 67 to 72 ms (p<0.001) and 71 to 75 ms (p<0.001) and T-wave amplitude from 0.12 to 0.14 mV (p<0.001) and from 0.17 to 0.21 mV (p<0.001), while QTc interval was shortened from 408 to 398 ms (p<0.001) and from 410 to 401 ms (p<0.001) among hypertensive men and controls, respectively. Cold exposure increased both low (from 390 to 630 ms2 (p<0.001) and 380 to 700 ms2 (p<0.001), respectively) and high frequency heart rate variability (from 90 to 190 ms2 (p<0.001) and 150 to 300 ms2 (p<0.001), respectively), while low-to-high frequency-ratio was reduced. In addition, the frequency of ventricular ectopic beats increased slightly during cold exposure. The cold induced changes were similar between untreated hypertensive men and controls.Conclusions
Short-term cold exposure with moderate facial and mild whole body cooling resulted in prolongation of T-peak to T-end interval and higher T-wave amplitude while QTc interval was shortened. These changes of ventricular repolarization may have resulted from altered cardiac autonomic regulation and were unaffected by untreated hypertension.Trial Registration
ClinicalTrials.gov NCT02007031相似文献158.
Volker Salewski Karl-Heinz Siebenrock Wesley M. Hochachka Friederike Woog Wolfgang Fiedler 《PloS one》2014,9(7)
Changes in morphology have been postulated as one of the responses of animals to global warming, with increasing ambient temperatures leading to decreasing body size. However, the results of previous studies are inconsistent. Problems related to the analyses of trends in body size may be related to the short-term nature of data sets, to the selection of surrogates for body size, to the appropriate models for data analyses, and to the interpretation as morphology may change in response to ecological drivers other than climate and irrespective of size. Using generalized additive models, we analysed trends in three morphological traits of 4529 specimens of eleven bird species collected between 1889 and 2010 in southern Germany and adjacent areas. Changes and trends in morphology over time were not consistent when all species and traits were considered. Six of the eleven species displayed a significant association of tarsus length with time but the direction of the association varied. Wing length decreased in the majority of species but there were few significant trends in wing pointedness. Few of the traits were significantly associated with mean ambient temperatures. We argue that although there are significant changes in morphology over time there is no consistent trend for decreasing body size and therefore no support for the hypothesis of decreasing body size because of climate change. Non-consistent trends of change in surrogates for size within species indicate that fluctuations are influenced by factors other than temperature, and that not all surrogates may represent size appropriately. Future analyses should carefully select measures of body size and consider alternative hypotheses for change. 相似文献
159.
Andreas Buechner Karl-Heinz Dyballa Phillipp Hehrmann Stefan Fredelake Thomas Lenarz 《PloS one》2014,9(4)