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11.
Benno Cardini Katrin Watschinger Martin Hermann Peter Obrist Rupert Oberhuber Gerald Brandacher Surawee Chuaiphichai Keith M. Channon Johann Pratschke Manuel Maglione Ernst R. Werner 《PloS one》2014,9(11)
Objective
Aim of this study was to identify the nitric oxide synthase (NOS) isoform involved in early microcirculatory derangements following solid organ transplantation.Background
Tetrahydrobiopterin donor treatment has been shown to specifically attenuate these derangements following pancreas transplantation, and tetrahydrobiopterin-mediated protective effects to rely on its NOS-cofactor activity, rather than on its antioxidant capacity. However, the NOS-isoform mainly involved in this process has still to be defined.Methods
Using a murine pancreas transplantation model, grafts lacking one of the three NOS-isoforms were compared to grafts from wild-type controls. Donors were treated with either tetrahydrobiopterin or remained untreated. All grafts were subjected to 16 h cold ischemia time and transplanted into wild-type recipients. Following 4 h graft reperfusion, microcirculation was analysed by confocal intravital fluorescence microscopy. Recipient survival was monitored for 50 days.Results
Transplantation of the pancreas from untreated wild-type donor mice resulted in microcirculatory damage of the transplanted graft and no recipient survived more than 72 h. Transplanting grafts from untreated donor mice lacking either endothelial or inducible NOS led to similar outcomes. In contrast, donor treatment with tetrahydrobiopterin prevented microcirculatory breakdown enabling long-term survival. Sole exception was transplantation of grafts from untreated donor mice lacking neuronal NOS. It resulted in intact microvascular structure and long-term recipient survival, either if donor mice were untreated or treated with tetrahydrobiopterin.Conclusion
We demonstrate for the first time the crucial involvement of neuronal NOS in early microcirculatory derangements following solid organ transplantation. In this model, protective effects of tetrahydrobiopterin are mediated by targeting this isoform. 相似文献12.
M Preukschas C Hagel A Schulte K Weber K Lamszus H Sievert N Pällmann C Bokemeyer J Hauber M Braig S Balabanov 《PloS one》2012,7(8):e43468
Glioblastomas are highly aggressive brain tumors of adults with poor clinical outcome. Despite a broad range of new and more specific treatment strategies, therapy of glioblastomas remains challenging and tumors relapse in all cases. Recent work demonstrated that the posttranslational hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is a crucial regulator of cell proliferation, differentiation and an important factor in tumor formation, progression and maintenance. Here we report that eIF-5A as well as the hypusine-forming enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) are highly overexpressed in glioblastoma patient samples. Importantly, targeting eIF-5A and its hypusine modification with GC7, a specific DHS-inhibitor, showed a strong antiproliferative effect in glioblastoma cell lines in vitro, while normal human astrocytes were not affected. Furthermore, we identified p53 dependent premature senescence, a permanent cell cycle arrest, as the primary outcome in U87-MG cells after treatment with GC7. Strikingly, combined treatment with clinically relevant alkylating agents and GC7 had an additive antiproliferative effect in glioblastoma cell lines. In addition, stable knockdown of eIF-5A and DHS by short hairpin RNA (shRNA) could mimic the antiproliferative effects of GC7. These findings suggest that pharmacological inhibition of eIF-5A may represent a novel concept to treat glioblastomas and may help to substantially improve the clinical course of this tumor entity. 相似文献
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15.
Predictive Mapping of Plant Species and Communities Using GIS and Landsat Data in a Southern Mongolian Mountain Range 总被引:1,自引:0,他引:1
Henrik von Wehrden Heike Zimmermann Jan Hanspach Katrin Ronnenberg Karsten Wesche 《Folia Geobotanica》2009,44(3):211-225
We assessed presence/absence prediction of plant species and communities in a southern Mongolian mountain range from geospatial data using a randomized sampling approach. One hundred randomized vegetation samples (3?×?3 m) were collected within the 2?×?2 km summit region of the Dund Saykhan range, which forms part of the core zone of the Gobi Gurvan Saykhan National Park in arid southern Mongolia. Using logistic regression, habitat preference models for all abundant species (n?=?52) and communities (n?=?5) were constructed; predictors were derived from Landsat 5 imagery and a digital elevation model. Nagelkerkes r 2 was used for an initial data mining, and all significant models were validated by splitting the data and using one half for accuracy assessment based on the AUC (Area Under the receiver operating characteristic Curve)-values. Significant models could be built for half of the species. Altitude proved to be the most important predictor followed by variables derived from Landsat data. The clear altitudinal distribution patterns most definitely reflect precipitation; overall biodiversity in this arid environment is widely controlled by moisture availability. The chosen approach may prove valuable for applied studies wherever spatial data on species distributions are required for conservation efforts. 相似文献
16.
Peter Braubach Murat Orynbayev Zoita Andronache Tanja Hering Georg Bernhard Landwehrmeyer Katrin S. Lindenberg Werner Melzer 《The Journal of general physiology》2014,144(5):393-413
Huntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat within the gene encoding the protein huntingtin. The resulting elongated glutamine (poly-Q) sequence of mutant huntingtin (mhtt) affects both central neurons and skeletal muscle. Recent reports suggest that ryanodine receptor–based Ca2+ signaling, which is crucial for skeletal muscle excitation–contraction coupling (ECC), is changed by mhtt in HD neurons. Consequently, we searched for alterations of ECC in muscle fibers of the R6/2 mouse, a mouse model of HD. We performed fluorometric recordings of action potentials (APs) and cellular Ca2+ transients on intact isolated toe muscle fibers (musculi interossei), and measured L-type Ca2+ inward currents on internally dialyzed fibers under voltage-clamp conditions. Both APs and AP-triggered Ca2+ transients showed slower kinetics in R6/2 fibers than in fibers from wild-type mice. Ca2+ removal from the myoplasm and Ca2+ release flux from the sarcoplasmic reticulum were characterized using a Ca2+ binding and transport model, which indicated a significant reduction in slow Ca2+ removal activity and Ca2+ release flux both after APs and under voltage-clamp conditions. In addition, the voltage-clamp experiments showed a highly significant decrease in L-type Ca2+ channel conductance. These results indicate profound changes of Ca2+ turnover in skeletal muscle of R6/2 mice and suggest that these changes may be associated with muscle pathology in HD. 相似文献
17.
Katrin Anders Alexander Gutt Wolfgang G?rtner Lars-Oliver Essen 《The Journal of biological chemistry》2014,289(37):25590-25600
Phytochromes are photoreceptors using a bilin tetrapyrrole as chromophore, which switch in canonical phytochromes between red (Pr) and far red (Pfr) light-absorbing states. Cph2 from Synechocystis sp., a noncanonical phytochrome, harbors besides a cyanobacteriochrome domain a second photosensory module, a Pr/Pfr-interconverting GAF-GAF bidomain (SynCph2(1-2)). As in the canonical phytochromes, a unique motif of the second GAF domain, the tongue region, seals the bilin-binding site in the GAF1 domain from solvent access. Time-resolved spectroscopy of the SynCph2(1-2) module shows four intermediates during Pr → Pfr phototransformation and three intermediates during Pfr → Pr back-conversion. A mutation in the tongue''s conserved PRXSF motif, S385A, affects the formation of late intermediate R3 and of a Pfr-like state but not the back-conversion to Pr via a lumi-F-like state. In contrast, a mutation in the likewise conserved WXE motif, W389A, changes the photocycle at intermediate R2 and causes an alternative red light-adapted state. Here, back-conversion to Pr proceeds via intermediates differing from SynCph2(1-2). Replacement of this tryptophan that is ∼15 Å distant from the chromophore by another aromatic amino acid, W389F, restores native Pr → Pfr phototransformation. These results indicate large scale conformational changes within the tongue region of GAF2 during the final processes of phototransformation. We propose that in early intermediates only the chromophore and its nearest surroundings are altered, whereas late changes during R2 formation depend on the distant WXE motifs of the tongue region. Ser-385 within the PRXSF motif affects only late intermediate R3, when refolding of the tongue and docking to the GAF1 domain are almost completed. 相似文献
18.
The Chromaffin Cell and its Development 总被引:1,自引:0,他引:1
19.
Wyatt PG Allen MJ Borthwick AD Davies DE Exall AM Hatley RJ Irving WR Livermore DG Miller ND Nerozzi F Sollis SL Szardenings AK 《Bioorganic & medicinal chemistry letters》2005,15(10):2579-2582
This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the determination of the stereochemistry of the most potent compounds. 相似文献
20.
Investigation of the role of extracellular nucleotides in nervous system has been one of the main topics of the P2Y receptor research throughout the years. In parallel to numerous studies on primary culture systems, various neuronal and non-neuronal cell lines have been used to model in vitro the processes mediated by extracellular nucleotides. In this review article, a survey of expression profiles of G protein-coupled P2Y receptor subtypes in nervous-system-derived cell lines is presented, by analysing the receptor expression at the mRNA, protein, and functional level. The variability of receptor expression profiles in established cell lines is further discussed, bringing forward some general properties for neuronal and glial malignant cell lines. 相似文献