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81.
B. Rickling B. Hans R. Kramarczyk G. Krumbiegel R. Weyhenmeyer 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1995,670(2):267-277
A combination of two stereoselective assays was developed using column-switching HPLC with electrochemical detection for the determination of free (unconjugated) silibinin and RP-HPLC with UV detection for the measurement of total (free and conjugated) silibinin in human plasma. After extraction of free silibinin and the internal standard hesperetin with diethyl ether the compounds were pre-separated on a RP-CN column. A cut fraction of eluate containing the analytes was then transferred to the RP-18 main column by means of a switching valve for final separation of the compounds. The limit of quantification with electrochemical detection for free silibinin was 0.25 ng/ml per diastereomer. For the determination of total silibinin diastereomers all conjugates were cleaved enzymatically using β-glucuronidase/arylsulfatase at pH 5.6 followed by extraction with diethyl ether of the pH 8.5 alkalized solution. Separation of the diastereomers and of the internal standard naringenin was achieved on a RP-18 column. The limit of quantification with UV detection at 288 nm for total silibinin was 5 ng/ml per diastereomer. Both assays were successfully applied to the stereospecific analysis of silibinin in plasma samples from a pharmacokinetic study of silymarin in human volunteers. 相似文献
82.
17Beta-estradiol attenuates PDGF signaling in vascular smooth muscle cells at the postreceptor level
Kappert K Caglayan E Huntgeburth M Bäumer AT Sparwel J Uebel M Rosenkranz S 《American journal of physiology. Heart and circulatory physiology》2006,290(2):H538-H546
Estrogens are known to display significant vasoprotective effects in premenopausal women. PDGF is an important mediator of vascular smooth muscle cell (VSMC) migration and proliferation, and thus atherogenesis. We analyzed the effects of 17beta-estradiol (E2) on beta-PDGF receptor (beta-PDGFR) expression/activation and PDGF-dependent VSMC proliferation, migration, and downstream signaling events. Pretreatment of VSMCs with E2 (0.3 microM-0.1 mM) for 24 h concentration-dependently inhibited PDGF-induced proliferation and migration up to 85.5 +/- 15.8% and 79.4 +/- 9.8%, respectively (both P < 0.05). These effects were prevented by coincubation with the ER antagonist ICI-182780. E2 did not alter beta-PDGFR expression, nor did it impair the ligand-induced tyrosine phosphorylation of the beta-PDGFR and consecutive binding of the receptor-associated signaling molecules Src homology region 2-containing phosphatase-2, PLC-gamma, phosphatidylinositol 3-kinase, and RasGAP. Thus estrogens inhibited PDGF-induced cellular responses at the postreceptor level. Although stimulation of VSMCs with PDGF-BB led to a transient increase of rac-1 activity, pretreatment with E2 for 24 h concentration-dependently inhibited PDGF-induced rac-1 activation. Furthermore, inhibition of rac-1 by Clostridium sordellii lethal toxin or overexpression of dominant-negative rac-1 (rac-N17) significantly inhibited PDGF-induced VSMC migration, indicating that rac-1 activity is essential for PDGF-dependent cellular responses. E2 did not further reduce PDGF-induced migration in rac-N17-overexpressing cells, suggesting that it diminishes VSMC migration by altering rac-1 activity. We conclude that E2 attenuates PDGF-dependent cellular functions of VSMCs downstream of the beta-PDGFR via inhibition of rac-1. These observations offer a molecular explanation for the vasoprotective effects of estrogens. 相似文献
83.
84.
Lilli Anselm David W. Banner Jörg Benz Katrin Groebke Zbinden Jacques Himber Hans Hilpert Walter Huber Bernd Kuhn Jean-Luc Mary Michael B. Otteneder Narendra Panday Fabienne Ricklin Martin Stahl Stefan Thomi Wolfgang Haap 《Bioorganic & medicinal chemistry letters》2010,20(17):5313-5319
A series of (3R,4R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized. 相似文献
85.
Habitat fragmentation is believed to be a key threat to biodiversity as it decreases the probability of survival of populations,
reduces gene flow among populations and increases the possibility of inbreeding and loss of genetic diversity within populations.
Heathlands represent excellent systems to study fragmentation effects as the spatial and temporal course of fragmentation
is well documented for these habitats. At the beginning of the nineteenth century, heathlands were widespread in northern
Germany, but they became increasingly fragmented at the end of the nineteenth century until only few fragments had been left.
As many insect species are strongly specialized on heathland habitats, they represent ideal study systems to test the genetic
effects of such recent fragmentation processes. The solitary bee Andrena fuscipes is strongly specialized on heather (Calluna vulgaris) and, therefore, occurs exclusively in heathland habitats. The species is red-listed in Germany and other parts of Europe.
Here, we present an analysis of the genetic structure of 12 populations of A. fuscipes using eight microsatellite loci. The populations showed little geographical structure and the degree of genetic differentiation
was low. Compared to related bee species, inbreeding coefficients were relatively low and seem to be mainly affected by the
bees’ solitary nesting behaviour. 相似文献
86.
Schwarzinger S Horn AH Ziegler J Sticht H 《Journal of biomolecular structure & dynamics》2006,23(6):581-590
The prion protein is thought to induce prion diseases by changing its conformation from the cellular form, PrP(C), into the infectious Scrapie-form, PrP(Sc). Little is known about the structural and dynamical features of this conformational change. We here introduce a novel concept that involves rare large scale motions between the subdomains beta1-alpha1-beta2 and alpha2-alpha3 in the carboxy-terminal, globular part of PrP. The interface between these two subdomains carries most pathogenic mutations known to be associated with prion diseases. Based on computational simulations as well as experimental results we propose that such a large scale motion subsequently destabilizes large parts of the cellular conformer PrP(C), thus, rendering it prone to structural rearrangements, including aggregation of now partially unfolded parts of the PrP sequence. We hypothesize that such large scale motions occur as a rare event even under equilibrium conditions and that the interaction of such partially destabilized PrP(C)-conformers, which we named PrP(C*), contributes to the formation of pathogenic oligomeric species of the prion protein. 相似文献
87.
This study analyzes the variations in the structure and composition of ant communities in burned Pinus nigra forests in central Catalonia (NE Spain). Pinus nigra forests do not recover after fire, changing to shrublands and oak coppices. For this reason, we suggest that ant communities of burned P. nigra forests will change after fire, because the post‐fire scenario, in particular with the increase of open areas, is different to the unburned one, and more favourable for some species than for others. In four locations previously occupied by P. nigra forests where different fires occurred 1, 5, 13 and 19 yr before the sampling, we sampled the structure and composition of ant communities with pitfall traps, tree traps and net sweeping in unburned plots and in plots affected by canopy and understory fire. The results obtained suggest that canopy and understory fire had little effect on the structure of ant communities. Thus, many variables concerning ant communities were not modified either by fire type (understory or canopy fire) or by time since fire. However, a number of particular species were affected, either positively or negatively, by canopy fire: three species characteristic of forest habitats decreased after fire, while eight species characteristic of open habitats increased in areas affected by canopy fire, especially in the first few years after fire. These differences in ant community composition between burned and unburned plots imply that the maximum richness is achieved when there is a mixture of unburned forests and areas burned with canopy fire. Moreover, as canopy cover in P. nigra forests burned with canopy fire is not completed in the period of time studied, the presence of the species that are characteristic of burned areas remains along the chronosequence studied, while the species that disappear after fire do not recover in the period of time considered. Overall, the results obtained indicate that there is a persistent replacement of ant species in burned P. nigra forests, as is also the case with vegetation. 相似文献
88.
Geiger A Russo L Gensch T Thestrup T Becker S Hopfner KP Griesinger C Witte G Griesbeck O 《Biophysical journal》2012,102(10):2401-2410
Genetically encoded calcium indicators have become instrumental in imaging signaling in complex tissues and neuronal circuits in vivo. Despite their importance, structure-function relationships of these sensors often remain largely uncharacterized due to their artificial and multimodular composition. Here, we describe a combination of protein engineering and kinetic, spectroscopic, and biophysical analysis of the Förster resonance energy transfer (FRET)-based calcium biosensor TN-XXL. Using fluorescence spectroscopy of engineered tyrosines, we show that two of the four calcium binding EF-hands dominate the FRET output of TN-XXL and that local conformational changes of these hands match the kinetics of FRET change. Using small-angle x-ray scattering and NMR spectroscopy, we show that TN-XXL changes from a flexible elongated to a rigid globular shape upon binding calcium, thus resulting in FRET signal output. Furthermore, we compare calcium titrations using fluorescence lifetime spectroscopy with the ratiometric approach and investigate potential non-FRET effects that may affect the fluorophores. Thus, our data characterize the biophysics of TN-XXL in detail and may form a basis for further rational engineering of FRET-based biosensors. 相似文献
89.
Stephan Schwarzinger Anselm H. C. Horn Jan Ziegler Heinrich Sticht 《Journal of biomolecular structure & dynamics》2013,31(6):581-590
Abstract The prion protein is thought to induce prion diseases by changing its conformation from the cellular form, PrPc, into the infectious Scrapie-form, PrPSc. Little is known about the structural and dynamical features of this conformational change. We here introduce a novel concept that involves rare large scale motions between the subdomains βl-αl-β2 and α2-α3 in the carboxy-terminal, globular part of PrP. The interface between these two subdomains carries most pathogenic mutations known to be associated with prion diseases. Based on computational simulations as well as experimental results we propose that such a large scale motion subsequently destabilizes large parts of the cellular conformer PrPc, thus, rendering it prone to structural rearrangements, including aggregation of now partially unfolded parts of the PrP sequence. We hypothesize that such large scale motions occur as a rare event even under equilibrium conditions and that the interaction of such partially destabilized PrPc-conformers, which we named PrPc*, contributes to the formation of pathogenic oligomeric species of the prion protein. 相似文献
90.
Dennis Gmehlin Anselm B. M. Fuermaier Stephan Walther Rudolf Debelak Mirjam Rentrop Celina Westermann Anuradha Sharma Lara Tucha Janneke Koerts Oliver Tucha Matthias Weisbrod Steffen Aschenbrenner 《PloS one》2014,9(12)