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121.
Britt-Marie Swahn David Wensbo Johan Sandell Daniel Sohn Can Slivo David Pyring Jonas Malmström Erwan Arzel Michaela Vallin Margareta Bergh Fredrik Jeppsson Allan E. Johnson Anders Juréus Jan Neelissen Samuel Svensson 《Bioorganic & medicinal chemistry letters》2010,20(6):1976-1980
The syntheses and SAR of new series of β-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21. 相似文献
122.
Bettina L?ffler Muzaffar Hussain Matthias Grundmeier Michaela Brück Dirk Holzinger Georg Varga Johannes Roth Barbara C. Kahl Richard A. Proctor Georg Peters 《PLoS pathogens》2010,6(1)
The role of the pore-forming Staphylococcus aureus toxin Panton-Valentine leukocidin (PVL) in severe necrotizing diseases is debated due to conflicting data from epidemiological studies of community-associated methicillin-resistant S. aureus (CA-MRSA) infections and various murine disease-models. In this study, we used neutrophils isolated from different species to evaluate the cytotoxic effect of PVL in comparison to other staphylococcal cytolytic components. Furthermore, to study the impact of PVL we expressed it heterologously in a non-virulent staphylococcal species and examined pvl-positive and pvl-negative clinical isolates as well as the strain USA300 and its pvl-negative mutant. We demonstrate that PVL induces rapid activation and cell death in human and rabbit neutrophils, but not in murine or simian cells. By contrast, the phenol-soluble modulins (PSMs), a newly identified group of cytolytic staphylococcal components, lack species-specificity. In general, after phagocytosis of bacteria different pvl-positive and pvl-negative staphylococcal strains, expressing a variety of other virulence factors (such as surface proteins), induced cell death in neutrophils, which is most likely associated with the physiological clearing function of these cells. However, the release of PVL by staphylococcal strains caused rapid and premature cell death, which is different from the physiological (and programmed) cell death of neutrophils following phagocytosis and degradation of virulent bacteria. Taken together, our results question the value of infection-models in mice and non-human primates to elucidate the impact of PVL. Our data clearly demonstrate that PVL acts differentially on neutrophils of various species and suggests that PVL has an important cytotoxic role in human neutrophils, which has major implications for the pathogenesis of CA-MRSA infections. 相似文献
123.
124.
Mauricio Hunsche Kathrin Bürling Amina Sirag Saied Michaela Schmitz-Eiberger Muhammad Sohail Jens Gebauer Georg Noga Andreas Buerkert 《Plant Growth Regulation》2010,61(3):253-263
Seedlings of the salt-tolerant plant grewia [Grewia tenax (Forssk.) Fiori] and the moderately salt-tolerant tamarind (Tamarindus indica L.) were grown under controlled conditions and treated daily with NaCl solutions to investigate mechanisms of tolerance to
salinity. Leaf micromorphology, cuticular wax load, chlorophyll fluorescence and light remission, as well as antioxidative
potential were evaluated. As confirmed by energy-dispersive X-ray microanalysis in both species, absorption of sodium and
chlorine increased with rising NaCl concentration in the treatment solution. In parallel, accumulation of calcium in grewia
leaves was strongly reduced, leading to less crystals of calcium oxalate in leaf tissue. In grewia the cuticular wax load,
chlorophyll content, and electron transport rate (ETR) were significantly reduced by comparatively low NaCl concentrations.
In tamarind, in contrast, wax load and ETR were not significantly affected, while the decrease of chlorophyll content was
less pronounced. Measurements of the antioxidative capacity and the imbalance between values of lipophilic and hydrophilic
extracts at different NaCl concentrations confirmed that grewia is more salt tolerant than tamarind. This higher tolerance
degree seemed to be associated with grewias’ more efficient scavenging of free radicals and the regulation of the antioxidative
potential in lipophilic and hydrophilic extracts. 相似文献
125.
126.
127.
Bernd Liedert Ulf Forssmann Peter Wolna Michaela Golob Andreas Kovar 《BMC clinical pharmacology》2010,10(1):14
Background
Somatropin is recombinant human growth hormone (GH) used for the treatment of growth failure in children and GH deficiency in adults. Two concentrations of a liquid formulation have been developed: 5.83 and 8.0 mg/mL. This trial compared the pharmacokinetics (PK), safety and tolerability of these two liquid concentrations against the freeze-dried (FD) formulation in healthy volunteers. 相似文献128.
129.
Artwohl M Muth K Kosulin K de Martin R Hölzenbein T Rainer G Freudenthaler A Huttary N Schmetterer L Waldhäusl WK Baumgartner-Parzer SM 《American journal of physiology. Endocrinology and metabolism》2007,293(3):E681-E689
Lipoic acid was recently demonstrated to improve endothelial dysfunction or retinopathy not only in rats but also in diabetic patients. We tested the hypothesis that R-(+)-alpha-lipoic acid (LA) directly affects human endothelial cell (EC) function (e.g., apoptosis, proliferation, and protein expression), independent of the cells' vascular origin. Macrovascular EC (macEC), isolated from umbilical (HUVEC) and adult saphenous veins and from aortae, as well as microvascular EC (micEC) from retinae, skin, and uterus, were exposed to LA (1 mumol/l-1 mmol/l) with/without different stimuli (high glucose, TNF-alpha, VEGF, wortmannin, LY-294002). Apoptosis, proliferation, cell cycle distribution, and protein expression were determined by DNA fragmentation assays, [(3)H]thymidine incorporation, FACS, and Western blot analyses, respectively. In macro- and microvascular EC, LA (1 mmol/l) reduced (P < 0.05) basal (macEC, -36 +/- 4%; micEC, -46 +/- 6%) and stimulus-induced (TNF-alpha: macEC, -75 +/- 11%; micEC, -68 +/- 13%) apoptosis. In HUVEC, inhibition of apoptosis by LA (500 mumol/l) was paralleled by reduction of NF-kappaB. LA's antiapoptotic activity was reduced by PI 3-kinase inhibitors (wortmannin, LY-294002), being in line with LA-induced Akt phosphorylation (Ser(437), +159 +/- 43%; Thr(308), +98 +/- 25%; P < 0.01). LA (500 mumol/l) inhibited (P < 0.001) proliferation of macEC (-29 +/- 3%) and micEC (-29 +/- 3%) by arresting the cells at the G(1)/S transition due to an increased ratio of cyclin E/p27(Kip) (4.2-fold), upregulation of p21(WAF-1/Cip1) (+104 +/- 21%), and reduction of cyclin A (-32 +/- 11%), of hyperphosphorylated retinoblastoma protein (macEC: -51 +/- 7%; micEC: -50 +/- 15%), and of E2F-1 (macEC: -48 +/- 3%; micEC: -31 +/- 10%). LA's ability to inhibit apoptosis and proliferation of ECs could beneficially affect endothelial dysfunction, which precedes manifestation of late diabetic vascular complications. 相似文献
130.
Hansen K Wagner B Hamel W Schweizer M Haag F Westphal M Lamszus K 《Journal of neurochemistry》2007,103(1):259-275
The neurotrophin receptor tropomyosin-related kinase A (TrkA) and its ligand nerve growth factor (NGF) are expressed in astrocytomas, and an inverse association of TrkA expression with malignancy grade was described. We hypothesized that TrkA expression might confer a growth disadvantage to glioblastoma cells. To analyze TrkA function and signaling, we transfected human TrkA cDNA into the human glioblastoma cell line G55. We obtained three stable clones, all of which responded with striking cytoplasmic vacuolation and subsequent cell death to NGF. Analyzing the mechanism of cell death, we could exclude apoptosis and cellular senescence. Instead, we identified several indications of autophagy: electron microscopy showed typical autophagic vacuoles; acridine orange staining revealed acidic vesicular organelles; acidification of acidic vesicular organelles was prevented using bafilomycin A1; cells displayed arrest in G2/M; increased processing of LC3 occurred; vacuolation was prevented by the autophagy inhibitor 3-methyladenine; no caspase activation was detected. We further found that both activation of ERK and c-Jun N-terminal kinase but not p38 were involved in autophagic vacuolation. To conclude, we identified autophagy as a novel mechanism of NGF-induced cell death. Our findings suggest that TrkA activation in human glioblastomas might be beneficial therapeutically, especially as several of the currently used chemotherapeutics also induce autophagic cell death. 相似文献