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31.
Binderup E Björkling F Hjarnaa PV Latini S Baltzer B Carlsen M Binderup L 《Bioorganic & medicinal chemistry letters》2005,15(10):2491-2494
To overcome pharmacokinetic and solubility problems observed in early clinical trials with the potent anticancer compound CHS828, we synthesised a series of prodrugs with improved properties. The best compound obtained was EB1627, with a tetraethyleneglycol moiety attached to the parent drug via a carbonate linkage. This compound was found soluble enough to be given i.v. and the drug was rapidly released in vivo exerting a very potent inhibitory activity alone and in combination with known cytostatics (etoposide) in animal models in vivo. 相似文献
32.
The effects of ceramides with varying saturated N-linked acyl chains (C2-C14) on cholesterol displacement from sphingomyelin-rich domains and on the stability of ordered domains were studied. The bilayers examined were made from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), D-erythro-N-palmitoyl-sphingomyelin (PSM), D-erythro-N-acyl-sphingosine, and cholesterol (60:15:15:10 mol%, respectively). Cholestatrienol (CTL) or D-erythro-N-trans-parinoyl-sphingomyelin (tParSM) were used as reporter molecules (at 1 mol%) for the ordered domains, and 1-palmitoyl-2-stearoyl-(7-doxyl)-sn-glycero-3-phosphocholine (7SLPC) as a fluorescence quencher (30 mol%, replacing POPC) in the liquid-disordered phase. The results indicate that the ceramide had to have an N-linked acyl chain with at least 8 methylene units in order for it to displace cholesterol from the sphingomyelin-rich domains at the concentration used. The melting of the sphingomyelin-rich domain shifted to higher temperatures (compared to the ceramide-free control) with C2, C12 and longer chain ceramides, whereas C4-C10 ceramides led to domain melting at lower temperatures than control. This study shows that short-chain ceramides do not have the same effects on sterol- and sphingomyelin-rich domains as naturally occurring longer-chain ceramides have. 相似文献
33.
Søren Bak Susanne Michelle Paquette Marc Morant Anne Vinther Morant Shigeki Saito Nanna Bjarnholt Mika Zagrobelny Kirsten Jørgensen Sarah Osmani Henrik Toft Simonsen Raquel Sanchez Pérez Torbjørn Bordier van Heeswijck Bodil Jørgensen Birger Lindberg Møller 《Phytochemistry Reviews》2006,5(2-3):309-329
Cyanogenic glycosides are ancient biomolecules found in more than 2,650 higher plant species as well as in a few arthropod species. Cyanogenic glycosides are amino acid-derived β-glycosides of α-hydroxynitriles. In analogy to cyanogenic plants, cyanogenic arthropods may use cyanogenic glycosides as defence compounds. Many of these arthropod species have been shown to de novo synthesize cyanogenic glycosides by biochemical pathways that involve identical intermediates to those known from plants, while the ability to sequester cyanogenic glycosides appears to be restricted to Lepidopteran species. In plants, two atypical multifunctional cytochromes P450 and a soluble family 1 glycosyltransferase form a metabolon to facilitate channelling of the otherwise toxic and reactive intermediates to the end product in the pathway, the cyanogenic glycoside. The glucosinolate pathway present in Brassicales and the pathway for cyanoalk(en)yl glucoside synthesis such as rhodiocyanosides A and D in Lotus japonicus exemplify how cytochromes P450 in the course of evolution may be recruited for novel pathways. The use of metabolic engineering using cytochromes P450 involved in biosynthesis of cyanogenic glycosides allows for the generation of acyanogenic cassava plants or cyanogenic Arabidopsis thaliana plants as well as L. japonicus and A. thaliana plants with altered cyanogenic, cyanoalkenyl or glucosinolate profiles. 相似文献
34.
Donaubauer B Busch T Lachmann R Deja M Petersen B Francis R Träger A Ebsen M Boemke W Kaisers U 《Experimental biology and medicine (Maywood, N.J.)》2006,231(6):960-966
Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET(A) receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO2) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO2, 319 +/- 44 mm Hg vs. 57 +/- 3 mm Hg; MPAP, 32 +/- 2 mm Hg vs. 41 +/- 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 +/- 0.06 fmol/ml after induction of ALI to a maximum of 1.17 +/- 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 +/- 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET(A) receptor antagonist. 相似文献
35.
Busch T Petersen B Deja M Donaubauer B Laudi S Jaumann S Bercker S Boemke W Kaisers U 《Experimental biology and medicine (Maywood, N.J.)》2006,231(6):974-978
Beneficial effects of inhaled nitric oxide (iNO) on arterial oxygenation in acute lung injury (ALI) suggest the presence of vasoconstriction in ventilated lung regions and this may be influenced by endothelin-1 (ET-1). We studied a possible interaction between ET-1 and iNO in experimental ALI. Sixteen piglets were anesthetized and mechanically ventilated (inspired O2 fraction, 1.0). After induction of ALI by surfactant depletion, animals were randomly assigned to either inhale 30 ppm NO (iNO group, n = 8), or to receive no further intervention (controls, n = 8). Measurements were performed during the following 4 hrs. In all animals, induction of ALI significantly decreased arterial oxygen tension (PaO2) from 569 +/- 15 (prelavage) to 58 +/- 3 mm Hg. Inhaled NO significantly increased PaO2 when compared with controls (iNO group: 265 +/- 51 mm Hg; controls: 50 +/- 4 mm Hg, values at 4 hrs, P < 0.01). Prelavage ET-1 plasma levels were comparable between groups (iNO: 0.74 +/- 0.03, controls: 0.71 +/- 0.03 fmol/ml, NS). During the protocol, the ET-1 levels increased and were different at 3 hrs (iNO: 0.93 +/- 0.06, controls: 1.25 +/- 0.09 fmol/ml; P < 0.05). PaO2 changes induced by iNO revealed a moderate and significant correlation with ET-1 plasma levels (R = 0.548, P = 0.001). Our data suggest that endogenous ET-1 production influences the efficacy of iNO in ALI. Furthermore, iNO reduced ET-1 plasma levels, possibly indicating anti-inflammatory properties of iNO in the early phase of ALI. 相似文献
36.
Benthic infaunal biomass and abundance may be changing in Bering Sea communities. This study compared benthic infaunal biomass,
abundance, and community composition southwest of St. Lawrence Island in an important forage area for benthic-feeding birds
and mammals between 1970–1974 and 2006. Invertebrate biomass and abundance were significantly greater in 2006 than in 1970–1974
primarily due to high nuculid (Bivalvia) biomass and abundance that contributed 13.2% (biomass) and 8.5% (abundance) to differences
in community structure between the sampling periods. This is in contrast to St. Lawrence Island Polynya studies conducted
in the 1980s and 1990s that documented decreases in benthic biomass and abundance. Spatial scale of sampling, selective predation,
a strong recruitment event, and/or sampling design may account for the difference in trends among the studies. 相似文献
37.
Ritchie EG Elmhagen B Glen AS Letnic M Ludwig G McDonald RA 《Trends in ecology & evolution》2012,27(5):265-271
Recent advances highlight the potential for predators to restore ecosystems and confer resilience against globally threatening processes, including climate change and biological invasions. However, releasing the ecological benefits of predators entails significant challenges. Here, we discuss the economic, environmental and social considerations affecting predator-driven ecological restoration programmes, and suggest approaches for reducing the undesirable impacts of predators. Because the roles of predators are context dependent, we argue for increased emphasis on predator functionality in ecosystems and less on the identities and origins of species and genotypes. We emphasise that insufficient attention is currently given to the importance of variation in the social structures and behaviours of predators in influencing the dynamics of trophic interactions. Lastly, we outline experiments specifically designed to clarify the ecological roles of predators and their potential utility in ecosystem restoration. 相似文献
38.
Yang Z Drew DP Jørgensen B Mandel U Bach SS Ulvskov P Levery SB Bennett EP Clausen H Petersen BL 《The Journal of biological chemistry》2012,287(15):11911-11923
Mucin-type O-glycosylation is an important post-translational modification that confers a variety of biological properties and functions to proteins. This post-translational modification has a particularly complex and differentially regulated biosynthesis rendering prediction and control of where O-glycans are attached to proteins, and which structures are formed, difficult. Because plants are devoid of GalNAc-type O-glycosylation, we have assessed requirements for establishing human GalNAc O-glycosylation de novo in plants with the aim of developing cell systems with custom-designed O-glycosylation capacity. Transient expression of a Pseudomonas aeruginosa Glc(NAc) C4-epimerase and a human polypeptide GalNAc-transferase in leaves of Nicotiana benthamiana resulted in GalNAc O-glycosylation of co-expressed human O-glycoprotein substrates. A chimeric YFP construct containing a 3.5 tandem repeat sequence of MUC1 was glycosylated with up to three and five GalNAc residues when co-expressed with GalNAc-T2 and a combination of GalNAc-T2 and GalNAc-T4, respectively, as determined by mass spectrometry. O-Glycosylation was furthermore demonstrated on a tandem repeat of MUC16 and interferon α2b. In plants, prolines in certain classes of proteins are hydroxylated and further substituted with plant-specific O-glycosylation; unsubstituted hydroxyprolines were identified in our MUC1 construct. In summary, this study demonstrates that mammalian type O-glycosylation can be established in plants and that plants may serve as a host cell for production of recombinant O-glycoproteins with custom-designed O-glycosylation. The observed hydroxyproline modifications, however, call for additional future engineering efforts. 相似文献
39.
Frankow-Lindberg BE 《Oecologia》2012,169(3):793-802
Species richness of plant communities has been demonstrated to provide resistance to invasion by unsown species, though the relationship with resource availability varies between studies. The present work involved five grassland species grown in monocultures and in four-species mixtures sown in accordance with a simplex design. The species used represented different functional groups (i.e. grasses, legumes and non-N(2)-fixing species), each of which differed internally in terms of competitiveness. I hypothesized that sown diversity would negatively affect invader performance by decreasing the availability of light and soil nitrogen (N) for invading species, and that functional composition of the sown diversity would affect the functional composition of the invading flora. The experimental plots were harvested for two years, and were fertilized with 100 kg N ha(-1) each year. The number of unsown species (classified into four functional groups) invading each plot and their proportion of the biomass harvested were recorded. The penetration of incoming light through the canopy, the apparent N uptake by the sown species from the soil, and the mineral N content in the soil were measured. I found that diverse communities captured more resources both above- and belowground, and the number of invading species and their biomass production were smaller in mixed than in monoculture plots. However, the sampling effect of one grass was also strong. These results suggest that increased resource use in diverse communities can reduce invasion. 相似文献
40.
Bodil Arnbak Charlotte Leboeuf-Yde Tue Secher Jensen 《Arthritis research & therapy》2012,14(2):R55-12