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Benjamin R. Bellenie Nicholas P. Barton Amanda J. Emmons Jag P. Heer Cristian Salvagno 《Bioorganic & medicinal chemistry letters》2009,19(3):990-994
A novel oxytocin antagonist was identified by ‘scaffold-hopping’ using Cresset FieldScreen molecular field similarity searching. A single cycle of optimization driven by an understanding of the key pharmacophoric elements required for activity led to the discovery of a potent, selective and highly ligand-efficient oxytocin receptor antagonist. Selectivity over vasopressin receptors was rationalized based on differences in the structure of the natural ligands. 相似文献
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Erica van Oort Pleuni G de Heer W Astrid van Leeuwen Ninotska I L Derksen Marcel Müller Stephan Huveneers Rob C Aalberse Ronald van Ree 《European journal of biochemistry》2002,269(2):671-679
The mature cysteine protease from Dermatophgoides pteronyssinus, Der p 1, is a major house dust mite allergen. Its enzymatic activity has been shown to have pro-inflammatory effects that could also negatively influence efficacy of allergen-specific immunotherapy. The aim of this study was to express recombinant pro-Der p 1 (rpro-Der p 1) in the yeast Pichia pastoris and to study its maturation. Expression was achieved at a concentration ranging from 45 mg.L-1 (methanol-induced expression) to 168 mg.L-1 (constitutive expression). No significant spontaneous maturation of the secreted proenzyme was observed. rpro-Der p 1 with a sequence-based molecular mass of 34 kDa was hyperglycosylated by the yeast, migrating at 50-60 kDa on SDS/PAGE. Compared with its natural counterpart (nDer p 1), the recombinant proenzyme demonstrated decreased IgE reactivity, resulting in a 30-fold lower capacity to induce histamine release from human basophils. Decreased immunoreactivity was also shown by competitive RIA and sandwich ELISA with Der p 1-specific antibody reagents. CD spectra of rpro-Der p 1 and nDer p 1 revealed significant structural differences. Deglycosylation of rpro-Der p 1 with endoglycosidase H resulted in a decrease in apparent molecular mass from 50 kDa to 34 kDa, but did not affect nDer p 1. On removal of N-glycans from rpro-Der p 1, which harbours two putative N-glycosylation sites in both propeptide and mature sequence, the mature rDer p 1 appeared. This suggests that hyperglycosylation hampers spontaneous maturation. Maturation of the recombinant pro-enzyme was also achieved by addition of the active natural cysteine protease, nDer p 1. In conclusion, high-level expression of rpro-Der p 1 in P. pastoris results in a stable hypoallergenic proenzyme with potential for use in allergen-specific immunotherapy. 相似文献
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Tobias Roth Elias Bader Patrick Frara Lorenz Heer Heinz Flück Thomas Lüthi Barbara Schlup Thomas Schwaller 《Ecology and evolution》2017,7(10):3567-3573
Individual variation in postjuvenile molt in male Black Redstart is pronounced with about 90% of young males retaining female‐like coloration (cairei plumage type) and about 10% acquiring adult male‐like feathers (paradoxus plumage type). We examined whether autumn migration timing and body condition differed between individuals of the two plumage types. We used the data of 10,977 Black Redstarts captured during autumn at a ringing site in northern Switzerland where a protocol to record plumage types of captures has been applied since 1980. As cairei individuals cannot be distinguished from young females while sexing is comparatively easy for paradoxus individuals, the proportion of missing data on sex was likely to be higher for cairei individuals than for paradoxus individuals. We formally accounted for captures with unidentified sex using a Bayesian approach and conducted a simulation study to show that our approach was able to provide unbiased results even if the proportion of unsexed captures was high. Applying the method to the Black Redstart data, we found that the proportion of individuals with paradoxus plumage type increased from 7.6% in 1980 to 18.1% in 2013. Individuals with the paradoxus plumage type were on average 0.25 g heavier and had 0.62 mm longer third primaries than individuals with the cairei plumage type. However, we found no support for our expectation of later migration of paradoxus males compared to cairei individuals based on the assumption that paradoxus individuals should occupy autumn territories like adult males. Our results shed new light on the understudied timing of autumn migration in birds and are in line with available studies on Black Redstarts, suggesting a molt‐constraint that allows only young males in good body condition to molt into adult‐like plumages. 相似文献
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Arti Heer Sanjay Guleria V. K. Razdan 《Journal of plant biochemistry and biotechnology.》2017,26(2):191-198
The essential oil (EO) obtained from the fresh and dried leaves of Cinnamomum tamala was analysed by gas chromatography/mass spectrometry. EO from fresh leaves showed the presence of 21 compounds, whereas, EO from the dried leaves of C. tamala showed the presence of 20 compounds. In vitro assays namely scavenging ability against 1,1-diphenyl-2-picrylhydrazyl, reducing power and chelating ability on Fe2+ ions were used to determine the antioxidant potential of EO of C. tamala. With regard to antifungal activity, EO from dried leaves was more effective against Alternaria alternata and Curvularia lunata than the EO from fresh leaves. Similarly, EO from C. tamala leaves also showed potent antibacterial activity against two Gram negative and two Gram positive bacteria namely, Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus and Pseudomonas aeruginosa. Furthermore, bioactive molecule from C. tamala EO having antifungal and antioxidant activity was isolated and characterized using bioautography, preparative thin layer chromatography and GC/MS analysis and was determined as eugenol. Its minimum inhibitory amount against A. alternata and C. lunata was determined using bioautography assay and was found to be 9.5 and 8.2 µg respectively. 相似文献
67.
Nowak A Rahman H Heer C Schueth A Laatsch H Hardeland R 《Redox report : communications in free radical research》2008,13(3):102-108
The melatonin metabolite N(1)-acetyl-5-methoxykynuramine (AMK) has previously been shown to interact with various free radicals. Using the ABTS cation radical [ABTS = 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid)] as an electron abstracting reactant, which does not destroy the aromate, we found that the reactive intermediate derived from AMK strongly interacts with the benzene rings of other AMK molecules to form di- and oligomers. Since oligomerization is rather unlikely at physiological concentrations, we investigated reactions with other putative reaction partners. The incubation of tyrosine or several of its structural analogs with AMK in the presence of the ABTS cation radical led to numerous products, amongst which were compounds not detected when one of the educts was incubated with the ABTS cation radical alone. With tyrosine and most of its analogs, the number of products formed in the presence of AMK and ABTS cation radical was relatively high and included numerous oligomers. To optimize the yield of products of interest as well as their separation from other compounds, especially oligomers, we investigated the interaction with 4-ethylphenol, which represents the side chain of tyrosine lacking the carboxyl and amino residues of the amino acid, which otherwise can undergo additional reactions. A prominent product was chromatographically separated and analyzed by mass spectrometry [(+)-ESI-MS, (-)-ESI-MS, (+)-HRESI-MS], (1)H-NMR, and H,H-COSY correlations. The substance was identified as N-{3-[2'-(5'-ethyl-2'-hydroxyphenylamino)-5'-methoxyphenyl]-3-oxopropyl} acetamide. This chemically novel compound represents an adduct in which the amino nitrogen of AMK is attached to the C-2 atom of 4-ethylphenol, which corresponds to the C-3 atom in the benzene ring of tyrosine. This finding suggests that, upon interaction of AMK with an electron-abstracting radical, the kynuric intermediate may modify proteins at superficially accessible tyrosine residues. In fact, protein modification by an unidentified melatonin metabolite has been observed in an earlier study. The possibility of protein AMKylation may be of interest with regard to an eventual interference with tyrosine nitration or, more importantly, with tyrosine phosphorylation. 相似文献
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Wagenaar GT ter Horst SA van Gastelen MA Leijser LM Mauad T van der Velden PA de Heer E Hiemstra PS Poorthuis BJ Walther FJ 《Free radical biology & medicine》2004,36(6):782-801
Oxidative stress is an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants characterized by arrested alveolar and vascular development of the immature lung. We investigated differential gene expression with DNA microarray analysis in premature rat lungs exposed to prolonged hyperoxia during the saccular stage of development, which closely resembles the development of the lungs of premature infants receiving neonatal intensive care. Expression profiles were largely confirmed by real-time RT-PCR (27 genes) and in line with histopathology and fibrin deposition studied by Western blotting. Oxidative stress affected a complex orchestra of genes involved in inflammation, coagulation, fibrinolysis, extracellular matrix turnover, cell cycle, signal transduction, and alveolar enlargement and explains, at least in part, the pathological alterations that occur in lungs developing BPD. Exciting findings were the magnitude of fibrin deposition; the upregulation of chemokine-induced neutrophilic chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), amphiregulin, plasminogen activator inhibitor-1 (PAI-1), secretory leukocyte proteinase inhibitor (SLPI), matrix metalloproteinase-12 (MMP12), p21, metallothionein, and heme oxygenase (HO); and the downregulation of fibroblast growth factor receptor-4 (FGFR4) and vascular endothelial growth factor (VEGF) receptor-2 (Flk-1). These findings are not only of fundamental importance in the understanding of the pathophysiology of BPD, but also essential for the development of new therapeutic strategies. 相似文献
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