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Jonas G. Barlind Linda K. Buckett Sharon G. Crosby Öjvind Davidsson Hans Emtenäs Anne Ertan Ulrik Jurva Malin Lemurell Pablo Morentin Gutierrez Karolina Nilsson Gavin O’Mahony Annika U. Petersson Alma Redzic Fredrik Wågberg Zhong-Qing Yuan 《Bioorganic & medicinal chemistry letters》2013,23(9):2721-2726
[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to na?ve, p <0.01) in plasma triacylglycerol (TAG) concentration. 相似文献
13.
Alterations in C3 activation and binding caused by phosphorylation by a casein kinase released from activated human platelets. 总被引:5,自引:0,他引:5
A casein kinase released from activated human platelets phosphorylates a number of plasma proteins extracellularly, and that activation of platelets in systemic lupus erythematosus patients parallels an increase in the phosphate content of plasma proteins, including C3. The present study was undertaken to characterize this platelet protein kinase and to further elucidate the effect(s) on C3 function of phosphorylation by platelet casein kinase. The phosphate content of human plasma C3 was increased from 0.15 to 0.60 mol phosphate/mol of C3 after platelet activation in whole blood or platelet-rich plasma. The platelet casein kinase was distinct from other casein kinases in terms of its dependence on cations, inhibition by specific protein kinase inhibitors, and immunological reactivity. C3 that had been phosphorylated with platelet casein kinase was tested for its susceptibility to cleavage by trypsin or the classical and alternative pathway convertases and its binding to EAC and IgG. Phosphorylation did not affect the cleavage of C3 into C3a and C3b, but the binding of fragments from phosphorylated C3 to EAC14oxy2 cells and to IgG in purified systems and in serum was increased by 1.6-4.5 times over that of unphosphorylated C3. A covariation was seen between the enhanced binding of C3 fragments to IgG after phosphorylation and an increased ratio of glycerol/glycine binding, from 2.0 for unphosphorylated C3 to 4.9 for phosphorylated C3. The present study suggests that an overall effect of phosphorylation of C3 by platelet casein kinase is to enhance the opsonization of immune complexes. 相似文献
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We have used variations in the trypsin sensitivity of eukaryotic protein synthesis elongation factor 2 (eEF-2) to probe for structural alterations induced by phosphorylation, ribosomal binding, or guanosine nucleotides. We could not detect any nucleotide-related effect on the tryptic cleavage rate of Arg66. However, eEF-2 was protected from trypsin after ribosomal binding. Also, phosphorylation of eEF-2 led to a protection of Arg66. This indicates that phosphorylation leads to a structural rearrangement that could explain the reduced affinity of the phosphorylated factor for ribosomes (Carlberg, U., Nilsson, A., and Nyg?rd, O. (1990) Eur. J. Biochem. 191, 639-645). Cleavage of Arg66 led to a complete loss of the ability of the factor to be phosphorylated. Furthermore, ribosome-bound eEF-2 was found to be inaccessible for phosphorylation. Based on these findings and previously published data, we suggest that the region around the sites of phosphorylation and trypsin cleavage is vitally important for the factor function and ribosomal binding. 相似文献
16.
Gerda Nilsson 《Archives of microbiology》1959,34(1):30-35
Summary If the aseptic plant material is regarded as a substrate for preservative microbial activity, it may be said that both the nitrogen and carbohydrate components undergo changes due to the influence of native enzymes in the plant material. These changes may very well be reflected in the microbial activity in a silage.It is interesting to compare the findings of this investigation, which show that during the days immediately after ensilage practically no changes take place when no bacteria are present. In a non-sterile ensilage, on the other hand, it is during this early stage that the briskest bacterial activity takes place.The chances of, say, an acid-forming microbial process actually lowering the pH in order that preservation of the material may take place are directly counteracted by the action of native enzymes of the vegetable material. During the days immediately after ensilage, however, if other conditions are favourable, microbial activity may clearly determine the whole course of events, and may possibly even inactivate the processes of the plant material itself.As is evident from the experiments described above, the activities inherent in the ensiled material itself are of no mean proportions. Further study of the mutual relationship of the ensilage and the various microbial fractions is therefore particularly necessary in order to be able to understand a number of processes of fundamental importance in biological preservation of plant material. 相似文献
17.
Host discrimination studies were conducted with different species of Asobara, which are larval endo-parasitoids of Drosophilidae. Results indicated variable host discrimination which depended on the relatedness of the species. The closely related sibling species Asobara tabida (Nees) and A. rufescens (Foerster) were not only capable of intraspecific discrimination, but also avoided multiparasitism by discriminating between unparasitized host larvae and larvae previously parasitized by females of the other species. This ability to discriminate interspecifically does not seem functional as each species occupies its own microhabitat. As it was shown to be absent in less closely related Asobara species we concluded that interspecific discrimination by A. tabida and A. rufescens was due to their close relationship. 相似文献
18.
P. E. Nilsson 《Archives of microbiology》1957,26(3):285-301
Summary A short survey of different problems connected with the aseptic cultivation of higher plants is given.Accounts have been given of experiments in which antibiotics and fungicides have been used, as well separately as in combination, as surface-sterilizing agents.The use of chlorine as a sterilizing agent for the surface-sterilization of pea seed has been investigated and an account given of the importance of damage to the skin of the seed in the procedure.Procedures for the surface sterilization of oats and barley, and for pea seed, have been developed.Various arrangements in which the aseptic cultivation of higher plants may be carried out are described. 相似文献
19.
A M Dunning R Houlston J Frosteg?rd J Revill J Nilsson A Hamsten P Talmud S Humphries 《Biochimica et biophysica acta》1991,1096(3):231-237
We have searched for sequence differences in the region of the apolipoprotein B (apo B) gene encoding amino acids 3130-3630 in eight individuals with reduced affinity of low density lipoprotein (LDL) for the normal LDL-receptor. All individuals were hypercholesterolaemic and were selected either on the basis of reduced fractional catabolic rate (FCR) of autologous LDL or substantially reduced binding of their LDL to normal LDL-receptors determined by an in vitro cell growth assay using the U937 macrophage-like cell line. Segments of the apo B gene were amplified by the polymerase chain reaction. Using a combination of cloning and sequencing the amplified fragment, together with chemical cleavage mismatch analysis, no sequence differences were identified in this region of the gene. We therefore conclude that variation outside the region of the apo B gene that codes for amino acids 3130-3630 must be responsible for the reduced LDL clearance in these patients. 相似文献
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