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991.
Proglucagon, which is encoded by the glucagon gene (Gcg), is the precursor of several peptide hormones, including glucagon and glucagon-like peptide 1 (GLP-1). Whereas glucagon stimulates hepatic glycogenolysis and gluconeogenesis, GLP-1 stimulates insulin secretion to lower blood glucose and also supports ß-cell proliferation and protection from apoptotic stimuli. Pregnancy is a strong inducer of change in islet function, however the roles of proglucagon-derived peptides in pregnancy are only partially understood. In the present study, we analyzed fertility and pregnancy-associated changes in homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcggfp/gfp), which lack all the peptides derived from proglucagon. Female Gcggfp/gfp mice could deliver and raise Gcggfp/gfp pups to weaning and Gcggfp/gfp pups from Gcggfp/gfp dams were viable and fertile. Pregnancy induced ß-cell proliferation in Gcggfp/gfp mice as well as in control mice. However, serum insulin levels in pregnant Gcggfp/gfp females were lower than those in control pregnant females under ad libitum feeding, and blood glucose levels in pregnant Gcggfp/gfp females were higher after gestational day 12. Gcggfp/gfp females showed a decreased pregnancy rate and smaller litter size. The rate of successful breeding was significantly lower in Gcggfp/gfp females and was not improved by experience of breeding. Taken together, proglucagon-derived peptides are not required for pregnancy-associated ß-cell proliferation, however, are required for regulation of blood glucose levels and normal reproductive capacity. Gcggfp/gfp mice may serve as a novel model to analyze the effect of mild hyperglycemia during late gestational periods. 相似文献
992.
993.
Shirai J Sugiyama H Morimoto S Maezaki H Yamamoto Y Okanishi S Kamo I Matsumoto S Ishigami K Inatomi N Imanishi A Kawamoto M Tarui N Hashimoto T Ikeura Y 《Bioorganic & medicinal chemistry》2012,20(2):962-977
The synthesis and biological evaluation of a series of novel 3-phenylpiperidine-4-carboxamide derivatives are described. These compounds are generated by hybridization of the substructures from two types of tachykinin NK(1) receptor antagonists. Compound 42 showed high metabolic stability and excellent efficacy in the guinea-pig GR-73637-induced locomotive activity assay at 1 and 24h after oral administration. It also exhibited good pharmacokinetic profiles in four animal species, and a low potential in a pregnane X receptor induction assay. 相似文献
994.
Ijuin R Takashima T Watanabe Y Sugiyama Y Suzuki M 《Bioorganic & medicinal chemistry》2012,20(12):3703-3709
Drug transporters mediate the uptake and elimination of drugs in various organs; therefore, having knowledge of how a transporter functions in the body would play a key role in ensuring drug efficacy in in vivo systems. In this context, we designed and synthesized [(11)C]dehydropravastatin, a novel PET probe that would be potentially useful for evaluation of the functions of the OATP1B1 and MRP2 transporters, based on the use of palladium(0)-mediated rapid C-[(11)C]methylation (viz., the rapid cross-coupling between [(11)C]methyl iodide and a boron intermediate). 相似文献
995.
Smirnov SV Sokolov PM Kodera T Sugiyama M Hibi M Shimizu S Yokozeki K Ogawa J 《FEMS microbiology letters》2012,331(2):97-104
L-isoleucine-4-hydroxylase (IDO) is a recently discovered member of the Pfam family PF10014 (the former DUF 2257 family) of uncharacterized conserved bacterial proteins. To uncover the range of biochemical activities carried out by PF10014 members, eight in silico-selected IDO homologues belonging to the PF10014 were cloned and expressed in Escherichia coli. L-methionine, L-leucine, L-isoleucine and L-threonine were found to be catalysed by the investigated enzymes, producing L-methionine sulfoxide, 4-hydroxyleucine, 4-hydroxyisoleucine and 4-hydroxythreonine, respectively. An investigation of enzyme kinetics suggested the existence of a novel subfamily of bacterial dioxygenases within the PF10014 family for which free L-amino acids could be accepted as in vivo substrates. A hypothesis regarding the physiological significance of hydroxylated l-amino acids is also discussed. 相似文献
996.
Yong-Woon Han Tomoko Matsumoto Hiroaki Yokota Gengo Kashiwazaki Hironobu Morinaga Kaori Hashiya Toshikazu Bando Yoshie Harada Hiroshi Sugiyama 《Nucleic acids research》2012,40(22):11510-11517
N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides are small organic molecules that bind to DNA with sequence specificity and can be used as synthetic DNA-binding ligands. In this study, five hairpin eight-ring Py–Im polyamides 1–5 with different number of Im rings were synthesized, and their binding behaviour was investigated with surface plasmon resonance assay. It was found that association rate (ka) of the Py–Im polyamides with their target DNA decreased with the number of Im in the Py–Im polyamides. The structures of four-ring Py–Im polyamides derived from density functional theory revealed that the dihedral angle of the Py amide carbonyl is 14∼18°, whereas that of the Im is significantly smaller. As the minor groove of DNA has a helical structure, planar Py–Im polyamides need to change their conformation to fit it upon binding to the minor groove. The data explain that an increase in planarity of Py–Im polyamide induced by the incorporation of Im reduces the association rate of Py–Im polyamides. This fundamental knowledge of the binding of Py–Im polyamides to DNA will facilitate the design of hairpin Py–Im polyamides as synthetic DNA-binding modules. 相似文献
997.
S Omodaka T Inoue K Funamoto S Sugiyama H Shimizu T Hayase A Takahashi T Tominaga 《Journal of biomechanics》2012,45(14):2355-2361
Threshold image intensity for reconstructing patient-specific vascular models is generally determined subjectively. We assessed the effects of threshold image intensity differences on computational fluid dynamics (CFD) using a simple method of threshold determination. This study included 11 consecutive patients with internal carotid artery aneurysms collected retrospectively between April 2009 and March 2010. In 3-dimensional rotational angiography image data, we set a line probe across the coronal cross-section of the parent internal carotid artery, and calculated a profile curve of the image intensity along this line. We employed the threshold coefficient (C(thre)) value in this profile curve, in order to determine the threshold image intensity objectively. We assessed the effects of C(thre) value differences on vascular model configuration and the wall shear stress (WSS) distribution of the aneurysm. The threshold image intensity increased as the C(thre) value increased. The frequency of manual editing increased as the C(thre) value decreased, while disconnection of the posterior communicating artery occurred more frequently as the C(thre) value increased. The volume of the vascular model decreased and WSS increased according to the C(thre) value increase. The pattern of WSS distribution changed remarkably in one case. Threshold image intensity differences can produce profound effects on CFD. Our results suggest the uniform setting of C(thre) value is important for objective CFD. 相似文献
998.
Motose H Tominaga R Wada T Sugiyama M Watanabe Y 《The Plant journal : for cell and molecular biology》2008,54(5):829-844
To study cellular morphogenesis genetically, we isolated loss-of-function mutants of Arabidopsis thaliana , designated ibo1 . The ibo1 mutations cause local outgrowth in the middle of epidermal cells of the hypocotyls and petioles, resulting in the formation of a protuberance. In Arabidopsis, the hypocotyl epidermis differentiates into two alternate cell files, the stoma cell file and the non-stoma cell file, by a mechanism involving TRANSPARENT TESTA GLABRA1 ( TTG1 ) and GLABRA2 ( GL2 ). The ectopic protuberances of the ibo1 mutants were preferentially induced in the non-stoma cell files, which express GL2 . TTG1-dependent epidermal patterning is required for protuberance formation in ibo1 , suggesting that IBO1 functions downstream from epidermal cell specification. Pharmacological and genetic analyses demonstrated that ethylene promotes protuberance formation in ibo1 , implying that IBO1 acts antagonistically to ethylene to suppress radial outgrowth. IBO1 is identical to NEK6 , which encodes a Never In Mitosis A (NIMA)-related protein kinase (Nek) with sequence similarity to Neks involved in microtubule organization in fungi, algae, and animals. The ibo1-1 mutation, in which a conserved Glu residue in the activation loop is substituted by Arg, completely abolishes its kinase activity. The intracellular localization of GFP-tagged NEK6 showed that NEK6 mainly accumulates in cytoplasmic spots associated with cortical microtubules and with a putative component of the γ-tubulin complex. The localization of NEK6 is regulated by the C-terminal domain, which is truncated in the ibo1-2 allele. These results suggest that the role of NEK6 in the control of cellular morphogenesis is dependent on its kinase action and association with the cortical microtubules. 相似文献
999.
1000.
Kinetics of biliary excretion of the main two bilirubin photoproducts after injection into Gunn rats. 下载免费PDF全文
S Onishi N Kawade S Itoh K Isobe S Sugiyama T Hashimoto H Narita 《The Biochemical journal》1981,198(1):107-112
The kinetics of biliary excretion of the main two photoproducts after injection into Gunn rats were examined. The photoproducts that are obtained from experiments in vitro consist of unknown pigment, photobilirubin IXa and a small amount of (ZZ)-bilirubin IXa. It was confirmed previously that the first two photoproducts are identical with the main two photoproducts obtained in vivo. In experiments on four animals, the average of total biliary recoveries of unknown pigment was 81.4%, and that of photobilirubin IXa in the bile estimated by the Sigma-minus method was 29.8 min and that for unknown pigment was 4.3 min. The rate of thermal reversion of photobilirubin IXa to (ZZ)-bilirubin IXa in the bile at 37 degrees C was very rapid, i.e. its half-life was 6.2 min. 相似文献