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排序方式: 共有446条查询结果,搜索用时 31 毫秒
61.
Hirabayashi A Mukaiyama H Kobayashi H Shiohara H Nakayama S Ozawa M Tsuji E Miyazawa K Misawa K Ohnota H Isaji M 《Bioorganic & medicinal chemistry》2008,16(20):9247-9260
Spleen tyrosine kinase (Syk) and zeta-associated protein kinase of 70k Da (ZAP-70) are members of the Syk family and non-receptor-type protein tyrosine kinases, which play crucial roles in B- and T-cell activation. Therefore, a Syk family tyrosine kinases inhibitor would be a useful therapeutic agent for the treatment of various allergic disorders and autoimmune diseases. Previously, we reported that 1,2,4-triazolo[4,3-c]pyrimidine derivative 1 and 1,2,4-triazolo[1,5-c]pyrimidine derivative 2 showed strong inhibitory activities against Syk family kinases. These compounds also exhibited high-level suppression of IL-2 in cellular assays. However, their oral efficacies were poor in a mouse model of IL-2 production. To improve oral effectiveness, we investigated a new series of Syk family kinases inhibitors. We found that imidazo[1,2-c]pyrimidine derivatives potently inhibited the Syk family kinases. Among these agents, compound 9f not only showed strong inhibitory activities against Syk and ZAP-70 kinases in vitro, but its oral administration resulted in the in vivo suppression of both the passive cutaneous anaphylaxis reaction and Concanavalin A-induced IL-2 production in a mouse model. 相似文献
62.
Tetsuichiro Inai Akihito Sengoku Eiji Hirose Hiroshi Iida Yosaburo Shibata 《Histochemistry and cell biology》2009,131(6):681-690
Claudins constitute tight junction (TJ) strands. In order to examine the function of the second extracellular loop (ECL2),
we constructed 1CLΔFY and 1CLΔPL in which highly conserved amino acids, FY or PL, in the ECL2 of mouse claudin-1 were deleted.
They were then tagged with either EGFP at the NH2-terminus (EGFP1CLΔFY and EGFP1CLΔPL) or the myc-epitope at the COOH-terminus (1CLΔFYmyc and 1CLΔPLmyc). The expression of
EGFP1CLΔFY and EGFP1CLΔPL in TJ-free HEK293 cells formed TJ strands resembling those formed by wild-type claudin-1. The expression
of 1CLΔPLmyc in TJ-bearing MDCK II cells induced aberrant TJ strands in the lateral plasma membranes whose intramembranous
particles were almost equally distributed in the P- and E-face. In contrast, 1CLΔFYmyc formed aggregates of short continuous
strands which were frequently associated with vesicle-like structures. Coculture experiments with MDCK II cells showed that
1CLΔPLmyc was localized at heterotypic cell–cell junctions but 1CLΔFYmyc was not. These results suggest that changes in the
TJ morphology due to the expression of either 1CLΔFYmyc or 1CLΔPLmyc may be caused by some factors specific to epithelial
MDCK II cells including endogenous claudins.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
63.
Specific induction of a 72-kDa heat shock protein protects esophageal mucosa from reflux esophagitis
Yuko Izumi Michiro Otaka Taiji Takahashi Makiko Takada Yuji Shimada Daisuke Asaoka Akihito Nagahara Hideaki Itoh Sumio Watanabe 《Life sciences》2009,84(15-16):517-522
AimsThe aim of this study is to investigate the expression and cytoprotective function of a 72-kDa heat shock protein (HSP72) using a reflux esophagitis model in rats.Main methodsExpression of HSP60, HSP72, and HSP90 in rat esophageal mucosa was evaluated by Western blot analysis before and after hyperthermia (42.5 °C, 20 min). Rats received the operation to produce reflux esophagitis with or without pretreatment with hyperthermia to induce HSPs. The esophageal mucosal damage was evaluated 12 h after the operation.Key findingsExpression of HSP72 was significantly increased by hyperthermia in rat esophageal mucosa. Reflux esophagitis was dramatically prevented when HSP72 was preinduced by hyperthermia. Furthermore, activation of TNF-α and IL-1β in esophageal mucosa was also suppressed.SignificanceThese results suggested that hyperthermia protects the esophageal mucosa in reflux esophagitis model by inducing HSP72 and suppressing proinflammatory cytokine activation. These findings might suggest that HSP-inducing therapy could be a novel and unique therapy for reflux esophagitis. 相似文献
64.
Samuel R. Ward Akihito Tomiya Gilad J. Regev Bryan E. Thacker Robert C. Benzl Choll W. Kim Richard L. Lieber 《Journal of biomechanics》2009,42(10):1384-1389
The purpose of this study was to compare the passive mechanical properties and titin isoform sizes of the multifidus, longissimus, and iliocostalis muscles. Given our knowledge of each muscle's architecture and the multifidus’ operating range, we hypothesized that multifidus would have higher elastic modulus with corresponding smaller titin isoforms compared to longissimus or iliocostalis muscles. Single-fiber and fiber-bundle material properties were derived from passive stress–strain tests of excised biopsies (n=47). Titin isoform sizes were quantified via sodium dodecyl sulfate-vertical agarose gel electrophoresis (SDS-VAGE) analysis. We found that, at the single-fiber level, all muscles had similar material properties and titin isoform sizes. At the fiber-bundle level, however, we observed significantly increased stiffness (~45%) in multifidus compared to longissimus and iliocostalis muscles. These data demonstrate that each muscle may have a different scaling relationship between single-fiber and fiber-bundle levels, suggesting that the structures responsible for higher order passive mechanical properties may be muscle specific. Our results suggest that divergent passive material properties are observed at size scales larger than the single cell level, highlighting the importance of the extracellular matrix in these muscles. In addition to architectural data previously reported, these data further support the unique stabilizing function of the multifidus muscle. These data will provide key input variables for biomechanical modeling of normal and pathologic lumbar spine function and direct future work in biomechanical testing in these important muscles. 相似文献
65.
Chie Nishioka Takayuki Ikezoe Jing Yang Akihito Yokoyama 《Apoptosis : an international journal on programmed cell death》2010,15(7):795-804
We previously showed that the MEK inhibitor AZD6244 induced apoptosis in acute myelogenous leukemia (AML) HL60 cells. However,
the mechanisms of AZD6244 to induce apoptosis remain to be fully elucidated. This study found that exposure of HL60 cells
to AZD6244 down-regulated the levels of phosphor (p)-4E-binding protein 1 (4E-BP1), a substrate of mammalian target of rapamycin
complex 1 (mTORC1), and anti-apoptotic protein Mcl-1. On the other hand, exposure of EOL-1 and MOLM13 cells to AZD6244 failed
to induce apoptosis and levels of p-4E-BP1 and Mcl-1 were not down-regulated in these cells. These observations prompted us
to hypothesize that down-regulation od 4E-BP1 and Mcl-1 might play an important role in AZD6244-mediated apoptosis. As expected,
down-regulation of 4E-BP1 by an siRNA sensitized EOL-1 cells to AZD6244-mediated apoptosis in parallel with down-regulation
of Mcl-1. Moreover, we found that blockade of mTORC1 by RAD001 synergistically enhanced the action of AZD6244 in leukemia
cells. 相似文献
66.
67.
Lynn S. Model Michael R. Hall Daniel J. Wong Akihito Muto Yuka Kondo Kenneth R. Ziegler Amanda Feigel Clay Quint Laura Niklason Alan Dardik 《The Yale journal of biology and medicine》2014,87(3):359-371
Vein graft adaptation to the arterial environment is characterized by loss of venous identity, with reduced Ephrin type-B receptor 4 (Eph-B4) expression but without increased Ephrin-B2 expression. We examined changes of vessel identity of human saphenous veins in a flow circuit in which shear stress could be precisely controlled. Medium circulated at arterial or venous magnitudes of laminar shear stress for 24 hours; histologic, protein, and RNA analyses of vein segments were performed. Vein endothelium remained viable and functional, with platelet endothelial cell adhesion molecule (PECAM)-expressing cells on the luminal surface. Venous Eph-B4 expression diminished (p = .002), Ephrin-B2 expression was not induced (p = .268), and expression of osteopontin (p = .002) was increased with exposure to arterial magnitudes of shear stress. Similar changes were not found in veins placed under venous flow or static conditions. These data show that human saphenous veins remain viable during ex vivo application of shear stress in a bioreactor, without loss of the venous endothelium. Arterial magnitudes of shear stress cause loss of venous identity without gain of arterial identity in human veins perfused ex vivo. Shear stress alone, without immunologic or hormonal influence, is capable of inducing changes in vessel identity and, specifically, loss of venous identity. 相似文献
68.
69.
Furutani-Seiki M Sasado T Morinaga C Suwa H Niwa K Yoda H Deguchi T Hirose Y Yasuoka A Henrich T Watanabe T Iwanami N Kitagawa D Saito K Asaka S Osakada M Kunimatsu S Momoi A Elmasri H Winkler C Ramialison M Loosli F Quiring R Carl M Grabher C Winkler S Del Bene F Shinomiya A Kota Y Yamanaka T Okamoto Y Takahashi K Todo T Abe K Takahama Y Tanaka M Mitani H Katada T Nishina H Nakajima N Wittbrodt J Kondoh H 《Mechanisms of development》2004,121(7-8):647-658
A large-scale mutagenesis screen was performed in Medaka to identify genes acting in diverse developmental processes. Mutations were identified in homozygous F3 progeny derived from ENU-treated founder males. In addition to the morphological inspection of live embryos, other approaches were used to detect abnormalities in organogenesis and in specific cellular processes, including germ cell migration, nerve tract formation, sensory organ differentiation and DNA repair. Among 2031 embryonic lethal mutations identified, 312 causing defects in organogenesis were selected for further analyses. From these, 126 mutations were characterized genetically and assigned to 105 genes. The similarity of the development of Medaka and zebrafish facilitated the comparison of mutant phenotypes, which indicated that many mutations in Medaka cause unique phenotypes so far unrecorded in zebrafish. Even when mutations of the two fish species cause a similar phenotype such as one-eyed-pinhead or parachute, more genes were found in Medaka than in zebrafish that produced the same phenotype when mutated. These observations suggest that many Medaka mutants represent new genes and, therefore, are important complements to the collection of zebrafish mutants that have proven so valuable for exploring genomic function in development. 相似文献
70.
Yoda H Hirose Y Yasuoka A Sasado T Morinaga C Deguchi T Henrich T Iwanami N Watanabe T Osakada M Kunimatsu S Wittbrodt J Suwa H Niwa K Okamoto Y Yamanaka T Kondoh H Furutani-Seiki M 《Mechanisms of development》2004,121(7-8):715-728
We screened for mutations affecting retinotectal axonal projection in Medaka, Oryzias latipes. In wild-type Medaka embryos, all the axons of retinal ganglion cells (RGCs) project to the contralateral tectum, such that the topological relationship of the retinal field is maintained. We labeled RGC axons using DiI/DiO at the nasodorsal and temporoventral positions of the retina, and screened for mutations affecting the pattern of stereotypic projections to the tectum. By screening 184 mutagenized haploid genomes, seven mutations in five genes causing defects in axonal pathfinding were identified, whereas mutations affecting the topographic projection of RGC axons were not found. The mutants were grouped into two classes according to their phenotypes. In mutants of Class I, a subpopulation of the RGC axons branched out either immediately after leaving the eye or after reaching the midline, and this axonal subpopulation projected to the ipsilateral tectum. In mutants of Class II, subpopulations of RGC axons branched out after crossing the midline and projected aberrantly. These mutants will provide clues to understanding the functions of genes essential for axonal pathfinding, which may be conserved or partly divergent among vertebrates. 相似文献