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排序方式: 共有160条查询结果,搜索用时 31 毫秒
91.
Cywin CL Dahmann G Prokopowicz AS Young ER Magolda RL Cardozo MG Cogan DA Disalvo D Ginn JD Kashem MA Wolak JP Homon CA Farrell TM Grbic H Hu H Kaplita PV Liu LH Spero DM Jeanfavre DD O'Shea KM White DM Woska JR Brown ML 《Bioorganic & medicinal chemistry letters》2007,17(1):225-230
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds. 相似文献
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Embryonic stem cells (ESCs) are derived from the inner cell mass of the preimplantation stage embryo and are capable of prolonged symmetrical self-renewal (both daughter cells remain escs) as well as differentiation into derivatives of all three embryonic germ layers. ESCs therefore have the potential to provide an unlimited supply of transplantable cells to replace or regenerate damaged or diseased tissues. However, several barriers must be overcome before successful clinical trials are possible: for example, pure populations of the desired cell type need to be selected and expanded in clinically relevant numbers, and a method for preventing immunological rejection of the transplanted cells without long-term immunosuppressive therapy is also required. In this review, we highlight recent developments in human ESC derivation and expansion, outline current understanding of the signalling pathways underlying stem cell renewal, and discuss challenging problems related to the selective differentiation and immune properties of human ESCs. 相似文献
95.
Kölle S Stojkovic M Reese S Reichenbach HD Wolf E Sinowatz F 《Cell and tissue research》2004,317(1):101-108
Growth hormone (GH) has recently been shown to promote the development of preimplantation embryos. The aim of our study was therefore to analyze the effects of GH on the morphology and ultrastructure of the cells of bovine preimplantation embryos produced by in vitro fertilization (IVF). In order to determine the physiologically optimal morphology of blastocysts, ex vivo embryos obtained by uterine flushing were also included in the study. As shown by transmission electron microscopy, treatment with GH induced the elimination of glycogen storage in cells of the inner cell mass of 7-day-old embryos. GH also stimulated the exocytosis of lipid vesicles in the inner cell mass and trophectoderm cells of these embryos. Quantitative analysis of micrographs demonstrated a higher volume density of embryonic mitochondria in 7-day-old embryos cultured with GH than in control embryos. Treatment with GH regularly resulted in an improvement of the ultrastructural features of embryos produced in vitro, thus resembling the morphology of ex vivo embryos. Scanning electron-microscopy studies demonstrated that GH altered the structure and the pore size of the zona pellucida of blastocysts. Our studies imply that GH can modulate carbohydrate, lipid, and energy metabolism and influence transportation processes in the early IVF embryo.This work was supported by the Deutsche Forschungsgemeinschaft (FOR 478/1) 相似文献
96.
Valeri Zakhartchenko Miodrag Stojkovic Gottfried Brem Eckhard Wolf 《Molecular reproduction and development》1997,48(3):332-338
To evaluate the effect of karyoplast-cytoplast ratio on the development of nuclear transfer embryos, karyoplasts from day 4, day 5, and day 6 embryos were transferred to oocytes enucleated with different volumes of cytoplasm: Type 1, removal of a small volume of cytoplasm equivalent to the first polar body, Type 2, removal of a volume of cytoplasm approximately equal to the volume of the respective karyoplast, and Type 3, removal of half of the oocyte volume. In addition, the effect of experimental reduction of karyoplast cytoplasm was investigated in day 4 and day 5 karyoplasts. Intact day 4 karyoplasts fused to Type 3 cytoplasts did not support development to blastocysts, whereas these karyoplasts yielded blastocysts in combination with Type 1 (7%) and Type 2 cytoplasts (12%). After experimental reduction of cytoplasmic volume in day 4 karyoplasts, blastocysts (10%) were also obtained after fusion with Type 3 cytoplasts, probably due to reduction of cytoplasmic chimerism. With day 5 karyoplasts, blastocyst rate was higher in combination with Type 2 (34%) than with Type 1 (19%) and Type 3 cytoplasts (16%; P < 0.05). The use of day 6 intact karyoplasts resulted in a significantly (P < 0.05) higher proportion of blastocysts when fused with Type 2 (38%) or Type 1 cytoplasts (34%) than with Type 3 cytoplasts (16%). These results suggest that enucleation of oocytes with a volume similar to that of the respective karyoplast creates better conditions for cell cycle interactions with all types of karyoplasts than enucleation with minimal or large volume of cytoplasm. Mol. Reprod. Dev. 48:332–338, 1997. © 1997 Wiley-Liss, Inc. 相似文献
97.
Leon Grayfer Erick Garcia Garcia Miodrag Belosevic 《The Journal of biological chemistry》2010,285(31):23537-23547
Unlike mammals, bony fish have two type II interferons, IFNγ and IFNγrel, whose pro-inflammatory functions have not been fully characterized. To elucidate the distinct roles of these type II interferons of bony fish, we examined the effects of recombinant goldfish (rg) IFNγ and IFNγrel on the macrophage antimicrobial responses, immune gene expression, and their signaling pathways. Our findings indicate that rgIFNγ and rgIFNγrel possess unique capacities to mediate each of the above processes. Q-PCR analysis revealed similar expression of both cytokines in tissues and immune cell populations of the goldfish, although IFNγ mRNA levels were generally higher in most tissues and cell types. Whereas rgIFNγ had long-lasting effects on the priming of goldfish monocyte ROI production, the rgIFNγrel had relatively short-lived ROI priming potential and eventually down-regulated the priming of ROI production induced by rgIFNγ or rgTNFα2. Whereas rgIFNγ induced relatively modest phagocytic and nitric oxide responses of goldfish macrophages, rgIFNγrel induced significantly higher phagocytosis, iNOSA and iNOSB gene expression and nitric oxide production compared with rgIFNγ. The rgIFNγ and rgIFNγrel induced different gene expression profiles in goldfish monocytes. These differences included significantly higher induction of TNFα2, CXCL8, ceruloplasmin, and interferon regulatory factor (IRFs) expression after activation of monocytes with rgIFNγrel. The rgIFNγrel was more abundant in whole cell lysates compared with rgIFNγ. Both cytokines induced the phosphorylation of Stat1, while the nuclear localization of Stat1 was only observed following treatment of monocytes with rgIFNγ. Our findings suggest the presence of functional segregation of the induction of macrophage antimicrobial functions by type II interferons of bony fish. 相似文献
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T Ginsburg-Shmuel M Haas D Grbic G Arguin Y Nadel FP Gendron G Reiser B Fischer 《Bioorganic & medicinal chemistry》2012,20(18):5483-5495
P2Y(6) nucleotide receptor (P2Y(6)-R) plays important physiological roles, such as insulin secretion and reduction of intraocular pressure. However, this receptor is still lacking potent and selective agonists to be used as potential drugs. Here, we synthesized uracil nucleotides and dinucleotides, substituted at the C5 and/or P(α) position with methoxy and/or borano groups, 18-22. Compound 18A, R(p) isomer of 5-OMe-UDP(α-B), is the most potent and P2Y(6)-R selective agonist currently known (EC(50) 0.008μM) being 19-fold more potent than UDP and showing no activity at uridine nucleotide receptors, P2Y(2)- and P2Y(4)-R. Analogue 18A was highly chemically stable under conditions mimicking gastric juice acidity (t(1/2)=16.9h). It was more stable to hydrolysis by nucleotide pyrophosphatases (NPP1,3) than UDP (15% and 28% hydrolysis by NPP1 and NPP3, respectively, vs 50% and 51% hydrolysis of UDP) and metabolically stable in blood serum (t(1/2)=17 vs 2.4, 11.9, and 21h for UDP, 5-OMe-UDP, and UDP(α-B), respectively). This newly discovered highly potent and physiologically stable P2Y(6)-R agonist may be of future therapeutic potential. 相似文献
100.
Signaling through the colony-stimulating factor-1 receptor (CSF-1R) mediates the proliferation, differentiation, and activation of macrophages and their progenitors. In this study we report on the use of an anti-goldfish CSF-1R antibody to specifically recognize a population of CSF-1R positive cells from goldfish tissues. Furthermore, using our previously characterized primary kidney macrophage culture system, we show that CSF-1R positive cells include monocytes, macrophages, and their progenitor cells. Freshly isolated progenitor cells had a higher median florescent intensity ratio than those progenitor cells cultured for up to four days. The decrease in CSF-1R expression on the progenitor cells coincides with the appearance and development of monocytes and macrophages. Monocytes were consistently CSF-1R+ and maintained the high level of CSF-1R expression as they developed into macrophages. Like that of mammalian systems, CSF-1R is expressed on all macrophage sub-populations (progenitors, monocytes, macrophages), and CSF-1R expression increases with macrophage development in teleosts. 相似文献