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排序方式: 共有4733条查询结果,搜索用时 15 毫秒
41.
Zhe Nie Victoria Feher Srinivasa Natala Christopher McBride Andre Kiryanov Benjamin Jones Betty Lam Yan Liu Stephen Kaldor Jeffrey Stafford Kouki Hikami Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Shin-ichi Matsumoto Nobuyuki Amano Lilly Zhang David Hosfield Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2013,23(12):3662-3666
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. 相似文献
42.
Masafumi Komiya Shigehiro Asano Nobuyuki Koike Erina Koga Junetsu Igarashi Shogo Nakatani Yoshiaki Isobe 《Bioorganic & medicinal chemistry》2012,20(23):6840-6847
Based on 2-(4-phenoxybenzoyl)-5-hydroxyindole (2), a novel structural class of CaMKII inhibitors were synthesized and further optimized. The strong acidity of the hydroxyl group and the lipophilic group at the 4 and 6-positions were found to be necessary for strong CaMKII inhibition. Compound 25 was identified as a promising compound with 50-fold more potent inhibitory activity for CaMKII than 2. Compound 25 also showed high selectivity for CaMKII over off-target kinases. 相似文献
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44.
Endothelial NO Synthase (eNOS) phosphorylation regulates coronary diameter during ischemia-reperfusion in association with oxidative stress 总被引:3,自引:0,他引:3
Hoshino S Kikuchi Y Nakajima M Kimura H Tsuyama S Uemura K Yoshida K 《Free radical research》2005,39(5):481-489
The link between endothelial nitric oxide synthase (eNOS) activation and vascular diameter during ischemia-reperfusion was investigated in the rat heart. After short (<30 min) and long (>45 min) time of ischemia conferred by coronary artery occlusion of the rats, reperfusion caused dilatation and constriction of arterioles, respectively. Partial oxygen pressure (pO2) measurement of the heart by the electrode confirmed the hyper-perfusion and no-reflow phenomena during reperfusion, as well as myocardial ischemia. The vascular diameter was correlated with phosphorylation of Akt and serine 1177 residue of eNOS, and formation of NO-bound guanylate cyclase (GC) by immuoflorescence study. Western blotting confirmed the phosphorylation of eNOS-Ser1177 depending on ischemia time. The constriction during reperfusion after 45 min of ischemia is supposedly caused by the inhibition of Akt-mediated eNOS-Ser1177 phosphorylation, which was suppressed by a PKC inhibitor chelerythrine, or ROS scavengers N-2-mercaptopropionyl glycine (MPG) and 4,5-Dihydroxy-1, 3-benzenedisulfonic acid disodium salt (Tiron). However, an endothelin receptor antagonist BQ123 alleviated the vasoconstriction by increasing NO availability but not eNOS-Ser1177 phosphorylation. Thus, vascular patency is correlated with eNOS-Ser1177 phosphorylation in association with ROS, and PKC during reperfusion. Endothelin inhibits vasodilatation by reducing NO availability during reperfusion. 相似文献
45.
Characterization of the cells in the repair tissue of full-thickness articular cartilage defects 总被引:1,自引:0,他引:1
H. Nakajima Tatsuhiko Goto Osamu Horikawa Toshiyuki Kikuchi Masayuki Shinmei 《Histochemistry and cell biology》1998,109(4):331-338
It is well established that a full-thickness articular cartilage defect is repaired with a fibrocartilaginous tissue, cells
of which are derived from undifferentiated mesenchymal stem cells in the bone marrow. To characterize the repair cells biochemically,
full-thickness defects were created in rabbit knee joints and the repair tissues taken at 3, 6, and 12 weeks after surgery.
The repair cells were cultured and examined biochemically to investigate the effects of four exogenous growth factors with
regard to the metabolism of type II collagen and proteoglycans. A significant increase of carboxy-terminal type II procollagen
peptide production was observed in the conditional medium of the repair cells, especially taken at 6 weeks after surgery,
in the presence of each growth factor. Glycosaminoglycan content was also increased and proteoglycan synthesis stimulated.
The repair cells taken at the early stage of the repair process could originally have more activity of type II collagen synthesis,
and the growth factors used could enhance the differentiation of the repair cells in vitro.
Accepted: 3 November 1997 相似文献
46.
Kato H Nakajima S Saito Y Takahashi S Katoh R Kitamura M 《Cell death and differentiation》2012,19(2):310-320
Mammalian target of rapamycin (mTOR) has a key role in the regulation of an array of cellular function. We found that rapamycin, an inhibitor of mTOR complex 1 (mTORC1), attenuated endoplasmic reticulum (ER) stress-induced apoptosis. Among three major branches of the unfolded protein response, rapamycin selectively suppressed the IRE1-JNK signaling without affecting PERK and ATF6 pathways. ER stress rapidly induced activation of mTORC1, which was responsible for induction of the IRE1-JNK pathway and apoptosis. Activation of mTORC1 reduced Akt phosphorylation, which was an event upstream of IRE-JNK signaling and consequent apoptosis. In vivo, administration with rapamycin significantly suppressed renal tubular injury and apoptosis in tunicamycin-treated mice. It was associated with enhanced phosphorylation of Akt and suppression of JNK activity in the kidney. These results disclosed that, under ER stress conditions, mTORC1 causes apoptosis through suppression of Akt and consequent induction of the IRE1-JNK pathway. 相似文献
47.
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49.
Katsumi Iizuka Hiromu Nakajima Mitsuyoshi Namba Jun ichiro Miyagawa Junichi Miyazaki Toshiaki Hanafusa Yuji Matsuzawa 《Biochimica et biophysica acta》2002,1586(1):23-31
Long-term exposure of the pancreatic beta cells to free fatty acid (FFA) reportedly inhibits glucose-stimulated insulin secretion. We here studied the impact of FFA on glucose and lipid metabolism in pancreatic beta cells with special reference to insulin secretion. Pancreatic beta-cell line MIN6 was exposed to various concentrations of palmitate for 3 days. Glucose-stimulated insulin secretion and insulin content were decreased corresponding to the concentration of the palmitate exposed. Glycolytic flux and ATP synthesis was unchanged, but pyruvate-stimulated change in NAD(P)H concentration was decreased. Pyruvate carboxylase was decreased at the protein level, which was restored by the removal of palmitate or the inhibition of beta-oxidation. Intracellular content of triglyceride and FFA were elevated, beta-oxidation was increased, and de novo lipogenesis from glucose was decreased. NADPH content and citrate output into the medium, which reflected pyruvate malate shuttle flux, were decreased, but malic enzyme activity was unaffected. The malic enzyme inhibitor alone inhibited insulin response to glucose. In conclusion, long-term exposure of FFA to beta cells inhibits glucose-stimulated insulin secretion via the decreased NADPH contents due to the inhibition of pyruvate carboxylase and malate pyruvate shuttle flux. 相似文献
50.
Hemoglobin-haptoglobin receptor in rat liver plasma membrane 总被引:4,自引:0,他引:4
K Kino H Tsunoo Y Higa M Takami H Hamaguchi H Nakajima 《The Journal of biological chemistry》1980,255(20):9616-9620
The presence of a receptor specific for the hemoglobin . haptoglobin complex is demonstrated in rat liver plasma membranes. Hemoglobin . haptoglobin complex, administered intravenously to rats, was cleared from the circulation at a constant rate with exclusive incorporation of the molecule into hepatocytes. This incorporation was unaffected by the simultaneous injection of asialoglycoprotein or heme . hemopexin complex. In vitro experiments with isolated liver plasma membranes indicated the absence of competitive binding of these molecules to the membrane and suggested that this receptor might recognize an altered conformation of the haptoglobin moiety of the complex resulting from the binding with hemoglobin. These observations suggest that the mechanism of recognition and binding of hemoglobin . haptoglobin complex by the receptor is different from that of the asialoglycoprotein receptor or heme . hemopexin receptor. 相似文献