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排序方式: 共有499条查询结果,搜索用时 555 毫秒
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Yamamoto N Takeshita K Shichijo M Kokubo T Sato M Nakashima K Ishimori M Nagai H Li YF Yura T Bacon KB 《The Journal of pharmacology and experimental therapeutics》2003,306(3):1174-1181
Spleen tyrosine kinase (Syk) tyrosine kinase plays essential roles in receptors for Fc portion of immunoglobulins and B cell receptor complex signaling in various inflammatory cells; therefore, inhibitors of Syk kinase may show potential as antiasthmatic/allergic therapeutics. We identified 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]-nicotinamide dihydrochloride (BAY 61-3606), a potent (Ki = 7.5 nM) and selective inhibitor of Syk kinase. BAY 61-3606 inhibited not only degranulation (IC50 values between 5 and 46 nM) but also lipid mediator and cytokine synthesis in mast cells. BAY 61-3606 was highly efficacious in basophils obtained from healthy human subjects (IC50 = 10 nM) and seems to be at least as potent in basophils obtained from atopic (high serum IgE) subjects (IC50 = 8.1 nM). B cell receptor activation and receptors for Fc portion of IgG signaling in eosinophils and monocytes were also potently suppressed by BAY 61-3606. Oral administration of BAY 61-3606 to rats significantly suppressed antigen-induced passive cutaneous anaphylactic reaction, bronchoconstriction, and bronchial edema at 3 mg/kg. Furthermore, BAY 61-3606 attenuated antigen-induced airway inflammation in rats. Based on these anti-inflammatory effects of BAY 61-3606 both in vitro and in vivo, it was demonstrated that Syk may play a very critical role in the pathogenesis of allergic reactions. 相似文献
44.
Masato Iwata Satoki Inoue Masahiko Kawaguchi Toshitaka Kimura Takashi Tojo Shigeki Taniguchi Hitoshi Furuya 《Journal of anesthesia》2010,24(1):31-37
Background and objective
Propofol injection during induction of anesthesia induces pain. Ketamine has been shown to reduce the injection pain. However, ketamine has unfavorable adverse effects, including increased secretion production and hemodynamic responses, which might induce pulmonary or hemodynamic adverse events, especially in patients undergoing lung surgery who require a double-lumen tube (DLT). The aim of this study was to determine whether ketamine can safely reduce propofol injection pain during induction of anesthesia for lung surgery. 相似文献45.
46.
Fujino H Kitaoka Y Hayashi Y Munemasa Y Takeda H Kumai T Kobayashi S Ueno S 《Acta neuropathologica》2009,117(1):75-84
Brain-derived neurotrophic factor (BDNF) is a potent survival and developmental factor that is regulated by cyclic AMP-response
element binding protein (CREB) and has a protective effect against retinal ganglion cell (RGC) death. However, the effect
of BDNF on the optic nerve axonal degeneration remains to be examined. In this study, we show that intravitreal injection
of tumor necrosis factor (TNF)-α induces transient increases in phosphorylated-CREB (p-CREB) and BDNF expression in the optic
nerve. Administration of exogenous BDNF further increased the p-CREB and endogenous BDNF level and exerted a neuroprotective
effect against TNF-α-induced axonal loss. The increases in BDNF mRNA and protein induced by TNF-α were inhibited significantly
by a CRE decoy oligonucleotide. The protective effect of exogenous BDNF on axons was also inhibited by the CRE decoy oligonucleotide.
These results suggest that the protective effect of exogenous BDNF may be associated with increases in CREB phosphorylation
and endogenous BDNF in the optic nerve. 相似文献
47.
Naoe M Ogawa Y Hasebe Y Morita J Shichijo T Igarashi A Fuji K Iwamoto S Suzuki T Terao S 《Oncology research》2011,19(10-11):479-486
Metastatic renal cell carcinoma (mRCC) treatment consists of molecular targeted agents and cytokines that have fundamentally different mechanisms of action. Clinical responses also differ; complete response is rare with molecular targeted agents but is sometimes achieved with cytokine therapies. Because of the relatively high efficacy of combination therapy with low-dose interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) against mRCC, it is important to reevaluate cytokine therapies in vitro. Here, we show that when IL-2 is administered in combination with IFN-alpha, a stronger cytotoxic effect of PBMCs on RCC cell lines is observed than when IL-2 is administered alone. The upregulation of TNF-related apoptosis-inducing ligand on NK cell by IL-2 and suppression of regulatory T cells (Tregs) by IFN-alpha were recognized at the same time when cytotoxicity of peripheral blood mononuclear cells (PBMCs) was enhanced. IL-2 is known to activate natural killer cell cytotoxicity; however, IL-2 also stimulates Treg expansion, which enhances immunosuppression. On the other hand, IFN-alpha negatively regulates Treg cells, thereby increasing the function of immune effector cells. Our in vitro results may explain, at least in part, the clinical efficacy of combination low-dose IL-2 and IFN-alpha therapy against mRCC. 相似文献
48.
49.
It is possible that SMP-797 will be administered frequently in combination with statins to hyperlipidemic patients. OATP1B1 is thought to be the major transporter that mediates the hepatic uptake of statins. This study investigated whether SMP-797 interacts with statins via OATP1B1 by two approaches. Firstly, the effects of SMP-797 on OATP1B1-mediated uptake of estrone-3-sulfate (ES) by human hepatocytes and by oocytes expressing OATP1B1 were examined. Since OATP1B1-mediated uptake of ES is known to be biphasic (high- and low-affinity sites), concentrations of [(3)H]ES were set lower than the respective K(m) values. Two representative statins were used to assure that statins share OATP1B1 with [(3)H]ES in this in vitro system. Rosuvastatin inhibited OATP1B1-mediated uptake of [(3)H]ES through both sites and pravastatin inhibited a high-affinity site. The inhibition by the positive control (cyclosporin A) was significant. Thus, it is considered that this system was applicable to examine drug-drug interaction with statins on OATP1B1-mediated uptake. In this condition, no apparent inhibition to each site by SMP-797 was observed up to a concentration 3,000-fold higher than the clinical level. Secondly, the uptake of [(14)C]SMP-797 by oocytes expressing OATP1B1 was examined and the activity was negligible. In conclusion, these data suggest that SMP-797 has little potential to interact with statins on OATP1B1. 相似文献
50.
Hirano Y Shichijo M Deguchi M Nagira M Suzuki N Nishitani Y Hattori M Arimura A 《European journal of pharmacology》2007,560(1):81-88
Prostaglandin (PG) D2, a major cyclooxygenase metabolite generated predominantly from immunologically stimulated mast cells, is thought to contribute to the pathogenesis of allergic diseases via the two PGD2 receptors, prostanoid DP receptor and chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2). Monocytes are known to express the prostanoid DP receptor, however, the role of it in inflammatory responses is still unclear. In the present study, to clarify the functional roles of prostanoid DP receptor on monocytes, we examined the effect of PGD2 on the production of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 from a human monocytic cell line, THP-1. Single activation of prostanoid DP receptor hardly produced any cytokines or chemokines. However, activation with PGD2 in the presence of tumor necrosis factor (TNF)-α mediated significant production of MCP-1 and IL-8, but not the other cytokines and chemokines, in comparison to single stimulation with TNF-α. In addition, the selective prostanoid DP receptor antagonist, pinagladin ((Z)-7-[(1R,2R,3S,5S)-2-(benzothiophen-3-ylcarbonylamide)-10-norpinan-3-yl]hept-5-enoic acid) inhibited the production of MCP-1 and IL-8 upon combined stimulation with PGD2 and TNF-α. The synergistic production of MCP-1 and IL-8 by PGD2 was mimicked by dibutyryl cAMP (db-cAMP) and was inhibited by a protein kinase A (PKA) inhibitor. Our findings suggest that activation of the prostanoid DP receptor on THP-1 cells enhances TNF-α-induced MCP-1 and IL-8 production via the cAMP/PKA signaling pathway. 相似文献