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91.
Nawata R Yujiri T Nakamura Y Ariyoshi K Takahashi T Sato Y Oka Y Tanizawa Y 《Oncogene》2003,22(49):7774-7780
Bcr-Abl tyrosine kinase, a chimeric oncoprotein responsible for chronic myelogenous leukemia, constitutively activates several signal transduction pathways that stimulate cell proliferation and prevent apoptosis in hematopoietic cells. The antiapoptotic function of Bcr-Abl is necessary for hematopoietic transformation, and also contributes to leukemogenesis. Herein, we show for the first time that cell transformation induced by Bcr-Abl leads to increased expression and kinase activity of MEK kinase 1 (MEKK1), which acts upstream of the c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK) and NF-kappaB signaling pathways. Inhibition of MEKK1 activity using a dominant-negative MEKK1 mutant (MEKK1km) diminished the ability of Bcr-Abl to protect cells from genotoxin-induced apoptosis, but had no effect on the proliferation of Bcr-Abl-transformed cells. Expression of MEKK1km also reduced NF-kappaB activation, and inhibited antiapoptotic c-IAP1 and c-IAP2 mRNA expression in response to the genotoxin. By contrast, neither JNK nor ERK activation was affected. These results indicate that MEKK1 is a downstream target of Bcr-Abl, and that the antiapoptotic effect of Bcr-Abl in chronic myelogenous leukemia cells is mediated via the MEKK1-NF-kappaB pathway. 相似文献
92.
Takeo S Niimura M Miyake-Takagi K Nagakura A Fukatsu T Ando T Takagi N Tanonaka K Hara J 《British journal of pharmacology》2003,138(4):642-654
1. Accumulated evidence indicates that the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signal transduction system may be linked to learning and memory function. 2. The effects of nefiracetam, which has been developed as a cognition enhancer, on spatial memory function and the AC/cAMP/PKA/CREB signal transduction system in rats with sustained cerebral ischaemia were examined. 3. Microsphere embolism (ME)-induced sustained cerebral ischaemia was produced by injection of 700 microspheres (48 micro m in diameter) into the right hemisphere of rats. Daily oral administration of nefiracetam (10 mg kg(-1) day(-1)) was started from 15 h after the operation. 4. The delayed treatment with nefiracetam attenuated the ME-induced prolongation of the escape latency in the water maze task that was examined on day 7 to 9 after ME, but it did not reduce the infarct size. 5. ME decreased Ca(2+)/calmodulin (CaM)-stimulated AC (AC-I) activity, cAMP content, cytosolic PKA Cbeta level, nuclear PKA Calpha and Cbeta levels, and reduced the phosphorylation and DNA-binding activity of CREB in the nucleus in the right parietal cortex and hippocampus on day 3 after ME. The ME-induced changes in these variables did not occur by the delayed treatment with nefiracetam. 6. These results suggest that nefiracetam preserved cognitive function, or prevented cognitive dysfunction, after sustained cerebral ischaemia and that the effect is, in part, attributable to the prevention of the ischaemia-induced impairment of the AC/cAMP/PKA/CREB signal transduction pathway. 相似文献
93.
Characterization of microsphere embolism-induced impairment of learning and memory function and the cholinergic system 总被引:3,自引:0,他引:3
Takagi K Miyake K Takagi N Tadokoro M Nakayama E Nagakura A Takeo S 《Biological & pharmaceutical bulletin》2001,24(1):43-49
The impairments of learning and memory function and of the cholinergic system were examined in rats with microsphere embolism. Microsphere embolism was induced by injection of 900 microspheres with a diameter of 48 microm into the right internal carotid artery. The retention latency of a passive avoidance test was shortened and the escape latency of a water maze test was prolonged, when the animals were tested on the 5th to 10th day after the embolism, suggesting learning and memory dysfunction. Cholinergic parameters of the striatum and hippocampus, such as acetylcholine (ACh) content (67 and 60% decrease, respectively), choline acetyltransferase (ChAT) activity (45 and 56% decrease, respectively), and Bmax of muscarinic acetylcholine M1-receptor (43 and 37% decrease, respectively), were reduced on the 11th day after the embolism, suggesting attenuation of ACh synthesis and a decrease in the number of muscarinic acetylcholine M1-receptors mainly in the striatum and hippocampus. Areas not stained with triphenyltetrazolium chloride, an indication of infarction, were detected mainly in the striatum and hippocampus and partly in the frontal cortex on the 11th day after the embolism. The results suggest that an animal with microsphere embolism may be a good ischemic model with relatively sustained impairments of learning and memory function and of the striatal and hippocampal cholinergic system. 相似文献
94.
Oouchi A Nagakura H Sakata K Hareyama M 《Nihon Igaku Hōshasen Gakkai zasshi. Nippon acta radiologica》2001,61(4):163-168
This paper demonstrates that a biologically equivalent dose distribution including volume effect can be generated. Since the time-dose-fractionation (TDF) concept is convenient for comparing various radiation treatment schedules, TDF distribution maps are made on the basis of the physical dose distribution. On the other hand, the dose volume histogram is useful to evaluate volume effect, but is not necessarily an easy approach owing to the absence of spatial linkage. If distribution maps also representing the volume effect could actually be made, it would become easier to simultaneously predict both tumor control probability and the normal tissue complication rate. Because such tools should be very useful for planning radiotherapy, we proposed an experimental volume effect model. In this, one pixel is affected by all its surrounding pixels and the effect depends on the distance between pixels, volume, and the irradiated dose of another pixel. When the model was adapted to the conventional power law model, we could acquire a new equation with mathematical analysis. This permitted us to calculate the volume effect on each voxel within the treatment volume. Using a personal computer and treatment planning system, we calculated the "TDF-volume" distribution and drew maps based on this equation and the TDF values of each voxel for radiotherapy of a pelvic tumor. 相似文献
95.
Adenosine A1 receptor blockade reverses dysmotility induced by ischemia-reperfusion in rat colon 总被引:2,自引:0,他引:2
Kadowaki M Tokita K Nagakura Y Takeda M Hanaoka K Tomoi M 《European journal of pharmacology》2000,409(3):319-323
This study was designed to assess whether adenosine A1 receptor antagonists [(R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)] reverse dysmotility induced by ischemia-reperfusion in the rat colon. The gene of adenosine A1 receptor was expressed in the colon. Clamping (30 min) of the colonic marginal vessels was followed by reperfusion, and the propulsive colonic motility was evaluated. Propulsion was significantly slowed by ischemia-reperfusion, while FK352 and DPCPX abolished this delay. In contrast, the non-selective adenosine receptor antagonist, 8-phenyltheophylline, failed to affect the dysmotility. Thus, adenosine A1 receptor antagonists have potent therapeutic potential against ischemia-reperfusion-induced dysmotility in the colon. 相似文献
96.
Ito H Kiso T Miyata K Kamato T Yuki H Akuzawa S Nagakura Y Yamano M Suzuki M Naitoh Y Sakai H Iwaoka K Yamaguchi T 《European journal of pharmacology》2000,409(2):195-201
We investigated the in vitro pharmacological profile of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate). In cloned human 5-HT3A receptors, YM-31636 had a pKi value of 9.67 vs. ramosetron and pKi values for other 5-HT3 receptor agonists were less than 7. YM-31636 showed very low affinities for other receptors. YM-31636 induced contraction of isolated guinea pig distal colon. The intrinsic activity was approximately 0.90 compared with 5-hydroxytryptamine's (5-HT) 1.0, and the potency was 26 times greater than that of 5-HT. YM-31636 increased short-circuit current (Isc) in the isolated guinea pig distal colon. In this case, the relative intrinsic activity was approximately 0.19. In isolated guinea pig right atrium, YM-31636 induced tachycardia with the relative intrinsic activity of approximately 0.23. All these effects of YM-31636 were antagonized by ramosetron, a selective 5-HT3 receptor antagonist. These results suggest that YM-31636 is a potent and selective 5-HT3 receptor agonist, preferentially acting on the contraction of the colon. 相似文献
97.
98.
Shubash C Das Naoki Isobe Yukinori Yoshimura 《American journal of reproductive immunology (New York, N.Y. : 1989)》2008,60(6):477-481
A unique property of the avian oviduct is to store sperm for a prolonged period. The sperm storage tubules (SST) are located in the utero‐vaginal junction of the oviduct, where sperm can be stored and survived for a few weeks after insemination or natural mating. The immune system in the oviduct is essential to prevent tissue infection by various microorganisms, and it may also affect the fate and survivability of sperm in the oviduct. Anti‐sperm immunoresponses including infiltration of leukocytes may be induced in the vagina of the oviduct. Sperm that will participate in fertilization may be selected by these immunoresponses. However, sperm stored in the SST may be protected from the immunoresponse by SST structures and transforming growth factor β, whose expression is increased during sperm storage in the SST. In this review, the mechanism of sperm survivability with reference to the regulation of anti‐sperm immunoresponses in hen oviduct is emphasized. 相似文献
99.
Ryugo Teranishi Tsuyoshi Takahashi Yuuki Obata Toshirou Nishida Shuichi Ohkubo Hiromi Kazuno Yurina Saito Satoshi Serada Minoru Fujimoto Yukinori Kurokawa Takuro Saito Kazuyoshi Yamamoto Kotaro Yamashita Koji Tanaka Tomoki Makino Kiyokazu Nakajima Seiichi Hirota Tetsuji Naka Hidetoshi Eguchi Yuichiro Doki 《International journal of cancer. Journal international du cancer》2023,152(12):2580-2593
Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways. 相似文献
100.