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91.
Garcia-Calvo M Lisnock J Bull HG Hawes BE Burnett DA Braun MP Crona JH Davis HR Dean DC Detmers PA Graziano MP Hughes M Macintyre DE Ogawa A O'neill KA Iyer SP Shevell DE Smith MM Tang YS Makarewicz AM Ujjainwalla F Altmann SW Chapman KT Thornberry NA 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(23):8132-8137
Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia, but its molecular target has been elusive. Using a genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as a critical mediator of cholesterol absorption and an essential component of the ezetimibe-sensitive pathway. To determine whether NPC1L1 is the direct molecular target of ezetimibe, we have developed a binding assay and shown that labeled ezetimibe glucuronide binds specifically to a single site in brush border membranes and to human embryonic kidney 293 cells expressing NPC1L1. Moreover, the binding affinities of ezetimibe and several key analogs to recombinant NPC1L1 are virtually identical to those observed for native enterocyte membranes. KD values of ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively. Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPC1L1 as the direct target of ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport. 相似文献
92.
Relationship between flow dynamics in the left atrium and hemostatic abnormalities in patients with nonvalvular atrial fibrillation 总被引:10,自引:0,他引:10
Shinohara H Fukuda N Soeki T Takeichi N Yui Y Tamura Y Oki T 《Japanese heart journal》1998,39(6):721-730
To investigate the relationship between left atrial (LA) flow dynamics and hemostatic markers in nonvalvular atrial fibrillation (AF), 45 patients with nonvalvular AF who had not received anticoagulants were evaluated by transesophageal echocardiography. We determined the LA appendage flow and the presence of LA spontaneous echo contrast (SEC) or thrombus. We measured plasma levels of thrombin-antithrombin III complex (TAT), fibrinopeptide A, D-dimer, beta-thromboglobulin, and platelet factor 4 in peripheral blood as hemostatic markers. The patients were divided into a low-velocity group (n = 19; sum of peak emptying and filling LA appendage flow velocities < 40 cm/s) and a high-velocity group (n = 26; > or = 40 cm/s). The maximum LA diameter was significantly greater and the LA expansion fraction was significantly smaller in the low-velocity group than in the high-velocity group. LA SEC or thrombus was observed in 11 patients (58%) in the low-velocity group, but not in any patients in the high-velocity group (p < 0.001). The plasma levels of TAT, fibrinopeptide A, D-dimer, beta-thromboglobulin, and platelet factor 4 were significantly higher in the low-velocity group than in the high-velocity group. The plasma levels of TAT, fibrinopeptide A, beta-thromboglobulin, and platelet factor 4 were significantly higher in 8 patients without LA SEC or thrombus in the low-velocity group than in 26 patients in the high-velocity group. Patients with nonvalvular AF accompanied by an enlarged and dysfunctioning LA and a decreased LA appendage flow velocity had increased intravascular coagulation-fibrinolysis activity and platelet activation. These abnormalities may be closely related to the thrombogenetic state in patients with nonvalvular AF. 相似文献
93.
Usefulness of contrast‐enhanced ultrasonography using Sonazoid for the assessment of therapeutic response to percutaneous radiofrequency ablation for hepatocellular carcinoma 下载免费PDF全文
94.
Eri Imagawa Ken Higashimoto Yasunari Sakai Chikahiko Numakura Nobuhiko Okamoto Satoko Matsunaga Akihide Ryo Yoshinori Sato Masafumi Sanefuji Kenji Ihara Yui Takada Gen Nishimura Hirotomo Saitsu Takeshi Mizuguchi Satoko Miyatake Mitsuko Nakashima Noriko Miyake Hidenobu Soejima Naomichi Matsumoto 《Human mutation》2017,38(6):i-i
95.
96.
Soeki T Tamura Y Bandou K Tanaka H Takeichi N Shinohara H Yui Y Fukuda N Sui O 《Japanese heart journal》1998,39(6):743-751
To examine the long-term effects of the angiotensin-converting enzyme (ACE) inhibitor enalapril on chronic heart failure, 10 patients (7 men and 3 women, mean age: 62 +/- 11 years) with chronic stable heart failure, classified as New York Heart Association (NYHA) functional class 2-3 for more than 3 months, and a left ventricular ejection fraction less than 45% were treated with 2.5-5.0 mg of enalapril once a day for 3-15 months (mean 7 months). The causes of heart failure were old myocardial infarction (n = 7), hypertension (n = 2), and atrial fibrillation (n = 1). Radioiodinated metaiodobenzyl guanidine (123I-MIBG) imaging, radionuclide angiography, and treadmill exercise test were performed before and after the treatment. With enalapril treatment, (1) left ventricular ejection fraction (LVEF) increased significantly from 38.3 +/- 6.9% to 47.5 +/- 14.7%; (2) sub-maximal exercise time increased significantly from 205 +/- 112 to 272 +/- 120 seconds; (3) the heart to mediastinum (H/M) ratio of 123I-MIBG increased significantly (early image: 1.99 +/- 0.38 versus 2.20 +/- 0.50; delayed image: 1.86 +/- 0.44 versus 2.09 +/- 0.51); and (4) the washout rate of 123I-MIBG decreased slightly from 29.1 +/- 9.1% to 25.4 +/- 7.0%. The improvement rate of LVEF was significantly correlated with the improvement rates of the H/M ratio and washout rate after treatment with enalapril. Thus, the long-term effects of enalapril can be observed in the cardiac sympathetic nervous system, and 123I-MIBG imaging appears to be useful for evaluating the therapeutic effects of enalapril on the cardiac sympathetic nervous system in patients with chronic heart failure. 相似文献
97.
Changing prognostic significance of tumor stage and nodal stage in patients with squamous cell carcinoma of the oropharynx in the human papillomavirus era 下载免费PDF全文
98.
Kawamura K Yui J Konno F Yamasaki T Hatori A Wakizaka H Fujinaga M Kumata K Yoshida Y Ogawa M Nengaki N Yanamoto K Fukumura T Zhang MR 《Nuclear medicine and biology》2012,39(1):89-99
IntroductionTo explore the possible use of positron emission tomography (PET) probes for imaging of I2-imidazoline receptors (I2Rs) in peripheral tissues, we labeled two new I2R ligands, 2-[2-(o-tolyl)vinyl]-4,5-dihydro-1H-imidazole (Ki for I2Rs, 3.7 nM) and 2-[2-(o-tolyl)ethyl]-4,5-dihydro-1H-imidazole (Ki for I2Rs, 1.7 nM) with 11C ([11C]metrazoline and [11C]TEIMD), respectively, and evaluated these ligands and the recently developed I2R ligand 2-[3-fluoro-[4-11C]tolyl]-4,5-dihydro-1H-imidazole ([11C]FTIMD) by in vivo studies.Methods[11C]Metrazoline and [11C]TEIMD were prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11C]methyl iodide. Their biodistribution in mice was investigated by tissue dissection. In addition, PET scans and metabolite analysis were performed.Results[11C]Metrazoline and [11C]TEIMD were successfully synthesized with a suitable radioactivity for injection. In the liver and pancreas expressing I2Rs, coinjection with the high-affinity I2R ligand, BU224, induced a reduction in the radioactivity level at 30 min after injection of [11C]metrazoline and [11C]FTIMD. However, the radioactivity level after injection of [11C]TEIMD was unchanged. In the PET study, coinjection with BU224 induced a decrease in the radioactivity level in the liver and pancreas after more than 15 min of injection of [11C]metrazoline and [11C]FTIMD as compared with the results obtained for controls. In metabolite analysis, coinjection with BU224 induced a significant reduction in the percentage of unchanged [11C]metrazoline at 30 min after injection as compared with that in the control, although no significant difference was observed in the percentage of unchanged [11C]FTIMD.Conclusion[11C]Metrazoline may be a more useful PET probe than [11C]FTIMD for imaging of I2Rs in peripheral tissues. 相似文献
99.
Kawamura K Kimura Y Yui J Wakizaka H Yamasaki T Hatori A Kumata K Fujinaga M Yoshida Y Ogawa M Nengaki N Fukumura T Zhang MR 《Nuclear medicine and biology》2012,39(2):199-206
IntroductionWe recently developed a selective 11C-labeled I2-imidazoline receptor (I2R) ligand, 2-(3-fluoro-4-[11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). [11C]FTIMD showed specific binding to I2Rs in rat brains having a high density of I2R, as well as to I2Rs those in monkey brains, as illustrated by positron emission tomography (PET) and autoradiography. However, [11C]FTIMD also showed moderate non-specific binding in rat brains. In order to increase the specificity for I2R in rat brains, we synthesized [11C]FTIMD with ultra-high specific activity and evaluated its binding.Methods[11C]FTIMD with ultra-high specific activity was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11C]methyl iodide, which was produced by iodination of [11C]methane using the single-pass method. Dynamic PET scans were conducted in rats, and the kinetic parameters were estimated.Results[11C]FTIMD with ultra-high specific activity was successfully synthesized with an appropriate level of radioactivity and ultra-high specific activity (4470±1660 GBq/μmol at end of synthesis, n=11) for injection. In the PET study, distribution volume (VT) values in all the brain regions investigated whether I2R expression was greatly reduced in BU224-pretreatead rats compared with control rats (29–45% decrease). Differences in VT values between control and BU224-pretreated rats using [11C]FTIMD with ultra-high specific activity were greater than those using [11C]FTIMD with normal specific activity (17–34% decrease) in all brain regions investigated.ConclusionQuantitative PET using [11C]FTIMD with ultra-high specific activity can contribute to the detection of small changes in I2R expression in the brain. 相似文献
100.
Higashino-Matsui Y Shirato K Suzuki Y Kawashima Y Someya Y Sato S Shiraishi A Jinde M Matsumoto A Ideno H Tachiyashiki K Imaizumi K 《Environmental health and preventive medicine》2012,17(2):157-163