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51.
Wan Z Hall A Jin Y Xiang JN Yang E Eatherton A Smith B Yang G Yu H Wang J Ye L Lau LF Yang T Mitchell W Cai W Zhang X Sang Y Wang Y Tong Z Cheng Z Hussain I Elliott JD Matsuoka Y 《Bioorganic & medicinal chemistry letters》2011,21(13):4016-4019
SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain the levels of total Aβ. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat. 相似文献
52.
This study is concerned with validating the measurement of the plasma half-life of 11alpha-(2)H cortisol in an attempt to accurately assess the in vivo activity of 11beta-HSD2 in man. Oral administration of 5mg of cortisol-(13)C(4),(2)H(1) to a human subject after repeated ingestions of 130mg/day of glycyrrhetinic acid for 5 days resulted in a decrease in the rate constant of the cortisol-(13)C(4),(2)H(1) to cortisone-(13)C(4) conversion, a direct index reflecting 11beta-HSD2 activity. The reduced 11beta-HSD2 activity led to an increase in the elimination half-life of cortisol-(13)C(4),(2)H(1), indicating that the loss of 11alpha-(2)H is a sensitive in vivo means of assessing 11beta-HSD2 activity. A simultaneous oral administration of 3mg each of [1,2,4,19-(13)C(4),11alpha-(2)H]cortisol (cortisol-(13)C(4),(2)H(1)) and 11alpha-(2)H cortisol to another human subject confirmed the bioequivalency of the two labeled cortisols. The information obtained from the kinetic analysis of the 11beta-HSD2-catalyzed conversion of cortisol-(13)C(4),(2)H(1) to cortisone-(13)C(4) indicated that the elimination half-life of 11alpha-(2)H cortisol was a sensitive index of renal 11beta-HSD2 activity. The use of 11alpha-(2)H cortisol as a tracer appears to offer a significant advance in evaluating human 11beta-HSD2 activity in vivo. 相似文献
53.
Mizuno K Sawa M Harada H Taoka I Yamashita H Oue M Tsujiuchi H Arai Y Suzuki S Furutani Y Kato S 《Bioorganic & medicinal chemistry》2005,13(3):855-868
The synthesis and evaluation of a novel series of 1,7-cyclized indole-based human adrenergic receptor (beta3-AR) agonists are reported. The synthesis of a variety of 1,7-cyclized indole part was accomplished by the Mitsunobu reaction or a ring closing metathesis (RCM) reaction. SAR studies revealed that expansion of the ring size resulted in considerable selectivity against the beta1- and beta2-ARs. Compound 26, an eight-membered ring analogue with a double bond on its 1,7-linker portion, was found to be a potent beta3-AR agonist (EC50 = 0.75 nM, IA = 90%) with extremely high selectivity for the beta3-AR over the beta1- and beta2-ARs. 相似文献
54.
Sawa M Mizuno K Harada H Tateishi H Arai Y Suzuki S Oue M Tsujiuchi H Furutani Y Kato S 《Bioorganic & medicinal chemistry letters》2005,15(4):1061-1064
The continued SAR investigation of tryptamine-based human beta(3)-adrenergic receptor (AR) agonists is reported. Prior efforts resulted in the identification of 2 as a potent beta(3)-AR agonist. Further modification of the left side arylsulfonamide portion in 2 provided compounds with good cell permeability, which have potent agonistic activity for beta(3)-AR. Cinnamylamine analog 16i exhibited an excellent agonistic profile in vitro and good oral bioavailability in rats. 相似文献
55.
Ku genes play a key role in the non-homologous end-joining pathway. We have identified Ku70 and Ku80 homologs in the koji molds Aspergillus sojae and Aspergillus oryzae, and have constructed the disruption mutants of Ku70, Ku80, and Ku70-80 to characterize the phenotypic change in these mutants. Neither Ku70- nor Ku80-disrupted strains show hypersensitivity to the DNA damaging agents methylmethane sulfonate (MMS) and phleomycin. Moreover, undesirable phenotypes, such as poor growth or repressed conidiospore formation, were not observed in the Ku-disrupted A. sojae and A. oryzae. 相似文献
56.
Hirose H Sakuma N Kaji N Suhara T Sekijima M Nojima T Miyakoshi J 《Bioelectromagnetics》2006,27(6):494-504
A large-scale in vitro study focusing on low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields induce apoptosis or other cellular stress response that activate p53 or the p53-signaling pathway. First, we evaluated the response of human cells to microwave exposure at a specific absorption rate (SAR) of 80 mW/kg, which corresponds to the limit of the average whole-body SAR for general public exposure defined as a basic restriction by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. Second, we investigated whether continuous wave (CW) and wideband code division multiple access (W-CDMA) modulated signal RF fields at 2.1425 GHz induced apoptosis or any signs of stress. Human glioblastoma A172 cells were exposed to W-CDMA radiation at SARs of 80, 250, and 800 mW/kg, and CW radiation at 80 mW/kg for 24 or 48 h. Human IMR-90 fibroblasts from fetal lungs were exposed to both W-CDMA and CW radiation at a SAR of 80 mW/kg for 28 h. Under the RF field exposure conditions described above, no significant differences in the percentage of apoptotic cells were observed between the test groups exposed to RF signals and the sham-exposed negative controls, as evaluated by the Annexin V affinity assay. No significant differences in expression levels of phosphorylated p53 at serine 15 or total p53 were observed between the test groups and the negative controls by the bead-based multiplex assay. Moreover, microarray hybridization and real-time RT-PCR analysis showed no noticeable differences in gene expression of the subsequent downstream targets of p53 signaling involved in apoptosis between the test groups and the negative controls. Our results confirm that exposure to low-level RF signals up to 800 mW/kg does not induce p53-dependent apoptosis, DNA damage, or other stress response in human cells. 相似文献
57.
Fujinaga M Maeda J Yui J Hatori A Yamasaki T Kawamura K Kumata K Yoshida Y Nagai Y Higuchi M Suhara T Fukumura T Zhang MR 《Journal of neurochemistry》2012,120(1):115-124
Neurovascular degeneration contributes to the pathogenesis of Alzheimer's disease (AD). Because erythropoietin (EPO) promotes endothelial regeneration, we investigated the therapeutic effects of EPO in animal models of AD. In aged Tg2576 mice, EPO receptors (EPORs) were expressed in the cortex and hippocampus. Tg2576 mice were treated with daily injection of EPO (5000 IU/kg/day) for 5 days. At 14 days, EPO improved contextual memory as measured by fear-conditioning test. EPO enhanced endothelial proliferation and the level of synaptophysin expression in the brain. EPO also increased capillary density, and decreased the level of the receptor for advanced glycation endproducts (RAGE) in the brain, while decreasing in the amount of amyloid plaque and amyloid-β (Aβ). In cultured human endothelial cells, EPO enhanced angiogenesis and suppressed the expression of the RAGE. These results show that EPO improves memory and ameliorates endothelial degeneration induced by Aβ in AD models. This pre-clinical evidence suggests that EPO may be useful for the treatment of AD. 相似文献
58.
Glutaminase is an enzyme that catalyzes the hydrolysis of l-glutamine to l-glutamate, and it plays an important role in the production of fermented foods by enhancing the umami taste. By using the genome sequence and expressed sequence tag data available for Aspergillus oryzae RIB40, we cloned a novel glutaminase gene (AsgahA) from Aspergillus sojae, which was similar to a previously described gene encoding a salt-tolerant, thermostable glutaminase of Cryptococcus nodaensis (CnGahA). The structural gene was 1,929 bp in length without introns and encoded a glutaminase, AsGahA, which shared 36% identity with CnGahA. The introduction of multiple copies of AsgahA into A. oryzae RIB40 resulted in the overexpression of glutaminase activity. AsGahA was subsequently purified from the overexpressing transformant and characterized. While AsGahA was located at the cell surface in submerged culture, it was secreted extracellularly in solid-state culture. The molecular mass of AsGahA was estimated to be 67 kDa and 135 kDa by SDS-PAGE and gel filtration chromatography, respectively, indicating that the native form of AsGahA was a dimer. The optimal pH of the enzyme was 9.5, and its optimal temperature was 50°C in sodium phosphate buffer (pH 7.0). Analysis of substrate specificity revealed that AsGahA deamidated not only free l-glutamine and l-asparagine but also C-terminal glutaminyl or asparaginyl residues in peptides. Collectively, our results indicate that AsGahA is a novel peptidoglutaminase-asparaginase. Moreover, this is the first report to describe the gene cloning and purification of a peptidoglutaminase-asparaginase. 相似文献
59.
Hironobu Fujiwara Hiroshi Ito Fumitoshi Kodaka Yasuyuki Kimura Harumasa Takano Tetsuya Suhara 《PloS one》2012,7(11)
The mesencephalic dopamine (DA) system is the main DA system related to affective and cognitive functions. The system consists of two different cell groups, A9 and A10, which originate from different regions of the midbrain. The striatum is the main input from the midbrain, and is functionally organized into associative, sensorimotor and limbic subdivisions. At present, there have been few studies investigating the associations of DA functions between striatal subdivisions and extrastriatal regions. The aim of this study was to investigate the relationship of DA D1 receptor (D1R) expression between striatal subdivisions and extrastriatal regions in humans using positron emission tomography (PET) with voxel-by-voxel whole brain analysis. The PET study was performed on 30 healthy subjects using [11C] to measure D1R expression. Parametric images of binding potentials (BP
ND) were created using the simplified reference tissue model. Regions of interest were defined for striatal subdivisions. Multiple regression analysis was undertaken to determine extrastriatal regions that were associated with each striatal subdivision in BP
ND using statistical parametric mapping 5. The BP
ND values of associative, sensorimotor and limbic subdivisions were similarly correlated with those of multiple brain regions. Regarding the interrelationships among striatal subdivisions, mutual correlations were found among associative, sensorimotor and limbic subdivisions in BP
ND as well. The relationships in BP
ND between striatal subdivisions and extra-striatal regions suggest that differential striatal subdivisions and extrastriatal regions have a similar biological basis of D1R expression. Different DA projections from the midbrain did not explain the associations between striatal subdivisions and extrastriatal regions in D1R expression, and the DA-related neural networks among the midbrain, striatum and the other regions would contribute to a similar D1R expression pattern throughout the whole brain. SCH23390相似文献
60.
Shibasaki H Nakayama H Furuta T Kasuya Y Tsuchiya M Soejima A Yamada A Nagasawa T 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2008,870(2):164-169
Individual variability of the pharmacokinetics of prednisolone based on the unbound concentration in plasma is of significant clinical consideration. The unbound concentrations of prednisolone were measured in 10 patients with nephrotic syndrome, two patients with systemic lupus erythematosus, and one patient with dermatomyositis by examining protein bindings of prednisolone on one or more occasions during prednisolone treatment. In this study, plasma concentrations of prednisolone, prednisone, cortisol, and cortisone were simultaneously analyzed by GC-MS by using stable isotope-labeled internal standards. Equilibrium dialysis was employed to accurately estimate the unbound fractions of prednisolone in plasma. The unbound fraction of prednisolone changed depending on plasma total prednisolone concentration and plasma albumin concentration. The unbound fraction of prednisolone (Y) is calculated: Y=(-0.0101x' + 0.0736) x + 10.23, where x' is the plasma albumin concentration and x is the total prednisolone concentration. The estimated concentrations of unbound prednisolone by using the above equation were in good agreement with the measured concentrations of unbound prednisolone. Since the protein binding of prednisolone did not change in the presence of prednisone (114.0 ng/ml), it appeared that prednisone produced from the therapeutic dose of prednisolone did not affect the unbound fraction of prednisolone. 相似文献