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排序方式: 共有732条查询结果,搜索用时 218 毫秒
191.
Tomoharu Tsukada Mizuki Takahashi Toshiyasu Takemoto Osamu Kanno Takahiro Yamane Sayako Kawamura Takahide Nishi 《Bioorganic & medicinal chemistry letters》2010,20(3):1004-1007
With the goal of improving metabolic stability and further enhancing FBPase inhibitory activity, a series of tricyclic 8H-indeno[1,2-d][1,3]thiazoles was designed and synthesized with the aid of structure-based drug design. Extensive SAR studies led to the discovery of 19a with an IC50 value of 1 nM against human FBPase. X-ray crystallographic studies revealed that high affinity of 19a was due to the hydrophobic interaction arising from better shape complementarity and to the hydrogen bonding network involving the side chain on the tricyclic scaffold. 相似文献
192.
Tomoharu Tsukada Osamu Kanno Takahiro Yamane Jun Tanaka Taishi Yoshida Akira Okuno Takeshi Shiiki Mizuki Takahashi Takahide Nishi 《Bioorganic & medicinal chemistry》2010,18(14):5346-5351
With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys. 相似文献
193.
Nobuaki Hirota Daisuke Yasuda Tomomi Hashidate Teruyasu Yamamoto Satoshi Yamaguchi Teruyuki Nagamune Takahide Nagase Takao Shimizu Motonao Nakamura 《The Journal of biological chemistry》2010,285(8):5931-5940
Several residues are conserved in the transmembrane domains (TMs) of G-protein coupled receptors. Here we demonstrate that a conserved proline, Pro247, in TM6 of platelet-activating factor receptor (PAFR) is required for endoplasmic reticulum (ER) export and trafficking after agonist-induced internalization. Alanine-substituted mutants of the conserved residues of PAFRs, including P247A, were retained in the ER. Because a PAFR antagonist, Y-24180, acted as a pharmacological chaperone to rescue ER retention, this retention is due to misfolding of PAFR. Methylcarbamyl (mc)-PAF, a PAFR agonist, did not increase the cell surface expression of P247A, even though another ER-retained mutant, D63A, was effectively trafficked. Signaling and accumulation of the receptors in the early endosomes were observed in the mc-PAF-treated P247A-expressing cells, suggesting that P247A was trafficked to the cell surface by mc-PAF, and thereafter disappeared from the surface due to aberrant trafficking, e.g. enhanced internalization, deficiency in recycling, and/or accelerated degradation. The aberrant trafficking was confirmed with a sortase-A-mediated method for labeling cell surface proteins. These results demonstrate that the conserved proline in TM6 is crucial for intracellular trafficking of PAFR. 相似文献
194.
Brantley EC Guo L Zhang C Lin Q Yokoi K Langley RR Kruzel E Maya M Kim SW Kim SJ Fan D Fidler IJ 《Translational oncology》2010,3(6):380-388
Experimental metastases in the brain of mice are infiltrated by microglia, and parabiosis experiments of green fluorescent protein (GFP(+)) and GFP(-) mice revealed that these microglia are derived from circulating monocytes (GFP(+), F4/80(+), and CD68(+)). These findings raised the question as to whether microglia (specialized macrophages) possess tumoricidal activity. C8-B4 murine microglia cells were incubated in vitro in medium (control) or in medium containing both lipopolysaccharide and interferon-γ. Control microglia were not tumoricidal against a number of murine and human tumor cells, whereas lipopolysaccharide/interferon-γ-activated microglia lysed murine and human tumor cells by release of nitric oxide. Parallel experiments with murine peritoneal macrophages produced identical results. Neither activated microglia nor activated macrophages lysed nontumorigenic murine or human cells. Collectively, these data demonstrate that brain metastasis-associated microglia are derived from circulating mononuclear cells and exhibit selective and specific tumoricidal activity. 相似文献
195.
Cytoplasmic dynein is an AAA(+)-type molecular motor whose major components are two identical heavy chains containing six AAA(+) modules in tandem. It moves along a single microtubule in multiple steps which are accompanied with multiple ATP hydrolysis. This processive sliding is crucial for cargo transports in vivo. To examine how cytoplasmic dynein exhibits this processivity, we performed in vitro motility assays of two-headed full-length or truncated single-headed heavy chains. The results indicated that four to five molecules of the single-headed heavy chain were required for continuous microtubule sliding, while approximately one molecule of the two-headed full-length heavy chain was enough for the continuous sliding. The ratio of the stroking time to the total ATPase cycle time, which is a quantitative indicator of the processivity, was approximately 0.2 for the single-headed heavy chain, while it was approximately 0.6 for the full-length molecule. When two single-headed heavy chains were artificially linked by a coiled-coil of myosin, the processivity was restored. These results suggest that the two heads of a single cytoplasmic dynein communicate with each other to take processive steps along a microtubule. 相似文献
196.
Hiroshi Yamamoto Takahide Nagase Takayuki Shindo Shinji Teramoto Tomoko Aoki-Nagase Yasuhiro Yamaguchi Yoko Hanaoka Hiroki Kurihara Yasuyoshi Ouchi 《Journal of applied physiology》2007,102(6):2361-2368
Adrenomedullin (ADM), a newly identified vasodilating peptide, is reported to be expressed in lungs and have a bronchodilating effect. We hypothesized whether ADM could be involved in the pathogenesis of bronchial asthma. We examined the role of ADM in airway responsiveness using heterozygous ADM-deficient mice (AM+/-) and their littermate control (AM+/+). Here, we show that airway responsiveness is enhanced in ADM mutant mice after sensitization and challenge with ovalbumin (OVA). The immunoreactive ADM level in the lung tissue after methacholine challenge was significantly greater in the wild-type mice than that in the mutant. However, the impairment of ADM gene function did not affect immunoglobulins (OVA-specific IgE and IgG1), T helper 1 and 2 cytokines, and leukotrenes. Thus the conventional mechanism of allergen-induced airway responsiveness is not relevant to this model. Furthermore, morphometric analysis revealed that eosinophilia and airway hypersecretion were similarly found in both the OVA-treated ADM mutant mice and the OVA-treated wild-type mice. On the other hand, the area of the airway smooth muscle layer of the OVA-treated mutant mice was significantly greater than that of the OVA-treated wild-type mice. These results suggest that ADM gene disruption may be associated with airway smooth muscle hyperplasia as well as enhanced airway hyperresponsiveness. ADM mutant mice might provide novel insights to study the pathophysiological role of ADM in vivo. 相似文献
197.
Nishiura M Kon T Shiroguchi K Ohkura R Shima T Toyoshima YY Sutoh K 《The Journal of biological chemistry》2004,279(22):22799-22802
A cytoplasmic dynein is a microtubule-based motor protein involved in diverse cellular functions, such as organelle transport and chromosome segregation. The dynein has two ring-shaped heads that contain six repeats of the AAA domain responsible for ATP hydrolysis. It has been proposed that the ATPase-dependent swing of a stalk and a stem emerging from each of the heads generates the power stroke (Burgess, S.A. (2003) Nature 421, 715-718). To understand the molecular mechanism of the dynein power stroke, it is essential to establish an easy and reproducible method to express and purify the recombinant dynein with full motor activities. Here we report the expression and purification of the C-terminal 380-kDa fragment of the Dictyostelium cytoplasmic dynein heavy-chain fused with an affinity tag and green fluorescent protein. The purified single-headed recombinant protein drove the robust minus-end-directed sliding of microtubules at a velocity of 1.2 microm/s. This recombinant protein had a high basal ATPase activity (approximately 4s(-1)), which was further activated by >15-fold on the addition of 40 microM microtubules. These results show that the 380-kDa recombinant fragment retains all the structures required for motor functions, i.e. the ATPase activity highly stimulated by microtubules and the robust motility. 相似文献
198.
A strain of B. subtilis produced 1.8 times more laccase on sporulation medium than on non-sporulation medium. Spores oxidized mono- and di-methoxyphenols (0.1 mM) at 50 °C. The half-life of laccase bound to spores was about 2 d and the substrate was repeatedly removed by spores recovered from the reaction mixture. 相似文献
199.
Nickel deficiency diminishes sperm quantity and movement in rats 总被引:3,自引:0,他引:3
Early studies on nickel essentiality with rats and goats indicated that nickel deprivation impaired reproductive performance.
Nickel also has been found to influence cyclic nucleotide gated channels (CNG); these types of channels are important in sperm
physiology. Thus, two experiments were conducted to test the hypothesis that nickel deficiency affects sperm physiology in
a manner consistent with nickel having an essential function related to CNG channel functions. The experiments were factorially
arranged with four treatment groups of eight weanling rats in each. In experiment 1, the treatments were supplemental dietary
nickel of 0 and 1 mg/kg and N
ω
-nitro-l-arginine methyl ester (l-NAME, a nitric oxide synthase inhibitor) added to the drinking water (50 mg/100 mL) the last 3 wk of an 8-wk experiment.
In experment 2, the treatments were supplemental dietary nickel at 0 and 1 mg/kg and supplemental dietary sodium chloride
(NaCl) at 0 and 80 g/kg. The NaCl and l-NAME variables were included to act as stressors affecting CNG channel activity. The basal diet contained per kilogram about
27 μg of nickel and 1 g of sodium. After 8 wk in experiment 1 and 16 wk in experiment 2, urine while fasting and testes and
epididymis in both experiments, and seminal vesicles and prostates in experiment 2 were harvested for analysis. Nickel deprivation
significantly decreased spermatozoa motility and density in the epididymides, epididymal transit time of spermatozoa, and
testes sperm production rate. Nickel deficiency also significantly decreased the weights of the seminal vesicles and prostate
glands. Excessive NaCl had no effect on sperm physiology; however, it decreased prostate gland weights. The findings support
the hypothesis that nickel has an essential function that possibly could affect reproductive performance in higher animals,
perhaps through affecting a CNG channel function.
Part of the data was presented at the Experimental Biology 2001 Meeting, Orlando, FL, March 31–April 4, 2001. (F. H. Nielsen, E. O. Uthus and K. Yokoi, Dietary nickel deprivation decreases sperm motility and
evokes hypertension in rats, FASEB J.
15, A972 (2001), and K. Yokoi, E. O. Uthus and F. H. Nielsen, Nickel deficiency induces renal damages and hypertension in rats
which is augmented by sodium chloride, FASEB J.
15, A973 (2001).
The US Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative
action employer and all agency services are available without discrimination.
Mention of a trademark or proprietary product does not constitute a guarantee or warranty of the product by the US Department
of Agriculture and does not imply its approval to the exclusion of the products that may also be suitable. 相似文献
200.
Nakajima N Sugimoto M Yokoi H Tsuji H Ishihara K 《Bioscience, biotechnology, and biochemistry》2003,67(8):1828-1831
The acylated plant pigments synthesized by lipase-catalyzed transesterification with aromatic acids were compared in respect of their light-resistance and radical-scavenging ability. With both the flavonols and anthocyanins, their acylated derivatives were more stable against illumination with fluorescent light than their non-acylated glucosides. Their radical-scavenging ability partially decreased or was retained by acylation to the glucoside molecules. 相似文献