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931.
Issei Tsukamoto Hiroyuki Koshio Takahiro Kuramochi Chikashi Saitoh Hiroko Yanai-Inamura Chika Kitada-Nozawa Eisaku Yamamoto Takeyuki Yatsu Yoshiaki Shimada Shuichi Sakamoto Shin-ichi Tsukamoto 《Bioorganic & medicinal chemistry》2009,17(8):3130-3141
A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives was synthesized, and their structure–activity relationships were examined in order to identify potent and selective arginine vasopressin V2 receptor agonists. Attempts to substitute other chemical groups in place of the 2-pyridilmethyl moiety of 1a led to the discovery that potent V2 binding affinity could be obtained with a wide range of functional groups. This structural tolerance allowed for the manipulation of other attributes, such as selectivity against V1a receptor affinity or avoidance of the undesirable inhibition of cytochrome P450 (CYP), without losing potent affinity for the V2 receptor. Some representative compounds obtained in this study were also found to decrease urine volume in awake rats. 相似文献
932.
933.
Daniela Corda Takahiro Kudo Pasquale Zizza Cristiano Iurisci Eri Kawai Norihisa Kato Noriyuki Yanaka Stefania Mariggi�� 《The Journal of biological chemistry》2009,284(37):24848-24856
The glycerophosphodiester phosphodiesterase enzyme family involved in the hydrolysis of glycerophosphodiesters has been characterized in bacteria and recently identified in mammals. Here, we have characterized the activity and function of GDE3, one of the seven mammalian enzymes. GDE3 is up-regulated during osteoblast differentiation and can affect cell morphology. We show that GDE3 is a glycerophosphoinositol (GroPIns) phosphodiesterase that hydrolyzes GroPIns, producing inositol 1-phosphate and glycerol, and thus suggesting specific roles for this enzyme in GroPIns metabolism. Substrate specificity analyses show that wild-type GDE3 selectively hydrolyzes GroPIns over glycerophosphocholine, glycerophosphoethanolamine, and glycerophosphoserine. A single point mutation in the catalytic domain of GDE3 (GDE3R231A) leads to loss of GroPIns enzymatic hydrolysis, identifying an arginine residue crucial for GDE3 activity. After heterologous GDE3 expression in HEK293T cells, phosphodiesterase activity is detected in the extracellular medium, with no effect on the intracellular GroPIns pool. Together with the millimolar concentrations of calcium required for GDE3 activity, this predicts an enzyme topology with an extracellular catalytic domain. Interestingly, GDE3 ectocellular activity is detected in a stable clone from a murine osteoblast cell line, further confirming the activity of GDE3 in a more physiological context. Finally, overexpression of wild-type GDE3 in osteoblasts promotes disassembly of actin stress fibers, decrease in growth rate, and increase in alkaline phosphatase activity and calcium content, indicating a role for GDE3 in induction of differentiation. Thus, we have identified the GDE3 substrate GroPIns as a candidate mediator for osteoblast proliferation, in line with the GroPIns activity observed previously in epithelial cells.The glycerophosphodiester phosphodiesterases (GP-PDEs)5 were initially characterized in bacteria, where they have functional roles for production of metabolic carbon and phosphate sources from glycerophosphodiesters (1, 2) and in adherence to and degradation of mammalian host-cell membranes (3). The GP-PDEs have a catalytic region of 56 amino acids (4). After their characterization in bacteria, mammalian glycerophosphodiesterases were identified, with the definition of a family of seven members (5). The first of these, GDE1, is an interactor of regulator of G-protein signaling (RGS)16, and was subsequently defined as a GP-PDE regulated by G-protein signaling (4). Indeed, GDE1 expression in HEK293T cells showed increased enzymatic activity upon α/β-adrenergic and lysophospholipid receptor stimulation (4). The second member, GDE2, was isolated by homology searches in neuronal tissues and its physiological role involves neuronal differentiation (6, 7). In contrast, GDE3 has been characterized as a marker of osteoblast differentiation and was isolated through a differential display method (8). GDE4 was isolated only recently with three-dimensional modeling defining it as a GP-PDE, although no functional activity has been correlated to its expression (9). The remaining members were cloned following data base searches, with further studies required for the definition of their properties (5). The diversity among these family members, in terms of tissue distribution, subcellular localization, and substrate specificity, suggests they selectively regulate biological functions and have distinct physiological roles (5).The only GP-PDE activity that has been biochemically characterized to date followed GDE1 overexpression in HEK293T cells, which showed a selectivity for the glycerophosphoinositols (GPIs) as substrate (4), in contrast to the bacterial GP-PDEs that show broad substrate specificities with respect to the alcohol moiety of the glycerophosphodiesterases (1, 2). The GPIs are naturally occurring, biologically active metabolites of the phosphoinositides that were originally investigated in the context of Ras-transformed cells (10). They are present in virtually all cell types, where their intracellular levels can also be modulated according to cell activation, differentiation, and development (Refs. 11 and 12 and references therein). Recently, glycerophosphoinositol (GroPIns) was characterized as a mediator of purinergic and adrenergic regulation of PCCl3 thyroid cell proliferation (13), while GroPIns 4-phosphate (GroPIns4P) has been shown to induce reorganization of the actin cytoskeleton in fibroblasts and in T-lymphocytes, by promoting a sustained and robust activation of the Rho GTPases (14–16).The GPIs appear to rapidly equilibrate across the plasma membrane when added exogenously to cells, to exert their actions within the cell (12). The plasma membrane transporter for GroPIns characterized in yeast is the protein GIT1 (17), with one of its orthologs in mammalian cells identified as the human permease Glut2 (18). This specific transporter has been proposed to mediate both GroPIns uptake and release, which depends on the GroPIns concentration gradient across the plasma membrane. Under physiological conditions, this gradient can arise from the formation of GPIs from the phosphoinositides inside cells following activation of a specific isoform of phospholipase A2, PLA2IVα (13, 19).The release of the GPIs into the extracellular medium can affect their paracrine targets (16) or initiate their catabolism. This is supported by our characterization of GDE1 activity, and now of GDE3 activity, both of which show a substrate selectivity toward GroPIns, and catalytic activity after heterologous expression that can only be monitored in the extracellular space. Interestingly, GDE3 activity appears to be related to modulation of osteoblast functions, delineating a role for GDE3 in promoting osteoblast differentiation, and mainly regulating osteoblast proliferation. 相似文献
934.
Plasmodiphora brassicae is a soil-borne obligate parasite. The pathogen has three stages in its life cycle: survival in soil, root hair infection,
and cortical infection. Resting spores of P. brassicae have a great ability to survive in soil. These resting spores release primary zoospores. When a zoospore reaches the surface
of a root hair, it penetrates through the cell wall. This stage is termed the root hair infection stage. Inside root hairs
the pathogen forms primary plasmodia. A number of nuclear divisions occur synchronously in the plasmodia, followed by cleavage
into zoosporangia. Later, 4–16 secondary zoospores are formed in each zoosporangium and released into the soil. Secondary
zoospores penetrate the cortical tissues of the main roots, a process called cortical infection. Inside invaded roots cells,
the pathogen develops into secondary plasmodia which are associated with cellular hypertrophy, followed by gall formation
in the tissues. The plasmodia finally develop into a new generation of resting spores, followed by their release back into
soil as survival structures. In vitro dual cultures of P. brassicae with hairy root culture and suspension cultures have been developed to provide a way to nondestructively observe the growth
of this pathogen within host cells. The development of P. brassicae in the hairy roots was similar to that found in intact plants. The observations of the cortical infection stage suggest that
swelling of P. brassicae-infected cells and abnormal cell division of P. brassicae-infected and adjacent cells will induce hypertrophy and that movement of plasmodia by cytoplasmic streaming increases the
number of P. brassicae-infected cells during cell division. 相似文献
935.
Koji Watanabe Toshiko Tanaka Takahiro Shigemi Yutaka Hayashida Kenshi Maki 《Journal of trace elements in medicine and biology》2009,23(2):93-99
To examine the standard Mn and Cu concentrations in mixed saliva from children and the relationship between these levels and dental caries, resting mixed saliva samples obtained from 527 children of an elementary school in Kitakyushu City were collected at 10:00–11:30 a.m. during December 2004. The Mn and Cu concentrations were determined using simultaneous multi-element atomic absorption spectrometry. The standard Mn and Cu levels were 22.0±15.2 and 3.8±4.1 ng/mL, respectively, in the sound teeth group. Mn levels were significantly higher in boys (25.4±17.4 ng/mL) than girls (19.1±12.3 ng/mL) and also higher in upper (25.5±16.4 ng/mL) than lower (19.0±13.5 ng/mL) grades. The Cu level was unaffected by sex and age in the sound teeth group. The Cu level in children with caries experience (5.7±5.3 ng/mL) was significantly higher than that of the sound teeth group. Moreover, the Cu levels in children with untreated caries were significantly higher than that of the sound teeth group, and increased with the number of untreated teeth. No significant difference was found in the Cu concentrations between the group in which all decayed teeth were treated and the sound teeth group. The Mn levels were similar with or without caries and treatment. These findings indicate that the Mn level in mixed saliva depended on sex and age, and suggest the possibility of Cu dissolving into mixed saliva by demineralization due to dental caries. 相似文献
936.
Chisako Fujita Fumito Ichikawa Toshiaki Teratani Gen Murakami Takahiro Okada Masaki Shinohara Suguru Kawato Yoshihiro Ohta 《The Journal of steroid biochemistry and molecular biology》2009,117(1-3):50-55
Glucocorticoids are known to decrease intracellular ATP levels in the brain. This study was performed to investigate whether corticosterone at physiological levels depresses mitochondrial ATP production by directly acting on mitochondria. Mitochondria were isolated from immortalized hypothalamic GT1-7 neurons. ATP levels were determined using a luciferase–luciferin assay. When malate, α-ketoglutarate or pyruvate was used as a respiration substrate, corticosterone at ≥100 nM decreased ATP production by 10%. In contrast, corticosterone did not affect ATP production when succinate or N,N,N′,N′-tetramethyl-p-phenylenediamine + ascorbate were used. To investigate the specificity of corticosterone inhibition, we examined several steroids. All steroids tested suppressed mitochondrial ATP production by 10% at a concentration of 100 nM, in a manner similar to that of corticosterone. To examine the effects of corticosterone on GT1-7 cell physiology, we incubated GT1-7 cells with t-butyl hydroperoxide (t-BuOOH) with corticosterone. Corticosterone largely enhanced t-BuOOH-induced cell death. These results indicate that corticosterone non-specifically inhibits mitochondrial ATP production by suppressing electron transfer from NADH to the electron transfer chain through complex I. Partial inhibition of mitochondrial ATP production by corticosterone may contribute to oxidative stress-induced cell death. 相似文献
937.
Takahiro Sato Naoki Ashizawa Koji Matsumoto Takashi Iwanaga Hiroshi Nakamura Tsutomu Inoue Osamu Nagata 《Bioorganic & medicinal chemistry letters》2009,19(21):6225-6229
Our previous study identified 2-[2-(2-methoxy-ethoxy)-ethoxy]-5-[5-(2-methyl-4-pyridyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile (2) as a safe and potent xanthine oxidoreductase (XOR) inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole (FYX-051, compound 39) to be one of the most potent XOR inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4-inhibitory activity and a better pharmacokinetic profile than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial. 相似文献
938.
In various kinds of cultured cells, it has been reported that the membrane potential exhibits fluctuations with long-term correlations, although the underlying mechanism remains to be elucidated. A cardiac muscle cell culture serves as an excellent experimental system to investigate this phenomenon because timings of excitations can be determined over an extended time period in a noninvasive manner through visualization of contractions, although the properties of beat-timing fluctuations of cardiac muscle cells at the single-cell level remains to be fully clarified. In this article, we report on our investigation of spontaneous contractions of cultured rat cardiac muscle cells at the single-cell level. It was found that single cells exhibit several typical temporal patterns of contractions and spontaneous transitions among them. Detrended fluctuation analysis on the time series of interbeat intervals revealed the presence of 1/fβ noise at sufficiently large timescales. Furthermore, multifractality was also found in the time series of interbeat intervals. These experimental trends were successfully explained using a simple mathematical model, incorporating correlated noise into ionic currents. From these findings, it was established that singular fluctuations accompanying 1/fβ noise and multifractality are intrinsic properties of single cardiac muscle cells. 相似文献
939.
Kiyotaka Nakano Junichi Nezu Iwao Ohizumi Koh Furugaki Takahiro Ishiguro Tatsuhiko Kodama Hisafumi Yamada-Okabe Masayuki Tsuchiya 《Biochemical and biophysical research communications》2009,378(2):279-284
Glypican 3 (GPC3), a GPI-anchored heparan sulfate proteoglycan, is expressed in the majority of hepatocellular carcinoma (HCC) tissues. Using MRL/lpr mice, we successfully generated a series of anti-GPC3 monoclonal antibodies (mAbs). GPC3 was partially cleaved between Arg358 and Ser359, generating a C-terminal 30-kDa fragment and an N-terminal 40-kDa fragment. All mAbs that induced antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) against cells expressing GPC3 recognized the 30-kDa fragment, indicating that the C-terminal region of GPC3 serves as an epitope for mAb with ADCC and/or CDC inducing activities. Chimeric mAbs with Fc replaced by human IgG1 were created from GC33, one of the mAbs that reacted with the C-terminal 30-kDa fragment. Chimeric GC33 induced not only ADCC against GPC3-positive human HCC cells but also was efficacious against the Huh-7 human HCC xenograft. Thus, mAbs against the C-terminal 30-kDa fragment such as GC33 are useful in therapy targeting HCC. 相似文献
940.
Mizue Nakajima Takahiro Ueda Makoto Migita Yuki Oue Takashi Shimada 《Biochemical and biophysical research communications》2009,389(2):290-294
Full-term cord blood (TCB) hematopoietic stem/progenitor cells (HSC/HPCs) are used for stem cell transplantation and are well characterized. However, the properties of preterm cord blood (PCB) HSC/HPCs remain unclear. In the present study, we compared HSC/HPCs from TCB and PCB with respect to their expression of surface markers, homing capacity and ability to repopulate HSCs in the NOD/Shi-scid mice bone marrow. The proportion of CD34+CD38− cells was significantly higher in PCB. On the other hand, the engraftment rate of TCB CD34+ cells into NOD/Shi-scid mice was significantly higher than PCB CD34+ cells. The expression of VLA4 was stronger among TCB CD34+ cells than PCB CD34+ cells. Moreover, there was a positive correlation between the proportion of CD34+CXCR4+ cells and gestational age. These data suggest that the homing ability of HSCs increases during gestation, so that TCB may be a better source of HSCs for transplantation than PCB. 相似文献