43 results on '"Hashimoto, Seiichi"'
Search Results
2. K-252a, a Potent Protein Kinase Inhibitor, Blocks Nerve Growth Factor-Induced Neurite Outgrowth and Changes in the Phosphorylation of Proteins in PC12h Cells
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Hashimoto, Seiichi
- Published
- 1988
3. Up-regulation of circadian clock gene Period 2 in the prostate mesenchymal cells during flutamide-induced apoptosis
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Yoshida, Kaoru, He, Pei-jian, Yamauchi, Nobuhiko, Hashimoto, Seiichi, and Hattori, Masa-aki
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- 2010
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4. Progesterone, but not estradiol, synchronizes circadian oscillator in the uterus endometrial stromal cells
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Hirata, Masami, He, Pei-Jian, Shibuya, Nozomi, Uchikawa, Miho, Yamauchi, Nobuhiko, Hashimoto, Seiichi, and Hattori, Masa-aki
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- 2009
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5. Different circadian expression of major matrix-related genes in various types of cartilage: modulation by light–dark conditions
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Honda, Kiyomasa K., Kawamoto, Takeshi, Ueda, Hiroki R., Nakashima, Ayumu, Ueshima, Taichi, Yamada, Rikuhiro G, Nishimura, Masahiro, Oda, Ryo, Nakamura, Shigeo, Kojima, Tomoko, Noshiro, Mitsuhide, Fujimoto, Katsumi, Hashimoto, Seiichi, and Kato, Yukio
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- 2013
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6. Gonadotropic regulation of circadian clockwork in rat granulosa cells
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He, Pei-Jian, Hirata, Masami, Yamauchi, Nobuhiko, Hashimoto, Seiichi, and Hattori, Masa-aki
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- 2007
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7. Universality and flexibility in gene expression from bacteria to human
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Ueda, Hiroki R., Hayashi, Satoko, Matsuyama, Shinichi, Yomo, Tetsuya, Hashimoto, Seiichi, Kay, Steve A., Hogenesch, John B., and Iino, Masamitsu
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Biological research -- Research ,Biology, Experimental -- Research ,Science and technology - Abstract
Highly parallel experimental biology is offering opportunities to not just accomplish work more easily, but to explore for underlying governing principles. Recent analysis of the large-scale organization of gene expression has revealed its complex and dynamic nature. However, the underlying dynamics that generate complex gene expression and cellular organization are not yet understood. To comprehensively and quantitatively elucidate these underlying gene expression dynamics, we have analyzed genome-wide gene expression in many experimental conditions in Escherichia coil, Saccharomyces cerevisiae, Arabidopsis thaliana, Drosophila melanogaster, Mus musculus, and Homo sapiens. Here we demonstrate that the gene expression dynamics follows the same and surprisingly simple principle from E. coli to human, where gene expression changes are proportional to their expression levels, and show that this 'proportional' dynamics or 'rich-travel-more' mechanism can regenerate the observed complex and dynamic organization of the transcriptome. These findings provide a universal principle in the regulation of gene expression, show how complex and dynamic organization can emerge from simple underlying dynamics, and demonstrate the flexibility of transcription across a wide range of expression levels. systems biology | DNA microarray | gene expression dynamics | transcription | transcriptional organization
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- 2004
8. Regional circadian period difference in the suprachiasmatic nucleus of the mammalian circadian center
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Koinuma, Satoshi, Asakawa, Takeshi, Nagano, Mamoru, Furukawa, Keiichi, Sujino, Mitsugu, Masumoto, Koh-Hei, Nakajima, Yoshihiro, Hashimoto, Seiichi, Yagita, Kazuhiro, and Shigeyoshi, Yasufumi
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- 2013
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9. A transcription factor response element for gene expression during circadian night
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Ueda, Hiroki R., Chen, Wenbin, Adachi, Akihito, Wakamatsu, Hisanori, Hayashi, Satoko, Takasugi, Tomohiro, Nagano, Mamoru, Nakahama, Ken-ichi, Suzuki, Yutaka, Sugano, Sumio, Iino, Masamitsu, Shigeyoshi, Yasufumi, and Hashimoto, Seiichi
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Hiroki R. Ueda (corresponding author) [1, 2]; Wenbin Chen [1]; Akihito Adachi [3]; Hisanori Wakamatsu [1]; Satoko Hayashi [1]; Tomohiro Takasugi [1]; Mamoru Nagano [3]; Ken-ichi Nakahama [3]; Yutaka [...]
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- 2002
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10. Angiopoietin-Like 2, a Circadian Gene, Improves Type 2 Diabetes Through Potentiation of Insulin Sensitivity in Mice Adipocytes
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Kitazawa, Masashi, Nagano, Mamoru, Masumoto, Koh-hei, Shigeyoshi, Yasufumi, Natsume, Tohru, and Hashimoto, Seiichi
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- 2011
11. Identification of functional clock-controlled elements involved in differential timing of Per1 and Per2 transcription
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Yamajuku, Daisuke, Shibata, Yasutaka, Kitazawa, Masashi, Katakura, Toshie, Urata, Hiromi, Kojima, Tomoko, Nakata, Osamu, and Hashimoto, Seiichi
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- 2010
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12. Proinsulin C-Peptide Stimulates a PKC/IκB/NF-κB Signaling Pathway to Activate COX-2 Gene Transcription in Swiss 3T3 Fibroblasts
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Kitazawa, Masashi, Shibata, Yasutaka, Hashimoto, Seiichi, Ohizumi, Yasushi, and Yamakuni, Tohru
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- 2006
13. Enantio-differentiating hydrogenation of methyl acetoacetate over tartaric acid-NaBr-modified supported nickel catalyst prepared from nickel acetylacetonate
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Osawa, Tsutomu, Mita, Shinya, Iwai, Akiko, Takayasu, Osamu, Hashiba, Hideto, Hashimoto, Seiichi, Harada, Tadao, and Matsuura, Ikuya
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- 2000
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14. Purification and properties of human serum dopamine-β -hydroxylase
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Ikeno, Takeyuki, Hashimoto, Seiichi, Kuzuya, Hiroshi, and Nagatsu, Toshiharu
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- 1977
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15. Cellular DBP and E4BP4 proteins are critical for determining the period length of the circadian oscillator
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Yamajuku, Daisuke, Shibata, Yasutaka, Kitazawa, Masashi, Katakura, Toshie, Urata, Hiromi, Kojima, Tomoko, Takayasu, Satoko, Nakata, Osamu, and Hashimoto, Seiichi
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- 2011
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16. The nuclear receptor REV- ERB α represses the transcription of growth/differentiation factor 10 and 15 genes in rat endometrium stromal cells.
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Zhao, Lijia, Isayama, Keishiro, Chen, Huatao, Yamauchi, Nobuhiko, Shigeyoshi, Yasufumi, Hashimoto, Seiichi, and Hattori, Masa‐aki
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NUCLEAR receptors (Biochemistry) ,GROWTH factors ,GENE expression ,BIOLUMINESCENCE ,STROMAL cells - Abstract
Cellular oscillators in the uterus play critical roles in the gestation processes of mammals through entraining of the clock proteins to numerous downstream genes, including growth/differentiation factor ( Gdf) 10 and Gdf15. The expression of Gdf10 and Gdf15 is significantly increased in the uterus during decidualization, but the mechanism underlying the regulation of Gdf gene expression in the uterus is poorly understood. Here, we focused on the function of the cellular oscillators in the expression of Gdf family by using uterine endometrial stromal cells ( UESCs) isolated from pregnant Per2- dLuc transgenic rats. A significant decline of Per2- dLuc bioluminescence activity was induced in in vitro decidualized UESCs, and concomitantly the expression of canonical clock genes was downregulated. Conversely, the expression of Gdf10 and Gdf15 of the Gdf was upregulated. In UESCs transfected with Bmal1-specific si RNA, in which Rev-erbα expression was downregulated, Gdf10 and Gdf15 were upregulated. However, Gdf5, Gdf7, and Gdf11 were not significantly affected by Bmal1 silencing. The expression of Gdf10 and Gdf15 was enhanced after treatment with a REV- ERB α antagonist in the presence or absence of progesterone. Chromatin immunoprecipitation- PCR analysis revealed the inhibitory effect of REV- ERB α on the expression of Gdf10 and Gdf15 in UESCs by recognizing their gene promoters. Collectively, our findings indicate that the attenuation of REV- ERB α leads to an upregulation of Gdf10 and Gdf15 in decidual cells, in which cellular oscillators are impaired. Our results provide novel evidence regarding the functions of cellular oscillators regulating the expression of downstream genes during the differentiation of UESCs. [ABSTRACT FROM AUTHOR]
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- 2016
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17. Integration of the nuclear receptor REV-ERBα linked with circadian oscillators in the expressions of Alas1, Ppargc1a, and Il6 genes in rat granulosa cells.
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Chen, Huatao, Isayama, Keishiro, Kumazawa, Makoto, Zhao, Lijia, Yamauchi, Nobuhiko, Shigeyoshi, Yasufumi, Hashimoto, Seiichi, and Hattori, Masa-aki
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NUCLEAR receptors (Biochemistry) ,CIRCADIAN rhythms ,GENE expression ,GENETIC transcription ,PROMOTERS (Genetics) - Abstract
The nuclear receptor REV-ERBα links circadian rhythms and numerous physiological processes, but its physiological role in ovaries remains largely unknown. The aim of this study was to determine the potential role of REV-ERBα in the regulation of the transcription of its putative target genes in granulosa cells (GCs) prepared from Per2-destablized luciferase ( dLuc) reporter gene transgenic rats. Alas1, Ppargc1a, and Il6 were chosen as representatives for genes analysis. A real-time monitoring system of Per2 promoter activity was performed to detect Per2-dLuc circadian oscillations. Two agonists (GSK4112, heme) and an antagonist (SR8278) of REV-ERBα as well as Rev-erbα siRNA knockdown were used to identify its target genes. Clear Per2-dLuc circadian oscillations were generated in matured GCs after synchronization with GSK4112 or SR8278. GSK4112 treatment lengthened and SR8278 treatment shortened the period of circadian oscillations in matured GCs stimulated with or without luteinizing hormone (LH). GSK4112 showed an inhibitory effect on the amplitude of circadian oscillations and caused an arrhythmic expression of canonical clock genes. SR8278 also had a subtle effect on their daily expression profiles, but the treatment resulted only in the arrhythmic expression of Rev-erbα. These findings indicate the functional biological activity of REV-ERBα in response to its ligands. Its natural ligand heme further elongated the period of circadian oscillations and alleviated their amplitudes in GCs cultured with LH. Heme treatment also repressed the expressions of clock genes, Alas1, Il6, and Ppargc1a. Rev-erbα knockdown up-regulated these transcript levels. Collectively, these data extend the recent finding to rat GCs and demonstrate that REV-ERBα represses the expressions of Alas1, Ppargc1a, and Il6, providing novel insights into the physiological significance of REV-ERBα in ovarian circadian oscillators. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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18. Profiling of circadian genes expressed in the uterus endometrial stromal cells of pregnant rats as revealed by DNA microarray coupled with RNA interference.
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Tasaki, Hirotaka, Lijia Zhao, Isayama, Keishiro, Huatao Chen, Yamauchi, Nobuhiko, Shigeyoshi, Yasufumi, Hashimoto, Seiichi, and Hattori, Masa-aki
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OSCILLATING genes ,STROMAL cells ,CELL cycle ,GLUTATHIONE ,MITOGEN-activated protein kinases ,RNA interference ,BLASTOCYST ,GENE expression in mammals - Abstract
The peripheral circadian oscillator plays an essential role in synchronizing local physiology to operate in a circadian manner via regulation of the expression of clock-controlled genes. The present study aimed to evaluate the circadian rhythms of clock genes and clock-controlled genes expressed in the rat uterus endometrial stromal cells (UESCs) during the stage of implantation by a DNA microarray. Of 12,252 genes showing significantly expression, 7,235 genes displayed significant alterations. As revealed by the biological pathway analysis using the database for annotation, visualization, and integrated discovery online annotation software, genes were involved in cell cycle, glutathione metabolism, MAPK signaling pathway, fatty acid metabolism, ubiquitin mediated proteolysis, focal adhesion, and PPAR signaling pathway. The clustering of clock genes were mainly divided into four groups: the first group was Rorα,Timeless, Npas2, Bmal1, Id2, and Cry2; the second group Per1, Per2, Per3, Dec1, Tef, and Dbp; the third group Bmal2, Cry1, E4bp4, Rorβ, and Clock; the fourth group Rev-erbα. Eleven implantation-related genes and 24 placenta formation-related genes displayed significant alterations, suggesting that these genes involved in implantation and placenta formation are controlled under circadian clock. Some candidates as clock-controlled genes were evaluated by using RNA interference to Bmal1 mRNA. Down-regulation of Igf1 gene expression was observed by Bmal1 silencing, whereas the expression of Inhβa was significantly increased. During active oscillation of circadian clock, the apoptosis-related genes Fas and Caspase3 remained no significant changes, but they were significantly increased by knockdown of Bmal1 mRNA. These results indicate that clock-controlled genes are up-or down-regulated in rat UESCs during the stage of decidualization. DNA microarray analysis coupled with RNA interference will be helpful to understand the physiological roles of some oscillating genes in blastocyst implantation and placenta formation. [ABSTRACT FROM AUTHOR]
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- 2013
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19. Quantitative Analysis of Phase Wave of Gene Expression in the Mammalian Central Circadian Clock Network.
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Fukuda, Hirokazu, Tokuda, Isao, Hashimoto, Seiichi, and Hayasaka, Naoto
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QUANTITATIVE research ,GENE expression ,SUPRACHIASMATIC nucleus ,BIOLUMINESCENCE assay ,BIOLOGICAL neural networks ,NEURONS ,ROBUST control ,SIMULATION methods & models - Abstract
Background: The suprachiasmatic nucleus (SCN), the master circadian clock, is a heterogeneous oscillator network, yet displays a robust synchronization dynamics. Recent single-cell bioluminescent imaging revealed temporal gradients in circadian clock gene expression in the SCN ex vivo. However, due to technical difficulty in biological approaches to elucidate the entire network structure of the SCN, characteristics of the gradient, which we refer to as phase wave, remain unknown. Methodology/Principal Findings: We implemented new approaches, i.e., quantitative analysis and model simulation to characterize the phase waves in Per2::Luciferase clock reporter gene expression of the rat SCN slice. Our quantitative study demonstrated not only a high degree of synchronization between the neurons and regular occurrence of the phase wave propagation, but also a significant amount of phase fluctuations contained in the wave. In addition, our simulations based on local coupling model suggest that the intercellular coupling strength estimated by the model simulations is significantly higher than the critical value for generating the phase waves. Model simulations also suggest that heterogeneity of the SCN neurons is one of the main factors causing the phase wave fluctuations. Furthermore, robustness of the SCN network against dynamical noise and variation of the natural frequencies inherent in these neurons was quantitatively assessed. Conclusions/Significance: To our knowledge, this is the first quantitative evaluation of the phase wave and further characterization of the SCN neuronal network features generating the wave i.e., intercellular synchrony, phase fluctuation, strong local coupling, heterogeneous periodicity and robustness. Our present study provides an approach, which will lead to a comprehensive understanding of mechanistic and/or biological significance of the phase wave in the central circadian oscillatory system. [ABSTRACT FROM AUTHOR]
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- 2011
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20. Alterations of Circadian Clockworks During Differentiation and Apoptosis of Rat Ovarian Cells.
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Chu, Guiyan, Yoshida, Kaoru, Narahara, Sayoko, Uchikawa, Miho, Kawamura, Madoka, Yamauchi, Nobuhiko, Xi, Yongmei, Shigeyoshi, Yasufumi, Hashimoto, Seiichi, and Hattori, Masa-aki
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CIRCADIAN rhythms ,APOPTOSIS ,CELL differentiation ,CELL proliferation ,DEXAMETHASONE ,POLYMERASE chain reaction ,LUTEINIZING hormone ,OVARIES - Abstract
Ovarian development is related to cell proliferation, differentiation, and apoptosis of granulosa cells and luteal cells under the control of various modulators, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and growth factors. In the present study, the expression of clock genes and the related regulation mechanism were analyzed in different ovarian cell types during differentiation and apoptosis. The authors focused on the circadian expression of Per2 as a core clock gene for the maintenance of circadian rhythms. By using a real-time monitoring system of the Per2 promoter activity, the circadian oscillation was analyzed in the granulosa and luteal cells from preantral follicles, antral follicles, and corpora lutea of immature Per2 promoter--destabilized luciferase transgenic rats that were primed with diethylstilbestrol, equine chorionic gonadotropin (eCG), and//or human CG. In addition, transcript levels of Per2, Bmal1, Clock, and Nampt were quantified by quantitative polymerase chain reaction (qPCR). Immunohistochemical studies revealed strong circadian rhythmicity of PER2 protein in the luteal cells, but apparently little rhythmicity in granulosa cells of both preantral and antral follicles. In vitro monitoring of promoter activity showed generation of several oscillations in luteal cells after exposure to dexamethasone (DXM), whereas oscillatory amplitudes of immature and mature granulosa cells were rapidly attenuating. The circadian rhythm of the Bmal1 transcript levels, but not the Per2 transcript, was very weak in the granulosa cells, as compared with that in luteal cells. Granulosa cells gained a strong circadian rhythm ability of the Per2 promoter activity after stimulation with FSH for 3 days. In contrast, LH had little effect on the circadian rhythm before stimulation of granulosa cells with FSH, probably owing to lack of LH receptor. In luteal cells, induction of apoptosis by inhibiting progesterone synthesis resulted in deregulation of Per2 circadian oscillation. Transcript levels of Bmal1 and Clock, but not Per2 and Nampt, were significantly decreased in apoptotic luteal cells. The Bmal1 transcript level was particularly reduced. Consequently, these results strongly suggest the circadian clockwork alters in ovarian cells during follicular development, luteinization, and apoptosis, and expression of Bmal1 may be related to the switch-on and switch-off of the circadian oscillation. (Author correspondence: ) [ABSTRACT FROM AUTHOR]
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- 2011
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21. Improved Method of Blind Speech Separation with Low Computational Complexity.
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Kondo, Kazunobu, Takahashi, Yu, Hashimoto, Seiichi, Saruwatari, Hiroshi, Nishino, Takanori, and Takeda, Kazuya
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COMPUTATIONAL complexity ,INDEPENDENT component analysis ,TRANSFER functions ,PERFORMANCE evaluation ,SIGNAL-to-noise ratio ,COMPUTER simulation ,ELECTRIC distortion ,ESTIMATION theory - Abstract
A blind speech separation method with low computational complexity is proposed. This method consists of a combination of independent component analysis with frequency band selection, and a frame-wise spectral soft mask method based on an interchannel power ratio of tentative separated signals in the frequency domain. The soft mask cancels the transfer function between sources and separated signals. A theoretical analysis of selection criteria and the soft mask is given. Performance and effectiveness are evaluated via source separation simulations and a computational estimate, and experimental results show the significantly improved performance of the proposed method. The segmental signal-to-noise ratio achieves 7 [dB] and 3 [dB], and the cepstral distortion achieves 1 [dB] and 2.5 [dB], in anechoic and reverberant conditions, respectively. Moreover, computational complexity is reduced by more than 80% compared with unmodified FDICA. [ABSTRACT FROM AUTHOR]
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- 2011
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22. Screening and evaluation of new inhibitors of hepatic glucose production.
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Hashimoto, Junko, Motohashi, Keiichiro, Sakamoto, Kazutoshi, Hashimoto, Seiichi, Yamanouchi, Maasa, Tanaka, Hiroshi, Takahashi, Takashi, Takagi, Motoki, and Shin-ya, Kazuo
- Published
- 2009
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23. Regular Feeding Plays an Important Role in Cholesterol Homeostasis Through the Liver Circadian Clock.
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Yamajuku, Daisuke, Okubo, Shingo, Haruma, Tomonori, Inagaki, Takahiko, Okuda, Yuji, Kojima, Tomoko, Noutomi, Keiji, Hashimoto, Seiichi, and Oda, Hiroaki
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CHOLESTEROL ,CHOLESTEROL content of food ,HOMEOSTASIS ,CIRCADIAN rhythms ,DISEASE susceptibility ,ETIOLOGY of diseases ,NUTRITIONALLY induced diseases ,METABOLIC syndrome - Abstract
The article examines the liver clock's physiological functions. It notes that peripheral clock control and the importance of the circadian rhythm to physiology and disease are important queries in mammalian circadian biology. It mentions that a suppressed feeding schedule regimen was established wherein rat that were exposed to the regiment developed hypercholesteremia. It stresses that the amount, quality of food, and timing of meals has important implications to health.
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- 2009
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24. Nerve Growth Factor-Induced Transient Increase in the Phosphorylation of Ribosomal Protein S6 Mediated Through a Mechanism Independent of Cyclic AMP-Dependent Protein Kinase and Protein Kinase C.
- Author
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Hashimoto, Seiichi and Hagino, Akihiko
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- 1990
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25. Blockage of Nerve Growth Factor Action in PC12h Cells by Staurosporine, a Potent Protein Kinase Inhibitor.
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Hashimoto, Seiichi and Hagino, Akihiko
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- 1989
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26. Wheat Germ Agglutinin Inhibits the Effects of Nerve Growth Factor on the Phosphorylation of Proteins in PC12h Cells.
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Hashimoto, Seiichi, Ikeno, Takeyuki, and Kuzuya, Hiroshi
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- 1985
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27. Unusual Pigmentation on the Skin over Trunk Bones and Extremities.
- Author
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Tanigaki, Takehiko, Hata, Seiichiro, Kitano, Yukio, Nomura, Masao, Sano, Shigeharu, Endo, Hidehiko, Tsuda, Michio, and Hashimoto, Seiichi
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- 1985
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28. Pervanadate stimulation of wortmannin-sensitive and -resistant 2-deoxyglucose transport in adipocytes
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Ida, Motoko, Imai, Kiyoshi, Hashimoto, Seiichi, and Kawashima, Hiroyuki
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- 1996
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29. Contact dermatitis due to diisopropanolamine.
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Fujimoto, Keiichi, Hashimoto, Seiichi, Kozuka, Takehito, and Yoshikawa, Kunihiko
- Subjects
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CONTACT dermatitis , *PROPANOLAMINES , *AMINO alcohols , *GOUT , *ARTHRITIS , *ERYTHEMA , *STEROIDS - Abstract
A sixty-year-old man, with four year history of gout, used indomethacin ointment for painful episodes. He then used the same ointment on the lower leg for itchy skin. After some time, an erythema developed on the extensor surface of legs and lesions gradually worsened. Treatment with oral antihistamine and topical steroid was ineffective. Oral prenisolone was given and resulted in rapid healing of the skin condition. The patient was first tested by the topical application of indomethacin ointment, which was applied at the back. An itchy eruption was seen at the application site after two days.
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- 1989
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30. Identification of a new clock-related element EL-box involved in circadian regulation by BMAL1/CLOCK and HES1
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Ueshima, Taichi, Kawamoto, Takeshi, Honda, Kiyomasa K., Noshiro, Mitsuhide, Fujimoto, Katsumi, Nakao, Sanae, Ichinose, Natsuhiro, Hashimoto, Seiichi, Gotoh, Osamu, and Kato, Yukio
- Subjects
- *
SUPRACHIASMATIC nucleus , *ANALYSIS of variance , *GENETIC transcription regulation , *CIRCADIAN rhythms , *GENE expression , *CELLULAR control mechanisms , *HEART physiology , *IMMUNOPRECIPITATION - Abstract
Abstract: Several cis-acting elements play critical roles in maintaining circadian expression of clock and clock-controlled genes. Using in silico analysis, we identified 10 sequence motifs that are correlated with the circadian phases of gene expression in the cartilage. One of these motifs, an E-box-like clock-related element (EL-box; GGCACGAGGC), can mediate BMAL1/CLOCK-induced transcription, which is typically regulated through an E-box or E′-box. Expression of EL-box-containing genes, including Ank, Dbp, and Nr1d1 (Rev-erbα), was induced by BMAL1/CLOCK or BMAL1/NPAS2. Compared with the E-box, the EL-box elements had distinct responsiveness to DEC1, DEC2, and HES1: suppressive actions of DEC1 and DEC2 on the EL-box were less potent than those on the E-box. HES1, which is known to bind to the N-box (CACNAG), suppressed enhancer activity of the EL-box, but not the E-box. In the Dbp promoter, an EL-box worked cooperatively with a noncanonical (NC) E-box to mediate BMAL1/CLOCK actions. These findings suggest that in addition to known clock elements, the EL-box element may contribute to circadian regulation of clock and clock-controlled genes. [Copyright &y& Elsevier]
- Published
- 2012
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31. Rev-erbα regulates circadian rhythms and StAR expression in rat granulosa cells as identified by the agonist GSK4112
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Chen, Huatao, Chu, Guiyan, Zhao, Lijia, Yamauchi, Nobuhiko, Shigeyoshi, Yasufumi, Hashimoto, Seiichi, and Hattori, Masa-aki
- Subjects
- *
CIRCADIAN rhythms , *GENE expression , *GENETIC regulation , *TRANSCRIPTION factors , *METABOLISM , *BIOSYNTHESIS , *LABORATORY rats - Abstract
Abstract: The Rev-erbα gene is regarded as a circadian clock gene and clock-regulated gene which regulates the circadian transcriptional/translational loop in a subtle way. Here, we first detected the circadian oscillation in mature granulosa cells from antral follicles using a real-time monitoring system of Per2 promoter activity with the addition of FSH. Then we used GSK4112, an agonist ligand of Rev-erbα, to investigate the function of Rev-erbα. GSK4112 treatment significantly reduced the Per2-dLuc amplitude and induced the Per2 oscillation phase advance shift. GSK4112 significantly inhibited Bmal1 mRNA expression, whereas it did clearly stimulate expression of StAR mRNA in a dose-dependent manner. Our data are the first to show the Rev-erbα function in the steroid biosynthesis of rat granulosa cells, and to suggest that Rev-erbα may coordinate circadian rhythm and metabolism in rat ovaries. [Copyright &y& Elsevier]
- Published
- 2012
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32. The nuclear receptor REV-ERBα represses the transcription of growth/differentiation factor 10 and 15 genes in rat endometrium stromal cells.
- Author
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Zhao L, Isayama K, Chen H, Yamauchi N, Shigeyoshi Y, Hashimoto S, and Hattori MA
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- Animals, Cell Differentiation, Chromatin Immunoprecipitation, Endometrium cytology, Female, Growth Differentiation Factor 10 genetics, Growth Differentiation Factor 15 genetics, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Pregnancy, RNA, Small Interfering, Rats, Rats, Transgenic, Stromal Cells cytology, Stromal Cells metabolism, Transcription, Genetic, Transfection, Endometrium metabolism, Gene Expression Regulation physiology, Growth Differentiation Factor 10 metabolism, Growth Differentiation Factor 15 metabolism, Nuclear Receptor Subfamily 1, Group D, Member 1 metabolism
- Abstract
Cellular oscillators in the uterus play critical roles in the gestation processes of mammals through entraining of the clock proteins to numerous downstream genes, including growth/differentiation factor (Gdf)10 and Gdf15. The expression of Gdf10 and Gdf15 is significantly increased in the uterus during decidualization, but the mechanism underlying the regulation of Gdf gene expression in the uterus is poorly understood. Here, we focused on the function of the cellular oscillators in the expression of Gdf family by using uterine endometrial stromal cells (UESCs) isolated from pregnant Per2-dLuc transgenic rats. A significant decline of Per2-dLuc bioluminescence activity was induced in in vitro decidualized UESCs, and concomitantly the expression of canonical clock genes was downregulated. Conversely, the expression of Gdf10 and Gdf15 of the Gdf was upregulated. In UESCs transfected with Bmal1-specific siRNA, in which Rev-erbα expression was downregulated, Gdf10 and Gdf15 were upregulated. However, Gdf5, Gdf7, and Gdf11 were not significantly affected by Bmal1 silencing. The expression of Gdf10 and Gdf15 was enhanced after treatment with a REV-ERBα antagonist in the presence or absence of progesterone. Chromatin immunoprecipitation-PCR analysis revealed the inhibitory effect of REV-ERBα on the expression of Gdf10 and Gdf15 in UESCs by recognizing their gene promoters. Collectively, our findings indicate that the attenuation of REV-ERBα leads to an upregulation of Gdf10 and Gdf15 in decidual cells, in which cellular oscillators are impaired. Our results provide novel evidence regarding the functions of cellular oscillators regulating the expression of downstream genes during the differentiation of UESCs., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)
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- 2016
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33. Removal of Rev-erbα inhibition contributes to the prostaglandin G/H synthase 2 expression in rat endometrial stromal cells.
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Isayama K, Zhao L, Chen H, Yamauchi N, Shigeyoshi Y, Hashimoto S, and Hattori MA
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- 5' Untranslated Regions, ARNTL Transcription Factors antagonists & inhibitors, ARNTL Transcription Factors genetics, ARNTL Transcription Factors metabolism, Animals, Cells, Cultured, Cyclooxygenase 2 genetics, Endometrium cytology, Endometrium enzymology, Female, Nuclear Receptor Subfamily 1, Group D, Member 1 antagonists & inhibitors, Nuclear Receptor Subfamily 1, Group D, Member 1 genetics, Nuclear Receptor Subfamily 1, Group F, Member 1 genetics, Nuclear Receptor Subfamily 1, Group F, Member 1 metabolism, Pregnancy, Prolactin analogs & derivatives, Prolactin genetics, Prolactin metabolism, RNA Interference, RNA, Small Interfering, Rats, Rats, Transgenic, Response Elements, Stromal Cells cytology, Stromal Cells enzymology, Circadian Clocks, Cyclooxygenase 2 metabolism, Endometrium metabolism, Gene Expression Regulation, Enzymologic, Nuclear Receptor Subfamily 1, Group D, Member 1 metabolism, Placentation, Stromal Cells metabolism
- Abstract
The rhythmic expression of clock genes in the uterus is attenuated during decidualization. This study focused on Ptgs2, which is essential for decidualization, as a putative clock-controlled gene, and aimed to reveal the functions of clock genes in relation to Ptgs2 during decidualization. We compared the transcript levels of clock genes in the rat uterus on days 4.5 (D4.5) and 6.5 of pregnancy. The transcript levels of clock genes (Per2, Bmal1, Rorα, and Rev-erbα) had decreased at implantation sites on day 6.5 (D6.5e) compared with those on D4.5, whereas Ptgs2 transcripts had increased on D6.5e. Similar observations of Rev-erbα and Ptgs2 were also obtained in the endometrium on D6.5e by immunohistochemistry. In the decidual cells induced by medroxyprogesterone and 2-O-dibutyryl-cAMP, the rhythmic expression levels of clock genes were attenuated, whereas Ptgs2 transcription was induced. These results indicate that decidualization causes the attenuation of clock genes and the induction of Ptgs2. Furthermore, in the experiment of Bmal1 siRNA, the rhythmic expression of clock genes and Ptgs2 was attenuated by the siRNA. Transcript levels of Ptgs2 and prostaglandin (PG)E₂ production were increased by treatment with the Rev-erbα antagonist, suggesting the contribution of the nuclear receptor Rev-erbα to Ptgs2 expression. Moreover, Rev-erbα knockdown enhanced the induction of Ptgs2 transcription and PGE₂ production by forskolin. Chromatin immunoprecipitation-PCR analysis revealed that Rev-erbα could directly bind to a proximal RORE site of Ptgs2. Collectively, this study demonstrates that the attenuation of the circadian clock, especially its core component Rev-erbα, contributes to the induction of Ptgs2 during decidualization., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
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- View/download PDF
34. Inhibitory role of REV-ERBα in the expression of bone morphogenetic protein gene family in rat uterus endometrium stromal cells.
- Author
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Tasaki H, Zhao L, Isayama K, Chen H, Yamauchi N, Shigeyoshi Y, Hashimoto S, and Hattori MA
- Subjects
- Animals, Cells, Cultured, Female, Gene Expression Regulation, Pregnancy, Rats, Rats, Transgenic, Stromal Cells metabolism, Uterus cytology, Uterus metabolism, Bone Morphogenetic Proteins antagonists & inhibitors, Bone Morphogenetic Proteins biosynthesis, Endometrium cytology, Endometrium metabolism, Nuclear Receptor Subfamily 1, Group D, Member 1 biosynthesis
- Abstract
Uterus circadian rhythms have been implicated in the gestation processes of mammals through entraining of the clock proteins to numerous downstream genes. Bone morphogenetic proteins (BMPs), having clock-controlled regulatory sites in their gene promoters, are expressed in the uterus during decidualization, but the regulation of the Bmp gene expression is poorly understood. The present study was designed to dissect the physiological roles of the uterus oscillators in the Bmp expression using the uterus endometrial stromal cells (UESCs) isolated from Per2-dLuc transgenic rats on day 4.5 of gestation. The in vitro decidualization of UESCs was induced by medroxyprogesterone acetate and 2-O-dibutyryl cAMP. A significant decline of Per2-dLuc bioluminescence activity was induced in decidual cells, and concomitantly, the expression of canonical clock genes was downregulated. Conversely, the expression of the core Bmp genes Bmp2, Bmp4, Bmp6, and Bmp7 was upregulated. In UESCs transfected with Bmal1-specific siRNA, in which Rev-erbα expression was downregulated, Bmp genes, such as Bmp2, Bmp4, and Bmp6 were upregulated. However, Bmp1, Bmp7, and Bmp8a were not significantly affected by Bmal1 silencing. The expression of all Bmp genes was enhanced after treatment with the REV-ERBα antagonist (SR8278), although their rhythmic profiles were differed from each other. The binding of REV-ERBα to the proximal regions of the Bmp2 and Bmp4 promoters was revealed by chromatin immunoprecipitation-PCR analysis. Collectively, these results indicate that the Bmp genes are upregulated by the attenuation of the cellular circadian clock; in particular, its core component REV-ERBα functions as a transcriptional silencer in the Bmp gene family., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
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- View/download PDF
35. Downregulation of core clock gene Bmal1 attenuates expression of progesterone and prostaglandin biosynthesis-related genes in rat luteinizing granulosa cells.
- Author
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Chen H, Zhao L, Kumazawa M, Yamauchi N, Shigeyoshi Y, Hashimoto S, and Hattori MA
- Subjects
- ARNTL Transcription Factors biosynthesis, ARNTL Transcription Factors genetics, Animals, CLOCK Proteins antagonists & inhibitors, CLOCK Proteins biosynthesis, Cells, Cultured, Female, Gene Expression Regulation, Mice, Progesterone biosynthesis, Progesterone genetics, Prostaglandins biosynthesis, Rats, Rats, Transgenic, ARNTL Transcription Factors antagonists & inhibitors, CLOCK Proteins genetics, Down-Regulation genetics, Luteal Cells metabolism, Progesterone antagonists & inhibitors, Prostaglandins genetics
- Abstract
Ovarian circadian oscillators have been implicated in the reproductive processes of mammals. However, there are few reports regarding the detection of ovarian clock-controlled genes (CCGs). The present study was designed to unravel the mechanisms through which CCG ovarian circadian oscillators regulate fertility, primarily using quantitative RT-PCR and RNA interference against Bmal1 in rat granulosa cells. Mature granulosa cells were prepared from mouse Per2-destabilized luciferase (dLuc) reporter gene transgenic rats. A real-time monitoring system of Per2 promoter activity was employed to detect Per2-dLuc oscillations. The cells exposed to luteinizing hormone (LH) displayed clear Per2-dLuc oscillations and a rhythmic expression of clock genes (Bmal1, Per1, Per2, Rev-erbα, and Dbp). Meanwhile, the examined ovarian genes (Star, Cyp19a1, Cyp11a1, Ptgs2, Lhcgr, and p53) showed rhythmic transcript profiles except for Hsd3b2, indicating that these rhythmic expression genes may be CCGs. Notably, Bmal1 small interfering (si)RNA treatment significantly decreased both the amplitude of Per2-dLuc oscillations and Bmal1 mRNA levels compared with nonsilencing RNA treatment in luteinizing granulosa cells. Depletion of Bmal1 by siRNA decreased the transcript levels of clock genes (Per1, Per2, Rev-erbα, and Dbp) and examined ovarian genes (Star, Cyp19a1, Cyp11a1, Ptgs2, Hsd3b2, and Lhcgr). Accordingly, knockdown of Bmal1 also inhibited the synthesis of progesterone and prostaglandin E2, which are associated with crucial reproductive processes. Collectively, these data suggest that ovarian circadian oscillators regulate the synthesis of steroid hormones and prostaglandins through ovarian-specific CCGs in response to LH stimuli. The present study provides new insights into the physiologic significance of Bmal1 related to fertility in ovarian circadian oscillators.
- Published
- 2013
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- View/download PDF
36. FSH induces the development of circadian clockwork in rat granulosa cells via a gap junction protein Cx43-dependent pathway.
- Author
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Chen H, Zhao L, Chu G, Kito G, Yamauchi N, Shigeyoshi Y, Hashimoto S, and Hattori MA
- Subjects
- Animals, Cell Differentiation drug effects, Cells, Cultured, Chorionic Gonadotropin metabolism, Circadian Rhythm Signaling Peptides and Proteins biosynthesis, Circadian Rhythm Signaling Peptides and Proteins genetics, Circadian Rhythm Signaling Peptides and Proteins metabolism, Connexin 43 antagonists & inhibitors, Connexin 43 genetics, Dexamethasone pharmacology, Female, GABA-A Receptor Antagonists pharmacology, Gap Junctions drug effects, Genes, Reporter drug effects, Glucocorticoids pharmacology, Granulosa Cells cytology, Granulosa Cells drug effects, Membrane Transport Modulators pharmacology, Mice, Period Circadian Proteins biosynthesis, Period Circadian Proteins genetics, Period Circadian Proteins metabolism, Rats, Rats, Transgenic, Receptors, LH biosynthesis, Receptors, LH genetics, Receptors, LH metabolism, Circadian Clocks drug effects, Connexin 43 metabolism, Follicle Stimulating Hormone metabolism, Gap Junctions metabolism, Granulosa Cells metabolism, Up-Regulation drug effects
- Abstract
The present study was designed to assess the relationship between gap junctions and the maturation of a clock system in rat granulosa cells stimulated by follicle-stimulating hormone (FSH). Immature and mature granulosa cells were prepared by puncturing the ovaries of diethylstilbestrol- and equine chorionic gonadotropin (eCG)-treated mouse Period2 (Per2)-dLuc reporter gene transgenic rats, respectively. Mature granulosa cells exposed to dexamethasone (DXM) synchronization displayed several Per2-dLuc oscillations and a rhythmic expression of clock genes. Intriguingly, we observed clear evidence that the FSH stimulation significantly increased the amplitude of Per2 oscillations in the granulosa cells, which was confirmed by the elevation of the Per2 and Rev-erbα (Nr1d1) mRNA levels. FSH also induced a major phase-advance shift of Per2 oscillations. The mature granulosa cells cultured for 2 days with FSH expressed higher mRNA levels of Per2, Rev-erbα, Bmal1 (Arnt1), Lhcgr, and connexin (Cx) 43 (Gja1) compared with the immature granulosa cells. Consistently, our immunofluorescence results revealed abundant Cx43 protein in antral follicles stimulated with eCG and weak or no fluorescence signal of Cx43 in primary and preantral follicles. Similar results were confirmed by Western blotting analysis. Two gap junction blockers, lindane and carbenoxolone (CBX), significantly decreased the amplitude of Per2 oscillations, which further adhered significant decreases in Per2 and Rev-erbα transcript levels. In addition, both lindane and CBX induced a clear phase-delay shift of Per2 oscillations. These findings suggest that FSH induces the development of the clock system by increasing the expression of Cx43.
- Published
- 2013
- Full Text
- View/download PDF
37. Contribution of FSH and triiodothyronine to the development of circadian clocks during granulosa cell maturation.
- Author
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Chu G, Misawa I, Chen H, Yamauchi N, Shigeyoshi Y, Hashimoto S, and Hattori MA
- Subjects
- Animals, Circadian Rhythm Signaling Peptides and Proteins biosynthesis, Circadian Rhythm Signaling Peptides and Proteins genetics, Culture Media, Serum-Free, Diethylstilbestrol pharmacology, Estrogens, Non-Steroidal pharmacology, Female, Genes, Reporter, Luminescence, Ovary cytology, Ovary growth & development, Period Circadian Proteins biosynthesis, Period Circadian Proteins genetics, RNA biosynthesis, RNA genetics, Rats, Real-Time Polymerase Chain Reaction, Transcription, Genetic physiology, Circadian Rhythm physiology, Follicle Stimulating Hormone physiology, Granulosa Cells physiology, Triiodothyronine physiology
- Abstract
The involvement of FSH and triiodothyronine (T(3)) in circadian clocks was investigated using immature granulosa cells of ovaries during the progress of cell maturation. Granulosa cells were prepared from preantral follicles of mouse Period2 (Per2)-dLuc reporter gene transgenic rats injected subcutaneously with the synthetic nonsteroidal estrogen diethylstilbestrol. Analysis of the cellular clock of the immature granulosa cells was performed partly using a serum-free culture system. Several bioluminescence oscillations of Per2-dLuc promoter activity were generated in the presence of FSH + fetal bovine serum, but not in the presence of either FSH or serum. As revealed by bioluminescence recording and analysis of clock gene expression, the granulosa cells lack the functional cellular clock at the immature stage, although Lhr was greatly expressed during the period of cell maturation. The granulosa cells gained a strong circadian rhythm of bioluminescence during stimulation with FSH, whereas LH reset the cellular clock of matured granulosa cells. During strong circadian rhythms of clock genes, the Star gene showed significant expression in matured granulosa cells. In contrast, T(3) showed an inhibitory effect on the development of the functional cellular clock during the period of cell maturation. These results indicate that FSH provides a cue for the development of the functional cellular clock of the immature granulosa cells, and T(3) blocks the development of the cellular clock.
- Published
- 2012
- Full Text
- View/download PDF
38. Real-time monitoring in three-dimensional hepatocytes reveals that insulin acts as a synchronizer for liver clock.
- Author
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Yamajuku D, Inagaki T, Haruma T, Okubo S, Kataoka Y, Kobayashi S, Ikegami K, Laurent T, Kojima T, Noutomi K, Hashimoto S, and Oda H
- Subjects
- Animals, Biological Clocks genetics, Blotting, Northern, Cell Culture Techniques, Cell Line, Cells, Cultured, Circadian Rhythm genetics, Circadian Rhythm physiology, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental physiopathology, Gene Expression drug effects, Gene Expression Profiling, Hepatocytes cytology, Hepatocytes drug effects, Hypoglycemic Agents metabolism, Hypoglycemic Agents pharmacology, Insulin pharmacology, Liver cytology, Liver drug effects, Luciferases genetics, Luciferases metabolism, Male, Oligonucleotide Array Sequence Analysis, Period Circadian Proteins genetics, Rats, Rats, Transgenic, Rats, Wistar, Biological Clocks physiology, Hepatocytes metabolism, Insulin metabolism, Liver metabolism
- Abstract
Resetting the peripheral clock and understanding the integration between the circadian rhythm and metabolic pathways are fundamental questions. To test whether insulin acts as a synchronizer for the hepatic clock by cell-autonomous mechanisms, the phase-resetting capabilities of insulin were investigated in cultured hepatic cells. We provide evidence that three-dimensional (3D) cell culture conditions that preserve the differentiated state of primary hepatocytes sustained the robustness of the molecular clock, while this robustness rapidly dampened under classical monolayer cell culture conditions. Herein, we established a 3D cell culture system coupled with a real-time luciferase reporter, and demonstrated that insulin directly regulates the phase entrainment of hepatocyte circadian oscillators. We found that insulin-deficient diabetic rats had a pronounced phase advance in their hepatic clock. Subsequently, a single administration of insulin induced phase-dependent bi-directional phase shifts in diabetic rat livers. Our results clearly demonstrate that insulin is a liver clock synchronizer.
- Published
- 2012
- Full Text
- View/download PDF
39. Angiopoietin-related growth factor suppresses gluconeogenesis through the Akt/forkhead box class O1-dependent pathway in hepatocytes.
- Author
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Kitazawa M, Ohizumi Y, Oike Y, Hishinuma T, and Hashimoto S
- Subjects
- Angiopoietin-Like Protein 6, Angiopoietin-like Proteins, Angiopoietins, Animals, Biological Factors physiology, Cell Line, Tumor, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Forkhead Transcription Factors antagonists & inhibitors, Glucose biosynthesis, Glucose-6-Phosphatase metabolism, Immunohistochemistry, Male, Nerve Tissue Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Rats, Rats, Wistar, Biological Factors pharmacology, Forkhead Transcription Factors physiology, Gluconeogenesis drug effects, Hepatocytes drug effects, Hepatocytes enzymology, Hepatocytes metabolism, Nerve Tissue Proteins physiology, Proto-Oncogene Proteins c-akt physiology, Recombinant Proteins pharmacology
- Abstract
Angiopoietin-related growth factor (AGF; or Angptl6) is a liver-derived, circulating factor and is considered to be a regulator of metabolic homeostasis. AGF is capable of counteracting both obesity and obesity-related insulin resistance. However, the target tissues and the molecular mechanisms underlying the antiobesity and antidiabetic actions of AGF have not been completely defined. Using rat hepatoma H4IIEc3 cells or primary hepatocytes, we demonstrate that AGF suppresses glucose production in a concentration-dependent manner through reduced expression of a key gluconeogenic enzyme, glucose-6-phosphatase (G6Pase), at both transcriptional and translational levels. The action of AGF on glucose production was inhibited by pretreatment of the cells with LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], a phosphoinositide 3-kinase (PI3K) inhibitor, and Akt (protein kinase B) inhibitors. AGF increased the phosphorylation of Akt and its substrates, glycogen synthase kinase 3beta and forkhead box class O1 (FoxO1), a key transcription factor for G6Pase expression. Furthermore, an immunohistochemical approach with anti-FoxO1 antibody demonstrated that AGF stimulation promoted translocation of FoxO1 from the nucleus to the cytoplasm in the cells. These results suggest that in hepatocytes, AGF suppresses gluconeogenesis via reduced transcriptional activity of FoxO1 resulting from the activation of PI3K/Akt signaling cascades.
- Published
- 2007
- Full Text
- View/download PDF
40. The disruption of circadian clockwork in differentiating cells from rat reproductive tissues as identified by in vitro real-time monitoring system.
- Author
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He PJ, Hirata M, Yamauchi N, Hashimoto S, and Hattori MA
- Subjects
- Animals, Animals, Genetically Modified, Cell Cycle Proteins metabolism, Cell Differentiation physiology, Cells, Cultured, Computer Systems, Corpus Luteum cytology, Female, Male, Nuclear Proteins metabolism, Period Circadian Proteins, Pregnancy, Promoter Regions, Genetic, RNA, Messenger analysis, Rats, Stromal Cells metabolism, Testis metabolism, Uterus metabolism, Biological Clocks genetics, Cell Cycle Proteins genetics, Gene Expression Regulation, Nuclear Proteins genetics
- Abstract
The circadian clock, regulating hormonal secretion and metabolisms in accordance with the environmental light-dark cycle, resides in almost all peripheral tissues as well as in the superchiasmatic nucleus. Clock gene expression has been found to be noncyclic during spermatogenesis and the differentiation of thymocytes. However, currently little is known about how cell differentiation could affect circadian clockwork. We performed this study using the in vitro real-time oscillation monitoring system to examine the clockwork in several types of differentiating cells originated from reproductive tissues of transgenic rats (constructed with Period gene 2 (Per2) promoter-destabilized luciferase reporter gene). After treatment with dexamethasone (DXM), persistent oscillation of Per2 expression was observed in both gonadotropin-induced and pregnant ovarian luteal cells, proliferative uterine stromal cells (USCs), and nondifferentiating testicular interstitial cells, with a cyclic period of ~24 h. In contrast to these cell types, only one cycle of oscillation was sustained in granulosa cells undergoing differentiation. Additionally, Per2 oscillation was irregular in USCs undergoing decidualization induced by medroxyprogesterone acetate plus N6, 2-O-dibutyryl adenosine 3':5'-cyclic monophosphate. Furthermore, no oscillation of Per2 expression was evoked by DXM in Leydig cells and thymocytes. In conclusion, the present study characterized the oscillation of Per2 gene expression in several types of ovarian, uterine, and testicular cells, and it is strongly suggested that circadian clockwork is affected during cellular differentiation.
- Published
- 2007
- Full Text
- View/download PDF
41. Proinsulin C-peptide stimulates a PKC/IkappaB/NF-kappaB signaling pathway to activate COX-2 gene transcription in Swiss 3T3 fibroblasts.
- Author
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Kitazawa M, Shibata Y, Hashimoto S, Ohizumi Y, and Yamakuni T
- Subjects
- Animals, Blotting, Western, Carbazoles pharmacology, Cyclooxygenase 2 genetics, Fibroblasts cytology, Fibroblasts drug effects, Fibroblasts metabolism, I-kappa B Proteins genetics, Indoles pharmacology, Luciferases genetics, Luciferases metabolism, Maleimides pharmacology, Mice, NF-kappa B antagonists & inhibitors, NF-kappa B genetics, Nitriles pharmacology, Phosphorylation drug effects, Plasmids genetics, Proinsulin chemistry, Promoter Regions, Genetic genetics, Protein Kinase C antagonists & inhibitors, Protein Kinase C genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Signal Transduction genetics, Sulfones pharmacology, Swiss 3T3 Cells, Transcription, Genetic drug effects, Transfection, C-Peptide pharmacology, Cyclooxygenase 2 metabolism, I-kappa B Proteins metabolism, NF-kappa B metabolism, Protein Kinase C metabolism
- Abstract
Proinsulin C-peptide causes multiple molecular and physiological effects, and improves renal and neuronal dysfunction in patients with diabetes. However, whether C-peptide controls the inhibitor kappaB (IkappaB)/NF-kappaB-dependent transcription of genes, including inflammatory genes is unknown. Here we showed that 1 nM C-peptide increased the expression of cyclooxygenase-2 (COX-2) mRNA and its protein in Swiss 3T3 fibroblasts. Consistently, C-peptide enhanced COX-2 gene promoter-activity, which was inhibited by GF109203X and Go6976, specific PKC inhibitors, and BAY11-7082, a specific nuclear factor-kappaB (NF-kappaB) inhibitor, accompanied by increased phosphorylation and degradation of IkappaB. These results suggest that C-peptide stimulates the transcription of inflammatory genes via activation of a PKC/IkappaB/NF-kappaB signaling pathway.
- Published
- 2006
- Full Text
- View/download PDF
42. System-level identification of transcriptional circuits underlying mammalian circadian clocks.
- Author
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Ueda HR, Hayashi S, Chen W, Sano M, Machida M, Shigeyoshi Y, Iino M, and Hashimoto S
- Subjects
- Animals, Cells, Cultured, Computational Biology, DNA-Binding Proteins genetics, G-Box Binding Factors, Gene Expression Regulation, Genes, Regulator, Genes, erbA, Genes, rev, Rats, Trans-Activators genetics, Transcription Factors genetics, Circadian Rhythm genetics, Transcription, Genetic
- Abstract
Mammalian circadian clocks consist of complexly integrated regulatory loops, making it difficult to elucidate them without both the accurate measurement of system dynamics and the comprehensive identification of network circuits. Toward a system-level understanding of this transcriptional circuitry, we identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of their transcriptional dynamics. Here we report the roles of E/E' boxes, DBP/E4BP4 binding elements and RevErbA/ROR binding elements in nine, seven and six genes, respectively. Our results indicate that circadian transcriptional circuits are governed by two design principles: regulation of E/E' boxes and RevErbA/ROR binding elements follows a repressor-precedes-activator pattern, resulting in delayed transcriptional activity, whereas regulation of DBP/E4BP4 binding elements follows a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Our analysis further suggests that regulation of E/E' boxes is a topological vulnerability in mammalian circadian clocks, a concept that has been functionally verified using in vitro phenotype assay systems.
- Published
- 2005
- Full Text
- View/download PDF
43. Genome-wide transcriptional orchestration of circadian rhythms in Drosophila.
- Author
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Ueda HR, Matsumoto A, Kawamura M, Iino M, Tanimura T, and Hashimoto S
- Subjects
- Animals, Chromosomes ultrastructure, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Circadian Rhythm genetics, Drosophila genetics, Genome, Oligonucleotide Array Sequence Analysis, Transcription, Genetic
- Abstract
Circadian rhythms govern the behavior, physiology, and metabolism of living organisms. Recent studies have revealed the role of several genes in the clock mechanism both in Drosophila and in mammals. To study how gene expression is globally regulated by the clock mechanism, we used a high density oligonucleotide probe array (GeneChip) to profile gene expression patterns in Drosophila under light-dark and constant dark conditions. We found 712 genes showing a daily fluctuation in mRNA levels under light-dark conditions, and among these the expression of 115 genes was still cycling in constant darkness, i.e. under free-running conditions. Unexpectedly the expression of a large number of genes cycled exclusively under constant darkness. We found that cycling in most of these genes was lost in the arrhythmic Clock (Clk) mutant under light-dark conditions. Expression of periodically regulated genes is coordinated locally on chromosomes where small clusters of genes are regulated jointly. Our findings reveal that many genes involved in diverse functions are under circadian control and reveal the complexity of circadian gene expression in Drosophila.
- Published
- 2002
- Full Text
- View/download PDF
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