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101.
Yoriko Yukitatsu Masaki Hata Koji Yamanegi Naoko Yamada Hideki Ohyama Keiji Nakasho Yusuke Kojima Hideki Oka Kenzo Tsuzuki Masafumi Sakagami Nobuyuki Terada 《Cell and tissue research》2013,352(3):647-657
VE-cadherin and claudin-5 are major components of adherens and tight junctions of vascular endothelial cells and a decrease in their expression and an increase in the tyrosine-phosphorylation of VE-cadherin are associated with an increase in endothelial paracellular permeability. To clarify the mechanism underlying the development of edema in nasal polyps, we studied these molecules in polyp microvessels. Normal inferior turbinate mucosal tissues and nasal polyps from patients treated with or without glucocorticoid were stained for VE-cadherin or claudin-5 and CD31 by a double-immunofluorescence method and the immunofluorescence intensities were graded 1–3 with increasing intensity. To correct for differences in fluorescence intensity attributable to a different endothelial area being exposed in a section or to the thickness of a section, the relative immunofluorescence intensity was estimated by dividing the grade of VE-cadherin or claudin-5 by that of CD31 in each microvessel. Tyrosine-phosphorylation of VE-cadherin was examined by Western blot analysis. The relative intensities of VE-cadherin and claudin-5 in the CD31-positive microvessels significantly decreased in the following order; inferior turbinate mucosa, treated polyps and untreated polyps. The ratio of tyrosine-phosphorylated VE-cadherin to VE-cadherin was significantly higher in untreated polyps than in the inferior turbinate mucosa and treated polyps, between which no significant difference in the ratio was seen. Thus, in nasal polyps, the barrier function of endothelial adherens and tight junctions is weakened, although glucocorticoid treatment improves this weakened barrier function. 相似文献
102.
Ryotaro Nishi Wataru Sakai Daisuke Tone Fumio Hanaoka Kaoru Sugasawa 《Nucleic acids research》2013,41(14):6917-6929
Centrin-2 is an evolutionarily conserved, calmodulin-related protein, which is involved in multiple cellular functions including centrosome regulation and nucleotide excision repair (NER) of DNA. Particularly to exert the latter function, complex formation with the XPC protein, the pivotal NER damage recognition factor, is crucial. Here, we show that the C-terminal half of centrin-2, containing two calcium-binding EF-hand motifs, is necessary and sufficient for both its localization to the centrosome and interaction with XPC. In XPC-deficient cells, nuclear localization of overexpressed centrin-2 largely depends on co-overexpression of XPC, and mutational analyses of the C-terminal domain suggest that XPC and the major binding partner in the centrosome share a common binding surface on the centrin-2 molecule. On the other hand, the N-terminal domain of centrin-2 also contains two EF-hand motifs but shows only low-binding affinity for calcium ions. Although the N-terminal domain is dispensable for enhancement of the DNA damage recognition activity of XPC, it contributes to augmenting rather weak physical interaction between XPC and XPA, another key factor involved in NER. These results suggest that centrin-2 may have evolved to bridge two protein factors, one with high affinity and the other with low affinity, thereby allowing delicate regulation of various biological processes. 相似文献
103.
104.
Michio Nakamura Nadia Corp Mariko Fujimoto Shiho Fujita Shunkichi Hanamura Hitoshige Hayaki Kazuhiko Hosaka Michael A. Huffman Agumi Inaba Eiji Inoue Noriko Itoh Nobuyuki Kutsukake Mieko Kiyono-Fuse Takanori Kooriyama Linda F. Marchant Akiko Matsumoto-Oda Takahisa Matsusaka William C. McGrew John C. Mitani Hitonaru Nishie Koshi Norikoshi Tetsuya Sakamaki Masaki Shimada Linda A. Turner James V. Wakibara Koichiro Zamma 《Primates; journal of primatology》2013,54(2):171-182
We have analyzed the ranging patterns of the Mimikire group (M group) of chimpanzees in the Mahale Mountains National Park, Tanzania. During 16 years, the chimpanzees moved over a total area of 25.2 or 27.4 km2, as estimated by the grid-cell or minimum convex polygon (MCP) methods, respectively. Annually, the M group used an average of 18.4 km2, or approximately 70 %, of the total home-range area. The chimpanzees had used 80 % of their total home range after 5 years and 95 % after 11 years. M group chimpanzees were observed more than half of the time in areas that composed only 15 % of their total home range. Thus, they typically moved over limited areas, visiting other parts of their range only occasionally. On average, the chimpanzees used 7.6 km2 (in MCP) per month. Mean monthly range size was smallest at the end of the rainy season and largest at the end of the dry season, but there was much variability from year to year. The chimpanzees used many of the same areas every year when Saba comorensis fruits were abundant between August and January. In contrast, the chimpanzees used several different areas of their range in June. Here range overlap between years was relatively small. Over the 16 years of the study we found that the M group reduced their use of the northern part of their range and increased their frequency of visits to the eastern mountainous side of their home range. Changes in home-range size correlated positively with the number of adult females but not with the number of adult males. This finding does not support a prediction of the male-defended territory model proposed for some East African chimpanzee unit-groups. 相似文献
105.
Yuriko Furuya Atsushi Inagaki Masud Khan Kaoru Mori Josef M. Penninger Midori Nakamura Nobuyuki Udagawa Kazuhiro Aoki Keiichi Ohya Kohji Uchida Hisataka Yasuda 《The Journal of biological chemistry》2013,288(8):5562-5571
To date, parathyroid hormone is the only clinically available bone anabolic drug. The major difficulty in the development of such drugs is the lack of clarification of the mechanisms regulating osteoblast differentiation and bone formation. Here, we report a peptide (W9) known to abrogate osteoclast differentiation in vivo via blocking receptor activator of nuclear factor-κB ligand (RANKL)-RANK signaling that we surprisingly found exhibits a bone anabolic effect in vivo. Subcutaneous administration of W9 three times/day for 5 days significantly augmented bone mineral density in mouse cortical bone. Histomorphometric analysis showed a decrease in osteoclastogenesis in the distal femoral metaphysis and a significant increase in bone formation in the femoral diaphysis. Our findings suggest that W9 exerts bone anabolic activity. To clarify the mechanisms involved in this activity, we investigated the effects of W9 on osteoblast differentiation/mineralization in MC3T3-E1 (E1) cells. W9 markedly increased alkaline phosphatase (a marker enzyme of osteoblasts) activity and mineralization as shown by alizarin red staining. Gene expression of several osteogenesis-related factors was increased in W9-treated E1 cells. Addition of W9 activated p38 MAPK and Smad1/5/8 in E1 cells, and W9 showed osteogenesis stimulatory activity synergistically with BMP-2 in vitro and ectopic bone formation. Knockdown of RANKL expression in E1 cells reduced the effect of W9. Furthermore, W9 showed a weak effect on RANKL-deficient osteoblasts in alkaline phosphatase assay. Taken together, our findings suggest that this peptide may be useful for the treatment of bone diseases, and W9 achieves its bone anabolic activity through RANKL on osteoblasts accompanied by production of several autocrine factors. 相似文献
106.
Zhe Nie Victoria Feher Srinivasa Natala Christopher McBride Andre Kiryanov Benjamin Jones Betty Lam Yan Liu Stephen Kaldor Jeffrey Stafford Kouki Hikami Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Shin-ichi Matsumoto Nobuyuki Amano Lilly Zhang David Hosfield Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2013,23(12):3662-3666
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. 相似文献
107.
Yuusuke Tamura Kyouhei Hayashi Naoki Omori Yuji Nishiura Kana Watanabe Nobuyuki Tanaka Masahiko Fujioka Naoki Kouyama Akira Yukimasa Yukari Tanaka Takeshi Chiba Hideki Tanioka Hirohide Nambu Hideo Yukioka Hiroki Sato Takayuki Okuno 《Bioorganic & medicinal chemistry letters》2013,23(1):90-95
Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain. 相似文献
108.
Yuji Nakamura Teppei Fujimoto Yasuyuki Ogawa Hidenori Namiki Sayaka Suzuki Masayoshi Asano Chie Sugita Akiyoshi Mochizuki Shojiro Miyazaki Kazuhiko Tamaki Yoko Nagai Shin-ichi Inoue Takahiro Nagayama Mikio Kato Katsuyoshi Chiba Kiyoshi Takasuna Takahide Nishi 《Bioorganic & medicinal chemistry》2013,21(11):3175-3196
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure–activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h. 相似文献
109.
Nobuyuki Yamasaki Tomomitsu Hatakeyama Hideki Ohba Gunki Funatsu 《Bioscience, biotechnology, and biochemistry》2013,77(8):2227-2232
Chemical modification of tryptophan residues in ricin E was investigated with regard to saccharide-binding. Two out of ten tryptophan residues in ricin E were modified with N- bromosuccinimide at pH 4.5 in the absence of specific saccharide accompanied by a marked decrease in the cytoagglutinating activity. Such a loss of the cytoagglutinating activity was found to be principally due to the oxidation of one tryptophan residue per B-chain. In the presence of lactose, one tryptophan residue/mol was protected from the modification with retention of a fairly high cytoagglutinating activity. However, G a IN Ac did not show such a protective effect. The binding of lactose to ricin E altered the environment of the tryptophan residue at the low affinity binding site of ricin E, leading to a blue shift of the fluorescence spectrum and an UV-difference spectrum with a maximum at 290 nm and a trough at 300 nm. The ability to generate such spectroscopic changes induced by lactose was retained in the derivative in which one tryptophan residue/mol was oxidized in the presence of lactose, but not in the derivative in which two tryptophan residues/mol were oxidized in the absence of lactose. Based on these results, it is suggested that one of the two surface-localized tryptophan residues is responsible for saccharide binding at the low affinity binding site of ricin E, which can bind lactose but lacks the ability to bind GalNAc. 相似文献
110.
Hidehiko Yokogoshi Shouichi Tani Nobuyuki Amano 《Bioscience, biotechnology, and biochemistry》2013,77(12):3281-3286
Caffeine and caffeine-containing beverages (instant coffee, black tea, green tea, or oolong tea) caused a significant decrease in serum tryptophan, and significant increases in brain tryptophan, serotonin, and 5-hydroxyindole acetic acid over those in rats fed a control diet. Adenosine supplementation partially counteracted the increase of brain serotonin caused by caffeine. These results are interpreted as indicating that caffeine-containing beverages may have some nutritional and behavioral effects. 相似文献