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131.
Stefan C. Genet Yoshihiro Fujii Junko Maeda Masami Kaneko Matthew D. Genet Kiyoshi Miyagawa Takamitsu A. Kato 《Journal of cellular physiology》2013,228(7):1473-1481
Hyperthermia has long been known as a radio‐sensitizing agent that displays anti‐tumor effects, and has been developed as a therapeutic application. The mechanisms of hyperthermia‐induced radio‐sensitization are highly associated with inhibition of DNA repair. Our investigations aimed to show how hyperthermia inactivate homologous recombination repair in the process of sensitizing cells to ionizing radiation by using a series of DNA repair deficient Chinese Hamster cells. Significant differences in cellular toxicity attributable to hyperthermia at and above 42.5°C were observed. In wild‐type and non‐homologous end joining repair mutants, cells in late S phase showed double the amount heat‐induced radio‐sensitization effects of G1‐phase cells. Both radiation‐induced DNA double strand breaks and chromatin damage resulting from hyperthermia exposure was measured to be approximately two times higher in G2‐phase cells than G0/G1 cells. Additionally, G2‐phase cells took approximately two times as long to repair DNA damage over time than G0/G1‐phase cells. To supplement these findings, radiation‐induced Rad51 foci formations at DNA double strand break sites were observed to gradually dissociate in response to the temperature and time of hyperthermia exposure. Dissociated Rad51 proteins subsequently re‐formed foci at damage sites with time, and occurred in a trend also related to temperature and time of hyperthermia exposure. These findings suggest Rad51's dissociation and subsequent reformation at DNA double strand break sites in response to varying hyperthermia conditions plays an important role in hyperthermia‐induced radio‐sensitization. J. Cell. Physiol. 228: 1473–1481, 2013. © 2012 Wiley Periodicals, Inc. 相似文献
132.
Yuki Matsushita Kei Sakamoto Yoshihiro Tamamura Yasuaki Shibata Tokutaro Minamizato Tasuku Kihara Masako Ito Ken-ichi Katsube Shuichi Hiraoka Haruhiko Koseki Kiyoshi Harada Akira Yamaguchi 《The Journal of biological chemistry》2013,288(27):19973-19985
CCN3, a member of the CCN protein family, inhibits osteoblast differentiation in vitro. However, the role of CCN3 in bone regeneration has not been well elucidated. In this study, we investigated the role of CCN3 in bone regeneration. We identified the Ccn3 gene by microarray analysis as a highly expressed gene at the early phase of bone regeneration in a mouse bone regeneration model. We confirmed the up-regulation of Ccn3 at the early phase of bone regeneration by RT-PCR, Western blot, and immunofluorescence analyses. Ccn3 transgenic mice, in which Ccn3 expression was driven by 2.3-kb Col1a1 promoter, showed osteopenia compared with wild-type mice, but Ccn3 knock-out mice showed no skeletal changes compared with wild-type mice. We analyzed the bone regeneration process in Ccn3 transgenic mice and Ccn3 knock-out mice by microcomputed tomography and histological analyses. Bone regeneration in Ccn3 knock-out mice was accelerated compared with that in wild-type mice. The mRNA expression levels of osteoblast-related genes (Runx2, Sp7, Col1a1, Alpl, and Bglap) in Ccn3 knock-out mice were up-regulated earlier than those in wild-type mice, as demonstrated by RT-PCR. Bone regeneration in Ccn3 transgenic mice showed no significant changes compared with that in wild-type mice. Phosphorylation of Smad1/5 was highly up-regulated at bone regeneration sites in Ccn3 KO mice compared with wild-type mice. These results indicate that CCN3 is up-regulated in the early phase of bone regeneration and acts as a negative regulator for bone regeneration. This study may contribute to the development of new strategies for bone regeneration therapy. 相似文献
133.
Kazuyuki Nakamura Hirofumi Kodera Tenpei Akita Masaaki Shiina Mitsuhiro Kato Hideki Hoshino Hiroshi Terashima Hitoshi Osaka Shinichi Nakamura Jun Tohyama Tatsuro Kumada Tomonori Furukawa Satomi Iwata Takashi Shiihara Masaya Kubota Satoko Miyatake Eriko Koshimizu Kiyomi Nishiyama Mitsuko Nakashima Yoshinori Tsurusaki Noriko Miyake Kiyoshi Hayasaka Kazuhiro Ogata Atsuo Fukuda Naomichi Matsumoto Hirotomo Saitsu 《American journal of human genetics》2013
134.
Takayuki Manabe Mayu KatoTakayuki Ueno Kiyoshi Kawasaki 《Biochemical and biophysical research communications》2013
Gram-negative bacteria, including Escherichia coli, release outer membrane vesicles (OMVs) that are derived from the bacterial outer membrane. OMVs contribute to bacterial cell–cell communications and host–microbe interactions by delivering components to locations outside the bacterial cell. In order to explore the molecular machinery involved in OMV biogenesis, the role of a major OMV protein was examined in the production of OMVs from E. coli W3110, which is a widely used standard E. coli K-12 strain. In addition to OmpC and OmpA, which are used as marker proteins for OMVs, an analysis of E. coli W3110 OMVs revealed that they also contain abundant levels of FliC, which is also known as flagellin. A membrane-impermeable biotin-labeling reagent did not label FliC in intact OMVs, but labeled FliC in sonically disrupted OMVs, suggesting that FliC is localized in the lumen of OMV. Compared to the parental strain expressing wild-type fliC, an E. coli strain with a fliC-null mutation produced reduced amounts of OMVs based on both protein and phosphate levels. In addition, an E. coli W3110-derived strain with a null-mutation in flgK, which encodes flagellar hook-associated protein that is essential along with FliC for flagella synthesis, also produced fewer OMVs than the parental strain. Taken together, these results indicate that the ability to form flagella, including the synthesis of flagella proteins, affects the production of E. coli W3110 OMVs. 相似文献
135.
Toshihiro Aoki Ikumi Hyohdoh Noriyuki Furuichi Sawako Ozawa Fumio Watanabe Masayuki Matsushita Masahiro Sakaitani Kazutomo Ori Kenji Takanashi Naoki Harada Yasushi Tomii Mitsuyasu Tabo Kiyoshi Yoshinari Yuko Aoki Nobuo Shimma Hitoshi Iikura 《Bioorganic & medicinal chemistry letters》2013,23(23):6223-6227
Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC50 = 8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50 = 4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment 相似文献
136.
Kentaro Takai Yasunao Inoue Yasuko Konishi Atsushi Suwa Yoshiharu Uruno Harumi Matsuda Tomokazu Nakako Mutsuko Sakai Hiroyuki Nishikawa Gakuji Hashimoto Takeshi Enomoto Atsushi Kitamura Yasuaki Uematsu Akihiko Kiyoshi Takaaki Sumiyoshi 《Bioorganic & medicinal chemistry letters》2013,23(16):4644-4647
We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M1 and M4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats. 相似文献
137.
138.
Keiji Saito Akira Nakao Tsuyoshi Shinozuka Kousei Shimada Satoshi Matsui Kiyoshi Oizumi Kazuki Yano Keiko Ohata Daisuke Nakai Yoko Nagai Satoru Naito 《Bioorganic & medicinal chemistry》2013,21(7):1628-1642
A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4-phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6 weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10 mg/kg/day. 相似文献
139.
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
140.
Wataru Ohira Kiyoshi Honda Masahiko Nagai Anuchit Ratanasuwan 《Trees - Structure and Function》2013,27(1):141-148
The submerged tree volume and the projection area of mangroves play a significant role in damping tsunami inundation flow with a distinct root formation above ground. We modeled the stilt root morphology of the Rhizophora sp., especially to incorporate into a hydraulic drag of tsunami inundation simulation. The equivalent Manning’s roughness coefficient has been used as the hydraulic drag of mangroves for the computation of inundation flow [Yanagisawa et al. (Coast Shelf Sci 81: 27–37, 2009)], but it could not elucidate the effectiveness under different tree conditions. The field data from 18 sample trees in Ranong Province, Thailand, were measured. The total number of primary roots, the root height at trunk, and the root-spread distance, the root diameter, and the vertical root angle from trunk could be estimated with the diameter of the breast height. The quadratic equation expressed the root curve of the primary stilt root, and functions to estimate root volume and projected area were derived by the integration of the equation that will be used to calculate drag force in tsunami simulation. 相似文献