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991.
The ATR-Chk1 pathway plays a role in the generation of centrosome aberrations induced by Rad51C dysfunction 下载免费PDF全文
Mari Katsura Takanori Tsuruga Osamu Date Takashi Yoshihara Mari Ishida Yoshitaka Tomoda Miyuki Okajima Motoki Takaku Hitoshi Kurumizaka Aiko Kinomura Hiromu K. Mishima Kiyoshi Miyagawa 《Nucleic acids research》2009,37(12):3959-3968
Rad51C is a central component of two complexes formed by five Rad51 paralogs in vertebrates. These complexes are involved in repairing DNA double-strand breaks through homologous recombination. Despite accumulating evidence suggesting that the paralogs may prevent aneuploidy by controlling centrosome integrity, Rad51C's role in maintaining chromosome stability remains unclear. Here we demonstrate that Rad51C deficiency leads to both centrosome aberrations in an ATR-Chk1-dependent manner and increased aneuploidy in human cells. While it was reported that Rad51C deficiency did not cause centrosome aberrations in interphase in hamster cells, such aberrations were observed in interphase in HCT116 cells with Rad51C dysfunction. Caffeine treatment and down-regulation of ATR, but not that of ATM, reduced the frequency of centrosome aberrations in the mutant cells. Silencing of Rad51C by RNA interference in HT1080 cells resulted in similar aberrations. Treatment with a Chk1 inhibitor and silencing of Chk1 also reduced the frequency in HCT116 mutants. Accumulation of Chk1 at the centrosome and nuclear foci of γH2AX were increased in the mutants. Moreover, the mutant cells had a higher frequency of aneuploidy. These findings indicate that the ATR-Chk1 pathway plays a role in increased centrosome aberrations induced by Rad51C dysfunction. 相似文献
992.
Yuasa T Sato K Ashihara E Takeuchi M Maita S Tsuchiya N Habuchi T Maekawa T Kimura S 《Cancer immunology, immunotherapy : CII》2009,58(4):493-502
Background Superficial bladder cancers are usually managed with transurethral resection followed by the intravesical administration of
Bacillus Calmette-Guerin which requires major histocompatibility complex (MHC) class I expression on cancer cells. Since cancer
cells often loose MHC expression, a novel immunotherapy such as MHC-unrestricted γδ T cell therapy is desired.
Objective To clarify the relationship between the expression of MHC class I and clinicopathological features in bladder cancer patients,
and investigate the effects of the administration of intravesical γδ T cells on bladder cancer.
Methods Samples from 123 patients who had undergone either transurethral resection or radical cystectomies were examined for MHC expression
and the relationship between this and the clinicopathological features was analyzed statistically. The in vitro and in vivo
effects of γδ T cells expanded by zoledronic acid (ZOL) against several types of cancer cell line and an orthotopic bladder
cancer murine model which was pretreated with ZOL were investigated.
Results MHC-diminished superficial bladder cancer was significantly more progressive than MHC-conservative bladder cancer (P = 0.047). In addition, there was a significant association between diminished MHC expression and poor disease free survival
(P = 0.041) and overall survival (P = 0.018) after radical cystectomy. In vitro, all of the cell lines pretreated with 5-μM ZOL showed a marked increase in sensitivity
to lysis by γδ T cells. Moreover, intravesical administration of γδ T cells with 5-μM ZOL significantly demonstrated antitumor
activity against bladder cancer cells in the orthotopic murine model (P < 0.001), resulting in prolonged survival.
Conclusion The present murine model provides a potentially interesting option to develop immunotherapy using γδ T cells for bladder cancer
in human.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
T. Yuasa and K. Sato contributed equally to the study. 相似文献
993.
Tanikawa M Kim TS Okuda K Ryoo ZY Park SB Shin JH Park CK Lee DS 《Animal reproduction science》2009,114(1-3):32-42
Interleukin (IL)-1alpha is a potent stimulator of prostaglandin production in bovine endometrium, and IL-1 affects plasminogen activator (PA) activity in several types of cells. In this study, we determined the effects of IL-1alpha and IL-1beta on production of the prostaglandins PGF(2alpha) and PGE(2) and on PA activity in cultured bovine endometrial epithelial and stromal cells. We also determined the effects of PGE(2) and PGF(2alpha) on PA activity in these cells. Finally, we used RT-PCR to examine the expression of IL-1alpha, IL-1beta, and IL-1 receptor type 1 (IL-1R) mRNA in cultured bovine endometrial cells. This analysis revealed that IL-1alpha mRNA was present only in the stromal cells, whereas IL-1beta and IL-1R mRNAs were present in both cell types. When cultured cells were exposed to IL-1alpha and IL-1beta at concentrations ranging from 0.006 to 3 nM for 24h, IL-1alpha and IL-1beta were found to dose-dependently stimulate PGE(2) and PGF(2alpha) production in stromal cells (P<0.05) but not in epithelial cells. On the other hand, exposure to IL-1alpha and IL-1beta dose-dependently increased PA activity in the epithelial cells, whereas neither stimulated PA production in the stromal cells. When cells were exposed to IL-1alpha and IL-1beta at concentrations ranging from 0.06 to 3 nM for 24h, the two IL-1s differed in their effects on both PGE(2) and PGF(2alpha) production in stromal cells and had significantly differed in their effects on PA activity in epithelial cells. Exposure to PGE(2) and PGF(2alpha) did not affect PA activity in either stromal or epithelial cells (P>0.05). Taken together, these results suggest the possibility that both IL-1alpha and IL-1beta are produced by the stromal cells, that IL-1beta is produced by the epithelial cells, and that IL-1alpha is a far more potent stimulator than IL-1beta of prostaglandin and PA production in cultured bovine endometrial epithelial and stromal cells. 相似文献
994.
Tetsuro Yoshida Kimihiko Kato Tetsuo Fujimaki Kiyoshi Yokoi Mitsutoshi Oguri Sachiro Watanabe Norifumi Metoki Hidemi Yoshida Kei Satoh Yukitoshi Aoyagi Yutaka Nishigaki Masashi Tanaka Yoshinori Nozawa Yoshiji Yamada 《Genomics》2009,93(3):221-226
The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease (CKD) in Japanese individuals with metabolic syndrome. The study population comprised 2150 Japanese individuals with metabolic syndrome, including 411 subjects with CKD [estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m2] and 1739 controls (eGFR ≥ 60 mL/min/1.73m2). The genotypes for 100 polymorphisms of 80 candidate genes were determined. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that nine polymorphisms of APOE, ABCA1, PTGS1, TNF, CPB2, AGTR1, OR13G1, and GNB3 were associated (P < 0.05) with the prevalence of CKD. Among these polymorphisms, the ? 219G → T polymorphism of APOE (rs405509) was most significantly associated with CKD in Japanese individuals with metabolic syndrome. 相似文献
995.
Life cycle inventory analysis on Bio-DME and/or Bio-MeOH products through BLUE tower process 总被引:1,自引:0,他引:1
Background, aims, and scope
In this study, we focused on the biomass di-methyl ether (Bio-DME) and the biomass methanol (Bio-MeOH) in BTL (Biomass to Liquid) fuels which might bring a solution on an energy storage and/or CO2 emissions abatement. For these fuels, our object is to estimate CO2 emissions and energy intensities (the specific energy consumption in each sub-process) for the biomass liquefaction system, which is expanded to material’s transportation, energy conversion and fuel transportation in detail. 相似文献996.
997.
Satoshi Niizuma Masao Tsukazaki Hitomi Suda Takeshi Murata Jun Ohwada Sawako Ozawa Hiroshi Fukuda Chikako Murasaki Masami Kohchi Kenji Morikami Kiyoshi Yoshinari Mika Endo Masako Ura Hiromi Tanimura Yoko Miyazaki Tsuyoshi Takasuka Akira Kawashima Eitaro Nanba Kounosuke Nakano Kotaro Ogawa Nobuo Shimma 《Bioorganic & medicinal chemistry letters》2009,19(7):2018-2021
Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines. 相似文献
998.
Kiyoshi Kikuchi Ko-ichi Kawahara Kamal Krishna Biswas Salunya Tancharoen Fumiyo Matsuda Kazunori Takenouchi Noboru Arimura Xiaojie Meng Shinichiro Arimura Kentaro Mera Yoshiko Ohno Yoshihiro Yoshida Hisaaki Uchikado Kenji Nakayama Teruto Hashiguchi 《Biochemical and biophysical research communications》2009,385(2):132-136
High mobility group box-1 (HMGB1), a non-histone DNA-binding protein, is massively released into the extracellular space from neuronal cells after ischemic insult and exacerbates brain tissue damage in rats. Minocycline is a semisynthetic second-generation tetracycline antibiotic which has recently been shown to be a promising neuroprotective agent. In this study, we found that minocycline inhibited HMGB1 release in oxygen-glucose deprivation (OGD)-treated PC12 cells and triggered the activation of p38mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK1/2). The ERK kinase (MEK)1/2 inhibitor U-0126 and p38MAPK inhibitor SB203580 blocked HMGB1 release in response to OGD. Furthermore, HMGB1 triggered cell death in a dose-dependent fashion. Minocycline significantly rescued HMGB1-induced cell death in a dose-dependent manner. In light of recent observations as well as the good safety profile of minocycline in humans, we propose that minocycline might play a potent neuroprotective role through the inhibition of HMGB1-induced neuronal cell death in cerebral infarction. 相似文献
999.
We identified a gene encoding a novel secreted protein in mice, humans, and zebrafish. As the protein of 222 amino acids is similar to Brorin, a secreted BMP antagonist, which is a member of the Chordin family, we named it Brorin-like. Recombinant Brorin-like protein weakly but significantly inhibited the activity of BMP in mouse preosteoblastic cells and promoted neurogenesis in mouse neural precursor cells. Brorin-like was predominantly expressed in the adult brain and embryonic neural tissues. The inhibition of Brorin-like functions in zebrafish resulted in the impairment of neural development. Brorin-like potentially plays roles in neural development and functions. 相似文献
1000.
Christophe Bodenreider David Beer Thomas H. Keller Sebastian Sonntag Daying Wen LiJian Yap Yin Hoe Yau Susana Geifman Shochat Danzhi Huang Ting Zhou Amedeo Caflisch Xun-Cheng Su Kiyoshi Ozawa Gottfried Otting Subhash G. Vasudevan Julien Lescar Siew Pheng Lim 《Analytical biochemistry》2009,395(2):195-204
In drug discovery, the occurrence of false positives is a major hurdle in the search for lead compounds that can be developed into drugs. A small-molecular-weight compound that inhibits dengue virus protease at low micromolar levels was identified in a screening campaign. Binding to the enzyme was confirmed by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). However, a structure–activity relationship study that ensued did not yield more potent leads. To further characterize the parental compound and its analogues, we developed a high-speed, low-cost, quantitative fluorescence quenching assay. We observed that specific analogues quenched dengue protease fluorescence and showed variation in IC50 values. In contrast, nonspecifically binding compounds did not quench its fluorescence and showed similar IC50 values with steep dose–response curves. We validated the assay using single Trp-to-Ala protease mutants and the competitive protease inhibitor aprotinin. Specific compounds detected in the binding assay were further analyzed by competitive ITC, NMR, and surface plasmon resonance, and the assay’s utility in comparison with these biophysical methods is discussed. The sensitivity of this assay makes it highly useful for hit finding and validation in drug discovery. Furthermore, the technique can be readily adapted for studying other protein–ligand interactions. 相似文献