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781.
Hosono K Ishigami C Takahashi M Park DH Hirami Y Nakanishi H Ueno S Yokoi T Hikoya A Fujita T Zhao Y Nishina S Shin JP Kim IT Yamamoto S Azuma N Terasaki H Sato M Kondo M Minoshima S Hotta Y 《PloS one》2012,7(2):e31036
Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease including autosomal recessive (ar), autosomal dominant (ad), and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog), which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation). Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2) and c.8868C>A (p.Y2956X), were identified in 16 patients and accounted for 57.1% (20/35 alleles) of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing and counseling of RP patients in Japan. 相似文献
782.
783.
Li Y Hamasaki T Teruya K Nakamichi N Gadek Z Kashiwagi T Yan H Kinjo T Komatsu T Ishii Y Shirahata S 《Cytotechnology》2012,64(3):281-297
Insulin-producing cells express limited activities of anti-oxidative enzymes. Therefore, reactive oxygen species (ROS) produced in these cells play a crucial role in cytotoxic effects. Furthermore, diabetes mellitus (DM) development is closely linked to higher ROS levels in insulin-producing cells. Hita Tenryosui Water® (Hita T. W., Hita, Japan) and Nordenau water (Nord. W., Nordenau, Germany), referred to as natural reduced waters (NRWs), scavenge ROS in cultured cells, and therefore, might be a possibility as an alternative to conventional pharmacological agents against DM. Therefore, this study aimed to investigate the role of NRWs in alloxan (ALX)-induced β-cell apoptosis as well as in ALX-induced diabetic mice. NRWs equally suppressed DNA fragmentation levels. Hita T. W. and Nord. W. ameliorated ALX-induced sub-G1 phase production from approximately 40% of control levels to 8.5 and 11.8%, respectively. NRWs restored serum insulin levels (p < 0.01) and reduced blood glucose levels (p < 0.01) in ALX-induced mice. Hita T. W. restored tissue superoxide dismutase (SOD) (p < 0.05) activity but not tissue catalase activity. Hita T. W. did not elevate SOD or catalase activity in HIT-T15 cells. Nord. W. restored SOD (p < 0.05) and catalase (p < 0.05) activity in both cultured cells and pancreatic tissue to normal levels. Even though variable efficacies were observed between Hita T. W. and Nord. W., both waters suppressed ALX-induced DM development in CD-1 male mice by administering NRWs for 8 weeks. Our results suggest that Hita T. W. and Nord. W. protect against ALX-induced β-cell apoptosis, and prevent the development of ALX-induced DM in experimental animals by regulating ALX-derived ROS generation and elevating anti-oxidative enzymes. Therefore, the two NRWs tested here are promising candidates for the prevention of DM development. 相似文献
784.
Byun EB Korematsu S Ishikawa T Nishizuka T Ohshima S Kanda T Matsui T 《The Journal of nutritional biochemistry》2012,23(3):278-286
Apple procyanidins (AP), one of the polyphenol-rich compounds, showed an endothelial-dependent vasorelaxation in rat aorta, but the mechanisms of beneficial effects are still unclear. The present study was designed to clarify the potential role of AP in rat aorta endothelial cells (RAECs). The treatment of RAECs with AP (1-10 μg/ml) resulted in a dose-dependent hyperpolarization with a maximum effect at 10 μg/ml, and for this reason, AP (10 μg/ml) was used in all the following experiments. AP-induced hyperpolarization was significantly inhibited by pretreatment of nonspecific K(+) inhibitor, tetraethyl ammonium chloride or specific K(+) channel inhibitors, iberiotoxin, glibenclamide, 4-aminopyridine and BaCl(2), as well as by high KCl or Ca(2+)-free solution. AP-induced hyperpolarization was also proved using 64-channel multielectrode dish system that can monitor a direct and real-time change of membrane potential. Furthermore, AP treatment caused a significant increase of nitric oxide (NO) production and cyclic guanosine monophosphate levels via endothelial NO synthase messenger RNA expression. The NO production was inhibited by N(G)-monoethyl-l-arginine or Ca(2+)-free solution and was completely abolished by their combination. Also, AP inhibited endothelial proliferation, while the effect was significantly abolished by N(G)-monoethyl-l-arginine or tetraethyl ammonium chloride. These findings suggest that AP induces both hyperpolarization of RAECs via multiple activation of K(+) channels and activation of NO/cyclic guanosine monophosphate pathway via increasing NO production or is responsible for antiangiogenic effect. Diminishment of hyperpolarization as well as NO production of AP in Ca(2+)-free solution implicated that AP would play a crucial role in promoting Ca(2+) influx into endothelial cells so as to promote both actions. 相似文献
785.
Tanaka S Saito Y Kunisawa J Kurashima Y Wake T Suzuki N Shultz LD Kiyono H Ishikawa F 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(12):6145-6155
Although physiological development of human lymphoid subsets has become well documented in humanized mice, in vivo development of human myeloid subsets in a xenotransplantation setting has remained unevaluated. Therefore, we investigated in vivo differentiation and function of human myeloid subsets in NOD/SCID/IL2rγ(null) (NSG) mouse recipients transplanted with purified lineage(-)CD34(+)CD38(-) cord blood hematopoietic stem cells. At 4-6 mo posttransplantation, we identified the development of human neutrophils, basophils, mast cells, monocytes, and conventional and plasmacytoid dendritic cells in the recipient hematopoietic organs. The tissue distribution and morphology of these human myeloid cells were similar to those identified in humans. After cytokine stimulation in vitro, phosphorylation of STAT molecules was observed in neutrophils and monocytes. In vivo administration of human G-CSF resulted in the recruitment of human myeloid cells into the recipient circulation. Flow cytometry and confocal imaging demonstrated that human bone marrow monocytes and alveolar macrophages in the recipients displayed intact phagocytic function. Human bone marrow-derived monocytes/macrophages were further confirmed to exhibit phagocytosis and killing of Salmonella typhimurium upon IFN-γ stimulation. These findings demonstrate the development of mature and functionally intact human myeloid subsets in vivo in the NSG recipients. In vivo human myelopoiesis established in the NSG humanized mouse system may facilitate the investigation of human myeloid cell biology including in vivo analyses of infectious diseases and therapeutic interventions. 相似文献
786.
Doi T Muraoka T Ohshiro T Matsuda D Yoshida M Takahashi T Omura S Tomoda H 《Bioorganic & medicinal chemistry letters》2012,22(1):696-699
A conformationally restricted oxazoline analog 7 was designed on the basis of a SAR study of beauveriolide III (2) and its analogs reported previously. Conformational analysis by molecular mechanics calculation suggested that the three side chains of 7 mostly occupy the same spaces as those of 2. The analog 7 was synthesized by peptide coupling of the d-cyclohexylglycine-containing ester 11 and d-Ser-containing dipeptide 12, macrolactamization, and cyclodehydration of 6 for the construction of an oxazoline ring. The bicyclic 7 exhibited potential inhibitory activity for cholesteryl ester synthesis similar to that by 2. These results revealed biologically important 3D spaces of the three side chains in inhibitory activity for cholesteryl ester synthesis. In addition, we accomplished the synthesis of a biotin-labeled probe 8 by copper-catalyzed (3+2) cycloaddition of a biotin-containing alkyne 16 and azido-containing beauveriolide analog 15 prepared from 6. 相似文献
787.
788.
Imaoka S Muraguchi T Kinoshita T 《Biochemical and biophysical research communications》2007,355(2):419-425
Hypoxia is an important physiological condition during embryonic development. Hypoxia-inducible factor (HIF) is the mediator of hypoxic response of cells. The prolyl hydroxylase (PHD) of HIF plays a key role in stabilizing of HIF and the oxygen homeostasis of organisms. In this study, we isolated two PHD proteins, PHD45 and PHD28, and characterized them during the embryonic development of Xenopus laevis, which is an excellent model for embryonic development because of the ease of embryonic manipulation and the feasibility of transgenesis. Based on amino acid sequences, Xenopus PHD45 and PHD28 were homologous with human PHD2 and PHD3, respectively. In embryonic development, PHD45 expression was complementary to that of PHD28. xHIF-1alpha protein level was at a maximum around stage 20 when expression of PHD45 disappeared, while expression of PHD28 reached a maximum at stage 20, suggesting that PHD28 is inducible by HIF-1alpha. Recently, Siah2 was found to be an ubiquitin ligase of PHD proteins and to regulate degradation of PHD proteins. Over-expression of xSiah2 decreased PHD45 but not PHD28 and caused the small-eye phenotype of Xenopus. Additional over-expression of PHD47 rescued the abnormality caused by xSiah2, suggesting that the level of expression or activity of PHD proteins is important to the maintenance of homeostasis in embryonic development. 相似文献
789.
790.
Kazuyuki Akasaka Akihiro Maeno Taichi Murayama Hideki Tachibana Yuzo Fujita Hitoki Yamanaka 《朊病毒》2014,8(4):314-318
The crucial step for the fatal neurodegenerative prion diseases involves the conversion of a normal cellular protein, PrPC, into a fibrous pathogenic form, PrPSc, which has an unusual stability against heat and resistance against proteinase K digestion. A successful challenge to reverse the reaction from PrPSc into PrPC is considered valuable, as it would give a key to dissolving the complex molecular events into thermodynamic and kinetic analyses and may also provide a means to prevent the formation of PrPSc from PrPC eventually in vivo. Here we show that, by applying pressures at kbar range, the “proteinase K-resistant” fibrils (rHaPrPres) prepared from hamster prion protein (rHaPrP [23–231]) by seeding with brain homogenate of scrapie-infected hamster, becomes easily digestible. The result is consistent with the notion that rHaPrPres fibrils are dissociated into rHaPrP monomers under pressure and that the formation of PrPSc from PrPC is thermodynamically controlled. Moreover, the efficient degradation of prion fibrils under pressure provides a novel means of eliminating infectious PrPSc from various systems of pathogenic concern. 相似文献