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91.
Yan P Nanamori M Sun M Zhou C Cheng N Li N Zheng W Xiao L Xie X Ye RD Wang MW 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(10):7050-7058
Cyclosporin A (CsA) is a fungus-derived cyclic undecapeptide with potent immunosuppressive activity. Its analog, cyclosporin H (CsH), lacks immunosuppressive function but can act as an antagonist for the human formyl peptide receptor (FPR). More recent studies have shown that CsA also inhibits fMLF-induced degranulation in differentiated HL-60 promyelocytic leukemia cells. However, it is unclear whether CsA interferes with ligand-receptor interaction, G protein activation, or other downstream signaling events. In this study we used human neutrophils, differentiated HL-60 cells, and rat basophilic leukemia (RBL)-2H3 cells expressing human FPR (RBL-FPR) to identify the action site of CsA. In functional assays, CsA inhibited fMLF-stimulated degranulation, chemotaxis, calcium mobilization, and phosphorylation of the MAPKs ERK 1/2 and the serine/threonine protein kinase Akt. CsA also blocked Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm)-induced functions in RBL-FPR cells. Concentrations for half-maximal inhibition with CsA are generally 6- to 50-fold higher than that of CsH. CsA was compared with another immunosuppressant, ascomycin, relative to the inhibitory effects on FPR-mediated chemotaxis, calcium mobilization, and degranulation. In these experiments, ascomycin produced no inhibitory effects at low micromolar concentrations (1-4 microM), whereas the inhibitory effects of CsA were prominent at comparable concentrations. Finally, CsA dose-dependently inhibited the uptake of fNle-Leu-Phe-Nle-Tyr-Lys-fluoresceine and [3H]fMLF or [125I]WKYMVm binding to FPR. However, CsA and CsH did not show any obvious inhibitory effect on FPR-like 1-mediated cellular functions. These results demonstrate that CsA is a selective antagonist of FPR and that its inhibition of fMLF-stimulated leukocyte activation is at the level of cognate ligand binding. 相似文献
92.
Yoshihiro Kino Chika Washizu Yoko Oma Hayato Onishi Yuriko Nezu Noboru Sasagawa Nobuyuki Nukina Shoichi Ishiura 《Nucleic acids research》2009,37(19):6477-6490
The expression and function of the skeletal muscle chloride channel CLCN1/ClC-1 is regulated by alternative splicing. Inclusion of the CLCN1 exon 7A is aberrantly elevated in myotonic dystrophy (DM), a genetic disorder caused by the expansion of a CTG or CCTG repeat. Increased exon 7A inclusion leads to a reduction in CLCN1 function, which can be causative of myotonia. Two RNA-binding protein families—muscleblind-like (MBNL) and CUG-BP and ETR-3-like factor (CELF) proteins—are thought to mediate the splicing misregulation in DM. Here, we have identified multiple factors that regulate the alternative splicing of a mouse Clcn1 minigene. The inclusion of exon 7A was repressed by MBNL proteins while promoted by an expanded CUG repeat or CELF4, but not by CUG-BP. Mutation analyses suggested that exon 7A and its flanking region mediate the effect of MBNL1, whereas another distinct region in intron 6 mediates that of CELF4. An exonic splicing enhancer essential for the inclusion of exon 7A was identified at the 5′ end of this exon, which might be inhibited by MBNL1. Collectively, these results provide a mechanistic model for the regulation of Clcn1 splicing, and reveal novel regulatory properties of MBNL and CELF proteins. 相似文献
93.
Shigehiro Asano Hitoshi Ban Kouichi Kino Katsuhisa Ioriya Masami Muraoka 《Bioorganic & medicinal chemistry letters》2009,19(4):1062-1065
A family of 1,4-diarylpiperidine-4-methylureas were designed and synthesized as novel dual effectors on ACAT and LDL receptor expression. We examined SAR of the synthesized compounds focusing on substitution at the three aromatic parts of the starting compound 1 and succeeded in identifying essential substituents for inhibition of ACAT and up-regulation of hepatic LDL receptor expression. Especially, we found that compound 12f, which can easily be prepared, has biological properties comparable to those of SMP-797, a promising ACAT inhibitor. In addition, the in vitro effects of 12f on lipid metabolism were substantially superior to those of a known ACAT inhibitor, Avasimibe. 相似文献
94.
95.
Norimitsu Izawa Takeshi Suzuki Masakatsu Watanabe Makio Takeda 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2009,152(4):346-351
Arylalkylamine N-acetyltransferase (AANAT), constituting a large family of enzymes, catalyzes the transacetylation from acetyl-CoA to monoamine substrates, although homology among species is not very high. AANAT in vertebrates is photosensitive and mediates circadian regulation. Here, we analyzed AANAT of the cricket, Dianemobius nigrofasciatus. The central nervous system contained AANAT activity. The optimum pHs were 6.0 (a minor peak) and 10.5 (a major peak) with crude enzyme solution. We analyzed the kinetics at pH 10.5 using the sample containing collective AANAT activities, which we term AANAT. Lineweaver-Burk plot and secondary plot yielded a Km for tryptamine as substrate of 0.42 µM, and a Vmax of 9.39 nmol/mg protein/min. The apparent Km for acetyl-CoA was 59.9 µM and the Vmax was 8.14 nmol/mg protein/min. AANAT of D. nigrofasciatus was light-sensitive. The activity was higher at night-time than at day-time as in vertebrates. To investigate most effective wavelengths on AANAT activity, a series of monochromatic lights was applied (350, 400, 450, 500, 550, 600 and 650 nm). AANAT showed the highest sensitivity to around 450 nm and 550 nm. 450 nm light was more effective than 550 nm light. Therefore, the most effective light affecting AANAT activity is blue light, which corresponds to the absorption spectrum of blue wave (BW)-opsin. 相似文献
96.
Daisuke Ikeno Kazuhiko Kimachi Yoichiro Kino Seiichi Harada Kayo Yoshida Shinji Tochihara Shigeyuki Itamura Takato Odagiri Masato Tashiro Kenji Okada Chiaki Miyazaki Kohji Ueda 《Microbiology and immunology》2010,54(2):81-88
The immunogenicity and safety profile of an inactivated whole‐virion influenza A (H5N1, NIBRG‐14) vaccine with alum adjuvant that was administered by IM or SC injection in a phase I clinical study involving 120 healthy Japanese men aged 20–40 years is described. The serological response of the IM group was stronger than that of the SC group. Local adverse events were less severe with IM injection than with SC injection, while similar systemic adverse events were seen in both groups. These results indicate that, when administering an inactivated whole virion vaccine with alum adjuvant for pandemic influenza, IM injection may achieve better immunogenicity and safety than SC injection. 相似文献
97.
98.
Cytochrome P450 enzymes (P450s) are able to regioselectively and stereoselectively introduce oxygen into organic compounds
under mild reaction conditions. These monooxygenases in particular easily catalyze the insertion of oxygen into less reactive
carbon–hydrogen bonds. Hence, P450s are of considerable interest as oxidation biocatalysts. To date, although several P450s
have been discovered through screening of microorganisms and have been further genetically engineered, the substrate range
of these biocatalysts is still limited to fulfill the requirements for a large number of oxidation processes. On the other
hand, the recent rapid expansion in the number of reported microbial genome sequences has revealed the presence of an unexpectedly
vast number of P450 genes. This large pool of naturally evolved P450s has attracted much attention as a resource for new oxidation
biocatalysts. In this review, we focus on aspects of the genome mining approach that are relevant for the discovery of novel
P450 biocatalysts. This approach opens up possibilities for exploitation of the catalytic potential of P450s for the preparation
of a large choice of oxidation biocatalysts with a variety of substrate specificities. 相似文献
99.
Divergent selection on opsins drives incipient speciation in Lake Victoria cichlids 总被引:2,自引:1,他引:1 下载免费PDF全文
Terai Y Seehausen O Sasaki T Takahashi K Mizoiri S Sugawara T Sato T Watanabe M Konijnendijk N Mrosso HD Tachida H Imai H Shichida Y Okada N 《PLoS biology》2006,4(12):e433
Divergent natural selection acting on ecological traits, which also affect mate choice, is a key element of ecological speciation theory, but has not previously been demonstrated at the molecular gene level to our knowledge. Here we demonstrate parallel evolution in two cichlid genera under strong divergent selection in a gene that affects both. Strong divergent natural selection fixed opsin proteins with different predicted light absorbance properties at opposite ends of an environmental gradient. By expressing them and measuring absorbance, we show that the reciprocal fixation adapts populations to divergent light environments. The divergent evolution of the visual system coincides with divergence in male breeding coloration, consistent with incipient ecological by-product speciation. 相似文献
100.
Kino H Suzuki T Oishi H Suzuki S Yamagiwa S Ishiguro M 《Parasitology international》2006,55(3):201-206
Sweetfish, Plecoglossus altivelis, obtained from 18 rivers in Shizuoka Prefecture were examined for metacercarial infection of 2 flukes, Metagonimus yokogawai and Metagonimus miyatai. The infection rate and density of metacercariae in the fish were higher in eastern and western regions than in central region of the prefecture. After infection of hamsters with metacercariae derived from the scale, 98.7% of the adult worms obtained from the intestine was found to be M. miyatai. Conversely, from infection with metacercariae from the flesh, 90.0% of the worms was M. yokogawai. Since the worms had no exclusivity in the tissues, we conclude that the flukes have location preference with the former primarily preferring the scale, and the latter the flesh. Fish from two rivers located in adjacent areas in the western region had relatively a higher ratio of M. yokogawai in the scale relative to other rivers, suggesting an intraspecific genetic variation due to geographical isolation. On examination of adult worms in the hamster's intestine, M. yokogawai was mainly located towards the anterior part of the intestine, unlike M. miyatai, suggesting that in mammalian host too, the parasites have site preference. 相似文献