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51.
Ali HI Tomita K Akaho E Kambara H Miura S Hayakawa H Ashida N Kawashima Y Yamagishi T Ikeya H Yoneda F Nagamatsu T 《Bioorganic & medicinal chemistry》2007,15(1):242-256
Novel 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides were prepared as a new class of antitumor agents and showed significant antitumor activities against NCI-H 460, HCT 116, A 431, CCRF-HSB-2, andKB cell lines. In vivo investigation, 2-deoxo-10-methyl-2-phenyl-5-deazaflavin exhibited the effective antitumor activity against A 431 human adenocarcinoma cells transplanted subcutaneously into nude mouse. Furthermore, AutoDock study has been done by binding of the flavin analogs into PTK pp60(c-src), where a good correlation between their IC(50) and AutoDock binding free energy was exhibited. In particular, 2-deoxo-2-phenylflavin-5-oxides exhibited the highest potential binding affinity within the binding pocket of PTK. 相似文献
52.
Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease 总被引:9,自引:0,他引:9
Lee JP Jeyakumar M Gonzalez R Takahashi H Lee PJ Baek RC Clark D Rose H Fu G Clarke J McKercher S Meerloo J Muller FJ Park KI Butters TD Dwek RA Schwartz P Tong G Wenger D Lipton SA Seyfried TN Platt FM Snyder EY 《Nature medicine》2007,13(4):439-447
Intracranial transplantation of neural stem cells (NSCs) delayed disease onset, preserved motor function, reduced pathology and prolonged survival in a mouse model of Sandhoff disease, a lethal gangliosidosis. Although donor-derived neurons were electrophysiologically active within chimeric regions, the small degree of neuronal replacement alone could not account for the improvement. NSCs also increased brain beta-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (beta-hexosaminidase substrate inhibitors) were combined with NSC transplantation, substantial synergy resulted. Efficacy extended to human NSCs, both to those isolated directly from the central nervous system (CNS) and to those derived secondarily from embryonic stem cells. Appreciating that NSCs exhibit a broad repertoire of potentially therapeutic actions, of which neuronal replacement is but one, may help in formulating rational multimodal strategies for the treatment of neurodegenerative diseases. 相似文献
53.
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55.
El-Farrash MA Aly HH Watashi K Hijikata M Egawa H Shimotohno K 《Microbiology and immunology》2007,51(1):127-133
Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma worldwide. We previously reported that cyclosporin A (CsA) inhibits HCV-1b replication. However, its inhibition of JFH-1 (HCV-2a) was much less. Since HCV genotype clearly affects the in vitro and in vivo response to anti-viral therapy, we wished to examine the effect of CsA and its non-immunosuppressive derivative NIM811 on HCV genotype 4a replication. We first established an in vitro system supporting HCV-4a infection and replication using immortalized human hepatocytes, HuS-E7/DN24 (HuS) cells, and these cells were infected with sera obtained from Egyptian patients with chronic HCV-4a infection. HuS cells supported more robust HCV-4a replication than both HuH-7.5 and PH5CH8 cells, and HCV-4a infection and replication were completely inhibited by 3 mug/ml CsA and 0.5 mug/ml NIM811. Thus, HuS cells are a good model system supporting the infection and high-level replication of HCV-4a, and both CsA and NIM811 effectively inhibit HCV-4a replication in this system. 相似文献
56.
In eukaryotic cells, it is known that N-glycans play a pivotal role in quality control of carrier proteins. Although "free" forms of oligosaccharides (fOSs) are known to be accumulated in the cytosol, the precise mechanism of their formation, degradation and biological relevance remains poorly understood. It has been shown that, in budding yeast, almost all fOSs are formed from misfolded glycoproteins. Precise structural analysis of fOSs revealed that several yeast fOSs bear a yeast-specific modification by Golgi-resident α-1,6-mannosyltransferase, Och1. In this study, structural diversity of fOSs in och1Δ cells was analyzed. To our surprise, several fOSs in och1Δ cells have unusual α-1,3-linked mannose residues at their non-reducing termini. These mannose residues were not observed in wild-type cells, suggesting that the addition of these unique mannoses occurred as a compensation of Och1 defect. A significant increase in the amount of fOSs modified by Golgi-localized mannosyltransferases was also observed in och1Δ cells. Moreover, the amount of processed fOSs and intracellular α-mannosidase (Ams1) both increased in this mutant. Up-regulation of Ams1 activity was also apparent for cells treated with cell wall perturbation reagent. These results provide an insight into a possible link between catabolism of fOSs and cell wall stress. 相似文献
57.
Mitsui H Aoyama T Furu M Ito K Jin Y Maruyama T Kanaji T Fujimura S Sugihara H Nishiura A Otsuka T Nakamura T Toguchida J 《Arthritis research & therapy》2011,13(5):R146-13
Introduction
Osteoarthritis (OA) is a common cause of disability in older adults. We have previously reported that an agonist for subtypes EP2 of the prostaglandin E2 receptor (an EP2 agonist) promotes the regeneration of chondral and osteochondral defects. The purpose of the current study is to analyze the effect of this agonist on articular cartilage in a model of traumatic degeneration.Methods
The model of traumatic degeneration was established through transection of the anterior cruciate ligament and partial resection of the medial meniscus of the rabbits. Rabbits were divided into 5 groups; G-S (sham operation), G-C (no further treatment), G-0, G-80, and G-400 (single intra-articular administration of gelatin hydrogel containing 0, 80, and 400 μg of the specific EP2 agonist, ONO-8815Ly, respectively). Degeneration of the articular cartilage was evaluated at 2 or 12 weeks after the operation.Results
ONO-8815Ly prevented cartilage degeneration at 2 weeks, which was associated with the inhibition of matrix metalloproteinase-13 (MMP-13) expression. The effect of ONO-8815Ly failed to last, and no effects were observed at 12 weeks after the operation.Conclusions
Stimulation of prostaglandin E2 (PGE2) via EP2 prevents degeneration of the articular cartilage during the early stages. With a system to deliver it long term, the EP2 agonist could be a new therapeutic tool for OA. 相似文献58.
Hikikoshi Iwane A Tanaka H Morimoto S Ishijima A Yanagida T 《Journal of molecular biology》2005,353(2):213-221
In order to study the role of the neck domain of myosin in muscle contraction, we measured the steps of individual myosin II molecules engineered to have no neck domain (light chain-binding domain) by optical trapping nanometry. The actin filament and myosin cofilaments interacted on a glass surface to minimize the angle between them, and to minimize the interaction between myosin and the glass surface. The results showed that the average myosin stepsize did not change much when the neck domain was removed, but the sliding velocity decreased approximately fivefold. Furthermore, the duration of steps for neckless myosin was several times longer at saturated ATP concentration, indicating that the slower velocity was due to a slower dissociation rate of myosin heads from actin. From these data, we conclude that the neck domain of myosin-II primarily regulates the actomyosin kinetics, not the mechanics. 相似文献
59.
Hashikawa K Tahara S Terashi H Ichinose A Nomura T Omori M Sanno T 《Plastic and reconstructive surgery》2005,115(2):388-393
The restoration of velopharyngeal function after extensive soft palate resection to treat malignant oropharyngeal tumors is a major challenge to reconstructive surgeons. The authors had previously reconstructed soft palatal defects routinely with the folded forearm flap. A patient who had more than half of the soft palate excised experienced postoperative velopharyngeal dysfunction. To restore efficient velopharyngeal function, pharyngoplasty was additively applied where the folded ridge of the forearm flap was sutured to the posterior pharyngeal wall in an inverse manner of the pharyngeal flap technique. The essence of the procedure was positive narrowing of the nasopharyngeal space. Five patients who underwent this pharyngoplasty and another five who did not were evaluated for postoperative functions of speech intelligibility and of nasal regurgitation during oral feeding. The velopharyngeal movements of all patients were examined under a nasopharyngeal endoscope. The evaluations demonstrated that this surgical procedure afforded satisfactory results. This positive narrowing pharyngoplasty technique is simple, easy, and minimally invasive to the remaining healthy tissue, and it is the method of choice for the reconstruction of the soft palate after malignant tumor resection. 相似文献
60.
Ohta H Khan MA Nagai I Umemoto N Hamasaki T Ozoe Y 《Archives of insect biochemistry and physiology》2005,59(3):150-160
Tyramine (TA), a biogenic amine, attenuates intracellular cAMP production by acting on its receptor in insects. Several non-biogenic amines were examined for their actions on native and heterologously expressed silkworm TA receptors. 5-(4-Hydroxyphenyl)oxazole, which showed an attenuating effect on cAMP production in silkworm-head membranes, did not attenuate forskolin-stimulated cAMP production in HEK-293 cells expressing the silkworm TA receptor, although the compound bound to the cloned receptor. 2-Phenylethylamines (2-PEAs), which showed positive and negative effects on cAMP production in silkworm-head membranes, inhibited [3H]TA binding to the cloned TA receptor. 2-Chloro-2-(4-chlorophenyl)ethylamine was the most potent inhibitor of [3H]TA binding among the 2-PEAs tested, with an IC50 of 30.4 nM. This compound acted as an antagonist and abolished TA-attenuation of forskolin-stimulated cAMP production in the cloned TA receptor. The discrepancy in the effects of the non-biogenic amines on the native and cloned TA receptors remains to be further examined. A newly synthesized 2-PEA, 2-chloro-2-(4-hydroxyphenyl)ethylamine, attenuated forskolin-stimulated cAMP production in the cloned TA receptor, indicating that the para-hydroxy group is important for the agonist action. 相似文献