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161.
162.
Shigeaki Ito Shigeki Hamada Hiroyuki Ito Hirokazu Matsui Tadahiro Ozawa Hidenori Taguchi Susumu Ito 《Biotechnology letters》2009,31(7):1065-1071
The cellobiose 2-epimerase from Ruminococcus albus (RaCE) catalyzes the epimerization of cellobiose and lactose to 4-O-β-d-glucopyranosyl-d-mannose and 4-O-β-d-galactopyranosyl-d-mannose (epilactose). Based on the sequence alignment with N-acetyl-d-glucosamine 2-epimerases of known structure and on a homology-modeled structure of RaCE, we performed site-directed mutagenesis
of possible catalytic residues in the enzyme, and the mutants were expressed in Escherichia coli cells. We found that R52, H243, E246, W249, W304, E308, and H374 were absolutely required for the activity of RaCE. F114
and W303 also contributed to catalysis. These residues protruded into the active-site cleft in the model (α/α)6 core barrel structure. 相似文献
163.
164.
Fumihito Muro Shin Iimura Yoshiyuki Yoneda Jun Chiba Toshiyuki Watanabe Masaki Setoguchi Gensuke Takayama Mika Yokoyama Tohru Takashi Atsushi Nakayama Nobuo Machinaga 《Bioorganic & medicinal chemistry》2009,17(3):1232-1243
During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease (3, IC50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC50 = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC50 = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats. 相似文献
165.
Sumiyo Morita Akemi Hara Itaru Kojima Takuro Horii Mika Kimura Tadahiro Kitamura Takahiro Ochiya Katsumi Nakanishi Ryo Matoba Kenichi Matsubara Izuho Hatada 《PloS one》2009,4(1)
Dicer1, an essential component of RNA interference and the microRNA pathway, has many important roles in the morphogenesis of developing tissues. Dicer1 null mice have been reported to die at E7.5; therefore it is impossible to study its function in adult tissues. We previously reported that Dicer1-hypomorphic mice, whose Dicer1 expression was reduced to 20% in all tissues, were unexpectedly viable. Here we analyzed these mice to ascertain whether the down-regulation of Dicer1 expression has any influence on adult tissues. Interestingly, all tissues of adult (8–10 week old) Dicer1-hypomorphic mice were histologically normal except for the pancreas, whose development was normal at the fetal and neonatal stages; however, morphologic abnormalities in Dicer1-hypomorphic mice were detected after 4 weeks of age. This suggested that Dicer1 is important for maintaining the adult pancreas. 相似文献
166.
167.
Matsumoto K Takayama H Ishikawa H Aimi N Ponglux D Watanabe K Horie S 《Life sciences》2006,78(19):2265-2271
Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa that is reported to have opioid agonistic properties. The 9-demethyl analogue of mitragynine, 9-hydroxycorynantheidine, is synthesized from mitragynine. 9-Hydroxycorynantheidine inhibited electrically stimulated guinea-pig ileum contraction, but its maximum inhibition was weaker than that of mitragynine and its effect was antagonized by naloxone, suggesting that 9-hydroxycorynantheidine possesses partial agonist properties on opioid receptors. Receptor binding assays revealed that 9-hydroxycorynantheidine has high affinity for mu-opioid receptors. In an assay of the guinea-pig ileum, naloxone shifted the concentration-response curves for [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO), (5alpha,7alpha,8beta)-(+)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69593) and 9-hydroxycorynantheidine to the right in a competitive manner. The pA(2) values of naloxone against 9-hydroxycorynantheidine and DAMGO were very similar, but not that against U69593. As indicated by the two assay systems, the opioid effect of 9-hydroxycorynantheidine is selective for the mu-opioid receptor. 9-Hydroxycorynantheidine shifted the concentration-response curve for DAMGO slightly to the right. Pretreatment with the mu-opioid selective and irreversible antagonist beta-funaltorexamine hydrochloride (beta-FNA) shifted the concentration-response curve for DAMGO to the right without affecting the maximum response. On the other hand, beta-FNA did not affect the curve for 9-hydroxycorynantheidine, but decreased the maximum response because of the lack of spare receptors. These studies suggest that 9-hydroxycorynantheidine has partial agonist properties on mu-opioid receptors in the guinea-pig ileum. 相似文献
168.
Low-intensity pulsed ultrasound (LIPUS) is known to accelerate bone regeneration, but the precise cellular mechanism is still unclear. The purpose of this study was to determine the effect of LIPUS on the differentiation of pluripotent mesenchymal cell line C2C12. The cells were cultured in differentiation medium with or without the addition of LIPUS stimulation. The ultrasound signal consisted of 1.5 MHz at an intensity of 70 mW/cm2 for 20 min for all cultures. To verify the cell lineage after LIPUS stimulation, mRNA expression of cellular phenotype-specific markers characterizing osteoblasts (Runx2, Msx2, Dlx5, AJ18), chondroblasts (Sox9), myoblasts (MyoD), and adipocytes (C/EBP, PPARgamma) was studied using real-time polymerase chain reaction analysis. The protein expression of Runx2 and activated phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) were performed using Western blotting. The mRNA expression of Runx2, Msx2, Dlx5, AJ18, and Sox9 was increased markedly by the LIPUS stimulation, whereas the expression of MyoD, C/EBP, and PPARgamma was drastically decreased. In the Western blot analysis, LIPUS stimulation increased Runx2 protein expression and phosphorylation of ERK1/2 and p38 MAPK. Our study demonstrated that LIPUS stimulation converts the differentiation pathway of C2C12 cells into the osteoblast and/or chondroblast lineage via activated phosphorylation of ERK1/2 and p38 MAPK. 相似文献
169.
A novel method to produce extensive gastric antral ulcer in rats: pharmacological factors involved in the etiology of antral ulceration. 总被引:1,自引:0,他引:1
Gastric antral area is the most susceptible region to gastric ulceration in man. However, only limited information is available on animal models. In the present paper, we have developed an improved method for inducing gastric antral ulcers by the administration of 1.0 M HCl after refeeding for 1 h in rats. On day 4, the severe ulcer was found covering extensively the whole area of the antrum, and penetrated through the muscularis mucosae. The incidence of ulceration was 100% and the mean ulcer index was 37.1 +/- 16.6 mm2. In contrast, none of the erosive lesions were observed in the corpus area. Before 24 h, only slight hyperemia was observed in the antral region, suggesting that some submucosal mechanisms are involved in the ulceration processes other than the direct erosive action of HCl on the mucosal surface. Additional treatment with diethyldithiocarbamate (125 mg x kg(-1), s.c.), superoxide dismutase inhibitor, significantly aggravated this antral ulcer, and the ulcer index was 66.0 +/- 13.6 mm2. Allopurinol (50 mg x kg(-1), p.o.) significantly prevented ulcer formation induced by HCl plus DDC. GSH (150 mg x kg(-1), i.p.) also markedly prevented the ulceration. However, DMSO (0.5%, 5 mL x kg(-1), p.o.) was found not to affect ulcer formation. Famotidine (20 mg x kg(-1), p.o.) almost completely inhibited ulcer formation. From the above results, it was concluded that gastric antral ulcer can be induced by the simple treatment of 1.0 M HCl in refed rats, and the antrum has a different defensive mechanism from that in the corpus area. In addition. oxygen derived radicals, especially superoxide anion and endogenous acid secretion were found to be involved in the etiology of the aggravation of the gastric antral ulcer induced by DDC. 相似文献
170.
The structures of proteins in crystals are fixed by molecular interactions with neighboring molecules, except in non-contacting flexible regions. Thus, it is difficult to imagine what conformational changes occur in solution. However, if molecular interactions can be changed by manipulating molecular packing in crystals, it may be possible to visualize conformational responses of proteins at atomic resolution by diffraction experiments. For this purpose, it is suitable to control the molecular packing in protein crystals by changing the volume of solvent channels through variation of the environmental relative humidity. Here, we studied conformational responses of hen egg white lysozyme (HEWL) in the tetragonal crystal by X-ray diffraction experiments using a humidity-control apparatus, which provided air flow of 20-98%rh at 298 K. First, we monitored the lattice parameters and crystalline order during dehydration and rehydration of HEWL crystal between 61 and 94%rh at 300 K. Then two crystal structures at a resolution of 2.1 ? using diffraction data obtained at 84.2 and 71.9%rh were determined to discuss the conformational responses of HEWL against the external perturbation induced by changes in molecular packing. The structure at 71.9%rh displayed a closure movement that was likely induced by the molecular contacts formed during dehydration and could be approximated by ten low-frequency normal modes for the crystal structure obtained at 84.2%rh. In addition, we observed reorganization of hydration structures at the molecular interfaces between symmetry neighbors. These findings suggest that humidity-controlled X-ray crystallography is an effective tool to investigate the responses of inherent intramolecular motions of proteins to external perturbations. 相似文献