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201.
Akie Homma Haruhiko Sato Tatsuya Tamura Akira Okamachi Takashi Emura Takenori Ishizawa Tatsuya Kato Tetsu Matsuura Shigeo Sato Yoshinobu Higuchi Tomoyuki Watanabe Hidetomo Kitamura Kentaro Asanuma Tadao Yamazaki Masahisa Ikemi Hironoshin Kitagawa Tadashi Morikawa Hitoshi Ikeya Kazuaki Maeda Koichi Takahashi Ryohchi Suzuki 《Bioorganic & medicinal chemistry》2010,18(3):1062-1075
We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA–MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like synoviocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis. 相似文献
202.
Akiyoshi Hoshino Tadahiro Iimura Satoshi Ueha Sanshiro Hanada Yutaka Maruoka Mitsuori Mayahara Keiko Suzuki Toshio Imai Masako Ito Yoshinobu Manome Masato Yasuhara Takaaki Kirino Akira Yamaguchi Kouji Matsushima Kenji Yamamoto 《The Journal of biological chemistry》2010,285(37):28826-28837
Chemokines are characterized by the homing activity of leukocytes to targeted inflammation sites. Recent research indicates that chemokines play more divergent roles in various phases of pathogenesis as well as immune reactions. The chemokine receptor, CCR1, and its ligands are thought to be involved in inflammatory bone destruction, but their physiological roles in the bone metabolism in vivo have not yet been elucidated. In the present study, we investigated the roles of CCR1 in bone metabolism using CCR1-deficient mice. Ccr1−/− mice have fewer and thinner trabecular bones and low mineral bone density in cancellous bones. The lack of CCR1 affects the differentiation and function of osteoblasts. Runx2, Atf4, Osteopontin, and Osteonectin were significantly up-regulated in Ccr1−/− mice despite sustained expression of Osterix and reduced expression of Osteocalcin, suggesting a lower potential for differentiation into mature osteoblasts. In addition, mineralized nodule formation was markedly disrupted in cultured osteoblastic cells isolated from Ccr1−/− mice. Osteoclastogenesis induced from cultured Ccr1−/− bone marrow cells yielded fewer and smaller osteoclasts due to the abrogated cell-fusion. Ccr1−/− osteoclasts exerted no osteolytic activity concomitant with reduced expressions of Rank and its downstream targets, implying that the defective osteoclastogenesis is involved in the bone phenotype in Ccr1−/− mice. The co-culture of wild-type osteoclast precursors with Ccr1−/− osteoblasts failed to facilitate osteoclastogenesis. This finding is most likely due to a reduction in Rankl expression. These observations suggest that the axis of CCR1 and its ligands are likely to be involved in cross-talk between osteoclasts and osteoblasts by modulating the RANK-RANKL-mediated interaction. 相似文献
203.
204.
Sakakibara K Ifuku S Tsujii Y Kamitakahara H Takano T Nakatsubo F 《Biomacromolecules》2006,7(6):1960-1967
A novel cellulose derivative, 6-O-dihydrophytylcellulose (DHPC), was first synthesized via a ring-opening polymerization and allowed to self-assemble onto an air-water interface. Langmuir-Blodgett (LB) films were characterized with atomic force microscope (AFM), UV-vis spectroscopy, and Fourier transform infrared spectroscopy. The surface pressure-area (pi-A) isotherms for DHPC and beta-carotene (betaC) mixture indicated strong interaction between these compounds to pack well. Thus, DHPC has the ability to anchor betaC in the monolayer. It was proved that a betaC-DHPC monolayer was transferred successfully onto a substrate, yielding Y-type LB films by UV spectroscopic analysis. The transmission and reflection-absorption IR spectra (RAS) indicated that the dihydrophytyl chains had almost trans-zigzag conformation and were oriented nearly perpendicular to the substrate. AFM section analysis revealed the thickness per layer to be 2.32 nm. Consequently, DHPC was found to be an appropriate matrix to fabricate the mixed LB films containing betaC. 相似文献
205.
Mori I Goshima F Watanabe D Ito H Koide N Yoshida T Liu B Kimura Y Yokochi T Nishiyama Y 《Microbes and infection / Institut Pasteur》2006,8(7):1806-1812
A role for the US3 protein kinase of herpes simplex virus (HSV) in regulating virus-induced neuronal apoptosis was investigated in an experimental mouse system, in which wild-type HSV invades the central nervous system (CNS) via the olfactory and vomeronasal systems upon intranasal infection. Wild-type HSV-2 strain 186 infected a fraction of olfactory and vomeronasal chemosensory neurons without inducing apoptosis and was transmitted to the CNS, precipitating lethal encephalitis. In sharp contrast, an US3-disrupted mutant, L1BR1, induced neuronal apoptosis in these peripheral conduits upon infection, blocking viral transmission to the CNS and causing no signs of disease. An US3-repaired mutant, L1B(-)11, behaved similarly to the wild-type virus. Only 5 p.f.u. of L1BR1 was sufficient to compromise mice when the mutant virus was introduced directly into the olfactory bulb, a viral entry site of the CNS. These results suggest that the US3 protein kinase of HSV regulates virus-induced neuronal apoptosis in peripheral conduits and determines the neuroinvasive phenotype of HSV. Furthermore, virus-induced neuronal apoptosis of peripheral nervous system cells may be a protective host response that blocks viral transmission to the CNS. 相似文献
206.
207.
BACKGROUND: Amebiasis is a parasitic infection with Entamoeba histolytica. Pulmonary amebiasis is rare since the infection is commonly manifested as amebic colitis or liver abscess. Most pleuropulmonary amebiasis is seen in patients with amebic liver abscesses. A pulmonary amebic lesion without either a liver abscess or amebic colitis is extremely rare. Thus, reported cases of sputum cytologic diagnosis of a pulmonary amebic lesion from a patient without a liver abscess are also very rare. CASE: A 53-year-old man presented with a dry cough and mild fever. Chest radiography revealed an abnormal solitary mass lesion in the right upper lung field. The clinical diagnosis was a bacterial lung abscess. Sputum cytologic examination demonstrated many trophozoites of E. histolytica. Following sputum cytodiagnosis, serologic tests revealed a slightly high but almost normal titer of IgG antibodies to E. histolytica, indicating the possible presence of the pathogen. Polymerase chain reaction (PCR) using E. histolytica-specific primers for DNA extracted from the sputum sample revealed specific DNA product. CONCLUSION: Pulmonary amebiasis without either a liver abscess or amebic colitis must be distinguished from bacterial abscesses and neoplastic disease. A sputum cytologic examination combined with PCR for DNA extracted from a sputum sample is a good approach to the diagnosis of a pulmonary amebic abscess. 相似文献
208.
One of the basement membrane (BM) proteins, laminin-5 (LN5), is known to support efficient cell adhesion and migration through interaction with integrins on the basal plasma membrane. Here, we show that a soluble form of LN5 induced migration of human epithelial cells and carcinoma cells by interacting with integrins on the apical cell surface. Although both LN5 and laminin-10/11 (LN10/11) promoted cell migration when coated onto a plastic surface as insoluble substrata, only LN5 stimulated cell migration in its soluble form on other substrata such as fibronectin (FN), vitronectin (VN) and collagen. Soluble LN5 interacted with integrins alpha3beta1 and alpha6beta1 on the apical cell surface and stimulated cell migration, while the cell morphology was largely dependent on the underlying substratum. Thus, integrin signals from the apical surface and the basal surface synergistically regulated cytoskeletal organization and cell motility. Soluble and insoluble LN5 induced cell motility by activating signal pathways via protein kinase C (PKC), phosphoinositide 3-OH kinase (PI3-K) and MAP kinase. The PKC dependency was more prominent for soluble LN5 than insoluble LN5, and was absent in the stimulation by insoluble LN10/11. In vitro scratch assays with keratinocytes, self-produced soluble LN5 bound to the apical cell surface of migrating cells at the scratched edges, suggesting that soluble LN5 may contribute to cell migration in pathological conditions such as wound healing and tumor invasion. 相似文献
209.
Characterization of a novel acid phosphatase from embryonic axes of kidney bean exhibiting vanadate-dependent chloroperoxidase activity 总被引:1,自引:0,他引:1
Yoneyama T Shiozawa M Nakamura M Suzuki T Sagane Y Katoh Y Watanabe T Ohyama T 《The Journal of biological chemistry》2004,279(36):37477-37484
A novel colorless acid phosphatase (KeACP), which was distinct from the kidney bean purple acid phosphatase, was purified to apparent homogeneity and cloned from embryonic axes of kidney bean (Phaseolus vulgaris L. Ohfuku) during germination. When orthovanadate (VO(4)(-3)) is added to the apo form of the enzyme, KeACP uniquely exhibits the chloroperoxidase activity with loss of phosphatase activity. This is the first demonstration that KeACP is a vanadate-dependent chloroperoxidase in plants to be characterized and suggests that KeACP may play a role in modifying a wide variety of chlorinated compounds that are present in higher plants. The enzyme is a dimer that presents three forms made up of the combination of the dominant 56-kDa and the minor 45-kDa subunits, and both subunits contain carbohydrate. The full-length cDNA of the KeACP gene is 1641 nucleotides, and this sequence is predicted to encode a protein having 457 amino acid residues (52,865 Da), including a signal peptide. The complete nucleotide sequence of the genomic DNA (3228 bp) of KeACP consists of seven exons and six introns. Northern blot analysis demonstrated that the KeACP gene was expressed specifically in embryonic axes of the kidney bean, and its expression coincided with elongation of the embryonic axis during germination. 相似文献
210.
Auesukaree C Homma T Tochio H Shirakawa M Kaneko Y Harashima S 《The Journal of biological chemistry》2004,279(17):17289-17294
In Saccharomyces cerevisiae, the phosphate signal transduction pathway (PHO pathway) is known to regulate the expression of several phosphate-responsive genes, such as PHO5 and PHO84. However, the fundamental issue of whether cells sense intracellular or extracellular phosphate remains unresolved. To address this issue, we have directly measured intracellular phosphate concentrations by (31)P NMR spectroscopy. We find that PHO5 expression is strongly correlated with the levels of both intracellular orthophosphate and intracellular polyphosphate and that the signaling defect in the Deltapho84 strain is likely to result from insufficient intracellular phosphate caused by a defect in phosphate uptake. Furthermore, the Deltaphm1Deltaphm2, Deltaphm3, and Deltaphm4 strains, which lack intracellular polyphosphate, have higher intracellular orthophosphate levels and lower expression of PHO5 than the wild-type strain. By contrast, the Deltaphm5 strain, which has lower intracellular orthophosphate and higher polyphosphate levels than the wild-type strain, shows repressed expression of PHO5, similar to the wild-type strain. These observations suggest that PHO5 expression is under the regulation of intracellular orthophosphate, although orthophosphate is not the sole signaling molecule. Moreover, the disruption of PHM3, PHM4, or of both PHM1 and PHM2 in the Deltapho84 strain suppresses, although not completely, the PHO5 constitutive phenotype by increasing intracellular orthophosphate, suggesting that Pho84p affects phosphate signaling largely by functioning as a transporter. 相似文献