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排序方式: 共有747条查询结果,搜索用时 15 毫秒
621.
Akie Homma Haruhiko Sato Akira Okamachi Takashi Emura Takenori Ishizawa Tatsuya Kato Tetsu Matsuura Shigeo Sato Tatsuya Tamura Yoshinobu Higuchi Tomoyuki Watanabe Hidetomo Kitamura Kentaro Asanuma Tadao Yamazaki Masahisa Ikemi Hironoshin Kitagawa Tadashi Morikawa Hitoshi Ikeya Kazuaki Maeda Koichi Takahashi Ryochi Suzuki 《Bioorganic & medicinal chemistry》2009,17(13):4647-4656
Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA–MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA–MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis. 相似文献
622.
Maternal feeding controls fetal biological clock 总被引:1,自引:0,他引:1
Ohta H Xu S Moriya T Iigo M Watanabe T Nakahata N Chisaka H Hanita T Matsuda T Ohura T Kimura Y Yaegashi N Tsuchiya S Tei H Okamura K 《PloS one》2008,3(7):e2601
Background
It is widely accepted that circadian physiological rhythms of the fetus are affected by oscillators in the maternal brain that are coupled to the environmental light-dark (LD) cycle.Methodology/Principal Findings
To study the link between fetal and maternal biological clocks, we investigated the effects of cycles of maternal food availability on the rhythms of Per1 gene expression in the fetal suprachiasmatic nucleus (SCN) and liver using a transgenic rat model whose tissues express luciferase in vitro. Although the maternal SCN remained phase-locked to the LD cycle, maternal restricted feeding phase-advanced the fetal SCN and liver by 5 and 7 hours respectively within the 22-day pregnancy.Conclusions/Significance
Our results demonstrate that maternal feeding entrains the fetal SCN and liver independently of both the maternal SCN and the LD cycle. This indicates that maternal-feeding signals can be more influential for the fetal SCN and particular organ oscillators than hormonal signals controlled by the maternal SCN, suggesting the importance of a regular maternal feeding schedule for appropriate fetal molecular clockwork during pregnancy. 相似文献623.
Aims
The purpose of this study was to examine HRQOL depending on whether the participants have family members with disabilities or not. In addition, we examined the relationship between HRQOL and social networks among family caregivers in Japan. 相似文献624.
Shiraishi T Kadono S Haramura M Kodama H Ono Y Iikura H Esaki T Koga T Hattori K Watanabe Y Sakamoto A Yoshihashi K Kitazawa T Esaki K Ohta M Sato H Kozono T 《Bioorganic & medicinal chemistry letters》2008,18(16):4533-4537
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. Compound 1 was discovered from focused screening of serine protease-directed compounds from our internal collection. Using parallel synthesis supported by structure-based drug design, we identified peptidemimetic FVIIa/TF inhibitors (compounds 4-11) containing L-Gln or L-Met as the P2 moiety. However, these compounds lacked the selectivity of other serine proteases in the coagulation cascade, especially thrombin. Further optimization of these compounds was carried out with a focus on the P4 moiety. Among the optimized compounds, 12b-f showed improved selectivity. 相似文献
625.
Matsumura K Kaihatsu K Mori S Cho HH Kato N Hyon SH 《Biochemical and biophysical research communications》2008,377(4):1118-1122
(−)-Epigallocatechin-3-O-gallate (EGCG) monoesters modified with butanoyl (EGCG-C4), octanoyl (EGCG-C8), palmitoyl groups (EGCG-C16) were synthesized by a lipase-catalyzed transesterification method and their antitumor activities were investigated in vitro and in vivo. The in vitro antitumor activities of EGCG-monoester derivatives increased in an alkyl chain length-dependent manner. The cytotoxicity of EGCG, EGCG-C4, EGCG-C8 was mainly caused by H2O2 which was generated with their oxidation. On the other hand, EGCG-C16 was more stable than EGCG and it did not generate H2O2 in the cell culture medium. Furthermore, EGCG-C16 inhibited cell proliferation and induced apoptosis in the presence of catalase. EGCG-C16 was found to inhibit the phosphorylation of the epidermal growth factor receptor (EGFR), which is related to various types of tumor growth. EGCG-C16 suppressed tumor growth in vivo in colorectal tumor bearing mice in comparison to an untreated control, vector control (DMSO) and EGCG. 相似文献
626.
Ishii T Murayama Y Katano A Maki K Kuwajima K Sano M 《Biochemical and biophysical research communications》2008,375(4):586-591
Single-molecule manipulation techniques have given experimental access to unfolding intermediates of proteins that are inaccessible in conventional experiments. A detailed characterization of the intermediates is a challenging problem that provides new possibilities for directly probing the energy landscape of proteins. We investigated single-molecule mechanical unfolding of a small globular protein, staphylococcal nuclease (SNase), using atomic force microscopy. The unfolding trajectories of the protein displayed sub-molecular and stochastic behavior with typical lengths corresponding to the size of the unfolded substructures. Our results support the view that the single protein unfolds along multiple pathways as suggested in recent theoretical studies. Moreover, we found the drastic change, caused by the ligand and inhibitor bindings, in the mechanical unfolding dynamics. 相似文献
627.
Neuroprotective effect of sonic hedgehog up-regulated in Schwann cells following sciatic nerve injury 总被引:1,自引:0,他引:1
Hashimoto M Ishii K Nakamura Y Watabe K Kohsaka S Akazawa C 《Journal of neurochemistry》2008,107(4):918-927
The physiological roles of sonic hedgehog (Shh) have been intensively characterized in development of various organs. However, their functions in adult tissues have not been fully elucidated. We investigated the expression and the potential function of Shh in crush-injured adult rat sciatic nerves. The Shh expression was up-regulated in Schwann cells adjacent to the injured site. The time-course analyses of various neurotrophic factors revealed the up-regulation of Shh mRNA followed by that of brain-derived neurotrophic factor (BDNF) mRNA. The continuous administration of cyclopamine, a hedgehog signal inhibitor, to the injured site suppressed the increase of BDNF expression and deteriorated the survival of motor neurons in lumbar spinal cord. Treatment of exogenous Shh in cultured Schwann cells enhanced the BDNF expression. The BDNF promoter activity (exon I and II) was increased in IMS32 cells co-transfected with Shh and its receptor Smoothened. These findings imply that the up-regulated expression of Shh in Schwann cells may play an important role in injured motor neurons through the induction of BDNF. 相似文献
628.
Omori E Morioka S Matsumoto K Ninomiya-Tsuji J 《The Journal of biological chemistry》2008,283(38):26161-26168
Mice with a keratinocyte-specific deletion of Tak1 exhibit severe skin inflammation due to hypersensitivity to tumor necrosis factor (TNF) killing. Here we have examined the mechanisms underlying this hypersensitivity. We found that TAK1 deficiency up-regulates reactive oxygen species (ROS) resulting in cell death upon TNF or oxidative stress challenge. Because blockade of NF-kappaB did not increase ROS or did not sensitize cells to oxidative stress in keratinocytes TAK1 regulates ROS mainly through the mechanisms other than those mediated by NF-kappaB. We found that c-Jun was decreased in TAK1-deficient keratinocytes and that ectopic expression of c-Jun could partially inhibit TNF-induced increase of ROS and cell death. Finally, we show that, in an in vivo setting, the antioxidant treatment could reduce an inflammatory condition in keratinocyte-specific Tak1 deletion mice. Thus, TAK1 regulates ROS partially through c-Jun, which is important for preventing ROS-induced skin inflammation. 相似文献
629.
630.
Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. 总被引:16,自引:0,他引:16
Masanori Asakura Masafumi Kitakaze Seiji Takashima Yulin Liao Fuminobu Ishikura Tsuyoshi Yoshinaka Hiroshi Ohmoto Koichi Node Kohichiro Yoshino Hiroshi Ishiguro Hiroshi Asanuma Shoji Sanada Yasushi Matsumura Hiroshi Takeda Shintaro Beppu Michihiko Tada Masatsugu Hori Shigeki Higashiyama 《Nature medicine》2002,8(1):35-40
G-protein-coupled receptor (GPCR) agonists are well-known inducers of cardiac hypertrophy. We found that the shedding of heparin-binding epidermal growth factor (HB-EGF) resulting from metalloproteinase activation and subsequent transactivation of the epidermal growth factor receptor occurred when cardiomyocytes were stimulated by GPCR agonists, leading to cardiac hypertrophy. A new inhibitor of HB-EGF shedding, KB-R7785, blocked this signaling. We cloned a disintegrin and metalloprotease 12 (ADAM12) as a specific enzyme to shed HB-EGF in the heart and found that dominant-negative expression of ADAM12 abrogated this signaling. KB-R7785 bound directly to ADAM12, suggesting that inhibition of ADAM12 blocked the shedding of HB-EGF. In mice with cardiac hypertrophy, KB-R7785 inhibited the shedding of HB-EGF and attenuated hypertrophic changes. These data suggest that shedding of HB-EGF by ADAM12 plays an important role in cardiac hypertrophy, and that inhibition of HB-EGF shedding could be a potent therapeutic strategy for cardiac hypertrophy. 相似文献