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論文
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Nakai, Makoto ; Yoshihara, Shuichi ; Morohashi, Hajime ; Ishido, Keinosuke ; Sasaki, Mutsuo
概要:
Hyaluronan (HA) is a major component of the pericellular matrix, and is implicated in cell adhesion, invasion. and tumor metastasis. We have reported that 4-methylumbelliferone (MU) inhibits HA synthesis by cultured skin
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fibroblasts, melanoma cells, and pancreatic cancer cells. We focused in the present study, on mesothelioma which has an extremely poor prognosis, and in which no effective therapy has yet been established. We investigated dealing with this neoplasm whether MU and 4-methylesculetin (ME), a MU derivative, are able to inhibit HA synthesis by the mesothelioma cell line NCI-H2052. MU inhibited HA synthesis by about 20%, and ME by about 40%, in comparison with the control group. MU inhibited the adhesion of NCI-H2052 cells by about 30%, and ME by about 50%, compared with the untreated control. MU inhibited cell locomotion by about 30%. and ME by about 40%. It is suggested through these results suggest that MU and ME inhibit HA synthesis. adhesion, and locomotion by human mesothelioma cells and weaken their pericellular matrix, and that the inhibitory effect of ME on HA synthesis is stronger than that of MU. It is presumed that both MU and ME may have potential as new therapeutic or prophylactic medicines against mesothelioma.
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| 2.
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論文
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Kakizaki, Ikuko ; Suto, Shinichiro ; Tatara, Yota ; Endo, Masahiko
概要:
Hyaluronan and chondroitin sulfate sugar chains play important roles as major components of extracellular matrix. They a
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re attractive molecules for biochemical research and are also used in pharmaceutical agents. However, details of the relationships between their oligosaccharide structures and functions are not known because of a lack of availability of model oligosaccharides with known structures. In order to, in the future, investigate their functions based on structure, we synthesized hybrid oligosaccharides by the in vitro transglycosylation reaction of hyaluronidase using various combinations of acceptors and donors. A total of 18 kinds of pyridylaminated hyaluronan/chondroitin sulfate hybrid oligosaccharides （from octasaccahride to dodecasaccharide）, which have not been found in nature, were synthesized.
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論文
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Sawada, Naoya ; Mikami, Kenichiro ; Igarashi, Go ; Endo, Tetsu ; Sato, Ken ; Kakizaki, Ikuko ; Fukuda, Shinsaku
概要:
Background & Aims: Liver fibrosis progresses to cirrhosis as the consequence of chronic liver injury. 4-methylumbellifer
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one （4-MU）, a derivative of coumarin, has been used as an approved drug to treat biliary spasm. Recent publications have reported that 4-MU inhibits production of hyaluronan （HA）, which is a key component of extracellular matrix deposition in fibrotic and cirrhotic liver. We investigated the effect of 4-MU on fibrotic liver in rats. Methods: Liver fibrosis was induced by bile duct ligation（ BDL）. Male Sprague-Dawley rats received a standard diet or the same diet containing 1% or 5% of 4-MU from 1 week before BDL. The rats were sacrificed at 3 weeks after BDL. Results: Administration of 4-MU increased serum 4-MU concentration levels, thereby decreasing serum HA levels in a dose-dependent manner. 4-MU treatment suppressed liver fibrosis in interlobular and pericentral areas with reduced alpha-smooth muscle actin expression, which suggested hepatic stellate cell activation.Conclusion: Treatment with 4-MU suppressed the experimental hepatic fibrosis accompanied by inhibition of HA production. Although further experimental studies are needed, 4-MU could protect against fibrogenesis and may be repurposed as a safe therapeutic application for hepatic fibrosis.
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論文
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Endo, Yasufumi ; Takahashi, Gen ; Kakizaki, Ikuko ; Endo, Masahiko
概要:
Abstract: Hyaluronan （HA） is a ubiquitous glycosaminoglycan comprising N-acetylglucosamine and glucuronic acid and is in
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volved in matrix formation and cell maintenance. 4-Methylumbelliferone （MU） exhibits anti-tumor activities by inhibiting HA synthesis. In this study, we aimed to elucidate the association between HA and numerous matrix molecules.Materials and Methods: We created HA-knock down extracellular matrix （ECM） by culturing human skin fibroblasts（ HSF） in the presence of MU（ 0.5 mM） for 3 days after confluence. Following culture in the presence or absence of MU, the cell layer and culture medium were collected and ECM molecules were measured using enzymelinked immunosolvent assay, and the［ 35S］-sulfate uptake method.Results: Proteoglycans and type I collagen were released into the medium as HA decreased. However, type collagen, but not proteoglycans, was immediately replenished. Fibronectin and CD44 in the cell layer decreased, but were not replenished, as HA decreased. On contrary, laminin, cadherin, and vitronectin were not affected by HA decrease.Conclusions: HA knockdown by MU treatment elucidated the dynamic interactions between HA and ECM components. Our findings suggest that HA interacts with other ECM components through various ways, including
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