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Studies on biological activities of small molecules regulating the NF-κB signaling pathway induced by inflammatory cytokines
http://hdl.handle.net/10212/2421
http://hdl.handle.net/10212/242138cee2fd-6e6b-49ae-b58e-46094ce82b5a
| 名前 / ファイル | ライセンス | アクション |
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全文 (8.2 MB)
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内容・審査結果の要旨 (196.9 KB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||||
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| 公開日 | 2019-09-17 | |||||||||
| タイトル | ||||||||||
| タイトル | Studies on biological activities of small molecules regulating the NF-κB signaling pathway induced by inflammatory cytokines | |||||||||
| 言語 | en | |||||||||
| その他のタイトル | ||||||||||
| その他のタイトル | 炎症性サイトカインによって誘導されるNF-κBシグナル伝達経路を制御する小分子化合物の生物活性に関する研究 | |||||||||
| 言語 | ja | |||||||||
| 作成者 |
クワッ トゥ フエィ
× クワッ トゥ フエィ
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| アクセス権 | ||||||||||
| アクセス権 | open access | |||||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | irciniastatin A | |||||||||
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| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | extracellular signal-regulated kinase | |||||||||
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| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | translation inhibitor | |||||||||
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| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | ribotoxic stress response | |||||||||
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| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | eudesmane | |||||||||
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| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | lymphotoxin β | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | nuclear factor κB | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | relB | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | sesquiterpene lactone | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | allantopyrone A | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | RIP1 | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | TNF-α | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | TNF receptor 1 | |||||||||
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| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | TRAF2 | |||||||||
| 内容記述 | ||||||||||
| 内容記述タイプ | Abstract | |||||||||
| 内容記述 | The nuclear factor κB (NF-κB) signaling pathway plays a crucial role in our immune system. Small molecules with selective inhibitory activities are highly attractive agents to regulate NF-κB activation. Irciniastatin A is a pederin-type marine product that potently inhibits translation. In A549 cells, irciniastatin A induced a marked and sustained activation of extracellular signal-regulated kinase (ERK) and slightly induced the activation of p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK). Moreover, the TNF receptor 1 (TNF-R1) shedding induced by irciniastatin A was blocked by the ERK kinase inhibitor, neither by p38 MAP kinase inhibitor nor JNK inhibitor. In consequence, these results indicated that irciniastatin A is a unique translation inhibitor that induces a potent and sustained activation of the ERK pathway, and thereby promotes the ectodomain shedding of TNF receptor 1 in A549 cells. Previous research showed that eudesmane-type sesquiterpene lactones inhibited multiple steps of the canonical NF-κB signaling pathway. This study revealed that (11S)-2α-bromo-3-oxoeudesmano-12,6α-lactone, also known as santonin-related compound 2 (SRC2), not only blocked the LTβ-induced-NF-κB luciferase responsiveness but also restrained the nuclear translocation of NF-B subunits RelB and p52 without affecting the proteolytic processing of p100. Unlike (–)-dehydroxymethylepoxyquinomicin (DHMEQ), SRC2 inhibited the LTβ-induced nuclear translocation of both RelB wildtype and RelB (C144S) mutant whereas (–)-DHMEQ weakly inhibited the nuclear RelB (C144S). Furthermore, eudesmane-type sesquiterpenes lactones that possessed α-bromo ketones exerted stronger inhibitory activity than those compounds possessing a single α,β-unsaturated carbonyl moiety. Allantopyrone A-a natural compound synthesized from endophytic fungus, was found to induce the cross-linking of the components of TNF-R1 complex, including receptor-interacting protein 1 (RIP1), TNF receptor-associated factor 2 and inhibitor of NF-κB kinase β, and the NF-κB subunit RelA in A549 cells. The extracellular cysteine-rich domains of TNF-R1 were cross-linked by allantopyrone A more preferentially than its intracellular portion. This study showed that allantopyrone A interferes with multiple components of the TNF-R1 complex and blocks RIP1 modifications in the TNF-α-induced NF-κB signaling pathway. | |||||||||
| 言語 | en | |||||||||
| 日付 | ||||||||||
| 日付 | 2017-09-25 | |||||||||
| 日付タイプ | Issued | |||||||||
| 言語 | ||||||||||
| 言語 | eng | |||||||||
| 資源タイプ | ||||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||||
| 資源タイプ | doctoral thesis | |||||||||
| 出版タイプ | ||||||||||
| 出版タイプ | VoR | |||||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||||
| 学位授与番号 | ||||||||||
| 学位授与番号 | 甲第845号 | |||||||||
| 学位名 | ||||||||||
| 言語 | ja | |||||||||
| 学位名 | 博士（学術） | |||||||||
| 学位授与年月日 | ||||||||||
| 学位授与年月日 | 2017-09-25 | |||||||||
| 学位授与機関 | ||||||||||
| 学位授与機関識別子Scheme | kakenhi | |||||||||
| 学位授与機関識別子 | 14303 | |||||||||
| 言語 | ja | |||||||||
| 学位授与機関名 | 京都工芸繊維大学 | |||||||||
