| アイテムタイプ |
学術雑誌論文 / Journal Article(1) |
| 公開日 |
2025-08-19 |
| タイトル |
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タイトル |
Inhibition of the TLR4/RAGE pathway by clearance of extracellular HMGB1 is a potential therapeutic target for radiation-damaged salivary glands |
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言語 |
en |
| 言語 |
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|
言語 |
eng |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
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資源タイプ |
journal article |
| 著者 |
I, Takashi
Kanai, Riho
Seki, Makoto
Agata, Hideki
Kagami, Hideaki
Murata, Hiroshi
Asahina, Izumi
Tran, Simon D.
Sumita, Yoshinori
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| 抄録 |
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内容記述タイプ |
Abstract |
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内容記述 |
Introduction: We recently developed a new therapy using effective-mononuclear cells (E-MNCs) and demonstrated its efficacy in treating radiation-damaged salivary glands (SGs). The activity of E-MNCs in part involves constituent immunoregulatory -CD11b/macrophage scavenger receptor 1(Msr1)-positive-M2 macrophages, which exert anti-inflammatory and tissue-regenerating effects via phagocytic clearance of extracellular high mobility group box 1 (HMGB1). Focusing on the phenomena, this study investigated significance of regulating the HMGB1/toll-like receptor 4 (TLR4)/receptor for advanced glycation end products (RAGE) signaling pathway in the treatment of SG dysfunction caused by radiation damage. Methods: E-MNCs were transplanted into radiation-damaged mice SGs, and changes of TLR4/RAGE expression were observed. Furthermore, the activation of downstream signals was investigated in both intact SGs and cultured SG epithelial cells after irradiation. Subsequently, TLR4-knock-out (KO) mice were employed to examine how HMGB1/TLR4/RAGE signaling affected damage progression. Results: Expression of both TLR4 and RAGE was diminished in ductal cells and macrophages/vascular endothelial cells of damaged SGs with E-MNC transplantation, respectively. Meanwhile, expression of TLR2/4 and RAGE in damaged SGs markedly increased in association with extracellular HMGB1 accumulation. Downstream signals were activated, and intranuclear localization of phospho-nuclear factor-kappa B (p–NF–KB) in ductal cells and production of IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were observed. Additionally, culture supernatant of irradiated cultured SG epithelial cells contained damaged associated molecular pattern (DAMP)/senescence-associated secretory phenotype (SASP) factors. Treatment of cultured SG epithelial cells with this supernatant activated TLR4 signaling pathway and induced cellular senescence. In TLR4-KO mice, onset of radiogenic SG dysfunction was markedly delayed. However, TLR2/RAGE signalings were alternatively activated, and SG function was impaired. Conclusions: Clearance of DAMPs such as HMGB1 may attenuate sterile inflammation in damaged SGs via suppression of the TLR4/RAGE signaling pathway. This cellular mechanism may have significant implications for the development of future cell-based regenerative therapies. |
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言語 |
en |
| 書誌情報 |
en : Regenerative Therapy
巻 30,
p. 476-490,
発行日 2025-07-31
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| 出版者 |
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出版者 |
Elsevier BV |
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言語 |
en |
| ISSN |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
23523204 |
| DOI |
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関連タイプ |
isIdenticalTo |
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識別子タイプ |
DOI |
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関連識別子 |
10.1016/j.reth.2025.07.004 |
| 権利 |
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権利情報 |
© 2025 The Author(s). Published by Elsevier BV on behalf of The Japanese Society for Regenerative Medicine. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
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言語 |
en |
| 著者版フラグ |
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出版タイプ |
VoR |
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出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| 引用 |
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内容記述タイプ |
Other |
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内容記述 |
Regenerative Therapy, 30, pp.476-490; 2025 |
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言語 |
en |
RT30_476.pdf (13.3 MB)
