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01 奈良県立医科大学 >
012 大学院 >
0122 学位請求論文 >
01221 博士論文(医学) >
2024年度 >
このアイテムの引用には次の識別子を使用してください:
http://hdl.handle.net/10564/4452
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タイトル: | Cabozantinib prevents the progression of metabolic dysfunction-associated steatohepatitis by inhibiting the activation of hepatic stellate cell and macrophage and attenuating angiogenic activity |
その他のタイトル: | カボザンチニブは、肝星細胞とマクロファージの活性化を阻害し、血管新生活性を減弱することで代謝機能障害関連脂肪肝の進展を抑制する |
著者: | Matsuda, Takuya Kaji, Kosuke Nishimura, Norihisa Asada, Shohei Koizumi, Aritoshi Tanaka, Misako Yorioka, Nobuyuki Tsuji, Yuki Kitagawa, Koh Sato, Shinya Namisaki, Tadashi Akahane, Takemi Hitoshi, Yoshij |
キーワード: | Angiogenesis Liver fibrosis MASH Inflammation Hepatocarcinogenesis |
発行日: | 2024年9月 |
出版者: | Elsevier |
引用: | Heliyon. 2024 Sep, vol.10, no.19, p.e38647 |
抄録: | Cabozantinib, a multiple tyrosine kinase inhibitor targeting AXL, vascular endothelial growth factor receptor (VEGFR), and MET, is used clinically to treat certain cancers, including hepato cellular carcinoma. This study aimed to assess the impact of cabozantinib on liver fibrosis and hepatocarcinogenesis in a rat model of metabolic dysfunction-associated steatohepatitis (MASH). MASH-based liver fibrosis and hepatocarcinogenesis were induced in rats by feeding them a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for eight and 16 weeks, respectively. Cabozantinib (1 or 2 mg/kg, daily) was administered concurrently with the diet in the fibrosis model and after eight weeks in the carcinogenesis model. Treatment with cabozantinib significantly attenuated hepatic inflammation and fibrosis without affecting hepatocyte steatosis and ballooning in CDAHFD-fed rats. Cabozantinib-treated rats exhibited a marked reduction in α-smooth muscle actin+ activated hepatic stellate cell (HSC) expansion, CD68+ macrophage infiltration, and CD34+ pathological angiogenesis, along with reduced hepatic AXL, VEGF, and VEGFR2 expression. Consistently, cabozantinib downregulated the hepatic expression
of profibrogenic markers (Acta2, Col1a1, Tgfb1), inflammatory cytokines (Tnfa, Il1b, Il6), and proangiogenic markers (Vegfa, Vwf, Ang2). In a cell-based assay of human activated HSCs, cabozantinib inhibited Akt activation induced by GAS6, a ligand of AXL, leading to reduced cell proliferation and profibrogenic activity. Cabozantinib also suppressed lipopolysaccharide induced proinflammatory responses in human macrophages, VEGFA-induced collagen expres sion and proliferation in activated HSCs, and VEGFA-stimulated proliferation in vascular endothelial cells. Meanwhile, administration of cabozantinib did not affect Ki67+ hepatocyte proliferation or serum albumin levels, indicating no negative impact on regenerative capacity. Treatment with cabozantinib also reduced the placental glutathione transferase+ preneoplastic
lesions in CDAHFD-fed rats. In conclusion, cabozantinib shows promise as a novel option for preventing MASH progression. |
内容記述: | 権利情報:© 2024 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
URI: | http://hdl.handle.net/10564/4452 |
ISSN: | 2405-8440 |
DOI: | https://doi.org/10.1016/j.heliyon.2024.e38647 |
学位授与番号: | 24601甲第957号 |
学位授与年月日: | 2025-03-14 |
学位名: | 博士(医学) |
学位授与機関: | 奈良県立医科大学 |
出現コレクション: | 2024年度
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