Natural compound fraxinellone ameliorates intestinal fibrosis in mice via direct intervention of HSP47-collagen interaction in the epithelium
© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society..
Intestinal fibrosis is a common complication of inflammatory bowel disease. There is still a lack of effective drugs for the prevention or treatment of intestinal fibrosis. Heat shock protein 47 (HSP47) plays a key role in the development of intestinal fibrosis. In this study we investigated the therapeutic potential and underlying mechanisms of fraxinellone, a degraded limonoid isolated from the root bark of Dictamnus dasycarpus, in the treatment of intestinal fibrosis. Intestinal fibrosis was induced in mice by dextran sodium sulfate (DSS) treatment. DDS-treated mice were administered fraxinellone (7.5, 15, 30 mg·kg-1·d-1, i.g.) for 45 days. We showed that fraxinellone administration dose-dependently alleviated DSS-induced intestinal impairments, and reduced the production of intestinal fibrosis biomarkers such as α-smooth muscle actin (SMA), collagen I, hydroxyproline, fibronectin and laminin, and cytokines such as TGF-β, TNF-α and IL-β. We then established in vitro intestinal fibrosis cell models in SW480 and HT-29 cells, and demonstrated that treatment with fraxinellone (3, 10, 30 μM) significantly relieved TGF-β-induced fibrosis responses by inhibiting the TGF-β/Smad2/3 signaling pathway. Molecular docking suggested that the fraxinellone might disrupt the interaction between HSP47 and collagen, which was confirmed by coimmunoprecipitation experiments. SPR analysis showed that fraxinellone had a high affinity for HSP47 with a Kd value of 3.542 × 10-5 M. This study provides a new example of HSP47-collagen intervention by a natural compound and has important implications for the clinical treatment of inflammation-induced issue fibrosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:44 |
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| Enthalten in: |
Acta pharmacologica Sinica - 44(2023), 12 vom: 14. Dez., Seite 2469-2478 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Jie [VerfasserIn] |
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| Links: |
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| Themen: |
28808-62-0 |
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| Anmerkungen: |
Date Completed 04.12.2023 Date Revised 05.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41401-023-01143-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM360798209 |
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| 520 | |a © 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society. | ||
| 520 | |a Intestinal fibrosis is a common complication of inflammatory bowel disease. There is still a lack of effective drugs for the prevention or treatment of intestinal fibrosis. Heat shock protein 47 (HSP47) plays a key role in the development of intestinal fibrosis. In this study we investigated the therapeutic potential and underlying mechanisms of fraxinellone, a degraded limonoid isolated from the root bark of Dictamnus dasycarpus, in the treatment of intestinal fibrosis. Intestinal fibrosis was induced in mice by dextran sodium sulfate (DSS) treatment. DDS-treated mice were administered fraxinellone (7.5, 15, 30 mg·kg-1·d-1, i.g.) for 45 days. We showed that fraxinellone administration dose-dependently alleviated DSS-induced intestinal impairments, and reduced the production of intestinal fibrosis biomarkers such as α-smooth muscle actin (SMA), collagen I, hydroxyproline, fibronectin and laminin, and cytokines such as TGF-β, TNF-α and IL-β. We then established in vitro intestinal fibrosis cell models in SW480 and HT-29 cells, and demonstrated that treatment with fraxinellone (3, 10, 30 μM) significantly relieved TGF-β-induced fibrosis responses by inhibiting the TGF-β/Smad2/3 signaling pathway. Molecular docking suggested that the fraxinellone might disrupt the interaction between HSP47 and collagen, which was confirmed by coimmunoprecipitation experiments. SPR analysis showed that fraxinellone had a high affinity for HSP47 with a Kd value of 3.542 × 10-5 M. This study provides a new example of HSP47-collagen intervention by a natural compound and has important implications for the clinical treatment of inflammation-induced issue fibrosis | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a antifibrotic drugs | |
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| 700 | 1 | |a Bai, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Cui |e verfasserin |4 aut | |
| 700 | 1 | |a An, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiao-Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Rong-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Zhi-Yao |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xu-Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xue-Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Qiang |e verfasserin |4 aut | |
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