Abstract
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.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Nos. 82073910, 82173871, 21937005), the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China (Grant No. KF-GN-202101), and Fundamental Research Funds for the Central University (021414380503).
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JW, XFW, and QX designed research. JW, MB, CZ, NA, and LW performed research and analyzed data. XNW, RHD, YS, XDW, XFW, ZYY, and QX contributed new reagents. JW and XFW wrote the paper. All of the authors have approved the final manuscript.
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Wang, J., Bai, M., Zhang, C. et al. Natural compound fraxinellone ameliorates intestinal fibrosis in mice via direct intervention of HSP47-collagen interaction in the epithelium. Acta Pharmacol Sin 44, 2469–2478 (2023). https://doi.org/10.1038/s41401-023-01143-1
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DOI: https://doi.org/10.1038/s41401-023-01143-1
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