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Locostatin Alleviates Liver Fibrosis Induced by Carbon Tetrachloride in Mice

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Abstract

Background and Aims

Liver fibrosis is featured with excessive deposition of extracellular matrix and fibrous connective tissue hyperplasia. The specific inhibitor of Raf-1 kinase inhibitor protein, locostatin, inhibits the migration of hepatic stellate cells. In this study, we investigated the effect of locostatin on liver fibrosis and its underlying mechanism.

Methods

Carbon tetrachloride (CCl4) was used to induce liver fibrosis in mice, and locostatin was injected intraperitoneally. Liver fibrosis was assessed by Masson and Sirius red staining, hydroxyproline (HYP) assay, and collagen percentage area. Collagen I, collagen III, and α-SMA were detected by RT-PCR and western blot. The levels of MMP-13, MMP-2, TIMP-1, and TIMP-2 were estimated by ELISA. Liver inflammation was evaluated by HE staining and immunohistochemistry; liver myeloperoxidase (MPO), superoxide dismutase, and malondialdehyde were measured by ELISA; and cytokines were by Mouse Cytokine Array Q4000.

Results

Compared to the CCl4 group, HYP (208.56 ± 6.12) µg/g, percentage of total collagen at overall region (1.91 ± 0.13), MMP-13/TIMP-1 (0.19 ± 0.01), MPO (1.45 ± 0.04) U/g, TGF-β (2652 ± 91.20), PDGF-AA (3897 ± 290.69), and E-selectin (1569 ± 66.48) in the liver tissues were decreased significantly in the locostatin-treated group.

Conclusions

Locostatin mitigated liver fibrosis and inflammation induced by CCl4. The mechanism is via inhibition inflammatory cytokines, TGF-β, PDGF-AA, and E-selectin.

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Acknowledgments

This work was supported by grants to JJM from the National Natural Science Foundation of China (No. 81200311), the National Natural Science Foundation of Hebei Province (China, H2015206431), the scientific research projects funded by talents engineering training in Hebei (China, A2016005065), the Hebei medical research key project (China, 20130184), and the Hebei youth talents project. The authors thank all the members of Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology.

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  1. Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China

    Junji Ma, Yuzi Qiu, Min Wang, Ming Zhang, Xiaoyi Zhao & Huiqing Jiang

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  1. Junji Ma
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  2. Yuzi Qiu
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Correspondence to Junji Ma.

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Ma, J., Qiu, Y., Wang, M. et al. Locostatin Alleviates Liver Fibrosis Induced by Carbon Tetrachloride in Mice. Dig Dis Sci 64, 2570–2580 (2019). https://doi.org/10.1007/s10620-019-05588-5

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