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Hepatoprotective effect of genistein against dimethylnitrosamine-induced liver fibrosis in rats by regulating macrophage functional properties and inhibiting the JAK2/STAT3/SOCS3 signaling pathway.
Front Biosci (Landmark Ed). 2021 12 30; 26(12):1572-1584.FB

Abstract

BACKGROUND

Liver fibrosis is a dysregulated wound-healing process in response to diverse liver injuries, and an effective drug therapy is not yet available. Genistein, which is one of the most active natural flavonoids mainly derived from soybean products (e.g., Cordyceps sinensis mycelium), exhibits various biological effects, including hepatoprotective and anti-inflammatory properties. However, the anti-hepatic fibrosis mechanisms of genistein are poorly understood. The aim of our research is to explore the effect and the possible mechanism of genistein against liver fibrosis.

MATERIALS AND METHODS

Cell counting kit-8, EdU, and flow cytometry assays were applied to evaluate the effects of genistein on cell viability, proliferation, and cell cycle arrest in human hepatic stellate cell (HSC) line LX2 cells. HSC activation was induced by transforming growth factor-β1 in LX2 cells and liver fibrosis model was established by the intraperitoneal injection of dimethylnitrosamine (DMN) in rats to assess the anti-fibrosis effects of genistein in vivo and in vitro models. HSC activation was assessed by qRT-PCR, Western blot, immunohistochemistry, and immunofluorescent assay. Liver injury and collagen deposition were evaluated by histopathological assay, serum biochemistry, and hepatic hydroxyproline content assays. The mRNA expressions of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and inflammation related-factors were assessed by qRT-PCR assay. Furthermore, the functional properties of macrophage in the liver were assessed by immunohistochemistry assay. The expression levels of the JAK2/STAT3/SOCS3 signaling pathway related-protein were assessed by Western blot analysis.

RESULTS

Genistein significantly inhibited cell viability and proliferation and induced cell cycle arrest at G0/G1 phase in LX2 cells, respectively. Furthermore, oral administration of genistein significantly ameliorated liver injury and the collagen deposition in rats with DMN-induced fibrosis model. Genistein suppressed the expression levels of HSC activation marker α-smooth muscle actin and collagen type I alpha 1 in vivo and in vitro. Genistein significantly decreased the mRNA expression levels of extracellular matrix degradation genes MMP2/9 and TIMP1 in rats. Genistein alleviated the mRNA expression levels of IL-1β, IL-6, TNF-α, and MCP-1 and regulated the protein expressions of CD68, CD163, and CD206 in the liver. Moreover, genistein attenuated the expressions of p-JAK2/JAK2, p-STAT3/STAT3, and SOCS3 protein both in vivo and in vitro.

CONCLUSION

Taken together, our results showed that genistein could be improved liver fibrosis both in vivo and in vitro, probably through regulating the functional properties of macrophage and inhibiting the JAK2/STAT3/SOCS3 signaling pathway.

Authors+Show Affiliations

Experiment Center of Teaching & Learning, Institute of Chinese Materia Medica, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Experiment Center of Teaching & Learning, Institute of Chinese Materia Medica, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Experiment Center of Teaching & Learning, Institute of Chinese Materia Medica, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Experiment Center of Teaching & Learning, Institute of Chinese Materia Medica, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.Experiment Center of Teaching & Learning, Institute of Chinese Materia Medica, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34994171

Citation

Xu, Ying, et al. "Hepatoprotective Effect of Genistein Against Dimethylnitrosamine-induced Liver Fibrosis in Rats By Regulating Macrophage Functional Properties and Inhibiting the JAK2/STAT3/SOCS3 Signaling Pathway." Frontiers in Bioscience (Landmark Edition), vol. 26, no. 12, 2021, pp. 1572-1584.
Xu Y, Zhang D, Yang H, et al. Hepatoprotective effect of genistein against dimethylnitrosamine-induced liver fibrosis in rats by regulating macrophage functional properties and inhibiting the JAK2/STAT3/SOCS3 signaling pathway. Front Biosci (Landmark Ed). 2021;26(12):1572-1584.
Xu, Y., Zhang, D., Yang, H., Liu, Y., Zhang, L., Zhang, C., Chen, G., Hu, Y., Chen, J., Zhang, H., Mu, Y., Liu, P., & Liu, W. (2021). Hepatoprotective effect of genistein against dimethylnitrosamine-induced liver fibrosis in rats by regulating macrophage functional properties and inhibiting the JAK2/STAT3/SOCS3 signaling pathway. Frontiers in Bioscience (Landmark Edition), 26(12), 1572-1584. https://doi.org/10.52586/5050
Xu Y, et al. Hepatoprotective Effect of Genistein Against Dimethylnitrosamine-induced Liver Fibrosis in Rats By Regulating Macrophage Functional Properties and Inhibiting the JAK2/STAT3/SOCS3 Signaling Pathway. Front Biosci (Landmark Ed). 2021 12 30;26(12):1572-1584. PubMed PMID: 34994171.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatoprotective effect of genistein against dimethylnitrosamine-induced liver fibrosis in rats by regulating macrophage functional properties and inhibiting the JAK2/STAT3/SOCS3 signaling pathway. AU - Xu,Ying, AU - Zhang,Dingqi, AU - Yang,Hailin, AU - Liu,Yu, AU - Zhang,Linzhang, AU - Zhang,Congcong, AU - Chen,Gaofeng, AU - Hu,Yonghong, AU - Chen,Jiamei, AU - Zhang,Hua, AU - Mu,Yongping, AU - Liu,Ping, AU - Liu,Wei, PY - 2021/10/16/received PY - 2021/12/01/revised PY - 2021/12/10/accepted PY - 2022/1/7/entrez PY - 2022/1/8/pubmed PY - 2022/1/14/medline KW - Genistein KW - Hepatic stellate cells (HSC) KW - JAK2/STAT3/SOCS3 signaling pathway KW - Liver fibrosis KW - Macrophage functional properties SP - 1572 EP - 1584 JF - Frontiers in bioscience (Landmark edition) JO - Front Biosci (Landmark Ed) VL - 26 IS - 12 N2 - BACKGROUND: Liver fibrosis is a dysregulated wound-healing process in response to diverse liver injuries, and an effective drug therapy is not yet available. Genistein, which is one of the most active natural flavonoids mainly derived from soybean products (e.g., Cordyceps sinensis mycelium), exhibits various biological effects, including hepatoprotective and anti-inflammatory properties. However, the anti-hepatic fibrosis mechanisms of genistein are poorly understood. The aim of our research is to explore the effect and the possible mechanism of genistein against liver fibrosis. MATERIALS AND METHODS: Cell counting kit-8, EdU, and flow cytometry assays were applied to evaluate the effects of genistein on cell viability, proliferation, and cell cycle arrest in human hepatic stellate cell (HSC) line LX2 cells. HSC activation was induced by transforming growth factor-β1 in LX2 cells and liver fibrosis model was established by the intraperitoneal injection of dimethylnitrosamine (DMN) in rats to assess the anti-fibrosis effects of genistein in vivo and in vitro models. HSC activation was assessed by qRT-PCR, Western blot, immunohistochemistry, and immunofluorescent assay. Liver injury and collagen deposition were evaluated by histopathological assay, serum biochemistry, and hepatic hydroxyproline content assays. The mRNA expressions of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and inflammation related-factors were assessed by qRT-PCR assay. Furthermore, the functional properties of macrophage in the liver were assessed by immunohistochemistry assay. The expression levels of the JAK2/STAT3/SOCS3 signaling pathway related-protein were assessed by Western blot analysis. RESULTS: Genistein significantly inhibited cell viability and proliferation and induced cell cycle arrest at G0/G1 phase in LX2 cells, respectively. Furthermore, oral administration of genistein significantly ameliorated liver injury and the collagen deposition in rats with DMN-induced fibrosis model. Genistein suppressed the expression levels of HSC activation marker α-smooth muscle actin and collagen type I alpha 1 in vivo and in vitro. Genistein significantly decreased the mRNA expression levels of extracellular matrix degradation genes MMP2/9 and TIMP1 in rats. Genistein alleviated the mRNA expression levels of IL-1β, IL-6, TNF-α, and MCP-1 and regulated the protein expressions of CD68, CD163, and CD206 in the liver. Moreover, genistein attenuated the expressions of p-JAK2/JAK2, p-STAT3/STAT3, and SOCS3 protein both in vivo and in vitro. CONCLUSION: Taken together, our results showed that genistein could be improved liver fibrosis both in vivo and in vitro, probably through regulating the functional properties of macrophage and inhibiting the JAK2/STAT3/SOCS3 signaling pathway. SN - 2768-6698 UR - https://www.unboundmedicine.com/medline/citation/34994171/Hepatoprotective_effect_of_genistein_against_dimethylnitrosamine_induced_liver_fibrosis_in_rats_by_regulating_macrophage_functional_properties_and_inhibiting_the_JAK2/STAT3/SOCS3_signaling_pathway_ L2 - https://www.fbscience.com/Landmark/articles/10.52586/5050 DB - PRIME DP - Unbound Medicine ER -