{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T19:05:45Z","timestamp":1793300745543,"version":"4.5.0"},"reference-count":72,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National University Development Project at Jeonbuk National University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatic fibrosis is a form of irregular wound-healing response with acute and chronic injury triggered by the deposition of excessive extracellular matrix. Epithelial\u2013mesenchymal transition (EMT) is a dynamic process that plays a crucial role in the fibrogenic response and pathogenesis of liver fibrosis. In the present study, we postulated a protective role of 3,3\u2032-diindolylmethane (DIM) against TGF-\u03b21 mediated epithelial\u2013mesenchymal transition (EMT) in vitro and carbon tetrachloride (CCl4)-induced liver fibrosis in mice. TGF-\u03b21-induced AML-12 hepatocyte injury was evaluated by monitoring cell morphology, measuring reactive oxygen species (ROS) and mitochondrial membrane potential, and quantifying apoptosis, inflammatory, and EMT-related proteins. Furthermore, CCl4-induced liver fibrosis in mice was evaluated by performing liver function tests, including serum ALT and AST, total bilirubin, and albumin to assess liver injury and by performing H&amp;E and Sirius red staining to determine the degree of liver fibrosis. Immunoblotting was performed to determine the expression levels of inflammation, apoptosis, and Nrf2\/HO-1 signaling-related proteins. DIM treatment significantly restored TGF-\u03b21-induced morphological changes, inhibited the expression of mesenchymal markers by activating E-cadherin, decreased mitochondrial membrane potential, reduced ROS intensity, and upregulated levels of Nrf2-responsive antioxidant genes. In the mouse model of CCl4-induced liver fibrosis, DIM remarkably attenuated liver injury and liver fibrosis, as reflected by the reduced ALT and AST parameters with increased serum Alb activity and fewer lesions in H&amp;E staining. It also mitigated the fibrosis area in Sirius red and Masson staining. Taken together, our results suggest a possible molecular mechanism of DIM by suppressing TGF-\u03b21-induced EMT in mouse hepatocytes and CCl4-induced liver fibrosis in mice.<\/jats:p>","DOI":"10.3390\/ijms231911407","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T23:12:12Z","timestamp":1664320332000},"page":"11407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Hepatoprotective Effects of a Natural Flavanol 3,3\u2032-Diindolylmethane against CCl4-Induced Chronic Liver Injury in Mice and TGF\u03b21-Induced EMT in Mouse Hepatocytes via Activation of Nrf2 Cascade"],"prefix":"10.3390","volume":"23","author":[{"given":"Suvesh","family":"Munakarmi","sequence":"first","affiliation":[{"name":"Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamuna","family":"Gurau","sequence":"additional","affiliation":[{"name":"Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juna","family":"Shrestha","sequence":"additional","affiliation":[{"name":"Alka Hospital Private Limited, Jwalakhel, Kathmandu 446010, Nepal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabodh","family":"Risal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medical Sciences, Kathmandu University, Dhulikhel 45200, Nepal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Sung","family":"Park","sequence":"additional","affiliation":[{"name":"Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea"},{"name":"Department of Pathology, Jeonbuk National University Hospital, Jeonju 54907, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Beak","family":"Shin","sequence":"additional","affiliation":[{"name":"Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea"},{"name":"Department of Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6635-4627","authenticated-orcid":false,"given":"Yeon Jun","family":"Jeong","sequence":"additional","affiliation":[{"name":"Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea"},{"name":"Department of Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6799","DOI":"10.1002\/jcp.26541","article-title":"Ursolic acid ameliorates CCl4-induced liver fibrosis through the NOXs\/ROS pathway","volume":"233","author":"Gan","year":"2018","journal-title":"J. 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