{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:02:52Z","timestamp":1791385372537,"version":"4.3.3"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2014,6,17]],"date-time":"2014-06-17T00:00:00Z","timestamp":1402963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The aim of this study was to examine the effect of standardized extract of Salvia miltiorrhiza (SME) on gene and protein expression of non-alcoholic steatohepatitis (NASH)-related factors in activated human hepatic stellate cells (HSC), and in mice with steatohepatitis induced by a methionine-choline deficient (MCD) diet. Male C57BL\/6J mice were placed on an MCD or control diet for 8 weeks and SME (0, 0.1, 0.5 and 1 mg\/kg body weight) was administered orally every other day for 4 or 6 weeks. HSCs from the LX-2 cell line were treated with transforming growth factor \u03b2-1 (TGF-\u03b21) or TGF-\u03b21 plus SME (0.1\u201310 \u03bcg\/mL). To investigate the effect of SME on reactive oxygen species  (ROS)-induced condition, LX-2 cells were treated with hydrogen peroxide (H2O2) or H2O2 plus SME (0.1\u2013100 \u03bcg\/mL). MCD administration for 12 weeks increased mRNA expression of tumor necrosis factor (TNF-\u03b1), TGF-\u03b21, interleukin-1\u03b2 (IL-1\u03b2), C-reactive protein (CRP), \u03b1-smooth muscle actin (\u03b1-SMA), type I collagen, matrix metalloproteinase-2 (MMP-2) and MMP-9. TGF-\u03b21-induced LX-2 cells exhibited similar gene expression patterns. SME treatment significantly reduced the mRNA and protein expression of NASH-related factors in the mouse model and HSCs. Histopathological liver analysis showed improved non-alcoholic fatty liver disease (NAFLD) activity and fibrosis score in SME-treated mice. The in vivo studies showed that SME had a significant effect at low doses. These results suggest that SME might be a potential therapeutic candidate for NAFLD treatment.<\/jats:p>","DOI":"10.3390\/molecules19068189","type":"journal-article","created":{"date-parts":[[2014,6,17]],"date-time":"2014-06-17T10:57:13Z","timestamp":1403002633000},"page":"8189-8211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Standardized Salvia miltiorrhiza Extract Suppresses Hepatic Stellate Cell Activation and Attenuates Steatohepatitis Induced by a Methionine-Choline Deficient Diet in Mice"],"prefix":"10.3390","volume":"19","author":[{"given":"Hak","family":"Lee","sequence":"first","affiliation":[{"name":"Natural Products Research Institute, College of Pharmacy, Seoul National University,  1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea"},{"name":"Research Center, Samil Pharmaceutical Co. Ltd., 216 Sandan-ro, Danwon-gu,  Ansan 425-852, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo-Chan","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center,  88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Eun","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center,  88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bon","family":"Koo","sequence":"additional","affiliation":[{"name":"Research Center, Samil Pharmaceutical Co. Ltd., 216 Sandan-ro, Danwon-gu,  Ansan 425-852, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Natural Products Research Institute, College of Pharmacy, Seoul National University,  1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S104","DOI":"10.1016\/j.jhep.2008.01.009","article-title":"Non-alcoholic fatty liver disease: The mist gradually clears","volume":"48","author":"Day","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0002-9343(99)00271-5","article-title":"Association of nonalcoholic fatty liver disease with insulin resistance","volume":"107","author":"Marchesini","year":"1999","journal-title":"Am. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1172\/JCI200422422","article-title":"Molecular mediators of hepatic steatosis and liver injury","volume":"114","author":"Browning","year":"2004","journal-title":"J. Clin. Invest."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1002\/hep.20842","article-title":"Histopathology of pediatric nonalcoholic fatty liver disease","volume":"42","author":"Schwimmer","year":"2005","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1097\/00042737-200411000-00001","article-title":"Non-alcoholic steatohepatitis","volume":"16","author":"Jansen","year":"2004","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1055\/s-2004-823104","article-title":"The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: A four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis","volume":"24","author":"Wanless","year":"2004","journal-title":"Semin. Liver Dis."},{"key":"ref_7","first-page":"2714","article-title":"Nonalcoholic steatohepatitis: What we know in the new millennium","volume":"97","author":"Harrison","year":"2002","journal-title":"Am. J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.jhep.2005.09.002","article-title":"Non-alcoholic steatohepatitis: From cell biology to clinical practice","volume":"44","author":"Day","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.0959-9673.2006.00465.x","article-title":"Mouse models in non-alcoholic fatty liver disease and steatohepatitis research","volume":"87","author":"Anstee","year":"2006","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1172\/JCI8814","article-title":"Cyp2e1 and cyp4a as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis","volume":"105","author":"Leclercq","year":"2000","journal-title":"J. Clin. Invest."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1582-4934.2002.tb00518.x","article-title":"Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats fed with a choline-deficient diet","volume":"6","author":"Oliveira","year":"2002","journal-title":"J. Cell Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1056\/NEJM200011163432007","article-title":"Cytokines in alcoholic and nonalcoholic steatohepatitis","volume":"343","author":"Tilg","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2174\/156652409787847191","article-title":"Nonalcoholic fatty liver disease: The pathogenetic roles of insulin resistance and adipocytokines","volume":"9","author":"Polyzos","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1053\/gast.2002.32995","article-title":"Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat","volume":"122","author":"Ikejima","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1053\/jhep.2001.28457","article-title":"Transforming growth factor beta and the liver","volume":"34","author":"Bissell","year":"2001","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/S0168-8278(97)80151-1","article-title":"Effect of tumour necrosis factor-alpha on proliferation, activation and protein synthesis of rat hepatic stellate cells","volume":"27","author":"Knittel","year":"1997","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"22341","DOI":"10.1074\/jbc.M010839200","article-title":"Transforming growth factor-beta-and tumor necrosis factor-alpha -mediated induction and proteolytic activation of mmp-9 in human skin","volume":"276","author":"Han","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"G245","DOI":"10.1152\/ajpgi.2000.279.2.G245","article-title":"Fibrogenesis, II. Metalloproteinases and their inhibitors in liver fibrosis","volume":"279","author":"Arthur","year":"2000","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1165\/ajrcmb\/7.2.120","article-title":"The matrix metalloproteinases and their inhibitors","volume":"7","author":"Murphy","year":"1992","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1172\/JCI114270","article-title":"Lipocytes from normal rat liver release a neutral metalloproteinase that degrades basement membrane (type iv) collagen","volume":"84","author":"Arthur","year":"1989","journal-title":"J. Clin. Invest."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/S0168-8278(99)80007-5","article-title":"Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: Regulation by tnf-alpha and tgf-beta1","volume":"30","author":"Knittel","year":"1999","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.pharmthera.2007.09.008","article-title":"Ameliorating effects of compounds derived from salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion","volume":"117","author":"Han","year":"2008","journal-title":"Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2006.04.044","article-title":"Tanshinone iia inhibits lps-induced nf-kappab activation in raw 264.7 cells: Possible involvement of the nik-ikk, erk1\/2, p38 and jnk pathways","volume":"542","author":"Jang","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0024-3205(99)00642-6","article-title":"Antioxidative activity of natural products from plants","volume":"66","author":"Ng","year":"2000","journal-title":"Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/emm.1999.28","article-title":"Tanshinone iia, an ingredient of salvia miltiorrhiza bunge, induces apoptosis in human leukemia cell lines through the activation of caspase-3","volume":"31","author":"Sung","year":"1999","journal-title":"Exp. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.jsbmb.2009.01.011","article-title":"The anti-inflammatory activities of tanshinone iia, an active component of tcm, are mediated by estrogen receptor activation and inhibition of inos","volume":"113","author":"Fan","year":"2009","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s12272-001-1209-2","article-title":"Effects of tanshinone iia on the hepatotoxicity and gene expression involved in alcoholic liver disease","volume":"31","author":"Yin","year":"2008","journal-title":"Arch. Pharm. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"262","DOI":"10.3736\/jintegrmed2013034","article-title":"Bioactivity of five components of Chinese herbal formula jiangzhi granules against hepatocellular steatosis","volume":"11","author":"Song","year":"2013","journal-title":"J. Integr. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/j.lfs.2007.08.043","article-title":"Tanshinone iia inhibits atherosclerotic plaque formation by down-regulating mmp-2 and mmp-9 expression in rabbits fed a high-fat diet","volume":"81","author":"Fang","year":"2007","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/labinvest.2009.112","article-title":"Curcumin limits the fibrogenic evolution of experimental steatohepatitis","volume":"90","author":"Vizzutti","year":"2010","journal-title":"Lab. Invest."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"23916","DOI":"10.1074\/jbc.M312676200","article-title":"A choline-deficient diet in mice inhibits neither the cdp-choline pathway for phosphatidylcholine synthesis in hepatocytes nor apolipoprotein b secretion","volume":"279","author":"Kulinski","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.jhep.2009.03.025","article-title":"Farnesoid x receptor agonist way-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis","volume":"51","author":"Zhang","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"G1070","DOI":"10.1152\/ajpgi.00228.2004","article-title":"Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease","volume":"287","author":"Gao","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1055\/s-2002-26761","article-title":"Oxidative stress, plant-derived antioxidants and liver fibrosis","volume":"68","author":"Gebhardt","year":"2002","journal-title":"Planta Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/labinvest.3700109","article-title":"Asbestos-derived reactive oxygen species activate tgf-beta1","volume":"84","author":"Pociask","year":"2004","journal-title":"Lab. Invest."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/jcb.10498","article-title":"Mitochondrial and microsomal derived reactive oxygen species mediate apoptosis induced by transforming growth factor-beta1 in immortalized rat hepatocytes","volume":"89","author":"Albright","year":"2003","journal-title":"J. Cell Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15488","DOI":"10.1016\/S0021-9258(17)40705-8","article-title":"Suppression of antioxidative enzyme expression by transforming growth factor-beta 1 in rat hepatocytes","volume":"269","author":"Kayanoki","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.24127","article-title":"Nonalcoholic fatty liver disease (nafld) activity score and the histopathologic diagnosis in nafld: Distinct clinicopathologic meanings","volume":"53","author":"Brunt","year":"2011","journal-title":"Hepatology"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/19\/6\/8189\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:12:34Z","timestamp":1760217154000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/19\/6\/8189"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,17]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2014,6]]}},"alternative-id":["molecules19068189"],"URL":"https:\/\/doi.org\/10.3390\/molecules19068189","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,17]]}}}