{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:55:40Z","timestamp":1791050140508,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2013,2,6]],"date-time":"2013-02-06T00:00:00Z","timestamp":1360108800000},"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>During the course of our attempts to develop a potential herbal medicine, we had previously prepared PF2401-SF, a standardized fraction of S. miltiorrhiza, and reported its hepatoprotective activity in vitro as well as in vivo. Since apoptosis of activated hepatic stellate cells (HSCs) is a well-accepted anti-fibrotic strategy, in this study, we investigated the direct effect of PF2401-SF on t-HSC\/Cl-6 cells in vitro and on CCl4-induced liver injury in vivo. We evaluated the activation and cleavage of hallmarkers of apoptosis, namely, caspase 3, 8, 9 and PARP. Upregulation of the pro-apoptotic Bax protein and downregulation of the anti-apoptotic Bcl2 protein were also analyzed. Furthermore, in the PF2401-SF treated rats, apoptosis induction of activated HSCs was demonstrated by reduced distribution of \u03b1-SMA-positive cells and the presence of high number of TUNEL-positive cells in vivo. Our data suggest that PF2401-SF can mediate HSCs apoptosis induction, and may be a potential herbal medicine for the treatment of liver fibrosis.<\/jats:p>","DOI":"10.3390\/molecules18022122","type":"journal-article","created":{"date-parts":[[2013,2,6]],"date-time":"2013-02-06T11:02:06Z","timestamp":1360148526000},"page":"2122-2134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["PF2401-SF, Standardized Fraction of Salvia miltiorrhiza, Induces Apoptosis of Activated Hepatic Stellate Cells in Vitro and in Vivo"],"prefix":"10.3390","volume":"18","author":[{"given":"Daya","family":"Parajuli","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Jeonbuk 570-749, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Jeon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Jeonbuk 570-749, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian-Hua","family":"Che","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Jeonbuk 570-749, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Jeonbuk 570-749, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youn-Chul","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Jeonbuk 570-749, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Sohn","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Jeonbuk 570-749, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Jeonbuk 570-749, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0168-8278(02)00429-4","article-title":"Liver fibrosis-from bench to bedside","volume":"1","author":"Friedman","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1172\/JCI30542","article-title":"Models of liver fibrosis: Exploring the dynamic nature of inflammation and repair in a solid organ","volume":"117","author":"Iredale","year":"2007","journal-title":"J. Clin. Invest."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"159","DOI":"10.7326\/0003-4819-152-3-201002020-00007","article-title":"Narrative review: Fibrotic diseases: Cellular and molecular mechanisms and novel therapies","volume":"152","author":"Rosenbloom","year":"2010","journal-title":"Ann. Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.jhep.2010.04.025","article-title":"Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells","volume":"53","author":"Trebicka","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1152\/ajpgi.00451.2010","article-title":"Therapeutic targets in liver fibrosis","volume":"300","author":"Fallofield","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1002\/hep.20974","article-title":"Reversal of hepatic fibrosis-fact or fantassy?","volume":"43","author":"Friedman","year":"2006","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1136\/gut.48.4.548","article-title":"Apoptosis of hepatic stellate cells: Involvement in resolution of biliary fibrosis and regulation by soluble growth factors","volume":"48","author":"Issa","year":"2001","journal-title":"Gut"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jhep.2010.10.040","article-title":"Ursolic acid ameliorates hepatic fibrosis in the rat by specific induction of apoptosis in hepatic stellate cells","volume":"55","author":"Wang","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0378-8741(02)00363-X","article-title":"IDN 5082, a standardized extract of salvia miltiorrhiza, delays acquisition of alcohol drinking behavior in rats","volume":"85","author":"Brunetti","year":"2003","journal-title":"J. Ethnopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1177\/0091270005282630","article-title":"Danshen: An overview of its chemistry, pharmacology, pharmacokineics and clinical use","volume":"45","author":"Zhou","year":"2005","journal-title":"J. Clin. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/S0168-8278(98)80257-2","article-title":"Salvia miltiorrhiza reduces experimental-induced hepatic fibrosis in rats","volume":"29","author":"Wasser","year":"1998","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s11373-004-8167-7","article-title":"Antifibrotic effects of Salvia miltiorrhiza on dimethylnitorsamine-intoxicated rats","volume":"12","author":"Hsu","year":"2005","journal-title":"J. Biomed. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1211\/jpp.58.5.0011","article-title":"Water-soluble extract of Salvia miltiorrhiza ameliorates carbon tetrachloride-mediated hepatic apoptosis in rats","volume":"58","author":"Lee","year":"2006","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/ptr.2265","article-title":"Antifibrotic effects of herbal combination regimen on hepatic fibrotic rats","volume":"22","author":"Lin","year":"2008","journal-title":"Phytother. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1016\/j.fct.2007.04.005","article-title":"PF2401-SF, standardized fraction of Salvia miltiorrhiza and its constituents, tanshinon I, tanshinone IIA, and cryptotansinone, protect primary cultured rat hepatocytes from bile acid-induced apoptosis by inhibiting JNK phosphorylation","volume":"45","author":"Park","year":"2007","journal-title":"Food Chem. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1016\/j.fct.2009.08.007","article-title":"Preventive effects of apurified extract isolated from Salvia miltiorrhiza enriched with tanshinone I, tanshinone IIA and cryptotanshinone on hepatocyte injury in vitro and in vivo","volume":"47","author":"Park","year":"2009","journal-title":"Food Chem. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1007\/s10495-012-0700-y","article-title":"C\/EBP-a ameliorates CCl4-induced liver fibrosis in mice through promoting apoptosis of hepatic stellate cells with little apoptosis effect on hepatocytes in vitro and in vivo","volume":"17","author":"Tao","year":"2012","journal-title":"Apoptosis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1053\/jhep.2001.26518","article-title":"Leptin augments inflammatory and profibrogenic response in the murine liver induced by hepatotoxic chemicals","volume":"34","author":"Ikejima","year":"2001","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1053\/gast.2001.27188","article-title":"Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats","volume":"121","author":"Wright","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2011\/103039","article-title":"Hepatoprotective effects of Orthoisphon stamineus extract on thioacetamide-induced liver cirrhosis in rats","volume":"2011","author":"Alshawsh","year":"2011","journal-title":"J. Evid. Based Complementary Altern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1136\/bmj.327.7407.143","article-title":"Cirrhosis: New research provides a basis for rational and targeted treatments","volume":"327","author":"Iredale","year":"2003","journal-title":"BMJ"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.lfs.2005.09.012","article-title":"Drug discovery from medicinal plants","volume":"78","author":"Balnus","year":"2005","journal-title":"Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.jep.2011.02.013","article-title":"Hepatoprotective effects of Yi Guan Jian, an herbal medicine, in rats with dimethylnitrosamine-induced liver fibrosis","volume":"134","author":"Lin","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1042\/CS20060242","article-title":"Liver fibrosis: Cellular mechanisms of progression and resolution","volume":"112","author":"Henderson","year":"2007","journal-title":"Clin. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nrm2312","article-title":"Apoptosis: Controlled demolition at the cellular level","volume":"9","author":"Taylor","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejphar.2011.01.067","article-title":"2'4'6'-Tris(methoxymethoxy) chalcone induces apoptosis by enhancing Fas-ligand in activated hepatic stellate cells","volume":"658","author":"Lee","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1146\/annurev.cellbio.15.1.269","article-title":"Biochemical pathways of caspase activation during apoptosis","volume":"15","author":"Budihardjo","year":"1999","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1139\/o97-043","article-title":"Cleavage of poly polymerase (ADP-robose)","volume":"74","author":"Duriez","year":"1997","journal-title":"Biochem. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.jhep.2010.11.035","article-title":"Inhibition of PDGF, TGF-\u03b2, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib","volume":"55","author":"Liu","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrm2308","article-title":"The BCL-2 protein family: Opposing activities that mediate cell death","volume":"9","author":"Youle","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0092-8674(00)00003-9","article-title":"Apoptotic pathways: Paper wraps stone blunts scissors","volume":"102","author":"Green","year":"2000","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0092-8674(04)00046-7","article-title":"Cell death: Critical control points","volume":"116","author":"Danial","year":"2004","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jhep.2010.03.025","article-title":"The NF-kappa B p50:p50:HDAC-a repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes","volume":"53","author":"Elsharkawy","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Invest."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1034\/j.1600-0773.2003.920410.x","article-title":"Induction of apoptosis by tanshinone I via cytochrome c release in activated hepatic stellae cells","volume":"92","author":"Kim","year":"2003","journal-title":"Pharmacol. Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1211\/0022357021771823","article-title":"Curcumin inhibits collagen synthesis and hepatic stellate cell activation in vivo and in vitro","volume":"54","author":"Kang","year":"2002","journal-title":"J. Pharm. Pharmacol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/18\/2\/2122\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:44:50Z","timestamp":1760219090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/18\/2\/2122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,6]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2013,2]]}},"alternative-id":["molecules18022122"],"URL":"https:\/\/doi.org\/10.3390\/molecules18022122","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,6]]}}}