{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T19:48:04Z","timestamp":1762458484358,"version":"3.28.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2006,5,1]],"date-time":"2006-05-01T00:00:00Z","timestamp":1146441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Apoptosis is one of the events that are involved in liver fibrogenesis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. We have recently reported that Salvia miltiorrhiza plays a protective role in carbon tetrachloride (CCl4)-induced hepatic fibrosis. In this study, we aimed to evaluate whether S. miltiorrhiza modulated CCl4-induced hepatic apoptosis in rats. Male Wistar rats were given orally either vehicle or water-extract of S. miltiorrhiza (50 mg kg\u22121 twice daily) for nine weeks beginning from the start of CCl4 administration. A group of normal rats was included for comparison. Hepatocyte DNA fragmentation and cytosolic caspase-3 and caspase-8 activity were determined in the experimental animals. Hepatic cytosolic Bax, Bcl-2, cytochrome c, and calpain-\u03bc expressions were measured by Western blot analysis. Hepatic mitochondrial glutathione levels were assessed by colorimetric assay. Compared with normal rats, rats receiving CCl4 alone showed profound DNA fragmentation associated with an increased cytosolic fraction of cytochrome c and calpain-\u03bc protein expressions and a decreased mitochondrial glutathione level. In contrast, a decreased laddering of DNA fragmentation was noted in rats receiving CCl4 plus S. miltiorrhiza extract. The mitochondrial glutathione level was significantly increased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. Additionally, cytosolic caspase-3 activity and cytosolic fractions of Bax, Bcl-2, cytochrome c, and calpain-\u03bc protein expressions were decreased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. The cytosolic caspase-8 activity in rats receiving CCl4 alone was no different from those receiving CCl4 plus S. miltiorrhiza extract. These results indicated that chronic administration of S. miltiorrhiza ameliorated CCl4-mediatd hepatic apoptosis in rats. This effect may be related to the antioxidant properties of S. miltiorrhiza.<\/jats:p>","DOI":"10.1211\/jpp.58.5.0011","type":"journal-article","created":{"date-parts":[[2006,4,23]],"date-time":"2006-04-23T23:14:28Z","timestamp":1145834068000},"page":"659-665","source":"Crossref","is-referenced-by-count":54,"title":["Water-soluble extract of <i>Salvia miltiorrhiza<\/i> ameliorates carbon tetrachloride-mediated hepatic apoptosis in rats"],"prefix":"10.1093","volume":"58","author":[{"given":"Tzung-Yan","family":"Lee","sequence":"first","affiliation":[{"name":"Graduate Institute of Traditional Chinese Medicine, Chang Gung University , Taoyuan,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hen-Hong","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Traditional Chinese Medicine, Chang Gung University , Taoyuan,","place":["Taiwan"]},{"name":"Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital , Taoyuan,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guei-Jane","family":"Wang","sequence":"additional","affiliation":[{"name":"National Research Institute of Chinese Medicine , Taipei,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jen-Hwey","family":"Chiu","sequence":"additional","affiliation":[{"name":"Institute of Traditional Medicine, National Yang-Ming University School of Medicine , Taipei,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying-Ying","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine , Taipei,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han-Chieh","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine , Taipei,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2006,5,1]]},"reference":[{"key":"2024103109340355100_cit1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0300-483X(03)00157-4","article-title":"Carbon tetrachloride-induced lipid peroxidation: eicosanoid formation and their regulation by antioxidant nutrients","volume":"189","author":"Basu","year":"2003","journal-title":"Toxicology"},{"key":"2024103109340355100_cit2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0300-483X(03)00058-1","article-title":"Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress","volume":"187","author":"Beddowes","year":"2003","journal-title":"Toxicology"},{"key":"2024103109340355100_cit3","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/S0168-8278(99)80218-9","article-title":"Inhibition of hepatic cell nuclear DNA fragmentation by zinc in carbon tetrachloride-treated rats","volume":"31","author":"Cabre","year":"1999","journal-title":"J. Hepatol"},{"key":"2024103109340355100_cit4","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0378-4274(01)00283-1","article-title":"Liver toxicity and apoptosis: role of TGF-\u03b21, cytochrome c and the apoptosome","volume":"120","author":"Cain","year":"2001","journal-title":"Toxicol. Lett."},{"key":"2024103109340355100_cit5","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0753-3322(98)80011-5","article-title":"Apoptosis and liver fibrosis: antifibrotic strategies","volume":"52","author":"Cales","year":"1998","journal-title":"Biomed. Pharmacother"},{"key":"2024103109340355100_cit6","first-page":"876","article-title":"Pharmacology of Salvia miltiorrhiza","volume":"19","author":"Chen","year":"1993","journal-title":"Acta. Pharm. Sin."},{"key":"2024103109340355100_cit7","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/0005-2728(86)90203-3","article-title":"Studies on the effect of copper deficiency on rat liver mitochondria. III. Effects on adenine nucleotide translocase","volume":"848","author":"Davis","year":"1986","journal-title":"Biochim. Biophys. Acta."},{"key":"2024103109340355100_cit8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-1097(03)00100-9","article-title":"Role of oxidative stress and mitochondrial changes in cyanobacteria-induced apoptosis and hepatotoxicity","volume":"220","author":"Ding","year":"2003","journal-title":"FEMS Microbiol. Lett."},{"key":"2024103109340355100_cit9","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S0168-8278(97)80189-4","article-title":"Apoptosis in liver disease","volume":"27","author":"Galle","year":"1997","journal-title":"J. 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