{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:34:22Z","timestamp":1790735662903,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2495,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,11]]},"abstract":"<jats:sec>\n            <jats:title>Abstract<\/jats:title>\n            <jats:p>\n                                 <jats:bold>Oxidative injury to hepatocytes occurs as a result of hepatitis C virus (HCV) infection and replication. Modulation of host cell antioxidant enzymes such as heme oxygenase-1 (HO-1) may be useful therapeutically to minimize cellular injury, reduce viral replication, and attenuate liver disease. In this report, we evaluated the effects of HO-1 overexpression on HCV replication and hepatocellular injury. Full-length (FL) (Con1) or nonstructural (NS) replicons (I 389 NS3-3\u2032) were transfected with complete human HO-1 sequences or empty vector for control. Cell lines overexpressing HO-1 (twofold to sixfold above basal values) or empty vector were isolated, and their HCV RNA synthesis, pro-oxidant levels, and resistance to oxidative injury were assessed. HO-1 overexpression decreased HCV RNA replication in both FL and NS replicons without affecting cellular growth or DNA synthesis. The attenuation of HCV replication was significantly reversed in both replicon systems with HO-1 small interfering RNA (siRNA) knockdown. Both FL and NS replicons that overexpress HO-1 showed reduced prooxidant levels at baseline and increased resistance to oxidant-induced cytotoxicity. HO-1 induction with hemin also markedly decreased HCV replication in both parental FL and NS replicon cell lines. Conversely, knockdown of HO-1 messenger RNA (mRNA) by siRNA in parental FL or NS replicons did not significantly affect HCV replication, suggesting that less than basal levels of HO-1 had minimal effect on HCV replication.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 <\/jats:bold>\n                                 <jats:bold>Overexpression or induction of HO-1 results in decreased HCV replication as well as protection from oxidative damage. These findings suggest a potential role for HO-1 in antiviral therapy and therapeutic protection against hepatocellular injury in HCV infection. (Hepatology 2008.)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.22491","type":"journal-article","created":{"date-parts":[[2008,7,16]],"date-time":"2008-07-16T14:12:34Z","timestamp":1216217554000},"page":"1430-1439","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":120,"title":["Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury"],"prefix":"10.1097","volume":"48","author":[{"given":"Zhaowen","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne T.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meleah M.","family":"Mathahs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle E.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce A.","family":"Luxon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren N.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-12-20241201","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1055\/s-2000-9505","article-title":"Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on longterm outcome.","volume":"20","author":"Alter","year":"2000","journal-title":"Semin Liver Dis"},{"key":"R2-12-20241201","first-page":"1631","article-title":"Replication of hepatitis C virus.","volume":"81","author":"Bartenschlager","year":"2000","journal-title":"J Gen Virol"},{"key":"R3-12-20241201","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1126\/science.290.5498.1972","article-title":"Efficient initiation of HCV RNA replication in cell culture.","volume":"290","author":"Blight","year":"2000","journal-title":"Science"},{"key":"R4-12-20241201","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1126\/science.285.5424.110","article-title":"Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.","volume":"285","author":"Lohmann","year":"1999","journal-title":"Science"},{"key":"R5-12-20241201","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1136\/gut.2005.076646","article-title":"Treating viral hepatitis C: efficacy, side effects, and complications.","volume":"55","author":"Manns","year":"2006","journal-title":"Gut"},{"key":"R6-12-20241201","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.arcmed.2006.09.002","article-title":"Current and future hepatitis C therapies.","volume":"38","author":"Firpi","year":"2007","journal-title":"Arch Med Res"},{"key":"R7-12-20241201","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000150366","article-title":"Immunological aspects of HCV infection.","volume":"37","author":"Cerny","year":"1994","journal-title":"Intervirology"},{"key":"R8-12-20241201","first-page":"1368","article-title":"Tcellmediated autologous hepatocytotoxicity in patients with chronic hepatitis C virus infection.","volume":"22","author":"Liaw","year":"1995","journal-title":"HEPATOLOGY"},{"key":"R9-12-20241201","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1086\/423488","article-title":"Downregulation of heme oxygenase1 by hepatitis C virus infection in vivo and by the in vitro expression of hepatitis C core protein.","volume":"190","author":"Abdalla","year":"2004","journal-title":"J Infect Dis"},{"key":"R10-12-20241201","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/jmv.20388","article-title":"Hepatitis C viruscore and non structural proteins lead to different effects on cellular antioxidant defenses.","volume":"76","author":"Abdalla","year":"2005","journal-title":"J Med Virol"},{"key":"R11-12-20241201","doi-asserted-by":"crossref","first-page":"9599","DOI":"10.1073\/pnas.171311298","article-title":"Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT3 and NFkB.","volume":"98","author":"Gong","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R12-12-20241201","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1053\/jhep.2002.32968","article-title":"Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells.","volume":"35","author":"Li","year":"2002","journal-title":"HEPATOLOGY"},{"key":"R13-12-20241201","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1053\/gast.2002.30983","article-title":"Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.","volume":"122","author":"Okuda","year":"2002","journal-title":"Gastroenterology"},{"key":"R14-12-20241201","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1042\/bj20031587","article-title":"Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis C virus replication: role of JNK, p38 MAR and AP1.","volume":"378","author":"Qadri","year":"2004","journal-title":"Biochem J"},{"key":"R15-12-20241201","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/jmv.10567","article-title":"Increased prooxidant production and enhanced susceptibility to glutathione depletion in HepG2 cells coexpressing HCV core protein and CYP2E1.","volume":"72","author":"Wen","year":"2004","journal-title":"J Med Virol"},{"key":"R16-12-20241201","first-page":"479","article-title":"Heme oxygenase1 as a potential therapeutic target for hepatoprotection.","volume":"39","author":"Farombi","year":"2006","journal-title":"J Biochem Mol Biol"},{"key":"R17-12-20241201","doi-asserted-by":"crossref","first-page":"L1029","DOI":"10.1152\/ajplung.2000.279.6.L1029","article-title":"Heme oxygenase: Colors of defense against cellular stress.","volume":"279","author":"Otterbein","year":"2000","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"R18-12-20241201","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.2174\/0929867043365080","article-title":"Heme oxygenase1: a novel therapeutic target in oxidative tissue injuries.","volume":"11","author":"Takahashi","year":"2004","journal-title":"Curr Med Chem"},{"key":"R19-12-20241201","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/S0006-2952(00)00443-3","article-title":"Gene regulation of heme oxygenase1 as a therapeutic target.","volume":"60","author":"Immenschuh","year":"2000","journal-title":"Biochem Pharmacol"},{"key":"R20-12-20241201","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.4049\/jimmunol.176.7.4252","article-title":"Hemin activation ameliorates HIV1 infection via heme oxygenase1 induction.","volume":"176","author":"Devadas","year":"2006","journal-title":"J Immunol"},{"key":"R21-12-20241201","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1038\/sj.gt.3301540","article-title":"Adenovirusmediated transfer of heme oxygenase1 cDNA attenuates severe lung injury induced by the influenza virus in mice.","volume":"8","author":"Hashiba","year":"2001","journal-title":"Gene Ther"},{"key":"R22-12-20241201","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s10565-007-9027-9","article-title":"Hepatitis C core protein inhibits induction of heme oxygenase1 and sensitizes hepatocytes to cytotoxicity.","volume":"24","author":"Wen","year":"2008","journal-title":"Cell Biol Toxicol"},{"key":"R23-12-20241201","doi-asserted-by":"crossref","first-page":"13001","DOI":"10.1128\/JVI.76.24.13001-13014.2002","article-title":"Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication.","volume":"76","author":"Blight","year":"2002","journal-title":"J Virol"},{"key":"R24-12-20241201","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/S0016-5085(99)70185-X","article-title":"Realtime detection system for quantification of hepatitis C virus genome.","volume":"116","author":"Takeuchi","year":"1999","journal-title":"Gastroenterology"},{"key":"R25-12-20241201","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1128\/JVI.77.5.3007-3019.2003","article-title":"Viral and cellular determinants of hepatitis C virus RNA replication in cell culture.","volume":"77","author":"Lohmann","year":"2003","journal-title":"J Virol"},{"key":"R27-12-20241201","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1128\/JVI.75.3.1252-1264.2001","article-title":"Characterization of cell lines carrying selfreplicating hepatitis C virus RNAs.","volume":"75","author":"Pietschmann","year":"2001","journal-title":"J Virol"},{"key":"R28-12-20241201","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1046\/j.1523-1755.2001.059002645.x","article-title":"Different effects of angiotensin II and catecholamine on renal cell apoptosis and proliferation in rats.","volume":"59","author":"Aizawa","year":"2001","journal-title":"Kidney Int"},{"key":"R29-12-20241201","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/jcp.10274","article-title":"Heme oxygenase1 in growth control and its clinical application to vascular disease.","volume":"195","author":"Durante","year":"2003","journal-title":"J Cell Physiol"},{"key":"R30-12-20241201","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/S0891-5849(99)00061-1","article-title":"Dihydrofluorescein diacetate is superior for detecting intracellular oxidants: comparison with 2,7dichlorodihydrofluorescein diacetate, 5(and 6)carboxy2,7dichlorodihydrofluorescein diacetate, and dihydrorhodamine 123.","volume":"27","author":"Hempel","year":"1999","journal-title":"Free Radic Biol Med"},{"key":"R31-12-20241201","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1016\/S0024-3205(01)01417-5","article-title":"Modulation of heme oxygenase in tissue injury and its implication in protection against gastrointestinal diseases.","volume":"69","author":"Guo","year":"2001","journal-title":"Life Sci"},{"key":"R32-12-20241201","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1096\/fj.04-3485cmt","article-title":"Heme oxygenase1: a therapeutic amplification funnel.","volume":"19","author":"Bach","year":"2005","journal-title":"FASEB J"},{"key":"R33-12-20241201","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.jhep.2005.12.020","article-title":"HCV proteins increase expression of heme oxygenase1 (HO1) and decrease expression of Bach1 in human hepatoma cells.","volume":"45","author":"Ghaziani","year":"2006","journal-title":"J Hepatol"},{"key":"R34-12-20241201","first-page":"A824","article-title":"An antagomir of mir122 downregulates hepatitis c virus infection and upregulates herne oxygenase1 expression in human hepatocytes Abstract.","volume":"132","author":"Shan","year":"2007","journal-title":"Gastroenterology"},{"key":"R35-12-20241201","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1053\/j.gastro.2007.07.021","article-title":"Antiviral activity and hepatoprotection by heme oxygenase1 in hepatitis B virus infection.","volume":"133","author":"Protzer","year":"2007","journal-title":"Gastroenterology"},{"key":"R36-12-20241201","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S1471-4906(03)00181-9","article-title":"Heme oxygenase1: unleashing the protective properties of heme.","volume":"24","author":"Otterbein","year":"2003","journal-title":"Trends Immunol"},{"key":"R37-12-20241201","doi-asserted-by":"crossref","first-page":"9049","DOI":"10.1074\/jbc.M412687200","article-title":"Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus.","volume":"280","author":"Fillebeen","year":"2005","journal-title":"J Biol Chem"},{"key":"R38-12-20241201","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0168-8278(96)80231-5","article-title":"Threshold effect of liver iron content on hepatic inflammation and fibrosis in hepatitis B and C.","volume":"25","author":"Beinker","year":"1996","journal-title":"J Hepatol"},{"key":"R39-12-20241201","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1478-3231.2005.01022.x","article-title":"Hemosiderosis is associated with accelerated decompensation and decreased survival in patients with cirrhosis.","volume":"25","author":"Kayali","year":"2005","journal-title":"Liver Int"},{"key":"R40-12-20241201","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/hep.20001","article-title":"Reactive oxygen species suppress hepatitis C virus RNA replication in human hepatoma cells.","volume":"39","author":"Choi","year":"2004","journal-title":"HEPATOLOGY"},{"key":"R41-12-20241201","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1128\/JVI.79.3.1569-1580.2005","article-title":"Hepatitis C virus (HCV) constitutively activates STAT3 via oxidative stress: role of STAT3 in HCV replication.","volume":"79","author":"Waris","year":"2005","journal-title":"J Virol"},{"key":"R42-12-20241201","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S0955-0674(98)80147-6","article-title":"Oxygen radicals and signaling.","volume":"10","author":"Finkel","year":"1998","journal-title":"Curr Opin Cell Biol"},{"key":"R43-12-20241201","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/BF02778986","article-title":"Reactive oxygen species and nitric oxide in viral diseases.","volume":"56","author":"Peterhans","year":"1997","journal-title":"Biol Trace Elem Res"},{"key":"R44-12-20241201","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nm0302-240","article-title":"Heme oxygenase1 mediates the antiinflammatory effect of interleukin10 in mice.","volume":"8","author":"Lee","year":"2002","journal-title":"Nat Med"},{"key":"R45-12-20241201","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jhep.2005.12.019","article-title":"Regulation of rat heme oxygenase1 expression by interleukin6 via the JakSTAT pathway in hepatocytes.","volume":"45","author":"Tron","year":"2006","journal-title":"J Hepatol"},{"key":"R46-12-20241201","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1136\/gut.2005.070060","article-title":"Altered expression and activation of signal transducers and activators of transcription (STATs) in hepatitis C virus infection: in vivo and in vitro studies.","volume":"55","author":"Larrea","year":"2006","journal-title":"Gut"},{"key":"R47-12-20241201","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1099\/vir.0.80204-0","article-title":"Hepatitis C virus NS5A: tales of a promiscuous protein.","volume":"85","author":"Macdonald","year":"2004","journal-title":"J Gen Virol"},{"key":"R48-12-20241201","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0168-1702(95)00034-N","article-title":"Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein.","volume":"37","author":"Ray","year":"1995","journal-title":"Virus Res"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.22491","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200811000-00012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T13:42:20Z","timestamp":1733060540000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200811000-00012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2008]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.22491","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2008,11]]}}}