{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:25:52Z","timestamp":1789172752746,"version":"build-2803163510"},"reference-count":42,"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":5417,"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":[[2000,11]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Recombinant adeno\u2013associated virus (rAAV) transduction is limited <jats:italic toggle=\"yes\">in vivo<\/jats:italic>, yet can be enhanced by hydroxyurea, ultraviolet\u2013irradiation, or adenovirus coinfection, possibly via mechanisms involving stress in the host cell. Because chronic ethanol induces oxidative stress, it was hypothesized that chronic ethanol would increase rAAV transduction <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. To test this hypothesis, rAAV encoding \u03b2\u2013galactosidase was given to Wistar rats that later received either ethanol diet or high\u2013fat control diet via an enteral\u2013feeding protocol for 3 weeks. Expression and activity of \u03b2\u2013galactosidase in the liver were increased nearly 5\u2013fold by ethanol. The increase in transgene expression was inhibited by antioxidant diphenylene iodonium (DPI), which is consistent with the hypothesis that ethanol causes an increase in rAAV transduction via oxidative stress. Ethanol increased DNA synthesis only slightly; however, it increased the nuclear transcription factor \u03baB (NF\u03baB) 4\u2013fold, a phenomenon also sensitive to DPI. Moreover, a 6\u2013fold increase in rAAV transgene expression was observed in an acute ischemia\u2013reperfusion model of oxidative stress. Transgene expression was transiently increased 24 hours after ischemia\u2013reperfusion 3 days and 3 weeks after rAAV infection. Further, adenoviral expression of superoxide dismutase or I\u03baB\u03b1 superrepressor inhibited rAAV transgene expression caused by ischemia\u2013reperfusion. Therefore, it is concluded that ethanol increases rAAV transgene expression via mechanisms dependent on oxidative stress, and NF\u03baB likely through enhancement of cytomegaloviral (CMV) promoter elements. Alcoholic liver disease is an attractive target for gene therapy because consumption of ethanol could theoretically increase expression of therapeutic genes (<jats:italic toggle=\"yes\">e.g.<\/jats:italic>, superoxide dismutase). Moreover, this study has important implications for rAAV gene therapy and potential enhancement and regulation of transgene expression in liver.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2000.19339","type":"journal-article","created":{"date-parts":[[2003,6,21]],"date-time":"2003-06-21T14:16:51Z","timestamp":1056205011000},"page":"1050-1059","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":25,"title":["Chronic Ethanol Increases Adeno\u2013Associated Viral Transgene Expression in Rat Liver Via Oxidant and Nf\u03baB\u2013Dependent Mechanisms"],"prefix":"10.1097","volume":"32","author":[{"given":"Michael D.","family":"Wheeler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin E.","family":"Arteel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"McCarty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard Jude","family":"Samulski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald 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