{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:10:07Z","timestamp":1772118607864,"version":"3.50.1"},"reference-count":22,"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":304,"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":[[2014,11]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>Malnutrition in the advanced fibrosis stage of chronic hepatitis C (CH-C) impairs interferon (IFN) signaling by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. However, the effect of profibrotic signaling on IFN signaling is not known. Here, the effect of transforming growth factor (TGF)-\u03b2 signaling on IFN signaling and hepatitis C virus (HCV) replication was examined in Huh-7.5 cells by evaluating the expression of forkhead box O3A (Foxo3a), suppressor of cytokine signaling 3 (Socs3), c-Jun, activating transcription factor 2, ras homolog enriched in brain, and mTORC1. The findings were confirmed in liver tissue samples obtained from 91 patients who received pegylated-IFN and ribavirin combination therapy. TGF-\u03b2 signaling was significantly up-regulated in the advanced fibrosis stage of CH-C. A significant positive correlation was observed between the expression of TGF-\u03b22 and mothers against decapentaplegic homolog 2 (Smad2), Smad2 and Foxo3a, and Foxo3a and Socs3 in the liver of CH-C patients. In Huh-7.5 cells, TGF-\u03b21 activated the Foxo3a promoter through an AP1 binding site; the transcription factor c-Jun was involved in this activation. Foxo3a activated the Socs3 promoter and increased HCV replication. TGF-\u03b21 also inhibited mTORC1 and IFN signaling. Interestingly, c-Jun and TGF-\u03b2 signaling was up-regulated in treatment-resistant IL28B minor genotype patients (TG\/GG at rs8099917), especially in the early fibrosis stage. Branched chain amino acids or a TGF-\u03b2 receptor inhibitor canceled these effects and showed an additive effect on the anti-HCV activity of direct-acting antiviral drugs (DAAs).<\/jats:bold>\n                      <jats:bold>Conclusion<\/jats:bold>\n                      <jats:bold>: Blocking TGF-\u03b2 signaling could potentiate the antiviral efficacy of IFN- and\/ or DAA-based treatment regimens and would be useful for the treatment of difficult-to-cure CH-C patients. (Hepatology 2014;60:1519\u20131530)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.27277","type":"journal-article","created":{"date-parts":[[2014,6,25]],"date-time":"2014-06-25T03:24:11Z","timestamp":1403666651000},"page":"1519-1530","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":33,"title":["Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway"],"prefix":"10.1097","volume":"60","author":[{"given":"Takayoshi","family":"Shirasaki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masao","family":"Honda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuro","family":"Shimakami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhisa","family":"Murai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Shiomoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hikari","family":"Okada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riuta","family":"Takabatake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Tokumaru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshio","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taro","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanley M.","family":"Lemon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seishi","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuichi","family":"Kaneko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-13-20250207","doi-asserted-by":"crossref","first-page":"174181","DOI":"10.7326\/0003-4819-131-3-199908030-00003","article-title":"Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan IHIT Study Group. 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