{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:21:04Z","timestamp":1784557264056,"version":"3.55.0"},"reference-count":47,"publisher":"Bioscientifica","issue":"3","content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,3]]},"abstract":"\n The transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in oxidative stress responses. Although activation of Nrf2 signaling is known to exert anti-inflammatory effects, the function of Nrf2 in inflammation-mediated autoimmune disorders, such as type 1 diabetes, is not well established. To address the roles of Nrf2 in protection against autoreactive T-cell-induced type 1 diabetes, we used non-obese diabetic (NOD) mice, which are a polygenic model of human type 1 diabetes, to generate a genetic model for assessment of the contribution of Nrf2 activation to prevention and\/or treatment of type 1 diabetes. Because Keap1 (Kelch-like ECH-associated protein 1) negatively regulates Nrf2, we used\n Keap1<\/jats:italic>\n gene knockdown driven by either hypomorphic or knockout\n Keap1<\/jats:italic>\n alleles, which enhanced Nrf2 signaling to moderate or excess levels, respectively. Nrf2 activation in the NOD::\n Keap1<\/jats:italic>\n \n FA\/<\/jats:sup>\n <\/jats:italic>\n \n \u2013<\/jats:sup>\n <\/jats:italic>\n mice inhibited T-cell infiltration within or near the islets, ameliorated impairment of insulin secretion and prevented the development of diabetes mellitus. Notably, Nrf2 activation decreased both the plasma interferon-\u03b3 (IFN-\u03b3) levels and the IFN-\u03b3-positive cell numbers in the pancreatic islets. The amelioration of diabetes was also observed in the NOD mice with two hypomorphic Keap1 alleles (\n Keap1<\/jats:italic>\n \n FA\/FA<\/jats:sup>\n <\/jats:italic>\n ) by intermediate activation of Nrf2. Both NOD::\n Keap1<\/jats:italic>\n \n FA\/<\/jats:sup>\n <\/jats:italic>\n \n \u2013<\/jats:sup>\n <\/jats:italic>\n and NOD::\n Keap1<\/jats:italic>\n \n FA\/FA<\/jats:sup>\n <\/jats:italic>\n mice had a decreased incidence of diabetes mellitus, demonstrating that activation of Nrf2 signaling prevented the onset of type 1 diabetes mellitus in NOD mice. Thus, Nrf2 appears to be a potential target for the prevention and treatment of type 1 diabetes.\n <\/jats:p>","DOI":"10.1530\/joe-18-0355","type":"journal-article","created":{"date-parts":[[2019,1,9]],"date-time":"2019-01-09T06:37:44Z","timestamp":1547015864000},"page":"403-416","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":48,"title":["Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice"],"prefix":"10.1530","volume":"240","author":[{"given":"Yoko","family":"Yagishita","sequence":"first","affiliation":[{"name":"1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan"},{"name":"2Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Uruno","sequence":"additional","affiliation":[{"name":"1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan"},{"name":"3Tohoku Medical-Megabank Organization, Tohoku University, Sendai, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dionysios V","family":"Chartoumpekis","sequence":"additional","affiliation":[{"name":"2Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W","family":"Kensler","sequence":"additional","affiliation":[{"name":"2Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan"},{"name":"3Tohoku Medical-Megabank Organization, Tohoku University, Sendai, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"ref121","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev.pharmtox.46.120604.141046","article-title":"Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway","volume":"47","year":"2007","journal-title":"Annual Review of Pharmacology and Toxicology"},{"key":"ref111","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1080\/01621459.1958.10501452","article-title":"Nonparametric estimation from incomplete observations","volume":"53","year":"1958","journal-title":"Journal of the American Statistical Association"},{"key":"ref411","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1023\/B:JOCI.0000019783.61674.1d","article-title":"The expression of cytokine genes in the peritoneal macrophages and splenic CD4- and CD8-positive lymphocytes of the nonobese diabetic 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