{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:56:55Z","timestamp":1790312215326,"version":"4.1.0"},"reference-count":51,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,4,1]]},"abstract":"<jats:p>Many diseases of aging including AD (Alzheimer's disease) and T2D (Type 2 diabetes) are strongly associated with common risk factors, suggesting that there may be shared aging mechanisms underlying these diseases, with the scope to identify common cellular targets for therapy. In the present study we have examined the insulin-like signalling properties of an experimental AD 8-hydroxyquinoline drug known as CQ (clioquinol). The IIS [insulin\/IGF-1 (insulin-like growth factor-1) signalling] kinase Akt\/PKB (protein kinase B) inhibits the transcription factor FOXO1a (forkhead box O1a) by phosphorylating it on residues that trigger its exit from the nucleus. In HEK (human embryonic kidney)-293 cells, we found that CQ treatment induces similar responses. A key transcriptional response to IIS is the inhibition of hepatic gluconeogenic gene expression, and, in rat liver cells, CQ represses expression of the key gluconeogenic regulatory enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). The effects on FOXO1a and gluconeogenic gene expression require the presence of Zn2+ ions, reminiscent of much earlier studies examining diabetogenic properties of 8-hydroxyquinolines. Comparative investigation of the signalling properties of a panel of these compounds demonstrates that CQ alone exhibits FOXO1a regulation without diabetogenicity. Our results suggest that Zn2+-dependent regulation of FOXOs and gluconeogenesis may contribute to the therapeutic properties of this drug. Further investigation of this signalling response might illuminate novel pharmacological strategies for the treatment of age-related diseases.<\/jats:p>","DOI":"10.1042\/bj20112124","type":"journal-article","created":{"date-parts":[[2012,1,17]],"date-time":"2012-01-17T09:26:20Z","timestamp":1326792380000},"page":"57-64","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a"],"prefix":"10.1042","volume":"443","author":[{"given":"Amy\u00a0R.","family":"Cameron","sequence":"first","affiliation":[{"name":"Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Wallace","sequence":"additional","affiliation":[{"name":"Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Logie","sequence":"additional","affiliation":[{"name":"Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan\u00a0R.","family":"Prescott","sequence":"additional","affiliation":[{"name":"Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry\u00a0G.","family":"Unterman","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, U.S.A."},{"name":"Jesse Brown Veterans Administration Medical Center, Chicago, IL 60612, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Harthill","sequence":"additional","affiliation":[{"name":"Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Rena","sequence":"additional","affiliation":[{"name":"Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2012,3,14]]},"reference":[{"key":"2021112217264773500_B1","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1096\/fj.07-9261com","article-title":"Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice","volume":"22","author":"Selman","year":"2008","journal-title":"FASEB J."},{"key":"2021112217264773500_B2","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/40194","article-title":"The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans","volume":"389","author":"Ogg","year":"1997","journal-title":"Nature"},{"key":"2021112217264773500_B3","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1126\/science.278.5341.1319","article-title":"daf-16: an HNF-3\/forkhead family member that can function to double the life-span of Caenorhabditis elegans","volume":"278","author":"Lin","year":"1997","journal-title":"Science"},{"key":"2021112217264773500_B4","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/S0140-6736(98)07019-6","article-title":"Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type\u00a02 diabetes (UKPDS 33)","volume":"352","author":"UK Prospective Diabetes Study (UKPDS) Group","year":"1998","journal-title":"Lancet"},{"key":"2021112217264773500_B5","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1007\/s00125-006-0176-9","article-title":"Risk of mortality and adverse cardiovascular outcomes in type\u00a02 diabetes: a comparison of patients treated with sulfonylureas and metformin","volume":"49","author":"Evans","year":"2006","journal-title":"Diabetologia"},{"key":"2021112217264773500_B6","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1136\/bmj.315.7115.1045","article-title":"Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein e4 phenotype: cross sectional population based study","volume":"315","author":"Kuusisto","year":"1997","journal-title":"Br. 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