{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T18:23:44Z","timestamp":1790101424372,"version":"4.0.1"},"reference-count":44,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T00:00:00Z","timestamp":1630108800000},"content-version":"vor","delay-in-days":4008,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,12,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>The study was performed using diabetic apolipoprotein E\/GPx1 (ApoE\u2212\/\u2212GPx1\u2212\/\u2212)-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db10-0195","type":"journal-article","created":{"date-parts":[[2010,9,7]],"date-time":"2010-09-07T21:06:21Z","timestamp":1283893581000},"page":"3198-3207","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":110,"title":["Antiatherosclerotic and Renoprotective Effects of Ebselen in the Diabetic Apolipoprotein E\/GPx1-Double Knockout Mouse"],"prefix":"10.2337","volume":"59","author":[{"given":"Phyllis","family":"Chew","sequence":"first","affiliation":[{"name":"Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek Y.C.","family":"Yuen","sequence":"additional","affiliation":[{"name":"Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nada","family":"Stefanovic","sequence":"additional","affiliation":[{"name":"Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefa","family":"Pete","sequence":"additional","affiliation":[{"name":"Diabetic Complications Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda T.","family":"Coughlan","sequence":"additional","affiliation":[{"name":"Diabetic Complications Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin A.","family":"Jandeleit-Dahm","sequence":"additional","affiliation":[{"name":"Diabetic Complications Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merlin C.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Diabetic Complications Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franklin","family":"Rosenfeldt","sequence":"additional","affiliation":[{"name":"Cardiac Surgical Research Unit, Alfred Hospital, Melbourne, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Diabetic Complications Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy B. de","family":"Haan","sequence":"additional","affiliation":[{"name":"Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2010,9,7]]},"reference":[{"key":"2022031217540573800_B1","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1161\/01.CIR.0000095676.90936.80","article-title":"Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention","volume":"108","author":"Sarnak","year":"2003","journal-title":"Circulation"},{"key":"2022031217540573800_B2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1056\/NEJM199807233390404","article-title":"Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction","volume":"339","author":"Haffner","year":"1998","journal-title":"N Engl J Med"},{"key":"2022031217540573800_B3","first-page":"39","article-title":"Renal dysfunction and coronary disease: a high-risk combination","volume":"22","author":"Schiele","year":"2009","journal-title":"J Nephrol"},{"key":"2022031217540573800_B4","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1007\/s00467-009-1199-5","article-title":"Tipping the redox balance of oxidative stress in fibrogenic pathways in chronic kidney disease","volume":"24","author":"Okamura","year":"2009","journal-title":"Pediatr Nephrol"},{"key":"2022031217540573800_B5","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2174\/1570161043385538","article-title":"Antioxidant therapy in diabetic complications: what is new?","volume":"2","author":"Da Ros","year":"2004","journal-title":"Curr Vasc Pharmacol"},{"key":"2022031217540573800_B6","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1001\/jama.294.1.56","article-title":"Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial","volume":"294","author":"Lee","year":"2005","journal-title":"JAMA"},{"key":"2022031217540573800_B7","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1001\/jama.2008.600","article-title":"Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial","volume":"300","author":"Sesso","year":"2008","journal-title":"JAMA"},{"key":"2022031217540573800_B8","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/S1359-6446(04)03139-3","article-title":"Catalytic antioxidants: a radical approach to new therapeutics","volume":"9","author":"Day","year":"2004","journal-title":"Drug Discov Today"},{"key":"2022031217540573800_B9","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.biopha.2005.07.002","article-title":"A review on the role of antioxidants in the management of diabetes and its complications","volume":"59","author":"Rahimi","year":"2005","journal-title":"Biomed Pharmacother"},{"key":"2022031217540573800_B10","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1161\/CIRCULATIONAHA.106.664250","article-title":"Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice","volume":"115","author":"Lewis","year":"2007","journal-title":"Circulation"},{"key":"2022031217540573800_B11","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1056\/NEJMoa030535","article-title":"Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease","volume":"349","author":"Blankenberg","year":"2003","journal-title":"N Engl J Med"},{"key":"2022031217540573800_B12","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.2337\/diabetes.53.9.2455","article-title":"Functional variants in the glutathione peroxidase-1 (GPx-1) gene are associated with increased intima-media thickness of carotid arteries and risk of macrovascular diseases in japanese type 2 diabetic patients","volume":"53","author":"Hamanishi","year":"2004","journal-title":"Diabetes"},{"key":"2022031217540573800_B13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/00019501-200304000-00007","article-title":"Glutathione peroxidase 1 genotype is associated with an increased risk of coronary artery disease","volume":"14","author":"Winter","year":"2003","journal-title":"Coron Artery Dis"},{"key":"2022031217540573800_B14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.nutr.19.1.1","article-title":"Responsiveness of selenoproteins to dietary selenium","volume":"19","author":"Allan","year":"1999","journal-title":"Annu Rev Nutr"},{"key":"2022031217540573800_B15","first-page":"297","article-title":"The two faces of selenium\u2014deficiency and toxicity\u2014are similar in animals and man","volume":"50","author":"Koller","year":"1986","journal-title":"Can J Vet Res"},{"key":"2022031217540573800_B16","doi-asserted-by":"crossref","first-page":"4594","DOI":"10.1002\/chem.200601584","article-title":"Synthesis, characterization, and antioxidant activity of some ebselen analogues","volume":"13","author":"Bhabak","year":"2007","journal-title":"Chemistry"},{"key":"2022031217540573800_B17","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0891-5849(93)90028-S","article-title":"Ebselen, a selenoorganic compound as glutathione peroxidase mimic","volume":"14","author":"Sies","year":"1993","journal-title":"Free Radic Biol Med"},{"key":"2022031217540573800_B18","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1080\/08037050500210781","article-title":"Effect of glutathione peroxidase mimic ebselen (PZ51) on endothelium and vascular structure of stroke-prone spontaneously hypertensive rats","volume":"14","author":"Sui","year":"2005","journal-title":"Blood Press"},{"key":"2022031217540573800_B19","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1161\/01.STR.29.1.12","article-title":"Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group","volume":"29","author":"Yamaguchi","year":"1998","journal-title":"Stroke"},{"key":"2022031217540573800_B20","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1177\/1099800403261350","article-title":"Ebselen decreases oxygen free radical production and iron concentrations in the hearts of chronically iron-overloaded mice","volume":"6","author":"Davis","year":"2004","journal-title":"Biol Res Nurs"},{"key":"2022031217540573800_B21","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1161\/01.RES.0000111802.09964.EF","article-title":"Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen","volume":"94","author":"Brodsky","year":"2004","journal-title":"Circ Res"},{"key":"2022031217540573800_B22","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1097\/01.ASN.0000135971.88164.2C","article-title":"Nephropathy in Zucker diabetic fat rat is associated with oxidative and nitrosative stress: prevention by chronic therapy with a peroxynitrite scavenger ebselen","volume":"15","author":"Chander","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"2022031217540573800_B23","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1161\/ATVBAHA.109.186619","article-title":"Site-specific antiatherogenic effect of the antioxidant ebselen in the diabetic apolipoprotein E-deficient mouse","volume":"29","author":"Chew","year":"2009","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022031217540573800_B24","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s00125-009-1540-3","article-title":"The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice","volume":"53","author":"Watson","journal-title":"Diabetologia"},{"key":"2022031217540573800_B25","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1093\/jn\/131.12.3208","article-title":"Bioavailability and antioxidant activity of some food supplements in men and women using the D-Roms test as a marker of oxidative stress","volume":"131","author":"Cornelli","year":"2001","journal-title":"J Nutr"},{"key":"2022031217540573800_B26","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1081\/DMR-100102340","article-title":"The isoprostanes: their quantification as an index of oxidant stress status in vivo","volume":"32","author":"Morrow","year":"2000","journal-title":"Drug Metab Rev"},{"key":"2022031217540573800_B27","doi-asserted-by":"crossref","first-page":"20831","DOI":"10.1074\/jbc.M101821200","article-title":"Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals","volume":"276","author":"Schneider","year":"2001","journal-title":"J Biol Chem"},{"key":"2022031217540573800_B28","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1083\/jcb.85.3.597","article-title":"Codistribution of collagen types IV and AB2 in basement membranes and mesangium of the kidney. an immunoferritin study of ultrathin frozen sections","volume":"85","author":"Roll","year":"1980","journal-title":"J Cell Biol"},{"key":"2022031217540573800_B29","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1179\/135100003125001378","article-title":"An imbalance in antioxidant defense affects cellular function: the pathophysiological consequences of a reduction in antioxidant defense in the glutathione peroxidase-1 (Gpx1) knockout mouse","volume":"8","author":"De Haan","year":"2003","journal-title":"Redox Rep"},{"key":"2022031217540573800_B30","doi-asserted-by":"crossref","first-page":"F544","DOI":"10.1152\/ajprenal.00088.2005","article-title":"Kidney expression of glutathione peroxidase-1 is not protective against streptozotocin-induced diabetic nephropathy","volume":"289","author":"de Haan","year":"2005","journal-title":"Am J Physiol Renal Physiol"},{"key":"2022031217540573800_B31","doi-asserted-by":"crossref","first-page":"22528","DOI":"10.1074\/jbc.273.35.22528","article-title":"Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide","volume":"273","author":"de Haan","year":"1998","journal-title":"J Biol Chem"},{"key":"2022031217540573800_B32","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1161\/01.ATV.0000105054.43931.f0","article-title":"Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators","volume":"24","author":"VanderLaan","year":"2004","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022031217540573800_B33","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1046\/j.1523-1755.2001.0590041342.x","article-title":"Selenium-deficient diet induces renal oxidative stress and injury via TGF-\u03b21 in normal and diabetic rats","volume":"59","author":"Reddi","year":"2001","journal-title":"Kidney Int"},{"key":"2022031217540573800_B34","doi-asserted-by":"crossref","first-page":"27812","DOI":"10.1074\/jbc.272.44.27812","article-title":"Glutathione peroxidase protects against peroxynitrite-mediated oxidations. A new function for selenoproteins as peroxynitrite reductase","volume":"272","author":"Sies","year":"1997","journal-title":"J Biol Chem"},{"key":"2022031217540573800_B35","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S1054-3589(08)60986-2","article-title":"Ebselen as a glutathione peroxidase mimic and as a scavenger of peroxynitrite","volume":"38","author":"Sies","year":"1997","journal-title":"Adv Pharmacol"},{"key":"2022031217540573800_B36","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/414813a","article-title":"Biochemistry and molecular cell biology of diabetic complications","volume":"414","author":"Brownlee","year":"2001","journal-title":"Nature"},{"key":"2022031217540573800_B37","doi-asserted-by":"crossref","first-page":"S241","DOI":"10.1097\/01.ASN.0000077410.66390.0F","article-title":"Reactive oxygen species-regulated signaling pathways in diabetic nephropathy","volume":"14","author":"Lee","year":"2003","journal-title":"J Am Soc Nephrol"},{"key":"2022031217540573800_B38","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1097\/01.ASN.0000133025.23732.46","article-title":"Accelerated nephropathy in diabetic apolipoprotein e-knockout mouse: role of advanced glycation end products","volume":"15","author":"Lassila","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"2022031217540573800_B39","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1046\/j.1523-1755.2003.00164.x","article-title":"Lipoproteins in the DCCT\/EDIC cohort: associations with diabetic nephropathy","volume":"64","author":"Jenkins","year":"2003","journal-title":"Kidney Int"},{"key":"2022031217540573800_B40","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/ki.1989.111","article-title":"Glomerular localization of type III collagen in human kidney disease","volume":"35","author":"Yoshioka","year":"1989","journal-title":"Kidney Int"},{"key":"2022031217540573800_B41","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1172\/JCI119853","article-title":"Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy","volume":"100","author":"Horie","year":"1997","journal-title":"J Clin Invest"},{"key":"2022031217540573800_B42","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1681\/ASN.2004080648","article-title":"Mouse models of diabetic nephropathy","volume":"16","author":"Breyer","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"2022031217540573800_B43","doi-asserted-by":"crossref","first-page":"30","DOI":"10.2337\/diacare.23.1.30","article-title":"Cardiovascular morbidity and early mortality cluster in parents of type 1 diabetic patients with diabetic nephropathy","volume":"23","author":"Tarnow","year":"2000","journal-title":"Diabetes Care"},{"key":"2022031217540573800_B44","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ejphar.2003.11.079","article-title":"Ebselen inhibits p38 mitogen-activated protein kinase-mediated endothelial cell death by hydrogen peroxide","volume":"485","author":"Ali","year":"2004","journal-title":"Eur J Pharmacol"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/59\/12\/3198\/396965\/zdb01210003198.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/59\/12\/3198\/396965\/zdb01210003198.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T12:22:30Z","timestamp":1667391750000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/59\/12\/3198\/26133\/Antiatherosclerotic-and-Renoprotective-Effects-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,9,7]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2010,9,7]]},"published-print":{"date-parts":[[2010,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db10-0195","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,9,7]]}}}