{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T14:49:49Z","timestamp":1786459789321,"version":"build-2736575974"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform \u03b3-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of \u03b3-tocotrienol in a house dust mite (HDM) experimental asthma model. BALB\/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory biomarkers. Sera were assayed for IgE and \u03b3-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. \u03b3-Tocotrienol displayed better free radical\u2013neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including \u03b1-tocopherol. Besides, \u03b3-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mechanistically, \u03b3-tocotrienol was found to block nuclear NF-\u03baB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did \u03b1-tocopherol and prednisolone. More importantly, \u03b3-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform \u03b3-tocotrienol in allergic asthma.<\/jats:p>","DOI":"10.4049\/jimmunol.1500362","type":"journal-article","created":{"date-parts":[[2015,6,4]],"date-time":"2015-06-04T11:15:25Z","timestamp":1433416525000},"page":"437-444","source":"Crossref","is-referenced-by-count":46,"title":["Vitamin E Isoform \u03b3-Tocotrienol Downregulates House Dust Mite\u2013Induced Asthma"],"prefix":"10.1093","volume":"195","author":[{"given":"Hong Yong","family":"Peh","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System , Singapore 119228"},{"name":"Immunology Program, Life Science Institute, National University of Singapore , Singapore 117456"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxing Eugene","family":"Ho","sequence":"additional","affiliation":[{"name":"Saw Swee Hock School of Public Health, National University Health System , Singapore 117597"},{"name":"Singapore\u2013MIT Alliance for Research and Technology, National University of Singapore , Singapore 117543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System , Singapore 119228"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tze Khee","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System , Singapore 119228"},{"name":"Immunology Program, Life Science Institute, National University of Singapore , Singapore 117456"},{"name":"Singapore\u2013MIT Alliance for Research and Technology, National University of Singapore , Singapore 117543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Ching Genevieve","family":"Seow","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System , Singapore 119228"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert Y H","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital , Singapore 308433"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chee Wai","family":"Fong","sequence":"additional","affiliation":[{"name":"Davos Life Science Private Limited , Singapore 637795"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kok Yong","family":"Seng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System , Singapore 119228"},{"name":"Defence Medical and Environmental Research Institute, Defence Science Organisation National Laboratories , Singapore 117510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choon Nam","family":"Ong","sequence":"additional","affiliation":[{"name":"Saw Swee Hock School of Public Health, National University Health System , Singapore 117597"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W S Fred","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System , Singapore 119228"},{"name":"Immunology Program, Life Science Institute, National University of Singapore , Singapore 117456"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,7,15]]},"reference":[{"key":"2025030703442237500_r1","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1056\/NEJMra0804579","article-title":"Asthma","volume":"360","author":"Fanta","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"2025030703442237500_r2","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1513\/pats.200808-087RM","article-title":"Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies","volume":"6","author":"Fahy","year":"2009","journal-title":"Proc. Am. Thorac. Soc."},{"key":"2025030703442237500_r3","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1089\/ars.2007.1937","article-title":"Oxidative and nitrative stress in bronchial asthma","volume":"10","author":"Sugiura","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"2025030703442237500_r4","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1164\/rccm.200707-1096OC","article-title":"Nuclear factor-\u03baB activation in airway epithelium induces inflammation and hyperresponsiveness","volume":"177","author":"Pantano","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030703442237500_r5","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1084\/jem.20050538","article-title":"Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice","volume":"202","author":"Rangasamy","year":"2005","journal-title":"J. Exp. Med."},{"key":"2025030703442237500_r6","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/j.rmed.2006.03.031","article-title":"Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment","volume":"100","author":"Peters","year":"2006","journal-title":"Respir. Med."},{"key":"2025030703442237500_r7","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.mam.2007.03.001","article-title":"Tocotrienols in health and disease: the other half of the natural vitamin E family","volume":"28","author":"Sen","year":"2007","journal-title":"Mol. Aspects Med."},{"key":"2025030703442237500_r8","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1016\/j.bcp.2010.07.043","article-title":"Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases","volume":"80","author":"Aggarwal","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"2025030703442237500_r9","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1164\/rccm.201303-0503ED","article-title":"Two faces of vitamin E in the lung","volume":"188","author":"Cook-Mills","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030703442237500_r10","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.neuropharm.2009.06.013","article-title":"Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy","volume":"57","author":"Kuhad","year":"2009","journal-title":"Neuropharmacology"},{"key":"2025030703442237500_r11","doi-asserted-by":"crossref","first-page":"905","DOI":"10.3892\/mmr.2012.770","article-title":"\u03b3-Tocotrienol attenuates TNF-\u03b1-induced changes in secretion and gene expression of MCP-1, IL-6 and adiponectin in 3T3-L1 adipocytes","volume":"5","author":"Matsunaga","year":"2012","journal-title":"Mol Med Rep"},{"key":"2025030703442237500_r12","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/S0278-6915(01)00025-4","article-title":"Oral toxicity of a tocotrienol preparation in rats","volume":"39","author":"Nakamura","year":"2001","journal-title":"Food Chem. Toxicol."},{"key":"2025030703442237500_r13","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.tox.2008.07.003","article-title":"Induction of characteristic hepatocyte proliferative lesion with dietary exposure of Wistar Hannover rats to tocotrienol for 1 year","volume":"250","author":"Tasaki","year":"2008","journal-title":"Toxicology"},{"key":"2025030703442237500_r14","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Reagan-Shaw","year":"2008","journal-title":"FASEB J."},{"key":"2025030703442237500_r15","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/nm.1946","article-title":"House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells","volume":"15","author":"Hammad","year":"2009","journal-title":"Nat. Med."},{"key":"2025030703442237500_r16","doi-asserted-by":"crossref","DOI":"10.1021\/pr5003615","article-title":"Metabolomics reveals inflammatory-linked pulmonary metabolic alterations in a murine model of house dust mite-induced allergic asthma","author":"Ho","year":"2014","journal-title":"J. Proteome Res."},{"key":"2025030703442237500_r17","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.freeradbiomed.2012.05.021","article-title":"Anti-malarial drug artesunate ameliorates oxidative lung damage in experimental allergic asthma","volume":"53","author":"Ho","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"2025030703442237500_r18","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.tiv.2013.01.016","article-title":"Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay: a quantitative method for oxidative stress assessment of nanoparticle-treated cells","volume":"27","author":"Aranda","year":"2013","journal-title":"Toxicol. In Vitro"},{"key":"2025030703442237500_r19","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.4049\/jimmunol.1202416","article-title":"Receptor-interacting protein 2 gene silencing attenuates allergic airway inflammation","volume":"191","author":"Goh","year":"2013","journal-title":"J. Immunol."},{"key":"2025030703442237500_r20","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1373\/clinchem.2003.022681","article-title":"Simultaneous determination of tocotrienols, tocopherols, retinol, and major carotenoids in human plasma","volume":"49","author":"Lee","year":"2003","journal-title":"Clin. Chem."},{"key":"2025030703442237500_r21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/BF03190258","article-title":"Sparse sampling for assessment of drug exposure in toxicological studies","volume":"21","author":"Burtin","year":"1996","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"2025030703442237500_r22","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1021\/jf803537k","article-title":"Antioxidant assays for plant and food components","volume":"57","author":"Moon","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"2025030703442237500_r23","doi-asserted-by":"crossref","first-page":"L1111","DOI":"10.1152\/ajplung.00208.2006","article-title":"Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma","volume":"292","author":"Abdala-Valencia","year":"2007","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025030703442237500_r24","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1146\/annurev.pharmtox.010909.105600","article-title":"Mechanisms of cell protection by heme oxygenase-1","volume":"50","author":"Gozzelino","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2025030703442237500_r25","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1074\/jbc.M610028200","article-title":"\u03b3-Tocotrienol inhibits nuclear factor-\u03baB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis","volume":"282","author":"Ahn","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2025030703442237500_r26","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1164\/rccm.200412-1647OC","article-title":"I\u03ba-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma","volume":"172","author":"Birrell","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030703442237500_r27","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/j.jaci.2007.03.048","article-title":"Eosinophil trafficking in allergy and asthma","volume":"119","author":"Rosenberg","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030703442237500_r28","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.jaci.2012.06.025","article-title":"Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients","volume":"130","author":"Jia","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030703442237500_r29","doi-asserted-by":"crossref","first-page":"6236","DOI":"10.4049\/jimmunol.0900614","article-title":"Regulation of airway MUC5AC expression by IL-1\u03b2 and IL-17A; the NF-\u03baB paradigm","volume":"183","author":"Fujisawa","year":"2009","journal-title":"J. Immunol."},{"key":"2025030703442237500_r30","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jaci.2005.10.024","article-title":"IL-4\/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma","volume":"117","author":"Kabesch","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030703442237500_r31","doi-asserted-by":"crossref","first-page":"L196","DOI":"10.1152\/ajplung.00055.2013","article-title":"Antigen-induced mast cell expansion and bronchoconstriction in a mouse model of asthma","volume":"306","author":"Li","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025030703442237500_r32","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.immuni.2009.08.007","article-title":"Regulatory T cells in asthma","volume":"31","author":"Lloyd","year":"2009","journal-title":"Immunity"},{"key":"2025030703442237500_r33","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1111\/j.1398-9995.2011.02576.x","article-title":"Th17 cells: new players in asthma pathogenesis","volume":"66","author":"Cosmi","year":"2011","journal-title":"Allergy"},{"key":"2025030703442237500_r34","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1165\/rcmb.2011-0322OC","article-title":"Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism","volume":"47","author":"Dai","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030703442237500_r35","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1067\/mai.2002.126780","article-title":"Oxidative stress in allergic respiratory diseases","volume":"110","author":"Bowler","year":"2002","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030703442237500_r36","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/j.jaci.2009.08.039","article-title":"Levels of nitric oxide oxidation products are increased in the epithelial lining fluid of children with persistent asthma","volume":"124","author":"Fitzpatrick","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030703442237500_r37","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.jaci.2003.10.046","article-title":"Leukotrienes and 8-isoprostane in exhaled breath condensate of children with stable and unstable asthma","volume":"113","author":"Zanconato","year":"2004","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030703442237500_r38","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1111\/j.1471-4159.2007.04450.x","article-title":"Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase\/Akt neuroprotective signaling pathway","volume":"102","author":"Delgado-Esteban","year":"2007","journal-title":"J. Neurochem."},{"key":"2025030703442237500_r39","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.bbrc.2010.05.019","article-title":"Transcriptional regulation of NADPH oxidase isoforms, Nox1 and Nox4, by nuclear factor-\u03baB in human aortic smooth muscle cells","volume":"396","author":"Manea","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025030703442237500_r40","first-page":"3847","article-title":"Superoxide dismutase as a longitudinal biomarker of lung function in asthma","volume":"38","author":"Comhair","year":"2011","journal-title":"Eur. Respir. J."},{"key":"2025030703442237500_r41","doi-asserted-by":"crossref","first-page":"351","DOI":"10.3109\/02770903.2011.560319","article-title":"Activities of antioxidant enzymes in relation to oxidative and nitrosative challenges in childhood asthma","volume":"48","author":"Fabian","year":"2011","journal-title":"J. Asthma"},{"key":"2025030703442237500_r42","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.4049\/jimmunol.1302984","article-title":"IL-33 and thymic stromal lymphopoietin mediate immune pathology in response to chronic airborne allergen exposure","volume":"193","author":"Iijima","year":"2014","journal-title":"J. Immunol."},{"key":"2025030703442237500_r43","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.jaci.2013.04.016","article-title":"IL-13 receptor \u03b12 contributes to development of experimental allergic asthma","volume":"132","author":"Chen","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030703442237500_r44","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.jaci.2013.08.052","article-title":"Increased density of intraepithelial mast cells in patients with exercise-induced bronchoconstriction regulated through epithelially derived thymic stromal lymphopoietin and IL-33","volume":"133","author":"Lai","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030703442237500_r45","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/sj.bjp.0704191","article-title":"Role of nitric oxide and superoxide in allergen-induced airway hyperreactivity after the late asthmatic reaction in guinea-pigs","volume":"133","author":"de Boer","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"2025030703442237500_r46","doi-asserted-by":"crossref","first-page":"5811","DOI":"10.4049\/jimmunol.1301329","article-title":"Epithelial NF-\u03baB orchestrates house dust mite-induced airway inflammation, hyperresponsiveness, and fibrotic remodeling","volume":"191","author":"Tully","year":"2013","journal-title":"J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/2\/437\/61501849\/1500362.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/2\/437\/61501849\/1500362.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T03:45:18Z","timestamp":1741319118000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/195\/2\/437\/7961088"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7]]},"references-count":46,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2015,7,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1500362","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,7]]},"published":{"date-parts":[[2015,7]]}}}