Chronic inflammation constitutes one of the major etiologies of degenerative diseases including cancer, and cardiovascular and neurodegenerative diseases; chronic inflammation also contributes to rheumatoid arthritis, asthma and hepatitis. These diseases are among the leading causes of death and disability in the world. During inflammation, several pro-inflammatory mediators including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), as well as cytokines, such as TNF-alpha, play central roles in regulating inflammatory response and inflammation-mediated damage. Vitamin E comprises eight structurally related molecules, alpha-,beta-, gamma-, delta-tocopherol, and alpha-,beta-, gamma-, delta -tocotrienol. Among them, only alpha -tocopherol (alphaT) has been extensively studied. Recent studies indicate that other forms of vitamin E have unique properties, which are not shared by alphaT, but are important to human disease prevention and therapy. Gamma-Tocopherol (gammaT) and its metabolite, but not aT, exhibit anti-inflammatory effects by inhibiting cyclooxygenase (COX)- catalyzed formation of PGE2. In a rat inflammation model, gammaT inhibits not only PGE2, but also LTB4, and TNF-alpha. These results suggest that gammaT may be superior to some commonly used non-steroid anti-inflammatory drugs (NSAIDs), such as COX inhibitors, most of which only inhibit the COX-mediated pathway. Preliminary studies also indicate that delta- tocopherol and gamma-tocotrienol, compared with gammaT, are even stronger inhibitors of the COX-catalyzed formation of PGE2. These observations led to the current hypothesis that certain forms of vitamin E and their combinations have unique pharmaceutical utility as anti-inflammatory drugs, or as supplements that complement and improve current treatments for inflammatory diseases. This hypothesis will be tested by pursuit of the following Specific Aims in cell culture and animal experiments: 1. Investigate in vitro anti-inflammatory properties of individual vitamin E forms and their combinations; 2. Investigate and compare in vivo anti-inflammatory activities of individual vitamin E forms and their combinations; and 3. Investigate the potentially improved effects of combining certain forms of vitamin E and NSAIDs, such as aspirin, in a rat inflammation model. Our studies may lead to the discovery of novel and better therapy for treating and preventing inflammatory diseases, and provide the scientific rationale, the experimental evidence and the biochemical basis for future human studies.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
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Nutrition Study Section (NTN)
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Pontzer, Carol H
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Purdue University
Other Domestic Higher Education
West Lafayette
United States
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Jiang, Qing; Rao, Xiayu; Kim, Choon Young et al. (2012) Gamma-tocotrienol induces apoptosis and autophagy in prostate cancer cells by increasing intracellular dihydrosphingosine and dihydroceramide. Int J Cancer 130:685-93
Jiang, Ziying; Yin, Xinmin; Jiang, Qing (2011) Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively. J Immunol 186:1173-9
Yang, Wen-Chu; Regnier, Fred E; Jiang, Qing et al. (2010) In vitro stable isotope labeling for discovery of novel metabolites by liquid chromatography-mass spectrometry: Confirmation of gamma-tocopherol metabolism in human A549 cell. J Chromatogr A 1217:667-75
Freiser, Helene; Jiang, Qing (2009) Gamma-tocotrienol and gamma-tocopherol are primarily metabolized to conjugated 2-(beta-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman and sulfated long-chain carboxychromanols in rats. J Nutr 139:884-9
Jiang, Qing; Moreland, Michelle; Ames, Bruce N et al. (2009) A combination of aspirin and gamma-tocopherol is superior to that of aspirin and alpha-tocopherol in anti-inflammatory action and attenuation of aspirin-induced adverse effects. J Nutr Biochem 20:894-900
Freiser, Helene; Jiang, Qing (2009) Optimization of the enzymatic hydrolysis and analysis of plasma conjugated gamma-CEHC and sulfated long-chain carboxychromanols, metabolites of vitamin E. Anal Biochem 388:260-5
Jiang, Qing; Yin, Xinmin; Lill, Markus A et al. (2008) Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. Proc Natl Acad Sci U S A 105:20464-9
Reiter, Elke; Jiang, Qing; Christen, Stephan (2007) Anti-inflammatory properties of alpha- and gamma-tocopherol. Mol Aspects Med 28:668-91
Jiang, Qing; Freiser, Helene; Wood, Karl V et al. (2007) Identification and quantitation of novel vitamin E metabolites, sulfated long-chain carboxychromanols, in human A549 cells and in rats. J Lipid Res 48:1221-30
Walter, Patrick B; Fung, Ellen B; Killilea, David W et al. (2006) Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. Br J Haematol 135:254-63

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