Postmenopausal osteoporotic bone loss occurs mainly due to cessation of ovarian function, a condition associated with increased free radicals. Vitamin E, a lipid-soluble vitamin, is a potent antioxidant which can scavenge free radicals in the body. In this study, we investigated the effects of alpha-tocopherol and pure tocotrienol on bone microarchitecture and cellular parameters in ovariectomized rats. Three-month-old female Wistar rats were randomly divided into ovariectomized control, sham-operated, and ovariectomized rats treated with either alpha-tocopherol or tocotrienol. Their femurs were taken at the end of the four-week study period for bone histomorphometric analysis. Ovariectomy causes bone loss in the control group as shown by reduction in both trabecular volume (BV/TV) and trabecular number (Tb.N) and an increase in trabecular separation (Tb.S). The increase in osteoclast surface (Oc.S) and osteoblast surface (Ob.S) in ovariectomy indicates an increase in bone turnover rate. Treatment with either alpha-tocopherol or tocotrienol prevents the reduction in BV/TV and Tb.N as well as the increase in Tb.S, while reducing the Oc.S and increasing the Ob.S. In conclusion, the two forms of vitamin E were able to prevent bone loss due to ovariectomy. Both tocotrienol and alpha-tocopherol exert similar effects in preserving bone microarchitecture in estrogen-deficient rat model.

Purpose. This paper explores the effects of vitamin E on bone structural changes.

Methods. A systematic review of the literature was conducted to identify relevant studies about vitamin E and osteoporosis/bone structural changes. A comprehensive search in Medline and CINAHL for relevant studies published between the years 1946 and 2012 was conducted. The main inclusion criteria were published in English, studies had to report the association or effect of vitamin E and osteoporosis-related bone changes, and the osteoporosis-related bone changes should be related to lifestyle variables, aging, or experimentally-induced conditions.

Results. The literature search identified 561 potentially relevant articles, whereby 11 studies met the inclusion criteria. There were three human epidemiological studies and eight animal experimental studies included in this paper. Four animal studies reported positive bone structural changes with vitamin E supplementation. The rest of the studies had negative changes or no effect. Studies with positive changes reported better effects with tocotrienol vitamin E isomer supplementation.

Conclusions. This evidence-based review underscores the potential of vitamin E being used for osteoporosis. The effect of one of the vitamin E isomers, tocotrienols, on bone structural changes warrants further exploration. Controlled human observational studies should be conducted to provide stronger evidence.

Postmenopausal osteoporosis is the commonest cause of osteoporosis. It is associated with increased free radical activity induced by the oestrogen-deficient state. Therefore, supplementation with palm-oil-derived tocotrienols, a potent antioxidant, should be able to prevent this bone loss. Our earlier studies have shown that tocotrienol was able to prevent and even reverse osteoporosis due to various factors, including oestrogen deficiency. In this study we compared the effects of supplementation with palm tocotrienol mixture or calcium on bone biomarkers and bone formation rate in ovariectomised (oestrogen-deficient) female rats. Our results showed that palm tocotrienols significantly increased bone formation in oestrogen-deficient rats, seen by increased double-labeled surface (dLS/Bs), reduced single-labeled surface (sLS/BS), increased mineralizing surface (MS/BS), increased mineral apposition rate (MAR), and an overall increase in bone formation rate (BFR/BS). These effects were not seen in the group supplemented with calcium. However, no significant changes were seen in the serum levels of the bone biomarkers, osteocalcin, and cross-linked C-telopeptide of type I collagen, CTX. In conclusion, palm tocotrienol is more effective than calcium in preventing oestrogen-deficient bone loss. Further studies are needed to determine the potential of tocotrienol as an antiosteoporotic agent.

Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol

Gopalan A, Yu W, Sanders BG, Kline K.

Cancer Lett. 2012 Oct 9. [Epub ahead of print]

Present study shows that drug resistant human breast cancer cells are enriched in cancer stem-like cells (CSCs) and express elevated levels of Stat-3 signaling mediators, which contribute to CSC enrichment. Simvastatin (SVA) and gamma-tocotrienol (γT3) eliminate enriched CSCs and suppress expression of Stat-3 signaling mediators via inhibition of the mevalonate pathway and activation of de novo ceramide synthesis pathway, respectively. Combination of SVA+γT3 at low doses enhanced these actions via inhibition of the mevalonate pathway. Data demonstrate that SVA and γT3 alone or in combination possess the ability to eliminate CSCs in drug resistant human breast cancer cells.

Involvement of de novo ceramide synthesis in gamma-tocopherol and gamma-tocotrienol-induced apoptosis in human breast cancer cells

Gopalan A, Yu W, Jiang Q, Jang Y, Sanders BG, Kline K.

Mol Nutr Food Res. 2012 Oct 15.

Scope: This study further examines mechanisms involved in the pro-apoptotic action of gamma-tocopherol (γT) and gamma-tocotrienol (γT3) in human breast cancer cell lines.

Methods And Results: γT upregulates phospho-JNK (pJNK), CCAAT/enhancer-binding protein homologous protein (CHOP), and death receptor-5 (DR5) protein expression as detected by Western blot assays. siRNA knockdown of JNK, CHOP, or DR5 shows that γT-induced apoptosis is JNK/CHOP/DR5 signaling dependent, which is similar to γT3-mediated apoptotic signaling. Furthermore, both γT and γT3 induce increased levels of cellular ceramides and dihydroceramides as determined by LC-MS/MS analyses. Inhibition of de novo ceramide synthesis using chemical inhibitors blocked the ability of γT and γT3 to induce apoptosis as detected by Annexin V-FITC/PI assay and to activate JNK/CHOP/DR5 pro-apoptotic signaling thereby demonstrating the involvement of de novo ceramide synthesis in γT- and γT3-induced apoptosis.

Conclusion: Taken together, data show that both γT and γT3 induce apoptosis via de novo ceramide synthesis dependent activation of JNK/CHOP/DR5 pro-apoptotic signaling.

We have conducted a comprehensive literature review regarding the effect of vitamin E on lifespan in model organisms including single-cell organisms, rotifers, Caenorhabditis elegans (C. elegans), Drosophila melanogaster and laboratory rodents. We searched Pubmed and ISI Web of knowledge for studies up to 2011 using the terms “tocopherols”, “tocotrienols”, “lifespan” and “longevity” in the above mentioned model organisms. Twenty four studies were included in the final analysis. While some studies suggest an increase in lifespan due to vitamin E, other studies did not observe any vitamin E-mediated changes in lifespan in model organisms. Furthermore there are several studies reporting a decrease in lifespan in response to vitamin E supplementation. Different outcomes between studies may be partly related to species-specific differences, differences in vitamin E concentrations and the vitamin E congeners administered. The findings of our literature review suggest that there is no consistent beneficial effect of vitamin E on lifespan in model organisms which is consistent with reports in human intervention studies.

Tocopherols and tocotrienols plasma levels are associated with cognitive impairment

Francesca Mangialasche, Weili Xu, Miia Kivipelto, Emanuela Costanzi, Sara Ercolani, Martina Pigliautile, Roberta Cecchetti, Mauro Baglioni, Andrew Simmons, Hilkka Soininen, Magda Tsolaki, Iwona Kloszewska, Bruno Vella, Simon Lovestone, Patrizia Mecocci,

Neurobiol Aging. 2012 Oct;33(10):2282-90.

Vitamin E includes 8 natural compounds (4 tocopherols, 4 tocotrienols) with potential neuroprotective activity. α-Tocopherol has mainly been investigated in relation to cognitive impairment. We examined the relation of all plasma vitamin E forms and markers of vitamin E damage (α-tocopherylquinone, 5-nitro-γ-tocopherol) to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, α-tocopherylquinone, and 5-nitro-γ-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Compared with cognitively normal subjects, AD and MCI had lower levels of total tocopherols, total tocotrienols, and total vitamin E. In multivariable-polytomous-logistic regression analysis, both MCI and AD cases had 85% lower odds to be in the highest tertile of total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased vitamin E damage. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD.

Gamma Tocotrienol for Breast Cancer Prevention and Treatment

Byron J. Richards

 After reviewing the available science and biochemistry on gamma tocotrienol Specialized form of vitamin E. Powerful antioxidant showing positive benefits for cholesterol, cardiovascular, neurological health and cancer risk reduction. and cancer, researchers from the University of Louisiana at Monroe proclaimed, “The synergistic anti-proliferative and apoptotic effects demonstrated by combined low dose treatment of gamma tocotrienol Specialized form of vitamin E. Powerful antioxidant showing positive benefits for cholesterol, cardiovascular, neurological health and cancer risk reduction. with other chemotherapeutic agents may provide significant health benefits in the prevention and/or treatment of breast cancer in women, while at the same time avoiding tumor resistance and toxic side effects associated with high dose monotherapy.”

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