Uncategorized

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.

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.

Osteoclastogenesis and osteoblastogenesis, the balancing acts for optimal bone health, are under the regulation of small guanosine triphosphate-binding proteins (GTPases) including Ras, Rac, Rho and Rab. The activities of GTPases require post-translational modification with mevalonate-derived prenyl pyrophosphates. Mevalonate deprivation induced by competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (e.g., statins) prevents the activation of GTPases, suppresses the expression of the receptor for activation of nuclear factor kappa B (NFκB) ligand (RANKL) and activation of NFκB and, consequently, inhibits osteoclast differentiation and induces osteoclast apoptosis. In contrast, statin-mediated inactivation of GTPases enhances alkaline phosphatase activity and the expression of bone morphogenetic protein-2, vascular epithelial growth factor, and osteocalcin in osteoblasts and induces osteoblast proliferation and differentiation. Animal studies show that statins inhibit bone resorption and increase bone formation. The anabolic effect of statins and other mevalonate pathway-suppressive pharmaceuticals resembles the anti-osteoclastogenic and bone-protective activities conferred by dietary isoprenoids, secondary products of plant mevalonate metabolism. The tocotrienols, vitamin E molecules with HMG CoA reductase-suppressive activity, induce mevalonate deprivation and concomitantly suppress the expression of RANKL and cyclooxygenase-2, the production of prostaglandin E2 and the activation of NFκB. Accordingly, tocotrienols inhibit osteoclast differentiation and induce osteoclast apoptosis, impacts reminiscent of those of statins. In vivo studies confirm the bone protective activity of tocotrienols at nontoxic doses. Blends of tocotrienols, statins and isoprenoids widely found in fruits, vegetables, grains, herbs, spices, and essential oils may synergistically suppress osteoclastogenesis while promoting osteoblastogenesis, offering a novel approach to bone health that warrants clinical studies.

The vitamin E family consists of eight isomers known as alpha-, beta-, gamma-, and delta-tocopherols and alpha-, beta-, gamma-, and delta-tocotrienols. Numerous studies focused on the health benefits of these isomers have been performed since the discovery of vitamin E in 1922. Recent discoveries on the potential therapeutic applications of tocotrienols have revolutionized vitamin E research. Nevertheless, despite the abundance of literature, only 1% of vitamin E research has been conducted on tocotrienols. Many new advances suggest that the use of tocotrienols for health improvement or therapeutic purposes is promising. Although the mechanisms of action of tocotrienols in certain disease conditions have been explored, more detailed investigations into the fundamentals of the health-promoting effects of these molecules must be elucidated before they can be recommended for health improvement or for the treatment or prevention of disease. Furthermore, many of the studies on the effects of tocotrienols have been carried out using cell lines and animal models. The effects in humans must be well established before tocotrienols are used as therapeutic agents in various disease conditions, hence the need for more evidence-based human clinical trials.

Supplementation to an AIN93G-based diet of tocotrienol (T3) for 13 weeks administered to Fischer 344/slc rats showed a safety profile with no side effects. Dose-dependent T3 levels were detected in many tissues. Under the present experimental conditions, a continuous intake of the T3 concentrate would be safe in the rats as long as the T3 content was less than 0.20% of the dietary intake.

The vitamin E family consists of 4 tocopherol and 4 tocotrienol compounds. During recent years, tocotrienols have gained increased interest due to their biological activities that are beyond the vitamin E activity. Here we report the engineering of plasmid-free Escherichia coli strains for an efficient synthesis of 2-methyl-6-geranylgeranyl-benzoquinol (MGGBQ), the central precursor for all four natural tocotrienol compounds. Heterologous genes needed for the in vivo synthesis of MGGBQ in E. coli (crtE, hpd, and hpt) were individually integrated into the chromosome of E. coli. The yield of MGGBQ after cultivation of the plasmid-free recombinant E. coli strain was significantly higher (604μg/gcdw) compared to an E. coli strain that carries these biosynthesis genes on a multi-copy expression plasmid (325μg/gcdw). Further chromosomal integration of an additional copy of the isopentenyl-diphosphate isomerase gene (idi) and a subsequent increase in expression level of the deoxy-xylulose synthase gene (dxs) increased the MGGBQ yield by 80% (1110μg/gcdw) and 135% (1425μg/gcdw), respectively. MGGBQ which accumulated in the membrane fraction of the recombinant E. coli cells was isolated and its structure was completely elucidated by 1D and 2D NMR and MS measurements. The engineered, plasmid-free E. coli strain is a promising host for the heterologous in vivo production of tocotrienol and its derivatives.

Although vitamin E has been known as an essential nutrient for almost 80 years, we are far from a complete understanding of all the aspects related to bioavailability and its effects on health and milk quality in dairy cows. Vitamin E is a generic descriptor for two families of lipid-soluble compounds, the tocopherols and the tocotrienols, of which α-tocopherol has the highest biological activity. Commercially available α-tocopherol supplements for dairy cows contain either the natural RRR form or the synthetic (all-rac) form, which contains all the eight possible stereoisomers (four possessing the 2R and four possessing the 2S configuration) in equimolar amounts. Recent data clearly suggest that an almost complete discrimination against the 2S isomers occurs in dairy cows. Thus, 1 g of the all-rac form is essentially equivalent to 0.5 g of the RRR form. With respect to the effect of vitamin E supplementation of dairy cows on health and milk quality, the majority of published studies suggests that vitamin E supplementation at the level 1000 to 4000 IU/cow per day during the dry period reduces both the frequency of intramammary infection and that of clinical mastitis and improves milk quality, as shown by a reduction in the levels of somatic cell count (SCC)/ml in milk, decreased plasmin activity and increased oxidative stability of milk. However, a recent study from the Netherlands suggested that vitamin E supplementation at the 3000 IU/cow per day level during the dry period when combined with high levels of plasma vitamin E at dry-off (>14.5 μmol/l) increases the incidence of mastitis. Data from previously unpublished survey studies and those from published vitamin E feeding trials, in which high levels of blood vitamin E were observed, were reanalyzed. All farms selected for the analysis implemented oral administration of vitamin E at the 3000 IU/cow per day level throughout or during the late dry period (4 weeks before the expected day of parturition). Dairy cows were divided into three groups, depending on blood α-tocopherol levels at dry-off: high (>6.25 μg/ml), medium (between 6.25 and 4.25 μg/ml) and low (<4.25 μg/ml). Data indicate that there were no differences in the incidence of mastitis and in the level of SCC/ml of milk between the three groups. Thus, supplementation of 3000 IU vitamin E/cow per day in the late dry period remains recommended because it is generally associated with decreased risk of mastitis. Conditional or opposite effects have not been repeated and require further research before changing recommendations for vitamin E supplementation.

Statins are HMGCoA reductase inhibitors and had been demonstrated to stimulate bone formation in rodents after high oral doses. Observational studies on patients treated with oral statins were varied. Delta-tocotrienol had been found to stimulate the cleavage of HMGCoA reductase and inhibit its activity. Tocotrienols were found to have both catabolic and anabolic effects on bone in different animal models of osteoporosis. The current study aimed to ascertain the effects of delta-tocotrienol and lovastatin combination on biochemical and static bone histomorphometric parameters in a postmenopausal rat model at clinically tolerable doses. 48 Sprague Dawley female rats were randomly divided into 6 groups: (1) baseline control group; (2) sham-operated control group; (3) ovariectomised control group; (4) ovariectomised and 11 mg/kg lovastatin; (5) ovariectomised and 60 mg/kg delta-tocotrienol; (6) ovariectomised and 60 mg/kg delta-tocotrienol + 11 mg/kg lovastatin. These treatments were given daily via oral gavage for 8 weeks. Delta-tocotrienol plus lovastatin treatment significantly increased bone formation and reduced bone resorption compared to the other groups. Therefore, the combined treatment may have synergistic or additive effects and have the potential to be used as an antiosteoporotic agent in patients who are at risk of both osteoporosis and hypercholesterolemia, especially in postmenopausal women.

Oxidative stress and apoptosis can disrupt the bone formation activity of osteoblasts which can lead to osteoporosis. This study was conducted to investigate the effects of γ-tocotrienol on lipid peroxidation, antioxidant enzymes activities, and apoptosis of osteoblast exposed to hydrogen peroxide (H(2)O(2)). Osteoblasts were treated with 1, 10, and 100 μM of γ-tocotrienol for 24 hours before being exposed to 490 μM (IC(50)) H(2)O(2) for 2 hours. Results showed that γ-tocotrienol prevented the malondialdehyde (MDA) elevation induced by H(2)O(2) in a dose-dependent manner. As for the antioxidant enzymes assays, all doses of γ-tocotrienol were able to prevent the reduction in SOD and CAT activities, but only the dose of 1 μM of GTT was able to prevent the reduction in GPx. As for the apoptosis assays, γ-tocotrienol was able to reduce apoptosis at the dose of 1 and 10 μM. However, the dose of 100 μM of γ-tocotrienol induced an even higher apoptosis than H(2)O(2). In conclusion, low doses of γ-tocotrienol offered protection for osteoblasts against H(2)O(2) toxicity, but itself caused toxicity at the high doses.