Studies published in international peer-reviewed journals have highlighted Vitamin E’s neuroprotective benefits, an activity largely attributed to Vitamin E’s antioxidant properties. Oxidative stress plays a major role in the development and progression of AD. Results from the Rotterdam Study, one of the largest study to date on the effects of dietary antioxidant intake on dementia risk in over 5,000 subjects have shown that high intake of vitamin E- rich food sources can modestly reduce the long-term risk of dementia and AD. [1]

A series of clinical studies by Mangialasche et al have shown that high plasma levels of vitamin E tocotrienol is associated with reduced Alzheimer Disease risk. [2]Recently, Mangialasche et al confirms vitamin E’s neuroprotective abilities this time in subjects with varying degrees of cognitive impairment. In the AdNeuroMed Trial, a longitudinal multi-centred study, Mangialsche et al focused not just on alpha-tocopherol levels but also measured tocotrienol levels and combined these with imaging measures to help differentiate patients with AD from those without. Results from the AdNeuroMed Study has shown that plasma levels of vitamin E tocotrienols when taken together with MRI measures can help enhance the accuracy of differentiating patients with varying degree of cognitive impairment. Interestingly, this multi-modal approach can also help predict the progression of milder forms of cognitive impairment to Alzheimer’s Disease (AD). This combined MRI and Vitamin E biomarker approach is also more readily available and less invasive compared to conventional imaging measures e.g. MRI/PET. [3]

Tocotrienol has over 40 to 60 times more powerful antioxidant activity than alpha-tocopherol. [4] Palm tocotrienol significantly alleviates oxidative stress not only by its potent free radical scavenging properties but also by interacting directly and strongly with antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. [5] Vitamin E tocotrienol particularly its alpha isoform is closely associated with neuroprotective activity. [6] Alpha-tocotrienol can readily reach high concentrations in the blood after oral supplementation suggesting that dietary intake of tocotrienols can adequately support neuroprotection. [7]

Apart from highlighting tocotrienol’s role as a potential nutritional biomarker in patients with AD, results from these studies show that supplementation with tocotrienol may reduce the long-term risk of dementia and AD and may adequately protect against full progression of AD in those with mild cognitive impairment.

References

1. Devore EE, et al. Dietary antioxidants and long-term risk of dementia. Arch Neurol, 2010. 67(7): 819-25.

2. Mangialasche F et al. Tocopherols and tocotrienols plasma levels are associated with cognitive impairment. Neurobiol Aging, 2011.

3. Mangialasche F et al. Classification and prediction of clinical diagnosis of Alzheimer’s disease based on MRI and plasma measures of alpha-/gamma-tocotrienols and gamma-tocopherol. J Intern Med, 2013.

4. Serbinova E, K.V., Han D and Packer L.Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol. . Free Radic Biol Med 1991. 10(5):263-75. .

5. Packer, L., S.U. Weber, and G. Rimbach. Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr, 2001. 131(2):369S-73S.

6. Sen, C.K., C. Rink, and S. Khanna. Palm oil-derived natural vitamin E alpha-tocotrienol in brain health and disease. J Am Coll Nutr, 2010. 29(3 Suppl):314S-323S.

7. Patel, V., et al., Natural vitamin E alpha-tocotrienol: retention in vital organs in response to long-term oral supplementation and withdrawal. Free Radic Res, 2006. 40(7):763-71

High Intake of Vitamin E Tocotrienol May Reduce Alzheimer’s Risk

Studies published in international peer-reviewed journals have highlighted Vitamin E’s neuroprotective benefits, an activity largely attributed to Vitamin E’s antioxidant properties. Oxidative stress plays a major role in the development and progression of AD. Results from the Rotterdam Study, one of the largest study to date on the effects of dietary antioxidant intake on dementia risk in over 5,000 subjects have shown that high intake of vitamin E- rich food sources can modestly reduce the long-term risk of dementia and AD.

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In the show’s January 3, 2013 episode, Dr Oz   and his guest, Bryce Wylde, recommend red palm oil particularly for its palm tocotrienol, a novel form of vitamin E found in the palm fruit. On his show Dr Oz called the red palm oil as the “most miraculous find of 2013”.

Power-Packed Contents

Red palm oil’s health promoting properties are largely attributed to its high antioxidant and anti-inflammatory contents. Red palm oil is a rich source of tocotrienol, a powerful form of vitamin E, lycopene and carotenoids, the latter being responsible for the oil’s distinctive red color in its unprocessed state.

Red Palm Oil and Cardiovascular Health

Red palm oil has repeatedly stunned researchers with its heart-protective and cholesterol-lowering properties.  Studies have shown that adding palm oil in the diet can reduce plaque build-up in arteries and, therefore, reverse the process of plaque and prevent blockages formation within blood vessel walls. Science now understands that inflammation in the artery lining is what causes cholesterol to deposit in the first place. So, it makes sense that the protective effects come from the high antioxidant, anti-inflammatory content of the red palm oil which works to quench free radicals and keep inflammation under control. Apart from helping tear away plaque from blood vessel walls, red palm oil also helps maintain healthy blood pressure and cholesterol levels.

Red Palm Oil and Brain Health

Alpha-tocotrienol, one of the natural vitamin E forms found in high amounts in red palm oil is known for its neuro-protective properties. Studies funded by the National Institutes of Health (NIH) have shown that alpha-tocotrienol can help reduce the effects of stroke by 50%. When it comes to your brain, the special form of vitamin-E (tocotrienol) in red palm oil stops destructive damage and improves blood flow to brain cells, which can also help to prevent Alzheimer’s disease and dementia.

Oil Palm Fruit (Eleais guinensis)

Red Palm Oil as Anti-Cancer Food

The high antioxidant content of red palm oil makes it a potent anti-cancer food. Though tocotrienols can be found in rice bran, barley and wheat, red palm oil is the richest source of tocotrienol. Research suggests that this form of vitamin E may help fight skin, stomach, pancreas, liver, lung, colon, prostate, breast, and other cancers.

Other Health Benefits of Red Palm Oil

Research is showing that the antioxidant power of red palm oil can be of help in protecting against a variety of health problems, including osteoporosis, asthma, cataracts, macular degeneration, arthritis, and liver disease. It can even slow down the premature aging processes by protecting the skin against damaging UV rays.

Additionally, research has shown that red palm oil promotes nutrient utilization, improves liver detoxification pathways and improves immune function.

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Scientists have found tocotrienol supplementation lower plasma triglyceride levels in patients undergoing chronic hemodialysis.coQ10heart

The study was conducted by Professor Pramod Khosla’s group in Wayne State University. End-stage renal disease patients on chronic (at least 3 months prior to the study) dialysis treatment were recruited from a local dialysis clinic in Detroit. 81 Patients were randomized to receive either 180 mg tocotrienol rich fraction or placebo daily for 16 weeks. The patient compliance was measured by pill counting. After 12 weeks supplementation, the group receiving tocotrienol supplementation have decreased plasma triglyceride levels from 144 ± 91mg/dL to 113± 47 mg/dL (p <0.05). The triglyceride levels remained low (103± 45 mg/dL) at week 16. In the control group, the plasma triglyceride levels were unchanged.

Triglycerides are produced from energy sources like carbohydrates. High plasma triglyceride levels (> 150 mg/dL) indicate increased risk of cardiovascular diseases. In end-stage renal disease patients, dyslipidemia is highly prevalent with elevated plasma triglyceride levels. This study indicated the lipid-regulation and potential cardio-protection effect of tocotrienol in these patients.

The triglyceride-lowering effect of tocotrienol observed in this clinical study agrees with a previous publication by Davos Life Science, in which supplementation with 120 mg γδ-tocotrienol in 10 hypercholesterolemic subjects for 8 weeks led to a 28% reduction in plasma triglyceride levels.

Both the tocotrienol supplementation group and the control group have decreased levels of total cholesterol, higher levels of high density lipoprotein cholesterol (HDLC) and decreased levels of low-density lipoprotein cholesterol (LDLC) at week 16. This could be due to the effect of the cholesterol-lowering drug statin of which 30-40% of the patients were taking concurrently.

This study reinforced the cardiovascular benefits of palm-derived tocotrienols in lowering triglyceride levels in subjects with mild to moderate dyslipidemia.

Reference:

Daud ZA, Tubie B, Sheyman M, Osia R, Adams J, Tubie S, Khosla P. (2013) Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients. Vasc Health Risk Manag. 9:747-61.

Zaiden, N., Yap, W., Ong, S., & Xu, C. (2010) Gamma delta tocotrienols reduce hepatic triglyceride synthesis and VLDL secretion. J Atherosclerosis Thrombosis. 4911: 1019–1032.

brain

Alzheimer’s disease (AD) affects millions of people in the world with symptoms of deteriorating memory and loss of bodily functions.  Currently there is no cure for this disease and researches focus on preventing the onset and slowing the progression of the disease.

A clinical study published in JAMA found that patients with mild to moderate Alzheimer’s disease benefited from high dose of Vitamin E supplementation with delayed disease progression over a study period of 5 years.

613 patients participated in the Trial of Vitamin E and Memantine in Alzheimer’s disease (TEAM-AD). The participants were randomized to receive either 200O IU/d α-tocopherol, 20 mg/d of memantine (NMDA antagonist), the combination, or placebo. The participants were assessed every 6 months for functional abilities to perform daily living activities such as dressing or bathing, cognitive function and dementia severity, memory, language and praxis functions in AD using a range of questionnaires and instruments. The time on which caregivers spend assisting AD patients in daily activities were also surveyed. Drug compliance was monitored by measuring the serum levels of α-tocopherol and memantine.

The patients receiving Vitamin E have a delay of 19% per year or approximately 6.2 months in the clinical progression compared to the control, followed by a reduction of 2 hour/d of caregiver time. Despite the high dose of α-tocopherol used in this study, the annual mortality rate in the group receiving α-tocopherol (7.3%) was not increased compared to those in the placebo group (9.4%).

Vitamin E has neuroprotective benefits which are largely attributed to its antioxidant properties. Palm tocotrienols alleviate oxidative stress by free radical scavenging as well as interacting with antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. Oxidative stress plays a major role in the development and progression of AD.  A series of clinical studies by Mangialasche et al. have shown that high plasma levels of vitamin E tocotrienol are associated with reduced Alzheimer Disease risk. The plasma levels of vitamin E tocotrienols could be used as a biomarker for diagnosis of cognitive impairment when combined with MRI measures.

The study highlights Vitamin E’s potential in benefiting AD patients. Tocotrienol, being a more potent antioxidant, may confer neuroprotection similar to α-tocopherol.

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Tocotrienols exhibit a plethora of unique biological activities, including neuro-protection, radio-protection, anti-cancer, anti-inflammation and lipid-lowering. However, the plasma concentrations of tocotrienols were found to be lower compare to tocopherols. Fu et al. has published a review article: Bioavailability of tocotrienols: evidence in human studies in Nutrition & Metabolism.Biochemistry

The pharmacokinetics of tocotrienols has been studies using single dose of tocotrienol-rich fractions (TRF) derived from palm oil. Tocotrienols were mainly detected in the HDL cholesterol at 4 to 8 hours before clearance. The rapid clearance of tocotrienols from the plasma within 24 hours could be partly due to the low affinity of α-tocopherol transport protein for tocotrienols. Human clinical studies suggest that the plasma concentrations of tocotrienols can be increased by at least 2-fold in the fed state. The significant increase in tocotrienol bioavailability under fed state was probably attributed to the increase of TAG from meal followed by bile secretion. A dosing schedule of tocotrienols twice daily is sufficient for the plasma concentration to reach the steady state within 3 days. An acute dose of mixed tocotrienols ranging from 200 to 1011 mg were considered to be safe for human consumption with no adverse events.

The review article also discussed the therapeutic efficacy of tocotrienols based on three variables: dose, formulation and study population. The authors concluded that the outcome of clinical evaluations is not only affected by the bioavailability of tocotrienols, but also closely dependent on the study designs.

Gamma-tocotrienol enhances the chemosensitivity of human oral cancer cells to docetaxel through the downregulation of the expression of NF-kappaB-regulated anti-apoptotic gene products

Kani K, Momota Y, Harada m, et al

Int J Oncol. 2013 Jan;42(1):75-82.

Taxanes, including docetaxel, are widely used for the treatment of squamous cell carcinoma of the head and neck. However, the gastrointestinal toxicity of docetaxel has limited its high-dose clinical use. In this study, we examined the synergistic anticancer effects of combined low-dose docetaxel and gamma-tocotrienol treatment on human oral cancer (B88) cells. We treated B88 cells with docetaxel and gamma-tocotrienol at concentrations of 0.5 nM and 50 microM, respectively. When cells were treated with either agent alone at a low dose, no significant cytotoxic effect was observed. However, the simultaneous treatment of cells with both agents almost completely suppressed cell growth. Whereas docetaxel stimulated the expression of nuclear factor-kappaB (NF-kappaB) p65 protein in B88 cells, gamma-tocotrienol slightly inhibited the expression of constitutive nuclear p65 protein. Of note, the combined treatment with both agents inhibited docetaxel-induced nuclear p65 protein expression. Electrophoretic mobility shift assay (EMSA) revealed that the simultaneous treatment with these agents suppressed the NF-kappaB DNA binding activity in B88 cells. In addition, gamma-tocotrienol downregulated the docetaxel-induced expression of NF-kappaB-regulated gene products associated with the inhibition of apoptosis. Furthermore, the activation of initiator caspases, caspases-8 and -9, and the effector caspase, caspase-3, was detected following treatment with both agents. Finally, apoptosis was also clearly observed as demonstrated by the cleavage of poly(ADP-ribose) polymerase (PARP) and nuclear fragmentation through the activation of caspase-3 by combined treatment with docetaxel and gamma-tocotrienol. These findings suggest that the combination treatment with these agents may provide enhanced therapeutic response in oral cancer patients, while avoiding the toxicity associated with high-dose beta-tubulin stabilization monotherapy.

Gamma-tocotrienol reduces the triacylglycerol level in rat primary hepatocytes through regulation of fatty acid metabolism

Muto C, Yachi R, Aoki Y, et al

J Clin Biochem Nutr. 2013 Jan;52(1):32-7

The present study was carried out to investigate the effect of vitamin E analogs, especially gamma-tocotrienol (gamma-T3), on hepatic TG accumulation and enzymes related to fatty acid metabolism in three types of rat primary hepatocytes: (1) normal hepatocytes, (2) hepatocytes incubated in the presence of palmitic acid (PA), and (3) hepatocytes with fat accumulation. Our results showed that gamma-T3 significantly reduced the TG content of normal hepatocytes. gamma-T3 also increased the expression of carnitine palmitoyltransferase 1 (CPT1A) mRNA, and tended to reduce that of sterol regulatory element binding protein 1c (SREBP-1c) mRNA. In addition, gamma-T3 markedly suppressed the gene expression of both C/EBP homologous protein (CHOP) and SREBP-1c induced by PA. As these two genes are located downstream of endoplasmic reticulum (ER) stress, their suppression by gamma-T3 might result from a decrease of ER stress. Moreover, gamma-T3 suppressed the expression of interleukin 1beta (IL-1beta), which lies downstream of CHOP signaling. Taken together, our data suggest that gamma-T3 might prevent hepatic steatosis and ameliorate ER stress and subsequent inflammation in the liver.

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Mitochondrial-dependent anticancer activity of delta-tocotrienol and its synthetic derivatives in HER-2/neu overexpressing breast adenocarcinoma cells

Viola V, Ciffolilli S, Legnaioli, S et al

Biofactors; epub Jan30,2013

Anticancer activity and mitochondrial mechanism of the vitamin E form delta-tocotrienol (delta-T3) was investigated in HER-2/neu-overexpressing human SKBR3 and murine TUBO breast cancer cells. delta-T3 was confirmed to possess high cytotoxic and apoptotic activity in SKBR3 cells as compared with all natural forms of vitamin E and several synthetic forms that included novel derivatives with the same backbone of delta-T3 such as delta-tocotrienyl-succinyl amide (delta-T3AS) and the redox-active analogue delta-tocotrienyl amine (delta-T3NH2). As observed in the case of alpha-TOS, a prototypical anticancer drug derived from alpha-tocopherol, succinylation of delta-T3 enhanced citotoxicity and apoptotic activity of the vitamer. delta-T3 induced apoptosis of SKBR3 cells was associated with mitochondrial destabilization, energy failure, and unbalanced activity of stress/survival MAPKs, namely p38 and ERK1/2 pathways. An increased generation of ROS followed to such a series of early events. Enhanced activity of delta-T3 in this human carcinoma cell line was characterized by the sustained uptake and oxidative transformation to the quinone derivative delta-T3Q, thereby suggesting redox effects in SKBR3 mitochondria by this vitamer. Viability and uptake data show a different pattern of responses in TUBO cells with higher response to synthetic derivatives of delta-T3 than in SKBR3 cells. In conclusion, synthetic derivatives of delta-T3 with enhanced apoptotic activity in breast carcinoma cells are investigated for the first time in this study also describing mechanistic aspects of mitochondrial effects of delta-T3. Further investigation in preclinical models of HER2/neu-high breast adenocarcinoma is underway to identify other and more effective forms of VE in this type of cancer.

Vitamin E delta-Tocotrienol Induces p27(Kip1)-Dependent Cell-Cycle Arrest in Pancreatic Cancer Cells via an E2F-1-Dependent Mechanism

Hodul, PJ Dong Y, Husain K et al

PLoS One,2013;8(2):e52526

Vitamin E delta-tocotrienol has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we demonstrated that delta-tocotrienol exerted significant cell growth inhibition pancreatic ductal cancer (PDCA) cells without affecting normal human pancreatic ductal epithelial cell growth. We also showed that delta-tocotrienol-induced growth inhibition occurred concomitantly with G(1) cell-cycle arrest and increased p27(Kip1) nuclear accumulation. This finding is significant considering that loss of nuclear p27(Kip1) expression is a well-established adverse prognostic factor in PDCA. Furthermore, delta-tocotrienol inactivated RAF-MEK-ERK signaling, a pathway known to suppress p27(Kip1) expression. To determine whether p27(Kip1) induction is required for delta-tocotrienol inhibition of PDCA cell proliferation, we stably silenced the CDKN1B gene, encoding p27(Kip1), in MIAPaCa-2 PDCA cells and demonstrated that p27(Kip1) silencing suppressed cell-cycle arrest induced by delta-tocotrienol. Furthermore, delta-tocotrienol induced p27(Kip1) mRNA expression but not its protein degradation. p27(Kip1) gene promoter activity was induced by delta-tocotrienol through the promoter’s E2F-1 binding site, and this activity was attenuated by E2F-1 depletion using E2F-1 small interfering RNA. Finally, decreased proliferation, mediated by Ki67 and p27(Kip1) expression by delta-tocotrienol, was confirmed in vivo in a nude mouse xenograft pancreatic cancer model. Our findings reveal a new mechanism, dependent on p27(Kip1) induction, by which delta-tocotrienol can inhibit proliferation in PDCA cells, providing a new rationale for p27(Kip1) as a biomarker for delta-tocotrienol efficacy in pancreatic cancer prevention and therapy.

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