Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation, Oxidative stress and Hepatic Steatosis in Patients with Nonalcoholic Fatty Liver Disease

Pervez MA, Khan DA, Ijaz A, Khan S.

Turk J Gastroenterol. 2018 Mar;29(2):170-176. doi: 10.5152/tjg.2018.17297.

Abstract

BACKGROUND/AIMS:

Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and is associated with increased morbidity and mortality. Currently, there is no definitive treatment for this disease. δ-Tocotrienol has potent anti-inflammatory and antioxidant properties and may reduce liver injury in NAFLD. The present study aims to evaluate the efficacy and safety of δ-tocotrienol in the treatment of NAFLD.

MATERIALS AND METHODS:

The present study was a randomized, double-blind, placebo-controlled pilot study conducted in patients aged > 20 years, belonging to both sexes, having ultrasound-proven fatty liver disease, having a fatty liver index (FLI) of ≥ 60, and persistent elevation of alanine transaminase. A total of 71 patients were assigned to receive either oral δ-tocotrienol (n=35, 300 mg twice daily) or placebo (n=36) for 12 weeks. At the baseline and at the end of the study, clinical and biochemical parameters, including lipid profile, liver function tests, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were measured. Body mass index and FLI were calculated, and ultrasound grading of hepatic steatosis was performed.

RESULTS:

Out of 71 enrolled patients, 64 patients, 31 in the δ-tocotrienol group and 33 in the placebo group, completed the study. After 12 weeks of supplementation, δ-tocotrienol showed greater efficacy than placebo by decreasing serum aminotransferases, hs-CRP, MDA, and FLI score (p<0.001). However, it did not improve hepatic steatosis on ultrasound examination. No adverse effects were reported.

CONCLUSION:

δ-Tocotrienol was safe, and it effectively improved aminotransferase levels and inflammatory and oxidative stress markers in patients with NAFLD. Large-scale randomized clinical trials are warranted to further support these findings.

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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

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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Classification and prediction of clinical diagnosis of Alzheimer’s disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol

Mangialasche F, Westman E, Kivipelto M, et al

J Intern Med. 2013 Jan 24. doi: 10.1111/joim.12037. [Epub ahead of print]

Published

OBJECTIVES:The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects.

 

SUBJECTS AND DESIGN: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis.

 

RESULTS: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year.

 

CONCLUSIONS: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI cases from CTL subjects, and to prospectively predict MCI conversion to AD. Our results suggest the potential role of nutritional biomarkers detected in plasma – tocopherols and tocotrienols – as indirect indicators of AD pathology, and the utility of a multimodality approach. © 2013 The Association for the Publication of the Journal of Internal Medicine.

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A Phase I Dose-Escalation Study Evaluating the Pharmacokinetics, Safety and Tolerability of Oral Gamma-Delta-Tocotrienol (GDT) in Patients with Castration-Resistant Prostate Cancer (CRPC)

Prof Azad Hassan A. Razack, University of Malaya Medical Centre, Malaysia

Ongoing

Objective:
 In this study, we intend to determine Gamma-Delta Tocotrienol’s (GDT) safety and tolerability in patients with castrate-resistant prostate cancer (CRPC). In addition, GDT’s pharmacokinetic profile in this cohort of patients will be investigated.

Study Type: Interventional

Study Design: Dose-escalation, pharmacokinetics study

Subjects: Castrate-resistant prostate cancer patients

Intervention: Gamma-Delta Tocotrienol (GDT; Davos Life Science Pte Ltd)

Primary Outcome:

  • Safety and tolerability
  • GDT isomer plasma concentration [ time frame: 0, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours ]

Secondary Outcome: Circulating tumor cell (CTC) levels and inflammatory biomarkers (IL-8, MCP-1, MIP-1 alpha, IFN-gamma, IL-1B, IL-4, IL-6, IL-10, IL-12 (p70), IL-17A, Il-23, IL-27, TNF-alpha, MIP-3 alpha, CRP) [time frame: baseline and day 22]

Methodology: During pharmacokinetic evaluation wherein GDT will be taken as a single dose, participants will receive oral GDT for 21 days at 400, 800, 1600, 2400 and 3200 mg/day for 21 days. Pharmakokinetic and safety profiles will be evaluated on the 8th, 15th and 22nd day.

A Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Vitamin E δ-Tocotrienol Administered to Subjects With Resectable Pancreatic Exocrine Neoplasia

Gregory Springett, M.D., Ph.D.H., Moffitt Cancer Center (USA)

Ongoing

Objective: The purpose of this study is to determine the safest dose of the study drug Vitamin E delta-tocotrienol, how often it should be taken, and how well people with pancreatic tumors tolerate Vitamin E delta-tocotrienol.

Study Type: Interventional

Study Design: Open Label, Safety Efficacy Study

Subjects: Patients with resectable pancreatic neoplasia

Intervention: Vitamin E delta-tocotrienol

Primary Outcome: To determine the recommended Phase II dose of Vitamin E δ-Tocotrienol which will be defined as the biologic effective dose (BED) which induces significant apoptosis in the pancreatic neoplastic cells of resected tumor specimens following oral administration of Vitamin E δ-Tocotrienol twice daily for 14 (± 2)days prior to surgery, and one dose the day of surgery.

Secondary Outcome: To characterize the safety and tolerability of Vitamin E δ-Tocotrienol when orally administered at up to 5.6 times the predicted biological effective dose (1600mg twice daily) for 14 (± 2) consecutive days and one dose the day of surgery in patients with pancreatic neoplasia.

Methodology: This study consists of the following: (1) A Pre-Treatment Period in which participants are consented and qualified for the study; (2) A Study Treatment Period in which participant will receive Vitamin E δ-Tocotrienol administered orally twice daily for 14 (±2) consecutive days and once on the day of surgery, with associated pharmacokinetic and pharmacodynamic sampling; (3) A Post Treatment Period in which laboratory and physical examinations are performed. Adverse events will be recorded throughout the study.

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“First evidence that gamma-tocotrienol inhibits the growth of human gastric cancer and chemosensitizes it to capecitabine in a xenograft mouse model through the modulation of NF-kappaB pathway.”

Manu, K. A., Shanmugam, M. K., Ramachandran, L., Li, F., Fong, C. W., Kumar, A. P., Tan, P., Sethi, G.

Clin Cancer Res. 2012 Apr 15;18(8):2220-9.

Purpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether gamma-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.

Experimental Design: The effect of gamma-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-kappaB activation by DNA-binding assay, and gene expression by Western blotting. The effect of gamma-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.

Results: gamma-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-kappaB, and suppressed the NF-kappaB-regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of gamma-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and gamma-tocotrienol. As compared with vehicle control, gamma-tocotrienol also suppressed the NF-kappaB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.

Conclusions: Overall our results show that gamma-tocotrienol can potentiate the effects of capecitabine through suppression of NF-kappaB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.

Tocotrienols reverse cardiovascular, metabolic and liver changes in high carbohydrate, high fat diet-fed rats

Wong WY, Poudyal H, Ward LC, Brown L

Nutrients, 2012;4(10):1527-41

Tocotrienols have been reported to improve lipid profiles, reduce atherosclerotic lesions, decrease blood glucose and glycated haemoglobin concentrations, normalise blood pressure in vivo and inhibit adipogenesis in vitro, yet their role in the metabolic syndrome has not been investigated. In this study, we investigated the effects of palm tocotrienol-rich fraction (TRF) on high carbohydrate, high fat diet-induced metabolic, cardiovascular and liver dysfunction in rats. Rats fed a high carbohydrate, high fat diet for 16 weeks developed abdominal obesity, hypertension, impaired glucose and insulin tolerance with increased ventricular stiffness, lower systolic function and reduced liver function. TRF treatment improved ventricular function, attenuated cardiac stiffness and hypertension, and improved glucose and insulin tolerance, with reduced left ventricular collagen deposition and inflammatory cell infiltration. TRF improved liver structure and function with reduced plasma liver enzymes, inflammatory cell infiltration, fat vacuoles and balloon hepatocytes. TRF reduced plasma free fatty acid and triglyceride concentrations but only omental fat deposition was decreased in the abdomen. These results suggest that tocotrienols protect the heart and liver, and improve plasma glucose and lipid profiles with minimal changes in abdominal obesity in this model of human metabolic syndrome.

Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population

Luk, S. U.,Yap, W. N.,Chiu, Y. T.,Lee, D. T.,Ma, S.,Lee, T. K.,Vasireddy, R. S.,Wong, Y. C.,Ching, Y. P.,Nelson, C.,Yap, Y. L.,Ling, M. T.

Int J Cancer, 2011. 128(9):2182-91

Emerging evidence supports that prostate cancer originates from a rare subpopulation of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma-tocotrienols (gamma-T3) is one of the vitamin-E constituents, which have been shown to have anticancer effects against a wide range of human cancers. Recently, we have reported that gamma-T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel-induced apoptosis, suggesting that gamma-T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that gamma-T3 can downregulate the expression of prostate CSC markers (CD133/CD44) in androgen-independent prostate cancer cell lines (PC-3 and DU145), as evident from Western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by gamma-T3 treatment. In addition, pretreatment of PC-3 cells with gamma-T3 was found to suppress tumor initiation ability of the cells. More importantly, although CD133-enriched PC-3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to gamma-T3 treatment as the CD133-depleted population. Our data suggest that gamma-T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.

Clinical evaluation of photoprotective effect by a topical antioxidants combination (tocopherols and tocotrienols)

Pedrelli VF, Lauriola MM, Pigatto PD.

J Eur Acad Dermatol Venereol. 2011 Sep 14.

Background: Vitamin E is among the earliest recognized antioxidants. Recent findings suggested that tocotrienols have superior activity than tocopherols. Moreover, vitamin A is well-known in dermatology for its actions, including the ultraviolet radiation absorbing property.

Objectives: In view of experimental evidence for the photoprotective properties of these antioxidants, we evaluated in 30 patients with photosensitivity, the prophylactic efficacy of a new topical agent, containing tocopherols 10% and tocotrienols 0.3%, compared with retinol, simple vehicle and untreated areas.

Methods: After determination of the minimal UVB erythema dose (MED), two areas of 2 × 2 cm were selected on the buttocks of each subject, one of which was treated with the antioxidant formulation whereas the other field did not undergo any treatment. Therefore, both areas were irradiated with a twofold MED. As further controls, other two similar areas, selected on the forearm of 15 patients, were photo-irradiated similarly, 30 min after application of the simple vehicle to a field and of vitamin A in the same vehicle to the other. Reactions (erythema/oedema/itch/vesciculation) assessment was carried out assigning scores indicative of their intensity; then, mean values +DS of scores were calculated. Results  The pre-treatment with the vitamin E formulation highly protects against photosensitivity, and all reactions to irradiation were significantly lower in the areas treated with the topical vitamin E formulation compared to those treated with the simple vehicle or vitamin A.

Conclusions: The use of a new topical formulation containing significant concentrations of tocotrienols and tocopherols represents a promising strategy to reduce the photo-induced skin damage.

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