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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Validation of a HPLC/FLD Method for Quantification of Tocotrienols in Human Plasma.

Che HL, Tan DM, Meganathan P, Gan YL, Abdul Razak G, Fu JY.

Int J Anal Chem. 2015;2015:357609

Abstract

Quantification of tocotrienols in human plasma is critical when the attention towards tocotrienols on its distinctive properties is arising. We aim to develop a simple and practical normal-phase high performance liquid chromatography method to quantify the amount of four tocotrienol homologues in human plasma. Using both the external and internal standards, tocotrienol homologues were quantified via a normal-phase high performance liquid chromatography with fluorescence detector maintained at the excitation wavelength of 295 nm and the emission wavelength of 325 nm. The fourtocotrienol homologues were well separated within 30 minutes. A large interindividual variation between subjects was observed as the absorption oftocotrienols is dependent on food matrix and gut lipolysis. The accuracies of lower and upper limit of quantification ranged between 92% and 109% for intraday assays and 90% and 112% for interday assays. This method was successfully applied to quantify the total amount of four tocotrienol homologues in human plasma.

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Effect of Tocotrienols enriched canola oil on glycemic control and oxidative status in patients with type 2 diabetes mellitus: A randomized double-blind placebo-controlled clinical trial.

Vafa M, Haghighat N, Moslehi N, Eghtesadi S, Heydari I.

J Res Med Sci. 2015 Jun;20(6):540-7

Abstract

BACKGROUND:

Tocotrienols have been shown to improve glycemic control and redox balance in an animal study, but their effects on patients with diabetes are unknown. The study aimed to investigate whether tocotrienols improves glycemic control, insulin sensitivity, and oxidative stress in individuals with type 2 diabetes mellitus (T2DM).

MATERIALS AND METHODS:

This study was a double-blinded, placebo-controlled, randomized trial. A total of 50 patients, aged 35-60 years, with T2DM treated by noninsulin hypoglycemic drugs were randomly assigned to receive either 15 mL/day tocotrienols (200 mg) enriched canola oil (n = 25) or pure canola oil (n = 25) for 8 weeks. Fasting blood sugar (FBS), fasting insulin, total antioxidant capacity (TAC), malondialdehyde (MDA), and homeostatic model assessment for insulin resistance (HOMA-IR) were determined before and after the intervention. The data were compared between and within groups, before and after the intervention.

RESULTS:

Baseline characteristics of participants including age, sex, physical activity, disease duration, and type of drug consumption were not significantly different between the two groups. In tocotrienol enriched canola oil, FBS (mean percent change: -15.4% vs. 3.9%; P = 0.006) and MDA (median percent change: -35.6% vs. 16.3%; P = 0.003) were significantly reduced while TAC was significantly increased (median percent change: 21.4% vs. 2.3%; P = 0.001) compared to pure canola oil. At the end of the study, patients who treated with tocotrienols had lower FBS (P = 0.023) and MDA (P = 0.044) compared to the pure canola oil group. However, tocotrienols had no effect on insulin concentrations and HOMA-IR.

CONCLUSION:

Tocotrienols can improve FBS concentrations and modifies redox balance in T2DM patients with poor glycemic control and can be considered in combination with hypoglycemic drugs to better control of T2DM.

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Focus on Pivotal Role of Dietary Intake (Diet and Supplement) and Blood Levels of Tocopherols and Tocotrienols in Obtaining Successful Aging.

Rondanelli M, Faliva MA, Peroni G, Moncaglieri F, Infantino V, Naso M, Perna S.

Int J Mol Sci. 2015 Sep 25;16(10):23227-49.

Abstract

Numerous specific age-related morbidities have been correlated with low intake and serum levels of tocopherols and tocotrienols. We performed a review in order to evaluate the extant evidence regarding: (1) the association between intake and serum levels of tocopherols and tocotrienols and age-related pathologies (osteoporosis, sarcopenia and cognitive impairment); and (2) the optimum diet therapy or supplementation with tocopherols and tocotrienols for the treatment of these abnormalities. This review included 51 eligible studies. The recent literature underlines that, given the detrimental effect of low intake and serum levels of tocopherols and tocotrienols on bone, muscle mass, and cognitive function, a change in the lifestyle must be the cornerstone in the prevention of these specific age-related pathologies related to vitamin E-deficient status. The optimum diet therapy in the elderly for avoiding vitamin E deficiency and its negative correlates, such as high inflammation and oxidation, must aim at achieving specific nutritional goals. These goals must be reached through: accession of the elderly subjects to specific personalized dietary programs aimed at achieving and/or maintaining body weight (avoid malnutrition); increase their intake of food rich in vitamin E, such as derivatives of oily seeds (in particular wheat germ oil), olive oil, hazelnuts, walnuts, almonds, and cereals rich in vitamin E (such as specific rice cultivar rich in tocotrienols) or take vitamin E supplements. In this case, vitamin E can be correctly used in a personalized way either for the outcome from the pathology or to achieve healthy aging and longevity without any adverse effects.

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The Effects of Tocotrienols Added to Canola Oil on Microalbuminuria, Inflammation, and Nitrosative Stress in Patients with Type 2 Diabetes: A Randomized, Double-blind, Placebo-controlled Trial.

Haghighat N, Vafa M, Eghtesadi S, Heidari I, Hosseini A, Rostami A.

BACKGROUND:

Tocotrienols (T3) were neglected in the past; today, get attentions due to their antioxidant and none-antioxidant activity. The objective of this study was to evaluate the effects of the daily intake of 200 mg T3 added in canola oil over 8 weeks on microalbuminuria, inflammation, and nitrosative stress in type 2 diabetic patients.

METHODS:

This study was a double-blinded, placebo-controlled, randomized trial. A total of 50 patients with T2DM and FBS >126 mg/dl treated by non-insulin hypoglycemic drugs were randomly assigned to receive either 15 ml T3-enriched canola oil (200 mg/day T3) or pure canola oil for 8 weeks. Urine microalbumin, volume and creatinine levels, serum hs-CRP, and nitric oxide (NO) levels were measured before and after intervention.

RESULTS:

From 50 patients participated in this study, 44 completed the study. There were no significant differences in baseline characteristics, dietary intake, and physical activity between groups. Urine microalbumin and serum hs-CRP were declined significantly in T3-treated group. At the end of the study, patients who treated with T3 had lower urine microalbumin (11 (9, 25) vs. 22 (15, 39.75) nmol/dl, P = 0.003) and hs-CRP changes (-10.91 ± 15.5 vs. -9.88 ± 27.5 Pg/ml, P = 0.048) than control group. A non-significant decrease was also observed in serum NO level in T3-treated group with no changes in urine volume and creatinine levels.

CONCLUSIONS:

These findings indicate that T3 leads to ameliorate proteinuria and can protect the kidney against inflammation (hs-CRP) and nitrosative stress (NO).

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The Effect of Supplemental Adjuvants for Intracellular Nutrition and Treatment on Diabetic Macular Edema and Neovascular Age-Related Macular Degeneration

Nabil M Jabbour, MD, FACS M.A.R.C., West Virginia University

Ongoing

Objective: Nutritional supplements have an augmentative effect on the outcomes of standard treatment of diabetic macular edema (DME) and Neovascular Age-Related Macular Degeneration (NAMD).

Study Type: Interventional

Study Design: Randomized, Double-blind Study

Subjects: Subjects with age-related macular degeneration

Intervention:
Drug — Neutral pills with no medicinal effect
Dietary Supplement —  Inosine; Tocopherols, Tocotrienol, CoQ10 combination capsule; Niacinamide SR; Viatmin C; N-acetyl Cysteine; Complete Multivitamin with all minerals

Drug: Inosine; Tocopherol, Tocotrienol, CoQ10 combination capsule; Niacinamide; Vitamin C; N-acetyl Cysteine; Complete Multivitamin with all minerals; Minocycline

Primary Outcome: Anatomic and visual outcomes

Secondary Outcome: 1) Effect on HbA1C [ Time Frame: Monthly ]

2) Effect on Blood pressure [ Time Frame: Monthly ]

3) Effect on serum uric acid [ Time Frame: Monthly ]

Methodology: It has been shown that in chronic diseases, oxidative stress results from Nitric acid reacting with oxygen to form toxins that damage both somatic and mitochondrial DNA. The potential for protecting the DNA and promoting repair by using nutritional supplements will be tested by augmenting standard treatments for DME and NAMD with such supplements. The patients will be randomized to treatment group and placebo group and followed up for a year in a double masked fashion. Anatomic and visual outcomes, as well as side effects will be assessed and analyzed. If the results are promising, this pilot study can be used to design alternative (cheaper, better and longer lasting) treatments for DME, NAMD and perhaps other chronic illnesses.

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Reduction of DNA damage in older healthy adults by Tri E Tocotrienol supplementation

Chin SF, Hamid NA, Latiff AA, Zakaria Z, Mazlan M, Yusof YA, Karim AA, Ibahim J, Hamid Z, Ngah WZ.

Nutrition. 2008 Jan;24(1):1-10. Epub 2007 Sep 20.

Published

Objectives: To evaluate the effect of tocotrienol (Tri E) on DNA damage in humans

Study design: Randomized, double-blinded placebo-controlled study

Subjects: Healthy volunteers

Intervention: Tocotrienol

Primary Outcome: DNA damage (comet assay, sister chromatid exchange and chromosome 4 aberrations)

Methodology: A randomized, double-blinded placebo-controlled study was undertaken to evaluate the effect of tocotrienol on DNA damage. Sixty four subjects 37-78 y old completed the study. A daily dose of 160 mg of Tri E Tocotrienol was given for 6 months. Blood samples were analyzed forDNA damage using comet assay, frequency of sister chromatid exchange (SCE), and chromosome 4 aberrations.

Results: Results showed a significant reduction in DNA damage as measured by comet assay after 3 mo (P < 0.01) and remained low at 6 mo (P < 0.01). The frequency of SCE was also reduced after 6 mo of supplementation (P < 0.05), albeit more markedly in the >50 y-old group (P < 0.01) whereas urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels were significantly reduced (P < 0.05). A strong positive correlation was observed between SCE with age, whereas weak positive correlations were observed in DNA damage and 8-OHdG, which were reduced with supplementation. However, no translocation or a stable insertion was observed in chromosome 4.

Conclusion: Tri E Tocotrienol supplementation may be beneficial by reducing DNA damage as indicated by a reduction in DNA damage, SCE frequency, and urinary 8-OHdG.

Dose dependent elevation of plasma tocotrienol levels and its effect on arterial compliance, plasma total antioxidant status, and lipid profile in healthy humans supplemented with tocotrienol rich vitamin E

Rasool AH, Yuen KH, Yusoff K, Wong AR, Rahman AR.

J Nutr Sci Vitaminol (Tokyo). 2006 Dec;52(6):473-8.

Published

Objectives: To assess the effects of 3 doses of tocotrienol-rich vitamin E (TRE) on plasma tocotrienol isomer concentration, arterial compliance, plasma total antioxidant status (TAS), aortic systolic blood pressure (ASBP), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in healthy males.

Study design: Randomised, blinded end-point, placebo-controlled

Subjects: Healthy male volunteers

Intervention: Tocotrienol-rich Vitamin E at 80 mg, 160 mg or 320 mg versus placebo

Primary outcome: Plasma tocotrienol isomer concentration, arterial compliance, plasma total antioxidant status (TAS), aortic systolic blood pressure (ASBP), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C)

Methodology: This randomised, blinded end-point, placebo-controlled clinical trial with a parallel design involved 36 healthy male subjects who took either an oral placebo or TRE at doses of 80, 160 or 320 mg daily for 2 mo. Baseline and end-of-treatment measurements of vitamin E concentration, arterial compliance [assessed by aortic femoral pulse wave velocity (PWV) and augmentation index (AI)], ASBP, plasma TAS, serum TC and LDL-C were taken.

Results: Baseline tocotrienol isomer concentrations were low and not detectable in some subjects. Upon supplementation, all TRE-treated groups showed significant difference from placebo for their change in alpha, gamma and delta tocotrienol concentrations from baseline to end of treatment. There was a linear dose and blood level relationship for all the isomers. There was no significant difference between groups for their change in PWV, AI, plasma TAS, ASBP, TC or LDL-C from baseline to end of treatment. Groups 160 mg (p = 0.024) and 320 mg (p = 0.049) showed significant reductions in their ASBP. Group 320 mg showed a significant 9.2% improvement in TAS.

Conclusion: TRE at doses up to 320 mg daily were well tolerated. Treatment significantly increased alpha, delta, and gamma tocotrienolconcentrations but did not significantly affect arterial compliance, plasma TAS, serum TC or LDL-C levels in normal subjects.

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