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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Abstract

Gamma and delta tocotrienols are isomers of Vitamin E with established potency in pre-clinical anti-cancer research. This single-dose, randomized, crossover study aimed to compare the safety and bioavailability of a new formulation of Gamma Delta Tocotrienol (GDT) in comparison with the existing Tocotrienol-rich Fraction (TRF) in terms of gamma and delta isomers in healthy volunteers. Subjects were given either two 300 mg GDT (450 mg γ-T3 and 150 mg δ-T3) capsules or four 200 mg TRF (451.2 mg γ-T3 &102.72 mg δ-T3) capsules and blood samples were taken at several time points over 24 hours. Plasma tocotrienol concentrations were determined using HPLC method. The 90% CI for gamma and delta tocotrienols for the ratio of log-transformation of GDT/TRF for Cmax and AUC0-∞ (values were anti-logged and expressed as a percentage) were beyond the bioequivalence limits (106.21-195.46, 154.11-195.93 and 52.35-99.66, 74.82-89.44 respectively). The Wilcoxon Signed Rank Test for Tmax did not show any significant difference between GDT and TRF for both isomers (p > 0.05). No adverse events were reported during the entire period of study. GDT was found not bioequivalent to TRF, in terms of AUC and Cmax. Gamma tocotrienol in GDT showed superior bioavailability whilst deltatocotrienol showed less bioavailability compared to TRF.

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Safety and lipid-altering efficacy of a new omega-3 fatty acid and antioxidant-containing medical food in men and women with elevated triacylglycerols.

Maki KC, Geohas JG, Dicklin MR, Huebner M, Udani JK.

Prostaglandins Leukot Essent Fatty Acids. 2015 May 30.

Abstract

This randomized, double-blind, placebo-controlled multi-center trial investigated the lipid-altering effects of a medical food (PDL-0101) providing 1.8g/d eicosapentaenoic acid; 12mg/d astaxanthin, a marine algae-derived carotenoid; and 100mg/d tocopherol-free gamma/delta tocotrienolsenriched with geranylgeraniol, extracted from annatto, on triacylglycerols (TAG), other lipoprotein lipids, and oxidized low-density lipoprotein (LDL) in 102 subjects with TAG 150-499mg/dL (1.69-5.63mmol/L) and LDL cholesterol (LDL-C) ≥70mg/dL (1.81mmol/L). Compared to placebo, after eight weeks of treatment, PDL-0101 significantly reduced median TAG (-9.5% vs. 10.6%, p<0.001), while not significantly altering mean LDL-C (-3.0% vs. -8.0% for PDL-0101 and placebo, respectively, p=0.071), mean high-density lipoprotein cholesterol (~3% decrease in both groups, p=0.732), or median oxidized LDL concentrations (5% vs. -5% for PDL-0101 and placebo, respectively, p=0.112). These results demonstrate that PDL-0101 is an effective medical food for the management of elevated TAG.

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Short-term effects of a combined nutraceutical of insulin-sensitivity, lipid level and indexes of liver steatosis: a double-blind, randomized, cross-over clinical trial.

Cicero AF,, Rosticci M, Parini A, M M, Urso R, Grandi E, Borghi C.

Nutr J. 2015 Mar 28;14(1):30.

Abstract

BACKGROUND:

Overweight subjects easily develop alterations of the glucose and lipid metabolism and are exposed to an increased cardiometabolic risk. This condition is potentially reversible through the improvement of dietary and behavioural habits. However, a well-assembled nutraceutical would be a useful tool to better improve the metabolic parameters associated to overweight and insulin resistance.

METHODS:

To evaluate the effect of a combined nutraceutical containing berberine, chlorogenic acid and tocotrienols, we performed a double blind, cross-over designed trial versus placebo, in 40 overweight subjects with mixed hyperlipidaemia. After the first 8 weeks of treatment (or placebo), patients were asked to observe a 2-week washout period, and they were then assigned to the alternative treatment for a further period of 8 weeks. Clinical and laboratory data associated to hyperlipidaemia and insulin resistance have been obtained at the baseline, at the end of the first treatment period, after the washout, and again after the second treatment period.

RESULTS:

Both groups experienced a significant improvement of anthropometric and biochemical parameters versus baseline. However, total cholesterol, LDL cholesterol, triglycerides, non-HDL cholesterol, fasting insulin, HOMA-IR, GOT and Lipid Accumulation Product decreased more significantly in the nutraceutical group versus placebo.

CONCLUSIONS:

This combination seems to improve a large number of metabolic and liver parameters on the short-term in overweight subjects. Further studies are needed to confirm these observations on the middle- and long-term.

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A combination of palm oil tocotrienols and citrus peel polymethoxylated flavones does not influence elevated LDL cholesterol and high-sensitivity C-reactive protein levels.

Schuchardt JP, Heine S, Hahn A.

Eur J Clin Nutr. 2015 Apr 1

Abstract

BACKGROUND/OBJECTIVES:

Lipid-lowering and anti-inflammatory effects have been individually described for tocotrienols (TTs) and polymethoxylated flavones (PMFs). This study investigated low-density lipoprotein-cholesterol (LDL-C)- and high-sensitivity C-reactive protein (hsCRP)-reducing effects of combined TT-PMF treatment in low doses in hypercholesterolemic individuals with subclinical inflammation.

SUBJECTS/METHODS:

In the double-blind, placebo-controlled study, 240 Caucasians with LDL-C ⩾3.36 mmol/l and hsCRP ⩾1 mg/l were enrolled and randomized into group S1 (12 mg/day TT and 103 mg/day PMF), group S2 (27 mg/day TT and 32 mg/day PMF) or placebo.

RESULTS:

Twenty-three subjects dropped out of the study, 13 were excluded from the analysis because of lack of compliance. A total of 204 subjects per-protocol analysis were included. After 12 weeks of treatment, no significant differences in LDL-C levels (primary outcome) were observed between groups. LDL-C levels significantly decreased in all intervention groups (S1: -5.2%, S2: -4.8% and P: -4.2%). Total cholesterol and hsCRP (secondary outcome) did not change significantly.

CONCLUSIONS:

PMF-TT supplements had no effect beyond that of placebo on elevated LDL-C and hsCRP levels.European Journal of Clinical Nutrition advance online publication, 1 April 2015; doi:10.1038/ejcn.2015.44.

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Abstract

Vitamin E (α-, β-, γ- and δ-tocopherol and -tocotrienol) is an essential factor in the human diet and regularly taken as a dietary supplement by many people, who act under the assumption that it may be good for their health and can do no harm. With the publication of meta-analyses reporting increased mortality in persons taking vitamin E supplements, the safety of the micronutrient was questioned and interactions with prescription drugs were suggested as one potentially underlying mechanism. Here, we review the evidence in the scientific literature for adverse vitamin E-drug interactions and discuss the potential of each of the eight vitamin E congeners to alter the activity of drugs. In summary, there is no evidence from animal models or randomised controlled human trials to suggest that the intake of tocopherols and tocotrienols at nutritionally relevant doses may cause adverse nutrient-drug interactions. Consumption of high-dose vitamin E supplements ( ≥  300 mg/d), however, may lead to interactions with the drugs aspirin, warfarin, tamoxifen and cyclosporine A that may alter their activities. For the majority of drugs, however, interactions with vitamin E, even at high doses, have not been observed and are thus unlikely.

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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