Supplementation with tocotrienol-rich fraction alters the plasma levels of Apolipoprotein A-I precursor, Apolipoprotein E precursor, and C-reactive protein precursor from young and old individuals

Heng, E. C., Karsani, S. A., Abdul Rahman, M., Abdul Hamid, N. A., Hamid, Z., Wan Ngah, W. Z.

2013

Objective: Tocotrienol possess beneficial effects not exhibited by tocopherol. In vitro studies using animal models have suggested that these effects are caused via modulation of gene and protein expression. However, human supplementation studies using tocotrienol-rich isomers are limited. This study aims to identify plasma proteins that changed in expression following tocotrienol-rich fraction (TRF) supplementation within two different age groups.

METHODS: Subjects were divided into two age groups-32 +/- 2 (young) and 52 +/- 2 (old) years old. Four subjects from each group were assigned with TRF (78 % tocotrienol and 22 % tocopherol, 150 mg/day) or placebo capsules for 6 months. Fasting plasma were obtained at 0, 3, and 6 months. Plasma tocopherol and tocotrienol levels were determined. Plasma proteome was resolved by 2DE, and differentially expressed proteins identified by MS. The expressions of three proteins were validated by Western blotting.

RESULTS: Six months of TRF supplementation significantly increased plasma levels of tocopherols and tocotrienols. Proteins identified as being differentially expressed were related to cholesterol homeostasis, acute-phase response, protease inhibitor, and immune response. The expressions of Apolipoprotein A-I precursor, Apolipoprotein E precursor, and C-reactive protein precursor were validated. The old groups showed more proteins changing in expression.

CONCLUSIONS: TRF appears to not only affect plasma levels of tocopherols and tocotrienols, but also the levels of plasma proteins. The identity of these proteins may provide insights into how TRF exerts its beneficial effects. They may also be potentially developed into biomarkers for the study of the effects and effectiveness of TRF supplementation.

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A Double Blind Placebo Controlled Study On The Neuroprotective And Anti-Atherogenic Effects Of Palm Tocotrienol Rich Fraction (Palm Vitamin E)

Yuen Kah Hay, Phd

Ongoing

Objective: The purpose of the study is to assess the neuroprotective, anti atherogenic and hepatoprotective properties of tocotrienols (palm vitamin E) supplementation as determined by white matter lesion load on serial magnetic resonance imaging (MRI), carotid artery magnetic resonance angiography (MRA) and liver ultrasound (US) as well as lipid profile analysis.

Study Type: Interventional

Study Design:  Phase 2, Randomized, Double –Blind

Subjects: Patients with cerebrovascular disorders

Intervention: Tocotrienol, placebo

Primary Outcome: Regression of white matter lesion load in terms of numbers and size in the brain [ Time Frame: 1 to 2 years ]

Secondary Outcome: 1) Regression of the carotid artery stenoses in terms of percentage [ Time Frame: 1 to 2 years ]

2) The improvement in the lipid profile other markers associated with increased cardiovascular risk [ Time Frame: 1 to 2 years ]

3) Improvement in liver echogenicity. [ Time Frame: 1 to 2 years ] [ Designated as safety issue: No ]

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Suppression of Nitric Oxide Production and Cardiovascular Risk Factors in Healthy Seniors and Hypercholesterolemic Subjects by a Combination of Polyphenols and Vitamins

Qureshi AA, Khan DA, Mahjabeen W, Papasian CJ, Qureshi N.

J Clin Exp Cardiolog. 2012 Jun 7;S5:8.

Published

Objectives: To determine whether serum nitric oxide (NO) levels increase with age in humans, and whether the combined cholesterol-lowering and inflammation-reducing properties of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid would reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

Subjects: Healthy Seniors and Hypercholesterolemic Subjects

Intervention: δ-tocotrienol, resveratrol, pterostilbene, Morin hydrate, quercetin, riboflavin, and nicotinic acid

Primary outcome: Serum NO, C-reactive protein (CRP), γ-glutamyltransferase (γ-GT) activity, uric acid, total antioxidant status (TAS), total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides levels

Methodology: Elderly human subjects were stratified into two groups based on total serum cholesterol levels. Initial total serum cholesterol levels were normal and elevated in Group 1 and 2 subjects, respectively. Baseline serum NO, C-reactive protein (CRP), γ-glutamyltransferase (γ-GT) activity, uric acid, total antioxidant status (TAS), total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides levels were established over a four week period. Group 1 subjects subsequently received nutritional supplementation with one of two different combinations (NS-7 = 25 mg of each, resveratrol, pterostilbene, quercetin, δ-tocotrienol, nicotinic acid, morin hydrate or NS-6 = morin hydrate replaced with quercetin, 50 mg/capsule). Group 2subjects also received these nutritional supplements (two capsules/d), but an AHA Step-1 diet was also implemented. After these interventions were administered for four weeks, the above parameters were re-measured and changes from baseline levels determined. Nitric acid (NO) levels in children, young adults, and seniors were also compared.

Results: The key results of the current study were: 1) that serum NO levels were significantly increased in seniors compared to both children (~80%) and young adults (~65%); 2) that the intake of two capsules/d of NS-7 or NS-6 for four weeks significantly (P < 0.05) decreased serum NO (39%, 24%), CRP (19%, 21%), uric acid (6%, 12%) levels, and γ-GT activity (8%, 6%), respectively in free-living healthy seniors; 3) that serum NO (36%, 29%), CRP (29%, 20%), uric acid (6%, 9%) γ-GT activity (9%, 18%), total cholesterol (8%, 11%), LDL-cholesterol (10%, 13%), and triglycerides (16%, 23%) levels were significantly (P < 0.02) decreased in hypercholesterolemic subjects restricted to AHA Step-1 diet plus intake of SN-7 or SN-6 (two capsules/d), respectively; 4) that TAS was increased (3%, 9%; P < 0.05) in free-living healthy seniors receiving NS-7 or NS-6 alone, and in hypercholesterolemic subjects plus AHA Step-1 diet (20%, 12%; P < 0.02) with either of the combinations tested.

Conclusions: Serum NO levels are elevated in elderly humans compared to children or young adults. Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study

Chin, S. F.,Ibahim, J.,Makpol, S.,Abdul Hamid, N. A.,Abdul Latiff, A.,Zakaria, Z.,Mazlan, M.,Mohd Yusof, Y. A.,Abdul Karim, A.,Wan Ngah, W. Z.

Nutr Metab (Lond) 2011;8(1):42

BACKGROUND: Vitamin E supplements containing tocotrienols are now being recommended for optimum health but its effects are scarcely known. The objective was to determine the effects of Tocotrienol Rich Fraction (TRF) supplementation on lipid profile and oxidative status in healthy older individuals at a dose of 160 mg/day for 6 months.

METHODS: Sixty-two subjects were recruited from two age groups: 35-49 years (n = 31) and above 50 years (n = 31), and randomly assigned to receive either TRF or placebo capsules for six months. Blood samples were obtained at 0, 3rd and 6th months.

RESULTS: HDL-cholesterol in the TRF-supplemented group was elevated after 6 months (p < 0.01). Protein carbonyl contents were markedly decreased (p < 0.001), whereas AGE levels were lowered in the > 50 year-old group (p < 0.05). Plasma levels of total vitamin E particularly tocopherols were significantly increased in the TRF-supplemented group after 3 months (p < 0.01). Plasma total tocotrienols were only increased in the > 50 year-old group after receiving 6 months of TRF supplementation. Changes in enzyme activities were only observed in the > 50 year-old group. SOD activity was decreased after 3 (p < 0.05) and 6 (p < 0.05) months of TRF supplementation whereas CAT activity was decreased after 3 (p < 0.01) and 6 (p < 0.05) months in the placebo group. GPx activity was increased at 6 months for both treatment and placebo groups (p < 0.05).

CONCLUSION: The observed improvement of plasma cholesterol, AGE and antioxidant vitamin levels as well as the reduced protein damage may indicate a restoration of redox balance after TRF supplementation, particularly in individuals over 50 years of age.

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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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Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia

Mustad VA, Smith CA, Ruey PP, Edens NK, DeMichele SJ.

Am J Clin Nutr. 2002 Dec;76(6):1237-43.

Published

Objectives: The objective was to study the relative effect of tocotrienol supplements of different compositions (mixed alpha- plus gamma-, high gamma-, or P25-complex tocotrienol) on blood lipids, fasting blood glucose, and the excretion of 8-iso-prostaglandin F(2alpha), a measure of oxidative stress, in healthy hypercholesterolemic men and women.

Study design: Double-blind, randomized, parallel-design study

Subjects: Healthy hypercholesterolemic subjects

Intervention: Mixed tocotrienol versus placebo (safflower oil)

Primary outcome: Fasting blood lipids, fasting blood glucose, and the excretion of 8-iso-prostaglandin F(2alpha), a measure of oxidative stress.

Methodology: In this study, subjects consumed 1 of 3 commercially available tocotrienol supplements or a safflower oil placebo for 28 days. Blood and urine samples were obtained before and after the 28-d supplementation phase for analysis of fasting blood lipids, glucose, tocotrienols and tocopherols, and 8-iso-prostaglandin F(2alpha).

Results: Overall, serum tocotrienols were increased in subjects who consumed tocotrienols, which showed that the putatively active components were absorbed. No significant differences in mean lipid or glucose concentrations were observed among the 4 treatment groups at the end of the 28-dsupplementation phase. However, when the values were expressed as a percentage change from the concentrations during the presupplementation run-in phase, LDL cholesterol increased slightly (7 +/- 2%) but significantly (P < 0.05) in the group consuming the mixed alpha- plus gamma-tocotrienol supplement when compared with LDL cholesterol in the group consuming the P25-complex tocotrienol. Neither mean concentrations nor the percentage change in 8-iso-prostaglandin F(2alpha) differed significantly among treatments.

Conclusion: Supplementation with 200 mg tocotrienols/d from 3 commercially available sources has no beneficial effect on key cardiovascular disease risk factors in highly compliant adults with elevated blood lipid concentrations.

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Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis

Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML.

Lipids. 1995 Dec;30(12):1179-83.

Published

Objectives: Antioxidants may have a role in the prevention of atherosclerosis. In the present trial, we investigate the antioxidant properties of a gamma-tocotrienol (Palmvitee), and alpha-tocopherol enriched fraction of palm oil, in patients with carotid atherosclerosis.

Subjects: Patients with carotid atherosclerosis

Intervention: Gamma-Tocotrienol

Primary outcome: Serum lipids, fatty acid peroxides, platelet aggregation and changes in carotid artery stenosis (duplex ultrasonography)

Methodology:  In the present trial, we investigated the antioxidant properties of gamma-tocotrienol and alpha-tocopherol enriched fraction of palm oil, in patients with carotid atherosclerosis. Serum lipids, fatty acid peroxides, platelet aggregation and carotid artery stenosis were measured over an 18-month period in fifty patients with cerebrovascular disease. Change in stenosis was measured with duplex ultrasonography. Ultrasound scans were done at six months, twelve months, and yearly thereafter.

Results: Bilateral duplex ultrasonography revealed apparent carotid atherosclerotic regression in seven and progression in two of the 25 tocotrienol patients, while none of the control group exhibited regression and ten of 25 showed progression (P < 0.002). Serum thiobarbituric acid reactive substances, an ex vivo indicator of maximal platelet peroxidation, decreased in the treatment group from 1.08 +/- 0.70 to 0.80 +/- 0.55 microM/L (P < 0.05) after 12 mon, and in the placebo group, they increased nonsignificantly from 0.99 +/- 0.80 to 1.26 +/- 0.54 microM/L. Both tocotrienol and placebo groups displayed significantly attenuated collagen-induced platelet aggregation responses (P < 0.05) as compared with entry values. Serum total cholesterol, low density lipoprotein cholesterol, and triglyceride values remained unchanged in both groups, as did the plasma high density lipoprotein cholesterol values.

Conclusion: These findings suggest that antioxidants, such as tocotrienols, may influence the course of carotid atherosclerosis.

Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (Palmvitee)

Qureshi AA, Qureshi N, Wright JJ, Shen Z, Kramer G, Gapor A, Chong YH, DeWitt G, Ong A, Peterson DM, et al.

Am J Clin Nutr. 1991 Apr;53(4 Suppl):1021S-1026S.

Published

Objectives: The present study was carried out to assess the effect of tocotrienol-rich fraction as a dietary supplement in hypercholesterolemic human subjects.

Study design: Double-blind, crossover, 8 week study

Subjects: Subjects with elevated cholesterol levels

Intervention: Tocotrienol-rich fraction (Palmvitee) 200 mg versus placebo (300 mg corn oil capsules)

Primary outcome: To determine the cholesterol lowering effect of palmvitee

Methodology: A double-blind, crossover experimental design was used to control within-subject variability of cholesterol measurements and the effect of order of the administration of the two supplements (palmvitec and corn oil for a placebo). Subjects were radomly assigned to one of two groups. In group I, each subject was observed for 2-wk baseline period, a 4-wk palmvitee-capsule supplementation period, and a 4-wk corn-oil-capsule supplementation period. In group II, each subject was observed for a 2 wk baseline period, a 4-wk corn-oil-capsule supplementation period, and a 4-6-wk palmvitee supplementation period.

Results: Concentrations of serum total cholesterol (-15%), LDL cholesterol (-8%), Apo B (-10%), thromboxane (-25%), platelet factor 4 (-16%), and glucose (-12%) decreased significantly only in the 15 subjects given palmvitee during the initial 4 wk. The crossover confirmed these actions of palmvitee. There was a carry over effect of palmvitee. Serum cholesterol concentrations of seven hypercholesterolemic subjects (greater than 7.84 mmol/L) decreased 31% during a 4-wk period in which they were given 200 mg gamma-tocotrienol/d.

Conclusion: This indicates that gamma-tocotrienol may be the most potent cholesterol inhibitor in palmvitee capsules. The results of this pilot study are very encouraging.

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