Regarding eye health

Vitamin E has long been regarded as a beneficial nutrient to support eye health and was included in the original Age‐Related Eye Disease Study (AREDS) and in AREDS2, which also examined other antioxidants, such as lutein and zeaxanthin. AREDS investigated only alpha‐tocopherol, but newer studies suggest that tocotrienols warrant dedicated research. Owing to inhibition of angiogenesis, tocotrienols may have application in improving ocular conditions related to abnormal neovascularization, such as macular degeneration and diabetic retinopathy. Tocotrienol is a potent anti‐angiogenic agent, with delta‐tocotrienol being the most effective._1,2

As a powerful antioxidant, tocotrienol accumulates in the eye to combat cataract development, among the most common eye problems in the aging population.₃ Rodent models show that tocotrienol administration delayed the onset and progression of cataracts by reducing lenticular oxidative and nitrosative stress,₄ and in diabetic rats, tocotrienol application arrested cataract progression and restored lens transparency to normal.₅ (It should be noted, however, that these studies used topically applied tocotrienols through eye drops.  Annatto E protects the lens of the eye, the macula, and supports healthy eye circulation, cornea and eyelid health.

• delta-Tocotrienol suppresses VEGF induced angiogenesis whereas alpha-tocopherol does not. 
  Link: https://pubmed.ncbi.nlm.nih.gov/19702331/
• Antiangiogenic and anticancer potential of unsaturated vitamin E (tocotrienol) 
  Link: https://pubmed.ncbi.nlm.nih.gov/19071006/
• Distribution of tocopherols and tocotrienols to rat ocular tissues after topical ophthalmic administration 
  Link: https://pubmed.ncbi.nlm.nih.gov/15506242/
• Effects of topically applied tocotrienol on cataractogenesis and lens redox status in galactosemic rats. 
  Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057512/
• Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats. 
  Link: https://pubmed.ncbi.nlm.nih.gov/28350848/

The Vitamin E Story

Vitamin E is not a single nutrient, but rather a complex made up of eight distinct compounds: four tocopherols and four tocotrienols. These components have slightly different chemical structures, and these differences impart unique properties that influence their biochemical functions and their effects in the body. Most conventional supplements are typically rich in tocopherols — alpha-tocopherol, in particular — but the tocotrienol fractions have unique effects across a variety of tissues that make them desirable to supplement on their own, without tocopherols.

Rich sources of vitamin E include whole grains, such as wheat (especially wheat germ), rice, barley, oats, corn, select leafy green vegetables, and palm fruit. Most of these foods, however, are higher in tocopherols than tocotrienols.
The richest known source of naturally occurring tocotrienols is annatto, derived from the seeds of a tree native to Latin America. Annatto is virtually free of tocopherols and contains nearly 100% tocotrienols, all in the most potent forms. The tocotrienols in this product are sourced from annatto, so they’re exclusively tocotrienols.

Benefits of Tocotrienols

Tocotrienols have shown impressive effects in supporting cardiovascular health, particularly in regard to supporting healthy cholesterol and triglyceride metabolism. They may also be beneficial for promoting a healthy inflammatory response. Tocotrienols also support healthy blood pressure in relation to their support of healthy blood vessel function.*

Owing to their promotion of normal blood lipid metabolism, tocotrienols may be beneficial for metabolic support related to blood glucose and insulin metabolism. New research also suggests tocotrienols may be a valuable addition to the supplement regimens of those who need nutritional support for strong, healthy bones.

Perhaps the best-known role for the vitamin E complex is that of an antioxidant. Tocopherols have antioxidant effects, but tocotrienols are more potent at protecting against cellular damage from harmful free radicals. The powerful antioxidant function of tocotrienols has been demonstrated in studies of skin and eye health, where damage from oxidation can lead to premature aging of the skin and compromised visual acuity. Abnormal growth of blood vessels in the eyes can also lead to problems with vision. Tocotrienols have been shown to help reduce this issue.*

Why No Tocopherols?

Supplements claiming to contain vitamin E are often only alpha- tocopherol. Although alpha-tocopherol has beneficial effects of its own, it has been shown to interfere with the positive effects of tocotrienols, which also inhibits absorption of tocotrienols and causes them to break down faster. For this reason, it is best to take tocotrienols independently of any other supplements that contain alpha-tocopherol, and it is recommended to separate tocotrienol and tocopherol supplementation by at least 6 hours.

Tocotrienols may be beneficial for:

• Supporting a healthy inflammatory response
• Cell protection and improving antioxidant status
• Supporting healthy cholesterol metabolism
• Eye and bone health

Vitamin E research has come a long way in recent decades. Vitamin E is not a single nutrient, but rather a complex comprising four tocopherols and four tocotrienols. Each of these components has a different molecular weight and a slightly different chemical structure, which impart distinct properties that influence their biochemical functions. Commercial supplements are typically rich in tocopherols — alpha‐tocopherol, in particular — but the tocotrienol fractions have unique effects across a variety of tissues that make them desirable to supplement alone, without tocopherols.

Rich sources of vitamin E include whole grains, such as wheat (especially the germ), rice, barley, oats, and corn, as well as palm fruit and annatto. Most of these foods, however, are higher in tocopherols than in tocotrienols (T3). The vitamin E in rice, for example, is comprised of 50% tocopherols, 35% delta‐ and gamma‐T3, and 15% alpha‐ and beta‐T3, which are less potent than the delta and gamma forms. Palm is a bit higher in tocotrienols: 25% tocopherols, 25% alpha‐ and beta‐T3, and 50% delta‐ and gamma‐T3. The richest known source of naturally occurring tocotrienols, however, is annatto, which is virtually free of tocopherols and contains 100% tocotrienols (90% delta and 10% gamma).

The tocotrienols in Annatto‐ETM are sourced from annatto, so they are exclusively tocotrienols. This was a deliberate choice by Designs for Health, because research indicates that tocopherols — especially alpha‐tocopherol — interfere with key therapeutic effects of tocotrienols, so it may be best to dose tocotrienols alone, or with 6 hours between tocotrienols and products containing alpha‐tocopherol. (See “Why No Tocopherols?” on page 4.) The tocotrienols in this product are provided as Delta Gold®, a patented tocotrienol formula from American River Nutrition. They are manufactured in the U.S. and have the Generally Recognized as Safe (GRAS) status from the Food and Drug Administration (FDA).

Dyslipidemia and Cardiovascular Health

Tocotrienols enhance the degradation of 3‐hydroxy‐3‐methylglutaryl–coenzyme A (HMG–CoA) reductase, a key enzyme in the mevalonate pathway, by which cholesterol is synthesized.1,2 Animal studies indicate the potency of inhibition of cholesterol synthesis by tocotrienols is: delta > gamma > alpha > beta. Tocopherols are inactive in lowering cholesterol.₃ Unlike statin drugs, however, which directly inhibit HMG‐CoA reductase, tocotrienols do not appear to impair synthesis of CoQ10. According to research conducted by prominent vitamin E expert, Barrie Tan, PhD, tocotrienols may reduce cholesterol by 15 to 20% with a concurrent 5% increase in CoQ10, likely owing to increased liver synthesis of CoQ10.4 Delta and gamma‐T3 also block processing of sterol regulatory element‐binding protein, which has implications for potentially reducing triglycerides.

Unlike tocotrienols, tocopherols do not have cholesterol‐lowering effects.₁ In fact, the opposite is true: alpha‐tocopherol has been repeatedly shown to attenuate or interfere with the cholesterol‐lowering action of tocotrienols.5 Combinations effective in cholesterol‐lowering consist of 15% or less alpha‐tocopherol and 60% or more gamma‐ and delta‐T3, whereas formulas consisting of 20% or more alpha‐tocopherol and 45% or less gamma‐ and delta‐T3 have been shown to be ineffective. Substantiating these formulating guidelines are clinical studies in which supplements with high alpha‐tocopherol content did not contribute to the lowering of cholesterol,_6‐8 whereas supplements containing low amounts of alpha‐tocopherol and high amounts of gamma‐ and delta‐tocotrienol led to a significant decrease in total and LDL cholesterol._9,10‐12

A clinical trial tested the dose‐dependent effects of annatto tocotrienols ranging from 125 mg to 750 mg per day on hypercholesterolemic individuals.9 Results showed that after only 4 weeks, a daily dose of 250 mg decreased total cholesterol by 15%, low‐density lipoprotein (LDL) cholesterol levels by 18%, and triglycerides by 14%. Additionally, cytokines associated with cardiovascular disease and their gene expression (tumor necrosis factor‐α, interleukin [IL]‐2, IL‐4, IL‐6, and IL‐8), were downregulated 39% to 64%.

Inflammation is increasingly recognized as a major driver of cardiovascular disease. In a clinical trial of supplementation with delta‐T3 in hypercholesterolemic subjects, 250 mg of delta‐T3 decreased C‐reactive protein (CRP) and malondialdehyde (MDA) by 40% and 34%, respectively, with a 22% increase in total antioxidant status.₁₃ One of the first steps of atherogenesis is fatty streak formation in arteries, which begins with the adherence of circulating monocytes to the endothelium. Tocotrienols have been shown to reduce cellular adhesion molecule expression and monocytic cell adherence._14,15 In particular, delta‐T3 showed the most profound inhibitory effect compared with tocopherols and other tocotrienol isomers. Delta‐ and gamma‐tocotrienol were 60 and 30 times more potent than alpha‐tocopherol, respectively.₁₆

There may be a role for tocotrienols in hypertension. In hypertensive rats, gamma‐T3 was shown to reduce systolic blood pressure and improve nitric oxide synthase activity, both of which play a critical role in the pathogenesis of essential hypertension.₁₇ In humans, tocotrienols have been shown to increase arterial compliance and reduce blood pressure._18,19

Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease

Rodent models of metabolic syndrome show that tocotrienol supplementation improves insulin sensitivity and reduces triglycerides, adipocyte size, abdominal adiposity, and liver fat deposition._20,21 Human studies using rice bran extracts (>90% tocotrienols) reduced hyperglycemia, glycosylated hemoglobin, and hyperlipidemia in subjects with both type 1 and type 2 diabetes.₂₂ Within 60 days, tocotrienol supplementation was shown to decrease total cholesterol and LDL cholesterol by 30% and 42%, respectively.₂₃ When taken apart from alpha‐tocopherol, tocotrienols were shown to lower total cholesterol, LDLs, and triglycerides 15% to 20%.9 Moreover, tocotrienols also lowered CRP and other inflammatory markers by 35% to 60%.₁₃

Non‐alcoholic fatty liver disease (NAFLD) is a growing epidemic and is closely related to metabolic syndrome and insulin resistance. A double‐blind, randomized controlled trial among 71 subjects showed that with NAFLD, 12 weeks of supplementation with delta‐T3 resulted in significant improvements in biomarkers of hepatic stress, including a 15% to 16% reduction in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), an 11% decrease in triglycerides, a 14% reduction in malondialdehyde (MDA), and an 18% decrease in high sensitivity CRP.₂₄ (However, ultrasound examination revealed no improvement in the hepatic steatosis.)

Antioxidant Capacity

Antioxidants are abundant in the food supply, but vitamin E is uniquely shaped to reside within cell membranes to protect the integrity of the structural lipids. In this regard, tocotrienols were shown to be about 50 times more potent than tocopherols.₂₅ The antioxidant efficiency of tocotrienols was evaluated as the ability of the compounds to inhibit lipid peroxidation and reactive oxygen species production. Delta‐tocotrienol was found to have the greatest antioxidant properties among the tocotrienol isomers.₂₆ In lipid oxygen radical absorbance capacities (ORAC) studies, delta‐ and gamma‐tocotrienols had the highest antioxidant value of all vitamin E isomers at 5.5 and 3 times the potency of alpha‐tocopherol, respectively.₂₇

Skin and Eye Health

Promising research indicates that tocotrienols may help reduce the adverse effects of UV‐irradiation of the skin and UV‐induced melanogenesis._28,29‐31 Tocotrienols may also have a role in improving wound healing and fending off skin infections. In methicillin‐resistant Staphylococcus aureus (MRSA)‐infected mice, given alone, tocotrienol reduced bacterial load by a factor of 10, and antibiotics alone by 1,000 times. In combination, however, tocotrienols and daptomycin reduced bacterial load by 10,000 times, suggesting a highly synergistic effect between the two.₃₂ This synergy is believed to be due to tocotrienols enhancing the activity of natural killer cells.

Regarding eye health, vitamin E has long been regarded as a beneficial nutrient to support eye health and was included in the original Age‐Related Eye Disease Study (AREDS) and in AREDS2, which also examined other antioxidants, such as lutein and zeaxanthin. AREDS investigated only alpha‐tocopherol, but newer studies suggest that tocotrienols warrant dedicated research. Owing to inhibition of angiogenesis, tocotrienols may have application in improving ocular conditions related to abnormal neovascularization, such as macular degeneration and diabetic retinopathy. Tocotrienol is a potent anti‐angiogenic agent, with delta‐tocotrienol being the most effective._{33, 34}

As a powerful antioxidant, tocotrienol accumulates in the eye to combat cataract development, among the most common eye problems in the aging population.₃₅ Rodent models show that tocotrienol administration delayed the onset and progression of cataracts by reducing lenticular oxidative and nitrosative stress,₃₆ and in diabetic rats, tocotrienol application arrested cataract progression and restored lens transparency to normal.₃₇ (It should be noted, however, that these studies used topically applied tocotrienols through eye drops.)

Chemoprotection

Given at higher doses, tocotrienols have shown impressive effects across a range of cancers, including breast, prostate, colon, and pancreatic cancers, and melanoma. There are several possible mechanisms of action for tocotrienols as adjuncts to conventional cancer therapies. Among these are inhibition of angiogenesis, vascular endothelial growth factor,_38,39 and induction of apoptosis through the caspase‐3 pathways.₄₀ Tocotrienols, but not tocopherols, and in particular, not alpha‐tocopherol, have been shown repeatedly to inhibit proliferation and induce cancer cell death, and cells with the greatest degree of malignancy appear to be the most sensitive to the apoptotic actions of tocotrienol._40‐42

Bone Health

Vitamin E tocotrienols are being explored for applications beyond their more traditional uses for lipid management, cardiovascular health, and antioxidant status. Bone health is one of these new areas, with many pre‐clinical studies already having shown promise for supporting stronger bones._43‐45 A double‐blind, placebo‐controlled trial showed that, among post‐menopausal women with osteopenia, compared to a placebo, showed that tocopherol‐free tocotrienols administered at two different dosages (300 mg/day and 600 mg/day, respectively) for 12 weeks resulted in decreased bone resorption and improved bone turnover rate.₄₈ Osteoporosis is not solely a women’s issue. Men are not immune to bone loss as they age, and bone loss may also be an undesirable side‐effect of androgen deprivation therapies. Rodent models of this scenario show that supplementation with annatto tocotrienols resulted in significantly higher bone volume, calcium content, trabecular thickness, and improved biomechanical strength of the femur._49,50

Other osteopenic rat models show that tocotrienols improve osteoblast number, bone formation, mineral deposition, and bone microarchitecture.46 Metabolic syndrome and type 2 diabetes increase risk for osteoporosis, likely owing to systemic hormonal alterations and inflammatory processes. A rodent model showed that supplementation with annatto tocotrienols (60 mg/kg and 100 mg/kg) improved bone strength and trabecular bone microstructure and increased osteoclast number in male rats with metabolic syndrome induced by a high‐carbohydrate, high‐fat diet.₅₁ Along with these improvements in bone health, annatto tocotrienol supplementation also resulted in improvements in several metabolic syndrome parameters, including decreased triglycerides, blood pressure, and fasting glucose. A separate rodent model had similar findings: in male mice with diet‐induced type 2 diabetes, supplementation with annatto tocotrienols (400 mg/kg and 1,600 mg/kg) for 14 weeks resulted in increased trabecular bone volume and cortical thickness, with increased markers of bone formation and decreased markers of bone resorption.₅₂ Additionally, the tocotrienol supplemented mice also had a lower area under the curve for glucose and insulin. Notably, these improvements were greater than those seen in a separate group of diabetic mice treated with metformin (200 mg/kg).

It is believed that tocotrienols may upregulate antioxidant defenses in osteoclasts and “indirectly act against free radical signaling essential in osteoclastogenesis.”₅₃ It is worth noting that alpha‐tocopherol, the most common vitamin E subfraction in conventional supplements, may have adverse effects on bone formation, partly due to interference with the “anabolic effect” of gamma‐tocopherol on the bone.₅₄

Why No Tocopherols?

Alpha‐tocopherol compromises several of the beneficial effects of tocotrienols. For example, it attenuates their cholesterol and triglyceride‐reducing effects,_5,55,56 lowers their antioxidant capacity,₅₇ attenuates cancer cell inhibition,_58,59 blocks absorption of tocotrienols, and induces their catabolism,_60‐64 and prevents adipose and liver storage of tocotrienols.₅₅

References

Annatto‑E™

27. Pearce BC, Parker RA, Deason ME, Qureshi AA, Wright JJ. Hypocholesterolemic activity of synthetic and natural tocotrienols. J Med Chem. 1992;35(20):3595‑3606. doi:10.1021/jm00098a002.
28. Song BL, DeBose‑Boyd RA. Insig‑dependent ubiquitination and degradation of 3‑hydroxy‑3‑methylglutaryl coenzyme a reductase stimulated by delta‑ and gamma‑tocotrienols. J Biol Chem. 2006;281:25054‑25061. doi:10.1074/jbc.M605575200.
29. Yu SG, Thomas AM, Gapor A, Tan B, Qureshi N, Qureshi AA. Dose‑response impact of various tocotrienols on serum lipid parameters in 5‑week‑old female chickens. Lipids. 2006;41(5):453‑461. doi:10.1007/s11745‑006‑5119‑1.
30. Tan B, Mueller AM. Tocotrienols in cardiometabolic diseases. In: Watson R, Preedy V, eds. Tocotrienols: Vitamin E Beyond Tocopherol. Boca Raton, FL: AOCS/CRC Press; 2008:257‑273.
31. Qureshi AA, Pearce BC, Nor RM, Gapor A, Peterson DM, Elson CE. Dietary alpha‑tocopherol attenuates the impact of gamma‑tocotrienol on hepatic 3‑ hydroxy‑3‑methylglutaryl coenzyme A reductase activity in chickens. J Nutr. 1996;126(2): 389‑394. doi:10.1093/jn/126.2.389.
32. Mensink RP, van Houwelingen AC, Kromhout D, Hornstra G. A vitamin E concentrate rich in tocotrienols had no effect on serum lipids, lipoproteins, or platelet function in men with mildly elevated serum lipid concentrations. Am J Clin Nutr. 1999;69(2):213‑219. doi.org/10.1093/ajcn/69.2.213.
33. Mustad VA, Smith CA, Ruey PP, Edens NK, DeMichele SD. Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia. Am J Clin Nutr. 2002;76(6):1237‑1243. doi: 10.1093/ajcn/76.6.1237.
34. Heng KS, Hejar AR. Potential of mixed tocotrienol supplementation to reduce cholesterol and cytokines level in adults with metabolic syndrome. Malays J Nutr. 2015;22(2):231‑243.
35. Qureshi AA, Dilshad AK, Wajiha M, Qureshi N. Dose‑dependent modulation of lipid parameters, cytokines, and RNA by delta‑ tocotrienol in hypercholesterolemic subjects restricted to AHA Step‑1 diet. Br J Med Med Res. 2015;6(4):351‑366. doi.org/10.9734/BJMMR/2015/13820.
36. Qureshi AA, Sami SA, Salser WA, Khan FA. Synergistic effect of tocotrienol‑rich fraction (TRF(25)) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans. J Nutr Biochem. 2001;12(6):318‑329. doi:10.1016/s0955‑2863(01)00144‑9.
37. Qureshi AA, Sami, SA, Salser WA, Khan FA. Dose‑dependent suppression of serum cholesterol by tocotrienol‑rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Atherosclerosis. 2002;161(1):199‑207. doi: 10.1016/s0021‑9150(01)00619‑0.
38. Trias AM, Tan B. Alpha‑tocopherol: a detriment to tocotrienol benefits. In: Tan B, Watson R, and Preedy V, Eds. Tocotrienols: Vitamin E Beyond Tocopherols, 2nd ed. Boca Raton, FL: CRC Press; 2013:61‑78.
39. Qureshi AA, Khan DA, Mahjabeen W, Trias AM, Silswal N, Quereshi N. Impact of delta‑tocotrienol on inflammatory biomarkers and oxidative stress in hypercholesterolemic subjects. J Clin Exp Cardiolog. 2015;6(4): 1000367. doi:10.4172/2155‑9880.1000367.
40. Chao JT, Gapor A, Theriault A. Inhibitory effect of delta‑tocotrienol, a HMG CoA reductase inhibitor, on monocyte‑endothelial cell adhesion. J Nutr Sci Vitaminol (Tokyo). 2002;48(5):332‑337. doi:10.3177/jnsv.48.332.
41. Theriault A, Chao JT, Gapor A. Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. Atherosclerosis. 2002;160(1):21‑30. doi:10.1016/s0021‑9150(01)00540‑8.
42. Naito Y, Shimozawa M, Kuroda M. Tocotrienols reduce 25‑hydroxycholesterol‑induced monocyte‑endothelial cell interaction by inhibiting the surface expression of adhesion molecules. Atherosclerosis. 2005;180(1):19‑25. doi:10.1016/j.atherosclerosis.2004.11.017
43. Newaz MA, Yousefipour Z, Nawal N, Adeeb N. Nitric oxide synthase activity in blood vessels of spontaneously hypertensive rats: antioxidant protection by gamma‑tocotrienol. J Physiol Pharmacol. 2003;54(3):319‑327.
44. Rasool AHG, Rahman ARA, Yuen KH, Wong AR. Arterial compliance and vitamin E blood levels with a self emulsifying preparation of tocotrienol rich vitamin E. Arch Pharm Res. 2008;31(9):1212‑1217. doi:10.1007/s12272‑001‑1291‑1295.
45. Rasool AH, Yuen KH, Yusoff K, Wong AR, Rahman ARA. 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. J Nutr Sci Vitaminol (Tokyo). 2006;52(6):473‑478. doi:10.3177/jnsv.52.473.doi:10.3177/jnsv.52.473.
46. Wong WY, Ward LC, Fong CW, Yap WN, Brown L. Anti‑inflammatory γ‑ and δ‑tocotrienols improve cardiovascular, liver and metabolic function in diet‑induced obese rats. Eur J Nutr. 2017;56(1):133‑150. doi:10.1007/s00394‑015‑1064‑1.
47. Allen L, Ramalingam L, Menikdiwela K, et al. Effects of delta‑tocotrienol on obesity‑related adipocyte hypertrophy, inflammation and hepatic steatosis in high‑fat‑fed mice. J Nutr Biochem. 2017;48:128‑137.
48. Qureshi AA, Sami SA, Khan FA. Effects of stabilized rice bran, its soluble and fiber fractions on blood glucose levels and serum lipid parameters in humans with diabetes mellitus Types I and II. J Nutr Biochem. 2002;13(3):175‑187. doi:10.1016/s0955‑2863(01)00211‑x.
49. Baliarsingh S, Beg ZH, Ahmad J. The therapeutic impacts of tocotrienols in type 2 diabetic patients with hyperlipidemia. Atherosclerosis. 2005;182(2):367‑374. doi:10.1016/j.atherosclerosis.2005.02.020.
50. Pervez MA, Khan DA, Ijaz A, Khan S. Effects of delta‑tocotrienol supplementation on liver enzymes, inflammation, oxidative stress and hepatic steatosis in patients with nonalcoholic fatty liver disease. Turk J Gastroenterol. 2018;29(2):170‑176. doi:10.5152/tjg.2018.17297.
51. Serbinova E, Vagan V, Han D, 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):263‑275. doi:10.1016/0891‑5849(91)90033‑y.
52. Palozza P, Verdecchia S, Avanzi L et al. Comparative antioxidant activity of tocotrienols and the novel chromanyl‑polyisoprenyl molecule FeAox‑6 in isolated membranes and intact cells. Mol Cell Biochem. 2006;287(1‑2):21‑32. doi:10.1007/s11010‑005‑9020‑7.
53. Muller L, Theile K, Bohm V. In vitro antioxidant activity of tocopherols and tocotrienols and comparison of vitamin E concentration and lipophilic antioxidant capacity in human plasma. Mol Nutr Food Res. 2010;54(5):731‑742. doi:10.1002/mnfr.200900399.
54. Traber MG, Podda M, Weber C, Thiele J, Rallis TM, Packer L. Diet‑derived and topically applied tocotrienols accumulate in skin and protect the tissue against ultraviolet light‑induced oxidative stress. Asia Pac J Clin Nutr. 1997;6(1):63‑67.
55. Michihara A, Morita, S, Hirokawa Yae, Ago S. Delta‑tocotrienol causes decrease of melanin content in mouse melanoma cells. J Health Sci. 2009;55(2):314‑318. doi:10.1248/jhs.55.314.
56. Michihara A, Ogawa S, Kamizaki Y, Akasaki K. Effect of delta‑tocotrienol on melanin content and enzymes for melanin synthesis in mouse melanoma cells. Biol Pharm Bull. 2010;33(9):1471‑1476. doi:10.1248/bpb.33.1471.
57. Yap WN, et al. Gamma‑ and delta‑tocotrienols inhibit cutaneous melanosis (hallmark of melanoma) by suppressing constitutive and UV‑induced tyrosinase activation. Presented at the 102nd Annual Meeting of the American Association for Cancer Research. Orlando, FL: 2011.
58. Pierpaoli E, Orlando F, Cironi O, Simonetti O, Giacometti A, Provinciali M. Supplementation with tocotrienols from Bixa orellana improves the in vivo efficacy of daptomycin against methicillin‑resistant Staphylococcus aureus in a mouse model of infected wound. Phytomedicine. 2017;36:50‑53. doi:10.1016/j.phymed.2017.09.011.
59. Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Oikawa S, Miyazawa T. delta‑Tocotrienol suppresses VEGF induced angiogenesis whereas alpha‑tocopherol does not. J Agric Food Chem. 2009;57(18):8696‑8704. doi:10.1021/jf9012899.
60. Miyazawa T, Shibata A, Sookwong P, et al. Antiangiogenic and anticancer potential of unsaturated vitamin E (tocotrienol). J Nutr Biochem. 2009;20(2):79‑86. doi:10.1016/j.jnutbio.2008.09.003.
61. Tanito M, Itoh N, Yoshida Y, Hayakawa M, Ohira A, Niki E. Distribution of tocopherols and tocotrienols to rat ocular tissues after topicalophthalmic administration. Lipids. 2004;39(5):469‑474. doi:10.1007/s11745‑004‑1252‑0.
62. Abdul Nasir NA. Agarwal R, Vasudevan S, Tripathy M, Alyautdin R, Ismail NM. Effects of topically applied tocotrienol on cataractogenesis and lens redox status in galactosemic rats. Mol Vis. 2014;20:822‑835.
63. Abdul Nasir NA, Agarwal R, Kadir SHSA, et al. Reduction of oxidative‑nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin‑induced diabetic rats. PLoS One. 2017;12(3):e0174542.
64. Miyazawa T, Shibata A, Nakagawa K, Tsuzuki T, et al. Anti‑angiogenic function of tocotrienol. Asia Pac J Clin Nutr. 2008;17(Suppl 1):253‑256.
65. Nakagawa K, Eitsuka T, Inokuchi H, Miyazawa T, et al. DNA chip analysis of comprehensive food function: inhibition of angiogenesis and telomerase activity with unsaturated vitamin E, tocotrienol. Biofactors. 2004;21(1‑4):5‑10. doi.org/10.1002/biof.552210102.
66. Sylvester P, Theriault A. Role of tocotrienols in the prevention of cardiovascular disease and breast cancer. Curr Top Nutraceutical Res. 2003;1(2):121‑136.
67. Wada S, Satomi Y, Murakoshi M, Noguchi N, Yoshikawa T, Nishino H. Tumor suppressive effects of tocotrienol in vivo and in vitro. Cancer Lett. 2005;229(2):181‑91. doi:10.1016/j.canlet.2005.06.036.
68. Yano Y, Satoh, H, Fukumoto K, et al . Induction of cytotoxicity in human lung adenocarcinoma cells by 6‑O‑carboxypropyl‑alpha‑ tocotrienol, a redox‑silent derivative of alpha‑tocotrienol. Int J Cancer. 2005;115(5):839‑846. doi:10.1002/ijc.20809.
69. Chin KY, Abdul‑Majeed S, Mohamed N, Ima‑Nirwana S. The effects of tocotrienol and lovastatin co‑supplementation on bone dynamic histomorphometry and bone morphogenetic protein‑2 expression in rats with estrogen deficiency. Nutrients. 2017;9(2):143. doi:10.3390/nu9020143.
70. Chin KY, Gengatharan D, Nasru FSM, et al. The effects of annatto tocotrienol on bone biomechanical strength and bone calcium content in an animal model of osteoporosis due to testosterone deficiency. Nutrients. 2016;8(12):80‑8. doi:10.3390/nu8120808.
71. Chin KY, Ima‑Nirwana S. Effects of annatto‑derived tocotrienol supplementation on osteoporosis induced by testosterone deficiency in rats. Clin Interv Aging. 2014;9:1247‑1259. doi:10.2147/CIA.S67016.
72. Chin KY, Ima‑Nirwana S. The biological effects of tocotrienol on bone: a review on evidence from rodent models. Drug Des Devel Ther. 2015;9:2049‑2061. doi:10.2147/DDDT.S79660.
73. Shen CL, Klein A, Chin K‑Y, et al. Tocotrienols for bone health: a translational approach. Ann N Y Acad Sci. 2017;1401(1):150‑165. doi:10.1111/nyas.13449.
74. Shen CL, Yang S, Tomison MD, Romera AW, Felton CK, Mo H. Tocotrienol supplementation suppressed bone resorption and oxidative stress in postmenopausal osteopenic women: a 12‑week randomized double‑blinded placebo‑controlled trial. Osteoporos Int. 2018;29(4):881‑891. doi:10.1007/s00198‑017‑4356‑x.
75. Mohamad NV1, Soelaiman IN, Chin KY. Effects of tocotrienol from Bixa orellana (annatto) on bone histomorphometry in a male osteoporosis model induced by buserelin. Biomed Pharmacother. 2018;103:453‑462. doi:10.1016/j.biopha.2018.04.083.
76. Mohamad N‑V, Ima‑Nirwana S, Chin K‑Y. Effect of tocotrienol from Bixa orellana (annatto) on bone microstructure, calcium content, and biomechanical strength in a model of male osteoporosis induced by buserelin. Drug Des Devel Ther. 2018;12:555‑564. doi:10.2147/DDDT.S158410.
77. Wong SK, Chin KY, Suhaimi FH, Ahmad F, Ima‑Nirwana S. Exploring the potential of tocotrienol from Bixa orellana as a single agent targeting metabolic syndrome and bone loss. Bone. 2018;116:8‑21. doi:10.1016/j.bone.2018.07.003.
78. Shen C‑L, Kaur G, Wanders D, et al. Annatto‑extracted tocotrienols improve glucose homeostasis and bone properties in high‑fat diet‑induced type 2 diabetic mice by decreasing the inflammatory response. Sci Rep. 2018;8:11377.
79. Chin K‑Y, Mo H, Soelaiman I‑N. A review of the possible mechanisms of action of tocotrienol – a potential antiosteoporotic agent. Curr Drug Targets. 2013;14(13):1533‑1541. Doi:10.2174/13894501113149990178.
80. Hamidi MS, Corey PN, Cheung AM. Effects of vitamin E on bone turnover markers among US postmenopausal women. J Bone Miner Res. 2012;27(6):1368‑1380. doi:10.1002/jbmr.1566.
81. Shibata A, Kawakami Y, Kimura T, Miyazawa T, Nakagawa K, et al. α‑Tocopherol attenuates the triglyceride‑ and cholesterol‑lowering effects of rice bran tocotrienol in rats fed a western diet. J Agric Food Chem. 2016;64(26):5361‑5366.
82. Khor HT, Ng TT. Effects of administration of alpha‑tocopherol and tocotrienols on serum lipids and liver HMG CoA reductase activity. Int J Food Sci Nutr. 2000;51(Suppl): S3‑S11.
83. Qureshi AA, Mo H, Packer L, Peterson DM. Isolation and structural identification of novel tocotrienols from rice bran with hypocholesterolemic, antioxidant and antitumor properties. J Agric Food Chem. 2000(131):223‑230. doi.org/10.1021/jf000099t.
84. Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Asai A, Miyazawa T. alpha‑Tocopherol attenuates the cytotoxic effect of delta‑tocotrienol in human colorectal adenocarcinoma cells. Biochem Biophys Res Commun. 2010;397(2):214‑219. doi:10.1016/j.bbrc.2010.05.087.
85. Guthrie N, Gapor A, Chambers AF, Carroll KK. Inhibition of proliferation of estrogen receptor‑negative MDA‑MB‑435 and ‑positive MCF‑7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination. J Nutr. 1997;127(3):544S‑548S. doi.org/10.1093/jn/127.3.544S.
86. Ikeda S, Tohyama T, Yoshimura H, Hamamura K, Abe K, Yamashita K. Dietary alpha‑tocopherol decreases alpha‑tocotrienol but not gamma‑tocotrienol concentration in rats. J Nutr. 2003;133(2):428‑434. doi:10.1093/jn/133.2.428.
87. Khanna S, Patel V, Rink C, Roy S, Sen CK. Delivery of orally supplemented alpha‑tocotrienol to vital organs of rats and tocopherol‑transport protein deficient mice. Free Radic Biol Med. 2005;39(10):1310‑1319. doi:10.1016/j.freeradbiomed.2005.06.013.
88. Uchida T, Nomura S, Ichikawa T, Abe C, Ikeda S. Tissue distribution of vitamin E metabolites in rats after oral administration of tocopherol or tocotrienol. J Nutr Sci Vitaminol (Tokyo). 2011;57(5):326‑332. doi:10.3177/jnsv.57.326.
89. Shibata A, Nakagawa K, Tsuduki T, Miyazawa T. α‑Tocopherol suppresses antiangiogenic effect of delta‑tocotrienol in human umbilical vein endothelial cells. J Nutr Biochem. 2015;26(4): 345‑350. doi:10.1016/j.jnutbio.2014.11.010.
90. Sontag TJ, Parker RS. Influence of major structural features of tocopherols and tocotrienols on their omega–oxidation by tocopherol–omega–hydroxylase. J Lipid Res. 2007;48(5):1090‑1098. doi:10.1194/jlr.M600514‑JLR200.

Additional Reference Sources

1. Evans HM, Bishop KS. On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science. 1922;56:650‑651. doi:10.1126/science.56.1458.650.
2. Pennock JF, Hemming FW, Kerr JD. A reassessment of tocopherol in chemistry. Biochem Biophys Res Commun. 1964;17(5):542‑548. doi:10.1016/0006‑291X(64)90062‑2.
3. Olcott HS, Emerson OH. Antioxidants and autoxidation of fats: the antioxidant properties of tocopherols. J Am Chem Soc. 1937;59:1008‑1009. doi.org/10.1021/ja01285a013.
4. Mo H, Elson CE. Studies of the isoprenoid‑mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention. Exp Biol Med. 2004(229):567‑585. doi:10.1177/153537020422900701.
5. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1): 39‑51. doi:10.1001/jama.2008.864.
6. Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549‑1556. doi:10.1001/jama.2011.1437.
7. Miller ER 3rd, Pastor‑Barriuso R, Dalal D, et al. Meta‑analysis: high‑dosage vitamin E supplementation may increase all‑cause mortality. Ann Intern Med. 2005;142(1):37‑46. doi:10.7326/0003‑4819‑142‑1‑200501040‑00110.
8. Kooyenga DK, Watkins TR, Geller M, Bierenbaum ML. Antioxidants modulate the course of carotid atherosclerosis: a four‑year report. In: Nesaretnam K, Packer L, eds. Micronutrients and Health. Champaign, Illinois: AOCS Press, 2001:366‑375.
9. Atkinson J, Epand RF, Epand RM. Tocopherols and tocotrienols in membranes: a critical review. Free Radic Biol Med. 2008;44(5):739‑764. doi:10.1016/j.freeradbiomed.2007.11.010.
10. Brigelius‑Flohe R. Adverse effects of vitamin E by induction of drug metabolism. Genes Nutr. 2007;2(3):249‑256. doi:10.1007/s12263‑007‑0055‑0.
11. Peralta EA, Brewer AT, Louis S, Dunnington GL. Vitamin E increases biomarkers of estrogen stimulation when taken with tamoxifen. J Surg Res. 2009;153(1):143‑147. doi:10.1016/j.jss.2008.03.030.
12. Uchihara Y, Kidokoro T, Tago K, Mashino T, Tamura H, Funakoshi‑Tago M. A major component of vitamin E, α‑tocopherol inhibits the anti‑tumor activity of crizotinib against cells transformed by EML4‑ALK. Eur J Pharmacol. 2018;825:1‑9. doi:10.1016/j.ejphar.2018.02.012.
13. Khor HT, Chirng DY, Ong KK. Tocotrienols inhibit HMG‑CoA reductase activity in the guinea pig. Nutr Res. 1995(15):537‑544. doi.org/10.1016/0271‑5317(95)00021‑6.
14. Miyamoto K, Shiozaki M, Shibata M, Koike M, Uchiyama Y, Gotow T. Very‑high‑dose alpha‑tocopherol supplementation increases blood pressure and causes possible adverse central nervous system effects in stroke‑prone spontaneously hypertensive rats. J Neurosci Res. 2009;87(2):556‑566. doi:10.1002/jnr.21851.
15. Li Z, Evans C, Cade J. Dietary vitamin E intake and blood pressure in UK adolescents: a longitudinal study (P20‑106). In: Current Developments in Nutrition. Boston, MA: Oxford University Press; 2018:77‑78.
16. Campbell SE, Rudder B, Phillips RB, et al. γ‑Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer. Free Radic Biol Med. 2011;50(10):1344‑1354. doi:10.1016/j.freeradbiomed.2011.02.007.
17. Bjorkblom B. Metabolomic screening of pre‑diagnostic serum samples identifies association between α‑ and γ‑tocopherols and glioblastoma risk. Oncotarget. 2016;7(24):3704337053. doi:10.18632/oncotarget.9242.
18. Khanna S, Heigel M, Weist J, et al. Excessive α‑tocopherol exacerbates microglial activation and brain injury caused by acute ischemic stroke. Faseb J. 2015;29(3):828‑836. doi:10.1096/fj.14‑263723.
19. Fujita K, Iwasaki M, Ochi H, et al. Vitamin E decreases bone mass by stimulating osteoclast fusion. Nat Med. 2012;18(4):589‑594. doi:10.1038/nm.2659. doi:10.1038/nm.2659.

20. Carr AC, Zhu BZ, Frei B. Potential antiatherogenic mechanisms of ascorbate (vitamin C) and alpha‑ tocopherol (vitamin E). Circ Res. 2000;87(5):349‑354. doi:10.1161/01.res.87.5.349.
21. Pearson CK, Barnes MM. The absorption and distribution of the naturally occurring tocochromanols in the rat. Br J Nutr. 1970;24:581‑587. doi:10.1079/bjn19700056.
22. Patel V, Rink C, Gordillo GM, et al. Oral tocotrienols are transported to human tissues and delay the progression of the model for end‑stage liver disease score in patients. J Nutr. 2012;142(3):513‑519. doi:10.3945/jn.111.151902.
23. Anwar K, Iqbal J, Hussain MM. Mechanisms involved in vitamin E transport by primary enterocytes and in vivo absorption. J Lipid Res. 2007;48(9):2028‑2038. doi:10.1194/jlr.M700207‑JLR200.
24. Fairus S, Nor RM, Change HM, Sundram K. Alpha‑tocotrienol is the most abundant tocotrienol isomer circulated in plasma and lipoproteins after postprandial tocotrienol‑rich vitamin E supplementation. Nutr J. 2012;11:5. doi: 10.1186/1475‑2891‑11‑5.
25. Qureshi AA, Khan DA, Saleem S, et al. Pharmacokinetics and bioavailability of annatto δ‑tocotrienol in healthy fed subjects. J Clin Exp Cardiolog. 2015;6(11):1000411. doi:10.4172/2155‑9880.1000411.
26. Qureshi AA, Khan DA, Silswal N, Saleem S, Qureshi N. Evaluation of pharmacokinetics, and bioavailability of higher doses of tocotrienols in healthy fed humans. J Clin Exp Cardiolog. 2016;7(4):434. doi:10.4172/2155‑9880.1000434.
27. Yap SP, Yuen KH, Wong JW. Pharmacokinetics and bioavailability of alpha‑, gamma‑ and delta‑tocotrienols under different food status. J Pharm Pharmacol. 2001;53(1):67‑71. doi:10.1211/0022357011775208.
28. Zou L, Akoh CC. Antioxidant activities of annatto and palm tocotrienol‑rich fractions in fish oil and structured lipid‑based infant formula emulsion. Food Chem. 2015;168:504‑511. doi:10.1016/j.foodchem.2014.07.098.
29. Tan B. Appropriate spectrum vitamin E and new perspectives on desmethyl tocopherols and tocotrienols. http://www.tocotrienolresearch.org/appropriate‑spectrum‑vitamin‑e‑and‑new‑perspectives‑on‑desmethyl‑tocopherols‑and‑tocotrienols/. June 17, 2005.

30. Winkler‑Moser JK, Bakota EL, Hwang HS. Stability and antioxidant activity of annatto (Bixa orellana L.) tocotrienols during frying and in fried tortilla chips. J Food Sci. 2018;83(2):266‑274. doi:10.1111/1750‑3841.14037. doi:10.1111/1750‑3841.14037.

31. Benjamin EJ, Blaha M, Chiuve SE, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146‑e603. doi:10.1161/CIR.0000000000000485.

32. Qureshi AA, Burger WC, Peterson DM, Elson CE. The structure of an inhibitor of cholesterol biosynthesis isolated from barley. J Biol Chem. 1986;261(23):10544‑10550.

33. Qureshi AA, Reis JC, Papasian CJ, Morrison DC, Qureshi N. Tocotrienols inhibit lipopolysaccharide‑induced pro‑inflammatory cytokines in macrophages of female mice. Lipids Health Dis. 2011;9(1):143. doi:10.1186/1476‑511X‑9‑143.

34. Qureshi AA, Khan DA, Mahjabeen W, Papasian CJ, Qureshi N. Suppression of nitric oxide production and cardiovascular risk factors in healthy seniors and hypercholesterolemic subjects by a combination of polyphenols and vitamins. J Clin Exp Cardiolog. 2012;S5:8. doi:10.4172/2155‑9880.S5‑008.

35. Qureshi AA, Khan DA, Mahjabeen W, Papasian CJ, Qureshi N. Nutritional supplement‑5 with a combination of proteasome inhibitors (resveratrol, quercetin, δ‑tocotrienol) modulate age‑associated biomarkers and cardiovascular lipid parameters in human subjects. J Clin Exp Cardiolog. 2013;4(3). doi:10.4172/2155‑9880.1000238.

36. Passwater RA. Health benefits beyond vitamin E activity: solving the tocotrienol riddle an interview with Dr. Barrie Tan. Whole Foods Magazine; June‑July 2008.

37. O’Byrne D, Grundy S, Packer L, et al. Studies of LDL oxidation following alpha‑, gamma‑, or delta‑tocotrienyl acetate supplementation of hypercholesterolemic humans. Free Radic Biol Med. 2000;29(9):834‑845. doi:10.1016/s0891‑5849(00)00371‑3.

38. Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011‑2012. NCHS Data Brief. 2013(133):1‑8.

39. Newaz MA, Nawal NN. Effect of gamma‑tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens. 1999;21(8):1297313. doi:10.3109/10641969909070850.

40. Strong JP, Malcom GT, McMahan A, et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA 1999;281(8):727‑735. doi:10.1001/jama.281.8.727.

41. Black TM, Wang P, Madea N, Coleman RA. Palm tocotrienols protect ApoE +/‑ mice from diet‑induced atheroma formation. J Nutr. 2000;130:2420‑2426. doi:10.1093/jn/130.10.2420.

42. Qureshi AA, Salser WA, Parmar R, Emeson EE. Novel tocotrienols of rice bran inhibit atherosclerotic lesions in C57BL/6 Apo Edeficient mice. J Nutr. 2001;131(10):2606‑2618. doi.org/10.1093/jn/131.10.2606.

43. Muid S, Froemming GRA, Rahman T, Ali AM. Delta‑ and gamma‑tocotrienol isomers are potent in inhibiting inflammation and endothelial activation in stimulated human endothelial cells. Food Nutr Res. 2016;60:31526. doi:10.3402/fnr.v60.31526.

44. Rahman TA, Hassim NF, Zulkafli N, Muid S, Kornain NK, Nawawi H. Atheroprotective effects of pure tocotrienol supplementation in the treatment of rabbits with experimentally induced early and established atherosclerosis. Food Nutr Res. 2016;60:31525. doi:10.3402/fnr.v60.31525.

45. Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML. Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids. 1995;30(12):1179‑1183. doi:10.1007/BF02536621.

46. Watkins TR, et al. Hypocholesterolemic and antioxidant effect of rice bran oil non‑saponifiables in hypercholesterolemic subjects. Env and Nutr Int. 1999;3:115‑122.

47. Flegal KM, et al. Trends in obesity among adults in the United States, 2005 to 2014. JAMA. 2016;315(21):2284‑2291. doi:10.1001/jama.2016.6458.

48. Expert Panel on the Detection and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001:2486‑2497.

49. World Health Organization. Definition, diagnosis, and classification of diabetes mellitus and its complications: report of a WHO consultation. Geneva, 1999.

50. Kim Y, Gromovsky AD, Brown JM, Chung S. Gamma‑tocotrienol attenuates the aberrant lipid mediator production in NLRP3 inflammasome‑stimulated macrophages. J Nutr Biochem. 2018;58:169‑177. doi: 10.1016/j.jnutbio.2018.05.007.

51. Buckner T, Fan R, Kim Y, Kim J, Chung S. Annatto tocotrienol attenuates NLRP3 inflammasome activation in macrophages. Curr Dev Nutr. 2017;1(6):e000760. doi:10.3945/cdn.117.000760.

52. Kim Y, Wang W, Okla M, Kang I, Moreau R, Chung S. Suppression of NLRP3 inflammasome by γ‑tocotrienol ameliorates type 2 diabetes. J Lipid Res. 2016;57(1):66‑76. doi:10.1194/jlr.M062828.

53. Montonen J, Knekt P, Ritva Järvinen, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care. 2004;27(2):362‑366. doi:10.2337/diacare.27.2.362.

54. Gan YL, Fu J‑Y, Lai O‑M, et al. Effect of palm‑based tocotrienols and tocopherol mixture supplementation on platelet aggregation in subjects with metabolic syndrome: a randomised controlled trial. Sci Rep. 2017;7(1):11542. doi:10.1038/s41598‑017‑11813‑w.

55. Theriault A, Chao JT, Wang Q, Gapor A, Adeli K. Tocotrienol: a review of its therapeutic potential. Clin Biochem. 1999;32(5):30919. doi:10.1016/s0009‑9120(99)00027‑2.

56. Elson CE. Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in cancer and cardiovascular disease. J Nutr. 1995;125(6 Suppl):1666S‑1672S. doi:10.1093/jn/125.suppl_6.1666S.

57. Nesaretnam K, Guthrie N, Chambers AF, Carroll KK. Effect of tocotrienols on the growth of a human breast cancer cell line in culture. Lipids. 1995;30(12):1139‑1143. doi:10.1007/BF02536615.

58. Nesaretnam K, Stephen R, Dils R, Darbre P. Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. Lipids. 1998;33(5):461‑469. doi:10.1007/s11745‑998‑0229‑3.

59. Nesaretnam K, Meganathan P. Tocotrienols: inflammation and cancer. Ann N Y Acad Sci. 2011;1229(1):18‑22.
60. Shun MC, Yu W, Gapor A, et al. Pro‑apoptotic mechanisms of action of a novel vitamin E analog (alpha‑TEA) and a naturally occurring form of vitamin E (delta‑tocotrienol) in MDA‑MB‑435 human breast cancer cells. Nutr Cancer. 2004;48(1):95‑105. doi:10.1207/s15327914nc4801_13.

61. Malafa MP, Sebti S. Delta‑tocotrienol treatment and prevention of pancreatic cancer. 2008. Lee Moffitt Cancer Center & Research Institute. University of South Florida, Tampa, FL. Patent No. US2008/0004233.

62. Springett G, Moffitt Cancer Center. A phase I dose‑escalation study of the safety, PK, and PD of vitamin E delta‑tocotrienol administered to subjects with resectable exocrine neoplasia. Presented at: 102nd Annual Meeting of the American Association for Cancer Research, 2011: Orlando, FL.

63. Husain K, Francois RA, Hutchinson SZ, et al. Vitamin E δ‑tocotrienol levels in tumor and pancreatic tissue of mice after oral administration. Pharmacology. 2009;83(3):157‑163. doi:10.1159/000190792.

64. Husain K, Francois RA, Yamauchi T, Perez M, Sebti SM, Malafa MP. Vitamin E δ‑tocotrienol augments the antitumor activity of gemcitabine and suppresses constitutive NF‑kappa B activation in pancreatic cancer. Mol Cancer Ther. 2011;10(12):2363‑2372. doi:10.1158/1535‑7163.MCT‑11‑0424.

65. Hussein D, Mo H. d‑δ‑tocotrienol‑mediated suppression of the proliferation of human PANC‑1, MIA PaCa‑2, and BxPC‑3 pancreatic carcinoma cells. Pancreas. 2009;38(4):e124‑e136. doi:10.1097/MPA.0b013e3181a20f9c.

66. Husain K, Centeno BA, Chen D‑T, Hingorani SR, Sebti SM, Malafa MP. Vitamin E δ‑tocotrienol prolongs survival in the LSL‑KrasG12D/+;LSL‑Trp53R172H/+;Pdx‑1‑Cre (KPC) transgenic mouse model of pancreatic cancer. Cancer Prev Res (Phila). 2013;6(10):1074‑1083. doi:10.1158/1940‑6207.CAPR‑13‑0157.

67. Husain K, Centeno BA, Coppola D, Trevino J, Sebti SM, Malafa MP. δ‑Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem‑like cells and prevents pancreatic cancer metastasis. Oncotarget. 2017;8(19):31554‑31567. doi:10.18632/oncotarget.15767.

68. Palapattu GS, Sutcliffe S, Bastian PJ, et al. Prostate carcinogenesis and inflammation: emerging insights. Carcinogenesis. 2005;26(7):1170‑1181. doi:10.1093/carcin/bgh317.

69. Constantinou C, Hyatt JA, Vraka PS, et al. Induction of caspase‑independent programmed cell death by vitamin E natural homologs and synthetic derivatives. Nutr Cancer. 2009;61(6):864‑874. doi:10.1080/01635580903285130.

70. Sugahara R, Sato A, Uchida A, et al. Annatto tocotrienol induces a cytotoxic effect on human prostate cancer PC3 Cells via the simultaneous inhibition of Src and Stat3. J Nutr Sci Vitaminol (Tokyo). 2015;61(6): 497‑501. doi:10.3177/jnsv.61.497.

71. Kaneko S, Sato C, Shiozawa N, et al. Suppressive effect of delta‑tocotrienol on hypoxia adaptation of prostate cancer stemlike cells. Anticancer Res. 2018;38(3):1391‑1399. doi:10.21873/anticanres.12362.

72. Ji X, Wang Z, Geamanu A, Sarkar FH, Gupta SV. Inhibition of cell growth and induction of apoptosis in non‑small cell lung cancer cells by delta‑tocotrienol is associated with Notch‑1 down‑regulation. J Cell Biochem. 2011;May 19. doi:10.1002/jcb.23184.

73. Ji X, Wang Z, Geamanu A, Goja A, Sarkar FH, Gupta SV. Delta‑tocotrienol suppresses Notch‑1 pathway by upregulating miR‑34a in nonsmall cell lung cancer cells. Int J Cancer. 2012;131(11): 2668‑2677. doi:10.1002/ijc.27549.

74. Ji X, Wang Z, Sarkar FH, Gupta SV. Delta‑tocotrienol augments cisplatin‑induced suppression of non‑small cell lung cancer cells via inhibition of the Notch‑1 pathway. Anticancer Res. 2012;32(7):2647‑2655.

75. Nasr M, Nafee N, Saad H, Kazem A. Improved antitumor activity and reduced cardiotoxicity of epirubicin using hepatocytetargeted nanoparticles combined with tocotrienols against hepatocellular carcinoma in mice. Eur J Pharm Biopharm. 2014;88(1):216‑225. doi:10.1016/j.ejpb.2014.04.016.

76. Qureshi AA, Khan DA, Mushtaq S, Ye SQ, Xiong M, Qureshi N. δ‑Tocotrienol feeding modulates gene expression of EIF2, mTOR, protein ubiquitination through multiple‑signaling pathways in chronic hepatitis C patients. Lipids Health Dis. 2018;17(1):167. doi:10.1186/s12944‑018‑0804‑7.

77. American Cancer Society. Key Statistics for Colorectal Cancer, 2018. https://www.cancer.org/cancer/colon‑rectal‑cancer/about/key‑statistics.html.