Almost a century has passed since Evans and Bishop (Evans & Bishop, 1922) first described a “substance X” (today known as vitamin E) as a critical factor for post-fertilization placental development in rats. Recently, the Center for Disease Control and Prevention (CDC) estimated that more than 10% of the U.S. population may have nutritional deficiencies, including vitamin E. These deficiencies may result from inadequate consumption of nutrient-rich foods; lack of absorption in the digestive tract; illness and disease; interactions among prescription medications, over-the-counter (OTC) medicine and dietary supplements; and following “fad” diets that limit the intake of a variety of foods.

Since its discovery, vitamin E has been extensively researched by a large number of investigators in an attempt to understand its role in a variety of pathophysiological contexts. However, several recent randomized controlled trials have generated negative images of this well-publicized vitamin.

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Synergistic effect of combined treatment with gamma-tocotrienol and statin on human malignant mesothelioma cells.

Tuerdi G, Ichinomiya S, Sato H, Siddig S, Suwa E, Iwata H, Yano T, Ueno K.

Cancer Lett. 2013 Jul 20. pii: S0304-3835(13)00535-1. doi: 10.1016/j.canlet.2013.07.015. [Epub ahead of print]

Summary:

The present study is the first to demonstrate the synergetic effect of statins (atorvastatin and simvastatin) and gamma-tocotrienol (γ-T3) on human malignant mesothelioma (MM). Statin + γ-T3 combinations induced greater cell growth inhibition more than each single treatment via inhibition of mevalonate pathway, a well-known target of both γ-T3 and statins. γ-T3 was necessary for endoplasmic reticulum stress markers CHOP and GRP78, whereas an intrinsic apoptotic marker, caspase 3 activation was induced only in the presence of statins. Overall, the combination of γ-T3 and statins could be useful for MM therapy and functions in a complementary style.

A Review on the use of Statins and Tocotrienols, Individually or in Combination for the Treatment of Osteoporosis.

Abdul-Majeed S, Mohamed N, Soelaiman IN.

Curr Drug Targets. 2013 Jul 8. [Epub ahead of print]

Summary:

Skeletal tissue undergoes continuous remodeling which makes it unique among other body tissues. Osteoporosis is a common bone metabolic disorder affecting both men and women. Osteoporosis and its complications mainly osteoporotic fractures, have a high impact on health and economy. Current approved medications are associated with numerous side effects, which limit their use. Identification of a new and safe therapy is mandatory. Statins, also known as HMGCoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia and for the prevention of morbidity and mortality associated with cardiovascular disease. Statins improved bone health status in intact and ovariectomised rodents following high clinically intolerable oral doses. However, this beneficial effect of statins could not be significantly demonstrated in humans. The reason behind this discrepancy might be due to the safety and bioavailability of the currently used oral statins. Vitamin E, especially the tocotrienols at the dose 60 mg/kg/day provided significant anti-osteoporotic effects in different animal models of osteoporosis. The use of the aforementioned dose of tocotrienols was shown to be safe in both humans and animals. Enhancement of bone formation and reduction of bone resorption were achieved more effectively by a combination of tocotrienols and statins than by either treatment when supplemented separately at clinically tolerable doses. Therefore, the adverse effects associated with high statin doses might be avoided with the coadministration of tocotrienols. Moreover, the combination therapy strategy might be useful for patients who are at high risk of osteoporosis, cardiovascular events and hypercholesterolaemia.

A Review of the Possible Mechanisms of Action of Tocotrienol – A Potential Antiosteoporotic Agent.

Chin KY, Mo H, Ima-Nirwana S.

Curr Drug Targets. 2013 Jun 26. [Epub ahead of print]

Summary:

Osteoporosis is posing a tremendous healthcare problem globally. Much effort has been invested in finding novel antiosteoporotic agents to stop the progression of this disease. Tocotrienol, one of the isoforms of vitamin E, is poised as a potential antiosteoporotic agent. Previous studies showed that tocotrienol as a single isomer or as a mixture demonstrated both anabolic and antiresorptive effects in various rodent models of osteoporosis. In vitro experiments further demonstrated that tocotrienol could up-regulate genes related to osteoblastogenesis and modify receptor activator of nuclear factor kappa B signaling against osteoclastogenesis. Additionally, tocotrienol was also shown to be a strong 3-hydroxy-3-methyl-glutaryl-CoA reductase down-regulator with a mechanism different from that of statins. Inhibition of the mevalonate pathway affects both osteoblast and osteoclast formation in favor of the former. Tocopherol, a more commonly used isoform of vitamin E does not possess similar effects. Tocotrienol is also a potent antioxidant. It can scavenge free radicals and prevent oxidative damage on osteoblast thus promoting its survival. It may also up-regulate the antioxidant defense network in osteoclast and indirectly act against free radical signaling essential in osteoclastogenesis. The effects of tocotrienol on Wnt/β-catenin signaling essential in osteoblastogenesis have not been determined. More mechanistic studies need to be conducted to illustrate the antiosteoporotic effects of tocotrienol. Clinical trials are also required to confirm its effects in humans. In conclusion, tocotrienol demonstrates great potential as an antiosteoporotic agent and much research effort should be invested to develop it as an agent to curb osteoporosis.

SUmmary

From an enzyme kinetic study using rat liver microsomes, α-tocopherol has been suggested to accelerate the other vitamin E catabolism by stimulating vitamin E ω-hydroxylation, the late limiting reaction of the vitamin E catabolic pathway. To test the effect of α-tocopherol on catabolism of the other vitamin E isoforms in vivo, we determined whether α-tocopherol accelerates depletion of γ-tocopherol and tocotrienol and excretion of their metabolites in rats. Male Wistar rats were fed a γ-tocopherol-rich diet for 6 weeks followed by a γ-tocopherol-free diet with or without α-tocopherol for 7 days. Intake of γ-tocopherol-free diets lowered γ-tocopherol concentrations in serum, liver, adrenal gland, small intestine, and heart, but there was no effect of dietary α-tocopherol on γ-tocopherol concentrations. The level of urinary excretion of γ-tocopherol metabolite was not affected by dietary α-tocopherol. Next, the effect of α-tocopherol on tocotrienol depletion was examined using rats fed a tocotrienol-rich diet for 6 weeks. Subsequent intake of a tocotrienol-free diet with or without α-tocopherol for 7 days depleted concentrations of α- and γ-tocotrienol in serum and tissues, which was accompanied by a decrease in the excretion of γ-tocotrienol metabolite. However, neither the tocotrienol concentration nor γ-tocotrienol metabolite excretion was affected by dietary α-tocopherol. These data showed that dietary α-tocopherol did not accelerate the depletion of γ-tocopherol andtocotrienol and their metabolite excretions, suggesting that the positive effect of α-tocopherol on vitamin E ω-hydroxylase is not sufficient to affect the other isoform concentrations in tissues.

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Rice bran extract protects from mitochondrial dysfunction in guinea pig brains.

Hagl S, Kocher A, Schiborr C, Eckert S, Ciobanu I, Birringer M, El-Askary H, Helal A, Khayyal MT, Frank J, Muller WE, Eckert GP.

Pharmacol Res. 2013 Jul 1. pii: S1043-6618(13)00105-9. doi: 10.1016/j.phrs.2013.06.008. [Epub ahead of print]

Summary

Mitochondrial dysfunction plays a major role in the development of age-related neurodegenerative diseases and recent evidence suggests that food ingredients can improve mitochondrial function. In the current study we investigated the effects of feeding a stabilized rice bran extract (RBE) on mitochondrial function in the brain of guinea pigs. Key components of the rice bran are oryzanols, tocopherols and tocotrienols, which are supposed to have beneficial effects on mitochondrial function. Concentrations of α-tocotrienol and γ-carboxyethyl hydroxychroman (CEHC) but not γ-tocotrienol were significantly elevated in brains of RBE fed animals and thus may have provided protective properties. Overall respiration and mitochondrial coupling were significantly enhanced, which suggests improved mitochondrial function in brains of RBE fed animals. Cells isolated from brains of RBE fed animals showed significantly higher MMP and ATP levels after sodium nitroprusside (SNP) challenge indicating resistance against mitochondrial dysfunction. Experimental evidence indicated increased mitochondrial mass in guinea pig brains, such as enhanced citrate synthase activity, increased cardiolipin as well as respiratory chain complex I and II and TIMM levels. In addition levels of Drp1 and fis1 were also increased in brains of guinea pigs fed RBE, indicating enhanced fission events. Thus, RBE represents a potential nutraceutical for the prevention of mitochondrial dysfunction and oxidative stress in brain aging and neurodegenerative diseases.

Tocopherols and tocotrienols as anticancer treatment for lung cancer: future nutrition.

Zarogoulidis P, Cheva A, Zarampouka K, Huang H, Li C, Huang Y, Katsikogiannis N, Zarogoulidis K.

J Thorac Dis. 2013 Jun;5(3):349-52. doi: 10.3978/j.issn.2072-1439.2013.04.03.

Summary

Nutrition has been known for ages to shield the immune system against several formulations that deregulate normal DNA repair mechanisms, and induce tumorigenesis. Vitamins and in specific Vit E and its members tocopherols (α-, β-, γ-, δ-) and tocotrienols (α-, β-, γ-, δ-) have demonstrated strong association with the prevention of cancer and inhibition of tumor, both in vitro and in vivo. Vitamin E has also demonstrated effective role against chemotherapy resistant cancer cell evolution and a protective role in acute interstitial disease. Several formulations of Vitamin E have been investigated conjugated with different carriers as nano-formulations and administered in different forms. Additionally, several tumorigenic pathways have been investigated separately in an effort to identify which member of Vitamin E inhibits efficiently every pathway. Vitamin E presented efficiency against specific subhistology types of lung cancer. Finally, in the current work up to date information regarding novel formulations with Vitamin E and inhibition pathways are going to be presented and commented.

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γ-Tocotrienol induced cell cycle arrest and apoptosis via activating the Bax-mediated mitochondrial and AMPK signaling pathways in 3T3-L1 adipocytes.

Wu SJ, Huang GY, Ng LT.

Food Chem Toxicol, 2013 Jun 28 [Epub ahead of print]

This study aimed to examine the anti-proliferative effects of α-, γ- and δ-tocotrienols (αT3, γT3 and δT3), and α-tocopherol on 3T3-L1 adipocytes. Results showed that compared with other vitamin E analogues, γT3 demonstrated the most potent anti-proliferative effect on 3T3-L1 cells. It significantly caused a reduction in mitochondrial membrane potential (Δψm) and an increase in ROS formation, as well as inducing cell apoptosis and cell cycle arrest at S phase. Further studies showed that it down-regulated Bcl-2 and PPAR-γ expression, suppressed Akt and ERK activation and phosphorylation, and caused cytochrome c release from mitochondria to cytosol, whereas it up-regulated CD95 (APO-1/CD95) and Bax expression, and caused caspase-3 and JNK activation, PARP cleavage and AMPK phosphorylation. Pretreatments with caspase-3 (z-DEVD-fmk) and AMPK (CC) inhibitors significantly suppressed the γT3-induced ROS production and cell death. Caspase-3 inhibitor also efficiently blocked CD95 (APO-1/CD95) and Bax expression, caspase-3 activation and PARP cleavage, whereas antioxidant N-acetyl-L-cysteine, AMPK inhibitor and AMPK siRNA effectively blocked the AMPK phosphorylation. Taken together, these results conclude that the potent anti-proliferative and anti-adipogenic effects of γT3 on 3T3-L1 adipocytes could be through the Bax-mediated mitochondrial and AMPK signaling pathways.

Rice varietal differences in bioactive bran components for inhibition of colorectal cancer cell growth.

Forster GM, Raina K, Kumar A, Kumar S, Agarwal R, Chen MH, Bauer JE, McClung AM, Ryan EP.

Food Chem. 2013 Nov 15;141(2):1545-52. Epub 2013 Apr 17.

Summary

Rice bran chemical profiles differ across rice varieties and have not yet been analysed for differential chemopreventive bioactivity. A diverse panel of seven rice bran varieties was analysed for growth inhibition of human colorectal cancer (CRC) cells. Inhibition varied from 0% to 99%, depending on the variety of bran used. Across varieties, total lipid content ranged 5-16%, individual fatty acids had 1.4- to 1.9-fold differences, vitamin E isoforms (α-, γ-, δ-tocotrienols, and tocopherols) showed 1.3- to 15.2-fold differences, and differences in γ-oryzanol and total phenolics ranged between 100-275ng/mg and 57-146ngGAE/mg, respectively. Spearman correlation analysis was used to identify bioactive compounds implicated in CRC cell growth inhibitory activity. Total phenolics and γ-tocotrienol were positively correlated with reduced CRC cell growth (p<0.05). Stoichiometric variation in rice bran components and differential effects on CRC viability merit further evaluation elucidate their role in dietary CRC chemoprevention.

Effect of the tocotrienol-rich fraction on the lifespan and oxidative biomarkers in Caenorhabditis elegans under oxidative stress.

Aan GJ, Zainudin MS, Karim NA, Ngah WZ.

Clinics (Sao Paulo). 2013; 68(5): 599–604.

Summary

OBJECTIVE:

This study was performed to determine the effect of the tocotrienol-rich fraction on the lifespan and oxidative status of C. elegans under oxidative stress.

METHOD:

Lifespan was determined by counting the number of surviving nematodes daily under a dissecting microscope after treatment with hydrogen peroxide and the tocotrienol-rich fraction. The evaluated oxidative markers included lipofuscin, which was measured using a fluorescent microscope, and protein carbonyl and 8-hydroxy-2′-deoxyguanosine, which were measured using commercially available kits.

RESULTS:

Hydrogen peroxide-induced oxidative stress significantly decreased the mean lifespan of C. elegans, which was restored to that of the control by the tocotrienol-rich fraction when administered before or both before and after the hydrogen peroxide. The accumulation of the age marker lipofuscin, which increased with hydrogen peroxide exposure, was decreased with upon treatment with the tocotrienol-rich fraction (p<0.05). The level of 8-hydroxy-2′-deoxyguanosine significantly increased in the hydrogen peroxide-induced group relative to the control. Treatment with the tocotrienol-rich fraction before or after hydrogen peroxide induction also increased the level of 8-hydroxy-2′-deoxyguanosine relative to the control. However, neither hydrogen peroxide nor the tocotrienol-rich fraction treatment affected the protein carbonyl content of the nematodes.

CONCLUSION:

The tocotrienol-rich fraction restored the lifespan of oxidative stress-induced C. elegans and reduced the accumulation of lipofuscin but did not affect protein damage. In addition, DNA oxidation was increased.

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