Nanoemulsion enhances α-tocopherol succinate bioavailability in rats.

Gao Y, Qi X, Zheng Y, Ji H, Wu L, Zheng N, Tang J.

Int J Pharm. 2016 Oct 13;515(1-2):506-514. doi: 10.1016/j.ijpharm.2016.10.026. [Epub ahead of print]

Abstract

The vitamin E analogue, α-tocopherol succinate (α-TOS), has a broad anti-tumor effect. α-TOS can induce cancer cells apoptosis and suppress tumor growth by targeting mitochondria. Low bioavailability of α-TOS is the major problem encountered with formulation development. In our study, α-TOS nanoemulsion (α-TOS-NE) was demonstrated as a new drug delivery system of α-TOS to increase the bioavailability. MTT-based cytotoxicity assay and mitochondrial membrane potential (ΔY) were performed on human breast cancer cell lines MCF-7 and human oral epithelial cancer cell lines KB to evaluate in vitro anticancer efficacy of α-TOS-NE. In comparison with free α-TOS, α-TOS-NE exhibited a stronger cytotoxicity and decreased ΔΨ. Pharmacokinetic profiles of I.V. α-TOS-NE group, I.P. α-TOS-NE group, and I.P. free α-TOS group (7% DMSO/93% PEG) were drawn. First of all, nanoemultion (NE) enables the I.V. injection of α-TOS, make it possible to be an I.V. preparation. Second, compare to the I.P. free α-TOS group, I.P. α-TOS-NE group had a higher bioavailability. Thus, NE improved the strong anti-cancer efficacy of α-TOS while increasing its in vivo bioavailability in rats. In conclusion, our laboratory-made NE was a safe drug delivery system for clinical trials and could be a promising formulation for α-TOS by I.V administration.

Read More

Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes.

Finno CJ, Bordbari MH, Valberg SJ, Lee D, Herron J, Hines K, Monsour T, Scott E, Bannasch DL, Mickelson J, Xu L.

Free Radic Biol Med. 2016 Oct 15;101:261-271. doi: 10.1016/j.freeradbiomed.2016.10.009. [Epub ahead of print]

Abstract

Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid α-tocopherol (α-TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the α-TOH transfer protein gene (TTPA). Mutations in TTPA are not present with eNAD and the molecular basis remains unknown. Given the neuropathologic phenotypic similarity of the conditions, we assessed the molecular basis of eNAD by global transcriptome sequencing of the cervical spinal cord. Differential gene expression analysis identified 157 significantly (FDR<0.05) dysregulated transcripts within the spinal cord of eNAD-affected horses. Statistical enrichment analysis identified significant downregulation of the ionotropic and metabotropic group III glutamate receptor, synaptic vesicle trafficking and cholesterol biosynthesis pathways. Gene co-expression analysis identified one module of upregulated genes significantly associated with the eNAD phenotype that included the liver X receptor (LXR) targets CYP7A1, APOE, PLTP and ABCA1. Validation of CYP7A1 and APOE dysregulation was performed in an independent biologic group and CYP7A1 was found to be additionally upregulated in the medulla oblongata of eNAD horses. Evidence of LXR activation supports a role for modulation of oxysterol-dependent LXR transcription factor activity by tocopherols. We hypothesize that the protective role of α-TOH in eNAD may reside in its ability to prevent oxysterol accumulation and subsequent activation of the LXR in order to decrease lipid peroxidation associated neurodegeneration.

Read More

Serum Metabolomic Response to Long-Term Supplementation with all-rac-α-Tocopheryl Acetate in a Randomized Controlled Trial.

Mondul AM, Moore SC, Weinstein SJ, Evans AM, Karoly ED, Männistö S, Sampson JN, Albanes D.

J Nutr Metab. 2016;2016:6158436. Published online 2016 Oct 20. doi: 10.1155/2016/6158436

Abstract

Background. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a randomized controlled cancer prevention trial, showed a 32% reduction in prostate cancer incidence in response to vitamin E supplementation. Two other trials were not confirmatory, however. Objective. We compared the change in serum metabolome of the ATBC Study participants randomized to receive vitamin E to those who were not by randomly selecting 50 men from each of the intervention groups (50 mg/day all-racα-tocopheryl acetate (ATA), 20 mg/day β-carotene, both, placebo). Methods. Metabolomic profiling was conducted on baseline and follow-up fasting serum (Metabolon, Inc.). Results. After correction for multiple comparisons, five metabolites were statistically significantly altered (β is the change in metabolite level expressed as number of standard deviations on the log scale): α-CEHC sulfate (β = 1.51, p = 1.45 × 10-38), α-CEHC glucuronide (β = 1.41, p = 1.02 × 10-31), αtocopherol (β = 0.97, p = 2.22 × 10-13), γtocopherol(β = -0.90, p = 1.76 × 10-11), and βtocopherol (β = -0.73, p = 9.40 × 10-8). Glutarylcarnitine, beta-alanine, ornithine, and N6-acetyllysine were also decreased by ATA supplementation (β range 0.40 to -0.36), but not statistically significantly. Conclusions. Comparison of the observed metabolite alterations resulting from ATA supplementation to those in other vitamin E trials of different populations, dosages, or formulations may shed light on the apparently discordant vitamin E-prostate cancer risk findings.

Read More

Mono-epoxy-tocotrienol-α enhances wound healing in diabetic mice and stimulates in vitro angiogenesis and cell migration.

Xu C, Bentinger M, Savu O, Moshfegh A, Sunkari V, Dallner G, Swiezewska E, Catrina SB, Brismar K, Tekle M.

J Diabetes Complications. 2016 Oct 18. pii: S1056-8727(16)30706-1. doi: 10.1016/j.jdiacomp.2016.10.010. [Epub ahead of print]

Abstract

Diabetes mellitus is characterized by hyperglycemia and capillary hypoxia that causes excessive production of free radicals and impaired antioxidant defense, resulting in oxidative stress and diabetes complications such as impaired wound healing. We have previously shown that modified forms of tocotrienols possess beneficial effects on the biosynthesis of the mevalonate pathway lipids including increase in mitochondrial CoQ. The aim of this study is to investigate the effects of mono-epoxy-tocotrienol-α on in vitro and in vivo wound healing models as well as its effects on mitochondrial function. Gene profiling analysis and gene expression studies on HepG2 cells and human dermal fibroblasts were performed by microarray and qPCR, respectively. In vitro wound healing using human fibroblasts was studied by scratch assay and in vitro angiogenesis using human dermal microvascular endothelial cells was studied by the tube formation assay. In vivo wound healing was performed in the diabetic db/db mouse model. For the study of mitochondrial functions and oxygen consumption rate Seahorse XF-24 was employed. In vitro, significant increase in wound closure and cell migration (p<0.05) both in normal and high glucose and in endothelial tube formation (angiogenesis) (p<0.005) were observed. Microarray profiling analysis showed a 20-fold increase of KIF26A gene expression and 11-fold decrease of lanosterol synthase expression. Expression analysis by qPCR showed significant increase of the growth factors VEGFA and PDGFB. The epoxidated compound induced a significantly higher basal and reserve mitochondrial capacity in both HDF and HepG2 cells. Additionally, in vivo wound healing in db/db mice, demonstrated a small but significant enhancement on wound healing upon local application of the compound compared to treatment with vehicle alone. Mono-epoxy-tocotrienol-α seems to possess beneficial effects on wound healing by increasing the expression of genes involved in cell growth, motility and angiogenes as well as on mitochondrial function.

Read More

Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits.

Shahidi F, de Camargo AC.

Int J Mol Sci. 2016 Oct 20;17(10). pii: E1745. Review.

Abstract

Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible oils with considerable contents of tocopherols and tocotrienols. Tocopherols are among the most important lipid-soluble antioxidants in food as well as in human and animal tissues. Tocopherols are found in lipid-rich regions of cells (e.g., mitochondrial membranes), fat depots, and lipoproteins such as low-density lipoprotein cholesterol. Their health benefits may also be explained by regulation of gene expression, signal transduction, and modulation of cell functions. Potential health benefits of tocols include prevention of certain types of cancer, heart disease, and other chronic ailments. Although deficiencies of tocopherol are uncommon, a continuous intake from common and novel dietary sources of tocopherols and tocotrienols is advantageous. Thus, this contribution will focus on the relevant literature on common and emerging edible oils as a source of tocols. Potential application and health effects as well as the impact of new cultivars as sources of edible oils and their processing discards are presented. Future trends and drawbacks are also briefly covered.

Read More

Acute effects of a single dose of tocotrienols on insulinemic and inflammatory responses in metabolic syndrome subjects after a high-fat challenge.

Che HL, Kanthimathi MS, Loganathan R, Yuen KH, Tan AT, Selvaduray KR, Nesaretnam K, Teng KT.

Eur J Clin Nutr. 2016 Oct 19. doi: 10.1038/ejcn.2016.200. [Epub ahead of print]

Abstract

Evident shows that tocotrienols potentially reverse various chronic disease progressions caused by the metabolic syndrome. We aimed to investigate the acute effects of a single-dose supplementation of gamma and delta tocotrienols (γδ-T3, 1:4 ratio) compared with those in placebo on the insulinemic, anti-inflammatory and anti-thrombogenic responses in metabolic syndrome subjects. Results show Plasma vitamin E levels reflected the absorption of γδ-T3 after treatments. Postprandial changes in serum C-peptide, serum insulin, plasma glucose, triacylglycerol, non-esterified fatty acid and adiponectin did not differ between treatments, with women displaying delayed increase in the aforementioned markers. No significant difference between treatments was observed for plasma cytokines (interleukin-1 beta, interleukin-6 and tumor necrosis factor alpha) and thrombogenic markers (plasminogen activator inhibitor type 1 and D-dimer). In summary, Supplementation of a single dose of γδ-T3 did not change the insulinemic, anti-inflammatory and anti-thrombogenic responses in metabolic syndrome subjects.

 

Read More

Tocotrienol-Rich Tocomin Attenuates Oxidative Stress and Improves Endothelium-Dependent Relaxation in Aortae from Rats Fed a High-Fat Western Diet.

Ali SF, Nguyen JC, Jenkins TA, Woodman OL.

Front Cardiovasc Med. 2016 Oct 17;3:39.

Abstract

We have previously reported that tocomin, a mixture high in tocotrienol content and also containing tocopherol, acutely preserves endothelial function in the presence of oxidative stress. In this study, we investigated whether tocomin treatment would preserve endothelial function in aortae isolated from rats fed a high-fat diet known to cause oxidative stress. Wistar hooded rats were fed a western diet (WD, 21% fat) or control rat chow (standard diet, 6% fat) for 12 weeks. Tocomin (40 mg/kg/day sc) or its vehicle (peanut oil) was administered for the last 4 weeks of the feeding regime. Aortae from WD rats showed an impairment of endothelium-dependent relaxation that was associated with an increased expression of the NADPH oxidase Nox2 subunit and an increase in the vascular generation of superoxide measured using L-012 chemiluminescence. The increase in vascular oxidative stress was accompanied by a decrease in basal NO release and impairment of the contribution of NO to ACh-induced relaxation. The impaired relaxation is likely contributed to by a decreased expression of eNOS, calmodulin, and phosphorylated Akt and an increase in caveolin. Tocotrienol rich tocomin, which prevented the diet-induced changes in vascular function, reduced vascular superoxide production and abolished the diet-induced changes in eNOS and other protein expression. Using selective inhibitors of nitric oxide synthase (NOS), soluble guanylate cyclase (sGC) and calcium-activated potassium (KCa) channels we demonstrated that tocomin increased NO-mediated relaxation, without affecting the contribution of endothelium-dependent hyperpolarization type relaxation to the endothelium-dependent relaxation. The beneficial actions of tocomin in this diet-induced model of obesity suggest that it may have potential to be used as a therapeutic agent to prevent vascular disease in obesity.

Read More

γ-Tocotrienol prevents cell cycle arrest in aged human fibroblast cells through p16INK4a pathway.

Zainuddin A, Chua KH, Tan JK, Jaafar F, Makpol S.

J Physiol Biochem. 2016 Oct 14. [Epub ahead of print]

Abstract

Human diploid fibroblasts (HDFs) proliferation in culture has been used as a model of aging at the cellular level. Growth arrest is one of the most important mechanisms responsible for replicative senescence. Recent researches have been focusing on the function of vitamin E in modulating cellular signaling and gene expression. Therefore, the aim of this study was to elucidate the effect of palm γ-tocotrienol (vitamin E) in modulating cellular aging through p16INK4a pathway in HDF cells. Primary culture of senescent HDFs was incubated with 70 μM of palm γ-tocotrienol for 24 hours. Silencing of p16INK4a was carried out by siRNA transfection. RNA was extracted from the different treatment groups and gene expression analysis was carried out by real-time reverse transcription polymerase chain reaction. Proteins that were regulated by p16INK4a were determined by western blot technique. The finding of this study showed that p16INK4a mRNA was overexpressed in senescent HDFs, and hypophosphorylated-pRb and cyclin D1 protein expressions were increased (p < 0.05). However, downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions (p < 0.05) by γ-tocotrienol led to modulation of the cell cycle regulation during cellular aging. In conclusion, senescent HDFs showed change in biological process specifically in cell cycle regulation with elevated expression of genes and proteins which may contribute to cell cycle arrest. Palm γ-tocotrienol may delay cellular senescence of HDFs by regulating cell cycle through downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions.

Read More

δ and γ tocotrienols suppress human hepatocellular carcinoma cell proliferation via regulation of Ras-Raf-MEK-ERK pathway-associated upstream signaling.

Burdeos GC, Ito J, Eitsuka T, Nakagawa K, Kimura F, Miyazawa T.

Food Funct. 2016 Oct 12;7(10):4170-4174.

Abstract

Tocotrienol (T3) has recently gained increasing interest due to its anti-cancer effect. Here, we investigated the modulating effect of δ and γ T3 on the Ras-Raf-MEK-ERK oncogenic upstream signaling pathway in human hepatocellular carcinoma HepG2 cells. The results indicated that T3 regulated the upstream signaling cascades of this pathway.

Read More

Vitamin E administration may decrease the incidence of pneumonia in elderly males.

Hemilä H.

Clin Interv Aging. 2016 Oct 3;11:1379-1385.

Abstract

Vitamin E has influenced the immune system in laboratory studies. Dozens of animal experiments have found that vitamin E offered protection against infections caused by viruses and bacteria. Previously, significant heterogeneity was found in the effect of vitamin E supplementation on pneumonia in humans. The aim of this study was to examine how the effect of vitamin E on pneumonia risk depends on age. Although the evidence of benefit from vitamin E against pneumonia in elderly males is strong in this analysis, the overall findings about vitamin E have been complex. Further research on vitamin E in nonsmoking elderly males is warranted.

Read More