Few people pay attention to the importance of vitamin E, much less to the multi-fractioned mirror image versions of the vitamin known as isomers (consisting of tocotrienols and tocopherols). Vitamin E has long been known as a nutrient that may play a role in maintaining heart health, but extensive new research explains that the vitamin in all its potent forms is required to dramatically lower the risk of heart disease and heart attack.
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Lung cancer is the leading cause of death among all cancers. Non-small cell lung cancer accounts for 80% of lung cancer with a 5-year survival rate of 16%. Notch pathway, especially Notch-1 is up-regulated in a subgroup of non-small cell lung cancer patients. Since Notch-1 signaling plays an important role in cell proliferation, differentiation, and apoptosis, down-regulation of Notch-1 may exert anti-tumor effects. The objective of this study was to investigate whether delta-tocotrienol, a naturally occurring isoform of Vitamin E, inhibits non-small cell lung cancer cell growth via Notch signaling. Treatment with delta-tocotrienol resulted in a dose and time dependent inhibition of cell growth, cell migration, tumor cell invasiveness, and induction of apoptosis. Real-time RT-PCR and western blot analysis showed that antitumor activity by delta-tocotrienol was associated with a decrease in Notch-1, Hes-1, Survivin, MMP-9, VEGF, and Bcl-XL expression. In addition, there was a decrease in NF-κB-DNA binding activity. These results suggest that down-regulation of Notch-1, via inhibition of NF-κB signaling pathways by delta-tocotrienol, could provide a potential novel approach for prevention of tumor progression in non-small cell lung cancer.
Background: Inflammation has been implicated in a variety of diseases associated with ageing, including cancer, cardiovascular, and neurologic diseases. We have recently established that the proteasome is a pivotal regulator of inflammation, which modulates the induction of inflammatory mediators such as TNF-α, IL-1, IL-6, and nitric oxide (NO) in response to a variety of stimuli. The present study was undertaken to identify non-toxic proteasome inhibitors with the expectation that these compounds could potentially suppress the production of inflammatory mediators in ageing humans, thereby decreasing the risk of developing ageing related diseases. We evaluated the capacity of various proteasome inhibitors to suppress TNF-α, NO and gene suppression of TNF-α, and iNOS mRNA, by LPS-stimulated macrophages from several sources. Further, we evaluated the mechanisms by which these agents suppress secretion of TNF-α, and NO production. Over the course of these studies, we measured the effects of various proteasome inhibitors on the RAW 264.7 cells, and peritoneal macrophages from four different strains of mice (C57BL/6, BALB/c, proteasome double subunits knockout LMP7/MECL-1-/-, and peroxisome proliferator-activated receptor-α,-/- (PPAR-α,-/-) knockout mice. We also directly measured the effect of these proteasome inhibitors on proteolytic activity of 20S rabbit muscle proteasomes.
Results: There was significant reduction of chymotrypsin-like activity of the 20S rabbit muscle proteasomes with dexamethasone (31%), mevinolin (19%), δ-tocotrienol (28%), riboflavin (34%), and quercetin (45%; P < 0.05). Moreover, quercetin, riboflavin, and δ-tocotrienol also inhibited chymotrypsin-like, trypsin-like and post-glutamase activities in RAW 264.7 whole cells. These compounds also inhibited LPS-stimulated NO production and TNF-α, secretion, blocked the degradation of P-IκB protein, and decreased activation of NF-κB, in RAW 264.7 cells. All proteasome inhibitors tested also significantly inhibited NO production (30% to 60% reduction) by LPS-induced thioglycolate-elicited peritoneal macrophages derived from all four strains of mice. All five compounds also suppressed LPS-induced TNF-α, secretion by macrophages from C57BL/6 and BALB/c mice. TNF-α, secretion, however, was not suppressed by any of the three proteasome inhibitors tested (δ-tocotrienol, riboflavin, and quercetin) with LPS-induced macrophages from LMP7/MECL-1-/- and PPAR-α,-/- knockout mice. Results of gene expression studies for TNF-α, and iNOS were generally consistent with results obtained for TNF-α, protein and NO production observed with four strains of mice.
Conclusions: Results of the current study demonstrate that δ-tocotrienol, riboflavin, and quercetin inhibit NO production by LPS-stimulated macrophages of all four strains of mice, and TNF-α, secretion only by LPS-stimulated macrophages of C57BL/6 and BALB/c mice. The mechanism for this inhibition appears to be decreased proteolytic degradation of P-IκB protein by the inhibited proteasome, resulting in decreased translocation of activated NF-κB to the nucleus, and depressed transcription of gene expression of TNF-α, and iNOS. Further, these naturally-occurring proteasome inhibitors tested appear to be relatively potent inhibitors of multiple proteasome subunits in inflammatory proteasomes. Consequently, these agents could potentially suppress the production of inflammatory mediators in ageing humans, thereby decreasing the risk of developing a variety of ageing related diseases.
During the last two decades, several exciting reports have provided many advances in the role and biosynthesis of l-ascorbic acid (AsA) and tocochromanols, including tocopherols and tocotrienols, in higher plants. There are increasing bodies of experimental evidence that demonstrate that AsA and tocochromanols (especially tocopherols) play an important role as antioxidants and nutrients in mammals and photosynthetic organisms and are also involved in plant responses to stimuli. Although AsA and tocochromanol biosynthesis pathways have been well characterized using Arabidopsis, these pathways are still poorly understood in rice, which is an economically important monocot cereal crop. In this study using computational analysis of sequenced rice genome, we identified eight and seven potential non-redundant members involved in AsA and tocochromanol biosynthetic pathways, respectively. The results reveal that the common feature of these gene promoters is the combination of light-responsive, hormone-responsive, and stress-responsive elements. These findings, together with expression analysis in the MPSS database, indicate that AsA and tocochromanols might be co-related with the complex signaling pathways involved in plant responses.
The eight vitamin E isomers [α-, β-, γ-, and δ-tocopherols (T) and α-, β-, γ-, and δ-tocotrienols (T3)] and γ-oryzanol are known to possess diverse biological activities. This study examined the contents of these compounds and their distribution in 16 commercial rice varieties in Taiwan. Results showed that the order of vitamin E, total T, total T3, and γ-oryzanol contents was rice bran > brown rice > rice husk > polished rice. γ-T3 was the highest vitamin E isomer present in all rice samples, while β-T, β-T3, δ-T, and δ-T3 were present in trace amounts. The Japonica varieties contained a higher total T, total T3, and γ-oryzanol than the Indica varieties. They also have a higher level of α-T and α-T3 but a lower level of γ-T and γ-T3 than the Indica varieties. However, no obvious difference in total T, total T3, and γ-oryzanol content was noted between black- and red-colored rice varieties.
A recent and growing body of research has shown that members of this vitamin E family posses unique biologic functions. Tocotrienols have garnered much of this recent attention, and in particular alpha-tocotrienol has been shown to be the most potent neuroprotective form of vitamin E. Protection exclusively mediated through tocotrienols has been arbitrated to many mechanisms including inhibition of 12-LOX, c-Src, PLA2 and through up-regulation of MRP1. Further, tocotrienols have recently been shown to induce arteriogenesis through induction of TIMP1 and decreased activation of MMP2. However, the unique therapeutic potential of tocotrienols is not limited to neuroprotection. Tocotrienols have been shown to have molecular targets including: apoptotic regulators, cytokines, adhesion molecules, enzymes, kinases, receptors, transcription factors, and growth factors. In spite of this large and unique therapeutic potential, scientific literature on tocotrienols only accounts for approximately 1% of vitamin E research. Given the potential of tocotrienols and relatively scant literature, further investigation is warranted.
Skin aging may occur as a result of increased free radicals in the body. Vitamin E, the major chain-breaking antioxidant, prevents propagation of oxidative stress, especially in biological membranes. In this study, the molecular mechanism of tocotrienol-rich fraction (TRF) in preventing oxidative stress-induced skin aging was evaluated by determining the rate of total collagen synthesis and its gene expression in human skin fibroblasts.
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The intestinal absorption of tocotrienols (TCT) in dogs is, to our knowledge, so far unknown. Adult Beagle dogs (n 8) were administered a single oral dosage of a TCT-rich fraction (TRF; 40 mg/kg body weight) containing 32 % α-TCT, 2 % β-TCT, 27 % γ-TCT, 14 % δ-TCT and 25 % α-tocopherol (α-TCP). Blood was sampled at baseline (fasted), 1, 2, 3, 4, 5, 6, 8 and 12 h after supplementation. Plasma and chylomicron concentrations of TCT and α-TCP were measured at each time point. Plasma TAG were measured enzymatically, and plasma antioxidant capacity was assessed by the Trolox equivalent antioxidant capacity assay. In fasted dogs, levels of TCT were 0·07 (sd 0.03) μmol/l. Following the administration of the TRF, total plasma TCT peaked at 2 h (7.16 (SD 3.88) μmol/l; P < 0.01) and remained above baseline levels (0.67 (SD 0.44) μmol/l; P < 0.01) at 12 h. The TCT response in chylomicrons paralleled the increase in TCT in plasma with a maximum peak (3.49 (SD 2.06) μmol/l; P < 0.01) at 2 h post-dosage. α-TCP was the major vitamin E detected in plasma and unaffected by TRF supplementation. The Trolox equivalent values increased from 2 h (776 (SD 51.2) μmol/l) to a maximum at 12 h (1130 (SD 7.72) μmol/l; P < 0.01). The results show that TCT are detected in postprandial plasma of dogs. The increase in antioxidant capacity suggests a potential beneficial role of TCT supplementation in the prevention or treatment of several diseases in dogs.