Objective: To investigate the correlation between in vivo δ-tocotrienol (DT3) pharmacokinetcs, pharmacodynamics and radiation protection, and to evaluate the effect of DT3 pre-treatment on radiation-induced alterations in apoptotic and autophagic pathways.Methods: We evaluated pharmacokinetics (plasma, 0.5 to 12 h) and pharmacodynamics (peripheral blood indices, day 3, 7, 10 and 14) after a single subcutaneous injection of 300 mg kg DT3 in unirradiated CD2F1 mice. Next, we monitored 30-day post-irradiation survival (9.25 Gy) and haematopoietic recovery of DT3-treated mice (7 Gy) exposed to cobalt-60 γ irradiation. The effects of DT3 on irradiated bone marrow apoptosis and autophagy were determined by analyses of key caspases (3, 7, 9 and 8), beclin-1 and LC3 conversion.Results: Plasma concentration of DT3 reached ∼195 µM (Cmax) 1 h after injection (Tmax), and DT3 was eliminated from plasma 12 h later. In unirradiated mice, DT3 significantly increased white blood cells (WBCs), neutrophils, lymphocytes (day 3 post-DT3 injection) and platelets (day 7) by 1.5-2-fold, over vehicle-treated control. DT3 pre-treatment improved 30-day survival to 100% (∼15% in control) and accelerated recovery of reticulocytes, platelets, WBCs, neutrophils, lymphocytes and monocytes in peripheral blood. DT3 reduced activation of caspase-8, caspases-3 and -7, inherent to apoptosis, while increasing autophagy-related beclin-1 expression in irradiated bone marrow.Conclusion: These data indicate that DT3 stimulates multilineage haematopoiesis, protects against radiation-induced apoptosis downstream of the mitochondria and stimulates cytoprotective autophagy. Apart from a potent antioxidant activity, DT3 may elicit survival advantage following irradiation by enhancing haematopoiesis and modulating signalling pathways.
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Gamma Tocotrienol E Can Help Asthma
Byron J. Richards
Tocotrienols are a unique form of vitamin E that possess many biologically active properties that plain vitamin E does not. Researchers have now shown that gamma tocotrienol can influence gene signals of immune cells in the lungs in a way that prevents key problems involved with the pathogenesis of asthma.
Researchers Probe the Potential Health Benefits of Palm Oil
Neel Chowdhury
Palm oil has a pretty bad reputation. The product of this hard-shell red fruit, harvested primarily on plantations in Southeast Asia, is typically used as cheap cooking oil for fried foods like noodles and curry puffs. Indeed, by the time the palm oil is processed, much of its nutritional value is destroyed. And the fact that it can congeal at room temperature makes it even look extra artery clogging.
Tocotrienol attenuates triglyceride accumulation in HepG2 cells and F344 rats
Burdeos GC, Nakagawa K, Kimura F, Miyazawa T.
Lipids. 2012 May;47(5):471-81. Epub 2012 Feb 26.
Tocotrienol (T3) is an important phytonutrient found in rice bran and palm oil. T3 has gained much interest for lipid lowering effects, especially for cholesterol (Cho) by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Also, usefulness of T3 in improving triglyceride (TG) profiles has been suggested, but its efficacy and mechanism have been unclear. We investigated how T3 decreases TG concentration in cultured cells and animals. In a cell culture study, human hepatoma cells (HepG2) were incubated in a control or a fat (1 mM oleic acid)-loaded medium containing γ-T3 for 24 h. We found that 10-15 μM γ-T3 inhibited cellular TG accumulation significantly, especially in the fat-loaded medium. This manifestation was supported by mRNA and protein expressions of fatty acid synthase, carnitine palmitoyltransferase 1, and cytochrome P450 3A4. In concordance with these results, rice bran T3 supplementation to F344 rats (5 or 10 mg T3/day/rat) receiving a high fat diet for 3 weeks significantly reduced TG and the oxidative stress marker (phospholipid hydroperoxides, PLOOH) in the liver and blood plasma. T3 supplementation did not show changes in the Cho level. These results provided new information and the mechanism of the TG-lowering effect of T3. The lipid lowering effects of dietary T3 might be mediated by the reduction of TG synthesis.
γ-Tocotrienol (γ-T3), a member of the vitamin E family, has been reported to possess an anticancer activity. γ-T3 is a lipophilic compound with low oral bioavailability. Previous studies showed that γ-T3 has low intestinal permeability. Thus, we have hypothesized that enhancing γ-T3 intestinal permeability will increase its oral bioavailability. Solid lipid nanoparticles (SLN) were tested as a model formulation to enhance γ-T3 permeability and bioavailability. γ-T3 intestinal permeability was compared using in situ rat intestinal perfusion, followed by in vivo relative oral bioavailability studies. In addition, in vitro cellular uptake of γ-T3 from SLN was compared to mixed micelles (MM) in a time and concentration-dependent studies. To elucidate the uptake mechanism(s) of γ-T3 from SLN and MM the contribution of NPC1L1 carrier-mediated uptake, endocytosis and passive permeability were investigated. In situ studies demonstrated SLN has tenfold higher permeability than MM. Subsequent in vivo studies showed γ-T3 relative oral bioavailability from SLN is threefold higher. Consistent with in situ results, in vitro concentration dependent studies revealed γ-T3 uptake from SLN was twofold higher than MM. In vitro mechanistic characterization showed that while endocytosis contributes to γ-T3 uptake from both formulations, the reduced contribution of NPC1L1 to the transport of γ-T3, and passive diffusion enhancement of γ-T3 are primary explanations for its enhanced uptake from SLN. In conclusion, SLN successfully enhanced γ-T3 oral bioavailability subsequent to enhanced passive permeability.
Attenuation of NF-κβ mediated apoptotic signaling by tocotrienol ameliorates cognitive deficits in rats postnatally exposed to ethanol
Tiwari V, Arora V, Chopra K.
Neurochem Int. 2012 May 18;61(3):310-320
Ethanol-induced damage in the developing brain may result in cognitive impairment including deficits on neuropsychological tests of learning, memory and executive function, yet the underlying mechanisms remain elusive. In the present study we investigated the protective effect of tocotrienol against cognitive deficit, neuroinflammation and neuronal apoptosis in rat pups postnatally exposed to ethanol. Pups were administered ethanol (5g/kg, 12% v/v) by intragastric intubation on postnatal days 7, 8 and 9. Ethanol-exposed pups showed significant memory impairment in Morris water maze task as evident from increase in escape latency and total distance travelled to reach the hidden platform. Time spent in target quadrant, % total distance traversed in target quadrant and frequency of appearance in target quadrant was also significantly decreased in ethanol exposed pups in probe trial. Poor memory retention was exhibited by ethanol-exposed pups in elevated plus maze test also. Impaired cognition was associated with significantly enhanced acetylcholinesterase activity, increased neuroinflammation (oxidative-nitrosative stress, TNF-α, IL-1β and TGF-β1) and neuronal apoptosis (NF-κβ and Caspase-3) in different brain regions of ethanol-exposed pups. Co-administration with tocotrienol significantly ameliorated all the behavioral, biochemical and molecular alterations in the different brain regions of ethanol exposed pups. The current study thus demonstrates the possible involvement of NF-κβ mediated apoptotic signaling in cognitive deficits associated with postnatal ethanol exposure in rats and points to the potential of tocotrienol in the prevention of cognitive deficits in children with fetal alcohol spectrum disorders (FASDs).
Ima Nirwana Soelaiman
OSTEOPOROSIS is a generalised, degenerative disorder of the skeleton. As a person ages, the bone will lose its density and become thinner and more porous. This will make the bone more susceptible to fractures. There are many causes of osteoporosis, such as lack of the sex hormones oestrogen and testosterone, which occurs as a woman or a man ages, heavy smoking, calcium and vitamin D deficiency, as well as excess of thyroid and steroid hormones.
γ-Tocotrienol attenuates TNF-α-induced changes in secretion and gene expression of MCP-1, IL-6 and adiponectin in 3T3-L1 adipocytes
Matsunaga T, Shoji A, Gu N, Joo E, Li S, Adachi T, Yamazaki H, Yasuda K, Kondoh T, Tsuda K.
Mol Med Report. 2012 Apr;5(4):905-9. Epub 2012 Jan 30.
Tocotrienols, members of the vitamin E family, have been shown to possess anti-inflammatory properties and display activity against a variety of chronic diseases, such as cancer, cardiovascular and neurological diseases. However, whether tocotrienols contribute to the prevention of inflammatory responses in adipose tissue remains to be elucidated. In this study, we examined the effects of γ-tocotrienol, the most commontocotrienol isomer, on tumor necrosis factor-α (TNF-α)-induced inflammatory responses by measuring the expression of the adipokines, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and adiponectin in 3T3-L1 adipocytes. Exposure to TNF-α (10 ng/ml) for 24 h increased MCP-1 and IL-6 secretion, and decreased adiponectin secretion and peroxisome proliferator-activated receptor-γ (PPARγ) mRNA expression. γ-tocotrienoleffectively improved the TNF-α-induced adverse changes in MCP-1, IL-6 and adiponectin secretion, and in MCP-1, IL-6, adiponectin and PPARγ mRNA expression. Furthermore, TNF-α-mediated IκB-α phosphorylation and nuclear factor-κB (NF-κB) activation were significantly suppressed by the γ-tocotrienol treatment. Our results suggest that γ-tocotrienol may improve obesity-related functional abnormalities in adipocytes by attenuating NF-κB activation and the expression of inflammatory adipokines.
The objective of this study was to optimize a novel tocotrienol (TRF)-rich Self Emulsified Drug Delivery System (SEDDS). In the first part, an unusual phenomenon was investigated. It was observed that by sub-stituting Tween® 80 with Cremophor® EL in the SEDDS it was possible to emulsify > 55% TRF (by weight of the formulation) into submicron (<200 nm) emulsion. With Tween®, only 17.5% of the loaded TRF could be emulsified into crude emulsion. The superiority of Cremophor® was attributed to the special arrange-ment of the surfactant at the oil/water interface, which was confirmed by modelling and docking studies. In the second part of this study, the composition of the secondary ingredients in the TRF-rich SEDDS were optimized by the modified Multisimplex® approach. SEDDS were manufactured at pre-defined step-size and tested for their dissolution behavior. Testing was performed sequentially until the optimum compo-sition that can emulsify 50% of the loaded TRF into a stable < 150 nm submicron emulsion was obtained. Optimization end-point was identified when the “membership value” approached 1, which was con-firmed by a second Multisimplex® run. Overall, this study demonstrated the utility of docking studies and the Multisimplex® approach in product development when little is known about the experimental “design space”.
γ-Tocotrienol has attracted much attention owing to its multiple health benefits. This study developed and validated a simple, specific, sensitive and reliable LC/MS/MS method to analyze γ-tocotrienol in rat plasma. Plasma samples (50mL) were extracted with internal standard solution (25 ng/mL of itraconazole) in acetonitrile (200mL) with an average recovery of 44.7% and an average matrix effect of -2.9%. The separation of γ-tocotrienol and internal standard from the plasma components was achieved with a Waters XTerraW MS C18 column with acetonitrile–water as mobile phase. Analysis was performed under positive ionization electrospray mass spectrometer via the multiple reaction monitoring. The standard curve was linear over a concentration range of 10–1000 ng/mL with correlation coefficient values >0.997. The method was validated with intra- and inter-day accuracy (relative error) ranging from 1.79 to 9.17% and from 2.16 to 9.66%, respectively, and precision (coefficient of variation) ranged from 1.94 to 9.25% and from 2.37 to 10.08%, respectively. Short-term stability, freeze–thaw stability and the processed sample stability tests were performed. This method was further applied to analyze γ-tocotrienol plasma concentrations in rats at various time points after administration of a 2 mg/kg single intravenous dose, and a pharmacokinetic profile was successfully obtained.