The amount and types of fatty acids acutely affect insulin, glycemic and gastrointestinal peptide responses but not satiety in metabolic syndrome subjects.

PURPOSE: Limited clinical evidence is available on the effects of amount and types of dietary fats on postprandial insulinemic and gastrointestinal peptide responses in metabolic syndrome subjects. We hypothesized that meals enriched with designated: (1) amount of fats (50 vs 20 g), (2) fats with differing fatty acid composition (saturated, SFA; monounsaturated, MUFA or n-6 polyunsaturated fatty acids, PUFA) would affect insulinemic and gastrointestinal peptide releases in metabolic syndrome subjects. METHODS: Using a randomized, crossover and double-blinded design, 15 men and 15 women with metabolic syndrome consumed high-fat meals enriched with SFA, MUFA or n-6 PUFA, or a low-fat/high-sucrose (SUCR) meal. C-peptide, insulin, glucose, gastrointestinal peptides and satiety were measured up to 6 h. RESULTS: As expected, SUCR meal induced higher C-peptide (45 %), insulin (45 %) and glucose (49 %) responses compared with high-fat meals regardless of types of fatty acids (P < 0.001). Interestingly, incremental area under the curve (AUC0-120min) for glucagon-like peptide-1 was higher after SUCR meal compared with MUFA (27 %) and n-6 PUFA meals (23 %) (P = 0.01). AUC0-120min for glucose-dependent insulinotropic polypeptide was higher after SFA meal compared with MUFA (23 %) and n-6 PUFA meals (20 %) (P = 0.004). Significant meal x time interaction (P = 0.007) was observed for ghrelin, but not cholecystokinin and satiety. CONCLUSIONS: The amount of fat regardless of the types of fatty acids affects insulin and glycemic responses. Both the amount and types of fatty acids acutely affect the gastrointestinal peptide release in metabolic syndrome subjects, but not satiety.

Tumor regression and modulation of gene expression via tumor-targeted tocotrienol niosomes.

AIM: To develop 6-O-palmitoyl-ascorbic acid-based niosomes targeted to transferrin receptor for intravenous administration of tocotrienols (T3) in breast cancer. MATERIALS & METHODS: Niosomes were prepared using film hydration and ultrasonication methods. Transferrin was coupled to the surface of niosomes via chemical linker. Nanovesicles were characterized for size, zeta potential, morphology, stability and biological efficacy. RESULTS: When evaluated in MDA-MB-231 cells, entrapment of T3 in niosomes caused 1.5-fold reduction in IC50 value compared with nonformulated T3. In vivo, the average tumor volume of mice treated with tumor-targeted niosomes was 12-fold lower than that of untreated group, accompanied by marked downregulation of three genes involved in metastasis. CONCLUSION: Findings suggested that tumor-targeted niosomes served as promising delivery system for T3 in cancer therapy.

Effect of palm-based tocotrienols and tocopherol mixture supplementation on platelet aggregation in subjects with metabolic syndrome: a randomised controlled trial.

Tocotrienols, the unsaturated form of vitamin E, were reported to modulate platelet aggregation and thrombotic mechanisms in pre-clinical studies. Using a Food and Drug Administration (FDA)-approved cartridge-based measurement system, a randomised, double-blind, crossover and placebo-controlled trial involving 32 metabolic syndrome adults was conducted to investigate the effect of palm-based tocotrienols and tocopherol (PTT) mixture supplementation on platelet aggregation reactivity. The participants were supplemented with 200 mg (69% tocotrienols and 31% α-tocopherol) twice daily of PTT mixture or placebo capsules for 14 days in a random order. After 14 days, each intervention was accompanied by a postprandial study, in which participants consumed 200 mg PTT mixture or placebo capsule after a meal. Blood samples were collected on day 0, day 14 and during postprandial for the measurement of platelet aggregation reactivity. Subjects went through a 15-day washout period before commencement of subsequent intervention. Fasting platelet aggregation reactivity stimulated with adenosine diphosphate (ADP) did not show substantial changes after supplementation with PTT mixture compared to placebo (p = 0.393). Concomitantly, changes in postprandial platelet aggregation reactivity remained similar between PTT mixture and placebo interventions (p = 0.408). The results of this study highlight the lack of inhibitory effect on platelet aggregation after short-term supplementation of PTT mixture in participants with metabolic syndrome.

Effects of exchanging carbohydrate or monounsaturated fat with saturated fat on inflammatory and thrombogenic responses in subjects with abdominal obesity: A randomized controlled trial.

BACKGROUND & AIMS: Modification of the amount and type of dietary fat has diverse effects on cardiovascular risk. METHODS: We recruited 54 abdominally obese subjects to participate in a prospective cross-over design, single-blind trial comparing isocaloric 2000 kcal MUFA or carbohydrate-enriched diet with SFA-enriched diet (control). The control diet consisted of 15E% protein, 53E% carbohydrate and 32E% fat (12E% SFA, 13E% MUFA). A total of ∼7E% of MUFA or refined carbohydrate was exchanged with SFA in the MUFA-rich and carbohydrate-rich diets respectively for 6-weeks. Blood samples were collected at fasting upon trial commencement and at week-5 and 6 of each dietary-intervention phase to measure levels of cytokines (IL-6, IL-1ß), C-reactive protein (CRP), thrombogenic markers (E-selectin, PAI-1, D-dimer) and lipid subfractions. Radial pulse wave analysis and a 6-h postprandial mixed meal challenge were carried out at week-6 of each dietary intervention. Blood samples were collected at fasting, 15 and 30 min and hourly intervals thereafter till 6 h after a mixed meal challenge (muffin and milkshake) with SFA or MUFA (872.5 kcal, 50 g fat, 88 g carbohydrates) or CARB (881.3 kcal, 20 g fat, 158 g carbohydrates)- enrichment corresponding to the background diets. RESULTS: No significant differences in fasting inflammatory and thrombogenic factors were noted between diets (P > 0.05). CARB meal was found to increase plasma IL-6 whereas MUFA meal elevated plasma D-dimer postprandially compared with SAFA meal (P < 0.05). Comparing the 3 meals, there were similar postprandial elevations in IL-6 and D-dimer and postprandial reductions in PAI-1, augmentation index and pressure (time effect: P < 0.05). CARB diet was found to reduce HDL3 by 7.8% and increase small dense HDL (sdHDL) by 8.6% compared with SFA diet (P < 0.05). SFA diet increased large HDL subfractions compared with both CARB and MUFA diets by 4.9% and 6.6% (P < 0.05), respectively. CONCLUSIONS: Overall, the evidence presented in this study suggests that the replacement of SFA with MUFA or refined carbohydrates may not improve inflammatory and thrombogenic markers in abdominally overweight individuals. Indeed increased refined carbohydrates consumption adversely impacts fasting HDL subfractions. This trial was registered under ClinicalTrials.gov. Identifier no. NCT01665482.

Adverse effects on insulin secretion of replacing saturated fat with refined carbohydrate but not with monounsaturated fat: A randomized controlled trial in centrally obese subjects.

BACKGROUND: Current dietary guidelines recommend the replacement of saturated fatty acids (SAFAs) with carbohydrates or monounsaturated fatty acids (MUFAs) based on evidence on lipid profile alone, the chronic effects of the mentioned replacements on insulin secretion and insulin sensitivity are however unclear. OBJECTIVE: To assess the chronic effects of the substitution of refined carbohydrate or MUFA for SAFA on insulin secretion and insulin sensitivity in centrally obese subjects. METHODS: Using a crossover design, randomized controlled trial in abdominally overweight men and women, we compared the effects of substitution of 7% energy as carbohydrate or MUFA for SAFA for a period of 6 weeks each. Fasting and postprandial blood samples in response to corresponding SAFA, carbohydrate, or MUFA-enriched meal-challenges were collected after 6 weeks on each diet treatment for the assessment of outcomes. RESULTS: As expected, postprandial nonesterified fatty acid suppression and elevation of C-peptide, insulin and glucose secretion were the greatest with high-carbohydrate (CARB) meal. Interestingly, CARB meal attenuated postprandial insulin secretion corrected for glucose response; however, the insulin sensitivity and disposition index were not affected. SAFA and MUFA had similar effects on all markers except for fasting glucose-dependent insulinotropic peptide concentrations, which increased after MUFA but not SAFA when compared with CARB. CONCLUSION: In conclusion, a 6-week lower-fat/higher-carbohydrate (increased by 7% refined carbohydrate) diet may have greater adverse effect on insulin secretion corrected for glucose compared with isocaloric higher-fat diets. In contrast, exchanging MUFA for SAFA at 7% energy had no appreciable adverse impact on insulin secretion.

Tocotrienols induce endoplasmic reticulum stress and apoptosis in cervical cancer cells.

BACKGROUND: We have previously reported that γ- and δ-tocotrienols (γ- and δ-T3) induce gene expression and apoptosis in human breast cancer cells (MDA-MB-231 and MCF-7). This effect is mediated, at least in part, by a specific binding and activation of the estrogen receptor-ß (ERß). Transcriptomic data obtained within our previous studies, interrogated by different bioinformatic tools, suggested the existence of an alternative pathway, activated by specific T3 forms and leading to apoptosis, also in tumor cells not expressing ER. In order to confirm this hypothesis, we conducted a study in HeLa cells, a line of human cervical cancer cells void of any canonical ER form. RESULTS: Cells were synchronized by starvation and treated either with a T3-rich fraction from palm oil (10-20 µg/ml) or with purified α-, γ-, and δ-T3 (5-20 µg/ml). α-tocopherol (TOC) was utilized as a negative control. Apoptosis, accompanied by a significant expression of caspase 8, caspase 10, and caspase 12 was observed at 12 h from treatments. The interrogation of data obtained from transcriptomic platforms (NuGO Affymetrix Human Genechip NuGO_Hs1a520180), further confirmed by RT-PCR, suggested that the administration of γ- and δ-T3 associates with Ca2+ release. Data interrogation were confirmed in living cells; in fact, Ca-dependent signals were observed followed by the expression and activation of IRE-1α and of other molecules involved in the unfolded protein response, the core pathway coping with endoplasmic reticulum stress in eukaryotic cells, finally leading to apoptosis. CONCLUSIONS: Our study demonstrates that γ- and δ-T3 induce apoptosis also in tumor cells lacking of ERß by triggering signals originating from endoplasmic reticulum stress. Our observations suggest that tocotrienols could have a significant role in tumor cell physiology and a possible therapeutic potential.

A new formulation of Gamma Delta Tocotrienol has superior bioavailability compared to existing Tocotrienol-Rich Fraction in healthy human subjects.

Gamma and delta tocotrienols are isomers of Vitamin E with established potency in pre-clinical anti-cancer research. This single-dose, randomized, crossover study aimed to compare the safety and bioavailability of a new formulation of Gamma Delta Tocotrienol (GDT) in comparison with the existing Tocotrienol-rich Fraction (TRF) in terms of gamma and delta isomers in healthy volunteers. Subjects were given either two 300 mg GDT (450 mg γ-T3 and 150 mg δ-T3) capsules or four 200 mg TRF (451.2 mg γ-T3 &102.72 mg δ-T3) capsules and blood samples were taken at several time points over 24 hours. Plasma tocotrienol concentrations were determined using HPLC method. The 90% CI for gamma and delta tocotrienols for the ratio of log-transformation of GDT/TRF for Cmax and AUC0-∞ (values were anti-logged and expressed as a percentage) were beyond the bioequivalence limits (106.21-195.46, 154.11-195.93 and 52.35-99.66, 74.82-89.44 respectively). The Wilcoxon Signed Rank Test for Tmax did not show any significant difference between GDT and TRF for both isomers (p > 0.05). No adverse events were reported during the entire period of study. GDT was found not bioequivalent to TRF, in terms of AUC and Cmax. Gamma tocotrienol in GDT showed superior bioavailability whilst delta tocotrienol showed less bioavailability compared to TRF.

Effects of amount and type of dietary fats on postprandial lipemia and thrombogenic markers in individuals with metabolic syndrome.

OBJECTIVE: Postprandial lipemia has been reported to affect endothelial function by thrombogenic and inflammatory pathways. We set out to investigate the impact of a) specific amount (50 g vs 20 g fat), and b) type of fatty acids (saturated, monounsaturated or n-6 polyunsaturated fatty acids; SFA, MUFA, PUFA) on postprandial lipemia, thrombogenic and inflammatory factors in metabolic syndrome subjects. DESIGN: 30 subjects (15 men, 15 women) participated in a double-blind, randomized crossover design study with both the subjects and investigators blinded to treatments. Blood samples were collected at fasting and 30 min, hourly interval for a total of 6 h. RESULTS: As expected, lower triacylglycerol response was observed for low fat/high carbohydrate meal; whereas no difference was detected between the types of fatty acids. The incremental area under the curve (iAUC) for low fat/high carbohydrate meal was 70%, 81% and 61% lower than the SFA, MUFA and PUFA meals, respectively. The iAUC 0-6 h for triacylglycerol was 42% lower in women compared with the men (P = 0.024), with the similar trend observed for non-esterified fatty acids. There were significant meal × time interaction (P = 0.000) for plasma plasminogen activator inhibitor-1 and thromboxane B2 (P = 0.022) from baseline. No differences were observed between meals for plasma D-dimer, interleukin-6, interleukin-1ß, tumor necrosis factor-α and high sensitivity C-reactive protein. CONCLUSION: These data indicate that in metabolic syndrome subjects, only the amount of dietary fatty acids affects postprandial lipemia but both amount and type of dietary fats alter thrombogenic factors. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov (NCT01571947).

Supplementation with red palm oil increases ß-carotene and vitamin A blood levels in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) show decreased plasma concentrations of antioxidants due to malabsorption of lipid soluble vitamins and consumption by chronic pulmonary inflammation. ß-Carotene is a major source of retinol and therefore is of particular significance in CF. The aim of this study was to investigate the effect of daily intake of red palm oil (RPO) containing high amounts of ß-carotene on the antioxidant levels in CF patients. Sixteen subjects were recruited and instructed to enrich their food with 2 to 3 tablespoons of RPO (~1.5 mg of ß-carotene) daily over 8 weeks. Carotenoids, retinol, and α-tocopherol were measured in plasma at baseline and after intervention. In addition ß-carotene, lycopene, α-tocopherol, and vitamin C were measured in buccal mucosa cells (BMC) to determine the influence of RPO on antioxidant tissue levels. Eleven subjects completed the study properly. Plasma ß-carotene, retinol, and α-carotene of these patients increased, but plasma concentrations of other carotenoids and α-tocopherol as well as concentrations of ß-carotene, lycopene, α-tocopherol, and vitamin C in BMC remained unchanged. Since RPO on a daily basis did not show negative side effects the data suggest that RPO may be used to elevate plasma ß-carotene in CF.

Modulation of obesity-induced inflammation by dietary fats: mechanisms and clinical evidence.

Obesity plays a pivotal role in the development of low-grade inflammation. Dietary fatty acids are important modulators of inflammatory responses. Saturated fatty acids (SFA) and n-6 polyunsaturated fatty acids (PUFA) have been reported to exert pro-inflammatory effects. n-3 PUFA in particular, possess anti-inflammatory properties. Numerous clinical studies have been conducted over decades to investigate the impact of dietary fatty acids on inflammatory response in obese individuals, however the findings remained uncertain. High fat meals have been reported to increase pro-inflammatory responses, however there is limited evidence to support the role of individual dietary fatty acids in a postprandial state. Evidence in chronic studies is contradictory, the effects of individual dietary fatty acids deserves further attention. Weight loss rather than n-3 PUFA supplementation may play a more prominent role in alleviating low grade inflammation. In this context, the present review provides an update on the mechanistic insight and the influence of dietary fats on low grade inflammation, based on clinical evidence from acute and chronic clinical studies in obese and overweight individuals.

Research advancements in palm oil nutrition.

Palm oil is the major oil produced, with annual world production in excess of 50 million tonnes. About 85% of global palm oil produced is used in food applications. Over the past three decades, research on nutritional benefits of palm oil have demonstrated the nutritional adequacy of palm oil and its products, and have resulted in transitions in the understanding these attributes. Numerous studies have demonstrated that palm oil was similar to unsaturated oils with regards to effects on blood lipids. Palm oil provides a healthy alternative to trans-fatty acid containing hydrogenated fats that have been demonstrated to have serious deleterious effects on health. The similar effects of palm oil on blood lipids, comparable to other vegetable oils could very well be due to the structure of the major triglycerides in palm oil, which has an unsaturated fatty acid in the stereospecific numbers (sn)-2 position of the glycerol backbone. In addition, palm oil is well endowed with a bouquet of phytonutrients beneficial to health, such as tocotrienols, carotenoids, and phytosterols. This review will provide an overview of studies that have established palm oil as a balanced and nutritious oil.

Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer.

Tocotrienol-rich fraction (TRF) from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC)-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL) from 4T1 cells (DC+TL) once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF) inhibited (p<0.05) tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC)-treated 4T1 cells produced higher (p<0.05) levels of IFN-γ and IL-12. The cytotoxic T-lymphocyte (CTL) assay also showed enhanced tumor-specific killing (p<0.05) by CD8(+) T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines.

Supplementation with natural forms of vitamin E augments antigen-specific TH1-type immune response to tetanus toxoid.

This study compared the ability of three forms of vitamin E [tocotrienol-rich fraction (TRF), alpha-tocopherol (α-T), and delta-tocotrienol (δ-T3)] to enhance immune response to tetanus toxoid (TT) immunisation in a mouse model. Twenty BALB/c mice were divided into four groups of five mice each. The mice were fed with the different forms of vitamin E (1 mg) or vehicle daily for two weeks before they were given the TT vaccine [4 Lf] intramuscularly (i.m.). Booster vaccinations were given on days 28 and 42. Serum was collected (days 0, 28, and 56) to quantify anti-TT levels. At autopsy, splenocytes harvested were cultured with TT or mitogens. The production of anti-TT antibodies was augmented (P < 0.05) in mice that were fed with δ-T3 or TRF compared to controls. The production of IFN-γ and IL-4 by splenocytes from the vitamin E treated mice was significantly (P < 0.05) higher than that from controls. The IFN-γ production was the highest in animals supplemented with δ-T3 followed by TRF and finally α-T. Production of TNF-α was suppressed in the vitamin E treated group compared to vehicle-supplemented controls. Supplementation with δ-T3 or TRF can enhance immune response to TT immunisation and production of cytokines that promote cell-mediated (TH1) immune response.

The effects of prenatal and early postnatal tocotrienol-rich fraction supplementation on cognitive function development in male offspring rats.

BACKGROUND: Recent findings suggest that the intake of specific nutrients during the critical period in early life influence cognitive and behavioural development profoundly. Antioxidants such as vitamin E have been postulated to be pivotal in this process, as vitamin E is able to protect the growing brain from oxidative stress. Currently tocotrienols are gaining much attention due to their potent antioxidant and neuroprotective properties. It is thus compelling to look at the effects of prenatal and early postnatal tocotrienols supplementation, on cognition and behavioural development among offsprings of individual supplemented with tocotrienols. Therefore, this study is aimed to investigate potential prenatal and early postnatal influence of Tocotrienol-Rich Fraction (TRF) supplementation on cognitive function development in male offspring rats. Eight-week-old adult female Sprague Dawley (SD) rats were randomly assigned into five groups of two animals each. The animals were fed either with the base diet as control (CTRL), base diet plus vehicle (VHCL), base diet plus docosahexanoic acid (DHA), base diet plus Tocotrienol-Rich fraction (TRF), and base diet plus both docosahexaenoic acid, and tocotrienol rich fraction (DTRF) diets for 2 weeks prior to mating. The females (F0 generation) were maintained on their respective treatment diets throughout the gestation and lactation periods. Pups (F1 generation) derived from these dams were raised with their dams from birth till four weeks post natal. The male pups were weaned at 8 weeks postnatal, after which they were grouped into five groups of 10 animals each, and fed with the same diets as their dams for another eight weeks. Learning and behavioural experiments were conducted only in male off-spring rats using the Morris water maze. Eight-week-old adult female Sprague Dawley (SD) rats were randomly assigned into five groups of two animals each. The animals were fed either with the base diet as control (CTRL), base diet plus vehicle (VHCL), base diet plus docosahexanoic acid (DHA), base diet plus Tocotrienol-Rich fraction (TRF), and base diet plus both docosahexaenoic acid, and tocotrienol rich fraction (DTRF) diets for 2 weeks prior to mating. The females (F0 generation) were maintained on their respective treatment diets throughout the gestation and lactation periods. Pups (F1 generation) derived from these dams were raised with their dams from birth till four weeks post natal. The male pups were weaned at 8 weeks postnatal, after which they were grouped into five groups of 10 animals each, and fed with the same diets as their dams for another eight weeks. Learning and behavioural experiments were conducted only in male off-spring rats using the Morris water maze. RESULTS: Results showed that prenatal and postnatal TRF supplementation increased the brain (4-6 fold increase) and plasma α-tocotrienol (0.8 fold increase) levels in male off-springs. There is also notably better cognitive performance based on the Morris water maze test among these male off-springs. CONCLUSION: Based on these results, it is concluded that prenatal and postnatal TRF supplementation improved cognitive function development in male progeny rats.

Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients.

The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP) and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg α-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1-96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. α-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans.

Tocotrienols and breast cancer: the evidence to date.

Breast cancer is the second most frequent cancer affecting women worldwide after lung cancer. The toxicity factor associated with synthetic drugs has turned the attention toward natural compounds as the primary focus of interest as anticancer agents. Vitamin E derivatives consisting of the well-established tocopherols and their analogs namely tocotrienols have been extensively studied due to their remarkable biological properties. While tocopherols have failed to offer protection, tocotrienols, in particular, α-, δ-, and γ-tocotrienols alone and in combination have demonstrated anticancer properties. The discovery of the antiangiogenic, antiproliferative, and apoptotic effects of tocotrienols, as well as their role as an inducer of immunological functions, not only reveals a new horizon as a potent antitumor agent but also reinforces the notion that tocotrienols are indeed more than antioxidants. On the basis of a transcriptomic platform, we have recently demonstrated a novel mechanism for tocotrienol activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicate a high affinity of specific forms of tocotrienols for ERß, but not for ERα. Moreover, we have demonstrated that specific tocotrienols increase ERß translocation into the nucleus which, in turn, activates the expression of estrogen-responsive genes (MIC-1, EGR-1 and Cathepsin D) in breast cancer cells only expressing ERß cells (MDA-MB-231) and in cells expressing both ER isoforms (MCF-7). The binding of specific tocotrienol forms to ERß is associated with the alteration of cell morphology, caspase-3 activation, DNA fragmentation, and apoptosis. Furthermore, a recently concluded clinical trial seems to suggest that tocotrienols in combination with tamoxifen may have the potential to extend breast cancer-specific survival.

Palm tocotrienols decrease levels of pro-angiogenic markers in human umbilical vein endothelial cells (HUVEC) and murine mammary cancer cells.

Anti-angiogenic therapy is widely being used to halt tumour angiogenesis. In this study, the anti-angiogenic activity of palm tocotrienol-rich fraction (TRF) and its individual components (γ- and δ-tocotrienol) were first investigated in vitro in human umbilical vein endothelial cells (HUVEC) and 4T1 mouse mammary cancer cells. Results showed reduced levels of Interkeukin (IL)-8 and IL-6, two pro-angiogenic cytokines in HUVEC treated with palm tocotrienols compared with α-tocopherol (α-T) and control cells (P < 0.05). The production of IL-8 and IL-6 was lowest in δ-tocotrienol (δ-T3)-treated cells followed by γ-tocotrienol (γ-T3) and TRF. There was significant (P < 0.05) reduction in IL-8 and vascular endothelial growth factor (VEGF) production in 4T1 cells treated with TRF or δ-T3. There was decreased expression of VEGF and its receptors; VEGF-R1 (fms-like tyrosine kinase, Flt-1) and VEGF-R2 (Kinase-insert-domain-containing receptor, KDR/Flk-2) in tumour tissues excised from mice supplemented with TRF were observed. There was also decreased expression of VEGF-R2 in lung tissues of mice supplemented with TRF. These observations correlate with the smaller tumour size recorded in the tocotrienol-treated mice. This study confirms previous observations that palm tocotrienols exhibit anti-angiogenic properties that may inhibit tumour progression.

Diets high in palmitic acid (16:0), lauric and myristic acids (12:0 + 14:0), or oleic acid (18:1) do not alter postprandial or fasting plasma homocysteine and inflammatory markers in healthy Malaysian adults.

BACKGROUND: Dietary fat type is known to modulate the plasma lipid profile, but its effects on plasma homocysteine and inflammatory markers are unclear. OBJECTIVE: We investigated the effects of high-protein Malaysian diets prepared with palm olein, coconut oil (CO), or virgin olive oil on plasma homocysteine and selected markers of inflammation and cardiovascular disease (CVD) in healthy adults. DESIGN: A randomized-crossover intervention with 3 dietary sequences of 5 wk each was conducted in 45 healthy subjects. The 3 test fats, namely palmitic acid (16:0)-rich palm olein (PO), lauric and myristic acid (12:0 + 14:0)-rich CO, and oleic acid (18:1)-rich virgin olive oil (OO), were incorporated at two-thirds of 30% fat calories into high-protein Malaysian diets. RESULTS: No significant differences were observed in the effects of the 3 diets on plasma total homocysteine (tHcy) and the inflammatory markers TNF-α, IL-1ß, IL-6, and IL-8, high-sensitivity C-reactive protein, and interferon-γ. Diets prepared with PO and OO had comparable nonhypercholesterolemic effects; the postprandial total cholesterol for both diets and all fasting lipid indexes for the OO diet were significantly lower (P < 0.05) than for the CO diet. Unlike the PO and OO diets, the CO diet was shown to decrease postprandial lipoprotein(a). CONCLUSION: Diets that were rich in saturated fatty acids prepared with either PO or CO, and an OO diet that was high in oleic acid, did not alter postprandial or fasting plasma concentrations of tHcy and selected inflammatory markers. This trial was registered at clinicaltrials.gov as NCT00941837.

Tocotrienols: inflammation and cancer.

Inflammation is an organism's response to environmental assaults. It can be classified as acute inflammation that leads to therapeutic recovery or chronic inflammation, which may lead to the development of cancer and other ailments. Genetic changes that occur within cancer cells themselves are responsible for many aspects of cancer development but are dependent on ancillary processes for tumor promotion and progression. Inflammation has long been associated with the development of cancer. The distinct characteristics of cancer cells to proliferate, metastasize, evade apoptotic signals, and develop chemoresistance have been linked to the inflammatory response. Due to the involvement of multiple genes and various pathways, current drugs that target single genes have not been effective in providing a therapeutic cure. On the other hand, natural products target multiple genes and therefore have better success compared to drugs. Tocotrienols, the potent isoforms of vitamin E, are such a natural product. This review will discuss the relationship between cancer and inflammation with particular focus on the roles played by NF-κB, STAT3, and COX-2.