Red palm oil: Nutritional, physiological and therapeutic roles in improving human wellbeing and quality of life

Oguntibeju OO, Esterhuyse AJ, Truter EJ.

Br J Biomed Sci. 2009;66(4):216-22.

The link between dietary fats and cardiovascular disease has created a growing interest in dietary red palm oil research. Also, the link between nutrition and health, oxidative stress and the severity or progression of disease has stimulated further interest in the potential role of red palm oil (a natural antioxidant product) to improve oxidative status by reducing oxidative stress in patients with cardiovascular disease, cancer and other chronic diseases. In spite of its level of saturated fatty acid content (50%), red palm oil has not been found to promote atherosclerosis and/or arterial thrombosis. This is probably due to the ratio of its saturated fatty acid to unsaturated fatty acid content and its high concentration of antioxidants such as beta-carotene, tocotrienols, tocopherols and vitamin E. It has also been reported that the consumption of red palm oil reduces the level of endogenous cholesterol, and this seems to be due to the presence of the tocotrienols and the peculiar isomeric position of its fatty acids. The benefits of red palm oil to health include a reduction in the risk of arterial thrombosis and/or atherosclerosis, inhibition of endogenous cholesterol biosynthesis, platelet aggregation, a reduction in oxidative stress and a reduction in blood pressure. It has also been shown that dietary red palm oil, taken in moderation in animals and humans, promotes the efficient utilisation of nutrients, activates hepatic drug metabolising enzymes, facilitates the haemoglobinisation of red blood cells and improves immune function. This review provides a comprehensive overview of the nutritional, physiological and biochemical roles of red palm oil in improving wellbeing and quality of life.

Induction of caspase-independent programmed cell death by vitamin E natural homologs and synthetic derivatives

Constantinou C, Hyatt JA, Vraka PS, Papas A, Papas KA, Neophytou C, Hadjivassiliou V, Constantinou AI.

Nutr Cancer. 2009;61(6):864-74.

Current observations in the literature suggest that vitamin E may be a suitable candidate for cancer chemotherapy. To investigate this further, we examined the ability of the vitamin E natural homologs [alpha-, beta-, gamma-, delta-tocopherols (alpha-TOC, beta-TOC, gamma-TOC, delta-TOC) and alpha-, beta-, gamma-, delta-tocotrienols (alpha-TT, beta-TT, gamma-TT, delta-TT)] and their corresponding succinate synthetic derivatives [alpha-, beta-, gamma-, delta-tocopheryl succinates and alpha-, beta-, gamma-, delta-tocotrienyl succinates (alpha-TS, beta-TS, gamma-TS, delta-TS)] to induce cell death in AR- (DU145 and PC3) and AR+ (LNCaP) prostate cancer cell lines. The most effective of all the natural homologs of vitamin E was determined to be delta-TT, whereas delta-TS was the most potent of all the natural and synthetic compounds of vitamin E examined. Both gamma-TT and delta-TT induced caspase activity selectively in AR+ LNCaP cells, suggesting a possible role for AR for the activation of caspase-dependent programmed cell death (CD-PCD). More important, however, gamma-TT, delta-TT, gamma-TS, and delta-TS activated dominant caspase-independent programmed cell death (CI-PCD) in all prostate cancer cell lines examined. Thus, vitamin E homologs and synthetic derivatives may find applications in the treatment of prostate tumors that are resistant to caspase-activating therapeutic agents.

Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells

Wali VB, Bachawal SV, Sylvester PW.

Apoptosis. 2009 Nov;14(11):1366-77.

Gamma-Tocotrienol, a member of the vitamin E family of compounds, induces apoptosis in a variety of cancer cell types. However, previous studies have clearly demonstrated that gamma-tocotrienol-induced apoptosis in neoplastic mouse +SA mammary epithelial cells is not mediated through mitochondrial stress or death receptor apoptotic signaling. Therefore, studies were conducted to determine the role of endoplasmic reticulum (ER) stress in mediating gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells. Treatment with 15-40 microM gamma-tocotrienol induced +SA cell death in a dose-responsive manner, and these effects were associated with a corresponding increase in poly (ADP-ribose) polymerase (PARP)-cleavage and activation of protein kinase-like endoplasmic reticulum kinase/eukaryotic translational initiation factor/activating transcription factor 4 (PERK/eIF2alpha/ATF-4) pathway, a marker of ER stress response. These treatments also caused a large increase in C/EBP homologous protein (CHOP) levels, a key component of ER stress mediated apoptosis that increases expression of tribbles 3 (TRB3). Knockdown of CHOP by specific siRNAs attenuated gamma-tocotrienol-induced PARP-cleavage, CHOP and TRB3 expression. gamma-Tocotrienol treatment also reduced full-length caspase-12 levels, an indication of caspase-12 cleavage and activation. Intracellular levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase, an ER-transmembrane enzyme catalyzing the synthesis of mevalonate, decreased following gamma-tocotrienol treatment, but combined treatment with mevalonate did not reverse gamma-tocotrienol-induced apoptosis, suggesting that a decrease in HMGCoA reductase activity is not required for gamma-tocotrienol induced apoptosis. These results demonstrate that ER stress apoptotic signaling is associated with gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells.

Suppression of neuro-inflammatory signaling cascade by tocotrienol can prevent chronic alcohol-induced cognitive dysfunction in rats

Tiwari V, Kuhad A, Chopra K.

Behav Brain Res. 2009 Nov 5;203(2):296-303.

Chronic alcohol intake is known to induce the selective neuronal damage associated with increase oxidative-nitrosative stress and activation of inflammatory cascade finally resulting in neuronal apoptosis and thus dementia. In the present study, we investigated the comparative effect of both the isoforms of vitamin E, alpha-tocopherol and tocotrienol against chronic alcohol-induced cognitive dysfunction in rats. Male Wistar rats were given ethanol (10g/kg; oral gavage) for 10 weeks, and treated with alpha-tocopherol and tocotrienol for the same duration. The learning and memory behavior was assessed using Morris water maze and elevated plus maze test. The rats were sacrificed at the end of 10th week and cytoplasmic fractions of cerebral cortex and hippocampus were prepared for the quantification of acetylcholinesterase activity, oxidative-nitrosative stress parameters, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). From the 6th week onwards, ethanol-treated rats showed significant increase in transfer latency in both the behavioral paradigms which was coupled with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, TNF-alpha and IL-1beta levels in different brain regions of ethanol-treated rats. Co-administration of alpha-tocopherol as well as tocotrienol significantly and dose-dependently prevented these behavioral, biochemical and molecular changes in the brains of ethanol-treated rats. However, the effects were more pronounced with tocotrienol. The current study thus demonstrates the possible involvement of oxidative-nitrosative stress mediated activation of inflammatory cascade in chronic alcohol-induced cognitive dysfunction and also suggests the effectiveness of vitamin E isoforms, of which tocotrienol being more potent, in preventing the cognitive deficits associated with chronic alcohol consumption.

Suppression in mevalonate synthesis mediates antitumor effects of combined statin and gamma-tocotrienol treatment

Wali VB, Bachawal SV, Sylvester PW.

Lipids. 2009 Oct;44(10):925-34. Epub 2009 Sep 24.

Statins directly inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity, while gamma-tocotrienol, an isoform of vitamin E, enhances the degradation and reduces cellular levels of HMGR in various tumor cell lines. Since treatment with statins or gamma-tocotrienol alone induced a dose-responsive inhibition, whereas combined treatment with subeffective doses of these agents resulted in a synergistic inhibition in +SA mammary tumor cell growth, studies were conducted to investigate the role of the HMGR pathway in mediating the antiproliferative effects of combined low dose statin and gamma-tocotrienol. Treatment with 8 microM simvastatin inhibited cell growth and isoprenylation of Rap1A and Rab6, and supplementation with 2 microM mevalonate reversed these effects. However, the growth inhibitory effects of 4 microM gamma-tocotrienol were not dependent upon suppression in mevalonate synthesis. Treatment with subeffective doses of simvastatin (0.25 microM), lovastatin (0.25 microM), mevastatin (0.25 microM), pravastatin (10 microM), or gamma-tocotrienol (2 muM) alone had no effect on protein prenylation or mitogenic signaling, whereas combined treatment with these agents resulted in a significant inhibition in +SA cell growth, and a corresponding decrease in total HMGR, Rap1A and Rab6 prenylation, and MAPK signaling, and mevalonate supplementation reversed these effects. These findings demonstrate that the synergistic antiproliferative effects of combined low dose statin and gamma-tocotrienol treatment are directly related to an inhibition in HMGR activity and subsequent suppression in mevalonate synthesis.

Tocotrienol ameliorates behavioral and biochemical alterations in the rat model of alcoholic neuropathy

Tiwari V, Kuhad A, Chopra K. Source

Pain. 2009 Sep;145(1-2):129-35. Epub 2009 Jun 21

Chronic alcohol consumption produces a painful peripheral neuropathy for which there is no reliable successful therapy, which is mainly due to lack of understanding of its pathobiology. Alcoholic neuropathy is characterized by spontaneous burning pain, hyperalgesia (an exaggerated pain in response to painful stimuli) and allodynia (a pain evoked by normally innocuous stimuli). Chronic alcohol intake is known to decrease the nociceptive threshold with increased oxidative-nitrosative stress and release of proinflammatory cytokines coupled with activation of protein kinase C. The aim of the present study is to investigate the effect of both isoforms of vitamin E, alpha-tocopherol (100mg/kg; oral gavage) and tocotrienol (50, 100 and 200mg/kg; oral gavage) against alcohol-induced neuropathic pain in rats. Male Wistar rats, were administered 35% v/v ethanol (10 g/kg; oral gavage) for 10 weeks, and were treated with alpha-tocopherol and tocotrienol for the same duration. Ethanol-treated animals showed a significant decrease in nociceptive threshold as evident from decreased tail flick latency (thermal hyperalgesia) and decreased paw-withdrawal threshold in Randall-Sellito test (mechanical hyperalgesia) and von-Frey hair test (mechanical allodynia) along with the reduction in nerve glutathione and superoxide dismutase levels. TNF-alpha and IL-1beta levels were also significantly increased in both serum and sciatic nerve of ethanol-treated rats. Treatment with alpha-tocopherol and tocotrienol for 10 weeks significantly improved all the above-stated functional and biochemical deficits in a dose-dependent manner with more potent effects observed with tocotrienol. The study demonstrates the effectiveness of tocotrienol in attenuation of alcoholic neuropathy.

Tocotrienols suppress proinflammatory markers and cyclooxygenase-2 expression in RAW264.7 macrophages

Yam ML, Abdul Hafid SR, Cheng HM, Nesaretnam K.

Lipids. 2009 Sep;44(9):787-97. Epub 2009 Aug 5.

Tocotrienols are powerful chain breaking antioxidant. Moreover, they are now known to exhibit various non-antioxidant properties such as anti-cancer, neuroprotective and hypocholesterolemic functions. This study was undertaken to investigate the anti-inflammatory effects of tocotrienol-rich fraction (TRF) and individual tocotrienol isoforms namely delta-, gamma-, and alpha-tocotrienol on lipopolysaccharide-stimulated RAW264.7 macrophages. The widely studied vitamin E form, alpha-tocopherol, was used as comparison. Stimulation of RAW264.7 with lipopolysaccharide induced the release of various inflammatory markers. 10 mcirog/ml of TRF and all tocotrienol isoforms significantly inhibited the production of interleukin-6 and nitric oxide. However, only alpha-tocotrienol demonstrated a significant effect in lowering tumor necrosis factor-alpha production. Besides, TRF and all tocotrienol isoforms except gamma-tocotrienol reduced prostaglandin E(2) release. It was accompanied by the down-regulation of cyclooxygenase-2 gene expression by all vitamin E forms except alpha-tocopherol. Collectively, the data suggested that tocotrienols are better anti-inflammatory agents than alpha-tocopherol and the most effective form is delta-tocotrienol.

Chronic treatment with tocotrienol, an isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative-nitrosative stress in rats

Tiwari V, Kuhad A, Bishnoi M, Chopra K.

Pharmacol Biochem Behav. 2009 Aug;93(2):183-9. Epub 2009 May 21.

Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, which is associated with increased oxidative stress in the brain of rats. In the present study, we investigated the effect of both the isoforms of vitamin E, alpha-tocopherol and tocotrienol against ICV STZ-induced cognitive impairment and oxidative-nitrosative stress in rats. Adult male Wistar rats were injected with ICV STZ (3 mg/kg) bilaterally. The learning and memory behavior was assessed using Morris water maze and elevated plus maze. The rats were sacrificed on day 21 and parameters of oxidative stress, nitrite levels and acetylcholinesterase activity were measured in brain homogenate. alpha-Tocopherol as well astocotrienol treated groups showed significantly less cognitive impairment in both the behavioral paradigms but the effect was more potent withtocotrienol. Both isoforms of vitamin E effectively attenuated the reduction in glutathione and catalase and reduced the malonaldehyde, nitrite as well as cholinesterase activity in the brains of ICV STZ rats in a dose dependent manner. The study demonstrates the effectiveness of vitamin E isoforms, of which tocotrienol being more potent in preventing the cognitive deficits caused by ICV STZ in rats and suggests its potential in the treatment of neurodegenerative diseases such as Alzheimer’s disease.

A novel mechanism of natural vitamin E tocotrienol activity: Involvement of ERbeta signal transduction

Comitato R, Nesaretnam K, Leoni G, Ambra R, Canali R, Bolli A, Marino M, Virgili F.

Am J Physiol Endocrinol Metab. 2009 Aug;297(2):E427-37.

Vitamin E is a generic term used to indicate all tocopherol (TOC) and tocotrienol (TT) derivates. In the last few years, several papers have shown that a TT-rich fraction (TTRF) extracted from palm oil inhibits proliferation and induces apoptosis in a large number of cancer cells. However, the molecular mechanism(s) involved in TT action is still unclear. In the present study, we proposed for the first time a novel mechanism for TT activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicated a high affinity of TTs for ERbeta but not for ERalpha. In addition, in ERbeta-containing MDA-MB-231 breast cancer cells, we demonstrated that TTs increase the ERbeta translocation into the nucleus, which in turn activates estrogen-responsive genes (MIC-1, EGR-1 and cathepsin D), as demonstrated by cell preincubation with the ER inhibitor ICI-182,780. Finally, we observed that TT treatment is associated with alteration of cell morphology, DNA fragmentation, and caspase-3 activation. Altogether, these experiments elucidated the molecular mechanism underling gamma- and delta-TT effects.

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A rice bran oil diet improves lipid abnormalities and suppress hyperinsulinemic responses in rats with streptozotocin/nicotinamide-induced type 2 diabetes

Chou TW, Ma CY, Cheng HH, Chen YY, Lai MH.

J Clin Biochem Nutr. 2009 Jul;45(1):29-36. Epub 2009 Jun 30.

The aim of this study was to determine the effects of rice bran oil (RBO) on lipid metabolism and insulin resistance in rats with streptozotocin/nicotinamide-induced type 2 diabetes mellitus (T2DM). Rats were divided into two groups: the control group (15% soybean oil, contains 0 g gamma-oryzanol and 0 g gamma-tocotrienol/150 g oil for 5 weeks) and the RBO group (15% RBO, contains 5.25 g gamma-oryzanol and 0.9 g gamma-tocotrienol/150 g oil for 5 weeks). Compared with the control group, the RBO group had a lower plasma nonesterified fatty acid concentration, ratio of total to high-density-lipoprotein cholesterol, hepatic cholesterol concentration, and area under the curve for insulin. The RBO group had a higher high-density-lipoprotein cholesterol concentration and greater excretion of fecal neutral sterols and bile acid than did the control group. RBO may improve lipid abnormalities, reduce the atherogenic index, and suppress the hyperinsulinemic response in rats with streptozotocin/nicotinamide-induced T2DM. In addition, RBO can lead to increased fecal neutral sterol and bile acid excretion.

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