Blog Archives

Estrogen receptor-mediated effect of δ-tocotrienol prevents neurotoxicity and motor deficit in the MPTP mouse model of Parkinson’s disease.

Nakaso K, Horikoshi Y, Takahashi T, Hanaki T, Nakasone M, Kitagawa Y, Koike T, Matsura T.

Neurosci Lett. 2016 Jan 1;610:117-22.

Abstract

Neuroprotection following signal transduction has been investigated recently as a strategy for Parkinson’s disease (PD) therapy. While oxidative stress is important in the pathogenesis of PD, neuroprotection using antioxidants such as α-tocopherol have not been successful. δ-tocotrienol(δT3), a member of the vitamin E family, has received attention because of activities other than its antioxidative effects. In the present study, we examined the estrogen receptor-β (ERβ)-mediated neuroprotective effects of δT3 in a mouse model of PD. ERβ is expressed in neuronal cells, including dopaminergic neurons in the substantia nigra. Daily forced oral administration of δT3 inhibited the loss of dopaminergic neurons in the substantia nigra. In addition, the ER inhibitor tamoxifen canceled the neuroprotective effects of δT3. Moreover, δT3 administration improved the performance of the PD mice in the wheel running activity, while tamoxifen inhibited this improved performance. These results suggest that the oral administration of δT3 may be useful in the treatment of PD patients, and ERβ may be a candidate target for the neuroprotection activity of δT3.

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Vitamin E derivatives: a patent review (2010 – 2015).

Koufaki M.

Expert Opin Ther Pat. 2015 Oct 29:1-13

Abstract

INTRODUCTION:

The vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol is the most studied member of this family for its antioxidant and non-antioxidant properties, while tocotrienols have attracted recent research interest. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets. Areas covered: This review includes the patent literature from 2010 – 2015 related to vitamin E derivatives and it is focused on 2-, 5- or 6-substituted chroman analogues. The patent search was performed using Reaxys® and esp@cenet. Expert opinion: The chroman moiety of vitamin E is a privileged structure and an essential pharmacophore which inspired organic chemists to synthesize new analogues with improved bioactivities. Modifications at the 2- and 5- positions of the chroman ring resulted in very interesting active compounds in cellular and animal models of diseases related to oxidative stress. More recent publications and patents reported 6-substituted chromans as anticancer agents in vitro and in vivo. Additionally, an emerging interest is observed towards the use of vitamin E analogues incorporated in drug delivery systems and for medical imaging as contrast agents or fluorescent probes.

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Antiproliferative effects of γ-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells.

Alawin OA, Ahmed RA, Ibrahim BA, Briski KP, Sylvester PW.

J Nutr Biochem. 2016 Jan;27:266-77.

Abstract

A large percentage of human breast cancers are characterized by excessive or aberrant HER2 activity. Lipid rafts are specialized microdomains within the plasma membrane that are required for HER2 activation and signal transduction. Since the anticancer activity of γ-tocotrienol is associated with suppression in HER2 signaling, studies were conducted to examine the effects of γ-tocotrienol on HER2 activation within the lipid raft microdomain in HER2-positive SKBR3 and BT474 human breast cancer cells. Treatment with 0-5μM γ-tocotrienol induced a significant dose-dependent inhibition in cancer cell growth after a 5-day culture period, and these growth inhibitory effects were associated with a reduction in HER2 dimerization and phosphorylation (activation). Phosphorylated HER2 was found to be primarily located in the lipid raft microdomain of the plasma membrane in vehicle-treated control groups, whereas γ-tocotrienol treatment significantly inhibited this effect. Assay of plasma membrane subcellular fractions showed that γ-tocotrienol also accumulates exclusively within the lipid raft microdomain. Hydroxypropyl-β-cyclodextrin (HPβCD) is an agent that disrupts lipid raft integrity. Acute exposure to 3mM HPβCD alone had no effect, whereas an acute 24-h exposure to 20μM γ-tocotrienol alone significantly decreased SKBR3 and BT474 cell viability. However, combined treatment with these agents greatly reduced γ-tocotrienol accumulation in the lipid raft microdomain and cytotoxicity. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are associated with its accumulation in the lipid raft microdomain and subsequent interference with HER2 dimerization and activation in SKBR3 and BT474 human breast cancer cells.

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The Effects of Targeted Deliveries of Lovastatin and Tocotrienol on Ossification-Related Gene Expressions in Fracture Healing in an Osteoporosis Rat Model.

Ibrahim N, Mohamed N, Soelaiman IN, Shuid AN.

Int J Environ Res Public Health. 2015 Oct 16;12(10):12958-76

Abstract

Osteoporotic drugs are used to prevent fragility fractures, but their role in fracture healing still remains unknown. Thus, alternative agents with suitable mode of delivery are needed to promote fracture healing. This study was performed to investigate the effects of direct deliveries of lovastatin and tocotrienol to fracture sites on ossification-related gene expression in fracture healing in a postmenopausal osteoporosis model. Forty-eight Sprague Dawley female rats were divided into six groups. Group I comprised the sham-operated rats, while Groups II-VI were ovariectomized rats. After 8 weeks, the right tibiae of all rats were fractured and stabilized. Group I and Group II were given two single injections of lovastatin andtocotrienol carriers. Group III was given an estrogen preparation at 64.5 µg/kg daily via oral gavages. Group IV was injected with lovastatin particles (750 µg/kg), while Group V was injected with tocotrienol particles (60 mg/kg). Group VI received two single injections of 750 µg/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks, the gene expressions were measured. Group VI showed significantly higher gene expressions of osteocalcin, BMP-2, VEGF-α, and RUNX-2 compared to Group II. In conclusion, combined treatment of lovastatin and tocotrienol upregulated the expression of genes related to fracture healing.

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This Vitamin Can Save Your Brain

vitamin-repair-brain-damage

Your brain has amazing abilities. And it can heal itself.

That’s not something you’re likely to hear from mainstream medicine — especially if you or a loved one suffer from the effects of stroke, Alzheimer’s, Parkinson’s or another form of dementia.

Here at the Sears Institute for Anti-Aging Medicine, I’ve seen many people with brain damage. And, sadly, most have been deemed “hopeless” by so-called medical experts.

But I can tell you there is nothing hopeless about dementia — no matter what its cause. With the right nutrients, there are times when brain damage can be reversed.

And now recent research from a university in Malaysia backs up what I’ve observed for years in my own clinic.

These new studies show that one, special vitamin not only prevents brain damage, but it can help repair it.

I’m talking about an overlooked form of vitamin E called tocotrienols.

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True Value of Palm Oil

Dr Jean Graille, a world renowned biotechnology expert who focuses on fats and lipids, completed his studies at the Ecole Nationale Supérieure de Chimie de Marseille [National Chemical Engineering Institute of Marseilles]. He began working as a researcher at the Institut des Corps Gras [Institute for Fats and Oils] before continuing his career in the Agribusiness Programme of CIRAD, where he managed the team for ‘Food and Non-Food Substances – Lipid Technology Sciences’. Dr Graille won the Chevreul medal in 1997 and went on to receive the Kaufmann Prize in 1999 – the first French person to do so. In an interview, he dismantles the myths perpetuated by the anti-palm oil lobby in France, and issues the timely reminder that there is no justification to avoid the use of this important product.

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Slide Show: Tocotrienols as Natural Neuroprotective Vitamins

Vitamin E is essential for normal neurological function, and antioxidant defenses are crucial to the brain to protect neural tissues from oxidative damage. Therefore, the majority of available research on the role of antioxidants has drawn much interest. This slide show, adapted from chapter 26 of CRC Press’ e-book, “Tocotrienols,” will explore the various forms of vitamin E, and its role in maintaining neurological structure and function.

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Preventive Effects of Tocotrienol on Stress-Induced Gastric Mucosal Lesions and Its Relation to Oxidative and Inflammatory Biomarkers.

Nur Azlina MF, Kamisah Y, Chua KH, Ibrahim IA, Qodriyah HM.

PLoS One. 2015 Oct 14;10(10):e0139348.

Abstract

This study aimed to investigate the possible gastroprotective effect of tocotrienol against water-immersion restraint stress (WIRS) induced gastric ulcers in rats by measuring its effect on gastric mucosal nitric oxide (NO), oxidative stress, and inflammatory biomarkers. Twenty-eight male Wistar rats were randomly assigned to four groups of seven rats. The two control groups were administered vitamin-free palm oil (vehicle) and the two treatment groups were given omeprazole (20 mg/kg) or tocotrienol (60 mg/kg) orally. After 28 days, rats from one control group and both treated groups were subjected to WIRS for 3.5 hours once. Malondialdehyde (MDA), NO content, and superoxide dismutase (SOD) activity were assayed in gastric tissue homogenates. Gastric tissue SOD, iNOS, TNF-α and IL1-β expression were measured. WIRS increased the gastric MDA, NO, and pro-inflammatory cytokines levels significantly when compared to the non-stressed control group. Administration of tocotrienol and omeprazole displayed significant protection against gastric ulcers induced by exposure to WIRS by correction of both ulcer score and MDA content. Tissue content of TNF-α and SOD activity were markedly reduced by the treatment with tocotrienol but not omeprazole. Tocotrienol significantly corrected nitrite to near normal levels and attenuated iNOS gene expression, which was upregulated in this ulcer model. In conclusion, oral supplementation with tocotrienol provides a gastroprotective effect in WIRS-induced ulcers. Gastroprotection is mediated through 1) free radical scavenging activity, 2) the increase in gastric mucosal antioxidant enzyme activity, 3) normalisation of gastric mucosal NO through reduction of iNOS expression, and 4) attenuation of inflammatory cytokines. In comparison to omeprazole, it exerts similar effectiveness but has a more diverse mechanism of protection, particularly through its effect on NO, SOD activity, and TNF-α.

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Regulation of inflammatory pathways by an a-tocopherol long-chain metabolite and a d-tocotrienol-related natural compound.

Schmölz L, Wallert M, Heise J, Galli F, Werz O, Birringer M, Lorkowski S.

Free Radic Biol Med. 2014 Oct;75 Suppl 1:S48

Abstract

Vitamin E is the most important lipid antioxidant which is widely used to prevent age-associated diseases. In the liver a-tocopherol (a-TOH), the most active isomer, is metabolized by side-chain truncation. Hydroxylation and oxidation steps in peroxisomes form the long-chain metabolite (LCM) a-13′-COOH, which has been recently reported by our group to occur in human serum. Only little is known about the modes of action of the LCM. We therefore investigate the influence of the physiologically relevant a-13′-COOH and the tocotrienol (T3)-related garcinoic acid (GA) on LPS-induced inflammatory response of murine macrophages (mMF). We report here that a-13′-COOH occurs in human serum and can be detected by LC/MS-QTOF which provides evidence for its systemic bioavailability. Translating these results into mechanistic studies we use semi-synthetically derived LCM starting with garcinoic acid, isolated from the bitternut Garcinia kola, because LCMs are not commercially available as pure compounds. We also report that a-13′-COOH and GA inhibit pro-inflammatory pathways in comparison to a-TOH in LPS-stimulated mMF. A screening of inflammation-related genes showed significant decreases of Il1ß by all compounds, while Il6 and Tnfa were only down-regulated by GA. However Cox2 and iNos were significantly reduced on mRNA and protein level by more than 70% and also the formation of signaling molecules, such as NO and PGE2, was significantly reduced by a-13′-COOH and GA. Key role in regulation of inflammatory response is regulated by activation of NF?B along with p65 subunit translocation. Neither expression nor translocation were regulated by a-13′-COOH and GA. The LCM and d-T3 show high activity in inhibiting pro-inflammatory pathways and associated signal transduction. We speculate that physiological a-LCM represent a new class of regulatory metabolites.

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Anti-inflammatory γ- and δ-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats.

Wong WY, Ward LC, Fong CW, Yap WN, Brown L.

Eur J Nutr. 2015 Oct 8

Abstract

PURPOSE:

This study tested the hypothesis that γ- and δ-tocotrienols are more effective than α-tocotrienol and α-tocopherol in attenuating the signs of diet-induced metabolic syndrome in rats.

METHODS:

Five groups of rats were fed a corn starch-rich (C) diet containing 68 % carbohydrates as polysaccharides, while the other five groups were fed a diet (H) high in simple carbohydrates (fructose and sucrose in food, 25 % fructose in drinking water, total 68 %) and fats (beef tallow, total 24 %) for 16 weeks. Separate groups from each diet were supplemented with either α-, γ-, δ-tocotrienol or α-tocopherol (85 mg/kg/day) for the final 8 of the 16 weeks.

RESULTS:

H rats developed visceral obesity, hypertension, insulin resistance, cardiovascular remodelling and fatty liver. α-Tocopherol, α-, γ- and δ-tocotrienols reduced collagen deposition and inflammatory cell infiltration in the heart. Only γ- and δ-tocotrienols improved cardiovascular function and normalised systolic blood pressure compared to H rats. Further, δ-tocotrienol improved glucose tolerance, insulin sensitivity, lipid profile and abdominal adiposity. In the liver, these interventions reduced lipid accumulation, inflammatory infiltrates and plasma liver enzyme activities.Tocotrienols were measured in heart, liver and adipose tissue showing that chronic oral dosage delivered tocotrienols to these organs despite low or no detection of tocotrienols in plasma.

CONCLUSION:

In rats, δ-tocotrienol improved inflammation, heart structure and function, and liver structure and function, while γ-tocotrienolproduced more modest improvements, with minimal changes with α-tocotrienol and α-tocopherol. The most important mechanism of action is likely to be reduction in organ inflammation.

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