Tocotrienol-rich fraction enhances cell proliferation and memory formation in hippocampal HT22 neuronal cells through BDNF/TrkB pathway
Journal of Functional Foods

Memory formation is influenced by neurogenesis and long-term potentiation (LTP) of neurons in the hippo-campus. In this study, we aimed to elucidate the mechanism of action of tocotrienol-rich fraction (TRF) involved in memory formation. Two cell models were employed, differentiated and undifferentiated HT22 neuronal cells. Our findings demonstrated that treatment with TRF increased cell proliferation of undifferentiated HT22 cells in a time-dependent manner by activating the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) pathway. Elevated levels of cyclin D and E were also observed, indicating an increase in cell cycle progression and proliferation. In differentiated HT22 cells, TRF upregulated expressions of BDNF, phosphory-lation of glutamate receptor 1 and Ca2+/calmodulin-dependent protein kinase II, potentially leading to stronger synaptic strength and contributing to LTP. Taken together, these findings suggest that TRF supplementation may enhance memory formation in HT22 cells through modulation of the BDNF/TrkB pathway.

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Tocotrienol-Rich Fraction Attenuates Blue Light-Induced Oxidative Stress and Melanogenesis in B16-F1 Melanocytes via Anti-Oxidative and Anti-Tyrosinase Properties
International Journal of Molecular Sciences

Our skin is constantly exposed to blue light (BL), which is abundant in sunlight and emitted by digital devices. Prolonged exposure to BL can lead to oxidative stress-induced damages and skin hyperpigmentation. For this study, we used a cell line-based model to examine the protective effects of tocotrienol-rich fraction (TRF) on BL-induced oxidative stress and hyperpigmentation in B16-F1 melanocytes. Alpha-tocopherol (αTP) was used as a comparator. Molecular assays such as cell viability assay, flow cytometry, western blotting, fluorescence imaging, melanin and tyrosinase analysis were performed. Our results showed that TRF effectively suppressed the formation of reactive oxygen species and preserved the mitochondrial membrane potential. Additionally, TRF exhibited anti-apoptotic properties by reducing the activation of the p38 mitogen-activated protein kinase molecule and downregulating the expression of cleaved caspase-3. Moreover, TRF modulated tyrosinase activity, resulting in a lowered rate of melanogenesis and reduced melanin production. In contrast, αTP did not exhibit significant protective effects against skin damages and pigmentation in BL-induced B16-F1 cells. Therefore, this study indicates that TRF may offer superior protective effects over αTP against the effects of BL on melanocytes. These findings demonstrate the potential of TRF as a protective natural ingredient that acts against BL-induced skin damages and hyperpigmentation via its anti-oxidative and anti-melanogenic properties.

Tocotrienol-Rich Fraction Attenuates Blue Light-Induced Oxidative Stress and Melanogenesis in B16-F1 Melanocytes via Anti-Oxidative and Anti-Tyrosinase Properties

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Tocotrienols improve urban particulate matter-induced skin damages by regulating skin barrier function and ROS/MAPK signalling pathway in keratinocytes
Atmospheric Pollution Research

Urban particulate matter (PM) is a major air pollutant that triggers molecular processes and is detrimental to the skin. We investigated the protective effects of tocotrienol-rich fraction (TRF) against urban PM-induced skin ageing, inflammation, and skin barrier dysfunction in human epidermal keratinocytes. Alpha-tocopherol (αTP) and retinoic acid (RA) were used as comparators. Our results showed that TRF significantly restored cell viability and alleviated increased intracellular reactive oxygen radicals in PM-treated keratinocytes. In addition, TRF significantly downregulated the activation of mitogen-activated protein kinases in PM-stimulated keratinocytes. This was substantiated by lower protein expression in the phosphorylation of extracellular signal-regulated kinase, Jun N-terminal kinase, and p38. This resulted in the inhibition of cyclooxygenase-2 expression, which is a downstream inflammatory mediator. TRF significantly protected skin barrier function upon exposure to PM by upregulating filaggrin, transglutaminase-1, and involucrin. In contrast, αTP and RA did not exhibit protective effects against skin damages in the PM-treated keratinocytes. Overall, this study suggests that TRF possesses antioxidant, anti-inflammatory, and skin barrier protective properties, and may serve as a potential ingredient in personal care and cosmeceutical industries to combat skin damage due to air pollution.

Tocotrienols improve urban particulate matter-induced skin damages by 
regulating skin barrier function and ROS/MAPK signalling pathway 
in keratinocytes

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Therapeutic effects of intranasal tocotrienol‑rich fraction on rhinitis symptoms in platelet‑activating factor induced allergic rhinitis
Allergy, Asthma & Clinical Immunology

Background: Platelet-activating factor (PAF) has been suggested to be a potent inflammatory mediator in Allergic rhinitis (AR) pathogenesis. Vitamin E, an essential nutrient that comprises tocopherol and tocotrienol, is known as a potential therapeutic agent for airway allergic inflammation. This study aimed to investigate the beneficial effects of intranasal Tocotrienol-rich fraction (TRF) on PAF-induced AR in a rat model.

Methods: Sprague Dawley rats were randomly assigned into 3 groups: Control, PAF-induced AR and PAF-induced AR with TRF treatment. To induce AR, 50 μl of 16 μg/ml PAF was nasally instilled into each nostril. From day 1 to 7 after AR induction, 10 μl of 16 μg/μl TRF was delivered intranasally to the TRF treatment group. Complete upper skulls were collected for histopathological evaluation on day 8.

Results: The average severity scores of AR were significantly higher in the PAF-induced AR rats compared to both control and PAF-induced AR with TRF treatment. The histologic examination of the nasal structures showed moderate degree of inflammation and polymorphonuclear cells infiltration in the lamina propria, mucosa damage and vascular congestion in the PAF-induced AR rats. TRF was able to ameliorate the AR symptoms by restoring the nasal structures back to normal. H&E staining demonstrated a statistically significant benefit upon TRF treatment, where minimal degree of inflammation, and a reduction in the infiltration of polymorphonuclear cells, mucosa damage and vascular congestion were observed.

Conclusion: TRF exhibited symptomatic relief action in AR potentially due to its antioxidant, anti-inflammatory and anti-allergic properties.

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An open-label, single-arm pilot study of tocotrienols supplementation on improving memory and attention in healthy young adults
Journal of Functional Foods

This study aimed to investigate the beneficial effects of tocotrienols (T3) supplementation on one’s attention and memory. Eleven healthy subjects were enrolled to receive placebo followed by T3 in 6 weeks. Psychomotor Vigilance Task (PVT) and Digit Span Test (DST) were used to access subjects’ sustained attention and working memory. Electroencephalogram (EEG) was used to examine the brainwave activity. T3 supplementation significantly improved the memory of the subjects in relative to the baseline as measured by average mean span for forward and reverse DST. Notably, a significant memory enhancement for T3 over placebo was observed. Subjects who consumed T3 have shown faster reaction as compared to placebo as assessed by PVT. T3 supple-mentation showed an overall reduction in alpha and low-beta power in comparison to placebo, indicating T3 promoted a higher neural efficacy. T3 supplementation may act as a potential nootropic in improving the mental performance and cognitive activity.

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Vitamin E in Atopic Dermatitis: From Preclinical to Clinical Studies

Background: Oxidative stress and inflammation are some of the proposed mechanisms involved in the pathogenesis of atopic dermatitis (AD). Current pharmacotherapeutic approaches are effective yet they are not without adverse effects. Vitamin E has great potential as an adjunctive treatment for AD owing to its antioxidant and anti-inflammatory bioactivities.

Summary: This review article summarizes the current available evidence from cellular, animal and clinical studies on the relationship between vitamin E and AD. The future prospects of vitamin E are also discussed. Vitamin E in practice does not show any toxicity to humans within a range of reasonable dosage. Albeit rarely, vitamin E as a contact allergen should be considered. Collectively, this review envisaged vitamin E as an adjunctive treatment for AD patients. Future research on the distinct effects of different vitamin E isoforms as well as their delivery system in skin disorders is needed.

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Oral Supplementation of Tocotrienol-Rich Fraction Alleviates Severity of Ulcerative Colitis in Mice
Journal of Nutritional Science and Vitaminology

Ulcerative colitis (UC) is characterized by damaged colonic mucosa and submucosa layers that are caused by excessive inflammatory reactions and oxidative stress. This study aimed to examine the use of tocotrienol-rich fraction (TRF) in mitigating damages caused by UC on the colon epithelium. Dextran sulfate sodium (DSS)-induced UC mice were treated with vehicle control, TRF, alpha-tocopherol (αTP) and 5-aminosalicylic acid (5-ASA). Observable clinical signs, quality of stool, histopathological scoring, inflammatory and oxidative markers were assessed. Vitamin E levels of colons and plasma were quantified. Oral supplementation of TRF significantly reduced the severity of DSS-induced UC by lowering the disease activity index (DAI) and histopathological inflammatory scoring. TRF also attenuated the DSS-induced enlargement of spleen and shortening of the colon. TRF has demonstrated marked anti-inflammatory and antioxidative properties indicated by the attenuation of DSS-induced upregulation of inflammation and oxidative stress markers including interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), nitric oxide (NO), malondialdehyde (MDA) and pNF-κB. These improvements were similar to that of 5-aminosalicylic acid (5-ASA) treatment. In contrast, αTP did not demonstrate evident clinical and histopathological improvements. The superior protective effect of TRF may be ascribed to the preferential absorption of TRF by the gut mucosa. TRF alleviated the signs and symptoms of acute UC in murine model via the reduction of local inflammatory reactions and oxidative stress. These effects suggested that TRF could serve as a gut health supplement for preventive measures for UC condition in patients.

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Tocotrienol is a cardioprotective agent against ageing-associated cardiovascular disease and its associated morbidities
Nutrition & Metabolism

Ageing is a nonmodifiable risk factor that is linked to increased likelihood of cardiovascular morbidities. Whilst many pharmacological interventions currently exist to treat many of these disorders such as statins for hypercholesterolemia or beta-blockers for hypertension, the elderly appear to present a greater likelihood of suffering non-related side effects such as increased risk of developing new onset type 2 diabetes (NODM). In some cases, lower efficacy in the elderly have also been reported. Alternative forms of treatment have been sought to address these issues, and there has been a growing interest in looking at herbal remedies or plant-based natural compounds. Oxidative stress and inflammation are implicated in the manifestation of ageing-related cardiovascular disease. Thus, it is natural that a compound that possesses both antioxidative and anti-inflammatory bioactivities would be considered. This review article examines the potential of tocotrienols, a class of Vitamin E compounds with proven superior antioxidative and anti-inflammatory activity compared to tocopherols (the other class of Vitamin E compounds), in ameliorating ageing-related cardiovascular diseases and its associated morbidities. In particular, the potential of tocotrienols in improving inflammaging, dyslipidemia and mitochondrial dysfunction in ageing-related cardiovascular diseases are discussed.

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Tocotrienol-rich fraction attenuates UV-induced inflammaging: A bench to bedside study
Journal of Cosmetic Dermatology

Background: UV radiation from the sun is the most common environmental stressor to damage the skin. It is now well established that photodamaged skin manifests signs of mild but chronic inflammation, termed as “inflammaging.” Thus, there is an urgent need for anti-inflammatory regimes that can limit the damage caused by inflammation.
Objectives: This study aimed to evaluate the possible palliative effects of a new topical nanoemulsion formulation containing tocotrienol-rich fraction (TRF) on UV-induced inflammation (erythema) of human skin.
Methods: An in vitro model was used to demonstrate the ability of TRF to alleviate photodamage via attenuation of UV-induced oxidative stress and inflammation. Two ex vivo models (skin antioxidative potential and radical sun protection factor) were used to determine the efficacy of different formulations of TRF on the skin. A UV-induced erythema protection test in 20 subjects was conducted.
Results: In vitro studies involving HaCaT keratinocytes revealed that TRF possesses marked anti-inflammatory properties, as indicated by the attenuation of UV-induced upregulation of pro-inflammatory cytokines. A 1% TRF formulation was found to be more effective in enhancing the endogenous antioxidative protection of skin com-pared to 1% TRF in medium chain triglycerides because of its higher penetration kinetic profile. The clinical study showed that formulated TRF was effective in reducing skin redness after UV irradiation as early as after 6 hours of application. A significant depigmentation was also observed in TRF treatment subjects.
Conclusion: TRF may serve as an anti-inflammatory compound that is safe to be applied daily to protect the skin from UV-induced inflammaging.

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Anti‑inflammatory γ‑ and δ‑tocotrienols improve cardiovascular, liver and metabolic function in diet‑induced obese rats
European Journal of Nutrition

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-tocotrienol produced 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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