Vitamin E in Atopic Dermatitis: From Preclinical to Clinical Studies
Dermatology

Background: Oxidative stress and inflammation are some of the proposed mechanisms involved in the pathogenesis of atopic dermatitis (AD). Current pharmacotherapeutic ap-proaches are effective yet they are not without adverse ef-fects. Vitamin E has great potential as an adjunctive treat-ment 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 con-tact allergen should be considered. Collectively, this review envisaged vitamin E as an adjunctive treatment for AD pa-tients. Future research on the distinct effects of different vi-tamin E isoforms as well as their delivery system in skin dis-orders 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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Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite−Induced Asthma
The Journal of Immunology

Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform g-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of g-tocotrienol in a house dust mite (HDM) experimental asthma model. BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory bio-markers. Sera were assayed for IgE and g-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. g-Tocotrienol displayed better free radical–neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including a-tocopherol. Besides, g-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mech-anistically, g-tocotrienol was found to block nuclear NF-kB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did a-tocopherol and prednisolone. More importantly, g-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform g-tocotrienol in allergic asthma.

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Comparative hepatoprotective effects of tocotrienol analogs against drug-induced liver injury
Redox Biology

Oxidative stress plays a major part in the pathogenesis of drug-induced liver injury. Yet, overcoming it with other xenobiotics impose additional risks. In this study, we consider the use of natural-occurring and purified Vitamin E analogs as hepatoprotective agents. Vitamin E is well-known for its intrinsic antioxidant property even though the differential effect of specific analogs of tocopherol (TP) and tocotrienol (T3) is still not ascertained. This study investigates the protective effect of T3 analogs (α-, δ-, γ􀀁) in comparison with α-TP followed by assessing the underlying mechanisms of the cytoprotective T3 analog(s) in two xenobiotics-induced liver injury models using (1) acetaminophen (APAP)- and (2) hydrogen peroxide (H2O2). Both α-TP and α-T3 exerted cytoprotective effects while only lower con-centration of γ-T3 was effective in inhibiting both toxicants induced injury. α-TP/α-T3 protected hepatocytes from APAP and H2O2-induced liver injury through arresting free radicals and inhibiting oxidative stress (inhibition of reactive oxygen species, lipid peroxidation and mitochondrial permeability transition). There was also demonstrable inhibition of the apoptotic pathway (inhibition of caspse-3 activity and overexpression of Bcl-XL), accompanied with an induction of liver regeneration (PCNA and NF-kB). The cellular uptake of α-T3 was higher than α-TP at the same treatment dosage after 24 h. Overall, α-T3 seems to be a more potent hepatoprotective analog among the tocotrienols and α-TP at the same in vitro treatment dosage. In summary, these results suggest that α-TP/α-T3 elicit hepatoprotective effects against toxicants-induced damage mainly through activation of antioxidant responses at an early stage to prevent the exacerbation of injury.

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γ-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model
Oncotarget

Angiogenesis is one of the key hallmarks of cancer. In this study, we investigated whether γ-tocotrienol can abrogate angiogenesis-mediated tumor growth in hepatocellular carcinoma (HCC) and if so, through what molecular mechanisms. We observed that γ-tocotrienol inhibited vascular endothelial growth factor (VEGF)-induced migration, invasion, tube formation and viability of HUVECs in vitro. Moreover, γ-tocotrienol reduced the number of capillary sprouts from matrigel embedded rat thoracic aortic ring in a dose-dependent manner. Also, in chick chorioallantoic membrane assay, γ-tocotrienol significantly reduced the blood vessels formation. We further noticed that γ-tocotrienol blocked angiogenesis in an in vivo matrigel plug assay. Furthermore, γ-tocotrienol inhibited VEGF-induced autophosphorylation of VEGFR2 in HUVECs and also suppressed the constitutive activation of AKT/mammalian target of rapamycin (mTOR) signal transduction cascades in HUVECs as well as in HCC cells. Interestingly, γ-tocotrienol was also found to significantly reduce the tumor growth in an orthotopic HCC mouse model and inhibit tumor-induced angiogenesis in HCC patient xenografts through the suppression of various biomarkers of proliferation and angiogenesis. Taken together, our findings strongly suggest that γ-tocotrienol might be a promising anti-angiogenic drug with significant antitumor activity in HCC.

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First Evidence That g-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-kB Pathway
American Association for Cancer Research

Purpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether g-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.
Experimental Design: The effect of g-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-kB activation by DNA-binding assay, and gene expression by Western blotting. The effect of g-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.
Results: g-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-kB, and suppressed the NF-kB–regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of g-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and g-tocotrienol. As compared with vehicle control, g-tocotrienol also suppressed the NF-kB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.
Conclusions: Overall our results show that g-tocotrienol can potentiate the effects of capecitabine through suppression of NF-kB–regulated markers of proliferation, invasion, angiogenesis, and metastasis.

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