Tocopherol Emulsions as Functional Autoantigen Delivery Vehicles Evoke Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis.

Griffin JD, Christopher MA, Thati S, Salash JR, Pressnall MM, Weerasekara DB, Lunte SM, Berkland CJ

Mol Pharm. 2019 Jan 7. doi: 10.1021/acs.molpharmaceut.8b00887. [Epub ahead of print]


Contemporary approaches to treating autoimmune diseases like Multiple Sclerosis broadly modulate the immune system and leave patients susceptible to severe adverse effects. Antigen-specific immunotherapies (ASIT) offer a unique opportunity to selectively suppress autoreactive cell populations, but have suffered from marginal efficacy even when employing traditional adjuvants to improve delivery. The development of immunologically active antigen delivery vehicles could potentially increase the clinical success of antigen-specific immunotherapies. An emulsion of the antioxidant tocopherol delivering an epitope of proteolipid protein autoantigen (PLP139-151) yielded significant efficacy in mice with experimental autoimmune encephalomyelitis (EAE). In vitro studies indicated tocopherol emulsions reduced oxidative stress in antigen presenting cells. Ex vivo analysis revealed that tocopherol emulsions shifted cytokines responses in EAE splenocytes. In addition, IgG responses against PLP139-151 were increased in mice treated with tocopherol emulsions delivering the antigen suggesting a possible skew in immunity. Overall, tocopherol emulsions provide a functional delivery vehicle for ASIT capable of ameliorating autoimmunity in a murine model.

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Kinetic Study of the Quenching Reaction of Singlet Oxygen by Eight Vegetable Oils in Solution

Mukai K, Ohara A, Ito J, Hirata M, Kobayashi E, Nakagawa K, Nagaoka SI

J Oleo Sci. 2019 Jan 1;68(1):21-31. doi: 10.5650/jos.ess18179. Epub 2018 Dec 12.


A kinetic study of the reaction of singlet oxygen (1O2) with eight vegetable oils 1-8 containing different concentrations of tocopherols (Tocs) and tocotrienols (Toc-3s) was performed. The second-order rate constants (kQ) for the reaction of 1O2 with vegetable oils 1-8 (rice bran, perilla, rape seed, safflower, grape seed, sesame, extra virgin olive, and olive oils) were measured in ethanol/chloroform/D2O (50:50:1, v/v/v) solution at 35°C using UV-vis spectrophotometry. Furthermore, comparisons of kQ values determined for the above oils 1-8 with the sum of the product {∑kQAO-i [AO-i]/105} of the kQAO-i values obtained for each antioxidant (AO-i) and concentration (in mg/100 g) ([AO-i]/105) of AO-i (Tocs and Toc-3s) contained in the oils 1-8 were performed. The observed kQ values were not reproduced by the kQ values calculated using only the concentrations of the four Tocs and Toc-3s. These results suggest that the contribution of fatty acids contained in the oils 1-8 is also necessary to fully explain the kQ values. Recently, the second-order rate constants (kS) for the reaction of aroxyl radical (ArO・) with the same vegetable oils 1-8 were measured in the same solvent at 25℃ using stopped-flow spectrophotometry (Ref. 23). The kS values obtained could be well explained as the sum of the product {Σ kSAO-i [AO-i]/105} of the kSAO-i and the [AO-i]/105 of AO-i (Tocs and Toc-3s) contained in the vegetable oils.

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The antioxidant effects of Hydroxytyrosol and Vitamin E on pediatric NAFLD, in a clinical trial: a new treatment?

Nobili V, Alisi A, Mosca A, Crudele A, Zaffina S, Denaro M, Smeriglio A, Trombetta D

Antioxid Redox Signal. 2018 Dec 27. doi: 10.1089/ars.2018.7704. [Epub ahead of print]



Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Several studies suggest that the improvement of oxidative stress is suggested as a possible therapeutic strategy for paediatric NASH. We performed a randomized double-blind placebo-controlled trial to test the potential efficacy, assessed by improvement of oxidative-stress parameters and liver ultrasound, and tolerability of a mixture of vitamin E and Hydroxytyrosol (HXT) in adolescents with biopsy-proven NAFLD.


440 consecutive patients were screened, 80 of these with biopsy-proven NAFLD were enrolled. Forty patients received an oral dose of HXT and vitamin E and 40 children received the capsules of placebo, for 4 months.


Seventy patients completed the study. Patients in the treatment arm showed a decrease of insulin-resistance, triglyceride levels, oxidative-stress parameters and steatosis grade. Noteworthy, the steatosis improvement correlates with the levels of advanced glycation end products and carbonylated proteins.


The HXT and vitamin E treatment improved the main oxidative-stress parameters, insulin resistance and steatosis in children with NAFLD. The use of two natural molecules that may have antioxidant effects seems a promising strategy that could be easily diet integrated to improve NAFLD related liver damage in children.

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Potential of Vitamin E Deficiency, Induced by Inhibition of α-Tocopherol Efflux, in Murine Malaria Infection

Suzuki H, Kume A, Herbas MS

nt J Mol Sci. 2018 Dec 24;20(1). pii: E64. doi: 10.3390/ijms20010064.


Although epidemiological and experimental studies have suggested beneficial effects of vitamin E deficiency on malaria infection, it has not been clinically applicable for the treatment of malaria owing to the significant content of vitamin E in our daily food. However, since α-tocopherol transfer protein (α-TTP) has been shown to be a determinant of vitamin E level in circulation, manipulation of α-tocopherol levels by α-TTP inhibition was considered as a potential therapeutic strategy for malaria. Knockout studies in mice indicated that inhibition of α-TTP confers resistance against malaria infections in murines, accompanied by oxidative stress-induced DNA damage in the parasite, arising from vitamin E deficiency. Combination therapy with chloroquine and α-TTP inhibition significantly improved the survival rates in murines with malaria. Thus, clinical application of α-tocopherol deficiency could be possible, provided that α-tocopherol concentration in circulation is reduced. Probucol, a recently found drug, induced α-tocopherol deficiency in circulation and was effective against murine malaria. Currently, treatment of malaria relies on the artemisinin-based combination therapy (ACT); however, when mice infected with malarial parasites were treated with probucol and dihydroartemisinin, the beneficial effect of ACT was pronounced. Protective effects of vitamin E deficiency might be extended to manage other parasites in future.

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Vitamin and antioxidant properties of tocopherols: characteristic of the molecular mechanisms of action

Sarkisyan VA, Kodentsova VM, Bessonov VV, Kochetkova AA

Vopr Pitan. 2018;87(3):5-11. doi: 10.24411/0042-8833-2018-10025. Epub 2018 May 11.


The molecular docking method was used to study the structural characteristics determining the competitive transport in the blood, and also the subsequent binding with enzymes of tocopherols and their metabolites to yield a specific biological activity. The target proteins were α-tocopherol-transport protein (α-TTP), tocopherol-associated protein 1 (TAP1), cyclooxygenase-2 (COX-2), protein phosphatase 2A (PP2A) and 3-hydroxy- 3-methylglutaryl-Coenzyme A (HMG-CoA) reductase. RRR-tocopherol (α-, β-, γ- and δ-forms), RRR-13′-carboxychromanol (α-, β-, γ- and δ-forms) and carboxyethyl hydroxychromanol (α-, β-, γ- and δ-forms) were used as ligands in this research. The conducted studies confirmed that among all homologues the α-tocopherol had the greatest affinity for the transport proteins α-TTP and TAP1 (ΔG=-11.40 and ΔG=-10.28 kcal/mol, respectively). It was shown that in all cases carboxyethyl hydroxychromanol metabolites had the greatest free binding energy (ΔG>-8 kcal/mol), that was why it has been concluded that they were not effective ligands for the proteins under study. In contrast, the metabolites of 13′-carboxychromanol, when bound to both α-TTP and TAP1 proteins, preferentially formed more stable complexes than their precursors. It was shown for the first time that γ-13′-carboxychromanol with TAP1 has less free binding energy (ΔG=-10.64 kcal/mol) in comparison to the α-tocopherol complex (ΔG=-10.28 kcal/mol). It has also been shown that 13′-carboxychromanole metabolites were more efficiently bound to COX-2 enzymes (ΔG=-9.56 kcal/mol for α-13′-carboxychromanol complex) and HMG-CoA reductase (ΔG=-9.46 kcal/mol for the complex with δ-13′-carboxychromanol). In relation to the PP2A protein, 13′-carboxychromanol metabolites had similar affinities as their precursors. The results of the work indicate the possibility of 13′-carboxychromanols to competitively bind to α-tocopherol transporters and act as effective ligands of COX-2 and HMG-CoA, that can be used to correct nutritional status in conditions accompanied by deficiency of tocopherols.

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Vitamin E: Regulatory role of metabolites

Birringer M, Lorkowski S

IUBMB Life. 2018 Dec 22. doi: 10.1002/iub.1988. [Epub ahead of print]


Vitamin E plays an important role as a lipophilic antioxidant in cellular redox homeostasis. Besides this function, numerous non-antioxidant properties of this vitamin have been discovered in the past. DNA microarray technology revealed a complex regulatory network influenced by the different vitamin E forms (Rimbach et al., Molecules, 15, 1746 (2010); Galli et al., Free Radic. Biol. Med., 102, 16 (2017)); however, little is known about the biological activity of vitamin E metabolites. A new chapter of vitamin E research was been opened when endogenous long-chain tocopherol metabolites were identified and their high biological activity in vitro and in vivo was recognized (Schmölz et al., World J. Biol. Chem., 7, 14 (2016); Torquato et al., J. Pharm. Biomed. Anal., 124, 399 (2016)). Just recently, it was shown that an endogenous metabolite of vitamin E inhibits 5-lipoxygenase at nanomolar concentrations, thereby limiting inflammation (Pein et al., Nat. Commun., 9, 3834 (2018)). Furthermore, long-chain vitamin E metabolites (LCM) exhibit hormone-like activities similar to the lipid soluble vitamins A and D (Galli et al., Free Radic. Biol. Med., 102, 16 (2017); Schubert et al., Antioxidants, 7 (2018)). This review aims at summarizing recent findings on the regulatory activities of vitamin E metabolites, especially of LCMs.

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The Effects of Magnesium and Vitamin E Co-Supplementation on Hormonal Status and Biomarkers of Inflammation and Oxidative Stress in Women with Polycystic Ovary Syndrome

Shokrpour M, Asemi Z

Biol Trace Elem Res. 2018 Dec 18. doi: 10.1007/s12011-018-1602-9. [Epub ahead of print]


Synergistic approach of magnesium and vitamin E may benefit clinical symptoms of patients with polycystic ovary syndrome (PCOS) through improving their metabolic profiles and reducing oxidative stress and inflammation. This study was designed to determine the effects of magnesium and vitamin E co-supplementation on hormonal status and biomarkers of inflammation and oxidative stress in women with PCOS. This randomized, double-blind, placebo-controlled trial was conducted among 60 women with PCOS, aged 18-40 years old. Participants were randomly divided into two groups to take 250 mg/day magnesium plus 400 mg/day vitamin E supplements or placebo (n = 30 each group) for 12 weeks. Fasting blood samples were taken at baseline and after the 12-week intervention to quantify related variables. Magnesium and vitamin E co-supplementation resulted in a significant reduction in hirsutism (β - 0.37; 95% CI, - 0.70, - 0.05; P = 0.02) and serum high-sensitivity C-reactive protein (hs-CRP) (β - 0.67 mg/L; 95% CI, - 1.20, - 0.14; P = 0.01), and a significant increase in plasma nitric oxide (NO) (β 3.40 μmol/L; 95% CI, 1.46, 5.35; P = 0.001) and total antioxidant capacity (TAC) levels (β 66.32 mmol/L; 95% CI, 43.80, 88.84; P < 0.001). Overall, magnesium and vitamin E co-supplementation for 12 weeks may benefit women with PCOS on hirsutism, serum hs-CRP, plasma NO, and TAC levels.

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Vitamin E: Regulatory Role on Signal Transduction

Zingg JM

IUBMB Life. 2018 Dec 17. doi: 10.1002/iub.1986. [Epub ahead of print]


Vitamin E modulates signal transduction pathways by several molecular mechanisms. As a hydrophobic molecule located mainly in membranes it contributes together with other lipids to the physical and structural characteristics such as membrane stability, curvature, fluidity, and the organization into microdomains (lipid rafts). By acting as the main lipid-soluble antioxidant, it protects other lipids such as mono- and poly-unsaturated fatty acids (MUFA and PUFA, respectively) against chemical reactions with reactive oxygen and nitrogen species (ROS and RNS, respectively) and prevents membrane destabilization and cellular dysfunction. In cells, vitamin E affects signaling in redox-dependent and redox-independent molecular mechanisms by influencing the activity of enzymes and receptors involved in modulating specific signal transduction and gene expression pathways. By protecting and preventing depletion of MUFA and PUFA it indirectly enables regulatory effects that are mediated by the numerous lipid mediators derived from these lipids. In recent years, some vitamin E metabolites have been observed to affect signal transduction and gene expression and their relevance for the regulatory function of vitamin E is beginning to be elucidated. In particular, the modulation of the CD36/FAT scavenger receptor/fatty acids transporter by vitamin E may influence many cellular signaling pathways relevant for lipid homeostasis, inflammation, survival/apoptosis, angiogenesis, tumorigenesis, neurodegeneration, and senescence. Thus, vitamin E has an important role in modulating signal transduction and gene expression pathways relevant for its uptake, distribution, metabolism, and molecular action that when impaired affect physiological and patho-physiological cellular functions relevant for the prevention of a number of diseases.

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Vitamin E Increases Antimicrobial Sensitivity by Inhibiting Bacterial Lipocalin Antibiotic Binding

Naguib MM, Valvano MA

mSphere. 2018 Dec 12;3(6). pii: e00564-18. doi: 10.1128/mSphere.00564-18.


Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes serious respiratory infections in patients with cystic fibrosis. Recently, we discovered that B. cenocepacia produces the extracellular bacterial lipocalin protein BcnA upon exposure to sublethal concentrations of bactericidal antibiotics. BcnA captures a range of antibiotics outside bacterial cells, providing a global extracellular mechanism of antimicrobial resistance. In this study, we investigated water-soluble and liposoluble forms of vitamin E as inhibitors of antibiotic binding by BcnA. Our results demonstrate that in vitro, both vitamin E forms bind strongly to BcnA and contribute to reduce the MICs of norfloxacin (a fluoroquinolone) and ceftazidime (a β-lactam), both of them used as model molecules representing two different chemical classes of antibiotics. Expression of BcnA was required for the adjuvant effect of vitamin E. These results were replicated in vivousing the Galleria mellonella larva infection model whereby vitamin E treatment, in combination with norfloxacin, significantly increased larva survival upon infection in a BcnA-dependent manner. Together, our data suggest that vitamin E can be used to increase killing by bactericidal antibiotics through interference with lipocalin binding.

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Effects of α-tocopherol on bone marrow mesenchymal cells derived from type II diabetes mellitus rats

Noguchi M, Yamawaki I, Takahashi S, Taguchi Y, Umeda M

J Oral Sci. 2018;60(4):579-587. doi: 10.2334/josnusd.17-0422.


It is widely accepted that vitamin E (VE) acts as an antioxidant and is involved in various metabolic systems including the regulation of gene expression and inhibition of cell proliferation. The most predominant isoform of VE in the living body is α-tocopherol. However, the influence of α-tocopherol on bone marrow mesenchymal cells (BMMCs) in a background of type II diabetes mellitus (DM) has not been investigated. The focus of the present study was to clarify the effect of α-tocopherol on BMMCs derived from rats with type II DM and the underlying mechanisms involved. BMMCs were isolated from rats with type II DM. The BMMCs were either untreated or exposed to α-tocopherol at concentrations of 1.0, 10, and 100 μM, and the resulting effects of α-tocopherol on cell proliferation, H2O2 activity, and antioxidant and inflammatory cytokine production were examined. At 100 μM, α-tocopherol had no effect on cell proliferation, but H2O2 activity was significantly increased. At 10 μM, α-tocopherol increased the gene expression of IL-1β, and markedly promoted that of TNF-α. Expression of catalase in the presence of 100 μM α-tocopherol was lower than for the other concentrations. At a low concentration, α-tocopherol exerted good antioxidant and anti-inflammatory effects on BMMCs. The study suggests that maintaining α-tocopherol at a low concentration might promote the recovery of BMMCs from oxidative stress.

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