Vitamin E: Regulatory Redox Interactions

Miyazawa T, Burdeos GC, Itaya M, Nakagawa K, Miyazawa T

IUBMB Life. 2019 Jan 25. doi: 10.1002/iub.2008. [Epub ahead of print]

Abstract

Vitamin E is an essential nutrient that was discovered in the 1920s. Many of the physiological functions of vitamin E, including its antioxidative effects, have been studied for nearly 100 years. Changes in redox balance induced by both endogenously and exogenously generated reactive oxygen species (ROS) are involved in various diseases, and are also a phenomenon that is considered essential for survival. Vitamin E is known to regulate redox balance in the body due to its high concentration among the lipid soluble vitamin groups, and exists ubiquitously in the whole body, including cell membranes and lipoproteins. However, it has been reported that the beneficial properties of vitamin E, including its antioxidative effects, are only displayed in vitro, and not in vivo. Therefore, there exists an ongoing debate regarding the biological functions of vitamin E and its relationship with redox balance. In this review, we introduce the relationship between vitamin Eand redox interactions with (i) absorption, distribution, metabolism, and excretion of vitamin E, (ii) oxidative stress and ROS in the body, (iii) mechanism of antioxidative effects, (iv) non-antioxidant functions of vitamin E, and (v) recent recognition of the field of oxidative stress research. Understanding the recent findings of the redox interaction of vitamin E may help to elucidate the different antioxidative phenomena observed for vitamin E in vitro and in vivo.

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Co-expression of the aryl hydrocarbon receptor and estrogen receptor in the developing teeth of rat offspring after rat mothers’ exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and the protective action of α-tocopherol and acetylsalicylic acid

Dobrzyński M, Kuropka P, Leśków A, Herman K, Tarnowska M, Wiglusz RJ

Adv Clin Exp Med. 2019 Jan 24. doi: 10.17219/acem/99613. [Epub ahead of print]

Abstract

BACKGROUND:

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can cause adverse effects in many organs. Toxic effects are caused due to the formation of a TCDD complex with the cytoplasmatic aryl hydrocarbon receptor (AhR), whose mechanism of action is similar to that of the estrogen receptor (ER). Some substances, including α-tocopherol (E) and acetylsalicylic acid (ASA), can reduce the toxic effects of TCDD in offspring.

OBJECTIVES:

The objective of this study was to evaluate the co-expression of AhR and ER in the incisors of rat offspring whose mothers were exposed to TCDD, using immunohistochemical and histological techniques. Moreover, the possible protective role of E and ASA was investigated.

MATERIAL AND METHODS:

Four groups of 2-day-old rat offspring, whose mothers were intoxicated by TCDD before mating, were established: control group (C), TCDD group, TCDD+E group and TCDD+ASA group.

RESULTS:

In the TCDD group, there was an increase in ER expression and a decrease in AhR expression in comparison with the C group. In the TCDD+E and TCDD+ASA groups, there was a weak or negative ER expression and slightly stronger expression of AhR than in the TCDD group.

CONCLUSIONS:

The co-expression of AhR and ER during tooth development suggests the role of AhR and ER in the control of this process. Both receptors are also involved in the process of detoxification of TCDD. The increase in AhR in TCDD+E and TCDD+ASA groups indicate a preventive action of antioxidant and antiinflammatory pharmaceutics, which may limit negative effects of TCDD.

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Gamma tocopherol effect on LPS-induced sputum neutrophilia is not modified by BMI or GSTM1 genotype

Sood AK, Burbank AJ, Duran CG, Enders K, Zhou H, Peden DB, Hernandez ML

J Allergy Clin Immunol. 2019 Jan 17. pii: S0091-6749(19)30031-4. doi: 10.1016/j.jaci.2018.12.1009. [Epub ahead of print]

Abstract

In an era of personalized and precision medicine, efficacy data of therapeutic agents targeting airway inflammation are increasingly taking into account effect modifiers to optimize treatment strategies. Neutrophilic airway inflammation is often less responsive to corticosteroid treatment,1 and there is a great unmet need for nonsteroidal therapies to target this specific type of inflammation. Obesity is a well-known risk factor for specific asthma phenotypes and negatively affects asthma severity and control, partially as a result of increased airway neutrophilic inflammation.

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The effect of α-tocopherol and dithiothreitol in ameliorating emamectin benzoate cytotoxicity in human K562 cells involving the modulation of ROS accumulation and NF-κB signaling

Luan S, Muhayimana S, Xu J, Zhang X, Xiao C, Huang Q

Ecotoxicol Environ Saf. 2019 Jan 15;167:114-121. doi: 10.1016/j.ecoenv.2018.09.125. Epub 2018 Oct 10.

Abstract

Emamectin benzoate (EMB) toxicity contributes a potential risk to environment and human health. To investigate the effect of α-tocopherol(VitE) and dithiothreitol (DTT) in ameliorating EMB-induced cytotoxicity in human K562 cells, in vitro cultured human K562 cells were incubated with different concentrations of EMB in supplement with VitE and DTT when the cells were in the logarithmic phase. Next, the cell growth inhibition was evaluated using the MTT assay and cellular morphology observation. Reactive oxygen species (ROS) production was monitored using DCFH-DA probe and NF-κB signaling was determined using Western blotting. The results demonstrated that treatment with EMB (time- and concentration-dependent) showed significantly greater inhibition on K562 cell viability, heavier chromatin condensation and DNA fragmentation, and stronger suppression of NF-κB/p105 and p65/RelA expression of K562 cells than the control group (p < 0.01). The supplementation of VitE or DTT could help protect K562 cells against EMB-induced cytotoxicity by improving cell viability, preventing ROS accumulation and up-regulating NF-κB signaling through their ameliorating effects against oxidative stress induced by EMB. VitE had a stronger synergistic effect in limiting EMB cytotoxicity than DTT. Our findings indicate that VitE and DTT are potent antioxidants for human K562 cells, offering a promising means of ameliorating EMB cytotoxicity.

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Tocotrienol-Rich Fraction (TRF) Treatment Promotes Proliferation Capacity of Stress-Induced Premature Senescence Myoblasts and Modulates the Renewal of Satellite Cells: Microarray Analysis

Lim JJ, Wan Zurinah WN, Mouly V, Norwahidah AK

Oxid Med Cell Longev. 2019 Jan 10;2019:9141343. doi: 10.1155/2019/9141343. eCollection 2019.

Abstract

Human skeletal muscle is a vital organ involved in movement and force generation. It suffers from deterioration in mass, strength, and regenerative capacity in sarcopenia. Skeletal muscle satellite cells are involved in the regeneration process in response to muscle loss. Tocotrienol, an isomer of vitamin E, was reported to have a protective effect on cellular aging. This research is aimed at determining the modulation of tocotrienol-rich fraction (TRF) on the gene expressions of stress-induced premature senescence (SIPS) human skeletal muscle myoblasts (CHQ5B). CHQ5B cells were divided into three groups, i.e., untreated young control, SIPS control (treated with 1 mM hydrogen peroxide), and TRF-posttreated groups (24 hours of 50 μg/mL TRF treatment after SIPS induction). The differential gene expressions were assessed using microarray, GSEA, and KEGG pathway analysis. Results showed that TRF treatment significantly regulated the gene expressions, i.e., p53 (RRM2B, SESN1), ErbB (EREG, SHC1, and SHC3), and FoxO (MSTN, SMAD3) signalling pathways in the SIPS myoblasts compared to the SIPS control group (p < 0.05). TRF treatment modulated the proliferation capacity of SIPS myoblasts through regulation of ErbB (upregulation of expression of EREGSHC1, and SHC3) and FoxO (downregulation of expression of MSTN and SMAD3) and maintaining the renewal of satellite cells through p53 signalling (upregulation of RRM2B and SESN1), MRF, cell cycle, and Wnt signalling pathways.

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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]

Abstract

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.

Abstract

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]

Abstract

TRIAL DESIGN:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

Abstract

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.

Abstract

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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