Vitamin E: Regulatory role of metabolites

Birringer M, Lorkowski S

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

Abstract

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.

Shokrpour M, Asemi Z

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

Abstract

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.

Zingg JM

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

Abstract

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.

Naguib MM, Valvano MA

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

Abstract

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.

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

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

Abstract

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.

Melčová M, Száková J, Mlejnek P, Zídek V, Fučíková A, Praus L, Zídková J, Mestek O, Kaňa A, Mikulík K, Tlustoš P

Pol J Vet Sci. 2018 Dec;21(4):731-740. doi: 10.24425/124312.

Abstract

The normotensive (Wistar) and spontaneously hypertensive (SHR) rats were examined to assess the response of the organism to selenium (Se) overdose. Moreover, the effect of zinc (Zn) and vitamin E, i.e. dietary components interacting in many biochemical processes with Se, on the Se uptake was evaluated. The control group was fed an untreated diet, and the diets of two other groups were overdosed with Se in the form of sodium selenite (9 mg/kg) and supplemented with Zn (13 mg/kg). Two experimental groups were fed a diet supplemented with Zn (13 mg/kg) and Se at an adequate level (0.009 mg/kg); a half of the animals was supplemented with vitamin E. The results showed significant differences in the Se contents between the rat strains in case of Se-overdosed groups, where in the liver and kidney tissue Se contents of SHR rats exceeded 3- and 7-fold the normotensive ones. The Se uptake was altered by the vitamin E; no effect of Zn was observed. Activities of antioxidant enzymes were determined in the animal tissues indicating different patterns according to rat strain, tissue analysed, and administered Se dose. Thus, Se overdose, for instance, via an incorrectly prepared dietary supplement, can result in serious imbalances of the biochemical status of the animals.

Stone CA Jr, Cook-Mills J, Gebretsadik T, Rosas-Salazar C, Turi K, Brunwasser SM, Connolly A, Russell P, Liu Z, Costello K, Hartert TV

J Pediatr. 2018 Dec 5. pii: S0022-3476(18)31552-X. doi: 10.1016/j.jpeds.2018.10.045. [Epub ahead of print]

Abstract

OBJECTIVES:

To test the hypothesis that maternal plasma alpha-tocopherol levels are associated with protection from childhood wheeze and that this protection is modified by gamma-tocopherol.

STUDY DESIGN:

We conducted a prospective nested study in the Infant Susceptibility to Pulmonary Infections and Asthma Following Respiratory Syncytial Virus Exposure birth cohort of 652 children with postpartum maternal plasma vitamin E isoforms used as a surrogate for pregnancy concentrations. Our outcomes were wheezing and recurrent wheezing over a 2-year period, ascertained using validated questionnaires. We assessed the association of alpha- and gamma-tocopherol with wheezing outcomes using multivariable adjusted logistic regression, and tested for interaction between the isoforms with respect to the risk for wheezing outcomes.

RESULTS:

Children with wheezing (n = 547, n = 167; 31%) and recurrent wheezing (n = 545, n = 55; 10.1%) over a 2-year period were born to mothers with significantly lower postpartum maternal plasma concentrations of alpha-tocopherol, P = .016 and P = .007, respectively. In analyses of IQR increases, alpha-tocopherol was associated with decreased risk of wheezing (aOR 0.70 [95% CI 0.53,0.92]) and recurrent wheezing (aOR 0.63 [95% CI 0.42,0.95]). For gamma-tocopherol, the aOR for wheezing was 0.79 (95% CI 0.56-1.10) and the aOR for recurrent wheezing was 0.56 (95% CI 0.33-0.94, with nonmonotonic association). The association of alpha-tocopherol with wheezing was modified by gamma-tocopherol (P interaction = .05).

CONCLUSIONS:

Increases in postpartum maternal plasma alpha-tocopherol isoform concentrations were associated with decreased likelihood of wheezing over a 2-year period. Gamma-tocopherol modified this association.

Goswami AR, Ghosh T

High Alt Med Biol. 2018 Dec 4. doi: 10.1089/ham.2018.0045. [Epub ahead of print]

Abstract

Vitamin E reduces hypobaric hypoxia-induced immune responses in male rats. High Alt Med Biol 00:000-000, 2018.-In hypobaric hypoxia (HH) at high altitude, the immune responses are changed probably due to oxidative stress-induced production of free radicals and nonradicals. Vitamin E is an antioxidant and protects the cells from oxidative damage. The present study was carried out to study the antioxidant role of vitamin E on the immune changes induced by oxidative stress in HH at high altitude. Select immune responses (phagocytic activity of white blood cell [WBC], cytotoxic activity of splenic mononuclear cells [MNCs], and delayed type of hypersensitivity [DTH]) and hematological changes (total count and differential count [DC] of WBC) were measured in male rats exposed to intermittent HH (at 5486.4 m in a simulated chamber for 8 hours/d for 6 consecutive days) and in normobaric condition with and without p.o. administration of vitamin E in three different doses (20, 40, and 60 mg/kg body weight). The increase of phagocytic activity of blood WBC, and reduction of cytotoxic activity of splenic MNC and DTH response were observed in rats exposed to HH. After the administration of vitamin E at different doses, the immune changes were blocked in a dose-dependent manner. Exposure to HH also led to the elevation of serum corticosterone (CORT), which was arrested after administration of vitamin E. The results indicate that the immune changes in HH at high altitude are probably mediated by the production of free radicals and nonradicals, and vitamin E can block these immune changes by its reactive oxygen species quenching effects.

Razak AM, Khor SC, Jaafar F, Karim NA, Makpol S

Genes Nutr. 2018 Nov 29;13:31. doi: 10.1186/s12263-018-0618-2. eCollection 2018.

Abstract

BACKGROUND:

Several muscle-specific microRNAs (myomiRs) are differentially expressed during cellular senescence. However, the role of dietary compounds on myomiRs remains elusive. This study aimed to elucidate the modulatory role of tocotrienol-rich fraction (TRF) on myomiRs and myogenic genes during differentiation of human myoblasts. Young and senescent human skeletal muscle myoblasts (HSMM) were treated with 50 μg/mL TRF for 24 h before and after inducing differentiation.

RESULTS:

The fusion index and myotube surface area were higher (p < 0.05) on days 3 and 5 than that on day 1 of differentiation. Ageing reduced the differentiation rate, as observed by a decrease in both fusion index and myotube surface area in senescent cells (p < 0.05). Treatment with TRF significantly increased differentiation at days 1, 3 and 5 of young and senescent myoblasts. In senescent myoblasts, TRF increased the expression of miR-206 and miR-486 and decreased PTEN and PAX7 expression. However, the expression of IGF1R was upregulated during early differentiation and decreased at late differentiation when treated with TRF. In young myoblasts, TRF promoted differentiation by modulating the expression of miR-206, which resulted in the reduction of PAX7 expression and upregulation of IGF1R.

CONCLUSION:

TRF can potentially promote myoblast differentiation by modulating the expression of myomiRs, which regulate the expression of myogenic genes.

Tan JK, Jaafar F, Makpol S

BMC Complement Altern Med. 2018 Nov 29;18(1):314. doi: 10.1186/s12906-018-2383-6.

Abstract

BACKGROUND:

Replicative senescence of human diploid fibroblasts (HDFs) has been used as a model to study mechanisms of cellular aging. Gamma-tocotrienol (γT3) is one of the members of vitamin E family which has been shown to increase proliferation of senescent HDFs. However, the modulation of protein expressions by γT3 in senescent HDFs remains to be elucidated. Therefore, this study aimed to determine the differentially expressed proteins (DEPs) in young and senescent HDFs; and in vehicle- and γT3-treated senescent HDFs using label-free quantitative proteomics.

METHODS:

Whole proteins were extracted and digested in-gel with trypsin. Peptides were detected by Orbitrap liquid chromatography mass spectrometry. Mass spectra were identified and quantitated by MaxQuant software. The data were further filtered and analyzed statistically using Perseus software to identify DEPs. Functional annotations of DEPs were performed using Panther Classification System.

RESULTS:

A total of 1217 proteins were identified in young and senescent cells, while 1218 proteins in vehicle- and γT3-treated senescent cells. 11 DEPs were found in young and senescent cells which included downregulation of platelet-derived growth factor (PDGF) receptor beta and upregulation of tubulin beta-2A chain protein expressions in senescent cells. 51 DEPs were identified in vehicle- and γT3-treated senescent cells which included upregulation of 70 kDa heat shock protein, triosephosphate isomerase and malate dehydrogenase protein expressions in γT3-treated senescent cells.

CONCLUSIONS:

PDGF signaling and cytoskeletal structure may be dysregulated in senescent HDFs. The pro-proliferative effect of γT3 on senescent HDFs may be mediated through the stimulation of cellular response to stress and carbohydrate metabolism. The expressions and roles of these proteins in relation to cellular senescence are worth further investigations. Data are available via ProteomeXchange with identifier PXD009933.