Brain Vitamin E Deficiency During Development Is Associated With Increased Glutamate Levels and Anxiety in Adult Mice

Desrumaux CM, Mansuy M, Lemaire S, Przybilski J, Le Guern N, Givalois L, Lagrost L

Front Behav Neurosci. 2018 Dec 11;12:310. doi: 10.3389/fnbeh.2018.00310. eCollection 2018.


Vitamin E, the most important lipophilic radical scavenging antioxidant in vivo, has a pivotal role in brain. In an earlier study, we observed that adult mice with a defect in the gene encoding plasma phospholipid transfer protein (PLTP) display a moderate reduction in cerebral vitamin Elevels, and exacerbated anxiety despite normal locomotion and memory functions. Here we sought to determine whether dietary vitamin Esupplementation can modulate neurotransmitter levels and alleviate the increased anxiety phenotype of PLTP-deficient (PLTP -/-) mice. To address this question, a vitamin E-enriched diet was used, and two complementary approches were implemented: (i) “early supplementation”: neurotransmitter levels and anxiety were assessed in 6 months old PLTP -/- mice born from vitamin E-supplemented parents; and (ii) “late supplementation”: neurotransmitter levels and anxiety were assessed in 6 months old PLTP -/- mice fed a vitamin E-enriched diet from weaning. Our results show for the first time that an inadequate supply of vitamin E during development, due to moderate maternal vitamin E deficiency, is associated with reduced brain vitamin E levels at birth and irreversible alterations in brain glutamate levels. They also suggest this deficiency is associated with increased anxiety at adulthood. Thus, the present study leads to conclude on the importance of the micronutrient vitamin E during pregnancy.

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Vitamin Е activates expression of С/EBP alpha transcription factor and G-CSF receptor in leukemic K562 cells

Shvachko LP, Zavelevich MP, Gluzman DF, Kravchuk IV, Telegeev GD

Exp Oncol. 2018 Dec;40(4):328-331.



Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the activity of BCR-ABL fusion oncogene. Tyrosine kinase inhibitors are the current treatment of CML, but secondary mutations finally contribute to therapy resistance and blast crisis of the disease. The search for the novel compounds for the effective control of CML is now in the spotlight. The progression of CML to blast crisis is correlated with down-modulation of C/EBP alpha. Therefore, C/EBP alpha may be considered as a putative target in differentiation therapies in myeloid leukemias. The aim of the study was to assess the potential of vitamin E as the possible inducer of C/EBP alpha expression in BCR-ABL-positive CML K562 cells.


RNA extracted from K562 cells cultured with valproic acid or vitamin E was converted to cDNA, RT-PCR reactions were carried out using HotStarTaq DNA polymerase with primers for C/EBP alpha and granulocyte colony-stimulating factor receptor (G-CSFR).


We have not found detectable expression of C/EBP alpha in K562 cells. Upon 48-h culture with vitamin E at a dose of 100 µM, K562 cells expressed both C/EBP alpha and G-CSFR.


Vitamin E restored the expression of C/EBP alpha mRNA in chronic myelogenous leukemia K562 cells. In this setting, G-CSFR expression in vitamin E treated K562 cells seems to suggest the activation to granulocytic differentiation. It should be further elucidated whether such effects of vitamin E on C/EBP alpha transcription factor are direct or mediated indirectly due to antioxidant properties of vitamin E.

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The effect of zinc and/or vitamin E supplementation on biochemical parameters of selenium-overdosed rats

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.


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.

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Noggin levels in nonalcoholic fatty liver disease: the effect of vitamin E treatment

Polyzos SA, Kountouras J, Anastasilakis AD, Makras P, Hawa G, Sonnleitner L, Missbichler A, Doulberis M, Katsinelos P, Terpos E

Hormones (Athens). 2018 Dec;17(4):573-579. doi: 10.1007/s42000-018-0083-8. Epub 2018 Nov 22.



The evaluation of (a) noggin levels in patients with simple steatosis (SS) vs. nonalcoholic steatohepatitis (NASH) vs. controls, and (b) the effect of combined spironolactone plus vitamin E vs. vitamin E monotherapy on noggin levels in biopsy-proven patients with nonalcoholic fatty liver disease (NAFLD).


In the case-control study, 15 patients with SS, 16 with NASH, and 24 controls were included. In the randomized controlled trial, NAFLD patients were assigned to vitamin E (400 IU/d) or spironolactone (25 mg/d) plus vitamin E for 52 weeks.


Noggin levels were lower in SS (5.8 ± 1.5 pmol/l) and NASH (8.7 ± 2.4 pmol/l) patients than in controls (13.7 ± 2.7 pmol/l; p for trend = 0.040), but were similar in SS and NASH patients. After adjustment for potential cofounders, log(noggin) remained different between groups. Log(noggin) levels similarly increased post-treatment in both groups: log(noggin) was not different between groups (p = 0.20), but increased within groups over time (p < 0.001), without a significant group × time interaction (p = 0.62). Log(noggin) significantly increased at month 2 post-treatment (p = 0.008 vs. baseline) and remained stable thereafter.


Lower noggin levels were observed in NAFLD patients than in controls. Noggin levels increased similarly by either combined low-dose spironolactone plus vitamin E or vitamin E monotherapy.

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Delineation of the Individual Effects of Vitamin E Isoforms on Early Life Incident Wheezing

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]



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.


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.


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).


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.

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Vitamin E Metabolic Effects and Genetic Variants: A Challenge for Precision Nutrition in Obesity and Associated Disturbances

Galmés S, Serra F, Palou A

Nutrients. 2018 Dec 4;10(12). pii: E1919. doi: 10.3390/nu10121919.


Vitamin E (VE) has a recognized leading role as a contributor to the protection of cell constituents from oxidative damage. However, evidence suggests that the health benefits of VE go far beyond that of an antioxidant acting in lipophilic environments. In humans, VE is channeled toward pathways dealing with lipoproteins and cholesterol, underlining its relevance in lipid handling and metabolism. In this context, both VE intake and status may be relevant in physiopathological conditions associated with disturbances in lipid metabolism or concomitant with oxidative stress, such as obesity. However, dietary reference values for VE in obese populations have not yet been defined, and VE supplementation trials show contradictory results. Therefore, a better understanding of the role of genetic variants in genes involved in VE metabolism may be crucial to exert dietary recommendations with a higher degree of precision. In particular, genetic variability should be taken into account in targets concerning VE bioavailability per se or concomitant with impaired lipoprotein transport. Genetic variants associated with impaired VE liver balance, and the handling/resolution of oxidative stress might also be relevant, but the core information that exists at present is insufficient to deliver precise recommendations.

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Vitamin E Reduces Hypobaric Hypoxia-Induced Immune Responses in Male Rats

Goswami AR, Ghosh T

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


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.

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Vitamin E Improves Transplant-free Survival and Hepatic Decompensation among Patients with NASH and Advanced Fibrosis

Vilar-Gomez E, Vuppalanchi R, Gawrieh S, Ghabril M, Saxena R, Cummings OW, Chalasani N

Hepatology. 2018 Dec 1. doi: 10.1002/hep.30368. [Epub ahead of print]


Vitamin E improves liver histology in non-diabetic adults with nonalcoholic steatohepatitis (NASH), but its impact on long-term patient outcomes is unknown. We evaluated whether vitamin E treatment improves clinical outcomes of NASH patients with bridging fibrosis or cirrhosis. Two hundred and thirty-six patients with biopsy-proven NASH and bridging fibrosis or cirrhosis seen at Indiana University Medical Center between October 2004, and January 2016 were included. Ninety of them took 800 IU/day of vitamin E for ≥ 2 years (vitamin E users) and were propensity matched to 90 adults who did not take vitamin E (controls) after adjusting for fibrosis severity, age, gender, body mass index, comorbidities and their treatment, LDL cholesterol, liver biochemistries and length of follow-up on vitamin E. Covariate-adjusted cox and competing risk regression models were assessed to evaluate association between vitamin E treatment and patient outcomes. The median follow-up was 5.62 (IQR: 4.3-7.5) and 5.6 (IQR: 4-6.9) years for vitamin E users and controls respectively. Vitamin E users had higher adjusted transplant-free survival (78% vs. 49%, P<.01) and lower rates of hepatic decompensation (37% vs. 62%, P=.04) than controls. After controlling for severity of fibrosis, calendar year of patient enrollment and other potential confounders, vitamin E treatment decreased the risk of death or transplant (adj. HR: 0.30, 95% CI: 0.12-0.74, P<.01) and hepatic decompensation (adj. sHR: 0.52, 95% CI: 0.28-0.96, P=.036). These benefits were evident in both diabetics as well as non-diabetics. Adjusted 10-year cumulative probability of HCC, vascular events and non-hepatic cancers were not different between vitamin E exposed and controls. CONCLUSION: vitamin E use was associated with improved clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis.

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Regulatory role of vitamin E in the immune system and inflammation

Lewis ED, Meydani SN, Wu D

IUBMB Life. 2018 Nov 30. doi: 10.1002/iub.1976. [Epub ahead of print]


Vitamin E, a potent lipid-soluble antioxidant, found in higher concentration in immune cells compared to other cells in blood, is one of the most effective nutrients known to modulate immune function. Vitamin E deficiency has been demonstrated to impair normal functions of the immune system in animals and humans, which can be corrected by vitamin E repletion. Although deficiency is rare, vitamin E supplementation above current dietary recommendations has been shown to enhance the function of the immune system and reduce risk of infection, particularly in older individuals. The mechanisms responsible for the effect of vitamin E on the immune system and inflammation have been explored in cell-based, pre-clinical and clinical intervention studies. Vitamin E modulates T cell function through directly impacting T cell membrane integrity, signal transduction, and cell division, and also indirectly by affecting inflammatory mediators generated from other immune cells. Modulation of immune function by vitamin E has clinical relevance as it affects host susceptibility to infectious diseases such as respiratory infections, in addition to allergic diseases such as asthma. Studies examining the role of vitamin E in the immune system have typically focused on α-tocopherol; however, emerging evidence suggests that other forms of vitamin E, including other tocopherols as well as tocotrienols, may also have potent immunomodulatory functions. Future research should continue to identify and confirm the optimal doses for individuals at different life stage, health condition, nutritional status, and genetic heterogeneity. Future research should also characterize the effects of non-α-alpha-tocopherol vitamin E on immune cell function as well as their potential clinical application.

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Increased plasma levels of the lipoperoxyl radical-derived vitamin E metabolite α-tocopheryl quinone are an early indicator of lipotoxicity in fatty liver subjects

Torquato P, Bartolini D, Giusepponi D, Piroddi M, Sebastiani B, Saluti G, Galarini R, Galli F

Free Radic Biol Med. 2018 Nov 30;131:115-125. doi: 10.1016/j.freeradbiomed.2018.11.036. [Epub ahead of print]


Lipid peroxidation is one of the earliest pathogenic events of non-alcoholic fatty liver disease (NAFLD). In this context, an increased oxidation of the lipoperoxyl radical scavenger α-tocopherol (α-TOH) should occur already in the subclinical phases of the disease to compensate for the increase oxidation of the lipid excess of liver and possibly of other tissues. However, this assumption remains unsupported by direct analytical evidence. In this study, GC-MS/MS and LC-MS/MS procedures have been developed and applied for the first time to measure the vitamin Eoxidation metabolite α-tocopheryl quinone (α-TQ) in plasma of fatty liver (FL) subjects that were compared in a pilot cross-sectional study with healthy controls. The protein adducts of 4-hydroxynonenal (4-HNE) and the free form of polyunsaturated free fatty acids (PUFA) were measured as surrogate indicators of lipid peroxidation. α-TQ formation was also investigated in human liver cells after supplementation with α-TOH and/or fatty acids (to induce steatosis). Compared with controls, FL subjects showed increased (absolute and α-TOH-corrected) levels of plasma α-TQ and 4-HNE, and decreased concentrations of PUFA. α-TQ levels positively correlated with indices of liver damage and metabolic dysfunction, such as alanine aminotransferase, bilirubin and triglycerides, and negatively correlated with HDL cholesterol. Fatty acid supplementation in human hepatocytes stimulated the generation of cellular oxidants and α-TOH uptake leading to increased α-TQ formation and secretion in the extracellular medium – both were markedly stimulated by α-TOH supplementation. In conclusion, plasma α-TQ represents an early biomarker of the lipoperoxyl radical-induced oxidation of vitamin E and lipotoxicity of the fatty liver.

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