Vitamin E, discovered in 1922, is essential for pregnant rats to carry their babies to term. However, 100 years later, the molecular mechanisms for the vitamin E requirement during embryogenesis remain unknown. Vitamin E’s role during pregnancy has been difficult to study and thus, a vitamin E-deficient (E-) zebrafish embryo model was developed. Vitamin E deficiency in zebrafish embryos initiates lipid peroxidation, depletes a specific phospholipid (DHA-phosphatidyl choline), causes secondary deficiencies of choline, betaine and critical thiols (such as glutathione), and dysregulates energy metabolism. Vitamin E deficiency not only distorts the carefully programmed development of the nervous system, but it leads to defects in several developing organs. Both the α-tocopherol transfer protein and vitamin E are necessary for embryonic development, neurogenesis and cognition in this model and likely in human embryos. Elucidation of the control mechanisms for the cellular and metabolic pathways involved in the molecular dysregulation caused by vitamin E deficiency will lead to important insights into abnormal neurogenesis and embryonic malformations.

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Natural α-tocopherol (α-TCP), but not tocotrienol, is preferentially retained in the human body. α-Tocopherol transfer protein (α-TTP) is responsible for binding α-TCP for cellular uptake and has high affinity and specificity for α-TCP but not α-tocotrienol. The purpose of this study was to examine the modification of α-TTP together with other related vitamin E-binding genes (i.e., TTPA, SEC14L2, and PI-TPNA) in regulating vitamin E uptake in neuronal cells at rest and under oxidative stress. Oxidative stress was induced with H2O2 for an hour which was followed by supplementation with different ratios of α-TCP and tocotrienol-rich fraction (TRF) for four hours. The cellular levels of vitamin E were quantified to determine bioavailability at cellular levels. The expression levels of TTPA, SEC14L2, and PI-TPNA genes in 0% α-TCP were found to be positively correlated with the levels of vitamin E in resting neuronal cells. In addition, the regulation of all the above-mentioned genes affect the distribution of vitamin E in the neuronal cells. It was observed that, increased levels of α-TCP secretion occur under oxidative stress. Thus, our results showed that in conclusion vitamin E-binding proteins may be modified in the absence of α-TCP to produce tocotrienols (TCT), as a source of vitamin E. The current study suggests that the expression levels of vitamin E transport proteins may influence the cellular concentrations of vitamin E levels in the neuronal cells.

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We examined the effects of the mixed ingestion of astaxanthin derived from Haematococcus pluvialis and tocotrienols on the cognitive function of healthy Japanese adults who feel a memory decline. Forty-four subjects were randomly but equally assigned to the astaxanthin-tocotrienols or placebo group. An astaxanthin-tocotrienols or placebo capsule was taken once daily before or after breakfast for a 12-week intervention period. The primary outcome was composite memory from the Cognitrax cognitive test, and the secondary outcomes were other cognitive functions and subjective symptoms for memory. Each group included 18 subjects in the efficacy analysis (astaxanthin-tocotrienols group, 55.4 ± 7.9 years; placebo group, 54.6 ± 6.9 years). The astaxanthin-tocotrienols group showed a significant improvement in composite memory and verbal memory in Cognitrax at Δ12 weeks compared with the placebo group. Additionally, the astaxanthin-tocotrienols group showed a significant improvement in the subjective symptom of “During the last week, have you had trouble remembering people’s names or the names of things?” compared with the placebo group after 12 weeks. No adverse events were observed in this study. The results demonstrated that taking an astaxanthin-tocotrienols combination improves the composite memory and verbal memory of Japanese adults who feel a memory decline (UMIN 000031758).

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There are several previous studies on the association of vitamin E with prevention of stroke but the findings remain controversial. We have conducted a systematic review, meta-analysis together with trial sequential analysis of randomised controlled trials to evaluate the effect of vitamin E supplementation versus placebo/no vitamin E on the risk reduction of total, fatal, non-fatal, haemorrhagic and ischaemic stroke. Relevant studies were identified by searching online databases through Medline, PubMed and Cochrane Central Register of Controlled Trials. A total of 18 studies with 148 016 participants were included in the analysis. There was no significant difference in the prevention of total stroke (RR (relative risk)=0.98, 95% CI 0.92-1.04, p=0.57), fatal stroke (RR=0.96, 95% CI 0.77-1.20, p=0.73) and non-fatal stroke (RR=0.96, 95% CI 0.88-1.05, p=0.35). Subgroup analyses were performed under each category (total stroke, fatal stroke and non-fatal stroke) and included the following subgroups (types of prevention, source and dosage of vitamin E and vitamin E alone vs control). The findings in all subgroup analyses were statistically insignificant. In stroke subtypes analysis, vitamin E showed significant risk reduction in ischaemic stroke (RR=0.92, 95% CI 0.85-0.99, p=0.04) but not in haemorrhagic stroke (RR=1.17, 95% CI 0.98-1.39, p=0.08). However, the trial sequential analysis demonstrated that more studies were needed to control random errors. Limitations of this study include the following: trials design may not have provided sufficient power to detect a change in stroke outcomes, participants may have had different lifestyles or health issues, there were a limited number of studies available for subgroup analysis, studies were mostly done in developed countries, and the total sample size for all included studies was insufficient to obtain a meaningful result from meta-analysis. In conclusion, there is still a lack of statistically significant evidence of the effects of vitamin E on the risk reduction of stroke. Nevertheless, vitamin E may offer some benefits in the prevention of ischaemic stroke and additional well-designed randomised controlled trials are needed to arrive at a definitive finding. PROSPERO registration number: CRD42020167827.

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Global cerebral ischemia/reperfusion (I/R) induces selective neuronal injury in the hippocampus, leading to severe impairment in behavior, learning, and memory functions. This study aimed to evaluate the neuroprotective effects of bisoprolol (biso) and vitamin E (vit E) treatment alone or in combination on cerebral ischemia/reperfusion (I/R) injury. A total of 30 male rats were divided randomly into five groups (n = 6), sham, I/R, I/R + biso, I/R + vit E, and I/R + biso+vit E. Cerebral I/R group underwent global ischemia by bilateral common carotid artery occlusion for 20 min. Treatment groups received drugs once daily intraperitoneally for 7 days before the I/R induction. Locomotive and cognitive behaviors were utilized by open-field and Morris water maze tests. After behavioral testing, the brain was removed and processed to evaluate cerebral infarct size, histopathologic changes, myeloperoxidase (MPO) activity, and malondialdehyde (MDA) level. In I/R group tissue MDA and MPO levels and cerebral infarct size were significantly increased in comparison with the sham group. Furthermore, significant deficits were observed in locomotion and spatial memory after I/R. The areas of cerebral infarction, MPO, and MDA levels in biso, vit E, and combination group were significantly reduced compared with I/R group. Histopathological analysis demonstrated a significant reduction in leukocyte infiltration in all treated groups with the most profound reduction in the combination group. According to the behavioral tests, administration of biso and/or vit E protected locomotive ability and improved spatial memory after cerebral I/R. Our findings show that biso and vit E have beneficial effects against the I/R injury and due to their synergistic effects when administered in combination, may have a more pronounced protective effect on the cerebral I/R injury.

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Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive cerebellar ataxia disorder that is caused by a mutation in the alpha-tocopherol transfer protein gene TTPA, leading to a lower level of serum vitamin E. Although it is almost clinically similar to Friedreich’s ataxia, its devastating neurological features can be prevented with appropriate treatment. In this study, we present a patient who was initially diagnosed with Friedreich’s ataxia, but was later found to have AVED. Frataxin gene screening revealed the absence of GAA expansion in homozygous or heterozygous state. However, TTPAgene sequencing showed the presence of the c.744delA mutation, leading to a premature stop codon (p.E249fx). In addition, the result of mutational analysis of MT-DNA genes revealed the presence of several variants, including the m.10044A>G mutation in MT-TG gene. Here, we report for the first time the coexistence of both mitochondrial and nuclear genes mutations in AVED.

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Vitamin E (VitE) deficiency results in embryonic lethality. Knockdown of the gene ttpa encoding for the VitE regulatory protein [α-tocopherol transfer protein (α-TTP)] in zebrafish embryos causes death within 24 h post-fertilization (hpf). To test the hypothesis that VitE, not just α-TTP, is necessary for nervous system development, adult 5D strain zebrafish, fed either VitE sufficient (E+) or deficient (E-) diets, were spawned to obtain E+ and E- embryos, which were subjected to RNA in situ hybridization and RT-qPCR. Ttpa was expressed ubiquitously in embryos up to 12 hpf. Early gastrulation (6 hpf) assessed by goosecoid expression was unaffected by VitE status. By 24 hpf, embryos expressed ttpa in brain ventricle borders, which showed abnormal closure in E- embryos. They also displayed disrupted patterns of paired box 2a (pax2a) and SRY-box transcription factor 10 (sox10) expression in the midbrain-hindbrain boundary, spinal cord and dorsal root ganglia. In E- embryos, the collagen sheath notochord markers (col2a1a and col9a2) appeared bent. Severe developmental errors in E- embryos were characterized by improper nervous system patterning of the usually carefully programmed transcriptional signals. Histological analysis also showed developmental defects in the formation of the fore-, mid- and hindbrain and somites of E- embryos at 24 hpf. Ttpa expression profile was not altered by the VitE status demonstrating that VitE itself, and not ttpa, is required for development of the brain and peripheral nervous system in this vertebrate embryo model.

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