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The Journal of Nutrition Dec 2020Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is...
BACKGROUND
Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood.
OBJECTIVES
The objective was to determine the impact of bio-potency-adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice.
METHODS
Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams.
RESULTS
A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz).
CONCLUSIONS
In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.
Topics: Animals; Brain; Diet; Female; Gene Expression Regulation; Hippocampus; Male; Mice; Milk; alpha-Tocopherol
PubMed: 32937657
DOI: 10.1093/jn/nxaa249 -
Nutrients Oct 2013Asthma and allergic diseases are complex conditions caused by a combination of genetic and environmental factors. Clinical studies suggest a number of protective dietary... (Review)
Review
Asthma and allergic diseases are complex conditions caused by a combination of genetic and environmental factors. Clinical studies suggest a number of protective dietary factors for asthma, including vitamin E. However, studies of vitamin E in allergy commonly result in seemingly conflicting outcomes. Recent work indicates that allergic inflammation is inhibited by supplementation with the purified natural vitamin E isoform α-tocopherol but elevated by the isoform γ-tocopherol when administered at physiological tissue concentrations. In this review, we discuss opposing regulatory effects of α-tocopherol and γ-tocopherol on allergic lung inflammation in clinical trials and in animal studies. A better understanding of the differential regulation of inflammation by isoforms of vitamin E provides a basis towards the design of clinical studies and diets that would effectively modulate inflammatory pathways in lung disease.
Topics: Animals; Antioxidants; Asthma; Diet; Dietary Supplements; Humans; Immunologic Factors; Inflammation; Lung; Pneumonia; Protein Isoforms; alpha-Tocopherol; gamma-Tocopherol
PubMed: 24184873
DOI: 10.3390/nu5114347 -
British Journal of Pharmacology Mar 2019Atherosclerosis is characterized by chronic low-grade inflammation with concomitant lipid accumulation in the arterial wall. Anti-inflammatory and anti-atherogenic...
BACKGROUND AND PURPOSE
Atherosclerosis is characterized by chronic low-grade inflammation with concomitant lipid accumulation in the arterial wall. Anti-inflammatory and anti-atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated-unsaturated fatty acids), formed during inflammation and digestion/absorption processes. The lipid-associated antioxidant α-tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and α-tocopherol, we designed and synthesized a novel nitroalkene-α-tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites.
EXPERIMENTAL APPROACH
We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro-inflammatory and cytoprotective pathways in macrophages in vitro. Moreover, we demonstrated its incorporation into lipoproteins and tissue both in vitro and in vivo, and determined its effect on atherosclerosis and inflammatory responses in vivo using the Apo E knockout mice model.
KEY RESULTS
NATOH exhibited similar antioxidant capacity to α-tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated in vivo into the VLDL/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down-regulated NF-κB-dependent expression of pro-inflammatory markers (including IL-1β and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice.
CONCLUSIONS AND IMPLICATIONS
In toto, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non-conventional anti-inflammatory compound (NATOH) with significant potential for clinical application.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Atherosclerosis; Cyclopentanes; Cytokines; Female; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Molecular Structure; Nitro Compounds; RAW 264.7 Cells; alpha-Tocopherol
PubMed: 30588602
DOI: 10.1111/bph.14561 -
Journal of Oleo Science 2024Vitamin E (VE) is a lipophilic vitamin, and Evans and Bishop demonstrated the existence of a hitherto unrecognized dietary factor essential for normal reproduction in...
Vitamin E (VE) is a lipophilic vitamin, and Evans and Bishop demonstrated the existence of a hitherto unrecognized dietary factor essential for normal reproduction in rat. During 100 years after the discovery, α-tocopherol (α-Toc) has been the representative species in VE homologues, and both naturally occurring and synthetically prepared α-Toc have been widely used and studied. Although it is indicated by a single-word VE, research on VE involves various chemical species. It is important to understand the fine structure and accurate characteristics of individual VE species when using VE. Each VE sample has compositional and/or isomer issues, and furthermore, the usability greatly varies depending on the modified species of esterification. The VE industry involves many interdisciplinary fields. Improvements in formulation technology and confirmation of the novel biological activity of VE greatly owns its utility and opens up new applications. As the interim period between the start and end of the agenda for Sustainable Development Goals (SDGs), in this minireview, the recent trends and future guidelines of VE, especially α- Toc, in relation to the SDGs have been demonstrated.
Topics: Rats; Animals; alpha-Tocopherol; Sustainable Development; Vitamin E; Vitamins; Isomerism
PubMed: 38556286
DOI: 10.5650/jos.ess23199 -
International Journal of Molecular... May 2023α-Tocopherol-13'-carboxychromanol (α-T-13'-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert...
α-Tocopherol-13'-carboxychromanol (α-T-13'-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G/G cell cycle arrest and apoptosis in macrophages triggered by α-T-13'-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl--glycero-3-phospho-(1'-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13'-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13'-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13'-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1).
Topics: alpha-Tocopherol; Tocopherols; Sterol Regulatory Element Binding Protein 1; Fatty Acids; Cell Death; Cell Cycle Checkpoints; Vitamin E; Stearoyl-CoA Desaturase
PubMed: 37298183
DOI: 10.3390/ijms24119229 -
International Journal of Molecular... Feb 2023α-tocopherol is the physiologically most active form of vitamin E, with numerous biological activities, such as significant antioxidant activity, anticancer...
α-tocopherol is the physiologically most active form of vitamin E, with numerous biological activities, such as significant antioxidant activity, anticancer capabilities, and anti-aging properties. However, its low water solubility has limited its potential use in the food, cosmetic, and pharmaceutical industries. One possible strategy for addressing this issue is the use of a supramolecular complex with large-ring cyclodextrins (LR-CDs). In this study, the phase solubility of the CD26/α-tocopherol complex was investigated to assess the possible ratios between host and guest in the solution phase. Next, the host-guest association of the CD26/α-tocopherol complex at different ratios of 1:2, 1:4, 1:6, 2:1, 4:1, and 6:1 was studied by all-atom molecular dynamics (MD) simulations. At 1:2 ratio, two α-tocopherol units interact spontaneously with CD26, forming an inclusion complex, as supported by the experimental data. In the 2:1 ratio, a single α-tocopherol unit was encapsulated by two CD26 molecules. In comparison, increasing the number of α-tocopherol or CD26 molecules above two led to self-aggregation and consequently limited the solubility of α-tocopherol. The computational and experimental results indicate that a 1:2 ratio could be the most suitable stoichiometry to use in the CD26/α-tocopherol complex to improve α-tocopherol solubility and stability in inclusion complex formation.
Topics: Cyclodextrins; alpha-Tocopherol; Dipeptidyl Peptidase 4; Antioxidants; Solubility
PubMed: 36901859
DOI: 10.3390/ijms24054425 -
Advanced Science (Weinheim,... Oct 2023Topical chemotherapy approaches are relevant for certain skin cancer treatments. This study observes that cabazitaxel (CTX), a broad-spectrum second-generation taxane...
Topical chemotherapy approaches are relevant for certain skin cancer treatments. This study observes that cabazitaxel (CTX), a broad-spectrum second-generation taxane cytotoxic agent, can be dissolved in α-tocopherol at high concentrations exceeding 100 mg mL . 2D nuclear magnetic resonance (NMR) analysis and molecular dynamics (MD) are used to study this phenomenon. The addition of 30% dimethyl sulfoxide (DMSO) to the α-tocopherol/CTX solution improves its working viscosity and enhances CTX permeation through human skin in vitro (over 5 µg cm within 24 h), while no detectable drug permeates when CTX is dissolved in α-tocopherol alone. In a transepidermal water loss assay, the barrier impairment induced by CTX in 30% DMSO in α-tocopherol, but not in pure DMSO, is reversible 8 h after the formulation removal from the skin surface. Antitumor efficacy of the topical CTX formulation is evaluated in nude mice bearing A431 human squamous carcinoma skin cancer xenografts. With topical application of concentrated CTX solutions (75 mg mL ), tumor growth is significantly suppressed compared to lower concentration groups (0, 25, or 50 mg mL CTX). Taken together, these findings show that topical delivery of CTX using a DMSO and α-tocopherol solvent warrants further study as a treatment for skin malignancies.
Topics: Mice; Animals; Humans; alpha-Tocopherol; Dimethyl Sulfoxide; Mice, Nude; Taxoids; Skin Neoplasms
PubMed: 37555802
DOI: 10.1002/advs.202302658 -
Journal of Veterinary Internal Medicine 2015Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on...
BACKGROUND
Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on α-tocopherol (α-TP)-deficient diet.
OBJECTIVE
Intramuscular α-TP and selenium (Se) administration at 4 days of age would have no significant effect on serum or cerebrospinal fluid (CSF) α-TP in healthy foals. Serum and CSF α-TP, but not Se, would be significantly decreased in NAD/EDM-affected foals during first year of life.
ANIMALS
Fourteen Quarter horse foals; 10 healthy foals supplemented with 0.02 mL/kg injectable α-TP and Se (n = 5) or saline (n = 5) at 4 days of age and 4 unsupplemented NAD/EDM-affected foals.
METHODS
Complete neurologic examinations were performed, blood and CSF were collected before (4 days of age) and after supplementation at 10, 30, 60, 120, 180, 240, and 360 days of age. Additional blood collections occurred at 90, 150, 210, and 300 days. At 540 days, NAD/EDM-affected foals and 1 unsupplemented healthy foal were euthanized and necropsies performed.
RESULTS
Significant decreases in blood, CSF α-TP and Se found in the first year of life in all foals, with most significant changes in serum α-TP from 4-150 days. Dam α-TP and Se significantly influenced blood concentrations in foals. Injection of α-TP and Se did not significantly increase CSF Se, blood or CSF α-TP in healthy foals. NAD/EDM-affected foals had significantly lower CSF α-TP through 120 days.
CONCLUSIONS AND CLINICAL IMPORTANCE
Injection of α-TP and Se at 4 days of age does not significantly increase blood or CSF α-TP. Despite all 14 foals remaining deficient in α-TP, only the 4 genetically predisposed foals developed NAD/EDM.
Topics: Animals; Animals, Newborn; Female; Genetic Predisposition to Disease; Horse Diseases; Horses; Male; Neuroaxonal Dystrophies; Selenium; alpha-Tocopherol
PubMed: 26391904
DOI: 10.1111/jvim.13618 -
Redox Biology Jan 2021α-tocopherol transfer protein (TTP) was previously reported to self-aggregate into 24-meric spheres (α-TTP) and to possess transcytotic potency across mono-layers of...
α-tocopherol transfer protein (TTP) was previously reported to self-aggregate into 24-meric spheres (α-TTP) and to possess transcytotic potency across mono-layers of human umbilical vein endothelial cells (HUVECs). In this work, we describe the characterisation of a functional TTP variant with its vitamer selectivity shifted towards γ-tocopherol. The shift was obtained by introducing an alanine to leucine substitution into the substrate-binding pocket at position 156 through site directed mutagenesis. We report here the X-ray crystal structure of the γ-tocopherol specific particle (γ-TTP) at 2.24 Å resolution. γ-TTP features full functionality compared to its α-tocopherol specific parent including self-aggregation potency and transcytotic activity in trans-well experiments using primary HUVEC cells. The impact of the A156L mutation on TTP function is quantified in vitro by measuring the affinity towards γ-tocopherol through micro-differential scanning calorimetry and by determining its ligand-transfer activity. Finally, cell culture experiments using adherently grown HUVEC cells indicate that the protomers of γ-TTP, in contrast to α-TTP, do not counteract cytokine-mediated inflammation at a transcriptional level. Our results suggest that the A156L substitution in TTP is fully functional and has the potential to pave the way for further experiments towards the understanding of α-tocopherol homeostasis in humans.
Topics: Endothelial Cells; Humans; Ligands; Mutagenesis, Site-Directed; Vitamin E; alpha-Tocopherol; gamma-Tocopherol
PubMed: 33197771
DOI: 10.1016/j.redox.2020.101773 -
Biological Trace Element Research Sep 2021Trace element status and metabolic milieu are sometimes overlooked in common veterinary clinical practice across animal species. The evaluation of requirements of trace...
Trace element status and metabolic milieu are sometimes overlooked in common veterinary clinical practice across animal species. The evaluation of requirements of trace elements, in fact, may be useful to prevent the perturbation of tissue-specific metabolic impair. In particular, essential trace elements in the diet play key roles within sub-cellular metabolic patterns with macro effects at the systemic level, like blood cell stability and semen quality. This effect was studied in breeding stallions, in which semen quality and haemogram are important for reproduction. A case-control feeding trial involved 40 stallions (age: 8-21 years; body weight, BW: 510-531 kg) of one stud centre, allotted to two experimental groups (n = 20 control, CON vs. n = 20 supplemented, SUPPL100), following a matched-pairs approach based on age. Supplemented stallions (SUPPL100) received a mixed mineral and vitamin supplement of Zn/Se and α-tocopherol (α-TOH) (100 g/day stallion) to compound feed, fed as control diet to horses of the control group (CON). Horses resulted deficient in circulating α-TOH and Zn at the start, though clinically healthy. After supplementation, different plasmatic levels of α-TOH, Zn and Se were found between groups. Circulating basophils (BASO) and mean cell haemoglobin concentration (MCHC) were affected by the dietary treatment (p < 0.05). Plasmatic Se affected monocyte count, haematocrit, mean cell volume and mean cell haemoglobin concentration. Semen traits were not affected by the dietary treatment per se, except for mobile/progressive sperm cells (%) of stallions aged > 13 years marginal circulating levels of α-TOH (p = 0.04). Ameliorating the micromineral status showed to improve the haemogram of stallions in view of circulating levels of Cu. Semen quality appeared to be strongly dependent on animal effects.
Topics: Animals; Breeding; Diet; Dietary Supplements; Horses; Male; Semen; Semen Analysis; Zinc; alpha-Tocopherol
PubMed: 33098077
DOI: 10.1007/s12011-020-02447-7