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Alcoholism affects about 2 billion people worldwide. Withdrawal causes a neuroinflammatory response that increases anxiety. α-tocopherol is the most important antioxidant that has its in vivo action currently known. Therefore, this study aimed to evaluate the effect of α-tocopherol on the neuroinflammatory process in brain regions involved in anxiety and its anxiolytic potential during alcohol withdrawal. For this, male Wistar rats were divided into four groups and submitted to a procedure of forced and chronic self-administration of liquid diet containing 6% and 8% ethanol for 15 days, followed by abrupt interruption of treatment. Animals in the control group received the liquid diet without ethanol. Twenty-four or 48 h after ethanol discontinuation, and 30 min after the last administration of α-tocopherol or saline, animals were evaluated in the elevated plus maze, light/dark box, and open field tests. At the end of the tests, each experimental group underwent brain tissue collection for analysis of cytokine levels. The results showed that: alcohol induces the neuroinflammatory process and anxiety; the stress generated by withdrawal can induce oxidative stress, which alters the production of inflammatory cytokines in the amygdaloid nuclei (AN) and medial hypothalamic nucleus (mHN); α-tocopherol exhibited anxiolytic and anti-inflammatory activity, attenuating the anxious behavior of abstinent animals and reducing neuroinflammation in AN and mHN; and the intensity of the anxiolytic and anti-inflammatory effect of α-tocopherol is dose-dependent. These results identify α-tocopherol as a potential therapeutic target supporting the fight against relapse during alcohol withdrawal.

Dendritic cells (DCs) vaccines are a major focus of future anti-tumor immunotherapy for their pivotal role in eliciting reactive tumor-specific T-cell responses. Tumor cell-mediated DCs (TC-DC) activation and tumor antigen-mediated DCs (TA-DC) activation are two conventional modes of DC vaccine construction in clinical studies. The former physiologically mimicks the tumor identification and rejection, significantly contributing to DC-based immune recognition and migration towards the complexed tumor microenvironment (TME). However, as immunosuppressive molecules may exist in TME, these TC-DC are generally characterized with aberrant lipid accumulation and inositol-requiring kinase 1α (IRE1α)-X-box binding protein 1 (XBP1) hyperactivation, which is provoked by overwhelming oxidative stress and endoplasmic reticulum (ER) stress, resulting in TC-DC malfunction. Oppositely, without contacting immunosuppressive TME, TA-DC vaccines perform better in T-cell priming and lymph nodes (LNs) homing, but are relatively weak in TME infiltration and identification. Herein, we prepared a KIRA6-loaded α-Tocopherol nanoemulsion (KT-NE), which simultaneously ameliorated oxidative stress and ER stress in the dysfunctional lipid-laden TC-DC. The TC-DC treated by KT-NE could maintain immunological activity, simultaneously, exhibited satisfactory chemotaxis towards LNs and tumor sites in vivo, and effectively suppressed malignant progression by unleashing activated tumor-reactive T cells. This study generated a new DC-vaccine that owned puissant aptitude to identify complicated TME as well as robust immunological activity to boost T-cell initiation, which may provide some insights into the design and application of DC-vaccines for clinical application.

BACKGROUND: Influenza A/H7N9 viruses have pandemic potential. METHODS: We conducted an open-label, randomized, controlled trial of AS03-adjuvanted 2017 inactivated influenza A/H7N9 vaccine (H7N9 IIV) in healthy adults. Group 1 received H7N9 IIV and seasonal quadrivalent influenza vaccine (IIV4) simultaneously, followed by H7N9 IIV three weeks later. Group 2 received IIV4 alone and then two doses of H7N9 IIV at three-week intervals. Group 3 received one dose of IIV4. We used hemagglutination inhibition (HAI) and microneutralization (MN) assays to measure geometric mean titers and seroprotection (≥1:40 titer) to vaccine strains and monitored for safety. RESULTS: Among 149 subjects, seroprotection by HAI three weeks after H7N9 IIV dose 2 was 51% (95 %CI 37%-65%) for Group 1 and 40% (95 %CI 25%-56%) for Group 2. Seroprotection by MN at the same timepoint was 84% (95 %CI 72%-93%) for Group 1 and 74% (95 %CI 60%-86%) for Group 2. By 180 days after H7N9 IIV dose 2, seroprotection by HAI or MN was low for Groups 1 and 2. Responses measured by HAI and MN against each IIV4 strain three weeks after IIV4 vaccination were similar in all groups. Solicited local and systemic reactions were similar after a single vaccination, while those receiving simultaneous H7N9 and IIV4 had slightly more reactogenicity. There were no serious adverse events or medically-attended adverse events related to study product receipt. CONCLUSIONS: Adjuvanted H7N9 IIV was modestly immunogenic whether administered simultaneously or sequentially with IIV4, though responses declined by 180 days. IIV4 was immunogenic regardless of schedule. CLINICAL TRIALS REGISTRATION: NCT03318315

BACKGROUND: Vitamin E (vitE) is hypothesized to attenuate age-related decline in pulmonary function. OBJECTIVES: We investigated the association between change in plasma vitE (∆vitE) and pulmonary function decline [forced expiratory volume in the first second (FEV(1))] and examined genetic and nongenetic factors associated with ∆vitE. METHODS: We studied 1144 men randomly assigned to vitE in SELECT (Selenium and Vitamin E Cancer Prevention Trial). ∆vitE was the difference between baseline and year 3 vitE concentrations measured with GC-MS. FEV(1) was measured longitudinally by spirometry. We genotyped 555 men (vitE-only arm) using the Illumina Expanded Multi-Ethnic Genotyping Array (MEGA(ex)). We used mixed-effects linear regression modeling to examine the ∆vitE–FEV(1) association. RESULTS: Higher ∆vitE was associated with lower baseline α-tocopherol (α-TOH), higher baseline γ-tocopherol, higher baseline free cholesterol, European ancestry (as opposed to African) (all P

Asthma and allergic disease result from interactions of environmental exposures and genetics. Vitamin E is one environmental factor that can modify development of allergy early in life and modify responses to allergen after allergen sensitization. Seemingly varied outcomes from vitamin E are consistent with the differential functions of the isoforms of vitamin E. Mechanistic studies demonstrate that the vitamin E isoforms α-tocopherol and γ-tocopherol have opposite functions in regulation of allergic inflammation and development of allergic disease, with α-tocopherol having anti-inflammatory functions and γ-tocopherol having pro-inflammatory functions in allergy and asthma. Moreover, global differences in prevalence of asthma by country may be a result, at least in part, of differences in consumption of these two isoforms of tocopherols. It is critical in clinical and animal studies that measurements of the isoforms of tocopherols be determined in vehicles for the treatments, and in the plasma and/or tissues before and after intervention. As allergic inflammation is modifiable by tocopherol isoforms, differential regulation by tocopherol isoforms provide a foundation for development of interventions to improve lung function in disease and raise the possibility of early life dietary interventions to limit the development of lung disease.

Introduction The aim of this study was to examine the potential application of a targeted proteomic predictive biomarker comprised predominantly of inflammatory proteins in distinguishing those who responded to a previously conducted clinical trial for Parkinson's disease (PD). Methods Plasma samples obtained from a biorepository were assayed from a total of n = 520 DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) clinical trial participants across treatment arms. Support vector machine analyses were conducted to distinguish responder status on primary (need for Levodopa) and secondary trial endpoints (UPDRS Motor and Total Scores). Results For the α-tocopherol and deprenyl placebo treatment arm (TOC), the targeted proteomic biomarker was able to distinguish responder status with an accuracy (area under the curve [AUC]) of 91% for the primary endpoint while it was 100% across secondary endpoints. For the deprenyl and α-tocopherol placebo treatment arm (DEP), the AUC was 93% for the primary endpoint and 99–100% for the secondary endpoints. For the combined treatment arm, AUC was 87% for the primary and 94–96% for the secondary endpoints. Discussion The targeted proteomic predictive biomarker was highly accurate in distinguishing responder status across treatment arms thereby supporting the application of a precision medicine approach to treating PD.

Scope The long-chain metabolites of (LCM) vitamin E are proposed as the active regulatory metabolites of vitamin E providing, with their anti-inflammatory properties, an explanatory approach for the inconsistent effects of vitamin E on inflammatory-driven diseases. We examined the modulation of cytokine expression and release from macrophages, a fundamental process in many diseases, to gain insights into the anti-inflammatory mechanisms of the α-tocopherol-derived LCM α-13′-COOH. Methods and results Suppressed gene expression of C–C motif chemokine ligand 2 (Ccl2), tumor necrosis factor (Tnf), and interleukin (Il) 6 in response to lipopolysaccharides by 24 h pre-treatment with α-13′-COOH in RAW264.7 macrophages was revealed using quantitative reverse transcription PCR. Further, reduced secretion of IL1β and CCL2 was found in this setup using flow cytometry. In contrast, 1 h pre-treatment suppressed only CCL2. Consequent gene expression analysis within 24 h of α-13′-COOH treatment revealed the induction of mitogen-activated protein kinases (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) negative feedback regulators including the ‘master regulators’ dual-specificity phosphatase 1 (Dusp1/Mkp1) and tumor necrosis factor induced protein 3 (Tnfaip3/A20). Approaches with immunoblots and chemical antagonists suggest a feedback induction via activation of extracellular-signal regulated kinase (ERK), p38 MAPK and NFκB pathways. Conclusions CCL2 is suppressed in murine macrophages by α-13′-COOH and the indirect suppression of MAPK and NFκB pathways is likely a relevant process contributing to anti-inflammatory actions of α-13′-COOH. These results improve the understanding of the effects of α-13′-COOH and provide a basis for new research strategies in the context of inflammatory diseases.

Summary Background and aim Cardiovascular diseases (CVDs) are the number one cause of mortality worldwide. Apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1), and ApoB/ApoA1 ratio are considered as predictors of CVD alongside with lipid profile. Evidence suggest that nutrients with antioxidant properties, especially vitamin E, are essential for a healthy cardiovascular system. The aim of present meta-analysis was to determine the effect alpha-tocopherol on ApoA1 and ApoB levels. Methods PubMed-Medline and SCOPUS databases and Google Scholar were searched up to July 2021. Random-effects model was employed to perform meta-analysis. In order to find heterogeneity sources, subgroup analysis was performed. Trim and fill analysis was performed in case of presence of publication bias. Quality assessment was performed using Cochrane Collaboration's tool. Results Seven eligible studies, involving 1284 individuals were included. Mean age of participants ranged between 25.4 and 59 years. There was no significant effect of vitamin E supplementation on Apo A1 (SMD = 0.22 IU/d; 95% CI: −0.38, 0.28; P = 0.481) and Apo B levels (SMD = −0.62 IU/d; 95% CI: −1.94, 0.70; P = 0.360). Conclusion No remarkable effect of vitamin E supplementation was observed on ApoA1 and ApoB levels in adults. Additional studies investigating the influence of vitamin E on apolipoproteins as primary outcome with larger sample size are suggested.

Vitamin E has eight different naturally occurring forms: four tocopherols and four tocotrienols. Because α-tocopherol has three asymmetric carbons, both natural α-tocopherol (RRR-α-tocopherol) and synthetic α-tocopherol (all-rac-α-tocopherol) are utilized in both pharmaceutical products and food additives. Therefore, determining the distribution of vitamin E in the body is very important. With regard to absorption, and transportation of vitamin E, it is suggested that the pathways mediated by three proteins (CD36, SR-BI, and NPC1L1) as well as passive diffusion affect absorption of vitamin E. Vitamin E homologs are mainly transported by very low−density lipoprotein (VLDL) with the α-tocopherol being recognized by the α-tocopherol transfer protein in liver. However, it is also suggested that chylomicrons (CMs) and high-density lipoprotein (HDL) are involved in transportation of vitamin E homologs from the small intestine to each section of peripheral tissue. In particular, it is speculated that vitamin E homologs transportation by CMs and HDL from enterocytes to peripheral tissues such as adipose tissue greatly affects the distribution of vitamin E homologs, excluding α-tocopherol. However, how lipoprotein lipase affects the incorporation of vitamin E homologs containing lipoprotein into peripheral tissues is unclear. Whether there is biodiscrimination when vitamin E homologs are incorporated into peripheral tissues from lipoprotein is an interesting question. It is likely that future research will reveal how individual vitamin E homologs are incorporated into peripheral tissue, especially the brain, adipose tissue, and skin.

α-Tocopherol transfer protein (α-TTP) is so far the only known protein that specifically recognizes α-tocopherol (α-Toc), the most abundant and most biologically active form of vitamin E, in higher animals. α-TTP is highly expressed in the liver where α-TTP selects α-Toc among vitamin E forms taken up via plasma lipoproteins and promotes its secretion to circulating lipoproteins. Thus, α-TTP is a major determinant of plasma α-Toc concentrations. Familial vitamin E deficiency, also called Ataxia with vitamin E deficiency, is caused by mutations in the α-TTP gene. More than 20 different mutations have been found in the α-TTP gene worldwide, among which some missense mutations provided valuable clues to elucidate the molecular mechanisms underlying intracellular α-Toc transport. In hepatocytes, α-TTP catalyzes the vectorial transport of α-Toc from the endocytotic compartment to the plasma membrane (PM) by targeting phosphatidylinositol phosphates (PIPs) such as PI(4,5)P2. By binding PIPs at the PM, α-TTP opens the lid covering the hydrophobic pocket, thus facilitating the release of bound α-Toc to the PM.

24(S)-Hydroxycholesterol (24S-OHC) and 25-hydroxycholesterol (25-OHC) are produced by cholesterol 24-hydroxylase and cholesterol 25-hydroxylase, respectively. The purpose of the present study was to determine the type of cell death induced by these oxysterols in neuronal cells, hepatic cells, and keratinocytes, and to elucidate the inhibitory effect of vitamin E homologues on various types of cell death. In human neuronal cells (SH-SY5Y cells), 24S-OHC and 25-OHC caused a cell death that was independent of caspase activation. We reported previously that the esterification of 24S-OHC by acyl-CoA:cholesterol acyltransferase 1 (ACAT1) and the resulting formation of a lipid droplet (LD)-like structure are responsible for the 24S-OHC-induced neuronal cell death. Here, we found that 25-OHC also induced ACAT1-mediated 25-OHC esterification and LD formation in neuronal cells. 25-OHC-induced cell death was inhibited by α-tocopherol (α-Toc) but not by α-tocotrienol (α-Toc3), as observed for 24S-OHC-induced cell death in SH-SY5Y cells. In human hepatic cells (HepG2 cells), these oxysterols caused a cell death that was caspase- and oxysterol-esterification-independent. This cell death was suppressed by both α-Toc and α-Toc3, suggesting the involvement of free-radical-mediated lipid peroxidation in the cell death induced by these oxysterols in hepatic cells. In human keratinocytes (HaCaT cells), these oxysterols caused a caspase-dependent but oxysterol-esterification-independent cell death that was inhibited by α-Toc but not by α-Toc3. These results suggest that α-Toc and α-Toc3 act as radical-scavenging antioxidants against oxysterol-induced cell death in the same way in hepatic cells, whereas their behavior is different in inhibition of cell death in neuronal cells and keratinocytes. Collectively, these results demonstrated that 24S-OHC and 25-OHC induced the same type of cell death in each of the cell types examined, and that α-Toc and α-Toc3 exerted different effects, depending on the type of cell death.

Inducing mitochondrial malfunction is an appealing strategy to overcome tumor multidrug resistance (MDR). Reported here a versatile mitochondrial-damaging molecule, vitamin E succinate (VES), is creatively utilized to assist MDR reversal of doxorubicin hydrochloride (DOX·HCl) via a nanovesicle platform self-assembled from amphiphilic polyphosphazenes containing pH-sensitive 1H-benzo-[d]imidazol-2-yl) methanamine (BIMA) groups. Driven by multiple non-covalent interactions, VES is fully introduced into the hydrophobic membrane of DOX·HCl-loaded nanovesicles with loading content of 23.5%. The incorporated VES also offers robust anti-leakage property toward DOX·HCl under normal physiological conditions. More importantly, upon release within acidic tumor cells, VES can target mitochondria and result in various dysfunctions including excessive generation of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) loss, and inhibited adenosine triphosphate (ATP) synthesis, which contribute to cell apoptosis and insufficient energy supply for drug efflux pumps. Consequently, the killing-effect of DOX·HCl is significantly enhanced toward drug resistant cancer cells at the optimal mass ratio of DOX·HCl to VES. Further in vivo antitumor investigation on nude mice bearing xenograft drug-resistant human chronic myelogenous leukemia K562/ADR tumors verifies the extremely enhanced anti-tumor efficacy of the dual drug-loaded nanovesicle with the tumor inhibition rate (TIR) of 82.38%. Collectively, this study provides a s safe, facile and promising strategy for both precise drug delivery and MDR eradication to improve cancer therapy.

Made available in DSpace on 2021-06-25T11:15:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-07-31 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) The high incidence and costs of chronic wounds in the elderly have motivated the search for innovations to improve product performance and the healing process while reducing costs. In this study, bioadhesive nanostructured lipid carriers (NLC) were developed for the co-encapsulation of compounds with antioxidant (α-tocopherol and quercetin) and antimicrobial (tea tree oil) activity for management of wounds. The NLC was produced with shea butter and argan oil, and modified with sodium alginate or chitosan to confer bioadhesive properties. Spherical nanoparticles of ~307–330 nm and zeta potential varying from −21.2 to +11.8 mV were obtained. Thermal analysis demonstrated that the lipid matrix reduced tea tree oil thermal loss (~1.8-fold). Regardless of the type of polysaccharide employed, the NLCs promoted cutaneous localization of antioxidants in damaged (subjected to incision) skin, with a ~74 to 180-fold higher delivery into the skin compared to percutaneous delivery. This result is consistent with the similar bioadhesive properties of chitosan or sodium alginate-modified NLC. Nanoencapsulation of tea tree oil did not preclude its antimicrobial effects against susceptible and resistant strains of S. aureus and P. aeruginosa, while co-encapsulation of antioxidants increased the NLC-induced fibroblasts migration, supporting their potential usefulness for management of wounds. Instituto de Ciências Biomédicas Universidade de São Paulo School of Pharmaceutical Sciences São Paulo State University (UNESP) Faculdade de Ciências Farmacêuticas Universidade de São Paulo School of Pharmaceutical Sciences São Paulo State University (UNESP) CAPES: 001 FAPESP: 2013/16617-7 FAPESP: 2015/07993-0 FAPESP: 2017/19059-6 FAPESP: 2017/19374-9 FAPESP: 2018/13877-1 FAPESP: 2019/26048-6 CNPq: 306866/2020-0

Background and aims: The accumulation of fat increases the formation of lipid perox-ides, which are partly scavenged by alpha-tocopherol (a-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary a-TOH metab-olites in middle-aged individuals. Methods and results: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N Z 511, 53% women; mean [SD] age of 55 [6.1] years), serum a-TOH and a-TOH metab-olites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (a-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (a-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were as-sessed using magnetic resonance imaging. Using multivariable-adjusted linear regression ana -lyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary a-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum a-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT. Conclusions: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized a-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

We recently reported the antisense properties of a DNA/RNA heteroduplex oligonucleotide consisting of a phosphorothioate DNA-gapmer antisense oligonucleotide (ASO) strand and its complementary phosphodiester RNA/phosphorothioate 2′-O-methyl RNA strand. When α-tocopherol was conjugated with the complementary strand, the heteroduplex oligonucleotide silenced the target RNA more efficiently in vivo than did the parent single-stranded ASO. In this study, we designed a new type of the heteroduplex oligonucleotide, in which the RNA portion of the complementary strand was replaced with phosphodiester DNA, yielding an ASO/DNA double-stranded structure. The ASO/DNA heteroduplex oligonucleotide showed similar activity and liver accumulation as did the original ASO/RNA design. Structure-activity relationship studies of the complementary DNA showed that optimal increases in the potency and the accumulation were seen when the flanks of the phosphodiester DNA complement were protected using 2′-O-methyl RNA and phosphorothioate modifications. Furthermore, evaluation of the degradation kinetics of the complementary strands revealed that the DNA-complementary strand as well as the RNA strand were completely cleaved in vivo. Our results expand the repertoire of chemical modifications that can be used with the heteroduplex oligonucleotide technology, providing greater design flexibility for future therapeutic applications., Graphical Abstract, Yokota, Seth, and colleagues have proposed a new concept of DNA/DNA double-stranded oligonucleotide, composed of a DNA-based antisense oligonucleotide and a DNA-based complementary strand. Systemic administration of this duplex conjugated with α-tocopherol significantly increased the target RNA-suppressing effect of the parent single-stranded antisense oligonucleotide following the degradation of complementary DNA in mouse liver.

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

Docosahexaenoic acid (DHA) is essential for health but easily oxidized. Yet the influence of DHA's exact location (sn-1, sn-2, or sn-3) in triacylglycerols on oxidative stability is currently unknown. This is the first study comparing oxidative stability of DHA in regio- and enantiopure triacylglycerols with or without RRR-α-tocopherol. Headspace solid-phase micro-extraction with gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy were applied. DHA in sn-2 was the most stable with or without added RRR-α-tocopherol resulting in differences in hydroperoxide formation. Without antioxidant, stability of DHA in sn-1 and sn-3 was mainly similar, with slight tendency towards better stability in sn-3. With RRR-α-tocopherol higher stability in sn-1 compared to sn-3 was observed. This points to diastereomeric interactions between RRR-α-tocopherol and DHA in sn-1. These results are highly relevant for enzymatic restructuring processes of DHA-rich fish or microalgae oil concentrates aimed for food supplements or food fortification.

The occurrence of the DFD defect shortens microbiological stability and reduces consumer acceptance of meat. The effect of a chokeberry leaf extract (ChLE) addition at concentrations of 0.01 %, 0.05 % and 0.1 % on the sensory and physicochemical properties of burgers prepared from DFD meat during refrigerated storage under vacuum for 10 days was assessed. The pH, water activity, texture, colour, degree of lipid oxidation, and content of α-tocopherol were measured. The extract at concentrations of 0.05 % and 0.1 % significantly influenced lower levels of lipid oxidation and higher content of α-tocopherol on each tested period. Moreover, these concentrations had a beneficial effect on the instrumental and sensory evaluation of texture parameters and on overall quality. It was concluded that the addition of 0.1 % extract was the most beneficial over the entire 10-day storage period. In summary, use of ChLE may reduce the loss of raw meat caused by DFD defect.

High-salt diet (HSD) affects the composition and function of the intestinal microbiota and cause health problems. This study confirmed that HSD aggravates dextran sulphate sodium (DSS)-induced colitis by changing the relative abundance of the gut microbiota, activating the NF-κB pathway, and up-regulating the mRNA levels of inflammatory factors. We explored the effect of L. plantarum 1201 in negating DSS-induced ulcerative colitis, which is aggravated by HSD for the first time. Results show that L. plantarum 1201 rebuilt the balance of intestinal flora by decreasing the ratio of Firmicutes/Bacteroidetes and increasing the relative abundance of Bifidobacterium, Lactobacillus and butyric-producing bacteria. Moreover, L. plantarum 1201 inhibited the up-regulation of inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6, IL-22, and IFN-γ) mRNA levels, increased colonic tight junction protein (ZO-1, ocludin, and claudin-3) expression, and increased serum levels of beneficial metabolites, including alpha-tocopherol (α-T) and D-mannose. By reconstructing an animal model of colitis, we further discovered that α-T and D-mannose inhibited the NF-κB pathway, improved tissue injury, and decreased the expression of pro-inflammatory cytokines (e.g., IL-1β, TNF-α, and IL-6). This study proves for the first time that L. plantarum 1201 attenuates high-salt-aggravated colitis by increasing the serum concentrations of endogenic D-mannose in mice serum and inhibiting the consumption of α-T through intestinal flora. Therefore, regulating the gut microbiota is a potential treatment for high-salt-aggravated colitis.

Finishing late-maturing bulls on grass may alter the antioxidant/prooxidant balance leading to beef with higher susceptibility to lipid oxidation and a lower colour stability compared to bulls finished on cereal concentrates. In this context, lipid oxidation and colour stability of beef from late-maturing bulls finished on pasture, with or without concentrate supplements, or indoors on concentrate was assessed. Charolais or Limousin sired bulls (n = 48) were assigned to four production systems: (1) pasture only (P), (2) pasture plus 25% dietary DM intake as barley-based concentrate (PC25), (3) pasture plus 50% dietary DM intake as barley-based concentrate (PC50) or (4) a barley-based concentrate ration (C). Following slaughter and postmortem ageing, M. Longissimus thoracis et lumborum was subjected to simulated retail display (4°C, 1000 lux for 12 h out of 24 h) for 3, 7, 10 and 14 days in modified atmosphere packs (O2 : CO2; 80 : 20). Lipid oxidation was determined using the 2-thiobarbituric acid-reactive substances assay; α-tocopherol was determined by HPLC; fatty acid methyl esters were determined using Gas Chromatography. Using a randomised complete block design, treatment means were compared by either ANOVA or repeated measures ANOVA using the MIXED procedure of SAS. Total polyunsaturated fatty acid (PUFA) concentrations were not affected by treatment, n-3 PUFAs were higher (P < 0.001) and the ratio of n-6 to n-3 PUFAs was lower (P < 0.001) in muscle from P, PC25 and PC50 compared to C. α-Tocopherol concentration was higher in muscle from P compared to PC50 and C bulls (P = 0.001) and decreased (P < 0.001) in all samples by day 14. Lipid oxidation was higher in muscle from C compared to P bulls on day 10 and day 14 of storage (P < 0.01). Finishing on pasture without supplementation did not affect beef colour stability and led to lower lipid oxidation, possibly due to the higher α-tocopherol concentration compared to concentrate finished beef.

BACKGROUND Determining the human vitamin E [α-tocopherol (α-T)] requirement is difficult, and novel approaches to assess α-T absorption and trafficking are needed. OBJECTIVE We hypothesized that the dual-isotope technique, using 2 deuterium-labeled [intravenous (IV) d6- and oral d3-] α-T, would be effective in determining α-T fractional absorption. Further, defined liquid meal (DLM) fat or fasting would modulate α-T fractional absorption and lipoprotein transport. METHODS A 3-phase cr ossover design was used. At 0 h, participants received IV d6-α-T and consumed d3-α-T with a 600-kcal DLM (40% or 0% fat) followed by controlled meals or by the 0% fat DLM, a 12-h fast, and then controlled meals. Blood samples and fecal samples were collected at intervals and analyzed by LC-MS. Pharmacokinetic parameters were calculated from plasma tracer concentrations and enrichments. Fractional absorption was calculated from d3- to d6-α-T areas under the curve, from a novel mathematical model, and from the balance method (oral d3-α-T minus fecal d3-α-T excreted). RESULTS Estimated α-T fractional absorption during the 40% fat intervention was 55% ± 3% (mean ± SEM; n = 10), which was 9% less than during the 0% fat intervention (64% ± 3%, n = 10; P

Research question Is a mixture of preconception serum lipids and lipophilic micronutrients associated with clinical pregnancy and live births? Design In this prospective cohort study, blood serum was collected on the day of oocyte retrieval for 180 women undergoing IVF at an academic reproductive health centre. Concentrations of lipids (phospholipids, total cholesterol, high- and low-density lipoproteins, and triglycerides) and lipophilic micronutrients (α-, δ-, and γ-tocopherols, retinol, β- and α-carotenes, β-cryptoxanthin, lutein and lycopene) were determined using diagnostic reagent kits and high-performance liquid chromatography. Poisson regression was used with robust variance estimation to evaluate changes in Z-scores for the mixture of serum lipid and lipophilic micronutrient concentrations as predictors of embryo implantation, clinical pregnancy and live birth, adjusted for age, body mass index (BMI), race, smoking status, infertility diagnosis, ovarian stimulation protocol and other measured lipid and lipophilic micronutrient concentrations. Results Each SD higher serum triglyceride concentration was associated with a lower chance of live birth (RR 0.54; 95% CI 0.33 to 0.90) whereas a 1 SD higher serum α-tocopherol concentration, as part of a mixture of serum lipids and lipophilic micronutrients, was associated with a higher likelihood for a live birth (RR 1.61; 95% CI 1.11 to 2.36). Serum β-carotene concentrations were associated with live birth in a non-linear fashion; low β-carotene was associated with a lower chance of live birth and high β-carotene with a higher chance of live birth. Conclusion Although components of a mixture of lipids and lipophilic micronutrients were associated with live birth outcomes after IVF, a larger investigation is necessary to fully evaluate the potential clinical implications.

Water-miscible vitamin E (WVE) has been known to be more bioavailable than conventional lipid-soluble vitamin E (LVE) in human foods because of its greater solubility in the gastrointestinal tract. However, no data regarding the comparison of the efficacy of WVE to LVE were available in poultry diets. The objective of the current experiment was to investigate the effect of vitamin E (VE) sources and inclusion levels in diets on growth performance, meat quality, alpha-tocopherol retention, and intestinal inflammatory cytokine expression in broiler chickens. A total of 420 6-d-old broiler chicks were allotted to 1 of 7 dietary treatments with 6 replicates in a completely randomized design. The corn-soybean meal-based basal diet was formulated without inclusion of supplemental VE. Additional 6 diets were prepared by supplementing the basal diet with either WVE or LVE at the inclusion levels of 33, 65, or 100 IU/kg in diets. Diets were fed to birds for 26 d. Results indicated that different VE sources and inclusion levels from 33 to 100 IU/kg in diets had no effects on growth performance in broilers. The VE sources did not affect lipid oxidation in both breast and thigh meat. However, increasing inclusion levels of VE decreased (linear and quadratic, P0.05) lipid oxidation in breast meat. Regardless of VE sources, increasing inclusion levels of VE increased (linear, P0.01) alpha-tocopherol concentrations in breast meat. Dietary WVE showed a greater reduction in the expression of both pro- and anti-inflammatory cytokine genes in the jejunum than dietary LVE. Increasing inclusion levels of both VE sources decreased (linear and quadratic, P0.05) the expression of both pro- and anti-inflammatory cytokine genes in the jejunum. The efficacy of dietary WVE for growth performance, meat quality, lipid oxidation, and alpha-tocopherol retention in broilers chickens is similar to that of dietary LVE. However, it is likely that dietary WVE is more effective in decreasing intestinal inflammatory responses than dietary LVE in broilers.

The present work details the nutritional and chemical compositions of borage and centaurea, at three flowering stages. Water was the main constituent, followed by total dietary fiber. Both flowers showed statistically different (p < 0.05) nutritional and chemical profiles, although in both, polyunsaturated fatty acids (PUFAs) (mainly linoleic and α-linolenic acids), free sugars (3.9–28.9% dw as fructose, glucose, and sucrose), tocopherols (with the major contribution of α-tocopherol from 1.24 to 2.75 mg/100 g dw), carotenoids (0.2–181.4 mg/100 g dw, mainly as lutein), and organic acids (6.1–14.4 g/100 g dw, mainly malic, succinic, and citric acids) were quantified. Concerning flowering, significant differences (p < 0.05) were found for some components, particularly carotenoids; however, no specific trend was observed in either of the two flower species. Thus, the present study shows that each flo The authors acknowledge the Portuguese Foundation for Science and Technology (FCT, Portugal) for the financial support provided by the research grant SFRH/BD/95853/2013 to Luana Fernandes and FCT/MEC for the financial support to QOPNA research Unit (FCT UID/ QUI/00062/2013) and LAQV Research Unit (UID/QUI/50006/2013 -POCI/01/0145/FEDER/007265) through national funds and co-financed by the FEDER, within the PT2020 Partnership Agreement. Furthermore, the authors are grateful to the Foundation for Science and Technology (FCT, Portugal) and FEDER under Programme PT2020 for financial support to CIMO (UID/AGR/00690/2013). info:eu-repo/semantics/publishedVersion

Lack of perfect insulin signaling can lead to the insulin resistance, which is the hallmark of diabetes mellitus. Activation of insulin and its binding to the receptor for signaling process initiates via B-chain C-terminal hinge conformational change through an open structure to “wide-open” conformation. Observational studies and basic scientific evidence suggest that vitamin D and E directly and/or indirectly prevent diabetes through improving glucose secretion and tolerance, activating calcium dependent endopeptidases and thus improving insulin exocytosis, antioxidant effect and reducing insulin resistance. On the contrary, clinical trials have yielded inconsistent results about the efficacy of vitamin D supplementations for the control of glucose hemostasis. In this work, best binding modes of vitamin D3 and E on insulin obtained from AutoDock Vina were selected for Molecular Dynamic, MD, study. The binding energy obtained from Molecular Mechanics- Poisson Boltzman Surface Area, MM-PBSA method, revealed that Vitamins D3 and E have good affinity to bind to the insulin and vitamin E has higher binding energy (−46 kj/mol) by engaging more residues in binding site. Distance and angle calculation results illustrated that vitamin E changes the B-chain conformation and it causes the formation of wide-open/active form of insulin. Vitamin E increases the ValB12-TyrB26 distance to ∼15 A and changes the hinge angle to ∼65°. Consequently, essential hydrophobic residues for binding to insulin receptor exposed to surface in the presence of vitamin E. However, our data illustrated that vitamin D3 cannot change B-chain conformation. Thus our MD simulations propose a model for insulin activation through vitamin E interaction for therapeutic approaches.

The aim of this study is to shed light on the evolution of the minor compounds in the corn oil oxidation process, through the information provided by direct immersion-microextraction in solid phase followed by gas chromatography/mass spectrometry (DI-SPME-GC/MS). This methodology enables one, in a single run, to establish the identity and abundance both of original oil minor components, some with antioxidant capacity, and of other compounds coming from both main and minor oil components oxidation. For the first time, some of the compounds formed from oil minor components degradation are proposed as new markers of oil incipient oxidation. Although the study refers to corn oil, the methodology can be applied to any other edible oil and constitutes a new approach to characterizing the oxidation state of edible oils. This work has been funded by the Spanish Ministry of Economy and Competitiveness (MINECO, AGL2015-65450-R) and by the Basque Government and its Departments of Universities and Research (EJ-GV, IT-916-16) and of Economic Development and Infrastructures, Area of Agriculture, Fisheries and Food Policy (EJ-GV, PA19/02). J. Alberdi-Cedeno thanks the EJ-GV for a predoctoral grant.

The present study evaluated silver nanoparticle (AgNPs) toxicity using biomarkers of oxidative and metabolic stress, immunological impairment and cellular damage in zebrafish (Danio rerio), as well as the optimal dose of vitamin E neutralizing undesirable effects. Fish were fed for ten days and eight study groups were investigated: controls, AgNPs exposure alone (1.5 mg L−1) and combined with three different vitamin E doses (1.5 mg L−1 of AgNPs + vitamin E 100, 200 or 400 mg kg−1 of food), also one positive control group exposed to AgNO3 alone or combined with the same vitamin E doses. D. rerio exposed to AgNPs alone or combined with the lower vitamin E dose showed overall worse results in comparison with the control groups and the groups combining nanoparticles and 200 or 400 mg kg−1 of food of vitamin E-supplemented diet. AgNPs caused cell impairment by increasing LDH activity and cortisol levels, generated oxidative stress by inhibiting SOD and CAT activity and immunosuppression by inhibiting ACH50 and lysozyme activity. The groups exposed to Ag salt showed the same response-pattern found for the NPs groups, reinforcing that Ag toxicity of AgNPs is mediated by Ag+. In conclusion, although AgNPs are toxic to Danio rerio, vitamin E supplementation at 200 or 400 mg kg−1 can act protectively against its toxic effects.

Alpha-tocopherol-selenium (ATS) and ascorbic acid (AA) are the potent antioxidants. The present study investigated whether supplementation of ATS and AA in periparturient sows has positive effects on amelioration of oxidative stress, serum immunoglobulin G (IgG), lipid profile and sows performance. For this, twenty-four pregnant multiparous sows (landrace×indigenous) were randomly distributed into four groups (6 sows per group) 20 days before expected date of farrowing as Control (basal diet); ATS (basal diet + ATS); AA (basal diet + AA) and ATS-AA (basal diet + ATS plus AA). The results of the study revealed that the concentrations of triglyceride and cholesterol significantly reduced from day -7 to day 7 of farrowing irrespective of supplementations to sows, but the leptin concentration significantly reduced on day 7 of farrowing in ATS-AA supplemented sows (p0.05). Moreover, sows of supplemented groups experienced decreased oxidative stress and cortisol level than control sows. The serum IgG concentration was significantly increased on day 7 post-farrowing in ATS group but it was much earlier on day 2 of farrowing in ATS-AA group (p0.001). Supplementing sows with ATS and/or AA did not influence significantly the birth weight, weaning weight and litter size at weaning (p0.05). Although piglet survival rate was not affected significantly by supplementation, however, piglet mortality rate was lowest in ATS-AA than any other groups. It was concluded that supplementation of ATS and/or AA to sows during late gestating and early lactating period ameliorated oxidative stress, improved lipid profile and serum IgG level without influencing reproductive performance.

Currently, there are limited treatment options for multi-drug resistant breast cancer. Lipid-modified cationic peptides have the potential to reach the mitochondria, which are attractive targets for the treatment of multi-drug resistant (MDR) breast cancer; yet, little is known about their mitochondrial targeting and anti-cancer activity. Interestingly, lipid-modified cationic peptides, typically used as gene transfection agents, exhibit similar structural features to mitochondrial targeted peptides. Using octahistidine-octaarginine (H8R8) as a model cationic peptide for cell penetration and endosomal escape, we explored the anti-cancer potential of lipid-modified cationic peptides as a function of amphiphilicity, biodegradability and lipid structure. We found that cationic peptides modified with a lipid that is at least 12 carbons in length exhibit potent anti-cancer activity in the low micromolar range in both EMT6/P and EMT6/AR-1 breast cancer cells. Comparing degradable and non-degradable linkers, as well as L- and D-amino acid sequences, we found that the anti-cancer activity is mostly independent of the biodegradation of the lipid-modified cationic peptides. Two candidates, stearyl-H8R8 (Str-H8R8) and vitamin E succinate-H8R8 (VES-H8R8) were cytotoxic to cancer cells by mitochondria depolarization. We observed increased reactive oxygen species (ROS) production, reduced cell bioenergetics and drug efflux, triggering apoptosis and G1 cell cycle arrest. Compared to Str-H8R8, VES-H8R8 showed enhanced cancer cell selectivity and drug efflux inhibition, thereby serving as a potential novel therapeutic agent. This study deepens our understanding of lipid-modified cationic peptides and uncovers their potential in multi-drug resistant breast cancer.

Radiation induced fibrosis is a common side-effect after radiotherapy. Pentoxifylline is reported to reverse radiation injuries when used in conjunction with D-α-tocopherol. However, pentoxifylline has a short half-life, limited oral bioavailability, and induces several systemic adverse effects. The objective of this study was to investigate the feasibility of using Er:YAG fractional laser ablation to enable simultaneous cutaneous delivery of pentoxifylline and D- α -tocopherol succinate from poly(lactide-co-glycolide) microparticles prepared using the freeze-fracture technique. In vitro release experiments demonstrated the different release profiles of the two molecules, which were influenced by their very different lipophilicities and aqueous solubilities. Experiments were then performed to investigate the effect of laser fluence on pore depth and so determine the pore volume available to host the topically applied microparticles. Application of the pentoxifylline and D-α-tocopherol succinate containing microparticles, prepared with RESOMER® RG 502H, to laser porated skin for 48 h, resulted in simultaneous delivery of pentoxifylline (69.63 ± 6.41 μg/cm2; delivery efficiency 46.4%) and D-α-tocopherol succinate (33.25 ± 8.91 μg/cm2; delivery efficiency 22.2%). After deposition into the micropores, the poly(lactide-co-glycolide) microparticles containing pentoxifylline and D-α-tocopherol succinate could serve as an intraepidermal depot to enable sustained drug delivery after micropore closure and thereby reduce the need for repeated microporation.

Co-encapsulation of multiple bioactive components is an emerging field that shows promise as an approach to develop functional foods. Hydrophobic components are generally dissolved in the inner oil phase of protein-stabilised emulsions. Some components may co-adsorb to oil droplet surfaces, due to the ligand-binding properties of proteins. In this study, α-tocopherol and resveratrol/naringenin were co-encapsulated in emulsions stabilised by whey protein isolate (WPI). α-Tocopherol was totally encapsulated and its partitioning inside oil droplets was about 3.3 times that bound by free WPI in the aqueous phase. The total encapsulation efficiency for resveratrol or naringenin was 52% and 58%, respectively. Addition of resveratrol improved digestive stability of α-tocopherol, but naringenin did not. Co-encapsulation with α-tocopherol had no significant influence on the digestive stability of resveratrol/naringenin. The data gathered here should be useful for the delivery of bioactive components with different solubilities.

Scope: Coffee consumption is widely recognized to improve the antioxidant status. We hypothesized a dark-roast coffee to reduce plasma oxidized LDL (oxLDL) and to improve alpha-tocopherol concentrations. Methods and results: After a 4 week, coffee-free run-in period, 86 healthy, randomized volunteers completed either a control (CTRL) or coffee (COFF) intervention in which either 750 mL water (CTRL) or coffee (COFF) were consumed daily for 8 weeks. Blood samples were taken at the begin and after the intervention. Mean changes in oxidized LDL concentrations after coffee consumption (−0.47 ± 15.4 U/L) differed from those of the CTRL-G (5.69 ± 18.8 U/L, p

Clinical and post-licensure data have demonstrated that AS03-adjuvanted inactivated split virion vaccines, many with reduced antigen content, are effective against influenza infection. The objective of this review is to provide a comprehensive assessment of the safety of trivalent seasonal, monovalent pre-pandemic and pandemic AS03-adjuvanted influenza vaccines, based on non-clinical, clinical and post-licensure data in various populations. Non-clinical studies on local tolerance, toxicology and safety pharmacology did not raise any safety concerns with AS03 administered alone or combined with various influenza antigens. Data from clinical trials with over 55,000 vaccinated subjects showed that AS03-adjuvanted influenza vaccines were generally well tolerated and displayed an acceptable safety profile, although the power to detect rare events was limited. Approximately 90 million doses of A/H1N1pdm09 pandemic influenza vaccines (Pandemrix and Arepanrix H1N1) were administered worldwide, which contributed post-licensure data to the collective safety data for AS03-adjuvanted influenza vaccines. An association between Pandemrix and narcolepsy was observed during the A/H1N1pdm09 pandemic, for which a role of a CD4 T cell mimicry sequence in the haemagglutinin protein of A/H1N1pdm09 cannot be excluded. Provided that future AS03-adjuvanted influenza vaccines do not contain this putative mimicry sequence, this extensive safety experience supports the further development and use of AS03-adjuvanted inactivated split virion candidate vaccines against seasonal and pandemic influenza infections.

Summary Background Oxidative stress has been associated with adverse neonatal outcomes, and vitamin E has powerful anti-oxidant properties. Vitamin E occurs in several different isoforms which differ in their ability to modulate inflammation and oxidative stress. Therefore, the purpose of this study was to evaluate the status of α-, γ- and δ-tocopherol in maternal-infant pairs, and the impact on maternal-newborn outcomes. Methods Vitamin E status was evaluated in 189 mother-infant pairs. Concentrations of α-, γ- and δ-tocopherol were measured using HPLC. Descriptive statistics were calculated and Spearman coefficients were used to assess correlations between maternal and cord measurements. Linear and logistic regression models were used to adjust for relevant confounders. A p Results Maternal and cord serum tocopherol concentrations were positively correlated for γ-tocopherol (r = 0.32, p ˂ 0.001) and δ-tocopherol (r = 0.46, p ˂ 0.001) but not for α-tocopherol. After adjustment for confounders, maternal concentrations of tocopherols were positively associated with Apgar scores (p = 0.02) and infant growth parameters at birth. Conversely, cord tocopherol levels were inversely associated with Apgar scores (p = 0.02) and infant growth. Cord concentrations of α-tocopherol were higher in infants born to mothers with a diagnosis of pre-eclampsia (p = 0.04). Conclusion Maternal-fetal transfer of γ- and δ-tocopherols is higher than α-tocopherol and may be mediated by either different or more efficient methods, conversely tissue uptake of α-tocopherol by the developing fetus may be higher. As serum levels of maternal tocopherols are positively associated with outcomes while higher cord levels show a negative impact, uptake and tissue deposition of vitamin E by the fetus may be crucial in growth and development. More research into the role of maternal diet, placental regulation, and fetal uptake of vitamin E tocopherols in relation to clinical outcomes is warranted.

Background Fish oil (FO) intravenous lipid emulsions (ILEs) are used as a monotherapy to treat parenteral nutrition (PN)-associated liver disease and provide essential fatty acids (EFAs) needed to sustain growth and prevent EFA deficiency (EFAD). Studies have suggested that medium-chain triglycerides (MCTs) and α-tocopherol have anti-inflammatory properties. Objective The purpose of this study was to test whether FO-ILEs containing MCTs and/or additional α-tocopherol decrease the inflammatory response to an endotoxin challenge compared with FO-ILE alone and preserve the ability to prevent PN-induced liver injury in mice. Methods A murine model of PN-induced hepatosteatosis was used to compare the effects of ILEs formulated in the laboratory containing varying ratios of FO and MCTs, and subsequently FO- and 50:50 FO:MCT-ILE plus 500 mg/L α-tocopherol (FO + AT and 50:50 + AT, respectively). C57BL/6 mice receiving unpurified diet (UPD), PN-equivalent diet (PN) + saline, and PN + soybean oil (SO)-ILE served as controls. After 19 d, mice received an intraperitoneal saline or endotoxin challenge 4 h before being killed. Serum and livers were harvested for histologic analysis, fatty acid profiling, and measurement of systemic inflammatory markers (tumor necrosis factor-α, interleukin-6). Results All ILEs were well tolerated and prevented biochemical EFAD. Livers of mice that received saline and SO developed steatosis. Mice that received 30:70 FO:MCT developed mild hepatosteatosis. All other FO-containing ILEs preserved normal hepatic architecture. Mice that received FO- or SO-ILE had significantly elevated systemic inflammatory markers after endotoxin challenge compared with UPD-fed controls, whereas 50:50 FO:MCT, 30:70 FO:MCT, FO + AT, and 50:50 + AT groups had significantly lower inflammatory markers similar to those seen in UPD-fed controls. Conclusions Mixed FO/MCT and the addition of α-tocopherol to FO improved the inflammatory response to endotoxin challenge compared with FO-ILE alone while still preventing PN-induced liver injury and EFAD in mice. There was no synergistic relation between α-tocopherol and MCTs.

The present study investigates the effect of exclusion of copper preparations from spray programs for disease control in integrated and organic tomato production systems on disease incidence, yield and fruit vitamin C, α-tocopherol and carotenoids content for Monroe, Optima and Paki cultivars. Open field trials were conducted in a randomized block system with four repetitions over two years. Treatment for plant disease control comprised four spraying programs, two within each production system. Yields were significantly affected by cultivar, pest management system and their interaction. Copper-free integrated and organic spraying programs were almost as effective in disease control as standard treatments which included copper preparations. The spraying program significantly affected the contents of vitamin C, α-tocopherol, phytoene, and β-carotene in fruits; however, the effect was cultivar related. The lycopene contents appeared to be unaffected by the spraying program or growing system.

Astaxanthin and alpha-tocopherol have various biological potential with induction of intracellular ROS production in cytosol, endoplasmic reticulum and mitochondrial site. The present study was performed to prepare nanoemulsion (NEs) formulation of astaxanthin and alpha-tocopherol with sodium caseinate (AS-AT/SC NEs) using spontaneous emulsification and ultrasonication for analyzing intracellular ROS production in apoptosis. NEs was characterized with standard analysis, which revealed a high stability of normal pH with a small size and unique zeta potential of spherical structure droplets with no toxicity and faster cell migration. It induced ROS production and confirmed using fluorescent stains due to their unique physicochemical and functional properties. Therefore, it played a significant role in the induction of oxidative stress inside the cell as dose-dependent cytotoxicity at different concentrations. AS-AT/SC NEs with protective effect in maintaining intracellular ROS, oxidative stress and mitochondrial membrane potential to reduced apoptosis morphology in cancer cells through mitochondria-mediated apoptosis that inhibits cell death, thus cell survival was initiated at greater extent. Thereby exhibiting a significant remarkable therapeutic effect in cancer field. To best of our knowledge, this is first study concluded that induction of apoptosis potential by AS-AT/SC NEs emerged as a potential way to eradicate cancer cells.

Among the eight forms of vitamin E, the liver preferentially releases α-tocopherol into the circulation and it is distributed to the non-liver tissues. In the hepatocytes, alpha tocopherol transfer protein (TTPA) specifically recognizes α-tocopherol with 2R-configuration and facilitates its intracellular transfer. The identification and characterization of TTPA expression have not been demonstrated in avian species. Therefore, the objectives of this study were to identify avian TTPAs, to compare the sequence conservation, phylogenetic relationship, protein interactions, and disease associations of chicken TTPA with those of human and vertebrate TTPA, and to characterize the tissue expression of the TTPA gene in chickens fed diets supplemented with different amounts of α-tocopherol. Our results suggest that the chicken TTPA was highly conserved with the human and vertebrate TTPA, and consisted of a cellular retinaldehyde binding protein and TRIO guanine exchange factor (CRAL_TRIO) domain. Feeding diets supplemented with increasing amounts of α-tocopherol (25 IU/Kg, 50 IU/Kg, or 100 IU/Kg) to broiler chickens had no effects on growth performance compared with feeding basal diets containing no supplemental α-tocopherol. The expression of TTPA gene was detected high in the liver of chickens in response to dietary α-tocopherol concentrations, whereas its expression was very low or undetectable in the non-liver tissues. In conclusion, the chicken TTPA protein sequence is highly conserved with other avian and vertebrate TTPA protein sequences. The higher expression of TTPA gene in the chicken liver in response to dietary α-tocopherol concentrations may suggest its crucial role in transporting α-tocopherol in the chicken liver.

Deficiency of vitamin-E or tocopherol causes neurological disorders in humans. α-tocopherol possessing the highest vitamin-E activity is present in low concentration in maize kernel. Nine lines and four testers possessing favourable allele of ZmVTE4 that significantly enhances vitamin-E activity were used to generate 36 hybrid combinations. Significant variation was observed for α- (5.95–39.03 μg/g), γ- (11.69–50.82 μg/g), δ- (4.09–10.76 μg/g) and total-tocopherol (33.18–90.53 μg/g). α-, γ- and δ-tocopherol constituted 36%, 53% and 11% of the total tocopherol, respectively. Majority of the experimental hybrids possessed significantly higher α-tocopherol (mean: 21.37 μg/g) than the check hybrids (mean: 11.16 μg/g). AMMI analysis revealed that across tocopherols, genotype and interaction effect accounted 35–77% and 23–45% of variation, respectively. The environmental effects were of minor magnitude. Non-additive gene action was predominant for α-, γ-, and total-tocopherol, while δ-tocopherol was conditioned predominantly by additive gene action. The information generated here assumes great significance in biofortification programme. This is the first report of variability, G × E interactions and combining ability for kernel tocopherol using maize hybrids possessing novel allele of ZmVTE4.

We aimed to compare the efficacy of δ-tocotrienol with α-tocopherol in the treatment of patients with non-alcoholic fatty liver disease (NAFLD).This study was a double-blinded, active-controlled trial. The patients with NAFLD were randomly assigned to receive either δ-tocotrienol 300 mg or α-tocopherol 268 mg twice daily for 48 weeks.The primary endpoints were change from baseline in fatty liver index (FLI), liver-to-spleen attenuation ratio (L/S ratio), and homeostatic model assessment for insulin resistance (HOMA-IR) at 48 weeks. Key secondary endpoints were change in markers of inflammation, oxidative stress, and hepatocyte apoptosis. Clinical assessment, biochemical analysis, and computed tomography scan of the liver were conducted at baseline, 24 and 48 weeks.A total of 100 patients (δ-tocotrienol = 50, α-tocopherol = 50) were randomized and included in the intention to treat analysis. Compared with baseline, there was a significant improvement (p .001) in FLI, L/S ratio, HOMA-IR, and serum malondialdehyde in both groups at 48 weeks that was not significant between the two groups. However, there was a significantly greater decrease in body weight, serum interleukin-6, tumor necrosis factor-alpha, leptin, cytokeratin-18, and increase in adiponectin in the δ-tocotrienol group compared to the α-tocopherol group at 48 weeks (p .05). No adverse events were reported.δ-tocotrienol and α-tocopherol exerted equally beneficial effects in terms of improvement in hepatic steatosis, oxidative stress, and insulin resistance in patients with NAFLD. However, δ-tocotrienol was more potent than α-tocopherol in reducing body weight, inflammation, and apoptosis associated with NAFLD. TRIAL REGISTRATION: Sri Lankan Clinical Trials Registry (https://slctr.lk/SLCTR/2019/038).

Vascular complications in β-thalassemia are associated with oxidative modification of lipoproteins under high oxidative stress. The lipid components of lipoproteins are oxidized via lipid peroxidation and produce lipid radicals (L•) as the key initial intermediates. Modification of lipid components, therefore, might result in alterations in the rate and products of lipid peroxidation. In this study, the kinetics of L• formation during the 2,2'-Azobis(2-amidinopropane) dihydrochloride (AAPH)- and hemin-induced oxidation of low-density and high-density lipoproteins (LDL and HDL) from β-thalassemia patients and healthy volunteers were investigated using a specific and sensitive fluorescence probe for L•. Kinetic parameters, including initial lag time, propagation rate and total L• production, were calculated by monitoring a fluorescence-active NBD-Pen-L• adduct. Oxidation of thalassemia lipoproteins exhibited a significantly shorter lag time but a slower propagation rate of L• formation when compared with healthy lipoproteins. LDL showed higher resistance to oxidation during the initiation phase but higher L• formation than HDL. Our results indicated that the levels of α-tocopherol determined the initial lag time, whereas the levels of core lipids and cholesteryl esters, especially cholesteryl linoleate (CL), determined the propagation rate and total L• production. The difference in potency of AAPH and hemin supported that hemin preferentially targeted core lipids. Moreover, analysis of 13-hydroxyoctadecadienoic acid cholesteryl ester (13-HODE-CE)/CE ratio indicated that thalassemia lipoproteins have higher susceptibility to oxidation than healthy lipoproteins. In conclusion, our findings suggested that CL and α-tocopherol were implicated in the susceptibility of lipoproteins to lipid peroxidation in physiological and pathological conditions of β-thalassemia.

The stabilization of fats and oils against oxidative lipid deterioration is still a great challenge. The synergistic interaction between phospholipids, l-ascorbate, and tocopherols have not yet been comprehensively understood. The mechanism of the synergistic antioxidant effect of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (PE) in mixtures with l-ascorbyl palmitate (AP) and α-tocopherol (α-Toc) was investigated in an ethyl linoleate model and sunflower oil at 110 °C. The mixture of PE, AP, and α-Toc is stabilized through continuous regeneration of α-Toc from its oxidation product α-tocopherylquinone (α-TQ). This reaction is catalyzed by acids and proceeded through the formation of the α-tocopherone ion (T

Application of a time-tested quantitative method of measuring peroxyl radical production in conjunction with the determination of the stoichiometry of the reaction of peroxyl radicals with α-tocopherol has permitted the conclusion that α-tocopherol is the major lipid-soluble chain-breaking antioxidant in human plasma and red cell membranes.

This in vitro study aimed to determine the effect of antioxidant solutions used after dental bleaching on the shear bond strength and adhesive interface sealing of ceramic laminate veneer luting. Additionally, effects on the enamel surface characteristics of hydrogen peroxide neutralization, surface energy, total free interaction energy, morphology, and chemical composition of enamel were assessed.Total 127 bovine incisors were divided into experimental groups, according to the surface treatment (unbleached and bleached enamel), antioxidant types (control; 10% ascorbic acid and 10% α-tocopherol), and periods of luting of ceramic laminates (24 h and after 14 days). Shear bond strength was assessed using microtensile test before and after thermal cycling (5760 cycles, 5-55 °C) (n = 6). The sealing of the adhesive interface was assessed using a confocal laser scanning microscope (n = 3). Hydrogen peroxide neutralization analysis was performed using a spectrophotometer (n = 5). The surface energy and total free interaction energy (n = 10) were measured using an automatic goniometer, while enamel morphology and chemical composition were assessed by scanning eletron microscopy (n = 3). Shear bond strength and enamel surface properties data were subjected to ANOVA followed by Tukey's test (α = 0.05). Adhesive interface micrographs were evaluated by the inter-examiner Kappa test and subjected to Kruskal-Wallis and Dunn's tests (α = 0.05).In general, thermal aging decreased the shear bond strength values of the luting agents to enamel (P .05). The α-tocopherol solution was able to reverse the oxidizing effect from dental bleaching, increasing the shear bond strength values and preserving the integrity of the adhesive interface sealing (P .05). Moreover, the α-tocopherol antioxidant agent promoted higher hydrogen peroxide neutralization after dental bleaching (P .05). Dental bleaching influenced the enamel surface, decreasing the surface energy and total free interaction energy values (P .05).α-tocopherol was able to reverse the oxidizing effects of dental bleaching, improving the enamel surface properties, as well as the adhesion and interface sealing of ceramic laminate veneer restorations.

This study aimed to analyze the effects of the quercetin (100 mg/kg), 1% glutamine and 1% α-tocopherol antioxidants in the myocardium of rats with streptozotocin-induced diabetes mellitus. Twenty male rats were subdivided into four groups (n = 5): N (normoglycemic); D (diabetic); NT (normoglycemic treated with antioxidants); and DT (diabetic treated with antioxidants) treated for 60 days. Clinical parameters, oxidative stress markers, inflammatory cytokines, myocardial collagen fibers and immunoexpression of superoxide dismutase 1 (SOD-1), glutathione peroxidase-1 (GPx-1), interleukin-1β (IL-1-β), transforming growth factor-beta (TGF-β), and fibroblast growth factor-2 (FGF-2) were evaluated. Results showed reduced body weight, hyperphagia, polydipsia and hyperglycemic state in groups D and DT. The levels of glutathione (GSH) were higher in NT and DT compared to N (p 0.01) and D (p 0.001) groups, respectively. Greater GSH levels were found in DT when compared to N animals (p 0.001). In DT, there was an increase in IL-10 in relation to N, D and NT (p 0.05), while GPx-1 expression was similar to N and lower compared to D (p 0.001). TGF-β expression in DT was greater than N (p 0.001) group, whereas FGF-2 in DT was higher than in the other groups (p 0.001). A significant reduction in collagen fibers (type I) was found in DT compared to D (p 0.05). The associated administration of quercetin, glutamine and α-tocopherol increased the levels of circulating interleukin-10 (IL-10) and GSH, and reduced the number of type I collagen fibers. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats.

Dietary supplementation of vitamin E (VitE) in a synthetic or natural form was examined. Forty-eight lambs were assigned (n = 16) to either a grain-based diet at moderate (MOD, 42 mg∙kg−1 VitE as all-rac α-tocopheryl acetate) or supranutritional (SUP, 285 mg∙kg−1 of vitE) levels of synthetic VitE or a lucerne hay-based diet (LUC; 37 mg∙kg−1 VitE) for 8 weeks. Meat from the LUC group had lower muscle n-6 and PUFA levels compared to meat from the MOD and SUP groups. Despite a similar VitE intake, muscle VitE was higher for LUC compared to MOD, while SUP lambs showed the highest VitE. Lipid oxidation did not differ between groups. For fresh meat, redness tended to be higher in LUC fed lambs than the other two groups, but brownness formation was only lower than the SUP group. For aged meat colour stability, redness tended to be higher in lambs fed SUP and LUC, whereas highest browning occurred in the MOD group.

Cadmium (Cd) is a widespread non-essential toxic heavy metal and usually arouses oxidative stress which impairs plant growth. The key lipophilic antioxidant α-tocopherol is synthesized from γ-tocopherol by γ- tocopherol-methyl-transferase (γ-TMT encoded by VTE4) in response to a variety of abiotic stresses. The main purpose of this study was to characterize the Cd-tolerant maize ZmVTE4 which was obtained through high-throughput survival screening in the presence of Cd. Further heterologous expression of a ZmVTE4 enhanced Cd tolerance in yeast as well in tobacco. Moreover, Cd treatment induced the increment of tocopherols in maize leaves. Similarly, transient overexpressing ZmVTE4 increased the content of γ-tocopherol and α-tocopherol thus enhancing the Cd tolerance in tobacco leaves. Visualized fluorescence indicated that ZmVTE4 was localized in chloroplasts, where tocopherols were synthesized. These results collectively implicated that ZmVTE4-mediated α-tocopherol generation facilitated plant tolerance to Cd.

The negative effects of oxidative damage on larval development, growth and survival are among the factors markedly affecting marine fish larvae production success. Whereas α-tocopherol (vit E) and l -ascorbic acid (vit C) are strong antioxidants, the potential antioxidant role of taurine (Tau) in fish diets and its relation with other antioxidant nutrients needs further clarification. The present study aimed to determine the potential interactions between the dietary levels of vit E plus vit C and Tau on survival, growth, bone development and oxidative metabolism in gilthead seabream larvae. Six micro-bound diets containing two levels of Tau combined with three levels of vit E plus vit C were manually fed 24 times/day to 16 dph larvae for 15 days. Elevation of dietary vit E and vit C over 3000 mg/kg, led to unbalanced body vit C/vit E ratio and up-regulation of genes coding for antioxidant enzymes, the highest incidence of bone anomalies and the lowest larval survival. Increase in dietary vit C + vit E up to 1800 mg/kg, down-regulated GPX expression, up-regulated OC expression and reduced maxillary bone anomalies. Increase in dietary Tau up to 7.1 g/kg significantly improved larval growth, down-regulated antioxidant enzyme genes and reduced the incidence of bone anomalies. Moreover, the pro-oxidative effects of the high supplementation of vit C and E where mitigated by increase in dietary Tau levels. Finally, increase in dietary vit E, vit C and Tau up to 1783 mg/kg, 1921 mg/kg and 7 g/kg lead to the highest larval survival and growth, the highest OC gene expression and the lowest incidence of bone anomalies, including lordosis, kyphosis, branchiostegal and maxillary bones anomalies.

The effects of low marine ingredient diets supplemented with graded levels (L1, L2, L3) of a micronutrient package (NP) on growth and metabolic responses were studied in diploid and triploid salmon parr. Diploids fed L2 showed significantly improved growth and reduced liver, hepatic steatosis, and viscerosomatic indices, while fish fed L3 showed suppressed growth rate 14 weeks post feeding. In contrast, dietary NP level had no effect on triploid performance. Whole body mineral composition, with exception of copper, did not differ between diet or ploidy. Whole fish total AAs and N-metabolites showed no variation by diet or ploidy. Free circulating AAs and white muscle N-metabolites were higher in triploids than diploids, while branch-chained amino acids were higher in diploids than triploids. Diploids had higher whole body α-tocopherol and hepatic vitamins K1 and K2 than triploids. Increased tissue B-vitamins for niacin and whole-body folate with dietary NP supplementation were observed in diploids but not triploids, while whole body riboflavin was higher in diploids than triploids. Hepatic transcriptome profiles showed that diploids fed diet L2 was more similar to that observed in triploids fed diet L3. In particular, sterol biosynthesis pathways were down-regulated, whereas cytochrome P450 metabolism was up-regulated. One‑carbon metabolism was also affected by increasing levels of supplementation in both ploidies. Collectively, results suggested that, for optimised growth and liver function, micronutrient levels be supplemented above current National Research Council (2011) recommendations for Atlantic salmon when fed low marine ingredient diets. The study also suggested differences in nutritional requirements between ploidy.

This work has presented a novel strategy for designing pH-sensitive TOS-H-DOX prodrug-loaded TPGS nanomicelles for co-delivery TOS and DOX to enhance tumor therapy and reduce the toxic side effects. DOX was covalently conjugated to the vitamin E succinate through hydrazone bond to produce an pH-sensitive prodrug TOS-H-DOX (amido bond as a control, TOS-A-DOX), which was responsive to the acidic environment in tumor cells, and the prodrugs were subsequently encapsulated in the core of TPGS nanomicelles via hydrophobic effects with a significant drug loading capacity. The pH-sensitive prodrug nanomicelles TOS-H-DOX/TPGS exhibited potent release of DOX in acidic media relative to the pH-insensitive prodrug nanomicelles TOS-A-DOX/TPGS, and further studies of their intracellular uptake and intracellular localization demonstrated that TOS-H-DOX/TPGS nanomicelles can be effectively taken up by cells and drugs can be released. In vitro results confirmed that TOS-H-DOX/TPGS nanomicelles exhibited significant antitumor cell proliferation activity compared to TOS-A-DOX/TPGS and free DOX, TPGS. Furthermore, in vivo studies further confirmed an excellent synergistic antitumor efficacy in MCF-7 tumor-bearing nude mice model. More importantly, the H&E staining of the heart, liver, kidney tissue sections of experimental nude mice showed that TOS-H-DOX/TPGS nanomicelles can reduce damage to them.