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Special Issue "Tocopherols and Tocotrienols: Metabolism and Properties"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (31 July 2016).

Special Issue Editors

Prof. Dr. Maria Laura Colombo
Website
Guest Editor
Department of Drug Science and Technology, University of Torino; Via Pietro Giuria 9, 10125 Torino, Italy
Interests: tocopherols and tocotrienols structure, tocotrienols and cholesterol
Prof. Dr. Laura Di Renzo
Website SciProfiles
Guest Editor
Division of Human Nutrition, Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy Via Montpellier n. 1, 00183 Rome, Italy
Interests: nutritional genomic (Nutrigenetic and Nutrigenomic); human body composition; metabolism; personalized nutritional assessment; food chemistry
Special Issues and Collections in MDPI journals
Dr. Rafat A. Siddiqui
Website SciProfiles
Guest Editor
Nutrition Science and Food Chemistry Laboratory, Virginia State University, 1 Hayden St, Petersburg, VA 23806, USA
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Studies focusing on food compounds for their functions in inflammation and oxidative stress have opened opportunities to prevent or treat the chronic non-communicable disease (CNCD). Although CNCDs progress slower and take longer to develop, they are non-infectious and non-transmissible. Examples of CNCDs include obesity, cardiovascular disease, diabetes, chronic kidney disease, osteoporosis, sarcopenia, Alzheimer's disease, and several types of cancer. The prevalence of CNCDs is rising rapidly, and WHO projections show that CNCD deaths are expected to increase by 15% globally between 2010 and 2020 (to 44 million deaths). The effects of dietary compounds on the metabolic and signaling pathways pertinent to CNCDs are currently a topic of great interest.  The recent developments have shifted traditional nutritional counseling toward a more complex approach based on the molecular and cellular effect of individual nutrients such as agonist/antagonist interaction with cell surface receptors, regulation of enzyme activities, and modulation of gene expression. These findings have provided a new perspective in nutrition science research.

a ,b, g, d tocopherols and a ,b, g, d tocotrienols, collectively known as Vitamin E homologs are well known and have been studied in the past, establishing a plethora of data in the literature.  The a tocopherols and to some extent the g tocopherols are the most investigated vitamin E homologs in human studies; however, the effects of other vitamin E homologs are not well known. In addition to their well-known anti-oxidation activities, these vitamins possess several other important biological activities. The purpose of this special issue is to comprehensively review all the important biological activities of vitamin E homologs to support the beneficial role of tocopherols and tocotrienols in disease prevention or treatment. We invite authors to submit original research and review articles that address the progress and current understanding of tocopherols and tocotrienols. Authors can write on any topic pertinent to Vitamin E homologs structure and functions; however, topics focused on analysis, intake, absorption and metabolism, cell signaling, gene expression, and variation in activities due to gene polymorphisms are desired.

Prof. Dr. Maria Laura Colombo
Dr. Laura Di Renzo
Dr. Rafat A. Siddiqui
Guest Editors
 Prof. Dr. Maria Laura Colombo  Dr. Laura Di Renzo Dr. Rafat A. Siddiqui

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Tocopherols
  • Tocotrienols
  • Metabolism
  • Antioxidant
  • beta-oxidation
  • Cholesterol reduction
  • Hypolipidemic
  • Nutrigenomic

Published Papers (17 papers)

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Research

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Open AccessArticle
Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells
Int. J. Mol. Sci. 2016, 17(12), 1973; https://doi.org/10.3390/ijms17121973 - 25 Nov 2016
Cited by 27
Abstract
Lipid peroxidation products, such as 7-ketocholesterol (7KC), may be increased in the body fluids and tissues of patients with neurodegenerative diseases and trigger microglial dysfunction involved in neurodegeneration. It is therefore important to identify synthetic and natural molecules able to impair the toxic [...] Read more.
Lipid peroxidation products, such as 7-ketocholesterol (7KC), may be increased in the body fluids and tissues of patients with neurodegenerative diseases and trigger microglial dysfunction involved in neurodegeneration. It is therefore important to identify synthetic and natural molecules able to impair the toxic effects of 7KC. We determined the impact of 7KC on murine microglial BV-2 cells, especially its ability to trigger mitochondrial and peroxisomal dysfunction, and evaluated the protective effects of α- and γ-tocopherol, Trolox, and oleic acid (OA). Multiple complementary chemical assays, flow cytometric and biochemical methods were used to evaluate the antioxidant and cytoprotective properties of these molecules. According to various complementary assays to estimate antioxidant activity, only α-, and γ-tocopherol, and Trolox had antioxidant properties. However, only α-tocopherol, γ-tocopherol and OA were able to impair 7KC-induced loss of mitochondrial transmembrane potential, which is associated with increased permeability to propidium iodide, an indicator of cell death. In addition, α-and γ-tocopherol, and OA were able to prevent the decrease in Abcd3 protein levels, which allows the measurement of peroxisomal mass, and in mRNA levels of Abcd1 and Abcd2, which encode for two transporters involved in peroxisomal β-oxidation. Thus, 7KC-induced side effects are associated with mitochondrial and peroxisomal dysfunction which can be inversed by natural compounds, thus supporting the hypothesis that the composition of the diet can act on the function of organelles involved in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessArticle
The Vitamin E Analog Gamma-Tocotrienol (GT3) and Statins Synergistically Up-Regulate Endothelial Thrombomodulin (TM)
Int. J. Mol. Sci. 2016, 17(11), 1937; https://doi.org/10.3390/ijms17111937 - 18 Nov 2016
Cited by 6
Abstract
Statins; a class of routinely prescribed cholesterol-lowering drugs; inhibit 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) and strongly induce endothelial thrombomodulin (TM); which is known to have anti-inflammatory; anti-coagulation; anti-oxidant; and radioprotective properties. However; high-dose toxicity limits the clinical use of statins. The vitamin E family member [...] Read more.
Statins; a class of routinely prescribed cholesterol-lowering drugs; inhibit 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) and strongly induce endothelial thrombomodulin (TM); which is known to have anti-inflammatory; anti-coagulation; anti-oxidant; and radioprotective properties. However; high-dose toxicity limits the clinical use of statins. The vitamin E family member gamma-tocotrienol (GT3) also suppresses HMGCR activity and induces TM expression without causing significant adverse side effects; even at high concentrations. To investigate the synergistic effect of statins and GT3 on TM; a low dose of atorvastatin and GT3 was used to treat human primary endothelial cells. Protein-level TM expression was measured by flow cytometry. TM functional activity was determined by activated protein C (APC) generation assay. Expression of Kruppel-like factor 2 (KLF2), one of the key transcription factors of TM, was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). TM expression increased in a dose-dependent manner after both atorvastatin and GT3 treatment. A combined treatment of a low-dose of atorvastatin and GT3 synergistically up-regulated TM expression and functional activity. Finally; atorvastatin and GT3 synergistically increased KLF2 expression. These findings suggest that combined treatment of statins with GT3 may provide significant health benefits in treating a number of pathophysiological conditions; including inflammatory and cardiovascular diseases. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessArticle
Tocotrienol Affects Oxidative Stress, Cholesterol Homeostasis and the Amyloidogenic Pathway in Neuroblastoma Cells: Consequences for Alzheimer’s Disease
Int. J. Mol. Sci. 2016, 17(11), 1809; https://doi.org/10.3390/ijms17111809 - 29 Oct 2016
Cited by 20
Abstract
One of the characteristics of Alzheimer´s disease (AD) is an increased amyloid load and an enhanced level of reactive oxidative species (ROS). Vitamin E has known beneficial neuroprotective effects, and previously, some studies suggested that vitamin E is associated with a reduced risk [...] Read more.
One of the characteristics of Alzheimer´s disease (AD) is an increased amyloid load and an enhanced level of reactive oxidative species (ROS). Vitamin E has known beneficial neuroprotective effects, and previously, some studies suggested that vitamin E is associated with a reduced risk of AD due to its antioxidative properties. However, epidemiological studies and nutritional approaches of vitamin E treatment are controversial. Here, we investigate the effect of α-tocotrienol, which belongs to the group of vitamin E, on AD-relevant processes in neuronal cell lines. In line with the literature, α-tocotrienol reduced the ROS level in SH-SY5Y cells. In the presence of tocotrienols, cholesterol and cholesterol esters, which have been shown to be risk factors in AD, were decreased. Besides the unambiguous positive effects of tocotrienol, amyloid-β (Aβ) levels were increased accompanied by an increase in the activity of enzymes responsible for Aβ production. Proteins and gene expression of the secretases and their components remained unchanged, whereas tocotrienol accelerates enzyme activity in cell-free assays. Besides enhanced Aβ production, tocotrienols inhibited Aβ degradation in neuro 2a (N2a)-cells. Our results might help to understand the controversial findings of vitamin E studies and demonstrate that besides the known positive neuroprotective properties, tocotrienols also have negative characteristics with respect to AD. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessArticle
Tocotrienol Nanoemulsion Platform of Curcumin Elicit Elevated Apoptosis and Augmentation of Anticancer Efficacy against Breast and Ovarian Carcinomas
Int. J. Mol. Sci. 2016, 17(11), 1792; https://doi.org/10.3390/ijms17111792 - 26 Oct 2016
Cited by 9
Abstract
Vitamin E (VE) tocotrienols (T3), recognized for their cancer-specific anti-proliferative and pro-apoptotic activities, have been previously fabricated into bio-active nanoemulsion (NE) formulations. Here, our viscosity-adapted δ-T3 NE platform was developed to additionally incorporate curcumin (CUR), which is known for its potent suppression of [...] Read more.
Vitamin E (VE) tocotrienols (T3), recognized for their cancer-specific anti-proliferative and pro-apoptotic activities, have been previously fabricated into bio-active nanoemulsion (NE) formulations. Here, our viscosity-adapted δ-T3 NE platform was developed to additionally incorporate curcumin (CUR), which is known for its potent suppression of signaling pathways involved in malignant cell growth, survival and metastasis. Thanks to efficient 70:30 wt % surfactant mix of Lutrol F-127:VE-TPGS, in conjunction with optimal CUR loading, a prototype CUR in δ-T3 NE was successfully prepared. Model CUR/δ-T3 NE demonstrated excellent nano-scale aspects (mean particle size = 261 nm, PDI = 0.27, and ζ-potential = −35 mV), pharmaceutical stability, and controlled release properties. Suitability for systemic administration was also verified via standardized in vitro biocompatibility and hemocompatibility assays. In two human cancer cells (MCF-7 and OVCAR-8), our CUR/δ-T3 NE prominently suppressed constitutive NF-κB activation, and significantly induced apoptosis. Finally, the combined CUR/δ-T3 NE produced superior cytotoxicity profiles, in concentration- and time-dependent manners (p ≤ 0.05), at least three to four folds lower IC50 than in closest CUR control. The strong synergism, estimated in both cultured carcinomas, revealed the augmented therapeutic efficacy of our CUR/δ-T3 NE combined platform, supporting its strong potential towards pharmaceutical development for cancer therapy. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessArticle
Oral Supplementation with a Special Additive of Retinyl Palmitate and Alpha Tocopherol Reduces Growth Retardation in Young Pancreatic Duct Ligated Pigs Used as a Model for Children Suffering from Exocrine Pancreatic Insufficiency
Int. J. Mol. Sci. 2016, 17(10), 1642; https://doi.org/10.3390/ijms17101642 - 28 Sep 2016
Cited by 1
Abstract
Pancreatic exocrine insufficiency (PEI) is a disease of diverse aetiology—e.g., majority of patients suffering from cystic fibrosis (CF) show PEI congenitally. Malnutrition and malabsorption of nutrients impair growth and nutritional status. As reduced fat digestion leads to a deficiency of fat-soluble vitamins the [...] Read more.
Pancreatic exocrine insufficiency (PEI) is a disease of diverse aetiology—e.g., majority of patients suffering from cystic fibrosis (CF) show PEI congenitally. Malnutrition and malabsorption of nutrients impair growth and nutritional status. As reduced fat digestion leads to a deficiency of fat-soluble vitamins the supplementation is standard, but absorption is a critical point in PEI-patients. The pancreatic duct ligated (PL) pig is an established model for PEI in humans and has been proven to be a suitable model to compare different vitamin additives for supplementation. In a former study, PEI caused distinct growth retardation in young piglets, but did not affect growth in older ones. Our study hypothesised that this age-dependent effect is caused by exhausted body reserves of fat-soluble vitamins and, therefore, extra supply reduces growth retardation. PEI was induced by PL at the age of seven (PL-7) or 16 weeks (PL-16). Controls (C) underwent a sham surgery. Some PL-7 pigs (PL-7 + Vit) were fed a special vitamin additive. PEI reduced the mean final body weight (kg) at 26 weeks of age significantly with lower effect in PL-16-pigs (C:117; PL-7:49.5; PL-7 + Vit:77.1; PL-16:96.4). Extra vitamin supply resulted in an increased growth and normalised serum concentration of alpha-tocopherol, underlining the importance of special supplementation in PEI-patients. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessArticle
Theoretical and Kinetic Tools for Selecting Effective Antioxidants: Application to the Protection of Omega-3 Oils with Natural and Synthetic Phenols
Int. J. Mol. Sci. 2016, 17(8), 1220; https://doi.org/10.3390/ijms17081220 - 29 Jul 2016
Cited by 21
Abstract
Radical-scavenging antioxidants play crucial roles in the protection of unsaturated oils against autoxidation and, especially, edible oils rich in omega-3 because of their high sensitivity to oxygen. Two complementary tools are employed to select, among a large set of natural and synthetic phenols, [...] Read more.
Radical-scavenging antioxidants play crucial roles in the protection of unsaturated oils against autoxidation and, especially, edible oils rich in omega-3 because of their high sensitivity to oxygen. Two complementary tools are employed to select, among a large set of natural and synthetic phenols, the most promising antioxidants. On the one hand, density functional theory (DFT) calculations provide bond dissociation enthalpies (BDEs) of 70 natural (i.e., tocopherols, hydroxybenzoic and cinnamic acids, flavonoids, stilbenes, lignans, and coumarins) and synthetic (i.e., 2,6-di-tert-butyl-4-methylphenol (BHT), 3-tert-butyl-4-hydroxyanisol (BHA), and tert-butylhydroquinone (TBHQ)) phenols. These BDEs are discussed on the basis of structure–activity relationships with regard to their potential antioxidant activities. On the other hand, the kinetic rate constants and number of hydrogen atoms released per phenol molecule are measured by monitoring the reaction of phenols with 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. The comparison of the results obtained with these two complementary methods allows highlighting the most promising antioxidants. Finally, the antioxidant effectiveness of the best candidates is assessed by following the absorption of oxygen by methyl esters of linseed oil containing 0.5 mmol L−1 of antioxidant and warmed at 90 °C under oxygen atmosphere. Under these conditions, some natural phenols namely epigallocatechin gallate, myricetin, rosmarinic and carnosic acids were found to be more effective antioxidants than α-tocopherol. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessArticle
Tissue-Specific Effects of Vitamin E Supplementation
Int. J. Mol. Sci. 2016, 17(7), 1166; https://doi.org/10.3390/ijms17071166 - 19 Jul 2016
Cited by 5
Abstract
A multivitamin and mineral supplementation study of 6 weeks was conducted with male and female mice. The control group received a standard dose of vitamins and minerals of 1× the Recommended Daily Intake (RDI), whereas a second group received 3× RDI. A third [...] Read more.
A multivitamin and mineral supplementation study of 6 weeks was conducted with male and female mice. The control group received a standard dose of vitamins and minerals of 1× the Recommended Daily Intake (RDI), whereas a second group received 3× RDI. A third group received a high dose of vitamin E (25× RDI), close to the upper limit of toxicity (UL), but still recommended and considered to be harmless and beneficial. The high dose of vitamin E caused a number of beneficial, but also adverse effects. Different biomarkers of tissue toxicity, oxidative stress related processes and inflammation were determined. These biomarkers did not change in plasma and erythrocytes to a large extent. In the liver of male mice, some beneficial effects were observed by a lower concentration of several biomarkers of inflammation. However, in the kidney of male mice, a number of biomarkers increased substantially with the higher dose of vitamin E, indicating tissue toxicity and an increased level of inflammation. Since this dose of vitamin E, which is lower than the UL, cause some adverse effects, even after a short exposure period, further studies are required to reconsider the UL for vitamin E. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Review

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Open AccessReview
α-Tocopherol and Hippocampal Neural Plasticity in Physiological and Pathological Conditions
Int. J. Mol. Sci. 2016, 17(12), 2107; https://doi.org/10.3390/ijms17122107 - 15 Dec 2016
Cited by 13
Abstract
Neuroplasticity is an “umbrella term” referring to the complex, multifaceted physiological processes that mediate the ongoing structural and functional modifications occurring, at various time- and size-scales, in the ever-changing immature and adult brain, and that represent the basis for fundamental neurocognitive behavioral functions; [...] Read more.
Neuroplasticity is an “umbrella term” referring to the complex, multifaceted physiological processes that mediate the ongoing structural and functional modifications occurring, at various time- and size-scales, in the ever-changing immature and adult brain, and that represent the basis for fundamental neurocognitive behavioral functions; in addition, maladaptive neuroplasticity plays a role in the pathophysiology of neuropsychiatric dysfunctions. Experiential cues and several endogenous and exogenous factors can regulate neuroplasticity; among these, vitamin E, and in particular α-tocopherol (α-T), the isoform with highest bioactivity, exerts potent effects on many plasticity-related events in both the physiological and pathological brain. In this review, the role of vitamin E/α-T in regulating diverse aspects of neuroplasticity is analyzed and discussed, focusing on the hippocampus, a brain structure that remains highly plastic throughout the lifespan and is involved in cognitive functions. Vitamin E-mediated influences on hippocampal synaptic plasticity and related cognitive behavior, on post-natal development and adult hippocampal neurogenesis, as well as on cellular and molecular disruptions in kainate-induced temporal seizures are described. Besides underscoring the relevance of its antioxidant properties, non-antioxidant functions of vitamin E/α-T, mainly involving regulation of cell signaling molecules and their target proteins, have been highlighted to help interpret the possible mechanisms underlying the effects on neuroplasticity. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
Genetic Variations Involved in Vitamin E Status
Int. J. Mol. Sci. 2016, 17(12), 2094; https://doi.org/10.3390/ijms17122094 - 13 Dec 2016
Cited by 12
Abstract
Vitamin E (VE) is the generic term for four tocopherols and four tocotrienols that exhibit the biological activity of α-tocopherol. VE status, which is usually estimated by measuring fasting blood VE concentration, is affected by numerous factors, such as dietary VE intake, VE [...] Read more.
Vitamin E (VE) is the generic term for four tocopherols and four tocotrienols that exhibit the biological activity of α-tocopherol. VE status, which is usually estimated by measuring fasting blood VE concentration, is affected by numerous factors, such as dietary VE intake, VE absorption efficiency, and VE catabolism. Several of these factors are in turn modulated by genetic variations in genes encoding proteins involved in these factors. To identify these genetic variations, two strategies have been used: genome-wide association studies and candidate gene association studies. Each of these strategies has its advantages and its drawbacks, nevertheless they have allowed us to identify a list of single nucleotide polymorphisms associated with fasting blood VE concentration and α-tocopherol bioavailability. However, much work remains to be done to identify, and to replicate in different populations, all the single nucleotide polymorphisms involved, to assess the possible involvement of other kind of genetic variations, e.g., copy number variants and epigenetic modifications, in order to establish a reliable list of genetic variations that will allow us to predict the VE status of an individual by knowing their genotype in these genetic variations. Yet, the potential usefulness of this area of research is exciting with regard to personalized nutrition and for future clinical trials dedicated to assessing the biological effects of the various isoforms of VE. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
Role of Endogenous and Exogenous Tocopherols in the Lipid Stability of Marine Oil Systems: A Review
Int. J. Mol. Sci. 2016, 17(12), 1968; https://doi.org/10.3390/ijms17121968 - 24 Nov 2016
Cited by 8
Abstract
In marine organisms primarily intended for human consumption, the quality of the muscle and the extracted oils may be affected by lipid oxidation during storage, even at low temperatures. This has led to a search for alternatives to maintain quality. In this sense, [...] Read more.
In marine organisms primarily intended for human consumption, the quality of the muscle and the extracted oils may be affected by lipid oxidation during storage, even at low temperatures. This has led to a search for alternatives to maintain quality. In this sense, antioxidant compounds have been used to prevent such lipid deterioration. Among the most used compounds are tocopherols, which, due to their natural origin, have become an excellent alternative to prevent or retard lipid oxidation and maintain the quality of marine products. Tocopherols as antioxidants have been studied both exogenously and endogenously. Exogenous tocopherols are often used by incorporating them into plastic packaging films or adding them directly to fish oil. It has been observed that exogenous tocopherols incorporated in low concentrations maintain the quality of both muscle and the extracted oils during food storage. However, it has been reported that tocopherols applied at higher concentrations act as a prooxidant molecule, probably because their reactions with singlet oxygen may generate free radicals and cause the oxidation of polyunsaturated fatty acids in fish oils. However, when tocopherols are included in a fish diet (endogenous tocopherols), the antioxidant effect on the muscle lipids is more effective due to their incorporation into the membrane lipids, which can help extend the shelf life of seafood by reducing the lipid deterioration that occurs due to antioxidant synergy with other phenolic compounds used supplements in fish muscle. This review focuses on the most important studies in this field and highlights the potential of using tocopherols as antioxidants in marine oils. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease
Int. J. Mol. Sci. 2016, 17(11), 1785; https://doi.org/10.3390/ijms17111785 - 26 Oct 2016
Cited by 30
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
Biological Properties of Tocotrienols: Evidence in Human Studies
Int. J. Mol. Sci. 2016, 17(11), 1682; https://doi.org/10.3390/ijms17111682 - 26 Oct 2016
Cited by 23
Abstract
Vitamin E has been recognized as an essential vitamin since their discovery in 1922. Although the functions of tocopherols are well established, tocotrienols have been the unsung heroes of vitamin E. Due to their structural differences, tocotrienols were reported to exert distinctive properties [...] Read more.
Vitamin E has been recognized as an essential vitamin since their discovery in 1922. Although the functions of tocopherols are well established, tocotrienols have been the unsung heroes of vitamin E. Due to their structural differences, tocotrienols were reported to exert distinctive properties compared to tocopherols. While most vegetable oils contain higher amount of tocopherols, tocotrienols were found abundantly in palm oil. Nature has made palm vitamin E to contain up to 70% of total tocotrienols, among which alpha-, gamma- and delta-tocotrienols are the major constituents. Recent advancements have shown their biological properties in conferring protection against cancer, cardiovascular diseases, neurodegeneration, oxidative stress and immune regulation. Preclinical results of these physiological functions were translated into clinical trials gaining global attention. This review will discuss in detail the evidence in human studies to date in terms of efficacy, population, disease state and bioavailability. The review will serve as a platform to pave the future direction for tocotrienols in clinical settings. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits
Int. J. Mol. Sci. 2016, 17(10), 1745; https://doi.org/10.3390/ijms17101745 - 20 Oct 2016
Cited by 90
Abstract
Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible [...] Read more.
Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible oils with considerable contents of tocopherols and tocotrienols. Tocopherols are among the most important lipid-soluble antioxidants in food as well as in human and animal tissues. Tocopherols are found in lipid-rich regions of cells (e.g., mitochondrial membranes), fat depots, and lipoproteins such as low-density lipoprotein cholesterol. Their health benefits may also be explained by regulation of gene expression, signal transduction, and modulation of cell functions. Potential health benefits of tocols include prevention of certain types of cancer, heart disease, and other chronic ailments. Although deficiencies of tocopherol are uncommon, a continuous intake from common and novel dietary sources of tocopherols and tocotrienols is advantageous. Thus, this contribution will focus on the relevant literature on common and emerging edible oils as a source of tocols. Potential application and health effects as well as the impact of new cultivars as sources of edible oils and their processing discards are presented. Future trends and drawbacks are also briefly covered. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review
Int. J. Mol. Sci. 2016, 17(10), 1605; https://doi.org/10.3390/ijms17101605 - 22 Sep 2016
Cited by 20
Abstract
Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, [...] Read more.
Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-κB suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the α-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of α-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
γ-Tocotrienol as a Promising Countermeasure for Acute Radiation Syndrome: Current Status
Int. J. Mol. Sci. 2016, 17(5), 663; https://doi.org/10.3390/ijms17050663 - 03 May 2016
Cited by 23
Abstract
The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of non-toxic, safe and effective medical countermeasures for radiological and nuclear emergency. To date, the U.S. Food and [...] Read more.
The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of non-toxic, safe and effective medical countermeasures for radiological and nuclear emergency. To date, the U.S. Food and Drug Administration (U.S. FDA) has approved only two growth factors, Neupogen (granulocyte colony-stimulating factor (G-CSF), filgrastim) and Neulasta (PEGylated G-CSF, pegfilgrastim) for the treatment of hematopoietic acute radiation syndrome (H-ARS) following the Animal Efficacy Rule. Promising radioprotective efficacy results of γ-tocotrienol (GT3; a member of the vitamin E family) in the mouse model encouraged its further evaluation in the nonhuman primate (NHP) model. These studies demonstrated that GT3 significantly aided the recovery of radiation-induced neutropenia and thrombocytopenia compared to the vehicle controls; these results particularly significant after exposure to 5.8 or 6.5 Gray (Gy) whole body γ-irradiation. The stimulatory effect of GT3 on neutrophils and thrombocytes (platelets) was directly and positively correlated with dose; a 75 mg/kg dose was more effective compared to 37.5 mg/kg. GT3 was also effective against 6.5 Gy whole body γ-irradiation for improving neutrophils and thrombocytes. Moreover, a single administration of GT3 without any supportive care was equivalent, in terms of improving hematopoietic recovery, to multiple doses of Neupogen and two doses of Neulasta with full supportive care (including blood products) in the NHP model. GT3 may serve as an ultimate radioprotector for use in humans, particularly for military personnel and first responders. In brief, GT3 is a promising radiation countermeasure that ought to be further developed for U.S. FDA approval for the ARS indication. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
Vitamin E Content and Composition in Tomato Fruits: Beneficial Roles and Bio-Fortification
Int. J. Mol. Sci. 2015, 16(12), 29250-29264; https://doi.org/10.3390/ijms161226163 - 08 Dec 2015
Cited by 22
Abstract
Several epidemiological studies have demonstrated that high vitamin E intakes are related to a reduced risk of non-communicable diseases, while other dietary antioxidants are not, suggesting that vitamin E exerts specific healthy functions in addition to its antioxidant role. In this regard, tomato [...] Read more.
Several epidemiological studies have demonstrated that high vitamin E intakes are related to a reduced risk of non-communicable diseases, while other dietary antioxidants are not, suggesting that vitamin E exerts specific healthy functions in addition to its antioxidant role. In this regard, tomato (Solanum lycopersicum), one of the most consumed vegetables of the whole world population, is an important source of both tocopherols and tocotrienols. However, vitamin E content may strongly depend on several biotic and abiotic factors. In this review we will debate the elements affecting the synthesis of tocopherols and tocotrienols in tomato fruit, such as environmental conditions, genotype, fruit maturity level, and the impact of classical processing methods, such as pasteurization and lyophilization on the amount of these compounds. In addition we will analyze the specific vitamin E mechanisms of action in humans and the consequent functional effects derived from its dietary intake. Finally, we will examine the currently available molecular techniques used to increase the content of vitamin E in tomato fruit, starting from the identification of genetic determinants and quantitative trait loci that control the accumulation of these metabolites. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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Open AccessReview
Focus on Pivotal Role of Dietary Intake (Diet and Supplement) and Blood Levels of Tocopherols and Tocotrienols in Obtaining Successful Aging
Int. J. Mol. Sci. 2015, 16(10), 23227-23249; https://doi.org/10.3390/ijms161023227 - 25 Sep 2015
Cited by 21
Abstract
Numerous specific age-related morbidities have been correlated with low intake and serum levels of tocopherols and tocotrienols. We performed a review in order to evaluate the extant evidence regarding: (1) the association between intake and serum levels of tocopherols and tocotrienols and age-related [...] Read more.
Numerous specific age-related morbidities have been correlated with low intake and serum levels of tocopherols and tocotrienols. We performed a review in order to evaluate the extant evidence regarding: (1) the association between intake and serum levels of tocopherols and tocotrienols and age-related pathologies (osteoporosis, sarcopenia and cognitive impairment); and (2) the optimum diet therapy or supplementation with tocopherols and tocotrienols for the treatment of these abnormalities. This review included 51 eligible studies. The recent literature underlines that, given the detrimental effect of low intake and serum levels of tocopherols and tocotrienols on bone, muscle mass, and cognitive function, a change in the lifestyle must be the cornerstone in the prevention of these specific age-related pathologies related to vitamin E-deficient status. The optimum diet therapy in the elderly for avoiding vitamin E deficiency and its negative correlates, such as high inflammation and oxidation, must aim at achieving specific nutritional goals. These goals must be reached through: accession of the elderly subjects to specific personalized dietary programs aimed at achieving and/or maintaining body weight (avoid malnutrition); increase their intake of food rich in vitamin E, such as derivatives of oily seeds (in particular wheat germ oil), olive oil, hazelnuts, walnuts, almonds, and cereals rich in vitamin E (such as specific rice cultivar rich in tocotrienols) or take vitamin E supplements. In this case, vitamin E can be correctly used in a personalized way either for the outcome from the pathology or to achieve healthy aging and longevity without any adverse effects. Full article
(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)
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