How vitamin E and its derivatives regulate tumour cells via the MAPK signalling pathway?'

In tumour cells, vitamin E and its derivatives play a critical role in the regulation of multiple signalling pathways through their oxidative and nonoxidative functions. To date, there are 8 known natural vitamin E forms and many kinds of derivatives, among which VES and α-TEA have excellent anticancer activities. The MAPK pathway consists of a complex cascade of proteins that control the proliferation, differentiation and apoptosis of tumour cells. The MAPK pathway includes four subfamilies, ERK1/2, JNK1/2, p38 MAPK, and ERK5. Most of the proteins in these subfamilies interact with each other in a complex manner. The anticancer function of vitamin E and its derivatives is closely related to the MAPK cascade. Studies have shown that in tumour cells, α-T/γ-T/γ-T3/δ-T3/VES/α-TEA regulated ERK1/2, prevent tumorigenesis, inhibit tumour cell growth and metastasis and induce cell differentiation, apoptosis, and cell cycle arrest; γ-T3/δ-T3/VES/α-TEA regulates JNK1/2, induce apoptosis, reduce ceramide synthesis and inhibit proliferation; and γ-T3/δ-T3/VES regulate p38 MAPK and induce apoptosis. This paper reviews the role of vitamin E and its derivatives in the MAPK cascade, and tumour cells are used as a model in an attempt to explore the mechanism of their interactions.

Vitamin E is necessary for zebrafish nervous system development.

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

Vitamin E: Regulatory role in the cardiovascular system.

Cardiovascular disease (CVD) is one of the major causes of morbidity and mortality, all around the world. Vitamin E is an important nutrient influencing key cellular and molecular mechanisms as well as gene expression regulation centrally involved in the prevention of CVD. Cell culture and animal studies have focused on the identification of vitamin E regulated signaling pathways and involvement on inflammation, lipid homeostasis, and atherosclerotic plaque stability. While some of these vitamin E functions were verified in clinical trials, some of the positive effects were not translated into beneficial outcomes in epidemiological studies. In recent years, the physiological metabolites of vitamin E, including the liver derived (long- and short-chain) metabolites and phosphorylated (α-, γ-tocopheryl phosphate) forms, have also provided novel mechanistic insight into CVD regulation that expands beyond the vitamin E precursor. It is certain that this emerging insight into the molecular and cellular action of vitamin E will help to design further studies, either in animal models or clinical trials, on the reduction of risk for CVDs. This review focuses on vitamin E-mediated preventive cardiovascular effects and discusses novel insights into the biology and mechanism of action of vitamin E metabolites in CVD. © 2019 IUBMB Life, 71(4):507-515, 2019.

Vitamin E: Regulatory role on gene and protein expression and metabolomics profiles.

Results from microarray analyzes have shown that both vitamin E deficiency and supplementation have a significant impact on the gene expression of various tissues and cells. Genes that were modulated by vitamin E supplementation were different depending on the tissue, which suggested that changes in gene expression are reflective of tissue function and the tissue-specific regulation of vitamin E. In addition, the magnitude of gene expression and types of genes whose expression was altered were differentially affected by the vitamin E forms used for intervention. Metabolite analyzes have provided better understanding of the vitamin E metabolic pathway and have established evidence for the regulation of energy, lipid, and glucose metabolism by vitamin E. However, there are a limited number of studies that have applied advanced genomics, proteomics, and metabolomics technologies to investigate vitamin E's biological functions and mechanisms of action. In this review, the effects of vitamin E on gene and protein expression investigated by microarray, transcriptome, and proteomics analysis are discussed. © 2019 IUBMB Life, 71(4):442-455, 2019.

Vitamin E: Regulatory Redox Interactions.

Vitamin E is an essential nutrient that was discovered in the 1920s. Many of the physiological functions of vitamin E, including its antioxidative effects, have been studied for nearly 100 years. Changes in redox balance induced by both endogenously and exogenously generated reactive oxygen species (ROS) are involved in various diseases, and are also a phenomenon that is considered essential for survival. Vitamin E is known to regulate redox balance in the body due to its high concentration among the lipid soluble vitamin groups, and exists ubiquitously in the whole body, including cell membranes and lipoproteins. However, it has been reported that the beneficial properties of vitamin E, including its antioxidative effects, are only displayed in vitro, and not in vivo. Therefore, there exists an ongoing debate regarding the biological functions of vitamin E and its relationship with redox balance. In this review, we introduce the relationship between vitamin E and redox interactions with (i) absorption, distribution, metabolism, and excretion of vitamin E, (ii) oxidative stress and ROS in the body, (iii) mechanism of antioxidative effects, (iv) non-antioxidant functions of vitamin E, and (v) recent recognition of the field of oxidative stress research. Understanding the recent findings of the redox interaction of vitamin E may help to elucidate the different antioxidative phenomena observed for vitamin E in vitro and in vivo. © 2019 IUBMB Life, 71(4):430-441, 2019.

Vitamin E: Regulatory Role on Signal Transduction.

Vitamin E modulates signal transduction pathways by several molecular mechanisms. As a hydrophobic molecule located mainly in membranes it contributes together with other lipids to the physical and structural characteristics such as membrane stability, curvature, fluidity, and the organization into microdomains (lipid rafts). By acting as the main lipid-soluble antioxidant, it protects other lipids such as mono- and poly-unsaturated fatty acids (MUFA and PUFA, respectively) against chemical reactions with reactive oxygen and nitrogen species (ROS and RNS, respectively) and prevents membrane destabilization and cellular dysfunction. In cells, vitamin E affects signaling in redox-dependent and redox-independent molecular mechanisms by influencing the activity of enzymes and receptors involved in modulating specific signal transduction and gene expression pathways. By protecting and preventing depletion of MUFA and PUFA it indirectly enables regulatory effects that are mediated by the numerous lipid mediators derived from these lipids. In recent years, some vitamin E metabolites have been observed to affect signal transduction and gene expression and their relevance for the regulatory function of vitamin E is beginning to be elucidated. In particular, the modulation of the CD36/FAT scavenger receptor/fatty acids transporter by vitamin E may influence many cellular signaling pathways relevant for lipid homeostasis, inflammation, survival/apoptosis, angiogenesis, tumorigenesis, neurodegeneration, and senescence. Thus, vitamin E has an important role in modulating signal transduction and gene expression pathways relevant for its uptake, distribution, metabolism, and molecular action that when impaired affect physiological and patho-physiological cellular functions relevant for the prevention of a number of diseases. © 2018 IUBMB Life, 71(4):456-478, 2019.

Vitamin E - The Next 100 Years.

α-Tocopherol is the only tocopherol that has been shown to prevent the human deficiency disease Ataxia with Isolated Vitamin E Deficiency (AVED), and thus it is the only one that, for humans, can be called vitamin E. Vitamin E in addition to preventing AVED has documented immune boosting properties and an activity against nonalcoholic hepatosteatosis and low-grade inflammation. Epidemiological studies indicating that vitamin E could prevent cardiovascular events, neurodegenerative disease, macular degeneration, and cancer were in general not confirmed by clinical intervention studies. Vitamin E and some of its metabolites modulate cell signaling and gene transcription. Future research is needed to achieve a better understanding of the molecular events leading to gene regulation by vitamin E, especially in its phosphorylated form. Isolation and characterization of the vitamin E kinase and vitamin E phosphate phosphatase will help in the understanding of cell regulation processes modulated by vitamin E. A clarification of the pathogenesis of AVED remains an important goal to be achieved. © 2018 IUBMB Life, 71(4):411-415, 2019.

Regulatory role of vitamin E in the immune system and inflammation.

Vitamin E, a potent lipid-soluble antioxidant, found in higher concentration in immune cells compared to other cells in blood, is one of the most effective nutrients known to modulate immune function. Vitamin E deficiency has been demonstrated to impair normal functions of the immune system in animals and humans, which can be corrected by vitamin E repletion. Although deficiency is rare, vitamin E supplementation above current dietary recommendations has been shown to enhance the function of the immune system and reduce risk of infection, particularly in older individuals. The mechanisms responsible for the effect of vitamin E on the immune system and inflammation have been explored in cell-based, pre-clinical and clinical intervention studies. Vitamin E modulates T cell function through directly impacting T cell membrane integrity, signal transduction, and cell division, and also indirectly by affecting inflammatory mediators generated from other immune cells. Modulation of immune function by vitamin E has clinical relevance as it affects host susceptibility to infectious diseases such as respiratory infections, in addition to allergic diseases such as asthma. Studies examining the role of vitamin E in the immune system have typically focused on α-tocopherol; however, emerging evidence suggests that other forms of vitamin E, including other tocopherols as well as tocotrienols, may also have potent immunomodulatory functions. Future research should continue to identify and confirm the optimal doses for individuals at different life stage, health condition, nutritional status, and genetic heterogeneity. Future research should also characterize the effects of non-α-alpha-tocopherol vitamin E on immune cell function as well as their potential clinical application. © 2018 IUBMB Life, 71(4):487-494, 2019.

Role of vitamin E in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. NAFLD manifests as hepatic lipid accumulation, insulin resistance, and inflammation, and can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, the underlying mechanisms of NAFLD, including those that drive its progression, are unclear. Both liver-resident (Kupffer cells) and recruited macrophages play a crucial role in the development of insulin resistance and NASH. Therefore, NALFD could potentially be ameliorated by modifying the polarization of macrophages/Kupffer cells. Reactive oxygen species induce oxidative stress, which is implicated in the progression of NASH. Micronutrients, including vitamins, are potent antioxidants that exert anti-inflammatory effects, and are used in the treatment of NAFLD. We review here the molecular mechanisms of the pathogenesis of NAFLD and the potential utility of vitamin E in its prevention and/or treatment. © 2018 IUBMB Life, 71(4):516-522, 2019.

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

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

Growth curves in Down syndrome with congenital heart disease / Curvas de crescimento na síndrome de Down com cardiopatia congênita

SUMMARY Introduction: To assess dietary habits, nutritional status and food frequency in children and adolescents with Down syndrome (DS) and congenital heart disease (CHD). Additionally, we attempted to compare body mass index (BMI) classifications according to the World Health Organization (WHO) curves and curves developed for individuals with DS. Method: Cross-sectional study including individuals with DS and CHD treated at a referral center for cardiology, aged 2 to 18 years. Weight, height, BMI, total energy and food frequency were measured. Nutritional status was assessed using BMI for age and gender, using curves for evaluation of patients with DS and those set by the WHO. Results: 68 subjects with DS and CHD were evaluated. Atrioventricular septal defect (AVSD) was the most common heart disease (52.9%). There were differences in BMI classification between the curves proposed for patients with DS and those proposed by the WHO. There was an association between consumption of vitamin E and polyunsaturated fatty acids. Conclusion: Results showed that individuals with DS are mostly considered normal weight for age, when evaluated using specific curves for DS. Reviews on specific curves for DS would be the recommended practice for health professionals so as to avoid precipitated diagnosis of overweight and/or obesity in this population.

RESUMO Objetivo: avaliar hábitos alimentares, estado nutricional e frequência alimentar em crianças e adolescentes com síndrome de Down (SD) portadores de cardiopatia congênita (CC). Adicionalmente, procurou-se comparar classificações de índice de massa corpórea (IMC) de acordo com curvas da Organização Mundial da Saúde (OMS) e curvas desenvolvidas para indivíduos com SD. Método: estudo transversal com indivíduos portadores de SD e CC atendidos em um centro de referência para cardiologia, com idade entre 2 e 18 anos. Foram aferidos peso, altura, IMC, valor energético total (VET) e frequência alimentar. O estado nutricional foi analisado por meio de IMC para gênero e idade, utilizando-se curvas específicas para SD e curvas da OMS. Resultados: foram avaliados 68 indivíduos portadores de SD com CC. O defeito do septo atrioventricular (DSAV) foi a cardiopatia mais frequente (52,9%). Houve diferença de classificação do IMC entre as curvas propostas para portadores de SD e pela OMS. Houve associação entre consumo de vitamina E e ácidos graxos poli-insaturados. Conclusão: resultados mostraram que indivíduos com SD são, em sua maioria, considerados eutróficos para a idade quando avaliados pelas curvas específicas para SD. Avaliá-los de acordo com as curvas específicas para SD seria o recomendado para a prática dos profissionais da saúde, evitando-se diagnósticos precipitados de sobrepeso e/ou obesidade nessa população.

Growth curves in Down syndrome with congenital heart disease.

INTRODUCTION: To assess dietary habits, nutritional status and food frequency in children and adolescents with Down syndrome (DS) and congenital heart disease (CHD). Additionally, we attempted to compare body mass index (BMI) classifications according to the World Health Organization (WHO) curves and curves developed for individuals with DS. METHOD: Cross-sectional study including individuals with DS and CHD treated at a referral center for cardiology, aged 2 to 18 years. Weight, height, BMI, total energy and food frequency were measured. Nutritional status was assessed using BMI for age and gender, using curves for evaluation of patients with DS and those set by the WHO. RESULTS: 68 subjects with DS and CHD were evaluated. Atrioventricular septal defect (AVSD) was the most common heart disease (52.9%). There were differences in BMI classification between the curves proposed for patients with DS and those proposed by the WHO. There was an association between consumption of vitamin E and polyunsaturated fatty acids. CONCLUSION: Results showed that individuals with DS are mostly considered normal weight for age, when evaluated using specific curves for DS. Reviews on specific curves for DS would be the recommended practice for health professionals so as to avoid precipitated diagnosis of overweight and/or obesity in this population.

Chasing great paths of Helmut Sies "Oxidative Stress".

Prof. Dr. Helmut Sies is a pioneer of "Oxidative Stress", and has published over 18 papers with the name of "Oxidative Stress" in the title. He has been Editor-in-Chief of the journal "Archives of Biochemistry and Biophysics" for many years, and is a former Editor-in-Chief of the journal "Free Radical Research". He has clarified our understanding of the causes of chronic developing diseases, and has studied antioxidant factors. In this article, importance of "Oxidative Stress" and our mitochondrial oxidative stress studies; roles of mitochondrial ROS, effects of vitamin E and its homologues in oxidative stress-related diseases, effects of antioxidants in vivo and in vitro, and a mitochondrial superoxide theory for oxidative stress diseases and aging are introduced, and some of our interactions with Helmut are described, congratulating and appreciating his great path.

Vitamin E: A Role in Signal Transduction.

Vitamin E modulates the activity of several signal transduction enzymes with consequent alterations of gene expression. At the molecular level, vitamin E may directly bind to these enzymes and compete with their substrates, or it may change their activity by redox regulation. The translocation of several of these enzymes to the plasma membrane is regulated by vitamin E, suggesting the modulation of protein-membrane interactions as a common mechanism for vitamin E action. Enzyme-membrane interactions can be affected by vitamin E by interference with binding to specific membrane lipids or by altering cellular structures such as membrane microdomains (lipid rafts). Moreover, competition by vitamin E for common binding sites within lipid transport proteins may alter the traffic of lipid mediators and thus affect their signaling and enzymatic conversion. In this review, the main effects of vitamin E on enzymes involved in signal transduction are summarized and possible molecular mechanisms leading to enzyme modulation are evaluated.

Vitamin E intake and pancreatic cancer risk: a meta-analysis of observational studies.

BACKGROUND: Some epidemiological studies have suggested that vitamin E intake reduces the risk of pancreatic cancer; however, this conclusion has not been supported by all the published studies. We conducted a meta-analysis to assess the relationship between vitamin E intake and the risk of pancreatic cancer by combining the results from published articles. MATERIAL/METHODS: We searched the published studies that reported the relationship between vitamin E intake and pancreatic cancer risk using the PubMed, Web of Science, and Embase databases through December 31st, 2014. Based on a fixed-effects or random-effects model, the RR and 95% CI were used to assess the combined risk. RESULTS: In total, 10 observational studies (6 case-control studies and 4 cohort studies) were included. The overall RR (95% CI) of pancreatic cancer for the highest vs. the lowest level of vitamin E intake was 0.81 (0.73, 0.89). We found little evidence of heterogeneity (I2=19.8%, P=0.255). In the subgroup analyses, we found an inverse association between vitamin E intake and pancreatic cancer risk both in the case-control and cohort studies. Additionally, this inverse association was not modified by different populations. CONCLUSIONS: In our meta-analysis, there was an inverse association between vitamin E intake and the risk of pancreatic cancer. A high level of vitamin E might be a protective factor for populations at risk for pancreatic cancer.

Age-associated changes in immune function: impact of vitamin E intervention and the underlying mechanisms.

Numerous studies have provided evidence suggesting that aging is associated with significant adverse changes in the immune system, a phenomenon often called immunosenescence, which may be responsible for an observed increase in morbidity and mortality from infectious disease and cancer in the elderly. While a variety of immune cells are known to be affected by aging, declined T cell function is the most striking and best characterized feature of immunosenescence. Both intrinsic changes in T cells and alteration in extrinsic factors are involved. Nutritional intervention has been promoted as a promising approach to delaying/reversing immunosenescence, and vitamin E is one of the best studied candidates in this regard. While vitamin E deficiency is rarely seen, both animal and human studies suggest that intake above currently recommended levels may help restore T cell function which becomes impaired with aging. This effect of vitamin E can be accomplished by directly impacting T cells as well as indirectly, by inhibiting production of prostaglandin E2, a T cell-suppressing lipid mediator known to increase with aging. Vitamin E-induced enhancements of immune functions may have significant clinical implications since vitamin E supplementation has been shown to be associated with both enhanced resistance to influenza infection in aged mice and reduced risk of acquiring upper respiratory infections in elderly human subjects. With a focus on our own work, this paper provides an overview on the beneficial effects of increased vitamin E intake on age-related decline in T cell function, the underlying mechanisms, and its clinical application in reducing the risk of infection.

Regulation of sheep α-TTP by dietary vitamin E and preparation of monoclonal antibody for sheep α-TTP.

α-Tocopherol transfer protein (α-TTP) is a cytosolic protein that plays an important role in regulating concentrations of plasma α-tocopherol (the most bio-active form of vitamin E). Despite the central roles that α-TTP plays in maintaining vitamin E adequacy, we have only recently proved the existence of the α-TTP gene in sheep and, for the first time, cloned its full-length cDNA. However, the study of sheep α-TTP is still in its infancy. In the present study, thirty-five local male lambs of Tan sheep with similar initial body weight were randomly divided into five groups and fed with diets supplemented with 0 (control group), 20, 100, 200, 2000IU·sheep(-1)·d(-1) vitamin E for 120 days. At the end of the experiment, the plasma and liver vitamin E contents were analyzed first and then α-TTP mRNA and protein expression levels were determined by quantitative real-time PCR (qRT-PCR) and Western-blot analysis, respectively. In addition, as no sheep α-TTP antibody was available, a specific monoclonal antibody (McAb) against the ovine α-TTP protein was prepared. The effect of vitamin E supplementation was confirmed by the significant changes in the concentrations of vitamin E in the plasma and liver. As shown by qRT-PCR and Western-blot analysis, dietary vitamin E does not affect sheep α-TTP gene expression, except for high levels of vitamin E supplementation, which significantly increased expression at the protein level. Importantly, the specific sheep anti-α-TTP McAb we generated could provide optimal recognition in ELISA, Western-blot and immunohistochemistry assays, which will be a powerful tool in future studies of the biological functions of sheep α-TTP.

How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo.

We present arguments for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiological evidence for disease prevention by dietary antioxidants and chemical evidence that such compounds react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymatic removal of nonradical electrophiles, such as hydroperoxides, in two-electron redox reactions is the major antioxidant mechanism. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. This maintenance of "nucleophilic tone," by a mechanism that can be called "para-hormesis," provides a means for regulating physiological nontoxic concentrations of the nonradical oxidant electrophiles that boost antioxidant enzymes, and damage removal and repair systems (for proteins, lipids, and DNA), at the optimal levels consistent with good health.