Vitamin E: Regulatory role in the cardiovascular system

Sozen E, Demirel T, Ozer NK

IUBMB Life. 2019 Feb 18. doi: 10.1002/iub.2020. [Epub ahead of print]


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.

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The Effectiveness of Vitamin E Treatment in Alzheimer’s Disease

Lloret A, Esteve D, Monllor P, Cervera-Ferri A, Lloret A

Int J Mol Sci. 2019 Feb 18;20(4). pii: E879. doi: 10.3390/ijms20040879.


Vitamin E was proposed as treatment for Alzheimer’s disease many years ago. However, the effectiveness of the drug is not clear. Vitamin Eis an antioxidant and neuroprotector and it has anti-inflammatory and hypocholesterolemic properties, driving to its importance for brain health. Moreover, the levels of vitamin E in Alzheimer’s disease patients are lower than in non-demented controls. Thus, vitamin E could be a good candidate to have beneficial effects against Alzheimer’s. However, evidence is consistent with a limited effectiveness of vitamin E in slowing progression of dementia; the information is mixed and inconclusive. The question is why does vitamin E fail to treat Alzheimer’s disease? In this paper we review the studies with and without positive results in Alzheimer’s disease and we discuss the reasons why vitamin E as treatment sometimes has positive results on cognition but at others, it does not.

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Serum vitamin E as a significant prognostic factor in patients with dyslipidemia disorders

Barzegar-Amini M, Ghazizadeh H, Seyedi SMR, Sadeghnia HR, Mohammadi A, Hassanzade-Daloee M, Barati E, Kharazmi-Khorassani S, Kharazmi-Khorassani J, Mohammadi-Bajgiran M, Tavallaie S, Ferns GA, Mouhebati M, Ebrahimi M, Tayefi M, Ghayour-Mobarhan M

Diabetes Metab Syndr. 2019 Jan - Feb;13(1):666-671. doi: 10.1016/j.dsx.2018.11.034. Epub 2018 Nov 13.



Obesity and overweight are among the main causes of cardiovascular disease (CVD) mortality. Dyslipidemia, fatty liver index, is strongly related to CVD. Vitamin E as an antioxidant protects the hepatic cells against oxidative stress and prevents fatty liver disease. The aim of the current study is to evaluate the relationship between anthropometric parameters and fasted lipid profile with serum vitamin Elevels.


A randomized trial was designed based on data from the Mashhad stroke and heart atherosclerotic disorders (MASHAD: 2010-2020).


363 CVD subjects (173 males and 190 females) was selected at random, among 9704 subjects in three regions of Mashhad, northeast of Iran to investigate the specific correlations among their serum vitamin E, lipid profile (TG, HDL-C, LDL-C and TC), and anthropometric features (height, weight, BMI, hip and waist circumferences.


The results indicated the significant relationships between vitamin E, and fasting serum lipid profile in subjects. Serum vitamin Ewas negatively correlated to TC, TG, and LDL-C and positively related to HDL-C. Also, statistically negative correlations were found between vitamin E and anthropometric parameters (weight, waist and hip circumference, middle Arm, and Systolic Blood Pressure). Moreover, vitamin E ratios such as vitamin E/(TC + TG) and vitamin E/TC values as standardized vitamin E, had significant negative correlation with BMI, the whole of anthropometric parameters, and dyslipidemia risk factors including TC, TG and LDL-C.


We found that vitamin E profile was significantly lower in the dyslipidemia subjects. It is generally suggested that vitamin E monitoring might be used as a useful prognostic and therapeutic agent in dyslipidemia disorder.

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Combined use of vitamin E and nimodipine ameliorates dibutyl phthalate-induced memory deficit and apoptosis in mice by inhibiting the ERK 1/2 pathway

Yan B, Sun Y, Zeng J, Chen Y, Li C, Song P, Zhang L, Yang X, Wu Y, Ma P

Toxicol Appl Pharmacol. 2019 Feb 15;368:1-17. doi: 10.1016/j.taap.2019.02.008. [Epub ahead of print]


Learning disabilities (LDs) in children are a serious global problem. Dibutyl phthalate (DBP), a plasticizer widely used in daily life, has been linked to triggering childhood LDs, however the mechanism underlying this remains unclear. Studies have shown that the ERK 1/2 pathway is closely related to apoptosis of hippocampal neurons. On the basis of these links between LDs, DBP and the ERK 1/2 pathway, we explore whether DBP induces hippocampal neuron apoptosis and increases behavioral disorders in mice via the ERK 1/2 pathway. We looked at oxidative stress, examined the calcium signal, detected the ERK 1/2 pathway and evaluated apoptosis as well as using histological observations, and found that DBP significantly increased oxidative damage and apoptosis in hippocampal neurons via the ERK 1/2 pathway in mice. We also found that pretreatment with the dihydropyridine’s (DHP’s) Ca2+ antagonist, nimodipine (NMDP), combined with the antioxidant Vitamin E (VE), attenuated ERK 1/2 phosphorylation and DBP-mediated disorders, suggesting that a combined use of VE and NMDP can ameliorate DBP-induced memory deficit and apoptosis via inhibiting the ERK 1/2 pathway. These results indicate that DBP predisposes oxidative damage and apoptosis in hippocampal neurons by activation of the ERK 1/2 pathway, and may be proposed as a possible mechanism underlying LDs in children. Moreover, VE and NMDP may play a certain protective role in the targeted treatment of childhood LDs.

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The Antioxidant Effects of Hydroxytyrosol and Vitamin E on Pediatric Nonalcoholic Fatty Liver Disease, in a Clinical Trial: A New Treatment?

Nobili V, Alisi A, Mosca A, Crudele A, Zaffina S, Denaro M, Smeriglio A, Trombetta D

Antioxid Redox Signal. 2019 Feb 11. doi: 10.1089/ars.2018.7704. [Epub ahead of print]


Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Several studies suggest that the improvement of oxidative stress is suggested as a possible therapeutic strategy for pediatric nonalcoholic steatohepatitis. We performed a randomized, double-blind placebo-controlled trial to test the potential efficacy, assessed by improvement of oxidative stress parameters and liver ultrasound, and tolerability of a mixture of vitamin E and hydroxytyrosol (HXT) in adolescents with biopsy-proven NAFLD. Four hundred forty consecutive patients were screened, 80 of these with biopsy-proven NAFLD were enrolled. Forty patients received an oral dose of HXT and vitamin E and 40 children received the capsules of placebo for 4 months. Seventy patients completed the study. Patients in the treatment arm showed a decrease of insulin resistance (IR), triglyceride levels, oxidative stress parameters, and steatosis grade. Noteworthy, the steatosis improvement correlates with the levels of advanced glycation end products and carbonylated proteins. The HXT and vitamin Etreatment improved the main oxidative stress parameters, IR, and steatosis in children with NAFLD. The use of two natural molecules that may have antioxidant effects seems a promising strategy that could be easily diet integrated to improve NAFLD-related liver damage in children.

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Vitamins E and C prevent apoptosis of testicular and ovarian tissues following mancozeb exposure in the first-generation mouse pups

Mahdi H, Tahereh H, Esmaiel S, Massood E

Toxicol Ind Health. 2019 Feb;35(2):136-144. doi: 10.1177/0748233718818692. Epub 2019 Jan 16.


The aim of this study was to evaluate the role of apoptosis in the first-generation pups’ testicular and ovarian tissue changes following mancozeb (MNZ) administration during intrauterine and lactating periods and also the preventive effect of the co-administration of vitamins E and C on these changes. Naval Medical Research Institute (NMRI) pregnant mice were randomly divided into six groups: control, vehicle, MNZ, vitamin E plus MNZ, vitamin C plus MNZ and vitamins E and C plus MNZ. Administered doses of MNZ and vitamins E and C were 500, 200 and 100 mg/kg of body weight, respectively. These agents were administered to the animals by oral gavage every 2 days. Vitamin treatment was carried out 30 min prior to MNZ administration. Treatment was started on the second day of gestation and continued until weaning. Separated testes and ovaries of animals were prepared for apoptosis detection by terminal deoxynucleotidyl transferase end-labeling (TUNEL) staining. The percentage of TUNEL-positive cells was reported using the 4,6-diamidino-2-phenylindole method. As compared to the control and vehicle groups, MNZ induced a significant increase ( p < 0.001) in the number of TUNEL-positive cells. The administration of both vitamins E and C alone and together significantly ( p < 0.001) prevented the apoptotic impacts of MNZ. The preventive effect of the co-administration of these vitamins on the ovary was greater compared to the single administration of vitamins E ( p < 0.001) or C ( p < 0.001). Meanwhile, the results revealed the stronger preventive effect of vitamin C as compared to E on testicular tissue ( p < 0.05). The apoptotic impact of MNZ exposure during intrauterine and lactating periods on first-generation testicular and ovarian tissues was significant. The co-administration of vitamins E and C could prevent MNZ-induced testicular and ovarian changes.

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δ-Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells

Fontana F, Moretti RM, Raimondi M, Marzagalli M, Beretta G, Procacci P, Sartori P, Montagnani Marelli M, Limonta P

Cell Prolif. 2019 Feb 4:e12576. doi: 10.1111/cpr.12576. [Epub ahead of print]



Prostate cancer, after the phase of androgen dependence, may progress to the castration-resistant prostate cancer (CRPC) stage, with resistance to standard therapies. Vitamin E-derived tocotrienols (TTs) possess a significant antitumour activity. Here, we evaluated the anti-cancer properties of δ-TT in CRPC cells (PC3 and DU145) and the related mechanisms of action.


MTT, Trypan blue and colony formation assays were used to assess cell viability/cell death/cytotoxicity. Western blot, immunofluorescence and MTT analyses were utilized to investigate apoptosis, ER stress and autophagy. Morphological changes were investigated by light and transmission electron microscopy.


We demonstrated that δ-TT exerts a cytotoxic/proapoptotic activity in CRPC cells. We found that in PC3 cells: (a) δ-TT triggers both the endoplasmic reticulum (ER) stress and autophagy pathways; (b) autophagy induction is related to the ER stress, and this ER stress/autophagy axis is involved in the antitumour activity of δ-TT; in autophagy-defective DU145 cells, only the ER stress pathway is involved in the proapoptotic effects of δ-TT; (c) in both CRPC cell lines, δ-TT also induces an intense vacuolation prevented by the ER stress inhibitor salubrinal and the protein synthesis inhibitor cycloheximide, together with increased levels of phosphorylated JNK and p38, supporting the induction of paraptosis by δ-TT.


These data demonstrate that apoptosis, involving ER stress and autophagy (in autophagy positive PC3 cells), and paraptosis are involved in the anti-cancer activity of δ-TT in CRPC cells.

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Molecular Mechanisms of Action of Tocotrienols in Cancer: Recent Trends and Advancements

Aggarwal V, Kashyap D, Sak K, Tuli HS, Jain A, Chaudhary A, Garg VK, Sethi G, Yerer MB

Int J Mol Sci. 2019 Feb 2;20(3). pii: E656. doi: 10.3390/ijms20030656.


Tocotrienols, found in several natural sources such as rice bran, annatto seeds, and palm oil have been reported to exert various beneficial health promoting properties especially against chronic diseases, including cancer. The incidence of cancer is rapidly increasing around the world not only because of continual aging and growth in global population, but also due to the adaptation of Western lifestyle behaviours, including intake of high fat diets and low physical activity. Tocotrienols can suppress the growth of different malignancies, including those of breast, lung, ovary, prostate, liver, brain, colon, myeloma, and pancreas. These findings, together with the reported safety profile of tocotrienols in healthy human volunteers, encourage further studies on the potential application of these compounds in cancer prevention and treatment. In the current article, detailed information about the potential molecular mechanisms of actions of tocotrienols in different cancer models has been presented and the possible effects of these vitamin E analogues on various important cancer hallmarks, i.e., cellular proliferation, apoptosis, angiogenesis, metastasis, and inflammation have been briefly analyzed.

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Molecular Understanding of the Cardiomodulation in Myocardial Infarction and the Mechanism of Vitamin E Protection

Zarkasi KA, Jen-Kit T, Jubri Z

Trop Anim Health Prod. 2019 Jan 31. doi: 10.1007/s11250-019-01826-0. [Epub ahead of print]


Myocardial infarction is a major cause of deaths globally. Modulation of several molecular mechanisms occur during the initial stages of myocardial ischemia prior to permanent cardiac tissue damage, which involve both pathogenic as well as survival pathways in the cardiomyocyte. Currently, there are increasing evidence regarding the cardioprotective role of vitamin E in alleviating the disease. This fat-soluble vitamin does not only act as a powerful antioxidant; it also has the ability to regulate several intracellular signalling pathways including HIF-1, PPAR-γ, Nrf-2, and NF-κB that influence the expression of a number of genes and their protein products. Essentially, it inhibits the molecular progression of tissue damage and preserves myocardial tissue viability. This review aims to summarize the molecular understanding of the cardiomodulation in myocardial infarction as well as the mechanism of vitamin E protection.

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A Nested Case-Control Study on Plasma Vitamin E and Risk of Cancer: Evidence of Effect Modification by Selenium.

Wang J, Guo H, Lin T, Song Y, Zhang H, Wang B, Zhang Y, Li J, Huo Y, Wang X, Qin X, Xu X.

J Acad Nutr Diet. 2019 Jan 31. pii: S2212-2672(18)30852-9. doi: 10.1016/j.jand.2018.11.017. [Epub ahead of print]



Evidence from epidemiologic studies has been inconsistent regarding the role of vitamin E in cancer incidence risk.


The aim of this study was to evaluate the prospective association between baseline plasma vitamin E levels and subsequent cancer risk in Chinese adults with hypertension, and to identify effect modifiers.


A nested, case-control study was conducted from 20,702 hypertensive participants in the China Stroke Primary Prevention Trial, a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013.


The current study included 229 new cancer cases and 229 controls matched for age (±1 year), sex, treatment group, and study site.


Plasma vitamin E was measured by liquid chromatography with tandem quadrupole mass spectrometers and plasma selenium was measured by inductively coupled plasma mass spectrometry using Thermo Fisher iCAP Q ICP-MS.


Odds ratios (OR) of cancer in relation to plasma concentrations of vitamin E were calculated using conditional logistic regression models.


Median follow-up duration was 4.5 years. Overall, vitamin E was not associated with subsequent risk of total cancer (per 1-mg/L [2.3 μmol/L] increase: OR 1.01, 95% CI 0.93 to 1.09) and non-gastrointestinal cancer (OR 1.10, 95% CI 0.98 to 1.24). However, there was a significant, inverse association between vitamin E and gastrointestinal cancer (OR 0.86, 95% CI 0.75 to 0.99), particularly esophageal cancer (OR 0.67, 95% CI 0.48 to 0.95). Moreover, high vitamin E decreased the risk of total cancer (OR 0.91, 95% CI 0.84 to 0.99) and gastrointestinal cancer (OR 0.83, 95% CI 0.73 to 0.95) among patients with high selenium levels (median≥83.7 μg/L [1.1 μmol/L]), and increased the risk of total cancer (OR 1.13, 95% CI 1.00 to 1.26) and non-gastrointestinal cancer (OR 1.25, 95% CI 1.03 to 1.50) among those with low selenium levels (<83.7 μg/L [1.1 μmol/L]).


This study suggests that higher levels of plasma vitamin E are associated with reduced risk of gastrointestinal cancer. High vitamin E decreased the risk of total cancer among patients with high selenium levels, but increased the risk of total cancer among those with low selenium levels.

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