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]

Abstract

OBJECTIVES:

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.

MATERIALS AND METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

Abstract

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]

Abstract

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]

Abstract

BACKGROUND:

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

OBJECTIVE:

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.

DESIGN:

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.

PARTICIPANTS:

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

MAIN OUTCOME MEASURES:

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.

STATISTICAL ANALYSES:

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

RESULTS:

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]).

CONCLUSIONS:

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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Immune boosting role of vitamin E against pulmonary tuberculosis

Hussain MI, Ahmed W, Nasir M, Mushtaq MH, Sheikh AA, Shaheen AY, Mahmood A

Pak J Pharm Sci. 2019 Jan;32(1(Supplementary)):269-276.

Abstract

Tuberculosis is one of the leading causes of mortality in Pakistan which is linked with malnutrition and weak immunity. Such people are more prone to chronic infections including TB. The current study aimed to assess the effect of supplementation of Vitamin E on the immune status of human subjects against pulmonary tuberculosis. A total of 80 patients with pulmonary TB were divided into treatment group (vitamin E) and control group (Anti-tuberculosis regime). Presence of acid fast bacilli in sputum sample, Erythrocyte sedimentation rate, total leucocytes counts, body mass index and mid arm muscle circumference (MAMC) were recorded as per standard protocol. Levels of vitamin E, IgG, IgM and T-Cell count were determined before and after treatment. The results showed that 16% males and 33% females were underweight who consumed 1145 kcal energy instead of 2270 kcal per day and 19.5 gram protein instead of 78.6 grams. A non significant effect of vitamin Eon ESR and TLC values was observed but significant increase in level of immunoglobulins (IgG, IgM) and T-cell types (CD4+ and CD8+) was observed in patients as compared to control group. Results indicate that vitamin E plays important role in enhancing immunity of patients against TB.

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Effects of antibiotics on degradation and bioavailability of different vitamin E forms in mice

Ran L, Liu AB, Lee MJ, Xie P, Lin Y, Yang CS

Biofactors. 2019 Jan 29. doi: 10.1002/biof.1492. [Epub ahead of print]

Abstract

Tocopherols (T) and tocotrienols (T3), all existing in α, β, γ, and δ-forms, are the eight forms of vitamin E (VE). In this study, we investigated the effects of gut microbiota on the degradation and tissue levels of different VE forms by treating mice with antibiotics in drinking water for 12 days. The mice also received an intragastric (i.g.) dose of VE mixture (mVE; α-T, γ-T, δ-T, γ-T3, and δ-T3, each at a dose of 75 mg/kg) every morning. Antibiotic treatment significantly increased the blood levels of all VE forms in mice that received an i.g. dose of mVE in the morning, 3 h before sacrifice. Without this morning dose, the blood levels of α-T were at the normal physiological levels, but those of the other VE forms were much lower; and the levels of all VE forms were not significantly affected by antibiotics. The liver levels of these VE forms were generally higher and followed the same pattern as the serum. On the contrary, the levels of most side-chain degradation metabolites of VE forms in the serum, liver, kidney, urine, and fecal samples were significantly decreased by antibiotics. The increased bioavailability of VE by antibiotics is probably due to increased absorption of VE or its decreased degradation by gut microbes. The results demonstrate the important roles of gut microbiota in the degradation of VE and in decreasing the bioavailabilities of VE forms.

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The effects of magnesium and vitamin E co-supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial

Afzali H, Jafari Kashi AH, Momen-Heravi M, Razzaghi R, Amirani E, Bahmani F, Gilasi HR, Asemi Z

Wound Repair Regen. 2019 Jan 28. doi: 10.1111/wrr.12701. [Epub ahead of print]

Abstract

This study was carried out to determine the effects of magnesium and vitamin E co-supplementation on wound healing and metabolic status in patients with diabetic foot ulcer (DFU). The current randomized, double-blind, placebo-controlled trial was conducted among 57 patients with grade 3 DFU. Participants were randomly divided into two groups to take either 250 mg magnesium oxide plus 400 IU vitamin E (n = 29) or placebo per day (n = 28) for 12 weeks. Compared with the placebo, taking magnesium plus vitamin E supplements reduced ulcer length (β [difference in the mean of outcomes measures between treatment groups] -0.56 cm; 95% CI, -0.92, -0.20; p = 0.003), width (β -0.35 cm; 95% CI, -0.64, -0.05; p = 0.02) and depth (β -0.18 cm; 95% CI, -0.33, -0.02; p = 0.02). In addition, co-supplementation led to a significant reduction in fasting plasma glucose (β -13.41 mg/dL; 95% CI, -20.96, -5.86; p = 0.001), insulin (β -1.45 μIU/ml; 95% CI, -2.37, -0.52; p = 0.003), insulin resistance (β -0.60; 95% CI, -0.99, -0.20; p = 0.003) and HbA1c (β -0.32%; 95% CI, -0.48, -0.16; p < 0.003), and a significant elevation in insulin sensitivity (β 0.007; 95% CI, 0.003, 0.01; p < 0.001) compared with the placebo. Additionally, compared with the placebo, taking magnesium plus vitamin E supplements decreased triglycerides (β -10.08 mg/dL; 95% CI, -19.70, -0.46; p = 0.04), LDL-cholesterol (β -5.88 mg/dL; 95% CI, -11.42, -0.34; p = 0.03), high sensitivity C-reactive protein (hs-CRP) (β -3.42 mg/L; 95% CI, -4.44, -2.41; p < 0.001) and malondialdehyde (MDA) (β -0.30 μmol/L; 95% CI, -0.45, -0.15; p < 0.001), and increased HDL-cholesterol (β 2.62 mg/dL; 95% CI, 0.60, 4.63; p = 0.01) and total antioxidant capacity (TAC) levels (β 53.61 mmol/L; 95% CI, 4.65, 102.57; p = 0.03). Overall, magnesium and vitamin E co-supplementation for 12 weeks to patients with DFU had beneficial effects on ulcer size, glycemic control, triglycerides, LDL- and HDL-cholesterol, hs-CRP, TAC, and MDA levels.

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Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E

Ambrogini P, Torquato P, Bartolini D, Albertini MC, Lattanzi D, Di Palma M, Marinelli R, Betti M, Minelli A, Cuppini R, Galli F

Biochim Biophys Acta Mol Basis Dis. 2019 Jan 28. pii: S0925-4439(19)30032-8. doi: 10.1016/j.bbadis.2019.01.026. [Epub ahead of print]

Abstract

Glutamate-mediated excitotoxicity, neuroinflammation, and oxidative stress are common underlying events in neurodegeneration. This pathogenic “triad” characterizes the neurobiology of epilepsy, leading to seizure-induced cell death, increased susceptibility to neuronal synchronization and network alterations. Along with other maladaptive changes, these events pave the way to spontaneous recurrent seizures and progressive degeneration of the interested brain areas. In vivo models of epilepsy are available to explore such epileptogenic mechanisms, also assessing the efficacy of chemoprevention and therapy strategies at the pre-clinical level. The kainic acid model of pharmacological excitotoxicity and epileptogenesis is one of the most investigated mimicking the chronicization profile of temporal lobe epilepsy in humans. Its pathogenic cues include inflammatory and neuronal death pathway activation, mitochondrial disturbances and lipid peroxidation of several regions of the brain, the most vulnerable being the hippocampus. The importance of neuroinflammation and lipid peroxidation as underlying molecular events of brain damage was demonstrated in this model by the possibility to counteract the related maladaptive morphological and functional changes of this organ with vitamin E, the main fat-soluble cellular antioxidant and “conditional” co-factor of enzymatic pathways involved in polyunsaturated lipid metabolism and inflammatory signaling. The present review paper provides an overview of the literature supporting the potential for a timely intervention with vitamin E therapy in clinical management of seizures and epileptogenic processes associated with excitotoxicity, neuroinflammation and lipid peroxidation, i.e. the pathogenic “triad”.

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Vitamin E: Regulatory Redox Interactions

Miyazawa T, Burdeos GC, Itaya M, Nakagawa K, Miyazawa T

IUBMB Life. 2019 Jan 25. doi: 10.1002/iub.2008. [Epub ahead of print]

Abstract

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 Eand 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.

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Co-expression of the aryl hydrocarbon receptor and estrogen receptor in the developing teeth of rat offspring after rat mothers’ exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and the protective action of α-tocopherol and acetylsalicylic acid

Dobrzyński M, Kuropka P, Leśków A, Herman K, Tarnowska M, Wiglusz RJ

Adv Clin Exp Med. 2019 Jan 24. doi: 10.17219/acem/99613. [Epub ahead of print]

Abstract

BACKGROUND:

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can cause adverse effects in many organs. Toxic effects are caused due to the formation of a TCDD complex with the cytoplasmatic aryl hydrocarbon receptor (AhR), whose mechanism of action is similar to that of the estrogen receptor (ER). Some substances, including α-tocopherol (E) and acetylsalicylic acid (ASA), can reduce the toxic effects of TCDD in offspring.

OBJECTIVES:

The objective of this study was to evaluate the co-expression of AhR and ER in the incisors of rat offspring whose mothers were exposed to TCDD, using immunohistochemical and histological techniques. Moreover, the possible protective role of E and ASA was investigated.

MATERIAL AND METHODS:

Four groups of 2-day-old rat offspring, whose mothers were intoxicated by TCDD before mating, were established: control group (C), TCDD group, TCDD+E group and TCDD+ASA group.

RESULTS:

In the TCDD group, there was an increase in ER expression and a decrease in AhR expression in comparison with the C group. In the TCDD+E and TCDD+ASA groups, there was a weak or negative ER expression and slightly stronger expression of AhR than in the TCDD group.

CONCLUSIONS:

The co-expression of AhR and ER during tooth development suggests the role of AhR and ER in the control of this process. Both receptors are also involved in the process of detoxification of TCDD. The increase in AhR in TCDD+E and TCDD+ASA groups indicate a preventive action of antioxidant and antiinflammatory pharmaceutics, which may limit negative effects of TCDD.

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