Has vitamin E any shreds of evidence in cisplatin-induced toxicity

Hakiminia B, Goudarzi A, Moghaddas A

J Biochem Mol Toxicol. 2019 May 21:e22349. doi: 10.1002/jbt.22349. [Epub ahead of print]

Abstract

Cisplatin is one of the highly consumed and effective antitumor agents whose clinical application is accompanied by nephrotoxicity adverse reaction. Also, other complications such as ototoxicity and hepatotoxicity are a matter of concern. Today, it is suggested that cisplatin-associated toxicities are mainly induced by free radicals production, which will result in oxidative organ injury. The evidence is growing over the protective effects of antioxidants on cisplatin-induced adverse reactions especially nephrotoxicity. The possible protective effects of vitamin E and its derivative in cisplatin-induced nephrotoxicity and ototoxicity are reviewed here at the light of pertinent results from basic and clinical research. Administration of vitamin E alone or in combination with other antioxidant agents could cause amelioration in oxidative stress biomarkers such as decreasing the level of malondialdehyde, reducing serum urea and creatinine, and also enhancing the activities of renal antioxidant enzymes including renal catalase, glutathione-S-transferase, and superoxide dismutase. Although the data from most of the studies are in favors of protective effects of vitamin E against cisplatin-induced toxicity, more clinical trials are needed to clarify the clinical importance of vitamin E administration as an antioxidant during cisplatin therapy in cancer condition.

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A Prospective Study of Serum Vitamin E and 28-Year Risk of Lung Cancer

Huang J, Weinstein SJ, Yu K, Männistö S, Albanes D

J Natl Cancer Inst. 2019 May 11. pii: djz077. doi: 10.1093/jnci/djz077. [Epub ahead of print]

Abstract

BACKGROUND:

Epidemiologic data are inconsistent regarding the vitamin E-lung cancer association, and no study has examined serologic changes in vitamin E status in relation to subsequent risk.

METHODS:

In a cohort of 22,781 male smokers in the ATBC Study, we ascertained 3,184 lung cancer cases during up to 28 years of observation. Cox proportional hazards models examined whether higher serum alpha-tocopherol concentrations at baseline, 3 years, or the interval change were associated with lower lung cancer risk. All statistical tests were two-sided.

RESULTS:

After adjustment for age, body mass index, smoking intensity and duration, serum total cholesterol, and trial intervention group, we found lower lung cancer risk in men with high baseline alpha-tocopherol (5th quintile (Q5) vs Q1, hazard ratio (HR)=0.76, 95%CI =0.66 to 0.87; Ptrend<0.001). A similar reduction in risk was seen for serum alpha-tocopherol at 3 years (Q5 vs Q1, HR = 0.78, 95%CI =0.67 to 0.91; Ptrend=0.004). The inverse risk association appeared stronger for younger men and those having smoked fewer years, but was similar across trial intervention groups. We also found reduced risk among un-supplemented men with a lower serum alpha-tocopherol at baseline who had greater increases in concentrations at 3 years (3rd tertile vs 1st tertile of serum alpha-tocopherol change, HR = 0.74, 95% CI = 0.59 to 0.91, P=0.005).

CONCLUSION:

Higher vitamin E status, as measured by serum alpha-tocopherol concentration, as well as repletion of a low vitamin E state, was related to decreased lung cancer risk during a 28-year period. Our findings provide evidence supporting the importance of adequate physiological vitamin E status for lung cancer risk reduction.

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α-Tocopherol, but Not γ-Tocopherol, Attenuates the Expression of Selective Tumor Necrosis Factor-Alpha-Induced Genes in Primary Human Aortic Cell Lines

Ranard KM, Kuchan MJ, Erdman JW Jr

Lipids. 2019 May;54(5):289-299. doi: 10.1002/lipd.12149. Epub 2019 Apr 16.

Abstract

Of the antioxidant vitamin E isoforms, α-tocopherol (αT) and γ-tocopherol (γT) are the most abundant in the human diet, and αT is consumed from both natural and synthetic sources. αT and γT may differentially impact inflammation and influence cardiovascular outcomes, in part by modulating gene expression. The goal of this study was to compare the effects of natural αT, synthetic αT, and γT on gene expression in two human cell lines. Human aortic smooth muscle cells (HASMC) and endothelial cells (HAEC) were either: (1) treated with 25 μM tocopherolsalone, or (2) pretreated with tocopherols prior to a pro-inflammatory cytokine (tumor necrosis factor-alpha, TNF-α) stimulation. The expression of atherosclerosis-related genes was measured using RT2 Profiler PCR arrays. Tocopherol treatments alone did not significantly modulate the expression of genes in unstimulated HASMC or HAEC. TNF-α stimulation significantly upregulated genes involved with apoptosis and stress response in both cell lines. Pretreating cells with tocopherols did not normalize the gene expression changes induced by TNF-α. However, αT pretreatments, but not γT pretreatments, attenuated TNF expression in both HASMC and HAEC. These findings suggest that under stimulated conditions, αT modestly modulates the expression of selective genes and that αT may be more anti-inflammatory than γT.

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Vitamin C and Vitamin E Mitigate the Risk of Pancreatic Ductal Adenocarcinoma from Meat-Derived Mutagen Exposure in Adults in a Case-Control Study

Li D, Tang H, Wei P, Zheng J, Daniel CR, Hassan MM

J Nutr. 2019 May 17. pii: nxz081. doi: 10.1093/jn/nxz081. [Epub ahead of print]

Abstract

BACKGROUND:

Previous studies have found that meat-derived mutagens increase, and vitamin C or E decrease, the risk of pancreatic cancer.

OBJECTIVE:

The aim of this study was to determine whether intake of vitamin C or E modulates the association between meat-derived mutagen exposure and risk of pancreatic cancer.

DESIGN:

We conducted a case-control study in 1321 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 1061 healthy controls (aged 28-88 y). Cases and controls were frequency-matched by age, sex, and race/ethnicity. Mutagen intake was assessed using a meat preparation questionnaire. Intakes of vitamin C, E, and other dietary components were assessed via a food-frequency questionnaire in a subset of 811 cases and 818 controls. ORs and 95% CIs were estimated in multivariable-adjusted logistic regression models.

RESULTS:

The risk of PDAC was not associated with meat intake but was associated with consumption of well-done grilled or barbecued chicken (OR: 1.57; 95% CI: 1.18, 2.09; P = 0.001). Intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was associated with increased PDAC risk (Ptrend = 0.047). Participants in the highest, as compared with the lowest, quintile of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (PhIP) intake experienced a 38% increased risk of PDAC (95% CI: 1.00, 1.90; P = 0.048). Intakes of total vitamin C or E from food and supplements or from supplements alone were each inversely associated with PDAC risk. Stratified analyses showed differential associations for PhIP intake and PDAC risk, such that risk increased among individuals with lower intake of vitamin C or E and decreased among those with higher vitamin intake. Significant interactions of dietary vitamin C, dietary vitamin E, and total vitamin E with PhIP intake were detected (Pinteraction = 0.023, <0.001, and 0.013, respectively).

CONCLUSIONS:

Consistent with experimental evidence, this study of 811 cases and 818 controls has shown that high intake of dietary vitamin C or E mitigates the risk of PhIP-related PDAC.

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Association of physical activity, vitamin E levels, and total antioxidant capacity with academic performance and executive functions of adolescents

Alghadir AH, Gabr SA, Iqbal ZA, Al-Eisa E

BMC Pediatr. 2019 May 17;19(1):156. doi: 10.1186/s12887-019-1528-1.

Abstract

BACKGROUND:

Although various studies have shown the effect of vigorous physical activity on academic achievements, no studies have investigated the effect of vitamin E levels on academic performance. The present study aimed to assess the association between physical activity, vitamin E levels and total antioxidant capacity on the academic performance and executive functions of adolescents aged 15-18 years.

METHODS:

The physical activity of participants was assessed according to the time spent engaging in moderate and intense exercise programs. Participants were classified into three groups representing mild, moderate, and high activity. Serum total antioxidant capacity was measured using a colorimetric assay kit. Vitamin E was estimated by the α- and γ-tocopherol levels in fasting serum samples using high-performance liquid chromatography paired with a diode array detector. School grades (ranging from 1.0, very poor; to 10.0, outstanding) were obtained at the end of the academic year to evaluate academic performance and executive functions.

RESULTS:

A total of 120 school students (mean age 16.36 ± 0.77 years; 70 boys, 50 girls) participated in the study. Academic performance was higher for students classified as moderately or highly active compared with those in the mild activity group. Serum levels of vitamin E, total antioxidant capacity, and leisure-time physical activity were also higher in the moderate and high activity groups. There was a significant correlation between age, gender, body mind index, α- and γ-tocopherol, total antioxidant capacity, leisure-time physical activity and academic performance.

CONCLUSIONS:

The academic performance and executive function scores were found to be positively correlated with age, gender, α- and γ-tocopherol, total antioxidant capacity, and physical activity; and were negatively correlated with body mind index. Our findings indicate that physical activity should be promoted during and after school hours, along with a healthy balanced diet including vitamin E.

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Transcriptomic Analysis of MAPK Signaling in NSC-34 Motor Neurons Treated with Vitamin E

Chiricosta L, Gugliandolo A, Tardiolo G, Bramanti P, Mazzon E

Nutrients. 2019 May 15;11(5). pii: E1081. doi: 10.3390/nu11051081.

Abstract

Vitamin E family is composed of different tocopherols and tocotrienols that are well-known as antioxidants but that exert also non-antioxidant effects. Oxidative stress may be involved in the progression of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), characterized by motor neuron death. The aim of the study was the evaluation of the changes induced in the transcriptional profile of NSC-34 motor neurons treated with α-tocopherol. In particular, cells were treated for 24 h with 10 µM α-tocopherol, RNA was extracted and transcriptomic analysis was performed using Next Generation Sequencing. Vitamin E treatment modulated MAPK signaling pathway. The evaluation revealed that 34 and 12 genes, respectively belonging to “Classical MAP kinase pathway” and “JNK and p38 MAP kinase pathway”, were involved. In particular, a downregulation of the genes encoding for p38 (Log2 fold change -0.87 and -0.67) and JNK (Log2 fold change -0.16) was found. On the contrary, the gene encoding for ERK showed a higher expression in cells treated with vitamin E (Log2 fold change 0.30). Since p38 and JNK seem more involved in cell death, while ERK in cell survival, the data suggested that vitamin E treatment may exert a protective role in NSC-34 motor neurons. Moreover, Vitamin E treatment reduced the expression of the genes which encode proteins involved in mitophagy. These results indicate that vitamin E may be an efficacious therapy in preventing motor neuron death, opening new strategies for those diseases that involve motor neurons, including ALS.

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Vitamin E analogues differentially inhibit human cytochrome P450 3A (CYP3A)-mediated oxidative metabolism of lithocholic acid: Impact of δ-tocotrienol on lithocholic acid cytotoxicity

Wong SY, Teo JSM, Chai SF, Yeap SL, Lau AJ

Toxicology. 2019 May 15;423:62-74. doi: 10.1016/j.tox.2019.05.005. [Epub ahead of print]

Abstract

Lithocholic acid is a cytotoxic bile acid oxidized at the C-3 position by human cytochrome P450 3A (CYP3A) to form 3-ketocholanoic acid, but it is not known whether this metabolite is cytotoxic. Tocotrienols, in their various isomeric forms, are vitamin E analogues. In the present study, the hypothesis to be tested is that tocotrienols inhibit CYP3A-catalyzed lithocholic acid 3-oxidation, thereby influencing lithocholic acid cytotoxicity. Our enzyme catalysis experiments indicated that human recombinant CYP3A5 in addition to CYP3A4, liver microsomes, and intestinal microsomes catalyzed lithocholic acid 3-oxidation to form 3-ketocholanoic acid. Liver microsomes with the CYP3A5*1/*3 and CYP3A5*3/*3 genotypes were associated with decreased lithocholic acid 3-oxidation. α-Tocotrienol, γ-tocotrienol, δ-tocotrienol, and a tocotrienol-rich vitamin E mixture, but not α-tocopherol (a vitamin E analogue), differentially inhibited lithocholic acid 3-oxidation catalyzed by liver and intestinal microsomes and recombinant CYP3A4 and CYP3A5. Compared to lithocholic acid 3-oxidation, CYP3A-catalyzed testosterone 6β-hydroxylation was inhibited to a lesser extent by α-tocotrienol, γ-tocotrienol, δ-tocotrienol, and a tocotrienol-rich vitamin Emixture. δ-Tocotrienol inhibited lithocholic acid 3-oxidation by a mixed mode. Like lithocholic acid, 3-ketocholanoic acid was also cytotoxic in human intestinal and liver cell models. δ-Tocotrienol decreased the extent of lithocholic acid 3-oxidation and this inhibition was associated with enhanced cytotoxicity in LS180 cells treated with δ-tocotrienol and lithocholic acid. Overall, vitamin E analogues inhibited in vitro lithocholic acid 3-oxidation in an isomer-dependent manner, with inhibition occurring with tocotrienols, but not α-tocopherol. The enhanced lithocholic acid toxicity by δ-tocotrienol in a human intestinal cell model warrants future investigations in vivo.

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Sesame oil and vitamin E co-administration may improve cardiometabolic risk factors in patients with metabolic syndrome: a randomized clinical trial

Farajbakhsh A, Mazloomi SM, Mazidi M, Rezaie P, Akbarzadeh M, Ahmad SP, Ferns GA, Ofori-Asenso R, Babajafari S

Eur J Clin Nutr. 2019 May 14. doi: 10.1038/s41430-019-0438-5. [Epub ahead of print]

Abstract

OBJECTIVES:

Metabolic syndrome (MetS) represents a clustering of metabolic abnormalities that are associated with an increased risk of type 2 diabetes and cardiovascular disease. We aimed to evaluate the effects of sesame oil enriched with vitamin E (vit E), sesame oil alone and sunflower oil on lipid profile, fasting blood glucose (FBG), malondialdehyde (MDA), high-sensitivity C-reactive protein (Hs-CRP), homeostatic model assessment (HOMA-IR), and blood pressure (BP) in patients with MetS.

SUBJECTS:

Overall, 75 individuals with MetS (aged 30-70 years) participated in this randomized, single-blind controlled trial. Patients were randomly allocated to: (1) Group A (n = 25): sesame oil (30 ml/day) enriched with vit E (400 mg/day), (2) Group B (n = 25): sesame oil (30 ml/day), (3) Group C (n = 25): sunflower oil (30 ml/day). Anthropometric data, dietary intake, blood pressure, and biochemical markers, including fasting serum lipids, FBG, serum insulin, MDA, and hs-CRP were measured at baseline and at week 8.

RESULTS:

In individuals in the sesame oil enriched with vit E group (Group A), there were significant reductions in serum total cholesterol (TC), triglycerides (TG), FBG, HOMA-IR, MDA, hs-CRP, high-density lipoprotein (HDL-C) systolic and diastolic BP (for all the comparison p < 0.02). Similarly, in Group B (taking sesame oil alone), TC, TG, FBG, HOMA-IR, MDA, systolic and diastolic BP were significantly improved (for all the comparison p < 0.025), while there were no significant changes in serum HDL (baseline = 35.9 ± 7.2 mg/dL vs. 36.4 ± 6.2 mg/dL, p = 0.432) and hs-CRP (baseline = 4.38 ± 1.34 mg/dL vs. week 8 = 3.96 ± 1.7 mg/dL, p = 0.057) in second group. No significant changes in any of the studied clinical and anthropometric data were found in Group C (on sunflower oil).

CONCLUSION:

Sesame oil (±vit E) was shown to beneficially affect several cardiometabolic indices (including lipids, FBG, BP, HOMA-IR, and MDA) in patients with MetS.

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Er:YAG fractional laser ablation for cutaneous co-delivery of pentoxifylline and d-α-tocopherol succinate: A new approach for topical treatment of radiation-induced skin fibrosis

Gou S, Del Rio-Sancho S, Singhal M, Laubach HJ, Kalia YN

Eur J Pharm Sci. 2019 May 10;135:22-31. doi: 10.1016/j.ejps.2019.05.007. [Epub ahead of print]

Abstract

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

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Preadministration of high-dose alpha-tocopherol improved memory impairment and mitochondrial dysfunction induced by proteasome inhibition in rat hippocampus

Nesari A, Mansouri MT, Khodayar MJ, Rezaei M

Nutr Neurosci. 2019 May 14:1-11. doi: 10.1080/1028415X.2019.1601888. [Epub ahead of print]

Abstract

OBJECTIVE:

The ubiquitin-proteasome system plays a key role in memory consolidation. Proteasome inhibition and free radical-induced neural damage were implicated in neurodegenerative states. In this study, it was tested whether alpha-tocopherol (αT) in low and high doses could improve the long-term memory impairment induced by proteasome inhibition and protects against hippocampal oxidative stress.

METHODS:

Alpha-tocopherol (αT) (60, 200 mg/kg, i.p. for 5 days) was administered to rats with memory deficit and hippocampal oxidative stress induced by bilateral intra-hippocampal injection of lactacystin (32 ng/μl) and mitochondrial evaluations were performed for improvement assessments.

RESULTS:

The results showed that lactacystin significantly reduced the passive avoidance memory performance and increased the level of malondialdehyde (MDA), reactive oxygen species (ROS) and diminished the mitochondrial membrane potential (MMP) in the rat hippocampus. Furthermore, Intraperitoneal administration of αT significantly increased the passive avoidance memory, glutathione content and reduced ROS, MDA levels and impaired MMP.

CONCLUSIONS:

The results suggested that αT has neuroprotective effects against lactacystin-induced oxidative stress and memory impairment via the enhancement of hippocampal antioxidant capacity and concomitant mitochondrial sustainability. This finding shows a way to prevent and also to treat neurodegenerative diseases associated with mitochondrial impairment.

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