Antioxidant, Anti-Inflammatory, and Metabolic Properties of Tocopherols and Tocotrienols: Clinical Implications for Vitamin E Supplementation in Diabetic Kidney Disease

Di Vincenzo A, Tana C, El Hadi H, Pagano C, Vettor R, Rossato M

nt J Mol Sci. 2019 Oct 15;20(20). pii: E5101. doi: 10.3390/ijms20205101.

Abstract

Diabetes mellitus is a metabolic disorder characterized by the development of vascular complications associated with high morbidity and mortality and the consequent relevant costs for the public health systems. Diabetic kidney disease is one of these complications that represent the main cause of end-stage renal disease in Western countries. Hyperglycemia, inflammation, and oxidative stress contribute to its physiopathology, and several investigations have been performed to evaluate the role of antioxidant supplementation as a complementary approach for the prevention and control of diabetes and associated disturbances. Vitamin E compounds, including different types of tocopherols and tocotrienols, have been considered as a treatment to tackle major cardiovascular outcomes in diabetic subjects, but often with conflicting or even negative results. However, their effects on diabetic nephropathy are even less clear, despite several intervention studies that showed the improvement of renal parameters after supplementation in patients with diabetic kidney disease. Then we performed a review of the literature about the role of vitamin E supplementation on diabetic nephropathy, also describing the underlying antioxidant, anti-inflammatory, and metabolic mechanisms to evaluate the possible use of tocopherols and tocotrienols in clinical practice.

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Bone Mineral Density in Premenopausal Women Is Associated with the Dietary Intake of α-Tocopherol: A Cross-Sectional Study

Odai T, Terauchi M, Hirose A, Kato K, Miyasaka N

Nutrients. 2019 Oct 15;11(10). pii: E2474. doi: 10.3390/nu11102474.

Abstract

This study aimed to investigate the relationship between the consumption of various nutrients and bone mineral density (BMD) in middle-aged women. This cross-sectional survey was conducted based on the clinical records of 157 women aged 38-76. Their lumbar spine BMD was measured with dual-energy X-ray absorptiometry and dietary habits were assessed with the brief-type self-administered diet history questionnaire. Participants were divided into premenopausal (n = 46) and postmenopausal (n = 111) groups and the correlation between the BMD Z-score (Z-score) and the intakes of 43 nutrients was investigated separately for each group. In premenopausal women, the daily intake of ash, calcium, and α-tocopherol was positively correlated with the Z-score (Pearson’s correlation coefficient, R = 0.31, 0.34, 0.33, p = 0.037, 0.020, 0.027, respectively). When dividing the consumption of ash, calcium, and α-tocopherol into low, middle, and high tertiles, the Z-score significantly differed only between the α-tocopherol tertiles. After adjustment for age, body mass index, and lifestyle factors, daily intake of α-tocopherol remained significantly associated with the Z-score (regression coefficient = 0.452, p = 0.022). No nutrient was found to be significantly correlated with the Z-score in postmenopausal women. Increase in the intake of α-tocopherol could help maintain bone mass in premenopausal women.

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Proteome-wide changes in primary skin keratinocytes exposed to diesel particulate extract-A role for antioxidants in skin health

Rajagopalan P, Jain AP, Nanjappa V, Patel K, Mangalaparthi KK, Babu N, Cavusoglu N, Roy N, Soeur J, Breton L, Pandey A, Gowda H, Chatterjee A, Misra N

J Dermatol Sci. 2019 Oct 15. pii: S0923-1811(19)30273-7. doi: 10.1016/j.jdermsci.2019.08.009.

Abstract

BACKGROUND:

Skin acts as a protective barrier against direct contact with pollutants but inhalation and systemic exposure have indirect effect on keratinocytes. Exposure to diesel exhaust has been linked to increased oxidative stress.

OBJECTIVE:

To investigate global proteomic alterations in diesel particulate extract (DPE)/ its vapor exposed skin keratinocytes.

METHODS:

We employed Tandem Mass Tag (TMT)-based proteomics to study effect of DPE/ DPE vapor on primary skin keratinocytes.

RESULTS:

We observed an increased expression of oxidative stress response protein NRF2, upon chronic exposure of primary keratinocytes to DPE/ its vapor which includes volatile components such as polycyclic aromatic hydrocarbons (PAHs). Mass spectrometry-based quantitative proteomics led to identification 4490 proteins of which 201 and 374 proteins were significantly dysregulated (≥1.5 fold, p ≤ 0.05) in each condition, respectively. Proteins involved in cellular processes such as cornification (cornifin A), wound healing (antileukoproteinase) and differentiation (suprabasin) were significantly downregulated in primary keratinocytes exposed to DPE/ DPE vapor. These results were corroborated in 3D skin models chronically exposed to DPE/ DPE vapor. Bioinformatics analyses indicate that DPE and its vapor affect distinct molecular processes in skin keratinocytes. Components of mitochondrial oxidative phosphorylation machinery were seen to be exclusively overexpressed upon chronic DPE vapor exposure. In addition, treatment with an antioxidant like vitamin E partially restores expression of proteins altered upon exposure to DPE/ DPE vapor.

CONCLUSIONS:

Our study highlights distinct adverse effects of chronic exposure to DPE/ DPE vapor on skin keratinocytes and the potential role of vitamin E in alleviating adverse effects of environmental pollution.

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Vitamin E attenuates alterations in learning, memory and BDNF levels caused by perinatal ethanol exposure

Mahdinia R, Goudarzi I, Lashkarbolouki T, Salmani ME

Nutr Neurosci. 2019 Oct 14:1-15. doi: 10.1080/1028415X.2019.1674523.

Abstract

Objective: Alcohol exposure during pregnancy affects the developing fetus and causes a variety of physical and neurological abnormalities. Here we aim to study the effects of vitamin E on spatial learning and memory deficits and on changes in hippocampal brain-derived neurotrophic factor (BDNF) levels following perinatal ethanol exposure in rats. Method: Pregnant Wistar rats received ethanol (4 g/kg) and vitamin E (doses of 100, 200, and 400 mg/kg) on day 0 of gestation (GD) until weaning (28 days). On postnatal days (PND) 29, the performance of spatial learning and memory of rats were measured using the Morris water maze (MWM). The expression of BDNF protein levels in the hippocampus was assayed using BDNF ELISA kits. Results: Ethanol exposed group showed higher escape latency during training, reduced time spent in the target quadrant, higher escape location latency and average proximity in probe test. Vitamin E with doses of 100, 200 and 400 mg/kg significantly reduced escape latency during training. Also, vitamin E (400 mg/kg) significantly increased time spent in target quadrant, decreased escape location latency and average proximity in probe test. Maternal ethanol treatment significantly reduced the expression of BDNF protein in the hippocampus of offspring, whereas administration of vitamin E (400 mg/kg) significantly increased hippocampal BDNF in ethanol-treated rats. Discussion: Vitamin E administration dose-dependently ameliorate learning and memory deficits induced by perinatal ethanol exposure and increased hippocampal BDNF levels. BDNF may be implicated in the beneficial effects of vitamin E on learning and memory in the perinatal ethanol-exposed rat.

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Study of the toxic effect and safety of vitamin E supplement in male albino rats after 30 days of repeated treatment

El-Hak HNG, ELaraby EE, Hassan AK, Abbas OA

Heliyon. 2019 Oct 12;5(10):e02645. doi: 10.1016/j.heliyon.2019.e02645

Abstract

The aim of these investigations was to study vitamin E supplement effect in male albino rats after 30 days of repeated treatment. Four groups of six male rats were orally administered distilled water (control), 500, 1000 and 2000 mg/kg body weight vitamin E daily for 30 days. The impact of the treatment on percent body weight and mortality was determined and compared to the control group. Some hematological analysis, biochemical parameters and histological examination of different body organs were assessed. The rats treated with different doses of vitamin E supplement showed no deaths recorded in 30 days. The treatment with higher dose Vitamin E supplementation” caused significant alteration at the hematological, biochemical and histological level. Therefore, oral administration of vitamin E supplement in rats for 30 days was not safe for the liver and kidney and in the other hand, safe for the testes therefore that side effect on the liver and kidney should be considered when recommended vitamin E for therapeutic purpose. Care should be taken in taking high doses of vitamin E.

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Role of α-Tocopherol Acetate on Nasal Respiratory Functions: Mucociliary Clearance and Rhinomanometric Evaluations in Primary Atrophic Rhinitis

Testa D, Marcuccio G, Lombardo N, Cocuzza SG, Guerra G, Motta G

Ear Nose Throat J. 2019 Oct 2:145561319870483. doi: 10.1177/0145561319870483.

Abstract

Primary atrophic rhinitis is a disease of the nose and of paranasalsinuses characterized by a progressive loss of function of nasal and paranasal mucosa caused by a gradual destruction of ciliary mucosalepithelium with atrophy of serous-mucous glands and loss of bonestructures.The aim of this study was to evaluate the therapeutic effects of topic α-tochopherol acetate (vitamin E) in patients with primary atrophicrhinitis based on subjective and objective data.We analyzed 44 patients with dry nose sensation and endoscopic evidence of atrophic nasal mucosa. We analyzed endoscopic mucosascore, anterior rhinomanometry, and nasal mucociliary clearance before and after 6 months of topic treatment with α-tochopherol acetate. For statistical analysis, we used paired samples t test (95% confidence interval [CI], P < .05) for rhinomanometric and muciliary transit time evaluations and analysis of variance 1-way test (95% CI, P < .05) for endoscopic evaluation. All patients showed an improvement in “dry nose” sensation and inperception of nasal airflow. Rhinomanometric examination showed increase of nasal airflow at follow-up (P < .05); nasal mucociliaryclearance showed a reduction in mean transit time (P < .05); and endoscopic evaluation showed significative improvement of hydration of nasalmucosa and significative decreasing nasal crusts and mucusaccumulation (P < .05). Medical treatment for primary atrophic rhinitis is not clearly documented in the literature; in this research, it was demonstrated that α-ochopherol acetate could be a possible treatment for atrophic rhinitis.

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α-Tocopherol preserves cardiac function by reducing oxidative stress and inflammation in ischemia/reperfusion injury

Wallert M, Ziegler M, Wang X, Maluenda A, Xu X, Yap ML, Witt R, Giles C, Kluge S, Hortmann M, Zhang J, Meikle P, Lorkowski S, Peter K

Redox Biol. 2019 Sep;26:101292. doi: 10.1016/j.redox.2019.101292.

Abstract

OBJECTIVE:

Myocardial infarction (MI) is a leading cause of mortality and morbidity worldwide and new treatment strategies are highly sought-after. Paradoxically, reperfusion of the ischemic myocardium, as achieved with early percutaneous intervention, results in substantial damage to the heart (ischemia/reperfusion injury) caused by cell death due to aggravated inflammatory and oxidative stress responses. Chronic therapy with vitamin E is not effective in reducing the cardiovascular event rate, presumably through failing to reduce atherosclerotic plaque instability. Notably, acute treatment with vitamin E in patients suffering a MI has not been systematically investigated.

METHODS AND RESULTS:

We applied alpha-tocopherol (α-TOH), the strongest anti-oxidant form of vitamin E, in murine cardiac ischemia/reperfusion injury induced by ligation of the left anterior descending coronary artery for 60 min. α-TOH significantly reduced infarct size, restored cardiac function as measured by ejection fraction, fractional shortening, cardiac output, and stroke volume, and prevented pathological changes as assessed by state-of-the-art strain and strain-rate analysis. Cardioprotective mechanisms identified, include a decreased infiltration of neutrophils into cardiac tissue and a systemic anti-inflammatory shift from Ly6Chigh to Ly6Clow monocytes. Furthermore, we found a reduction in myeloperoxidase expression and activity, as well as a decrease in reactive oxygen species and the lipid peroxidation markers phosphatidylcholine (PC) (16:0)-9-hydroxyoctadecadienoic acid (HODE) and PC(16:0)-13-HODE) within the infarcted tissue.

CONCLUSION:

Overall, α-TOH inhibits ischemia/reperfusion injury-induced oxidative and inflammatory responses, and ultimately preserves cardiac function. Therefore, our study provides a strong incentive to test vitamin E as an acute therapy in patients suffering a MI.

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The Effects of Tocotrienol on Bone Peptides in a Rat Model of Osteoporosis Induced by Metabolic Syndrome: The Possible Communication between Bone Cells

Wong SK, Chin KY, Ima-Nirwana S

Int J Environ Res Public Health. 2019 Sep 9;16(18). pii: E3313. doi: 10.3390/ijerph16183313.

Abstract

A positive association between metabolic syndrome (MetS) and osteoporosis has been demonstrated in previous animal studies. The mechanisms of MetS in orchestrating the bone remodelling process have traditionally focused on the interactions between mature osteoblasts and osteoclasts, while the role of osteocytes is unexplored. Our earlier studies demonstrated the bone-promoting effects of tocotrienol using a rat model of osteoporosis induced by MetS. This study aimed to investigate the expression of osteocyte-derived peptides in the bone of rats with MetS-induced osteoporosis treated with tocotrienol. Age-matched male Wistar rats (12-week-old; n = 42) were divided into seven experimental groups. Two groups served as the baseline and normal group, respectively. The other five groups were fed with a high-carbohydrate high-fat (HCHF) diet to induce MetS. The five groups of HCHF animals were treated with tocopherol-stripped corn oil (vehicle), annatto tocotrienol (60 and 100 mg/kg), and palm tocotrienol (60 and 100 mg/kg) starting from week 8. At the end of the study, the rats were sacrificed and their right tibias were harvested. Protein was extracted from the metaphyseal region of the proximal right tibia and levels of bone peptides, including osteoprotegerin (OPG), soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), sclerostin (SOST), Dickkopf-related protein 1 (DKK-1), fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH), were measured. The vehicle-treated animals displayed higher levels of sRANKL, SOST, DKK-1, FGF-23, and PTH as compared to the normal animals. Oral supplementation of annatto and palm tocotrienol (60 and 100 mg/kg) reduced the levels of sRANKL and FGF-23 in the HCHF animals. Only 100 mg/kg annatto and palm tocotrienol lowered SOST and DKK-1 levels in the HCHF animals. In conclusion, tocotrienol exerts potential skeletal-promoting benefit by modulating the levels of osteocytes-derived bone-related peptides.

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Tocopherols and Tocotrienols Are Bioavailable in Rats and Primarily Excreted in Feces as the Intact Forms and 13′-Carboxychromanol Metabolites

Liu KY, Jiang Q

J Nutr. 2019 Sep 9. pii: nxz217. doi: 10.1093/jn/nxz217.

Abstract

BACKGROUND:

Vitamin E α-, γ-, or δ-tocopherol (αT, γT, δT) and γ- or δ-tocotrienol (γTE, δTE) are metabolized to hydroxychromanols and carboxychromanols including 13′-carboxychromanol (13′-COOH), 11′-COOH, and carboxyethyl hydroxychroman (CEHC), some of which have unique bioactivities compared with the vitamers. However, the bioavailability of these metabolites has not been well characterized.

OBJECTIVE:

We investigated the pharmacokinetics (PK) of vitamin E forms and metabolites in rats.

METHODS:

Six-week-old male Wistar rats received 1-time gavage of γT-rich tocopherols (50 mg/kg) containing γT/δT/αT (57.7%, 21.9%, and 10.9%, respectively) or δTE-rich tocotrienols (35 mg/kg) containing δTE/γTE (8:1). We quantified the time course of vitamin E forms and metabolites in the plasma and their 24-h excretion to the urine and feces. The general linear model repeated measure was used for analyses of the PK data.

RESULTS:

In the rats’ plasma, Cmax of γT or δTE was 25.6 ± 9.1 μM (Tmax = 4 h) or 16.0 ± 2.3 μM (Tmax = 2 h), respectively, and sulfated CEHCs and sulfated 11′-COOHs were the predominant metabolites with Cmax of 0.4-0.5 μM (Tmax ∼5-7 h) or ∼0.3 μM (Tmax at 4.7 h), respectively. In 24-h urine, 2.7% of γT and 0.7% of δTE were excreted as conjugated CEHCs. In the feces, 17-45% of supplemented vitamers were excreted as unmetabolized forms and 4.9-9.2% as unconjugated carboxychromanols, among which 13′-COOHs constituted ∼50% of total metabolites and the amount of δTE-derived 13′-COOHs was double that of 13′-COOH derived from γT.

CONCLUSIONS:

PK data of vitamin E forms in rats reveal that γT, δT, γTE, and δTE are bioavailable in the plasma and are mainly excreted as unmetabolized forms and long-chain metabolites including 13′-COOHs in feces, with more metabolites from tocotrienols than from tocopherols.

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Activation of human insulin by vitamin E: A molecular dynamics simulation study

Soleymani H, Ghorbani M, Allahverdi A, Shojaeilangari S, Naderi-Manesh H

J Mol Graph Model. 2019 Sep;91:194-203. doi: 10.1016/j.jmgm.2019.06.006. Epub 2019 Jun 14.

Abstract

Lack of perfect insulin signaling can lead to the insulin resistance, which is the hallmark of diabetes mellitus. Activation of insulin and its binding to the receptor for signaling process initiates via B-chain C-terminal hinge conformational change through an open structure to “wide-open” conformation. Observational studies and basic scientific evidence suggest that vitamin D and E directly and/or indirectly prevent diabetes through improving glucose secretion and tolerance, activating calcium dependent endopeptidases and thus improving insulin exocytosis, antioxidant effect and reducing insulin resistance. On the contrary, clinical trials have yielded inconsistent results about the efficacy of vitamin D supplementations for the control of glucose hemostasis. In this work, best binding modes of vitamin D3 and E on insulin obtained from AutoDock Vina were selected for Molecular Dynamic, MD, study. The binding energy obtained from Molecular Mechanics- Poisson Boltzman Surface Area, MM-PBSA method, revealed that Vitamins D3 and E have good affinity to bind to the insulin and vitamin Ehas higher binding energy (-46 kj/mol) by engaging more residues in binding site. Distance and angle calculation results illustrated that vitamin E changes the B-chain conformation and it causes the formation of wide-open/active form of insulin. Vitamin E increases the ValB12-TyrB26 distance to ∼15 Å and changes the hinge angle to ∼65°. Consequently, essential hydrophobic residues for binding to insulin receptor exposed to surface in the presence of vitamin E. However, our data illustrated that vitamin D3 cannot change B-chain conformation. Thus our MD simulations propose a model for insulin activation through vitamin E interaction for therapeutic approaches.

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