Increased Anxiety-Like Behavior Is an Early Symptom of Vitamin E Deficiency That Is Suppressed by Adrenalectomy in Rats

Yuki Terada, Hiroya Ohashi, Yuki Otani, Kanako Tokunaga, Asako Takenaka

Br J Nutr . 2020 Jun 1;1-27. doi: 10.1017/S0007114520001889. Online ahead of print


We previously reported that dietary vitamin E deficiency increased anxiety-like behavior in rats exposed to social isolation. Here, we performed a detailed investigation of this phenomenon and its underlying mechanism. First, we fed Wistar rats with vitamin E-free diet for 3 days, 1 week, or 2 weeks and found an increase in anxiety-like behavior after 1 and 2 weeks of vitamin E deficiency based on behavioral indicators. Next, we examined the effect of a control diet (150 mg all-racemic α-tocopherol acetate/kg) on anxiety-like behaviors in rats that received a 4- week vitamin E-free diet. We found that increased anxiety-like behavior was reversed to control levels after refeeding vitamin E for 7 days but not for 1 or 3 days. Further, anxiety-like behavior increased or decreased gradually based on the amount of vitamin E intake; however, it had a quicker progression than physical symptoms of vitamin E deficiency. Moreover, rats fed with excess vitamin E (500 mg all-racemic α-tocopherol/kg diet) showed less anxiety-like behavior than control rats, indicating that vitamin E supplementation is effective for preventing anxiety increase under social isolation stress. Since plasma corticosterone levels were higher in vitamin E deficient rats, we investigated the effect of adrenalectomy on anxiety-like behavior and found that adrenal hormones played an essential role in the increased anxiety-like behavior induced by vitamin E deficiency. In conclusion, increased anxiety-like behavior is a symptom that emerges earlier than physical vitamin E deficiency and is caused by adrenal hormone-dependent mechanisms.

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Effects of Acrylamide in the Presence of Vitamin E on Sperm Parameters, Chromatin Quality, and Testosterone Levels in Mice

Morteza Anvari, Ali Reza Talebi, Esmat Mangoli, Abbas Shahedi, Mohammad Rasool Ghasemi, Majid Pourentezari

Clin Exp Reprod Med . 2020 Jun;47(2):101-107. doi: 10.5653/cerm.2019.03230. Epub 2020 Jun 1.


Objective: The present study investigated sperm chromatin quality and testosterone levels in acrylamide-treated mice and the possible protective effects of vitamin E on the fertility potential of spermatozoa.

Methods: Thirty-two adult male mice were divided equally into four groups. Group 1 was the control, group 2 received acrylamide (10 mg/kg, water solution), group 3 received vitamin E (100 mg/kg, intraperitoneal), and group 4 received both acrylamide and vitamin E. After 35 days, spermatozoa from the right cauda epididymis were analyzed in terms of count, motility, morphology, and viability. Sperm DNA integrity and chromatin condensation were assessed by acridine orange (AO), aniline blue (AB), toluidine blue (TB), and chromomycin A3 (CMA3) staining.

Results: In acrylamide-treated mice, significantly lower sperm concentration, viability, motility, and testosterone levels were found in comparison with the control and acrylamide+vitamin E groups (p<0.05). In the vitamin E group, significantly more favorable sperm parameters and testosterone levels were found than in the other groups (p<0.05). There were also significantly more spermatozoa with less condensed chromatin in the acrylamide-treated mice than in the other groups. Moreover, significantly more spermatozoa with mature nuclei (assessed by AB, CMA3, AO, and TB staining) were present in the vitamin E group than in the control and acrylamide+vitamin E groups.

Conclusion: This study revealed the deleterious effects of acrylamide on sperm parameters and sperm chromatin quality. Vitamin E can not only compensate for the toxic effects of acrylamide, but also improve sperm chromatin quality in mice.

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Effects of Royal Jelly and Tocotrienol Rich Fraction in Obesity Treatment of Calorie-Restricted Obese Rats: A Focus on White Fat Browning Properties and Thermogenic Capacity

Naimeh Mesri Alamdari, Pardis Irandoost, Neda Roshanravan, Mohammadreza Vafa, Mohammad Asghari Jafarabadi, Shahriar Alipour, Leila Roshangar, Mohammadreza Alivand, Farnaz Farsi, Farzad Shidfar

Nutr Metab (Lond) . 2020 Jun 1;17:42. doi: 10.1186/s12986-020-00458-8. eCollection 2020.


Background: Obesity has reached an alarming rate worldwide. Promoting thermogenesis via increasing the function of brown adipose tissue (BAT) or white adipose tissue (WAT) browning has been proposed as a new protective approach against obesity. The goal of this study was to evaluate the effects of Royal Jelly (RJ) and tocotrienol rich fraction (TRF) on BAT activation and WAT browning during calorie restriction diet (CRD) in obesity model.

Methods: In this experimental study, 50 obese Wistar rats were randomly divided into 5 groups and then received one of the following treatments for a period of 8-week: High-fat diet (HFD), CRD, RJ + CRD, TRF + CRD, and RJ + TRF + CRD. Effects of RJ and TRF, individually and in combination on body weight and the expression of key thermoregulatory genes in WAT and BAT were examined by quantitative real-time (qRT-PCR). Also, morphological alterations were assessed by hematoxylin and eosin staining.

Results: RJ (- 67.21 g ±4.84 g) and RJ + TRF (- 73.29 g ±4.51 g) significantly reduced weight gain relative to the CRD group (- 40.70 g ±6.50 g, P < 0.001). In comparison with the CRD group, RJ and RJ + TRF remarkably enhanced the uncoupling protein1 (UCP1) expression in WAT (5.81, 4.72 fold, P < 0.001) and BAT (4.99, 4.75 fold, P < 0.001). The expression of PR domain containing 16(PRDM 16), cAMP response element-binding protein1 (CREB1), P38 mitogen-activated protein kinases (P38MAPK), and Bone morphogenetic protein8B (BMP8B) have significantly increased following RJ and RJ + TRF treatments (P < 0.001). However, the expression levels of CCAAT/enhancer-binding protein beta (CEBPβ) and Bone morphogenetic protein7 ( BMP7) did not remarkably change. Multilocular beige cells in WAT and compacted dense adipocytes were also observed in BAT of RJ and RJ + TRF received groups. TRF showed no substantial effects on the expression of the mentioned thermoregulatory genes and brown fat-like phenotype.

Conclusion: Our results suggest that, Royal Jelly promotes thermogenesis and browning of WAT, contributing to an increase in energy expenditure. Thus, Royal Jelly may give rise to a novel dietary choice to attenuate obesity.

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Vitamin E – Phosphatidylethanolamine Interactions in Mixed Membranes With Sphingomyelin: Studies by 2 H NMR

Andres T Cavazos, Jacob J Kinnun, Justin A Williams, Stephen R Wassall

Chem Phys Lipids . 2020 May 31;104910. doi: 10.1016/j.chemphyslip.2020.104910. Online ahead of print.


Among the structurally diverse collection of lipids that comprise the membrane lipidome, polyunsaturated phospholipids are particularly vulnerable to oxidation. The role of α-tocopherol (vitamin E) is to protect this influential class of membrane phospholipid from oxidative damage. Whether lipid-lipid interactions play a role in supporting this function is an unanswered question. Here, we compare the molecular organization of polyunsaturated 1-[2H31]palmitoyl-2-docosahexaenoylphosphatidylethanolamine (PDPE-d31) and, as a control, monounsaturated 1-[2H31]palmitoyl-2-oleoylphosphatidylethanolamine (POPE-d31) mixed with sphingomyelin (SM) and α-tocopherol (α-toc) (2:2:1 mol) by solid-state 2H NMR spectroscopy. In both cases the effect of α-tocopherol appears similar. Spectral moments reveal that the main chain melting transition of POPE-d31 and PDPE-d31 is broadened beyond detection. A spectral component attributed to the formation of inverted hexagonal HII phase in coexistence with lamellar Lα phase by POPE-d31 (20 %) and PDPE-d31 (18 %) is resolved following the addition of α-toc. Order parameters in the remaining Lα phase are increased slightly more for POPE-d31 (7%) than PDPE-d31 (4%). Preferential interaction with polyunsaturated phospholipid is not apparent in these results. The propensity for α-toc to form phase structure with negative curvature that is more tightly packed at the membrane surface, nevertheless, may restrict the contact of free radicals with lipid chains on phosphatidylethanolamine molecules that accumulate polyunsaturated fatty acids.

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Metabolic Benefits of Annatto-Extracted Tocotrienol on Glucose Homeostasis, Inflammation, and Gut Microbiome

Eunhee Chung, Moamen M Elmassry, Pratibha Kottapalli, Kameswara Rao Kottapalli, Gurvinder Kaur, Jannette M Dufour, Kandis Wright, Latha Ramalingam, Naima Moustaid-Moussa, Rui Wang, Abdul N Hamood, Chwan-Li Shen

Nutr Res . 2020 May;77:97-107. doi: 10.1016/j.nutres.2020.04.001. Epub 2020 Apr 17.


Emerging evidence suggests that the gut microbiome plays an important role in the pathophysiology of both obesity and type 2 diabetes mellitus. We previously reported that dietary annatto-extracted tocotrienol exerts beneficial effects by modulating inflammatory responses in mice fed a high-fat diet (HFD). The purpose of this study was to test the hypothesis that tocotrienol supplementation when combined with an HFD would result in an altered gut microbiota composition. For 14 weeks, forty-eight male C57BL/6J mice were assigned to 4 groups-low-fat diet, HFD, HFD supplemented with annatto-extracted tocotrienol at 800 mg/kg diet (AT), and HFD supplemented with metformin at 200 mg/kg diet. Glucose homeostasis was assessed by glucose and insulin tolerance tests, serum and pancreas insulin levels, and histological assessments of insulin and glucagon in pancreatic tissue. The concentrations of adipokines were measured in white adipose tissues. For the gut microbiome analysis, cecal content was collected, DNA was extracted, and 16S rRNA gene sequencing was performed. AT supplementation improved glucose homeostasis and lowered resistin, leptin, and interleukin-6 levels in white adipose tissue. Relative to the HFD group, AT-supplemented mice showed a decrease in the Firmicutes to Bacteroidetes ratio and had a lower abundance of Ruminococcus lactaris, Dorea longicatena, and Lachnospiraceae family. The relative abundance of Akkermansia muciniphila was increased in the AT group compared to the low-fat diet group. The association between the metabolic improvements and the identified bacterial taxa suggests a potential metabolic modulation caused by AT supplementation through the gut microbiota composition in mice fed an HFD.

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Effect of Folic Acid and Vitamin E on Promoter DNA Methylation and Expression of TGF-β1, ESR-1 and CDH-1 in the Uterus of STZ-induced Diabetic Rats

Maryam Tabebordbar, Mostafa Moradi Sarabi, Sina Vakili, Razieh Zare, Fatemeh Zal

Arch Physiol Biochem . 2020 May 29;1-7. doi: 10.1080/13813455.2020.1770798.


The present study is the first attempt made to investigate the effects of diabetes on expression and promoter DNA methylation of TGF-β1, ESR-1, and CDH-1 genes and also the effects of folic acid (FA) and vitamin E (Vit E) supplementations on improving diabetes mellitus. STZ-induced diabetic rats were treated with Vit E (200 mg/kg/day) and FA (25 mg/kg/day) for 8 weeks and expression and DNA methylation of TGF-β1, ESR-1, and CDH-1 genes in uterus were analysed. Data indicated that diabetes increases the expression of TGFβ-1 and ESR-1 and decreases CDH-1 expression and TGFβ-1 promoter methylation in the uterus of rats. Vit E and FA improved the negative effects of diabetes by decreasing the expression of TGFβ-1 and ESR-1 and increasing that of CDH-1 in diabetic rats. In conclusion, these findings emphasise that Vit E and FA supplementations could improve negative effects caused by diabetes on uterus function and fertility in diabetic rats.

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Vitamin E-Bonded Membranes Do Not Influence Markers of Oxidative Stress in Hemodialysis Patients With Homozygous Glutathione Transferase M1 Gene Deletion

Petar Djuric, Sonja Suvakov, Tatjana Simic, Dragana Markovic, Djurdja Jerotic, Aleksandar Jankovic 1, Ana Bulatovic, Jelena Tosic Dragovic, Tatjana Damjanovic, Jelena Marinkovic, Radomir Naumovic, Nada Dimkovic

Toxins (Basel) . 2020 May 27;12(6):E352. doi: 10.3390/toxins12060352.


Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first study to use the vitamin E-bonded membranes (VEM) in patients with homozygous GSTM1 gene deletion, and we aimed to determine the effect of VEM on oxidative and inflammatory status in HD patients with homozygous GSTM1 gene deletion.

Methods: GSTM1 genotypes were determined by polymerase chain reaction (PCR) in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VEM, while the other forty were dialyzed with high-flux same-surface polysulfone dialyzers. Markers of protein and lipid oxidative damage and inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined.

Results: Seventy-five patients finished the study. There were no differences at baseline in markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, and thiol groups increased significantly in both groups, but without statistical significance between groups. SOD and C reactive protein (CRP) did not change significantly during the three-month period. IL-6 increased in the control group, and at the same time, decreased in the VEM group, but without statistical significance. Hemoglobin (Hb) value, red blood cells, erythropoiesis resistance index (ERI), serum ferritin and iron did not change significantly within or between groups. Regarding other laboratory parameters, proteins, albumins, triglycerides, serum phosphorus, serum bicarbonate and Kt/V showed significant improvements within groups but with no significant difference between groups.

Conclusions: Our data shows that therapy with VEM over three months had no benefit over standard polysulfone membrane in decreasing by-products of oxidative stress and inflammation in dialysis patients lacking GSTM1 enzyme activity.

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Effects of Coadministration of DHA and Vitamin E on Spermatogram, Seminal Oxidative Stress, and Sperm Phospholipids in Asthenozoospermic Men: A Randomized Controlled Trial

Ghazaleh Eslamian, Naser Amirjannati, Nazanin Noori, Mohammad-Reza Sadeghi, Azita Hekmatdoost

Am J Clin Nutr . 2020 May 26;nqaa124. doi: 10.1093/ajcn/nqaa124. Online ahead of print.


Background: It is unknown which compounds in spermatozoa or seminal plasma may be involved in the regulation of sperm motility.

Objectives: The aim of this study was to investigate the effects of DHA (22:6n-3), vitamin E, and their probable interactions in men with asthenozoospermia.

Methods: A factorial, randomized, double-blind, placebo-controlled trial was conducted in infertility clinics in Tehran, Iran. The participants were idiopathic asthenozoospermic men aged 20-45 y, with normal endocrine function. Their concentration of spermatozoa and percentage of morphologically normal spermatozoa were equal to or above the lower reference limits, according to the fifth edition of the WHO guideline. Out of 717 men referred to the infertility clinics, 180 asthenozoospermic men were randomly assigned to 1 of 4 groups according to stratified blocked randomization by age and sperm concentration. Participants took daily 465 mg DHA plus 600 IU vitamin E (DE), 465 mg DHA plus placebo (DP), 600 IU vitamin E plus placebo (EP), or both placebo capsules (PP) for 12 wk. Sperm characteristics, oxidative stress of seminal plasma, serum and sperm membrane fatty acids, dietary intakes, anthropometric measurements, and physical activity were measured at baseline and after 12 wk.

Results: After the intervention, mean ± SD sperm progressive motility was greater in the DE group (27.9 ± 2.8) than in the DP (25.7 ± 3.4), EP (26.1 ± 2.8), and PP (25.8 ± 2.6) groups (P < 0.05). Sperm count (P = 0.001) and concentration (P = 0.044) increased significantly in the DE group compared with the other 3 groups, whereas other semen parameters were not significantly different between the groups after the intervention. Serum concentrations of n-3 PUFAs were significantly higher in the DE and DP groups than in the EP and PP groups.

Conclusions: Combined DHA and vitamin E supplements led to increased sperm motility; however, no significant changes occurred in sperm morphology and vitality in asthenozoospermic men.

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Anti-Inflammatory Effects of Vitamin E in Response to Candida albicans

Silvana Barros, Ana Paula D Ribeiro, Steven Offenbacher, Zvi G Loewy

Microorganisms . 2020 May 26;8(6):E804. doi: 10.3390/microorganisms8060804.


Oral mucositis, inflammation, and ulceration that occur in the oral cavity can manifest in significant pain. A formulation was designed to investigate the potential of vitamin E to ameliorate inflammation resulting from Candida albicans in cell-based systems. Human gingival fibroblasts and THP1 cells were stimulated with heat killed C. albicans and Porphyromonas gingivalis LPS (agonists). Unstimulated cells were included as controls. Cells were also simultaneously treated with a novel denture adhesive formulation that contains vitamin E (antagonist). The experimental conditions included cells exposed to the experimental formulation or the vehicle for 2 h for mRNA extraction and analysis, and cells left for 24 h under those experimental conditions for analysis of protein expression by ELISA. ssAffymetrix expression microarray pathway analyses demonstrated that the tested formulation exhibited a statistically significant (p < 0.05) inhibition of the following key inflammatory pathways: TLR 6, IL-1 signaling (IRAK, A20), NF-kappaB, IL-6 signaling (gp130, JK2 and GRB2), TNF signaling (TNF receptor) and Arachidonic acid metabolism (PLA2). Quantitative PCR array analysis confirmed the downregulation of key inflammatory genes when cells under adhesive treatment were challenged with heat killed C. albicans. PGE2 secretion was inhibited by the tested formulation only on THP1 cells after 24 h stimulation with C. albicans. These results suggest that the active formulation containing vitamin E acetate can modulate inflammatory responses, through anti-inflammatory actions as indicated by in vitro experimental conditions.

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Targeted Nutritional Intervention for Patients With Mild Cognitive Impairment: The Cognitive impAiRmEnt Study (CARES) Trial 1

Rebecca Power, John M Nolan, Alfonso Prado-Cabrero, Robert Coen, Warren Roche, Tommy Power, Alan N Howard, Ríona Mulcahy

J Pers Med . 2020 May 25;10(2):E43. doi: 10.3390/jpm10020043.


Omega-3 fatty acids (ω-3FAs), carotenoids, and vitamin E are important constituents of a healthy diet. While they are present in brain tissue, studies have shown that these key nutrients are depleted in individuals with mild cognitive impairment (MCI) in comparison to cognitively healthy individuals. Therefore, it is likely that these individuals will benefit from targeted nutritional intervention, given that poor nutrition is one of the many modifiable risk factors for MCI. Evidence to date suggests that these nutritional compounds can work independently to optimize the neurocognitive environment, primarily due to their antioxidant and anti-inflammatory properties. To date, however, no interventional studies have examined the potential synergistic effects of a combination of ω-3FAs, carotenoids and vitamin E on the cognitive function of patients with MCI. Individuals with clinically confirmed MCI consumed an ω-3FA plus carotenoid plus vitamin E formulation or placebo for 12 months. Cognitive performance was determined from tasks that assessed global cognition and episodic memory. Ω-3FAs, carotenoids, and vitamin E were measured in blood. Carotenoid concentrations were also measured in tissue (skin and retina). Individuals consuming the active intervention (n = 6; median [IQR] age 73.5 [69.5-80.5] years; 50% female) exhibited statistically significant improvements (p < 0.05, for all) in tissue carotenoid concentrations, and carotenoid and ω-3FA concentrations in blood. Trends in improvements in episodic memory and global cognition were also observed in this group. In contrast, the placebo group (n = 7; median [IQR] 72 (69.5-75.5) years; 89% female) remained unchanged or worsened for all measurements (p > 0.05). Despite a small sample size, this exploratory study is the first of its kind to identify trends in improved cognitive performance in individuals with MCI following supplementation with ω-3FAs, carotenoids, and vitamin E.

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