Vitamin E and selenium supplementation synergistically alleviate the injury induced by hydrogen peroxide in bovine granulosa cells

Meimei Wang, Yan Li, Adrian Molenaar, Qiufeng Li, Yufeng Cao, Yizhao Shen, Panliang Chen, Jinling Yan, Yanxia Gao, Jianguo Li

Theriogenology . 2021 Aug;170:91-106. doi: 10.1016/j.theriogenology.2021.04.015. Epub 2021 May 5.


Dairy cows are susceptible to reproductive disorders, which are thought to be associated with oxidative stress. In the study, we investigated the effects of vitamin E (VE) and selenium (Se) on the proliferation, apoptosis, and steroidogenesis in bovine ovarian granulosa cells under hydrogen peroxide (H2O2) – induced oxidative stress and elaborated the underlying mechanisms. Our results showed that VE or Se could stimulate the granulosa cell proliferation, possibly due to up-regulating the expression of CCND1 and decreasing the P21 levels under oxidative stress. VE or Se treatment also increased the secretion of estradiol (E2) and progesterone (P4), which could be owing to improving the expression of genes associated with steroidogenesis (StAR, HSD3β1, and CYP19A1) expression. VE or Se treatment down-regulated the apoptosis-related genes (BAX, CASP3) expression and decreased cell apoptosis. Furthermore, VE or Se treatment inhibited reactive oxidative species (ROS) and malondialdehyde (MDA) generation, increased total antioxidant capacity (T-AOC), and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Additionally, VE or Se treatment also alleviated the endoplasmic reticulum stress, activated the nuclear factor erythroid 2-related factor 2 (NRF2), and up-regulated the expression of its downstream genes, including NQO1, HO-1, GCLM, GCLC. More importantly, compared with either VE or Se treatment alone, their combined treatment showed a better protective effect against oxidative damage. Overall, our results indicated that VE and Se synergistically stimulated the granulosa cell proliferation and steroidogenesis, decreased cell apoptosis, mitigated the endoplasmic reticulum stress by activating the NRF2 signal pathway.

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In vitro antiaging evaluation of sunscreen formulated from nanostructured lipid carrier and tocotrienol-rich fraction

Chee Chin Chu, Zafarizal Aldrin Bin Azizul Hasan, Chin Ping Tan, Kar Lin Nyam

J Pharm Sci . 2021 Aug 20;S0022-3549(21)00423-8. doi: 10.1016/j.xphs.2021.08.020.


Chronic exposure to ultraviolet (UV) radiation leads to photoaging. There is a tremendous rise in products having a dual activity of photoprotection and antiaging. In vitro analysis in dermal fibroblasts and their biological mechanisms involved are critical to determine antiaging potential. The study aimed to investigate the antiaging potential of sunscreen formulated from nanostructured lipid carrier and tocotrienol-rich fraction (NLC-TRF sunscreen). The antioxidant activity of the NLC-TRF sunscreen was evaluated by radical scavenging and hydrogen peroxide inhibition properties. Also, collagenase, elastase and matrix metalloproteinase-1 (MMP-1) inhibition activities, and type I collagen and elastin protein expression were studied. Quantitative real-time polymerase chain reaction (qPCR) was used to evaluate the mRNA expression of fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), type I collagen (COL1A1), elastin (ELN), MMP-1, MMP-2, and tissue inhibitor matrix metalloproteinase-1 (TIMP-1). The results suggested that NLC-TRF sunscreen is effective in radical, anti-hydrogen peroxide, and collagenase, elastase and MMP-1 inhibition activities. Besides, a significant increase for type I collagen (3.47-fold) and elastin (2.16-fold) protein and fibroblast regeneration genes (FGF (2.12-fold), VEGF (1.91-fold), TGF-β1 (2.84-fold), TIMP-1 (1.42-fold), ELN (2.13-fold)) were observed after sample treatment. These findings support the therapeutic potential of NLC-TRF sunscreen in antiaging.

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Systematic review and meta-analyses of vitamin E (alpha-tocopherol) supplementation and blood lipid parameters in patients with diabetes mellitus

Abolfathi Mohammad, Ebrahim Falahi, Mohd Yusof Barakatun-Nisak, Zubaidah Nor Hanipah, S Mohd Redzwan, Loqman Mohamad Yusof, Mohsen Gheitasvand, Farahnaz Rezaie

Diabetes Metab Syndr . Jul-Aug 2021;15(4):102158. doi: 10.1016/j.dsx.2021.05.031. Epub 2021 May 31.


Background and aims: The studies have shown that α-tocopherol supplementation could improve lipid profile in diabetes mellitus (DM) patients. Nonetheless, the result remains inconsistent. Therefore, this meta-analysis was performed to evaluate the efficacy of α-tocopherol supplement on lipid parameters in DM patients.

Methods: We conducted an extensive search via Cochrane Library, PubMed, Scopus, and Web of Science databases to acquire the reported RCTs up to October 2020.

Results: The results showed no effects of α-tocopherol supplementation on lipid profile in DM patients except when used ≥12 weeks.

Conclusions: α-tocopherol supplementation in DM patients had no significant effect on lipid profiles.

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Fruit tree leaves as valuable new source of tocopherol and tocotrienol compounds

Aneta Wojdyło, Igor Piotr Turkiewicz, Karolina Tkacz, Francisca Hernandez

J Sci Food Agric . 2021 Aug 16. doi: 10.1002/jsfa.11481. Online ahead of print.


Background: Nowadays it is highly important to find new, cheap and widely available sources of tocopherol and tocotrienol compounds, and leaves are promising unconventional sources. The main goal of this study was to extend the currently limited knowledge concerning tocopherol and tocotrienol isomers composition determined using ultra-high performance liquid chromatography with fluorescence detection analysis for various fruit tree leaves such as apple, pear, quince, apricot, peach, plum, sour cherry and sweet cherry. The leaves were collected 2 weeks after tree blooming and after fruit collection. Tocopherol and tocotrienol isomers were identified and quantified for the first time in all fruit tree leaves.

Results: The total tocopherol content ranged from 203.34 to 260.86 μg g-1 dry weight for spring leaves and from 23.83 to 235.62 μg g-1 dry weight for autumn leaves and consisted mainly of α-tocopherol. The rest of the isomers of tocopherol and tocotrienols were also found, but in trace amounts. A significantly lower content of tocopherols and tocotrienols was detected in leaves after autumn collection of fruits compared to leaves collected after blooming. Among the analyzed leaves, time collected and species were significantly more important than their cultivars. Regarding quantification analysis, apricot > peach > > plums > apples leaves were identified as the best sources of tocopherols, and sweet and sour cherry leaves exhibited a lower content.

Conclusion: Fruit tree leaves are a novel significant source and good material for isolation of α-tocopherol for application in cosmetics, pharmaceuticals or in the food industry – for example, production of beverages or other functional foods.

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Vitamins E and C do not effectively inhibit low density lipoprotein oxidation by ferritin at lysosomal pH

Oluwatosin O Ojo, David S Leake

Free Radic Res . 2021 Aug 16;1-10. doi: 10.1080/10715762.2021.1964494. Online ahead of print.


Low density lipoprotein (LDL) might be oxidized by iron in the lysosomes of macrophages in atherosclerotic lesions. We have shown previously that the iron-storage proteinferritin can oxidize LDL at lysosomal pH. We have now investigated the roles of the most important antioxidant contained in LDL, α-tocopherol (the main form of vitamin E) and of ascorbate (vitamin C), a major water-soluble antioxidant, on LDL oxidation by ferritin at lysosomal pH (pH 4.5). We incubated LDL with ferritin at pH 4.5 and 37 °C and measured its oxidation by monitoring the formation of conjugated dienes at 234 n min a spectrophotometer. α-Tocopherol is well known to inhibit LDL oxidation at pH 7.4, but enrichment of LDL with α-tocopherol was unable to inhibit LDL oxidation by ferritin at pH 4.5. Ascorbate had a complex effect on LDL oxidation by ferritin at lysosomal pH and exhibited both antioxidant and pro-oxidant effects. It had no antioxidant effect on partially oxidized LDL, only a pro-oxidant effect. Ascorbate completely inhibited LDL oxidation by copper at pH 7.4 for a long period, but in marked contrast did not inhibit LDL oxidation by copper at lysosomal pH. Dehydroascorbate, the oxidation product of ascorbate, had a pronounced pro-oxidant effect on LDL incubated with ferritin at pH 4.5. The inability of α-tocopherol and ascorbate to effectively inhibit LDL oxidation by ferritin at lysosomal pH might help to explain why the large clinical trials with these vitamins failed to show protection against cardiovascular diseases.

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Dietary intake of tocopherols and risk of incident disabling dementia

Shoko Aoki, Kazumasa Yamagishi, Koutatsu Maruyama, Rie Kishida, Ai Ikeda, Mitsumasa Umesawa, Cui Renzhe, Yasuhiko Kubota, Mina Hayama-Terada, Yuji Shimizu, Isao Muraki, Hironori Imano, Tomoko Sankai, Takeo Okada, Akihiko Kitamura, Masahiko Kiyama, Hiroyasu Iso

Sci Rep . 2021 Aug 12;11(1):16429. doi: 10.1038/s41598-021-95671-7.


Tocopherols, strong antioxidants, may be useful in preventing dementia, but the epidemiological evidence is insufficient. We performed a community-based follow-up study of Japanese, the Circulatory Risk in Community Study, involving 3739 people aged 40-64 years at baseline (1985-1999). Incident disabling dementia was followed up from 1999 through 2020. For subtype analysis, we classified disabling dementia into that with and that without a history of stroke. Dietary intake of tocopherols (total, α, β, γ, and δ) were estimated using 24-h recall surveys. During a median follow-up of 19.7 years, 670 cases of disabling dementia developed. Total tocopherol intake was inversely associated with risk of disabling dementia with multivariable hazard ratios (95% confidence intervals) of 0.79 (0.63-1.00) for the highest versus lowest quartiles of total tocopherol intake (P for trend = 0.05). However, the association was strengthened when further adjusted for α-linolenic acid intake (Spearman correlation with total tocopherol intake = 0.93), with multivariable hazard ratios of 0.50 (0.34-0.74) (P for trend = 0.001) but was weakened and nonsignificant when further adjusted for linoleic acid intake (Spearman correlation with total tocopherol intake = 0.92), with multivariable hazard ratios of 0.69 (0.47-1.01) (P for trend = 0.05). Similar but nonsignificant inverse associations were observed for α-, γ-, and δ-tocopherols but not for β-tocopherol. These results were similar regardless of the presence of a history of stroke. Dietary tocopherol intake was inversely associated with risk of disabling dementia, but its independent effect was uncertain owing to a high intercorrelation of α-linolenic linoleic acids with total tocopherol intake. Even with such confounding, a diet high in tocopherols may help prevent the onset of dementia.

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Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

Konstantin Neukirch, Khaled Alsabil, Chau-Phi Dinh, Rossella Bilancia, Martin Raasch, Alexia Ville, Ida Cerqua, Guillaume Viault, Dimitri Bréard, Simona Pace, Veronika Temml, Elena Brunner, Paul M Jordan, Marta C Marques, Konstantin Loeser, André Gollowitzer 1 2, Stephan Permann, Jana Gerstmeier, Stefan Lorkowski, Hermann Stuppner, Ulrike Garscha, Tiago Rodrigues, Gonçalo J L Bernardes, Daniela Schuster, Denis Séraphin, Pascal Richomme, Antonietta Rossi, Alexander S Mosig, Fiorentina Roviezzo, Oliver Werz, Jean-Jacques Helesbeux, Andreas Koeberle

J Med Chem . 2021 Aug 12;64(15):11496-11526. doi: 10.1021/acs.jmedchem.1c00806. Epub 2021 Jul 19.


Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.

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Effect of δ-Tocopherol on Mice Adipose Tissues and Mice Adipocytes Induced Inflammation

Chikako Kiyose, Haruka Takeuchi, Yoshimi Yabe, Tomoki Nojima, Mana Nagase, Chie Takahashi-Muto, Rieko Tanaka-Yachi

J Oleo Sci . 2021 Aug 6. doi: 10.5650/jos.ess21124. Online ahead of print.


The study aim was to evaluate the potential anti-inflammatory effects of vitamin E analogs, especially α-tocopherol and δ-tocopherol. We used male C57BL/6JJcl mice, which were divided into four groups: the control (C), high-fat and high-sucrose diet (H), high-fat and high-sucrose diet+α-tocopherol (Ha) and high-fat and high-sucrose diet+δ-tocopherol (Hd) groups. The mice were fed for 16 weeks. To the high-fat and high-sucrose diet, 800 mg/kg of α-tocopherol or δ-tocopherol was added more. The final body weight was significantly higher in the H group than in the C group. On the other hand, the final body weight was drastically lower in the Ha group and Hd group than in the H group. However, the energy intake was not significantly different among all groups. Therefore, we assumed that α-tocopherol and δ-tocopherol have potential anti-obesity effect. Besides, inflammatory cytokine gene expression was significantly higher in the epididymal fat of the H group than in the C group. These results showed that inflammation was induced by epididymal fat of mice fed a high-fat and high-sucrose diet for 16 weeks. Unfortunately, addition of α-tocopherol or δ-tocopherol to the diet did not restrain inflammation of epididymal fat. Investigation of the anti-inflammatory effects of α-tocopherol or δ-tocopherol in co-cultured 3T3-L1 cells and RAW264.7 cells showed that δ-tocopherol inhibited increased gene expression of the inflammatory cytokines, IL-1β, IL-6, and iNOS. These results suggest that an anti-inflammatory effect in the δ-tocopherol is stronger than that in the α-tocopherol in vitro. We intend to perform an experiment by in vivo sequentially in the future.

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PEGylated phospholipid micelles containing D-α-tocopheryl succinate as multifunctional nanocarriers for enhancing the antitumor efficacy of doxorubicin

Weiwei Jiang, Qing Fan, Jing Wang, Bingning Zhang, Tangna Hao, Qixian Chen, Lei Li, Lixue Chen, Hongxia Cui, Zhen Li

Int J Pharm . 2021 Aug 6;120979. doi: 10.1016/j.ijpharm.2021.120979. Online ahead of print.


The aim of this investigation is to clarify the effect of D-α-tocopheryl succinate (vitamin E succinate, VES) and distearoylphosphatidyl ethanolamine-poly(ethylene glycol) (DSPE-PEG) on the encapsulation and controlled release of doxorubicin (DOX) in nano-assemblies and their consequences on the anti-tumor efficacy of DOX. DOX molecules were successfully loaded into the hybrid micelles with VES and DSPE-PEG (VDPM) via thin-film hydration method, exhibiting a small hydrodynamic particle size (∼30 nm) and a weak negative zeta potential of around -5 mv. The obtained DOX-loaded VDPM2 displayed retarded DOX release at pH of 7.4, while substantially accelerated drug release at acidic pH of 5.0. Furthermore, the DOX-loaded VDPM2 exhibited substantially slower drug release rate at pH 7.4 compared with the drug-loaded VDPM1 or DPM preparation, benefiting for decreasing the premature DOX release during blood circulation. In vitro cell experiment indicated that DOX-Loaded micelles (DPM, VDPM1 and VDPM2) improved the cellular uptake of DOX in 4T1 and MDA-MB-231 cells. The existence of VES component in the structure of DOX-loaded micelles had no obvious influence on the subcellular distribution of the encapsulated DOX molecules. However, the DOX-loaded VDPM2 exhibited more pronounced cytotoxicity to 4T1 and MDA-MB-231 cancerous cells compared with DOX-loaded DPM and free DOX solution. The hybrid nanocarriers including VES and DSPE-PEG selectively induced intracellular ROS accumulation and increased level of cytoplasmic calcium ion in cancerous cells by interacting with mitochondria and endoplasmic reticulum, bringing about the improved cytotoxicity of DOX. In vivo antitumor efficacy investigation of DOX-loaded VDPM2 against 4T1 xenograft-bearing mice displayed satisfied therapeutic activity with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The proposed DOX-loaded VDPM preparation, as a mulifunctional chemotherapeutic nanomedicine system, holds great potential and bright prospect for clinical tumor therapy.

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Supplementation of antihypertensive drug regimen with vitamin E ameliorates alterations of primary haemodynamic parameters and total antioxidant capacity in ovariectomised rats

Temitayo Olabisi Ajibade, Foluso B Bolaji-Alabi, Ademola Adetokunbo Oyagbemi, Ifeoluwa W Ajileye, Temidayo Olutayo Omobowale

J Basic Clin Physiol Pharmacol . 2021 Aug 6. doi: 10.1515/jbcpp-2020-0097. Online ahead of print.


Objectives: Ovariectomy induces heightened response to vasoconstrictors, alters vasorelaxation and consequently causes hypertension due to increased oxidative stress in rats.

Methods: This study evaluated the ameliorative effects of ramipril and vitamin E, on primary haemodynamic parameters and cardiac antioxidant defence status, in ovariectomised rats using 64 adult female rats of the Wistar strain randomly divided as follows: Control (sham); Ovariectomised (OVX); OVX plus Ramipril; OVX plus vitamin E; and OVX plus Ramipril plus vitamin E.

Results: The plasma level of oestrogen was significantly lower (p<0.05), in the ovariectomised rats compared with the sham. The systolic, diastolic and mean arterial blood pressure of ovariectomised rats increased significantly (p<0.05), but the alteration was significantly reduced by the administration of ramipril alone or in combination with vitamin E. Significant decrease (p<0.05) was observed in the serum level of nitric oxide in OVX group compared with Sham. Also, analysed markers of oxidative stress: Malondialdehyde (MDA) contents and hydrogen peroxide (H2O2) generated decreased significantly (p<0.05), but systemic antioxidants: reduced glutathione (GSH) contents; glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities increased significantly (p<0.05) in the ovariectomised rats treated with ramipril and vitamin E compared with untreated ovariectomised rats. The study concludes that alteration, in the primary haemodynamic parameters, associated with ovariectomy in rats is potently ameliorated by co-administration of the antihypertensive drug ramipril and vitamin E.

Conclusions: The supplementation of antihypertensive regimen with antioxidants such as vitamin E in the treatment of hypertension is therefore justifiable especially in ovariectomised or hypogonadal patients.

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