Effect of vitamin E on low density lipoprotein oxidation at lysosomal pH

Hadeel K M Alboaklah, David S Leake

Free Radic Res . 2020 Sep 16;1-11. doi: 10.1080/10715762.2020.1817912. Online ahead of print.


Many cholesterol-laden foam cells in atherosclerotic lesions are macrophages and much of their cholesterol is present in their lysosomes and derived from low density lipoprotein (LDL). LDL oxidation has been proposed to be involved in the pathogenesis of atherosclerosis. We have shown previously that LDL can be oxidised in the lysosomes of macrophages. α-Tocopherol has been shown to inhibit LDL oxidation in vitro, but did not protect against cardiovascular disease in large clinical trials. We have therefore investigated the effect of α-tocopherol on LDL oxidation at lysosomal pH (about pH 4.5). LDL was enriched with α-tocopherol by incubating human plasma with α-tocopherol followed by LDL isolation by ultracentrifugation. The α-tocopherol content of LDL was increased from 14.4 ± 0.2 to 24.3 ± 0.3 nmol/mg protein. LDL oxidation was assessed by measuring the formation of conjugated dienes at 234 nm and oxidised lipids (cholesteryl linoleate hydroperoxide and 7-ketocholesterol) by HPLC. As expected, LDL enriched with α-tocopherol was oxidised more slowly than control LDL by Cu2+ at pH 7.4, but was not protected against oxidation by Cu2+ or Fe3+ or a low concentration of Fe2+ at pH 4.5 (it was sometimes oxidised faster by α-tocopherol with Cu2+ or Fe3+ at pH 4.5). α-Tocopherol-enriched LDL reduced Cu2+ and Fe3+ into the more pro-oxidant Cu+ and Fe2+ faster than did control LDL at pH 4.5. These findings might help to explain why the large clinical trials of α-tocopherol did not protect against cardiovascular disease.

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Brain α-Tocopherol Concentration and Stereoisomer Profile Alter Hippocampal Gene Expression in Weanling Mice

Justin S Rhodes, Catarina Rendeiro, Jonathan G Mun, Kristy Du, Pragya Thaman, Amanda Snyder, Heinrich Pinardo, Jenny Drnevich, Sriram Chandrasekaran, Chron-Si Lai, Karen J Schimpf, Matthew J Kuchan

J Nutr . 2020 Sep 16;nxaa249. doi: 10.1093/jn/nxaa249. Online ahead of print.


Background: Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood.

Objectives: The objective was to determine the impact of bio-potency-adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice.

Methods: Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams.

Results: A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz).

Conclusions: In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.

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Reply “Comment on: Food for Bone: Evidence for a Role for Delta-Tocotrienol in the Physiological Control of Osteoblast Migration. Int. J. Mol. Sci. 2020, 21, 4661”

Lavinia Casati, Francesca Pagani, Roberto Maggi, Francesco Ferrucci, Valeria Sibilia

Int J Mol Sci . 2020 Sep 12;21(18):E6675. doi: 10.3390/ijms21186675.

Dear Editor,
We have carefully read the Letter to the Editor by Pang and Chin related to our paper entitled “Food for bone: evidence for a role for delta-tocotrienol in the physiological control of osteoblast migration” [1] published in the International Journal of Molecular Science.
We have some issues regarding the points raised by the authors.
  • The paper from Shen and colleagues 2018 [2] clearly shows the effect of dietary supplementation of tocotrienol in the suppression of bone resorption, probably mediated by the reduction of oxidative stress. Our statement “osteoporosis has been correlated with low intake, and serum levels of TTs” refers to this paper. We disagree with the authors that “dietary tocotrienol level has not been shown to correlate with bone health, probably due to the absence of a reliable dietary questionnaire that could assess the tocotrienol intake”, since Shen and colleagues (2018) have reported that a 12 week annatto-derived tocotrienol supplementation, previously used to examine the effects of tocotrienol on bone turnover, resulted in a significant increase in serum delta-tocotrienol levels in postmenopausal osteoporotic women [2].

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Comment on: Food for Bone: Evidence for a Role for Delta-Tocotrienol in the Physiological Control of Osteoblast Migration. Int. J. Mol. Sci. 2020, 21, 4661

Kok-Lun Pang, Kok-Yong Chin

Int J Mol Sci . 2020 Sep 12;21(18):E6674. doi: 10.3390/ijms21186674.

Dear Editor,
We applaud the innovative work by Casati et al., which explored the effects of delta-tocotrienol (δ-TT) in promoting osteoblast migration [1]. Vitamin E is reported as a nutrient important for maintaining bone health in epidemiological studies [2]. However, the statement “osteoporosis has been correlated with low intake, and serum levels of TTs” is inaccurate because dietary tocotrienol level has not been shown to correlate with bone health, probably due to the absence of a reliable dietary questionnaire that could assess the tocotrienol intake. Nevertheless, there is an abundance of preclinical evidence on the beneficial skeletal effects of tocotrienol. Most in vitro studies focus on the differentiation of osteoblasts, while the animal studies used bone cellular histomorphometry to quantify the bone cells in osteopenic rats treated with tocotrienol [3,4]. The work by Casati et al. is the first that focuses on the influence of tocotrienol on osteoblast migration, which plays an essential role in fracture healing. More accurately, mesenchymal stem cells migrated to the fracture site during fibrovascular phase and callus formation will differentiate into osteoblasts and perform bone formation [5]. A previous study also showed that particles incorporated with annatto tocotrienol rich in δ-TT could enhance callus strength of male rats with long bone fracture fixed with plate and screws [6]. The finding of δ-TT enhances the transcriptional activities of β-catenin also echoes our previous study, which demonstrated that annatto tocotrienol supplementation (60 mg/kg/day for 2 months) increased beta-catenin gene expression in the bone of orchidectomized rats [7].

Finding of Remarkable Synergistic Effect on the Aroxyl-Radical-Scavenging Rates (k s) under the Coexistence of Vitamin E Homologues (or Vegetable Oils) and Ubiquinol-10: Proposal of A New Mechanism to Explain An Increase of k s Value

Kazuo Mukai, Yasuhiro Maruoka, Saya Kitagaki, Shin-Ichi Nagaoka

J Oleo Sci . 2020 Sep 10. doi: 10.5650/jos.ess20091. Online ahead of print.


Measurements of aroxyl (ArO・)-radical-scavenging rate constants (ksAOH) of antioxidants (AOHs) (i.e., α-, β-, γ-, δ-Tocopherol (TocH) and ubiquinol-10 (UQ10H2)) were performed in ethanol/chloroform/H2O (50/50/1, v/v) solution, using stopped-flow spectrophotometry. ksAOH values were measured not only for each AOH, but also for the mixtures of two AOHs (i.e., TocH and UQ10H2). ksTocH values for α-, β-, γ-, δ-TocH increased 1.21, 1.28, 1.55, and 1.19 times, respectively, under the coexistence of constant concentrations of UQ10H2. Similar measurements were performed for eight vegetable oils 1 – 8, containing different concentrations of α-, β-, γ-, δ-tocopherol (TocH) and -tocotrienol (Toc-3H). ksOil values of all eight vegetable oils 1 – 8 also increased 1.24 – 1.54 times under the coexistence of constant concentrations of UQ10H2. A new mechanism to explain the notable increase of ksAOH values under the coexistence of two kinds of phenolic AOHs was proposed. UV-vis absorption of α-, β-, γ-Toc · radicals, produced by reaction of α-, β-, γ-TocHs (or vegetable oils 1 – 8) with ArO ·, disappeared under the coexistence of TocHs (or oils) and UQ10H2, suggesting that the prooxidant reaction resulting from the presence of Toc · radicals is suppressed in the presence of UQ10H2.

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4-HNE Immunohistochemistry and Image Analysis for Detection of Lipid Peroxidation in Human Liver Samples Using Vitamin E Treatment in NAFLD as a Proof of Concept

Maren C Podszun, Joon-Yong Chung, Kris Ylaya, David E Kleiner, Stephen M Hewitt, Yaron Rotman

J Histochem Cytochem . 2020 Sep;68(9):635-643. doi: 10.1369/0022155420946402.


Lipid peroxidation is a common feature of liver diseases, especially non-alcoholic fatty liver disease (NAFLD). There are limited validated tools to study intra-hepatic lipid peroxidation, especially for small specimen. We developed a semi-quantitative, fully automated immunohistochemistry assay for the detection of 4-hydroxynoneal (4-HNE) protein adducts, a marker of lipid peroxidation, for adaptation to clinical diagnostics and research. We used Hep G2 cells treated with 4-HNE to validate specificity, sensitivity, and dynamic range of the antibody. Staining and semi-quantitative automated readout were confirmed in human needle-biopsy liver samples from subjects with NAFLD and normal liver histology. The ability to detect changes in lipid peroxidation was tested in paired liver biopsies from NAFLD subjects, obtained before and after 4 weeks of treatment with the antioxidant vitamin E (ClinicalTrials.gov NCT01792115n=21). The cellular calibrator was linear and NAFLD patients had significantly higher levels of 4-HNE adducts compared to controls (p=0.02). Vitamin E treatment significantly decreased 4-HNE (p=0.0002). Our findings demonstrate that 4-HNE quantification by immunohistochemistry and automated image analysis is feasible and able to detect changes in hepatic lipid peroxidation in clinical trials. This method can be applied to archival and fresh samples and should be considered for use in assessing NAFLD histology.

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Osteoprotective effect of green tea polyphenols and annatto-extracted tocotrienol in obese mice is associated with enhanced microbiome vitamin K 2 biosynthetic pathways

Moamen M Elmassry, Eunhee Chung, Jay J Cao, Abdul N Hamood, Chwan-Li Shen

J Nutr Biochem . 2020 Sep 10;108492. doi: 10.1016/j.jnutbio.2020.108492. Online ahead of print.


The role of the gut microbiome in bone health has received significant attention in the past decade. We investigated the effects of green tea polyphenols (GTP) and annatto-extracted tocotrienols (AT) on bone properties and gut microbiome in obese mice. Male mice were assigned to a two (no AT vs. 400 mg/kg diet AT)×two (no GTP vs. 0.5% w/v GTP) factorial design, namely control, G, T, and G+T group respectively, for 14 weeks. The 4th lumbar vertebra (LV-4) and femur were harvested for bone microstructural analysis using μ-CT. Microbiome analysis using 16S rRNA gene sequencing of cecal feces was performed. AT increased bone volume at distal femur. GTP increased serum procollagen type 1 N-terminal propeptide concentration, bone volume at the distal femur and the LV-4, and trabecular number at distal femur; whereas GTP decreased trabecular separation at distal femur. Interactions between GTP and AT were observed in serum C-terminal telopeptide of type I collagen level (control>G=T=G+T) as well as the cortical bone area (control<G=T=G+T) and thickness (T≥G+T≥G≥control) at femur mid-diaphysis. Redundancy analysis showed a significant difference in the gut microbiome profile among different groups and the relative abundance of Akkermansia muciniphila, Clostridum saccharogumia, and Subdoligranulum variabile was increased in the GTP- and AT-supplemented groups. Functional profiling of the gut microbiome showed the combination of GTP and AT induced biosynthetic pathways for vitamin K2. Our results suggest that GTP and AT supplementation benefits bone properties in obese mice through modifying gut microbiome composition and function.

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Tocopherol Moderately Induces the Expressions of Some Human Sulfotransferases, which are Activated by Oxidative Stress

Sangita MaitiDutta, Guangping Chen, Smarajit Maiti

Cell Biochem Biophys . 2020 Sep 8. doi: 10.1007/s12013-020-00938-x. Online ahead of print.


Oxidative stress is generated in biological system by several endogenous/exogenous factors like environmental-pollution/toxicity/diseases and by daily-life-stress. We previously showed that oxidative-stress impaired the activities/expressions of phase-II drug-metabolizing enzyme, sulfotransferases (SULTs). The SULT catalyzes sulfation of endogenous/exogenous compounds. Vitamin E is globally consumed by a large number of individuals for the cellular protection from oxidative stress and aging. Here, vitamin E (tocopherol; α/γ and tocotrienol; α/γ; 0, 1, 10, or 100 μM) was tested in human carcinoma cell line, HepG2 for their influences on SULTs expression/(western blotting). The effects of oxidant (glutathione-oxidized/GSSG) or reductant (glutathione-reduced/GSH, Dithiothreitol/DTT) on SULT activities were studied in rat-liver/human intestinal tissues. Results suggest, tocopherol is more inductive to monoamine-SULT (MPST) and Dehydroepiandrosterone-SULT (DHEAST) compared to that of tocotrienol (inconsistent change in PPST, phenol sulfotransferase/MPST/EST, estrogen sulfotransferase). The nuclear-factor constitutive androstane receptor (CAR) was found to be induced moderately. This study overall describes that vitamin E moderately influences SULTs expression. The induction ability of tocopherol should be judged taking into account its long-term consummation. Oxidative stress activates rat and human SULTs activities and expressions. Further studies are necessary in this regard.

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Vitamin E and ginseng supplementation to enhance female sexual function: a randomized, double-blind, placebo-controlled, clinical trial

Kiandokht Ghamari, Ladan Kashani, Morteza Jafarinia, Borna Tadayon Najafabadi, Kamyar Shokraee, Sophia Esalatmanesh, Shahin Akhondzadeh

Women Health . 2020 Sep 6;1-10. doi: 10.1080/03630242.2020.1803465. Online ahead of print.


Female sexual disorders (FSD) are a spectrum of disorders common among women, especially in their middle age, which can reduce the female quality of life substantially. We aimed to evaluate the effects of a combined vitamin E and ginseng supplement on amelioration of female sexual dysfunction. In a 6-week, double-blind, randomized, placebo-controlled clinical trial, participants, suffering from sexual dysfunction based on the female sexual function index (FSFI) questionnaire, were randomly allocated to receive the supplement (100 IU vitamin E, 67 mg Korean ginseng, and 40 mg Siberian ginseng) or placebo daily. The primary outcome in our trial was the change in the FSFI total score. Sixty-nine participants were enrolled, but only 31 in each group completed the trial. Changes in the FSFI total score and its domain scores were significant during the trial course within each group. However, the supplement only ameliorated desire and satisfaction domains superior to the placebo. In case of the total score and other domains, the changes were insignificantly different between the treatment groups. Although our study could not find additional benefits for the vitamin E and ginseng supplement over placebo in enhancing sexual function overall, the supplement worked better in enhancing sexual desire and satisfaction.

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Vitamin E supplementation in people with cystic fibrosis

Peter O Okebukola, Sonal Kansra, Joanne Barrett

Cochrane Database Syst Rev . 2020 Sep 6;9:CD009422. doi: 10.1002/14651858.CD009422.pub4.


Background: People with cystic fibrosis are at an increased risk of fat-soluble vitamin deficiency, including vitamin E. Vitamin E deficiency can cause a host of conditions such as haemolytic anaemia, cerebellar ataxia and cognitive difficulties. Vitamin E supplementation is widely recommended for people with cystic fibrosis and aims to ameliorate this deficiency. This is an updated version of the review.

Objectives: To determine the effects of any level of vitamin E supplementation on the frequency of vitamin E deficiency disorders in people with cystic fibrosis.

Search methods: We searched the Cochrane Group’s Cystic Fibrosis Trials Register and also searched international online trial registries for any ongoing clinical trials that were not identified during our register search. Date of last search of the Register: 11 August 2020. Date of last search of international online trial registries: 20 July 2020.

Selection criteria: Randomised controlled trials and quasi-randomised controlled trials comparing any preparation of vitamin E supplementation to placebo or no supplement, regardless of dosage or duration.

Data collection and analysis: Two authors extracted outcome data from each study (published information) and assessed the risk of bias of each included study. They assessed the quality of the evidence using GRADE.

Main results: Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and two did not specify participants’ age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo. There was limited detail about randomisation and blinding in the included studies which compromises the quality of the evidence base for the review. The heterogeneous mix of the formulations with differing biovailabilities among these studies also limits the generalisability of the data to the wider cystic fibrosis population. None of the studies in either comparison report the review’s primary outcomes of vitamin E total lipid ratio or the incidence of vitamin E-specific deficiency disorders, or the secondary outcomes lung function or quality of life. Water-soluble vitamin E Water-soluble vitamin E may improve serum vitamin E levels compared with control at six months, one study (45 participants), mean difference (MD) 19.74 umol/L (95% confidence interval (CI) 13.48 to 26.00) (low-quality evidence). Similar results were also seen at one month, two studies (32 participants), MD 17.66 umol/L (95% CI 10.59 to 24.74) and at three months, one study (45 participants), MD 11.61 umol/L (95% CI 4.77 to 18.45). Only one study (45 participants) reported weight (secondary outcome of growth and nutritional status) at one and six months, but showed no difference between treatment and control at either time point. Fat-soluble vitamin E Two studies (36 participants) reported higher levels of serum vitamin E at one month with fat-soluble vitamin E compared with control, MD 13.59 umol/L (95% CI 9.52 to 17.66); however, at three months one study (36 participants) showed no difference between treatment and control. No studies in this comparison reported on growth or nutritional status.

Authors’ conclusions: Vitamin E supplementation may lead to an improvement in vitamin E levels in people with cystic fibrosis, although evidence we assessed was low quality. No data on other outcomes of interest were available to allow conclusions about any other benefits of this therapy. In future, larger studies are needed, especially in people already being treated with enteric-coated pancreatic enzymes and supplemented with vitamin E, to look at more specific outcome measures such as vitamin E status, lung function and nutritional status. Future studies could also look at the optimal dose of vitamin E required to achieve maximal clinical effectiveness.

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