δ-tocotrienol suppresses the migration and angiogenesis of trophoblasts in preeclampsia and promotes their apoptosis via miR-429/ ZEB1 axis

Mei Shi, Xiuyun Chen, Hui Li, Lixia Zheng

Bioengineered . 2021 Dec;12(1):1861-1873. doi: 10.1080/21655979.2021.1923238.

Abstract

Preeclampsia (PE) is a severe medical disorder during pregnancy and there has been controversy about the effects of vitamin E on PE. This research intended to explore if δ-tocotrienol (δ-TT), an isomer of vitamin E, could impact PE. Preeclamptic and normal placentas were obtained and total RNA was extracted. The expression of different genes was analyzed through quantitative real-time polymerase chain reaction (qRT-PCR) and Pearson correlation analysis was conducted. After that, HTR-8/SVneo cells (human trophoblasts) were chosen and they were subjected to δ-tocotrienol treatment and then Cell Counting Kit-8 was used to test cell viability. To assess the effects of δ-TT on trophoblasts, wound healing assay and Transwell invasion assay were performed. How miR-429 interacts with ZEB1 was examined via dual luciferase reporter assay. Also, protein expression was evaluated via Western blotting. Our results have shown that δ-TT can impair the viability of trophoblasts and induce their apoptosis. Additionally, it can repress the growth, migration, epithelial-mesenchymal transition (EMT), invasion and angiogenesis in trophoblasts. Mechanistically, δ-TT exerts these effects on trophoblasts via downregulating miR-429 and upregulating ZEB1. Furthermore, miR-429 can bind ZEB1 directly. Clinical sample analysis has revealed that miR-429 expression in preeclamptic placenta is higher than that in normal placenta, but ZEB1 expression in preeclamptic placenta is downregulated. Also, there is a negative association between miR-429 and ZEB1 expression in preeclamptic placentas. These discoveries imply that δ-TT may be hazardous to pregnancy and should not be used in preeclamptic patients. In addition, targeting miR-429 might treat PE.

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Associations of Dietary and Circulating Vitamin E Level With Metabolic Syndrome. A Meta-Analysis of Observational Studies

Yi Zhang, Jun Ding, Hongbin Guo, Ze Liu, Qi Liu, Yusheng Li, Dianzhong Zhang, Jieyu Liang

Front Nutr . 2021 Dec 8;8:783990. doi: 10.3389/fnut.2021.783990. eCollection 2021.

Abstract

Objective: The associations of dietary and circulating vitamin E level with metabolic syndrome (MetS) remains conflicting. This meta-analysis of observational study was therefore employed to investigate the issue above. Methods: The PubMed, Web of Science and Embase database were searched up to April 2021. The observational studies on the associations of dietary and circulating vitamin E level with MetS were specified. The pooled relative risk (RR) of MetS for the highest vs. lowest dietary and circulating vitamin E level, and the standard mean difference (SMD) of dietary and circulating vitamin E level for MetS vs. control subjects, were calculated. Results: A total of 25 observational studies with 51,276 participants, were included in this meta-analysis. The overall multi-variable adjusted RR demonstrated that the dietary vitamin E level was inversely associated with MetS (RR = 0.92, 95%CI: 0.85-1.00; P = 0.044). In addition, the dietary vitamin E level in MetS was also lower than that in control subjects according to the overall combined SMD (SMD = -0.08, 95%CI: -0.14 to -0.02; P = 0.024). On the other hand, the overall multi-variable adjusted RR showed no significant relationship between the circulating vitamin E level and MetS (RR = 1.46, 95%CI: 0.85-2.48; P = 0.17). However, the circulating vitamin E level in MetS was lower than that in control subjects according to the overall combined SMD (SMD = -0.58, 95%CI: -1.04 to -0.13; P = 0.013). Conclusions: The results of this meta-analysis suggest that the dietary vitamin E level is inversely associated with MetS. On the other hand, current evidence is still insufficient to conclude a relationship between the circulating vitamin E level and MetS. More well-designed prospective cohort studies are needed to address the issues further.

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Serum vitamin E concentration is negatively associated with body mass index change in girls not boys during adolescence

Xiao-Dong Zang, Qing-Hui Hu, Xiao-Xu Liu, Min Da, Zhao-Cong Yang, Ji-Rong Qi, Xu-Ming Mo

World J Pediatr . 2021 Oct;17(5):517-526. doi: 10.1007/s12519-021-00454-9. Epub 2021 Sep 1.

Abstract

Background: Vitamin E is the most abundant lipid-soluble antioxidants present in plasma; however, the relationship between serum vitamin E and change in body mass index (BMI)-for-age Z scores in adolescents has not been well described.

Methods: This study is a cross-sectional study. Data were analyzed from 4014 adolescents who participated in the National Health and Nutrition Examination Survey. The nutritional status was calculated by BMI Z scores and was classified into normal weight, overweight, and obese. Multivariable-adjusted logistic regression was used to examine the association between serum vitamin E levels with overweight/obesity. Besides, the interaction effects between potential confounders and vitamin E on obesity were further evaluated.

Results: After adjusting potential confounders, serum vitamin E levels were negatively associated with overweight/obesity in girls but not in boys. Per standard deviation increment in vitamin E concentrations was associated with a 92% decreased risk of obesity in females. Besides, lower quartiles of serum vitamin E were associated with a higher risk of overweight/obesity in girls. Moreover, the inverse association between serum vitamin E levels and obesity was also found in most subgroups through subgroup analysis.

Conclusions: Our study supports the negative association between serum vitamin E levels and overweight/obesity in adolescents. A higher serum vitamin E level may be associated with a reduced probability of obesity in girls, but not in boys.

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Expanding role of vitamin E in protection against metabolic dysregulation: Insights gained from model systems, especially the developing nervous system of zebrafish embryos

Brian Head, Maret G Traber

Free Radic Biol Med . 2021 Sep 20;176:80-91. doi: 10.1016/j.freeradbiomed.2021.09.016. Online ahead of print.

Abstract

This review discusses why the embryo requires vitamin E (VitE) and shows that its lack causes metabolic dysregulation and impacts morphological changes at very early stages in development, which occur prior to when a woman knows she is pregnant. VitE halts the chain reactions of lipid peroxidation (LPO). Metabolomic analyses indicate that thiols become depleted in E- embryos because LPO generates products that require compensation using limited amino acids and methyl donors that are also developmentally relevant. Thus, VitE protects metabolic networks and the integrated gene expression networks that control development. VitE is critical especially for neurodevelopment, which is dependent on trafficking by the α-tocopherol transfer protein (TTPa). VitE-deficient (E-) zebrafish embryos initially appear normal, but by 12 and 24 h post-fertilization (hpf) E- embryos are developmentally abnormal with expression of pax2a and sox10 mis-localized in the midbrain-hindbrain boundary, neural crest cells and throughout the spinal neurons. These patterning defects indicate cells that are especially in need of VitE-protection. They precede obvious morphological abnormalities (cranial-facial malformation, pericardial edema, yolksac edema, skewed body-axis) and impaired behavioral responses to locomotor activity tests. The TTPA gene (ttpa) is expressed at the leading edges of the brain ventricle border. Ttpa knockdown using morpholinos is 100% lethal by 24 hpf, while E- embryo brains are often over- or under-inflated at 24 hpf. Further, E- embryos prior to 24 hpf have increased expression of genes involved in glycolysis and the pentose phosphate pathway, and decreased expression of genes involved in anabolic pathways and transcription. Combined data from both gene expression and the metabolome in E- embryos at 24 hpf suggest that the activity of the mechanistic Target of Rapamycin (mTOR) signaling pathway is decreased, which may impact both metabolism and neurodevelopment. Further evaluation of VitE deficiency in neurogenesis and its subsequent impact on learning and behavior is needed.

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The plasma antioxidant vitamin status of the INTAPP cohort examined: The unsuspected importance of β-carotene and γ-tocopherol in preeclampsia

Jean-François Bilodeau, Amélie Gagné, Karine Greffard, François Audibert, William D Fraser, Pierre Julien

Pregnancy Hypertens . 2021 Aug;25:213-218. doi: 10.1016/j.preghy.2021.06.009. Epub 2021 Jun 12.

Abstract

Objective: Examine the levels of plasma antioxidant vitamins before and during a treatment with placebo or vitamin E + C supplement to prevent preeclampsia (PE).

Study design: Per-protocol analysis of a subset group of pregnant women (n = 295) from the International Trial of Antioxidants for the Prevention of PE (INTAPP) randomized case-control study. Normotensive receiving placebo or vitamins (n = 115 and 87 respectively) were compared to gestational hypertension (GH) without proteinuria (n = 30 and 27) and PE (n = 21 and 15). Vitamin quantification was performed at 12-18, 24-26 and 32-34 weeks of gestation.

Main outcome measures: Coenzyme (Co) Q10, β-carotene and vitamins E (α and γ forms) plasma levels.

Results: Vitamin E + C supplementation was found to increase the α-tocopherol levels by 40% but was associated with a 57% decrease in the γ-tocopherol isoform for all study groups (p < 0.001). The β -carotene was lower in the PE than in the normotensive and GH groups (p < 0.001) while the level of CoQ10 remained unaffected.

Conclusions: A more personalized approach that target the suboptimal levels of specific antioxidants without disturbing the α/γ-tocopherol ratio could be a more successful approach to counteract oxidative stress in PE.

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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.

Abstract

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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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.

Abstract

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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High cholesterol diet activates ER stress mediated apoptosis in testes tissue: Role of α-tocopherol

Erdi Sozen, Tugce Demirel-Yalciner, M Kutay Koroglu, Merve Acikel Elmas, Feriha Ercan, Nesrin Kartal Ozer

IUBMB Life . 2021 Aug 4. doi: 10.1002/iub.2535. Online ahead of print.

Abstract

The seminiferous tubules where spermatogenesis occurs are enveloped and protected by the Sertoli cells to support germ cells undergoing meiosis to produce haploid gametes. Clearly, induction of apoptosis in seminiferous tubules leads to abnormalities in spermatogenesis and male infertility. Studies demonstrated that increased hyperlipidemia impairs male infertility and spermatogenesis by enhancing seminiferous tubules apoptosis. However, molecular mechanisms underlying high-cholesterol-mediated testicular damage remain poorly elucidated. In this scope, we established a rabbit model and investigated the role of endoplasmic reticulum (ER) stress on high cholesterol diet induced seminiferous tubule apoptosis. Histopatological examinations revealed increased seminifer tubule apoptosis in testes of rabbits fed high cholesterol diet. In addition, phosphorylated forms of IRE1 and PERK, two well-identified markers of ER stress, were significantly induced in accordance with high cholesterol diet. High cholesterol diet also exhibited CHOP induction in testes, indicating increased ER stress related apoptosis. Supplementation of α-tocopherol significantly attenuated cholesterol mediated ER stress, and restored seminiferous tubules apoptosis. Taken together, our findings suggest that α-tocopherol might be capable to reduce testicular damage via ameliorating histopatological features and inhibiting seminiferous tubules apoptosis in hypercholesterolemic rabbits.

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Associations of metabolomic profiles with circulating vitamin E and urinary vitamin E metabolites in middle-aged individuals

Jiao Luo, Yasufumi Hashimoto, Leon G Martens, Fleur L Meulmeester, Nadia Ashrafi, Dennis O Mook-Kanamori, Frits R Rosendaal, J Wouter Jukema, Ko Willems van Dijk, Kevin Mills, Saskia le Cessie, Raymond Noordam, Diana van Heemst

Nutrition . 2021 Jul 29;93:111440. doi: 10.1016/j.nut.2021.111440. Online ahead of print.

Abstract

Vitamin E (α-tocopherol [α-TOH]) is transported in lipoprotein particles in blood, but little is known about the transportation of its oxidized metabolites. In the Netherlands Epidemiology of Obesity Study, we aimed to investigate the associations of 147 circulating metabolomic measures obtained through targeted nuclear magnetic resonance with serum α-TOH and its urinary enzymatic (α-CEHC) and oxidized (α-TLHQ) metabolites from 24-h urine quantified by liquid chromatography with tandem mass spectrometry. Multivariable linear regression analyses, in which multiple testing was taken into account, were performed to assess associations between metabolomic measures (determinants; standardized to mean = 0, SD = 1) and vitamin E metabolites (outcomes), adjusted for demographic factors. We analyzed 474 individuals (55% women, 45% men) with a mean (SD) age of 55.7 (6.0) y. Out of 147 metabolomic measures, 106 were associated (P < 1.34 × 10-3) with serum α-TOH (median β [interquartile range] = 0.416 [0.383-0.466]), predominantly lipoproteins associated with higher α-TOH. The associations of metabolomic measures with urinary α-CEHC have directions similar to those with α-TOH, but effect sizes were smaller and non-significant (median β [interquartile range] = 0.065 [0.047-0.084]). However, associations of metabolomic measures with urinary α-TLHQ were markedly different from those with both serum α-TOH and urinary α-CEHC, with negative and small-to-null relations to most very-low-density lipoproteins and amino acids. Therefore, our results highlight the differences in the lipoproteins involved in the transportation of circulating α-TOH and oxidized vitamin E metabolites. This indicates that circulating α-TOH may be representative of the enzymatic but not the antioxidative function of vitamin E.

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Association of measures of body fat with serum alpha-tocopherol and its metabolites in middle-aged individuals

Fleur L Meulmeester, Jiao Luo, Leon G Martens, Nadia Ashrafi, Renée de Mutsert, Dennis O Mook-Kanamori, Hildo J Lamb, Frits R Rosendaal, Ko Willems van Dijk, Kevin Mills, Diana van Heemst, Raymond Noordam

Nutr Metab Cardiovasc Dis . 2021 Jul 22;31(8):2407-2415. doi: 10.1016/j.numecd.2021.05.001. Epub 2021 May 18.

Abstract

Background and aims: The accumulation of fat increases the formation of lipid peroxides, which are partly scavenged by alpha-tocopherol (α-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary α-TOH metabolites in middle-aged individuals.

Methods and results: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N = 511, 53% women; mean [SD] age of 55 [6.1] years), serum α-TOH and α-TOH metabolites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (α-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (α-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were assessed using magnetic resonance imaging. Using multivariable-adjusted linear regression analyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary α-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum α-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT.

Conclusions: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized α-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead.

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