Tocotrienol in Pre-Eclampsia Prevention: A Mechanistic Analysis in Relation to the Pathophysiological Framework

Zaleha Abdullah Mahdy, Kok-Yong Chin, Nik Lah Nik-Ahmad-Zuky, Aida Kalok, Rahana Abdul Rahman

Cells . 2022 Feb 10;11(4):614. doi: 10.3390/cells11040614.

Abstract

The pathophysiology of pre-eclampsia involves two major pathways, namely systemic oxidative stress and subsequent generalised inflammatory response, which eventually culminates in endothelial cell injury and the syndrome of pre-eclampsia with multi-organ dysfunction. Aspirin has been used to reduce the risk of pre-eclampsia, but it only possesses anti-inflammatory properties without any antioxidant effect. Hence, it can only partially alleviate the problem. Tocotrienols are a unique form of vitamin E with strong antioxidant and anti-inflammatory properties that can be exploited as a preventive agent for pre-eclampsia. Many preclinical models showed that tocotrienol can also prevent hypertension and ischaemic/reperfusion injury, which are the two main features in pre-eclampsia. This review explores the mechanism of action of tocotrienol in relation to the pathophysiology of pre-eclampsia. In conclusion, the study provides sufficient justification for the establishment of a large clinical trial to thoroughly assess the capability of tocotrienol in preventing pre-eclampsia.

Amanda D'Espessailles, Valeria Campos, Nevenka Juretić, Gladys S Tapia, Paulina Pettinelli

Nutrition . 2022 Feb;94:111539. doi: 10.1016/j.nut.2021.111539. Epub 2021 Nov 17.

Abstract

Objectives: An altered retinol metabolism might play a role in the development of nonalcoholic fatty liver disease (NAFLD). Tocopherols (TF) modulate metabolic pathways and have been proposed as a complementary treatment of obesity-induced metabolic alterations. Moreover, there is evidence suggesting that TF may modulate retinol metabolism. The aim of this study was to evaluate whether the dietary supplementation of α- and γ-TF modulates the expression of hepatic retinaldehyde dehydrogenases, RALDH1, RALDH2, and RALDH3 (involved in retinol metabolism) and, lipogenic factors sterol regulatory element binding protein-1c (SREBP-1c) and cluster differentiation 36 (CD36) in an animal model of diet-induced NAFLD.

Methods: Male C57BL/6J mice were divided into four groups: a control diet (CD) group (10% fat, 20% protein, 70% carbohydrates); a CD + TF group (α-tocopherol: 0.7 mg·kg·d^-1, γ-tocopherol: 3.5 mg·kg·d^-1); a high-fat diet (HFD) group (60% fat, 20% protein, 20% carbohydrates); and a HFD + TF group (0.01 mL·g body weight·d^-1), for 12 wk. General parameters (body-adipose tissue weight, glucose-triacylglyceride serum levels), liver steatosis (histology, liver triacylglycerides content), and hepatic RALDH1, RALDH2, RALDH3, SREBP-1c and CD36 (qPCR, quantitative polymerase chain reaction; IHQ, immunohistochemistry) were measured.

Results: TF supplementation in HFD-fed mice decreased the presence of lipid vesicles (90%) and total lipid content (75%) and downregulated the expression of RALDH1, RALDH3, SREBP-1c, and CD36.

Conclusions: The present study demonstrated that α- and γ-TF (1:5 ratio) might play a role in modulating retinol metabolism in the prevention of NAFLD induced by a HFD.

Mu Hu, Jielai Yang, Yang Xu

Bioengineered . 2022 Feb;13(2):3958-3968. doi: 10.1080/21655979.2022.2031399.

Abstract

Acute respiratory distress syndrome (ARDS) leads to the acute lung injury (ALI), a form of diffused alveolars injury, accompanied by severe inflammation and oxidative damage of alveolar epithelial cells. α-Tocopherol (α-TOH), one of the eight isoforms of vitamin E, is a natural antioxidant-free radical. We aimed to understand the effect of α-TOH and mechanism involved in inducing the ALI. Lipopolysaccharide (LPS) is injected into the trachea of mice to generate ALI mouse models. α-TOH was used to administrate the mice intragastrically to detect the expression of inflammatory factors and antioxidant molecules by enzyme linked immunosorbent assay, hematoxylin-eosin staining and immunohistochemical staining. Mouse alveolar epithelial cell line (MLE-12 cells) was used to determine the effect of α-TOH on alveolar epithelial cells. Inflammatory factors such as, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α shows significant increase in the lung tissues of the mice induced by LPS and reduction in the expressions of superoxide dismutase (SOD)1/2 and glutathione peroxidase (GSH-Px). After treatment with α-TOH, the inflammation and oxidative stress levels shows substantial reduction in the lung tissues of the mice. Moreover, α-TOH also increases the proliferation ability of MLE-12 cells in vitro and reduces apoptosis level. In addition, α-TOH reduces p65 phosphorylation and nuclear translocation in alveolar epithelial cells in vivo and in vitro, thus, inhibiting the activity of the nuclear factor kappa-B (NF-κB) signaling pathway. α-TOH reduces the inflammation and oxidative stress of lung tissue by inhibiting the NF-κB signaling pathway, thereby alleviating the LPS-induced ALI.

Sarah Kolnik, Kylie Corry, Kate Hildahl, Jeremy Filteau, Olivia White, Olivia Brandon, Lily Farid, AnnaMarie Shearlock, Daniel Moralejo, Sandra E Juul, Elizabeth Nance, Thomas R Wood

Dev Neurosci . 2022 Feb 8. doi: 10.1159/000522485. Online ahead of print.

Abstract

The gyrencephalic ferret brain is an excellent model in which to study hypoxia-ischemia (HI), a significant contributor to neurological injury in neonates. Vitamin E, an essential fat-soluble antioxidant, reduces oxidative stress and inflammation in both animal models and neonates. The aim of this study was to assess the effects of Vitamin E after oxygen glucose deprivation (OGD) in an organotypic ferret brain slice model of neonatal HI. We hypothesized that Vitamin E would decrease cytotoxicity, inflammation, and oxidative stress in OGD-exposed brain slices. Term-equivalent ferrets were sacrificed at postnatal (P) day 21-23 and 300µM whole hemisphere brain slices were obtained. During a 24h rest period, slices were cultured in either non-treated control conditions or with Erastin, a promotor of oxidative stress. Slices were then exposed to 2h of OGD followed by Vitamin E (25-100 IU/kg), Erastin (10µM) or Ferrostatin (1µM), an inhibitor of ferroptosis. Relative cytotoxicity was determined using an LDH assay, cell death was quantified via nuclear propidium iodide (PI) staining, oxidative stress was quantified via cellular GSH (glutathione) levels and target genes responsive to oxidative stress and inflammation were evaluated by qRT-PCR. OGD increased cytotoxicity, which was significantly reduced by treatment with Vitamin E. Vitamin E also preserved GSH after OGD and decreased amplification of certain markers of oxidative stress (CHAC1, SLC7A11) and inflammation (TNF-alpha, IL-8). Vitamin E remained protective after pretreatment with Erastin and was more protective than Ferrostatin, presumably due to its added anti-inflammatory properties. Results from the ferret whole hemisphere OGD model support the premise that Vitamin E neuroprotection is mediated by restoring GSH and acutely decreasing inflammation and oxidative stress after neonatal HI brain injury.

Ainsley Ryan Yan Bin Lee, Areeba Tariq, Grace Lau, Nicholas Wee Kiat Tok, Wilson Wai San Tam, Cyrus Su Hui Ho

Nutrients . 2022 Feb 3;14(3):656. doi: 10.3390/nu14030656.

Abstract

Background: Recently, it has been discovered that anti-inflammatory and anti-oxidative pathways play a role in depression and anxiety. Lower serum levels of antioxidants, such as vitamin E, have been implicated in both depression and anxiety.

Methods: This PROSPERO-registered systematic review (Reference: CRD42021260058) is reported according to PRISMA guidelines. PubMed, EMBASE, CENTRAL, PsycINFO, and CINAHL were searched from inception to June 2021.

Results: Twelve studies were included in this systematic review, and nine in meta-analysis of vitamin E versus placebo. For depression, meta-analysis of 354 participants showed a standardised mean difference of -0.88 (95% CI: -1.54, -0.21; I2 = 87%) favouring vitamin E. For anxiety, meta-analysis of 306 participants showed a standardised mean difference of -0.86 (95% CI: -2.11, 0.40; I2 = 95%) favouring vitamin E. Three of the studies involved a pure comparison of vitamin E against placebo, while others included constituents such as omega-3 fatty acids. Nine of the studies were at low risk of bias, two had some concerns, and one was at high risk of bias.

Conclusion: Vitamin E supplementation has shown inconclusive results in ameliorating both depression and anxiety. Containing a reassuring safety profile and low cost, future studies would be of promise, and they would benefit from both larger sample sizes and from excluding other constituents, such as omega-3 fatty acids, from experimental and comparator arms.

Irene Villalón-García, Mónica Álvarez-Córdoba, Suleva Povea-Cabello, Marta Talaverón-Rey, Marina Villanueva-Paz, Raquel Luzón-Hidalgo, Juan M Suárez-Rivero 1, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Joaquín J Salas, Rafael Falcón-Moya, Antonio Rodríguez-Moreno, José A Armengol, José A Sánchez-Alcázar

Neurobiol Dis . 2022 Feb 2;105649. doi: 10.1016/j.nbd.2022.105649. Online ahead of print.

Abstract

Background: PLA2G6-Associated Neurodegeneration (PLAN) is a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the NBIA (Neurodegeneration with Brain Iron Accumulation) group. Although the pathogenesis of the disease remains largely unclear, lipid peroxidation seems to play a central role in the pathogenesis. Currently, there is no cure for the disease.

Objective: In this work, we examined the presence of lipid peroxidation, iron accumulation and mitochondrial dysfunction in two cellular models of PLAN, patients-derived fibroblasts and induced neurons, and assessed the effects of α-tocopherol (vitamin E) in correcting the pathophysiological alterations in PLAN cell cultures.

Methods: Pathophysiological alterations were examined in fibroblasts and induced neurons generated by direct reprograming. Iron and lipofuscin accumulation were assessed using light and electron microscopy, as well as biochemical analysis techniques. Reactive Oxygen species production, lipid peroxidation and mitochondrial dysfunction were measured using specific fluorescent probes analysed by fluorescence microscopy and flow cytometry.

Results: PLAN fibroblasts and induced neurons clearly showed increased lipid peroxidation, iron accumulation and altered mitochondrial membrane potential. All these pathological features were reverted with vitamin E treatment.

Conclusions: PLAN fibroblasts and induced neurons reproduce the main pathological alterations of the disease and provide useful tools for disease modelling. The main pathological alterations were corrected by Vitamin E supplementation in both models, suggesting that blocking lipid peroxidation progression is a critical therapeutic target.

Keying Xu, Jing Li, Qingyi Han, Dingding Zhang, Libing Zhang, Zhen Zhang, Xiaoquan Lu

Analyst . 2022 Jan 31;147(3):398-403. doi: 10.1039/d1an02289j.

Abstract

The rapid and sensitive surface-enhanced Raman scattering (SERS) detection of molecular biomarkers from real samples is still a challenge because the intrinsically trace analytes may have a low molecular affinity for metal surfaces. Herein, we develop a smart signal conversion and amplification strategy based on silver-gold-silica core-satellite structure nanoparticles (Ag@Au@SiO₂ NPs) to sensitively detect low adsorptive vitamin E using SERS, which has been considered a biomarker of neuromuscular disorders when its abnormal content is measured in the serum of patients. Through the reducibility of vitamin E, Ag⁺ ions are rapidly reduced to Ag atoms, resulting in the epitaxial growth of Ag nanocrystals on gold nanoparticles forming satellite particle-particle gap-narrowed Ag@Au@SiO₂ NPs. The generated strong plasmonic field dramatically enhances the Raman signal of the Raman reporter molecule 4-aminothiophenol (4-ATP) and the detected vitamin E molecules at an estimated level of 58.19 nmol L^-1. The sensitivity of this operational SERS strategy provides tremendous prospects for the screening of neuromuscular disorders.

Maya Idriss, Maria Younes, Sonia Abou Najem, Mohammad Hassan Hodroj, Rajaa Fakhoury, Sandra Rizk

Curr Mol Pharmacol . 2022 Jan 31. doi: 10.2174/1874467215666220131095611. Online ahead of print.

Abstract

Background: Breast Cancer is one of the most commonly diagnosed cancers worldwide and a major cause of death among women. Although chemotherapeutic agents remain the keystones in cancer therapy, significant side effects have failed to provide a safe and tolerable treatment for cancer patients. Dietary antioxidant vitamins were extensively investigated over the past years and their relevance in cancer chemotherapy remains to be elucidated.

Objective: In the current study, we aimed to investigate the anti-proliferative and apoptotic effects of combining γ-tocotrienol, a member of the vitamin E family, with the chemotherapeutic drug etoposide in MCF-7 and MDA-MB-231 breast cancer cell lines.

Methods: The antiproliferative effect of etoposide combined with γ-tocotrienol was measured using MTS viability reagent. The pro-apoptotic effect was elucidated through Cell Death ELISA and dual Annexin V/PI staining followed by flow cytometric analysis.

Results: Our results showed that etoposide significantly decreased the cell growth of both cell lines with MDA-MB-231 cells being more sensitive to etoposide treatment than MCF-7. Moreover, the simultaneous treatment of both breast cancer cell lines with low doses of γ-tocotrienol and etoposide induced a synergistic antiproliferative effect (CI<1). Furthermore, the combination therapy significantly increased the percentage of total apoptotic cells in the MDA-MB-231 cell line and the degree of DNA fragmentation as compared to treatment with either compound alone.

Conclusion: In conclusion, our results provide evidence for the profound anti-tumorigenic effect of combined etoposide and γ-tocotrienol in the breast cancer cell lines.

Xue Jiao 1, Bin Shen 1, Min Li 1, Lidan Ye 1 2, Hongwei Yu 1

ACS Synth Biol . 2022 Jan 31. doi: 10.1021/acssynbio.1c00484. Online ahead of print.

Abstract

Tocotrienols as important components of vitamin E have attracted increasing attention, with recent progress made in their heterologous biosynthesis, but all as intracellular products. Aiming to further improve the tocotrienol production capacity of engineered yeast and to advance toward industrial fermentation of tocotrienols, we first optimized the synthetic pathway to enhance the tocotrienol yield and then attempted to realize their secretory production by exploring biphasic extractive fermentation conditions and screening for endogenous transporters. Finally, a Saccharomyces cerevisiae strain with tocotrienol yield of 25.57 mg/g dry cell weight was generated, and the tocotrienol titer reached 82.68 mg/L in shake-flask cultures, with 73.66% of the product secreted into the organic phase. For the first time, we have reported that the vitamin E components could be harvested as extracellular products of microbial cell factories, which could largely simplify the downstream process and could be of significance for fermentative production of these products.

Jean-Marc Zingg, Christina Stamatiou, Giulia Montalto, Sylvia Daunert

Biofactors . 2022 Jan 27. doi: 10.1002/biof.1821. Online ahead of print.

Abstract

The CD36/FAT scavenger receptor/fatty acids transporter regulates cellular lipid accumulation important for inflammation, atherosclerosis, lipotoxicity, and initiation of cellular senescence. Here we compared the regulatory effects of the vitamin E analogs alpha-tocopherol (αT), alpha-tocopheryl phosphate (αTP), and αTP/βCD (a nanocarrier complex between αTP and β-cyclodextrin [βCD]) and investigated their regulatory effects on lipid accumulation, phagocytosis, and senescence in THP-1 monocytes and macrophages. Both, αTP and αTP/βCD inhibited CD36 surface exposition stronger than αT leading to more pronounced CD36-mediated events such as inhibition of DiI-labeled oxLDL uptake, phagocytosis of fluorescent Staphylococcus aureus bioparticles, and cell proliferation. When compared to βCD, the complex of αTP/βCD extracted cholesterol from cellular membranes with higher efficiency and was associated with the delivery of αTP to the cells. Interestingly, both, αTP and more so αTP/βCD inhibited lysosomal senescence-associated beta-galactosidase (SA-β-gal) activity and increased lysosomal pH, suggesting CD36-mediated uptake into the endo-lysosomal phagocytic compartment. Accordingly, the observed pH increase was more pronounced with αTP/βCD in macrophages whereas no significant increase occurred with αT, alpha-tocopheryl acetate (αTA) or βCD. In contrast to αT and αTA, the αTP molecule is di-anionic at neutral pH, but upon moving into the acidic endo-lysosomal compartment becomes protonated and thus is acting as a base. Moreover, it is expected to be retained in lysosomes since it still carries one negative charge, similar to lysosomotropic drugs. Thus, treatment with αTP or αTP/βCD and/or inhibition of conversion of αTP to αT as it occurs in aged cells may counteract CD36-mediated overlapping inflammatory, senescent, and atherosclerotic events.