Ultrasensitive detection of vitamin E by signal conversion combined with core-satellite structure-based plasmon coupling effect

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.


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.

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Gamma-tocotrienol Synergistically Promotes the Anti-proliferative and Pro-apoptotic Effects of Etoposide on Breast Cancer Cell Lines

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.


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.

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Secretory Production of Tocotrienols in Saccharomyces cerevisiae

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.


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.

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Modulation of CD36-mediated lipid accumulation and senescence by vitamin E analogs in monocytes and macrophages

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

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


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.

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Randomised single centre double-blind placebo controlled phase II trial of Tocovid SupraBio in combination with pentoxifylline in patients suffering long-term gastrointestinal adverse effects of radiotherapy for pelvic cancer: the PPALM study

H Jervoise N Andreyev, Jennifer Matthews, Carolyn Adams, Lone Gothard, Claire Lucy, Holly Tovey, Sue Boyle, Selvakumar Anbalagan, Annette Musallam, John Yarnold, David Abraham, Judith Bliss, Bahja Ahmed Abdi, Alexandra Taylor, Martin Hauer-Jensen

Radiother Oncol . 2022 Jan 27;S0167-8140(22)00029-9. doi: 10.1016/j.radonc.2022.01.024. Online ahead of print.


Background: Preclinical data suggest that combined gamma-tocotrienol with pentoxifylline ameliorates radiotherapy-induced gastrointestinal damage.

Aim: To test whether gastrointestinal symptoms arising after radiotherapy, and persisting after maximal medical therapy, can be improved using Tocovid SupraBio 200mg and pentoxifylline 400mg orally twice daily for one year. Patients stratified by severity of symptoms, and randomised to active treatment or matched placebo were assessed after 12 months. The primary end point was improvement in gastrointestinal symptoms measured using the Inflammatory Bowel Disease Questionnaire, bowel subset score. Changes in bio-markers of fibrosis were assessed.

Results: 62 patients, median age 66, 34(55%) treated for prostate, 21(34%) gynaecological, 6(10%) anal and one(1%) rectal cancer were recruited; 40(65%) randomised to treatment, 22(35%) to placebo, 39 months (median) after radiotherapy completion. Gamma tocotrienol was not detected in serum in 41% of treated patients, despite good compliance with study medication. Treatment was completed in 28(70%) and 17(77%) patients in the treatment and placebo groups respectively. No improvement in symptom scores nor in quality of life was identified. Thirteen serious adverse events occurred. A transient ischaemic attack, was possibly related to pentoxifylline, others were assessed as unlikely to be related to treatment. Levels of EGF, PDGF and FGF were significantly reduced and consistent trends in reduced inflammation were seen during treatment but were not sustained once treatment ended.

Summary: This single centre study closed prematurely and therefore data interpretation is of necessity limited. No clinical benefit was demonstrated. However, biochemical data suggest that this intervention does have anti-inflammatory and anti-fibrotic effects.

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Palm tocotrienol rich fraction with palm kernel oil supplementation prevents development of liver steatosis in high fat diet ICR mice

Mohd Danial Mohd Efendy Goon, Nur Izzati Zulkanain, Siti Hamimah Sheikh Abdul Kadir, Sharaniza Ab Rahim, Musalmah Mazlan, Normala Abd Latip, Mardiana Abdul Aziz, Norizal Mohd Noor

Transl Gastroenterol Hepatol . 2022 Jan 25;7:2. doi: 10.21037/tgh.2020.02.20. eCollection 2022.


Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) in Asian countries is increasing at concerning level. Currently, no specific treatment available to prevent its oxidative stress and progression except for diet and lifestyle changes. Vitamin E such as tocotrienol-rich fraction (TRF) has a promising potential in preventing NAFLD progression. TRF is a potent antioxidant but has low bioavailability due to the use of long-chain triglycerides (LCT) as its carrier. Testing of potential therapeutic agents such as TRF are commonly carried out using animal models. These animal models are often costly due to limited access to the supply especially Asian countries and predisposed to high transportation cost. Lower expenditure of NAFLD model should be investigated without forfeiting the outcome of study. Therefore, this study addresses the gap by utilizing the ICR mice as NAFLD model through dietary modification and testing on the newly formulated TRF with combination of palm kernel oil (PKO) as a medium-chain triglycerides (MCT) carrier.

Methods: Fifteen ICR strain mice were randomly group into two control and one treatment group. Control groups received high-fat diet (HFD) only and standard diet while treatment group was given HFD with TRF (200 mg/kg/day). Study was carried out for 10 weeks. Weights were recorded twice a week. At the end of study, all mice were euthanized and data such weights, waist circumference and random blood glucose were recorded. Liver from each mouse were prepared for histology assessment.

Results: Mice mean weights and random blood sugar showed no difference between group (P>0.05) while significance waist circumference was larger in HFD and TRF groups compared to SD (P<0.05). Histology assessment showed steatosis in TRF group had lower severity compared to HFD group. NAFLD activity score (NAS) was lower in treatment group compared to HFD group.

Conclusions: TRF showed promising potential as an agent to reduce NAFLD progression in ICR mice. Further study at gene and protein levels are required to fully elucidate the mechanism of this new TRF formulation in reducing NAFLD progression.

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Transport of Vitamin E from Ethanol/Water Solution into Contact Lenses and Impact on Drug Transport

Zhen Liu, Meredith Overton, Anuj Chauhan

J Ocul Pharmacol Ther . 2022 Jan 19. doi: 10.1089/jop.2021.0094. Online ahead of print.


Purpose: Contact lens-based drug delivery has many advantages over eye drops including higher bioavailability and sustained release. Commercial contact lenses release drug rapidly necessitating integration of control-release mechanisms into the lenses such as incorporation of vitamin E diffusion barriers. In prior publications, vitamin E barriers are loaded by placing the lenses in vitamin E-ethanol solution, followed by the ethanol extraction. In this article, we investigate feasibility of manufacturing vitamin E barriers by soaking contact lenses in vitamin E dissolved in ethanol-water solutions to minimize swelling. Methods: Contact lenses are soaked in solutions of vitamin E dissolved in ethanol-water mixtures. The dynamics of vitamin E transport into the measured and fitted to diffusion equation to determine diffusivity and partition coefficient. Vitamin E loaded lenses are imaged and transport of hydrophilic drug timolol is measured. Results: The partition coefficient of vitamin E increases more than 5 and 10-fold when the water content in the loading solution reaches 15% and 25% (v/v), respectively. The solubility of vitamin E in the solutions decreases as water fraction increases but the increase in partition coefficient allows for loading > 20% vitamin E in the lens. The barriers manufactured by this approach are effective at sustaining release of glaucoma drug timolol. Conclusions: Vitamin E barriers can be incorporated into contact lenses by soaking in solutions of vitamin E in water and ethanol. Vitamin E barriers extended hydrophilic drug release and the reduced swelling is beneficial in minimizing the possibility of lens damage during loading of vitamin E.

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Change in plasma alpha-tocopherol associations with attenuated pulmonary function decline and with CYP4F2 missense variation

Jiayi Xu, Kristin A Guertin, Nathan C Gaddis, Anne H Agler, Robert S Parker, Jared M Feldman, Alan R Kristal, Kathryn B Arnold, Phyllis J Goodman, Catherine M Tangen, Dana B Hancock, Patricia A Cassano

Am J Clin Nutr . 2022 Jan 18;nqac013. doi: 10.1093/ajcn/nqac013. Online ahead of print.


Background: Vitamin E (vitE) is hypothesized to attenuate age-related decline in pulmonary function.

Objectives: We investigated the association between change in plasma vitE (∆vitE) and pulmonary function decline (forced expiratory volume in the first second [FEV1]) and examined genetic and non-genetic factors associated with ∆vitE.

Design: We studied 1,144 men randomized to vitE in the Selenium and Vitamin E Cancer Prevention Trial. ∆vitE was the difference between baseline and year 3 vitE concentrations measured with gas chromatography-mass spectrometry. FEV1 was measured longitudinally by spirometry. We genotyped 555 men (vitE-only arm) using the Illumina MEGAex array. We used mixed-effects linear regression modeling to examine the ∆vitE-FEV1 association.

Results: Higher ∆vitE was associated with lower baseline α-tocopherol, higher baseline γ-tocopherol, higher baseline free cholesterol, European ancestry (vs. African) (all P < 0.05), and the minor allele of a missense variant in CYP4F2 (rs2108622-T; 2.4 µmol/L higher ∆vitE, SE = 0.8, P = 0.0032). Higher ∆vitE was associated with attenuated FEV1 decline, with stronger effects in adherent participants (≥80% of supplements consumed): a statistically significant ∆vitE × time interaction (P = 0.014) indicated that a 1-unit increase in ∆vitE was associated with a 2.2 mL/year attenuation in FEV1 decline (SE = 0.9). The effect size for 1 standard deviation higher ∆vitE (+4 µmol/mmol free-cholesterol-adjusted α-tocopherol) is ∼¼ of the effect of one year of aging, but in the opposite direction. The ∆vitE-FEV1 association was similar in never smokers (2.4 mL/year attenuated FEV1 decline, SE = 1.0, P = 0.017, n = 364), and current smokers (2.8 mL/year, SE = 1.6, P = 0.079, n = 214), but there was little to no effect in former smokers (-0.64 mL/year, SE = 0.9, P = 0.45, n = 564).

Conclusions: Greater response to vitamin E supplementation was associated with attenuated FEV1 decline. The response to supplementation differed by rs2108622 such that individuals with the C allele, compared to the T allele, may need a higher dietary intake to reach the same plasma vitamin E concentration.

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Vitamin E for Skin: Benefits and How to Use

In beauty, there’s a new novelty ingredient pushed to the forefront of the industry practically every single day, with each new formula lauded better and more innovative than the last. While we’re all for trying something new, there’s something to be said about sticking with an old favorite. Enter vitamin E, which is popular in both oil and capsulated forms.

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α-tocopherol prevents oxidative stress-induced proliferative dysfunction in first-trimester human placental (HTR-8/SVneo) cells

Lígia Pinto-Ribeiro, Cláudia Silva, Nelson Andrade, Fátima Martel

Reprod Biol . 2022 Jan 8;22(1):100602. doi: 10.1016/j.repbio.2022.100602. Online ahead of print.


Extravillous trophoblasts (EVTs) are the main participants in the process of placentation, an early process critical for placental growth and function involving an adequate invasion and complete remodelling of the maternal spiral arteries during early pregnancy. An increase in oxidative stress during pregnancy is associated with the onset and progression of several pregnancy disorders, including preeclampsia and gestational diabetes mellitus and it also occurs due to exposure of pregnant women to some xenobiotics (eg. alcohol). This study aimed to investigate how oxidative stress affects EVTs, and the ability of several distinct antioxidant agents to prevent these changes. For this, we exposed HTR8/SVneo cells to tert-butylhydroperoxide (0.5 μM; 24 h), which was able to increase lipid peroxidation and protein carbonyl levels. Under these conditions, there was a decrease in proliferation rates, culture growth, migratory and angiogenic capacities and an increase in the apoptosis rates. The antiproliferative effect of TBH was supressed by simultaneous treatment of the cells with α-tocopherol, but other antioxidants (vitamin C, allopurinol, apocynin, N-acetylcysteine, quercetin and resveratrol) were ineffective. α-tocopherol was also able to abolish the effect of TBH on lipid peroxidation and protein carbonyl levels. Overall, our results show that oxidative stress interferes with EVT characteristics essential for the placentation process, which may contribute to the association between oxidative stress and pregnancy disorders. Our results also show that the nature of the in vitro model of oxidative stress-induction is an important determinant of the cellular consequences of oxidative stress and, therefore, of the efficacy of antioxidants.

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