Food for Bone: Evidence for a Role for Delta-Tocotrienol in the Physiological Control of Osteoblast Migration

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

Int J Mol Sci . 2020 Jun 30;21(13):4661. doi: 10.3390/ijms21134661.

Abstract

Bone remodeling and repair require osteogenic cells to reach the sites that need to be rebuilt, indicating that stimulation of osteoblast migration could be a promising osteoanabolic strategy. We showed that purified δ-tocotrienol (δ-TT, 10 μg/mL), isolated from commercial palm oil (Elaeis guineensis) fraction, stimulates the migration of both MC3T3-E1 osteoblast-like cells and primary human bone marrow mesenchymal stem cells (BMSC) as detected by wound healing assay or Boyden chamber assay respectively. The ability of δ-TT to promote MC3T3-E1 cells migration is dependent on Akt phosphorylation detected by Western blotting and involves Wnt/β-catenin signalling pathway activation. In fact, δ-TT increased β-catenin transcriptional activity, measured using a Nano luciferase assay and pretreatment with procaine (2 µM), an inhibitor of the Wnt/β-catenin signalling pathway, reducing the wound healing activity of δ-TT on MC3T3-E1 cells. Moreover, δ-TT treatment increased the expression of β-catenin specific target genes, such as Osteocalcin and Bone Morphogenetic Protein-2, involved in osteoblast differentiation and migration, and increased alkaline phosphatase and collagen content, osteoblast differentiation markers. The ability of δ-TT to enhance the recruitment of BMSC, and to promote MC3T3-E1 differentiation and migratory behavior, indicates that δ-TT could be considered a promising natural anabolic compound.

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Studies on the growth inhibiting and non-cytotoxic effects of tocotrienols on selected cancer cell lines

Aleksandra Szulczewska-Remi, Małgorzata Nogala-Kalucka

Acta Sci Pol Technol Aliment . Apr-Jun 2020;19(2):139-147. doi: 10.17306/J.AFS.0787.

Abstract

Background: Tocotrienols found in certain plant oils, like palm, rice bran, grapeseed and annatto seeds, have been reported to possess beneficial properties for humans, including cancer prevention. Since studies on their beneficial effects on human breast cancer cells have been extensively reviewed, the current understanding of how tocotrienols affect other cancer cells deserves further research. Therefore, the aim of this study was to investigate the antiproliferative and non-cytotoxic effects of tocotrienols on human hepatoma HepG2 and colon colorectal Caco-2 cell cultures.

Methods: The cells were exposed to alpha-, beta-, gamma- or delta-tocotrienols at various concentrations and the antiproliferative activities were measured using MTS-based CellTiter 96 followed by a methylene blue assay for counting cells to evaluate the potential toxicity.

Results: The research on HepG2 showed statistically similar cytotoxic effects for both beta- and delta-T3 with no effects for alpha- and gamma-T3. Promising results were found for alpha-, beta- and gamma-T3 against CaCo-2.

Conclusions: The exact reasons for the sensitivity of liver cancer cells to tocotrienols are unknown. Inhibition is time and dose-dependent, therefore tocotrienols’ homologs show very high toxic or no effects. Tocotrienols appeared to be effective against colon cancer cells. Still, future investigation is necessary to explain the different mechanism of actions to support the antiproliferative effects of these homologs against colon cancer cells.

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Vitamin E Deficiency: An Under-Recognized Cause of Dystonia and Ataxia Syndrome

Harsh V Gupta, Steven Swank, Vibhash D Sharma

Ann Indian Acad Neurol . May-Jun 2020;23(3):372-374. doi: 10.4103/aian.AIAN_29_20.

A 43-year-old right-handed man was seen in the clinic for an evaluation of progressive gait difficulty. He initially developed tingling in his hands and feet at the age of 30 years. After 3 years of initial symptoms, he developed weakness in his lower distal extremities. His symptoms progressed over the years and he developed unsteady gait, double vision, speech changes, and tremor in his right hand and head. He also complained of diarrhea (five to six loose watery bowel movements a day) and required frequent emergency evaluations for the management of the same. He was found to have colonic dilatation (11.4 cm). His past medical history was significant for jejunal resection at the time of birth. There was no family history of similar neurological problems.

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Melatonin and vitamin E alleviate homocysteine-induced oxidative injury and apoptosis in endothelial cells

Gurkan Aykutoglu, Musa Tartik, Ekrem Darendelioglu, Adnan Ayna, Giyasettin Baydas

Mol Biol Rep . 2020 Jun 26. doi: 10.1007/s11033-020-05607-z. Online ahead of print.

Abstract

A relationship exists between hyperhomocysteinemia and cardiovascular diseases, although the underlying mechanisms are still incompletely defined. One possibility involves a homocysteine (Hcy)-induced increased oxidative stress. Melatonin (Mel) and vitamin E (vitE) are important anti-oxidants. The main purpose of this study was (1) to compare the effect of treatments with Mel, vitE or both, on Hcy-induced apoptosis in human umbilical vein endothelial cells (HUVECs), and (2) to investigate the underlying mechanisms. Cell proliferation assay was carried out by Water Soluble Tetrazolium-1 (WST-1) assay kit. Apoptotic index was calculated by TUNEL Assay. Anti-oxidant parameters were studied by measurement of reactive oxygen species (ROS) and lipid peroxidation (LPO) levels. mRNA and protein expression levels of apoptotic and anti-apoptotic genes and proteins were studied by quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting experiments respectively. The results showed that treatments with Mel, vitE or Mel + vitE suppressed Hcy-induced cell death, with a higher efficiency for the Mel and Mel + vitE treatments. Our results suggests that the mechanisms by which these anti-oxidants protected endothelial cells include the decrease in ROS and LPO levels, an increase in cell migration, the downregulation of pro-apoptotic proteins Cas 3, Cas 9, Cyt C and Bax and the upregulation of anti-apoptotic protein Bcl 2. Collectively, these results revealed the protective role of vitE and Mel against Hcy-induced cell apoptosis, which may add insight into therapeutic approaches to Hcy-induced damages.

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Vitamin E Savior?

A new study gives hope that vitamin E may defend against catastrophic disease. The research, recently published in the Journal of Cerebral Blood Flow & Metabolism, discovered that 10 weeks of preventive use of the tocotrienol (TCT) form of vitamin E on dogs offered robust protection in the event of a stroke.

Vitamin E occurs naturally in eight forms, including tocopherols and TCTs. “Most of the previous studies on vitamin E was on tocopherols,” says lead author Chandan Sen, PhD. “Tocotrienols are hardly studied, but we found that it’s much more neural protective than the others.

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Tocotrienols Influence Body Weight Gain and Brain Protein Expression in Long-Term High-Fat Diet-Treated Mice

Yugo Kato, Yoshinori Aoki, Koji Fukui

Int J Mol Sci . 2020 Jun 25;21(12):4533. doi: 10.3390/ijms21124533.

Abstract

Obesity induces serious diseases such as diabetes and cardiovascular disease. It has been reported that obesity increases the risk of cognitive dysfunction. Cognitive dysfunction is a characteristic symptom of Alzheimer’s and Parkinson’s diseases. However, the detailed mechanisms of obesity-induced cognitive dysfunction have not yet been elucidated. The onset and progression of obesity-induced severe secondary diseases such as diabetes, cardiovascular events, and hypertension are deeply connected to oxidative stress. We hypothesized that obesity induces cognitive dysfunction via acceleration of reactive oxygen species (ROS) production. Vitamin E, which is a lipophilic vitamin, has strong antioxidative effects and consists of two groups: tocopherols and tocotrienols. Recently, it has been demonstrated that tocotrienols have strong neuroprotective and anti-obesity effects. In this study, we fed mice a high-fat diet (HFD) from 9 to 14 months of age and assessed the effect of tocotrienols treatment on body weight, brain oxidation levels, and cognitive function. The results revealed that treatment with tocotrienols inhibited body weight gain; further, tocotrienols reached the brain and attenuated oxidation in HFD-treated mice. These results indicate that tocotrienols have anti-obesity effects and inhibit obesity-induced brain oxidation.

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Culprit or Correlate? An Application of the Bradford Hill Criteria to Vitamin E Acetate

Ryan Feldman, Jonathan Meiman, Matthew Stanton, David D Gummin

Arch Toxicol . 2020 Jun;94(6):2249-2254. doi: 10.1007/s00204-020-02770-x. Epub 2020 May 25.

Abstract

Vitamin E acetate (VEA) has come under significant scrutiny due to its association with e-cigarette, or vaping, product use-associated lung injury (EVALI). In 1965, Sir Austin Bradford Hill proposed a set of criteria used to critically assess an association for causality. In this article, we apply the Bradford Hill causation criteria to VEA and the EVALI outbreak to clarify what further areas of study are needed to strengthen the causal argument. Additionally, we highlight the need for systematized approaches to rapidly identify the cause of mass poisoning events of unknown etiology.

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Deuteration of the Farnesyl Terminal Methyl Groups of δ-Tocotrienol and Its Effects on the Metabolic Stability and Ability of Inducing G-CSF Production

Xingui Liu, Zhengya Gao, Qiang Fu, Lin Song, Peiyi Zhang, Xuan Zhang, Howard Hendrickson, Peter A Crooks, Daohong Zhou, Guangrong Zheng

Bioorg Med Chem . 2020 Jun 1;28(11):115498. doi: 10.1016/j.bmc.2020.115498. Epub 2020 Apr 8.

Abstract

δ-tocotrienol (DT3), a member of vitamin E family, has been shown to have a potent radio-protective effect. However, its application as a radioprotectant is limited, at least in part, by its short plasma elimination half-life and low bioavailability. In an effort to increase the metabolic stability of DT3, a deuterium substituted DT3 derivative, d6-DT3, was designed and synthesized. d6-DT3 showed improved in vitro and in vivo metabolic stability compared to DT3. The unexpected lower potency of d6-DT3 in inducing granulocyte-colony stimulating factor (G-CSF) production in mouse revealed that the metabolite(s) of DT3 might play a major role in inducing G-CSF induction.

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