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.

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.

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.

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.

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.

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.

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.

Mustafa Coskun, Tamer Kayis, Emre Gulsu, Emel Alp

Sci Rep . 2020 Jun 19;10(1):9953. doi: 10.1038/s41598-020-67072-9.

Abstract

To understand the effects of micronutrients have particular biological functions that are involved mainly in the antioxidant system, which has essential implications for the development of diseases, this study investigated how vitamin E, selenium, and their combination affect lipid, protein, carbohydrate, and malondialdehyde (MDA) content; antioxidant enzyme (catalase [CAT], superoxide dismutase [SOD], glutathione-S-transferase [GST]) activity; and the total hemocyte count (THC) in larvae of Galleria mellonella L. fed different diets. Diet 1 (100 µg of selenium) significantly decreased carbohydrate and lipid content. Diets 2 (100 µg of vitamin E), 3 (100 µg of selenium and vitamin E each), and 5 (Tween 80) did not significantly affect protein and carbohydrate content. Diet 2 significantly increased the lipid content compared to diet 4 (control). Diet 1 increased CAT, SOD, and GST activity and MDA content (highest at 27.64 nmol/mg protein). Diet 2 significantly decreased SOD activity and MDA content compared to other diets. Diet 1 significantly decreased the THC compared to other diets. These results suggested that selenium changes oxidative stress parameters, energy reserves, and THC in G. mellonella. These changes could be a physiological adaptation against selenium-induced oxidative stress. Vitamin E could play a protective role in selenium toxicity.

Kyoung-Woon Kim, Bo-Mi Kim, Ji-Yeon Won, Hong Ki Min, Seoung Joon Lee, Sang-Heon Lee, Hae-Rim Kim

Korean J Intern Med . 2020 Jun 19. doi: 10.3904/kjim.2019.372. Online ahead of print.

Abstract

Background/aims: The present study aimed to investigate whether tocotrienol regulates interleukin 17 (IL-17)-induced osteoclastogenesis in rheumatoid arthritis (RA).

Methods: We evaluated the effect of tocotrienol on IL-17-induced receptor activator of nuclear factor kappa B ligand (RANKL) production using RA fibroblast-like synoviocyte (FLS), together with real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Osteoclast differentiation was confirmed after culturing IL-17-treated RA FLS and Th17 cells with tocotrienol and monocytes. We analyzed the suppressive effect of tocotrienol on Th17 cells percentage or Th17-cytokine levels among peripheral blood mononuclear cells using flow cytometry.

Results: We found that IL-17 stimulated FLS to produce RANKL and tocotrienol decreased this IL-17-induced RANKL production. Tocotrienol decreased the IL-17-induced activation of mammalian target of rapamycin, extracellular signal-regulated kinase, and inhibitor of kappa B-alpha. When monocytes were incubated with IL-17, RANKL, IL-17-treated FLS or Th17 cells, osteoclasts were differentiated and tocotrienol decreased this osteoclast differentiation. Tocotrienol reduced Th17 cell differentiation and the production of IL-17 and sRANKL; however, tocotrienol did not affect Treg cell differentiation.

Conclusions: Tocotrienol inhibited IL-17- activated RANKL production in RA FLS and IL-17-activated osteoclast formation. In addition, tocotrienol reduced Th17 differentiation. Therefore, tocotrienol could be a new therapeutic choice to treat bone destructive processes in RA.

W Y Meng, W T Huang, J Zhang, M Y Jiao, L Jin, L Jin

Beijing Da Xue Xue Bao Yi Xue Ban . 2020 Jun 18;52(3):470-478.

Abstract

Objective: To investigate the incidence of hypertension disorders complicating pregnancy (HDCP) and vitamin E (VE) nutritional status among pregnant women in Beijing, and to determine the relationship between serum VE concentration in the first trimester of pregnancy and the risk of developing HDCP.

Methods: A retrospective cohort study was performed including 22 283 cases of pregnant women who underwent singleton deliveries in Tongzhou Maternal & Child Health Hospital of Beijing from January 2016 through December 2018 and received tests of serum VE concentrations in the first trimester of pregnancy. Nonconditional Logistic regression model was used to analyze the association between serum VE concentration levels and the risk of developing HDCP.

Results: The total incidence of HDCP was 5.4%, with the incidence of gestational hypertension around 2.1% and the incidence of preeclampsia-eclampsia around 3.3%. The median concentration of serum VE in early pregnancy was 10.1 (8.8-11.6) mg/L, and 99.7% of the participants had normal serum VE concentrations. The incidence of gestational hypertension and that of preeclampsia-eclampsia had been annually increasing in three years; a linear-by-linear association had also been observed between the serum VE concentrations and the years of delivery. According to the results of the univariable and the multivariable Logistic regression analyses, higher risks of developing HDCP had been observed among women with higher serum VE concentrations. Compared to those with serum VE concentrations in interquartile range (P₂₅–P₇₅) of all the participants, the women whose serum VE concentrations above P₇₅ were at higher risks to be attacked by HDCP (OR = 1.34, P < 0.001), gestational hypertension (OR = 1.39, P = 0.002), or preeclampsia-eclampsia (OR = 1.34, P = 0.001), as suggested by the results of the multivariable Logistic regression model analyses. In addition, the women with serum VE concentrations of 11.2 mg/L or above had a significantly higher risk of developing HDCP than those whose serum VE concentrations of P₄₀–P₆₀ of all the participants, and this risk grew higher as serum VE concentrations in the first trimester of pregnancy increased.

Conclusion: Women in Beijing are at good nutritional status. From January 2016 to December 2018, the incidence of HDCP increased with serum VE concentration level, and serum VE concentration of 11.2 mg/L is an indicator of an increased risk of developing HDCP, suggesting that pregnant women should take nutritional supplements containing VE carefully.