Tocotrienols Modulate Breast Cancer Secretomes and Affect Cancer-Signaling Pathways in MDA-MB-231 Cells: A Label-Free Quantitative Proteomic Analysis.

Ramdas P, Radhakrishnan AK, Abdu Sani AA, Abdul-Rahman PS

Nutr Cancer. 2019;71(8):1263-1271. doi: 10.1080/01635581.2019.1607407

Abstract

Tocotrienols (T3), a family of vitamin E, are reported to possess potent anti-cancer effects but the molecular mechanisms behind these effects still remain unclear. The aim of this study was to investigate how T3 exert anti-cancer effects on MDA-MB-231 human breast cancer cells. The MDA-MB-231 cells were chosen for this study as they are triple-negative and highly metastatic cells, which form aggressive tumors in experimental models. The MDA-MB-231 cells were treated with varying concentrations (0-20 µg mL^-1) of gamma (γ) or delta (δ) T3 and the secretome profiles of these cells treated with half maximal inhibitory concentration (IC₅₀) of γT3 (5.8 µg mL^-1) or δT3 (4.0 µg mL^-1) were determined using label-free quantitative proteomic strategy. A total of 103, 174 and 141 proteins were identified with ProteinLynx Global Server (PLGS) score of more than 200 and above 25% sequence coverage in the untreated control and T3-treated cell culture supernatant respectively. A total of 18 proteins were dysregulated between untreated control and T3 (δT3 or γT3) treated conditions. The results showed that T3 treatment downregulated the exogenous Cathepsin D and Serpine1 proteins but upregulated Profilin-1 protein, which play a key role in breast cancer in the MDA-MB-231 cells. These findings strongly suggest that T3 may induce differential expression of secreted proteins involved in the cytoskeletal regulation of RHO GTPase signaling pathway.

Wan Nasri WN, Makpol S, Mazlan M, Tooyama I, Wan Ngah WZ, Damanhuri HA

J Alzheimers Dis. 2019;70(s1):S239-S254. doi: 10.3233/JAD-180496.

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive abilities. AD is associated with aggregation of amyloid-β (Aβ) deposited in the hippocampal brain region. Our previous work has shown that tocotrienol rich fraction (TRF) supplementation was able to attenuate the blood oxidative status, improve behavior, and reduce fibrillary-type Aβ deposition in the hippocampus of an AD mouse model. In the present study, we investigate the effect of 6 months of TRF supplementation on transcriptome profile in the hippocampus of APPswe/PS1dE9 double transgenic mice. TRF supplementation can alleviate AD conditions by modulating several important genes in AD. Moreover, TRF supplementation attenuated the affected biological process and pathways that were upregulated in the AD mouse model. Our findings indicate that TRF supplementation can modulate hippocampal gene expression as well as biological processes that can potentially delay the progression of AD.

Hamezah HS, Durani LW, Yanagisawa D, Ibrahim NF, Aizat WM, Makpol S, Wan Ngah WZ, Damanhuri HA, Tooyama I

J Alzheimers Dis. 2019;72(1):229-246. doi: 10.3233/JAD-181171.

Abstract

Tocotrienol-rich fraction (TRF) is a mixture of vitamin E analogs derived from palm oil. We previously demonstrated that supplementation with TRF improved cognitive function and modulated amyloid pathology in AβPP/PS1 mice brains. The current study was designed to examine proteomic profiles underlying the therapeutic effect of TRF in the brain. Proteomic analyses were performed on samples of hippocampus, medial prefrontal cortex (mPFC), and striatum using liquid chromatography coupled to Q Exactive HF Orbitrap mass spectrometry. From these analyses, we profiled a total of 5,847 proteins of which 155 proteins were differentially expressed between AβPP/PS1 and wild-type mice. TRF supplementation of these mice altered the expression of 255 proteins in the hippocampus, mPFC, and striatum. TRF also negatively modulated the expression of amyloid beta A4 protein and receptor-type tyrosine-protein phosphatase alpha protein in the hippocampus. The expression of proteins in metabolic pathways, oxidative phosphorylation, and those involved in Alzheimer’s disease were altered in the brains of AβPP/PS1 mice that received TRF supplementation.

Shah AK, Yeganehjoo H

Mol Cell Biochem. 2019 Dec;462(1-2):173-183. doi: 10.1007/s11010-019-03620-w

Abstract

Osteoblasts and osteoclasts play essential and opposite roles in maintaining bone homeostasis. Osteoblasts fill cavities excavated by osteoclasts. The mevalonate pathway provides essential prenyl pyrophosphates for the activities of GTPases that promote differentiation of osteoclasts but suppress that of osteoblasts. Preclinical and clinical studies suggest that mevalonate suppressors such as statins increase bone mineral density and reduce risk of bone fracture. Tocotrienols down-regulate 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway. In vivo studies have shown the bone-protective activity of tocotrienols. We hypothesize that d-δ-tocotrienol, a mevalonate suppressor, induces differentiation of murine MC3T3-E1 preosteoblasts. Alizarin staining showed that d-δ-tocotrienol (0-25 μmol/L) induced mineralized nodule formation in a concentration-dependent manner in MC3T3-E1 preosteoblasts. d-δ-Tocotrienol (0-25 μmol/L), but not D-α-tocopherol (25 μmol/L), significantly induced alkaline phosphatase activity, an indicator of preosteoblast differentiation. The expression of differentiation marker genes including BMP-2 and VEGFα was stimulated dose dependently by d-δ-tocotrienol (0-25 μmol/L). Concomitantly, Western blot analysis showed that d-δ-tocotrienol down-regulated HMG CoA reductase. d-δ-Tocotrienol (0-25 μmol/L) had no impact on the viability of MC3T3-E1 preosteoblasts following 48-h incubation, suggesting lack of cytotoxicity at these doses. Tocotrienols and other mevalonate suppressors have potential in maintaining bone health.

Zarkasi KA, Jen-Kit T, Jubri Z

Mini Rev Med Chem. 2019;19(17):1407-1426. doi: 10.2174/1389557519666190130164334.

Abstract

Myocardial infarction is a major cause of deaths globally. Modulation of several molecular mechanisms occurs during the initial stages of myocardial ischemia prior to permanent cardiac tissue damage, which involves both pathogenic as well as survival pathways in the cardiomyocyte. Currently, there is increasing evidence regarding the cardioprotective role of vitamin E in alleviating the disease. This fat-soluble vitamin does not only act as a powerful antioxidant; but it also has the ability to regulate several intracellular signalling pathways including HIF-1, PPAR-γ, Nrf-2, and NF-κB that influence the expression of a number of genes and their protein products. Essentially, it inhibits the molecular progression of tissue damage and preserves myocardial tissue viability. This review aims to summarize the molecular understanding of the cardiomodulation in myocardial infarction as well as the mechanism of vitamin E protection.

Fukui K.

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S185-S187. doi: 10.3177/jnsv.65.S185.

Abstract

Vitamin E is a natural lipophilic vitamin, and the most famous function of vitamin E is an antioxidant activity. Because we have α-tocopherol transfer protein, many vitamin E-related reports are about α-tocopherol. Recently, other vitamin E isoforms, tocotrienols are focusing. Because tocotrienols have unique biological functions such as induction of apoptosis, neuroprotective and anti-obesity effects. Tocotrienols contain in annatto, palm, whole wheat and rice bran. Rice is a typical food in the East Asian countries and Japan. Recently, intake of whole rice is a popular in young women of Japan. Previously, we demonstrated that treatment with tocotrienols on the neuronal cells shows a strong antioxidant effect compared to the tocopherols. In this review, I introduce about neuroprotective and anti-obesity effects of tocotrienols. I would like to show daily intake of whole rice is very good for our health in this review.

Matsura T.

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S51-S53. doi: 10.3177/jnsv.65.S51.

Abstract

Parkinson’s disease (PD) is a common progressive neurodegenerative disease. It has been reported that oxidative stress contributes, at least in part, to its pathogenesis. Although dietary epidemiological studies suggest that sufficient intake of vitamin E may prevent the onset of PD, antioxidative therapy for PD with exogenous antioxidants involving α-tocopherol has not been successful in the clinical setting thus far. In recent years, the non-antioxidant activities of vitamin E have been given attention to. In the present study, to determine the antioxidant-independent cytoprotective activity of vitamin E, we investigated whether tocotrienols (T3s), another members of vitamin E family, exhibit the neuroprotective effect in cell and mouse models of PD independently of their antioxidant activities. Treatment with T3s, especially γ- and δ-T3s, exhibited cytoprotective effects via activation of PI3K/Akt signaling pathway in a cellular PD model. We also identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling and demonstrated the direct binding of T3 to ERβ in vitro. Silencing expression of caveolin suppressed the cytoprotective effects of T3, indicating that caveola formation plays an important role in the cytoprotection by T3 via ERβ/PI3K/Akt signaling pathway. Thus it has been shown that T3 exerts cytoprotective function by a novel mechanism, which includes membrane ERβ/PI3K/Akt signaling via caveola formation as well as its antioxidant activity. Furthermore, we revealed that δ-T3 treatment relieved PD-related symptoms in PD model mice. These results suggest that T3 elicits the cytoprotective effects via ERβ/PI3K/Akt signaling pathway in cellular and murine PD models.

Hosseini M, Sarveazad A, Babahajian A, Baikpour M, Vaccaro AR, Chapman JR, Yousefifard M, Rahimi-Movaghar V

Nutr Rev. 2019 Dec 4. pii: nuz076. doi: 10.1093/nutrit/nuz076.

Abstract

CONTEXT:

Many animal studies have evaluated the role of vitamins in the recovery of motor function after spinal cord injury, but their results have been contradictory and no consensus has been reached.

OBJECTIVE:

This meta-analysis aimed to investigate the effects of vitamin C and vitamin E on recovery of motor function after spinal cord injury in animal models.

DATA SOURCES:

Two authors independently collected the records of relevant articles published in MEDLINE, Embase, Scopus, and Web of Science through November 2018.

STUDY SELECTION:

All studies conducted in animal models to evaluate the therapeutic effects of vitamin C or vitamin E or both on recovery of motor function after spinal cord injury were included. Studies that lacked a control group or a standard treatment, lacked an assessment of motor function, included genetically modified/engineered animals, included animals pretreated with vitamin C or vitamin E, or combined vitamin treatment with other methods, such as cell therapies, were excluded.

DATA EXTRACTION:

Data from 10 articles met the inclusion criteria for meta-analysis, conducted in accordance with PRISMA guidelines.

RESULTS:

Daily supplementation with vitamin C (P < 0.0001) and vitamin E (P < 0.0001) significantly improved the recovery of motor function in animals affected by spinal cord injury. Vitamin C supplementation is effective only when administered intraperitoneally (P < 0.0001). Concurrent supplementation with both vitamins does not show better efficacy than treatment with either one alone.

CONCLUSION:

Administration of vitamin C and vitamin E in animal models of spinal cord injury significantly improves the recovery of motor function.

Ishida Y, Hino S, Morita T, Ikeda S, Nishimura N

Br J Nutr. 2019 Dec 3:1-25. doi: 10.1017/S0007114519003118.

Abstract

We investigated whether non-digestible saccharide fermentation-derived hydrogen molecules (H2) in rat colon could improve the in vivo reduction-oxidation balance via regeneration of α-tocopherol, by assessing their effect on hydroxyl radicals, the α-tocopherol concentration and the reduction-oxidation balance. In experiment 1, a Fenton reaction with phenylalanine (0 or 1.37 mmol/L of H2) was conducted. In experiment 2, rats received intraperitoneally 400 mg/kg of corn oil containing phorone, 7 days after drinking ad libitum water containing 0 or 4% fructooligosaccharides (groups CP and FP, respectively). In experiment 3, rats unable to synthesise ascorbic acid, drank ad libitum for 14 days, water with 240 mg/L (group AC), 20 mg of ascorbic acid/L (group DC) or 20 mg of ascorbic acid/L and 4% fructooligosaccharides (group DCF). In the Fenton reaction, H2 reduced tyrosine produced from phenylalanine to 72% when platinum was added and to 92% when platinum was excluded. In experiment 2, liver glutathione was depleted by administration of phorone to rats. However, compared with CP, no change in the m-tyrosine concentration in the liver of FP was detected. In experiment 3, net H2 excretion was higher in DCF than in the other rats, 3 days after the experiment ended. Furthermore, the concentrations of H2 and α-tocopherol and the reduction-oxidation glutathione ratio in perirenal adipose tissue of rats were significantly higher and lower, respectively, in DCF than in DC. To summarise, in rat colon, fermentation-derived H2 further reduced the reduction-oxidation balance in perirenal adipose tissue through increased regeneration of α-tocopherol.

Bolotta A, Pini A, Abruzzo PM, Ghezzo A, Modesti A, Gamberi T, Ferreri C, Bugamelli F, Fortuna F, Vertuani S, Manfredini S, Zucchini C, Marini M

Exp Biol Med (Maywood). 2019 Dec 3:1535370219890873. doi: 10.1177/1535370219890873.

Abstract Friedreich’s ataxia is an autosomal recessive disorder characterized by impaired mitochondrial function, resulting in oxidative stress. In this study, we aimed at evaluating whether tocotrienol, a phytonutrient that diffuses easily in tissues with saturated fatty layers, could complement the current treatment with idebenone, a quinone analogue with antioxidant properties. Five young Friedreich’s ataxia patients received a low-dose tocotrienol supplementation (5 mg/kg/day), while not discontinuing idebenone treatment. Several oxidative stress markers and biological parameters related to oxidative stress were evaluated at the time of initiation of treatment and 2 and 12 months post-treatment. Some oxidative stressrelated parameters and some inflammation indices were altered in Friedreich’s ataxia patients taking idebenone alone and tended to be normal values following tocotrienol supplementation; likewise, a cardiac magnetic resonance study showed some improvement following one-year tocotrienol treatment. The pathway by which tocotrienol affects the Nrf2 modulation of hepcidin gene expression, a peptide involved in iron handling and in inflammatory responses, is viewed in the light of the disruption of the iron intracellular distribution and of the Nrf2 anergy characterizing Friedreich’s ataxia. This research provides a suitable model to analyze the efficacy of therapeutic strategies able to counteract the excess free radicals in Friedreich’s ataxia, and paves the way to long-term clinical studies.