Effects of pentoxifylline and tocopherol on a rat-irradiated jaw model using micro-CT cortical bone analysis

Nguyen TTH, Eo MY, Seo MH, Myoung H, Kim SM, Lee JH

Eur Arch Otorhinolaryngol. 2019 Dec;276(12):3443-3452. doi: 10.1007/s00405-019-05600-8.

Abstract

PURPOSE:

A combination of pentoxifylline (PTX) and tocopherol (TP) is believed to reduce chronic fibrosis and induce bone healing in osteoradionecrosis (ORN) of the mandible, but evidence of its therapeutic effectiveness for cortical bone is lacking. This study was designed to determine the effect of combined PTX and TP (PTX + TP) on mandibular cortical bone remodeling in a rat model of ORN, using micro-CT and histological analysis.

METHODS:

Forty-eight 8-week-old male Sprague-Dawley rats were randomly divided into irradiated (n = 40) and non-irradiated (n = 8) groups. Animals in the irradiated group were divided into four sub-groups, including PTX, TP, PTX + TP, and normal saline. Three weeks after irradiation, mandibular posterior tooth extraction was performed, and animals were sacrificed 7 weeks after irradiation. The mandibles were analyzed using micro-CT and histological evaluation.

RESULTS:

The alveolar bone height, cortical bone thickness, cortical bone volume, and total cortical bone surface of the PTX + TP group were significantly greater than those of other irradiated groups (p < 0.05). In 3D reconstructed images, the residual volumes of cortical and cancellous bone were inadequate in the irradiated groups.

CONCLUSION:

We found that a combination of PTX and TP improved quality and quantity of cortical bone in irradiated rat mandibles, thus providing supporting evidence of its utility as a treatment and prophylactic agent in ORN. We observed inadequate volumes of cortical and cancellous bone in ORN mandibles, suggesting that cortical bone could play an important role in further ORN studies.

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Novel Antioxidative Activity of Astaxanthin and Its Synergistic Effect with Vitamin E

Kogure K

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S109-S112. doi: 10.3177/jnsv.65.S109.

Abstract

Astaxanthin (Asx) is known to be a potent quencher of singlet oxygen and an efficient scavenger of superoxide anion. However, the scavenging activity of Asx toward the hydroxyl radical was currently unclear because the high lipophilicity of Asx prevents analysis of such activity in water. Liposomes containing Asx (Asx-lipo) were previously shown to be dispersed in water. Analysis of the hydroxyl radical scavenging activity of Asx-lipo demonstrated a dose-dependence in water, with the effect of Asx being more potent than the vitamin E α-tocopherol (α-T). Furthermore, liposomes co-encapsulating Asx and vitamin E derivatives, namely tocotrienols (T3), showed a synergistic elimination effect on singlet oxygen and hydroxyl radical, although the antioxidative activity of liposomes co-encapsulating Asx and α-T was lower than the calculated additive value of each independent activity. A calculation of the most stable structure of Asx in the presence of α-T or T3, suggested that only T3 was able to hydrogen bond with Asx, and the Asx polyene chain partially interacting with the α-T3 triene chain, which could explain the synergistic effect between Asx and T3, but not Asx and α-T. This review introduces the hydroxyl radical scavenging activity of Asx, and its synergistic effect with T3.

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Preventive Effect of Polyunsaturated Fatty Acid and Vitamin E in Rice Bran Oil on Lifestyle-Related Diseases

Fujiwara Y

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S34-S37. doi: 10.3177/jnsv.65.S34.

Abstract

The dietary fat intake of Japanese is thought to be more appropriate than in Western countries; however there is a range of differences of individuals in the amounts of fat intake and n-6/n-3 ratio. Therefore, it is important what kind of vegetable oils are used for cooking in order to consider the total balance of fat intake. Rice bran oil (RBO) is expected to reduce plasma cholesterol and be useful for prevention of cardiovascular disease because it contains several effective ingredients. RBO is rich in linoleic and oleic acid. RBO contains γ-oryzanol, which is well known to reduce plasma cholesterol levels. Furthermore, it contains tocotrienols, which are analogs of vitamin E, reported to have unique bioactivity different from that of α-tocopherol. The biological function of these components and their potential to prevent Japanese lifestyle-related diseases are discussed.

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Tocotrienols and Cancer: From the State of the Art to Promising Novel Patents

Fontana F, Raimondi M, Marzagalli M, Moretti RM, Marelli MM, Limonta P

Recent Pat Anticancer Drug Discov. 2019;14(1):5-18. doi: 10.2174/1574892814666190116111827.

Abstract

BACKGROUND:

Tocotrienols (TTs) are vitamin E derivatives naturally occurring in several plants and vegetable oils. Like Tocopherols (TPs), they comprise four isoforms, α, β, γ and δ, but unlike TPs, they present an unsaturated isoprenoid chain. Recent studies indicate that TTs provide important health benefits, including neuroprotective, anti-inflammatory, anti-oxidant, cholesterol lowering and immunomodulatory effects. Moreover, they have been found to possess unique anti-cancer properties.

OBJECTIVE:

The purpose of this review is to present an overview of the state of the art of TTs role in cancer prevention and treatment, as well as to describe recent patents proposing new methods for TTs isolation, chemical modification and use in cancer prevention and/or therapy.

METHODS:

Recent literature and patents focusing on TTs anti-cancer applications have been identified and reviewed, with special regard to their scientific impact and novelty.

RESULTS:

TTs have demonstrated significant anti-cancer activity in multiple tumor types, both in vitro and in vivo. Furthermore, they have shown synergistic effects when given in combination with standard anti-cancer agents or other anti-tumor natural compounds. Finally, new purification processes and transgenic sources have been designed in order to improve TTs production, and novel TTs formulations and synthetic derivatives have been developed to enhance their solubility and bioavailability.

CONCLUSION:

The promising anti-cancer effects shown by TTs in several preclinical studies may open new opportunities for therapeutic interventions in different tumors. Thus, clinical trials aimed at confirming TTs chemopreventive and tumor-suppressing activity, particularly in combination with standard therapies, are urgently needed.

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γ-Tocotrienol Suppression of the Warburg Effect Is Mediated by AMPK Activation in Human Breast Cancer Cells

Dronamraju V, Ibrahim BA, Briski KP, Sylvester PW

Nutr Cancer. 2019;71(7):1214-1228. doi: 10.1080/01635581.2019.1599969.

Abstract

Cancer cell metabolism is characterized by aerobic glycolysis or the “Warburg effect”. Enhanced Akt signaling is associated with activation of various downstream enzymes involved in the glycolytic process, whereas activation of 5′-AMP-activated kinase (AMPK) acts to terminate energy expending mechanisms and decrease glycolytic enzyme expression. Studies were conducted to determine if the anticancer effects of γ-tocotrienol, are mediated through a suppression in aerobic glycolysis. Results show that treatment with 0-7 μM γ-tocotrienol throughout a 4-day culture period resulted in a dose-responsive increase in AMPK activation, and corresponding decrease in Akt activity in human MCF-7 and MDA-MB-231 breast cancer cells. γ-Tocotrienol treatment was also found to induce a dose-responsive decrease in phosphorylated-Fox03 (inactivated), a transcription factor that acts to inhibit in the levels of glycolytic enzyme, and this decrease was associated with a reduction in glycolytic enzyme levels and activity, as well as glucose consumption in these cells. PCR microarray analysis shows that γ-tocotrienol treatment decreases the expression of genes associate with metabolic signaling and glycolysis in MCF-7 and MDA-MB-231 breast cancer cells. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are mediated, at least in part, by a suppression in the Warburg effect.

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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.

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Tocotrienol Rich Fraction Supplementation Modulate Brain Hippocampal Gene Expression in APPswe/PS1dE9 Alzheimer’s Disease Mouse Model

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.

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Modulation of Proteome Profile in AβPP/PS1 Mice Hippocampus, Medial Prefrontal Cortex, and Striatum by Palm Oil Derived Tocotrienol-Rich Fraction

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.

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The stimulatory impact of d-δ-Tocotrienol on the differentiation of murine MC3T3-E1 preosteoblasts

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.

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Molecular Understanding of the Cardiomodulation in Myocardial Infarction and the Mechanism of Vitamin E Protections

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.

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