Astaxanthin-alpha tocopherol nanoemulsion formulation by emulsification methods: Investigation on anticancer, wound healing, and antibacterial effects

Shanmugapriya K, Kim H, Saravana PS, Chun BS, Kang HW

Colloids Surf B Biointerfaces. 2018 Aug 20;172:170-179. doi: 10.1016/j.colsurfb.2018.08.042. [Epub ahead of print]

Abstract

Emulsion-based delivery systems have been fabricated and developed to increase the bioavailability of astaxanthin and alpha-tocopherol as active compounds for various biomedical applications. Astaxanthin-alpha tocopherol nanoemulsion (ATNE) is well known for its potential 6.-6.30 effect. The current study investigated ATNE by spontaneous (SENE) and ultrasonication emulsification (USNE) methods to optimally fabricate oil/water nanoemulsion characterized for biomedical applications. The two methods were compared by using a response surface method of 3-level Box-Behnken design (BBD) with significant factors. Transmission electron microscopy (TEM) confirmed spherical-shaped nanoemulsion from SENE and USNE methods and dynamic light scattering (DLS) proved the good stability of the fabricated nanoemulsion. Cytotoxicity studies on three different cancer cells confirmed that the nanoemulsion at higher concentrations was more toxic than one at lower concentrations by accompanying a significant decrease in the cellular viability after 24 and 48 h of exposure. The wound-healing potential using scratch assay evidenced faster healing effect of the nanoemulsion. Both minimal inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC) methods confirmed significant antibacterial activity to disrupt the integrity of the bacterial cell membrane. The current results suggested that ATNE act as effectively targeted drug delivery vehicles in the future for cancer treatment applications due to its significant results of anticancer, wound healing, and antimicrobial effects.

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γ-tocotrienol inhibits the invasion and migration of human gastric cancer cells through downregulation of cyclooxygenase-2 expression.

Zhang YH, Ma K, Liu JR, Wang HX, Tian WX, Tu YH, Sun WG

Oncol Rep. 2018 Aug;40(2):999-1007. doi: 10.3892/or.2018.6497. Epub 2018 Jun 14.

Abstract

γ-tocotrienol (γ-T3), a tocotrienol isoform belonging to the vitamin E family, has been revealed to exert inhibitory effects on proliferation, migration and invasion in human gastric cancer cells. However, its precise mechanism of action is still unclear and needs to be further tested. Cyclooxygenase-2 (COX-2) is well known for its key role in promoting the migration and invasion abilities of human gastric cancer cells. In light of these data, our study aimed to validate whether the inhibitory actions of γ-T3 could be achieved by downregulation of COX-2 activity in vitro. In the present study, a Cell Counting Kit-8 (CCK-8) assay was performed to observe proliferation in human gastric cancer cells (SGC-7901 and MGC-803 cells), and wound healing and Transwell chamber assays were performed to detect migration and invasion. Western blot analyses were performed to analyse the relative expression of COX-2, matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) proteins, and enzyme-linked immunosorbent assays (ELISA) were used to determine the exocrine roles of MMP-2 and MMP-9. The results revealed that γ-T3 exerted significant inhibitory effects on proliferation, migration, invasion and COX-2 protein expression, as well as on exocrine functions of MMP-2 and MMP-9 in SGC-7901 and MGC-803 cells. Therefore, our results indicated that γ-T3 exerts inhibitory effects on migration and invasion, which may be mediated through downregulation of COX-2 expression in SGC-7901 and MGC-803 cells.

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Determination of tocopherols and tocotrienols in human breast adipose tissue with the use of high performance liquid chromatography-fluorescence detection

Bartosińska E, Jacyna J, Borsuk-De Moor A, Kaliszan M, Kondej K, Jankau J, Renkielska A, Kruszewski WJ, Markuszewski MJ, Siluk D

Biomed Chromatogr. 2018 Aug 16:e4361. doi: 10.1002/bmc.4361. [Epub ahead of print]

Abstract

Tocopherols and tocotrienols have been extensively studied due to their anticancer potential, especially against breast cancer. Therefore, the aim of this study was to quantitatively determine tocochromanols in human breast adipose tissue with the use of HPLC-FLD. The sample preparation procedure included homogenization and solvent extraction with isopropanol/ethanol/0.1% formic acid mixture prior to solid phase extraction (SPE). After implementation of central composite design (CCD), satisfactory separation of all eight target compounds was achieved within 10.5 min. Chromatographic runs were carried out with the use of a naphthylethyl chromatographic column with methanol/water mixture (89/11, v/v) as the mobile phase. Fluorescence detection of tocochromanols was performed with excitation and emission wavelengths 298 and 330 nm, respectively. The method was validated in terms of linearity, carryover, recovery, precision, accuracy and stability. Extraction yield was also determined for accurate evaluation of vitamin E content in human breast adipose tissue samples. Finally, concentrations of particular tocochromanols compounds were assessed in human breast adipose tissue samples obtained from 99 patients, including women with breast cancer, healthy volunteers and women deceased by accident. The raw data was transformed according to the newly developed equation for accurate estimation of tocochromanols’ concentrations in breast adipose tissue samples. Results obtained in the study indicated that proposed analytical assay could be useful in breast cancer research.

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Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase

Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, McCusker KP, Amagata A, Davis D, Hoff KG, Kahn-Kirby AH, Kim V, Kosaka Y, Lee E, Malone SA, Mei JJ, Richards SJ, Rivera V, Miller G, Trimmer JK, Shrader WD

PLoS One. 2018 Aug 15;13(8):e0201369. doi: 10.1371/journal.pone.0201369. eCollection 2018.

Abstract

Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme’s non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.

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Delta-tocotrienol inhibits non-small-cell lung cancer cell invasion via the inhibition of NF-κB, uPA activator, and MMP-9

Rajasinghe LD, Pindiprolu RH, Gupta SV

Send to Onco Targets Ther. 2018 Jul 24;11:4301-4314. doi: 10.2147/OTT.S160163. eCollection 2018.

Abstract

BACKGROUND:

Delta-tocotrienol (δT), an isomer of vitamin E, exhibits anticancer properties in different cancer types including non-small-cell lung cancer (NSCLC). Yet, anti-invasive effects of δT and its underlying cellular mechanism in NSCLC have not been fully explored. Matrix metalloproteinase 9 (MMP-9)-based cell migration and invasion are critical cellular mechanisms in cancer development. The current evidence indicates that MMP-9 is upregulated in most patients, and the inhibition of MMPs is involved in decreasing invasion and metastasis in NSCLC. Therefore, its suppression is a promising strategy for attenuating cell invasion and metastasis processes in NSCLC.

PURPOSE:

The aim of this study was to evaluate the possibility of MMP-9 inhibition as the underlying mechanism behind the antimetastatic properties of δT on NSCLC cells.

METHODS:

The effects of δT on cell proliferation, migration, invasion, adhesion, and aggregation capabilities were investigated using different cell-based assays. An inhibitory effect of MMP-9 enzyme activity with δT was also identified using gel zymography. Using real-time PCR and Western blot analysis, a number of cellular proteins, regulatory genes, and miRNA involved in the Notch-1 and urokinase-type plasminogen activator (uPA)-mediated MMP-9 pathways were examined.

RESULTS:

The study found that δT inhibited cell proliferation, cell migration, invasion, aggregation, and adhesion in a concentration-dependent manner and reduced MMP-9 activities. Real-time PCR and Western blot analysis data revealed that δT increased miR-451 expressions and downregulated Notch-1-mediated nuclear factor-κB (NF-κB), which led to the repressed expression of MMP-9 and uPA proteins.

CONCLUSION:

δT attenuated tumor invasion and metastasis by the repression of MMP-9/uPA via downregulation of Notch-1 and NF-κB pathways and upregulation of miR-451. The data suggest that δT may have potential therapeutic benefit against NSCLC metastasis.

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Combination of vitamin E and L-carnitine is superior in protection against Isoproterenol-induced cardiac affection: a histopathological evidence

Huwait EA

Folia Morphol (Warsz). 2018 Aug 14. doi: 10.5603/FM.a2018.0070. [Epub ahead of print]

Abstract

BACKGROUND:

L-carnitine and Vitamin E have antioxidant properties. This study aimed to assess the effectiveness of L-carnitine, Vitamin Eand the combination of them in protection against isoproterenol (ISO)-induced biochemical and histopathological changes in rat heart.

MATERIAL AND METHODS:

Fifty male Wistar rats assigned to 5 groups; control, ISO-treated group (100 mg/kg), ISO+vitamin E-treated group (100 IU/kg), ISO+L-carnitine (100 mg/kg) and ISO+vitamin E+L-carnitine treated group. At the end of the experiment, serum cardiac enzyme as well as the cardiac level Malondialdehyde (MDA), antioxidant enzymes and inflammatory cytokines IL-6, TNF-alpha were assessed. Histopathological changes in the left ventricle wall was assessed using the light and electron microscopy.

RESULTS:

Treating rats with vitamin E and L-carnitine could alleviate ISO-induced changes as it significantly reduced the serum level cardiac enzymes, MDA and IL-6, TNF-alpha and improved the antioxidants enzymes (SOD, GSPxase and GSRase). Histopathological, they improved cardiac fibers atrophy, hemorrhages between cardiac fibers, lost striations, and disturbed sarcomere structure. The combined effect of vitamin E and L-carnitine was more superior compared to the other groups.

CONCLUSION:

Combined administration of vitamin E, L-carnitine ameliorated the biochemical and histopathological cardiac affection induced by ISO. The effect seemed to be mediated through the antioxidant and anti-inflammatory effect of vitamin E, L-carnitine. Administration of these two element is recommended for patient at risk for myocardial infarction.

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Perspective: Should Vitamin E Recommendations for Older Adults Be Increased?

Meydani SN, Lewis ED, Wu D

Adv Nutr. 2018 Aug 11. doi: 10.1093/advances/nmy035. [Epub ahead of print]

Abstract

Current vitamin E requirements are uniformly applied across the population for those >14 y of age. However, aging is associated with alterations in cellular and physiologic functions, which are affected by vitamin E. Therefore, it is questionable whether vitamin E requirements can be uniformly applied to all adult age categories. With aging, there is dysregulation of the immune system in which there are decreased cell-mediated and pathogen defense responses coupled with an overactive, prolonged inflammatory state. Both animal and human studies in the aged suggest that intake above currently recommended levels of vitamin E may improve immune and inflammatory responses and be associated with a reduced risk of infectious disease. We review the evidence that was considered in establishing the current requirements for vitamin E and highlight data that should be considered in determining the vitamin E requirements in older adults, particularly focusing on the evidence suggesting a benefit of increased vitamin E intake on immune function and inflammatory processes and resistance to infection. The main objective of this Perspective is to initiate the discussion of whether the current Dietary Reference Intake for vitamin E should be increased for the older population. We make this suggestion on the basis of mechanistic studies showing biological plausibility, correction of a major cellular dysfunction in older adults, and strong evidence from several animal and a few human studies indicating a reduction in risk and morbidity from infections.

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Vitamin E administration erases an enhanced oxidation in multiple sclerosis

Guan JZ, Guan WP, Maeda T

Can J Physiol Pharmacol. 2018 Aug 9. doi: 10.1139/cjpp-2018-0246. [Epub ahead of print]

Abstract

Systemic peroxidation status has been reported as a pathogenic factor for multiple sclerosis (MS). Systemically elevated oxidation levels are associated with serum lipid peroxidation and somatic telomere length (TL) shortening. We investigated whether vitamin E (VE) administration suppresses peroxidation and improves clinical symptoms in 34 MS patients. We analyzed serum lipid peroxidation and degree of TL in circulating leukocytes of MS patients before and after VE treatment. The oxidation level was enhanced and TL was shortened in MS. The MS population treated with VE 400 mg/day for 3 months showed significantly reduced serum lipid oxidation level with maintenance of TL. These findings showed that systemic peroxidation is associated with the development of MS. Antioxidants such as vitamin E can be candidates for supplementary therapeutic agents for MS.

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An Evaluation of Crude Palm Oil (CPO) and Tocotrienol Rich Fraction (TRF) of Palm Oil as Percutaneous Permeation Enhancers Using Full-Thickness Human Skin

Singh I, Nair RS, Gan S, Cheong V, Morris A

Pharm Dev Technol. 2018 Aug 7:1-25. doi: 10.1080/10837450.2018.1509347. [Epub ahead of print]

Abstract

The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright ‘Franz-type’ diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log P values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2.h and 23.0 µg/cm2.h respectively, compared to the control with a flux of 16.2 µg/cm2.h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil.

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α-Tocopherol transfer protein does not regulate the cellular uptake and intracellular distribution of α- and γ-tocopherols and -tocotrienols in cultured liver cells

Irías-Mata A, Sus N, Flory S, Stock D, Woerner D, Podszun M, Frank J

Redox Biol. 2018 Aug 5;19:28-36. doi: 10.1016/j.redox.2018.07.027. [Epub ahead of print]

Abstract

Liver cells express a cytosolic α-tocopherol transfer protein (αTTP) with high binding affinity for α-tocopherol (αT) and much lower affinities for the non-αT congeners. The role of αTTP in the intracellular distribution of the different vitamin E forms is currently unknown. We therefore investigated the intracellular localization of αT, γ-tocopherol (γT), α-tocotrienol (αT3), and γ-tocotrienol (γT3) in cultured hepatic cells with and without stable expression of αTTP. We first determined cellular uptake of the four congeners and found the methylation of the chromanol ring and saturation of the sidechain to be important factors, with tocotrienols being taken up more efficiently than tocopherols and the γ-congeners more than the α-congeners, irrespective of the expression of αTTP. This, however, could perhaps also be due to an observed higher stability of tocotrienols, compared to tocopherols, in culture media rather than a higher absorption. We then incubated HepG2 cells and αTTP-expressing HepG2 cells with αT, γT, αT3, or γT3, isolated organelle fractions by density gradient centrifugation, and determined the concentrations of the congeners in the subcellular fractions. All four congeners were primarily associated with the lysosomes, endoplasmic reticulum, and plasma membrane, whereas only αT correlated with mitochondria. Neither the chromanol ring methylation or sidechain saturation, nor the expression of αTTP were important factors for the intracellular distribution of vitamin E. In conclusion, αTTP does not appear to regulate the uptake and intracellular localization of different vitamin E congeners in cultured liver cells.

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