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Cancer Cell International 2019Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and...
BACKGROUND
Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects.
METHODS
We report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells.
RESULTS
When combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, 2, 3 or death receptors 4 and 5. Enforced expression of c-FLIP substantially attenuated VEDT/TRAIL-induced apoptosis. Thus, c-FLIP reduction plays an important part in mediating VEDT/TRAIL-induced apoptosis. Moreover, VEDT increased c-FLIP ubiquitination and degradation but did not affect its transcription, suggesting that VEDT decreases c-FLIP levels through promoting its degradation. Of note, degradation of c-FLIP and enhanced TRAIL-induced apoptosis in pancreatic cancer cells were observed only with the anticancer bioactive vitamin E compounds δ-, γ-, and β-tocotrienol but not with the anticancer inactive vitamin E compounds α-tocotrienol and α-, β-, γ-, and δ-tocopherol.
CONCLUSIONS
c-FLIP degradation is a key event for death receptor-induced apoptosis by anticancer bioactive vitamin E compounds in pancreatic cancer cells. Moreover, VEDT augmented TRAIL inhibition of pancreatic tumor growth and induction of apoptosis in vivo. Combination therapy with TRAIL agonists and bioactive vitamin E compounds may offer a novel strategy for pancreatic cancer intervention.
PubMed: 31367187
DOI: 10.1186/s12935-019-0876-0 -
International Journal of Molecular... Jun 2019Retinoids are present in human tissues exposed to light and under increased risk of oxidative stress, such as the retina and skin. Retinoid cation radicals can be formed...
Retinoids are present in human tissues exposed to light and under increased risk of oxidative stress, such as the retina and skin. Retinoid cation radicals can be formed as a result of the interaction between retinoids and other radicals or photoexcitation with light. It has been shown that such semi-oxidized retinoids can oxidize certain amino acids and proteins, and that α-tocopherol can scavenge the cation radicals of retinol and retinoic acid. The aim of this study was to determine (i) whether β-, γ-, and δ-tocopherols can also scavenge these radicals, and (ii) whether tocopherols can scavenge the cation radicals of another form of vitamin A-retinal. The retinoid cation radicals were generated by the pulse radiolysis of benzene or aqueous solution in the presence of a selected retinoid under oxidizing conditions, and the kinetics of retinoid cation radical decays were measured in the absence and presence of different tocopherols, Trolox or urate. The bimolecular rate constants are the highest for the scavenging of cation radicals of retinal, (7 to 8) × 10 M·s, followed by retinoic acid, (0.03 to 5.6) × 10 M·s, and retinol, (0.08 to 1.6) × 10 M·s. Delta-tocopherol is the least effective scavenger of semi-oxidized retinol and retinoic acid. The hydrophilic analogue of α-tocopherol, Trolox, is substantially less efficient at scavenging retinoid cation radicals than α-tocopherol and urate, but it is more efficient at scavenging the cation radicals of retinoic acid and retinol than δ-tocopherol. The scavenging rate constants indicate that tocopherols can effectively compete with amino acids and proteins for retinoid cation radicals, thereby protecting these important biomolecules from oxidation. Our results provide another mechanism by which tocopherols can diminish the oxidative damage to the skin and retina and thereby protect from skin photosensitivity and the development and/or progression of changes in blinding retinal diseases such as Stargardt's disease and age-related macular degeneration (AMD).
Topics: Cations; Chromans; Free Radical Scavengers; Retinoids; Tocopherols; Uric Acid
PubMed: 31181693
DOI: 10.3390/ijms20112799 -
International Journal of Molecular... May 2019seed oil is commonly used as a source for biodiesel fuel. Its phytochemical composition is similar to the extracted oil from seeds, which exhibit beneficial effects...
seed oil is commonly used as a source for biodiesel fuel. Its phytochemical composition is similar to the extracted oil from seeds, which exhibit beneficial effects for skin wound healing. Since seed shows no cyanogenic property, it could be a potential candidate for the treatment of skin wounds. Thus, we evaluated the effectiveness of seed oil in the treatment of skin wounds. We characterized and quantified the fatty acids and unsaponifiable fractions (including β-sitosterol and δ-tocopherol) contained in seed-extracted oil by GC-MS and HPLC, respectively. Cell proliferation and migratory ability were evaluated by cell viability and scratch experiments using CCD-966SK cells treated with oil. The anti-inflammatory effects of the oil were evaluated by measuring the nitric oxide (NO) production in lipopolysaccharide-treated RAW 264.7 cells. Antimicrobial activity tests were performed with , , and using a modified Japanese Industrial Standard procedure. Uniform artificial wounds were created on the dorsum of rats. The wounds were treated with a carboxymethyl cellulose (CMC)/hyaluronic acid (HA)/sodium alginate (SA) hydrogel for releasing the seed oil. The wound sizes were measured photographically for 12 days and were compared to wounds covered with analogous membranes containing a saline solution. Our results showed that the seed oil used in this study contains abundant monounsaturated fatty acids, β-sitosterol, and δ-tocopherol. In the in vitro tests, seed oil prompted cell proliferation and migration capability. Additionally, the oil had significant anti-inflammatory and anti-microbial activities. In the in vivo animal experiments, seed oil-treated wounds revealed acceleration of sequential skin wound healing events after two days of healing. The size of oil-treated wound decreased to half the size of the untreated control after eight days of healing. The results suggest that seed oil could be a potential source for promoting skin wound healing.
Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Cell Line; Humans; Male; Mice; Plant Oils; RAW 264.7 Cells; Rats; Rats, Sprague-Dawley; Sapindus; Seeds; Skin; Wound Healing
PubMed: 31130677
DOI: 10.3390/ijms20102579 -
The Journal of Pharmacology and... Sep 2019Induction of lysosomal exocytosis alleviates lysosomal storage of undigested metabolites in cell models of lysosomal disorders (LDs). However, whether this strategy...
Induction of lysosomal exocytosis alleviates lysosomal storage of undigested metabolites in cell models of lysosomal disorders (LDs). However, whether this strategy affects other vesicular compartments, e.g., those involved in endocytosis, is unknown. This is important both to predict side effects and to use this strategy in combination with therapies that require endocytosis for intracellular delivery, such as lysosomal enzyme replacement therapy (ERT). We investigated this using -tocopherol as a model previously shown to induce lysosomal exocytosis and cell models of type A Niemann-Pick disease, a LD characterized by acid sphingomyelinase (ASM) deficiency and sphingomyelin storage. -Tocopherol and derivative CF3-T reduced net accumulation of fluid phase, ligands, and polymer particles via phagocytic, caveolae-, clathrin-, and cell adhesion molecule (CAM)-mediated pathways, yet the latter route was less affected due to receptor overexpression. In agreement, -tocopherol lowered uptake of recombinant ASM by deficient cells (known to occur via the clathrin pathway) and via targeting intercellular adhesion molecule-1 (associated to the CAM pathway). However, the net enzyme activity delivered and lysosomal storage attenuation were greater via the latter route. Data suggest stimulation of exocytosis by tocopherols is not specific of lysosomes and affects endocytic cargo. However, this effect was transient and became unnoticeable several hours after tocopherol removal. Therefore, induction of exocytosis in combination with therapies requiring endocytic uptake, such as ERT, may represent a new type of drug interaction, yet this strategy could be valuable if properly timed for minimal interference.
Topics: Animals; Cell Adhesion Molecules; Cells, Cultured; Combined Modality Therapy; Drug Interactions; Endocytosis; Enzyme Replacement Therapy; Exocytosis; Humans; Nanoparticles; Niemann-Pick Disease, Type A; Recombinant Proteins; Sphingomyelin Phosphodiesterase; Tocopherols
PubMed: 31101681
DOI: 10.1124/jpet.119.257345 -
Food Chemistry Aug 2019The aim of this study is to shed light on the evolution of the minor compounds in the corn oil oxidation process, through the information provided by direct...
The aim of this study is to shed light on the evolution of the minor compounds in the corn oil oxidation process, through the information provided by direct immersion-microextraction in solid phase followed by gas chromatography/mass spectrometry (DI-SPME-GC/MS). This methodology enables one, in a single run, to establish the identity and abundance both of original oil minor components, some with antioxidant capacity, and of other compounds coming from both main and minor oil components oxidation. For the first time, some of the compounds formed from oil minor components degradation are proposed as new markers of oil incipient oxidation. Although the study refers to corn oil, the methodology can be applied to any other edible oil and constitutes a new approach to characterizing the oxidation state of edible oils.
Topics: Antioxidants; Corn Oil; Fatty Acids; Gas Chromatography-Mass Spectrometry; Oxidation-Reduction; Solid Phase Microextraction; Squalene; Tocopherols
PubMed: 31000049
DOI: 10.1016/j.foodchem.2019.04.001 -
Pharmaceutics Apr 2019Phytosterols are plant sterols recommended as adjuvant therapy for hypercholesterolemia and tocopherols are well-established anti-oxidants. However, thermo-sensitivity,...
Development and Characterization of Liposomal Formulations Containing Phytosterols Extracted from Canola Oil Deodorizer Distillate along with Tocopherols as Food Additives.
Phytosterols are plant sterols recommended as adjuvant therapy for hypercholesterolemia and tocopherols are well-established anti-oxidants. However, thermo-sensitivity, lipophilicity and formulation-dependent efficacy bring challenges in the development of functional foods, enriched with phytosterols and tocopherols. To address this, we developed liposomes containing brassicasterol, campesterol and β-sitosterol obtained from canola oil deodorizer distillate, along with alpha, gamma and delta tocopherol. Three approaches; thin film hydration-homogenization, thin film hydration-ultrasonication and Mozafari method were used for formulation. Validated liquid chromatographic tandem mass spectrometry (LC-MS/MS) was utilized to determine the entrapment efficiency of bioactives. Stability studies of liposomal formulations were conducted before and after pasteurization using high temperature short time (HTST) technique for a month. Vesicle size after homogenization and ultrasonication (<200 nm) was significantly lower than by Mozafari method (>200 nm). However, zeta potential (-9 to -14 mV) was comparable which was adequate for colloidal stability. Entrapment efficiencies were greater than 89% for all the phytosterols and tocopherols formulated by all three methods. Liposomes with optimum particle size and zeta potential were incorporated in model orange juice, showing adequate stability after pasteurization (72 °C for 15 s) for a month. Liposomes containing phytosterols obtained from canola waste along with tocopherols were developed and successfully applied as a food additive using model orange juice.
PubMed: 30995762
DOI: 10.3390/pharmaceutics11040185 -
Turkish Journal of Urology Jul 2019Obstructive bladder dysfunction (OBD) caused by benign prostatic hyperplasia is a common medical problem in ageing men. As the prostate enlarges and compresses the...
OBJECTIVE
Obstructive bladder dysfunction (OBD) caused by benign prostatic hyperplasia is a common medical problem in ageing men. As the prostate enlarges and compresses the urethra, the bladder wall thickness and the bladder is termed "compensated" because its function is still relatively normal. Subsequently, bladder function begins to fail and this change is termed "decompensation." The extent of decompensation progresses from mild through severe. Bladder decompensation is mediated by cyclical ischemia followed by reperfusion (I/R) resulting in an increased generation of free radicals and oxidative stress. Previous studies demonstrated that both vitamin E (tocopherol) and alpha-lipoic acid (LA) showed significant antioxidant activity in experimental urinary bladder oxidative stress models. We hypothesized that co-drugs derived from these antioxidants would result in enhanced antioxidant activity relative to either individual compound for the treatment of oxidative stress in the lower urinary tract.
MATERIAL AND METHODS
Two ester co-drugs of TOC and LA, tocopherol ester (α-TOCE) and δ-TOCE were synthesized. Six adult male New Zealand White (NZW) rabbits were divided into two groups of three rabbits each. Eight full thickness strips from each rabbit bladder were taken for in vitro I/R experiments. The strips from the first set were control rabbits (24 strips). Six strips were not incubated, while the remaining strips were incubated in α-TOCE dissolved in 1% (n=6) or 2.5% ethanol (n=6) solutions. These strips were not subjected to in vitro I/R. The strips from the second set were processed as follows: 6 strips were not incubated, while the remaining strips were incubated in α-TOCE dissolved in 1% (n=6) or in δ-TOCE dissolved in 2.5% ethanol. These strips were subjected to 1 hour in vitro ischemia followed by two hours reperfusion.
RESULTS
Preliminary studies demonstrated that neither antioxidant had any effect on the contractile responses to 1% or 2.5% ethanol. Neither antioxidant had any effect on the control contractile responses. Both antioxidants protected the tissue from the initial effects of ischemia. Both antioxidants had significant protective effects on the contractile responses to all forms of stimulation after the reperfusion period.
CONCLUSION
Incubation with both antioxidants had similar protective effects on responses both to ischemia and to reperfusion.
PubMed: 30817293
DOI: 10.5152/tud.2018.48154 -
Scientific Reports Jan 2019Heat stress threatens agriculture worldwide. Plants acquire heat stress tolerance through priming, which establishes stress memory during mild or severe transient heat...
Heat stress threatens agriculture worldwide. Plants acquire heat stress tolerance through priming, which establishes stress memory during mild or severe transient heat stress. Such induced thermotolerance restructures metabolic networks and helps maintain metabolic homeostasis under heat stress. Here, we used an electrospray ionization mass spectrometry-based platform to explore the composition and dynamics of the metabolome of Arabidopsis thaliana under heat stress and identify metabolites involved in thermopriming. Primed plants performed better than non-primed plants under severe heat stress due to altered energy pathways and increased production of branched-chain amino acids, raffinose family oligosaccharides (RFOs), lipolysis products, and tocopherols. These metabolites serve as osmolytes, antioxidants and growth precursors to help plants recover from heat stress, while lipid metabolites help protect membranes against heat stress. The carbohydrate (e.g., sucrose and RFOs) and lipid superpathway metabolites showed the most significant increases. Under heat stress, there appears to be crosstalk between carbohydrate metabolism (i.e., the thermomemory metabolites stachyose, galactinol, and raffinose) and tyrosine metabolism towards the production of the thermomemory metabolite salidroside, a phenylethanoid glycoside. Crosstalk occurs between two glycerophospholipid pathways (the biosynthetic pathways of the thermomemory metabolite S-adenosyl-L-homocysteine and the terpenoid backbone) and the δ-tocopherol (chloroplast lipid) pathway, which favors the production of glycine betaine and other essential tocopherols, respectively, compounds which are essential for abiotic stress tolerance in plants. Therefore, metabolomic analysis can provide comprehensive insights into the metabolites involved in stress responses, which could facilitate plant breeding to maximize crop yields under adverse conditions.
Topics: Arabidopsis; Carbohydrate Metabolism; Heat-Shock Response; Homeostasis; Lipid Metabolism; Metabolic Networks and Pathways; Metabolomics; Spectrometry, Mass, Electrospray Ionization; Thermotolerance
PubMed: 30655560
DOI: 10.1038/s41598-018-36484-z -
Chemical & Pharmaceutical Bulletin 2019The present study proposes a method for the assessment of repeatability in supercritical fluid chromatography with electrochemical detection (SFC-ECD), based on the ISO...
The present study proposes a method for the assessment of repeatability in supercritical fluid chromatography with electrochemical detection (SFC-ECD), based on the ISO 11843 part 7 (ISO 11843-7:2018) which can theoretically provide detection limits and standard deviation (S.D.) through the stochastic properties of baseline noise without repetitive measurements of real samples. On the baseline noise of SFC-ECD, large-amplitude and periodic noises with less than 0.05 Hz were observed, and the power spectrum of the baseline noise showed 1/f fluctuation (f = frequency). It was found that the present power spectrum analysis, according to the law of error propagation, can provide suitable noise parameters to calculate S.D. of baseline noise and a relative S.D. (RSD) of peak area by ISO 11843-7. The chromatographic determinations of α-, β-, γ- and δ-tocopherol have been taken as examples. In the present SFC-ECD, the RSDs of peak areas for α-, β-, γ- and δ-tocopherol obtained by ISO 11843-7 were within 95% confidence intervals of the RSD of them obtained by repetitive measurements (n = 6). Thus, we found that ISO 11843-7 is applicable to the assessment of repeatability in SFC-ECD for determining tocopherols without repetitive measurements.
Topics: Chromatography, Supercritical Fluid; Electrochemical Techniques; Limit of Detection; Tocopherols
PubMed: 30606951
DOI: 10.1248/cpb.c18-00677 -
IUBMB Life Apr 2019The disappointing results from large clinical studies of α-tocopherol (αT), the major form of vitamin E in tissues, for prevention of chronic diseases including cancer... (Review)
Review
The disappointing results from large clinical studies of α-tocopherol (αT), the major form of vitamin E in tissues, for prevention of chronic diseases including cancer have cast doubt on not only αT but also other forms of vitamin E regarding their role in preventing carcinogenesis. However, basic research has shown that specific forms of vitamin E such as γ-tocopherol (γT), δ-tocopherol (δT), γ-tocotrienol (γTE) and δ-tocotrienol (δTE) can inhibit the growth and induce death of many types of cancer cells, and are capable of suppressing cancer development in preclinical cancer models. For these activities, these vitamin E forms are much stronger than αT. Further, recent research revealed novel anti-inflammatory and anticancer effects of vitamin E metabolites including 13'-carboxychromanols. This review focuses on anti-proliferation and induction of death in cancer cells by vitamin E forms and metabolites, and discuss mechanisms underlying these anticancer activities. The existing in vitro and in vivo evidence indicates that γT, δT, tocotrienols and 13'-carboxychromanols have anti-cancer activities via modulating key signaling or mediators that regulate cell death and tumor progression, such as eicosanoids, NF-κB, STAT3, PI3K, and sphingolipid metabolism. These results provide useful scientific rationales and mechanistic understanding for further translation of basic discoveries to the clinic with respect to potential use of these vitamin E forms and metabolites for cancer prevention and therapy. © 2018 IUBMB Life, 71(4):495-506, 2019.
Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cellular Senescence; Cholesterol; Endoplasmic Reticulum Stress; Humans; Molecular Targeted Therapy; Neoplasms; Phosphatidylinositol 3-Kinases; Signal Transduction; Sphingolipids; Tocotrienols; Vitamin E
PubMed: 30548200
DOI: 10.1002/iub.1978