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Oncology Reports Mar 2019Triple‑negative breast cancers (TNBCs) lack the estrogen receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Therefore, hormone...
Triple‑negative breast cancers (TNBCs) lack the estrogen receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Therefore, hormone or targeted therapies are not effective in the treatment of TNBC and thus the development of novel therapeutic strategies is crucial. Methotrexate (MTX), a folate antagonist, has been used in the treatment of various types of cancer; however, the anticancer effects of MTX treatment on breast cancer have thus far been ineffective. Vitamin E variants and derivatives have been applied for cancer therapy. Previous studies have indicated that vitamin E variants and derivatives exert distinct anticancer effects on different types of cancer. However, whether MTX plus vitamin E variants or its derivatives can inhibit TNBC remains unclear. The aim of the present study was to examine the anticancer effects and mechanisms of action of MTX in combination with vitamin E variants (α‑tocopherol) and derivatives (α‑tocopherol succinate) on TNBC. In the present study, MTT assay and western blot analysis were used to determine the cell survival rates and protein levels. The results demonstrated that combination treatment with MTX and α‑tocopherol suppressed TNBC cell proliferation. In addition, various concentrations of MTX exerted distinct cytotoxic effects on α‑tocopherol succinate‑treated cells. Furthermore, high‑dose MTX enhanced α‑tocopherol succinate‑induced anticancer activity; however, low‑dose MTX inhibited α‑tocopherol succinate‑induced anticancer activity. The present study also demonstrated that caspase‑3 activation and poly(adenosine diphosphate‑ribose) polymerase cleavage were observed in the α‑tocopherol succinate/MTX‑treated cells. In conclusion, the findings of the present study demonstrated that high‑dose MTX enhanced anticancer activity in α‑TOS‑treated TNBC, while low‑dose MTX reduced anticancer activity in α‑TOS‑treated TNBC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Methotrexate; Triple Negative Breast Neoplasms; alpha-Tocopherol
PubMed: 30628707
DOI: 10.3892/or.2019.6958 -
Archives of Environmental &... May 2017To investigate whether α-tocopherol supplementation in workers exposed to lead would reduce the oxidative stress intensity and decrease homocysteine level, the examined...
To investigate whether α-tocopherol supplementation in workers exposed to lead would reduce the oxidative stress intensity and decrease homocysteine level, the examined population was randomly divided into two groups. Workers in the first group (n = 49, reference group) were not administered any drugs. Workers in the second group (n = 34) were administered orally α-tocopherol, 200 mg per day for 12 weeks. The level of α-tocopherol significantly increased compared to the baseline and the reference group. The level of thiol groups significantly increased compared to the reference group. However, the levels of malondialdehyde and homocysteine did not significantly change. Animal studies suggest the ability of α-tocopherol administration to reverse adverse health effects of lead exposure, such as oxidative stress; however, the results of this study on humans do not confirm these protective effects.
Topics: Adult; Antioxidants; Homocysteine; Humans; Lead Poisoning; Middle Aged; Occupational Exposure; Oxidative Stress; alpha-Tocopherol
PubMed: 27120705
DOI: 10.1080/19338244.2016.1182112 -
Food Chemistry Apr 2020Among different stereoisomers of all-rac-α-tocopherol, 2R-stereoisomers have higher biological activities than their 2S-stereoisomers. Two experiments were conducted to...
Among different stereoisomers of all-rac-α-tocopherol, 2R-stereoisomers have higher biological activities than their 2S-stereoisomers. Two experiments were conducted to study the pharmacokinetics of stereoisomers of all-rac-α-tocopherol and investigated the discrimination and distribution of α-tocopherol stereoisomers in plasma and milk as well as quantitative secretion into milk with lactating Holstein cows after a single dose intramuscular injection of 2.50 g of all-rac-α-tocopheryl acetate. The highest half-life (2.92/h) and lowest elimination rate (0.36/h) were found for RRR-α-tocopherol. After a single dose injection of all-rac-α-tocopherol, highest maximal daily increase (S, 8.36 mg/day) and accumulation secretion (AS, 50.8 mg) were observed for milk RRR-α-tocopherol. The majority of the Ʃ2S stereoisomers were found in the liver 36 h post injection, while the 2R stereoisomers were more equal distributed between liver and plasma. The present findings showed a clear discrimination between RRR-α-tocopherol, synthetic 2R stereoisomers and Ʃ2S stereoisomers in milk and plasma of dairy cows.
Topics: Animals; Cattle; Female; Half-Life; Injections; Lactation; Liver; Milk; Stereoisomerism; alpha-Tocopherol
PubMed: 31835226
DOI: 10.1016/j.foodchem.2019.125931 -
The Journal of Nutrition Sep 2020α-Tocopherol (αT) in its natural form [2'R, 4'R, 8'R αT (RRR-αT)] is more bioactive than synthetic α-tocopherol (all rac-αT). All rac-αT is widely used in infant...
BACKGROUND
α-Tocopherol (αT) in its natural form [2'R, 4'R, 8'R αT (RRR-αT)] is more bioactive than synthetic α-tocopherol (all rac-αT). All rac-αT is widely used in infant formulas, but its accretion in formula-fed infant brain is unknown.
OBJECTIVE
We sought to compare αT and stereoisomer status in infant rhesus macaques (Macaca mulatta) fed infant formula (RRR-αT or all rac-αT) with a reference group fed a mixed diet of breast milk and maternal diet.
METHODS
From 1 d after birth until 6 mo of age, infants (n = 23) were either nursery reared and exclusively fed 1 of 2 formulas by staff personnel or were community housed with their mothers and consumed a mixed reference diet of breast milk (69 mL/d at 6 mo) transitioning to monkey diet at ∼2 mo (MF; n = 8). Formulas contained either 21 μmol RRR-αT/L (NAT-F; n = 8) or 30 μmol all rac-αT/L (SYN-F; n = 7). Total αT and αT stereoisomers were analyzed in breast milk at 2, 4, and 6 mo and in monkey plasma and liver and 6 brain regions at 6 mo of age. α-Tocopherol transfer protein (α-TTP), lipoprotein αT, and urinary α-carboxyethyl-hydroxychroman (α-CEHC) were measured. One-way ANOVA with Tukey's post-hoc test was used for analysis.
RESULTS
At study termination, plasma, liver, lipoprotein, and brain total αT did not differ between groups. However, the NAT-F-fed group had higher RRR-αT than the SYN-F-fed group (P < 0.01) and the MF group (P < 0.0001) in plasma (1.7- and 2.7-fold) and brain (1.5- and 2.5-fold). Synthetic αT 2R stereoisomers (SYNTH-2R) were generally 3- and 7-fold lower in brain regions of the NAT-F group compared with those of the SYN-F and MF groups (P < 0.05). SYNTH-2R stereoisomers were 2-fold higher in MF than SYN-F (P < 0.0001). The plasma percentage of SYNTH-2R was negatively correlated with the brain percentage of RRR-αT (r = -0.99, P < 0.0001). Brain αT profiles were not explained by α-TTP mRNA or protein expression. Urine α-CEHC was 3 times higher in the NAT-F than in the MF group (P < 0.01).
CONCLUSIONS
Consumption of infant formulas with natural (NAT-F) compared with synthetic (SYN-F) αT differentially impacted brain αT stereoisomer profiles in infant rhesus macaques. Future studies should assess the functional implications of αT stereoisomer profiles on brain health.
Topics: Animal Feed; Animals; Brain Chemistry; Carrier Proteins; Chromans; Diet; Gene Expression Regulation; Humans; Infant; Infant Food; Macaca mulatta; Milk; Propionates; alpha-Tocopherol
PubMed: 32614402
DOI: 10.1093/jn/nxaa174 -
Free Radical Biology & Medicine Dec 2011The role of hepatic xenobiotic regulatory mechanisms in modulating hepatic α-tocopherol concentrations during excess vitamin E administration remains unclear. We...
The role of hepatic xenobiotic regulatory mechanisms in modulating hepatic α-tocopherol concentrations during excess vitamin E administration remains unclear. We hypothesized that increased hepatic α-tocopherol would cause a marked xenobiotic response. Thus, we assessed cytochrome P450 oxidation systems (phase I), conjugation systems (phase II), and transporters (phase III) after daily α-tocopherol injections (100mg/kg body wt) for up to 9days in rats. α-Tocopherol injections increased hepatic α-tocopherol concentrations nearly 20-fold, along with a 10-fold increase in the hepatic α-tocopherol metabolites α-CEHC and α-CMBHC. Expression of phase I (CYP3A2, CYP3A1, CYP2B2) and phase II (SULT2A1) proteins and/or mRNAs was variably affected by α-tocopherol injections; however, expression of phase III transporter genes was consistently changed by α-tocopherol. Two liver efflux transporter genes, ABCB1b and ABCG2, were up-regulated after α-tocopherol injections, whereas OATP, a liver influx transporter, was down-regulated. Thus, an overload of hepatic α-tocopherol increases its own metabolism and increases expression of genes of transporters that are postulated to lead to increased excretion of both vitamin E and its metabolites.
Topics: ATP-Binding Cassette Transporters; Animals; Cytochrome P-450 Enzyme System; Hepatocytes; Male; Rats; Rats, Sprague-Dawley; alpha-Tocopherol
PubMed: 21945367
DOI: 10.1016/j.freeradbiomed.2011.08.033 -
Free Radical Biology & Medicine Jan 2010Approximately 40% of Americans take dietary supplements, including vitamin E (alpha-tocopherol). Unlike other fat-soluble vitamins, alpha-tocopherol is not accumulated...
Approximately 40% of Americans take dietary supplements, including vitamin E (alpha-tocopherol). Unlike other fat-soluble vitamins, alpha-tocopherol is not accumulated to toxic levels. Rather tissue levels are tightly regulated, in part via increased hepatic metabolism and excretion that could, theoretically, alter metabolism of drugs, environmental toxins, and other nutrients. To date, in vivo subcellular location(s) of alpha-tocopherol metabolism have not been identified. The proposed pathway of alpha-tocopherol metabolism proceeds via omega-hydroxylation to 13'-OH-alpha-tocopherol, followed by successive rounds of beta-oxidation to form alpha-CEHC. To test the hypothesis that alpha-tocopherol omega-hydroxylation occurs in microsomes while beta-oxidation occurs in peroxisomes, rats received daily injections of vehicle, 10 mg alpha-tocopherol, or 10 mg trolox/100 g body wt for 3 days, and then microsomes, mitochondria, and peroxisomes were isolated from liver homogenates. Homogenate alpha-tocopherol levels increased 16-fold in alpha-tocopherol-injected rats, while remaining unchanged in trolox- or vehicle-injected rats. Total alpha-tocopherol recovered in the three subcellular fractions represented 93+/-4% of homogenate alpha-tocopherol levels. In alpha-tocopherol-injected rats, microsome alpha-tocopherol levels increased 28-fold, while mitochondria and peroxisome levels increased 8- and 3-fold, respectively, indicating greater partitioning of alpha-tocopherol to the microsomes with increasing liver alpha-tocopherol. In alpha-tocopherol-injected rats, microsome 13'-OH-alpha-tocopherol levels increased 24-fold compared to controls, and were 7-fold greater than 13'-OH-alpha-tocopherol levels in peroxisome and mitochondrial fractions of alpha-tocopherol-injected rats. An unexpected finding was that alpha-CEHC, the end product of alpha-tocopherol metabolism, was found almost exclusively in mitochondria. These data are the first to indicate a mitochondrial role in alpha-tocopherol metabolism.
Topics: ATP-Binding Cassette Transporters; Animals; Blotting, Western; Chromans; Cytochrome P-450 CYP2B1; Injections, Subcutaneous; Male; Mitochondria, Liver; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Voltage-Dependent Anion Channels; alpha-Tocopherol
PubMed: 19819327
DOI: 10.1016/j.freeradbiomed.2009.10.024 -
Journal of Chromatography. A Nov 2001Tocopherols and tocotrienols (Vitamin E) are part of a group of "minor components" of main interest, present in the unsaponifiable fraction of many samples. Their... (Review)
Review
Tocopherols and tocotrienols (Vitamin E) are part of a group of "minor components" of main interest, present in the unsaponifiable fraction of many samples. Their importance in biological, metabolical and nutritional studies makes determination of tocopherols and related compounds of major interest. Present work critically reviews the different ways to perform sample pre-treatment and analysis of these compounds, related to the matrices, other analytes to be measured, sensitivity, and simplicity. The review includes well referenced tables that provide in-depth summaries of methodology for the chromatographic analysis of alpha-tocopherol and related compounds in foods, pharmaceuticals, plants, animal tissues and other matrices.
Topics: Chromatography, Gas; Chromatography, Liquid; alpha-Tocopherol
PubMed: 11762785
DOI: 10.1016/s0021-9673(01)01101-3 -
Research in Veterinary Science Apr 2019Among the eight forms of vitamin E, the liver preferentially releases α-tocopherol into the circulation and it is distributed to the non-liver tissues. In the...
Among the eight forms of vitamin E, the liver preferentially releases α-tocopherol into the circulation and it is distributed to the non-liver tissues. In the hepatocytes, alpha tocopherol transfer protein (TTPA) specifically recognizes α-tocopherol with 2R-configuration and facilitates its intracellular transfer. The identification and characterization of TTPA expression have not been demonstrated in avian species. Therefore, the objectives of this study were to identify avian TTPAs, to compare the sequence conservation, phylogenetic relationship, protein interactions, and disease associations of chicken TTPA with those of human and vertebrate TTPA, and to characterize the tissue expression of the TTPA gene in chickens fed diets supplemented with different amounts of α-tocopherol. Our results suggest that the chicken TTPA was highly conserved with the human and vertebrate TTPA, and consisted of a cellular retinaldehyde binding protein and TRIO guanine exchange factor (CRAL_TRIO) domain. Feeding diets supplemented with increasing amounts of α-tocopherol (25 IU/Kg, 50 IU/Kg, or 100 IU/Kg) to broiler chickens had no effects on growth performance compared with feeding basal diets containing no supplemental α-tocopherol. The expression of TTPA gene was detected high in the liver of chickens in response to dietary α-tocopherol concentrations, whereas its expression was very low or undetectable in the non-liver tissues. In conclusion, the chicken TTPA protein sequence is highly conserved with other avian and vertebrate TTPA protein sequences. The higher expression of TTPA gene in the chicken liver in response to dietary α-tocopherol concentrations may suggest its crucial role in transporting α-tocopherol in the chicken liver.
Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Biological Transport; Carrier Proteins; Chickens; Diet; Dietary Supplements; Gene Expression Regulation; Humans; Liver; Phylogeny; Vitamin E; alpha-Tocopherol
PubMed: 30599294
DOI: 10.1016/j.rvsc.2018.12.018 -
Physical Chemistry Chemical Physics :... Mar 2017α-Tocopherol is a natural preservative that prevents free radical chain oxidations in biomembranes. We have studied the location of α-tocopherol in model membranes...
α-Tocopherol is a natural preservative that prevents free radical chain oxidations in biomembranes. We have studied the location of α-tocopherol in model membranes formed by different unsaturated phosphatidylcholines, namely 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPC), 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) and 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (PDPC). Small angle X-ray diffraction revealed that α-tocopherol was well mixed with all the phospholipids. In all the cases only one lamellar phase was detected. Very modest changes occasioned by α-tocopherol were observed in the electron density profiles. The results obtained from quenching of α-tocopherol intrinsic fluorescence by acrylamide showed that this vitamin was inefficiently quenched in the four types of membranes, indicating that the fluorescent chromanol ring was poorly accessible for this hydrophilic quencher. Compatible with that, quenching by doxyl derivatives of phosphatidylcholines indicated that the chromanol ring was close in the four membranes to the nitroxide probe located at position 5. Quenching by doxyl-phosphatidylcholines also indicated that the efficiency of quenching was higher in POPC than in the other unsaturated phospholipids. H-MAS-NMR showed that α-tocopherol induced chemical shifts of protons from the phospholipids, especially of those bonded to carbons 2 and 3 of the acyl chains of the four phospholipids studied. The H-MAS-NMR NOESY results suggested that the lower part of the chromanol ring was located between the C3 of the fatty acyl chains and the centre of the hydrophobic monolayer for the four phospholipid membranes studied. Taken together, these results suggest that α-tocopherol is located, in all the membranes studied, with the chromanol ring within the hydrophobic palisade but not far away from the lipid-water interface.
Topics: Fats, Unsaturated; Membranes, Artificial; Phosphatidylcholines; Phospholipids; X-Ray Diffraction; alpha-Tocopherol
PubMed: 28211935
DOI: 10.1039/c6cp08872d -
Food Science and Technology... Jul 2019α-Tocopherol nanoemulsions were prepared in current research using various proportions of Polysorbate 20 and maltodextrin as binary stabilizer mixtures through...
α-Tocopherol nanoemulsions were prepared in current research using various proportions of Polysorbate 20 and maltodextrin as binary stabilizer mixtures through solvent-displacement technique. The effects of maltodextrin proportion in stabilizer mixture, on physicochemical characteristics of gained nanoemulsions, namely average particle size, polydispersity index (PDI), zeta potential, conductivity, in vitro antioxidant activity, in vitro cellular uptake and their rheological parameters were studied. The results show that using maltodextrin, as surface active biopolymer, together with Polysorbate 20, as small molecular stabilizer, could improve the characteristics of nanoemulsions considerably. The studied characteristics of all prepared shear-thinning (pseudo-plastic) nanoemulsions were well fitted to maltodextrin proportions via various polynomial models using regression statistical analysis. Thus, applying the surface active polysaccharides as stabilizer, in nanoemulsion formulations, and tuning its proportions to general used small molecular emulsifiers, can develop more desired functional lipid such as α-tocopherol nanoemulsions for various water-based food and pharmaceutical uses.
Topics: Chemical Phenomena; Drug Stability; Emulsions; Nanotechnology; Particle Size; Polysaccharides; Polysorbates; Solvents; Surface-Active Agents; Viscosity; alpha-Tocopherol
PubMed: 30704297
DOI: 10.1177/1082013219825893