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1.
Chem Biol Interact ; 348: 109646, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506764

RESUMO

Acetylcholinesterase (AChE) is reversibly inhibited by α-tocopherol (α-T). Steady state kinetic analysis shows that α-T is a mixed slow-binding inhibitor of type A of human enzyme (Kci = 0.49 µM; Kui = 1.6 µM) with a residence time of 2 min on target. Molecular dynamics (MD) simulations support this mechanism, and indicate that α-T first forms multiple non-specific interactions with AChE surface near the gorge entrance, then binds to the peripheral side with alkylene chain slowly sliding down the gorge, inducing no significant conformational change. α-T slightly modulates the progressive inhibition of AChE by the cyclic organophosphorus, cresyl saligenylphosphate, accelerating the fast pseudo-first order process of phosphorylation. A moderate accelerating effect of α-T on phosphorylation by paraoxon was also observed after pre-incubation of AChE in the presence of α-T. This accelerating effect of α-T on ex vivo paraoxon-induced diaphragm muscle weakness was also observed. The effect of α-T on AChE phosphylation was interpreted in light of molecular modeling results. From all results it is clear that α-T does not protect AChE against phosphylation by organophosphorus.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , alfa-Tocoferol/metabolismo , alfa-Tocoferol/farmacologia , Acetilcolinesterase/química , Humanos , Cinética , Modelos Moleculares , Fosforilação , Conformação Proteica
2.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207571

RESUMO

Tocopherols and tocotrienols are natural compounds of plant origin, available in the nature. They are supplied in various amounts in a diet, mainly from vegetable oils, some oilseeds, and nuts. The main forms in the diet are α- and γ-tocopherol, due to the highest content in food products. Nevertheless, α-tocopherol is the main form of vitamin E with the highest tissue concentration. The α- forms of both tocopherols and tocotrienols are considered as the most metabolically active. Currently, research results indicate also a greater antioxidant potential of tocotrienols than tocopherols. Moreover, the biological role of vitamin E metabolites have received increasing interest. The aim of this review is to update the knowledge of tocopherol and tocotrienol bioactivity, with a particular focus on their bioavailability, distribution, and metabolism determinants in humans. Almost one hundred years after the start of research on α-tocopherol, its biological properties are still under investigation. For several decades, researchers' interest in the biological importance of other forms of vitamin E has also been growing. Some of the functions, for instance the antioxidant functions of α- and γ-tocopherols, have been confirmed in humans, while others, such as the relationship with metabolic disorders, are still under investigation. Some studies, which analyzed the biological role and mechanisms of tocopherols and tocotrienols over the past few years described new and even unexpected cellular and molecular properties that will be the subject of future research.


Assuntos
Antioxidantes , Dieta , Tocotrienóis , alfa-Tocoferol , gama-Tocoferol , Antioxidantes/química , Antioxidantes/metabolismo , Humanos , Tocotrienóis/química , Tocotrienóis/metabolismo , alfa-Tocoferol/química , alfa-Tocoferol/metabolismo , gama-Tocoferol/química , gama-Tocoferol/metabolismo
3.
Commun Biol ; 4(1): 796, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172811

RESUMO

Mammalian hibernators endure severe and prolonged hypothermia that is lethal to non-hibernators, including humans and mice. The mechanisms responsible for the cold resistance remain poorly understood. Here, we found that hepatocytes from a mammalian hibernator, the Syrian hamster, exhibited remarkable resistance to prolonged cold culture, whereas murine hepatocytes underwent cold-induced cell death that fulfills the hallmarks of ferroptosis such as necrotic morphology, lipid peroxidation and prevention by an iron chelator. Unexpectedly, hepatocytes from Syrian hamsters exerted resistance to cold- and drug-induced ferroptosis in a diet-dependent manner, with the aid of their superior ability to retain dietary α-tocopherol (αT), a vitamin E analog, in the liver and blood compared with those of mice. The liver phospholipid composition is less susceptible to peroxidation in Syrian hamsters than in mice. Altogether, the cold resistance of the hibernator's liver is established by the ability to utilize αT effectively to prevent lipid peroxidation and ferroptosis.


Assuntos
Ferroptose/fisiologia , Hibernação/fisiologia , Fígado/metabolismo , alfa-Tocoferol/metabolismo , Animais , Temperatura Baixa , Cricetinae , Peroxidação de Lipídeos , Fígado/patologia , Masculino , Mesocricetus , Especificidade da Espécie
4.
J Oleo Sci ; 70(2): 247-252, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33456009

RESUMO

This study aimed to compare the distribution of vitamin E analogs, particularly α-tocopherol and δ-tocopherol, in mice fed with a normal diet and a high-fat and high-sucrose diet separately. We used male C57BL/6JJcl strain mice, which were divided into six groups (control [C], Cα, Cδ, high-fat and high-sucrose [H], Hα, and Hδ groups) and bred for 4 weeks. The additional quantity of α-tocopherol or E-mix D (containing 86.7% δ-tocopherol) into diet was 800 mg/kg diet. The final body weight was significantly higher in the H group than in the C group. However, the effects of vitamin E analog intake had no significant difference, with no synergy between vitamin E and diet. Similar results were obtained in epididymal fat weight. Moreover, α-tocopherol was mainly distributed in the liver in both the Cα group and Hα group, whereas δ-tocopherol mostly accumulated in the epididymal fat, in both the Cδ group and Hδ group. Also, δ-tocopherol was detected in all tissues in both groups. Both the α-tocopherol and δ-tocopherol levels in the epididymal fat were significantly lower in the H group than in the C group. In conclusion, our results suggest that a portion of δ-tocopherol was incorporated into the adipose tissue by chylomicron before arriving at the liver, and then it is metabolized in the liver.


Assuntos
Tecido Adiposo/metabolismo , Tocoferóis/metabolismo , Animais , Quilomícrons/metabolismo , Dieta da Carga de Carboidratos , Dieta Hiperlipídica , Sacarose na Dieta/administração & dosagem , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Vitamina E/análogos & derivados , Vitamina E/metabolismo , alfa-Tocoferol/metabolismo
5.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33479170

RESUMO

Photosystem II (PSII) is an intrinsic membrane protein complex that functions as a light-driven water:plastoquinone oxidoreductase in oxygenic photosynthesis. Electron transport in PSII is associated with formation of reactive oxygen species (ROS) responsible for oxidative modifications of PSII proteins. In this study, oxidative modifications of the D1 and D2 proteins by the superoxide anion (O2 •-) and the hydroxyl (HO•) radicals were studied in WT and a tocopherol cyclase (vte1) mutant, which is deficient in the lipid-soluble antioxidant α-tocopherol. In the absence of this antioxidant, high-resolution tandem mass spectrometry was used to identify oxidation of D1:130E to hydroxyglutamic acid by O2 •- at the PheoD1 site. Additionally, D1:246Y was modified to either tyrosine hydroperoxide or dihydroxyphenylalanine by O2 •- and HO•, respectively, in the vicinity of the nonheme iron. We propose that α-tocopherol is localized near PheoD1 and the nonheme iron, with its chromanol head exposed to the lipid-water interface. This helps to prevent oxidative modification of the amino acid's hydrogen that is bonded to PheoD1 and the nonheme iron (via bicarbonate), and thus protects electron transport in PSII from ROS damage.


Assuntos
Aminoácidos/química , Arabidopsis/enzimologia , Complexo de Proteína do Fotossistema II/química , Superóxidos/química , Tilacoides/enzimologia , alfa-Tocoferol/química , Aminoácidos/metabolismo , Arabidopsis/genética , Arabidopsis/efeitos da radiação , Sítios de Ligação , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Transferases Intramoleculares/química , Transferases Intramoleculares/genética , Transferases Intramoleculares/metabolismo , Ferro/química , Ferro/metabolismo , Luz , Modelos Moleculares , Mutação , Oxirredução , Oxigênio/química , Oxigênio/metabolismo , Fotossíntese/fisiologia , Fotossíntese/efeitos da radiação , Complexo de Proteína do Fotossistema II/genética , Complexo de Proteína do Fotossistema II/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Superóxidos/metabolismo , Termodinâmica , Thermosynechococcus/enzimologia , Thermosynechococcus/genética , Thermosynechococcus/efeitos da radiação , Tilacoides/genética , Tilacoides/efeitos da radiação , alfa-Tocoferol/metabolismo
6.
Bull Exp Biol Med ; 170(3): 294-298, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33452974

RESUMO

We studied the effect of long-term light deprivation which began at different stages of ontogeny on the content of α-tocopherol in rats during the first 3 months of postnatal development. In the offspring postnatally exposed to constant darkness, the level of α-tocopherol in the liver, kidneys, heart, skeletal muscles, and lungs was significantly decreased at the early stages of postnatal ontogeny (2 weeks and 1 month). In rats kept under constant darkness after birth, the content of α-tocopherol in the lungs was also reduced at the age of 1 month. The modulating effect of light deprivation on the level of α-tocopherol can be associated both with the impact of disturbed circadian rhythms and with increased content of melatonin in the body.


Assuntos
Rim/metabolismo , Luz , Fígado/metabolismo , Pulmão/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , alfa-Tocoferol/metabolismo , Animais , Feminino , Rim/efeitos da radiação , Fígado/efeitos da radiação , Pulmão/efeitos da radiação , Masculino , Músculo Esquelético/efeitos da radiação , Ratos , Ratos Wistar , alfa-Tocoferol/efeitos da radiação
7.
J Sci Food Agric ; 101(6): 2337-2344, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33006761

RESUMO

BACKGROUND: Olive-derived antioxidants have been shown to affect the oxidative status of meat and have also been associated with greater consumption of glucose, which might affect glycogen stores and muscle characteristics. This study evaluated the effect of oleuropein extract supplementation (OLE) versus vitamin E + Se (VE), and their combination (VEOLE), in pig diets, on pH, drip loss, the proportion of free fatty acids, and meat stability, and their prediction by blood oxidative status markers. RESULTS: The drip loss of muscle was lower in antioxidant-supplemented groups when compared with controls. α-Tocopherol concentration and total fatty acids profile were not affected by dietary oleuropein supplementation. However, OLE and VEOLE had lower free n-3 polyunsaturated fatty acid (PUFA) levels when compared with VE and tended to have higher free monounsaturated fatty acid (MUFA) levels. Furthermore, the VEOLE group had lower free n-6 PUFA levels when compared with controls or VE, whereas the OLE group had intermediated values. Muscle samples from pigs subjected to the antioxidant-mixed supplementation (VEOLE) had lower malondialdehyde concentration when compared with the others. The VE and OLE groups showed intermediate malondialdehyde values. Chilled meat stability was highly correlated with antioxidant status in vivo. CONCLUSION: The administration of 96 mg oleuropein kg-1 feed produced similar meat quality characteristics as the use of 100 mg kg-1 α-tocopheryl acetate +0.26 mg kg-1 sodium selenite and it would be an interesting alternative in Mediterranean countries. The VEOLE group was the most effective for reducing lipid oxidation and for the production of polyunsaturated free fatty acids in meat, which would result in lower rancidity formation and better aroma development in products. © 2020 Society of Chemical Industry.


Assuntos
Ácidos Graxos não Esterificados/metabolismo , Iridoides/metabolismo , Carne/análise , Selênio/metabolismo , Suínos/metabolismo , alfa-Tocoferol/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Ácidos Graxos não Esterificados/química , Glucosídeos Iridoides , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Oxirredução , Suínos/crescimento & desenvolvimento
8.
Biomed Pharmacother ; 134: 111108, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341670

RESUMO

Doxorubicin (DOX) is limited to use in clinical practice because of poor targeting, serious side effects and multidrug resistance (MDR). Vitamin E and its derivatives are currently considered as hydrophobic material that can reverse tumor MDR by suppressing the action of p-glycoprotein (p-gp). Therefore, reduction-sensitive amphiphilic heparosan polysaccharide-cystamine-vitamin E succinate (KSV) copolymers were designed to reverse breast cancer MDR cells. The spherical micelles (DOX/KSV) micelles which had suitable particle size presented redox-sensitive release character. Simultaneously, DOX-loaded reduction insensitive heparosan-adipic dihydrazide-vitamin E succinate (KV) micellar system was designed as a control. DOX/KSV and DOX/KV micelles had the higher capability to overcome tumor MDR than that free DOX. However, DOX/KSV had the highest amount of cellular uptake which might be caused by the synergistic intracellular drug release and inhibition of p-gp expression. The mechanism experiments revealed that DOX/KSV could be fast disassembled to release DOX after internalization into tumor cells. Moreover, DOX/KSV produced more ROS than free DOX and DOX/KV resulting in enhanced anticancer effect. In vivo tumor-bearing mice study suggested that DOX/KSV micelles could efficiently enhance antitumor effect by overcoming tumor MDR and reduce toxicity of DOX. The DOX/KSV micelles could synergistically increase the therapeutic effect of chemotherapeutic drug on tumor MDR cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cistamina/farmacologia , Dissacarídeos/farmacologia , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , alfa-Tocoferol/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antibióticos Antineoplásicos/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cistamina/metabolismo , Dissacarídeos/metabolismo , Doxorrubicina/metabolismo , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Camundongos Nus , Micelas , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , alfa-Tocoferol/metabolismo
9.
Sci Rep ; 10(1): 19646, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184329

RESUMO

Tocopherols, lipid-soluble antioxidants play a crucial role in the antioxidant defense system in higher plants. The antioxidant function of α-tocopherol has been widely studied; however, experimental data on the formation of its oxidation products is missing. In this study, we attempt to provide spectroscopic evidence on the detection of oxidation products of α-tocopherol formed by its interaction with singlet oxygen and lipid peroxyl radical. Singlet oxygen was formed using photosensitizer rose bengal and thylakoid membranes isolated from Arabidopsis thaliana. Singlet oxygen reacts with polyunsaturated fatty acid forming lipid hydroperoxide which is oxidized by ferric iron to lipid peroxyl radical. The addition of singlet oxygen to double bond carbon on the chromanol head of α-tocopherol forms α-tocopherol hydroperoxide detected using fluorescent probe swallow-tailed perylene derivative. The decomposition of α-tocopherol hydroperoxide forms α-tocopherol quinone. The hydrogen abstraction from α-tocopherol by lipid peroxyl radical forms α-tocopheroxyl radical detected by electron paramagnetic resonance. Quantification of lipid and protein hydroperoxide from the wild type and tocopherol deficient (vte1) mutant Arabidopsis leaves using a colorimetric ferrous oxidation-xylenol orange assay reveals that α-tocopherol prevents formation of both lipid and protein hydroperoxides at high light. Identification of oxidation products of α-tocopherol might contribute to a better understanding of the protective role of α-tocopherol in the prevention of oxidative damage in higher plants at high light.


Assuntos
Antioxidantes/química , Arabidopsis/metabolismo , Radicais Livres/química , Luz/efeitos adversos , Estresse Oxidativo , Oxigênio Singlete/química , Vitamina E/química , alfa-Tocoferol/química , Antioxidantes/metabolismo , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/efeitos da radiação , Radicais Livres/metabolismo , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Peróxidos Lipídicos/química , Peróxidos Lipídicos/metabolismo , Oxirredução , Oxigênio Singlete/metabolismo , Vitamina E/metabolismo , alfa-Tocoferol/metabolismo
11.
Molecules ; 25(20)2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33086686

RESUMO

Tocomonoenols are vitamin E derivatives present in foods with a single double bond at carbon 11' in the sidechain. The α-tocopherol transfer protein (TTP) is required for the maintenance of normal α-tocopherol (αT) concentrations. Its role in the tissue distribution of α-11'-tocomonoenol (αT1) is unknown. We investigated the tissue distribution of αT1 and αT in wild-type (TTP+/+) and TTP knockout (TTP-/-) mice fed diets with either αT or αT1 for two weeks. αT1 was only found in blood, not tissues. αT concentrations in TTP+/+ mice were in the order of adipose tissue > brain > heart > spleen > lungs > kidneys > small intestine > liver. Loss of TTP function depleted αT in all tissues. αT1, contrary to αT, was still present in the blood of TTP-/- mice (16% of αT1 in TTP+/+). Autoclaving and storage at room temperature reduced αT and αT1 in experimental diets. In conclusion, αT1 is bioavailable, reaches the blood in mice, and may not entirely depend on TTP function for secretion into the systemic circulation. However, due to instability of the test compounds in the experimental diets, further in vivo experiments are required to clarify the role of TTP in αT1 secretion. Future research should consider compound stability during autoclaving of rodent feed.


Assuntos
Proteínas de Transporte/genética , Fígado/metabolismo , Vitamina E/metabolismo , alfa-Tocoferol/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dieta , Humanos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Knockout , Baço/efeitos dos fármacos , Baço/metabolismo , alfa-Tocoferol/metabolismo
12.
J Nutr ; 150(12): 3075-3085, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-32937657

RESUMO

BACKGROUND: Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood. OBJECTIVES: The objective was to determine the impact of bio-potency-adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice. METHODS: Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams. RESULTS: A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz). CONCLUSIONS: In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , alfa-Tocoferol/metabolismo , Animais , Dieta , Feminino , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Leite/química , Leite/metabolismo , alfa-Tocoferol/química
13.
J Sci Food Agric ; 100(11): 4319-4328, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32388868

RESUMO

BACKGROUND: The aim of this study was to investigate the metabolism of α-tocopherol derived from vitamin E-enriched transgenic maize (VER) and its effects on antioxidant and immune functions in broilers aged 1-42 days. A total of 360 1-day-old male broilers were randomly divided into three groups containing six replicates with 20 broilers per replicate. The negative control (NC) group and the positive control (PC) group were given non-GM maize and non-GM maize plus exogenous vitamin E (VE), respectively, and the VER group was given VER, replacing the non-GM maize given to the NC group. Between days 1 and 21 and days 22 and 42, VE levels were 4.38 and 4.63 mg kg-1 in the NC group, and 14.11 and 14.91 mg kg-1 in the PC and VER group, respectively. RESULTS: The results showed that α-tocopherol from both VER and additives increased α-tocopherol transfer protein and cytochrome P450 concentrations. Serum α-tocopherol and α-tocopherylquinone levels of broilers in the PC and VER groups were also significantly higher than those in the NC group (P < 0.05). Compared with the NC group, broilers in both groups that received α-tocopherol had reduced NF-κB p65 concentrations, significantly decreased serum prostaglandin E2 , interleukin-6, malondialdehyde, and hydrogen peroxide levels (P < 0.05), and significantly increased glutathione, glutathione peroxidase, and total antioxidant capacity (P < 0.05). CONCLUSION: In summary, both VER and non-GM maize fortified with exogenous VE showed similar effects on broilers, indicating that the α-tocopherol in VER has sufficient biological activity. © 2020 Society of Chemical Industry.


Assuntos
Ração Animal/análise , Galinhas/metabolismo , Plantas Geneticamente Modificadas/química , Vitamina E/análise , Zea mays/química , alfa-Tocoferol/análise , Animais , Galinhas/sangue , Galinhas/crescimento & desenvolvimento , Alimentos Geneticamente Modificados , Glutationa/sangue , Masculino , Malondialdeído/sangue , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Vitamina E/metabolismo , Zea mays/genética , Zea mays/metabolismo , alfa-Tocoferol/metabolismo
14.
J Nutr Health Aging ; 24(3): 290-299, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115610

RESUMO

OBJECTIVES: Malnutrition of vitamin A (retinol) and vitamin E (α-tocopherol, α-TOH) was observed in type 2 diabetes mellitus (T2DM) or dementia patients. However, how these vitamins affect cognitive function of subjects with T2DM was seldom reported. The objective of this study was to determine the association of circulating retinol and α-TOH with cognition in aging subjects with T2DM. METHODS: A total of 448 T2DM subjects and 448 age, gender and education matched control subjects (aged 55-75 years) were included in the study. Demographic characters of the participants were collected. Food frequency questionnaire (FFQ) method was used to collect dietary intake information. To assess the status of cognition, the MoCA test was used. Circulating retinol and α-TOH levels were compared between T2DM and non-T2DM subjects. Correlation of circulating retinol and α-TOH levels with cognitive function was analyzed in T2DM subjects. The effect of serum retinol and α-TOH levels on the risk of MCI in T2DM patients was explored. RESULTS: We found that T2DM-MCI subjects demonstrate lower serum retinol level than T2DM-nonMCI subjects (P < 0.01). Serum retinol level was positively correlated to cognitive function in T2DM subject (P < 0.05). T2DM subjects with higher circulating retinol level demonstrate higher cognitive scores in visual and executive, attention, language, memory and delayed recall domains (P < 0.05). CONCLUSION: Diminished circulating retinol predicts an increased risk of MCI in T2DM patients. Our findings provide suggestions that optimal retinol nutritional status might benefit cognition and decrease the risk of MCI in aging subjects with T2DM.


Assuntos
Cognição/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Vitamina A/metabolismo , alfa-Tocoferol/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Br J Nutr ; 123(5): 537-544, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-31791424

RESUMO

We investigated whether non-digestible saccharide fermentation-derived hydrogen molecules (H2) in rat colon could improve the in vivo reduction-oxidation (redox) balance via regeneration of α-tocopherol, by assessing their effect on hydroxyl radicals, the α-tocopherol concentration and the redox balance. In Expt 1, a Fenton reaction with phenylalanine (0 or 1·37 mmol/l of H2) was conducted. In Expt 2, rats received intraperitoneally maize oil containing phorone (400 mg/kg) 7 d after drinking ad libitum water containing 0 or 4 % fructo-oligosaccharides (FOS) (groups CP and FP, respectively). In Expt 3, rats unable to synthesise ascorbic acid drank ad libitum for 14 d water with 240 mg ascorbic acid/l (group AC), 20 mg of ascorbic acid/l (group DC) or 20 mg of ascorbic acid/l and 4 % FOS (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 Expt 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 Expt 3, net H2 excretion was higher in DCF than in the other rats after 3 d of the experiment. Furthermore, the concentrations of H2 and α-tocopherol and the redox glutathione ratio in perirenal adipose tissue of rats were significantly higher in DCF than in DC. To summarise, in rat colon, fermentation-derived H2 further shifted the redox balance towards a more reducing status in perirenal adipose tissue through increased regeneration of α-tocopherol.


Assuntos
Hidrogênio/metabolismo , Oxirredução/efeitos dos fármacos , Regeneração/efeitos dos fármacos , alfa-Tocoferol/metabolismo , Tecido Adiposo/metabolismo , Animais , Colo/metabolismo , Carboidratos da Dieta/administração & dosagem , Fermentação , Rim/metabolismo , Oligossacarídeos/administração & dosagem , Ratos
16.
Transgenic Res ; 29(1): 95-104, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31673914

RESUMO

The vitamin E family includes tocopherols and tocotrienols, which are essential lipid-soluble antioxidants necessary for human and livestock health. The seeds of many plant species, including maize, have high gamma (γ)-tocopherol but low alpha (α)-tocopherol contents; however, α-tocopherol is the most effective antioxidant. Therefore, it is necessary to optimize the tocopherol composition in plants. α-Tocopherol is synthesized from γ-tocopherol by γ-tocopherol methyltransferase (γ-TMT, VTE4) in the final step of the tocopherol biosynthetic pathway. In the present study, the full-length coding sequence (CDS) of γ-TMT was isolated from Zea mays, named ZmTMT. The ZmTMT CDS was 1059 bp in size, encoding 352 amino acids. Recombinant ZmTMT was expressed in Escherichia coli and the purified protein effectively converted γ-tocopherol into α-tocopherol in vitro. A comparison of enzyme activities showed that the activity of ZmTMT was higher than that of GmTMT2a (Glycine max) and AtTMT (Arabidopsis thaliana). Overexpression of ZmTMT increased the α-tocopherol content 4-5-fold in transgenic Arabidopsis and around 6.5-fold in transgenic maize kernels, and increased the α-/γ-tocopherol ratio to approximately 15 and 17, respectively. These results show that it is feasible to overexpress ZmTMT to optimize the tocopherol composition in maize; such a corn product might be useful in the feed industry in the near future.


Assuntos
Arabidopsis/metabolismo , Metiltransferases/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Sementes/metabolismo , Zea mays/enzimologia , alfa-Tocoferol/metabolismo , Arabidopsis/genética , Metiltransferases/genética , Plantas Geneticamente Modificadas/genética , Sementes/genética
17.
Int J Cancer ; 146(2): 510-520, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173656

RESUMO

Recent data suggest that rhabdomyosarcoma (RMS) cells might be vulnerable to oxidative stress-induced cell death. Here, we show that RMS are susceptible to cell death induced by Erastin, an inhibitor of the glutamate/cystine antiporter xc - that can increase reactive oxygen species (ROS) production via glutathione (GSH) depletion. Prior to cell death, Erastin caused GSH depletion, ROS production and lipid peroxidation. Importantly, pharmacological inhibitors of lipid peroxidation (i.e., Ferrostatin-1, Liproxstatin-1), ROS scavengers (i.e., α-Tocopherol, GSH) and the iron chelator Deferoxamine inhibited ROS accumulation, lipid peroxidation and cell death, consistent with ferroptosis. Interestingly, the broad-spectrum protein kinase C (PKC) inhibitor Bisindolylmaleimide I as well as the PKCα- and ß-selective inhibitor Gö6976 significantly reduced Erastin-induced cell death. Similarly, genetic knockdown of PKCα significantly protected RMS cells from Erastin-induced cell death. Furthermore, the broad-spectrum nicotinamide adenine dinucleotide phosphate-oxidase (NOX) inhibitor Diphenyleneiodonium and the selective NOX1/4 isoform inhibitor GKT137831 significantly decreased Erastin-stimulated ROS, lipid ROS and cell death. These data provide new insights into the molecular mechanisms of ferroptosis in RMS, contributing to the development of new redox-based treatment strategies.


Assuntos
Ferroptose/efeitos dos fármacos , Rabdomiossarcoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cicloexilaminas/metabolismo , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenilenodiaminas/metabolismo , Piperazinas/metabolismo , Pirazóis/farmacologia , Pirazolonas , Piridinas/farmacologia , Piridonas , Espécies Reativas de Oxigênio/metabolismo , Rabdomiossarcoma/metabolismo , alfa-Tocoferol/metabolismo
18.
BMC Plant Biol ; 19(1): 510, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752696

RESUMO

BACKGROUND: Soybean is one of the most important crop sources of tocopherols (Toc). However, the content of α-Toc, an isoform with the highest vitamin E activity in humans, is low in most cultivars. With the aim of broadening genetic variability, we performed quantitative trait locus (QTL) analysis for a high seed α-Toc trait detected in a wild soybean and characterized the sequence polymorphisms and expression profiles of γ-tocopherol methyltransferase (γ-TMT) genes as potential candidates. RESULTS: A recombinant inbred line population was developed from a cross between the low α-Toc breeding line TK780 and the high α-Toc wild accession B04009. The α-Toc content in seeds correlated strongly with the ratio of α-Toc to γ-Toc contents. QTL analysis using a high-density map constructed with 7710 single nucleotide polymorphisms (SNPs) generated by restriction site-associated DNA sequencing detected six QTLs involved in α-Toc biosynthesis. Of these, three in chromosomes (Chr) 9, 11, and 12 produced consistent effects during a 2-year trial. B04009 allele at QTLs in Chr9 and Chr12 and TK780 allele at the QTL in Chr11 each promoted the conversion of γ-Toc to α-Toc, which elevated the seed α-Toc content. SNPs and indels were detected between the parents in three γ-TMT genes (γ-TMT1, γ-TMT2, and γ-TMT3) co-located in the QTLs in Chr9 and Chr12, of which some existed in the cis-regulatory elements associated with seed development and functions. In immature cotyledons, γ-TMT3 was expressed at higher levels in B04009 than TK780, irrespective of two thermal conditions tested, whereas the expression of γ-TMT2 was markedly upregulated under higher temperatures, particularly in B04009. CONCLUSIONS: We identified QTLs consistently controlling α-Toc biosynthesis in wild soybean seeds in 2-year trials. The QTL on Chr9 had been previously identified in soybean, whereas the QTLs on Chr11 and Chr12 were novel. Further molecular dissections and characterization of the QTLs may facilitate the use of high α-Toc alleles from wild soybean in soybean breeding and an understanding of the molecular mechanisms underlying α-Toc biosynthesis in soybean seeds.


Assuntos
Metiltransferases/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Soja/genética , alfa-Tocoferol/metabolismo , Alelos , Cruzamento , Alimento Funcional , Endogamia , Metiltransferases/genética , Fenótipo , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Sementes/genética , Sementes/fisiologia , Análise de Sequência de DNA , Soja/fisiologia , Tocoferóis
19.
Plant Physiol Biochem ; 144: 375-385, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31622940

RESUMO

Soybeans are known for its good source of protein (40%), oil (20%) and also serve as a source of nutraceutical compounds including tocopherols (toc). To know the molecular basis of differential α-toc accumulation in two contrasting soybean genotypes: DS74 (low α-toc - 1.36 µg/g and total-toc -29.72 µg/g) and Bragg (high α-toc - 10.48 µg/g and total-toc 178.91 µg/g), the analysis of γ-TMT3 promoter activity and its methylation patterns were carried out. The sequencing results revealed nucleotide variation between Bragg:γ-TMT3-P and DS74:γ-TMT3-P, however none of the variations were found in core-promoter region or in cis-elements. The histochemical GUS assay revealed higher promoter activity of Bragg:γ-TMT3-P than that of DS74:γ-TMT3-P and correlated with significantly higher and lower (P < 0.05) expression of γ-TMT3 gene respectively. To know the molecular basis of differential accumulation of α-toc in these contrasting soybean genotypes, the DNA methylation pattern of γ-TMT3 gene body and its promoter was studied in both varieties. The results showed higher percentage (62.5%) of methylation in DS74:γ-TMT3-P than in Bragg:γ-TMT3-P (50%). Out of all the methylation sites in the promoter region, one of methylation site was found at CAAT box (-190 bp) of DS74:γ-TMT3-P. Further gene body methylation patterns revealed lowest % (40%) of CG methylation in DS74:γ-TMT3 gene as compared to Bragg:γ-TMT3 (64.2%). Thus our study revealed that, expression of γ-TMT3 gene was influenced by its promoter activity and methylation patterns in cis-elements of γ-TMT3 promoter and gene body. This study will help us to understand the possible role of methylation and promoter activity in determining the α-toc content in soybean seeds.


Assuntos
Soja/metabolismo , Tocoferóis/metabolismo , alfa-Tocoferol/metabolismo , gama-Tocoferol/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Regiões Promotoras Genéticas/genética
20.
J Vet Intern Med ; 33(6): 2770-2779, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31660648

RESUMO

BACKGROUND: A subset of horses deficient in alpha-tocopherol (α-TP) develop muscle atrophy and vitamin E-responsive myopathy (VEM) characterized by mitochondrial alterations in the sacrocaudalis dorsalis medialis muscle (SC). OBJECTIVES: To quantify muscle histopathologic abnormalities in subclinical α-TP deficient horses before and after α-TP supplementation and compare with retrospective (r)VEM cases. ANIMALS: Prospective study; 16 healthy α-TP-deficient Quarter Horses. Retrospective study; 10 retrospective vitamin E-responsive myopathy (rVEM) cases . METHODS: Blood, SC, and gluteus medius (GM) biopsy specimens were obtained before (day 0) and 56 days after 5000 IU/450 kg horse/day PO water dispersible liquid α-TP (n = 8) or control (n = 8). Muscle fiber morphology and mitochondrial alterations were compared in samples from days 0 and 56 and in rVEM cases. RESULTS: Mitochondrial alterations more common than our reference range (<2.5% affected fibers) were present in 3/8 control and 4/8 treatment horses on day 0 in SC but not in GM (mean, 2.2; range, 0%-10% of fibers). Supplementation with α-TP for 56 days did not change the percentage of fibers with mitochondrial alterations or anguloid atrophy, or fiber size in GM or SC. Clinical rVEM horses had significantly more mitochondrial alterations (rVEM SC, 13% ± 7%; GM, 3% ± 2%) and anguloid atrophy compared to subclinical day 0 horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinically normal α-TP-deficient horses can have mitochondrial alterations in the SC that are less severe than in atrophied VEM cases and do not resolve after 56 days of α-TP supplementation. Preventing α-TP deficiency may be of long-term importance for mitochondrial viability.


Assuntos
Doenças dos Cavalos/etiologia , Doenças Musculares/veterinária , Deficiência de Vitamina E/veterinária , alfa-Tocoferol/metabolismo , Animais , Suplementos Nutricionais , Feminino , Cavalos , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/etiologia , Doenças Musculares/patologia , Estudos Retrospectivos , Deficiência de Vitamina E/patologia
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