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1.
J Nutr ; 150(8): 2223-2229, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32614427

RESUMO

BACKGROUND: Better methods are needed for determining vitamin A absorption efficiency in humans to support development of dietary recommendations and to improve the accuracy of predictions of vitamin A status. OBJECTIVES: We developed and evaluated a method for estimating vitamin A absorption efficiency based on compartmental modeling of theoretical data on postprandial plasma retinyl ester (RE) kinetics. METHODS: We generated data on plasma RE and retinol kinetics (30 min to 8 h or 56 d, respectively) after oral administration of labeled vitamin A for 12 theoretical adults with a range of values assigned for vitamin A absorption (55-90%); we modeled all data to obtain best-fit values for absorption and other parameters using Simulation, Analysis, and Modeling software. We then modeled RE data only (16 or 10 samples), with or without added random error, and compared assigned to predicted absorption values. We also compared assigned values to areas under RE response curves (RE AUCs). RESULTS: We confirmed that a unique value for vitamin A absorption cannot be identified by modeling plasma retinol tracer kinetics. However, when RE data were modeled, predicted vitamin A absorptions were within 1% of assigned values using data without error and within 12% when 5% error was included. When the sample number was reduced, predictions were still within 13% for 10 of the 12 subjects and within 23% overall. Assigned values for absorption were not correlated with RE AUC (P = 0.21). CONCLUSIONS: We describe a feasible and accurate method for determining vitamin A absorption efficiency that is based on compartmental modeling of plasma RE kinetic data collected for 8 h after a test meal. This approach can be used in a clinical setting after fasting subjects consume a fat-containing breakfast meal with a known amount of vitamin A or a stable isotope label.


Assuntos
Simulação por Computador , Modelos Biológicos , Período Pós-Prandial , Vitamina A/sangue , Vitamina A/farmacocinética , Transporte Biológico , Humanos , Vitamina A/metabolismo
2.
J Nutr ; 150(7): 1989-1995, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32369598

RESUMO

BACKGROUND: Although iron deficiency is known to interrupt vitamin A (VA) metabolism, the ability of iron repletion to restore VA metabolism and kinetics in iron-deficient rats is not well understood. OBJECTIVES: In the present study, we examined the effects of dietary iron repletion on VA status in rats with pre-existing iron deficiency. METHODS: Weanling Sprague-Dawley rats were fed a VA-marginal diet (0.35 mg retinol/kg diet) containing either a normal concentration of iron [35 ppm, control group (CN)] or reduced iron (3 ppm, iron-deficient group, ID-); after 5 wk, 4 rats/group were killed for baseline measurements. A 3H-labeled retinol emulsion was administered intravenously to the remaining rats (n = 6, CN; n = 10, ID-) as tracer to initiate the kinetic study. On day 21 after dosing, n = 5 ID- rats were switched to the CN diet, generating an iron-repletion group (ID+). Blood samples were collected at 34 time points ≤92 d after dose administration, when all rats were killed and iron and VA status were determined. RESULTS: At baseline, ID- rats had developed iron deficiency, with a reduced plasma VA concentration (0.67 compared with 1.20 µmol/L in ID- and CN rats, respectively; P < 0.01) and a tendency toward higher liver VA (265 compared with 187 nmol in ID- and CN rats, respectively; P = 0.10). On day 92, iron deficiency persisted in ID- rats, accompanied by 2-times higher liver VA (456 nmol compared with 190 nmol in ID- and CN rats, respectively; P < 0.001) but lower plasma VA (0.64 compared with 0.94 µmol/L in ID- and CN rats, respectively; P = 0.05). ID+ rats not only recovered from iron deficiency, but also exhibited less liver VA sequestration (276 nmol) and normal plasma VA (0.91 µmol/L, not different from CN rats). CONCLUSIONS: Our results suggest that iron repletion can remove the inhibitory effect of iron deficiency on hepatic mobilization of VA and restore plasma retinol concentrations in iron-deficient rats, setting the stage for kinetic studies of VA turnover in this setting.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Ferro na Dieta/administração & dosagem , Ferro na Dieta/farmacologia , Deficiência de Vitamina A/terapia , Vitamina A/metabolismo , Animais , Dieta , Feminino , Masculino , Ratos , Ratos Sprague-Dawley
3.
Proc Natl Acad Sci U S A ; 117(18): 9857-9864, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32300017

RESUMO

Vitamin A has diverse biological functions and is essential for human survival at every point from embryogenesis to adulthood. Vitamin A and its derivatives have been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental, but how its transport is regulated is poorly understood. STRA6 is a multitransmembrane domain cell-surface receptor and mediates vitamin A uptake from plasma retinol binding protein (RBP). STRA6 can mediate both cellular vitamin A influx and efflux, but what regulates these opposing activities is unknown. To answer this question, we purified and identified STRA6-associated proteins in a native mammalian cell type that takes up vitamin A through STRA6 using mass spectrometry. We found that the major protein repeatedly identified as STRA6-associated protein is calmodulin, consistent with the cryogenic electron microscopy (cryo-EM) study of zebrafish STRA6 associated with calmodulin. Using radioactivity-based, high-performance liquid chromatography (HPLC)-based and real-time fluorescence techniques, we found that calmodulin profoundly affects STRA6's vitamin A transport activity. Increased calcium/calmodulin promotes cellular vitamin A efflux and suppresses vitamin A influx through STRA6. Further mechanistic studies revealed that calmodulin enhances the binding of apo-RBP to STRA6, and this enhancement is much more pronounced for apo-RBP than holo-RBP. This study revealed that calmodulin regulates STRA6's vitamin A influx or efflux activity by modulating its preferential interaction with apo-RBP or holo-RBP. This molecular mechanism of regulating vitamin A transport may point to new directions to treat human diseases associated with insufficient or excessive vitamin A uptake.


Assuntos
Transporte Biológico/genética , Calmodulina/genética , Proteínas de Membrana/genética , Proteínas Plasmáticas de Ligação ao Retinol/genética , Vitamina A/metabolismo , Animais , Apoproteínas/genética , Apoproteínas/metabolismo , Cálcio/metabolismo , Bovinos , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Microscopia Crioeletrônica , Humanos , Proteínas de Membrana/metabolismo , Ligação Proteica/genética , Receptores de Superfície Celular/genética , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Vitamina A/genética , Peixe-Zebra/genética
4.
J Nutr ; 150(7): 1982-1988, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32297934

RESUMO

BACKGROUND: Iron deficiency can result in hyporetinolemia and hepatic vitamin A (VA) sequestration. OBJECTIVES: We used model-based compartmental analysis to determine the impact of iron repletion on VA metabolism and kinetics in iron-deficient rats. METHODS: At weaning, Sprague-Dawley rats were assigned to either a VA-marginal diet (0.35 mg retinol equivalent/kg) with adequate iron (35 ppm, control group [CN]) or reduced iron (3 ppm, iron-deficient group [ID-]), with an equivalent average body weight for each group. After 5 wk, n = 4 rats from each group were euthanized for baseline measurements of VA and iron indices, and the remaining rats (n = 6 CN, n = 10 ID-) received an intravenous injection of 3H-labeled retinol in an emulsion as tracer to initiate the kinetic study. On day 21 after dosing, half of the ID- rats were switched to the CN diet to initiate iron repletion, referred to as the iron-repletion group (ID+). From the time of dosing, 34 serial blood samples were collected from each rat over a 92-d time course. Plasma tracer and tissue tracee data were fitted to 6- and 4-compartment models, respectively, to analyze the kinetic behavior of VA in all groups. RESULTS: Our mathematical model indicated that ID- rats exhibited a nearly 6-fold decrease in liver VA secretion and >4-fold reduction in whole-body VA utilization, compared with CN rats, whereas these perturbed kinetic behaviors were notably corrected in ID+ rats, close to those from the CN group. CONCLUSIONS: Iron repletion can remove the inhibitory effect that iron deficiency exerts on hepatic mobilization of VA and restore retinol kinetic parameters to values similar to that of never-deficient CN rats. Together with improvements in iron and VA indices, our results suggest that restoration of an iron-adequate diet is sufficient to improve VA kinetics after a previous state of iron deficiency.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Ferro na Dieta/administração & dosagem , Ferro na Dieta/farmacologia , Fígado/metabolismo , Vitamina A/administração & dosagem , Vitamina A/metabolismo , Animais , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Deficiência de Vitamina A
5.
PLoS Pathog ; 16(4): e1008360, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32330185

RESUMO

Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to protect against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed higher Salmonella burden in colonic tissues early in the infection that associated with higher luminal and systemic loads of the pathogen at later stages. Higher pathogen burden in stopΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs.


Assuntos
Microbioma Gastrointestinal , Interleucina-18/metabolismo , Mucosa Intestinal/imunologia , Proteínas Associadas aos Microtúbulos/fisiologia , Infecções por Salmonella/prevenção & controle , Salmonella typhimurium/imunologia , Vitamina A/metabolismo , Animais , Interações Hospedeiro-Patógeno , Interferon gama/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores do Ácido Retinoico/metabolismo , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Infecções por Salmonella/patologia , Transdução de Sinais
6.
Subcell Biochem ; 95: 27-55, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32297295

RESUMO

The placenta, a hallmark of mammalian embryogenesis, allows nutrients to be exchanged between the mother and the fetus. Vitamin A (VA), an essential nutrient, cannot be synthesized by the embryo, and must be acquired from the maternal circulation through the placenta. Our understanding of how this transfer is accomplished is still in its infancy. In this chapter, we recapitulate the early studies about the relationship between maternal dietary/supplemental VA intake and fetal VA levels. We then describe how the discovery of retinol-binding protein (RBP or RBP4), the development of labeling and detection techniques, and the advent of knockout mice shifted this field from a macroscopic to a molecular level. The most recent data indicate that VA and its derivatives (retinoids) and the pro-VA carotenoid, ß-carotene, are transferred across the placenta by distinct proteins, some of which overlap with proteins involved in lipoprotein uptake. The VA status and dietary intake of the mother influence the expression of these proteins, creating feedback signals that control the uptake of retinoids and that may also regulate the uptake of lipids, raising the intriguing possibility of crosstalk between micronutrient and macronutrient metabolism. Many questions remain about the temporal and spatial patterns by which these proteins are expressed and transferred throughout gestation. The answers to these questions are highly relevant to human health, considering that those with either limited or excessive intake of retinoids/carotenoids during pregnancy may be at risk of obtaining improper amounts of VA that ultimately impact the development and health of their offspring.


Assuntos
Desenvolvimento Embrionário , Vitamina A/metabolismo , Animais , Feminino , Humanos , Gravidez , Complicações na Gravidez/metabolismo , Proteínas de Ligação ao Retinol/metabolismo , Deficiência de Vitamina A/metabolismo , beta Caroteno/metabolismo
7.
Sci Rep ; 10(1): 4214, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144294

RESUMO

Studies demonstrated that pneumonia can decrease vitamin A productions and vitamin A reduction/deficiency may promote asthma development. Our previous study showed that neonatal Streptococcus pneumoniae (S. pneumoniae) infection promoted asthma development. Whether neonatal S. pneumoniae pneumonia induced asthma was associated with vitamin A levels remains unclear. The aim of this study was to investigate the effects of neonatal S. pneumoniae pneumonia on vitamin A expressions, to explore the effects of vitamin A supplement after neonatal S. pneumoniae pneumonia on adulthood asthma development. Non-lethal S. pneumoniae pneumonia was established by intranasal inoculation of neonatal (1-week-old) female BALB/c mice with D39. S. pneumoniae pneumonia mice were supplemented with or without all-trans retinoic acid 24 hours after infection. Vitamin A concentrations in lung, serum and liver were measured post pneumonia until early adulthood. Four weeks after pneumonia, mice were sensitized and challenged with OVA to induce allergic airway disease (AAD). Twenty-four hours after the final challenge, the lungs and bronchoalveolar lavage fluid (BALF) were collected to assess AAD. We stated that serum vitamin A levels in neonatal S. pneumoniae pneumonia mice were lower than 0.7µmol/L from day 2-7 post infection, while pulmonary vitamin A productions were significantly lower than those in the control mice from day 7-28 post infection. Vitamin A supplement after neonatal S. pneumoniae pneumonia significantly promoted Foxp3+Treg and Th1 productions, decreased Th2 and Th17 cells expressions, alleviated airway hyperresponsiveness (AHR) and inflammatory cells infiltration during AAD. Our data suggest that neonatal S. pneumoniae pneumonia induce serum vitamin A deficiency and long-time lung vitamin A reduction, vitamin A supplement after neonatal S. pneumoniae pneumonia inhibit the progression of asthma by altering CD4+T cell subsets.


Assuntos
Asma/prevenção & controle , Suplementos Nutricionais , Pneumonia Pneumocócica/complicações , Hipersensibilidade Respiratória/prevenção & controle , Streptococcus pneumoniae/imunologia , Subpopulações de Linfócitos T/imunologia , Vitamina A/administração & dosagem , Animais , Animais Recém-Nascidos , Asma/etiologia , Asma/metabolismo , Asma/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/metabolismo , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Streptococcus pneumoniae/isolamento & purificação , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Vitamina A/metabolismo , Vitaminas/administração & dosagem , Vitaminas/metabolismo
8.
J Nutr ; 150(6): 1644-1651, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32135013

RESUMO

BACKGROUND: Retinol isotope dilution (RID) and model-based compartmental analysis are recognized techniques for assessing vitamin A (VA) status. Recent studies have shown that RID predictions of VA total body stores (TBS) can be improved by using modeling and that VA kinetics and TBS in children can be effectively studied by applying population modeling ("super-child" approach) to a composite data set. OBJECTIVES: The objectives were to model whole-body retinol kinetics and predict VA TBS in a group of Mexican preschoolers using the super-child approach and to use model predictions of RID coefficients to estimate TBS by RID in individuals. METHODS: Twenty-four healthy Mexican children (aged 3-6 y) received an oral dose (2.96 µmol) of [13C10]retinyl acetate in corn oil. Blood samples were collected from 8 h to 21 d after dosing, with each child sampled at 4 d and at 1 other time. Composite data for plasma labeled retinol compared with time were analyzed using a 6-component model to obtain group retinol kinetic parameters and pool sizes. Model-predicted TBS was compared with mean RID predictions at 4 d; RID estimates at 4 d were compared with those calculated at 7-21 d. RESULTS: Model-predicted TBS was 1097 µmol, equivalent to ∼2.4 y-worth of VA; using model-derived coefficients, group mean RID-predicted TBS was 1096 µmol (IQR: 836-1492 µmol). TBS at 4 d compared with a later time was similar (P = 0.33). The model predicted that retinol spent 1.5 h in plasma during each transit and recycled to plasma 13 times before utilization. CONCLUSIONS: The super-child modeling approach provides information on whole-body VA kinetics and can be used with RID to estimate TBS at any time between 4 and 21 d postdose. The high TBS predicted for these children suggests positive VA balance, likely due to large-dose VA supplements, and warrants further investigation.


Assuntos
Vitamina A/farmacocinética , Carga Corporal (Radioterapia) , Criança , Pré-Escolar , Feminino , Humanos , Técnicas de Diluição do Indicador , Masculino , México , Estado Nutricional , Vitamina A/metabolismo
9.
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
10.
Sci Rep ; 10(1): 2359, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047189

RESUMO

The effects of vitamin A and/or vitamin D deficiency were studied in an Arf-/- BCR-ABL acute lymphoblastic leukemia murine model. Vitamin D sufficient mice died earlier (p = 0.003) compared to vitamin D deficient (VDD) mice. Vitamin A deficient (VAD) mice fared worst with more rapid disease progression and decreased survival. Mice deficient for vitamins A and D (VADD) had disease progression similar to VAD mice. Regulatory T cells, previously shown to associate with poor BCR-ABL leukemia control, were present at higher frequencies among CD4+ splenocytes of vitamin A deficient vs. sufficient mice. In vitro studies demonstrated 1,25-dihydroxyvitamin D (1,25(OH)2VD3) increased the number of BCR-ABL ALL cells only when co-cultured with bone marrow stroma. 1,25(OH)2VD3 induced CXCL12 expression in vivo and in vitro in stromal cells and CXCL12 increased stromal migration and the number of BCR-ABL blasts. Vitamin D plus leukemia reprogrammed the marrow increasing production of collagens, potentially trapping ALL blasts. Vitamin A (all trans retinoic acid, ATRA) treated leukemic cells had increased apoptosis, decreased cells in S-phase, and increased cells in G0/G1. ATRA signaled through the retinoid X receptor to decrease BCR-ABL leukemic cell viability. In conclusion, vitamin A and D deficiencies have opposing effects on mouse survival from BCR-ABL ALL.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Vitamina A/metabolismo , Vitamina D/metabolismo , Animais , Apoptose , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores X Retinoide/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Vitamina A/genética , Vitamina A/farmacologia , Vitamina D/genética , Vitamina D/farmacologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-32105672

RESUMO

Vitamin A (retinol) is important for normal growth, vision and reproduction. It has a role in the immune response and the development of metabolic syndrome. Most of the retinol present in the body is stored as retinyl esters within lipid droplets in hepatic stellate cells (HSCs). In case of liver damage, HSCs release large amounts of stored retinol, which is partially converted to retinoic acid (RA). This surge of RA can mediate the immune response and enhance the regeneration of the liver. If the damage persists activated HSCs change into myofibroblast-like cells producing extracellular matrix, which increases the chance of tumorigenesis to occur. RA has been shown to decrease proliferation and metastasis of hepatocellular carcinoma. The levels of RA and RA signaling are influenced by the possibility to esterify retinol towards retinyl esters. This suggests a complex regulation between different retinoids, with an important regulatory role for HSCs.


Assuntos
Carcinoma Hepatocelular/patologia , Células Estreladas do Fígado/metabolismo , Neoplasias Hepáticas/patologia , Regeneração Hepática , Vitamina A/metabolismo , Carcinogênese/patologia , Ésteres/metabolismo , Matriz Extracelular/metabolismo , Células Estreladas do Fígado/citologia , Humanos , Gotículas Lipídicas/metabolismo , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Transdução de Sinais/fisiologia
12.
J Food Sci ; 85(3): 816-823, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32088926

RESUMO

The objective of this study was to evaluate the interaction of pro-vitamin A-rich sweet potato on iron bioavailability of biofortified cowpeas, using in vitro Caco-2 cells and in vivo depletion-repletion rat model. Mixtures of conventional rice with cultivars of iron-biofortified (Aracê, Xiquexique, and Tumucumaque) or conventional (Guariba) cowpeas with or without sweet potato biofortified with pro-vitamin A carotenoids were evaluated. The ratio of ferritin/total protein in Caco-2 cells was used as the index of cellular Fe uptake in the in vitro assay. The animal study evaluated the hemoglobin gain, the relative biological value, and the gene expression of transferrin and ferritin proteins by reverse transcription polymerase chain reaction. In the in vitro study, Xiquexique cowpea presented higher bioavailability of iron in the absence of sweet potato, and no difference was observed between the other cultivars of cowpea with and without sweet potato. The in vivo bioavailability (relative biological value of hemoglobin regeneration efficiency) differed statistically only between Guariba groups added to sweet potato and Tumucumaque. Ferritin mRNA expression did not differ between the test and control (ferrous sulfate) groups. Regarding the transferrin mRNA expression, there was a difference between the test and control groups except for the Xiquexique group. The association of rice and beans with sweet potato rich in carotenoids favored the gene expression of proteins involved in the iron metabolism, as well as its bioavailability, corroborating beneficial effects of this mixture. Xiquexique cowpea was shown to be the most promising compared to the other cultivars, exhibiting higher iron content in the digestible fraction, better in vitro bioavailability of iron, and transferrin gene expression. PRACTICAL APPLICATION: Data from the study indicated greater in vitro bioavailability of iron for Xiquexique cowpea and sweet potato mixtures, in addition to the greater regeneration efficiency of hemoglobin in vivo as the bioavailability of iron among biofortified beans, highlighting the promising benefits of biofortification.


Assuntos
Ipomoea batatas/metabolismo , Ferro/metabolismo , Vigna/metabolismo , Vitamina A/metabolismo , Animais , Biofortificação , Disponibilidade Biológica , Células CACO-2 , Carotenoides/análise , Carotenoides/metabolismo , Ferritinas/análise , Ferritinas/metabolismo , Alimentos Fortificados/análise , Hemoglobinas/análise , Hemoglobinas/metabolismo , Humanos , Ipomoea batatas/química , Ferro/química , Ratos , Ratos Wistar , Vigna/química , Vitamina A/química
14.
Int J Cancer ; 146(6): 1741-1753, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31361910

RESUMO

More than two-thirds of patients with hepatocellular carcinoma (HCC) cannot receive curative therapy and have poor survival due to late diagnosis and few prognostic directions. In our study, nontargeted and targeted metabolomics analyses were conducted by liquid chromatography-mass spectrometry to characterize metabolic features of HCC and identify diagnostic and prognostic biomarker candidate incorporating liver tissue and serum metabolites. A total of 552 subjects, including 432 with liver tissue and 120 with serum specimens, were recruited in China. In the discovery cohort, a series of 138 metabolites were identified to discriminate HCC tissues from matched nontumor tissues. Retinol presented with the highest area under the curve (AUC) of 0.991 and associated with Edmondson grade. In the validation cohort, all metabolites in retinol metabolism pathway were examined and the levels of retinol and retinal in tumor tissue and serum decreased in the order of normal to cirrhosis to HCC of Edmondson Grades I to IV. Retinol and retinal levels could also differentiate between HCC and cirrhosis, with AUCs of 0.996 and 0.994, respectively, in tissue and 0.812 and 0.744, respectively, in serum. The AUC of the combined retinol and retinal panel in serum was 0.852. Univariate and multivariate Cox regression identified this panel as an independent predictor for HCC and showed that low expression of retinol and retinal correlated with decreased survival time. In conclusion, the retinol metabolic signature had considerable diagnostic and prognostic value for identifying HCC patients who would benefit from prompt therapy and optimal prognostic direction.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/diagnóstico , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Metabolômica/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/mortalidade , China/epidemiologia , Diagnóstico Diferencial , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Retinaldeído/análise , Retinaldeído/metabolismo , Vitamina A/análise , Vitamina A/metabolismo , Adulto Jovem
15.
J Nutr ; 150(5): 989-993, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851323

RESUMO

Retinol isotope dilution (RID) is a well-accepted technique for assessing vitamin A status [i.e., total body stores (TBS)]. Here, in an effort to increase understanding of the method, we briefly review RID equations and discuss their included variables and their coefficients (i.e., assumptions that account for the efficiency of absorption of an orally administered tracer dose of vitamin A, mixing of the dose with endogenous vitamin A, and loss due to utilization). Then, we focus on contributions of another technique, model-based compartmental analysis and especially the "super-person" approach, that advance the RID method. Specifically, we explain how adding this modeling component, which involves taking 1 additional blood sample from each subject, provides population-specific estimates for the RID coefficients that can be used in the equation instead of values derived from the literature; using model-derived RID coefficients results in improved confidence in predictions of TBS for both a group and its individuals. We note that work is still needed to identify the optimal time for applying RID in different groups and to quantify vitamin A absorption efficiency. Finally, we mention other contributions of modeling, including the use of theoretical data to verify the accuracy of RID predictions and the additional knowledge that model-based compartmental analysis provides about whole-body vitamin A kinetics.


Assuntos
Técnicas de Diluição do Indicador , Vitamina A/metabolismo , Humanos , Modelos Biológicos
16.
J Sci Food Agric ; 100(2): 634-647, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31591722

RESUMO

BACKGROUND: Vitamin A deficiency (VAD) is widespread in sub-Saharan Africa (SSA). Unlike in developed countries, where the main source of vitamin A comes from meat, the diet of poor populations in SSA is largely plant based. It is thus important to identify local / popular plants with higher vitamin A content for combating VAD. Banana (including plantains) is an important staple food crop in this region. The identification and promotion of vitamin A-rich banana cultivars could contribute significantly to the alleviation of VAD in areas heavily dependent on the crop. We assessed pro-vitamin A carotenoid (pVACs) content in the fruit pulp of 48 local plantains from eastern Democratic Republic of Congo, to identify cultivars that could help reduce VAD, especially among young children and women of reproductive age. RESULTS: Mean pVACs content varied from 175-1756 µg/100 gfw in ripe fruits. Significant increases (P < 0.001) in total pVACs content occurred after ripening in all cultivars except 'UCG II'. Retinol activity equivalents (RAE) in ripe fruits ranged from 12-113 µg/100 gfw. Fifteen plantain cultivars, including 'Adili II', 'Nzirabahima', 'Mayayi', 'Buembe', and 'Sanza Tatu' (associated with RAE values of 44 µg/100 gfw and above) can be considered as good sources of pVACs. Modest consumption (250 or 500 gfw) of the fruit pulp of the five best plantain cultivars at ripening stage 5 meets between 39-71% and 44-81% of vitamin A dietary reference intake (DRI) respectively, for children below 5 years old and women of reproductive age. CONCLUSION: The 15 best plantain cultivars (especially the top 5) could potentially be introduced / promoted as alternative sources of pro-vitamin A in banana-dependent communities, and help to reduce cases of VAD substantially. © 2019 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Assuntos
Carotenoides/análise , Musa/química , Vitamina A/análise , Adolescente , Adulto , Carotenoides/metabolismo , Pré-Escolar , República Democrática do Congo , Feminino , Frutas/química , Frutas/metabolismo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Musa/classificação , Musa/metabolismo , Provitaminas/análise , Vitamina A/metabolismo , Deficiência de Vitamina A/dietoterapia , Deficiência de Vitamina A/metabolismo , Adulto Jovem
17.
Vet Res ; 50(1): 101, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783923

RESUMO

Vitamin A (VA) has pleiotropic effects on the immune system and is critical for mucosal immune function and intestinal lymphocyte trafficking. We hypothesized that oral VA supplementation of porcine epidemic diarrhea virus (PEDV)-infected pregnant gilts would enhance the gut-mammary gland-secretory IgA axis to boost lactogenic immunity and passive protection of nursing piglets against PEDV challenge. Gilts received daily oral retinyl acetate (30 000 IU) starting at gestation day 76 throughout lactation. At 3-4 weeks pre-partum, VA-supplemented (PEDV + VA) and non-supplemented (PEDV) gilts were PEDV or mock inoculated (mock + VA and mock, respectively). PEDV + VA gilts had decreased mean PEDV RNA shedding titers and diarrhea scores. To determine if lactogenic immunity correlated with protection, all piglets were PEDV-challenged at 3-5 days post-partum. The survival rate of PEDV + VA litters was 74.2% compared with 55.9% in PEDV litters. Mock and mock + VA litter survival rates were 5.7% and 8.3%, respectively. PEDV + VA gilts had increased PEDV IgA antibody secreting cells and PEDV IgA antibodies in serum pre-partum and IgA+ß7+ (gut homing) cells in milk post piglet challenge compared with PEDV gilts. Our findings suggest that oral VA supplementation may act as an adjuvant during pregnancy, enhancing maternal IgA and lactogenic immune protection in nursing piglets.


Assuntos
Imunidade Materno-Adquirida/imunologia , Imunoglobulina A/imunologia , Sus scrofa/imunologia , Vitamina A/metabolismo , Vitaminas/metabolismo , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Vírus da Diarreia Epidêmica Suína/imunologia , Distribuição Aleatória , Vitamina A/administração & dosagem , Vitaminas/administração & dosagem
18.
Sci Rep ; 9(1): 19493, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862954

RESUMO

The nuclear receptor Farnesoid X Receptor (FXR) is activated by bile acids and controls multiple metabolic processes, including bile acid, lipid, carbohydrate, amino acid and energy metabolism. Vitamin A is needed for proper metabolic and immune control and requires bile acids for efficient intestinal absorption and storage in the liver. Here, we analyzed whether FXR regulates vitamin A metabolism. Compared to control animals, FXR-null mice showed strongly reduced (>90%) hepatic levels of retinol and retinyl palmitate and a significant reduction in lecithin retinol acyltransferase (LRAT), the enzyme responsible for hepatic vitamin A storage. Hepatic reintroduction of FXR in FXR-null mice induced vitamin A storage in the liver. Hepatic vitamin A levels were normal in intestine-specific FXR-null mice. Obeticholic acid (OCA, 3 weeks) treatment rapidly reduced (>60%) hepatic retinyl palmitate levels in mice, concurrent with strongly increased retinol levels (>5-fold). Similar, but milder effects were observed in cholic acid (12 weeks)-treated mice. OCA did not change hepatic LRAT protein levels, but strongly reduced all enzymes involved in hepatic retinyl ester hydrolysis, involving mostly post-transcriptional mechanisms. In conclusion, vitamin A metabolism in the mouse liver heavily depends on the FXR and FXR-targeted therapies may be prone to cause vitamin A-related pathologies.


Assuntos
Ácidos e Sais Biliares/farmacologia , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Vitamina A/metabolismo , Aciltransferases/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/metabolismo , Ácido Quenodesoxicólico/farmacologia , Ácido Cólico/metabolismo , Ácido Cólico/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Camundongos , Camundongos Knockout
19.
J Phys Chem Lett ; 10(23): 7333-7339, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31714784

RESUMO

Due to the poor aqueous solubility of retinoids, evolution has tuned their binding to cellular proteins to address specialized physiological roles by modulating uptake, storage, and delivery to specific targets. With the aim to disentangle the structure-function relationships in these proteins and disclose clues for engineering selective carriers, the binding mechanism of the two most abundant retinol-binding isoforms was explored by using enhanced sampling molecular dynamics simulations and surface plasmon resonance. The distinctive dynamics of the entry portal site in the holo species was crucial to modulate retinol dissociation. Remarkably, this process is controlled to a large extent by the replacement of Ile by Leu in the two isoforms, thus suggesting that fine control of ligand release can be achieved through a rigorous selection of conservative mutations in accessory sites.


Assuntos
Proteínas Celulares de Ligação ao Retinol/metabolismo , Vitamina A/metabolismo , Sítios de Ligação , Humanos , Isomerismo , Cinética , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Proteínas Celulares de Ligação ao Retinol/química , Termodinâmica , Vitamina A/química
20.
Int J Mol Sci ; 20(22)2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739436

RESUMO

Macro- and micronutrients, essential for the maintenance of human metabolism, are assimilated daily through the diet. Wheat and other major cereals are a good source of nutrients, such as carbohydrates and proteins, but cannot supply a sufficient amount of essential micronutrients, including provitamin A. As vitamin A deficiency (VAD) leads to several serious diseases throughout the world, the biofortification of a major staple crop, such as wheat, represents an effective way to preserve human health in developing countries. In the present work, a key enzyme involved in the branch of carotenoids pathway producing ß-carotene, lycopene epsilon cyclase, has been targeted by a Targeting Induced Local Lesions in Genomes (TILLING) approach in a "block strategy" perspective. The null mutant genotype showed a strong reduction in the expression of the lcyE gene and also interesting pleiotropic effects on an enzyme (ß-ring hydroxylase) acting downstream in the pathway. Biochemical profiling of carotenoids in the wheat mutant lines showed an increase of roughly 75% in ß-carotene in the grains of the complete mutant line compared with the control. In conclusion, we describe here the production and characterization of a new wheat line biofortified with provitamin A obtained through a nontransgenic approach, which also sheds new light on the molecular mechanism governing carotenoid biosynthesis in durum wheat.


Assuntos
Biofortificação , Engenharia Genética , Triticum/genética , Triticum/metabolismo , Vitamina A/metabolismo , Alelos , Sequência de Bases , Carotenoides/metabolismo , Regulação da Expressão Gênica de Plantas , Marcação de Genes , Engenharia Genética/métodos , Genômica/métodos , Humanos , Liases Intramoleculares/genética , Liases Intramoleculares/metabolismo , Mutação , Filogenia , Plantas Geneticamente Modificadas
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