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1.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-33946898

RESUMEN

Oxidative stress-induced cell damage and death of the retinal pigmented epithelium (RPE), a polarized monolayer that maintains retinal health and homeostasis, lead to the development of age-related macular degeneration (AMD). Several studies show that the naturally occurring antioxidant Lutein (Lut) can protect RPE cells from oxidative stress. However, the poor solubility and low oral bioavailability limit the potential of Lut as a therapeutic agent. In this study, lutein diglutaric acid (Lut-DG), a prodrug of Lut, was synthesized and its ability to protect human ARPE-19 cells from oxidative stress was tested compared to Lut. Both Lut and Lut-DG significantly decreased H2O2-induced reactive oxygen species (ROS) production and protected RPE cells from oxidative stress-induced death. Moreover, the immunoblotting analysis indicated that both drugs exerted their protective effects by modulating phosphorylated MAPKs (p38, ERK1/2 and SAPK/JNK) and downstream molecules Bax, Bcl-2 and Cytochrome c. In addition, the enzymatic antioxidants glutathione peroxidase (GPx) and catalase (CAT) and non-enzymatic antioxidant glutathione (GSH) were enhanced in cells treated with Lut and Lut-DG. In all cases, Lut-DG was more effective than its parent drug against oxidative stress-induced damage to RPE cells. These findings highlight Lut-DG as a more potent compound than Lut with the protective effects against oxidative stress in RPE cells through the modulation of key MAPKs, apoptotic and antioxidant molecular pathways.


Asunto(s)
Antioxidantes/farmacología , Células Epiteliales/efectos de los fármacos , Luteína/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Profármacos/farmacología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Catalasa/biosíntesis , Catalasa/genética , Línea Celular , Citocromos c/biosíntesis , Citocromos c/genética , Evaluación Preclínica de Medicamentos , Células Epiteliales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión/biosíntesis , Glutatión/genética , Glutatión Peroxidasa/biosíntesis , Glutatión Peroxidasa/genética , Humanos , Peróxido de Hidrógeno/toxicidad , Luteína/química , Luteína/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Degeneración Macular/tratamiento farmacológico , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo , Epitelio Pigmentado de la Retina/citología
2.
Molecules ; 26(2)2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33477841

RESUMEN

Melilotus officinalis is known to contain several types of secondary metabolites. In contrast, the carotenoid composition of this medicinal plant has not been investigated, although it may also contribute to the biological activities of the drug, such as anti-inflammatory effects. Therefore, this study focuses on the isolation and identification of carotenoids from Meliloti herba and on the effect of isolated (all-E)-lutein 5,6-epoxide on primary sensory neurons and macrophages involved in nociception, as well as neurogenic and non-neurogenic inflammatory processes. The composition of the plant extracts was analyzed by high performance liquid chromatography (HPLC). The main carotenoid was isolated by column liquid chromatography (CLC) and identified by MS and NMR. The effect of water-soluble lutein 5,6-epoxide-RAMEB (randomly methylated-ß-cyclodextrin) was investigated on Ca2+-influx in rat primary sensory neurons induced by the activation of the transient receptor potential ankyrin 1 receptor agonist to mustard-oil and on endotoxin-induced IL-1ß release from isolated mouse peritoneal macrophages. (all-E)-Lutein 5,6-epoxide significantly decreased the percent of responsive primary sensory neurons compared to the vehicle-treated stimulated control. Furthermore, endotoxin-evoked IL-1ß release from macrophages was significantly decreased by 100 µM lutein 5,6-epoxide compared to the vehicle-treated control. The water-soluble form of lutein 5,6-epoxide-RAMEB decreases the activation of primary sensory neurons and macrophages, which opens perspectives for its analgesic and anti-inflammatory applications.


Asunto(s)
Luteína/análogos & derivados , Macrófagos/efectos de los fármacos , Melilotus/química , Células Receptoras Sensoriales/efectos de los fármacos , Animales , Luteína/análisis , Luteína/aislamiento & purificación , Luteína/farmacología , Macrófagos/citología , Ratones , Ratas , Células Receptoras Sensoriales/citología
3.
Annu Rev Nutr ; 36: 571-602, 2016 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-27431371

RESUMEN

Current evidence suggests lutein and its isomers play important roles in ocular development in utero and throughout the life span, in vision performance in young and later adulthood, and in lowering risk for the development of common age-related eye diseases in older age. These xanthophyll (oxygen-containing) carotenoids are found in a wide variety of vegetables and fruits, and they are present in especially high concentrations in leafy green vegetables. Additionally, egg yolks and human milk appear to be bioavailable sources. The prevalence of lutein, zeaxanthin, and meso-zeaxanthin in supplements is increasing. Setting optimal and safe ranges of intake requires additional research, particularly in pregnant and lactating women. Accumulating evidence about variable interindividual response to dietary intake of these carotenoids, based on genetic or metabolic influences, suggests that there may be subgroups that benefit from higher levels of intake and/or alternate strategies to improve lutein and zeaxanthin status.


Asunto(s)
Dieta Saludable , Suplementos Dietéticos , Oftalmopatías/prevención & control , Luteína/uso terapéutico , Modelos Biológicos , Trastornos de la Visión/prevención & control , Zeaxantinas/uso terapéutico , Factores de Edad , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/efectos adversos , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/uso terapéutico , Oftalmopatías/inmunología , Oftalmopatías/metabolismo , Oftalmopatías/patología , Humanos , Luteína/efectos adversos , Luteína/análogos & derivados , Luteína/metabolismo , Especificidad de Órganos , Estrés Oxidativo , Retina/crecimiento & desarrollo , Retina/inmunología , Retina/metabolismo , Retina/patología , Estereoisomerismo , Trastornos de la Visión/inmunología , Trastornos de la Visión/metabolismo , Trastornos de la Visión/patología , Zeaxantinas/efectos adversos , Zeaxantinas/química , Zeaxantinas/metabolismo
4.
Eur J Nutr ; 52(4): 1381-91, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23052623

RESUMEN

PURPOSE: Lutein and zeaxanthin are macular pigments with a protective function in the retina. These xanthophylls must be obtained from the diet or added to foods or supplements via easy-to-use, stable formulations. The technique employed to produce these formulations may affect the bioavailability of the xanthophylls. METHODS: Forty-eight healthy volunteers were randomized into this double-blind, cross-over study investigating the plasma kinetics of lutein provided as two different beadlet formulations. Subjects (n = 48) received a single dose of 20 mg of lutein as either a starch-matrix ("SMB", FloraGLO® Lutein 5 %) or as a cross-linked alginate-matrix beadlet ("AMB", Lyc-O-Lutein 20 %) formulation. Plasma concentrations of lutein and zeaxanthin were measured at 0, 1, 3, 6, 9, 12, 14, 24, 26, 28, 32, 36, 48, 72, 168, and 672 h. RESULTS: The mean plasma AUC(0-72h), AUC(0-672h), and C(max) for total lutein and zeaxanthin and their all-E-isomers were significantly increased (p < 0.001) from pre-dose concentrations in response to SMB and AMB. There was no difference in lutein T max between the two test articles. However, by 14 h post-dose, total plasma lutein increased by 7 % with AMB and by 126 % with SMB. Total lutein AUC(0-72h) and AUC(0-672h) were 1.8-fold and 1.3-fold higher, respectively, for SMB compared to AMB. Both formulations were well tolerated by subjects in this study. CONCLUSION: These findings confirm that the bioavailability of lutein and zeaxanthin critically depends on the formulation used and document a superiority of the starch-based over the alginate-based product in this study.


Asunto(s)
Antioxidantes/administración & dosificación , Suplementos Dietéticos , Luteína/administración & dosificación , Xantófilas/administración & dosificación , Adulto , Alginatos/química , Antioxidantes/efectos adversos , Antioxidantes/química , Antioxidantes/metabolismo , Estudios Cruzados , Suplementos Dietéticos/efectos adversos , Método Doble Ciego , Femenino , Aditivos Alimentarios/química , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Humanos , Cinética , Luteína/efectos adversos , Luteína/análogos & derivados , Luteína/metabolismo , Masculino , Persona de Mediana Edad , Valor Nutritivo , Pigmentos Retinianos/administración & dosificación , Pigmentos Retinianos/efectos adversos , Pigmentos Retinianos/química , Pigmentos Retinianos/metabolismo , Almidón/química , Estereoisomerismo , Xantófilas/efectos adversos , Xantófilas/química , Xantófilas/metabolismo , Adulto Joven , Zeaxantinas
5.
Ophthalmologica ; 225(2): 120-6, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-20948238

RESUMEN

PURPOSE: To assess the effects of nilvadipine on the progression of central visual field defect in retinitis pigmentosa (RP). DESIGN: Prospective, randomized, nonmasked, single-center trial. METHODS: Patients with RP were randomly divided into a treated group receiving oral nilvadipine at 4 mg/day for ≥30 months and a control group receiving tocopherol nicotinate at 300 mg/day, helenien at 15 mg/day or no medication for the same periods. Progression of RP was evaluated using the 10-2 SITA Fast Program of the Humphrey Visual Field Analyzer, and regression coefficients calculated from the time courses of mean deviation (MD slope) were compared between groups. RESULTS: Nineteen patients in the treated group and 14 patients in the control group completed the follow-up for ≥30 months. The mean (±standard deviation) duration of observation was 48.8 ± 11.8 months (median 48 months, range 30-66 months) for the treated group and 49.2 ± 18.1 months (median 48 months, range 30-90 months) for the control group (p = 0.94). Mean (±standard error of the mean, SEM) regression coefficients of the averaged MD values for the initial 30 months were -0.35 ± 0.17 dB/year in the treated group and -0.75 ± 0.06 dB/year in the control group (p < 0.01). Mean (±SEM) MD slopes for total observational periods were -0.49 ± 0.17 dB/year in the treated group and -0.89 ± 0.16 dB/year in the control group (mean ± SEM, p = 0.042). CONCLUSION: Nilvadipine at 4 mg/day significantly retarded progression of central visual field defects in RP in this small patient series.


Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Nifedipino/análogos & derivados , Retinitis Pigmentosa/tratamiento farmacológico , Trastornos de la Visión/prevención & control , Campos Visuales/efectos de los fármacos , Administración Oral , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Luteína/análogos & derivados , Luteína/uso terapéutico , Masculino , Persona de Mediana Edad , Nifedipino/uso terapéutico , Proyectos Piloto , Estudios Prospectivos , Retinitis Pigmentosa/fisiopatología , Tocoferoles/uso terapéutico , Trastornos de la Visión/fisiopatología , Pruebas del Campo Visual , Campos Visuales/fisiología , Adulto Joven
6.
J Nutr ; 140(10): 1824-31, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20739451

RESUMEN

Fucoxanthin, a xanthophyll present in brown algae consumed in Eastern Asia, can suppress carcinogenesis and obesity in rodents. We investigated the metabolism, tissue distribution, and depletion of fucoxanthin in ICR mice by comparison with those of lutein. The experiments comprised 14-d dietary supplementation with lutein esters or fucoxanthin, followed by 41- or 28-d, respectively, depletion periods with carotenoid-free diets. After lutein ester supplementation, 3'-hydroxy-ε,ε-caroten-3-one and lutein were the predominant carotenoids in plasma and tissues, accompanied by ε,ε-carotene-3,3'-dione. The presence of these keto-carotenoids in mouse tissues is reported here for the first time, to our knowledge. Lutein and its metabolites accumulated most in the liver (7.51 µmol/kg), followed by plasma (2.11 µmol/L), adipose tissues (1.01-1.44 µmol/kg), and kidney (0.87 µmol/kg). The half-life of the depletion (t(1/2)) of lutein metabolites varied as follows: plasma (1.16 d) < liver (2.63 d) < kidney (4.44 d) < < < adipose tissues (>41 d). Fucoxanthinol and amarouciaxanthin A were the main metabolites in mice fed fucoxanthin and partitioned more into adipose tissues (3.13-3.64 µmol/kg) than into plasma, liver, and kidney (1.29-1.80 µmol/kg). Fucoxanthin metabolites had shorter t(1/2) in plasma, liver, and kidneys (0.92-1.23 d) compared with those of adipose tissues (2.76-4.81 d). The tissue distribution of lutein and fucoxanthin metabolites was not associated with their lipophilicity, but depletion seemed to be slower for more lipophilic compounds. We concluded that mice actively convert lutein and fucoxanthin to keto-carotenoids by oxidizing the secondary hydroxyl groups and accumulate them in tissues.


Asunto(s)
Carotenoides/análisis , Luteína/análogos & derivados , Luteína/farmacocinética , Xantófilas/farmacocinética , Tejido Adiposo/química , Animales , Carotenoides/sangre , Suplementos Dietéticos , Ésteres/administración & dosificación , Semivida , Riñón/química , Hígado/química , Luteína/administración & dosificación , Luteína/análisis , Masculino , Ratones , Ratones Endogámicos ICR , Xantófilas/administración & dosificación
7.
J Nutr Biochem ; 21(2): 133-9, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19201183

RESUMEN

We assessed the bioavailability of lutein from lutein-fortified fermented milk using in vivo and in vitro approaches. Twenty-four volunteers were randomized to take lutein-fortified fermented milk at two levels of fortification. Single-dose bioavailability study (2x100 ml, ca. 8 or 16 mg of lutein) was performed using a three-point approach (baseline, 3.5 and 6.5 h). Multiple-dose study consisted of consuming one serving/day (ca. 4 or 8 mg/100 ml) for 14 days. Blood samples for biochemical, hematological and lutein analysis were drawn at baseline, Day 7 and Day 14. In vitro bioaccessibility was assessed by a static gastrointestinal digestion model. Lutein content, in vitro ester hydrolysis and micellarization, and lutein concentrations achieved in serum were analyzed by HPLC. In vivo, post-prandial response was higher using the high content fermented milk, but the percentage of absorption was not different according to the dose consumed. Net increments at Day 7 and Day 14 were significantly higher on consuming the high-dose milk as well. In vitro, lutein ester hydrolysis was incomplete regardless of the amount initially present. Free lutein released was higher using the high-dose fermented milk, but the percentage of hydrolysis was similar at both levels of fortification. In the micellar phase, the percentage of free and total lutein was not different according to the dose. Our results support the suitability of the fermented milk as a carrier of lutein esters and an in vivo dose-dependent effect upon regular consumption and suggest the usefulness of in vitro models to provide relevant information to predict in vivo responses.


Asunto(s)
Productos Lácteos Cultivados , Alimentos Funcionales , Luteína/farmacocinética , Adolescente , Adulto , Disponibilidad Biológica , Mezclas Complejas/administración & dosificación , Mezclas Complejas/metabolismo , Productos Lácteos Cultivados/química , Dieta , Digestión/efectos de los fármacos , Ésteres/administración & dosificación , Ésteres/metabolismo , Femenino , Alimentos Funcionales/análisis , Jugo Gástrico/metabolismo , Humanos , Hidrólisis , Luteína/análogos & derivados , Luteína/análisis , Luteína/sangre , Masculino , Micelas , Modelos Biológicos , Medición de Riesgo , Encuestas y Cuestionarios , Adulto Joven
8.
Artículo en Inglés | MEDLINE | ID: mdl-18582588

RESUMEN

Lutein and zeaxanthin are xanthophylls that can be found highly concentrated in the macula of the retina. They are thought to protect the macula through their role as blue-light filters and because of their antioxidant and singlet oxygen quenching properties. Examination of metabolites unique to lutein and zeaxanthin such as 3'-dehydro-lutein, and of their stereochemistry may provide insight to the mechanism by which they are formed and by which they exert protection. To evaluate the formation of such metabolites, eleven monkeys were raised on a xanthophyll-free diet, and supplemented with pure lutein or pure zeaxanthin (2.2 mg/kg body weight/d). The period of supplementation ranged between 12 and 92 weeks. At study start and throughout the study, serum samples were taken and analyzed for xanthophylls using different HPLC systems. Xanthophyll metabolites were identified using UV/VIS and HR-MS detection. Lutein and zeaxanthin metabolites were found in detectable amounts with 3'-dehydro-lutein being a common metabolite of both. Using chiral-phase HPLC, two diastereomers, (3R,6'R)-3'-dehydro-lutein and (3R,6'S)-3'-dehydro-lutein, were identified and shown to be present in nearly equimolar amounts. A pathway for their formation from either lutein or zeaxanthin is proposed. These findings were comparable to results obtained with human plasma.


Asunto(s)
Luteína/análogos & derivados , Luteína/metabolismo , Macaca mulatta/metabolismo , Xantófilas/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Dieta , Suplementos Dietéticos , Humanos , Luteína/sangre , Macaca mulatta/sangre , Espectrometría de Masas , Xantófilas/sangre , Zeaxantinas
9.
J Nat Prod ; 66(1): 67-72, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12542348

RESUMEN

Two dietary carotenoids, (3R,3'R,6'R)-lutein (1) and (3R,3'R)-zeaxanthin (2), and their metabolite (3R,3'S,6'R)-lutein (3'-epilutein) (3) accumulate in human serum, milk, and ocular tissues. There is increasing evidence that compounds 1 and 2 play an important role in the prevention of age-related macular degeneration. Therefore, the availability of these carotenoids for metabolic studies and clinical trials is essential. Compound 1 is isolated from extracts of marigold flowers (Tagete erecta) and is commercially available, whereas 2 is only accessible by a lengthy total synthesis, and a viable method for synthesis of 3 has not yet been developed. This report describes an efficient conversion of technical grade 1 to 2 via 3. Acid-catalyzed epimerization of 1 yields an equimolar mixture of diastereomers 1 and 3. The mixture was separated by enzyme-mediated acylation with lipase AK from Pseudomonas fluorescens that preferentially esterified 3 and after alkaline hydrolysis yielded this carotenoid in 90% diastereomeric excess (de). Compound 3 was also separated from 1 in 56-88% de by solvent extraction and low-temperature crystallization, Soxhlet extraction, or supercritical fluid extraction. Base-catalyzed isomerization of 3 gave 2 in excellent yield, providing a convenient alternative to the total synthesis of this important dietary carotenoid.


Asunto(s)
Carotenoides/metabolismo , Luteína/química , Luteína/metabolismo , Plantas Medicinales/química , Tagetes/química , beta Caroteno/análogos & derivados , Biotransformación , Carotenoides/análisis , Carotenoides/química , Cromatografía Líquida de Alta Presión , Suplementos Dietéticos , Flores , Humanos , Lipasa/metabolismo , Luteína/análogos & derivados , Luteína/análisis , Degeneración Macular/prevención & control , Espectrometría de Masas , Leche Humana/química , Estructura Molecular , Plasma/química , Pseudomonas fluorescens/enzimología , Espectrofotometría Ultravioleta , Estereoisomerismo , Xantófilas , Zeaxantinas , beta Caroteno/metabolismo
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