RESUMEN
OBJECTIVES: To assess the association between biomarkers of thyroid status and 5α-stanols in patients with sitosterolemia treated with ezetimibe (EZE). STUDY DESIGN: Eight patients with sitosterolemia (16-56 years of age) were studied during 14 weeks off EZE therapy and 14 weeks on EZE (10 mg/day). Serum thyroid biomarkers (free triiodothyronine [FT3], free thyroxine [FT4], FT3/FT4 ratio, thyroid-stimulating hormone), 5α-stanols (sitostanol and cholestanol), and cholestanol precursors (total cholesterol and its synthesis marker lathosterol, and 7α-hydroxy-4-cholesten-3-one cholestenol) were measured at baseline and during the 14 weeks off EZE and on EZE. RESULTS: EZE increased FT3/FT4 (10% ± 4%; P = .02). EZE reduced plasma and red blood cells sitostanol (-38% ± 6% and -20% ± 4%; all P < .05) and cholestanol (-18% ± 6% and -13% ± 3%; all P < .05). The change in plasma cholestanol level on EZE inversely correlated with the change in FT3/FT4 (r = -0.86; P = .01). EZE lowered total cholesterol (P < .0001) and did not affect 7α-hydroxy-4-cholesten-3-one cholestanol. EZE increased (P < .0001) lathosterol initially, but the level was not sustained, resulting in similar levels at week 14 off EZE and on EZE. CONCLUSION: In patients with STSL, 5α-stanols levels might be associated with thyroid function. EZE reduces circulating 5α-stanols while increasing FT3/FT4, implying increased conversion of T4 to T3, thus possibly improving thyroid hormone status. TRIAL REGISTRATION: ClinicalTrials.govNCT01584206.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Ezetimiba/uso terapéutico , Hipercolesterolemia/sangre , Hipercolesterolemia/tratamiento farmacológico , Enfermedades Intestinales/sangre , Enfermedades Intestinales/tratamiento farmacológico , Errores Innatos del Metabolismo Lipídico/sangre , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Fitosteroles/efectos adversos , Adolescente , Adulto , Colestanol/sangre , Colestenonas/sangre , Colesterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fitosteroles/sangre , Sitoesteroles/sangre , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangre , Adulto JovenRESUMEN
Mineralization of the skeleton starts within cell-derived matrix vesicles (MVs); then, minerals propagate to the extracellular collagenous matrix. Tissue-nonspecific alkaline phosphatase (TNAP) degrades inorganic pyrophosphate (PPi), a potent inhibitor of mineralization, and contributes Pi (Phosphate) from ATP to initiate mineralization. Compared to the plasma membrane, MVs are rich in Cholesterol (Chol) (â¼32%) and TNAP, but how Chol influences TNAP activity remains unclear. We have reconstituted TNAP in liposomes of dipalmitoylphosphatidylcholine (DPPC) or dioleoylphosphatidylcholine (DOPC) combined with Chol or its derivatives Cholestenone (Achol) and Ergosterol (Ergo). DPPC plus 36% sterols in liposome increased the catalytic activity of TNAP toward ATP. The presence of Chol also increased the propagation of minerals by 3.4-fold. The catalytic efficiency of TNAP toward ATP was fourfold lower in DOPC proteoliposomes as compared to DPPC proteoliposomes. DOPC proteoliposomes also increased biomineralization by 2.8-fold as compared to DPPC proteoliposomes. TNAP catalyzed the hydrolysis of ATP more efficiently in the case of the proteoliposome consisting of DOPC with 36% Chol. The same behavior emerged with Achol and Ergo. The organization of the lipid and the structure of the sterol influenced the surface tension (γ), the TNAP phosphohydrolytic activity in the monolayer, and the TNAP catalytic efficiency in the bilayers. Membranes in the Lα phase (Achol) provided better kinetic parameters as compared to membranes in the Lo phase (Chol and Ergo). In conclusion, the physical properties and the lateral organization of lipids in proteoliposomes are crucial to control mineral propagation mediated by TNAP activity during mineralization.
Asunto(s)
Fosfatasa Alcalina/metabolismo , Calcificación Fisiológica , Microambiente Celular , Colesterol/química , Minerales/metabolismo , 1,2-Dipalmitoilfosfatidilcolina/química , 1,2-Dipalmitoilfosfatidilcolina/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Células Cultivadas , Colestenonas/química , Colestenonas/metabolismo , Colesterol/metabolismo , Difosfatos/química , Difosfatos/metabolismo , Ergosterol/química , Ergosterol/metabolismo , Liposomas/química , Liposomas/metabolismo , Masculino , Osteoblastos/citología , Osteoblastos/metabolismo , Fosfatos/química , Fosfatos/metabolismo , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Ratas Wistar , Propiedades de SuperficieRESUMEN
OBJECTIVE: To establish age-related reference values for 7-alpha-hydroxy-4-cholesten-3-one (C4) in a pediatric population and to investigate bile acid malabsorption in children with short bowel syndrome (SBS). STUDY DESIGN: Serum was obtained between 8:00 a.m. and 11:00 a.m. from 100 healthy children (52% males, 9 months to 18 years of age) after 10 hours of fasting. Pediatric patients with SBS served as disease controls (n = 12). Following solid-phase extraction and purification, C4 was determined by high-performance liquid chromatography using a ultraviolet detector at a wavelength of 241 nm. The upper limit of normal for C4 concentrations was defined as the mean plus 2 SD of the log-normal distribution. RESULTS: The mean concentration and SD of C4 in healthy children was 22.8 ± 15.8 ng/mL with no relation to age or sex and an upper limit of normal of 66.5 ng/mL. Normal C4 values were found in 97 of 100 healthy children, and all 12 patients with SBS had C4 concentrations above 100 ng/mL (mean 299.6 ± 167.8 ng/mL; range 105.7-562.1 ng/mL, P < .0001 compared with controls). CONCLUSIONS: The determined upper limit of normal for C4 concentration in healthy children corresponds to previously published levels in healthy adults and is independent of age and sex. The consistently elevated C4 concentrations in our patients with SBS confirm the reliability of this noninvasive, nonisotopic method to assess bile acid malabsorption in children.
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Ácidos y Sales Biliares/metabolismo , Colestenonas/sangre , Síndromes de Malabsorción/sangre , Síndrome del Intestino Corto/sangre , Adolescente , Factores de Edad , Biomarcadores/sangre , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Lactante , Masculino , Valores de ReferenciaRESUMEN
Many viral infections are associated with the development of immunopathologies and autoimmune diseases, which are of difficult treatment and for which no vaccines are yet available. Obtaining compounds that conjugate both antiviral and immunomodulatory activities in the same molecule would be very useful for the prevention and/or treatment of these immunopathologies. The compound (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) displays anti-Herpes simplex virus type 1 activity in vitro and reduces the incidence of herpetic stromal keratitis (HSK) in mice, a chronic inflammatory syndrome induced by ocular HSV-1 infection. In the present study, compound 1 showed opposite immunomodulatory properties in vitro. It induced the release of pro-inflammatory cytokines in HSV-1-infected epithelial cells of ocular origin, and significantly reduced the production of these cytokines in LPS-activated macrophages. RNA microarrays revealed various overexpressed and repressed genes in compound 1 treated infected epithelial cells and activated macrophages, many of which are associated with innate immune responses and inflammatory processes. These immunomodulatory properties of compound 1, together with its previously reported antiviral activity, make it a potential drug for the treatment of HSK and many other immunopathologies of viral and non-viral origin.
Asunto(s)
Antivirales/farmacología , Colestenonas/química , Herpesvirus Humano 1/efectos de los fármacos , Factores Inmunológicos/química , Estigmasterol/análogos & derivados , Animales , Antivirales/química , Antivirales/uso terapéutico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Colestenonas/farmacología , Colestenonas/uso terapéutico , Sustancia Propia/citología , Sustancia Propia/virología , Citocinas/genética , Citocinas/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Células Epiteliales/virología , Perfilación de la Expresión Génica , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Queratitis Herpética/tratamiento farmacológico , Queratitis Herpética/inmunología , Queratitis Herpética/veterinaria , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Estigmasterol/química , Estigmasterol/farmacología , Estigmasterol/uso terapéutico , Activación Transcripcional/efectos de los fármacosRESUMEN
From the ethanolic extract of Lentinus edodes (Shiitake) eight known sterols were isolated and identified: ergosterol, ergosterol peroxide, (22E)-ergosta-5,7,9(11), 22-tetraen-3beta-ol, (22E)-ergosta-7,9(11),22-trien-3beta-ol, (22E)-ergosta-6,8,22-trien-3beta-ol, (22E)-norergosta-5,7,9,22-tetraen-3beta-ol, 3beta,5alpha-dihydroxy-(22E)-ergosta-7,22-dien-6-one, (22E)-ergosta-4,6,8(14),22-tetraen-3-one and, for the first time in mushrooms, (22E)-ergosta-6,22-diene-3beta,5alpha,8alpha-triol.
Asunto(s)
Hidroxiesteroides/química , Hidroxiesteroides/aislamiento & purificación , Fitosteroles/química , Fitosteroles/aislamiento & purificación , Hongos Shiitake/química , Colestenonas , Ergosterol/análogos & derivados , Ergosterol/química , Ergosterol/aislamiento & purificación , Estructura MolecularRESUMEN
Smallanthus sonchifolius is a traditional Andean plant which has been cultured mainly in Brazil, Japan and New Zealand due to its medicinal properties. A study of the endophytic fungi associated to the plant was carried out in order to characterize new cytotoxic agents. Thirty two fungal strains were isolated and submitted to cultivation and extraction producing 186 extracts. Of these, 12% displayed moderate to high cytotoxic activities and were considered promising anticancer compound sources. The ethyl acetate fractions of Nigrospora sphaerica and Phoma betae liquid fermentations contained the synergistic compounds 8-hydroxy-6-methoxy-3-methylisocoumarin and (22E,24R)-ergosta-4,6,8(14),22-tetraen-3-one which are potential compounds for drug discovery. Another isolated compound, pimara-7,15-dien-3-beta-ol diterpene is being characterized for the first time through a detailed spectroscopic analysis including GC/MS, homo- and hetero-nuclear correlated NMR experiments (HMQC, HMBC, COSY and NOEdiff) along with its optical rotation.
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Antineoplásicos/metabolismo , Ascomicetos/química , Asteraceae/microbiología , Abietanos/biosíntesis , Ascomicetos/aislamiento & purificación , Línea Celular Tumoral , Colestenonas/metabolismo , Descubrimiento de Drogas , Humanos , Isocumarinas/metabolismo , Estructura MolecularRESUMEN
BACKGROUND & AIMS: Gallstone disease is an important, costly health-care problem in Western societies. It is still unclear whether hepatic lipid regulatory enzymes play primary or secondary roles in gallstone formation. In this study, the aim was to investigate whether the synthesis of bile acids and cholesterol is increased in gallstone disease and to test whether such a metabolic change, if present, might occur before gallstone formation. METHODS: A total of 125 Chilean Hispanic women (80 without gallstones and 45 with gallstones) matched for age and body mass index were investigated, along with 40 Chilean Mapuche Indian women (20 without gallstones and 20 with gallstones), a population group in which the prevalence for gallstone disease is very high. Fasting blood plasma samples were assayed for 7 alpha-hydroxy-4-cholesten-3-one and lathosterol, 2 strong indicators for hepatic bile acid and body cholesterol synthesis, respectively. RESULTS: Plasma 7 alpha-hydroxy-4-cholesten-3-one levels, corrected for plasma cholesterol, were significantly increased by 50% in Hispanic women with gallstones as compared with gallstone-free Hispanics (P < 0.006). As compared with Hispanic women without gallstones, plasma 7 alpha-hydroxy-4-cholesten-3-one levels were increased by > or =100% (P < 0.002) in Mapuche Indian women, independently of whether gallstones were present. Plasma lathosterol, corrected for plasma cholesterol, was significantly increased by 22% in Hispanic women with gallstones and in Mapuche Indian women compared with Hispanic women. CONCLUSIONS: The results indicate that the synthesis of bile acids and cholesterol is induced in gallstone disease and precedes gallstone development. These inductions presumably occur as a response to an increased intestinal loss of bile acids.
Asunto(s)
Ácidos y Sales Biliares/biosíntesis , Cálculos Biliares/etiología , Hispánicos o Latinos , Adulto , Estudios de Casos y Controles , Chile/etnología , Colestenonas/sangre , Colesterol/sangre , Femenino , Cálculos Biliares/sangre , Humanos , Indígenas Sudamericanos , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Assay-guided fractionation of the ethanol extract of the twigs and leaves of Miconia trailii yielded two new flavanone glycosides, matteucinol 7-O-alpha-l-arabinopyranosyl(1-->6)-beta-d-glucopyranoside (miconioside A, 1) and farrerol 7-O-beta-d-apiofuranosyl(1-->6)-beta-d-glucopyranoside (miconioside B, 2), along with the known compounds matteucinol 7-O-beta-d-apiofuranosyl(1-->6)-beta-d-glucopyranoside (3), matteucinol (4), 2alpha,3beta,19alpha-trihydroxyolean-12-ene-24,28-dioic acid (bartogenic acid, 5), 2alpha,3beta,23-trihydroxyolean-12-ene-28-oic acid (arjunolic acid, 6), 2alpha,3alpha,19alpha, 23-tetrahydroxyurs-12-ene-28-oic acid (myrianthic acid, 7), and stigmast-4-ene-3,6-dione (8). The structures of 1-8 were elucidated by spectroscopic methods, including 2D NMR.
Asunto(s)
Flavonoides/aislamiento & purificación , Glicósidos/aislamiento & purificación , Melastomataceae/química , Plantas Medicinales/química , Colestenonas/química , Colestenonas/aislamiento & purificación , Cromonas/química , Cromonas/aislamiento & purificación , Flavonoides/química , Glicósidos/química , Hidrólisis , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Perú , EstereoisomerismoRESUMEN
Two new sulfated steroidal hexaglycosides, anasterosides A (2) and B (3), along with the known versicoside A (1) have been isolated from the Patagonian starfish Anasterias minuta. Their structures have been elucidated by spectroscopic analysis (NMR and FABMS) and chemical transformations. Compounds 1 and 2 and the synthetic pentaglycoside 1b derived from versicoside A showed antifungal activity against the plant pathogenic fungus Cladosporium cucumerinum. Desulfation of hexaglycoside 1 rendered a totally inactive saponin.