RESUMEN
BACKGROUND: Male EBP disorder with neurologic defects (MEND) syndrome is an X-linked disease caused by hypomorphic mutations in the EBP (emopamil-binding protein) gene. Modifier genes may explain the clinical variability among individuals who share a primary mutation. METHODS: We studied four males (Patient 1 to Patient 4) exhibiting a descending degree of phenotypic severity from a family with MEND syndrome. To identify candidate modifier genes that explain the phenotypic variability, variants of homeostasis cholesterol genes identified by whole-exome sequencing (WES) were ranked according to the predicted magnitude of their effect through an in-house scoring system. RESULTS: Twenty-seven from 105 missense variants found in 45 genes of the four exomes were considered significant (-5 to -9 scores). We found a direct genotype-phenotype association based on the differential accumulation of potentially functional gene variants among males. Patient 1 exhibited 17 variants, both Patients 2 and 3 exhibited nine variants, and Patient 4 exhibited only five variants. CONCLUSION: We conclude that APOA5 (rs3135506), ABCA1 (rs9282541), and APOB (rs679899 and rs12714225) are the most relevant candidate modifier genes in this family. Relative accumulation of the deficiencies associated with variants of these genes along with other lesser deficiencies in other genes appears to explain the variable expressivity in MEND syndrome.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Apolipoproteína A-V , Apolipoproteína B-100 , Colesterol , Exoma , Polimorfismo Genético , Síndrome de Waardenburg , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Apolipoproteína A-V/genética , Apolipoproteína A-V/metabolismo , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Colesterol/genética , Colesterol/metabolismo , Femenino , Estudios de Asociación Genética , Homeostasis/genética , Humanos , Masculino , Fenotipo , Índice de Severidad de la Enfermedad , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/metabolismo , Síndrome de Waardenburg/patologíaRESUMEN
ETNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels is a plant widely used in folk medicine to treat diabetes mellitus (DM). The tea from its leaves is frequently used by diabetics for lowering hyperglycemia. There is a close relationship between DM and atherosclerosis, a chronic immuno-inflammatory disease, were the early stages encompass oxidative and glycative modifications in the structure of low density lipoprotein (LDL). AIM OF THIS STUDY: To investigate the potential protective effects of aqueous-leaf extract from Syzygium cumini (S.cExt) against CuSO4-induced oxidation and methylglyoxal (MG)-induced glycation of human LDL in vitro. MATERIALS AND METHODS: LDL oxidative changes were evaluated by measuring conjugated dienes (CD) formation, thiobarbituric acid reactive substances (TBARS) levels, quenching of tryptophan (Trp) fluorescence and structural modifications in LDL particle. In LDL glycated by MG (glyLDL), we determined the levels of fluorescent advanced glycation end products (AGEs) and mobility by agarose gel electrophoresis. RESULTS: S.cExt blocked oxidative events induced by CuSO4 in human LDL, plasma and serum. Fourier transform infrared spectroscopy (FT-IR) revealed that specific regions of apoB100 were oxidized by CuSO4 in human LDL and that S.cExt reduced these oxidations. Unlike, the increased AGEs levels and eletrophoretic mobility observed in LDL MG-glycated were not modified by S.cExt. CONCLUSION: The findings herein indicate that S.cExt could be tested in atherogenesis models as potential protective agent against LDL oxidation.
Asunto(s)
Lipoproteínas LDL/metabolismo , Extractos Vegetales/farmacología , Syzygium/química , Apolipoproteína B-100/metabolismo , Sulfato de Cobre/administración & dosificación , Electroforesis en Gel de Agar , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Medicina Tradicional , Oxidación-Reducción , Hojas de la Planta , Espectroscopía Infrarroja por Transformada de Fourier , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Atherosclerosis is a pathology leading to cardiovascular diseases with high epidemiologic impact; thus, new therapies are required to fight this global health issue. Immunotherapy is a feasible approach to treat atherosclerosis and given that genetically engineered plants are attractive hosts for vaccine development; we previously proved that the plant cell is able to synthesize a chimeric protein called CTB:p210:CETPe, which is composed of the cholera toxin B subunit (CTB) as immunogenic carrier and target epitopes from the cholesteryl ester transfer protein (CETP461-476) and apolipoprotein B100 (p210). Since CTB:p210:CETPe was expressed in tobacco at sufficient levels to evoke humoral responses in mice, its expression in carrot was explored in the present study looking to develop a vaccine in a safe host amenable for oral delivery; avoiding the purification requirement. Carrot cell lines expressing CTB:p210:CETPe were developed, showing accumulation levels up to 6.1 µg/g dry weight. An immunoblot analysis revealed that the carrot-made protein is antigenic and an oral mice immunization scheme led to evidence on the immunogenic activity of this protein; revealing its capability of inducing serum IgG responses against p210 and CETP epitopes. This study represents a step forward in the development of an attractive oral low-cost vaccine to treat atherosclerosis.
Asunto(s)
Aterosclerosis/inmunología , Vacunas/inmunología , Administración Oral , Animales , Apolipoproteína B-100/metabolismo , Aterosclerosis/prevención & control , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Daucus carota/genética , Daucus carota/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Vacunación , Vacunas/administración & dosificaciónRESUMEN
Nonalcoholic fatty liver disease is currently one of the most common forms of liver disease, covering cases from simple steatosis without inflammation, to cases of steatohepatitis and fibrosis, and may lead to liver cirrhosis and hepatocellular carcinoma. The pathophysiology of nonalcoholic fatty liver disease is based on multiple events; changes in the secretion of lipoproteins can lead to steatosis. Liver lipid secretion is mediated by apoB100 and microsomal triglyceride transfer protein (MTP). The pharmacological suppression of MTP is suggested as a possible treatment for hyperlipidemia, although the upregulation of this protein can be a treatment for nonalcoholic steatohepatitis.
Asunto(s)
Proteínas Portadoras/metabolismo , Animales , Apolipoproteína B-100/metabolismo , Proteínas Portadoras/genética , Ácidos Grasos/biosíntesis , Hígado Graso/metabolismo , Hígado Graso/fisiopatología , Insulina/metabolismo , Metabolismo de los Lípidos , Lipoproteínas/metabolismo , Hígado/metabolismo , Hígado/fisiopatología , Cirrosis Hepática/metabolismo , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico , Polimorfismo Genético , Transducción de SeñalRESUMEN
Oxidative modifications in lipoproteins (LP), especially in low-density lipoproteins (LDL), are associated with initiation and progression of atherosclerosis. The levels of a sub-fraction of LDL with oxidative characteristics, named electronegative LDL [LDL(-)], minimally oxidized LDL, and minus LDL, are known to be increased in subjects with familial hypercholesterolemia, hypertriglyceridemia, nonalcoholic steatohepatitis, diabetes mellitus, coronary artery disease, patients undergoing hemodialysis, and athletes after aerobic exercise. In addition to the oxidative profile, physical and biological characteristics of LDL(-) consist of nonenzymatic glycosylation, increased expression and activity of platelet-activating factor acetylhydrolase (PAF-AH) and phospholipase A(2) (PLA(2)), enriched NEFA content, hemoglobin and ApoB-100 cross-linking, and increase in ApoC-III and ApoE in LDL. Herein, we summarize the state of the art of the up-to-date body of knowledge on the possible origin and impact of LDL(-) in health and disease. Further, the potential perspectives of using LDL(-) as a biomarker in conditions under metabolic stress are also discussed.
Asunto(s)
Lipoproteínas LDL/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Apolipoproteína B-100/metabolismo , Apolipoproteína C-III/metabolismo , Apolipoproteínas E/metabolismo , Humanos , Lipoproteínas LDL/química , Lipoproteínas LDL/inmunología , Oxidación-ReducciónRESUMEN
Se realizó una revisión de la bibliografía actual relacionada con el tema de las lipoproteínas y los factores de riesgo cardiovasculares con el objetivo de ofrecer una aproximación a la comprensión de los factores de riesgo relacionados con las enfermedades cardiovasculares. El perfil de riesgo cardiovascular se ha calculado, principalmente, por la Organización Mundial de la Salud, el estudio Framingham y a través de la razón ApoB/ApoA1. La Organización Mundial de la Salud ha elaborado una guía que integra los factores de riesgo para predecir un evento cardiovascular en los 10 años siguientes a la evaluación del enfermo. El estudio Framingham permitió identificar factores de riesgo mayores (hábito de fumar, hipertensión arterial, niveles elevados de colesterol total, bajos niveles de HDL colesterol, aumento de lipoproteína de baja densidad, diabetes mellitus y edad avanzada) y factores de riesgo no mayores (obesidad, sedentarismo, antecedentes familiares de enfermedad coronaria prematura, hipertrigliceridemia y aumento de la lipoproteína A). La razón ApoB/ApoA1 es un marcador predictivo de eventos mortales por enfermedad cardiovascular. Se concluye que los factores de riesgo no inducidos en las tablas de la Organización Mundial de la Salud y en el estudio Framingham pudieran modificar, incrementándolo, el índice de riesgo de enfermedad cardiovascular(AU)
A review of current bibliography was carried out related to the subject of lipoproteins and the cardiovascular risk factors. To offer a approximation to the understanding of the risk factors related to cardiovascular diseases. The cardiovascular risk profile has been estimated, mainly by WHO, the Framingham study and through ApoB/Apo1 reason. The WHO has designed a guideline that includes the risk factor to predict a cardiovascular event in the following ten years to ill person assessment. The Farmingham study allowed identifying the greater risk factors (smoking, arterial high blood pressure, high levels of total cholesterol, low levels of HDL cholesterol, increase of low density lipoprotein (LDL), diabetes mellitus and old age) and no greater risk factors (obesity, sedentary state, family backgrounds of a premature coronary disease, hypertriglyceridemia and increase of A lipoprotein). The ApoB/ApoA1 reason is a predictive marker of mortal events from cardiovascular disease. We conclude that the risk factors not included in the tables of the WHO and the Framingham study may to modify increasing it, the cardiovascular disease risk rate(AU)