ABSTRACT
The accumulation of amyloid-ß protein (Aß) in brain is linked to the early pathogenesis of Alzheimer's disease (AD). We previously reported that neuron-derived exosomes promote Aß clearance in the brains of amyloid precursor protein transgenic mice and that exosome production is modulated by ceramide metabolism. Here, we demonstrate that plant ceramides derived from Amorphophallus konjac, as well as animal-derived ceramides, enhanced production of extracellular vesicles (EVs) in neuronal cultures. Oral administration of plant glucosylceramide (GlcCer) to APP overexpressing mice markedly reduced Aß levels and plaque burdens and improved cognition in a Y-maze learning task. Moreover, there were substantial increases in the neuronal marker NCAM-1, L1CAM, and Aß in EVs isolated from serum and brain tissues of the GlcCer-treated AD model mice. Our data showing that plant ceramides prevent Aß accumulation by promoting EVs-dependent Aß clearance in vitro and in vivo provide evidence for a protective role of plant ceramides in AD. Plant ceramides might thus be used as functional food materials to ameliorate AD pathology.
Subject(s)
Alzheimer Disease/drug therapy , Amorphophallus/chemistry , Amyloid beta-Peptides/genetics , Extracellular Vesicles/metabolism , Glucosylceramides/adverse effects , Administration, Oral , Alzheimer Disease/genetics , Alzheimer Disease/psychology , Amyloid beta-Peptides/metabolism , Animals , Brain/cytology , CD56 Antigen/metabolism , Disease Models, Animal , Glucosylceramides/chemistry , Glucosylceramides/pharmacology , Maze Learning/drug effects , Mice , Mice, Transgenic , Neural Cell Adhesion Molecule L1/metabolism , Plant Extracts/chemistryABSTRACT
Background: The aim of this double-blind randomized cross-over trial was to evaluate the effect of oral intake of glucosylceramide extracted from pineapple on oral moisture and xerostomia symptoms. Methods: Sixteen participants who had xerostomia symptoms were randomly allocated into two groups. One group received, as test samples, tablets containing glucosylceramide extracted from pineapple (GCP) followed by placebo tablets. The other group received the test samples in the reverse order. Participants were instructed to take tablets of the first test sample once a day (after breakfast) for two consecutive weeks. Then, after a washout period of four weeks, participants were instructed to take the other test sample for two consecutive weeks. The oral moisture level of the lingual mucosa, xerostomia symptoms, and the number of fungiform papillae was evaluated. Results: The oral moisture significantly increased, and the visual analog scale (VAS) of "How is the dryness of your mouth?" significantly improved after GCP tablets intake and not after placebo tablets intake. The number of fungiform papillae was not significantly different following the intake of GCP tablets or placebo tablets. Conclusion: Results suggested that oral intake of GCP may improve the moisture level and xerostomia symptoms.
Subject(s)
Ananas/chemistry , Fruit/chemistry , Glucosylceramides/administration & dosage , Plant Extracts/administration & dosage , Xerostomia/drug therapy , Administration, Oral , Aged , Aged, 80 and over , Cross-Over Studies , Double-Blind Method , Glucosylceramides/adverse effects , Glucosylceramides/isolation & purification , Humans , Japan , Plant Extracts/adverse effects , Plant Extracts/isolation & purification , Prospective Studies , Recovery of Function , Tablets , Time Factors , Treatment Outcome , Xerostomia/diagnosis , Xerostomia/physiopathologyABSTRACT
Las enfermedades por depósito, representan un amplio espectro clínico de enfermedades. Una de las más frecuentes es la enfermedad de Gaucher, cuyo defecto primordial radica en el almacenamiento de glucosilceramida. Su prevalencia es 1/100.000 habitantes en países del Medio Oriente. En Suramérica es tan infrecuente que no se cuenta con estadísticas claras. Presentamos un paciente de 21 años de edad con antecedentes de diabetes mellitus tipo 1, quien inicia clínica 6 meses previos a su ingreso caracterizado por dolor en hipocondrio derecho, difuso, de moderada intensidad, intermitente, con periodos de acalmia de hasta 10 días, acompañado de náuseas, astenia, hiporexia y adinamia. Durante su hospitalización se realizan estudios de imagen que muestran hepatoesplenomegalia (homogénea) y en el laboratorio se encontraron transaminasas elevadas, anemia persistente y niveles de glucemia variables. Se realizan biopsias hepática y de medula ósea, compatibles con enfermedad por depósito tipo Gaucher. . Esta enfermedad es poco conocida en nuestro país, siendo la de mayor incidencia la enfermedad de Fabry. Se debe considerar la coexistencia con otras enfermedades metabólicas como diabetes tipo 1, que pudieran condicionar su aparición(AU)
Storage diseases represent a broad clinical spectrum. Gaucher´s disease, in which the primary defect lies in the storage of glucosylceramide has a prevalence of 1/100.000 in countries of the Middle East. In South America this disease is so infrequent, that there is no clear information about the prevalence. We present the case a 21-year old patient, with diabetes mellitus type 1 and a history of intermittent abdominal pain in the right hypochondrium, moderate intensity, nausea, asthenia, and hyporexia. The image studies showed homogeneous hepatosplenomegaly. The laboratory workup reported elevated transaminases, persistent anemia and fluctuating blood glucose levels. Hepatic and bone marrow biopsies were compatible with Gaucher type III disease. This disease is little known in our country, were Fabry´s disease is more common. Coexistence with other metabolic diseases such as diabetes should be considered(AU)
Subject(s)
Humans , Male , Adult , Diabetes Mellitus/genetics , Gaucher Disease/complications , Gaucher Disease/diagnostic imaging , Glucosylceramides/adverse effects , Genetic Diseases, InbornABSTRACT
CD1d-restricted natural killer T (NKT) cells are implicated in the pathogenesis of asthma. ß-Glucosylceramide (GC), a naturally occurring lipid, was previously shown to alter NKT cell distribution in the liver. We hypothesized that GC can affect lung and liver NKT cell distribution and ameliorate asthma. Mice were sensitized by intra-peritoneal injection of ovalbumin (OVA) for 2 weeks followed by repeated intranasal OVA challenges to induce lung injury mimicking asthma. OVA induced asthma groups were either treated by intranasal instillation of normal saline, intranasal instillation of GC or inhaled budesonide. To investigate the role of the liver, hepatic fibrosis was induced using carbon tetrachloride prior to asthma induction. Allergen induced bronchoconstriction was measured prior to sacrifice. Isolated lymphocytes from lungs, livers and spleens were analyzed for OVA induced proliferation and flow cytometry. Liver and lung histology, serum aminotransferase and anti-OVA antibodies level were assessed. Treatment with GC significantly reduced OVA induced airway responsiveness (p<0.001) similar to inhaled budesonide. GC significantly reduced the peri-bronchial and peri-vascular inflammatory infiltration mainly through an effect on T cells, as suggested by decreased T cell proliferation (p=0.009). Liver CD4 and NKT cells significantly increased after GC treatment suggesting liver involvement. Inducing hepatic fibrosis blunted the propagation of asthma in spite of sufficient increase of serum anti-OVA titers. GC has an immunomodulatory effect on a murine model of experimental asthma. We also suggest that the liver acts as an immunomodulatory organ and might have a regulatory effect on pulmonary diseases.
Subject(s)
Asthma/immunology , Glucosylceramides/administration & dosage , Liver Cirrhosis/immunology , Liver/metabolism , Lung/metabolism , Allergens/administration & dosage , Allergens/immunology , Animals , Asthma/chemically induced , Asthma/drug therapy , Asthma/pathology , Asthma/physiopathology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , Carbon Tetrachloride/administration & dosage , Cell Proliferation/drug effects , Cells, Cultured , Disease Models, Animal , Glucosylceramides/adverse effects , Immunomodulation , Liver/drug effects , Liver/immunology , Liver/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/pathology , Liver Cirrhosis/physiopathology , Lung/drug effects , Lung/immunology , Lung/pathology , Lymphocyte Activation/drug effects , Mice , Natural Killer T-Cells/drug effects , Natural Killer T-Cells/immunology , Natural Killer T-Cells/metabolism , Natural Killer T-Cells/pathology , Ovalbumin/administration & dosage , Ovalbumin/immunologyABSTRACT
INTRODUCTION: Parenteral OKT3 is used to treat transplant rejection and a humanized anti-CD3 Mab has shown positive clinical effects in new onset diabetes. Oral administration of anti-CD3 has not been tested in humans, but suppresses autoimmunity in animal models. Beta-glucosylceramide enhances NKT cell and regulatory T cell activity and enhances the effects of oral anti-CD3 in animals. MATERIALS AND METHODS: Fifteen healthy volunteers (three per group) received orally administered OKT3 over a dose range of 0.2 to 5.0 mg daily with or without beta-glucosylceramide 7.5 mg for 5 days. Safety and immune parameters were measured on days 5, 10, and 30. RESULTS AND DISCUSSION: Oral OKT3 enhanced T cell proliferation, suppressed Th1 and Th17 responses by 43% and 41%, respectively, increased TGF-beta/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells, and affected the IgG repertoire as measured by antigen arrays. Co-administration of oral beta-glucosylceramide induced similar effects. No side effects were observed and no subjects developed human anti-mouse antibodies. CONCLUSION: These findings demonstrate that oral anti-CD3 monoclonal antibody is safe and biologically active in humans and presents a new avenue for the treatment of autoimmune diseases.
