RESUMEN
Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Encéfalo/patología , Evaluación Preclínica de Medicamentos , Redes Reguladoras de Genes , Organoides/patología , Enfermedad de Alzheimer/genética , Cinamatos/farmacología , Cinamatos/uso terapéutico , Redes Reguladoras de Genes/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Modelos Biológicos , Reproducibilidad de los Resultados , Factores de RiesgoRESUMEN
OBJECTIVE: We investigated the effect and regulatory mechanism of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) isolated from Cleistocalyx operculatus on metabolic parameters in myotubes, adipocytes and an obese mouse model. MATERIALS AND METHODS: Myotubes and adipocytes were incubated with or without DMC. Glucose uptake, fatty acid oxidation, AMPK activation and adipocytes differentiation were investigated. To examine in vivo effect of DMC, 30mg/kg/day DMC was administered by oral gavage for 2weeks in high fat fed C57BL/6 male mice and intra-peritoneal glucose tolerance test was performed. In order to examine whether DMC directly activates AMPK, we performed cell free AMPK assay and surface plasmon resonance spectroscopy analysis. RESULT: DMC increases glucose uptake and fatty acid oxidation (FAO) in myotubes. Also, DMC inhibits adipocyte differentiation in 3T3-L1 cells. Interestingly, DMC stimulates phosphorylation of AMP-dependent protein kinase (AMPK) alpha subunit (T172) by directly binding to AMPK, which results in the activation of AMPK. Furthermore, DMC binds AMPK with a higher affinity than AMP. When AMPK was knocked down, the stimulatory effect of DMC on FAO and its inhibitory effect on adipogenesis were abolished. These results suggest that the effects of DMC were primarily mediated by AMPK activation. In addition, treating mice fed a high fat diet with DMC improved glucose tolerance and significantly increased FAO of the muscles. CONCLUSION: DMC, as a novel AMPK activator, shows anti-diabetic effects in cell culture systems, such as myotubes and adipocytes, and in a diet-induced obese mouse model.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Chalconas/uso terapéutico , Activadores de Enzimas/uso terapéutico , Intolerancia a la Glucosa/tratamiento farmacológico , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Animales , Diferenciación Celular , Células Cultivadas , Chalconas/aislamiento & purificación , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Masculino , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/efectos de los fármacos , Obesidad/metabolismo , Syzygium/químicaRESUMEN
Soluble oligomeric forms of amyloid beta (AßO) are regarded as a main cause of synaptic and cognitive dysfunction in Alzheimer's disease (AD) and have been a primary target in the development of drug treatments for AD. The present study utilized a mouse model of AD induced by intrahippocampal injection of AßO (10 µM) to investigate the effects of Gami-Chunghyuldan (GCD), a standardized multi-herbal medicinal formula, on the presentation of memory deficits and neurohistological pathogenesis. GCD (10 and 50mg/kg/day, 5 days, p.o.) improved AßO-induced memory impairment as well as reduced neuronal cell death, astrogliosis, and microgliosis in the hippocampus. In addition, GCD prevented AßO-triggered synaptic disruption and cholinergic fiber loss. These results suggest that GCD may be useful in the prevention and treatment of AD.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Medicamentos Herbarios Chinos/farmacología , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Memoria/efectos de los fármacos , Degeneración Nerviosa/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Medicamentos Herbarios Chinos/uso terapéutico , Hipocampo/patología , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/patología , Ratones , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Sinapsis/efectos de los fármacos , Sinapsis/patologíaRESUMEN
Four new chromone glycosides allo-aloeresin D (2) , C-2'-decoumaroyl-aloeresin G (8), 2'-O-coumaroyl-(S)-aloesinol (9), 2'-O-[ P-methoxy-(E)-cinnamoyl]-(S)-aloesinol (10) and nine known chromone glycosides ( 1, 3 - 7, 11 - 13) were isolated from two Aloe spp. plants, A. vera and A. nobilis. Among them, 1 and 8 showed significant inhibitory activity against BACE1 (beta-secretase) with IC (50) values of 39.0 and 20.5 x 10 (-6) M, as well as inhibition of Abeta (1-42) production by 7.4 and 12.3 %, respectively, in B103 neuroblastoma cells at 30 ppm. The preliminary structure-activity relationships of ALOE chromone glucosides were also discussed.
Asunto(s)
Aloe/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Cromonas/aislamiento & purificación , Glicósidos/aislamiento & purificación , Cromonas/química , Glicósidos/química , Estructura MolecularRESUMEN
Beta amyloid (Abeta) is believed one of the major pathogens of Alzheimer's disease (AD), and the reduction of Abeta is considered a primary therapeutic target. Immunization with Abeta can reduce Abeta burden and pathological features in transgenic AD model mice. Transgenic potato plants were made using genes encoding 5 tandem repeats of Abeta1-42 peptides with an ER retention signal. Amyloid precursor protein transgenic mice (Tg2576) fed with transgenic potato tubers with adjuvant showed a primary immune response and a partial reduction of Abeta burden in the brain. Thus, Abeta tandem repeats can be expressed in transgenic potato plants to form immunologically functional Abeta, and these potatoes has a potential to be used for the prevention and treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/uso terapéutico , Solanum tuberosum/genética , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/aislamiento & purificación , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/farmacología , Animales , Encéfalo/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Escherichia coli/genética , Humanos , Inmunización , Isoleucina/metabolismo , Ratones , Ratones Transgénicos , Modelos Biológicos , Datos de Secuencia Molecular , Plantas Modificadas Genéticamente , Placa Amiloide/genética , Placa Amiloide/patología , Solanum tuberosum/metabolismo , Secuencias Repetidas en Tándem/genética , Factores de Tiempo , Vacunas/uso terapéuticoRESUMEN
We tested the constituents of two Rhodiola plants, Rhodiola sacra S. H. Fu and R. sachalinensis A. BOR, and an Oriental crude drug, Tokaku-joki-to, for their neuroprotective effects. Of the 58 compounds tested, six had considerable protective effects against beta-amyloid-induced death of B103 neuronal cells in vitro. These six compounds also showed protective effects against staurosporine-induced cell death, and two of the six compounds protected neurons from H2O2-induced cell death. These results suggest that some of the tested compounds protect neurons from beta-amyloid toxicity based on antiapoptotic and antioxidative activity.