RESUMEN
OBJECTIVES: The pathogenesis of Alzheimer's disease (AD) is strongly correlated with the aggregation and deposition of the amyloid beta (Aß1-42) peptide in fibrillar form, and many studies have shown that plant-derived polyphenols are capable of attenuating AD progression in various disease models. In this study, we set out to correlate the effects of anthocyanoside extracts (Vaccinium myrtillus anthocyanoside (VMA)) obtained from bilberry on the in vitro progression of Aß fibril formation with the in vivo effects of this compound on AD pathogenesis. METHODS: Thioflavin T fluorescence assays and atomic force microscopy were used to monitor Aß amyloid formation in in vitro assays. Effects of Aß amyloids on cellular viability were assayed using cultured Neuro2a cells. Cognitive effects were probed using mice that simultaneously expressed mutant human Aß precursor and mutant presenilin-2. RESULTS: Addition of VMA inhibited the in vitro formation of Aß peptide fibrils and also reduced the toxicity of these aggregates toward Neuro2a cells. A diet containing 1% VMA prevented the cognitive degeneration in AD mice. Curiously, this diet-derived retention of cognitive ability was not accompanied by a reduction in aggregate deposition in brains; rather, an increase in insoluble deposits was observed compared with mice raised on a control diet. DISCUSSION: The paradoxical increase in insoluble deposits caused by VMA suggests that these polyphenols divert Aß aggregation to an alternate, non-toxic form. This finding underscores the complex effects that polyphenol compounds may exert on amyloid deposition in vivo.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Antocianinas/farmacología , Fragmentos de Péptidos/metabolismo , Extractos Vegetales/farmacología , Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/genética , Animales , Benzotiazoles , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Cognición/efectos de los fármacos , Trastornos del Conocimiento/prevención & control , Femenino , Humanos , Masculino , Ratones , Microscopía de Fuerza Atómica , Fragmentos de Péptidos/genética , Polifenoles/farmacología , Tiazoles/metabolismo , Vaccinium myrtillus/químicaRESUMEN
Chronic infection with hepatitis C virus (HCV) is a global public health burden. It has been only several decades since this virus was first identified. In the meantime, a lot of progress has been made in the fight against HCV. Although the development of pegylated interferon (PEG-IFN) and its combination with ribavirin (RBV) has significantly increased effectiveness of IFN-based treatment, candidate patients must be assessed for eligibility prior to the treatment due to side effects of the regimens and the rates of sustained virological response (SVR) were only around 50%. In 2011, the protease inhibitor (PI) Telaprevir was firstly approved as a direct-acting antiviral (DAA) for hepatitis C. The second generation of PIs was subsequently introduced and, by adding PI to Peg-IFN/RBV, the SVR rates were found to be raised to up to 80%. Further, with the recent approval of the NS5A inhibitors and the NS5B polymerase inhibitors and with the SVR rates reaching 90% or greater using IFN-free, DAA combination regimens, it is now expected that the majority of patients with chronic hepatitis C can be cured of infection in the near future.
Asunto(s)
Antivirales , Descubrimiento de Drogas/tendencias , Inhibidores Enzimáticos , Hepatitis C Crónica/tratamiento farmacológico , Oligopéptidos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Inhibidores Enzimáticos/uso terapéutico , Humanos , Interferón-alfa/uso terapéutico , Oligopéptidos/uso terapéutico , Ribavirina/uso terapéuticoRESUMEN
Paired-associative stimulation (PAS), combining electrical median nerve stimulation with transcranial magnetic stimulation (TMS) with a variable delay, causes long-term potentiation or depression (LTP/LTD)-like cortical plasticity. In the present study, we examined how PAS over the motor cortex affected a distant site, the somatosensory cortex. Furthermore, the influences of PAS on high-frequency oscillations (HFOs) were investigated to clarify the origin of HFOs. Interstimulus intervals between median nerve stimulation and TMS were 25 ms (PAS(25)) and 10 ms (PAS(10)). PAS was performed over the motor and somatosensory cortices. SEPs following median nerve stimulation were recorded before and after PAS. HFOs were isolated by 400-800 Hz band-pass filtering. PAS(25) over the motor cortex increased the N20-P25 and P25-N33 amplitudes and the HFOs significantly. The enhancement of the P25-N33 amplitude and the late HFOs lasted more than 60 min. After PAS(10) over the motor cortex, the N20-P25 and P25-N33 amplitudes decreased for 40 min, and the HFOs decreased for 60 min. Frontal SEPs were not affected after PAS over the motor cortex. PAS(25/10) over the somatosensory cortex did not affect SEPs and HFOs. PAS(25/10) over the motor cortex caused the LTP/LTD-like phenomena in a distant site, the somatosensory cortex. The PAS paradigms over the motor cortex can modify both the neural generators of SEPs and HFOs. HFOs may reflect the activation of GABAergic inhibitory interneurons regulating pyramidal neurons in the somatosensory cortex.
Asunto(s)
Relojes Biológicos/fisiología , Potenciales Evocados Somatosensoriales/fisiología , Corteza Motora/fisiología , Corteza Somatosensorial/fisiología , Adulto , Vías Aferentes/fisiología , Estimulación Eléctrica , Femenino , Humanos , Interneuronas/fisiología , Masculino , Nervio Mediano/fisiología , Corteza Motora/anatomía & histología , Inhibición Neural/fisiología , Vías Nerviosas/anatomía & histología , Vías Nerviosas/fisiología , Plasticidad Neuronal/fisiología , Células Piramidales/fisiología , Tiempo de Reacción/fisiología , Corteza Somatosensorial/anatomía & histología , Factores de Tiempo , Estimulación Magnética Transcraneal , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Excessive daytime sleepiness has been widely accepted as a common problem not only in Parkinson's disease (PD) but also in other related disorders. Lowered excretion of orexin A (hypocretin 1) into the cerebrospinal fluid (CSF) is known to play a pathological role in narcolepsy and secondary hypersomnia due to hypothalamic dysfunction. Although the levels of CSF orexin in PD have been previously examined, the results have been controversial, and no systematic investigation of CSF orexin excretion has been conducted on PD related disorders. In this study, orexin was measured in CSF collected by lumbar puncture in 62 patients with PD, 13 patients with dementia with Lewy bodies (DLB), 16 patients with progressive supranuclear palsy (PSP), and 7 patients with corticobasal degeneration (CBD). Levels of CSF orexin (mean+/-SD pg/ml) were 302+/-38 in PD, 297+/-48 in DLB, 258+/-37 in PSP, 246+/-90 in CBD. The occurrence of low orexin levels (Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/líquido cefalorraquídeo
, Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo
, Neuropéptidos/líquido cefalorraquídeo
, Enfermedad de Parkinson/líquido cefalorraquídeo
, Esclerodermia Difusa/líquido cefalorraquídeo
, Trastornos del Sueño-Vigilia/líquido cefalorraquídeo
, Anciano
, Anciano de 80 o más Años
, Biomarcadores/análisis
, Biomarcadores/líquido cefalorraquídeo
, Proteínas del Líquido Cefalorraquídeo/análisis
, Proteínas del Líquido Cefalorraquídeo/metabolismo
, Progresión de la Enfermedad
, Regulación hacia Abajo/fisiología
, Femenino
, Humanos
, Hipotálamo/metabolismo
, Hipotálamo/fisiopatología
, Enfermedad por Cuerpos de Lewy/diagnóstico
, Enfermedad por Cuerpos de Lewy/fisiopatología
, Masculino
, Persona de Mediana Edad
, Orexinas
, Enfermedad de Parkinson/diagnóstico
, Enfermedad de Parkinson/fisiopatología
, Valor Predictivo de las Pruebas
, Esclerodermia Difusa/diagnóstico
, Esclerodermia Difusa/fisiopatología
, Trastornos del Sueño-Vigilia/etiología
, Trastornos del Sueño-Vigilia/fisiopatología
, Punción Espinal