RESUMEN
RATIONALE: Tau hyperphosphorylation and aggregation is considered as a main pathological mechanism underlying Alzheimer's disease (AD). Rose Bengal (RB) is a synthetic dye used for disease diagnosis, which was reported to inhibit tau toxicity via inhibiting tau aggregation in Drosophila. However, it was unknown if RB could produce anti-AD effects in rodents. OBJECTIVES: The research aimed to investigate if and how RB could prevent ß-amyloid (Aß) oligomers-induced tau hyperphosphorylation in rodents. METHODS AND RESULTS: RB was tested in vitro (0.3-1 µM) and prevented Aß oligomers-induced tau hyperphosphorylation in PC12 cells. Moreover, RB (10-30 mg/kg, i.p.) effectively attenuated cognitive impairments induced by Aß oligomers in mice. Western blotting analysis demonstrated that RB significantly increased the expression of pSer473-Akt, pSer9-glycogen synthase kinase-3ß (GSK3ß) and reduced the expression of cyclin-dependent kinase 5 (CDK5) both in vitro and in vivo. Molecular docking analysis suggested that RB might directly interact with GSK3ß and CDK5 by acting on ATP binding sites. Gene Ontology enrichment analysis indicated that RB might act on protein phosphorylation pathways to inhibit tau hyperphosphorylation. CONCLUSIONS: RB was shown to inhibit tau neurotoxicity at least partially via inhibiting the activity of GSK3ß and CDK5, which is a novel neuroprotective mechanism besides the inhibition of tau aggregation. As tau hyperphosphorylation is an important target for AD therapy, this study also provided support for investigating the drug repurposing of RB as an anti-AD drug candidate.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratas , Ratones , Animales , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Proteínas tau/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Rosa Bengala/uso terapéutico , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Simulación del Acoplamiento Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Fosforilación , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/uso terapéuticoRESUMEN
One of the major noise components in electrocardiogram (ECG) is the baseline wander (BW). Effective methods for suppressing BW include the wavelet-based (WT) and the mathematical morphological filtering-based (MMF) algorithms. However, the T waveform distortions introduced by the WT and the rectangular/trapezoidal distortions introduced by MMF degrade the quality of the output signal. Hence, in this study, we introduce a method by combining the MMF and WT to overcome the shortcomings of both existing methods. To demonstrate the effectiveness of the proposed method, artificial ECG signals containing a clinical BW are used for numerical simulation, and we also create a realistic model of baseline wander to compare the proposed method with other state-of-the-art methods commonly used in the literature. The results show that the BW suppression effect of the proposed method is better than that of the others. Also, the new method is capable of preserving the outline of the BW and avoiding waveform distortions caused by the morphology filter, thereby obtaining an enhanced quality of ECG.