RESUMEN
With the rapid progress in deciphering the pathogenesis of Alzheimer's disease (AD), it has been widely accepted that the accumulation of misfolded amyloid ß (Aß) in the brain could cause the neurodegeneration in AD. Although much evidence demonstrates the neurotoxicity of Aß, the role of Aß in the nervous system are complex. However, more comprehensive studies are needed to understand the physiological effect of Aß40 monomers in depth. To explore the physiological mechanism of Aß, we employed mass spectrometry to investigate the altered proteomic events induced by a lower submicromolar concentration of Aß. Human neuroblastoma SH-SY5Y cells were exposed to five different concentrations of Aß1-40 monomers and collected at four time points. The proteomic analysis revealed the time-course behavior of proteins involved in biological processes, such as RNA splicing, nuclear transport and protein localization. Further biological studies indicated that Aß40 monomers may activate PI3K/AKT signaling to regulate p-Tau, Ezrin and MAP2. These three proteins are associated with dendritic morphogenesis, neuronal polarity, synaptogenesis, axon establishment and axon elongation. Moreover, Aß40 monomers may regulate their physiological forms by inhibiting the expression of BACE1 and APP via activation of the ERK1/2 pathway. A comprehensive exploration of pathological and physiological mechanisms of Aß is beneficial for exploring novel treatment.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Proteómica , Humanos , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Proteómica/métodos , Línea Celular Tumoral , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/genética , Fragmentos de Péptidos/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas tau/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Proteínas Proto-Oncogénicas c-akt/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteoma/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Sistema de Señalización de MAP QuinasasRESUMEN
Stimulus-responsive injectable hydrogel has the key characteristics of in situ drug-loading ability and the controlled drug release, enabling efficient delivery and precise release of chemotherapy drugs at the tumor site, thereby being used as a local drug delivery system for sustained tumor treatment. This article designed a smart responsive injectable hydrogel loaded with anti-tumor drugs and nanoparticles to achieve efficient and specific synergistic treatment of tumors. Hyaluronic acid (HA) hydrogel obtained by cross-linking HA-SH (HS) and HA-Tyr (HT) through horseradish peroxidase (HRP), and doxorubicin hydrochloride (DOX) and folic acid-polyethylene glycol-amine (FA-PEG-NH2) modified PDA (denoted as PPF) were encapsulated to construct the HS/HT@PPF/D hydrogel. The hydrogel had good biocompatibility, injectability, and could respond to multiple stimuli at the tumor site, thereby achieving controlled drug release. At the same time, PPF gave it excellent photothermal efficiency, photothermal stability and tumor targeting. In vitro and in vivo experimental results showed that the HS/HT@PPF/D hydrogel combined with near-infrared laser irradiation could significantly improve its anti-tumor effect and could almost eliminate the entire tumor mass without obvious adverse reactions. The HS/HT@PPF/D hydrogel could achieve multi-stimulus-responsive drug delivery and be used for precise chemo-photothermal synergistic tumor treatment, thus providing a new platform for local synergistic tumor treatment.