RESUMO
Brain amyloid-ß (Aß) governs the pathogenic process of Alzheimer's disease. Clinical trials to assess the disease-modifying effects of inhibitors or modulators of ß- and γ-secretases have not shown clinical benefit and can cause serious adverse events. Previously, we found that the interleukin-like epithelial-to-mesenchymal transition inducer (ILEI, also known as FAM3C) negatively regulates the Aß production through a decrease in Aß immediate precursor, without the inhibition of ß- and γ-secretase activity. Herein, we found that MS-275, a benzamide derivative that is known to inhibit histone deacetylases (HDACs), exhibits ILEI-like activity to reduce Aß production independent of HDAC inhibition. Chronic MS-275 treatment decreased Aß deposition in the cerebral cortex and hippocampus in an Alzheimer's disease mouse model. Overall, our results indicate that MS-275 is a potential therapeutic candidate for efficiently reducing brain Aß accumulation.
Assuntos
Doença de Alzheimer , Piridinas , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Benzamidas/farmacologia , Precursor de Proteína beta-AmiloideRESUMO
Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor that regulates the expression of genes related to fatty acid biosynthesis. Its high expression and activation in obesity and associated metabolic diseases make it a potential therapeutic target. However, the role of SREBP-1 in the development and exacerbation of these diseases remains unclear, partly because of the impossibility of inhibiting its function because of the lack of specific inhibitors. Here, we aimed to identify small-molecule compounds that directly bind to SREBP-1 using the recombinant N-terminal region of SREBP-1a, which is required for its transcriptional activity. A high-throughput screening campaign was conducted using a thermal shift assay and surface plasmon resonance assay to evaluate the compound affinity and specificity, which resulted in the identification of two compounds. Future analysis of their structure-activity relationships may lead to the development of specific SREBP-1 inhibitors, thereby potentially validating SREBP-1 as a therapeutic target for obesity and resultant atherosclerotic diseases.