In silico and in vitro analyses of a novel FoxO1 agonist reducing Aß levels via downregulation of BACE1.

AIMS: FoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1-specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD. METHODS: FoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH-SY5Y cells, respectively. Western blotting and enzyme-linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism. RESULTS: N-(3-methylisothiazol-5-yl)-2-(2-oxobenzo[d]oxazol-3(2H)-yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH-SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aß1-40 and Aß1-42 were also reduced. CONCLUSIONS: We present a novel small-molecule FoxO1 agonist with good anti-AD effects. This study highlights a promising strategy for new drug discovery for AD.

Realization of p-type gallium nitride by magnesium ion implantation for vertical power devices.

Implementing selective-area p-type doping through ion implantation is the most attractive choice for the fabrication of GaN-based bipolar power and related devices. However, the low activation efficiency of magnesium (Mg) ions and the inevitable surface decomposition during high-temperature activation annealing process still limit the use of this technology for GaN-based devices. In this work, we demonstrate successful p-type doping of GaN using protective coatings during a Mg ion implantation and thermal activation process. The p-type conduction of GaN is evidenced by the positive Seebeck coefficient obtained during thermopower characterization. On this basis, a GaN p-i-n diode is fabricated, exhibiting distinct rectifying characteristics with a turn-on voltage of 3 V with an acceptable reverse breakdown voltage of 300 V. Electron beam induced current (EBIC) and electroluminescent (EL) results further confirm the formation of p-type region due to Mg ion implantation and subsequent thermal activation. This repeatable and uniform manufacturing process can be implemented in mass production of GaN devices for versatile power and optoelectronic applications.