Licoflavonol Reduces Aß Secretion by Increasing BACE1 Phosphorylation to Facilitate BACE1 Degradation.

SCOPE: In the previous study, Glycyrrhiza uralensis Fisch extract (GUE) inhibited Aß secretion by inhibiting ß-site APP-cleaving enzyme 1 (BACE1) transcription, and the active compounds semilicoisoflavone B (SB) and licoflavonol (LF) inhibited Aß secretion. SB corresponds to the same mechanism as GUE, but LF has a different mechanism. In this study, the mechanism underlying inhibition of Aß by LF is investigated. METHODS AND RESULTS: The effects of LF on Aß, sAPPα, and sAPPß secretion are evaluated by ELISA, and the effect of LF on BACE1 expression is detected by western blotting. It is found that the effect of LF on Aß secretion is due to promotion of BACE1 protein degradation, and that the effect of LF on Aß and BACE1 expression is attenuated after cotreatment with the lysosome inhibitor chloroquine. In a subsequent mechanistic study, it is found that LF increases BACE1 phosphorylation to increase its interactions with ADP ribosylation factor-binding proteins 1 and 3 (GGA1 and GGA3, respectively) and eventually facilitate BACE1 delivery to lysosomes for degradation. CONCLUSION: This study is the first to demonstrate that the BACE1 phosphorylation inducer LF can modulate BACE1 trafficking and lead to facilitating degradation of BACE1, eventually decreasing Aß secretion.

Calcium-chelating alizarin and other anthraquinones inhibit biofilm formation and the hemolytic activity of Staphylococcus aureus.

Staphylococcal biofilms are problematic and play a critical role in the persistence of chronic infections because of their abilities to tolerate antimicrobial agents. Thus, the inhibitions of biofilm formation and/or toxin production are viewed as alternative means of controlling Staphylococcus aureus infections. Here, the antibiofilm activities of 560 purified phytochemicals were examined. Alizarin at 10 µg/ml was found to efficiently inhibit biofilm formation by three S. aureus strains and a Staphylococcus epidermidis strain. In addition, two other anthraquinones purpurin and quinalizarin were found to have antibiofilm activity. Binding of Ca(2+) by alizarin decreased S. aureus biofilm formation and a calcium-specific chelating agent suppressed the effect of calcium. These three anthraquinones also markedly inhibited the hemolytic activity of S. aureus, and in-line with their antibiofilm activities, increased cell aggregation. A chemical structure-activity relationship study revealed that two hydroxyl units at the C-1 and C-2 positions of anthraquinone play important roles in antibiofilm and anti-hemolytic activities. Transcriptional analyses showed that alizarin repressed the α-hemolysin hla gene, biofilm-related genes (psmα, rbf, and spa), and modulated the expressions of cid/lrg genes (the holin/antiholin system). These findings suggest anthraquinones, especially alizarin, are potentially useful for controlling biofilm formation and the virulence of S. aureus.