Anti-inflammatory and Quinone Reductase-Inducing Compounds from Beilschmiedia mannii.

Previous studies on the therapeutic potential of plant species found in the diet of chimpanzees living in Taï National Park have shown that they could be potential candidates for the search of new molecules useful for humans. Based on the screening of some of these plants, the fruits of Beilschmiedia mannii, whose dichloromethane extract showed cancer chemopreventive properties, were selected. Bioactivity-guided fractionation of the extract resulted in the isolation and identification of two γ-pyrones, including desmethoxydihydromethysticin (1: ), found in a natural source for the first time, and a new congener, beilschmiediapyrone (2: ), as well as five known alkamides (3:  - 7: ). Their structures were established by using nuclear magnetic resonance spectroscopy and mass spectrometry methods. The isolated compounds were evaluated for their cancer chemopreventive potential by using quinone reductase induction and nuclear factor-kappa B inhibition tests in Hepa 1c1c7 and HEK-293/NF-κB-Luc cells, respectively. Among them, compounds 1: and 2: were the most active. The concentrations to double the quinone reductase activity were 7.5 µM for compound 1: and 6.1 µM for compound 2: . Compounds 1: and 2: inhibited nuclear factor-kappa B with IC50 values of 2.1 and 3.4 µM, respectively. These results are promising with regard to cancer chemoprevention, especially because this plant is also used for cooking by the local population around the Taï forest.

The role of γ-secretase activating protein (GSAP) and imatinib in the regulation of γ-secretase activity and amyloid-ß generation.

γ-Secretase is a large enzyme complex comprising presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1 that mediates the intramembrane proteolysis of a large number of proteins including amyloid precursor protein and Notch. Recently, a novel γ-secretase activating protein (GSAP) was identified that interacts with γ-secretase and the C-terminal fragment of amyloid precursor protein to selectively increase amyloid-ß production. In this study we have further characterized the role of endogenous and exogenous GSAP in the regulation of γ-secretase activity and amyloid-ß production in vitro. Knockdown of GSAP expression in N2a cells decreased amyloid-ß levels. In contrast, overexpression of GSAP in HEK cells expressing amyloid precursor protein or in N2a cells had no overt effect on amyloid-ß generation. Likewise, purified recombinant GSAP had no effect on amyloid-ß generation in two distinct in vitro γ-secretase assays. In subsequent cellular studies with imatinib, a kinase inhibitor that reportedly prevents the interaction of GSAP with the C-terminal fragment of amyloid precursor protein, a concentration-dependent decrease in amyloid-ß levels was observed. However, no interaction between GSAP and the C-terminal fragment of amyloid precursor protein was evident in co-immunoprecipitation studies. In addition, subchronic administration of imatinib to rats had no effect on brain amyloid-ß levels. In summary, these findings suggest the roles of GSAP and imatinib in the regulation of γ-secretase activity and amyloid-ß generation are uncertain.