Squamosamide Derivative FLZ Protects Pancreatic ß-Cells from Glucotoxicity by Stimulating Akt-FOXO1 Pathway.

Chronic hyperglycemia increases apoptosis and reduces glucose-stimulated insulin secretion. Although protective agents have been searched extensively, none has been found so far. Here we tested FLZ, a synthetic derivative of squamosamide from a Chinese herb, as a potential candidate for antiglucotoxicity in INS-1E cells and mouse islets. Chronic culture of ß-cells in 30 mM glucose caused progressive reduction of cell viability, accompanied with increased apoptosis and reduced insulin secretion. These effects on apoptosis and insulin were reversed by FLZ in a dose-dependent manner. FLZ treatment also increased forkhead box O1 protein phosphorylation and reduced its nuclear location. On the contrary, FLZ increased pancreatic and duodenal homeobox-1 expression and its nuclear localization, an effect mediated by increased p-Akt. Consistently, Akt selective inhibitor MK-2206 completely abolished antiglucotoxicity effect of FLZ. Furthermore, FLZ treatment increased cytosolic ATP/ADP ratio. Taken together, our results suggest that FLZ could be a potential therapeutic agent to treat the hyperglycemia-induced ß-cell failure.

FLZ alleviates the memory deficits in transgenic mouse model of Alzheimer's disease via decreasing beta-amyloid production and tau hyperphosphorylation.

Alzheimer's disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated ß-amyloid (Aß) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ's neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aß accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased ß-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and ß-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aß production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ's inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3ß (GSK3ß) pathway. FLZ treatment increased Akt activity and inhibited GSK3ß activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3ß activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3ß pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aß production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3ß.

[Neurodegenerative conformational disease and heat shock proteins].

Many major neurodegenerative diseases are associated with proteins misfolding and aggregation, which are also called "neurodegenerative conformational disease". The interaction of gene mutation and environmental factors are probably primary events resulting in oligomer and aggregate formations of proteins. Moreover, the dysfunctions of protein control systems, i.e. the ubiquitin-proteasome system and autophagy-lysosomal system, also contribute to the neurodegenerative process. The present review mainly summarizes protein misfolding and aggregation in the development of neurodegenerative conformational disease and the underling mechanisms, as well as upregulation of heatshock proteins as a promising treatment method for this kind of disease.