ABSTRACT
The molecular targets and mechanisms of propolis ameliorating metabolic syndrome are not fully understood. Here, we report that Brazilian green propolis reduces fasting blood glucose levels in obese mice by disrupting the formation of CREB/CRTC2 transcriptional complex, a key regulator of hepatic gluconeogenesis. Using a mammalian two-hybrid system based on CREB-CRTC2, we identify artepillin C (APC) from propolis as an inhibitor of CREB-CRTC2 interaction. Without apparent toxicity, APC protects mice from high fat diet-induced obesity, decreases fasting glucose levels, enhances insulin sensitivity and reduces lipid levels in the serum and liver by suppressing CREB/CRTC2-mediated both gluconeogenic and SREBP transcriptions. To develop more potential drugs from APC, we designed and found a novel compound, A57 that exhibits higher inhibitory activity on CREB-CRTC2 association and better capability of improving insulin sensitivity in obese animals, as compared with APC. In this work, our results indicate that CREB/CRTC2 is a suitable target for developing anti-metabolic syndrome drugs.
Subject(s)
CREB-Binding Protein/metabolism , Drug Delivery Systems , Metabolic Syndrome/metabolism , Mice, Obese/metabolism , Propolis/metabolism , Transcription Factors/metabolism , Animals , Blood Glucose , Brazil , CREB-Binding Protein/genetics , Drug Development , Drug Discovery , Gluconeogenesis , Insulin Resistance , Liver/metabolism , Metabolic Syndrome/genetics , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Obese/genetics , Obesity/metabolism , Propolis/genetics , Transcription Factors/geneticsABSTRACT
Six new cardenolides (1, 2 and 11-14), along with ten known ones, were isolated from the root bark of Calotropis gigantea. The structural determination was accomplished by the 1D- and 2D-NMR spectrum as well as ESIMS analysis. The isolated compounds were evaluated for their in vitro growth inhibitory activity against human A549 and Hela cell lines. The results suggested that some of these cardenolides (compounds 1, 6, and 8) displayed potent cytotoxicities.
