Phenolic diterpenes from rosemary suppress cAMP responsiveness of gluconeogenic gene promoters.

The cAMP/protein kinase A/cAMP response element (CRE)-binding protein pathway is important for various physiological aspects including regulation of gluconeogenic gene expression. Rosemary, a well-known herb, has been reported to decrease blood glucose levels. We found that methanol extracts of rosemary suppressed forskolin (FSK)-stimulated luciferase expression under the control of CRE, as well as the promoters for cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and glucose-6-phosphatase (G6Pase) catalytic subunit genes in human hepatoma HepG2 cells. Three abietane-type diterpenes and two flavonoids were isolated from the rosemary extracts. Among these, 7-O-methylrosmanol (1) and royleanonic acid (3) effectively suppressed FSK-induced luciferase expression under the control of the CRE, PEPCK-C and G6Pase gene promoters. PEPCK-C and G6Pase, which play a key role in the homeostatic regulation of blood glucose levels, are important for managing type II diabetes mellitus. Therefore, the ability of rosemary and its components to suppress cAMP responsiveness of the PEPCK-C or G6Pase gene may contribute to its antihyperglycemic activity.

Piperine-like alkamides from Piper nigrum induce BDNF promoter and promote neurite outgrowth in Neuro-2a cells.

Black pepper (Piper nigrum) contains a variety of alkamides. Among them, piperine has been reported to have antidepressant-like effects in chronically stressed mice, but little is known about the biological activity of other alkamides. In this study, we investigated the effects of alkamides from white pepper (P. nigrum) on neuronal cells. Twelve alkamides were isolated from white pepper MeOH extracts, and their chemical structures were identified by NMR and MS analyses. The compounds were subjected to assays using the luciferase-reporter gene under the control of the BDNF promoter or cAMP response element in mouse neuroblastoma Neuro-2a cells. In both assays, marked reporter-inducing activity was observed for piperine (1), piperettine (2) and piperylin (7), all of which have in common an (E)-5-(buta-1,3-dien-1-yl)benzo[d] [1, 3] dioxole moiety. Piperettine (2) and piperylin (7) tended to increase endogenous BDNF protein levels. Furthermore, piperylin (7) promoted retinoic acid-induced neurite outgrowth. These results suggest that piperylin (7), or analogues thereof, may have a beneficial effect on disorders associated with dysregulation of BDNF expression, such as depression.