Glycolytic switch in response to betulinic acid in non-cancer cells.

The naturally occurring triterpenoid betulinic acid (BA) shows pronounced polypharmacology ranging from anti-inflammatory to anti-lipogenic activities. Recent evidence suggests that rather diverse cellular signaling events may be attributed to the same common upstream switch in cellular metabolism. In this study we therefore examined the metabolic changes induced by BA (10 µM) administration, with focus on cellular glucose metabolism. We demonstrate that BA elevates the rates of cellular glucose uptake and aerobic glycolysis in mouse embryonic fibroblasts with concomitant reduction of glucose oxidation. Without eliciting signs of obvious cell death BA leads to compromised mitochondrial function, increased expression of mitochondrial uncoupling proteins (UCP) 1 and 2, and liver kinase B1 (LKB1)-dependent activation AMP-activated protein kinase. AMPK activation accounts for the increased glucose uptake and glycolysis which in turn are indispensable for cell viability upon BA treatment. Overall, we show for the first time a significant impact of BA on cellular bioenergetics which may be a central mediator of the pleiotropic actions of BA.

Modulation of bacterial ghosts--induced nitric oxide production in macrophages by bacterial ghost-delivered resveratrol.

The present study aimed to investigate the capacity of resveratrol (RV) delivered into macrophages by bacterial ghosts (BGs), representing intact empty nonliving envelopes of Gram-negative bacteria, to modulate nitric oxide (NO) production related to the presence of the pathogen-associated molecular patterns on the surface of BGs. Incubation of the murine macrophage cell line RAW 264.7 with BGs leads to a dose-dependent activation of inducible NO synthase. To modify BG-induced NO formation in RAW 264.7 cells by RV; BGs were loaded with RV (RV-BGs) and incubated with murine macrophages in a dose-dependent manner. RV-BGs delivering RV to the target macrophages significantly reduced BG-induced NO production with concentration of RV more than one order of magnitude lower than the amount of RV capable of reducing NO formation when applied directly. Moreover, no cytotoxic impact of BGs on the viability of RAW 264.7 cells added to macrophages alone or loaded with RV was detected after a mutual 24 h incubation, whereas cell viability slightly decreased (~ 10%) when RV concentrations of 30 µm alone were applied. The results obtained in the present study clearly indicate that the intracellular delivery of RV by BGs significantly enhances the total RV effect.