Tailored PGE2 Immunomodulation of moDCs by Nano-Encapsulated EP2/EP4 Antagonists.

Prostaglandin E2 (PGE2) is an important maturation mediator for dendritic cells (DCs). However, increased PGE2 levels in the tumor exert immunosuppressive effects on DCs by signaling through two E-Prostanoid (EP) receptors: EP2 and EP4. Blocking EP-receptor signaling of PGE2 with antagonists is currently being investigated for clinical applications to enhance anti-tumor immunity. In this study, we investigated a new delivery approach by encapsulating EP2/EP4 antagonists in polymeric nanoparticles. The nanoparticles were characterized for size, antagonist loading, and release. The efficacy of the encapsulated antagonists to block PGE2 signaling was analyzed using monocyte-derived DCs (moDCs). The obtained nanoparticles were sized between 210 and 260 nm. The encapsulation efficacy of the EP2/EP4 antagonists was 20% and 17%, respectively, and was further increased with the co-encapsulation of both antagonists. The treatment of moDCs with co-encapsulation EP2/EP4 antagonists prevented PGE2-induced co-stimulatory marker expression. Even though both antagonists showed a burst release within 15 min at 37 °C, the nanoparticles executed the immunomodulatory effects on moDCs. In summary, we demonstrate the functionality of EP2/EP4 antagonist-loaded nanoparticles to overcome PGE2 modulation of moDCs.

Yin and Yang of mitochondrial ROS in Drosophila.

In this study, we test the hypothesis that Drosophila larvae producing mildly elevated levels of endogenous mitochondrial reactive oxygen species (ROS) benefit in stressful environmental conditions due to the priming of antioxidant responses. Reactive oxygen species (ROS) are produced as a by-product of oxidative phosphorylation and may be elevated when mutations decrease the efficiency of ATP production. In moderation, ROS are necessary for cell signaling and organismal health, but in excess can damage DNA, proteins, and lipids. We utilize two Drosophila melanogaster strains (Dahomey and Alstonville) that share the same nuclear genetic background but differ in their mitochondrial DNA haplotypes. Previously, we reported that Dahomey larvae harboring the V161L ND4 mtDNA mutation have reduced proton pumping and higher levels of mitochondrial ROS than Alstonville larvae when they are fed a 1:2 protein: carbohydrate (P:C) diet. Here, we explore the potential for mitochondrial ROS to provide resistance to dietary stressors by feeding larvae 1:2 P:C food supplemented with ethanol or hydrogen peroxide (H2O2). When fed a diet supplemented with ethanol or H2O2, Dahomey develop more quickly than Alstonville into larger pupae, while Alstonville developed faster on the control. Dahomey larvae displayed higher antioxidant capacity than Alstonville on all diets, with mitochondrial H2O2 levels unchanged after the addition of stressors. Addition of stressors to the diet did not affect the mitochondrial functions of Dahomey larvae as measured by mitochondrial membrane potential, respiratory control ratio, or larval survival after bacterial challenge. In contrast, Alstonville larvae developed slower, had lower pupal weight, higher cytosolic H2O2, and had reduced mitochondrial functions. Further, Alstonville larvae fed the ethanol treated diet had lower survival after bacterial infection than those fed the control diet. Surprisingly, they had greater survival when fed diet with H2O2 indicating a mitotype by stressor interaction that influences the immune response. Overall, these data suggest that elevated mitochondrial ROS in Dahomey can result in greater antioxidant capacity that prevents oxidative damage from exogenous stressors and may be a conserved response to high ethanol found in rotting fruit.