GABAergic signaling between enteric neurons and intestinal smooth muscle promotes innate immunity and gut defense in Caenorhabditis elegans.

The nervous system is critical for intestinal homeostasis and function, but questions remain regarding its impact on gut immune defense. By screening the major neurotransmitters of C. elegans, we found that γ-aminobutyric acid (GABA) deficiency enhanced susceptibility to pathogenic Pseudomonas aeruginosa PA14 infection.

Construction of engineered 3D islet micro-tissue using porcine decellularized ECM for the treatment of diabetes.

Islet transplantation improves diabetes patients' long-term blood glucose control, but its success and utility are limited by cadaver availability, quality, and considerable islet loss after transplantation due to ischemia and inadequate angiogenesis. This study used adipose, pancreatic, and liver tissue decellularized extracellular matrix (dECM) hydrogels in an effort to recapitulate the islet sites inside the pancreas , and successfully generated viable and functional heterocellular islet micro-tissues using islet cells, human umbilical vein endothelial cells, and adipose-derived mesenchymal stem cells. The three-dimensional (3D) islet micro-tissues maintained prolonged viability and normal secretory function, and showed high drug sensitivity in drug testing.

GABAergic Neuromuscular Junction Suppresses Intestinal Defense of by Attenuating Muscular Oxidative Phosphorylation.

Innate immunity is an ancient and evolutionarily conserved system that constitutes the first line of host defense against invading microbes. We previously determined that the GABAergic neuromuscular junction (NMJ) suppresses intestinal innate immunity via muscular insulin signaling. Here, we found that a muscular mitochondrial oxidative phosphorylation pathway of is involved in GABAergic NMJs-mediated intestinal defense.

Enolase2 and enolase1 cooperate against neuronal injury in stroke model.

Stroke is one of the leading causes of death in adults worldwide. However, the mechanism causing neuronal death remains poorly understood. Our previous report showed that enolase1 (ENO1), a key glycolytic enzyme, alleviates cerebral ischemia-induced neuronal injury.

Parasite-Mediated Degradation of Synthetic Ozonide Antimalarials Impacts Antimalarial Activity.

The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of drug stability and pulsed-exposure activity assays.

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria.

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate.