ExEmPLAR (Extracting, Exploring, and Embedding Pathways Leading to Actionable Research): a user-friendly interface for knowledge graph mining.

SUMMARY: Knowledge graphs are being increasingly used in biomedical research to link large amounts of heterogenous data and facilitate reasoning across diverse knowledge sources. Wider adoption and exploration of knowledge graphs in the biomedical research community is limited by requirements to understand the underlying graph structure in terms of entity types and relationships, represented as nodes and edges, respectively, and learn specialized query languages for graph mining and exploration. We have developed a user-friendly interface dubbed ExEmPLAR (Extracting, Exploring, and Embedding Pathways Leading to Actionable Research) to aid reasoning over biomedical knowledge graphs and assist with data-driven research and hypothesis generation. We explain the key functionalities of ExEmPLAR and demonstrate its use with a case study considering the relationship of Trypanosoma cruzi, the etiological agent of Chagas disease, to frequently associated cardiovascular conditions. AVAILABILITY AND IMPLEMENTATION: ExEmPLAR is freely accessible at https://www.exemplar.mml.unc.edu/. For code and instructions for the using the application, see: https://github.com/beasleyjonm/AOP-COP-Path-Extractor.

Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in NAD+ biosynthesis via salvage of NAM formed from catabolism of NAD+ by proteins with NADase activity (e.g., PARPs, SIRTs, CD38). Depletion of NAD+ in aging, neurodegeneration, and metabolic disorders is addressed by NAD+ supplementation. Conversely, NAMPT inhibitors have been developed for cancer therapy: many discovered by phenotypic screening for cancer cell death have low nanomolar potency in cellular models. No NAMPT inhibitor is yet FDA-approved. The ability of inhibitors to act as NAMPT substrates may be associated with efficacy and toxicity. Some 3-pyridyl inhibitors become 4-pyridyl activators or "NAD+ boosters". NAMPT positive allosteric modulators (N-PAMs) and boosters may increase enzyme activity by relieving substrate/product inhibition. Binding to a "rear channel" extending from the NAMPT active site is key for inhibitors, boosters, and N-PAMs. A deeper understanding may fulfill the potential of NAMPT ligands to regulate cellular life and death.

Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress.

Evidence supports boosting nicotinamide adenine dinucleotide (NAD+) to counteract oxidative stress in aging and neurodegenerative disease. One approach is to enhance the activity of nicotinamide phosphoribosyltransferase (NAMPT). Novel NAMPT positive allosteric modulators (N-PAMs) were identified. A cocrystal structure confirmed N-PAM binding to the NAMPT rear channel. Early hit-to-lead efforts led to a 1.88-fold maximum increase in the level of NAD+ in human THP-1 cells. Select N-PAMs were assessed for mitigation of reactive oxygen species (ROS) in HT-22 neuronal cells subject to inflammatory stress using tumor necrosis factor alpha (TNFα). N-PAMs that increased NAD+ more effectively in THP-1 cells attenuated TNFα-induced ROS more effectively in HT-22 cells. The most efficacious N-PAM completely attenuated ROS elevation in glutamate-stressed HT-22 cells, a model of neuronal excitotoxicity. This work demonstrates for the first time that N-PAMs are capable of mitigating elevated ROS in neurons stressed with TNFα and glutamate and provides support for further N-PAM optimization for treatment of neurodegenerative diseases.