Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition.

Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket. This finding is consistent with the promiscuous nature of ATX hydrolysis of multiple and diverse substrates and prior investigations of inhibitor impacts on ATX enzyme kinetics. The current study used virtual screening methods to guide experimental identification and characterization of inhibitors targeting the hydrophobic region of ATX. An initially discovered inhibitor, GRI392104 (IC50 4µM) was used as a lead for synthetic optimization. In total twelve newly synthesized inhibitors of ATX were more potent than GRI392104 and were selective for ATX as they had no effect on other LPC-specific NPP family members or on LPA1-5 GPCR.

Dietary Behavior and Diet Interventions among Structural Firefighters: A Narrative Review.

Structural firefighters (SFFs) are exposed to multiple occupational hazards that affect dietary behavior and can contribute to increased risks of cancer and cardiovascular disease compared to the United States' general population. Dietary behavior is a feasible modification for positive health outcomes. The objectives of this narrative review are to summarize the diet behavior of SFFs, review findings of diet interventions that positively modify diet behavior, identify research gaps, and suggest recommendations for addressing those gaps. PubMed, MEDLINE, Scopus, and CABI Web of Science were searched between February 2020 and June 2022 for peer-reviewed articles. The inclusion criteria were as follows: (1) study population must include SFFs; (2) investigate diet or diet intervention among SFFs; (3) report results specific to SFFs; and (4) be published in the English language. Thirty-four studies were included. Results indicate that SFFs recognize the importance of a healthy dietary pattern, but do not follow one, and that food choices are often influenced by colleagues. Diet interventions, such as the Mediterranean diet, were observed to have positive health improvements, such as improved lipid levels and lower CVD risk. Team counseling was found to be more effective for adopting healthier diets compared to one-on-one counseling; and general counseling was more effective than no counseling. A gap identified by this review is the lack of information concerning differences in dietary intake, diet quality, and dietary behaviors while on- and off-shift, and throughout the career. Diet is an important risk factor for occupational disease development; therefore, effective, consistent dietary interventions are necessary.