Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation.

Sterile particles cause several chronic, inflammatory diseases, characterized by repeating cycles of particle phagocytosis and inflammatory cell death. Recent studies have proposed that these processes are driven by the NLRP3 inflammasome, a platform activated by phagocytosed particles, which controls both caspase-1-dependent cell death (pyroptosis) and mature IL-1β secretion. After phagocytosis, particles can disrupt lysosomes, and inhibitor studies have suggested that the resulting release of a lysosomal protease-cathepsin B-into the cytosol somehow activates NLRP3.

Multiple Cathepsins Promote Pro-IL-1β Synthesis and NLRP3-Mediated IL-1β Activation.

Sterile particles induce robust inflammatory responses that underlie the pathogenesis of diseases like silicosis, gout, and atherosclerosis. A key cytokine mediating this response is IL-1β. The generation of bioactive IL-1β by sterile particles is mediated by the NOD-like receptor containing a pyrin domain 3 (NLRP3) inflammasome, although exactly how this occurs is incompletely resolved.

The role of mindfulness skills in terms of distress tolerance: a pilot test among adult daily smokers.

Background And Objectives: Low distress tolerance is associated with difficulties quitting smoking. Mindfulness is associated with improved cessation outcomes and may be one method by which to increase distress tolerance. The purpose of the current study was to examine the relationship between mindfulness skills and distress tolerance among regular smokers.

Drug discovery for neglected tropical diseases at the Sandler Center.

The Sandler Center's approach to target-based drug discovery for neglected tropical diseases is to focus on parasite targets that are homologous to human targets being actively investigated in the pharmaceutical industry. In this way we attempt to use both the know-how and actual chemical matter from other drug-development efforts to jump start the discovery process for neglected tropical diseases. Our approach is akin to drug repurposing, except that we seek to repurpose leads rather than drugs.

Cruzain : the path from target validation to the clinic.

Cruzain is the major papain-like cysteine protease of Trypanosoma cruzi, the etiological agent causing Chagas' disease in humans in South America. Cruzain is indispensable for the survival and propagation of this protozoan parasite and therefore, it has attracted considerable interest as a potential drug target. This chapter charts the path from the initial identification of this proteases activity and its validation as a bone fide drug target to the arduous task of the discovery of an inhibitor targeting this protease and finally the path towards the clinic.

Induction of angiogenesis by murine resistin: putative role of PI3-kinase and NO-dependent pathways.

Unlabelled: Adipose tissue is a highly active endocrine organ, secreting bioactive molecules, adipokines, into the circulation. Obesity results in dysregulated adipokine secretion, contributing to pathophysiologies associated with this disorder, including insulin resistance and cardiovascular disease.

Objectives: To establish whether resistin, a novel bioactive molecule produced by murine adipose tissue, and implicated in insulin resistance in rodents, can induce angiogenic responses in aortic tissues and endothelial cells in vitro, and to investigate the signal transduction pathways involved in these responses.

Resistin induces lipolysis and re-esterification of triacylglycerol stores, and increases cholesteryl ester deposition, in human macrophages.

Human resistin, found within atheroma, exerts inflammatory, angiogenic and proliferative effects in vascular cells and may predict coronary events. Here, we investigate mechanisms by which resistin contributes to macrophage 'foam cell' formation. Increases in macrophage (THP-1) cholesteryl ester mass, in the presence or absence of oxidized LDL, were not explained by altered cholesterol efflux.