Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule.

Progressive organ fibrosis accounts for one-third of all deaths worldwide, yet preclinical models that mimic the complex, progressive nature of the disease are lacking, and hence, there are no curative therapies. Progressive fibrosis across organs shares common cellular and molecular pathways involving chronic injury, inflammation, and aberrant repair resulting in deposition of extracellular matrix, organ remodeling, and ultimately organ failure. We describe the generation and characterization of an in vitro progressive fibrosis model that uses cell types derived from induced pluripotent stem cells. Our model produces endogenous activated transforming growth factor β (TGF-β) and contains activated fibroblastic aggregates that progressively increase in size and stiffness with activation of known fibrotic molecular and cellular changes. We used this model as a phenotypic drug discovery platform for modulators of fibrosis. We validated this platform by identifying a compound that promotes resolution of fibrosis in in vivo and ex vivo models of ocular and lung fibrosis

Late Transition Metal Complexes with Pincer Ligands that Comprise N-Heterocyclic Carbene Donor Sites

The incorporation of N-heterocyclic carbenes into the well-established pincer ligand platform entails a number of attractive benefits. For example, NHCs are strong donors, and the metal–carbene bond is often remarkably robust towards oxidative and hydrolytic conditions and thus sustains in air, moisture, and even highly acidic environments. Moreover, NHCs can be readily functionalized and modulated and thus provide excellent opportunities for fine-tuning the properties of a coordinated metal center. As a consequence, the combination of the concepts of pincer ligands and of NHCs has much appeal and continues to attract considerable interest. This chapter summarizes accomplishments over the last 5 years in the domain of pincer carbene complexes containing Group 8–10 metals, including synthetic aspects as well as application of these complexes, which has included in particular catalysis and to a lesser extent materials science and medicinal areas