The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

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Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor (FGF) family of proteins. The biological activity of FGF21 was first shown to induce insulin independent glucose uptake in adipocytes through the GLUT1 transporter. Subsequently, it was shown to have effects on the liver to increase fatty acid oxidation. FGF21 treatment provides beneficial metabolic effects in both animal models and patients with obesity, type 2 diabetes mellitus (T2D) and/or fatty liver disease. In this paper, we revisited the original finding and found that insulin independent glucose uptake in adipocytes is preserved in the presence of an insulin receptor antagonist. Using a 40 kDa PEGylated (PEG) and half-life extended form of FGF21 (FGF21-PEG), we extended these in vitro results to two different mouse models of diabetes. FGF21-PEG normalized plasma glucose in streptozotocin-treated mice, a model of type 1 diabetes (T1D), without restoring pancreatic β-cell function. FGF21-PEG also normalized plasma glucose levels and improved glucose tolerance in mice chronically treated with an insulin competitive insulin receptor antagonist, a model of autoimmune/Type-B insulin resistance. These data extend the pharmacological potential of FGF21 beyond the settings of T2D, fatty liver and obesity.

S ilicosis continues to be a lung disease with significant morbidity and mortality. Although silica-induced lung injury and cell activation and/or death have been investigated over the past several years, basic research continues to reveal the cell: cell and cell: mediator interactions critical to these events. This chapter will emphasize the production and participation of several inflammatory cytokines, mediators and cell processes in the development of silica-induced lung injury and fibrosis. Mediators to be discussed will include TNFa, IFNy, IL-ip, IL-12, IL-18, IL-9, TGFp, MMPs/TIMPs, ROS/RNS, caspases and Fas/FasL in die processes of cell activation, cell proliferation and cell death. The mediator networks and apoptotic pathways elicited by this inorganic particle are complex, driven by many cell types and affect numerous cell functions. Understanding these interactions will help in developing strategies for therapeutic intervention at difierent stages of the disease. Silica and SilicosisIn the United States alone, silicosis was listed as a primary or contributing cause of death in 4313 individuals from [1979][1980][1981][1982][1983][1984][1985][1986][1987][1988][1989][1990].^ With the significant occupational health risk posed by silica exposure, research endeavors to explore the cellular and inflammatory mechanisms underlying silica induced limg injury are critical.

Saline loading caused an increase in glomerular filtration rate in RAP mice but not in CBA mice. On the basis of progeny testing of F 2 hybrids, backcrosses to CBA, and inbred lines derived from backcrosses to RAP, it was concluded that the difference between the strains RAP and CBA was probably largely accounted for by a single gene locus. The use of this gene in physiological investigations of the control of glomerular filtration rate is suggested.

Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor (FGF) family of proteins. The biological activity of FGF21 was first shown to induce insulin independent glucose uptake in adipocytes through the GLUT1 transporter. Subsequently, it was shown to have effects on the liver to increase fatty acid oxidation. FGF21 treatment provides beneficial metabolic effects in both animal models and patients with obesity, type 2 diabetes mellitus (T2D) and/or fatty liver disease. In this paper, we revisited the original finding and found that insulin independent glucose uptake in adipocytes is preserved in the presence of an insulin receptor antagonist. Using a 40 kDa PEGylated (PEG) and half-life extended form of FGF21 (FGF21-PEG), we extended these in vitro results to two different mouse models of diabetes. FGF21-PEG normalized plasma glucose in streptozotocin-treated mice, a model of type 1 diabetes (T1D), without restoring pancreatic β-cell function. FGF21-PEG also normalized plasma glucose levels and improved glucose tolerance in mice chronically treated with an insulin competitive insulin receptor antagonist, a model of autoimmune/Type-B insulin resistance. These data extend the pharmacological potential of FGF21 beyond the settings of T2D, fatty liver and obesity.

Human pluripotent stem cell (hPSC)-derived tissues can be used to model diseases and validate targets in cell types that are challenging to harvest and study at scale, such as neutrophils. Neutrophil dysregulation, specifically unbalanced neutrophil extracellular trap (NET) formation, plays a critical role in the prognosis and progression of multiple diseases, including COVID-19. hPSCs can provide a limitless supply of neutrophils (iNeutrophils) to study these processes and discover and validate targets in vitro. However, current iNeutrophil differentiation protocols are inefficient and generate heterogeneous cultures consisting of different granulocytes and precursors, which can confound the study of neutrophil biology. Here, we describe a method to dramatically improve iNeutrophils′ yield, purity, functionality, and maturity through the deletion of the transcription factorGATA1.GATA1knockout (KO) iNeutrophils are nearly identical to primary neutrophils in cell surface marker expression, morphology, and host defense functions. Unlike wild type (WT) iNeutrophils,GATA1KO iNeutrophils generate NETs in response to the physiologic stimulant lipid polysaccharide (LPS), suggesting they could be used as a more accurate model when performing small-molecule screens to find NET inhibitors. Furthermore, we demonstrate thatGATA1KO iNeutrophils are a powerful tool in quickly and definitively determining involvement of a given protein in NET formation.

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