Vapor Sorption-Desorption Phenomena of HD and GB Simulants from Polyurethane Thin Films on Aluminum Oxide via a Quartz Crystal Microbalance.

Protection and decontamination of surfaces after exposure to chemical warfare agents (CWAs) are of considerable interest to the homeland defense and battlespace operation communities. In this work, polyurethane was spin-coated onto aluminum oxide quartz crystal microbalance (QCM) sensors. Polyurethane film thickness was varied by altering the concentration of the polymer/chloroform solution used for spin-coating. Atomic force microscopy confirmed the formation of smooth, homogeneous films on the QCM sensor surface. Aluminum oxide QCM sensors coated with polyurethane were exposed to saturated vapors of dichloropentane (DCP), a mustard gas (HD) simulant, and dimethyl methylphosphonate (DMMP), a sarin gas (GB) simulant, and the mass uptake, diffusion coefficient, volume fraction, and partition coefficient of the simulant in the film were determined from QCM data. Results showed that both DCP and DMMP readily sorbed into the films although the mass uptake of DCP was greater than that of DMMP owing to DCP's higher vapor pressure. Additionally, the CWA simulant uptake increased with polyurethane film thickness. Sorption diffusion coefficients were 1 × 10-13 cm2/s and 1 × 10-12 cm2/s for DCP and DMMP vapor, respectively. Simulant desorption was also measured and showed that some DMMP remained in the film/substrate system, while DCP sorption was fully reversible. Reversible desorption for both CWA simulants was relatively quick and independent over the range of film thicknesses studied, with average desorption diffusion coefficients of 2 × 10-9 cm2/s and 1 × 10-11 cm2/s for DCP and DMMP, respectively. Collectively, this study is expected to inform protection and decontamination strategies of equipment and structures upon exposure to CWAs.

Endothelin A receptor antagonist attenuated renal iron accumulation in iron overload heme oxygenase-1 knockout mice.

Progressive iron accumulation and renal impairment are prominent in both patients and mouse models of sickle cell disease (SCD). Endothelin A receptor (ETA) antagonism prevents this iron accumulation phenotype and reduces renal iron deposition in the proximal tubules of SCD mice. To better understand the mechanisms of iron metabolism in the kidney and the role of the ETA receptor in iron chelation and transport, we studied renal iron handling in a nonsickle cell iron overload model, heme oxygenase-1 (Hmox-1-/-) knockout mice. We found that Hmox-1-/- mice had elevated plasma endothelin-1 (ET-1), cortical ET-1 mRNA expression, and renal iron content compared with Hmox-1+/+ controls. The ETA receptor antagonist, ambrisentan, attenuated renal iron deposition, without any changes to anemia status in Hmox-1-/- mice. This was accompanied by reduced urinary iron excretion. Finally, ambrisentan had an important iron recycling effect by increasing the expression of the cellular iron exporter, ferroportin-1 (FPN-1), and circulating total iron levels in Hmox-1-/- mice. These findings suggest that the ET-1/ETA signaling pathway contributes to renal iron trafficking in a murine model of iron overload.

Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE).

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50 000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration's approval for the prophylactic treatment of HAE attacks in patients 12 years and older.

High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is characterized by chronic hemolytic anemia, vaso-occlusive crises, chronic inflammation, and activation of coagulation. The clinical complications such as painful crisis, stroke, pulmonary hypertension, nephropathy and venous thromboembolism lead to cumulative organ damage and premature death. High molecular weight kininogen (HK) is a central cofactor for the kallikrein-kinin and intrinsic coagulation pathways, which contributes to both coagulation and inflammation. OBJECTIVE: We hypothesize that HK contributes to the hypercoagulable and pro-inflammatory state that causes end-organ damage and early mortality in sickle mice. METHODS: We evaluated the role of HK in the Townes mouse model of SCD. RESULTS/CONCLUSIONS: We found elevated plasma levels of cleaved HK in sickle patients compared to healthy controls, suggesting ongoing HK activation in SCD. We used bone marrow transplantation to generate wild type and sickle cell mice on a HK-deficient background. We found that short-term HK deficiency attenuated thrombin generation and inflammation in sickle mice at steady state, which was independent of bradykinin signaling. Moreover, long-term HK deficiency attenuates kidney injury, reduces chronic inflammation, and ultimately improves survival of sickle mice.