Deliberately Losing Control of C−H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism

Combined photochemical arylation, “nuisance effect” (S_NAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with S_NAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.     

Design and characterization of PNVCL-based nanofibers and evaluation of their potential applications as scaffolds for surface drug delivery of hydrophobic drugs

In this work, nanofiber scaffolds for surface drug delivery applications were obtained by electrospinning poly(N-vinylcaprolactam) (PNVCL) and its blends with poly(ε-caprolactone) and poly(N-vinylcaprolactam)-b-poly(ε-caprolactone). The process parameters to obtain smooth and beadless PNVCL fibers were optimized. The average fibers diameter was less than 1 μm, and it was determined by scanning electron microscopy analyses. Their affinity toward water was evaluated by measuring the contact angle with water. The ketoprofen release behavior from the fibers was analyzed using independent and model-dependent approaches. The low values of the release exponent (n < 0.5) obtained for 20 and 42 °C, indicating a Fickian diffusion mechanism for all formulations. Dissolution efficiencies (DEs) revealed the effect of polymer composition, methodology used in the electrospinning process, and temperature on the release rate of ketoprofen. PNVCL/poly(N-vinylcaprolactam)-b-poly(ε-caprolactone)-based nanofibers showed greater ability to control the in vitro release of ketoprofen, in view of reduced kinetic constant and DE, making this material promising system for controlling release of hydrophobic drugs. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48472.     

Tensile testing and fracture mechanism analysis of polyvinyl alcohol nanofibrous webs

A tensile properties testing study was conducted to understand the influence of thickness, cross-head speed (speed of testing), gauge length (GL; specimen test length), and sample shape on important tensile properties of polyvinyl alcohol (PVA) nanofiber webs. The effects of each testing parameter on load at break, extension at break, Young's modulus, and tensile stress–strain curve of PVA nanofiber webs are analyzed. The Welch two sample t-tests show the significant difference among tested data. Using interaction plots, two-way analysis of variance, and margin mean plots, the interaction effects among testing parameters have been analyzed. Of all the factors, cross-head speed, the interaction among GL, and sample thickness (GL: Thickness) and the interaction among GL, testing speed and sample thickness (GL: Speed: Thickness) have significant influence on the tensile properties of PVA nanofiber webs. Moreover, the hypothesized model of mechanism of tensile strain–stress curve of PVA nanofiber webs has been proposed. Based on the model, the tensile strain–stress curve can be split into three stages: linear elastic, partial break up, and complete breakage. This study will provide a better understanding of tensile testing parameters' effects and their interaction effects on the tensile properties of nanowebs.     

Glibenclamide for the Treatment of Ischemic and Hemorrhagic Stroke

Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1–transient receptor potential melastatin 4 (Sur1–Trpm4) channels and, in some cases, microglial K_ATP (Sur1–Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.