Discovery of Novel NLRP3 Inflammasome Inhibitors Composed of an Oxazole Scaffold Bearing an Acylsulfamide.

The NLRP3 inflammasome plays an important role in the defense mechanism of the innate immune system and has recently attracted much attention as a drug target for various inflammatory disorders. Among the strategies for generating the novel chemotype in current drug discovery, scaffold hopping and bioisosteric replacement are known to be attractive approaches. As the results of our medicinal chemistry campaign, which involved exploration of core motifs using a ring closing approach, a five-membered oxazole-based scaffold was identified, and subsequent implementation of bioisosteric replacement led to discovery of a novel chemical class of NLRP3 inflammasome inhibitor bearing the acylsulfamide group. Further optimization of aniline and sulfamide moieties to improve potency in human whole blood assay led to the identification of the orally bioactive compound 32 in the LPS challenge model. Furthermore, compound 32 attenuated kidney injury in adriamycin-induced glomerulonephritis in mice. These investigations indicated that the NLRP3 inhibitor could be a potential therapeutic agent for glomerulonephritis.

Role for Neutrophil Extracellular Traps (NETs) and Platelet Aggregation in Early Sepsis-induced Hepatic Dysfunction.

BACKGROUND/AIM: Severe sepsis is associated with high morbidity and mortality rates. Inflammation and coagulation play pivotal roles in the pathogenesis of sepsis leading to multiple organ failure, especially in the liver. The aim of the present study was to assess the mechanism from sepsis to liver damage in a mouse model. MATERIALS AND METHODS: We created a sepsis model by injecting lipopolysaccharide (LPS) intraperitoneally in mice. At 0, 6, 12, and 24 h following intraperitoneal injection of LPS, mice were euthanised and analyzed. Primary antibodies against myeloperoxidase (MPO), hepatic sinusoidal endothelial cells (SE-1), and P-selectin (CD62p) were used. Expression and localization in neutrophil, sinusoidal endothelial, and platelet cells were assessed by immunohistochemistry. RESULTS: Immunohistochemical analyses revealed a positive staining for MPO, most abundantly in neutrophil granulocytes, within the hepatic sinusoids immediately after injection. Neutrophil extracellular trap (NET)-like structures stained for MPO, indicating the presence of neutrophils undergoing NETosis, were confirmed at 6 h after LPS administration. SE-1 staining for liver sinusoidal endothelial cells was significantly reduced at 12 h post-LPS administration through sinusoidal endothelial injury or detachment. Furthermore, the presence of extravasated platelets was confirmed in the space of Disse at 24 h after LPS administration. Blood sample analyses showed that white blood cell counts and platelet counts decreased gradually, while MPO amounts increased until 12 h after LPS administration. CONCLUSION: We conclude that NET formation and intravasated platelet aggregation are the first steps from sepsis to liver damage, and that extravasated platelet aggregation promoted by NET-facilitated detachment of sinusoidal endothelial cells is the origin of sepsis-induced liver dysfunction.

Relation between muscle fiber conduction velocity and exerted dynamic characteristics of muscular tension in patients with hemiplegia caused by stroke.

[Purpose] The aim of this study was to clarify the relationships among muscle fiber conduction velocity, time-force characteristics of muscle force production, and voluntary movement in patients with hemiplegia. [Subjects and Methods] The participants in the present study were 13 patients with hemiplegia. Muscle fiber conduction velocity, deep temperature of muscles and muscle thickness were measured for the tibialis anterior, and a time force curve was obtained from dorsiflexion of the ankle and lower thigh girth (maximum, minimum) for both sides. The maximum torque rate of change and maximum torque were calculated from the force-time curve. In addition, Brunnstrom Recovery Stage was used to evaluate the function of the hemiplegic side. [Results] In all the measurement items, significant differences were observed between the hemiplegic side and the healthy side. The maximum torque rate of change and Brunnstrom Recovery Stage showed a high degree of correlation. The muscle fiber conduction velocity and maximum torque rate of change or maximum torque showed a medium degree of correlation. However, muscle fiber conduction velocity was not significantly correlated with Brunnstrom Recovery Stage. [Conclusion] Brunnstrom Recovery Stage was good as a determination factor for the maximum torque rate of change. In addition, in patients with hemiplegia, it became clear that relationship is between muscle fiber conduction velocity and time-force characteristics of muscle force production as in healthy persons.

Detection of relative and uniform motion.

We measured the lowest velocity (velocity threshold) for discriminating motion direction in relative and uniform motion stimuli, varying the contrast and the spatial frequency of the stimulus gratings. The results showed significant differences in the effects of contrast and spatial frequency on the threshold, as well as on the absolute threshold level between the two motion conditions, except when the contrast was 1% or lower. Little effect of spatial frequency was found for uniform motion, whereas a bandpass property with a peak at approximately 5 cycles per degree was found for relative motion. It was also found that contrast had little effect on uniform motion, whereas the threshold decreased with increases in contrast up to 85% for relative motion. These differences cannot be attributed to possible differences in eye movements between the relative and the uniform motion conditions, because the spatial-frequency characteristics differed in the two conditions even when the presentation duration was short enough to prevent eye movements. The differences also cannot be attributed to detecting positional changes, because the velocity threshold was not determined by the total distance of the stimulus movements. These results suggest that there are two different motion pathways: one that specializes in relative motion and one that specializes in uniform or global motion. A simulation showed that the difference in the response functions of the two possible pathways accounts for the differences in the spatial-frequency and contrast dependency of the velocity threshold.