Sobetirome

Rationale: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a critical syndrome with a mortality rate of up to 40%, and it is characterized by a prominent inflammatory cascade. The inflammasome and pyroptosis play crucial regulatory roles in regulating various inflammatory-related diseases by serving as pivotal signaling platforms for inflammatory responses and mediating the release of substantial quantities of inflammatory factors. Our previous studies confirmed that GC-1, a clinical-stage thyroid hormone analog, effectively mitigated pulmonary fibrosis by restoring mitochondrial function in epithelial cells. However, the potential effects of GC-1 on macrophage inflammasome assembly and pyroptosis in lung injury as well as the underlying mechanisms, remain unclear. Methods: The effects of GC-1 on lung injury, oxidative damage and inflammation were evaluated in two murine models of ALI (LPS- or HCl-induced models) by assessing lung pathology, the concentrations of IL-1β and IL-18 in BAL fluid, inflammasome and the levels of inflammasome- and pyroptosis-related proteins. Additionally, the impact of GC-1 on ROS-mediated inflammasome assembly and pyroptosis was investigated by examining ROS levels, Nrf2 signaling, and inflammasome adaptor protein ASC levels in mouse alveolar macrophages and human THP-1 macrophages treated with LPS and ATP. The Nrf2 inhibitor ML385 and the mitochondrial-ROS inhibitor Mito-TEMPO were used to further elucidate the effect of GC-1 on the Nrf2-p53-ASC pathway. Results: GC-1 significantly alleviated inflammation and lung injury in ALI model mice, as indicated by pulmonary pathology, inflammatory cytokine levels, ROS production and pyroptosis rates. Consistently, GC-1 inhibited ASC recruitment and oligomerization in macrophages, which suppressed the gasdermin D-mediated release of IL-1β and IL-18. These findings indicated a reduction in inflammasome assembly and pyroptosis initiation. Further research revealed that GC-1 may mitigate oxidative stress induced by mitochondrial damage through Nrf2 signaling, thereby inhibiting the expression of ROS-activated p53 and the target gene ASC. This protective effect of GC-1 could be reversed by ML385 and mimicked by Mito-TEMPO. Conclusions: This study presents a novel mechanism for treating ALI in which GC-1 inhibits macrophage ROS-mediated inflammasome assembly and pyroptosis through Nrf2-p53-ASC pathway. These findings highlight the promising potential of the use of GC-1 as an anti-inflammatory and antioxidant drug in the treatment of ALI/ARDS.

The purpose of this study was to assess the effect of thermomechanical aging on fracture strength of CAD/CAM (computer aided design and computer aided manufacturing) anterior crowns.

A resin maxillary central incisor was prepared and 96 epoxy resin replicas were obtained. Anterior crowns were produced and divided into four groups: IPS (IPS e.max CAD, 1.5 mmthickness), CD (Celtra Duo, 1.5 mm thickness), GC (GC Initial UHT, 1.5 mm thickness) and GC1 (GC Initial UHT, 1 mm thickness). Twelve crowns of each group were subjected to a chewing simulator for 240,000 cycles, and the other 12 crowns were regarded as control. Fracture resistance of aged and non-aged crowns were tested using a universal testing machine (Shimadzu AGS-X). One-way ANOVA, Tukey post hoc and independent sample t-tests were used to analyze the data and a P value < .05 was considered significant.

IPS crowns without aging had the highest (2094.3 ± 399.31 N), and the GC1 crowns after aging had the lowest (1216.99 ± 302.96 N) fracture strength values. The difference of fracture strength among the same thickness samples without aging was not statistically significant (P > .05). The fracture strength of the GC1 group was significantly lower than those of the other groups (P < .05). After aging; GC group showed significantly higher fracture strength than the IPS and GC1 groups. The CD group's fracture strength was significantly higher than the GC1 group (P < .05). Aging significantly decreased the fracture strength of the IPS group (P < .05).

All monolithic crowns employed in this research proved to be resistant to physiological chewing forces in the anterior region.