Discovery of Novel Small Molecule Dual Inhibitor Targeting Toll-Like Receptors 7 and 9.

The aberrant secretion of proinflammatory cytokines by immune cells is the principal cause of inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Toll-like receptor 7 (TLR7) and TLR9, sequestered to the endosomal compartment of dendritic cells and macrophages, are closely associated with the initiation and progression of these diseases. Therefore, the development of drugs targeting dysregulated endosomal TLRs is imperative to mitigate systemic inflammation. Here, we applied the principles of computer-aided drug discovery to identify a novel low-molecular-weight compound, TLR inhibitory compound 10 (TIC10), and its potent derivative (TIC10g), which demonstrated dual inhibition of TLR7 and TLR9 signaling pathways. Compared to TIC10, TIC10g exhibited a more pronounced inhibition of the TLR7- and TLR9-mediated secretion of the proinflammatory cytokine tumor necrosis factor-α in a mouse macrophage cell line and mouse bone marrow dendritic cells in a concentration-dependent manner. While TIC10g slightly prevented TLR3 and TLR8 activation, it had no impact on cell surface TLRs (TLR1/2, TLR2/6, TLR4, or TLR5), indicating its selectivity for TLR7 and TLR9. Additionally, mechanistic studies suggested that TIC10g interfered with TLR9 activation by CpG DNA and suppressed downstream pathways by directly binding to TLR9. Western blot analysis revealed that TIC10g downregulated the phosphorylation of the p65 subunit of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase, p38-MAPK, and c-Jun N-terminal kinase. These findings indicate that the novel ligand, TIC10g, is a specific dual inhibitor of endosomal TLRs (TLR7 and TLR9), disrupting MAPK- and NF-κB-mediated proinflammatory gene expression.

High-Performance Photocatalytic Cementitious Materials Containing Synthetic Fibers and Shrinkage-Reducing Admixture.

This study aims to examine the mechanical, shrinkage and chemical properties of photocatalytic cementitious materials containing synthetic fibers and a shrinkage-reducing admixture (SRA). Two types of titanium dioxide (TiO2) powders and white Portland cement were considered along with ordinary Portland cement (OPC) as a control. Two types of synthetic fibers, i.e., glass and polyethylene (PE), and an SRA with contents varying from 0% to 3% were also considered. Using the TiO2 powders and the white Portland cement was effective in reducing the nitrogen oxides (NOx) concentration in cement composites. The use of PE fibers was more effective than glass fibers in terms of the mechanical properties, i.e., the compressive strength and tensile performance. With the addition of TiO2 powders and SRA or the replacement of OPC with white cement, the mechanical properties of the cement mortar generally deteriorated. The total shrinkage of the mortar could be reduced by incorporating the fibers at volume fractions greater than 1%, and the glass fiber was more effective than the PE fiber in this regard. The TiO2 powders had no significant impact on the shrinkage reduction of the cement mortar, whereas the SRA and the white Portland cement effectively reduced shrinkage. The addition of 3% SRA decreased the total shrinkage by 43%, while the replacement of the OPC with white cement resulted in a 20% reduction in the shrinkage.

Talofibular Bony Impingement in the Ankle.

BACKGROUND: Talofibular bony impingement has not previously been reported, since it is difficult to detect on plain radiograph, similar to the spur on the anterior border of the medial malleolus and anterior portion of the medial talar facet. We hypothesized that talofibular bony impingement can cause limited dorsiflexion of the ankle. The aim of this study was to evaluate talofibular bony impingement as a distinct form of impingement that limits dorsiflexion of the ankle. METHODS: This study included 20 consecutive patients (21 ankles) with talofibular impingement and 19 consecutive patients (19 ankles) with lateral ankle instability without talofibular impingement. Presence or absence of talofibular impingement was confirmed under direct intraoperative visualization. Dorsiflexion before and after excision of the impinging spurs was measured. Findings on plain radiographs and computed tomography were compared between the groups. Pre- and postoperative clinical assessments were done with Foot Function Index, visual analog scale for pain, and American Orthopaedic Foot & Ankle Society ankle-hindfoot score at a mean follow-up of 1.4 years. RESULTS: After removal of the bony impingement, the range of dorsiflexion increased by a mean 7.9 degrees (range, 2.5 to 11.0 degrees) in the impingement group. The mean distance between the fibula and lateral process of the talus on weight- bearing anteroposterior radiograph of the ankle was 1.2 mm (range, 0 to 4.5) in the impingement group and 3.2 mm (range, 1 to 4.5) in the control group. On axial computed tomography image, bony protrusion of the lateral process of the talus was frequently present in the impingement group, and the mean amount of protrusion was more than that of the control group. Clinical findings improved overall. CONCLUSIONS: Talofibular impingement was a cause of limited dorsiflexion, and the diagnosis was confirmed intraoperatively. LEVEL OF EVIDENCE: Level III, retrospective comparative study.