Sensitizer-Free Photochemical Regeneration of Benzimidazoline Organohydride.

Organohydrides are an important class of organic compounds that can provide hydride anions for chemical and biochemical reactions, as demonstrated by reduced nicotinamide adenine dinucleotides serving as important natural redox cofactors. The coupling of hydride transfer from the organohydride to the substrate and subsequent regeneration of the organohydride from its oxidized form can realize organohydride-catalyzed reduction reactions. Depending on the structure of the organohydride, its hydridicity and ease of regeneration vary. Benzimidazoline (BIH) is one of the strongest synthetic C-H hydride donors; however, its reductive regeneration requires highly reducing conditions. In this study, we synthesized various oxidized and reduced forms of BIH derivatives with aryl groups at the 2-position and investigated their photophysical and electrochemical properties. 4-(Dimethylamino)phenyl-substituted BIH exhibited salient red-shifted absorption compared with other synthesized BIH derivatives, and visible-light-driven regeneration without using an external photosensitizer was achieved. This knowledge has significant implications for the future development of solar-energy-based catalytic photoreduction technologies that utilize organohydride regeneration strategies.

Effects of combined application of fibroblast growth factor (FGF)-2 and carbonate apatite for tissue regeneration in a beagle dog model of one-wall periodontal defect.

Introduction: There has been an increasing desire for the development of predictive periodontal regenerative therapy for severe periodontitis. In this study, we investigated the effect of the combined use of fibroblast growth factor-2 (FGF-2), a drug for periodontal regeneration approved in Japan, and carbonated apatite (CO3Ap), bioresorbable and osteoconductive scaffold, on periodontal regeneration in beagle dog model of one-wall periodontal defect (severe intraosseous defect) for 24 weeks in comparison with CO3Ap or vehicle alone. Methods: One-wall periodontal defects were created (mesiodistal width × depth: 4 × 4 mm) on the mesial portion of the mandibular first molar (M1) of beagle dogs on both side. Mixture of FGF-2 and CO3Ap, vehicle and CO3Ap, or vehicle alone were administered to the defects and designated as groups FGF-2+CO3Ap, CO3Ap, and control, respectively. To assess the periodontal regeneration, radiographic analysis over time for 24 weeks, and micro computed tomography (µCT) and histological evaluation at 6 and 24 weeks were performed. Results: For the regenerated tissue in the defect site, the mineral content of the FGF-2+CO3Ap group was higher than that of the CO3Ap group in the radiographic analysis at 6-24 weeks. In the context of new bone formation and replacement, the FGF-2+CO3Ap group exhibited significantly greater new bone volume and smaller CO3Ap volume than the CO3Ap group in the µCT analysis at 6 and 24 weeks. Furthermore, the density of the new bone in the FGF-2+CO3Ap group at 24 weeks was similar to those in the control and CO3Ap groups. Histological evaluation revealed that the length of the new periodontal ligament and cementum in the FGF-2+CO3Ap group was greater than that in the CO3Ap group at 6 weeks. We also examined the effect of the combined use of the FGF-2 and CO3Ap on the existing bone adjacent to the defect and demonstrated that the existing bone height and volume in the FGF-2+CO3Ap group remained significantly greater than those in the CO3Ap group. Conclusion: This study demonstrated that the combination of FGF-2 and CO3Ap was effective not only in enhancing new bone formation and replacing scaffold but also in maintaining the existing bone adjacent to the defect site in a beagle dog model of one-wall periodontal defect. Additionally, new periodontal tissues induced by FGF-2 and CO3Ap may follow a maturation process similar to that formed by spontaneous healing. This suggests that the combined use of FGF-2 and CO3Ap would promote periodontal regeneration in severe bony defects of periodontitis patient.

Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration.

Exposure of T cells to inflammatory cytokines leads to phosphorylation-dependent activation of signal transducer and activator of transcription (STAT) 3. T cells from patients with systemic lupus erythematosus (SLE) display increased levels of total and phosphorylated STAT3 which resides primarily in the nucleus. Increased STAT3 is associated with increased expression of target genes. Silencing of STAT3 expression using a small interfering RNA approach resulted in decreased chemokine-provoked SLE T cell migration. Our data suggest that inhibition of STAT3 expression may reverse the signaling aberrations involved in SLE T cell migration.

Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune/inflammatory disease characterized by autoantibody production and abnormal T cells that infiltrate tissues through not well-known mechanisms. We report that SLE T lymphocytes display increased levels of CD44, ezrin, radixin, and moesin (ERM) phosphorylation, stronger actin polymerization, higher polar cap formation, and enhanced adhesion and chemotactic migration compared with T cells from patients with rheumatoid arthritis and normal individuals. Silencing of CD44 by CD44 small interfering RNA in SLE T cells inhibited significantly their ability to adhere and migrate as did treatment with Rho kinase and actin polymerization inhibitors. Forced expression of T567D-ezrin, a phosphorylation-mimic form, enhanced remarkably the adhesion and migration rate of normal T cells. Anti-CD3/TCR autoantibodies present in SLE sera caused increased ERM phosphorylation, adhesion, and migration in normal T cells. pERM and CD44 are highly expressed in T cells infiltrating in the kidneys of patients with lupus nephritis. These data prove that increased ERM phosphorylation represents a key molecular abnormality that guides T cell adhesion and migration in SLE patients.

2,3-Diphenylpropionic acids as potent VLA-4 antagonists.

The discovery and SAR of 2,3-diphenylpropionic acid derivatives as highly potent VLA-4 antagonists are described. One representative compound, 9cc has inhibited intercellular adhesion by a VCAM-1/VLA-4 interaction with an IC(50) of 1.7 nM, and has good pharmacokinetics and oral bioavailability.

Reverse hydroxamate-based selective TACE inhibitors.

Reverse hydroxamate-based selective TACE inhibitors are described. They have potent TACE inhibitory activities and excellent selectivities against MMP-1, 2, 3, 8, 9, 13, 14, and 17. One representative compound, 18 has demonstrated an excellent oral inhibitory activity of the lipopolysaccharide (LPS)-stimulated TNF-alpha production in rats.