We report herein a new strategy of the Rh(III)-catalyzed C-H activation/cyclization of indoles and pyrroles, for the divergent synthesis of privileged heterocycles. A simple derivation of indoles and pyrroles to N-carboxamides with oxidative bidentate directing group could enable rhodacycle formation and late-stage redox-neutral cyclization with alkynes, alkenes and diazo compounds, for access to five- and six-membered fused heterocycles, such as pyrimido[1,6-a]indol-1(2H)-one, 3,4-dihydropyrimido[1,6-a]indol-1(2H)-one, and 1H-imidazo[1,5-a]indol-3(2H)-ones. Kinetic isotope effect study was conducted, and a plausible mechanism was proposed. Furthermore, this protocol was applied to concise synthesis of 5-HT3 receptor antagonist in gram-scale.

Diabetes mellitus increases periodontitis and pathogenicity of the oral microbiome. To further understand mechanisms through which diabetes affects periodontitis, we examined its impact on periodontal ligament fibroblasts in vivo and in vitro. Periodontitis was induced by inoculation of Porphyromonas gingivalis and Fusobacterium nucleatum in normoglycemic and diabetic mice. Diabetes, induced by multiple low-dose injections of streptozotocin increased osteoclast numbers and recruitment of neutrophils to the periodontal ligament, which could be accounted for by increased CXC motif chemokine 2 (CXCL2) and receptor activator of nuclear factor kappa B ligand (RANKL) expression by these cells. Diabetes also stimulated a significant increase in nuclear factor kappa B (NF-κB) expression and activation in periodontal ligament (PDL) fibroblasts. Surprisingly, we found that PDL fibroblasts express a 2.3-kb regulatory unit of Col1α1 (collagen type 1, alpha 1) promoter typical of osteoblasts. Diabetes-enhanced CXCL2 and RANKL expression in PDL fibroblasts was rescued in transgenic mice with lineage-specific NF-κB inhibition controlled by this regulatory element. In vitro, high glucose increased NF-κB transcriptional activity, NF-κB nuclear localization, and RANKL expression in PDL fibroblasts, which was reduced by NF-κB inhibition. Thus, diabetes induces changes in PDL fibroblast gene expression that can enhance neutrophil recruitment and bone resorption, which may be explained by high glucose-induced NF-κB activation. Furthermore, PDL fibroblasts express a regulatory element in vivo that is typical of committed osteoblasts.

A Rh(III)-catalyzed selective coupling of N-methoxy-1H-indole-1-carboxamide and aryl boronic acids is reported. The coupling is mild and efficient toward diverse product formation, with selective C-C and C-C/C-N bond formation. Kinetic isotope effects studies were conducted to reveal a mechanism of C-H activation and electrophilic addition.

Neutrophils play an essential role in the innate immune response to microbial infection and are particularly important in clearing bacterial infection. We investigated the role of the transcription factor FOXO1 in the response of neutrophils to bacterial challenge with Porphyromonas gingivalis in vivo and in vitro. In these experiments, the effect of lineage-specific FOXO1 deletion in LyzM.Cre+FOXO1L/L mice was compared with matched littermate controls. FOXO1 deletion negatively affected several critical aspects of neutrophil function in vivo including mobilization of neutrophils from the bone marrow (BM) to the vasculature, recruitment of neutrophils to sites of bacterial inoculation, and clearance of bacteria. In vitro FOXO1 regulated neutrophil chemotaxis and bacterial killing. Moreover, bacteria-induced expression of CXCR2 and CD11b, which are essential for several aspects of neutrophil function, was dependent on FOXO1 in vivo and in vitro. Furthermore, FOXO1 directly interacted with the promoter regions of CXCR2 and CD11b. Bacteria-induced nuclear localization of FOXO1 was dependent upon toll-like receptor (TLR) 2 and/or TLR4 and was significantly reduced by inhibitors of reactive oxygen species (ROS and nitric oxide synthase) and deacetylases (Sirt1 and histone deacetylases). These studies show for the first time that FOXO1 activation by bacterial challenge is needed to mobilize neutrophils to transit from the BM to peripheral tissues in response to infection as well as for bacterial clearance in vivo. Moreover, FOXO1 regulates neutrophil function that facilitates chemotaxis, phagocytosis, and bacterial killing.