Lipopolysaccharide induces intestinal glucocorticoid synthesis in a TNFalpha-dependent manner

Stringent control of immune responses in the intestinal mucosa is critical for the maintenance of immune homeostasis and prevention of tissue damage, such as observed during inflammatory bowel disease. Intestinal epithelial cells, primarily thought to form a simple physical barrier, critically regulate intestinal immune cell functions by producing immunoregulatory glucocorticoids on T-cell activation. In this study we investigated whether stimulation of cells of the innate immune system results in the induction of intestinal glucocorticoids synthesis and what role TNF-alpha plays in this process. Stimulation of the innate immune system with lipopolysaccharide (LPS) led to an up-regulation of colonic steroidogenic enzymes and the induction of intestinal glucocorticoid synthesis. The observed induction was dependent on macrophage effector functions, as depletion of macrophages using clodronate-containing liposomes, but not absence of T and B cells, inhibited intestinal glucocorticoid synthesis. LPS-induced glucocorticoid synthesis was critically dependent on TNF-alpha as it was significantly decreased in TNF-alpha-deficient animals. Both TNF receptor-1 and -2 were found to be equally involved in LPS- and T-cell-induced intestinal GC synthesis. These results describe a novel and critical role of TNF-alpha in immune cell-induced intestinal glucocorticoid synthesis.

Conformationally Controlled Electron Delocalization in n-Type Rods: Synthesis, Structure, and Optical, Electrochemical, and Spectroelectrochemical Properties of Dicyanocyclophanes

A series of dicyanobiphenyl-cyclophanes 1-6 with various pi-backbone conformations and characteristic n-type semiconductor properties is presented. Their synthesis, optical, structural, electrochemical, spectroelectrochemical, and packing properties are investigated. The X-ray crystal structures of all n-type rods allow the systematic correlation of structural features with physical properties. In addition, the results are supported by quantum mechanical calculations based on density functional theory. A two-step reduction process is observed for all n-type rods, in which the first step is reversible. The potential gap between the reduction processes depends linearly on the cos(2) value of the torsion angle phi between the pi-systems. Similarly, optical absorption spectroscopy shows that the vertical excitation energy of the conjugation band correlates with the cos(2) value of the torsion angle phi. These correlations demonstrate that the fixed intramolecular torsion angle phi is the dominant factor determining the extent of electron delocalization in these model compounds, and that the angle phi measured in the solid-state structure is a good proxy for the molecular conformation in solution. Spectroelectrochemical investigations demonstrate that conformational rigidity is maintained even in the radical anion form. In particular, the absorption bands corresponding to the SOMO-LUMO+i transitions are shifted bathochromically, whereas the absorption bands corresponding to the HOMO-SOMO transition are shifted hypsochromically with increasing torsion angle phi.

Cyclooxygenase-2 inhibition selectively attenuates bone morphogenetic protein-6 synthesis and bone formation during guided tissue regeneration in a rat model

OBJECTIVES: Bone formation during guided tissue regeneration is a tightly regulated process involving cells, extracellular matrix and growth factors. The aims of this study were (i) to examine the expression of cyclooxygenase-2 (COX-2) during bone regeneration and (ii) the effects of selective COX-2 inhibition on osseous regeneration and growth factor expression in the rodent femur model. MATERIAL AND METHODS: A standardized transcortical defect of 5 x 1.5 mm was prepared in the femur of 12 male rats and a closed half-cylindrical titanium chamber was placed over the defect. The expression of COX-2 and of platelet-derived growth factor-B (PDGF-B), bone morphogenetic protein-6 (BMP-6) and insulin-like growth factor-I/II (IGF-I/II) was analyzed at Days 3, 7, 21 and 28 semiquantitatively by reverse transcriptase-polymerase chain reaction and immunohistochemistry. The effects of COX-2 inhibition by intraperitoneal injection of NS-398 (3 mg/kg/day) were analyzed in five additional animals sacrificed at Day 14. RESULTS: Histomorphometry revealed that new bone formation occurred in the cortical defect area as well as in the supracortical region, i.e. region within the chamber by Day 7 and increased through Day 28. Immunohistochemical evidence of COX-2 and PDGF-B levels were observed early (i.e. Day 3) and decreased rapidly by Day 7. BMP-6 expression was maximal at Day 3 and slowly declined by Day 28. In contrast, IGF-I/II expression gradually increased during the 28-day period. Systemic administration NS-398 caused a statistically significant reduction (P<0.05) in new bone formation (25-30%) and was associated with a statistically significant reduction in BMP-6 protein and mRNA expression (50% and 65% at P<0.05 and P<0.01, respectively). PDGF-B mRNA or protein expression was not affected by NS-398 treatment. CONCLUSION: COX-2 inhibition resulted in reduced BMP-6 expression and impaired osseous regeneration suggesting an important role for COX-2-induced signaling in BMP synthesis and new bone formation.

Synthesis and biological evaluation of epothilone A dimeric compounds

The preparation and biological evaluation of a novel series of dimeric epothilone A derivatives (1-6) are described. Two types of diacyl spacers were introduced to establish the various dimeric epothilone A constructs. The effect of these compounds on tubulin polymerization and their cytotoxicity against four different cancer cell lines are reported. Several of the newly synthesized compounds inhibit endothelial cell differentiation and endothelial cell migration that are key steps of the angiogenic process.

Immigrant students’ psychological adjustment in the school context: A meta-synthesis of qualitative research on acculturation

This contribution focuses on the characteristics of the school context and their impact on immigrant students’ acculturation and adjustment at school. Research suggests that the ways immigrants acculturate is related to their well being (e.g. Phinney, et al., 2001; Ward & Rana-Deuba, 1999), although findings have been contradictory across methods and studies (e.g. Rogler, 1991; Escobar & Vega, 2001). Debates in acculturation research currently center on issues of acculturation measurement (e.g. Berry, 2009; Rudmin, 2009), as most research is conducted in the quantitative tradition. In addition, some have suggested (Birman, 2011) that research on acculturation in the tradition of cross-cultural psychology adopts an overly individualistic perspective, and lacks attention to the specific contexts of acculturation. Alternatively, the contextual approach proposes that the relationship between acculturation and adjustment is shaped by the surrounding context (Birman & Simon, 2013). For immigrant children, schools are the setting where the process of acculturation unfolds, and an important context in which to study their adjustment and well being (Birman, et al., 2007; Makarova & Herzog, 2011). Though rarely used in this tradition of acculturation research (Chirkov, 2009), qualitative methods are uniquely suited to gain insight to facilitate theory development, as well as appreciate the contextual nature of the acculturation process. Yet we are not aware of efforts to synthesize the empirical qualitative literature on this topic. Applying the methodology of meta-synthesis for qualitatieve research (Walsh & Downe, 2005) our contribution attempts to integrate results from qualitative studies on impact of acculturation on immigrant students’ psychological adjustment in the school context. For this purpose 84 articles which matched the inclusion criteria were selected. Overall, the results of our study show that within the school context a number of structural as well as process characteristics can be identified as crucial for immigrant youth psychological adjustment. Moreover, our findings indicate that immigrant youths’ psychological adjustment is related to other individual outcomes of acculturation in the school context such as behavioral adjustment, peer-relationships, academic achievement and identity development of immigrant youth.

Total Synthesis of Aignopsanes, A Class of Sesquiterpenes: (+)-Aignopsanoic Acid A, (−)-Methyl Aignopsanoate A, and (−)-Isoaignopsanoic A

A general strategy for the synthesis of aignopsanes, a new family of sesquiterpene natural products of marine origin, is presented. The total synthesis of (+)-aignopsanoic acid A (1), (−)-methyl aignopsanoate A (2), and (−)-isoaignopsanoic A (3) has been achieved and their absolute configuration confirmed. (+)-Microcionin-1 (4), a structurally related furanosesquiterpene isolated in both enantiomeric forms from marine sponges, was also synthesized and its absolute configuration established in an unambiguous way. Interestingly, we report that (+)-microcionin-1 (4), can be converted by a simple oxidation process to aignopsanoic acid A (1). This transformation supports the hypothesis that (+)-microcionin-1 (4) may be an intermediate in the biosynthesis of aignopsanes.