New insights into the anti-inflammatory mechanisms of glucocorticoids : an emerging role for glucocorticoid-receptor-mediated transactivation

Glucocorticoids are anti-inflammatory drugs that are widely used for the treatment of numerous (autoimmune) inflammatory diseases. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor family of transcription factors. Upon ligand binding, the GR translocates to the nucleus, where it acts either as a homodimeric transcription factor that binds glucocorticoid response elements (GREs) in promoter regions of glucocorticoid (GC)-inducible genes, or as a monomeric protein that cooperates with other transcription factors to affect transcription. For decades, it has generally been believed that the undesirable side effects of GC therapy are induced by dimer-mediated transactivation, whereas its beneficial anti-inflammatory effects are mainly due to the monomer-mediated transrepressive actions of GR. Therefore, current research is focused on the development of dissociated compounds that exert only the GR monomer-dependent actions. However, many recent reports undermine this dogma by clearly showing that GR dimer-dependent transactivation is essential in the anti-inflammatory activities of GR. Many of these studies used GR(dim/dim) mutant mice, which show reduced GR dimerization and hence cannot control inflammation in several disease models. Here, we review the importance of GR dimers in the anti-inflammatory actions of GCs/GR, and hence we question the central dogma. We summarize the contribution of various GR dimer-inducible anti-inflammatory genes and question the use of selective GR agonists as therapeutic agents

The glucocorticoid receptor in inflammatory processes : transrepression is not enough

Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of anti-inflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile

Gase, Aerosole, Tropfen und Partikel in stehenden Ultraschallfeldern: Eine Untersuchung zur Anreicherung schwerer Gase, Verdampfung levitierter Tropfen, Kristall- und Partikelbildung

Die Anreicherung schwerer Gase in stehenden Ultraschallfeldern bei 20 kHz und Schalldruckpegeln von 165-175 dB wurde untersucht und eine theoretische Interpretation des Effekts gegeben. Aus Beobachtungen von Verdampfungsprozessen akustisch levitierter Tropfen mit Hilfe eines CCD-Kamerasystems und der IR-Thermographie wurden IR-Emissionskoeffizienten, Verdampfungstemperaturen und –konstanten sowie binäre Gasdiffusionskoeffizienten von reinen Lösungsmitteln und Lösungsmittelgemischen bestimmt. Unterschiedliche Kristallisationsmechanismen bei der Tropfenverdampfung gesättigter Salzlösungen konnten beobachtet und ein Verfahren zur Herstellung und Charakterisierung von monomolekularen Tensidfilmen zur Verdampfungshemmung an der Grenzschicht Wasser/Luft auf akustisch levitierten Tropfen implementiert werden. Sekundäre Partikelbildung durch akustische Agglomeration in stehenden Ultraschallfeldern wurde für Wassernebel, Zigarettenrauch und Eisaerosol nachgewiesen. Untersuchungen zum Einfluss stehender Ultraschallfelder auf die primäre Bildung von Wasserpartikeln aus der übersättigten Gasphase wurden in einer neu entwickelten, temperatur- und druckvariablen Messzelle mit Hilfe von FTIR-Spektrometrie durchgeführt.The trapping of heavy gases in stationary ultrasonic fields has been investigated at 20 kHz and sound pressure levels of 165-175 dB. A first theoretical interpretation of the effect is given. The evaporation of acoustically levitated droplets was monitored using a CCD-camera and an IR-thermography system. IR-emission coefficients, evaporation temperatures and evaporation constants, as well as binary gas diffusion coefficients for several pure and binary solvents were evaluated from these measurements. Different crystallisation mechanisms have been observed during the evaporation of acoustically levitated droplets of saturated electrolytes. A new technique for the generation and characterisation of mono-molecular films which inhibit evaporation at the water-air interface of acoustically levitated droplets has been implemented. Secondary particle formation in stationary ultrasonic fields has been observed in the case of water fog, cigarette smoke and ice aerosols. The influence of stationary ultrasonic fields on the primary production of particles from supersaturated water vapour has been investigated in a newly developed cooling cell by FTIR-spectroscopy

Glucocorticoids suppress Wnt16 expression in osteoblasts in vitro and in vivo

Glucocorticoid-induced osteoporosis is a frequent complication of systemic glucocorticoid (GC) therapy and mainly characterized by suppressed osteoblast activity. Wnt16 derived from osteogenic cells is a key determinant of bone mass. Here, we assessed whether GC suppress bone formation via inhibiting Wnt16 expression. GC treatment with dexamethasone (DEX) decreased Wnt16 mRNA levels in murine bone marrow stromal cells (mBMSCs) time- and dose-dependently. Similarly, Wnt16 expression was also suppressed after DEX treatment in calvarial organ cultures. Consistently, mice receiving GC-containing slow-release prednisolone pellets showed lower skeletal Wnt16 mRNA levels and bone mineral density than placebo-treated mice. The suppression of Wnt16 by GCs was GC-receptor-dependent as co-treatment of mBMSCs with DEX and the GR antagonist RU-486 abrogated the GC-mediated suppression of Wnt16. Likewise, DEX failed to suppress Wnt16 expression in GR knockout-mBMSCs. In addition, Wnt16 mRNA levels were unaltered in bone tissue of GC-treated GR dimerization-defective GRdim mice, suggesting that GCs suppress Wnt16 via direct DNA-binding mechanisms. Consistently, DEX treatment reduced Wnt16 promoter activity in MC3T3-E1 cells. Finally, recombinant Wnt16 restored DEX-induced suppression of bone formation in mouse calvaria. Thus, this study identifies Wnt16 as a novel target of GC action in GC-induced suppression of bone formation

Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1−/− mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1α and 1β) was impaired in DUSP1−/− mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1−/− mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo

Chemical analysis of acoustically levitated drops by Raman spectroscopy

An experimental apparatus combining Raman spectroscopy with acoustic levitation, Raman acoustic levitation spectroscopy (RALS), is investigated in the field of physical and chemical analytics. Whereas acoustic levitation enables the contactless handling of microsized samples, Raman spectroscopy offers the advantage of a noninvasive method without complex sample preparation. After carrying out some systematic tests to probe the sensitivity of the technique to drop size, shape, and position, RALS has been successfully applied in monitoring sample dilution and preconcentration, evaporation, crystallization, an acid–base reaction, and analytes in a surface-enhanced Raman spectroscopy colloidal suspension