Selective inhibition of 11beta-hydroxysteroid dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid

Elevated cortisol concentrations have been associated with metabolic diseases such as diabetes type 2 and obesity. 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, catalyzing the conversion of inactive 11-ketoglucocorticoids into their active 11beta-hydroxy forms, plays an important role in the regulation of cortisol levels within specific tissues. The selective inhibition of 11beta-HSD1 is currently considered as promising therapeutic strategy for the treatment of metabolic diseases. In recent years, natural compound-derived drug design has gained considerable interest. 18beta-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin, is not selective and inhibits both 11beta-HSD1 and 11beta-HSD2. Here, we compare the biological activity of 18beta-GA and its diastereomer 18alpha-GA against the two enzymes in lysates of transfected HEK-293 cells and show that 18alpha-GA selectively inhibits 11beta-HSD1 but not 11beta-HSD2. This is in contrast to 18beta-GA, which preferentially inhibits 11beta-HSD2. Using a pharmacophore model based on the crystal structure of the GA-derivative carbenoxolone in complex with human 11beta-HSD1, we provide an explanation for the differences in the activities of 18alpha-GA and 18beta-GA. This model will be used to design novel selective derivatives of GA

Overview of ASDEX Upgrade results

The medium size divertor tokamak ASDEX Upgrade (major and minor radii 1.65 m and 0.5 m, respectively, magnetic-field strength 2.5 T) possesses flexible shaping and versatile heating and current drive systems. Recently the technical capabilities were extended by increasing the electron cyclotron resonance heating (ECRH) power, by installing 2 × 8 internal magnetic perturbation coils, and by improving the ion cyclotron range of frequency compatibility with the tungsten wall. With the perturbation coils, reliable suppression of large type-I edge localized modes (ELMs) could be demonstrated in a wide operational window, which opens up above a critical plasma pedestal density. The pellet fuelling efficiency was observed to increase which gives access to H-mode discharges with peaked density profiles at line densities clearly exceeding the empirical Greenwald limit. Owing to the increased ECRH power of 4 MW, H-mode discharges could be studied in regimes with dominant electron heating and low plasma rotation velocities, i.e. under conditions particularly relevant for ITER. The ion-pressure gradient and the neoclassical radial electric field emerge as key parameters for the transition. Using the total simultaneously available heating power of 23 MW, high performance discharges have been carried out where feed-back controlled radiative cooling in the core and the divertor allowed the divertor peak power loads to be maintained below 5 MW m −2 . Under attached divertor conditions, a multi-device scaling expression for the power-decay length was obtained which is independent of major radius and decreases with magnetic field resulting in a decay length of 1 mm for ITER. At higher densities and under partially detached conditions, however, a broadening of the decay length is observed. In discharges with density ramps up to the density limit, the divertor plasma shows a complex behaviour with a localized high-density region in the inner divertor before the outer divertor detaches. Turbulent transport is studied in the core and the scrape-off layer (SOL). Discharges over a wide parameter range exhibit a close link between core momentum and density transport. Consistent with gyro-kinetic calculations, the density gradient at half plasma radius determines the momentum transport through residual stress and thus the central toroidal rotation. In the SOL a close comparison of probe data with a gyro-fluid code showed excellent agreement and points to the dominance of drift waves. Intermittent structures from ELMs and from turbulence are shown to have high ion temperatures even at large distances outside the separatrix

Overview of ASDEX Upgrade results

The medium size divertor tokamak ASDEX Upgrade (major and minor radii 1.65 m and 0.5 m, respectively, magnetic-field strength 2.5 T) possesses flexible shaping and versatile heating and current drive systems. Recently the technical capabilities were extended by increasing the electron cyclotron resonance heating (ECRH) power, by installing 2 × 8 internal magnetic perturbation coils, and by improving the ion cyclotron range of frequency compatibility with the tungsten wall. With the perturbation coils, reliable suppression of large type-I edge localized modes (ELMs) could be demonstrated in a wide operational window, which opens up above a critical plasma pedestal density. The pellet fuelling efficiency was observed to increase which gives access to H-mode discharges with peaked density profiles at line densities clearly exceeding the empirical Greenwald limit. Owing to the increased ECRH power of 4 MW, H-mode discharges could be studied in regimes with dominant electron heating and low plasma rotation velocities, i.e. under conditions particularly relevant for ITER. The ion-pressure gradient and the neoclassical radial electric field emerge as key parameters for the transition. Using the total simultaneously available heating power of 23 MW, high performance discharges have been carried out where feed-back controlled radiative cooling in the core and the divertor allowed the divertor peak power loads to be maintained below 5 MW m −2 . Under attached divertor conditions, a multi-device scaling expression for the power-decay length was obtained which is independent of major radius and decreases with magnetic field resulting in a decay length of 1 mm for ITER. At higher densities and under partially detached conditions, however, a broadening of the decay length is observed. In discharges with density ramps up to the density limit, the divertor plasma shows a complex behaviour with a localized high-density region in the inner divertor before the outer divertor detaches. Turbulent transport is studied in the core and the scrape-off layer (SOL). Discharges over a wide parameter range exhibit a close link between core momentum and density transport. Consistent with gyro-kinetic calculations, the density gradient at half plasma radius determines the momentum transport through residual stress and thus the central toroidal rotation. In the SOL a close comparison of probe data with a gyro-fluid code showed excellent agreement and points to the dominance of drift waves. Intermittent structures from ELMs and from turbulence are shown to have high ion temperatures even at large distances outside the separatrix

Overview of ASDEX Upgrade results

The ASDEX Upgrade (AUG) programme is directed towards physics input to critical elements of the ITER design and the preparation of ITER operation, as well as addressing physics issues for a future DEMO design. Since 2015, AUG is equipped with a new pair of 3-strap ICRF antennas, which were designed for a reduction of tungsten release during ICRF operation. As predicted, a factor two reduction on the ICRF-induced W plasma content could be achieved by the reduction of the sheath voltage at the antenna limiters via the compensation of the image currents of the central and side straps in the antenna frame. There are two main operational scenario lines in AUG. Experiments with low collisionality, which comprise current drive, ELM mitigation/suppression and fast ion physics, are mainly done with freshly boronized walls to reduce the tungsten influx at these high edge temperature conditions. Full ELM suppression and non-inductive operation up to a plasma current of I-p = 0.8 MA could be obtained at low plasma density. Plasma exhaust is studied under conditions of high neutral divertor pressure and separatrix electron density, where a fresh boronization is not required. Substantial progress could be achieved for the understanding of the confinement degradation by strong D puffing and the improvement with nitrogen or carbon seeding. Inward/outward shifts of the electron density profile relative to the temperature profile effect the edge stability via the pressure profile changes and lead to improved/decreased pedestal performance. Seeding and D gas puffing are found to effect the core fueling via changes in a region of high density on the high field side (HFSHD). The integration of all above mentioned operational scenarios will be feasible and naturally obtained in a large device where the edge is more opaque for neutrals and higher plasma temperatures provide a lower collisionality. The combination of exhaust control with pellet fueling has been successfully demonstrated. High divertor enrichment values of nitrogen E-N >= 10 have been obtained during pellet injection, which is a prerequisite for the simultaneous achievement of good core plasma purity and high divertor radiation levels. Impurity accumulation observed in the all-metal AUG device caused by the strong neoclassical inward transport of tungsten in the pedestal is expected to be relieved by the higher neoclassical temperature screening in larger devices.Peer reviewe

Evolution of nitrogen concentration and ammonia production in N-2-seeded H-mode discharges at ASDEX Upgrade

Ammonia formation was studied in a series of dedicated nitrogen seeded H-mode discharges at ASDEX Upgrade. The evolution of ammonia formation was investigated with a reference phase before the seeding, and a long, stable flat-top nitrogen-seeded phase. It was monitored with divertor spectroscopy and analysis of the exhaust gas. The amount of the detected ammonia increased continuously over the course of five discharges with the same nitrogen seeding rate. The same trend was observed in the nitrogen density in the core plasma, as measured by charge exchange recombination spectroscopy and other signals, linked to the effects of nitrogen seeding. The results show that the rate of ammonia formation exhibited the same trend as the nitrogen density in the plasma. This density, in turn, was strongly influenced by the nitrogen wall inventory. The spatial distribution of the detected ammonia suggests that a significant contribution to the net ammonia formation is made in plasma-shaded areas, through surface reactions of neutral species

Recent ASDEX upgrade research in support of ITER and DEMO

Recent experiments on the ASDEX Upgrade tokamak aim at improving the physics base for ITER and DEMO to aid the machine design and prepare efficient operation. Type I edge localized mode (ELM) mitigation using resonant magnetic perturbations (RMPs) has been shown at low pedestal collisionality (nu(*)(ped) < 0.4). In contrast to the previous high nu* regime, suppression only occurs in a narrow RMP spectral window, indicating a resonant process, and a concomitant confinement drop is observed due to a reduction of pedestal top density and electron temperature. Strong evidence is found for the ion heat flux to be the decisive element for the L-H power threshold. A physics based scaling of the density at which the minimum P-LH occurs indicates that ITER could take advantage of it to initiate H-mode at lower density than that of the final Q = 10 operational point. Core density fluctuation measurements resolved in radius and wave number show that an increase of R/L-Te introduced by off-axis electron cyclotron resonance heating (ECRH) mainly increases the large scale fluctuations. The radial variation of the fluctuation level is in agreement with simulations using the GENE code. Fast particles are shown to undergo classical slowing down in the absence of large scale magnetohydrodynamic (MHD) events and for low heating power, but show signs of anomalous radial redistribution at large heating power, consistent with a broadened off-axis neutral beam current drive current profile under these conditions. Neoclassical tearing mode (NTM) suppression experiments using electron cyclotron current drive (ECCD) with feedback controlled deposition have allowed to test several control strategies for ITER, including automated control of (3,2) and (2,1) NTMs during a single discharge. Disruption mitigation studies using massive gas injection (MGI) can show an increased fuelling efficiency with high field side injection, but a saturation of the fuelling efficiency is observed at high injected mass as needed for runaway electron suppression. Large locked modes can significantly decrease the fuelling efficiency and increase the asymmetry of radiated power during MGI mitigation. Concerning power exhaust, the partially detached ITER divertor scenario has been demonstrated at P-sep/R = 10 MW m(-1) in ASDEX Upgrade, with a peak time averaged target load around 5 MW m(-2), well consistent with the component limits for ITER. Developing this towards DEMO, full detachment was achieved at P-sep/R = 7 MW m(-1) and stationary discharges with core radiation fraction of the order of DEMO requirements (70% instead of the 30% needed for ITER) were demonstrated. Finally, it remains difficult to establish the standard ITER Q = 10 scenario at low q(95) = 3 in the all-tungsten (all-W) ASDEX Upgrade due to the observed poor confinement at low beta(N). This is mainly due to a degraded pedestal performance and hence investigations at shifting the operational point to higher beta(N) by lowering the current have been started. At higher q(95), pedestal performance can be recovered by seeding N-2 as well as CD4, which is interpreted as improved pedestal stability due to the decrease of bootstrap current with increasing Z(eff). Concerning advanced scenarios, the upgrade of ECRH power has allowed experiments with central ctr-ECCD to modify the q-profile in improved H-mode scenarios, showing an increase in confinement at still good MHD stability with flat elevated q-profiles at values between 1.5 and 2