Nuclear receptor CAR represses TNFα-induced cell death by interacting with the anti-apoptotic GADD45B

Background: Phenobarbital (PB) is the most well-known among numerous non-genotoxic carcinogens that cause the development of hepatocellular carcinoma (HCC). PB activates nuclear xenobiotic receptor Constitutive Active/Androstane Receptor (CAR; NR1I3) and this activation is shown to determine PB promotion of HCC in mice. The molecular mechanism of CAR-mediated tumor promotion, however, remains elusive at the present time. Here we have identified Growth Arrest and DNA Damage-inducible 45β (GADD45B) as a novel CAR target, through which CAR represses cell death. Methodology/Principal Findings: PB activation of nuclear xenobiotic receptor CAR is found to induce the Gadd45b gene in mouse liver throughout the development of HCC as well as in liver tumors. Given the known function of GADD45B as a factor that represses Mitogen-activated protein Kinase Kinase 7-c-Jun N-terminal Kinase (MKK7-JNK) pathway-mediated apoptosis, we have now demonstrated that CAR interacts with GADD45B to repress Tumor Necrosis Factor α (TNFα)-induced JNK1 phosphorylation as well as cell death. Primary hepatocytes, prepared from Car+/+, Car-/-, Gadd45b+/+ and Gadd45b-/- mice, were treated with TNFα and Actinomycin D to induce phosphorylation of JNK1 and cell death. Cotreatment with the CAR activating ligand TCPOBOP (1,4 bis[2-(3,5-dichloropyridyloxy)]benzene) has resulted in repression of both phosphorylation and cell death in the primary hepatocytes from Car+/+ but not Car2/2mice. Repression by TCPOBOP was not observed in those prepared from Gadd45b-/- mice. In vitro protein-protein interaction and phosphorylation assays have revealed that CAR interacts with MKK7 and represses the MKK7-mediated phosphorylation of JNK1. Conclusions/Significance: CAR can form a protein complex with GADD45B, through which CAR represses MKK7-mediated phosphorylation of JNK1. In addition to activating the Gadd45b gene, CAR may repress death of mouse primary hepatocytes by forming a GADD45B complex and repressing MKK7-mediated phosphorylation of JNK1. The present finding that CAR can repress cell death via its interaction with GADD45B provides an insight for further investigations into the CAR-regulated molecular mechanism by which PB promotes development of HCC

Prednisone and azathioprine in patients with inflammatory cardiomyopathy: systematic review and meta-analysis

Aims: Chronic non-viral myocarditis, also called inflammatory cardiomyopathy, can be treated with immune suppression on tops of optimal medical therapy (OMT) for heart failure, using a combination of prednisolone and azathioprine (IPA). However, there has been inconsistency in the effects of immunosuppression treatment. This meta-analysis is the first to evaluate all available data of the effect of this treatment on left ventricular ejection fraction (LVEF) and the combined clinical endpoint of cardiovascular mortality and/or heart transplantation-free survival. Methods and results: All trials with using IPA vs. OMT in this syndrome were searched using OVID Medline and ClinicalTrials. gov, following the PRISMA guidelines. Missing data were retrieved after contacting the corresponding authors. All data was reviewed and analysed using and standard meta-analysis methods. A random effect model was used to pool the effect sizes. A total of four trials (three randomised controlled trials and one propensity-matched retrospective registry) including 369 patients were identified. IPA on top of OMT did not improve LVEF [mean difference 9.9% (95% confidence interval -1.8, 21.7)] with significant heterogeneity. When we limited our pooled estimate to the published studies only, significant LVEF improvement by IPA was observed [14% (1.4, 26.6)]. No cardiovascular mortality benefit was observed with the intervention [risk ratio 0.34 (0.08, 1.51)]. Conclusions: At the moment, there is insufficient evidence supporting functional and prognostic benefits of IPA added to OMT in virus negative inflammatory positive cardiomyopathy. Further adequate-powered well-designed prospective RCTs should be warranted to explore the potential effects of adding immunosuppressive therapy to OMT

Proton NMR measurements of the local magnetic field in the paramagnetic metal and antiferromagnetic insulator phases of λ\lambda-(BETS)2_{2}FeCl4_{4}

Measurements of the $^{1}$H-NMR spectrum of a small ($\sim$ 4 $\mu$g) single crystal of the organic conductor $\lambda$-(BETS)$_{2}$FeCl$_{4}$ are reported with an applied magnetic field $\bf{B}$$_{0}$ = 9 T parallel to the a-axis in the $ac$-plane over a temperature $(T)$ range 2.0 $-$ 180 K. They provide the distribution of the static local magnetic field at the proton sites in the paramagnetic metal (PM) and antiferromagnetic insulator (AFI) phases, along with the changes that occur at the PM$-$AFI phase transition. The spectra have six main peaks that are significantly broadened and shifted at low $T$. The origin of these features is attributed to the large dipolar field from the 3d Fe$^{3+}$ ion moments (spin $S_{\rm{d}}$ = 5/2). Their amplitude and $T-$dependence are modeled using a modified Brillouin function that includes a mean field approximation for the total exchange interaction ($J_{0}$) between one Fe$^{3+}$ ion and its two nearest neighbors. A good fit is obtained using $J_{0}$ = $-$ 1.7 K. At temperatures below the PM$-$AFI transition temperature $T_{MI}$ = 3.5 K, an extra peak appears on the high frequency side of the spectrum and the details of the spectrum become smeared. Also, the rms linewidth and the frequency shift of the spectral distribution are discontinuous, consistent with the transition being first-order. These measurements verify that the dominant local magnetic field contribution is from the Fe$^{3+}$ ions and indicate that there is a significant change in the static local magnetic field distribution at the proton sites on traversing the PM to AFI phase transition.Comment: 11 pages, 7 figures. Revised version of cond-mat/0605044 resubmitted to Phys. Rev. B in response to comments of Editor and reviewer

Laboratory study on heterogeneous decomposition of methyl chloroform on various standard aluminosilica clay minerals as a potential tropospheric sink

International audienceMethyl chloroform (1,1,1-trichloroethane, CH3CCl3) was found to decompose heterogeneously on seven types of standard clay minerals (23 materials) in dry air at 313 K in the laboratory. All reactions proceeded through the elimination of HCl; CH3CCl3 was converted quantitatively to CH2=CCl2. The activities of the clay minerals were compared via their pseudo-first-order reaction rate constants (k1). A positive correlation was observed between the k1 value and the specific surface area (S) of clay minerals, where the S value was determined by means of the general Brunauer-Emmett-Teller (BET) equation. The k1 value was anti-correlated with the value of n, which was a parameter of the general BET equation and related to the average pore size of the clay minerals, and correlated with the water content that can be removed easily from the clay minerals. The reaction required no special pretreatment of clay minerals, such as heating at high temperatures; hence, the reaction can be expected to occur in the environment. Photoillumination by wavelengths present in the troposphere did not accelerate the decomposition of CH3CCl3, but it induced heterogeneous photodecomposition of CH2=CCl2. The temperature dependence of k1, the adsorption equilibrium coefficient of CH3CCl3 and CH2=CCl2, and the surface reaction rate constant of CH3CCl3 were determined for an illite sample. The k1 value increased with increasing temperature. The amount of CH3CCl3 adsorbed on the illite during the reaction was proportional to the partial pressure of CH3CCl3. The reaction was sensitive to relative humidity and the k1 value decreased with increasing relative humidity. However, the reaction was found to proceed at a relative humidity of 22% at 313 K, although the k1 value was about one-twentieth of the value in non-humidified air. The conditions required for the reaction may be present in major desert regions of the world. A simple estimation indicates that the possible heterogeneous decomposition of CH3CCl3 on the ground surface in arid regions is worth taking into consideration when inferring the tropospheric lifetime of CH3CCl3 and global OH concentration from the global budget concentration of CH3CCl3

Herschel PACS Spectroscopic Diagnostics of Local ULIRGs: Conditions and Kinematics in Mrk 231

In this first paper on the results of our Herschel PACS survey of local Ultraluminous Infrared Galaxies (ULIRGs), as part of our SHINING survey of local galaxies, we present far-infrared spectroscopy of Mrk 231, the most luminous of the local ULIRGs, and a type 1 broad absorption line AGN. For the first time in a ULIRG, all observed far-infrared fine-structure lines in the PACS range were detected and all were found to be deficient relative to the far infrared luminosity by 1 - 2 orders of magnitude compared with lower luminosity galaxies. The deficits are similar to those for the mid-infrared lines, with the most deficient lines showing high ionization potentials. Aged starbursts may account for part of the deficits, but partial covering of the highest excitation AGN powered regions may explain the remaining line deficits. A massive molecular outflow, discovered in OH and 18OH, showing outflow velocities out to at least 1400 km/sec, is a unique signature of the clearing out of the molecular disk that formed by dissipative collapse during the merger. The outflow is characterized by extremely high ratios of 18O / 16O suggestive of interstellar medium processing by advanced starbursts.Comment: Accepted for publication in the Astronomy and Astrophysics Herschel Special Issue, 5 pages, 4 figure