Evaluation of NV556, a Novel Cyclophilin Inhibitor, as a Potential Antifibrotic Compound for Liver Fibrosis

Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked to poor survival and an increased risk of developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is an unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding and conformational changes affecting the function of the targeted proteins. Due to their activity, cyclophilins have been presented as key factors in several stages of the fibrotic process. In this study, we investigated the antifibrotic effects of NV556, a novel potent sanglifehrin-based cyclophilin inhibitor, in vitro and in vivo. NV556 potential antifibrotic effect was evaluated in two well-established animal models of NASH, STAM, and methionine-choline-deficient (MCD) mice, as well as in an in vitro 3D human liver ECM culture of LX2 cells, a human hepatic stellate cell line. We demonstrate that NV556 decreased liver fibrosis in both STAM and MCD in vivo models and decreased collagen production in TGFβ1-activated hepatic stellate cells in vitro. Taken together, these results present NV556 as a potential candidate for the treatment of liver fibrosis

Hard photon and neutral pion production in cold nuclear matter

The production of hard photons and neutral pions in 190 MeV proton induced reactions on C, Ca, Ni, and W targets has been for the first time concurrently studied. Angular distributions and energy spectra up to the kinematical limit are discussed and the production cross-sections are presented. From the target mass dependence of the cross-sections the propagation of pions through nuclear matter is analyzed and the production mechanisms of hard photons and primordial pions are derived. It is found that the production of subthreshold particles proceeds mainly through first chance nucleon-nucleon collisions. For the most energetic particles the mass scaling evidences the effect of multiple collisions.Comment: submitted to Phys. Lett.

Dielectron Cross Section Measurements in Nucleus-Nucleus Reactions at 1.0 A GeV

We present measured dielectron production cross sections for Ca+Ca, C+C, He+Ca, and d+Ca reactions at 1.0 A GeV. Statistical uncertainties and systematic effects are smaller than in previous DLS nucleus-nucleus data. For pair mass < 0.35 GeV/c2 : 1) the Ca+Ca cross section is larger than the previous DLS measurement and current model results, 2) the mass spectra suggest large contributions from pi0 and eta Dalitz decays, and 3) dsigma/dM is proportional to ApAt. For M > 0.5 GeV/c2 the Ca+Ca to C+C cross section ratio is significantly larger than the ratio of ApAt values.Comment: Submitted to Physical Review Letters. Further analysis information will be posted on our web pages -- http://macdls.lbl.gov Figure 1 has been redrawn to make more legible. Text modified to support redrawn figur

Flow effects in intermediate-energy nuclear collisions

This study concerns the evolution of the information seeking and use models for professionals essentially, the information access practices. Coming from Anglo-Saxon literature, this new information science research trend, evolve with paradigms and different information seeking and use models have emerged, in order to explain how professional seeks information and what can be done in order to help them. Two main categories can be distinguished : the information seeking and use model versus the information retrieval model. So we will present today this diversity of models and we will evaluate them in order to see if a convergence is possible with the same vocabulary and procedures

The role of β(3)-adrenoceptors in mediating relaxation of porcine detrusor muscle

1. β-adrenoceptors mediate relaxation of bladder detrusor smooth muscle. This study investigates the contribution of β(3)-adrenoceptors to relaxation of the pig urinary bladder. 2. Cell membranes were prepared from detrusor muscle of the pig bladder dome and competition experiments with [(3)H]-dihydroalprenolol (DHA), a non-selective β-adrenoceptor antagonist was used as a specific radioligand to determine the presence of β-adrenoceptor subtypes. In functional experiments, isolated detrusor muscle strips were used to determine the potency of agonists and the affinity of antagonists. 3. In competition binding experiments, CGP20712A (β(1)-adrenoceptor selective) displaced [(3)H]-DHA from a single binding site with a low affinity. In contrast, displacement data for ICI 118551 (β(2)-adrenoceptor antagonist) and SR59230A (β(3)-adrenoceptor antagonist) best fitted a two-site model suggesting a predominant (70%) population of β(3)-adrenoceptors. 4. In functional studies, isoprenaline and salbutamol (β(2)-adrenoceptor agonist) relaxed KCl precontracted muscle strips with high potency (pEC(50) 7.7 and 7.2, respectively), whilst CGP12177 and BRL37344 (β(3)-adrenoceptor agonists) had low potency and were partial agonists. CGP20712A and atenolol (β(1)-adrenoceptor antagonists) antagonised responses with a low affinity. ICI118551 antagonized responses to isoprenaline and salbutamol with a high affinity (pK(B)=7.8 and 8.7, respectively), but the Schild slopes were low suggesting that responses were mediated by more than one β-adrenoceptor. The Schild plot for SR59230A was biphasic, apparent pK(B) values for 3 – 10 nM SR59230A being 8.6 and those for 30 nM – 1 μM being 7.7. 5. These data suggest that β(3)-adrenoceptors are the predominant β-adrenoceptor subtype present in the pig bladder and that β-adrenoceptor mediated responses of this tissue are mediated via both the β(2)- and β(3)-adrenoceptor subtypes