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

Does trocar-guided tension-free vaginal mesh (Prolift™) repair provoke prolapse of the unaffected compartments?

Contains fulltext : 88857.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: The objective of this study was to assess the effect of the tension-free vaginal mesh (Prolift) procedure on the non-treated and initially unaffected vaginal compartments. METHODS: This prospective observational cohort study involved 150 patients who underwent a Prolift procedure. Pelvic organ prolapse (POP) quantification and evaluation of prolapse symptoms with validated questionnaires was performed pre-operatively and 6 and 12 months postoperatively. Primary outcome was the rate of POP stage > or = II in the non-treated vaginal compartments. RESULTS: Twenty-three percent of all patients developed a de novo POP stage > or = II in the untreated compartment. This occurred in 46% and 25% of patients after an isolated anterior and isolated posterior Prolift, respectively. CONCLUSION: Tension-free vaginal mesh treatment of one vaginal compartment seems to provoke the development of vaginal prolapse in initially unaffected vaginal compartments, particularly after an isolated anterior Prolift procedure.1 maart 201

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

α1-Microglobulin (A1M) Protects Human Proximal Tubule Epithelial Cells from Heme-Induced Damage In Vitro

Oxidative stress is associated with many renal disorders, both acute and chronic, and has also been described to contribute to the disease progression. Therefore, oxidative stress is a potential therapeutic target. The human antioxidant α1-microglobulin (A1M) is a plasma and tissue protein with heme-binding, radical-scavenging and reductase activities. A1M can be internalized by cells, localized to the mitochondria and protect mitochondrial function. Due to its small size, A1M is filtered from the blood into the glomeruli, and taken up by the renal tubular epithelial cells. A1M has previously been described to reduce renal damage in animal models of preeclampsia, radiotherapy and rhabdomyolysis, and is proposed as a pharmacological agent for the treatment of kidney damage. In this paper, we examined the in vitro protective effects of recombinant human A1M (rA1M) in human proximal tubule epithelial cells. Moreover, rA1M was found to protect against heme-induced cell-death both in primary cells (RPTEC) and in a cell-line (HK-2). Expression of stress-related genes was upregulated in both cell cultures in response to heme exposure, as measured by qPCR and confirmed with in situ hybridization in HK-2 cells, whereas co-treatment with rA1M counteracted the upregulation. Mitochondrial respiration, analyzed with the Seahorse extracellular flux analyzer, was compromised following exposure to heme, but preserved by co-treatment with rA1M. Finally, heme addition to RPTE cells induced an upregulation of the endogenous cellular expression of A1M, via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-pathway. Overall, data suggest that A1M/rA1M protects against stress-induced damage to tubule epithelial cells that, at least partly, can be attributed to maintaining mitochondrial function

Mitochondrial respiration in human viable platelets--methodology and influence of gender, age and storage.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Studying whole cell preparations with intact mitochondria and respiratory complexes has a clear benefit compared to isolated or disrupted mitochondria due to the dynamic interplay between mitochondria and other cellular compartments. Platelet mitochondria have a potential to serve as a source of human viable mitochondria when studying mitochondrial physiology and pathogenic mechanisms, as well as for the diagnostics of mitochondrial diseases. The objective of the present study was to perform a detailed evaluation of platelet mitochondrial respiration using high-resolution respirometry. Further, we aimed to explore the limits of sample size and the impact of storage as well as to establish a wide range of reference data from different pediatric and adult cohorts. Our results indicate that platelet mitochondria are well suited for ex-vivo analysis with the need for minute sample amounts and excellent reproducibility and stability.Swedish Research Council 2011-3470 Royal Physiographic Society Foundation of the Swedish National Board of Health and Welfare Carl og Ellen Hertz' legat til Dansk laege- og naturvidenskab Lippman foundatio