Impairment of enzymatic antioxidant defenses is associated with bilirubin-induced neuronal cell death in the cerebellum of Ugt1 KO mice

Severe hyperbilirubinemia is toxic during central nervous system development. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced encephalopathy and eventually death by kernicterus. Despite extensive studies, the molecular and cellular mechanisms of bilirubin toxicity are still poorly defined. To fill this gap, we investigated the molecular processes underlying neuronal injury in a mouse model of severe neonatal jaundice, which develops hyperbilirubinemia as a consequence of a null mutation in the Ugt1 gene. These mutant mice show cerebellar abnormalities and hypoplasia, neuronal cell death and die shortly after birth because of bilirubin neurotoxicity. To identify protein changes associated with bilirubin-induced cell death, we performed proteomic analysis of cerebella from Ugt1 mutant and wild-type mice. Proteomic data pointed-out to oxidoreductase activities or antioxidant processes as important intracellular mechanisms altered during bilirubin-induced neurotoxicity. In particular, they revealed that down-representation of DJ-1, superoxide dismutase, peroxiredoxins 2 and 6 was associated with hyperbilirubinemia in the cerebellum of mutant mice. Interestingly, the reduction in protein levels seems to result from post-translational mechanisms because we did not detect significant quantitative differences in the corresponding mRNAs. We also observed an increase in neuro-specific enolase 2 both in the cerebellum and in the serum of mutant mice, supporting its potential use as a biomarker of bilirubin-induced neurological damage. In conclusion, our data show that different protective mechanisms fail to contrast oxidative burst in bilirubin-affected brain regions, ultimately leading to neurodegeneration. \ua9 2015 Macmillan Publishers Limited All rights reserved

BNC2 is a putative tumor suppressor gene in high-grade serous ovarian carcinoma and impacts cell survival after oxidative stress

Rs3814113 is the single-nucleotide polymorphism (SNP) showing the strongest association with high-grade serous ovarian carcinoma (HGSOC) incidence and is located in an intergenic region about 44\u2009kb downstream of basonuclin 2 (BNC2) gene. Lifetime number of ovulations is associated with increased risk to develop HGSOC, probably because of cell damage of extrauterine M\ufcllerian epithelium by ovulation-induced oxidative stress. However, the impact of low-penetrance HGSOC risk alleles (e.g. rs3814113) on the damage induced by oxidative stress remains unclear. Therefore, the purpose of this study was to investigate whether rs3814113 genetic interval regulates BNC2 expression and whether BNC2 expression levels impact on cell survival after oxidative stress. To do this, we analyzed gene expression levels of BNC2 first in HGSOC data sets and then in an isogenic cell line that we engineered to carry a 5\u2009kb deletion around rs3814113. Finally, we silenced BNC2 and measured surviving cells after hydrogen peroxide (H2O2) treatment to simulate oxidative stress after ovulation. In this paper, we describe that BNC2 expression levels are reduced in HGSOC samples compared with control samples, and that BNC2 expression levels decrease following oxidative stress and ovulation in vitro and in vivo, respectively. Moreover, deletion of 5\u2009kb surrounding rs3814113 decreases BNC2 expression levels in an isogenic cell line, and silencing of BNC2 expression levels increases cell survival after H2O2 treatment. Altogether, our findings suggest that the intergenic region located around rs3814113 regulates BNC2 expression, which in turn affects cell survival after oxidative stress response. Indeed, HGSOC samples present lower BNC2 expression levels that probably, in the initial phases of oncogenic transformation, conferred resistance to oxidative stress and ultimately reduced the clearance of cells with oxidative-induced damages

The importance of redox state in liver damage.

Oxidative stress is a major pathogenetic event occurring in several liver disorders ranging from metabolic to proliferative ones, and is a major cause of liver damage due to Ischemia/Reperfusion (I/R) during liver transplantation. The main sources of ROS are represented by mitochondria and cytocrome P450 enzymes in the hepatocyte, by Kupffer cells and by neutrophils. Cells are provided with efficient molecular strategies to strictly control the intracellular ROS level and to maintain the balance between oxidant and antioxidant molecules. A cellular oxidative stress condition is determined by an imbalance between the generation of ROS and the antioxidant defense capacity of the cell and can affect major cellular components including lipids, proteins and DNA. Proteins are very important signposts of cellular redox status and through their structure/function modulation, ROS can also influence gene expression profile by affecting intracellular signal transduction pathways. While several enzymatic (such as superoxide dismutase, catalase, glutathione peroxidase) and non enzymatic (such as 4-hydroxynonenal, decrease of glutathione, vitamin E, vitamin C, malondialdehyde) markers of chronic oxidative stress in liver are well known, early protein targets of oxidative injury are yet not well defined. Identification of these markers will enable early detection of liver diseases and will allow monitoring the degree of liver damage, the re1 Department of Biomedical Sciences and Technologies, University of Udine, P.le Kolbe 4, 33100 Udine, Italy. 2 Department of Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, via Giorgieri 1, 34127 Trieste, Italy. 3 Centro Studi Fegato, AREA Science Park Bldg Q, Campus Basovizza, ss 14, km 163.5, 34012 Trieste, Italy. Address for correspondence

Beyond ‘geo-economics’: advanced unevenness and the anatomy of German austerity

This article aims to shed new light on Germany’s domineering role in the eurocrisis. I argue that the realist-inspired depiction of Germany as a ‘geo-economic power’, locked into zero-sum competition with its European partners, is built around an empty core: unable to theorise how anarchy shapes the calculus of states where security competition has receded, it cannot explain why German state managers have insisted on an austerity response to the crisis despite its significant risks and costs even for Germany itself. To unlock this puzzle, this article outlines a version of uneven and combined development (UCD) that is better able to capture the international pressures and opportunities faced by policy elites in advanced capitalist states that no longer encounter one another as direct security rivals. Applied to Germany, this lens reveals a twofold unevenness in the historical structures and growth cycles of capitalist economies that shape its contradictory choice for austerity. In the long run, the reorientation of the export-dependent German economy from Europe towards Asian and Latin American late industrialisers renders the structural adjustment of the eurozone an opportunity—from the cost-saving view of German manufacturers producing in the European home market for export abroad, as well as for German state officials keen to sustain a crumbling class compromise centred on Germany’s world market success. In the short term, however, its exposed position between the divergent post-crisis trajectories of the US and Europe accelerates pressures for austerity beyond what German state and corporate elites would otherwise consider feasible

Measurement of O17(p,γ)F18 between the narrow resonances at Erlab=193 and 519keV

The O17(p,γ)F18 reaction sensitively influences hydrogen burning nucleosynthesis in a number of stellar sites, including classical novae. These thermonuclear explosions, taking place in close binary star systems, produce peak temperatures in the range of T=100-400 MK. Recent results indicate that the thermonuclear rates for this reaction in this particular temperature range are dominated by the direct capture process. We report on the measurement of the O17(p,γ)F18 cross section between the narrow resonances at Erlab=193 and 519keV, where the S factor is expected to vary smoothly with energy. We extract the direct capture contribution from the total cross section and demonstrate that earlier data are inconsistent with our results

LINC01605 Is a Novel Target of Mutant p53 in Breast and Ovarian Cancer Cell Lines

TP53 is the most frequently mutated gene in human cancers. Most TP53 genomic alterations are missense mutations, which cause a loss of its tumour suppressor functions while providing mutant p53 (mut_p53) with oncogenic features (gain-of-function). Loss of p53 tumour suppressor functions alters the transcription of both protein-coding and non-protein-coding genes. Gain-of-function of mut_p53 triggers modification in gene expression as well; however, the impact of mut_p53 on the transcription of the non-protein-coding genes and whether these non-protein-coding genes affect oncogenic properties of cancer cell lines are not fully explored. In this study, we suggested that LINC01605 (also known as lincDUSP) is a long non-coding RNA regulated by mut_p53 and proved that mut_p53 directly regulates LINC01605 by binding to an enhancer region downstream of the LINC01605 locus. We also showed that the loss or downregulation of LINC01605 impairs cell migration in a breast cancer cell line. Eventually, by performing a combined analysis of RNA-seq data generated in mut_TP53-silenced and LINC01605 knockout cells, we showed that LINC01605 and mut_p53 share common gene pathways. Overall, our findings underline the importance of ncRNAs in the mut_p53 network in breast and ovarian cancer cell lines and in particular the importance of LINC01605 in mut_p53 pro-migratory pathways

Resonance strength in Ne22(p,γ)Na23 from depth profiling in aluminum

A novel method for extracting absolute resonance strengths has been investigated. By implanting Ne22 ions into a thick aluminum backing and simultaneously measuring the Ne22+p and Al27+p reactions, the strength of the Erlab=479 keV resonance in Ne22(p,γ)Na23 was determined to be ωγ=0.524(51) eV. This result has significantly reduced uncertainties compared to earlier work. Our results are important for the absolute normalizations of resonance strengths in the Ne22(p,γ)Na23 hydrogen-burning reaction and in the Ne22+α s-process neutron-source reactions

Improved thermonuclear reaction rate for 18O(p,γ) 19F

For 0.8 Mȯ ≤ M ≤ 8.0 Mȯ stars, the final phase of nucleosynthesis occurs during the asymptotic giant branch (AGB) stage. Grain condensation and significant mass loss transpires during this stellar evolutionary period, and presolar grains recovered from comet and meteorite samples can often be attributed to this unique stellar environment. A subset of presolar oxide grain specimens exhibit dramatic 18O depletion that cannot be explained by standard AGB stellar burning stages and dredge-up models. An extra mixing process, referred to as cool bottom processing (CBP), was proposed for low-mass AGB stars to explain similar isotopic anomalies. The 18O depletion observed within certain stellar environments and within presolar grain samples may result from the 18O+p processes during CBP, and we report here on a study of the 18O(p,γ)19F reaction at low energies. The (p,γ) reaction rate at low temperatures was found to not be affected by a low-energy, unobserved, narrow resonance-ElabR = 95 keV-near the CBP Gamow peak. A new strength upper limit measurement was performed at TUNL's Laboratory for Experimental Nuclear Astrophysics, and an improved reaction rate was calculated. In addition, non-resonant cross section and astrophysical S-factor upper limits were measured at low bombarding energies

Thermonuclear reaction rate of 18O(p,γ)19F

For stars with 0.8 M⊙ ≤ M ≤ 8.0 M⊙, nucleosynthesis enters its final phase during the asymptotic giant branch (AGB) stage. During this evolutionary period, grain condensation occurs in the stellar atmosphere, and the star experiences significant mass loss. The production of presolar grains can often be attributed to this unique stellar environment. A subset of presolar oxide grains features dramatic 18O depletion that cannot be explained by the standard AGB star burning stages and dredge-up models. An extra mixing process, referred to as cool bottom processing (CBP), was proposed for low-mass AGB stars. The 18O depletion observed within certain stellar environments and within presolar grain samples may result from the 18O+p processes during CBP. We report here on a study of the 18O(p,γ)19F reaction at low energies. Based on our new results, we found that the resonance at ERlab=95 keV has a negligible affect on the reaction rate at the temperatures associated with CBP. We also determined that the direct capture S factor is almost a factor of 2 lower than the previously recommended value at low energies. An improved thermonuclear reaction rate for 18O(p,γ)19F is presented