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

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

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

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

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

Measurement of the e r c.m. = 138 keV resonance in the 23 Na(p, γ) 24 Mg reaction and the abundance of sodium in AGB stars

Globular clusters represent some of the oldest stellar aggregations in the universe. As such, they are used as testing grounds for theories of stellar evolution and nucleosynthesis. Astronomical observations have shown star-to-star abundance variations in light-mass elements in all galactic globular clusters that are not predicted by standard stellar evolution models. In particular, there exists a pronounced anticorrelation between Na and O in the cluster stars that is not observed in field stars of similar evolutionary state. The abundance of Na is regulated in part by the 23Na+p reaction, which is also a bridge between the NeNa and the MgAl mass regions, but the 23Na(p,γ)24Mg reaction rate is very uncertain for burning temperatures relevant to stars on the red giant and asymptotic giant branches. This uncertainty arises from an expected but unobserved resonance at Erc.m. = 138 keV. The resonance strength upper limit has been determined to be ωγUL(138 keV) ≤5.17×10-9 eV with indications of a signal at the 90% confidence level. New reaction rates have been calculated for the 23Na(p,γ)24Mg and 23Na(p,α)20Ne reactions and the recommended value for the 23Na(p,γ)24Mg rate has been reduced by over an order of magnitude at T9 = 0.07. This will have implications for the processing of material between the NeNa and MgAl mass regions