Targeting Oxidative Stress for the Treatment of Liver Fibrosis

Oxidative stress is a reflection of the imbalance between the production of reactive oxygen species (ROS) and the scavenging capacity of the antioxidant system. Excessive ROS, generated from various endogenous oxidative biochemical enzymes, interferes with the normal function of liver-specific cells and presumably plays a role in the pathogenesis of liver fibrosis. Once exposed to harmful stimuli, Kupffer cells (KC) are the main effectors responsible for the generation of ROS, which consequently affect hepatic stellate cells (HSC) and hepatocytes. ROS-activated HSC undergo a phenotypic switch and deposit an excessive amount of extracellular matrix that alters the normal liver architecture and negatively affects liver function. Additionally, ROS stimulate necrosis and apoptosis of hepatocytes, which causes liver injury and leads to the progression of end-stage liver disease. In this review, we overview the role of ROS in liver fibrosis and discuss the promising therapeutic interventions related to oxidative stress. Most importantly, novel drugs that directly target the molecular pathways responsible for ROS generation, namely, mitochondrial dysfunction inhibitors, endoplasmic reticulum stress inhibitors, NADPH oxidase (NOX) inhibitors, and Toll-like receptor (TLR)-affecting agents, are reviewed in detail. In addition, challenges for targeting oxidative stress in the management of liver fibrosis are discussed.</p

ALICE: Physics Performance Report, Volume II

ALICE is a general-purpose heavy-ion experiment designed to study the physics of strongly interacting matter and the quark\u2013gluon plasma in nucleus\u2013nucleus collisions at the LHC. It currently involves more than 900 physicists and senior engineers, from both the nuclear and high-energy physics sectors, from over 90 institutions in about 30 countries. The ALICE detector is designed to cope with the highest particle multiplicities above those anticipated for Pb\u2013Pb collisions (dNch/dy up to 8000) and it will be operational at the start-up of the LHC. In addition to heavy systems, the ALICE Collaboration will study collisions of lower-mass ions, which are a means of varying the energy density, and protons (both pp and pA), which primarily provide reference data for the nucleus\u2013nucleus collisions. In addition, the pp data will allow for a number of genuine pp physics studies. The detailed design of the different detector systems has been laid down in a number of Technical Design Reports issued between mid-1998 and the end of 2004. The experiment is currently under construction and will be ready for data taking with both proton and heavy-ion beams at the start-up of the LHC. Since the comprehensive information on detector and physics performance was last published in the ALICE Technical Proposal in 1996, the detector, as well as simulation, reconstruction and analysis software have undergone significant development. The Physics Performance Report (PPR) provides an updated and comprehensive summary of the performance of the various ALICE subsystems, including updates to the Technical Design Reports, as appropriate. The PPR is divided into two volumes. Volume I, published in 2004 (CERN/LHCC 2003-049, ALICE Collaboration 2004 J. Phys. G: Nucl. Part. Phys. 30 1517\u20131763), contains in four chapters a short theoretical overview and an extensive reference list concerning the physics topics of interest to ALICE, the experimental conditions at the LHC, a short summary and update of the subsystem designs, and a description of the offline framework and Monte Carlo event generators. The present volume, Volume II, contains the majority of the information relevant to the physics performance in proton\u2013proton, proton\u2013nucleus, and nucleus\u2013nucleus collisions. Following an introductory overview, Chapter 5 describes the combined detector performance and the event reconstruction procedures, based on detailed simulations of the individual subsystems. Chapter 6 describes the analysis and physics reach for a representative sample of physics observables, from global event characteristics to hard processes