Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study.

Sepsis management remains one of the most important challenges in modern clinical practice. Rapid progression from sepsis to septic shock is practically unpredictable, hence the critical need for sepsis biomarkers that can help clinicians in the management of patients to reduce the probability of a fatal outcome. Circulating nucleoproteins released during the inflammatory response to infection, including neutrophil extracellular traps, nucleosomes, and histones, and nuclear proteins like HMGB1, have been proposed as markers of disease progression since they are related to inflammation, oxidative stress, endothelial damage, and impairment of the coagulation response, among other pathological features. The aim of this work was to evaluate the actual potential for decision making/outcome prediction of the most commonly proposed chromatin-related biomarkers (i.e., nucleosomes, citrullinated H3, and HMGB1). To do this, we compared different ELISA measuring methods for quantifying plasma nucleoproteins in a cohort of critically ill patients diagnosed with sepsis or septic shock compared to nonseptic patients admitted to the intensive care unit (ICU), as well as to healthy subjects. Our results show that all studied biomarkers can be used to monitor sepsis progression, although they vary in their effectiveness to separate sepsis and septic shock patients. Our data suggest that HMGB1/citrullinated H3 determination in plasma is potentially the most promising clinical tool for the monitoring and stratification of septic patients.

Oxidative Stress and the Epigenetics of Cell Senescence: Insights from Progeroid Syndromes.

BACKGROUND: Cell senescence constitutes a critical process to respond to a variety of insults and adverse circumstances. Senescence involves the detention of DNA replication and cell proliferation, and hence, genetic programs associated with DNA damage response, chromosome stability, chromatin rearrangement, epigenetic reprogramming, and cell cycle are tightly linked to the senescent phenotype. Although senescence increases with age, the real implication of senescence regulation in the progress of aging in humans is largely discussed. In this context, reactive oxygen species (ROS) accumulation has also been postulated to play a critical role in cell homeostasis, aging processes, and control of proliferation. METHODS: The previous years have produced a high increase in data that refine our understanding of the role of ROS, and their relationship with epigenetic events, in determining cellular fate. RESULTS: The accumulating evidence regarding the epigenetic regulation of ROS-mediated processes provides promising tools to deepen in our comprehension of the process of senescence, and to develop novel therapeutic strategies. In this review, we aim to provide an overview of the relationships between oxidative stress and cell senescence. CONCLUSION: We provide information about the role of epigenetic regulation in senescence and aging, collecting recent data from some examples of progeroid syndromes in which cell senescence, oxidative stress and epigenetic mechanisms are severely impaired. Finally, a collection of data is presented regarding current pharmacological approaches that either target or use oxidative stress-related factors or epigenetic regulators as strategies for disease treatment.

Could thiazolidinediones increase the risk of heart failure in Friedreich's ataxia patients?

Clinical evidence and the recent decisions of the European Medicines Agency and the Food and Drug Administration challenge the safety of thiazolidinediones treatment. Recently, this treatment has been suggested for Friedreich's ataxia because thiazolidinediones improve neurological symptoms. Hypertrophic cardiomyopathy is the most prevalent cardiac feature and the cause of premature death in Friedreich's ataxia patients. We recommend that therapy with peroxisome proliferator-activated receptor-gamma agonists like thiazolidinediones be taken with caution, as they cause a decrease in the number of fast fibers and an increase in mitochondrial biogenesis in cardiac muscle because of the induction of peroxisome proliferator-activated receptor-gamma coactivator-1α. Furthermore, the incidence of heart failure may increase when thiazolidinediones are combined with insulin, and moreover, they produce cyclooxygenase 2 inhibition, inducing a thrombotic response. Thus, patients are predisposed to adverse cardiovascular outcomes. In our opinion, the possible fatal consequences must be taken into account when peroxisome proliferator-activated receptor-gamma agonist drugs are considered as possible therapeutic agents for Friedreich's ataxia patients.