Change of paradigm: oxidative stress versus redox signalling

Reactive oxygen species (ROS) are generally perceived as toxicants that may induce through oxidation of key biomolecules deleterious effects such as like cell dysfunctions, death or malignant transformation. Aerobic organisms have adapted to survive in the harsh oxidative environment by developing powerful antioxidant shielding. Recent findings point out that aerobic organisms have even learned to take advantage of apparently toxic ROS. Extensive evidence is accumulating that ROS are beneficially involved in many signalling pathways that control development and maintain cellular homeostasis. Subtle but highly targeted changes induced in signalling molecules by oxidation-reduction reactions were shown to transduce messages from cell membrane to the nucleus. Through a self-sustaining process mediated by the mitochondria network, the redox signal propagates within the cell and coordinates a “whole cell” signal transduction pattern.

The location, intensity and duration of the oxidative burst, along with the interconnected redox-sensitive signalling pathways, decide whether death or survival of normal and diseased cells occur in response to various stimuli and stressors. In physiological conditions, tightly regulated redox-sensitive antioxidant networks protect cells from the injurious attack of ROS, but if chronically altered, they promote various pathological conditions. Understanding the duality of ROS as cytotoxic molecules and key mediators in signalling cascades may provide novel insights into pathological mechanisms and new opportunities for improved therapeutic intervention.

The emerging tools of network medicine offer a platform to explore systematically the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, and the molecular relationships among apparently distinct (patho)phenotypes . According to the network medicine concept a revolutionary shift in paradigm is shaping by defining diseases based on molecular rather than clinical alterations, as represented in the diseasome map. In this map, a group of apparently clinically unrelated diseases were found to share a common patho-mechanism that is characterized by deregulated metabolism of ROS and inflammation, hence defining the redox diseasome. This opens new avenues in radiobiology, taking into account that the main deleterious effects of ionizing radiation are mediated by ROS, It accounts for various health alterations observed in professionals chronically exposed to low dose radiation, that are redox diseases such as cardiovascular and neurodegenerative diseases. Moreover, the network medicine approach led to the network pharmacology concept which brings a huge advance by highlighting the possibility of drug repurposing. The concept states that a drug that was developed for a specific pathology that is part of a particular diseasome, might be efficacious in other pathologies that are clustering in the very same diseasome. This is the approach that we will use in the case of exposure to space-relevant radiation. In the current project, in order to counteract deleterious ROS-mediated effects of nuclear radiation on mammalian cells we will use drugs that were shown to up-regulate the endogenous antioxidant system through activation of the transcription factor NRF2. 

Failure of traditional antioxidants – what to put instead?

EU-ROS: The European Network on Oxidative Stress and Redox Biology Research put forward the concept that “the failure of the traditional antioxidants such as vitamin C and E was predictable considering that, but that excessive formation of ROS (mostly termed “oxidative stress”) plays a role in disease development and progression or, at least, leads to stable biomarkers that can be used for diagnostic aspects in various diseases. In brief, the EU-ROS consortium believes that activation of intrinsic antioxidant processes (e.g. NRF2-dependent pathways), inhibition of disease-relevant sources of ROS, scavenging of disease-triggering ROS by site- and time-specific antioxidants or even repair of enzymes inactivated by oxidation represents clinically established or promising future antioxidant strategies”.

NRF2 – master regulator of the response to increased levels of reactive oxygen species

Nuclear factor erythroid 2-related factor 2 (NRF2) is a pivotal transcription factor in the defence against oxidative stress, that promotes transcription of cytoprotective genes in response to oxidative and electrophilic stresses. NRF2 controls the expression of more than 200 genes representing around 1% of human genome, which contain the Antioxidant Response Elements (ARE) in their regulatory regions. These genes include those involved in drug-metabolism, drug transport, cysteine homeostasis and glutathione biosynthesis, repair and degradation of oxidized proteins, synthesis of NADPH, proteasome activity, autophagy and DNA nucleotide excision. Tightly controlled redox-sensitive but also redox-independent mechanisms control the transcriptional activity of NRF2.