Changing Perspectives from Oxidative Stress to Redox Signaling-Extracellular Redox Control in Translational Medicine

Abstract

Extensive research has changed the understanding of oxidative stress that has been linked to every major disease. Today we distinguish oxidative eu- and distress, acknowledging that redox modifications are crucial for signal transduction in the form of specific thiol switches. Long underestimated, reactive species and redox proteins of the Thioredoxin (Trx) family are indeed essential for physiological processes. Moreover, extracellular redox proteins, low molecular weight thiols and thiol switches affect signal transduction and cell-cell communication. Here, we highlight the impact of extracellular redox regulation for health, intermediate pathophenotypes and disease. Of note, recent advances allow the analysis of redox changes in body fluids without using invasive and expensive techniques. With this new knowledge in redox biochemistry, translational strategies can lead to innovative new preventive and diagnostic tools and treatments in life sciences and medicine.

Keywords: biomarkers; extracellular redox regulation; glutathione; oxidative stress; reactive oxygen species; thioredoxin proteins; translational medicine.

Figure 1

Redox signaling states in physiology and pathology. Under physiological conditions (redox eustress), redox-active second messengers such as O2, NO act on thiol switches of target proteins inducing reversible cysteine modifications and activation of redox signaling. Dysregulated redox signaling caused, either by ROS increase or depletion, leads to oxidative or reductive stress, respectively. The transition from physiological to a pathological state represents a diagnostically relevant, but hitherto not well characterized “intermediate state” (yellow areas).

Figure 2

Intracellular and extracellular distribution of redoxins. Subcellular localization, presence of the redoxins in the extracellular and intravascular space, as well as in extracellular vesicles. Unconventional secretion pathways of protein: the majority of the redoxins are secreted via these pathways; some of them are Trx, TrxR, Prx1, Prx2. Conventional secretion pathway: from the thioredoxin family protein, PDIs and Prx4 are known to be secreted via the conventional pathway, possessing a leader peptide that enables their secretion. Representation of ROS generation as part of the redox signaling. TLR4: Toll-like receptor 4. GSH: Glutathione. NOX: NADPH oxidase. AQP: Aquaporin. SOD: Superoxide dismutase. Prx: Peroxiredoxin. Trx: Thioredoxin. TrxR: Thioredoxin reductase. EV: Extracellular vesicle.

Figure 3

Redox regulation in translational medicine: Redox regulation is essential for the normal function of organs such as the brain, the heart, the lungs, and the kidneys. Alterations can lead to oxidative distress and the onset and progression of diseases. Extracellular changes can be analyzed in body fluids, these changes can be assessed as risk factors and have the potential to be utilized as prognostic and diagnostic biomarkers. New therapeutic strategies for different disorders include the induction or inhibition of specific reactive species, for instance, via Nrf-2 modulation, or the inhibition of specific enzymes such as TrxR and PDIs.