Fundamentals of redox regulation in biology.

Oxidation-reduction (redox) reactions are central to the existence of life. Reactive species of oxygen, nitrogen and sulfur mediate redox control of a wide range of essential cellular processes. Yet, excessive levels of oxidants are associated with ageing and many diseases, including cardiological and neurodegenerative diseases, and cancer. Hence, maintaining the fine-tuned steady-state balance of reactive species production and removal is essential. Here, we discuss new insights into the dynamic maintenance of redox homeostasis (that is, redox homeodynamics) and the principles underlying biological redox organization, termed the 'redox code'. We survey how redox changes result in stress responses by hormesis mechanisms, and how the lifelong cumulative exposure to environmental agents, termed the 'exposome', is communicated to cells through redox signals. Better understanding of the molecular and cellular basis of redox biology will guide novel redox medicine approaches aimed at preventing and treating diseases associated with disturbed redox regulation.

Was H2O2 generated before oxygenic photosynthesis?

We obviously agree with Wu et al. that H2O2 might accumulate in the Archean land waters devoid of Fe2+. We do disagree on the topic of the half-life of H2O2, as the work cited in support for a longer half-live is not relevant to the conditions in the Archean ocean. While the existence of radicals in quartz is not in doubt, we do question the hypothesis that these radicals oxidize water to HO• and H2O2.

Was hydrogen peroxide present before the arrival of oxygenic photosynthesis? The important role of iron(II) in the Archean ocean.

We address the chemical/biological history of H2O2 back at the times of the Archean eon (2.5-3.9 billion years ago (Gya)). During the Archean eon the pO2 was million-fold lower than the present pO2, starting to increase gradually from 2.3 until 0.6 Gya, when it reached ca. 0.2 bar. The observation that some anaerobic organisms can defend themselves against O2 has led to the view that early organisms could do the same before oxygenic photosynthesis had developed at about 3 Gya. This would require the anaerobic generation of H2O2, and here we examine the various mechanisms which were suggested in the literature for this. Given the concentration of Fe2+ at 20-200 µM in the Archean ocean, the estimated half-life of H2O2 is ca. 0.7 s. The oceanic H2O2 concentration was practically zero. We conclude that early organisms were not exposed to H2O2 before the arrival of oxygenic photosynthesis.

Health position paper and redox perspectives - Disease burden by transportation noise.

Transportation noise is a ubiquitous urban exposure. In 2018, the World Health Organization concluded that chronic exposure to road traffic noise is a risk factor for ischemic heart disease. In contrast, they concluded that the quality of evidence for a link to other diseases was very low to moderate. Since then, several studies on the impact of noise on various diseases have been published. Also, studies investigating the mechanistic pathways underlying noise-induced health effects are emerging. We review the current evidence regarding effects of noise on health and the related disease-mechanisms. Several high-quality cohort studies consistently found road traffic noise to be associated with a higher risk of ischemic heart disease, heart failure, diabetes, and all-cause mortality. Furthermore, recent studies have indicated that road traffic and railway noise may increase the risk of diseases not commonly investigated in an environmental noise context, including breast cancer, dementia, and tinnitus. The harmful effects of noise are related to activation of a physiological stress response and nighttime sleep disturbance. Oxidative stress and inflammation downstream of stress hormone signaling and dysregulated circadian rhythms are identified as major disease-relevant pathomechanistic drivers. We discuss the role of reactive oxygen species and present results from antioxidant interventions. Lastly, we provide an overview of oxidative stress markers and adverse redox processes reported for noise-exposed animals and humans. This position paper summarizes all available epidemiological, clinical, and preclinical evidence of transportation noise as an important environmental risk factor for public health and discusses its implications on the population level.

Lester Packer: On His Life and His Legacy.

Lester Packer was an exceptional scientific leader, whose radiant personality inspired and encouraged generations of students and scientists for research to pursue oxidants and antioxidants in biology and medicine. For the FORUM dedicated to Professor Packer, we here describe key aspects of his professional career, from the early years at Brooklyn College, Yale University, and the Johnson Research Foundation at Philadelphia to his long-term base at the University of California, at UC Berkeley. The concept of the "Antioxidant Network" formed the core of his activities in later years. His welcoming and integrative personality led to a worldwide network of colleagues, starting with the Bay Area Oxygen Club, which turned into the Oxygen Club of California, and his leadership in the Society for Free Radical Research-International. To illustrate his warmth and outreach, which enabled him to form borderless global collaborations, we conclude with words from some of his many friends also from outside academia: Lester Packer's legacy. Antioxid. Redox Signal. 38, 768-774.

Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health.

AIMS: Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper aims to assess FMD values in apparently healthy individuals and provides reference values to facilitate wider clinical use. METHODS AND RESULTS: In 1,579 apparently healthy individuals (aged 18-76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body mass index, glucose, cholesterol, blood pressure, and brachial artery (BA) diameter. Significant multivariate predictors of FMD were age (-0.4%/decade), BMI (0.04%/kg/m2), smoking (-0.7%), and BA diameter (-0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (>6.8%) were younger, had smaller BA diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (<5.4%). After adding data from 385 patients with stable coronary artery disease (CAD), ROC analysis (c = 0.841, P < 0.001) showed that FMD of >6.5% excluded CAD (95% sensitivity; 60% specificity) and FMD <3.1% excluded 95% healthy individuals (95% specificity, 31% sensitivity). A meta-analysis and meta-regression of 82 clinical trials (11 countries, n = 3,509) using similar FMD methodology showed that despite considerable heterogeneity (I2 = 0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (-0.3%/decade, R2 = 0.13). CONCLUSIONS: We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of cardiovascular health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.

Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology.

'Reactive oxygen species' (ROS) is a generic term that defines a wide variety of oxidant molecules with vastly different properties and biological functions that range from signalling to causing cell damage. Consequently, the description of oxidants needs to be chemically precise to translate research on their biological effects into therapeutic benefit in redox medicine. This Expert Recommendation article pinpoints key issues associated with identifying the physiological roles of oxidants, focusing on H2O2 and O2.-. The generic term ROS should not be used to describe specific molecular agents. We also advocate for greater precision in measurement of H2O2, O2.- and other oxidants, along with more specific identification of their signalling targets. Future work should also consider inter-organellar communication and the interactions of redox-sensitive signalling targets within organs and whole organisms, including the contribution of environmental exposures. To achieve these goals, development of tools that enable site-specific and real-time detection and quantification of individual oxidants in cells and model organisms are needed. We also stress that physiological O2 levels should be maintained in cell culture to better mimic in vivo redox reactions associated with specific cell types. Use of precise definitions and analytical tools will help harmonize research among the many scientific disciplines working on the common goal of understanding redox biology.

Homeostatic control of redox status and health.

Research on oxidants and electrophiles has shifted from focusing on damage to biomolecules to the more fine-grained physiological arena. Redox transitions as excursions from a steady-state redox set point are continually ongoing in maintenance of redox balance. Current excitement on these topics results from the fact that recent research provided mechanistic insight, which gives rise to more concrete and differentiated questions. This Commentary focuses on redox eustress and the feedback restoration of steady state as concepts in active maintenance of physiological health, with brief discussion of redox stress response to viral infection, exemplified by COVID-19.

Oxidative eustress: On constant alert for redox homeostasis.

In the open metabolic system, redox-related signaling requires continuous monitoring and fine-tuning of the steady-state redox set point. The ongoing oxidative metabolism is a persistent challenge, denoted as oxidative eustress, which operates within a physiological range that has been called the 'Homeodynamic Space', the 'Goldilocks Zone' or the 'Golden Mean'. Spatiotemporal control of redox signaling is achieved by compartmentalized generation and removal of oxidants. The cellular landscape of H2O2, the major redox signaling molecule, is characterized by orders-of-magnitude concentration differences between organelles. This concentration pattern is mirrored by the pattern of oxidatively modified proteins, exemplified by S-glutathionylated proteins. The review presents the conceptual background for short-term (non-transcriptional) and longer-term (transcriptional/translational) homeostatic mechanisms of stress and stress responses. The redox set point is a variable moving target value, modulated by circadian rhythm and by external influence, summarily denoted as exposome, which includes nutrition and lifestyle factors. Emerging fields of cell-specific and tissue-specific redox regulation in physiological settings are briefly presented, including new insight into the role of oxidative eustress in embryonal development and lifespan, skeletal muscle and exercise, sleep-wake rhythm, and the function of the nervous system with aspects leading to psychobiology.

COVID-19 mortality as a fingerprint of biological age.

Corona virus disease 2019 (COVID-19) is a global emergency able to overwhelm the healthcare capacities worldwide and to affect the older generation especially. When addressing the pathophysiological mechanisms and clinical manifestations of COVID-19, it becomes evident that the disease targets pathways and domains affected by the main aging- and frailty-related pathophysiological changes. A closer analysis of the existing data supports a possible role of biological age rather than chronological age in the prognosis of COVID-19. There is a need for systematic, consequent action of identifying frail (not only older, not only multimorbid, not only symptomatic) persons at risk of poor outcomes.

Findings in redox biology: From H2O2 to oxidative stress.

My interest in biological chemistry proceeded from enzymology in vitro to the study of physiological chemistry in vivo Investigating biological redox reactions, I identified hydrogen peroxide (H2O2) as a normal constituent of aerobic life in eukaryotic cells. This finding led to developments that recognized the essential role of H2O2 in metabolic redox control. Further research included studies on GSH, toxicological aspects (the concept of "redox cycling"), biochemical pharmacology (ebselen), nutritional biochemistry and micronutrients (selenium, carotenoids, flavonoids), and the concept of "oxidative stress." Today, we recognize that oxidative stress is two-sided. It has its positive side in physiology and health in redox signaling, "oxidative eustress," whereas at higher intensity, there is damage to biomolecules with potentially deleterious outcome in pathophysiology and disease, "oxidative distress." Reflecting on these developments, it is gratifying to witness the enormous progress in redox biology brought about by the science community in recent years.

Oxidative Stress: Concept and Some Practical Aspects.

Oxidative stress is defined as "an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage". This Commentary presents basic features of this global concept which has attracted interest in biology and medicine. The term "antioxidants" in cellular defense against oxidants predominantly includes antioxidant enzymes with their substrates and coenzymes. Exogenous low-molecular-mass compounds also have a role, but this is more limited. Multiple biomarkers of damage due to oxidative stress have been identified for different molecular classes (protein, lipid, carbohydrate, and DNA), and the current state of practical aspects in health and disease is delineated.

Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections.

Ebselen is an organoselenium compound exhibiting hydroperoxide- and peroxynitrite-reducing activity, acting as a glutathione peroxidase and peroxiredoxin enzyme mimetic. Ebselen reacts with a multitude of protein thiols, forming a selenosulfide bond, which results in pleiotropic effects of antiviral, antibacterial and anti-inflammatory nature. The main protease (Mpro) of the corona virus SARS-CoV-2 is a potential drug target, and a screen with over 10,000 compounds identified ebselen as a particularly promising inhibitor of Mpro (Jin, Z. et al. (2020) Nature 582, 289-293). We discuss here the reaction of ebselen with cysteine proteases, the role of ebselen in infections with viruses and with other microorganisms. We also discuss effects of ebselen in lung inflammation. In further research on the inhibition of Mpro in SARS-CoV-2, ebselen can serve as a promising lead compound, if the inhibitory effect is confirmed in intact cells in vivo. Independently of this action, potential beneficial effects of ebselen in COVID-19 are ascribed to a number of targets critical to pathogenesis, such as attenuation of inflammatory oxidants and cytokines.

Reactive oxygen species (ROS) as pleiotropic physiological signalling agents.

'Reactive oxygen species' (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as 'oxidative distress'. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).