Hydrogen peroxide emerged as major redox metabolite operative in redox sensing, signaling and redox regulation. Generation, transport and capture of H2O2 in biological settings as well as their ...biological consequences can now be addressed. The present overview focuses on recent progress on metabolic sources and sinks of H2O2 and on the role of H2O2 in redox signaling under physiological conditions (1–10nM), denoted as oxidative eustress. Higher concentrations lead to adaptive stress responses via master switches such as Nrf2/Keap1 or NF-κB. Supraphysiological concentrations of H2O2 (>100nM) lead to damage of biomolecules, denoted as oxidative distress. Three questions are addressed: How can H2O2 be assayed in the biological setting? What are the metabolic sources and sinks of H2O2? What is the role of H2O2 in redox signaling and oxidative stress?
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•H2O2 is operative in redox sensing and redox signaling.•H2O2 reacts with metal centers and with sulfur/selenium compounds.•H2O2 links redox biology to phosphorylation/dephosphorylation.•Physiological (low-level, nM) steady-state of H2O2 is maintained in oxidative eustress.•Supraphysiological (pathological) level of H2O2 leads to oxidative distress.
"Oxidative stress" as a concept in redox biology and medicine has been formulated in 1985; at the beginning of 2015, approx. 138,000 PubMed entries show for this term. This concept has its merits and ...its pitfalls. Among the merits is the notion, elicited by the combined two terms of (i) aerobic metabolism as a steady-state redox balance and (ii) the associated potential strains in the balance as denoted by the term, stress, evoking biological stress responses. Current research on molecular redox switches governing oxidative stress responses is in full bloom. The fundamental importance of linking redox shifts to phosphorylation/dephosphorylation signaling is being more fully appreciated, thanks to major advances in methodology. Among the pitfalls is the fact that the underlying molecular details are to be worked out in each particular case, which is bvious for a global concept, but which is sometimes overlooked. This can lead to indiscriminate use of the term, oxidative stress, without clear relation to redox chemistry. The major role in antioxidant defense is fulfilled by antioxidant enzymes, not by small-molecule antioxidant compounds. The field of oxidative stress research embraces chemistry, biochemistry, cell biology, physiology and pathophysiology, all the way to medicine and health and disease research.
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.
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.
'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 (H
O
) and the superoxide anion radical (O
), 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, H
O
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).
Current issues in research on health effects by polyphenols are addressed. As to the cardiovascular system, flow-mediated dilation (FMD), a functional biomarker, can be used as surrogate marker for ...cardiovascular risk. Acute short-term effects peaking at 2
h after ingestion of polyphenol-rich food items are distinguished from longer-term effects over days and weeks. The role of polyphenol metabolites as bioactives is presented, underlining that specific target enzymes such as NADPH oxidases or lipoxygenases provide a basis for molecular action of polyphenols, rather than unspecific direct antioxidant effects. Cautionary words are given for the use of non-compositional assays of ‘total antioxidant capacity’ (TAC) in blood plasma. Enhanced interest emerges for polyphenols in the gastrointestinal tract. Recommendations for health professionals and the public are summarized, as well as prospects and challenges for future research.
In this contribution, I discuss the applicability of total antioxidant capacity (TAC) data obtained from plasma to human health issues and the use of TAC data for dietary items in epidemiological ...applications. Against the background of knowledge that major antioxidant defense is enzymatic, the use of the term "total" is not appropriate. Because dietary phytochemicals undergo uptake and metabolism, extrapolation to health effects requires direct molecular information, not a global parameter that uses an arbitrarily selected prooxidant source. Suitable alternatives are given in measuring functional biomarkers (surrogate endpoints). Although using TAC may be helpful in comparing different food items, the extrapolation to their contribution of antioxidant defense in vivo and, further, to health issues, should be discouraged, with the possible exception of the gastrointestinal tract. This is of particular importance because dietary phytochemicals and other small molecules have nonantioxidant activities. Direct assay of urate, ascorbate, and tocopherol, the major small-molecule contributors to TAC, is recommended.
Oxidative Stress Sies, Helmut; Berndt, Carsten; Jones, Dean P
Annual review of biochemistry,
06/2017, Volume:
86, Issue:
1
Journal Article
Peer reviewed
Oxidative stress is two sided: Whereas excessive oxidant challenge causes damage to biomolecules, maintenance of a physiological level of oxidant challenge, termed oxidative eustress, is essential ...for governing life processes through redox signaling. Recent interest has focused on the intricate ways by which redox signaling integrates these converse properties. Redox balance is maintained by prevention, interception, and repair, and concomitantly the regulatory potential of molecular thiol-driven master switches such as Nrf2 Keap1 or NF-κB IκB is used for system-wide oxidative stress response. Nonradical species such as hydrogen peroxide (H
2
O
2
) or singlet molecular oxygen, rather than free-radical species, perform major second messenger functions. Chemokine-controlled NADPH oxidases and metabolically controlled mitochondrial sources of H
2
O
2
as well as glutathione- and thioredoxin-related pathways, with powerful enzymatic back-up systems, are responsible for fine-tuning physiological redox signaling. This makes for a rich research field spanning from biochemistry and cell biology into nutritional sciences, environmental medicine, and molecular knowledge-based redox medicine.
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.
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•Ebselen, an organoselenium compound, exhibits anti-inflammatory and antiviral activity.•Ebselen is a glutathione peroxidase and peroxiredoxin mimetic.•Ebselen reacts with a multitude of protein thiols, resulting in pleiotropic effects.•Ebselen is an effective inhibitor of Mpro, the main protease of SARS-CoV-2.•Ebselen may serve as lead compound for drugs targeting COVID-19.
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