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“Oxidative stress” as a concept in redox biology and medicine has been formulated in 1985; at the beginning of 2015, approx. 140,000 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.
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Author’s Accepted Manuscript
Oxidative stress: a concept in redox biology and
medicine
Helmut Sies
PII: S2213-2317(15)00003-8
DOI: http://dx.doi.org/10.1016/j.redox.2015.01.002
Reference: REDOX247
To appear in: Redox Biology
Received date: 28 December 2014
Accepted date: 1 January 2015
Cite this article as: Helmut Sies, Oxidative stress: a concept in redox biology and
medicine, Redox Biology, http://dx.doi.org/10.1016/j.redox.2015.01.002
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Commentary
Oxidative stress: a concept in redox biology and medicine
Helmut Sies
Institute of Biochemistry and Molecular Biology I, Heinrich-Heine-University Düsseldorf,
Düsseldorf, Germany
For correspondence:Helmut Sies, Institute of Biochemistry and Molecular Biology I,
Heinrich-Heine-University Düsseldorf, Building 22.03, University Street 1, D-40225-
Düsseldorf, Germany. sies@uni-duesseldorf.de, Phone: +49-211-8115956
Abstract
“Oxidative stressas a concept in redox biology and medicine has been formulated in 1985;
at the beginning of 2015, approx. 140,000 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 obvious 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.
Keywords
Oxidative stress, redox balance, oxidants, antioxidants, redox signaling, adaptive response
Highlights
Oxidative stress denotes deviation from redox steady state
Oxidative stress is an attribute of aerobic metabolism
Oxidative stress evokes stress responses
Oxidative stress activates molecular redox switches
Introduction
The concept of oxidative stress has been introduced for research in redox biology
and medicine in 1985, now 30 years ago, in an introductory chapter (1) in a book entitled
'Oxidative Stress' (2). A concurrent comprehensive review entitled 'Biochemistry of
Oxidative Stress' (3) presented the knowledge on pro-oxidants and antioxidants and their
endogenous and exogenous sources and metabolic sinks. Since then, Redox Biology as a
research area has found fulminant development in a wide range of disciplines, starting from
chemistry and radiation biology through biochemistry and cell physiology all the way into
general biology and medicine.
A noteworthy insight, early on, was the perception that oxidation-reduction (redox)
reactions in living cells are utilized in fundamental processes of redox regulation, collectively
termed 'redox signaling' and 'redox control'. A book 'Antioxidant and Redox Regulation of
Genes' highlighted that development at an early stage (4). Since then, an overwhelming and
fascinating area of research has flourished, under the name of Redox Biology (5,6). The
concept of oxidative stress was updated to include the role of redox signaling (7), and there
were efforts of redefining oxidative stress (8, 9).
These developments were mirrored by the appearance of monographs, book series
and the establishment of new research journals. Many volumes were published in Methods in
Enzymology. An impressive number of new journals sprang up, Free Radical Research
(initially Free Radical Research Communications), Free Radicals in Biology and Medicine,
Redox Reports, Antioxidant Redox Signaling, and most recently Redox Biology.
Useful as the term 'oxidative stress' may be in research, there has been an
inflationary development in research circles and more so in the medical field and, even more
than that, in public usage outside scientific endeavors (I would call it ‗over-stressing‘ the
term). This led to a dilution of the meaning, to overuse and even misuse. Cautionary words
were published (10) and even explicit criticism was voiced (11,12). ―Over time, the
mechanistic basis of the concept was largely forgotten and instead of the oxidative stress
hypothesis becoming more precise in terms of molecular targets and mechanism, it became
diffuse and nonspecific‖ (12). In fact, an ‗oxidative stress hypothesis‘ has not been
formulated up to now. If anything, there were implicit deductions: for example, that because
of the redox balance concept any single compound, e.g. a small-molecule redox-active
vitamin, could alter the totality of the system. Such a view overlooks counterregulation and
redundancies in the redox network. There is specificity inherent in the strategies of
antioxidant defense (13). Obviously, a general term describing a global condition cannot be
meant to depict specific spatiotemporal chemical relationships in detail and in specific cells or
organ conditions. Rather, it entails these, and directed effort is warranted to unravel the exact
chemical and physical conditions and their significance in each case.
Given the enormous variety and range of pro-oxidant and antioxidant enzymes and
compounds, attempts were made to classify subforms of oxidative stress (7) and to
conceptually introduce intensity scales ranging from physiological oxidative stress to
excessive and toxic oxidative burden (14), as indicated in Table 1.
What are the merits and pitfalls of 'oxidative stress' today?
A comprehensive treatment of this question is to be deferred to an in-depth
treatment (in preparation). However, for the purpose of the present Commentary it may
suffice to collect a few thoughts: from its very nature, it is a challenge to combine the basic
chemical notion of oxidation-reduction, including electron transfer, free radicals, oxygen
metabolites (such as the superoxide anion radical, hydrogen peroxide, hydroxyl radical,
electronically excited states such as singlet molecular oxygen, as well as the nitric oxide
radical and peroxynitrite) with a biological concept, that of stress, first introduced by Selye in
his research of adaptive responses (15,16). The two words 'oxidative' and 'stress' elicit a
notion which, in a nutshell, focuses on an important sector of fundamental processes in
biology. This is a merit.
Pitfalls are close-by: in research, simply to talk of exposing cells or organisms to
oxidative stress should clearly be discouraged. Instead, the exact molecular condition
employed to change the redox balance of a given system is what is important; for example, in
an experimental study cells were exposed to hydrogen peroxide, not to oxidative stress. Such
considerations are even more appropriate in applications in the medical world. Quite often,
redox components which are thought to be centrally important in disease processes are flatly
denoted as oxidative stress; this can still be found in numerous schemes in the current
biomedical literature. The underlying biochemically rigorous foundation may often be
missing. Constructive criticism in this sense has been voiced repeatedly (11,12,17). A related
pitfall in this sense is the use of the term ROS, which stands for reactive oxygen species (the
individual chemical reactants which were named in the preceding paragraph); whenever the
specific chemical entity of the oxidant is known, that oxidant should be mentioned and
discussed, not the generic ‗ROS‘.
This ‗one-size-fits-all‘ mentality pervades also into the analytics: measuring so-
called ‗total antioxidant capacity (TAC)‘ in a blood plasma sample will not give useful
information on the state of the organism, and should be discouraged (18). Rather, individual
antioxidant enzyme activities and patterns of antioxidant molecules need to be assessed.
In view of the knowledge that the major burden of antioxidant defense is shouldered
by antioxidant enzymes (13), it seems puzzlingin hindsightthat large human clinical
studies based on one or two low-molecular-weight antioxidant compounds were undertaken.
What is attractive about ‘oxidative stress’?
Molecular redox switches. What seems to be attractive about the term is the implicit
notion of adaptation, coming from the general association of stress with stress response. This
goes back to Selye‘s concept of stress as the ‗general adaptation syndrome‘ (19). The
enormously productive field of molecular switches was opened by the discovery of
phosphorylation/dephosphorylation, serving a mechanism in molecular signaling (20). The
role of redox switches came into focus more recently, foremost the dynamic role of cysteines
in proteins, opening the field of the redox proteome, currently flourishing because of advances
in mass spectrometric and imaging methodology (21-24). A bridge between
phosphorylation/dephosphorylation and protein cysteine reduction/oxidation is given by the
redox sensitivity of critical cysteinyl residues in protein phosphatases, opening the molecular
pathway for signaling cascades as fundamental processes throughout biology,
What was particularly exciting to many researchers was the discovery of master
switch systems (25), prominent examples being OxyR in bacteria (26) and NFkB (27) and
Nrf2/Keap1 (28 ) in higher organisms. That batteries of enzyme activities are mustered by
activation of gene transcription through a 'simple' redox signal is still an exciting strategy.
Much of current effort in redox biology is addressed towards these response systems.
Obviously, medical and pharmacological intervention attempts are a consequence.
Outlook
Current interest into the linkage of oxidative stress to inflammation and inflammatory
responses is adding a new perspective. For example, inflammatory macrophages release
glutathionylated peroxiredoxin-2, which then acts as a ‗danger signal‘ to trigger the
production of tumor necrosis factor-alpha (29). The orchestrated responses to danger signals
related to damage-associated molecular patterns (DAMPs) include relations to oxidative stress
(30). Under oxidative stress conditions, a protein targeting factor, Get3 in yeast (mammalian
TRC40) functions as an ATP-independent chaperone (31). More detailed molecular
understanding will also deepen the translational impact into biology and medicine; as
mentioned above, these aspects are beyond this Commentary and will be treated elsewhere.
However, it might be mentioned, for example, that viral and bacterial infections are often
associated with deficiencies in micronutrients, including the essential trace element, selenium,
the redox-active moiety in selenoproteins. Selenium status may affect the function of cells in
both adaptive and innate immunity (32). Major diseases, now even diabetes Type 2, are being
considered as ‗redox disease‘ (33).
Molecular insight will enhance the thrust of the concept of oxidative stress, which is
intimately linked to cellular energy balance. Thus, the subcellular compartmentation of redox
processes and redox components is being studied at a new level, in mammalian cells (34) as
well as in phototrophic organisms (35). New insight from spatiotemporal organisation of
hydrogen peroxide metabolism (36) complements the longstanding interest in hydroperoxide
metabolism in mammalian organs and its relationship to bioenergetics (37).
The following quote attributed to Hans Selye [38] might well apply to the concept of
oxidative stress: ― If only stress could be seen, isolated and measured, I am sure we could
enormously lengthen the average human life span‖.
Acknowledgements.
I gratefully acknowledge the input and friendship of many colleagues in shaping ideas in this
multidisciplinary field; of many close associates, Enrique Cadenas and Wilhelm Stahl in
particular, and close colleagues Dean Jones, Bruce Ames, Lester Packer, Alberto Boveris.
Also to Masayasu Inoue for the translation of the book ‗Oxidative Stress‘ into Japanese. Last,
but not least, to the many active scientists in this research field, gathered under the umbrella
of the Society for Free Radical Research International (SFRRI) and related organisations such
as the Oxygen Club of California (OCC).
I also am thankful for the research support by the National Foundation of Cancer
Research (NFCR), Bethesda, MD, USA, and the Deutsche Forschungsgemeinschaft and the
Alexander-von-Humboldt Foundation.
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Graphical Abstract
Table 1.
Oxidative Stress: definition, specific forms, classification according to intensity.
Category Term Reference
Definition, original ―A disturbance in the prooxidant-antioxidant [1]
balance in favor of the former‖
updated ―An imbalance between oxidants and antioxidants [7]
in favor of the oxidants, leading to a disruption
of redox signaling and control and/or molecular
damage‖
Specific form Nutritional oxidative stress [7]
Dietary oxidative stress
Postprandial oxidative stress
Physiological oxidative stress
Photooxidative stress
Ultraviolet (UV-A, UV-B)
Infrared-A
Radiation-induced oxidative stress
Nitrosative stress
Reductive stress
Related terms Oxidant stress, Pro-oxidant stress
Oxidative stress status (OSS)
Classification Basal oxidative stress [14]
Low intensity oxidative stress
Intermediate intensity oxidative stress
High intensity oxidative stress

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Thesis
De nos jours, les pathologies cardiovasculaires représentent un enjeu de santé publique majeur dans les pays développés. Particulièrement, le remodelage ventriculaire gauche touche 30% des patients suite à un infarctus du myocarde et peut mener à terme à une insuffisance cardiaque. Le remodelage et l’insuffisance cardiaque sont associés au développement d’un stress oxydant, participant aux modifications structurales et fonctionnelles du coeur. L’objectif de ma thèse consistait en l’étude des modifications post-traductionnelles de la protéine anti-oxydante mitochondriale superoxyde dismutase 2 (SOD2), et plus particulièrement de son inactivation par acétylation, dans le contexte des pathologies cardiovasculaires.J’ai montré que l’inactivation de SOD2 par acétylation de la lysine 68 favorise le stress oxydant et la dysfonction mitochondriale. Parmi les différents isoformes SIRT, la protéine mitochondriale SIRT3 a été identifiée comme responsable de l’activation de SOD2 par désacétylation, tandis que la protéine acetyl transferase P300 serait impliquée dans la régulation transcriptionnelle de SOD2. J’ai également montré que la protéine SIRT3 protège les cardiomyocytes du stress oxydant et de l’hypertrophie induite par stimulation à l’isoprénaline en activant la protéine SOD2. Ces données m’ont permis d’identifier la protéine SOD2 comme cible moléculaire potentielle dans les stratégies thérapeutiques anti-oxydantes.J’ai donc étudié l’impact des anti-oxydants MitoQuinone (MitoQ, antioxydant mitochondrial) et EUK 134 (mimétique des SOD) sur les cardiomyocytes et montré les effets protecteurs de la MitoQ et du EUK 134 sur le stress oxydant et l’hypertrophie. Cependant, la MitoQ entraîne des dysfonctions mitochondriales et un arrêt de la mitophagie délétères pour les cardiomyocytes, contrairement au EUK 134 qui permet de restaurer la fonction mitochondriale en maintenant l’équilibre de la mitophagie. Ces données mettent en évidence le rôle primordial du métabolisme mitochondrial dans le développement des thérapies anti-oxydantes.
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