The literature in redox biology is vast. Here, you can find some papers that to my opinion are worth reading along with a short commentary. The list is highly subjective and not meant to be comprehensive. Of course, many good papers have passed my attention.
January 21, 2015
An excellent presentation on the basic chemistry and biochemistry of free radicals and antioxidants:
click here
July 10, 2013
Boycott AE. The blood as a tissue: hypertrophy and atrophy of the red corpuscles. Proc R Soc Med. 1929 November; 23(1): 15–25.
“We generally think of the blood as something which goes round the body and in so doing brings food to the tissues, takes away their excreta and helps to keep them in communication with one another. But we may also think of it, and sometimes more profitably, as a tissue or organ whose chief business it is to be itself and maintain its own individuality.” This quote from a 1929 paper shows that 85 years ago the “altruistic” nature of blood was a prevailing idea in biology and, in my mind, still is. This view seems to be also true in current redox biology. It is often convenient to consider blood as a passive fluid under the control of the tissues and organs of the body. Only that way what is measuring in the blood can describe in a reliable and valid way what happens in the most metabolically active tissue or organ. I think that, if more studies investigate the blood for its own sake and incorporate it in their theoretical framework as a central player, the importance of blood as a regulator of the systemic redox status will be clearer.
Bailey DM, Young IS, McEneny J, Lawrenson L, Kim J, Barden J, Richardson RS. Regulation of free radical outflow from an isolated muscle bed in exercising humans. Am J Physiol Heart Circ Physiol. 2004 Oct;287(4):H1689-99.
One of the most underrated papers in the field. This is probably the study that most convincingly showed that free radicals are released from the activating skeletal muscle to circulation. Equally important, the paper deserves a reading for the comparison of the methodological setups that are usually adopted in redox biology experiments using humans. The authors’ view is presented in Figure 1 of that paper and clearly shows how methodological choices at the physiological level can deeply affect the results measured at the molecular level.
Mishina NM, Tyurin-Kuzmin PA, Markvicheva KN, Vorotnikov AV, Tkachuk VA, Laketa V, Schultz C, Lukyanov S, Belousov VV. Does cellular hydrogen peroxide diffuse or act locally? Antioxid Redox Signal. 2011 Jan 1;14(1):1-7.
In case of redox signaling, the single most cited reactive oxygen species (ROS) capable of transmitting signals among cells is hydrogen peroxide (H2O2). However, this study shows that the diffusion volume of H2O2 is limited to a few micrometers, probably because cellular antioxidant systems degrade H2O2 before crossing the plasma membrane. I believe that, if this is the case for the most distant “traveler” of the ROS, then it is highly likely that all ROS are bound to act inside the cells that generate them.
August 30, 2012
Kirkwood TB, Kowald A. The free-radical theory of aging - older, wiser and still alive: Modelling positional effects of the primary targets of ROS reveals new support. Bioessays. 2012 Aug;34(8):692-700.
A mini-review supporting the view that our basic redox biology knowledge is fragmented (and, as a result, the experimental approaches applied are crude) so as to either accept or reject the free radical theory of aging. Mathematical modelling is applied to designate the importance of the dynamics of accumulation and removal of mitochondrial DNA oxidation. The revisited analogy between gasoline (antioxidants) and car (human body) performance highlights the limitations of the current thinking.
Pimenta A, Gorjão R, Silveira LR, Curi R. Changes of gene expression in electrically stimulated and contralateral rat soleus muscles. Muscle Nerve. 2009 Nov;40(5):838-46.
The cross-training effect is an inter-limb phenomenon describing the increase in force generating capacity of the opposite untrained limb that occurs as a result of unilateral resistance training. This paper employed the unilateral exercise model and found extensive alterations in the expression of enzymes related to redox homeostasis in the skeletal muscle of the rested limb. I believe that this finding implicates extramuscular factors, such as neural or other systemic factors (e.g., redox agents transported via circulation), in the regulation of tissue redox homeostasis.
1. Dorjgochoo T, Gao YT, Chow WH, Shu XO, Yang G, Cai Q, Rothman N, Cai H, Li H, Deng X, Franke A, Roberts LJ, Milne G, Zheng W, Dai Q. Major metabolite of F2-isoprostane in urine may be a more sensitive biomarker of oxidative stress than isoprostane itself. Am J Clin Nutr. 2012 Aug;96(2):405-14.
2. Breusing N, Grune T, Andrisic L, Atalay M, Bartosz G, Biasi F, Borovic S, Bravo L, Casals I, Casillas R, Dinischiotu A, Drzewinska J, Faber H, Fauzi NM, Gajewska A, Gambini J, Gradinaru D, Kokkola T, Lojek A, Luczaj W, Margina D, Mascia C, Mateos R, Meinitzer A, Mitjavila MT, Mrakovcic L, Munteanu MC, Podborska M, Poli G, Sicinska P, Skrzydlewska E, Vina J, Wiswedel I, Zarkovic N, Zelzer S, Spickett CM. An inter-laboratory validation of methods of lipid peroxidation measurement in UVA-treated human plasma samples. Free Radic Res. 2010 Oct;44(10):1203-15.
F2-isoprostanes are widely considered the best available oxidative damage biomarker. Yet, new studies cast doubt on this popular claim. Indeed, two independent studies have provided evidence that the major isoprostane metabolite 2,3-dinor-5,6-dihydro-15-F2t-isoprostane and the humble malondialdehyde are more valid and reliable biomarkers than F2-isoprostanes. To my opinion, for several reasons mostly related to the complexity of redox homeostasis, the quest of the best universal redox biomarker is largely an illusion. This is mainly because whether a biomarker adequately reflects or not a change in redox homeostasis is strongly dependent on the originating stimulus and the topology of it (i.e., the type of reactive species generated and in which part of the cell). For example, considering that different types of oxidant stimuli generate different types of reactive species at different cellular locations, it is possible that F2-isoprostanes may be found superior biomarkers in future papers that will employ other experimental models.
April 27, 2012
Argüelles S, García S, Maldonado M, Machado A, Ayala A. Do the serum oxidative stress biomarkers provide a reasonable index of the general oxidative stress status? Biochim Biophys Acta. 2004 Nov 1;1674(3):251-9.
To my knowledge, this is the first and one of the very few studies that investigated whether blood is able to provide a reasonable picture of the general redox status using a direct statistical approach (i.e., correlations between selected markers in blood and tissues).
Close GL, Ashton T, Cable T, Doran D, MacLaren DP. Eccentric exercise, isokinetic muscle torque and delayed onset muscle soreness: the role of reactive oxygen species. Eur J Appl Physiol. 2004 May;91(5-6):615-21.
This is probably the only study that measured directly the levels of free radicals in any tissue after muscle-damaging exercise. The investigators, using ESR spectroscopy, found gradually increased levels of free radicals in the blood immediately to 72 h post-exercise, at which time-point free radical value was significantly higher by 122% compared to the resting value. Another point that it is worth noting in this study is that it is the only relevant one that compared the effects of exercise with high eccentric component (downhill running) to exercise with low eccentric component (horizontal running). They reported increases in free radicals only after downhill running, providing the first evidence that eccentric exercise can increase free radical production for some days after exercise. Therefore, except for the well-documented increases in the concentration of free radicals that appear immediately after aerobic exercise of high intensity, muscle-damaging exercise seems able to increase free radical production some days after exercise.
Conti V, Corbi G, Russomanno G, Simeon V, Ferrara N, Filippelli W, Limongelli F, Canonico R, Grasso C, Stiuso P, Dicitore A, Filippelli A. Oxidative stress effects on endothelial cells treated with different athletes' sera. Med Sci Sports Exerc. 2012 Jan;44(1):39-49.
One of the intriguing questions in the field of redox biology of exercise is whether blood regulates tissue redox homeostasis. At present, the idea prevailing in the field is that blood plasma is largely considered an inert body fluid, a kind of “sink” which passively accepts reactive species and oxidative products produced mainly from exercising skeletal muscles. In my opinion, however, this frequently adopted cell- and muscle-centric point of view has not been put into rigorous test whatsoever. Recent evidence by Conti and colleagues is now challenging this notion. Using a novel approach, the researchers have conditioned endothelial cells with sera from triathletes (“aerobic” activity), sprint runners (“anaerobic” activity) and soccer players (mixed “aerobic-anaerobic” activity) and examined the effects of these sera on several parameters related to redox homeostasis in endothelial cells. Based on their evidence, it is inferred that changes in redox homeostasis are strongly dependent on the type of sport practicing by the volunteers provided the sera. Application of this original in vitro – in vivo technique (i.e., cultured cells incubated with fresh human serum) provided probably for the first time direct evidence that human serum strongly affects redox homeostasis of endothelial cells and that these effects are to a great extent dependent on the exercise training stimulus.
Davies KJ, Quintanilha AT, Brooks GA, Packer L. Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun. 1982 Aug 31;107(4):1198-205.
A classic paper in the redox biology of exercise field. Davies and colleagues 30 years ago were well aware of the potential “beneficial” role of reactive species in biology leading them to conclude: “It is tempting to propose that exercise induced free radicals may cause limited damage to mitochondrial membranes which, in a chronic training situation, may be the initiating stimulus to mitochondrial biogenesis.”
Fisher-Wellman K, Bloomer RJ. Acute exercise and oxidative stress: a 30 year history. Dyn Med. 2009 Jan 13;8:1.
The definitive source for finding the effect of every conceivable type of acute exercise on oxidative stress. Check out the additional file accompanying the main article where you can find a basic description of virtually every study in the field.
February 08, 2012
Azzi A. Oxidative stress: A dead end or a laboratory hypothesis? Biochem Biophys Res Commun. 2007 Oct 19;362(2):230-2.
A short critique of the oxidative stress concept.
Davies SS, Roberts LJ 2nd. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Radic Biol Med. 2011 Mar 1;50(5):559-66.
Probably the first attempt to use a redox biomarker (F2-isoprostanes) as an endpoint in interventional trials providing quantitative guidelines.
Halliwell B, Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br J Pharmacol. 2004 May;142(2):231-55.
Contains definitions of some nebulous concepts such as oxidative stress, oxidative damage and antioxidant. In addition, presents the authors’ criteria for the ideal biomarker of oxidative damage.
Jenkins RR. Exercise and oxidative stress methodology: a critique. Am J Clin Nutr. 2000 Aug;72(2 Suppl):670S-4S.
An article ahead of its time, highlighting some limitations of exercise redox biology which are still valid today.
Kerkweg U, Pamp K, Fieker J, Petrat F, Hider RC, de Groot H. Release of redox-active iron by muscle crush trauma: no liberation into the circulation. Shock. 2010 May;33(5):513-8.
One of the intriguing questions in the field of redox biology of exercise is the origin of blood plasma oxidative stress that appears after physical activity. In this paper, Kerkweg and co-workers employed both in vitro and in vivo experiments, in order to assess the biological relevance of their in vitro data. In vitro they elegantly demonstrated that redox-active iron is released from disrupted muscle tissue and induces lipid peroxidation within the muscle homogenate. In vivo they confirmed the occurrence of oxidative stress within the damaged muscle tissue. However, the liberation of redox-active iron from the injured muscle into the circulation and its contribution to oxidation of plasma lipids and proteins could not be verified. Consequently, the plasma oxidative stress that typically follows almost every type of physical activity may not be derived from the release of redox-active iron from the skeletal muscle into the blood plasma.
Lamprecht M, Greilberger J, Oettl K. Analytical aspects of oxidatively modified substances in sports and exercises. Nutrition. 2004 Jul-Aug;20(7-8):728-30.
One of the first integrative papers presenting the idea that reactive species are generated in multiple fluids and tissues during exercise.
Murphy MP, Holmgren A, Larsson NG, Halliwell B, Chang CJ, Kalyanaraman B, Rhee SG, Thornalley PJ, Partridge L, Gems D, Nyström T, Belousov V, Schumacker PT, Winterbourn CC. Unraveling the biological roles of reactive oxygen species. Cell Metab. 2011 Apr 6;13(4):361-6.
Some of the most respected authorities in the field have joined forces and discuss the chemistry and biology of reactive species. A checklist for assessing a role for reactive species in biological processes is also presented.
January 21, 2015
An excellent presentation on the basic chemistry and biochemistry of free radicals and antioxidants:
click here
July 10, 2013
Boycott AE. The blood as a tissue: hypertrophy and atrophy of the red corpuscles. Proc R Soc Med. 1929 November; 23(1): 15–25.
“We generally think of the blood as something which goes round the body and in so doing brings food to the tissues, takes away their excreta and helps to keep them in communication with one another. But we may also think of it, and sometimes more profitably, as a tissue or organ whose chief business it is to be itself and maintain its own individuality.” This quote from a 1929 paper shows that 85 years ago the “altruistic” nature of blood was a prevailing idea in biology and, in my mind, still is. This view seems to be also true in current redox biology. It is often convenient to consider blood as a passive fluid under the control of the tissues and organs of the body. Only that way what is measuring in the blood can describe in a reliable and valid way what happens in the most metabolically active tissue or organ. I think that, if more studies investigate the blood for its own sake and incorporate it in their theoretical framework as a central player, the importance of blood as a regulator of the systemic redox status will be clearer.
Bailey DM, Young IS, McEneny J, Lawrenson L, Kim J, Barden J, Richardson RS. Regulation of free radical outflow from an isolated muscle bed in exercising humans. Am J Physiol Heart Circ Physiol. 2004 Oct;287(4):H1689-99.
One of the most underrated papers in the field. This is probably the study that most convincingly showed that free radicals are released from the activating skeletal muscle to circulation. Equally important, the paper deserves a reading for the comparison of the methodological setups that are usually adopted in redox biology experiments using humans. The authors’ view is presented in Figure 1 of that paper and clearly shows how methodological choices at the physiological level can deeply affect the results measured at the molecular level.
Mishina NM, Tyurin-Kuzmin PA, Markvicheva KN, Vorotnikov AV, Tkachuk VA, Laketa V, Schultz C, Lukyanov S, Belousov VV. Does cellular hydrogen peroxide diffuse or act locally? Antioxid Redox Signal. 2011 Jan 1;14(1):1-7.
In case of redox signaling, the single most cited reactive oxygen species (ROS) capable of transmitting signals among cells is hydrogen peroxide (H2O2). However, this study shows that the diffusion volume of H2O2 is limited to a few micrometers, probably because cellular antioxidant systems degrade H2O2 before crossing the plasma membrane. I believe that, if this is the case for the most distant “traveler” of the ROS, then it is highly likely that all ROS are bound to act inside the cells that generate them.
August 30, 2012
Kirkwood TB, Kowald A. The free-radical theory of aging - older, wiser and still alive: Modelling positional effects of the primary targets of ROS reveals new support. Bioessays. 2012 Aug;34(8):692-700.
A mini-review supporting the view that our basic redox biology knowledge is fragmented (and, as a result, the experimental approaches applied are crude) so as to either accept or reject the free radical theory of aging. Mathematical modelling is applied to designate the importance of the dynamics of accumulation and removal of mitochondrial DNA oxidation. The revisited analogy between gasoline (antioxidants) and car (human body) performance highlights the limitations of the current thinking.
Pimenta A, Gorjão R, Silveira LR, Curi R. Changes of gene expression in electrically stimulated and contralateral rat soleus muscles. Muscle Nerve. 2009 Nov;40(5):838-46.
The cross-training effect is an inter-limb phenomenon describing the increase in force generating capacity of the opposite untrained limb that occurs as a result of unilateral resistance training. This paper employed the unilateral exercise model and found extensive alterations in the expression of enzymes related to redox homeostasis in the skeletal muscle of the rested limb. I believe that this finding implicates extramuscular factors, such as neural or other systemic factors (e.g., redox agents transported via circulation), in the regulation of tissue redox homeostasis.
1. Dorjgochoo T, Gao YT, Chow WH, Shu XO, Yang G, Cai Q, Rothman N, Cai H, Li H, Deng X, Franke A, Roberts LJ, Milne G, Zheng W, Dai Q. Major metabolite of F2-isoprostane in urine may be a more sensitive biomarker of oxidative stress than isoprostane itself. Am J Clin Nutr. 2012 Aug;96(2):405-14.
2. Breusing N, Grune T, Andrisic L, Atalay M, Bartosz G, Biasi F, Borovic S, Bravo L, Casals I, Casillas R, Dinischiotu A, Drzewinska J, Faber H, Fauzi NM, Gajewska A, Gambini J, Gradinaru D, Kokkola T, Lojek A, Luczaj W, Margina D, Mascia C, Mateos R, Meinitzer A, Mitjavila MT, Mrakovcic L, Munteanu MC, Podborska M, Poli G, Sicinska P, Skrzydlewska E, Vina J, Wiswedel I, Zarkovic N, Zelzer S, Spickett CM. An inter-laboratory validation of methods of lipid peroxidation measurement in UVA-treated human plasma samples. Free Radic Res. 2010 Oct;44(10):1203-15.
F2-isoprostanes are widely considered the best available oxidative damage biomarker. Yet, new studies cast doubt on this popular claim. Indeed, two independent studies have provided evidence that the major isoprostane metabolite 2,3-dinor-5,6-dihydro-15-F2t-isoprostane and the humble malondialdehyde are more valid and reliable biomarkers than F2-isoprostanes. To my opinion, for several reasons mostly related to the complexity of redox homeostasis, the quest of the best universal redox biomarker is largely an illusion. This is mainly because whether a biomarker adequately reflects or not a change in redox homeostasis is strongly dependent on the originating stimulus and the topology of it (i.e., the type of reactive species generated and in which part of the cell). For example, considering that different types of oxidant stimuli generate different types of reactive species at different cellular locations, it is possible that F2-isoprostanes may be found superior biomarkers in future papers that will employ other experimental models.
April 27, 2012
Argüelles S, García S, Maldonado M, Machado A, Ayala A. Do the serum oxidative stress biomarkers provide a reasonable index of the general oxidative stress status? Biochim Biophys Acta. 2004 Nov 1;1674(3):251-9.
To my knowledge, this is the first and one of the very few studies that investigated whether blood is able to provide a reasonable picture of the general redox status using a direct statistical approach (i.e., correlations between selected markers in blood and tissues).
Close GL, Ashton T, Cable T, Doran D, MacLaren DP. Eccentric exercise, isokinetic muscle torque and delayed onset muscle soreness: the role of reactive oxygen species. Eur J Appl Physiol. 2004 May;91(5-6):615-21.
This is probably the only study that measured directly the levels of free radicals in any tissue after muscle-damaging exercise. The investigators, using ESR spectroscopy, found gradually increased levels of free radicals in the blood immediately to 72 h post-exercise, at which time-point free radical value was significantly higher by 122% compared to the resting value. Another point that it is worth noting in this study is that it is the only relevant one that compared the effects of exercise with high eccentric component (downhill running) to exercise with low eccentric component (horizontal running). They reported increases in free radicals only after downhill running, providing the first evidence that eccentric exercise can increase free radical production for some days after exercise. Therefore, except for the well-documented increases in the concentration of free radicals that appear immediately after aerobic exercise of high intensity, muscle-damaging exercise seems able to increase free radical production some days after exercise.
Conti V, Corbi G, Russomanno G, Simeon V, Ferrara N, Filippelli W, Limongelli F, Canonico R, Grasso C, Stiuso P, Dicitore A, Filippelli A. Oxidative stress effects on endothelial cells treated with different athletes' sera. Med Sci Sports Exerc. 2012 Jan;44(1):39-49.
One of the intriguing questions in the field of redox biology of exercise is whether blood regulates tissue redox homeostasis. At present, the idea prevailing in the field is that blood plasma is largely considered an inert body fluid, a kind of “sink” which passively accepts reactive species and oxidative products produced mainly from exercising skeletal muscles. In my opinion, however, this frequently adopted cell- and muscle-centric point of view has not been put into rigorous test whatsoever. Recent evidence by Conti and colleagues is now challenging this notion. Using a novel approach, the researchers have conditioned endothelial cells with sera from triathletes (“aerobic” activity), sprint runners (“anaerobic” activity) and soccer players (mixed “aerobic-anaerobic” activity) and examined the effects of these sera on several parameters related to redox homeostasis in endothelial cells. Based on their evidence, it is inferred that changes in redox homeostasis are strongly dependent on the type of sport practicing by the volunteers provided the sera. Application of this original in vitro – in vivo technique (i.e., cultured cells incubated with fresh human serum) provided probably for the first time direct evidence that human serum strongly affects redox homeostasis of endothelial cells and that these effects are to a great extent dependent on the exercise training stimulus.
Davies KJ, Quintanilha AT, Brooks GA, Packer L. Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun. 1982 Aug 31;107(4):1198-205.
A classic paper in the redox biology of exercise field. Davies and colleagues 30 years ago were well aware of the potential “beneficial” role of reactive species in biology leading them to conclude: “It is tempting to propose that exercise induced free radicals may cause limited damage to mitochondrial membranes which, in a chronic training situation, may be the initiating stimulus to mitochondrial biogenesis.”
Fisher-Wellman K, Bloomer RJ. Acute exercise and oxidative stress: a 30 year history. Dyn Med. 2009 Jan 13;8:1.
The definitive source for finding the effect of every conceivable type of acute exercise on oxidative stress. Check out the additional file accompanying the main article where you can find a basic description of virtually every study in the field.
February 08, 2012
Azzi A. Oxidative stress: A dead end or a laboratory hypothesis? Biochem Biophys Res Commun. 2007 Oct 19;362(2):230-2.
A short critique of the oxidative stress concept.
Davies SS, Roberts LJ 2nd. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Radic Biol Med. 2011 Mar 1;50(5):559-66.
Probably the first attempt to use a redox biomarker (F2-isoprostanes) as an endpoint in interventional trials providing quantitative guidelines.
Halliwell B, Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br J Pharmacol. 2004 May;142(2):231-55.
Contains definitions of some nebulous concepts such as oxidative stress, oxidative damage and antioxidant. In addition, presents the authors’ criteria for the ideal biomarker of oxidative damage.
Jenkins RR. Exercise and oxidative stress methodology: a critique. Am J Clin Nutr. 2000 Aug;72(2 Suppl):670S-4S.
An article ahead of its time, highlighting some limitations of exercise redox biology which are still valid today.
Kerkweg U, Pamp K, Fieker J, Petrat F, Hider RC, de Groot H. Release of redox-active iron by muscle crush trauma: no liberation into the circulation. Shock. 2010 May;33(5):513-8.
One of the intriguing questions in the field of redox biology of exercise is the origin of blood plasma oxidative stress that appears after physical activity. In this paper, Kerkweg and co-workers employed both in vitro and in vivo experiments, in order to assess the biological relevance of their in vitro data. In vitro they elegantly demonstrated that redox-active iron is released from disrupted muscle tissue and induces lipid peroxidation within the muscle homogenate. In vivo they confirmed the occurrence of oxidative stress within the damaged muscle tissue. However, the liberation of redox-active iron from the injured muscle into the circulation and its contribution to oxidation of plasma lipids and proteins could not be verified. Consequently, the plasma oxidative stress that typically follows almost every type of physical activity may not be derived from the release of redox-active iron from the skeletal muscle into the blood plasma.
Lamprecht M, Greilberger J, Oettl K. Analytical aspects of oxidatively modified substances in sports and exercises. Nutrition. 2004 Jul-Aug;20(7-8):728-30.
One of the first integrative papers presenting the idea that reactive species are generated in multiple fluids and tissues during exercise.
Murphy MP, Holmgren A, Larsson NG, Halliwell B, Chang CJ, Kalyanaraman B, Rhee SG, Thornalley PJ, Partridge L, Gems D, Nyström T, Belousov V, Schumacker PT, Winterbourn CC. Unraveling the biological roles of reactive oxygen species. Cell Metab. 2011 Apr 6;13(4):361-6.
Some of the most respected authorities in the field have joined forces and discuss the chemistry and biology of reactive species. A checklist for assessing a role for reactive species in biological processes is also presented.