Biological and physiological role of reactive oxygen species--the good, the bad and the ugly.

Acta Physiol 2015, 214, 329–348

REVIEW

Biological and physiological role of reactive oxygen species – the good, the bad and the ugly L. Zuo,1,2 T. Zhou,1,2 B. K. Pannell,1 A. C. Ziegler1 and T. M. Best3 1 Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, Columbus, OH, USA 2 Biophysics Graduate Program, The Ohio State University, Columbus, OH, USA 3 Division of Sports Medicine, Department of Family Medicine, Sports Health & Performance Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Received 8 January 2015, revision requested 27 March 2015, revision received 31 March 2015, accepted 21 April 2015 Correspondence: L. Zuo, PhD, FACSM, Molecular Physiology and Rehabilitation Research Lab, School of Health and Rehabilitation Sciences, The Ohio State College of Medicine, The Ohio State University Wexner Medical Center, 453 W. 10th Ave., Columbus, OH 43210, USA. E-mail: [email protected]

Abstract Reactive oxygen species (ROS) are chemically reactive molecules that are naturally produced within biological systems. Research has focused extensively on revealing the multi-faceted and complex roles that ROS play in living tissues. In regard to the good side of ROS, this article explores the effects of ROS on signalling, immune response and other physiological responses. To review the potentially bad side of ROS, we explain the consequences of high concentrations of molecules that lead to the disruption of redox homeostasis, which induces oxidative stress damaging intracellular components. The ugly effects of ROS can be observed in devastating cardiac, pulmonary, neurodegenerative and other disorders. Furthermore, this article covers the regulatory enzymes that mitigate the effects of ROS. Glutathione peroxidase, superoxide dismutase and catalase are discussed in particular detail. The current understanding of ROS is incomplete, and it is imperative that future research be performed to understand the implications of ROS in various therapeutic interventions. Keywords antioxidant, oxidative stress, redox, signalling, vitamin.

Reactive oxygen species (ROS) are chemically reactive molecules produced within biological systems (Dillard et al. 1978, Allen & Tresini 2000). Due to their reactivity, initial research focused on examining the deleterious effects of ROS in tissues. Naturally generated antioxidants, such as superoxide dismutase (SOD), are able to scavenge excess oxidants and convert them into less harmful molecules (Powers & Jackson 2008). The generation of ROS is shown to be either beneficial or harmful depending on various conditions. In regard to the beneficial aspects of ROS, it has been revealed that ROS at normal levels are involved in mediating many cellular responses including cell growth and immunity (Valko et al. 2006, 2007). Indeed, ROS occur naturally as a result of basic

metabolic processes; however, the presence of excess ROS can lead to lipid peroxidation, DNA damage and even induce cell death (Halliwell 2006, Brieger et al. 2012). Studies on the complex interactions of ROS with various molecules help to elucidate their specific roles in biological systems. Current investigations target the involvement of ROS in various chronic conditions including cardiovascular and neurodegenerative diseases. Tissue ROS levels have been utilized as disease markers, and the manipulation of ROS levels may be a promising therapeutic strategy for ROS-induced injuries (Trachootham et al. 2009, Zuo et al. 2014b). Future research which explores the balance between the positive and negative effects of ROS in living systems, along with a

© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12515

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more complete understanding of ROS mechanisms, may be a key in discovering novel therapies which utilize ROS interactions. This review aims to provide a thorough discussion on the good, bad and ugly effects of ROS in biological systems (summarized in Table 1), as well as a detailed focus on the endogenous antioxidant-based techniques used today for ROS-related research.

ROS in physiology The source of ROS Naturally produced ROS are involved in cell growth, necrosis, apoptosis, protease activities and gene expressions (Dillard et al. 1978, Allen & Tresini 2000, Bushell et al. 2002, Yu et al. 2011, Choudhury

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et al. 2013). Common examples of ROS include superoxide (O 2 ), hydroxyl radical ( OH), peroxyni trite (ONOO ) and hydrogen peroxide (H2O2) (Uttara et al. 2009). Within normal functioning cells, mitochondria and NADPH oxidase (NOX) are two main sources of ROS production (Sagi & Fluhr 2006, Madamanchi & Runge 2007). Mitochondrial oxygen gains electrons through the leakage of the electron transport chain and subsequently forms O 2 (Sagi & Fluhr 2006, Madamanchi & Runge 2007). Endothelial cells also provide a source of ROS generation (De Keulenaer et al. 1998, Munzel et al. 1999). In addition, sarcolemma, sarcoplasmic reticulum and transverse tubules are all implicated as potent sources of O 2 due to the presence of NOX (Fig. 1; Powers & Jackson 2008). Other organelles and cell types including the endoplasmic reticulum, peroxisomes, plasma

Table 1 The good, bad and ugly of ROS Nature of ROS

Biology/Physiology

Effects of ROS

Citations

Good

Cellular activities

Involved in cellular response to stressors Regulates mitochondrial function, expression of certain stress proteins and antioxidant levels

Immune system

Activates NLRP3 inflammasomes or other immune-related receptors Helps combat invading pathogens Involved in the formation of LTP Leads to protein modification Influences protein translation Increases the susceptibility of proteins to proteolysis Induces mutagenesis Oxidizes nucleotides (guanine is particularly susceptible) Increases fatigue thus reducing muscle function Promotes oxidative damage to muscle protein

Allen & Tresini (2000), Banerjee Mustafi et al. (2009), Bushell et al. (2002), Chandel et al. (1996), Yamashita et al. (1997) Bedard & Krause (2007), Bonini & Malik (2014), Tschopp (2011)

Bad

Synaptic plasticity Protein degradation

DNA damage

Muscle fatigue

Ugly

Cancer

Pulmonary diseases

Cardiovascular diseases

Neurodegenerative disorders

Induces DNA mutation Upregulates HIF-1a, which is involved in tumor angiogenesis Enhances inflammation response and damages diaphragm function Contributes to pulmonary diseases such as COPD or asthma Involved in IR damage Causes hypertension via mechanisms such as lipid peroxidation Correlated with neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and ALS

Massaad & Klann (2011) Aiken et al. (2011), Breusing & Grune (2008), Cheeseman & Slater (1993), Stadtman (1991), Valko et al. (2007, 2006), Winrow et al. (1993) Sassa et al. (2013), Sheng et al. (2012)

Khassaf et al. (2001), Mangner et al. (2013), McArdle et al. (2001), Pattwell et al. (2004), Reid et al. (1992) Liao et al. (2007), Waris & Ahsan (2006)

Barreiro et al. (2005), Zuo et al. (2012, 2013a)

Zuo et al. (2013b, 2014c)

Brieger et al. (2012), Mitsumoto et al. (2014), Saccon et al. (2013), Sorce & Krause (2009)

ALS, amyotrophic lateral sclerosis; COPD, chronic obstructive pulmonary disease; HIF-1a, hypoxic-inducible transcription factor; IR, ischaemia–reperfusion; LTP, long-term potentiation; NLRP3, cryopyrin; ROS, reactive oxygen species.

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Figure 1 Schematic illustrating key factors of ROS generation in biological and physiological pathways. H/R, hypoxia/reoxygenation; LRRK2, leucinerich repeat kinase 2; NF-jb, nuclear factor kappa-light-chain-enhancer of activated B cells; PINK1, PTEN-induced putative kinase 1; ROS, reactive oxygen species.

membranes, nuclear membranes, macrophages and polymorphonuclear cells are all shown to be able to generate ROS (Samoylenko et al. 2013). Electron transport chain leakage and NOX formation are not the only studied mechanisms that lead to ROS production. Alternative mechanisms include arachidonic acid (AA) metabolism, nitric oxide (NO˙) and xanthine oxidase (XO; De Keulenaer et al. 1998, Cocco et al. 1999, Pou et al. 1999, Wong & Vanhoutte 2010). AA can be generated via the activation of phospholipase A2 (PLA2). By uncoupling mitochondrial electron transport, AA may increase ROS formation (Davis et al. 2008). Moreover, AA activates various enzymes including cyclooxygenase, cytochrome P450-dependent monooxygenase, lipoxygenase and XO, which further induce ROS generation (Okabe et al. 1985, Kukreja et al. 1986, Bondy & Naderi 1994, Parke & Sapota 1996, Woo et al. 2000a,b, Zuo et al. 2004). XO is also an indicator of ROS, in which a high concentration of XO leads to a higher O 2 release rate due to the breakdown of hypoxanthine (Granger 1988, Nanduri et al. 2013). XO metabolism has been studied extensively in rodent models (Gomez-Cabrera et al. 2005); however, its actual contribution towards ROS generation within humans is not completely understood due to the difficulty of measuring ROS at such a low level (Linder et al. 1999).

ROS in cellular activities Reactive oxygen species play an important role in the promotion and inhibition of cellular processes, which control hormone concentration, chemical equilibrium and enzyme activation. Thus, ROS regulation is

crucial for proper physiological functions (Powers & Jackson 2008, Jackson & McArdle 2011). Any alteration in the concentration of ROS has a significant impact on the physiological state of many biological systems (Lobo et al. 2010). The production of ROS in a cell is minimized by the activity of specific regulatory enzymes, such as catalase, glutathione peroxidase (GPx), haem-oxygenase-1 and two types of SODs, MnSOD and Cu–Zn SOD (Trachootham et al. 2008). Increased expression of some cytoprotective proteins, such as heat-shock proteins, can also reduce ROS formation (Bushell et al. 2002). ROS are also responsible for cellular responses to stressors (Allen & Tresini 2000, Bushell et al. 2002). For instance, ROS can induce the activation of nuclear factor kappa-lightchain-enhancer of activated B cells (NF-jB), a protein complex responsible for the control of DNA transcription (Fig. 1; Wang et al. 2011). Furthermore, ROS can influence changes in mitochondrial function, expression of certain stress proteins and the activity of antioxidants (Chandel et al. 1996, Yamashita et al. 1997, Banerjee Mustafi et al. 2009). ROS concentration is lowered by antioxidants (Fig. 1), and this can result in biological cascades that influence metabolism, vascular regulation and glucose uptake (De Keulenaer et al. 1998, Blair et al. 1999, Yu et al. 2011).

ROS in skeletal muscle In skeletal muscle, increased contractions can cause substantial ROS generation (Khassaf et al. 2001, McArdle et al. 2001, Pattwell et al. 2004). Excess ROS accumulation can hinder basic muscle function and result in early fatigue (Reid et al. 1992). Muscle preconditioning has resulted in adaptive changes of


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the tissue to stressors. In addition, beneficial effects of exercise training on oxidative balance are well documented. Tumour necrosis factor-a (TNF-a) induces muscular ROS generation resulting in the carbonylation of a-actin protein, leading to its degradation by proteasomes and reduced muscle force development (Mangner et al. 2013). A recent study has shown that exercise-trained mice exhibit lower levels of TNF-ainduced muscle dysfunction than sedentary mice. This result can be attributed to the antioxidant effect achieved through exercise training. Reducing the negative consequences of ROS may help to alleviate muscle fatigue (Mangner et al. 2013). Another form of stress shown to generate ROS in skeletal muscle is hypoxia (Zuo et al. 2014a). Interestingly, after muscle tissue is exposed to hypoxic conditions, further damage can occur when oxygen is rapidly restored to the tissue (Legrand et al. 2008), along with the increased intracellular Ca2+ concentration (Yu et al. 2007). Reoxygenation following hypoxia can activate mitogenactivated protein kinases in endothelial cells, causing a marked elevation in ROS levels (Fig. 1; Yu et al. 2007). Furthermore, the reoxygenation of mouse microvascular endothelial cells may cause the activation of extracellular signal-regulated kinases 1/2 and c-Jun N-terminal protein kinases, which is likely to alter cellular activities (Yu et al. 2007).

ROS in the immune system One of the major biological functions involving ROS is the immune response. ROS serve in cellular warfare by helping to combat invading pathogens (Fig. 1) and mediating immune responses (Bedard & Krause 2007, Bonini & Malik 2014). For example, current research has analysed Nod-like receptors (NLRs) and explored their role in the initiation of inflammatory responses (Tschopp 2011). NLRs monitor abnormalities in the cellular cytoplasm. When activated, NLRs form inflammasomes, multi-protein complexes related to increased levels of ROS (Fig. 1). NLRP3 (cryopyrin) inflammasomes are activated by the increased level of short-lived ROS (Tschopp 2011). In addition, the thioredoxin-interacting protein (TXNIP) interacts with NLRP3 in the presence of high levels of ROS (Tschopp 2011). Under normal ROS conditions, TXNIP is bound to oxidoreductase thioredoxin 1 (TRX1; Patwari et al. 2006). However, when ROS levels are elevated, TXNIP disassociates from TRX1 and binds to NLRP3, translocating the complex to the mitochondria. The specific role of mitochondria-associated TXNIP remains elusive, but it is speculated that TXNIP binds with thioredoxin 2 (TRX2) in mitochondria, which ultimately leads to the induction of cellular apoptosis (Tschopp 2011). Thus, cellular ROS 332

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levels in this instance can be used as an indicator for the host inflammatory response (Patwari et al. 2006). Interestingly, there is also evidence that ROS assist in the production of regulatory T cells (Todoric et al. 2013), further clarifying the role of ROS in the immune defence mechanism.

ROS in the nervous system Neurological synaptic plasticity is a crucial process underlying learning and memory formation (Massaad & Klann 2011). A common form of synaptic plasticity, long-term potentiation (LTP), is the complex process of memory formation, storage and retrieval, which has been extensively studied in the mammalian hippocampus. LTP has been shown to be a primary form of neurological synaptic strengthening, requiring the involvement of ROS (Block et al. 2007, Massaad & Klann 2011). However, excessive ROS accumulation is detrimental and can be a cause of neurotoxicity ultimately leading to cell death (Fig. 1; Block et al. 2007, Massaad & Klann 2011, Zhang et al. 2012). O 2 reacts with NO˙ to form ONOO (Kondo et al. 1997, Uttara et al. 2009). This product in the cellular level can lead to apoptosis, infarction, cerebral palsy and epilepsy (Beckman 1991, Kondo et al. 1997). ROS have also been implicated in the pathogenesis of Parkinson’s and Alzheimer’s disease (Uttara et al. 2009, Zhang et al. 2012). For example, proteins in Parkinson’s disease, such as PTEN-induced putative kinase 1 (PINK1) and leucine-rich repeat kinase 2 (LRRK2), can lead to mitochondrial dysfunction and subsequent ROS formation if mutated (Fig. 1; Zuo & Motherwell 2013). This build-up of ROS alters multiple signalling pathways that ultimately result in neural cell damage as evidenced by the inhibited cognitive abilities (Zuo & Motherwell 2013). Antioxidant treatments can help protect neural cells from these damages (Zuo & Motherwell 2013). For example, central nervous system damage resulting from cerebral ischaemia comes from the formation of brain oedema that is induced by the disintegration of the blood–brain barrier (BBB); Cu–Zn SOD, which is a O 2 scavenger, can impede vasogenic brain oedema formation after numerous kinds of injuries (Beckman 1991, Kondo et al. 1997).

Oxidative stress and protein activity As mentioned earlier, exposure to chronic or intense stressors can result in excessive ROS production (Ji et al. 2006, Powers et al. 2010), leading to oxidative stress (OS) and potential diseases (see Bad and ugly diseases; Valko et al. 2007, Powers & Jackson 2008). Dean Jones defined OS as ‘a disruption of redox


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identical subunits that form a planar configuration (Sunde & Hoekstra 1980). The active sites of GPx1 are situated in the flat depressions of the molecular surface and located closely to the interface of its four subunits (Ladenstein et al. 1979, Epp et al. 1983). GPx1 demonstrates an unexpectedly high specificity for its reducing substrate, glutathione (GSH) (Epp et al. 1983, Toppo et al. 2009). Most studies attribute this phenomenon to the electrostatic attraction between the carboxyl groups of GSH and the positively charged residues in GPx1’s active sites (Epp et al. 1983, Takebe et al. 2002, Toppo et al. 2009). GPx4 is a monomeric enzyme with a molecular weight of approx. 22 kDa and contains one Se atom per molecule (Ursini et al. 1985, Schuckelt et al. 1991). GPx4’s monomeric structure correlates well with its preference for a macrosubstrate, as enzymes with more than one subunit may limit the access of large biomolecules, especially when the active sites are located closely to the interface of the subunits, as in the case of GPx1 (Toppo et al. 2009). Although GPx1 and GPx4 are not structurally analogous, the highly conserved active site residues imply that a similar catalytic mechanism most likely exists between the two enzymes (Schuckelt et al. 1991). The formation of products and bi-substrates in GPx1’s enzymatic reaction is characterized by active cycles between the oxidization and reduction of SeCys-35 in the active site (Epp et al. 1983, Toppo et al. 2009, Lubos et al. 2011). Specifically, the exposed SeCys-35 is first oxidized by H2O2 to produce selenenic acid (R-Se-OH) and water (H2O) (Toppo et al. 2009). GSH, one of the most abundant antioxidants in the cell, then carries out a two-step reductive reaction on R-Se-OH (Rosemeyer 1987, Toppo et al. 2009). This process ultimately yields glutathione disulphide (GS-SG) and recovers GPx1 in preparation for more catalytic cycles (Toppo et al. 2009). The catalytic process is represented in reactions (1), (2) and (3) as shown below and an overall reaction equation shown in (4) (Bhabak & Mugesh 2010). The by-product, GS-SG is then recycled by glutathione reductase, a dimeric enzyme which employs NADPH to reduce GS-SG back to GSH (Rosemeyer 1987). The complete catalytic mechanism is illustrated in Figure 2 (Toppo et al. 2009, Bhabak & Mugesh 2010). R SeH þ H2 O2 ! RSe OH þ H2 O

ð1Þ

RSe OH þ GSH ! RSe SG þ H2 O

ð2Þ

RSe SG þ GSH ! R SeH þ GS SG

ð3Þ

RSeH H2 O2 þ 2GSH ! 2H2 O þ GS SG

ð4Þ

The first oxidative step of GPx1 can be considered a simple redox reaction due to the absence of an enzyme–substrate complex (Epp et al. 1983, Toppo 334

et al. 2009). This is consistent with the unexpectedly high rate constant, about 1 9 108 M1 s1 at 37 °C (Flohe et al. 1972, Toppo et al. 2009). On the contrary, during the reducing process, enzyme–GSH complexes have been detected in both of the reducing steps (Epp et al. 1983, Toppo et al. 2009). A combined catalytic scheme of GPx1 is presented in Figure 3 (Toppo et al. 2009). GPx4 displays a similar mechanism as GPx1 using the Se-involved redox cycle, which agrees with the observation that most of the amino acids in the active site of GPx4 are conserved from GPx1 (Schuckelt et al. 1991). The major difference between these two enzymes comes from their respective substrate preference (Takebe et al. 2002, Toppo et al. 2009). Although GSH can still be utilized as the reducing substrate for GPx4 with a relatively low specificity, GPx4 demonstrates a much higher catalysing rate by employing a wide range of other reducing substrates, such as dithiothreitol (Takebe et al. 2002, Toppo et al. 2009). Glutathione peroxidase has been implicated in the treatment of Huntington’s disease (HD), which is a genetic neurodegenerative disorder characterized by an expanded polyglutamine repeat in the Huntingtin protein (Htt) (Walker 2007, Mason et al. 2013). The mutant Htt protein (mHtt) can cause toxic effects on cells via various pathways such as amyloid deposits of misfolded Htt and mitochondrial dysfunction (Browne & Beal 2006, Stack et al. 2008). However, the initiating factor contributing to the pathogenesis of HD is unclear (Browne & Beal 2006). In recent studies, OS has been found to play an important role in HD progression as many cellular structures are observed suffering from severe oxidative damage, which may account for the typical neurodegeneration in HD (Stack et al. 2008). Therefore, an increasing number of recent studies are focusing on the upregulation of antioxidant levels to develop potential treatments (Yang et al. 2005, Mason et al. 2013). However, most models established via the overexpression of specific antioxidant enzymes such as SOD and catalase failed to alleviate HD symptoms (Mason et al. 2013). This paradox may be attributable to the weak protective effect of SOD and catalase particularly on certain neurone cells (Mason et al. 2013). A recent encouraging discovery revealed that increased GPx activity may be effective in reducing symptoms of HD (Mason et al. 2013). Particularly, GPx1 and GPx3 are identified as the two most potent suppressors of mHtt toxicity by scavenging excessive ROS without inhibiting crucial autophagy mechanisms (Mason et al. 2013). Similar efficacy can be achieved by employing a GPx mimic, ebselen, a small compound which can readily pass through the BBB and is encouraging in clinical trials


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Figure 2 Catalytic mechanism of GPx1 and recycling of GSH. H2O2, hydrogen peroxide; GSH, glutathione; GPx, glutathione peroxidase; RSe-SG, GPx1 intermediate; GS-SG, oxidized GSH; R-SeH, oxidized GPx1; R-Se-OH, selenenic acid.

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SOD3, a Cu–Zn-cofactored tetramer, is located extracellularly (Marklund 1982, Marklund et al. 1982, 1986). Deficiency in any type of SOD would result in decreased resistance to OS, leading to different levels of tissue damage (Li et al. 1995, Elchuri et al. 2005, Muller et al. 2006, Sentman et al. 2006). Most commonly found in eukaryotes, Cu–Zn SOD (dimer) is the earliest identified and most extensively studied type of SOD (McCord & Fridovich 1969, Abreu & Cabelli 2010). Cu–Zn SOD is composed of a subunit containing an 8-stranded antiparallel b-barrel (including a Greek key motif) and two external non-repetitive loops (Richardson et al. 1975, Tainer et al. 1982). Cu2+ and Zn2+ together, with their ambient interacting residues, make up the active site of SOD, which is located outside the b-barrel and between the two big loops (Tainer et al. 1983). The distance between Cu2+ and Zn2+ within a subunit is about 6 A and they are tightly connected by His 61 through imidazole, which is essential for structure stability loops (Richardson et al. 1975). The catalysing activity of SOD results from the cycling reduction and oxidation of Cu by O 2 (Abreu & Cabelli 2010). As a result, Cu switches between Cu+ and Cu2+ with the production of O2 and H2O2 respectively. This mechanism is demonstrated in Equations (5–7; Abreu & Cabelli 2010). The reduction process (Abreu & Cabelli 2010):

Figure 3 Combined catalytic pathway of GPx1. The two enzyme–substrate complexes in the reducing process are represented as (A) GSH and (B) GSH, the rate-limiting steps in this catalytic activity.

(Mason et al. 2013). Thus, this finding provides a promising potential therapeutic approach for HD utilizing the power of antioxidants (Colle et al. 2013, Pillai et al. 2014).

Superoxide dismutase Superoxide dismutase is an important enzyme due to its crucial role in scavenging O 2 . Specific metal atoms, such as copper (Cu), zinc (Zn), manganese (Mn), iron (Fe) and nickel (Ni), are essential cofactors of various types of SOD due to their high reactivity with O 2 (McCord & Fridovich 1969, Mazeaud et al. 1979, Youn et al. 1996). In humans and the other mammals, three types of SOD (SOD1, SOD2 and SOD3) have been identified based on their location of activation (Weisiger & Fridovic 1973, Marklund et al. 1982, Keller et al. 1991). SOD1, a Cu–Zn-cofactored dimer, is found in the cytoplasm (Chang et al. 1988, Keller et al. 1991, Crapo et al. 1992); SOD2, a tetramer cofactored with Mn, is found in mitochondria (Weisiger & Fridovic 1973, Barra et al. 1984); and

þ 2þ Cu2þ Zn2þ SOD þ O 2 ! Cu Zn SOD þ O2

ð5Þ

The oxidation process (Abreu & Cabelli 2010): 2þ 2þ þ Cuþ Zn2þ SOD þ O 2 ðþ2H Þ ! Cu Zn SOD þ H2 O2

ð6Þ Overall reaction: SOD

þ 2O 2 ðþ2H Þ ! O2 þ H2 O2

ð7Þ

Superoxide dismutase can implement its catalytic activity at a rate of about 2 9 109 M1 s1 independent of pH over a wide range of 5–9.5 (Tainer et al. 1983, Ellerby et al. 1996). In addition, Ellerby et al. (1996) have found that Zn plays a key role in this pHindependent phenomenon. Their observations showed that by removing Zn out of SOD (Cu-apoSOD), the catalysing activity became pH dependent. Furthermore, they also found that the rate constant of the first reduction step of the Zn-deficient SOD remained pH independent (Ellerby et al. 1996). This result attributed the pH dependence of the Cu-apoSOD catalysis to its second oxidation step (Ellerby et al. 1996). Therefore, it was concluded that Zn functions as the pH stabilizer in SOD through the formation of an imidazole bridge with Cu2+, which contributes to the fast dissociation of O 2 (Ellerby et al. 1996). Specifically, Zn ensured the


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protonation of the NE1 of His 61 by raising the pKa (Tainer et al. 1983). Due to the crucial role of Cu–Zn SOD in scavenging ROS, SOD inhibitors are commonly utilized in understanding ROS-mediated physiological pathways or pathologies (Siwik et al. 1999, Zuo et al. 2003, 2004, Dumay et al. 2006). CN, N3 and F have long been used as competitive anions which can inhibit the catalysis process of Cu–Zn SOD by fitting in either the Cu2+ or the water pit very well (Tainer et al. 1983). Currently, Cu chelators are the most popular type of inhibitor, which inactivates the Cu–Zn SOD by removing Cu out of the active site (Morpurgo et al. 1983, Kelner et al. 1988). A number of Cu chelators have been studied in terms of their inhibition efficiency (Kelner et al. 1988). For example, Kelner et al. (1988) found that to effectively inhibit the Cu–Zn SOD activity, the binding affinity of a Cu chelator inhibitor must be at least 12.6. In addition, the conformation of the inhibitor which determines its capability of chelating Cu in the active site also plays an important role in the efficacy of the inhibition (Kelner et al. 1988). Building on these observations, diethyldithiocarbamate, triethylenetetramine and tetraethylenepentamine are all found to be effective Cu–Zn SOD inhibitors, widely employed by current researchers (An & Hsie 1992, Siwik et al. 1999, Bartnikas & Gitlin 2003). Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a disease caused by the degeneration of motor neurones found in both sporadic and familial forms (Tandan & Bradley 1985). The linkage between the occurrence of ALS’s familial form and the genetic mutation of Cu–Zn SOD (SOD1) was proposed by Rosen et al. in 1993. About 20% of the familial patients with ALS were detected to carry the Cu–Zn SOD mutation (Gurney et al. 1994). Due to the crucial function of SOD to scavenge ROS, Rosen’s proposal was immediately explored by many researchers to further investigate the underlying mechanism of this linkage (Deng et al. 1993, Rosen et al. 1993, Gurney et al. 1994, Ripps et al. 1995). The result partially exposed the relationship between the SOD mutation and familial ALS. This type of mutation does not evoke the familial form of ALS through the deprivation of the SOD function as a ROS scavenger (Gurney et al. 1994, Ripps et al. 1995). However, the specific mechanism involved in this linkage remains unclear, demanding more related studies in the future.

Catalase Catalase, one of the first enzymes investigated in the peroxidase family, is known for its near universal expression among oxygen-exposed organisms (Schroe336

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der et al. 1982, Agar et al. 1986, Mueller et al. 1997, Bai & Cederbaum 2001, Zamocky et al. 2008). Primarily found in peroxisomes, catalase decomposes H2O2 into H2O and oxygen (Zamocky et al. 2008). As the accumulation of H2O2 and its product ·OH can cause severe oxidative damage to the cell, catalase provides essential protection for virtually every organism (Ho et al. 2004, Veal et al. 2007, Ray et al. 2012). Additionally, as H2O2 acts as an important cell signalling molecule, its decomposition is regulated by multiple antioxidant enzymes (Leaman et al. 1996, Bae et al. 2000, Brivanlou & Darnell 2002, Cai 2005, Veal et al. 2007). Related to catalase, peroxiredoxin (Prx) and GPx are both efficient H2O2 scavengers and are involved in the mediation of H2O2 levels (Mills 1957, Kim et al. 1988, Rhee et al. 2001, 2005b, Veal et al. 2007). Due to this diversity, the importance of catalase in regulating H2O2 was questioned with the discovery of GPx and Prx in 1957 and 1988 respectively (Mills 1957, Kim et al. 1988, Rhee et al. 2001). Specifically, in a catalase knock-out mouse model established by Ho et al. in 2004, catalase-absent mice developed no prominent defect under normal conditions; however, when specific oxidative injuries were imposed on various tissues such as the liver, lung and brain, these mice showed different levels of susceptibility to OS. Therefore, protection exerted by catalase is tissue dependent and influenced by the presence of the level of other antioxidant such as GPx (Ho et al. 2004). Catalase is a large haem-containing enzyme with four identical subunits. Each subunit is characterized by four domains each with a molecular weight of approx. 57 kDa (Tanford & Lovrien 1962, Reid et al. 1981, Fita & Rossmann 1985). The haem is identified about 20 A below the enzyme surface in each subunit, using a narrow hydrophobic channel that allows for substrate access (Reid et al. 1981, Fita & Rossmann 1985). In the active site, the deprotonated Try357 forms the 5th ligand of the haem by linking to the centre iron, which plays a significant role in stabilizing the haem structure and maintaining Fe at a high oxidation state in catalase (Pulsinelli et al. 1973, Fita & Rossmann 1985). The exact catalytic mechanism of catalase is not fully understood; however, this enzyme utilizes Fe to convert H2O2 into H2O and O2 through a two-step mechanism (Seah & Kaplan 1973, Bai & Cederbaum 2001, Zamocky et al. 2008). The first step is characterized by the oxidization of Fe (III) in the haem centre by H2O2 to generate the intermediate [Fe (IV)-enzyme = O] and H2O (Eqn 1). This is followed by the second reduction step in which another H2O2 molecule accesses and recovers catalase back to its normal state with the production of H2O and O2 as final products (Eqn 2) (Fita & Rossmann 1985,


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Zamocky et al. 2008). The fundamental catalytic process is presented in Equations (8) and (9) with the overall reaction shown in Equation (10) (Zamocky et al. 2008). 1st oxidization step (Zamocky et al. 2008): FeðIIIÞ Enzyme þ H2 O2 ! FeðIVÞ Enzyme ¼ O þ H2 O

ð8Þ

2nd oxidization step (Zamocky et al. 2008): FeðIVÞ Enzyme ¼ O þ H2 O2 ! FeðIIIÞ Enzyme þ H2 O þ O2 ð9Þ Overall reaction (Zamocky et al. 2008): catalase

2H2 O2 ! 2H2 O þ O2

ð10Þ

Peroxisomes perform their normal metabolic function largely through the process of oxidizing specific fatty acids or removing hydrogen atoms from organic compounds, which in turn generates a significant amount of H2O2 within the peroxisome (Rhee et al. 2005b). Catalase has been shown to act as the primary enzyme in preventing the accumulation of such H2O2 due to its widespread distribution in the peroxisome (Rhee et al. 2005b). Although catalase is mainly packed in the peroxisome, it can also exert protective effects on other organelles in the cell, limited only by its rate of diffusion (Rhee et al. 2005b). Moreover, it should not be overlooked that catalase demonstrates extraordinary activity in erythrocytes beyond this diffusion limitation due to its abundant expression in this particular cell type (Higashi & Peters 1963, Mueller et al. 1997). Within erythrocytes, GPx was previously considered to be a strong competitor for catalase due to its similar role in H2O2 scavenging (Mills 1957, Gaetani et al. 1996, Mueller et al. 1997). However, a series of studies in the 1990s verified the leading role of catalase in detoxifying H2O2 within erythrocytes, whereas GPx only accounts for a small degree of function (Gaetani et al. 1996, Mueller et al. 1997). This conclusion was largely based on the close examination of their respective activities demonstrated in the presence of varying H2O2 levels (Gaetani et al. 1996, Mueller et al. 1997). Catalase was found to display an accelerated catalytic rate directly proportional to the concentration of H2O2. Yet GPx becomes saturated with H2O2 at a concentration of 106 M, showing a much lower activity within the erythrocytes when compared to catalase (Cohen & Hochstein 1963, Gaetani et al. 1996). The high efficiency demonstrated by catalase when exposed to H2O2-abundant environments enhances its protective effect against H2O2, especially in erythrocytes where H2O2 accumulates (Cohen & Hochstein 1963, Agar et al.


1986, Rhee et al. 2005b). Numerous studies reveal the role of catalase in inflammation and OS-related diseases, including diabetes and pulmonary fibrosis (Agar et al. 1986, Goth & Eaton 2000, Odajima et al. 2010). Although the excessive accumulation of H2O2 can damage cells, H2O2 also functions as an important intracellular signalling molecule at certain concentrations. It is found to be substantially involved in the regulation of cell growth, proliferation, apoptosis and inflammatory responses (Ruiz-Gines et al. 2000, Zanetti et al. 2002, Cai 2005, Veal et al. 2007). Specific stimuli including cytokines and growth factors initiate intracellular cascades through the binding of receptors on the cell surface (Leaman et al. 1996, Brivanlou & Darnell 2002, Veal et al. 2007). This process stimulates the formation of H2O2 both intracellularly and extracellularly, which are then involved in the mediation of cellular activities (Bae et al. 2000, DeYulia et al. 2005). The specific mechanism of H2O2, acting as a mediating factor, is not fully understood. However, it is generally accepted that H2O2 can oxidize cysteine in the active site of the target proteins to modulate protein function (Bae et al. 2000, Veal et al. 2007). The level of H2O2, which is of quantitative significance in maintaining the normal physiological activities, is regulated by multiple mediators, chiefly antioxidant enzymes (Bae et al. 2000, Cai 2005, Veal et al. 2007). Interestingly, in tumor cell lines, catalase fulfils its regulative role mainly by altering its activity level in response to different H2O2 concentrations (Veal et al. 2007). This mediating process is shown to be accomplished via the c-Abl/Arg pathway and is characterized by a biphasic feedback mechanism (Kruh et al. 1990, Rhee et al. 2005b). When exposed to H2O2 at a low concentration, c-Abl and Arg, crucial types of tyrosine kinases, demonstrate an increased binding affinity with catalase and enhance catalase activity by phosphorylation (Dunphy & Kumagai 1991, Cao et al. 2003c, Rhee et al. 2005b). However, as the level of H2O2 increases, c-Abl and Arg begin to separate from catalase, leading to dephosphorylation and thus the dysfunction of catalase (Cao et al. 2003b,c, Rhee et al. 2005b). Therefore, in this cycle, H2O2 is engaged in the mediation of cellular functions depending on the control of catalase activity. The simplified c-Abl/Arg mediation mechanism involved is represented in Figure 4 (Cao et al. 2003a,c, Rhee et al. 2005b).

Additional H2O2 scavengers Despite the importance of catalase in scavenging H2O2, additional enzymes are required to fully perform this


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Figure 4 Mechanisms involved in the H2O2–catalase regulation of cellular activities via the c-Abl/Arg pathway in tumor cells.

function. Prx is well known to possess the ability to remove H2O2 (Wood et al. 2003a, Rhee et al. 2005b). Similar to catalase, it can act both as a protector and regulator of cellular activities by mediating the H2O2 levels (Mills 1957, Christophersen 1968, 1969, Little & O’Brien 1968, Nomura et al. 2000, Wood et al. 2003a, Rhee et al. 2005b). First purified in yeast in 1988 (Kim et al. 1988), Prx is a potent peroxidase distinguished by its extensive distribution among various species and in nearly all tissues (Rhee et al. 2001, 2005b). To date, six isoforms of Prx (i.e. Prx I–VI) have been identified in mammalian cells and are widely distributed in the cytosol, mitochondria, endoplasmic reticulum and peroxisome (Rhee et al. 2005b). Prx exists as either a monomer or homodimer, maintaining a highly conserved active site that indicates a similar catalytic mechanism across the different Prx classes (Wood et al. 2003b). Essentially, it utilizes a thiol group to reduce peroxide (Wood et al. 2003b). During the catalytic process, a functionally crucial cysteine is oxidized by peroxide to sulfenic acid and is then recovered by its reductive substrate, thioredoxin (Trx) (Wood et al. 2003b). Although Prx demonstrates a much lower catalytic efficiency as compared to GPx and catalase, its universal distribution is convincing evidence for its importance as an antioxidant (Rhee et al. 2001, Wood et al. 2003b). In fact, an increasing number of researchers are turning their attention towards the regulative role of Prx in the cell signalling, initiated by specific cytokines such as growth factors and TNF-a (Rhee et al. 2001, 2005a,b). Prx is shown to follow a similar regulative mechanism as catalase, engaged in the mediation of cellular activities by demonstrating different levels of activity, a process governed by H2O2 concentration (Wood et al. 2003b). Apart from the conventional H2O2 scavengers mentioned above, eosinophil peroxidase (EPO) expands the role of H2O2 towards a new field in which EPO, together with H2O2, forms a crucial defence system against external microbes (Jong & Klebanoff 1980, Wever et al. 1981, Barnes 1990). However, when this 338

protective mechanism is triggered by an inflammatory response, extreme damage to tissues can occur (Jong & Klebanoff 1980, Wever et al. 1981, Barnes 1990). EPO was purified from peritoneal cavities in rats and is primarily found in the eosinophil granule matrix (Archer et al. 1965). This enzyme demonstrates a distinctive catalytic feature and function via the employment of halides as its reductive substrate in the decomposition of H2O2 (Jong & Klebanoff 1980). The strong cytotoxic products of the reaction are composed of hypohalous acids, accounting for the significant antibiotic effect of EPO (Wever et al. 1981). However, in inflammatory diseases such as asthma, eosinophils can be activated and become a major source of H2O2 (Barnes 1990). With the accumulation of large quantities of H2O2, EPO causes further oxidative damage to pneumocytes via the generation of hypohalous acids (Agosti et al. 1987, Barnes 1990). Interestingly, such injuries can be partially inhibited by the application of catalase and SOD (McCord & Fridovich 1969), indicating an underlying mechanism of ROS formation in the context of the inflammatory response (Agosti et al. 1987, Yukawa et al. 1990).

Thioredoxin Thioredoxin (Trx) was first structurally described in 1975 by Holmgren et al. Trx contains 5 b-sheets and 4a helices (Collet & Messens 2010). As both ROS and Trx play important roles in redox homeostasis, the relationship between the two has recently become an area of interest (Hwang et al. 2014). Furthermore, it has been shown that at normal physiological levels, Trx plays a role in the mediation of other antioxidant action (Huang et al. 2014). For instance, Trx is involved in the regeneration of several antioxidants including lipoic acid, ubiquinone, selenium-containing substances and ascorbic acid (vitamin C) (Nordberg & Arner 2001). Such interplay between Trx and other antioxidants is significant in the regulation of redox homeostasis within the body.


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Unbalanced Trx levels have been implicated in a variety of diseases such as cancer, chronic obstructive pulmonary disease (COPD), viral disease, cardiac disorder, ischaemia–reperfusion (IR) injury, premature birth and asthma (Burke-Gaffney et al. 2005, Tonissen 2007, Holmgren & Lu 2010, Xu et al. 2012, Huang et al. 2014). Research has shown that murine embryos are extremely sensitive to changes in the environment prior to implantation and that deregulation of Trx specifically leads to changes in development that will last into adulthood (Feuer et al. 2014). Moreover, a study utilizing overdose of acetaminophen to induce liver failure found that human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein significantly decreased cellular oxidative and nitrosative stress (Tanaka et al. 2014). As a result, Trx may be a key component in a therapy against acetaminopheninduced hepatitis (Tanaka et al. 2014). By further exploring the mechanisms of Trx, it is possible that novel therapies may emerge for a variety of conditions. Proteins found in a heavily oxidized extracellular environment contain a higher proportion of disulphide bonds for structural stability (Arner & Holmgren 2000). In contrast, the intracellular setting is highly reduced and proteins with a greater number of disulphide bonds are uncommon (Arner & Holmgren 2000). There are many disulphide reductases that are involved in the redox homeostasis of sulphur-containing proteins such as Trx reductase (Arner & Holmgren 2000). In addition, as Trx plays a pivotal role in various diseases (Hwang et al. 2014), further exploration of the relationship between Trx and ROS is necessary for the understanding of these disorders.

Antioxidants and nutrition Some antioxidants can be produced naturally in the body, while others must be acquired (Lobo et al. 2010). Antioxidants such as vitamins A, C, D, E, b-carotene, selenium and manganese have the ability to scavenge ROS (Valko et al. 2007, Darvin et al. 2008, Flora 2009). For example, recent evidence has demonstrated the beneficial effects of antioxidants in mitigating cognitive decline after the consumption of b-carotene (Grodstein et al. 2007). Additionally, increased levels of vitamin E and coenzyme Q both led to a reduction in inflammation, a process requiring the involvement of ROS (Hensley et al. 2000, Wang et al. 2004). Furthermore, the anti-inflammatory effects were more prevalent when levels of both vitamin E and coenzyme Q increased (Wang et al. 2004). Many vitamins and minerals have the ability to affect each another’s absorption rate (Garcia-Casal et al. 1998). This suggests that nutritional benefits are optimal when dietary vitamins and minerals are properly

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balanced relative to each other. However, all substances should remain below a threshold level or the results can be detrimental. For example, high levels of the antioxidant vitamin E may be linked to the risk of lung cancer in smokers (Harvie 2014). Even though diet usually dictates the levels of antioxidants, various external sources also affect the concentrations of many antioxidants within an organism. For example, exposure to UV radiation and ionizing radiation can lead to a decrease in carotenoid levels in the skin (Darvin et al. 2010, Lademann et al. 2011). Furthermore, other stressors including fatigue, alcohol consumption, smoking and illness also contribute to reduced carotenoid levels (Darvin et al. 2008). Research has been focused on the potential variation of antioxidant intake and endogenous production. Carotenoids, vitamins as well as antioxidant enzymes including SOD, catalase and GPx can neutralize the deleterious effects of ROS (Valko et al. 2007, Darvin et al. 2008). However, other factors such as age, environment, diet and metabolic rate can all have an influence on antioxidant absorption (Darvin et al. 2008). Genetic variation also influences the production of antioxidants within living systems (Molyneux et al. 2005, Voruganti et al. 2009, Fairweather-Tait et al. 2011). Individualized antioxidant interventions, which are designed to alter redox homeostasis and reduce OS, have been of interest in lifestyle, health, supplementation and stress exposure (El-Agamey et al. 2004, Sharoni et al. 2004, Smith et al. 2004, Miller et al. 2005, Schrauzer 2006). For example, the dysfunction of diaphragmatic skeletal muscle due to hypoxic conditions could be significantly ameliorated by antioxidant treatment (Mohanraj et al. 1998). In addition, inhibition of the antioxidant cofactor selenium by chromium may decrease its antitumorigenic activity (Schrauzer 2006).

Bad and ugly diseases Oxidative stress has been implicated in a wide variety of ailments including cancer, hypertension, inflammatory diseases, IR injuries and neurodegenerative disorders (Valko et al. 2007, Brieger et al. 2012). ROS-caused DNA changes may ultimately result in oncogenesis (Waris & Ahsan 2006). Furthermore, ROS are linked to the upregulation of hypoxic-inducible transcription factor-1a (HIF-1a), which can contribute to angiogenesis, formation of new blood vessels, metastasis and tumour growth (Liao et al. 2007). The implications of ROS in many pulmonary diseases including adult respiratory distress syndrome, COPD, cystic fibrosis, pulmonary fibrosis and asthma have been well documented (Gillissen & Nowak


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1998, Zuo et al. 2013a). Excessive ROS production resulting from cellular damage can increase inflammatory responses and also decrease the maximal force of the diaphragm, both contributing to respiratory diseases such as asthma and COPD (Barreiro et al. 2005, Zuo et al. 2012, 2013a). As disease manifestation is highly associated with an imbalance in ROS concentration, therapeutic interventions that restore redox balance could be beneficial (Zuo et al. 2013a). Reactive oxygen species are also involved in the development of cardiovascular diseases, such as IR injury and hypertension (Dhalla et al. 2000, Zhang et al. 2009, Brieger et al. 2012). IR injury is characterized by tissue damage caused by reperfusion after a long period of ischaemia. However, therapies such as ischaemic preconditioning (IPC) train the myocardium by exposing it to brief periods of mild ischaemic stress. The low amounts of ROS generated during IPC have been shown to induce a cardioprotective effect (Zuo et al. 2013b). When NO˙ reacts with O 2 , ONOO is formed which leads to inflammation and can subsequently induce hypertension (Fig. 1) (Brieger et al. 2012, Harrison et al. 2012). The contribution of ROS in hypertension occurs through many different mechanisms including free radical-initiated lipid peroxidation (Zuo et al. 2014c). Therefore, antioxidant therapies have potential to relieve hypertension, neurological diseases and autoimmune disorders (Kondo et al. 1997, Uttara et al. 2009, Zuo et al. 2014c). High ROS levels have been implicated in numerous neurodegenerative disorders (Block et al. 2007, Sorce & Krause 2009). Amyloid, one of the key diagnostic aspects of Alzheimer’s disease, has been shown to be involved with chronic ROS formation and microglia activation. Both of these involvements contribute to neuronal damage and dementia (Brieger et al. 2012). Dopaminergic neurone degeneration, associated with Parkinson’s disease, is highly linked to OS (Sorce & Krause 2009), which is involved in the development and initiation of ALS (Mitsumoto et al. 2014). For instance, a point mutation in the SOD1 enzyme is linked with ALS (Sorce & Krause 2009) and up to 20% of familial cases of ALS involve mutations of SOD1. Interestingly, over 155 SOD1 mutations have been connected to ALS (Saccon et al. 2013). However, conflicting research indicates that both loss of function and gain of function of SOD1 are involved in ALS. Thus, it is difficult to study one independently of the other (Saccon et al. 2013).

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However, a recent article published in Nature showed that this is not always true (Zhu et al. 2014). Specifically, to investigate the extent by which ROS obey the dose–response relationship, Zhu et al. (2014) exposed four cancer cell lines and primary colon cancer cells to ROS. Cancer cells were treated with lactic acidosis, b-phenylethyl isothiocyanate, piperlongumine, doxorubicin and arsenic trioxide respectively (Zhu et al. 2014). Lactic acidosis treatment resulted in the highest level of ROS, but only slowed the progression of cancer cells without destroying them. Interestingly, the other treatments that either raised or lowered ROS concentrations showed the ability to effectively kill cancer cells (Fig. 5; Zhu et al. 2014). After ROS treatment, antioxidants were administered to balance ROS levels; however, cancer cell death still persisted (Zhu et al. 2014). Taken together, the data supported the idea that ROS does not obey the dose–response relationship (Fig. 5; Zhu et al. 2014). While many studies have still focused on elevating ROS levels as a conventional method for destroying cancer cells (Kim et al. 2013, Zhu et al. 2014), it was further proposed that selective disruption of mitochondrial ROS formation would decrease cancer cell proliferation and survival (Sabharwal & Schumacker 2014).

Conclusion In this review, we have thoroughly reviewed the complex involvement of ROS within living organisms. Both the positive and negative effects of intracellular ROS are discussed and reviewed. It is important to

Cancer therapy utilizing ROS Multiple studies have investigated the effectiveness of utilizing ROS for cancer treatment, with a few clinical trials currently in progress (Trachootham et al. 2009). 340

Figure 5 Schematic demonstrating the dose–response relationship and the results of a ROS-focused cancer therapy. ROS, reactive oxygen species.


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consider that while ROS are essential mediators in beneficial cellular processes, high levels of ROS can disrupt redox homeostasis and induce OS. Moreover, ROS have been shown to play a significant role in the pathogenesis of many diseases. Multiple regulatory enzymes such as GPx, SOD and catalase help maintain redox balance inside the cell to combat the deleterious effects of OS. Although ROS have already been the focus of abundant research, further investigation is paramount in elucidating the exact mechanisms of ROS and its implications in therapeutic interventions.

Conflict of interest No conflict of interests, financial or otherwise, is declared by the authors. We acknowledge the assistance of Andrew Graef, Chia-Chen Chuang and Benjamin Hemmelgarn for the manuscript preparation. Our manuscript is conformed to Persson PB. Good Publication Practice in Physiology 2013 Guidelines for Acta Physiologica. Acta Physiol (Oxf), 2013 Dec; 209(4):250–3.

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