Redox regulation of inflammation: old elements, a new story.

Redox Regulation of Inflammation: Old Elements, a New Story Yunlong Lei,1,2 ∗ Kui Wang,1 ∗ Longfei Deng,1 ∗ Yi Chen,3 Edouard C. Nice,4 and Canhua Huang1 1 State

Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P.R. China 2 Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, P.R. China 3 Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China 4 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.21330

䉲 Abstract: Inflammation is an essential immune response characterized by pain, swelling, redness, heat, and impaired function. A controlled acute inflammatory response is necessary to fight off infection and overcome injury. However, if the inflammatory process persists and enters into the chronic state, it can lead to local and systemic deleterious effects counterproductive to healing and instead constitutes a new pathology. Typically, inflamed tissues are associated with an elevated level of reactive species (reactive oxygen species (ROS)/reactive nitrogen species (RNS)). These ROS/RNS are generated during the respiratory burst of immune cells and are important factors in defense against invading pathogens. Additionally, reactive species are now known to trigger oxidative/nitrosative modifications of biomolecules. While most of these modifications lead to irreparable damage, some are subtle and fully reversible. The reversible modifications can initiate signaling cascades known as “redox signaling.” This redox signaling tightly modulates the inflammatory response. Thus, understanding the complex role of ROS/RNS-induced redox signaling in inflammation will assist in the design of relevant therapeutic intervention strategies for inflammation-associated diseases. This review will highlight the impact of oxidative stress and redox signaling on inflammation and inflammation-associated diseases, with a focus on redox modifications of C 2014 Wiley Periodicals, Inc. Med. Res. Rev., 00, No. 0, 1–35, 2014 inflammation-related proteins. Key words: ROS/RNS; inflammation; redox modifications; HMGB1; NF-κB

1. INTRODUCTION Inflammation is an evolutionarily conserved host reaction that has been appreciated for almost 2000 years, with the clinical symptoms of inflammation defined by the Roman doctor Cornelius ∗ These

authors contributed equally to this work.

Correspondence to: Canhua Huang, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P.R. China. E-mail: [email protected] Medicinal Research Reviews, 00, No. 0, 1–35, 2014 C 2014 Wiley Periodicals, Inc.

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Figure 1. Inflammatory response. Inflammation is a frequent occurrence caused by noxious stimuli and conditions such as infection and tissue injury. Induction of inflammation is triggered by receptors of the innate immune system, such as surface Tolllike receptors (TLRs) and cytoplasmic NOD (nucleotide-binding oligomerization-domain protein) like receptors (NLRs)). Engagement of TLRs or NLRs leads to activation of inflammation-associated signaling pathways and the production of inflammatory cytokines and chemokines, as well as prostaglandins. These inflammatory mediators then elicit an inflammatory exudate locally containing plasma proteins and leukocytes (mainly neutrophils) that are leaked from blood vessels because of vasodilatation and can induce relocalization and activation of macrophages at the site of infection or injury. The acute inflammatory response is normally terminated after removal of pathogens and cellular debris, which is known as the resolution of inflammation. Multiple mechanisms work in a coordinated manner to ensure resolution. PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; IL-10, interleukin-10; TGF-β, transforming growth factor β.

Celsus in the 1st century A.D.1 Inflammation leads to changes in tissue homeostasis and blood flow, activation and migration of immune cells, and secretion of cytokines, chemokines, and growth factors2 (Fig. 1). Inflammation is frequently caused by noxious stimuli and insults such as infection, tissue injury, exposure to allergens, radiation and toxic chemicals, consumption of alcohol, tobacco use, and a high-calorie diet.3 Of these, infection and tissue injury are two major causes of acute inflammation through activation of the immune system and coordinated delivery of blood components (plasma and leukocytes) to the site of infection or injury4 (Fig. 1). The desired result of acute inflammation is the elimination of infectious agents, repair of affected or injured tissues to their normal structural and functional state, followed by termination of the inflammatory response and transition to the homeostatic state (resolution).2 This type of inflammation persists for only a short time and is usually beneficial to the host.5 However, inflammation can become detrimental if it persists for a prolonged period of time and transitions from the acute phase to chronic inflammation. This occurs in a wide variety of chronic illnesses, including atherosclerosis, obesity, cancer, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, multiple sclerosis, neurodegenerative disease (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis), and autoimmune disorders during which the stroma is infiltrated both by macrophages and immature myeloid cells (such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and celiac disease).5 Reactive oxygen species (ROS)/reactive nitrogen species (RNS) are a family of reactive species derived from oxygen or nitric oxide (NO•), including superoxide anion (O2 − ), hydroxyl Medicinal Research Reviews DOI 10.1002/med

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Figure 2. Reactive oxygen species and reactive nitrogen species. Numerous biologically active proinflammatory mediators stimulate the generation of reactive species (ROS/RNS) by macrophages and neutrophils. ROS is a collective term that defines incomplete reduction of oxygen and includes the superoxide anion (O2 − ) and the hydroxyl radical (HO•). Major sources of cellular reactive ROS are from the mitochondrial electron transport chain (Mito-ETC), the NADPH oxidase (NOX) complex, and the endoplasmic reticulum. O2 − is the main initial free-radical species and can be converted to H2 O2 by superoxide dismutases (SODs). H2 O2 can be converted to HO• in the presence of transition metals or directly reduced to water by catalase. During the oxidative burst of activated neutrophils, H2 O2 can also be converted to hypochlorous acid (HOCl) or hypobromous acid (HOBr) in the presence of EPO (eosinophil peroxidase) or MPO (myeloperoxidase). To protect biological macromolecules from oxidative stress, mammalian cells have developed a complex antioxidant defense system that includes antioxidant enzymes, small antioxidant molecules, molecules able to sequestrate transition metal ions, as well as the thioredoxin (TRX) and glutaredoxin (GRX) systems. Nitric oxide (NO) is a reactive nitrogen species generated by nitric oxide synthase enzymes (NOS). Chemically, excessive production of NO during inflammatory and immune processes reacts with molecular O2 and ROS to generate a range of oxidation products, including nitrite (NO2 − ), nitrate (NO3 − ), and peroxynitrite (ONOO− ). At physiological pH, ONOO− will be protonated and undergo a homolytic scission to produce highly toxic free radicals, HO• and nitrogen dioxide (NO2 •). GFR, growth factor receptor; TNFR, tumor necrosis factor receptor; GRX, glutaredoxin; TRX, thioredoxin; GR, glutathione reductase; XO, xanthine oxidase; GPX, glutathione peroxidase; PRX, peroxiredoxin.

radical (HO•), and peroxynitrite (ONOO− ) (Fig. 2). Numerous biologically active proinflammatory mediators stimulate the generation of ROS/RNS by macrophages and neutrophils that infiltrate the sites of inflammation to kill invading pathogens or initiate repair processes.6 These diffusible ROS/RNS molecules are highly reactive and can interact with biomolecules including lipids, proteins, nucleic acids, carbohydrates, and small molecule metabolites.7 Through the promotion of oxidation, nitrosation, and nitration of a range of biomolecules, these reactive species govern cellular signaling, which in turn provokes inflammatory responses.8 ROS/RNS can be attenuated by antioxidant enzymes or natural antioxidants, leading to resolution of inflammation.9 It has become evident that the sustained overproduction of ROS/RNS due to the dysregulation of the cellular pro-oxidant–antioxidant systems, termed as “oxidative stress,” will damage important biomolecules and cells, leading to an overly Medicinal Research Reviews DOI 10.1002/med

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exuberant inflammatory response.10, 11 This concept is further supported by recent studies showing that, the deficiency of glutathione peroxidase-1 (GPX1), an important antioxidant enzyme, can trigger proinflammatory redox signaling.12, 13 In addition, cells lacking NADPH oxidase (NOX), one of the major sources of intracellular ROS, cannot produce ROS in response to angiotensin II infusion. In this context, monocytes without gp91phox (phagocytic NOX) lose the proinflammatory phenotype by decreasing infiltration to vascular tissues and onset of arterial hypertension.14–16 Oxidative stress-induced inflammation has been implicated in the pathogenesis of a number of disease states including pancreatitis, carcinogenesis and metastasis, diabetic complications, allergic asthma, cardiovascular, neurological, and pulmonary diseases.17–19

2. REGULATION OF THE INFLAMMATORY RESPONSE Inflammation is a complex process with multiple contributory factors. At least 81 genes have now been recognized as being involved in this process, with different combinations leading to distinct inflammatory progression.3 A typical inflammatory response consists of inducers, sensors, mediators, and effectors, which work in a coordinated manner and are mutually regulated.2 A. Infection-Induced Inflammation Induction of inflammation by bacterial and viral infections is triggered by receptors of the innate immune system, such as Toll-like receptors (TLRs) and NOD (nucleotide-binding oligomerization-domain protein)-like receptors (NLRs), which recognize molecular patterns that are expressed by the pathogens20 (Fig. 1). In addition to their expression in most host cells, TLRs are also expressed on tissue-resident macrophages to sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).21 NLRs are cytoplasmic counterparts of TLRs and sense both PAMP and DAMP that gain access to the cell.22, 23 In addition, NLRs are also involved in assembly of the inflammasome. The inflammasome is composed of an NLR (e.g., NLRP1, NLRP3, NLRC4), an adapter protein (e.g., apoptosis-associated speck-like protein containing a CARD (ASC)), and the effector protein pro-caspase-1.24 The inflammasome can induce activation of caspase-1 and the subsequent proteolytic maturation of inflammatory cytokines such as interleukin (IL) 1 and IL-18.22 Engagement of TLRs and NLRs leads to activation of inflammation-associated signaling pathways (e.g., nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) pathway) with concomitant production of inflammatory cytokines (e.g., tumor necrosis factor (TNF), IL-1, and IL-6) and chemokines (e.g., CCL2 and CXCL8), as well as prostaglandins.25 These inflammatory mediators then elicit a local inflammatory exudate. This exudate contains plasma proteins and leukocytes (mainly neutrophils) that leak from blood vessels due to vasodilatation, and can induce relocalization and activation of macrophages at the site of infection or injury.26 Neutrophils recruited from the circulation, tissue-resident macrophages, and mast cells act as the first line of defense for clearing invading pathogens.27 Plasma proteins can trigger inflammation by producing various inflammatory mediators and inducing vascular damage (Fig. 1). B. Sterile Inflammation In the case of tissue injury induced by trauma, ischemia–reperfusion injury or chemical injury in the absence of microbes, sterile inflammation will be evoked to promote tissue repair and Medicinal Research Reviews DOI 10.1002/med


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prevent colonization of the damaged tissues by opportunistic pathogens.28 In sterile inflammation, DAMPs, which are normally hidden, under normal physiological conditions, intracellularly from recognition by the immune system, are released from damaged cells and act as a molecular trigger for inflammation.29 More than 20 such DAMPs have been identified, including high-mobility group box 1 protein (HMGB1), heat shock proteins, DNA fragments, and metabolites (adenosine triphosphate (ATP), adenosine, and uric acid).30 DAMPs activate pattern recognition receptors and elicit a wide range of immune responses, including production of proinflammatory cytokines and localization of immune cells to the site of injury31 (Fig. 1). As the inflammation in response to sterile cell death or injury is similar to that observed during microbial infection, it is not surprising that they share the same host receptors, among which TLRs have been best characterized.28

C. Resolution of Inflammation The acute inflammatory response is normally terminated after removal of pathogens and cellular debris, known as the resolution of inflammation, which is characterized by clearance of inflammatory cells such as neutrophils, certain lymphocytes and macrophages, as well as suppression of inflammatory gene expression and cellular trafficking.32 Multiple mechanisms work in a coordinated manner to ensure resolution including macrophage activation switching, the switch from proinflammatory prostaglandins to anti-inflammatory resolution-inducing lipoxins, the accumulation of glucocorticoids, the involvement of inflammation-resolving cytokines such as TGF-β and IL-10, gaseous signals, oxygenated and nitrated lipids, purine, and a neurotransmitter. IL-10 and TGF-β are produced by macrophages, myeloid cells, and T lymphocytes that can suppress pro-inflammatory signaling from TLRs (Fig. 1). TGF-β seems to be tightly linked to phagocytosis of apoptotic neutrophils by macrophages and is also a critical mediator of tissue repair. IL-10 is produced as a result of the inflammatory response and functions as a feedback regulator of T cells.5

D. Inflammatory Signaling Pathways While the overall molecular mechanisms of intracellular signaling pathways of inflammation have not been fully clarified, it is clear that it is coordinated by a large range of mediators forming complex regulatory networks.25 There are several fully established innate immune signaling pathways that transmit inflammatory cytokine signals to the nucleus including NF-κB, MAPK, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT), which ultimately activate NF-κB, activator protein-1 (AP-1), STAT1, and STAT3 transcription factors, resulting in production of inflammatory mediators, cytokines, and growth factors.33 NF-κB is thought to play a central role in the regulation of genes encoding pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors, and inducible enzymes, and has been proposed as a promising therapeutic target for the treatment of inflammatory disease.34 The NF-κB pathway is activated through IκB kinase-dependent (IKK-dependent) phosphorylation, polyubiquitination, and subsequent proteasomal degradation of IκB proteins following stimulation with various inflammatory stimuli, such as TNF-α, the cytokine family, IL-1, and TLR ligands.35 Similar to NF-κB, STATs are also key participants in immune and inflammatory responses. The transcription factors STAT1 and STAT3 appear to play opposite roles: STAT1 is a central mediator of IFNs and can promote apoptosis and inflammation, while STAT3 often antagonizes this process by inducing the production of IL-10, inhibiting the maturation of dendritic cells and suppressing the immune response.36 Medicinal Research Reviews DOI 10.1002/med

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3. SOURCES AND FUNCTIONS OF REACTIVE SPECIES A. Reactive Oxygen Species ROS is a collective term for chemical species containing partially reduced oxygen. The most commonly found ROS are the superoxide anion (O2 − ), and the hydroxyl radical (HO•)37 (Fig. 2). Major sources of cellular ROS are the mitochondrial electron transport chain (Mito-ETC), NOX complexes, endoplasmic reticulum, and xanthine oxidase.38 Superoxide (O2 − ) is the main initial free-radical species and can be converted to H2 O2 by superoxide dismutases (SODs). H2 O2 can be then converted to hydroxyl radicals (HO•) in the presence of transition metals or directly reduced to water by catalase and GPX.39 During the oxidative burst of activated neutrophils, H2 O2 can also be converted to hypochlorous acid (HOCl) or hypobromous acid (HOBr) in the presence of eosinophil peroxidase or MPO (myeloperoxidase)40, 41 (Fig. 2). Primarily, ROS are thought to exert adverse cytotoxic and genotoxic effects by causing damage to lipids, proteins, and DNA. Thus, oxidative stress is frequently defined as an increased production and/or a decreased scavenging or metabolism of ROS.39 However, recent studies suggest that the function of ROS is determined by the intracellular redox state: excessive production of ROS usually results in cytotoxic effects and may lead to apoptotic cell death, while a certain level of ROS can act as a second messenger for regulation of diverse cellular processes such as cell survival, proliferation, and inflammation.37 To protect biological macromolecules from oxidative stress, mammalian cells have developed a complex antioxidant defense system that includes antioxidant enzymes (e.g., catalase, GPX, SOD), small antioxidant molecules (e.g., glutathione (GSH), ascorbic acid), molecules able to sequestrate transition metal ions (e.g., ferritin, amyloid-β), as well as TRX and GRX systems42 (Fig. 2). The most important antioxidant enzymes for superoxide scavenging are SOD, which have three major isoforms including the cytoplasmic Cu/Zn-SOD (SOD1), the mitochondrial Mn-SOD (SOD2), and the so-called EC-SOD (SOD3) that is secreted into the extracellular environment.43 There are various possible stimulating factors for oxidative stress, including increased cytokine and growth factor levels and inflammatory cell infiltration into the microenvironment, as well as hypoxia and increased glycolytic metabolism.39 ROS can act as inducers in cellular processes and are involved in the regulation of protein expression, posttranslational modifications, and modulation of protein stability.44 In addition to the induction of DNA mutation, ROS can also regulate protein expression by disrupting the transactivation activity of a range of transcription factors, including NF-κB, AP-1, hypoxiainducible factor-1α (HIF-1α), and p53, all containing redox-sensitive cysteine residues in their DNA-binding site.45, 46 Many phosphoproteins and proteinases also contain cysteine residues that, upon oxidation, result in the reversible formation of intramolecular disulfide bridges leading to the activation of signal transduction pathways.7, 47 These disulfide bridges can be reduced by either TRX or GRX, which themselves are reduced by NADPH-dependent TRXreductase or GSH.7 It is well known that ROS generally function as second messengers in ligand/receptorinitiated pathways, such as MAPK, PI3K, and NF-κB signaling pathways, which play a key role in inflammation.8, 48 There are three MAPK kinases, extracellular-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK), and p38. ERK1/2 is necessary for the proliferation, differentiation, and migration of inflammatory cells. ROS can inactivate phosphatases responsible for dephosphorylating ERK1/2, resulting in sustained ERK1/2 activation. ROS-induced activation of JNK and p38 is dependent on TRX oxidation that leads to disassociation from ASK-1, resulting in activation of JNK and p38 pathways through ASK-1 multimerization.45, 49 Similar to ERK1/2, ROS induce activation of the PI3K pathway by inactivating the tumor suppressor lipid phosphatase (PTEN) that can inhibit the activity of PI3K by dephosphorylating Medicinal Research Reviews DOI 10.1002/med


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PIP3.50 ROS also constitutively activate NF-κB, which is involved in inflammatory reactions, cell survival, and apoptosis.48, 51 For example, Brar et al. found that ROS, produced by NOX, enhanced melanoma cell proliferation via the activation of NF-κB.52 B. Nitric Oxide and RNS NO and RNS are involved in many physiological functions that are becoming increasingly implicated in the pathogenesis of inflammation.53 NO is a RNS generated by nitric oxide synthase (NOS) enzymes.54 NOS utilizes L-arginine, oxygen, and NADPH to yield NO and the coproduct L-citrulline.55 (Fig. 2). There are three NOS enzymes: neuronal NOS(NOS1) and endothelial NOS (eNOS, NOS3), both of which are constitutively expressed and exert their activity in a Ca2+ -dependent manner, as well as inducible NOS (iNOS/NOS2) whose expression is low in healthy tissue and can be induced by a variety of noxious stimuli, such as lipopolysaccharide (LPS), TNF-α, and IL-1.53 NO derived from iNOS appears to play paradoxical roles in inflammation, as it can act as either an exacerbator or inhibitor depending on its concentration and association with other biomolecules.55 In addition, the dimeric eNOS complex can be disrupt by S-glutathionylation of eNOS in response to oxidative stress, resulting in infiltration of immune cells and vascular dysfunction connected to inflammatory processes.56 NO can nitrosate thiol residues of proteins, resulting in alterations in protein structure and biological function, which may be involved in the regulation of inflammation.57 For example, excessive NO can induce S-nitrosylation and inactivation of NF-κB and drive apoptosis of inflammatory cells to induce the resolution of inflammation,53 whereas lower levels of NO can inhibit apoptosis of by S-nitrosation of caspase-3.58, 59 Excessive produced NO during inflammatory and immune processes reacts with molecular oxygen (O2 ) and its derivatives (ROS) to generate a range of oxidation products, including nitrite (NO2 − ), nitrate (NO3 − ), and peroxynitrite (ONOO− ).60 (Fig. 2). RNS has powerful proinflammatory effects by causing tissue injury, lipid peroxidation, and oxidative damage or modification of various proteins.61 The antioxidant enzyme SOD can catalyze the dismutation of superoxide into oxygen and hydrogen peroxide, thus counteracting ONOO− formation and preserving NO function. However, peroxynitrite can in turn inactivate SODs, especially SOD2 produced in mitochondria.62

4. REDOX MODIFICATIONS OF BIOLOGICAL MACROMOLECULES AND INFLAMMATION A. Oxidative Stress Induced DNA Damage and Mutation Occurring in Inflammation The increased DNA damage and mutation rates observed in an inflammatory microenvironment have been linked to oxidative stress causing DNA base deamination, the formation of exocyclic-DNA adducts, point mutations, aberrant DNA cross-linking, and single- and double-stranded breaks.63 During the initiation stage, activated inflammatory cells serve as sources of ROS/RNS, which induce DNA damage and genomic instability by introducing gene mutations and structural alterations into the DNA.63 ROS-induced mutagenesis may also result in inactivation or repression of DNA repair enzymes.63 Increased levels of oxidatively modified DNA bases (such as 5,6-dihydroxy-5,6-dihydrothymine (thymidine glycol), 5-hydroxymethyl-2-deoxyuridine (5-HMdU), 8-hydroxy-2 -deoxyguanosine (8-OHdG), 8-oxo7,8-dihydro-2-deoxyguanosine (8-oxodG), and 8-nitroguanosine 3 ,5 -cyclic monophosphate (8-nitro-cGMP) are believed to contribute significantly to chronic inflammation and associated diseases64–66 (Fig. 3, left). Moreover, during ROS/RNS-induced tissue injury, DNA singleor double-stranded breakage often occurs resulting in the activation of poly (ADP-ribose) Medicinal Research Reviews DOI 10.1002/med

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Figure 3. DNA and lipid oxidation in inflammation. (left), DNA oxidation, and inflammation. The increased DNA damage and mutation rates observed in the inflammatory microenvironment have been linked to oxidative stress related to oxidatively modified DNA bases, point mutations, aberrant DNA cross-linking, and single-stranded (SSB) and double-stranded breaks (DSB), which are believed to be a significant contributors to chronic inflammation and associated diseases such as aging, cancer, diabetes mellitus, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), hypertension(HTN), and pulmonary fibrosis (PF). In addition, the proximity of mtDNA to the mitochondrial electron transport chain makes it more vulnerable to oxidative damage, especially oxidation of nucleobases (predominantly at guanine (G)). Oxidized mtDNA can be rapidly released into the cytosol, where it can bind NLRP3 and drive assembly of inflammasome NLRP3/ASC/caspase-1 complexes assembly, culminating in caspase-1 cleavage and activation, and IL-1 processing. DNA repair enzymes (DREs) can recognize and provide repair mechanisms for damaged DNA to protect cells from oxidative stress. However, DREs are also sensitive to oxidants. ROS can regulate their activity by repression of expression or by direct oxidative modification of cysteine. (Right) Lipid oxidation and inflammation. In the initiation of inflammation, the expression of phospholipase A2 (PLA2) enzymes are upregulated in response to various cytokines and growth factors, which can cleave esterified fatty acids from membrane glycerophospholipids, such as 20-carbon arachidonic acid. Cyclooxygenase (COX) and lipoxygenase (LOX) can catalyze arachidonic acid oxygenation to produce eicosanoids including the prostaglandins (PGs), prostacyclins (PCs), thromboxanes (TXs), and leukotrienes (LTs), which have been shown to coordinate the initial events of acute inflammation. COX plays a central role in this process and its activity can be enhanced by ROS/RNS. LOX and COX can also induce conversion of arachidonate or 15hydroxyeicosatetraenoic acid into lipoxins (LXs), which are also eicosanoids and have anti-inflammatory effects. Other anti-inflammatory lipid mediators are also generated in the resolving phases, such as eicosapentaenoic acid (EPA) derived resolvins and docosahexaenoic acid (DHA) derived protectins and maresins. In particular, polyunsaturated fatty acids (PUFAs) are highly susceptible to oxidation and readily undergo peroxidation to generate various reactive electrophiles, such as reactive aldehydes and F2-isoprostanes (F2-IsoPs), which are shown to induce infiltration and activation of inflammatory cells. Reactive aldehydes such as 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA), acrolein (Arn), and crotonaldehyde (CrAld), can directly react with DNA and proteins. In addition, oxidation of low-density lipoprotein (oxLDL), oxidation of phophatidylcholine (oxPC), and oxidation of phosphatidylserine (oxPS), can be specifically recognized by the receptors of immune cells and induce activation of the inflammatory response. In contrast, high-density lipoprotein (HDL) has antioxidant and anti-inflammatory properties, by reducing cholesteryl ester hydroperoxides and oxLDL, as well as inactivating oxidized phospholipids. These roles of HDL can be inhibited by ROS/RNS-induced oxidation of apolipoprotein A1. PGH2, prostaglandin H2; AD, Alzheimer’s disease; PD, Parkinson’s disease; ALS, amyotrophic lateral sclerosis; HTN, hypertension; PF, pulmonary fibrosis; G, predominantly at guanine; SSB, single-stranded breaks; DSB, double-stranded breaks; PGH2, prostaglandin H2; PGs, prostaglandins, PCs, prostacyclins, TXs, thromboxanes; LTs, leukotrienes; LXs, lipoxins.

polymerase, which plays an important role in the inflammatory process.67 Thus, oxidative DNA damage products arising during chronic inflammation have potential as biomarkers in clinically accessible biofluids such as blood and urine for various pathologies, including aging, cancer, diabetes mellitus, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, hepatotoxicity, and hypertension64, 65 (Fig. 3, left). For example, 8-OHdG, the most widely used fingerprint for oxidative DNA damage, is frequently observed in inflammatory diseases such as diabetes mellitus, a number of cancers, and diverse gastrointestinal tract inflammatory diseases.68 Because 8-OHdG can cross the cell membrane, it can be detected in the urine Medicinal Research Reviews DOI 10.1002/med


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and serum of patients who have diseases associated with oxidative stress.68, 69 Once formed, 8-OHdG can undergo a keto-enol tautomerism, which leads to formation of the oxidized product 8-oxodG. 8-oxodG has been shown to induce deleterious G-T or G-A transversions and is an important mutagenic factor in cancerogenesis.65 Therefore, repair mechanisms for 8-oxodG in DNA, such as the 8-oxoguanine DNA glycosylase 1 (OGG1), which recognizes and excises 8-OHdG opposite cytosine residues, are crucial elements in the protection against carcinogen exposure.70, 71 Another excision repair enzyme, Myh, is important for the removal of adenines that are mismatched with 8-OHdG in DNA.72 However, Myh and OGG1 are themselves also sensitive to oxidants. Bravard et al. found that ROS could induce the oxidation of OGG1 Cys326 to form a disulfide bond with a proximal cysteine to decrease the activity of OGG1.73 Notably, the proximity of mtDNA to the Mito-ETC, a prominent site of superoxide anion generation, makes it more vulnerable to oxidative damage74 (Fig. 3, left). mtDNA damage results in mitochondrial dysfunction and has been recognized as a crucial event in the progression of multiple sclerosis and age-dependent vascular dysfunction.74, 75 Oxidized mtDNA can be rapidly released into the cytosol and binds to NLRP3, thus driving the inflammasome NLRP3/ASC/caspase-1 complex assembly, culminating in caspase-1 cleavage and activation, as well as production of IL-1.76

B. Lipid Oxidation: An Important Mediator in the Initiation and Resolution of Inflammation There is a general agreement that lipids play a pivotal role in both the initiation and resolution of inflammation as endogenous proinflammatory and anti-inflammatory mediators.77 Lipid-derived eicosanoids, which are derived from oxidation of the 20-carbon arachidonic acid, have been shown to coordinate the initial events of acute inflammation.78 Eicosanoids are mainly composed of four components including the prostaglandins, prostacyclins, thromboxanes (TXs), and leukotrienes,32 and can control blood flow and vessel dilation, which are needed for leukocytes to undergo firm adhesion and diapedesis5 (Fig. 3, right). Two enzyme families catalyze fatty acid oxygenation to produce the eicosanoids: cyclooxygenase (COX) and lipoxygenase (LOX).79 In physiological conditions, endothelial prostaglandin endoperoxide H2 (PGH2) triggered by COX can be converted to prostacyclin (PGI2), which has vasodilatory, antiaggregatory, and antiadhesive effects. While when inflammation occurs, prostacyclin (PGI2) synthase will be selectively nitrated and inactivated by peroxynitrite leading to PGH2 accumulation, which then activates the TXA2 receptor on the surface of smooth muscle cells to promote vasoconstriction and support the transmigration of immune cells from the blood.80, 81 In addition, peroxynitrite has multiple effects on COX activity: peroxynitrite can provide the peroxide tone necessary for COX activation, while in the absence of arachidonic acid, peroxynitrite will inhibit COX activity through nitration of an essential tyrosine residue (Tyr385).82 Diverse classes of oxygenated and nitrated lipids can also contribute to the resolution of inflammation.32, 77 When the signal for resolution is triggered, LOX and COX induce conversion of arachidonate or 15-hydroxyeicosatetraenoic acid into lipoxins, instead of generating prostaglandins.2 The lipoxins, which also belong to the eicosanoid family, have potent immunomodulatory and anti-inflammatory effects by reducing vascular permeability, retarding the entry of new neutrophils, and promoting the emigration of monocytes and their ingestion of apoptotic neutrophils.83 Other anti-inflammatory lipid mediators are also generated in the resolving phase, such as eicosapentaenoic acid (20:5) derived resolvins and docosahexaenoic acid (22:6) derived protectins and maresins, which can dominate the resolution phase by inhibiting the synthesis of inflammatory lipid mediators.32, 77 In addition, a population of natural antibodies can specifically recognize oxidized lipid epitopes such as oxidation products Medicinal Research Reviews DOI 10.1002/med

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of phophatidylcholine and oxidation products of phosphatidylserine, which otherwise could induce the initiation of inflammation and facilitate apoptotic cell phagocytosis by monocytes and macrophages6 (Fig. 3, right). Polyunsaturated fatty acids are particularly susceptible to oxidation and readily undergo peroxidation by enzymatic or free-radical chain reaction mechanisms.79 This leads to the generation of various reactive electrophiles, such as reactive aldehydes and F2-isoprostanes, which are shown to induce the infiltration and activation of inflammatory cells. Reactive aldehydes in biological tissues may be further complicated by the modification of biologically important molecules such as proteins and DNA bases.84 Reactive aldehydes derived from LPO, such as 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA), acrolein, and crotonaldehyde, can directly react with DNA to form exocyclic DNA adducts, which have been detected in a variety of inflammatory diseases.84, 85 Bartsch et al. found that etheno (epsilon) modified DNA bases, generated by reactions of DNA with HNE, existed in organs, blood, and urine from patients with cancer prone diseases (e.g., Wilsons disease, cirrhosis), especially when related to persistent inflammatory processes.86 In tissues, MDA and HNE can cause protein oxidation due to the close interaction between lipids and proteins and create neoantigens that can then cause immune reactions, stellate cell activation, and neutrophil chemotaxis.87, 88 In addition, oxidation of lipoproteins, and in particular low-density lipoprotein (LDL), plays important roles in inflammatory response.88 For example, phagocyte-derived MPO and its enzymatic products, HOCl and ONOO− , can oxidize the lipid moiety of LDLs and produce chlorinated and nitrated LDL, which in turn stimulate ROS production and respiratory burst activation by neutrophils and macrophages.89, 90 In particular, macrophage uptake of oxLDL results in excessive intracellular lipid accumulation and differentiation into foam cells that secrete a number of cytokines and growth factors to sustain a localized inflammatory response.91 High-density lipoproteins (HDLs) are also sensitive to oxidative stress and are well known to have antioxidant and anti-inflammatory properties.92, 93 The major proteins of HDL, apoAI, and apoA-II have antioxidant properties and can reduce cholesteryl ester hydroperoxides and oxidized LDL.92, 93 Enzymes carried by HDL, such as paraoxonase and possibly GSH phospholipid peroxidase, have been proposed to destroy lipid hydroperoxides that oxidize LDL phospholipids.92 These roles of HDLs can potentially reduce the detrimental effects of ROS such as chronic inflammation and associated diseases.93 MPO, which is a source of ROS during inflammation, can oxidize apolipoprotein A1 and thus impair the antioxidant and anti-inflammation activity of HDL.94, 95 C. Divergent Roles of Protein Oxidation in Inflammation The function and activity of proteins can be regulated by alteration in the intracellular levels of ROS through multiple mechanisms, including regulation of protein expression, posttranslational modifications, or changes in protein stability.7, 96 Side chain modifications, which include oxidation of cysteines, selenocysteine, methionines, tyrosines (tyrosine nitration to form nitrotyrosine), as well as carbonylation reactions, have a profound effect on catalytic activity, biomolecular interactions, subcellular localization, and the stability of target proteins.7, 46, 97 Although they have long been recognized as causing damage/inactivation factors of proteins in high levels, ROS may also constitute a stress signal that activates physiological and pathological intracellular signaling cascades that contribute to inflammation. In recent years, the roles of specific ROS in the reversible modifications of structurally and functionally important proteins have gained increasing attention.46 Both redox sensing and redox signaling often involve a sulfur-mediated nucleophilic attack of the peroxide O–O bond, particularly Cys residues that are sensitive to reversible oxidation such as the formation of sulfenic acid (R-SOH). The -SOH is typically highly reactive and its stability is influenced Medicinal Research Reviews DOI 10.1002/med


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Figure 4. Protein oxidation and inflammation. The function and activity of many proteins can be regulated through directed oxidation of their Cys, Tyr, and Met amino acids. The Cys residue is ideally suited for reaction with H2 O2 and the initial oxidation product of cysteine is sulfenic acid (-SOH). The -SOH is highly reactive, its stability being influenced by neighboring cysteine residues (Cys-SH) allowing generation of a more stable disulfide bond, including intra- or interchain disulfide bridges and mixed disulfides with reduced glutathione (GSH) through S-glutathionylation. Alternatively, sulfenic acids are further oxidized to form irreversible sulfinic acid (R-SO2 H) or sulfonic acid (R-SO3 H). NO/RNS is also available for covalent coupling of thiols and can induce S-nitrosylation of target proteins. Like other posttranslational modifications, oxidative thiol modifications are fully reversible, and the primary redox reductases are the thioredoxin (TRX) and glutaredoxin (GRX) systems. Various redox-sensitive proteins have been reported to be involved in the initiation, progression, and resolution of inflammatory response: The nitrosylation of HIF, pVHL, and RAS, S-glutathionylation of PTEN, RAS, and STAT3, disulfide bond formation in HMGB1, NEMO, and STAT3, oxidation of TRX-induced liberation of TXNIP and ASK1, nitration of p38, reversible oxidation of Met in S100A9 and Cys in Lyn and HDAC, and irreversible oxidation of S100A9, exert proinflammatory effect. By contrast, nitrosylation of S100A8, p50, and Keap1, S-glutathionylation of S100A9, p50, ICE (caspase-1), IκBα, IκBβ, c-Jun, and AMPK, disulfide bond formation in AKT and Keap1, nitration of p65, reversible oxidation of p50, Nrf2, HIF, P38, ICE, and UBC12, and irreversible oxidation of HMGB1 can contribute to the resolution of inflammation. ↑, activation of inflammation; ↓, resolution of inflammation.

by neighboring cysteine residues (Cys-SH), which can generate a more stable disulfide bond, or by the availability of a proximal nitrogen to form a sulfenamide in the presence of H2 O2 7 (Fig. 4). The formation of disulfide bridges, either between the same or different polypeptide chains, is important for protein structure and folding, and is often involved in the regulation of protein function by “locking and unlocking” of the functional cysteine, or through disulfide bond induced conformational changes.96 Alternatively, sulfenic acids can be overoxidized to form irreversible sulfinic acid (R-SO2 H) or sulfonic acid (R-SO3 H).98 An increasing body of evidence shows that covalent attachment of NO to a reactive cysteine in target proteins leads to the formation of S-nitrosothiol (SNO), a process commonly known as S-nitrosylation (Fig. 4). SNOs act as intermediates in NO signaling, and S-nitrosylation plays a pervasive role in the physiological and pathophysiological modulation of mammalian protein functions.99 Medicinal Research Reviews DOI 10.1002/med

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Similar to other posttranslational modifications, oxidative thiol modifications are fully reversible, and the primary redox-sensitive cysteine reductases are the TRX and GSH/GRX systems57 (Fig. 4). During reduction of target proteins, TRX facilitates the reduction of sulfenated, nitrosylated, and disulfide-bonded proteins, while GRX catalyzes fast and reversible thiol disulfide exchange between protein cysteine and GSH, which themselves are reduced by NADPH-dependent TRX- and GSH-reductases.7, 46 Low molecular weight thiol GSH participates in peroxide scavenging by assisting GPX or reducing the R-SOH that emanate from peroxide oxidation by formation of a S-glutathionylation adduct, which is important in protecting R-SOH from irreversible oxidation.46 This ability to rapidly and reversibly modify structurally and/or functionally important cysteine thiols has been shown to function as an excellent mechanism to regulate protein activity involved in transcription, translation, metabolism, stress protection, and signal transduction on a posttranslational level.7 Many enzymes that serve as ROS effectors possess special domains/motifs to maintain the reactivity of Cys residues, including phosphatases, various types of kinases, metabolic enzymes, as well as caspase-3.58, 98 Phosphorylation is an important mechanism for the regulation of protein function and is controlled by a network of kinases and phosphatases.6, 45 At the protein synthesis level, transcription of specific genes is known to be tightly controlled by redox balance. A number of transcription factors, such as NF-κB, AP-1 (c-Jun and c-Fos), HIF-1α, and p53, contain redox-sensitive cysteine residues strategically positioned within their DNA binding domains.46 Oxidation of these Cys residues can block DNA-binding activity and inhibit the expression of target genes. Antioxidant proteins, such as annexin A2, TRX, and peroxiredoxin family proteins can be directly modified by oxidation of their Cys, Tyr, and Met amino acids, which can counteract ROS accumulation and protect cells from oxidative stress.96 Protein–protein interactions are key determinants of protein function, which are sensitive to structural alteration and may be easily modulated by ROS/RNS if they include redox-sensitive proteins. Oxidative modifications of such interacting proteins by ROS/RNS often cause a dissociation of the protein complex leading to the release and activation of functional protein. ASK1–TRX, p53–JNK, and nuclear factor-erythroid 2-related factor (Nrf2)–Keap1 (including S-nitrosation of Keap1) complexes have been demonstrated to be regulated by such redox-senses mechanisms.96 Recently, the impact of redox modifications on signaling or structural proteins contributing to inflammation has come into focus.6, 8, 100 Various redox-sensitive proteins have been reported to be involved in the initiation, progression, and resolution of the inflammatory response. We will highlight recent advances in detail and describe how redox reactions regulate inflammation via protein oxidation. D. Redox Modifications of Inflammatory Mediators HMGB1 is an evolutionarily conserved chromatin-associated protein that is involved in transcription, DNA repair, and recombination by affecting chromosomal architecture.101 In response to pathogenic products, HMGB1 can be translocated to the cytoplasm, and secreted into the extracellular space of monocytes, macrophages, natural killer cells, dendritic cells, endothelial cells, platelets, and other immunologically competent cells. HMGB1 can then form complexes with various inflammatory mediators (e.g., TLR4, CXCL12, and RAGE), which lead to recruitment of inflammatory cells and production of TNF, IL-1, and IFN-γ .101 HMGB1 can also be passively released by injured or dying cells, which could serve as a DAMP and elicit an inflammatory reaction for tissue repair.30 HMGB1 contains three cysteines at positions 23, 45, and 106, and the redox state of these cysteines determines the outcome of HMGB1-mediated signaling (Fig. 5). For example, HMGB1 can interact with TLR4 to trigger potent inflammatory signaling in macrophages Medicinal Research Reviews DOI 10.1002/med


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Figure 5. Inflammation is tightly controlled by redox modification of HMGB1 and NF-κB. HMGB1 contains three cysteines at positions 23, 45, and 106. Redox reactions of these cysteines determine the outcome of HMGB1-induced inflammation. All-thiol-HMGB1 can be passively released from injured or necrotic cells and forms a heterocomplex with the chemokine CXCL12, which binds exclusively with CXCR4 to recruit inflammatory cells to the site of damage and initiatively produce more HMGB1 and reactive species. Increased ROS will lead to the formation of a disulfide bond between Cys23 and Cys45, which can interact with TLR4 to trigger the activation of NF-κB signaling. The activity of NF-κB signaling can also be regulated by redox modifications. Oxidation of Cys62 of DNA-interacting p50 subunit, S-nitrosylation, and glutathionylation of a critical thiol in p50 or its binding partner p65 inhibits its ability to bind DNA, which is reversible and can be reduced by the nuclear APE1/Ref-1/Trx1 system. In addition, nitration of Tyr-66 and Tyr-152 residues of p65 can induce sequestration of p65 in the cytoplasm, resulting in the rapid inactivation of NF-κB activity. Furthermore, ROS can enhance the NF-κB DNA binding activity through redox modifications and inactivation of HDAC. ROS can also regulate the NF-κB pathway through upstream regulation of NF-κB activating pathways. ROS can active NF-κB through formation of disulfide bonds between Cys54 and Cys 347 in NEMO, oxidation, glutathionylation, and inactivation of PTEN. Redox modification induced suppression of NF-κB mainly includes S-glutathionylation of IκBα on Cys189 and IKKβ on Cys179, oxidation, glutathionylation, and inactivation of ubiquitin-associated enzyme (UBC12) and proteasome 26S and 20S. MEKK1 and AKT, kinases upstream of IKK, are also redox sensitive. Oxidative stress inhibits MEKK1 by site-specific glutathionylation at Cys1238 in the ATP-binding domain, while disulfide bond formation between Cys297 and Cys311 can prevent AKT activation. Sustained ROS accumulation will further oxidize HMGB1 and lead to irreversible oxidation. The all-oxidized cysteine or Cys106-oxidized forms of HMGB1 have neither chemokine activity nor proinfammatory properties, which can contribute to inflammation resolution.

involving a cysteine in position 106.102 However, in apoptotic cells, caspase activation targets mitochondria to produce ROS, and oxidation of Cys106 results in the inactivation of the immunostimulatory activity of HMGB1.103 This enables the immune system to discriminate necrotic cells from apoptotic cells.103 In addition, the thiol of Cys106 and the Cys23-Cys45 disulfide bond are both required for HMGB1 to induce nuclear NF-κB translocation and TNF production in macrophages.104 Recently, Venereau et al. showed that HMGB1 orchestrates both processes by switching between the mutually exclusive redox states: reduced all-thiol-HMGB1 has only chemokine activity, whereas a disulfide bond between Cys23 and Cys45 converts it to a proinflammatory cytokine, while with all three cysteines oxidized or Cys106-oxidized, HMGB1 is inactive105, 106 (Fig. 5). As reviewed above, the very subtle redox regulation of HMGB1 is clearly associated with obviously different inflammatory process. Further studies Medicinal Research Reviews DOI 10.1002/med

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should try to identify the different dynamic redox status of HMGB1 in different stages of distinct inflammatory disease to facilitate further redox-targeting therapeutic strategies. H2 O2 has been implicated in rapid recruitment of leukocytes, particularly the initial responders of innate immunity, and the neutrophils, to wounds in zebrafish and drosophila.107 Yoo et al. identified the Src family kinase Lyn as a redox sensor that initiated neutrophil recruitment to wounds in zebrafish larvae. They found that Lyn was activated in neutrophils around wounds. A single cysteine residue, Cys466, was identified to be required for direct oxidation-mediated activation of Lyn, which is important for the neutrophil wound response and downstream signaling in vivo.108 Further studies to confirm the redox modifications of Lyn and the involved biological function in the inflammatory process should be conducted in mammals, and further possible redox modification patterns responsible for the function of Lyn should be identified. Several S100 Ca2+ -binding proteins (including S100A8 and S100A9) that are abundantly expressed in neutrophils and activated macrophages, are important proinflammatory factors in innate immunity and are associated with antimicrobial effects, degranulation, and migration of neutrophils.109, 110 S100A8 and S100A9 have also recently been described as DAMPs that can be released from necrotic cells (predominantly neutrophils).109, 110 These proteins initially function as potent antioxidants and themselves are particularly susceptible to oxidative modifications by various forms of reactive species such as peroxide, hypochlorite, and nitric oxide.110 Gomesa et al. found S100A8 was exquisitely sensitive to equimolar ratios of HOCl and HOBr. Exposure to these species generates sulfinic and sulfonic acid intermediates and novel oxathiazolidine oxide/dioxide forms on Cys42 and Met78 of S100A8.111 While evidence for oxidation of the single Cys3 residue in S100A9 by HOCl was weak, Met63, Met81, Met83, and Met94 could all be converted to sulfoxides in vitro.111 In addition, oxidized S100A8 was found to be prominent in lungs from patients with asthma and was significantly elevated in sputum compared to controls.111 In another study, Kumar et al., using a specific antibody, observed increased levels of disulfide S100A8 dimer in the cytosol after activation of human neutrophils with activated zymosan. Loss of S100A8 immunoreactivity could serve as a marker of localized neutrophil activation in tissues112 (Fig. 4). Met oxidation to methionine sulfoxide or sulfone in S100A9 is consistently detected in the cytosol of neutrophils activated with phorbol 12-myristate 13-acetate (PMA) or ionomycin, suggesting these modifications contribute to the inflammatory response.113 S100A8 and S100A9 are also susceptible to S-glutathionylation and S-nitrosylation, which may represent a ubiquitous mechanism by which NO can affect signal transduction in eukaryotic cells. Lim et al. showed that S-nitrosylated S100A8 was the preferred nitrosylation product. S-nitrosylated S100A8 was shown to regulate leukocyte-endothelial cell interactions in the microcirculation and suppress mast cell mediated inflammation, representing an additional anti-inflammatory property for S100A8.114 However, S-glutathionylation of S100A9 protects it from oxidation to higher oligomers and reduces neutrophil binding to the extracellular matrix, which may help limit tissue damage in acute inflammation.113 The AMP-activated protein kinase (AMPK) is a member of the Snf1/AMPK family of serine/threonine protein kinases, which play a fundamental role in regulating metabolic pathways.115 It has been reported that AMPK deficiency can upregulate inflammatory genes leading to a proinflammatory phenotype in angiotensin II induced hypertension.116 Activation of AMPK can inhibit NF-κB signaling and inflammation that is mediated by several downstream targets of AMPK, for example, SIRT1, PGC-1α, p53, and Forkhead box O (FoxO) factors.117–120 Studies from different cellular systems have shown several levels of interplay between ROS and AMPK.115 AMPK can be activated by ROS directly through redox modification on Cys299 and Cys304 of the AMPKα-subunit, including S-glutathionylation121 (Fig. 4). A more recent study showed that, during myocardial ischemia, the activity of AMPKα was negatively regulated by oxidation of Cys130 and Cys174 to form an intramolecular disulfide bond, which interferes with the interaction between AMPK and AMPK kinase.122 Interestingly, Medicinal Research Reviews DOI 10.1002/med


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AMPK is phosphorylated upon treatment with different NO donors, which results in the inactivation of IKK and subsequent decreased NF-κB activation, suggesting S-glutathionylation of AMPK could contribute to the anti-inflammatory responses.119 In turn, activation of the AMPK pathway can reduce intracellular ROS levels by activation of FOXO and upregulation of MnSOD, TRX, or UCP2, or by modulating NOX activation by the attenuation of NF-κBdependent expression of several NOX components.115, 120, 123 Although the redox modifications of AMPK (except S-glutathionylation) have not been characterized in inflammatory diseases, the altered function of AMPK upon oxidation has been firmly confirmed and will almost certainly play an important role during inflammation. Annexin A2 (ANXA2) is a widely distributed, calcium-dependent, anionic phospholipidbinding peripheral membrane protein, which exists as a monomer or a heterotetramer, and is distributed in different compartments of the cells, including the nucleus, cytoplasm, membrane, and extracellular space.124 ANXA2 has been shown to be involved in the regulation of the inflammatory response. ANXA2 is expressed on both the surface of macrophages and apoptotic lymphocytes, and neutralization of either (e.g., with an appropriate monoclonal antibody) will inhibit the phagocytosis of apoptotic targets, suggesting that ANXA2 can serve as both ligand and receptor in promoting phagocytosis and contributing to the resolution of inflammation.125 Swisher et al. showed that free ANXA2 tetramer could directly activate human macrophages by inducing activation of MAPK and NF-κB signaling pathways and production of inflammatory cytokine and chemokine through TLR4.126, 127 In recently years, evidence has been made to reveal that ANXA2 is tightly regulated by oxidative modifications. The expression of ANXA2 is dependent on the redox status in kidney cells, and persistent stimulation of this adaptive mechanism contributes to renal carcinogenesis and metastasis.128 In another study, Madureira et al. found that Cys8 of ANXA2 was a redox-sensitive cysteine, which can be reversibly modified by ROS and played an important role in intracellular redox regulation by protecting cells from oxidative stress.129 However, the involvement of ANXA2 redox modifications in inflammatory response remains unclear.

E. Oxidation- and Inflammatory-Associated Transcription Factors Increased production of ROS/RNS from both recruited inflammatory cells and host cells can activate signal transduction cascades as well as induce changes in transcription factors, such as NF-κB, STATs, HIF1-α, AP-1, and Nrf2, leading to subsequent expression of inflammatory cytokines, chemokines, and growth factors, which act by further recruiting inflammatory cells to the site of inflammation and thus lead to production of more reactive species.6, 25, 63 1. Redox Modifications of the NF-κB Pathway NF-κB proteins are a family of redox-sensitive transcription factors that have been viewed as having central roles in inflammation and immunity through the regulation of genes encoding proinflammatory cytokines, adhesion molecules, chemokines, and growth factors130, 131 (Fig. 5). NF-κB also participates in the regulation of many other vital biological processes, including development, cell growth, and survival and proliferation. Modulation of NF-κB activity can contribute to many pathological conditions.132 Accumulating evidence has shown that NF-κB can be activated by ROS.133 For example, H2 O2 and peroxynitrite can positively or negatively regulate the activity of NF-κB, suggesting that oxidative stress regulated NF-κB is context dependent.134 These interesting findings might be explained by the redox modifications of NFκB and related signaling molecules. Indeed, ROS/RNS-mediated oxidation or S-glutathiolation of redox-sensitive cysteines of NF-κB subunits seem to have various inhibitory or stimulatory roles in NF-κB signaling dependent on the level of ROS/RNS, the types of stimuli, and the Medicinal Research Reviews DOI 10.1002/med

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cell type.131, 132 The activity of NF-κB-nuclear DNA binding is determined by the redox status of NF-κB, which is spatially regulated by its subcellular localization.135, 136 Nishi et al. showed that the p65 subunit and most cysteine residues of the p50 subunit are reduced in the cytoplasm and nucleus, while Cys62 of p50 is highly oxidized in the cytoplasm and strongly reduced in the nucleus.137 Oxidation of this cysteine residue significantly inhibits its ability to bind DNA and decreases the transcription of NF-κB-regulated genes.137 This modification is reversible and can be reduced by the nuclear APE1/Ref-1/Trx1 system to restore the NF-κB-binding affinity. APE1/Ref-1 itself can also be modified by ROS on Cys65, which, however, is not involved in redox regulation.138, 139 The activity of NF-κB in vitro can also be inhibited by S-nitrosylation and glutathionylation of a critical thiol in the DNA-interacting p50 subunit (Cys62) or its binding partner p65 (Cys38), and this effect can be reversed by antioxidant agents.140 Park et al. found that nitration of p65 on residues Tyr66 and Tyr152 could induce its dissociation from p50, its association with IκB, and subsequent sequestration of p65 in the cytoplasm by IκB-mediated export, which resulted in the rapid inactivation of NF-κB activity.141 In addition to direct regulation of NF-κB heterodimers, ROS can also regulate upstream NF-κB-activating pathways. ROS can active the NF-κB pathway by inducing the formation of disulfide bonds between Cys54 and Cys347 in NEMO.142, 143 Sustained oxidative stress inhibits NF-κB activation by inhibiting the degradation of IκBα. This is accomplished either by S-glutathionylation of IκBα on Cys189 or by inactivation of the proteasome.144, 145 Another study showed that Cys189 of IKKβ was a central target for oxidative inactivation by S-glutathionylation, thus inactivating its kinase activity leading to inhibition of NFκB activity.146 Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and v-akt murine thymoma viral oncogene (Akt, also known as PKB), kinases upstream of IKK, are also redox sensitive. Oxidative stress inhibits MEKK1 by sitespecific glutathionylation at Cys1238 in the ATP-binding domain.47 Akt undergoes disulfide bond formation between Cys297 and Cys311 and subsequent dephosphorylation due to an increased association with protein phosphatase 2A: thus ROS can prevent IKK activation by inhibiting Akt.147 Furthermore, PTEN, an upstream inhibitor of Akt activation, can also be oxidized by ROS leading to a reversible inhibition of its phosphatase activity and, in turn, activation of Akt and IKK.50 NF-κB has been shown to involve the regulation of redox homeostasis.130 NF-κB can increase the expression of some antioxidant proteins, such as ferritin heavy chain, SOD2, and GSH S-transferase pi. These proteins prevent excessive ROS accumulation and oxidative damage.33, 130 Inactivation of NF-κB favors the accumulation of ROS and can induce oxidation of other proteins such as protein tyrosine phosphatases, including SHP1 and SHP2. Oxidation of SHP1 and SHP2 results in a loss of their phosphatase activity, the accumulation of phosphorylated JAK2, and activation of JAK2-STAT3 signaling, which attenuates macrophage activation and has been shown to prevent postoperative intestinal inflammation.33, 148 Given the important role of NF-κB in the regulation of inflammation, direct regulation of NF-κB activity could be a promising strategy to modulate inflammatory diseases. Various approaches have been reported including using small molecules or indirectly targeting IKK or IκB or upstream signaling molecules. Since increasing studies have highlighted the redox modification regulated activation of the NF-κB pathway, modulation of NF-κB activity in inflammatory process by manipulation of the redox status of critical biomolecules might be a method choice in the future. 2. Redox Modifications of Other Inflammatory-Associated Transcription Factors Aberrant expression of HIF has been observed during inflammation. HIF expression is linked to innate immunity by controlling proinflammatory gene expression, mediating bacterial killing, Medicinal Research Reviews DOI 10.1002/med


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influencing cell migration, and inducing macrophage phenotypic plasticity.149, 150 The prototype of the family is HIF-1, which is a heterodimeric transcription factor composed of a α and β subunit.151 The HIF-β protein subunit is constitutively expressed, while the level of HIF-1α is dependent on cellular oxygen levels.152 Under normoxic conditions, two proline residues of the HIF-1α subunit are modified by prolyl hydroxylase (PHD), the activity of which depends on the availability of oxygen, Fe(II), 2-oxoglutarate, and ascorbate.153 Hydroxylation of either of these prolyl residues results in polyubiquitylation via a specific von Hippel–Lindau (pVHL) E3 ligase complex and leads to HIF-1α degradation by the proteasome.149 When oxygen levels decrease (hypoxia), prolyl hydroxylation and degradation of HIF-1α are blocked. The accumulated HIF-1α then translocates to the nucleus and forms dimers with constitutive HIF-1β. In the nucleus, HIF-1 recruits and binds to coactivators such as CBP/p300, permitting transcriptional activation of many hypoxia-response element bearing genes.150 The stability of HIF-1α is sensitive to ROS stimuli.154 Under normoxia, ROS/RNS accumulation (e.g., in cells exposed to H2 O2 and NO releasing drugs) can stabilize and activate HIF-1α. This activation may be dependent on the inactivation of PHD through ROS-induced conversion of Fe2+ to Fe3+ , or on direct oxidative modifications such as S-nitrosylation of HIF-1α or pVHL.154 For example, in murine tumor associated macrophages, the generation of NO stimulated by ionizing radiation can induce S-nitrosylation of HIF-1α at Cys533 in the oxygen-dependent degradation domain and prevents its destruction independently of the PHD-based pathway, suggesting that the interaction between NO and HIF-1 may be involved in tumor response to treatment as well as the mammalian inflammation process.155 Furthermore, Yasinska et al. showed that S-nitrosation of HIF-1α at Cys800 recruited p300 coactivator protein to the HIF-1α C-terminal domain and stimulated its transcriptional activity,156 while S-nitrosylation of pVHL Cys162 appears to alter pVHL–HIF-1α interaction and decrease HIF1α ubiquitination.157 However, under hypoxic conditions, ROS can prevent hypoxia-induced HIF-1α DNA binding by blocking accumulation of HIF-1α protein or by reversible sulfhydryl oxidation that can be restored by overexpression of Trx and Ref-1.158 Thus, how oxidation controls HIF-1α activation might depend on the differential oxygen content in the specific context: oxidative modification stabilizes normoxic HIF-1α, but inhibits anoxic HIF-1α. Nonetheless, it is absolutely clear that the redox modifications of HIF-1α are important for the regulation of inflammation-associated genes but still require further investigation. AP-1 transcription factors are homodimers or heterodimers composed of several groups of basic leucine zipper domain proteins, including Jun (c-Jun, JunB, JunD), Fos (c-Fos, FosB, Fra-1, and Fra2), Maf (c-Maf, MafB, MafA, MafG/F/K, Nrl), and ATF (ATF2, LRF1/ATF3, B-ATF, JDP1, JDP2) subfamilies.159 AP-1 is commonly activated during microbial infection, either leading to expression of inflammatory mediators alone or interacts with other transcription factors.160, 161 The activity of AP-1 depends on the cellular redox state.162 For example, ethanol-induced oxidative stress can activate AP-1, which leads to sensitization of macrophages, and subsequent CD14 expression and production of proinflammatory cytokines. Overexpression of SOD1 abrogates both AP-1 activity and CD14 expression in the liver.163 In addition, AP-1 transcriptional activity is regulated by a direct association between TRX and Ref-1 in vitro.164 NO can also regulate AP-1 transcriptional activity by inducing the formation of an intermolecular disulfide bridge between cysteine residues in the leucine zipper site of c-Jun monomers, heterodimers between Jun and Fos proteins, or the formation of a mixed disulfide with GSH.165 Covalent dimerization of c-Jun did not appear to affect its DNA-binding activity, while S-glutathionylation at Cys269 in the DNA-binding site of c-Jun is involved in NO-mediated inhibition of c-Jun DNA binding.165 Furthermore, the activity of AP-1 proteins is tightly controlled by MAPK (including p38, ERK1/2, and JNK).166 Multiple lines of evidence show that ROS/RNS can lead to the activation and phosphorylation of MAPKs. MAPKs Medicinal Research Reviews DOI 10.1002/med

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themselves can be modified by ROS/RNS directly. Park et al. showed that endogenous NOmediated IFN-γ -induced suppression of JNK1 activation in macrophage cells by means of a thiol-redox mechanism.167 ONOO− can rapidly activate p38 by nitration of tyrosine residues.168 Conversely, p38 activity is inhibited by cysteine oxidation caused by H2 O2 or by the natural inflammatory lipid prostaglandin J2.169 Cytokines that can further contribute to the inflammatory progression are secreted by regulation of various signaling pathways, mainly involving the JAK-STAT pathways.36 Several members of the STAT transcription factor family, in particular STAT1, STAT2, STAT3, STAT4, and STAT6, have been shown to play a dual role in inflammation and immunity response by the concerted action of pro- and anti-inflammatory cytokines.36, 170 Several studies have shown that ROS produced by NOX, especially O2 − anions, are required for the transcriptional activity of STAT.171–173 In addition, Mazi`ere et al. found that oxidized LDL enhanced the binding activity of STAT1 and STAT3 to their respective consensus-binding sites.174 The activity of STAT is also directly regulated by redox modifications.175 A STAT3 dimer is formed by interchain disulfide bridging in response to oxidative stress, with cysteine 259 as the reactive residue.176 ROS/RNS can induce redox modification of cysteine residues in STAT3 by S-glutathionylation, resulting in decreased phosphorylation, nuclear translocation, and DNA-binding ability of STAT3 in response to IL-6.177 Further studies should investigate whether the redox-regulated STAT3 activity has an effect on the pro- and anti-inflammatory cytokines and more importantly, on the progress of inflammatory diseases. Nrf2 is a key transcription factor that is involved in inflammatory response.178, 179 Nrf2 is a basic “cap and collar” leucine zipper transcription factor, which regulates environmental stress response by transcribing genes for antioxidants, phase II detoxification enzymes, GSH-synthesis enzymes, and other cytoprotective proteins.179 Under resting conditions, Nrf2 localizes in the cytoplasm and binds to the cytosolic Keap1 (cytosolic inhibitor Kelch-like ECH-associated protein 1).180 Keap1 is an adaptor protein to the CUL3 (cullin-3) E3 ubiquitin ligase, which can induce ubiquitination and proteasomal degradation of Nrf2 to keep the cytosolic level of Nrf2 low.178, 180 ROS/RNS play a pivotal role in the activation of Nrf2 by dissociating Nrf2 from the Keap1/Nrf2 complex, which allows Nrf2 accumulation and nuclear translocation and leads to its binding with antioxidant responsive element (ARE) or electrophile responsive element.179 ROS/RNS-induced activation of Nrf2 mainly depends on the modification of Keap1 at active cysteine residues. Keap1 contains more than 20 conserved cysteines, but only Cys151, Cys273, and Cys288 are required for disrupting the Keap1–Nrf2 complex by formation of intramolecular or intermolecular disulfide bridges.178–180 In addition, NO and S-nitrosocysteine can cause time- and dose-dependent Keap1 thiol modification leading to nuclear accumulation of Nrf2 and upregulation of the ARE-regulated gene HO-1.178 More attractively, NO can induce the formation of 8-nitro-cGMP. 8-Nitro-cGMP then acts as an electrophile to react with the active thiol on Cys434 of KEAP1, causing S-guanylation of KEAP1, which led to Nrf2 activation and subsequent induction of antioxidant enzymes.181 The modification of cysteine residues in Nrf2 is also involved in the regulation of Nrf2 activity. Cys183 in the Neh5 domain of Nrf2 can serve as a redox-sensitive nuclear exporting signal.182 Cys506 in the DNA-binding domain is critical for the regulation of Nrf2-dependent activation of ARE-mediated gene expression, although it is not involved in the accumulation and nuclear translocation of Nrf2 upon oxidative stress.183 A recent study showed that Cys119, Cys235, and Cys506 of Nrf2 were all involved in regulating oxidant/electrophile sensing, repressing Keap1-dependent ubiquitination and proteasomal degradation, and promoting recruitment of coactivators.184 Nrf2 was reported to protect against airway inflammation and asthma by activating antioxidant enzymes to compromise oxidative stress. However, a recent study suggested that Nrf2 had a critical proinflammatory effect by mediating NLRP3 and AIM2 inflammasome activation in mouse macrophages. Medicinal Research Reviews DOI 10.1002/med


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These seemingly paradoxical results are probably due to the different biological context in the different studies, while the different redox modification patterns of Nrf2 and its regulatory molecules leading to different activity of Nrf2 should not be neglected. Peroxisome proliferators activated receptors (PPARs) are nuclear receptors belonging to the nuclear hormone receptor family, and can be activated by ligands such as nonesterified fatty acids, eicosanoids, and prostanoids.185 Following activation, PPARs have been established as transcriptional regulators involved in lipid metabolism and inflammation by binding to an identical peroxisome proliferator response element (PPRE) sequence motif.186, 187 PPARα has been shown to exert anti-inflammatory effects by inhibition of the production of NO and the secretion of proinflammatory cytokines including TNFα, IL-1β, and IL-6 in T lymphocytes and macrophages.188 In addition to transactivate genes by binding to their PPRE, the inhibitory action of PPARα on cytokine expression has also been shown to interfere with proinflammatory transcription factors such as AP-1, NF-κB, and STAT-1 in a non-DNA-bound manner.186, 189 PPARα activation can decrease the expression of NOX and increase the expression of SOD, resulting in inhibition of LDL oxidation that is beneficial for atherogenesis.187 Although, the specific redox modifications have not yet been identified, ROS have been demonstrated to play an important role in PPAR signaling and PPAR-dependent gene expression.185, 190 Interestingly, PPAR contains nine cysteine residues, eight of which are located in the two zinc finger motifs of the DNA-binding domain.191, 192 Redox modification of these cysteines may block DNA binding and lead to alternative protein–protein interactions.6, 192 Furthermore, one particular cysteine is present at the C-terminus of the hinge domain and a redox modification of this cysteine might affect ligand binding, which could then modify downstream signaling.6 These studies suggested that the PPAR has great potential as a redox sensor to exert its anti-inflammatory effects. F. Oxidation and the Inflammasome Recent studies suggest that ROS play a crucial role in the activation of the NLRP3 inflammasome, which senses pathogens and injury to induce the proteolytic maturation of inflammatory cytokines such as IL-1 and IL-18.22 A recent study found that inducers of the NLRP3 inflammasome caused aberrant mitochondrial homeostasis, which is the major source of the production of ROS, implying that ROS may play a role in the activation of the NLRP3 inflammasome.193 Indeed, inflammasome activators, including ATP, pathogens, and their PAMPs (malaria pathogenic crystal, hemozoin, influenza virus, and yeast Candida albicans), and large particles (uric acid crystals, alum, particulate metals, silica, and asbestos), have been shown to induce ROS generation and the activation of the NLRP3 inflammasome. The use of inhibitors or scavengers that block mitochondrial ROS or NOX in different immune cells, suppresses inflammasome activation, suggesting redox signaling is necessary for the activation of the inflammasome.194 ROS-induced activation of the inflammasome may either directly trigger the inflammasome assembly or act indirectly through signals that are sensitive to ROS.194 For example, Cruz et al. found that ATP-induced ROS accumulation could stimulate the PI3K pathway and subsequent Akt and ERK1/2 activation through the glutathionylation of PTEN, which is required for the activation of NLRP3 inflammasome and secretion of IL-1β and IL-18 in macrophages.50 In another study, Zhou et al. showed that TRX-interacting protein (TXNIP; also called VDUP1 or TBP-2) was involved in the ROS-induced activation of NLRP3 inflammasome.195 Upon stimulation by inflammasome activators such as uric acid crystals, TXNIP is released from TRX after oxidation of TRX by ROS, which allows TXNIP to bind and activate the NLRP3 inflammasome.195 This suggests that TXNIP is an important mediator in ROS-induced activation of the NLRP3 inflammasome.195 Intriguingly, in some cases, both ROS generation and activation of antioxidant defense systems are required for inflammasome activation. Tassi Medicinal Research Reviews DOI 10.1002/med

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et al. demonstrated that IL-1β processing and secretion induced by PAMP molecules in human monocytes was regulated by a biphasic redox event comprising a prompt oxidative stress and a delayed antioxidant response, because inhibitors of either NOX or TRX reductase could impair IL-1β secretion.196 Moreover, ROS production does not always result in inflammasome activation. Bauernfeind et al. showed that ROS inhibitors blocked priming, but not activation, of the NLRP3 inflammasome, based on the observation that NLRP3 activation was inhibited only when macrophages were treated with ROS inhibitor before, but not after, prolonged LPS priming.197 SOD1 deficiency in macrophages induced higher superoxide production, leading to a decreased cellular redox potential and specific inhibition of caspase-1 by reversible oxidation and glutathionylation of the redox-sensitive cysteine residues at Cys397 and Cys362.198 According to these paradoxical findings, the redox-regulated inflammasome might act in a context-dependent manner, in which the intensity and duration of ROS stimuli as well as the various pathophysiologic characteristics of distinct inflammatory processes and disease are significant determiners. In addition, the redox modifications of important molecules involved in the regulation of the inflammasome (such as caspase-1 and TRX-interacting proteins) will help facilitate our further understanding of redox-regulated inflammasomes. Taken together, redox regulation, particularly the redox modifications of various redoxsensitive proteins, is indeed required for the modulation of inflammatory responses and diseases. Redox modifications of certain molecules not only act as an “on-off” switch for their activities or biological functions, but also affect the signaling transduction cascades involved and are closely related to different biological status. Although only a few studies have clarified the direct correlation between the redox modifications of redox-sensitive proteins and the inflammatory process, the fact that many inflammation-associated proteins and related regulators are sensitive to redox modifications and can be activated or inactivated by redox modifications, reveals an important role of redox modifications of proteins in inflammatory responses. It is believed that increasing direct evidence will continue to emerge to further corroborate the inflammationrelated redox modifications. G. Biomarkers of Oxidative Stress for Inflammation-Related Diseases Oxidative stress induced inflammation has been implicated in the pathogenesis of a number of disease including pancreatitis, carcinogenesis and metastasis, diabetic complications, allergic asthma, cardiovascular, neurological, and pulmonary diseases. Thus, the oxidative modifications and damage of DNA (such as 8-OHdG), lipid (such as HNE), or proteins (such as advanced oxidation protein products) have been widely served as biomarkers for these inflammation-related diseases (Table I). Until now, the reversible oxidative modifications of proteins have not been used to as markers for inflammation-related diseases, although they play important roles in inflammation. One reason is that the dynamic redox status of proteins is prone to alter in the air, complicating the manipulation of sample preparation. Another reason is the deficient of specific antibodies that could identify different oxidative forms of redox sensors.

5. CONCLUSIONS The redox state of the tissue seems to represent a major determinant for the outcome of acute inflammation. On the one hand, ROS/RNS are important inflammatory effectors contributing to the clearance of invading pathogens and aiding tissue repair, accelerating the resolution of inflammation. On the other hand, ROS/RNS can create inflammatory initiators by damaging biomacromolecules such as lipids, proteins, and nucleic acids. This damage promotes cell death Medicinal Research Reviews DOI 10.1002/med


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Table I. Biomarkers of Oxidative Stress for Inflammation-Related Diseases Biomarkers of oxidative stress

Inflammation-related diseases

Refs

8-OHdG

Diabetes mellitus Diabetic nephropathy Small cell lung cancer Breast cancer Bladder and prostate cancers Atherosclerosis Gastrointestinal (GI) diseases Liver injury Ischemia-reperfusion injury Diabetes Chronic pancreatitis Crohn’s disease and ulcerative colitis Chronic airway inflammation Atopic ocular surface disease Kidney disease Kidney disease Type 2 diabetes mellitus Atherosclerosis Liver cirrhosis Chronic hepatitis C infection Allergic rhinitis Chronic obstructive pulmonary disease Multiple sclerosis Chronic rheumatic valve disease Chronic rheumatic diseases Crohn’s disease and ulcerative colitis Chagas’ disease

206

HNE

AOPP

207 208 209 210 211 64, 212 213–215 216 217 218 219 220 221 222, 223 224–229 230–232 36, 37 233 234 235 236 237 238 239 240, 241 242

8-OHdG, 8-hydroxy-2’-deoxyguanosine; HNE, 4-hydroxy-2-nonenal; AOPP, advanced oxidation protein products.

and tissue deterioration, which can lead to transition from acute to chronic inflammation. Thus, oxidative and nitrosative stress both play an important role in the development of various inflammatory diseases. Biomarkers of oxidative stress have been used to diagnose some disease processes,63, 69, 100, 199–201 and approaches have been targeted toward oxidative stress for the treatment of inflammatory-associated diseases such as cancer, Alzheimer’s disease, Parkinson’s disease, chronic obstructive pulmonary disease, cardiovascular disease, and diabetic complications.18, 63, 69, 100, 202–204 To date, therapeutic strategies based simply on the use of ROS scavengers, such as N-acetyl-cysteine, have shown limited clinical efficacy, and can even lead to disease aggravation.202–205 These disappointing results may in part be due to the difficulty in determining the precise dosage of ROS scavengers required to revert to the normal redox state. In addition, ROS/RNS are diffusible molecules that are susceptible to reaction with other biomolecules. Thus, a slight alteration in redox state may lead to significant functional changes of multiple biological pathways, further complicating the dosage problem. Therefore, more sensitive biomarkers, or biomarker panels, which can be used to precisely measure the level of oxidative stress, are urgently needed. As the ongoing rapid development of high-throughput quantitative redox proteomics enable the profiling of differentially modified redox patterns of redox sensors in different biological contexts, significant efforts on the Medicinal Research Reviews DOI 10.1002/med

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screening of redox-sensitive proteins that play important roles in a range of inflammatory responses and diseases will be made in the foreseeable future.

CONFLICT OF INTEREST The authors declare no conflict of interest.

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Yunlong Lei received his PhD from the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and has been appointed as an assistant professor in the Department of Biochemistry and Molecular Biology, and the Molecular Medicine and Cancer Research Center, Chongqing Medical University, P.R. China. His research interest focuses on the metabolic and oxidative stress in tumorigenesis. Kui Wang is a PhD candidate in State Key Laboratory of Biotherapy, West China Hospital, Sichuan University. His research interests focus on using proteomics strategies to investigate the role of oxidative stress and autophagy in cancer metabolism, and using chemical proteomics for drug-target deconvolution. Longfei Deng is a PhD candidate in the National R&D Platform for Novel Drugs, West China Hospital, Sichuan University. His research interests include the role of reactive oxygen species Medicinal Research Reviews DOI 10.1002/med


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and autophagy in human diseases, and chemistry-based functional proteomics for drug-target deconvolution. Yi Chen got his MD degree in West China Hospital, Sichuan University, and now is an attending surgeon in West China Hospital. His research interest is the molecular mechanisms of autophagy in carcinogenesis. Edouard Collins Nice is the Adjunct Professor of Department of Biochemistry and Molecular Biology in Monash University. He was the director of Monash Antibody Technologies Facility (MATF), and now is the head of the Clinical Biomarker Discovery and Validation in Monash University, the Conference Steward/Trade Liaison of Australian Peptide Association, and the Visiting Professor of West China Hospital, Sichuan University. His career has focused on the development of new techniques (e.g., micropreparative HPLC, novel chromatographic supports, biosensor analysis, and proteomics) for the microisolation, purification, characterization, and analysis of protein growth factors, their receptors, and associated signaling molecules to help understand their role in diseases. Dr. Nice has contributed to a number of scientific committees and organizations. Nice is currently co-chair of the HUPO Chromosome 7 initiative and is on both the finance and antibody committees of HUPO. He also is a member of the Association of Biomolecular Resources (ABRF) Antibody working group. He was a founding member of the Australian Peptide Association of which he is currently Co-chairman. He has also served as Vice Chairman (2001–2007) and Treasurer (1994–2001). Canhua Huang has been a professor and principal investigator at the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University since 2005. His research focuses on elucidation of the molecular mechanisms of virus-induced carcinogenesis using proteomics approaches. He is the chief scientist for Redox Proteomics, National Basic Research Program of China (973 Program). Dr. Huang is a member of Chinese Human Proteome Organization (CNHUPO). He serves on the Editorial Board of PROTEOMICS, World J Hepatol, as well as a Guest Editor for Comb Chem High Throughput Screen in 2012. He was awarded as “National Science Fund for Distinguished Young Scholars of China” in 2012. Supporting Information text & suppmat


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