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1.  Lipid Raft Redox Signaling: Molecular Mechanisms in Health and Disease 
Antioxidants & Redox Signaling  2011;15(4):1043-1083.
Lipid rafts, the sphingolipid and cholesterol-enriched membrane microdomains, are able to form different membrane macrodomains or platforms upon stimulations, including redox signaling platforms, which serve as a critical signaling mechanism to mediate or regulate cellular activities or functions. In particular, this raft platform formation provides an important driving force for the assembling of NADPH oxidase subunits and the recruitment of other related receptors, effectors, and regulatory components, resulting, in turn, in the activation of NADPH oxidase and downstream redox regulation of cell functions. This comprehensive review attempts to summarize all basic and advanced information about the formation, regulation, and functions of lipid raft redox signaling platforms as well as their physiological and pathophysiological relevance. Several molecular mechanisms involving the formation of lipid raft redox signaling platforms and the related therapeutic strategies targeting them are discussed. It is hoped that all information and thoughts included in this review could provide more comprehensive insights into the understanding of lipid raft redox signaling, in particular, of their molecular mechanisms, spatial-temporal regulations, and physiological, pathophysiological relevances to human health and diseases. Antioxid. Redox Signal. 15, 1043–1083.
I. Introduction
II. Redox Signaling and Redox Injury
A. Redox signaling
B. Redox signaling versus injury
C. Common ROS as messengers
III. Concepts of LRs and Their Clustering
A. Concepts of LRs and existing debates
B. Molecular models of LRs
C. LRs on cell membranes
1. Caveolar LRs
2. Noncaveolar LRs
3. Ceramide-enriched micro- and macrodomains
D. Intracellular LRs
E. LR clusters or signaling platforms
IV. Redox Molecules Associated with LRs
A. The NADPH oxidase family
1. Structure of the NADHP oxidase family and their tissue distribution
2. Assembly and activation of NOX
3. Regulation of NOX activity
B. Superoxide dismutase
C. Catalase
D. Thioredoxin
E. Transient receptor protein C3 and C4: redox sensors
F. Effects of redox molecules on LRs
V. Frequently Used Methods for Identifying LR Redox Signaling Platforms
A. Fluorescent confocal microscopic imaging
B. Fluorescence resonance energy transfer
C. Membrane fraction flotation
D. Superoxide production in LR platforms
E. Others
VI. Downstream Targets of LR Redox Signaling
A. Signaling in phagocytic process
B. Transmembrane signaling via receptors in nonphagocytic cells
C. LR redox signaling not via receptors
D. Interactions of intracellular vesicles or organelles through LR redox signaling
E. Hypothetic models of LR redox signaling platforms
VII. Mechanisms Mediating the Formation of LR Redox Signaling Platforms
A. Ceramide metabolizing pathways
B. Association of ceramide metabolism and its signaling pathway
C. Role of ceramide-enriched microdomains in LRs clustering
D. Lysosome fusion and targeting of ASMase in LRs clustering
E. Cytoskeletal components and LR clustering
F. Feedforward amplifying mechanism
VIII. Physiology and Pathophysiology of LR Redox Signaling Platforms
A. Host defense and infection
B. Vascular inflammation and atherosclerosis
C. AD and neurological disease
D. Kidney diseases
E. Obesity
F. Tumors
IX. Possible Therapeutic Strategies Targeting LR Redox Signaling Platforms
A. Targeting cholesterol
B. Targeting ASMase activity
C. Targeting protein palmitoylation
X. Conclusions and Perspectives
PMCID: PMC3135227  PMID: 21294649
2.  Functional Analysis of Novel Analogues of E3330 That Block the Redox Signaling Activity of the Multifunctional AP Endonuclease/Redox Signaling Enzyme APE1/Ref-1 
Antioxidants & Redox Signaling  2011;14(8):1387-1401.
APE1 is a multifunctional protein possessing DNA repair and redox activation of transcription factors. Blocking these functions leads to apoptosis, antiangiogenesis, cell-growth inhibition, and other effects, depending on which function is blocked. Because a selective inhibitor of the APE redox function has potential as a novel anticancer therapeutic, new analogues of E3330 were synthesized. Mass spectrometry was used to characterize the interactions of the analogues (RN8-51, 10-52, and 7-60) with APE1. RN10-52 and RN7-60 were found to react rapidly with APE1, forming covalent adducts, whereas RN8-51 reacted reversibly. Median inhibitory concentration (IC50 values of all three compounds were significantly lower than that of E3330. EMSA, transactivation assays, and endothelial tube growth-inhibition analysis demonstrated the specificity of E3330 and its analogues in blocking the APE1 redox function and demonstrated that the analogues had up to a sixfold greater effect than did E3330. Studies using cancer cell lines demonstrated that E3330 and one analogue, RN8-51, decreased the cell line growth with little apoptosis, whereas the third, RN7-60, caused a dramatic effect. RN8-51 shows particular promise for further anticancer therapeutic development. This progress in synthesizing and isolating biologically active novel E3330 analogues that effectively inhibit the APE1 redox function validates the utility of further translational anticancer therapeutic development. Antioxid. Redox Signal. 14, 1387–1401.
PMCID: PMC3061197  PMID: 20874257
3.  Redox Regulation of Multidrug Resistance in Cancer Chemotherapy: Molecular Mechanisms and Therapeutic Opportunities 
Antioxidants & Redox Signaling  2009;11(1):99-133.
The development of multidrug resistance to cancer chemotherapy is a major obstacle to the effective treatment of human malignancies. It has been established that membrane proteins, notably multidrug resistance (MDR), multidrug resistance protein (MRP), and breast cancer resistance protein (BCRP) of the ATP binding cassette (ABC) transporter family encoding efflux pumps, play important roles in the development of multidrug resistance. Overexpression of these transporters has been observed frequently in many types of human malignancies and correlated with poor responses to chemotherapeutic agents. Evidence has accumulated showing that redox signals are activated in response to drug treatments that affect the expression and activity of these transporters by multiple mechanisms, including (a) conformational changes in the transporters, (b) regulation of the biosynthesis cofactors required for the transporter's function, (c) regulation of the expression of transporters at transcriptional, posttranscriptional, and epigenetic levels, and (d) amplification of the copy number of genes encoding these transporters. This review describes various specific factors and their relevant signaling pathways that are involved in the regulation. Finally, the roles of redox signaling in the maintenance and evolution of cancer stem cells and their implications in the development of intrinsic and acquired multidrug resistance in cancer chemotherapy are discussed. Antioxid. Redox Signal. 11, 99–133.
Structure and Function of Multidrug-Resistance Transporter Protein Families
MDR/Pgp family
MRP/GS-X pump family
Non-ABC multidrug-resistance proteins
Redox Regulation of Multidrug-Resistance Transporters: Conformational Changes of the Transporters
Redox Regulation of Multidrug-Resistance Transporter Activity
Redox Regulation of Multidrug-Resistance Transporter Gene Expression
MDR/Pgp family
Transcriptional regulation
Posttranscriptional regulation
Epigenetic regulation
γ-Glutamylcysteine synthetase (γ-GCS)
Transcriptional regulation
Posttranscriptional regulation
MRP family
Redox Regulation of Multidrug-Resistance Transporters: Gene Amplification
Role of redox signaling in chromosomal breakage at fragile sites
Role of redox signal in sister chromatid fusion
Redox Signaling in the Evolution of Intrinsic Multidrug Resistance in Cancer
Evolution of intrinsic multidrug resistance (upfront resistance)
Signal-transduction pathways in the intrinsic multidrug resistance
The NF-κB pathway
The PI3 kinase pathway
The p53 pathway
Clinical Significance of Redox Signaling in Multidrug Resistance and Therapeutic Opportunities
Redox Signaling in Multidrug-Resistant Cancer Stem Cells
Multidrug-resistant hemopoietic stem cells
Multidrug-resistant cancer stem cells of solid tumors
Signaling pathways in cancer stem cells
The Wnt/β-catenin signaling
The Notch signaling
The sonic hedgehog signaling
Therapeutic Opportunities for Cancer Stem Cells
Conclusions: Challenges and Perspectives
PMCID: PMC2577715  PMID: 18699730
4.  Redox Control of Inflammation in Macrophages 
Antioxidants & Redox Signaling  2013;19(6):595-637.
Macrophages are present throughout the human body, constitute important immune effector cells, and have variable roles in a great number of pathological, but also physiological, settings. It is apparent that macrophages need to adjust their activation profile toward a steadily changing environment that requires altering their phenotype, a process known as macrophage polarization. Formation of reactive oxygen species (ROS), derived from NADPH-oxidases, mitochondria, or NO-producing enzymes, are not necessarily toxic, but rather compose a network signaling system, known as redox regulation. Formation of redox signals in classically versus alternatively activated macrophages, their action and interaction at the level of key targets, and the resulting physiology still are insufficiently understood. We review the identity, source, and biological activities of ROS produced during macrophage activation, and discuss how they shape the key transcriptional responses evoked by hypoxia-inducible transcription factors, nuclear-erythroid 2-p45-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor-γ. We summarize the mechanisms how redox signals add to the process of macrophage polarization and reprogramming, how this is controlled by the interaction of macrophages with their environment, and addresses the outcome of the polarization process in health and disease. Future studies need to tackle the option whether we can use the knowledge of redox biology in macrophages to shape their mediator profile in pathophysiology, to accelerate healing in injured tissue, to fight the invading pathogens, or to eliminate settings of altered self in tumors. Antioxid. Redox Signal. 19, 595–637.
I. Introduction
II. Macrophage Development
III. The Distinguished Redox Species: Nitric Oxide and Superoxide Radical Anion
A. Formation of NO and associated species
B. Formation of superoxide radical anion and associated species
IV. Macrophage Plasticity in the Light of Redox Biology
V. Redox Systems Modulate and Determine the Macrophage Phagocyte Function
A. Redox signaling in macrophages upon phagocytosis of pathogens
B. Redox reactions in dying cells modify their uptake by macrophages
C. Redox signals in macrophages modify apoptotic cell uptake
D. Redox reactions determine the outcome of cell death
VI. Redox Systems and Regulatory Macrophage Function
VII. Targets of the NO/O2− Redox Biology in Macrophage Function
A. sGC and cGMP formation
B. Redox signals and transcriptional/translational regulation
VIII. Redox Signals and Hypoxia-Inducible Macrophage Reponses
A. NO and the hypoxia-responsive system in macrophages
B. ROS and the hypoxia-responsive system in macrophages
C. The NO/ROS interplay in affecting the hypoxia-responsive system in macrophages
D. HIF in classically activated macrophages
E. HIF in alternatively activated macrophages
F. HIF target genes in macrophage biology
IX. Nrf2 at the Transition from Classical to Alternative Macrophage Activation
X. Alternative Macrophage Activation and PPARs
XI. ROS Support Classical Activation in Response to Modified Lipoproteins
A. NOX and mitochondrial-derived ROS in response to modified lipoproteins
B. Modified lipoproteins and endoplasmic reticulum stress
XII. ROS: Linking Classical Macrophage and Inflammasome Activation
XIII. Autophagy Dampens ROS-Dependent Inflammasome Activation
XIV. The Redox Sensor AMPK Favors Regulatory Macrophage Activation
XV. Iron Availability Dictates Macrophage Polarization
XVI. Conclusions
PMCID: PMC3718318  PMID: 23311665
5.  Thioredoxins, Glutaredoxins, and Peroxiredoxins—Molecular Mechanisms and Health Significance: from Cofactors to Antioxidants to Redox Signaling 
Antioxidants & Redox Signaling  2013;19(13):1539-1605.
Thioredoxins (Trxs), glutaredoxins (Grxs), and peroxiredoxins (Prxs) have been characterized as electron donors, guards of the intracellular redox state, and “antioxidants”. Today, these redox catalysts are increasingly recognized for their specific role in redox signaling. The number of publications published on the functions of these proteins continues to increase exponentially. The field is experiencing an exciting transformation, from looking at a general redox homeostasis and the pathological oxidative stress model to realizing redox changes as a part of localized, rapid, specific, and reversible redox-regulated signaling events. This review summarizes the almost 50 years of research on these proteins, focusing primarily on data from vertebrates and mammals. The role of Trx fold proteins in redox signaling is discussed by looking at reaction mechanisms, reversible oxidative post-translational modifications of proteins, and characterized interaction partners. On the basis of this analysis, the specific regulatory functions are exemplified for the cellular processes of apoptosis, proliferation, and iron metabolism. The importance of Trxs, Grxs, and Prxs for human health is addressed in the second part of this review, that is, their potential impact and functions in different cell types, tissues, and various pathological conditions. Antioxid. Redox Signal. 19, 1539–1605.
I. Introduction
A. Trx family of proteins
1. Structure and reaction mechanisms
2. Trx, Grx, and Prx family proteins in mammals
a. Trx systems
b. Grx systems
c. Peroxiredoxins
d. Trx-like proteins
B. The concept of redox signaling
C. Reversible post-translational redox modifications of protein thiols
1. Sulfenylation
2. Protein disulfides
3. Glutathionylation and cysteinylation
4. S-nitrosylation
5. Other reversible redox modifications
a. Persulfide formation
b. Methionine sulfoxidation
D. Oxidative stress in the concept of redox signaling
II. Mammalian Trx Family Proteins in Health and Disease
A. Specific pathways
1. Apoptosis
a. Cytosolic pathways
b. Mitochondrial pathways
2. Proliferation
3. Iron metabolism
a. Iron sulfur Grxs
b. Biogenesis of iron-sulfur centers
c. Regulation of iron metabolism
d. Intracellular iron distribution
B. Tissues, organ systems, and diseases
1. Development
2. Central nervous system
a. Expression profile of Trxs, Grxs, Prxs, and related proteins in the CNS
b. Trxs, Grxs, Prxs, and pathologies of the CNS
3. Sensory organs
a. Expression profile of Trx-related proteins in sensory organs
b. Pathologies of the eye
c. Pathologies related to tongue, olfactory system, and ear
4. Cardiovascular system
a. Expression pattern of Trxs, Grxs, and Prxs in cardiovascular tissue
b. Trxs, Grxs, and Prxs in pathologies of the cardiovascular system
5. Skin
6. Skeletal muscle
7. Respiratory system
a. Expression of Trx family proteins in the respiratory system
b. Trxs, Grxs, and Prxs in pathologies of the lung—interplay between ROS and inflammation
8. Infection, inflammation, and immune response
a. Expression pattern of Trx-related proteins in lymphoid tissues
b. Immune system
c. Infectious diseases
9. Metabolic and digestive system
a. Diabetes mellitus
10. Urinary tract and reproductive systems
a. Kidney
b. Urinary bladder
c. Male reproductive system
d. Female reproductive system
11. Ischemia and hypoxia
12. Cancer
a. Carcinogenesis
13. Aging
C. Therapeutic approaches
III. Concluding Remarks
PMCID: PMC3797455  PMID: 23397885
6.  Thiol-Redox Signaling, Dopaminergic Cell Death, and Parkinson's Disease 
Antioxidants & Redox Signaling  2012;17(12):1764-1784.
Significance: Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta, which has been widely associated with oxidative stress. However, the mechanisms by which redox signaling regulates cell death progression remain elusive. Recent Advances: Early studies demonstrated that depletion of glutathione (GSH), the most abundant low-molecular-weight thiol and major antioxidant defense in cells, is one of the earliest biochemical events associated with PD, prompting researchers to determine the role of oxidative stress in dopaminergic cell death. Since then, the concept of oxidative stress has evolved into redox signaling, and its complexity is highlighted by the discovery of a variety of thiol-based redox-dependent processes regulating not only oxidative damage, but also the activation of a myriad of signaling/enzymatic mechanisms. Critical Issues: GSH and GSH-based antioxidant systems are important regulators of neurodegeneration associated with PD. In addition, thiol-based redox systems, such as peroxiredoxins, thioredoxins, metallothioneins, methionine sulfoxide reductases, transcription factors, as well as oxidative modifications in protein thiols (cysteines), including cysteine hydroxylation, glutathionylation, and nitrosylation, have been demonstrated to regulate dopaminergic cell loss. Future Directions: In this review, we summarize major advances in the understanding of the role of thiol-redox signaling in dopaminergic cell death in experimental PD. Future research is still required to clearly understand how integrated thiol-redox signaling regulates the activation of the cell death machinery, and the knowledge generated should open new avenues for the design of novel therapeutic approaches against PD. Antioxid. Redox Signal. 17, 1764–1784.
PMCID: PMC3474187  PMID: 22369136
7.  Redox Signaling, Vascular Function, and Hypertension 
Antioxidants & Redox Signaling  2008;10(6):1045-1059.
Accumulating evidence supports the importance of redox signaling in the pathogenesis and progression of hypertension. Redox signaling is implicated in many different physiological and pathological processes in the vasculature. High blood pressure is in part determined by elevated total peripheral vascular resistance, which is ascribed to dysregulation of vasomotor function and structural remodeling of blood vessels. Aberrant redox signaling, usually induced by excessive production of reactive oxygen species (ROS) and/or by decreases in antioxidant activity, can induce alteration of vascular function. ROS increase vascular tone by influencing the regulatory role of endothelium and by direct effects on the contractility of vascular smooth muscle. ROS contribute to vascular remodeling by influencing phenotype modulation of vascular smooth muscle cells, aberrant growth and death of vascular cells, cell migration, and extracellular matrix (ECM) reorganization. Thus, there are diverse roles of the vascular redox system in hypertension, suggesting that the complexity of redox signaling in distinct spatial spectrums should be considered for a better understanding of hypertension. Antioxid. Redox Signal. 10, 1045–1059.
PMCID: PMC2828811  PMID: 18321201
8.  Compartmentalization of Redox Signaling Through NADPH Oxidase–Derived ROS 
Antioxidants & Redox Signaling  2009;11(6):1289-1299.
Reactive oxygen species (ROS) are generated in response to growth factors, cytokines, G protein–coupled receptor agonists, or shear stress, and function as signaling molecules in nonphagocytes. However, it is poorly understood how freely diffusible ROS can activate specific signaling, so-called “redox signaling.” NADPH oxidases are a major source of ROS and now recognized to have specific subcellular localizations, and this targeting to specific compartments is required for localized ROS production. One important mechanism may involve the interaction of oxidase subunits with various targeting proteins localized in lamellipodial leading edge and focal adhesions/complexes. ROS are believed to inactivate protein tyrosine phosphatases, thereby establishing a positive-feedback system that promotes activation of specific redox signaling pathways involved in various functions. Additionally, ROS production may be localized through interactions of NADPH oxidase with signaling platforms associated with caveolae/lipid rafts, endosomes, and nucleus. These indicate that the specificity of ROS-mediated signal transduction may be modulated by the localization of Nox isoforms and their regulatory subunits within specific subcellular compartments. This review summarizes the recent progress on compartmentalization of redox signaling via activation of NADPH oxidase, which is implicated in cell biology and pathophysiologies. Antioxid. Redox Signal. 11, 1289–1299.
PMCID: PMC2842113  PMID: 18999986
9.  Evolutionary Acquisition of Cysteines Determines FOXO Paralog-Specific Redox Signaling 
Antioxidants & Redox Signaling  2015;22(1):15-28.
Reduction–oxidation (redox) signaling, the translation of an oxidative intracellular environment into a cellular response, is mediated by the reversible oxidation of specific cysteine thiols. The latter can result in disulfide formation between protein hetero- or homodimers that alter protein function until the local cellular redox environment has returned to the basal state. We have previously shown that this mechanism promotes the nuclear localization and activity of the Forkhead Box O4 (FOXO4) transcription factor. Aims: In this study, we sought to investigate whether redox signaling differentially controls the human FOXO3 and FOXO4 paralogs. Results: We present evidence that FOXO3 and FOXO4 have acquired paralog-specific cysteines throughout vertebrate evolution. Using a proteome-wide screen, we identified previously unknown redox-dependent FOXO3 interaction partners. The nuclear import receptors Importin-7 (IPO7) and Importin-8 (IPO8) form a disulfide-dependent heterodimer with FOXO3, which is required for its reactive oxygen species-induced nuclear translocation. FOXO4 does not interact with IPO7 or IPO8. Innovation and Conclusion: IPO7 and IPO8 control the nuclear import of FOXO3, but not FOXO4, in a redox-sensitive and disulfide-dependent manner. Our findings suggest that evolutionary acquisition of cysteines has contributed to regulatory divergence of FOXO paralogs, and that phylogenetic analysis can aid in the identification of cysteines involved in redox signaling. Antioxid. Redox Signal. 22, 15–28.
PMCID: PMC4270166  PMID: 25069953
10.  Redox signaling, vascular function and hypertension 
Antioxidants & redox signaling  2008;10(6):1045-1059.
Accumulating evidence supports the importance of redox signaling in the pathogenesis and progression of hypertension. Redox signaling is implicated in many different physiological and pathological processes in the vasculature. High blood pressure is in part determined by elevated total peripheral vascular resistance, which is ascribed to dysregulation of vasomotor function and structural remodeling of blood vessels. Aberrant redox signaling, usually induced by excessive production of reactive oxygen species (ROS) and/or by decreases in antioxidant activity, can induce alteration of vascular function. ROS increase vascular tone by influencing the regulatory role of endothelium and by direct effects on the contractility of vascular smooth muscle. ROS contribute to vascular remodeling by influencing phenotype modulation of vascular smooth muscle cells, aberrant growth and death of vascular cells, cell migration, and extracellular matrix (ECM) reorganization. Thus, there are diverse roles of the vascular redox system in hypertension, suggesting that the complexity of redox signaling in distinct spatial spectrums should be considered for a better understanding of hypertension.
PMCID: PMC2828811  PMID: 18321201
11.  Reactive Oxygen Species and Thiol Redox Signaling in the Macrophage Biology of Atherosclerosis 
Antioxidants & Redox Signaling  2012;17(12):1785-1795.
Significance: Despite the recent decline in the prevalence of cardiovascular diseases, atherosclerosis remains the leading cause of death in industrialized countries. Monocyte recruitment into the vessel wall is a rate-limiting step in atherogenesis. Death of macrophage-derived foam cells promotes lesion progression and the majority of acute complications of atherosclerotic disease (e.g., myocardial infarction) occur in lesions that are intensely infiltrated with monocyte-derived macrophages, underlining the critical roles monocytes and macrophages play in this complex chronic inflammatory disease. Recent Advances: A rapidly growing body of literature supports a critical role for reactive oxygen species (ROS) in the regulation of monocyte and macrophage (dys)function associated with atherogenesis and macrophage death in atherosclerotic plaque. Critical Issues: In this review we highlight the important roles of NADHP oxidase 4 recently identified in monocytes and macrophages and the role of ROS and (thiol) redox signaling in different aspects of monocytes and macrophage biology associated with atherosclerosis. Future Directions: Studies aimed at identifying the intracellular targets of ROS involved in redox signaling in macrophages and at elucidating the redox signaling mechanisms that control differentiation, activation, polarization, and death of monocytes and macrophages may ultimately lead to the development of novel preventive and therapeutic strategies for atherosclerosis. Antioxid. Redox Signal. 17, 1785–1795.
PMCID: PMC3474194  PMID: 22540532
12.  Novel Redox-Sensing Modules: Accessory Protein- and Nucleic Acid-Mediated Signaling 
Antioxidants & Redox Signaling  2012;16(7):668-677.
Significance: Organisms have evolved both enzymatic and nonenzymatic pathways to prevent oxidative damage to essential macromolecules, including proteins and nucleic acids. Pathways modulated by different protein-based sensory and regulatory modules ensure a rapid and appropriate response. Recent Advances: In contrast to classical two-component systems that possess internal sensory and regulatory modules, an accessory protein-dependent redox-signaling system has been recently characterized in bacteria. This system senses extracellular iron-mediated oxidative stress signals via an extracellularly located protein (HbpS). In vivo and in vitro studies allowed the elucidation of molecular mechanisms governing this system. Moreover, recent studies show that nucleic acids may also participate in redox-signaling during antioxidative stress response. Critical Issues: Research for novel redox-signaling systems is often focused on known types of sensory and regulatory modules. It is also often considered that the oxidative attack of macromolecules, leading to modification and degradation processes, is the final step during oxidative stress. However, recent studies have demonstrated that oxidatively modified macromolecules can be intermediary states in the process of redox-signaling. Future Directions: Analyses of adjacent regions of genes encoding for known sensory and regulatory modules can identify potential accessory modules that may increase the complexity of sensing systems. Despite the fact that the involvement of DNA-mediated signaling in the modulation of one bacterial regulator protein has been analyzed in detail, further studies are necessary to identify additional regulators. Given the role of DNA in oxidative-stress response, it is tempting to hypothesize that RNA modules may also mediate redox-signaling. Antioxid. Redox Signal. 16, 668–677.
PMCID: PMC3277925  PMID: 22114914
13.  The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities 
Antioxidants & Redox Signaling  2012;16(7):705-743.
Dietary selenium (]Se), mainly through its incorporation into selenoproteins, plays an important role in inflammation and immunity. Adequate levels of Se are important for initiating immunity, but they are also involved in regulating excessive immune responses and chronic inflammation. Evidence has emerged regarding roles for individual selenoproteins in regulating inflammation and immunity, and this has provided important insight into mechanisms by which Se influences these processes. Se deficiency has long been recognized to negatively impact immune cells during activation, differentiation, and proliferation. This is related to increased oxidative stress, but additional functions such as protein folding and calcium flux may also be impaired in immune cells under Se deficient conditions. Supplementing diets with above-adequate levels of Se can also impinge on immune cell function, with some types of inflammation and immunity particularly affected and sexually dimorphic effects of Se levels in some cases. In this comprehensivearticle, the roles of Se and individual selenoproteins in regulating immune cell signaling and function are discussed. Particular emphasis is given to how Se and selenoproteins are linked to redox signaling, oxidative burst, calcium flux, and the subsequent effector functions of immune cells. Data obtained from cell culture and animal models are reviewed and compared with those involving human physiology and pathophysiology, including the effects of Se levels on inflammatory or immune-related diseases including anti-viral immunity, autoimmunity, sepsis, allergic asthma, and chronic inflammatory disorders. Finally, the benefits and potential adverse effects of intervention with Se supplementation for various inflammatory or immune disorders are discussed. Antioxid. Redox Signal. 16, 705–743.
I. Introduction
II. Bioactive Forms of Se and Their Effects
III. Incorporation of Dietary Se into Selenoproteins
IV. The Selenoprotein Family
A. An overview of selenoproteins
B. Selenoprotein functions
1. Glutathione peroxidases
2. Thioredoxin reductases
3. Deiodinases
4. Selenoprotein P
5. Selenoproteins K and S
6. Other selenoprotein family members
C. The hierarchy of selenoprotein expression
V. Selenoprotein Expression in Immune Tissues and Cells
A. Tissue and cellular distribution under physiological conditions
B. Selenoprotein expression in immune cells and tissues in response to Se changes
C. The selenoproteomic response during immune cell activation
VI. Se and Redox Signaling in Immune Cells
A. An overview
B. Types of ROS important for immune cell signaling
C. Se levels related to the production of ROS in immune cells
D. Se levels related to calcium and redox signaling in immune cells
1. H2O2 as a secondary messenger in leukocyte activation
2. The relationship between Ca2+ flux and oxidative burst
3. The effects of Se intake on Ca2+ flux and redox signaling in T cells
4. Se related to calcium and redox signaling in phagocytes
5. A novel link between Selk and the calpain/calpastatin system
VII. Se and Immune Cell Effector Functions
A. T helper cell differentiation
1. Se and T helper differentiation
2. Regulatory T helper cells
3. Epigenetic poising in naive T helper cells
B. B cell function and antibody production
C. Adherence and migration of leukocytes
1. Expression of adherence molecules
2. Migration
D. Se and eicosinoid synthesis in macrophages
E. Phagocytosis
F. Inflammation linked to ER stress
VIII. Linkages Between Se and Human Disease
A. Se supplementation to boost anti-viral immunity
1. Se levels can affect the virus itself
2. Human immunodeficiency virus 1/acquired immune deficiency syndrome
3. Influenza viruses
4. Poliovirus
B. Critical illness stress-induced immune suppression
C. Systemic inflammatory response syndrome
D. Intestinal inflammation and food-borne illnesses
E. Allergies and asthma
1. Epidemiology
2. Mouse models of allergic asthma
3. Intervention with Se supplementation for patients with asthma
F. Cystic fibrosis
G. Autoimmunity
H. Se supplementation and aging immunity
I. Lymphedema
J. Se supplementation and inflammation associated with diabetes
IX. Can Se Supplementation Be Targeted to the Immune System?
X. Information Gaps and Future Directions
PMCID: PMC3277928  PMID: 21955027
14.  Oxidative Stress, Redox Signaling, and Autophagy: Cell Death Versus Survival 
Antioxidants & Redox Signaling  2014;21(1):66-85.
Significance: The molecular machinery regulating autophagy has started becoming elucidated, and a number of studies have undertaken the task to determine the role of autophagy in cell fate determination within the context of human disease progression. Oxidative stress and redox signaling are also largely involved in the etiology of human diseases, where both survival and cell death signaling cascades have been reported to be modulated by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recent Advances: To date, there is a good understanding of the signaling events regulating autophagy, as well as the signaling processes by which alterations in redox homeostasis are transduced to the activation/regulation of signaling cascades. However, very little is known about the molecular events linking them to the regulation of autophagy. This lack of information has hampered the understanding of the role of oxidative stress and autophagy in human disease progression. Critical Issues: In this review, we will focus on (i) the molecular mechanism by which ROS/RNS generation, redox signaling, and/or oxidative stress/damage alter autophagic flux rates; (ii) the role of autophagy as a cell death process or survival mechanism in response to oxidative stress; and (iii) alternative mechanisms by which autophagy-related signaling regulate mitochondrial function and antioxidant response. Future Directions: Our research efforts should now focus on understanding the molecular basis of events by which autophagy is fine tuned by oxidation/reduction events. This knowledge will enable us to understand the mechanisms by which oxidative stress and autophagy regulate human diseases such as cancer and neurodegenerative disorders. Antioxid. Redox Signal. 21, 66–85.
PMCID: PMC4048575  PMID: 24483238
15.  Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy 
Antioxidants & Redox Signaling  2014;21(1):154-176.
Significance: Skeletal muscle is a highly plastic tissue. Exercise evokes signaling pathways that strongly modify myofiber metabolism and physiological and contractile properties of skeletal muscle. Regular physical activity is beneficial for health and is highly recommended for the prevention of several chronic conditions. In this review, we have focused our attention on the pathways that are known to mediate physical training-induced plasticity. Recent Advances: An important role for redox signaling has recently been proposed in exercise-mediated muscle remodeling and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) activation. Still more currently, autophagy has also been found to be involved in metabolic adaptation to exercise. Critical Issues: Both redox signaling and autophagy are processes with ambivalent effects; they can be detrimental and beneficial, depending on their delicate balance. As such, understanding their role in the chain of events induced by exercise and leading to skeletal muscle remodeling is a very complicated matter. Moreover, the study of the signaling induced by exercise is made even more difficult by the fact that exercise can be performed with several different modalities, with this having different repercussions on adaptation. Future Directions: Unraveling the complexity of the molecular signaling triggered by exercise on skeletal muscle is crucial in order to define the therapeutic potentiality of physical training and to identify new pharmacological compounds that are able to reproduce some beneficial effects of exercise. In evaluating the effect of new “exercise mimetics,” it will also be necessary to take into account the involvement of reactive oxygen species, reactive nitrogen species, and autophagy and their controversial effects. Antioxid. Redox Signal. 21, 154–176.
PMCID: PMC4048572  PMID: 24450966
16.  Autophagy, Redox Signaling, and Ventricular Remodeling 
Antioxidants & Redox Signaling  2009;11(8):1975-1988.
Autophagy is a catabolic process through which damaged or long-lived proteins, macromolecules, or organelles are recycled by using lysosomal degradation machinery. Although the occurrence of autophagy in several cardiac diseases including ischemic or dilated cardiomyopathy, heart failure, hypertrophy, and during ischemia/reperfusion injury have been reported, the exact role of autophagy in these diseases is not known. Emerging studies indicate that oxidative stress in cellular system could induce autophagy, and oxidatively modified macromolecules and organelles can be selectively removed by autophagy. Mild oxidative stress–induced autophagy could provide the first line of protection against major damage like apoptosis and necrosis. Cardiac-specific loss of Atg5, an autophagic gene involved in the formation of autophagosome, causes cardiac hypertrophy, left ventricular dilation, and contractile dysfunction. Recently, it was revealed that Atg4, another autophagic gene involved in the formation of autophagosomes, is controlled through redox regulation under the condition of starvation-induced autophagy. In this review, we discuss the function of autophagy in association with oxidative stress and redox signaling in the remodeling of cardiac myocardium. Further research is needed to explore the possibilities of redox regulation of other autophagic genes and the role of redox signaling–mediated autophagy in the heart. Antioxid. Redox Signal. 11, 1975–1988.
PMCID: PMC2848474  PMID: 19327038
17.  Lipid Rafts and Caveolae and Their Role in Compartmentation of Redox Signaling 
Antioxidants & Redox Signaling  2009;11(6):1357-1372.
Membrane (lipid) rafts and caveolae, a subset of rafts, are cellular domains that concentrate plasma membrane proteins and lipids involved in the regulation of cell function. In addition to providing signaling platforms for G-protein-coupled receptors and certain tyrosine kinase receptors, rafts/caveolae can influence redox signaling. This review discusses molecular characteristics of and methods to study rafts/caveolae, determinants that contribute to the localization of molecules in these entities, an overview of signaling molecules that show such localization, and the contribution of rafts/caveolae to redox signaling. Of particular note is the evidence that endothelial nitric oxide synthase (eNOS), NADPH oxygenase, and heme oxygenase, along with other less well-studied redox systems, localize in rafts and caveolae. The precise basis for this localization and the contribution of raft/caveolae-localized redox components to physiology and disease are important issues for future studies. Antioxid. Redox Signal. 11, 1357–1372.
PMCID: PMC2757136  PMID: 19061440
18.  Redox Signaling and the Innate Immune System in Alcoholic Liver Disease 
Antioxidants & Redox Signaling  2011;15(2):523-534.
The development of alcoholic liver disease (ALD) is a complex process involving both parenchymal and nonparenchymal cells resident in the liver. Although the mechanisms for ALD are not completely understood, it is clear that increased oxidative stress, and activation of the innate immune system are essential elements in the pathophysiology of ALD. Oxidative stress from ethanol exposure results from increased generation of reactive oxygen species and decreased hepatocellular antioxidant activity, including changes in the thioredoxin/peroxiredoxin family of proteins. Both cellular and circulating components of the innate immune system are activated by exposure to ethanol. For example, ethanol exposure enhances toll-like receptor-4 (TLR-4)-dependent cytokine expression by Kupffer cells, likely due, at least in part, to dysregulation of redox signaling. Similarly, complement activation in response to ethanol leads to increased production of the anaphylatoxins, C3a and C5a, and activation C3a receptor and C5a receptor. Complement activation thus contributes to increased inflammatory cytokine production and can influence redox signaling. Here we will review recent progress in understanding the interactions between oxidative stress and innate immunity in ALD. These data illustrate that ethanol-induced oxidative stress and activation of the innate immune system interact dynamically during ethanol exposure, exacerbating ethanol-induced liver injury. Antioxid. Redox Signal. 15, 523–534.
PMCID: PMC3118704  PMID: 21126203
19.  The Role of Redox Signaling in Epigenetics and Cardiovascular Disease 
Antioxidants & Redox Signaling  2013;18(15):1920-1936.
Significance: The term epigenetics refers to the changes in the phenotype and gene expression that occur without alterations in the DNA sequence. There is a rapidly growing body of evidence that epigenetic modifications are involved in the pathological mechanisms of many cardiovascular diseases (CVDs), which intersect with many of the pathways involved in oxidative stress. Recent Advances: Most studies relating epigenetics and human pathologies have focused on cancer. There has been a limited study of epigenetic mechanisms in CVDs. Although CVDs have multiple established genetic and environmental risk factors, these explain only a portion of the total CVD risk. The epigenetic perspective is beginning to shed new light on how the environment influences gene expression and disease susceptibility in CVDs. Known epigenetic changes contributing to CVD include hypomethylation in proliferating vascular smooth muscle cells in atherosclerosis, changes in estrogen receptor-α (ER-α) and ER-β methylation in vascular disease, decreased superoxide dismutase 2 expression in pulmonary hypertension (PH), as well as trimethylation of histones H3K4 and H3K9 in congestive heart failure. Critical Issues: In this review, we discuss the epigenetic modifications in CVDs, including atherosclerosis, congestive heart failure, hypertension, and PH, with a focus on altered redox signaling. Future Directions: As advances in both the methodology and technology accelerate the study of epigenetic modifications, the critical role they play in CVD is beginning to emerge. A fundamental question in the field of epigenetics is to understand the biochemical mechanisms underlying reactive oxygen species-dependent regulation of epigenetic modification. Antioxid. Redox Signal. 18, 1920–1936.
PMCID: PMC3624767  PMID: 23480168
20.  Mechanotransduction: Forces, Sensors, and Redox Signaling 
Antioxidants & Redox Signaling  2014;20(6):868-871.
Mechanotransduction describes the molecular mechanisms by which cells response to changes in their physical environment by translating mechanical stimuli into biochemical signals. It is now clear that reactive oxygen species (ROS) and redox signaling play a crucial role in mechanotransduction analogous to their role in chemotransduction. This Forum has particular emphasis on ROS generation with altered mechanical stress, the upstream signal transduction pathways that initiate ROS production, and the downstream effectors that lead to physiological responses. There is particular emphasis on the role of ion channels in the initial response and the role of NADPH oxidases as the major source of ROS. The latter enzyme serves as the fulcrum of the mechanotransduction cascade. Although it seems likely that all cells are mechanosensitive to some degree, we have highlighted the responses of unicellular organisms (bacteria), bone cells, and particularly cells of the vasculature (endothelial cells and vascular smooth muscle cells). These cell types have been useful for studying the responses to altered osmotic pressure, hemodynamic pressure, shear stress, and compressive forces while exploring the link between signal transduction and physiological/pathophysiological responses. Antioxid. Redox Signal. 20, 868–871.
PMCID: PMC3924810  PMID: 24354342
21.  Posttranslational Modification of Cysteine in Redox Signaling and Oxidative Stress: Focus on S-Glutathionylation 
Antioxidants & Redox Signaling  2012;16(6):471-475.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have become recognized as second messengers for initiating and/or regulating vital cellular signaling pathways, and they are known also as deleterious mediators of cellular stress and cell death. ROS and RNS, and their cross products like peroxynitrite, react primarily with cysteine residues whose oxidative modification leads to functional alterations in the proteins. In this Forum, the collection of six review articles presents a perspective on the broad biological impact of cysteine modifications in health and disease from the molecular to the cellular and organismal levels, focusing in particular on reversible protein-S-glutathionylation and its central role in transducing redox signals as well as protecting proteins from irreversible cysteine oxidation. The Forum review articles consider the role of S-glutationylation in regulation of the peroxiredoxin enzymes, the special redox environment of the mitochondria, redox regulation pertinent to the function of the cardiovascular system, mechanisms of redox-activated apoptosis in the pulmonary system, and the role of glutathionylation in the initiation, propagation, and treatment of neurodegenerative diseases. Several common themes emerge from these reviews; notably, the probability of crosstalk between signaling/regulation mechanisms involving protein-S-nitrosylation and protein-S-glutathionylation, and the need for quantitative analysis of the relationship between specific cysteine modifications and corresponding functional changes in various cellular contexts. Antioxid. Redox Signal. 16, 471–475.
PMCID: PMC3270050  PMID: 22136616
22.  Lipid rafts and caveolae and their role in compartmentation of redox signaling 
Antioxidants & redox signaling  2009;11(6):1357-1372.
Membrane (lipid) rafts and caveolae, a subset of rafts, are cellular domains that concentrate plasma membrane proteins and lipids involved in the regulation of cell function. In addition to providing signaling platforms for G-protein-coupled receptors and certain tyrosine kinase receptors, rafts/caveolae can influence redox signaling. This review discusses molecular characteristics of and methods to study rafts/caveolae, determinants that contribute to the localization of molecules in these entities, an overview of signaling molecules that show such localization, and the contribution of rafts/caveolae to redox signaling. Of particular note is the evidence that endothelial nitric oxide synthase (eNOS), NADPH oxygenase and heme oxygenase, along with other less well-studied redox systems, localize in rafts and caveolae. The precise basis for this localization and the contribution of raft/caveolae-localized redox components to physiology and disease are important issues for future studies.
PMCID: PMC2757136  PMID: 19061440
23.  Antioxidants, Redox Signaling, and Pathophysiology in Schizophrenia: An Integrative View 
Antioxidants & Redox Signaling  2011;15(7):2011-2035.
Schizophrenia (SZ) is a brain disorder that has been intensively studied for over a century; yet, its etiology and multifactorial pathophysiology remain a puzzle. However, significant advances have been made in identifying numerous abnormalities in key biochemical systems. One among these is the antioxidant defense system (AODS) and redox signaling. This review summarizes the findings to date in human studies. The evidence can be broadly clustered into three major themes: perturbations in AODS, relationships between AODS alterations and other systems (i.e., membrane structure, immune function, and neurotransmission), and clinical implications. These domains of AODS have been examined in samples from both the central nervous system and peripheral tissues. Findings in patients with SZ include decreased nonenzymatic antioxidants, increased lipid peroxides and nitric oxides, and homeostatic imbalance of purine catabolism. Reductions of plasma antioxidant capacity are seen in patients with chronic illness as well as early in the course of SZ. Notably, these data indicate that many AODS alterations are independent of treatment effects. Moreover, there is burgeoning evidence indicating a link among oxidative stress, membrane defects, immune dysfunction, and multineurotransmitter pathologies in SZ. Finally, the body of evidence reviewed herein provides a theoretical rationale for the development of novel treatment approaches. Antioxid. Redox Signal. 15, 2011–2035.
PMCID: PMC3159108  PMID: 21126177
24.  Role of the Multifunctional DNA Repair and Redox Signaling Protein Ape1/Ref-1 in Cancer and Endothelial Cells: Small-Molecule Inhibition of the Redox Function of Ape1 
Antioxidants & Redox Signaling  2008;10(11):1853-1867.
The DNA base excision-repair pathway is responsible for the repair of DNA damage caused by oxidation/alkylation and protects cells against the effects of endogenous and exogenous agents. Removal of the damaged base creates a baseless (AP) site. AP endonuclease1 (Ape1) acts on this site to continue the BER-pathway repair. Failure to repair baseless sites leads to DNA strand breaks and cytotoxicity. In addition to the repair role of Ape1, it also functions as a major redox-signaling factor to reduce and activate transcription factors such as AP1, p53, HIF-1α, and others that control the expression of genes important for cell survival and cancer promotion and progression. Thus, the Ape1 protein interacts with proteins involved in DNA repair, growth-signaling pathways, and pathways involved in tumor promotion and progression. Although knockdown studies with siRNA have been informative in studying the role of Ape1 in both normal and cancer cells, knocking down Ape1 does not reveal the individual role of the redox or repair functions of Ape1. The identification of small-molecule inhibitors of specific Ape1 functions is critical for mechanistic studies and translational applications. Here we discuss small-molecule inhibition of Ape1 redox and its effect on both cancer and endothelial cells. Antioxid. Redox Signal. 10, 1853–1867.
PMCID: PMC2587278  PMID: 18627350
25.  Oxidant and Redox Signaling in Vascular Oxygen Sensing: Implications for Systemic and Pulmonary Hypertension 
Antioxidants & Redox Signaling  2008;10(6):1137-1152.
It has been well known for >100 years that systemic blood vessels dilate in response to decreases in oxygen tension (hypoxia; low Po2), and this response appears to be critical to supply blood to the stressed organ. Conversely, pulmonary vessels constrict to a decrease in alveolar Po2 to maintain a balance in the ventilation-to-perfusion ratio. Currently, although little question exists that the Po2 affects vascular reactivity and vascular smooth muscle cells (VSMCs) act as oxygen sensors, the molecular mechanisms involved in modulating the vascular reactivity are still not clearly understood. Many laboratories, including ours, have suggested that the intracellular calcium concentration ([Ca2+ ]i), which regulates vasomotor function, is controlled by free radicals and redox signaling, including NAD(P)H and glutathione (GSH) redox. In this review article, therefore, we discuss the implications of redox and oxidant alterations seen in pulmonary and systemic hypertension, and how key targets that control [Ca2+ ]i, such as ion channels, Ca2+ release from internal stores and uptake by the sarcoplasmic reticulum, and the Ca2+ sensitivity to the myofilaments, are regulated by changes in intracellular redox and oxidants associated with vascular Po2 sensing in physiologic or pathophysiologic conditions. Antioxid. Redox Signal. 10, 1137–1152.
PMCID: PMC2443404  PMID: 18315496

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