Showing papers in "Antioxidants & Redox Signaling in 2006"

Redefining oxidative stress.

Abstract: Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants, which can be quantified in humans as the redox state of plasma GSH/GSSG. Plasma GSH redox in humans becomes oxidized with age, in response to oxidative stress (chemotherapy, smoking), and in common diseases (type 2 diabetes, cardiovascular disease). However, data also show that redox of plasma GSH/GSSG is not equilibrated with the larger plasma cysteine/cystine (Cys/CySS) pool, indicating that the "balance" of pro-oxidants and antioxidants cannot be defined by a single entity. The major cellular thiol/disulfide systems, including GSH/GSSG, thioredoxin- 1 (-SH2/-SS-), and Cys/CySS, are not in redox equilibrium and respond differently to chemical toxicants and physiologic stimuli. Individual signaling and control events occur through discrete redox pathways rather than through mechanisms that are directly responsive to a global thiol/disulfide balance such as that conceptualized in the common definition of oxidative stress. ...

Hydrogen peroxide: a signaling messenger.

Abstract: Hydrogen peroxide (H2O2) is a well-documented component of living cells. It plays important roles in host defense and oxidative biosynthetic reactions. In addition there is growing evidence that at low levels, H2O2 also functions as a signaling agent, particularly in higher organisms. This review evaluates the evidence that H2O2 functions as a signaling agent in higher organisms in light of the known biology and biochemistry of H2O2. All aerobic organisms studied to date from prokaryotes to humans appear to tightly regulate their intracellular H2O2 concentrations at relatively similar levels. Multiple biochemical strategies for rapidly reacting with these low endogenous levels of H2O2 have been elucidated from the study of peroxidases and catalases. Welldefined biochemical pathways involved in the response to exogenous H2O2 have been described in both prokaryotes and yeast. In animals and plants, regulated enzymatic systems for generating H2O2 have been described. In addition oxidation-dependent steps in ...

Reactive oxygen species-induced activation of the MAP kinase signaling pathways.

Abstract: An abundance of scientific literature exists demonstrating that oxidative stress influences the MAPK signaling pathways. This review summarizes these findings for the ERK, JNK, p38, and BMK1 pathways. For each of these different MAPK signaling pathways, the following is reviewed: the proteins involved in the signaling pathways, how oxidative stress can activate cellular signaling via these pathways, the types of oxidative stress that are known to induce activation of the different pathways, and the specific cell types in which oxidants induce MAPK responses. In addition, the functional outcome of oxidative stress-induced activation of these pathways is discussed. The purpose of this review is to provide the reader with an overall understanding and appreciation of oxidative stress-induced MAPK signaling.

NADPH oxidases in cardiovascular health and disease.

Abstract: Increased oxidative stress plays an important role in the pathophysiology of cardiovascular diseases such as hypertension, atherosclerosis, diabetes, cardiac hypertrophy, heart failure, and ischemia–reperfusion. Although several sources of reactive oxygen species (ROS) may be involved, a family of NADPH oxidases appears to be especially important for redox signaling and may be amenable to specific therapeutic targeting. These include the prototypic Nox2 isoform-based NADPH oxidase, which was first characterized in neutrophils, as well as other NADPH oxidases such as Nox1 and Nox4. These Nox isoforms are expressed in a cell- and tissue-specific fashion, are subject to independent activation and regulation, and may subserve distinct functions. This article reviews the potential roles of NADPH oxidases in both cardiovascular physiological processes (such as the regulation of vascular tone and oxygen sensing) and pathophysiological processes such as endothelial dysfunction, inflammation, hypertrophy, apoptosi...

The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control.

Abstract: The endoplasmic reticulum (ER) plays a major role in regulating synthesis, folding, and orderly transport of proteins. It is also essentially involved in various cellular signaling processes, primarily by its function as a dynamic Ca(2+) store. Compared to the cytosol, oxidizing conditions are found in the ER that allow oxidation of cysteine residues in nascent polypeptide chains to form intramolecular disulfide bonds. However, compounds and enzymes such as PDI that catalyze disulfide bonds become reduced and have to be reoxidized for further catalytic cycles. A number of enzymes, among them products of the ERO1 gene, appear to provide oxidizing equivalents, and oxygen appears to be the final oxidant in aerobic living organisms. Thus, protein oxidation in the ER is connected with generation of reactive oxygen species (ROS). Changes in the redox state and the presence of ROS also affect the Ca(2+) homeostasis by modulating the functionality of ER-based channels and buffering chaperones. In addition, a close relationship exists between oxidative stress and ER stress, which both may activate signaling events leading to a rebalance of folding capacity and folding demand or to cell death. Thus, redox homeostasis appears to be a prerequisite for proper functioning of the ER.

Oxidative Stress and Autophagy

Abstract: Organisms respond to oxidative injury by orchestrating a stress response to prevent further damage. An increase in the intracellular levels of antioxidant agents, and at the same time the removal of already damaged components, are both part of the oxidative stress response. Lysosomes have been classically considered one of the main targets of the reactive oxygen species. In fact, the destabilization of the lysosomal membrane during oxidizing conditions promotes the leakage of the enzymes contained in these organelles and contributes to cellular damage. However, recent evidence supports a protective role of the lysosomal system, which can eliminate altered intracellular components through autophagy, at least in the first stages of oxidative injury. Consequently, activation of the main intracellular proteolytic systems, the ubiquitin/proteasome, and also the lysosomal/autophagic system occurs during the oxidative stress response. The opposing roles for the lysosomal system under oxidizing conditions are dis...

NADPH oxidases in the kidney.

Abstract: NADPH oxidases have a distinct cellular localization in the kidney. Reactive oxygen species (ROS) are produced in the kidney by fibroblasts, endothelial cells (EC), vascular smooth muscle cells (VSMC), mesangial cells (MCs), tubular cells, and podocyte cells. All components of the phagocytic NADPH oxidase, as well as the Nox-1 and -4, are expressed in the kidney, with a prominent expression in renal vessels, glomeruli, and podocytes, and cells of the thick ascending limb of the loop of Henle (TAL), macula densa, distal tubules, collecting ducts, and cortical interstitial fibroblasts. NADPH oxidase activity is upregulated by prolonged infusion of angiotensin II (Ang II) or a high salt diet. Since these are major factors underlying the development of hypertension, renal NADPH oxidase may have an important pathophysiological role. Indeed, recent studies with small interference RNAs (siRNAs) targeted to p22 phox implicate p22 phox in Ang II-induced activation of renal NADPH oxidase and the development of oxid...

Nrf2 defends the lung from oxidative stress.

Abstract: Nuclear factor, erythroid 2 related factor 2 (Nrf2) belongs to the Cap'n'collar/basic region leucine zipper (CNC-bZIP) transcription factor family, and is activated by diverse oxidants, pro-oxidants, antioxidants, and chemopreventive agents. After phosphorylation and dissociation from the cytoplasmic inhibitor, Kelch-like ECH-associated protein 1 (Keap1), Nrf2 translocates to the nucleus and binds to an antioxidant response element (ARE). Through transcriptional induction of ARE-bearing genes that encode antioxidant-detoxifying proteins, Nrf2 activates cellular rescue pathways against oxidative injury, inflammation/immunity, apoptosis, and carcinogenesis. ARE-driven genes include direct antioxidants (e.g., GPx), thiol metabolism-associated detoxifying enzymes (e.g., GSTs), stress-response genes (e.g., HO-1), and others (e.g., PSMB5). Application of nrf2 germ-line mutant mice elucidated protective roles for Nrf2 in various models of human disorders in the liver, lung, kidney, brain, and circulation. In the...

The Molecular Inflammatory Process in Aging

Abstract: Emerging pathological evidence indicates that major chronic aging-related diseases such as atherosclerosis, arthritis, dementia, osteoporosis, and cardiovascular diseases, are inflammation-related. In this review, inflammation is examined as a possible underlying basis for the molecular alterations that link aging and age-related pathological processes. A proposal for the molecular inflammation hypothesis of the aging views the redox derangement that occurs during aging as the major factor for increased risk for age-related inflammation. Accumulated data strongly indicate the activation of redox-sensitive transcription factors and dysregulated gene expression under the age-related oxidative stress seems to be the major culprits. Key players involved in the inflammatory process are the age-related upregulation of NF-kappaB, IL-1beta, IL-6, TNFalpha, cyclooxygenase-2, adhesion molecules, and inducible NO synthase. Furthermore, data are presented on the molecular events involved in age-related NF-kappaB activation and phosphorylation by IkappaB kinase/NIK and MAPKs. Experimental data on anti-aging calorie restriction (CR) for its antiinflammatory efficacy by suppressing the upregulated proinflammatory mediators will be reviewed. Also, the involvement of another super family of transcription factors, PPARs (PPARalpha, gamma) as regulators of proinflammatory responses and NF-kappaB signaling pathway is described as well as a discussion on the physiological significance of a well-maintained balance between NF-kappaB and PPARs.

The Many Faces of Glutathione in Bacteria

Abstract: Glutathione is one of the most abundant thiols present in cyanobacteria and proteobacteria, and in all mitochondria or chloroplast-bearing eukaryotes. In bacteria, in addition to its key role in maintaining the proper oxidation state of protein thiols, glutathione also serves a key function in protecting the cell from the action of low pH, chlorine compounds, and oxidative and osmotic stresses. Moreover, glutathione has emerged as a posttranslational regulator of protein function under conditions of oxidative stress, by the direct modification of proteins via glutathionylation. This review summarizes the biosynthesis and function of glutathione in bacteria from physiological and biotechnological standpoints.

Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications.

Abstract: In this review, the impacts of mitochondrial reactive oxygen species (ROS) on diabetes and its complications are described. In endothelial cells, high-glucose treatment increases mitochondrial ROS and normalization of the ROS production by inhibitors of mitochondrial metabolism, or by overexpression of UCP-1 or MnSOD, prevents glucose-induced activation of PKC, formation of AGE, and accumulation of sorbitol, all of which are believed to be the main molecular mechanisms of diabetic complications. Glomerular hyperfiltration, one of the characteristics of early diabetic nephropathy, may be caused by mitochondrial ROS through activation of COX-2 gene transcription, followed by PGE2 overproduction. In pancreatic beta cells, hyperglycemia also increases mitochondrial ROS, which suppresses the first phase of glucose-induced insulin secretion, at least in part, through the suppression of GAPDH activity. In liver cells, similar to that in hyperglycemia, TNF-alpha increases mitochondrial ROS, which in turn activates apoptosis signal-regulating kinase 1 (ASK1) and c-jun NH2-terminal kinases (JNK), increases serine phosphorylation of IRS-1, and decreases insulin-stimulated tyrosine phosphorylation of IRS-1, leading to insulin resistance. These results suggest the importance of mitochondrial ROS in the pathogenesis of diabetes mellitus and its complications through modification of various cellular events in many tissues, including vessels, kidney, pancreatic beta cells, and liver.

Reactive oxygen species signaling in plants.

Abstract: The evolution of aerobic metabolism such as respiration and photosynthesis resulted in the generation of reactive oxygen species (ROS). A common property of all ROS types is that they can cause oxidative damage to proteins, DNA, and lipids. This toxicity of ROS explains the evolution of complex arrays of nonenzymatic and enzymatic detoxification mechanisms in plants. However, increasing evidence indicates that plants also make use of ROS as signaling molecules for regulating development and various physiological responses. In this review, novel insights into the mechanisms of how plants sense and respond to ROS are discussed in the context of the biological effects and functions of ROS in plants.

NADPH oxidases of the brain: distribution, regulation, and function.

Abstract: The NADPH oxidase is a multi-subunit enzyme that catalyzes the reduction of molecular oxygen to form superoxide (O2 •−). While classically linked to the respiratory burst in neutrophils, recent evidence now shows that O2 •− (and associated reactive oxygen species, ROS) generated by NADPH oxidase in nonphagocytic cells serves myriad functions in health and disease. An entire new family of NADPH Oxidase (Nox) homologues has emerged, which vary widely in cell and tissue distribution, as well as in function and regulation. Amajor concept in redox signaling is that while NADPH oxidase-derived ROS are necessary for normal cellular function, excessive oxidative stress can contribute to pathological disease. This certainly is true in the central nervous system (CNS), where normal NADPH oxidase function appears to be required for processes such as neuronal signaling, memory, and central cardiovascular homeostasis, but overproduction of ROS contributes to neurotoxicity, neurodegeneration, and cardiovascular disease...

Nrf2: a potential molecular target for cancer chemoprevention by natural compounds.

Abstract: One of the most prominent strategies of cancer chemoprevention might be protecting cells or tissues against various carcinogens and carcinogenic metabolites derived from exogenous or endogenous sources. This protection could be achieved through the induction of phase 2 detoxifying enzymes and antioxidant enzymes such as glutathione S-transferase, NAD(P)H quinone oxidoreductase 1, and heme oxygenase-1, a process that is mediated mainly by the antioxidant response elements (ARE) within the promoter regions of these genes. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap 'n' collar (CNC) family of basic regionleucine zipper transcription factors, plays a key role in ARE-mediated gene expression. Under normal condition, Nrf2 is sequestered in the cytoplasm by an actin-binding protein, Kelch-like ECH associating protein 1 (Keap1), and upon exposure of cells to inducers such as oxidative stress and certain chemopreventive agents, Nrf2 dissociates from Keap1, translocates to the nucleus, b...

Oxidative Stress, Accumulation of Biological 'Garbage', and Aging

Abstract: Normal metabolism is associated with unavoidable mild oxidative stress resulting in biomolecular damage that cannot be totally repaired or removed by cellular degradative systems, including lysosomes, proteasomes, and cytosolic and mitochondrial proteases. Consequently, irreversibly damaged and functionally defective structures (biological 'garbage') accumulate within long-lived postmitotic cells, such as cardiac myocytes and neurons, leading to progressive loss of adaptability and increased probability of death and characterizing a process called aging, or senescence. Intralysosomal 'garbage' is represented by lipofuscin (age pigment), an undegradable autophagocytosed material, while extralysosomal 'garbage' involves oxidatively modified cytosolic proteins, altered biomembranes, defective mitochondria and other organelles. In aged postmitotic cells, heavily lipofuscin-loaded lysosomes perform poorly, resulting in the enhanced accumulation of defective mitochondria, which in turn produce more reactive oxygen species causing additional damage (the mitochondrial-lysosomal axis theory). Potential anti-aging strategies may involve not only overall reduction of oxidative stress, but also the use of intralysosomal iron chelators hampering Fenton-type chemistry as well as the stimulation of cellular degradative systems.

A high glycolytic flux supports the proliferative potential of murine embryonic stem cells.

Abstract: Embryonic stem (ES) cells are immortal and present the ability to self-renew while retaining their ability to differentiate. In contrast, most primary cells possess a limited proliferative potentia...

Hydrogen sulfide protects HT22 neuronal cells from oxidative stress.

Abstract: Hydrogen sulfide (H2S) is a neuromodulator in the brain and a relaxant for smooth muscle. H2S protects primary cortical neurons from oxidative stress by increasing the intracellular concentrations of glutathione, the major antioxidant in cells. However, changes in glutathione alone are not sufficient to account for full protection in all types of nerve cells. H2S is here shown to protect an immortalized mouse hippocampal cell line from oxidative glutamate toxicity by activating ATP-dependent K+ (KATP) and Cl− channels, in addition to increasing the levels of glutathione. The present study therefore identifies a novel pathway for H2S protection from oxidative stress.

Oxidative damage in Huntington's disease pathogenesis.

Abstract: Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the progressive development of involuntary choreiform movements, cognitive impairment, neuropsychiatric symptoms, and premature death. These phenotypes reflect neuronal dysfunction and ultimately death in selected brain regions, the striatum and cerebral cortex being principal targets. The genetic mutation responsible for the HD phenotype is known, and its protein product, mutant huntingtin (mhtt), identified. HD is one of several "triplet repeat" diseases, in which abnormal expansions in trinucleotide repeat domains lead to elongated polyglutamine stretches in the affected gene's protein product. Mutant htt-mediated toxicity in the brain disrupts a number of vital cellular processes in the course of disease progression, including energy metabolism, gene transcription, clathrin-dependent endocytosis, intraneuronal trafficking, and postsynaptic signaling, but the crucial initiation mechanism induced by mhtt is still uncl...

Redox-Sensitive Kinases of the Nuclear Factor-κB Signaling Pathway

Abstract: NF-kappaB is an inducible transcription factor that plays a role in the expression of over one hundred genes involved in immunity, inflammation, proliferation, and in defense against apoptosis. NF-kappaB has been known to be redox regulated for some time and is a direct target for oxidation that can affect its ability to bind to DNA. Reactive oxygen species (ROS) have been identified as second messengers in cells, and play a role in receptor signaling and posttranslation modification of signaling molecules. These posttranslation modifications include oxidations of critical cysteines to sulfenic acids or mixed disulfides, which can affect the activity of proteins. Many kinases involved in direct or indirect activation of NF-kappaB are affected by oxidants and therefore, have the potential to alter NF-kappaB activity. This review will provide a summary of the NF-kappaB family, their activation and regulation, followed by a summary of cytoplasmic and nuclear kinases in this pathway whose activity is affected by oxidants. Additionally, recent investigations have revealed that the JNK signaling pathway, which is known to be redox regulated, and pro-apoptotic, is inhibited by NF-kappaB signaling. The crosstalk of NF-kappaB with other signaling pathways is therefore critical for cellular fate, notably survival or cell death under oxidative conditions, and will also be reviewed.

Regulation of inducible nitric oxide synthase gene in glial cells.

Abstract: Elevated levels of NO produced within the central nervous system (CNS) are associated with the pathogenesis of neuroinflammatory and neurodegenerative human diseases such as multiple sclerosis, HIV dementia, brain ischemia, trauma, Parkinson's disease, and Alzheimer's disease. Resident glial cells in the CNS (astroglia and microglia) express inducible nitric oxide synthase (iNOS) and produce high levels of NO in response to a wide variety of proinflammatory and degenerative stimuli. Although pathways resulting in the expression of iNOS may vary in two different glial cells of different species, the intracellular signaling events required for the expression of iNOS in these cells are slowly becoming clear. Various signaling cascades converge to activate several transcription factors that control the transcription of iNOS in glial cells. The present review summarizes different results and discusses current understandings about signaling mechanisms for the induction of iNOS expression in activated glial cells. A complete understanding of the regulation of iNOS expression in glial cells is expected to identify novel targets for therapeutic intervention in NO-mediated neurological disorders.

Sources and Targets of Reactive Oxygen Species in Synaptic Plasticity and Memory

Abstract: Increasing evidence suggests that reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, act as necessary signaling molecules in processes underlying cognition. Moreover, ROS have been shown to be necessary in molecular process underlying signal transduction, synaptic plasticity, and memory formation. Research from several laboratories suggests that NADPH oxidase is an important source of superoxide in the brain. Evidence is presented here to show that ROS are in fact important signaling molecules involved in synaptic plasticity and memory formation. Moreover, evidence that the NADPH oxidase complex is a key regulator of ROS generation in synaptic plasticity and memory formation is discussed. Understanding redox signaling in the brain, including the sources and molecular targets of ROS, are important for a full understanding of the signaling pathways that underlie synaptic plasticity and memory. Knowledge of ROS function in the brain also is critical for understanding aging and neurodegenerative diseases of the brain given that several of these disorders, including Alzheimer's disease and Parkinson disease, may be exacerbated by the unregulated generation of ROS.

Zinc coordination environments in proteins as redox sensors and signal transducers.

Abstract: Zinc/cysteine coordination environments in proteins are redox-active. Oxidation of the sulfur ligands mobilizes zinc, while reduction of the oxidized ligands enhances zinc binding, providing redox control over the availability of zinc ions. Some zinc proteins are redox sensors, in which zinc release is coupled to conformational changes that control varied functions such as enzymatic activity, binding interactions, and molecular chaperone activity. Whereas the released zinc ion in redox sensors has no known function, the redox signal is transduced to specific and sensitive zinc signals in redox transducers. Released zinc can bind to sites on other proteins and modulate signal transduction, generation of metabolic energy, mitochondrial function, and gene expression. The paradigm of such redox transducers is the zinc protein metallothionein, which, together with its apoprotein, thionein, functions at a central node in cellular signaling by redistributing cellular zinc, presiding over the availability of zinc, and interconverting redox and zinc signals. In this regard, the transduction of nitric oxide (NO) signals into zinc signals by metallothionein has received particular attention. It appears that redox-inert zinc has been chosen to control some aspects of cellular thiol/disulfide redox metabolism. Tight control of zinc is essential for redox homeostasis because both increases and decreases of cellular zinc elicit oxidative stress. Depending on its availability, zinc can be cytoprotective as a pro-antioxidant or cytotoxic as a pro-oxidant. Any condition with acute or chronic oxidative stress is expected to perturb zinc homeostasis.

The mechanistic basis of infarct healing.

Abstract: Myocardial infarction triggers an inflammatory cascade that results in healing and replacement of the damaged tissue with scar. Cardiomyocyte necrosis triggers innate immune mechanisms eliciting Toll-like receptor– mediated responses, activating the complement cascade and generating reactive oxygen species. Subsequent activation of NF-κB is a critical element in the regulation of cytokine, chemokine, and adhesion molecule expression in the ischemic myocardium. Chemokine induction mediates leukocyte recruitment in the myocardium. Pleiotropic proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, are also upregulated in the infarct and exert a wide range of effects on a variety of cell types. Timely repression of proinflammatory gene synthesis is crucial for optimal healing; IL-10 and TGF-β-mediated pathways may be important for suppression of chemokine and cytokine expression and for resolution of the leukocytic infiltrate. In addition, TGF-β may be critically involved in inducing myofibroblast differen...

Involvement of oxidative stress in the pathogenesis of diabetes.

Abstract: Pancreatic beta-cell failure is the common characteristic of type 1 and type 2 diabetes. Type 1 diabetes is induced by pancreatic beta-cell destruction, which is mediated by an autoimmune mechanism and consequent inflammatory process. Various inflammatory cytokines and oxidative stress produced by islet-infiltrating immune cells have been proposed to play an important role in mediating the destruction of beta cells. The JNK pathway is also activated by such cytokines and oxidative stress and is involved in beta-cell destruction. Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates, and insulin resistance is aggravated. This process is called "glucose toxicity." Under such conditions, oxidative stress is provoked, and the JNK pathway is activated, which is likely involved in pancreatic beta-cell dysfunction and insulin resistance. In addition, oxidative stress and activation of the JNK pathway are involved in the progression of atherosclerosis, which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress and subsequent activation of the JNK pathway are involved in the pathogenesis of type 1 and type 2 diabetes.

Is the Mitochondrial Free Radical Theory of Aging Intact

Abstract: The present state of the mitochondrial free radical theory of aging is reviewed. Available studies do not support the hypothesis that antioxidants control the rate of aging because: (a) they correlate inversely with maximum longevity in vertebrates, and (b) increasing their concentration by different methods does not increase maximum lifespan. On the other hand, comparative studies consistently show that long-lived mammals and birds have low rates of mitochondrial reactive oxygen species (ROS) production and low levels of oxidative damage in their mitochondrial DNA. Furthermore, caloric restriction, which extends longevity, also decreases mitochondrial ROS production at complex I and lowers mtDNA oxidative damage. Recent data show that these changes can also be obtained with protein restriction without strong caloric restriction. Another trait of long-lived mammals and birds is the possession of low degrees of unsaturation in their cellular membranes. This is mainly due to minimizing the presence of highl...

Protein Oxidation and Lipid Peroxidation in Brain of Subjects with Alzheimer's Disease: Insights into Mechanism of Neurodegeneration from Redox Proteomics

Abstract: Alzheimer's disease (AD), the leading cause of dementia, involves regionalized neuronal death, synaptic loss, and an accumulation of intraneuronal, neurofibrillary tangles and extracellular senile plaques. Although the initiating causes leading to AD are unknown, a number of previous studies reported the role of oxidative stress in AD brain. Postmortem analysis of AD brain showed elevated markers of oxidative stress including protein nitrotyrosine, carbonyls in proteins, lipid oxidation products, and oxidized DNA bases. In this review, we focus our attention on the role of protein oxidation and lipid peroxidation in the pathogenesis of AD. Particular attention is given to the current knowledge about the redox proteomics identification of oxidatively modified proteins in AD brain.

NOX2 and NOX4 mediate proliferative response in endothelial cells.

Abstract: Increased levels of reactive oxygen species (ROS) contribute to many cardiovascular diseases. In neutrophils, ROS are generated by a NADPH oxidase containing p22phox and NOX2. NADPH oxidases are also major sources of vascular ROS. Whereas an active NOX2-containing enzyme has been described in endothelial cells, the contribution of recently identified NOX homologues to endothelial ROS production and proliferation has been controversial. The authors, therefore, compared the role of NOX2 with NOX4 and NOX1 in endothelial EaHy926 and human microvascular endothelial cells. NOX2 and NOX4 were abundantly expressed, whereas NOX1 expression was less prominent. NOX2, NOX4, and NOX1 were simultaneously present in a single cell in a perinuclear compartment. NOX2 and NOX4 co-localized with the endoplasmic reticulum (ER) marker calreticulin. Additionally, NOX2 co-localized with F-actin at the plasma membrane. NOX2 and NOX4, which interacted with p22phox, as was shown by bimolecular fluorescent complementation, contribu...

Mechanisms and Significance of Eryptosis

Abstract: Suicidal death of erythrocytes (eryptosis) is characterized by cell shrinkage, membrane blebbing, activation of proteases, and phosphatidylserine exposure at the outer membrane leaflet. Exposed phosphatidylserine is recognized by macrophages that engulf and degrade the affected cells. Eryptosis is triggered by erythrocyte injury after several stressors, including oxidative stress. Besides caspase activation after oxidative stress, two signaling pathways converge to trigger eryptosis: (a) formation of prostaglandin E2 leads to activation of Ca2+-permeable cation channels, and (b) the phospholipase A2–mediated release of platelet-activating factor activates a sphingomyelinase, leading to formation of ceramide. Increased cytosolic Ca2+ activity and enhanced ceramide levels lead to membrane scrambling with subsequent phosphatidylserine exposure. Moreover, Ca2+ activates Ca2+-sensitive K2+ channels, leading to cellular KCl loss and cell shrinkage. In addition, Ca2+ stimulates the protease calpain, resulting in...

The Heme-Bach1 Pathway in the Regulation of Oxidative Stress Response and Erythroid Differentiation

Abstract: Heme—as a prosthetic group of proteins required for oxygen transport and storage, respiration, and biosynthetic pathways—is essential for practically all forms of life. Additionally, the degradation products of heme (i.e., carbon monoxide, biliverdin, and bilirubin) produced by the enzymatic actions of heme oxygenase (HO) and biliverdin reductase, possess various biological activities in vivo. In mammalian cells, heme also functions as an intracellular regulator of gene expression by virtue of its ability to bind to Bach1, a transcription factor that functions in association with small Maf proteins. Normally, such complexes function as repressors by binding to specific target sequences, the Maf recognition element (MARE), within enhancers of genes encoding proteins such as HO-1 and β-globin. By binding to Bach1, heme induces selective removal of the repressor from the gene enhancers permitting subsequent occupancy of the MAREs by activators that, interestingly, also contain small Maf proteins. Thus small ...

Role of Nox family NADPH oxidases in host defense.

Abstract: The phagocytic NADPH oxidase is recognized as a critical component of innate immunity, responsible for generation of microbicidal reactive oxygen species (ROS). This enzyme is one representative of...