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Redox Biology    [3 followers]  Follow    
  This is an Open Access Journal Open Access journal
     ISSN (Online) 2213-2317
     Published by Elsevier Homepage  [2556 journals]
  • Nox4 NADPH oxidase contributes to smooth muscle cell phenotypes associated
           with unstable atherosclerotic plaques
    • Abstract: Publication date: Available online 15 April 2014
      Source:Redox Biology
      Author(s): Shaoping Xu , Ali H. Chamseddine , Samuel Carrell , Francis J. Miller Jr.
      Plaque instability associated with acute coronary syndromes results in part from apoptosis and senescence of cells within the atherosclerotic (AS) lesion. Increased cellular oxidative stress has been proposed to contribute to plaque progression and changes in composition, leading to plaque instability. Our objective was to examine the role of NADPH oxidase in smooth muscle cell (SMC) phenotypes associated with an unstable plaque. Aortae were isolated from pre-lesion (8 wks of age) and post-lesion (35 wks of age) hypercholesterolemic mice (ApoE−/−/LDLR−/−, AS), and age-matched normal C57BL/6J mice. We observed an age-dependent increase in reactive oxygen species (ROS) in aorta from AS mice, with evidence for elevated ROS prior to lesion development. Whereas macrophage infiltration was restricted to the lesion, oxidized lipids extended beyond the plaque and into the vessel wall. Consistent with these findings, we observed dynamic changes in the expression of NADPH oxidases in AS vessels. Specifically, Nox1 expression was increased early and decreased with lesion progression, while induction of Nox4 was a late event. Nox2 and p22phox were elevated throughout lesion development. Similar to observations in aortae, SMCs isolated from the lesion of AS aortae had decreased Nox1 and increased Nox4 levels as compared to SMCs from normal mice. AS SMCs demonstrated increased generation of ROS, cell cycle arrest, evidence of senescence, and increased susceptibility to apoptosis. Overexpression of Nox4 in normal SMCs recapitulated the phenotypes of the AS SMCs. We conclude that increased expression of Nox4 in AS may drive SMC phenotypes that lead to the plaque instability and rupture responsible for myocardial infarction and stroke.
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      PubDate: 2014-04-16T21:25:03Z
       
  • Defective mitophagy driven by dysregulation of rheb and KIF5B contributes
           to mitochondrial Reactive Oxygen Species (ROS) -induced nod-like receptor
           3 (NLRP3) dependent proinflammatory response and aggravates lipotoxicity
    • Abstract: Publication date: Available online 12 April 2014
      Source:Redox Biology
      Author(s): Sijun Yang , Chunxiang Xia , Shali Li , Leilei Du , Lu Zhang , Ronbin Zhou
      High-fat diet (HFD) and inflammation are key contributors to insulin resistance and type 2 diabetes (T2D). Previous study shows fatty acid-induced accumulation of damaged, reactive oxygen species (ROS)-generating mitochondria, and this in turn activates the NLRP3 inflammasome interference with insulin signaling. Our previous research shows NLRP3 inflammasome activation signal originates from defects in autophagy. Yet how the fatty acid related to mitophagy alteration leads to the activation of NLRP3-ASC inflammasome has not been considered. Here we demonstrated that palmitate (PA) induced mitophagy deficiency, leading to damaged mitochondrion as characterized by mito-ROS production and loss of membrane potential. Antioxidant APDC or Ca2+ signaling inhibitor Nifedipine blocked PA-induced NLRP3 inflammasome activation. Further, we provided evidences that PA reduced expression of Ras homolog enriched in brain (Rheb) and disrupted Rheb recruitment to the mitochondrial outer membrane. In addition, sustained PA caused disassociation of kinesin family member 5B (KIF5B) from binding with mitochondria via Ca2+-dependent effects. Disruption of Rheb and KIF5B interaction with mitochondria blocked mitochondrial degradation along with IL-1β dependent insulin resistance, which was majorly attenuated by Rheb/KIF5B overexpression. In a consequence, defective mitophagy led to the accumulation of damaged-ROS-generating mitochondria, down pathway of NLRP3-ASC-Caspase 1 activation, and subsequently, insulin resistance. These findings provide insights into the association of inflammation, mitophagy and T2D.
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      PubDate: 2014-04-16T21:25:03Z
       
  • Formation of electrophilic oxidation products from mitochondrial
           cardiolipin in vitro and in vivo in the context of apoptosis and
           atherosclerosis
    • Abstract: Publication date: Available online 13 April 2014
      Source:Redox Biology
      Author(s): Huiqin Zhong , Jianhong Lu , Lin Xia , Mingjiang Zhu , Huiyong Yin
      Emerging evidence indicates that mitochondrial cardiolipins (CL) are prone to free radical oxidation and this process appears to be intimately associated with multiple biological functions of mitochondria. Our previous work demonstrated that a significant amount of potent lipid electrophiles including 4-hydroxy-nonenal (4-HNE) was generated from CL oxidation through a novel chemical mechanism. Here we provide further evidence that a characteristic class of CL oxidation products, epoxyalcohol-aldehyde-CL (EAA-CL), is formed through this novel mechanism in isolated mice liver mitochondria when treated with the pro-apoptotic protein t-Bid to induce cyt c release. Generation of these oxidation products are dose-dependently attenuated by a peroxidase inhibitor acetaminophen (ApAP). Using a mouse model of atherosclerosis, we detected significant amount of these CL oxidation products in liver tissue of low density lipoprotein receptor knockout (LDLR −/−) mice after Western diet feeding. Our studies highlight the importance of lipid electrophiles formation from CL oxidation in the settings of apoptosis and atherosclerosis as inhibition of CL oxidation and lipid electrophiles formation may have potential therapeutic value in diseases linked to oxidant stress and mitochondrial dysfunctions.
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      PubDate: 2014-04-16T21:25:03Z
       
  • Cytoplasmic hybrid (cybrid) cell lines as a practical model for
           mitochondriopathies
    • Abstract: Publication date: Available online 1 April 2014
      Source:Redox Biology
      Author(s): Heather M. Wilkins , Steven M. Carl , Russell H. Swerdlow
      Cytoplasmic hybrid (cybrid) cell lines can incorporate human subject mitochondria and perpetuate its mitochondrial DNA (mtDNA)-encoded components. Since the nuclear background of different cybrid lines can be kept constant, this technique allows investigators to study the influence of mtDNA on cell function. Prior use of cybrids has elucidated the contribution of mtDNA to a variety of biochemical parameters, including electron transport chain activities, bioenergetic fluxes, and free radical production. While the interpretation of data generated from cybrid cell lines has technical limitations, cybrids have contributed valuable insight into the relationship between mtDNA and phenotype alterations. This review discusses the creation of the cybrid technique and subsequent data obtained from cybrid applications.
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      PubDate: 2014-04-05T19:10:36Z
       
  • Role of GLUT1 in regulation of reactive oxygen species
    • Abstract: Publication date: Available online 25 March 2014
      Source:Redox Biology
      Author(s): Stanley Andrisse , Rikki M. Koehler , Joseph E. Chen , Gaytri D. Patel , Vivek R. Vallurupalli , Benjamin A. Ratliff , Daniel E. Warren , Jonathan S. Fisher
      In skeletal muscle cells, GLUT1 is responsible for a large portion of basal uptake of glucose and dehydroascorbic acid, both of which play roles in antioxidant defense We hypothesized that conditions that would decrease GLUT1-mediated transport would cause increased ROS levels in L6 myoblasts, while conditions that would increase GLUT1-mediated transport would result in decreased ROS levels. We found that the GLUT1 inhibitors fasentin and phloretin increased the ROS levels induced by antimycin A and the superoxide generator pyrogallol. However, indinavir, which inhibits GLUT4 but not GLUT1, had no effect on ROS levels. Ataxia telangiectasia mutated (ATM) inhibitors and activators, previously shown to inhibit and augment GLUT1-mediated transport, increased and decreased ROS levels, respectively. Mutation of an ATM target site on GLUT1 (GLUT1-S490A) increased ROS levels and prevented the ROS-lowering effect of the ATM activator doxorubicin. In contrast, expression of GLUT1-S490D lowered ROS levels during challenge with pyrogallol, prevented an increase in ROS when ATM was inhibited, and prevented the pyrogallol-induced decrease in insulin signaling and insulin-stimulated glucose transport. Taken together, the data suggest that GLUT1 plays a role in regulation of ROS and could contribute to maintenance of insulin action in the presence of ROS.


      PubDate: 2014-03-26T16:47:19Z
       
  • Aβ and tau toxicities in Alzheimer’s are linked via oxidative
           stress-induced p38 activation. Protective role of vitamin E
    • Abstract: Publication date: Available online 10 March 2014
      Source:Redox Biology
      Author(s): E. Giraldo , A. Lloret , T. Fuchsberger , J. Viña
      Oxidative stress is a hallmark of Alzheimer’s disease (AD). We propose that rather than causing damage because of the action of free radicals, oxidative stress deranges signaling pathways leading to tau hyperphosphorylation, a hallmark of the disease. Indeed, incubation of neurons in culture with 5 µM beta-amyloid peptide (Aβ) causes an activation of p38 MAPK (p38) that leads to tau hyperphosphorylation. Inhibition of p38 prevents Aβ-induced tau phosphorylation. Aβ-induced effects are prevented when neurons are co-incubated with trolox (the water-soluble analog of vitamin E). We have confirmed these results in vivo, in APP/PS1 double transgenic mice of AD. We have found that APP/PS1 transgenic mice exhibit a high level of P-p38 in the hippocampus but not in cortex and this is prevented by feeding animals with a diet supplemented with vitamin E. Our results underpin the role of oxidative stress in the altered cell signaling in AD pathology and suggest that antioxidant prevention may be useful in AD therapeutics.


      PubDate: 2014-03-11T17:23:13Z
       
  • Hydrogen peroxide signaling in vascular endothelial cells
    • Abstract: Publication date: Available online 1 March 2014
      Source:Redox Biology
      Author(s): Rosa Bretón-Romero , Santiago Lamas
      Redox signaling is implicated in different physiological and pathological events in the vasculature. Among the different reactive oxygen species, hydrogen peroxide (H2O2) is a very good candidate to perform functions as an intracellular messenger in the regulation of several biological events. In this review, we summarize the main physiological sources of H2O2 in the endothelium and the molecular mechanisms by which it is able to act as a signaling mediator in the vasculature.
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      PubDate: 2014-03-06T17:28:26Z
       
  • Redox Biology celebrates its first anniversary with over 100 articles and
           100,000 downloads and over 160 citations!
    • Abstract: Publication date: Available online 3 March 2014
      Source:Redox Biology
      Author(s): Victor Darley-Usmar , Tilman Grune , Santiago Lamas , Tak Yee Aw



      PubDate: 2014-03-06T17:28:26Z
       
  • Mechanism of faster NO scavenging by older stored red blood cells
    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): Chen Liu , Xiaohua Liu , John Janes , Ryan Stapley , Rakesh P. Patel , Mark T. Gladwin , Daniel B. Kim-Shapiro
      The blood storage lesion involves morphological and biochemical changes of red blood cells (RBCs) that occur during storage. These include conversion of the biconcave disc morphology to a spherical one, decreased mean corpuscular hemoglobin concentration, varied mean corpuscular volume, reduced integrity of the erythrocyte membrane with formation of microparticles, and increased cell-free hemoglobin. We studied the extent that older stored red blood cells scavenge nitric oxide (NO) faster than fresher stored red blood cells. Using electron paramagnetic resonance spectroscopy and stopped-flow absorption spectroscopy to measure the rate of NO uptake and reaction with hemoglobin in red cells, we found that older stored red blood cells scavenge NO about 1.8 times faster than fresher ones. Based on these experimental data, we simulated NO scavenging by fresher or older stored red blood cells with a biconcave or spherical geometry, respectively, in order to explore the mechanism of NO scavenging related to changes that occur during blood storage. We found that red blood cells with a spherical geometry scavenges NO about 2 times slower than ones with a biconcave geometry, and a smaller RBC hemoglobin concentration or volume increases NO scavenging by red blood cells. Our simulations demonstrate that even the most extreme possible changes in mean corpuscular hemoglobin concentration and mean corpuscular volume that favor increased NO scavenging are insufficient to account for what is observed experimentally. Therefore, RBC membrane permeability must increase during storage and we find that the permeability is likely to increase between 5 and 70 fold. Simulations using a two-dimensional blood vessel show that even a 5-fold increase in membrane permeability to NO can reduce NO bioavailability at the smooth muscle. Background Transfusion of older stored blood may be harmful. Results Older stored red blood cells scavenge nitric oxide more than fresher cells. Conclusion As stored red blood cells age, structural and biochemical changes occur that lead to faster scavenging. Significance Increased nitric oxide scavenging by red blood cells as a function of storage age contributes to deleterious effects upon transfusion.
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      PubDate: 2014-03-01T05:49:46Z
       
  • Methylglyoxal in cells elicits a negative feedback loop entailing
           transglutaminase 2 and glyoxalase 1
    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): Der-Yen Lee , Geen-Dong Chang
      Glyoxalase 1 (GlxI) is the key enzyme that converts the highly reactive α-oxo-aldehydes into the corresponding α-hydroxy acids using l-glutathione as a cofactor. In our preliminary data, GlxI was identified as a substrate of transglutaminase 2 (TG2), a ubiquitous enzyme with multiple functions. According to the catalytic properties of TG2, protein cross-linking, polyamine conjugation, and/or deamidation are potential post-translational modifications. In this article, we have demonstrated that TG2 catalyzes either polyamine conjugation or deamidation to GlxI depending on the presence of polyamines or not. Deamidation leads to activation of GlxI while polyamine conjugation results in activation of GlxI as well as stabilization of GlxI against denaturation treatment. In cultured HeLa cells, methylglyoxal challenge causes increase in intracellular levels of reactive oxygen species (ROS) and calcium leading to TG2 activation and subsequent transamidation and activation of GlxI. The inhibition of TG2 significantly weakens the cell resistance to the methylglyoxal challenge. Thus, GlxI is a novel substrate of TG2 and is activated by TG2 in vitro and in cellulo. Exposure to methylglyoxal elicits a negative feedback loop entailing ROS, calcium, TG2 and GlxI, thus leading to attenuation of the increase in the methylglyoxal level. The results imply that cancer cells highly express TG2 or GlxI can endure the oxidative stress derived from higher glycolytic flux and may gain extra growth advantage from the aerobic glycolysis.
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      PubDate: 2014-03-01T05:49:46Z
       
  • Concerted action of Nrf2-ARE pathway, MRN complex, HMGB1 and inflammatory
           cytokines- Implication in modification of radiation damage
    • Abstract: Publication date: Available online 28 February 2014
      Source:Redox Biology
      Author(s): Anuranjani , Madhu Bala
      Whole body exposure to low linear energy transfer (LET) ionizing radiations (IR) damages vital intracellular biomolecules leading to multiple cellular and tissue injuries as well as pathophysiologies such as inflammation, immunosuppression etc. Nearly 70% of damage is caused indirectly by radiolysis of intracellular water leading to formation of reactive oxygen species (ROS) and free radicals and producing a state of oxidative stress. The damage is also caused by direct ionization of biomolecules. The type of radiation injuries is dependent on the absorbed radiation dose. Sub-lethal IR dose produces more of DNA base damages, whereas higher doses produce more DNA single strands break (SSBs), and double strand breaks (DSBs). The Nrf2-ARE pathway is an important oxidative stress regulating pathway. The DNA DSBs repair regulated by MRN complex, immunomodulation and inflammation regulated by HMGB1 and various types of cytokines are some of the key pathways which interact with each other in a complex manner and modify the radiation response. Because the majority of radiation damage is via oxidative stress, it is essential to gain in depth understanding of the mechanisms of Nrf2-ARE pathway and understand its interactions with MRN complex, HMGB1 and cytokines to increase our understanding on the radiation responses. Such information is of tremendous help in development of medical radiation countermeasures, radioprotective drugs and therapeutics. Till date no approved and safe countermeasure is available for human use. This study reviews the Nrf2-ARE pathway and its crosstalk with MRN-complex, HMGB1 and cytokines (TNF-α, IL-6, IFN-γ etc.). An attempt is also made to review the modification of some of these pathways in presence of selected antioxidant radioprotective compounds or herbal extracts.
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      PubDate: 2014-03-01T05:49:46Z
       
  • Regulatory metabolites of vitamin E and their putative relevance for
           atherogenesis
    • Abstract: Publication date: Available online 19 February 2014
      Source:Redox Biology
      Author(s): Maria Wallert , Lisa Schmölz , Francesco Galli , Marc Birringer , Stefan Lorkowski
      Vitamin E is likely the most important antioxidant in the human diet and α-tocopherol is the most active isomer. α-Tocopherol exhibits anti-oxidative capacity in vitro, and inhibits oxidation of LDL. Beside this, α-tocopherol shows anti-inflammatory activity and modulates expression of proteins involved in uptake, transport and degradation of tocopherols, as well as the uptake, storage and export of lipids such as cholesterol. Despite promising anti-atherogenic features in vitro, vitamin E failed to be atheroprotective in clinical trials in humans. Recent studies highlight the importance of long-chain metabolites of α-tocopherol, which are formed as catabolic intermediate products in the liver and occur in human plasma. These metabolites modulate inflammatory processes and macrophage foam cell formation via mechanisms different than that of their metabolic precursor α-tocopherol and at lower concentrations. Here we summarize the controversial role of vitamin E as a preventive agent against atherosclerosis and point the attention to recent findings that highlight a role of these long-chain metabolites of vitamin E as a proposed new class of regulatory metabolites. We speculate that the metabolites contribute to physiological as well as pathophysiological processes.


      PubDate: 2014-02-24T15:42:16Z
       
  • Potential role of proteasome on c-jun related signaling in
           hypercholesterolemia induced atherosclerosis
    • Abstract: Publication date: Available online 22 February 2014
      Source:Redox Biology
      Author(s): Erdi Sozen , Betul Karademir , Burak Yazgan , Perinur Bozaykut , Nesrin Kartal Ozer
      Atherosclerosis and its complications are major causes of the death all over the world. One of the major risks for atherosclerosis is hypercholesterolemia. During atherosclerosis, oxidized low density lipoprotein (oxLDL) regulates CD36-mediated activation of c-jun amino terminal kinase-1 (JNK1) and modulates matrix metalloproteinase (MMP) induction which stimulates inflammation with an invasion of monocytes. Additionally, inhibition of proteasome leads to an accumulation of c-jun and phosphorylated c-jun and activation of activator protein-1 (AP-1) related increase of MMP expression. We have previously reported a significant increase in cluster of differentiation 36 (CD36) mRNA levels in hypercholesterolemic rabbits and shown that vitamin E treatment prevented the cholesterol induced increase in CD36 mRNA expression. In the present study, our aim was to identify the signaling molecules/transcription factors involved in the progression of atherosclerosis following CD36 activation in an in vivo model of hypercholesterolemic (induced by 2% cholesterol containing diet) rabbits. In this direction, proteasomal activities by fluorometry and c-jun, phospo c-jun, JNK1, MMP-9 expressions by quantitative RT-PCR and immunoblotting were tested in aortic tissues. The effects of vitamin E on these changes were also investigated in this model. As a result, c-jun was phosphorylated following decreased proteasomal degradation in hypercholesterolemic group. MMP-9 expression was also increased in cholesterol group rabbits contributing to the development of atherosclerosis. In addition, vitamin E showed its effect by decreasing MMP-9 levels and phosphorylation of c-jun.
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      PubDate: 2014-02-24T15:42:16Z
       
  • Hydrogen peroxide sensing, signaling and regulation of transcription
           factors
    • Abstract: Publication date: Available online 23 February 2014
      Source:Redox Biology
      Author(s): H. Susana Marinho , Carla Real , Luísa Cyrne , Helena Soares , Fernando Antunes
      The regulatory mechanisms by which hydrogen peroxide (H2O2) modulates the activity of transcription factors in bacteria (OxyR and PerR), lower eukaryotes (Yap1, Maf1, Hsf1 and Msn2/4) and mammalian cells (AP-1, NRF2, CREB, HSF1, HIF-1, TP53, NF-κB, NOTCH, SP1 and SCREB-1) are reviewed. The complexity of regulatory networks increases throughout the phylogenetic tree, reaching a high level of complexity in mammalians. Multiple H2O2 sensors and pathways are triggered converging in the regulation of transcription factors at several levels: (1) synthesis of the transcription factor by upregulating transcription or increasing both mRNA stability and translation; (ii) stability of the transcription factor by decreasing its association with the ubiquitin E3 ligase complex or by inhibiting this complex; (iii) cytoplasm-nuclear traffic by exposing/masking nuclear localization signals, or by releasing the transcription factor from partners or from membrane anchors; and, (iv) DNA binding and nuclear transactivation by modulating transcription factor affinity towards DNA, co-activators or repressors, and by targeting specific regions of chromatin to activate individual genes. We also discuss how H2O2 biological specificity results from diverse thiol protein sensors, with different reactivity of their sulfhydryl groups towards H2O2, being activated by different concentrations and times of exposure to H2O2. The specific regulation of local H2O2 concentrations is also crucial and results from H2O2 localized production and removal controlled by signals. Finally, we formulate equations to extract from typical experiments quantitative data concerning H2O2 reactivity with sensor molecules. Rate constants of 140 M-1s−1 and ≥ 1.3 × 103 M-1s−1 were estimated, respectively, for the reaction of H2O2 with KEAP1 and with an unknown target that mediates NRF2 protein synthesis. In conclusion, the multitude of H2O2 targets and mechanisms provides an opportunity for highly specific effects on gene regulation that depend on the cell type and on signals received from the cellular microenvironment.
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      PubDate: 2014-02-24T15:42:16Z
       
  • Molecular chaperones and proteostasis regulation during redox imbalance
    • Abstract: Publication date: Available online 30 January 2014
      Source:Redox Biology
      Author(s): Katerina Niforou , Christina Cheimonidou , Ioannis P. Trougakos
      Free radicals originate from both exogenous environmental sources and as by-products of the respiratory chain and cellular oxygen metabolism. Sustained accumulation of free radicals, beyond a physiological level, induces oxidative stress that is harmful for the cellular homeodynamics as it promotes the oxidative damage and stochastic modification of all cellular biomolecules including proteins. In relation to proteome stability and maintenance, the increased concentration of oxidants disrupts the functionality of cellular protein machines resulting eventually in proteotoxic stress and the deregulation of the proteostasis (homeostasis of the proteome) network (PN). PN curates the proteome in the various cellular compartments and the extracellular milieu by modulating protein synthesis and protein machines assembly, protein recycling and stress responses, as well as refolding or degradation of damaged proteins. Molecular chaperones are key players of the PN since they facilitate folding of nascent polypeptides, as well as holding, folding, and/or degradation of unfolded, misfolded, or non-native proteins. Therefore, the expression and the activity of the molecular chaperones are tightly regulated at both the transcriptional and post-translational level at organismal states of increased oxidative and, consequently, proteotoxic stress, including ageing and various age-related diseases (e.g. degenerative diseases and cancer). In the current review we present a synopsis of the various classes of intra- and extracellular chaperones, the effects of oxidants on cellular homeodynamics and diseases and the redox regulation of chaperones.
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      PubDate: 2014-02-04T10:21:55Z
       
  • Optogenetic control of ROS production
    • Abstract: Publication date: Available online 3 February 2014
      Source:Redox Biology
      Author(s): Andrew P. Wojtovich , Thomas H. Foster
      Reactive Oxygen Species (ROS) are known to cause oxidative damage to DNA, proteins and lipids. In addition, recent evidence suggests that ROS can also initiate signaling cascades that respond to stress and modify specific redox-sensitive moieties as a regulatory mechanism. This suggests that ROS are physiologically-relevant signaling molecules. However, these sensor / effector molecules are not uniformly distributed throughout the cell. Moreover, localized ROS damage may elicit site-specific compensatory measures. Thus, the impact of ROS can be likened to that of calcium, a ubiquitous second messenger, leading to the prediction that their effects are exquisitely dependent upon their location, quantity and even the timing of generation. Despite this prediction, ROS signaling is most commonly intuited through the global administration of chemicals that produce ROS or by ROS quenching through global application of antioxidants. Optogenetics, which uses light to control the activity of genetically-encoded effector proteins, provides a means of circumventing this limitation. Photo-inducible genetically-encoded ROS-generating proteins (RGPs) were originally employed for their phototoxic effects and cell ablation. However, reducing irradiance and/or fluence can achieve sub-lethal levels of ROS that may mediate subtle signaling effects. Hence, transgenic expression of RGPs as fusions to native proteins gives researchers a new tool to exert spatial and temporal control over ROS production. This review will focus on the new frontier defined by the experimental use of RGPs to study ROS signaling.
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      PubDate: 2014-02-04T10:21:55Z
       
  • Thiol-based H2O2 signalling in microbial systems
    • Abstract: Publication date: Available online 3 February 2014
      Source:Redox Biology
      Author(s): Susanna Boronat , Alba Domènech , Esther Paulo , Isabel A. Calvo , Sarela García-Santamarina , Patricia García , Javier Encinar del Dedo , Anna Barcons , Erica Serrano , Mercè Carmona , Elena Hidalgo
      Cysteine residues, and in particular their thiolate groups, react not only with reactive oxygen species but also with electrophiles and with reactive nitrogen species. Thus, cysteine oxidation has often been linked to the toxic effects of some of these reactive molecules. However, thiol-based switches are common in protein sensors of antioxidant cascades, in both prokaryotic and eukaryotic organisms. We will describe here three redox sensors, the transcription factors OxyR, Yap1 and Pap1, which respond by disulfide bond formation to hydrogen peroxide stress, focusing specially on the differences among the three peroxide-sensing mechanisms.
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      PubDate: 2014-02-04T10:21:55Z
       
  • Protein engineering to develop a redox insensitive endothelial nitric
           oxide synthase
    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): Ruslan Rafikov , Sanjiv Kumar , Saurabh Aggarwal , Daniel Pardo , Fabio V. Fonseca , Jessica Ransom , Olga Rafikova , Qiumei Chen , Matthew L. Springer , Stephen M. Black
      The zinc tetrathiolate (ZnS4) cluster is an important structural feature of endothelial nitric oxide synthase (eNOS). The cluster is located on the dimeric interface and four cysteine residues (C94 and C99 from two adjacent subunits) form a cluster with a Zn ion in the center of a tetrahedral configuration. Due to its high sensitivity to oxidants this cluster is responsible for eNOS dimer destabilization during periods of redox stress. In this work we utilized site directed mutagenesis to replace the redox sensitive cysteine residues in the ZnS4 cluster with redox stable tetra-arginines. Our data indicate that this C94R/C99R eNOS mutant is active. In addition, this mutant protein is insensitive to dimer disruption and inhibition when challenged with hydrogen peroxide (H2O2). Further, the overexpression of the C94R/C99R mutant preserved the angiogenic response in endothelial cells challenged with H2O2. The over-expression of the C94R/C99R mutant preserved the ability of endothelial cells to migrate towards vascular endothelial growth factor (VEGF) and preserved the endothelial monolayer in a scratch wound assay. We propose that this dimer stable eNOS mutant could be utilized in the treatment of diseases in which there is eNOS dysfunction due to high levels of oxidative stress.
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      PubDate: 2014-01-30T09:19:47Z
       
  • Circulating levels of linoleic acid and HDL-cholesterol are major
           determinants of 4-hydroxynonenal protein adducts in patients with heart
           failure
    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): Caroline Asselin , Anique Ducharme , Thierry Ntimbane , Matthieu Ruiz , Annik Fortier , Marie-Claude Guertin , Joël Lavoie , Ariel Diaz , Émile Levy , Jean-Claude Tardif , Christine Des Rosiers
      Objective Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA). Methods and results Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R 2=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only. Conclusion Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts.
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      PubDate: 2014-01-30T09:19:47Z
       
  • Mild exposure of RIN-5F β-cells to human islet amyloid polypeptide
           aggregates upregulates antioxidant enzymes via NADPH oxidase-RAGE: An
           hormetic stimulus
    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): Elisabetta Borchi , Valentina Bargelli , Valentina Guidotti , Andrea Berti , Massimo Stefani , Chiara Nediani , Stefania Rigacci
      The presence of amyloid aggregates of human islet amyloid polypeptide (hIAPP), a hallmark of type 2 diabetes, contributes to pancreatic β-cell impairment, where oxidative stress plays a key role. A contribution of NADPH oxidase to reactive oxygen species (ROS) generation after cell exposure to micromolar concentrations of hIAPP aggregates has been suggested. However, little is known about β-cells exposure to lower amounts of hIAPP aggregates, similar to those found in human pancreas. Thus, we aimed to investigate the events resulting from RIN-5F cells exposure to nanomolar concentrations of toxic hIAPP aggregates. We found an early and transient rise of NADPH oxidase activity resulting from increased Nox1 expression following the engagement of receptor for advanced glycation end-products (RAGE) by hIAPP aggregates. Unexpectedly, NADPH oxidase activation was not accompanied by a significant ROS increase and the lipoperoxidation level was significantly reduced. Indeed, cell exposure to hIAPP aggregates affected the antioxidant defences, inducing a significant increase of the expression and activity of catalase and glutathione peroxidase. We conclude that exposure of pancreatic β-cells to nanomolar concentrations of hIAPP aggregates for a short time induces an hormetic response via the RAGE-Nox1 axis; the latter stimulates the enzymatic antioxidant defences that preserve the cells against oxidative stress damage.
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      PubDate: 2014-01-30T09:19:47Z
       
  • Reactive metabolites and antioxidant gene polymorphisms in Type 2 diabetes
           mellitus
    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): Monisha Banerjee , Pushpank Vats
      Type 2 diabetes mellitus (T2DM), by definition is a heterogeneous, multifactorial, polygenic syndrome which results from insulin receptor dysfunction. It is an outcome of oxidative stress caused by interactions of reactive metabolites (RMs) interactions with lipids, proteins and other mechanisms of human body. Production of RMs mainly superoxide ( O 2 − ) has been found in a variety of predominating cellular enzyme systems including NAD(P)H oxidase, xanthine oxidase (XO), cyclooxygenase (COX), uncoupled endothelial nitric oxide synthase (eNOS) and myeloperoxidase (MPO). The four main RM related molecular mechanisms are: increased polyol pathway flux; increased advanced glycation end-product (AGE) formation; activation of protein kinase C (PKC) isoforms and increased hexosamine pathway flux which have been implicated in glucose-mediated vascular damage. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), nitric oxide synthase (NOS) are antioxidant enzymes involved in scavenging RMs in normal individuals. Functional polymorphisms of these antioxidant enzymes have been reported to be involved in pathogenesis of T2DM individuals. The low levels of antioxidant enzymes or their non-functionality results in excessive RMs which initiate stress related pathways thereby leading to insulin resistance and T2DM. An attempt has been made to review the role of RMs and antioxidant enzymes in oxidative stress resulting in T2DM.
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      PubDate: 2014-01-25T01:01:15Z
       
  • Oxidative stress and Nerve Damage: Role in Chemotherapy Induced Peripheral
           Neuropathy
    • Abstract: Publication date: Available online 18 January 2014
      Source:Redox Biology
      Author(s): Aparna Areti , Veera Ganesh Yerra , VGM Naidu , Ashutosh Kumar
      Peripheral neuropathy is a severe dose limiting toxicity associated with cancer chemotherapy. Ever since it was identified, the clear pathological mechanisms underlying chemotherapy induced peripheral neuropathy (CIPN) remain sparse and considerable involvement of oxidative stress and neuroinflammation has been realized recently. Despite of the empirical use of antioxidants in the therapy of CIPN, the oxidative stress mediated neuronal damage in peripheral neuropathy is still debatable. The current review focuses at nerve damage due to oxidative stress and mitochondrial dysfunction as key pathogenic mechanisms involved in CIPN. Oxidative stress as a central mediator of apoptosis, neuroinflammation, metabolic disturbances and bioenergetic failure in neurons has been highlighted in this review along with a summary of research on dietary antioxidants and other nutraceuticals which have undergone prospective controlled clinical trials in patients undergoing chemotherapy.
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      PubDate: 2014-01-21T12:25:57Z
       
  • Redox Regulation of Protein Damage in Plasma
    • Abstract: Publication date: Available online 20 January 2014
      Source:Redox Biology
      Author(s): Helen R. Griffiths , Irundika H.K. Dias , Rachel S. Willetts , Andrew Devitt
      The presence and concentrations of modified proteins circulating in plasma depend on rates of protein synthesis, modification and clearance. In early studies, the proteins most frequently analysed for damage were those which were more abundant in plasma (e.g. albumin and immunoglobulins) which exist at 10 orders of magnitude higher concentrations than other plasma proteins e.g. cytokines. However, advances in analytical techniques using mass spectrometry and immuno-affinity purification methods, have facilitated analysis of less abundant, modified proteins and the nature of modifications at specific sites is now being characterised. The damaging reactive species that cause protein modifications in plasma principally arise from reactive oxygen species (ROS) produced by NADPH oxidases (NOX), nitric oxide synthases (NOS) and oxygenase activities; reactive nitrogen species (RNS) from myeloperoxidase (MPO) and NOS activities; and hypochlorous acid from MPO. Secondary damage to proteins may be caused by oxidized lipids and glucose autooxidation. In this review, we focus on redox regulatory control of those enzymes which control protein maturation during synthesis, produce reactive species, repair and remove damaged plasma proteins. We have highlighted the potential for alterations in the extracellular redox compartment to regulate intracellular redox state and, conversely, for intracellular oxidative stress to alter the cellular secretome and composition of extracellular vesicles. Through secreted, redox-active regulatory molecules, changes in redox state may be transmitted to distant sites.


      PubDate: 2014-01-21T12:25:57Z
       
  • The Ubiquitin Proteasome System in Caenorhabditis elegans and its
           regulation
    • Abstract: Publication date: Available online 18 January 2014
      Source:Redox Biology
      Author(s): Nikoletta Papaevgeniou , Niki Chondrogianni
      Protein degradation constitutes a major cellular function that is responsible for maintenance of the normal cellular physiology either through the degradation of normal proteins or through the elimination of damaged proteins. The Ubiquitin-Proteasome System (UPS)1 is one of the main proteolytic systems that orchestrate protein degradation. Given that up- and down- regulation of the UPS system has been shown to occur in various normal (such as ageing) and pathological (such as neurodegenerative diseases) processes, the exogenous modulation of the UPS function and activity holds promise of (a) developing new therapeutic interventions against various diseases and (b) establishing strategies to maintain cellular homeostasis. Since the proteasome genes are evolutionarily conserved, their role can be dissected in simple model organisms, such as the nematode, Caenorhabditis elegans. In this review, we survey findings on the redox regulation of the UPS in C. elegans showing that the nematode is an instrumental tool in the identification of major players in the UPS pathway. Moreover, we specifically discuss UPS-related genes that have been modulated in the nematode and in human cells and have resulted in similar effects thus further exhibiting the value of this model in the study of the UPS.
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      PubDate: 2014-01-21T12:25:57Z
       
  • NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic
           responses
    • Abstract: Publication date: Available online 20 January 2014
      Source:Redox Biology
      Author(s): Fan Jiang , Guei-Sheung Liu , Gregory J. Dusting , Elsa C. Chan
      Uncontrolled fibrosis in organs like heart, kidney, liver and lung is detrimental and may lead to end-stage organ failure. Currently there is no effective treatment for fibrotic disorders. Transforming growth factor (TGF)-β has a fundamental role in orchestrating the process of fibrogenesis; however, interventions directly targeting TGF-β would have undesired systemic side effects due to the multiple physiological functions of TGF-β. Further characterization of the downstream signaling pathway(s) involved in TGF-β-mediated fibrosis may lead to discovery of novel treatment strategies for fibrotic disorders. Accumulating evidence suggests that Nox4 NADPH oxidase may be an important downstream effector in mediating TGF-β-induced fibrosis, while NADPH oxidase-dependent redox signaling may in turn regulate TGF-β/Smad signaling in a feed-forward manner. It is proposed that pharmacological inhibition of the Nox4 function may represent a novel approach in treatment of fibrotic disorders.


      PubDate: 2014-01-21T12:25:57Z
       
  • The role of Nox1 and Nox2 in GPVI-dependent platelet activation and
           thrombus formation
    • Abstract: Publication date: Available online 13 January 2014
      Source:Redox Biology
      Author(s): T.G. Walsh , M.C. Berndt , N. Carrim , J. Cowman , D. Kenny , P. Metharom
      Background Activation of the platelet-specific collagen receptor, glycoprotein (GP) VI, induces intracellular reactive oxygen species (ROS) production, however the relevance of ROS to GPVI-mediated platelet responses remains unclear. Objective The objective of this study was to explore the role of the ROS-producing NADPH oxidase (Nox)1 and 2 complexes in GPVI-dependent platelet activation and collagen-induced thrombus formation. Methods and Results ROS production was measured by quantitating changes in the oxidation-sensitive dye, H2DCF-DA, following platelet activation with the GPVI-specific agonist, collagen related peptide (CRP). Using a pharmacological inhibitor specific for Nox1, 2-acetylphenothiazine (ML171), and Nox2 deficient mice, we show that Nox1 is the key Nox homologue regulating GPVI-dependent ROS production. Nox1, but not Nox2, was essential for CRP-dependent thromboxane (Tx)A2 production, which was mediated in part through p38 MAPK signaling, while neither Nox1 nor Nox2 was significantly involved in regulating CRP-induced platelet aggregation/integrin α IIb β 3 activation, platelet spreading, or dense granule and α-granule release (ATP release and P-selectin surface expression, respectively). Ex-vivo perfusion analysis of mouse whole blood revealed that both Nox1 and Nox2 were involved in collagen-mediated thrombus formation at arterial shear. Conclusion Together these results demonstrate a novel role for Nox1 in regulating GPVI-induced ROS production, which is essential for optimal p38 activation and subsequent TxA2 production, providing an explanation for reduced thrombus formation following Nox1 inhibition.
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      PubDate: 2014-01-17T07:30:26Z
       
  • The proteasome and the degradation of oxidized proteins: Part III –
           Redox regulation of the proteasomal system
    • Abstract: Publication date: Available online 14 January 2014
      Source:Redox Biology
      Author(s): Tobias Jung Annika Höhn , Tilman Grune
      Here, we review shortly the current knowledge on the regulation of the proteasomal system during and after oxidative stress. After addressing the components of the proteasomal system and the degradation of oxidatively damaged proteins in part I and II of this series, we address here which changes in activity undergo the proteasome and the ubiquitin-proteasomal system itself under oxidative conditions. While several components of the proteasomal system undergo direct oxidative modification, a number of redox-regulated events are modulating the proteasomal activity in a way it can address the major tasks in an oxidative stress situation: the removal of oxidized proteins and the adaptation of the cellular metabolism to the stress situation.


      PubDate: 2014-01-17T07:30:26Z
       
  • New Insights into the Mechanisms of Polyphenols beyond Antioxidant
           Properties; Lessons from the Green tea Polyphenol, Epigallocatechin
           3-gallate
    • Abstract: Publication date: Available online 10 January 2014
      Source:Redox Biology
      Author(s): Jeong-a Kim , Hae-Suk Kim , Michael J. Quon
      Green tea is rich in polyphenol flavonoids including catechins. Epigallocatechin gallate (EGCG) is the most abundant and potent green tea catechin. EGCG has been extensively studied for its beneficial health effects as a nutriceutical agent. Based upon its chemical structure, EGCG is often classified as an antioxidant. However, treatment of cells with EGCG results in production of hydrogen peroxide and hydroxyl radicals in the presence of Fe (III). Thus, EGCG functions as a pro-oxidant in some cellular contexts. Recent investigations have revealed many other direct actions of EGCG that are independent from anti-oxidative mechanisms. In this review, we discuss these novel molecular mechanisms of action for EGCG. In particular, EGCG directly interacts with proteins and phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function, and autophagy to exert many of its beneficial biological actions.
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      PubDate: 2014-01-13T00:01:14Z
       
  • Positive oxidative stress in aging and aging-related disease tolerance
    • Abstract: Publication date: Available online 9 January 2014
      Source:Redox Biology
      Author(s): Liang-Jun Yan
      It is now well established that reactive oxygen species (ROS), reactive nitrogen species (RNS), and a basal level of oxidative stress are essential for cell survival. It is also well known that while severe oxidative stress often leads to widespread oxidative damage and cell death, a moderate level of oxidative stress, induced by a variety of stressors, can yield great beneficial effects on adaptive cellular responses to pathological challenges in aging and aging-associated disease tolerance such as ischemia tolerance. Here in this review, I term this moderate level of oxidative stress as positive oxidative stress, which usually involves imprinting molecular signatures on lipids and proteins via formation of lipid peroxidation by-products and protein oxidation adducts. As ROS/RNS are short-lived molecules, these molecular signatures can thus execute the ultimate function of ROS/RNS. Representative examples of lipid peroxidation products and protein oxidation adducts are presented to illustrate the role of positive oxidative stress in a variety of pathological settings, demonstrating that positive oxidative stress could be a valuable prophylactic and/or therapeutic approach targeting aging and aging-associated diseases.
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      PubDate: 2014-01-13T00:01:14Z
       
  • Endothelial nitric oxide synthase in red blood cells: Key to a new
           erythrocrine function'
    • Abstract: Publication date: Available online 9 January 2014
      Source:Redox Biology
      Author(s): Miriam M. Cortese-Krott , Malte Kelm
      Red blood cells (RBC) have been considered almost exclusively as a transporter of metabolic gases and nutrients for the tissues. It is an accepted dogma that RBCs take up and inactivate endothelium-derived NO via rapid reaction with oxyhemoglobin to form methemoglobin and nitrate, thereby limiting NO available for vasodilatation. Yet it has also been shown that RBCs not only act as “NO sinks”, but exert an erythrocrine function - i.e an endocrine function of RBC - by synthesizing, transporting and releasing NO metabolic products and ATP, thereby potentially controlling systemic NO bioavailability and vascular tone. Recent work from our and others laboratory demonstrated that human RBCs carry an active type 3, endothelial NO synthase (eNOS), constitutively producing NO under normoxic conditions, the activity of which is compromised in patients with coronary artery disease. In this review we aim to discuss the potential role of red cell eNOS in RBC signaling and function, and to critically revise evidence to this date showing a role of non-endothelial circulating eNOS in cardiovascular pathophysiology.
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      PubDate: 2014-01-13T00:01:14Z
       
  • Role of Advanced Glycation End Products in Cellular Signaling
    • Abstract: Publication date: Available online 9 January 2014
      Source:Redox Biology
      Author(s): Christiane Ott , Kathleen Jacobs , Elisa Haucke , Anne Navarrete Santos , Tilman Grune , Andreas Simm
      Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.


      PubDate: 2014-01-13T00:01:14Z
       
  • A review of the Mitochondrial and Glycolytic Metabolism in Human Platelets
           and Leukocytes; Implications for their use as Bioenergetic Biomarkers
    • Abstract: Publication date: Available online 10 January 2014
      Source:Redox Biology
      Author(s): Philip A. Kramer , Saranya Ravi , Balu Chacko , Michelle S. Johnson , Victor M. Darley-Usmar
      The assessment of metabolic function in cells isolated from human blood for treatment and diagnosis of disease is a new and important area of translational research. It is now becoming clear that a broad range of pathologies which present clinically with symptoms predominantly in one organ, such as the brain or kidney, also modulate mitochondrial energetics in platelets and leukocytes allowing these cells to serve as “the canary in the coal mine” for bioenergetic dysfunction. This opens up the possibility that circulating platelets and leukocytes can sense metabolic stress in patients and serve as biomarkers of mitochondrial dysfunction in human pathologies such as diabetes, neurodegeneration and cardiovascular disease. In this overview we will describe how the utilization of glycolysis and oxidative phosphorylation differs in platelets and leukocytes and discuss how they can be used in patient populations. Since it is clear that the metabolic programs between leukocytes and platelets are fundamentally distinct the measurement of mitochondrial function in distinct cell populations is necessary for translational research.


      PubDate: 2014-01-13T00:01:14Z
       
  • Dietary Restriction in Cerebral Bioenergetics and Redox State
    • Abstract: Publication date: Available online 11 January 2014
      Source:Redox Biology
      Author(s): Ignacio Amigo , Alicia J. Kowaltowski
      The brain has a central role in the regulation of energy stability of the organism. It is the organ with the highest energetic demands, the most susceptible to energy deficits, and is responsible for coordinating behavioral and physiological responses related to food foraging and intake. Dietary interventions have been shown to be a very effective means to extend lifespan and delay the appearance of age-related pathological conditions, notably those associated with brain functional decline. The present review focuses on the effects of these interventions on brain metabolism and cerebral redox state, and summarizes the current literature dealing with dietary interventions on brain pathology.


      PubDate: 2014-01-13T00:01:14Z
       
  • Preventive and therapeutic effects of nitrite supplementation in
           experimental inflammatory bowel disease
    • Abstract: Publication date: Available online 23 December 2013
      Source:Redox Biology
      Author(s): Cecilia Jädert , Mia Phillipson , Lena Holm , Jon O. Lundberg , Sara Borniquel
      Background Inorganic nitrate and nitrite have emerged as alternative substrates for nitric oxide (NO) generation in the gastrointestinal tract, and have shown to be protective against drug-induced gastric injury. The aim of this study was to investigate the preventive and therapeutic effects of nitrate and nitrite in a model of experimental colitis. Methods Colitis was induced in mice by administrating dextran sulfate sodium (DSS) with concurrent administration of nitrite (1mM) or nitrate (10mM) in the drinking water for 7 days. A therapeutic approach was also investigated by initiating nitrite treatment 3 days after DSS-induced colitis. Clinical and inflammatory markers were assessed and the colonic mucus thickness was measured in vivo. The effect of nitrite on wound healing was evaluated using colon epithelial cells. Results Concurrent administration of DSS and nitrite (1mM) alleviated inflammation as determined by reduced disease activity index score (DAI) and increased colon length, while nitrate (10mM) only reduced the DAI-score. Nitrite also displayed therapeutic effects by ameliorating established colonic inflammation with reduced colonic expression of iNOS and improving histopathology. DSS-induced decrease in colonic mucus thickness was completely prevented by nitrite administration. In addition, goblet cell abundance was lower by DSS treatment, but was increased by addition of nitrite. Further studies using colon epithelial cells revealed an NO-dependent improvement in wound healing with nitrite administration. Conclusion Nitrite exerts both preventive and therapeutic effects in colonic inflammation. The protective effects involve preservation of an intact adherent mucus layer and regulation of epithelial cell restitution.
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      PubDate: 2013-12-28T16:50:42Z
       
  • Autophagy as an essential cellular antioxidant pathway in
           neurodegenerative disease
    • Abstract: Publication date: Available online 25 December 2013
      Source:Redox Biology
      Author(s): Samantha Giordano , Victor Darley-Usmar , Jianhua Zhang
      Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: 1) radical scavenging antioxidants cannot reverse established damage to proteins and organelles; 2) radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and 3) since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy-lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles.
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      PubDate: 2013-12-28T16:50:42Z
       
  • Study Designs to Investigate Nox1 Acceleration of Neoplastic Progression
           in Immortalized Human Epithelial Cells by Selection of Differentiation
           Resistant Cells
    • Abstract: Publication date: Available online 21 December 2013
      Source:Redox Biology
      Author(s): Apsorn Sattayakhom , Warangkana Chunglok , Wanida Ittarat , Walee Chamulitrat
      To investigate the role of NADPH oxidase homolog Nox1 at an early step of cell transformation, we utilized human gingival mucosal keratinocytes immortalized by E6/E7 of human papillomavirus (HPV) type 16 (GM16) to generate progenitor cell lines either by chronic ethanol exposure or overexpression with Nox1. Among several cobblestone epithelial cell lines obtained, two distinctive spindle cell lines – FIB and NuB1 cells were more progressively transformed exhibiting tubulogenesis and anchorage-independent growth associated with increased invasiveness. These spindle cells acquired molecular markers of epithelial mesenchymal transition (EMT) including mesenchymal vimentin and simple cytokeratins (CK) 8 and 18 as well as myogenic alpha-smooth muscle actin and caldesmon. By overexpression and knockdown experiments, we showed that Nox1 on a post-translational level regulated the stability of CK18 in an ROS-, phosphorylation- and PKCepilon-dependent manner. PKCepilon may thus be used as a therapeutic target for EMT inhibition. Taken together, Nox1 accelerates neoplastic progression by regulating structural intermediate filaments leading to EMT of immortalized human gingival epithelial cells.
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      PubDate: 2013-12-24T10:32:53Z
       
  • Redox regulation of mitochondrial function with emphasis on cysteine
           oxidation reactions
    • Abstract: Publication date: Available online 19 December 2013
      Source:Redox Biology
      Author(s): Ryan J. Mailloux , Xiaolei Jin , William G. Willmore
      Mitochondria have a myriad of essential functions including metabolism and apoptosis. These chief functions are reliant on electron transfer reactions and the production of ATP and reactive oxygen species (ROS). The production of ATP and ROS are intimately linked to the electron transport chain (ETC). Electrons from nutrients are passed through the ETC via a series of acceptor and donor molecules to the terminal electron acceptor molecular oxygen (O2) which ultimately drives the synthesis of ATP. Electron transfer through the respiratory chain and nutrient oxidation also produces ROS. At high enough concentrations ROS can activate mitochondrial apoptotic machinery which ultimately leads to cell death. However, if maintained at low enough concentrations ROS can serve as important signaling molecules. Various regulatory mechanisms converge upon mitochondria to modulate ATP synthesis and ROS production. Given that mitochondrial function depends on redox reactions, it is important to consider how redox signals modulate mitochondrial processes. Here, we provide the first comprehensive review on how redox signals mediated through cysteine oxidation, namely S-oxidation (sulfenylation, sulfinylation), S-glutathionylation, and S-nitrosylation, regulate key mitochondrial functions including nutrient oxidation, oxidative phosphorylation, ROS production, mitochondrial permeability transition (MPT), apoptosis, and mitochondrial fission and fusion. We also consider the chemistry behind these reactions and how they are modulated in mitochondria. In addition, we also discuss emerging knowledge on disorders and disease states that are associated with deregulated redox signaling in mitochondria and how mitochondria-targeted medicines can be utilized to restore mitochondrial redox signaling.


      PubDate: 2013-12-20T05:56:16Z
       
  • The Proteasome and the Degradation of Oxidized Proteins: part I - Protein
           oxidation and proteasomal degradation
    • Abstract: Publication date: Available online 17 December 2013
      Source:Redox Biology
      Author(s): Tobias Jung Annika Höhn , Tilman Grune
      Here, we review the role of oxidative protein modification as a signal for recognition and degradation of proteins. It was clearly demonstrated that the ATP- and ubiquitin-independent 20S proteasome is playing a key role in the selective removal of oxidized proteins. Furthermore, the current knowledge of the substrate susceptibility on the degradation of oxidized proteins and the role of the immunoproteasome will be highlighted.


      PubDate: 2013-12-20T05:56:16Z
       
  • Novel liquid chromatography-mass spectrometry method shows that vitamin E
           deficiency depletes arachidonic and docosahexaenoic acids in zebrafish
           (Danio rerio) embryos
    • Abstract: Publication date: Available online 17 December 2013
      Source:Redox Biology
      Author(s): Katie M. Lebold , Jay S. Kirkwood , Alan W. Taylor , Jaewoo Choi , Carrie L. Barton , Galen W. Miller , Jane La Du , Donald B. Jump , J. Fredrick Stevens , Robert L. Tanguay , Maret G. Traber
      To test the hypothesis that embryogenesis depends upon α-tocopherol (E) to protect embryo polyunsaturated fatty acids (PUFA) from lipid peroxidation, new methodologies were applied to measure α-tocopherol and fatty acids in extracts from saponified zebrafish embryos. A solid phase extraction method was developed to separate the analyte classes, using a mixed mode cartridge (reverse phase, pi-pi bonding, strong anion exchange), then α-tocopherol and cholesterol were measured using standard techniques, while the fatty acids were quantitated using a novel, reverse phase liquid chromatography-mass spectrometry (LC-MS) approach. We also determined if α-tocopherol status alters embryonic lipid peroxidation products by analyzing 24 different oxidized products of arachidonic or docosahexaenoic (DHA) acids in embryos using LC with hybrid quadrupole-time of flight MS. Adult zebrafish were fed E- or E+ diets for 4 months, and then were spawned to obtain E- and E+ embryos. Between 24–72 hours post-fertilization (hpf), arachidonic acid decreased 3-times faster in E- (21pg/h) compared with E+ embryos (7pg/h, P<0.0001), while both α-tocopherol and DHA concentrations decreased only in E- embryos. At 36hpf, E- embryos contained double the 5-hydroxy-eicosatetraenoic acids and 7-hydroxy-DHA concentrations, while other hydroxy-lipids remained unchanged. Vitamin E deficiency during embryogenesis depleted DHA and arachidonic acid, and increased hydroxy-fatty acids derived from these PUFA, suggesting that α-tocopherol is necessary to protect these critical fatty acids.
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      PubDate: 2013-12-20T05:56:16Z
       
  • Effect of CO, NOx and SO2 on ROS production, photosynthesis and
           ascorbate-glutathione pathway to induce Fragaria × annasa as a
           hyperaccumulator
    • Abstract: Publication date: Available online 17 December 2013
      Source:Redox Biology
      Author(s): Sowbiya Muneer , Tae Hwan Kim , Byung Chul Choi , Beom Seon Lee , Jeong Hyun Lee
      A study was conducted to determine the effect of carbon monoxide (CO), Nitroxide (NO x ) and sulfur dioxide (SO2) on ROS production, photosynthesis and ascorbate-glutathione pathway in strawberry plants. The results showed that both singlet oxygen (O2 -1) and hydrogen peroxide (H2O2) content increased in CO, NO x and SO2 treated strawberry leaves. A drastic reduction of primary metabolism of plants (photosynthesis), with the closure of stomata, resulted in a reduction of protein, carbohydrate and Sucrose content due to production of reactive oxygen species (ROS) under prolonged exposure of gas stress. The resulting antioxidant enzymes were increased under a low dose of gas stress, whereas they were decreased due to a high dose of gas stress. Our results indicate that increased ROS may act as a signal to induce defense responses to CO, NOx and SO2 gas stress. The increased level of antioxidant enzymes plays a significant role in plant protection due to which strawberry plants can be used as a hyperaccumulator to maintain environmental pollution, however, the defense capacity cannot sufficiently alleviate oxidative damage under prolonged exposure of CO, NO x and SO2 stress.
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      PubDate: 2013-12-20T05:56:16Z
       
  • Selective inhibition of NADPH Oxidase reverses the over contraction of
           diabetic rat aorta
    • Abstract: Publication date: Available online 11 December 2013
      Source:Redox Biology
      Author(s): Atif ur Rehman , Elma Dugic , Chris Benham , Lisa Lione , Louise S Mackenzie
      Abnormal vascular responsiveness in diabetes has been attributed to a number of changes in contractile pathways, affected in part by the overproduction of reactive oxygen species (ROS). It has been reported that NADPH oxidase (NOX) is increased in diabetic (streptozotocin treated; STZ) rat arteries; however the pharmacological agents used to inhibit NOX activity are known to be unsuitable for in vitro studies and have a high level of non-selectivity. Here we have used the highly selective NOX inhibitor VAS2870 in diabetic rat aorta and compared its effects with apocynin, SOD, and allopurinol on phenylephrine and U46619 induced contraction. Male Wistar rats were injected intraperitoneally with 65mg/kg STZ and development of diabetes was confirmed by testing blood glucose levels. Rats were killed by CO2 asphyxiation, and the thoracic aorta removed and mounted in an organ bath under a tension of 1g. Diabetic rat aortas exhibit a greatly increased response to phenylephrine, which was reduced to a level consistent with control rat aorta by 10−5M VAS2870 and 150U/ml SOD.Incubation with VAS2870 led to an increase in normal rat aorta contraction, but led to a significant reduction in phenylephrine and U46619 induced tone in diabetic rat aorta, which indicates that ROS in diabetic rats directly contributes to these contractile responses. Apocynin and allopurinol had no effect on contraction in diabetic or normal rat aorta. This data is the first to show that selective inhibition of NOX reduces diabetic arterial contraction in direct comparison with inhibition of other known contributors of ROS.
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      PubDate: 2013-12-15T15:10:52Z
       
  • Oxidative stress responses to a graded maximal exercise test in older
           adults following explosive-type resistance training
    • Abstract: Publication date: Available online 12 December 2013
      Source:Redox Biology
      Author(s): Roberta Ceci , Maria Reyes Beltran Valls , Guglielmo Duranti , Ivan Dimauro , Federico Quaranta , Monica Pittaluga , Stefania Sabatini , Paolo Caserotti , Paolo Parisi , Attilio Parisi , Daniela Caporossi
      We recently demonstrated that low frequency, moderate intensity, explosive-type resistance training (EMRT) is highly beneficial in elderly subjects towards muscle strength and power, with a systemic adaptive response of anti-oxidant and stress-induced markers. In the present study, we aimed to evaluate the impact of EMRT on oxidative stress biomarkers induced in old people (70–75 years) by a single bout of acute, intense exercise. Sixteen subjects randomly assigned to either a control, not exercising group (n=8) or a trained group performing EMRT protocol for 12-weeks (n=8), were submitted to a graded maximal exercise stress test (GXT) at baseline and after the 12-weeks of EMRT protocol, with blood samples collected before, immediately after, 1 and 24 hours post-GXT test. Blood glutathione (GSH, GSSG, GSH/GSSG), plasma malonaldehyde (MDA), protein carbonyls and creatine kinase (CK) levels, as well as PBMCs cellular damage (Comet assay, apoptosis) and stress-protein response (Hsp70 and Hsp27 expression) were evaluated. The use of multiple biomarkers allowed us to confirm that EMRT per se neither affected redox homeostasis nor induced any cellular and oxidative damage. Following the GXT, the EMRT group displayed a higher GSH/GSSG ratio and a less pronounced increase in MDA, protein carbonyls and CK levels compared to control group. Moreover, we found that Hsp70 and Hsp27 proteins were induced after GXT only in EMRT group, while any significant modification within 24 hours was detected in untrained group. Apoptosis rates and DNA damage did not show any significant variation in relation to EMRT and/or GXT. In conclusion, the adherence to an EMRT protocol is able to induce a cellular adaptation allowing healthy elderly trained subjects to cope with the oxidative stress induced by an acute exercise more effectively than the aged-matched sedentary subjects.
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      PubDate: 2013-12-15T15:10:52Z
       
  • REDOX REGULATION OF THE PROTEASOME VIA S-GLUTATHIONYLATION
    • Abstract: Publication date: Available online 14 December 2013
      Source:Redox Biology
      Author(s): Marilene Demasi , Luis E.S. Netto , Gustavo M. Silva , Adrian Hand , Cristiano L.P. de Oliveira , Renata N. Bicev , Fabio Gozzo , Mario H. Barros , Janaina M.M. Leme , Erina Ohara
      The proteasome is a multimeric and multicatalytic intracellular protease responsible for the degradation of proteins involved in cell cycle control, various signaling processes, antigen presentation, and control of protein synthesis. The central catalytic complex of the proteasome is called the 20S core particle. The majority of these are flanked on one or both sides by regulatory units. Most common among these units is the 19S regulatory unit. When coupled to the 19S unit, the complex is termed the asymmetric or symmetric 26S proteasome depending on whether one or both sides are coupled to the 19S unit, respectively. The 26S proteasome recognizes poly-ubiquitinylated substrates targeted for proteolysis. Targeted proteins interact with the 19S unit where they are deubiquitinylated, unfolded, and translocated to the 20S catalytic chamber for degradation. The 26S proteasome is responsible for the degradation of major proteins involved in the regulation of the cellular cycle, antigen presentation and control of protein synthesis. Alternatively, the proteasome is also active when dissociated from regulatory units. This free pool of 20S proteasome is described in yeast to mammalian cells. The free 20S proteasome degrades proteins by a process independent of poly-ubiquitinylation and ATP consumption. Oxidatively modified proteins and other substrates are degraded in this manner. The 20S proteasome comprises two central heptamers (β-rings) where the catalytic sites are located and two external heptamers (α-rings) that are responsible for proteasomal gating. Because the 20S proteasome lacks regulatory units, it is unclear what mechanisms regulate the gating of α-rings between open and closed forms. In the present review, we discuss 20S proteasomal gating modulation through a redox mechanism, namely, S-glutathionylation of cysteine residues located in the α-rings, and the consequence of this post-translational modification on 20S proteasomal function.
      Graphical abstract image

      PubDate: 2013-12-15T15:10:52Z
       
  • Oxidative actions of hydrogen peroxide in human gingival and oral
           periosteal fibroblasts: Responses to glutathione and nicotine, relevant to
           healing in a redox environment
    • Abstract: Publication date: Available online 10 December 2013
      Source:Redox Biology
      Author(s): Federico Tinti , Mena Soory
      Background This study aims to validate pro-oxidant actions of nicotine (N), using hydrogen peroxide (H2O2) and the antioxidant glutathione (G) in an in vitro model of human gingival fibroblasts (HGF) and human oral periosteal fibroblasts (HPF); radiolabelled androgens are used as biomarkers of redox status. Oxidative stress is an important mediator of inflammatory repair. The androgen metabolite 5α-dihydrotestosterone (DHT) is an effective biomarker of oxidative stress and healing. Methods 6 cell-lines of HGF and HPF established in confluent monolayer culture were incubated in Eagle's MEM using 14C-testosterone and 14C-4-androstendione as substrate; in conjunction with effective concentrations of N, G and H2O2 established at N250, G3μg/ml and 3%H2O2 w/w, 0.5μl/ml. Combinations of H2O2G and H2O2GN were used in order to compare the oxidative effects of N / H2O2 and their responses to glutathione. At 24h, the medium was solvent extracted, evaporated to dryness and subjected to TLC in a benzene/ acetone solvent system 4:1v/v for the separation of metabolites. The separated metabolites were quantified using a radioisotope scanner. Results The mean trends of 6 cell-lines for both substrates and each cell type demonstrated that the yield of the main metabolite DHT was significantly reduced by N and H2O2 alone (2-fold, n=6; p<0.01). The inhibition caused by H2O2 was overcome by the antioxidant glutathione in the combination H2O2G, to values similar to those of controls (n=6; p<0.01). It is relevant that when N was added to this neutralized combination, the decrease in yields of DHT triggered by N were comparable to those induced by H2O2; and retaining the positive effect of G. Conclusion Oxidative stress mediated by H2O2 was overcome by glutathione and recurred when nicotine was added, suggestive of a pro- oxidant role for nicotine. Androgen biomarkers are a sensitive index of oxidative stress which affects wound healing.
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      PubDate: 2013-12-11T09:08:45Z
       
  • Adaptive responses induced by 24S-hydroxycholesterol through liver X
           receptor pathway reduce 7-ketocholesterol-caused neuronal cell death
    • Abstract: Publication date: Available online 4 December 2013
      Source:Redox Biology
      Author(s): Akishi Okabe , Yasuomi Urano , Sayoko Itoh , Naoto Suda , Rina Kotani , Yuki Nishimura , Yoshiro Saito , Noriko Noguchi
      Lipid peroxidation products have been known to induce cellular adaptive responses and enhance tolerance against subsequent oxidative stress through up-regulation of antioxidant compounds and enzymes. 24S-hydroxycholesterol (24SOHC) which is endogenously produced oxysterol in the brain plays an important role in maintaining brain cholesterol homeostasis. In this study, we evaluated adaptive responses induced by brain-specific oxysterol 24SOHC in human neuroblastoma SH-SY5Y cells. Cells treated with 24SOHC at sub-lethal concentrations showed significant reduction in cell death induced by subsequent treatment with 7-ketocholesterol (7KC) in both undifferentiated and retinoic acid-differentiated SH-SY5Y cells. These adaptive responses were also induced by other oxysterols such as 25-hydroxycholesterol and 27-hydroxycholesterol which are known to be ligands of liver X receptor (LXR). Co-treatment of 24SOHC with 9-cis retinoic acid, a retinoid X receptor ligand, enhanced the adaptive responses. Knockdown of LXRβ by siRNA diminished the adaptive responses induced by 24SOHC almost completely. The treatment with 24SOHC induced the expression of LXR target genes, such as ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1). The 24SOHC-induced adaptive responses were significantly attenuated by siRNA for ABCG1 but not by siRNA for ABCA1. Taken together, these results strongly suggest that 24SOHC at sub-lethal concentrations induces adaptive responses via transcriptional activation of LXR signaling pathway, thereby protecting neuronal cells from subsequent 7KC-induced cytotoxicity.
      Graphical abstract image

      PubDate: 2013-12-06T23:57:47Z
       
  • Pharmacological Ascorbate and Ionizing Radiation (IR) Increase Labile Iron
           in Pancreatic Cancer
    • Abstract: Publication date: Available online 26 November 2013
      Source:Redox Biology
      Author(s): Justin C. Moser , Malvika Rawal , Brett A. Wagner , Juan Du , Joseph J. Cullen , Garry R. Buettner
      Labile iron, i.e. iron that is weakly bound and is relatively unrestricted in its redox activity, has been implicated in both the pathogenesis as well as treatment of cancer. Two cancer treatments where labile iron may contribute to their mechanism of action are pharmacological ascorbate and ionizing radiation (IR). Pharmacological ascorbate has been shown to have tumor-specific toxic effects due to the formation of hydrogen peroxide. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of hydrogen peroxide; labile iron can also react with hydrogen peroxide. Here we have investigated the magnitude of the labile iron pool in tumor and normal tissue. We also examined the ability of pharmacological ascorbate and IR to change the size of the labile iron pool. Although a significant amount of labile iron was seen in tumors (Mia PaCa-2 cells in athymic nude mice), higher levels were seen in murine tissues that were not susceptible to pharmacological ascorbate. Pharmacological ascorbate and irradiation were shown to increase the labile iron in tumor homogenates from this murine model of pancreatic cancer. As both IR and pharmacological ascorbate may rely on labile iron for their effects on tumor tissues, our data suggest that pharmacological ascorbate could be used as a radio-sensitizing agent for some radio-resistant tumors.
      Graphical abstract image

      PubDate: 2013-11-29T13:55:32Z
       
  • Ozone Inhalation Modifies the Rat Liver Proteome
    • Abstract: Publication date: Available online 27 November 2013
      Source:Redox Biology
      Author(s): Whitney S. Theis , Kelly K. Andringa , Telisha Millender-Swain , Dale A. Dickinson , Edward M. Postlethwait , Shannon M. Bailey
      Ozone (O3) is a serious public health concern. Recent findings indicate that the damaging health effects of O3 extend to multiple systemic organ systems. Herein, we hypothesize that O3 inhalation will cause downstream alterations to the liver. To test this, male Sprague-Dawley rats were exposed to 0.5ppm O3 for 8h/day for 5 days. Plasma liver enzyme measurements showed that 5 day O3 exposure did not cause liver cell death. Proteomic and mass spectrometry analysis identified 10 proteins in the liver that were significantly altered in abundance following short-term O3 exposure and these included several stress responsive proteins. Glucose-regulated protein 78 and protein disulfide isomerase increased, whereas glutathione S-transferase M1 was significantly decreased by O3 inhalation. In contrast, no significant changes were detected for the stress response protein heme oxygenase-1 or cytochrome P450 2E1 and 2B in liver of O3 exposed rats compared to controls. In summary, these results show that an environmentally-relevant exposure to inhaled O3 can alter the expression of select proteins in the liver. We propose that O3 inhalation may represent an important unrecognized factor that can modulate hepatic metabolic functions.
      Graphical abstract image

      PubDate: 2013-11-29T13:55:32Z
       
  • Epalrestat increases intracellular glutathione levels in Schwann cells
           through transcription regulation
    • Abstract: Publication date: Available online 19 November 2013
      Source:Redox Biology
      Author(s): Keisuke Sato , Kaori Yama , Yu Murao , Ryosuke Tatsunami , Yoshiko Tampo
      Epalrestat (EPS), approved in Japan, is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Here we report that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH), which is important for protection against oxidative injury, through transcription regulation. Treatment of Schwann cells with EPS caused a dramatic increase in intracellular GSH levels. EPS increased the mRNA levels of γ-glutamylcysteine synthetase (γ-GCS), the enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that plays a central role in regulating the expression of γ-GCS. ELISA revealed that EPS increased nuclear Nrf2 levels. Knockdown of Nrf2 by siRNA suppressed the EPS-induced GSH biosynthesis. Furthermore, pretreatment with EPS reduced the cytotoxicity induced by H2O2, tert-butylhydroperoxide, 2,2’-azobis (2-amidinopropane) dihydrochloride, and menadione, indicating that EPS plays a role in protecting against oxidative stress. This is the first study to show that EPS induces GSH biosynthesis via the activation of Nrf2. We suggest that EPS has new beneficial properties that may prevent the development and progression of disorders caused by oxidative stress.
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      PubDate: 2013-11-21T17:22:49Z
       
  • Over-expressed Copper/Zinc Superoxide Dismutase Localizes to Mitochondria
           in Neurons Inhibiting the Angiotensin II-Mediated Increase in
           Mitochondrial Superoxide
    • Abstract: Publication date: Available online 18 November 2013
      Source:Redox Biology
      Author(s): Shumin Li , Adam J. Case , Rui-Fang Yang , Harold D. Schultz , Matthew C. Zimmerman
      Angiotensin II (AngII) is the main effector peptide of the renin-angiotensin system (RAS), and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2 •−). Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2 •−. We have previously reported that over-expression of manganese superoxide dismutase (MnSOD), a mitochondrial matrix-localized O2 •− scavenging enzyme, inhibits AngII intra-neuronal signaling. Interestingly, over-expression of copper/zinc superoxide dismutase (CuZnSOD), which is believed to be primarily localized to the cytoplasm, similarly inhibits AngII intra-neuronal signaling and provides protection against AngII-mediated neurogenic hypertension. Herein, we tested the hypothesis that CuZnSOD over-expression in central neurons localizes to mitochondria and inhibits AngII intra-neuronal signaling by scavenging mitochondrial O2 •−. Using a neuronal cell culture model (CATH.a neurons), we demonstrate that both endogenous and adenovirus-mediated over-expressed CuZnSOD (AdCuZnSOD) is present in mitochondria. Furthermore, we show that over-expression of CuZnSOD attenuates the AngII-mediated increase in mitochondrial O2 •− levels and the AngII-induced inhibition of neuronal potassium current. Taken together, these data clearly show that over-expressed CuZnSOD in neurons localizes in mitochondria, scavenges AngII-induced mitochondrial O2 •−, and inhibits AngII intra-neuronal signaling.
      Graphical abstract image

      PubDate: 2013-11-21T17:22:49Z
       
  • Co-Treatment with Conjugated Linoleic Acid and Nitrite Protects Against
           Myocardial Infarction
    • Abstract: Publication date: Available online 7 November 2013
      Source:Redox Biology
      Author(s): Natia Qipshidze-Kelm , Kellianne M. Piell , Jane C. Solinger , Marsha P. Cole
      According to the CDC, the most common type of heart disease is coronary artery disease, which commonly leads to myocardial infarction (MI). Therapeutic approaches to lessen the resulting cardiovascular injury associated with MI are limited. Recently, MicroRNAs (miRNAs) have been shown to act as negative regulators of gene expression by inhibiting mRNA translation and/or stimulating mRNA degradation. A single miRNA can modulate physiological or disease phenotypes by regulating whole functional systems. Importantly, miRNAs can regulate cardiac function, thereby modulating heart muscle contraction, heart growth and morphogenesis. MicroRNA-499 (miRNA-499) is a cardiac-specific miRNA that when elevated causes cardiomyocyte hypertrophy, in turn preventing cardiac dysfunction during MI. Previous studies revealed that combination treatment with conjugated linoleic acid (cLA) and nitrite preserved cardiovascular function in mice. Therefore, it was hypothesized that cLA and nitrite may regulate miRNA-499, thus providing cardiac protection during MI. To test this hypothesis, 12-week old mice were treated with cLA (10mg/kg/d-via osmotic mini-pump) or cLA and nitrite (50ppm-drinking water) 3 days prior to MI (ligation of the left anterior descending artery). Echocardiography and pressure-volume (PV)-loop analysis revealed that cLA and nitrite-treated MI mice had improved heart function (10 days following MI) compared to untreated MI mice. Treatment with cLA and nitrite significantly induced levels of miRNA-499 compared to untreated MI mice. In addition, treatment with cLA and nitrite abolished MI-induced protein expression of p53 and dynamin-related protein-1 (DRP-1). Moreover, the antioxidant enzyme expression of heme oxygenase-1 (HO-1) was elevated in MI mice treated with cLA and nitrite compared to untreated MI mice. Confocal imaging on heart tissue confirmed expression the levels of HO-1 and p53. Taken together, these results suggest that therapeutic treatment with cLA and nitrite may provide significant protection during MI through regulation of both cardiac specific miRNA-499 and upregulation of phase 2 antioxidant enzyme expression.
      Graphical abstract image

      PubDate: 2013-11-08T20:39:02Z
       
 
 
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