for Journals by Title or ISSN
for Articles by Keywords
help
Followed Journals
Journal you Follow: 0
 
Sign Up to follow journals, search in your chosen journals and, optionally, receive Email Alerts when new issues of your Followed Jurnals are published.
Already have an account? Sign In to see the journals you follow.
Journal Cover Redox Biology
   [3 followers]  Follow    
  This is an Open Access Journal Open Access journal
     ISSN (Online) 2213-2317
     Published by Elsevier Homepage  [2563 journals]
  • Polyphenol fraction of extra virgin olive oil protects against endothelial
           dysfunction induced by high glucose and free fatty acids through
           modulation of nitric oxide and endothelin-1

    • Abstract: Publication date: Available online 21 July 2014
      Source:Redox Biology
      Author(s): Carolina Emilia Storniolo , Joan Roselló-Catafau , Xavier Pintó , María Teresa Mitjavila , Juan José Moreno
      Epidemiological and clinical studies have reported that olive oil reduces the incidence of cardiovascular disease. However, the mechanisms involved in this beneficial effect have not been delineated. The endothelium plays an important role in blood pressure regulation through the release of potent vasodilator and vasoconstrictor agents such as nitric oxide (NO) and endothelin-1 (ET-1), respectively, events that are disrupted in type 2 diabetes. Extra virgin olive oil contains polyphenols, compounds that exert a biological action on endothelial function. This study analyzes the effects of olive oil polyphenols on endothelial dysfunction using an in vitro model that simulates the conditions of type 2 diabetes. Our findings show that high glucose and linoleic and oleic acids decrease endothelial NO synthase phosphorylation, and consequently intracellular NO levels, and increase ET-1 synthesis by ECV304 cells. These effects may be related to the stimulation of reactive oxygen species production in these experimental conditions. Hydroxytyrosol and the polyphenol extract from extra virgin olive oil partially reversed the above events. Moreover, we observed that high glucose and free fatty acids reduced NO and increased ET-1 levels induced by acetylcholine through the modulation of intracellular calcium concentrations and endothelial NO synthase phosphorylation, events also reverted by hydroxytyrosol and polyphenol extract. Thus, our results suggest a protective effect of olive oil polyphenols on endothelial dysfunction induced by hyperglycemia and free fatty acids.
      Graphical abstract image

      PubDate: 2014-07-25T21:39:30Z
       
  • Biochemical methods for monitoring protein thiol redox states in
           biological systems

    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): Olena Rudyk , Philip Eaton
      Oxidative post-translational modifications of proteins resulting from events that increase cellular oxidant levels play important roles in physiological and pathophysiological processes. Evaluation of alterations to protein redox states is increasingly common place because of methodological advances that have enabled detection, quantification and identification of such changes in cells and tissues. This mini-review provides a synopsis of biochemical methods that can be utilized to monitor the array of different oxidative and electrophilic modifications that can occur to protein thiols and can be important in the regulatory or maladaptive impact oxidants can have on biological systems. Several of the methods discussed are valuable for monitoring the redox state of established redox sensing proteins such as Keap1.


      PubDate: 2014-07-25T21:39:30Z
       
  • Wine consumption and intestinal redox homeostasis

    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): Fiorella Biasi , Monica Deiana , Tina Guina , Paola Gamba , Gabriella Leonarduzzi , Giuseppe Poli
      Regular consumption of moderate doses of wine is an integral part of the Mediterranean diet, which has long been considered to provide remarkable health benefits. Wine׳s beneficial effect has been attributed principally to its non-alcoholic portion, which has antioxidant properties, and contains a wide variety of phenolics, generally called polyphenols. Wine phenolics may prevent or delay the progression of intestinal diseases characterized by oxidative stress and inflammation, especially because they reach higher concentrations in the gut than in other tissues. They act as both free radical scavengers and modulators of specific inflammation-related genes involved in cellular redox signaling. In addition, the importance of wine polyphenols has recently been stressed for their ability to act as prebiotics and antimicrobial agents. Wine components have been proposed as an alternative natural approach to prevent or treat inflammatory bowel diseases. The difficulty remains to distinguish whether these positive properties are due only to polyphenols in wine or also to the alcohol intake, since many studies have reported ethanol to possess various beneficial effects. Our knowledge of the use of wine components in managing human intestinal inflammatory diseases is still quite limited, and further clinical studies may afford more solid evidence of their beneficial effects.


      PubDate: 2014-07-25T21:39:30Z
       
  • Variants of mitochondrial autophagy: Types 1 and 2 mitophagy and
           micromitophagy (Type 3)

    • Abstract: Publication date: 2014
      Source:Redox Biology, Volume 2
      Author(s): John J. Lemasters
      Mitophagy (mitochondrial autophagy), which removes damaged, effete and superfluous mitochondria, has several distinct variants. In Type 1 mitophagy occurring during nutrient deprivation, preautophagic structures (PAS) grow into cup-shaped phagophores that surround and sequester individual mitochondria into mitophagosomes, a process requiring phosphatidylinositol-3-kinase (PI3K) and often occurring in coordination with mitochondrial fission. After sequestration, the outer compartment of the mitophagosome acidifies, followed by mitochondrial depolarization and ultimately hydrolytic digestion in lysosomes. Mitochondrial damage stimulates Type 2 mitophagy. After photodamage to single mitochondria, depolarization occurs followed by decoration and then coalescence of autophagic LC3-containing structures on mitochondrial surfaces. Vesicular acidification then occurs. By contrast to Type 1 mitophagy, PI3K inhibition does not block Type 2 mitophagy. Further, Type 2 mitophagy is not associated with phagophore formation or mitochondrial fission. A third form of self-eating of mitochondria is formation of mitochondria-derived vesicles (MDVs) enriched in oxidized mitochondrial proteins that bud off and transit into multivesicular bodies. Topologically, the internalization of MDV by invagination of the surface of multivesicular bodies followed by vesicle scission into the lumen is a form of microautophagy, or micromitophagy (Type 3 mitophagy). Cell biological distinctions are the basis for these three types of mitophagy. Future studies are needed to better characterize the molecular and biochemical differences between Types 1, 2 and 3 mitophagy.


      PubDate: 2014-07-25T21:39:30Z
       
  • Zinc regulates iNOS-derived nitric oxide formation in endothelial cells

    • Abstract: Publication date: Available online 16 July 2014
      Source:Redox Biology
      Author(s): Miriam M. Cortese-Krott , Larissa Kulakov , Christian Opländer , Victoria Kolb-Bachofen , Klaus-D. Kröncked , Christoph V. Suschek
      Aberrant production of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in the pathogenesis of endothelial dysfunction and vascular disease. Mechanisms responsible for the fine-tuning of iNOS activity in inflammation are still not fully understood. Zinc is an important structural element of NOS enzymes and is known to inhibit its catalytical activity. In this study we aimed to investigate the effects of zinc on iNOS activity and expression in endothelial cells. We found that zinc down-regulated the expression of iNOS (mRNA + protein) and decreased cytokine-mediated activation of the iNOS promoter. Zinc-mediated regulation of iNOS expression was due to inhibition of NF-κB transactivation activity, as determined by a decrease in both NF-κB-driven luciferase reporter activity and expression of NF-κB target genes, including cyclooxygenase 2 and IL-1β. However, zinc did not affect NF-κB translocation into the nucleus, as assessed by Western blot analysis of nuclear and cytoplasmic fractions. Taken together our results demonstrate that zinc limits iNOS-derived high output NO production in endothelial cells by inhibiting NF-κB-dependent iNOS expression, pointing to a role of zinc as a regulator of iNOS activity in inflammation.
      Graphical abstract image

      PubDate: 2014-07-25T21:39:30Z
       
  • Oxidative damage in the gastrocnemius of patients with peripheral artery
           disease is myofiber type selective

    • Abstract: Publication date: Available online 18 July 2014
      Source:Redox Biology
      Author(s): Panagiotis Koutakis , Dustin J. Weiss , Dimitrios Miserlis , Valerie K. Shostrom , Evlampia Papoutsi , Duy M. Ha , Lauren A. Carpenter , Rodney D. McComb , George P. Casale , Iraklis I. Pipinos
      Background Peripheral artery disease (PAD), a manifestation of systemic atherosclerosis that produces blockages in the arteries supplying the legs, affects approximately 5% of Americans. We have previously, demonstrated that a myopathy characterized by myofiber oxidative damage and degeneration is central to PAD pathophysiology. Objectives In this study, we hypothesized that increased oxidative damage in the myofibers of the gastrocnemius of PAD patients is myofiber-type selective and correlates with reduced myofiber size. Methods Needle biopsies were taken from the gastrocnemius of 53 PAD patients (28 with early PAD and 25 with advanced PAD) and 25 controls. Carbonyl groups (marker of oxidative damage), were quantified in myofibers of slide-mounted tissue, by quantitative fluorescence microscopy. Myofiber cross-sectional area was determined from sarcolemma labeled with wheat germ agglutinin. The tissues were also labeled for myosin I and II, permitting quantification of oxidative damage to and relative frequency of the different myofiber Types (Type I, Type II and mixed Type I/II myofibers). We compared PAD patients in early (N = 28) versus advanced (N = 25) disease stage for selective, myofiber oxidative damage and altered morphometrics. Results The carbonyl content of gastrocnemius myofibers was higher in PAD patients compared to control subjects, for all three myofiber types (p < 0.05). In PAD patients carbonyl content was higher (p < 0.05) in Type II and I/II fibers compared to Type I fibers. Furthermore, the relative frequency and cross-sectional area of Type II fibers were lower, while the relative frequencies and cross-sectional area of Type I and Type I/II fibers were higher, in PAD compared to control gastrocnemius (p < 0.05). Lastly, the type II-selective oxidative damage and reduced size increased as the disease progressed from the early to advanced stage. Conclusions Our data confirm increased myofiber oxidative damage and reduced myofiber size in PAD gastrocnemius and demonstrate that the damage is selective for type II myofibers and is worse in the most advanced stage of PAD.
      Graphical abstract image

      PubDate: 2014-07-25T21:39:30Z
       
  • Sources of superoxide/H2O2 during mitochondrial proline oxidation

    • Abstract: Publication date: Available online 18 July 2014
      Source:Redox Biology
      Author(s): Renata L.S. Goncalves , Daniel E. Rothschild , Casey L. Quinlan , Gary K. Scott , Christopher C. Benz , Martin D. Brand
      p53 inducible gene 6 (PIG6) encodes mitochondrial proline dehydrogenase (PRODH) and is up-regulated severalfold upon p53 activation. Proline dehydrogenase is proposed to generate radicals that contribute to cancer cell apoptosis. However, there are at least ten mitochondrial sites that can produce superoxide and/or H2O2, and it is unclear whether proline dehydrogenase generates these species directly, or instead drives production by other sites. Amongst six cancer cell lines, ZR75-30 human breast cancer cells had the highest basal proline dehydrogenase levels, and mitochondria isolated from ZR75-30 cells consumed oxygen and produced H2O2 with proline as sole substrate. Insects use proline oxidation to fuel flight, and mitochondria isolated from Drosophila melanogaster were even more active with proline as sole substrate than ZR75-30 mitochondria. Using mitochondria from these two models we identified the sites involved in formation of superoxide/H2O2 during proline oxidation. In mitochondria from Drosophila the main sites were respiratory complexes I and II. In mitochondria from ZR75-30 breast cancer cells the main sites were complex I and the oxoglutarate dehydrogenase complex. Even with combinations of substrates and respiratory chain inhibitors designed to minimize the contributions of other sites and maximize any superoxide/H2O2 production from proline dehydrogenase itself, there was no significant direct contribution of proline dehydrogenase to the observed H2O2 production. Thus proline oxidation by proline dehydrogenase drives superoxide/H2O2 production, but it does so mainly or exclusively by providing anaplerotic carbon for other mitochondrial dehydrogenases and not by producing superoxide/H2O2 directly.
      Graphical abstract image

      PubDate: 2014-07-25T21:39:30Z
       
  • Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates
           arachidonate metabolism and prostaglandin synthesis through lipid peroxide
           production in LPS-stimulated RAW 264.7 macrophages

    • Abstract: Publication date: Available online 21 July 2014
      Source:Redox Biology
      Author(s): M. Allegra , F. D’Acquisto , L. Tesoriere , A. Attanzio , M.A. Livrea
      Macrophages come across active prostaglandin (PG) metabolism during inflammation, shunting early production of pro-inflammatory towards anti-inflammatory mediators terminating the process. This work for the first time provides evidence that a phytochemical may modulate the arachidonate (AA) metabolism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, promoting the ultimate formation of anti-inflammatory cyclopentenone 15deoxy-PGJ2. Added 1 h before LPS, indicaxanthin from Opuntia Ficus Indica prevented activation of nuclear factor-B (NF-κB) and over-expression of PGE2 synthase-1 (mPGES-1), but up-regulated cyclo-oxygenase-2 (COX-2) and PGD2 synthase (H-PGDS), with final production of the anti-inflammatory cyclopentenone. The effects were positively related with concentration between 50 and 100 µM. Indicaxanthin did not have any effect in the absence of LPS. A kinetic study investigating the redox status of LPS-stimulated macrophages between 0.5–12 h, either in the absence or in the presence of 50–100 µM indicaxanthin, revealed a differential control of ROS production, with early (0.5–3 h) modest inhibition, followed by a progressive (3–12 h) concentration-dependent enhancement over the level induced by LPS alone. In addition, indicaxanthin caused early (0.5–3 h) concentration-dependent elevation of conjugated diene lipid hydroperoxides, and production of hydroxynonenal-protein adducts, over the amount induced by LPS. In LPS-stimulated macrophages indicaxanthin did not affect PG metabolism when co-incubated with either an inhibitor of NADPH oxidase or vitamin E. It is concluded that LPS-induced pro-oxidant activity of indicaxanthin at the membrane level allows formation of signaling intermediates whose accumulation modulates PG biosynthetic pathway in inflamed macrophages.
      Graphical abstract image

      PubDate: 2014-07-25T21:39:30Z
       
  • Mitochondrial reactive oxygen species: A double edged sword in
           ischemia/reperfusion vs preconditioning

    • Abstract: Publication date: Available online 1 June 2014
      Source:Redox Biology
      Author(s): Theodore Kalogeris , Yimin Bao , Ronald J. Korthuis
      Reductions in the blood supply produce considerable injury if the duration of ischemia is prolonged. Paradoxically, restoration of perfusion to ischemic organs can exacerbate tissue damage and extend the size of an evolving infarct. Being highly metabolic organs, the heart and brain are particularly vulnerable to the deleterious effects of ischemia/reperfusion (I/R). While the pathogenetic mechanisms contributing to I/R-induced tissue injury and infarction are multifactorial, the relative importance of each contributing factor remains unclear. However, an emerging body of evidence indicates that the generation of reactive oxygen species (ROS) by mitochondria plays a critical role in damaging cellular components and initiating cell death. In this review, we summarize our current understanding of the mechanisms whereby mitochondrial ROS generation occurs in I/R and contributes to myocardial infarction and stroke. In addition, mitochondrial ROS have been shown to participate in preconditioning by several pharmacologic agents that target potassium channels (eg, ATP-sensitive potassium (mKATP) channels or large conductance, calcium-activated potassium (mBKCa) channels) to activate cell survival programs that render tissues and organs more resistant to the deleterious effects of I/R. Finally, we review novel therapeutic approaches that selectively target mROS production to reduce postischemic tissue injury, which may prove efficacious in limiting myocardial dysfunction and infarction and abrogating neurocognitive deficits and neuronal cell death in stroke.


      PubDate: 2014-06-05T14:49:58Z
       
  • Oxidative post-translational modifications and their involvement in the
           pathogenesis of autoimmune diseases

    • Abstract: Publication date: Available online 28 May 2014
      Source:Redox Biology
      Author(s): Brent J. Ryan , Ahuva Nissim , Paul G. Winyard
      Tissue inflammation results in the production of numerous reactive oxygen, nitrogen and chlorine species, in addition to the products of lipid and sugar oxidation. Some of these products are capable of chemically modifying amino acids. This in turn results in changes to the structure and function of proteins. Increasing evidence demonstrates that such oxidative post-translational modifications result in the generation of neo-epitopes capable of eliciting both innate and adaptive immune responses in both health and disease. In this paper, we focus on how free radicals and other species generated in inflammatory environments modulate the antigenicity of self-proteins, resulting in immune responses which involve the generation of autoantibodies against key autoantigens in autoimmune diseases. As examples, we will focus on type-II collagen in rheumatoid arthritis and Ro-60 and C1q in systemic lupus erythematosus. This review also covers some of the emerging literature which demonstrates that neo-epitopes generated by oxidation are conserved, as exemplified by the evolutionarily conserved PAMPs (pathogen-associated molecular patterns). We discuss how these observations relate to the pathogenesis of both human autoimmune diseases and inflammatory disease, such as atherosclerosis. The potential for these neo-epitopes and the immune responses against them to act as biomarkers or therapeutic targets is also discussed.
      Graphical abstract image

      PubDate: 2014-06-05T14:49:58Z
       
  • Oxygen delivery, consumption, and conversion to reactive oxygen species in
           experimental models of diabetic retinopathy

    • Abstract: Publication date: Available online 18 April 2014
      Source:Redox Biology
      Author(s): Randa S. Eshaq , William S. Wright , Norman R. Harris
      Retinal tissue receives its supply of oxygen from two sources – the retinal and choroidal circulations. Decreases in retinal blood flow occur in the early stages of diabetes, with the eventual development of hypoxia thought to contribute to pathological neovascularization. Oxygen consumption in the retina has been found to decrease in diabetes, possibly due to either a reduction in neuronal metabolism or to cell death. Diabetes also enhances the rate of conversion of oxygen to superoxide in the retina, with experimental evidence suggesting that mitochondrial superoxide not only drives the overall production of reactive oxygen species, but also initiates several pathways leading to retinopathy, including the increased activity of the polyol and hexosamine pathways, increased production of advanced glycation end products and expression of their receptors, and activation of protein kinase C.
      Graphical abstract image

      PubDate: 2014-04-21T05:38:26Z
       
  • Redox status in mammalian cells and stem cells during culture in vitro:
           Critical roles of Nrf2 and cystine transporter activity in maintenance of
           redox balance

    • Abstract: Publication date: Available online 18 April 2014
      Source:Redox Biology
      Author(s): Tetsuro Ishii , Giovanni E. Mann
      Culturing cells and tissues in vitro has provided valuable insights into the molecular mechanisms regulating redox signaling in cells with implications for medicine. However, standard culture techniques maintain mammalian cells in vitro under an artificial physicochemical environment such as ambient air and 5% CO2. Oxidative stress is caused by the rapid oxidation of cysteine to cystine in culture media catalyzed by transition metals, leading to diminished intracellular cysteine and glutathione (GSH) pools. Some cells, such as fibroblasts and macrophages, express cystine transport activity, designated as system x c-, which enables cells to maintain these pools to counteract oxidative stress. Additionally, many cells have the ability to activate the redox sensitive transcription factor Nrf2, a master regulator of cellular defenses against oxidative stress, and to upregulate xCT, the subunit of the x c- transport system leading to increases in cellular GSH. In contrast, some cells, including lymphoid cells, embryonic stem cells and iPS cells, express relatively low levels of xCT and cannot maintain cellular cysteine and GSH pools. Thus, fibroblasts have been used as feeder cells for the latter cell types based on their ability to supply cysteine. Other key Nrf2 regulated gene products include heme oxygenase 1, peroxiredoxin 1 and sequestosome1. In macrophages, oxidized LDL activates Nrf2 and upregulates the scavenger receptor CD36 forming a positive feedback loop to facilitate removal of the oxidant from the vascular microenvironment. This review describes cell type specific responses to oxygen derived stress, and the key roles that activation of Nrf2 and membrane transport of cystine and cysteine play in the maintenance and proliferation of mammalian cells in culture.
      Graphical abstract image

      PubDate: 2014-04-21T05:38:26Z
       
  • 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.
      Graphical abstract image

      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.
      Graphical abstract image

      PubDate: 2014-04-05T19:10:36Z
       
  • 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.
      Graphical abstract image

      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
       
  • 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.
      Graphical abstract image

      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
       
  • 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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      PubDate: 2014-02-04T10:21:55Z
       
  • 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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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 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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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
       
  • 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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2014