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Journal Cover Redox Biology
  [SJR: 2.382]   [H-I: 24]   [1 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2213-2317
   Published by Elsevier Homepage  [3038 journals]
  • Direct measurement of actual levels of nitric oxide (NO) in cell culture
           conditions using soluble NO donors

    • Authors: Weilue He; Megan C. Frost
      Pages: 1 - 14
      Abstract: Publication date: October 2016
      Source:Redox Biology, Volume 9
      Author(s): Weilue He, Megan C. Frost
      Applying soluble nitric oxide (NO) donors is the most widely used method to expose cells of interest to exogenous NO. Because of the complex equilibria that exist between components in culture media, the donor compound and NO itself, it is very challenging to predict the dose and duration of NO cells actually experience. To determine the actual level of NO experienced by cells exposed to soluble NO donors, we developed the CellNO Trap, a device that allows continuous, real-time monitoring of the level of NO adherent cells produce and/or experience in culture without the need to alter cell culturing procedures. Herein, we directly measured the level of NO that cells grown in the CellNO Trap experienced when soluble NO donors were added to solutions in culture wells and we characterized environmental conditions that effected the level of NO in in vitro culture conditions. Specifically, the dose and duration of NO generated by the soluble donors S-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), S-nitrosocysteine (CysNO) and the diazeniumdiolate diethyltriamine (DETA/NO) were investigated in both phosphate buffered saline (PBS) and cell culture media. Other factors that were studied that potentially affect the ultimate NO level achieved with these donors included pH, presence of transition metals (ion species), redox level, presence of free thiol and relative volume of media. Then murine smooth muscle cell (MOVAS) with different NO donors but with the same effective concentration of available NO were examined and it was demonstrated that the cell proliferation ratio observed does not correlate with the half-lives of NO donors characterized in PBS, but does correlate well with the real-time NO profiles measured under the actual culture conditions. This data demonstrates the dynamic characteristic of the NO and NO donor in different biological systems and clearly illustrates the importance of tracking individual NO profiles under the actual biological conditions.
      Graphical abstract image

      PubDate: 2016-06-14T19:55:24Z
      DOI: 10.1016/j.redox.2016.05.002
      Issue No: Vol. 9 (2016)
       
  • Redox mechanisms in age-related lung fibrosis

    • Authors: Ashish Kurundkar; Victor J. Thannickal
      Pages: 67 - 76
      Abstract: Publication date: October 2016
      Source:Redox Biology, Volume 9
      Author(s): Ashish Kurundkar, Victor J. Thannickal
      Redox signaling and oxidative stress are associated with tissue fibrosis and aging. Aging is recognized as a major risk factor for fibrotic diseases involving multiple organ systems, including that of the lung. A number of oxidant generating enzymes are upregulated while antioxidant defenses are deficient with aging and cellular senescence, leading to redox imbalance and oxidative stress. However, the precise mechanisms by which redox signaling and oxidative stress contribute to the pathogenesis of lung fibrosis are not well understood. Tissue repair is a highly regulated process that involves the interactions of several cell types, including epithelial cells, fibroblasts and inflammatory cells. Fibrosis may develop when these interactions are dysregulated with the acquisition of pro-fibrotic cellular phenotypes. In this review, we explore the roles of redox mechanisms that promote and perpetuate fibrosis in the context of cellular senescence and aging.
      Graphical abstract image

      PubDate: 2016-07-09T14:19:36Z
      DOI: 10.1016/j.redox.2016.06.005
      Issue No: Vol. 9 (2016)
       
  • The Impact of High and Low Dose Ionising Radiation on the Central Nervous
           System

    • Authors: Calina Betlazar; Ryan J. Middleton; Richard B. Banati; Guo-Jun Liu
      Pages: 144 - 156
      Abstract: Publication date: Available online 10 August 2016
      Source:Redox Biology
      Author(s): Calina Betlazar, Ryan J. Middleton, Richard B. Banati, Guo-Jun Liu
      Responses of the central nervous system (CNS) to stressors and injuries, such as ionising radiation, are modulated by the concomitant responses of the brains innate immune effector cells, microglia. Exposure to high doses of ionising radiation in brain tissue leads to the expression and release of biochemical mediators of ‘neuroinflammation’, such as pro-inflammatory cytokines and reactive oxygen species (ROS), leading to tissue destruction. Contrastingly, low dose ionising radiation may reduce vulnerability to subsequent exposure of ionising radiation, largely through the stimulation of adaptive responses, such as antioxidant defences. These disparate responses may be reflective of non-linear differential microglial activation at low and high doses, manifesting as an anti-inflammatory or pro-inflammatory functional state. Biomarkers of pathology in the brain, such as the mitochondrial Translocator Protein 18kDa (TSPO), have facilitated in vivo characterisation of microglial activation and ‘neuroinflammation’ in many pathological states of the CNS, though the exact function of TSPO in these responses remains elusive. Based on the known responsiveness of TSPO expression to a wide range of noxious stimuli, we discuss TSPO as a potential biomarker of radiation-induced effects.
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      PubDate: 2016-08-14T19:35:18Z
      DOI: 10.1016/j.redox.2016.08.002
      Issue No: Vol. 9 (2016)
       
  • Redox signaling in cardiovascular pathophysiology: A focus on hydrogen
           peroxide and vascular smooth muscle cells

    • Authors: Chang Hyun Byon; Jack M. Heath; Yabing Chen
      Pages: 244 - 253
      Abstract: Publication date: Available online 26 August 2016
      Source:Redox Biology
      Author(s): Chang Hyun Byon, Jack M Heath, Yabing Chen
      Oxidative stress represents excessive intracellular levels of reactive oxygen species (ROS), which plays a major role in the pathogenesis of cardiovascular disease. Besides having a critical impact on the development and progression of vascular pathologies including atherosclerosis and diabetic vasculopathy, oxidative stress also regulates physiological signaling processes. As a cell permeable ROS generated by cellular metabolism involved in intracellular signaling, hydrogen peroxide (H2O2) exerts tremendous impact on cardiovascular pathophysiology. Under pathological conditions, increased oxidase activities and/or impaired antioxidant systems results in uncontrolled production of ROS. In a pro-oxidant environment, vascular smooth muscle cells (VSMC) undergo phenotypic changes which can lead to the development of vascular dysfunction such as vascular inflammation and calcification. Investigations are ongoing to elucidate the mechanisms for cardiovascular disorders induced by oxidative stress. This review mainly focuses on the role of H2O2 in regulating physiological and pathological signals in VSMC.

      PubDate: 2016-08-29T22:38:05Z
      DOI: 10.1016/j.redox.2016.08.015
      Issue No: Vol. 9 (2016)
       
  • Mitochondrial GSH replenishment as a potential therapeutic approach for
           Niemann Pick type C disease

    • Authors: Sandra Torres; Nuria Matías; Anna Baulies; Susana Nuñez; Cristina Alarcon-Vila; Laura Martinez; Natalia Nuño; Anna Fernandez; Joan Caballeria; Thierry Levade; Alba Gonzalez-Franquesa; Pablo Garcia-Rovés; Elisa Balboa; Silvana Zanlungo; Gemma Fabrías; Josefina Casas; Carlos Enrich; Carmen Garcia-Ruiz; José C. Fernández-Checa
      Pages: 60 - 72
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Sandra Torres, Nuria Matías, Anna Baulies, Susana Nuñez, Cristina Alarcon-Vila, Laura Martinez, Natalia Nuño, Anna Fernandez, Joan Caballeria, Thierry Levade, Alba Gonzalez-Franquesa, Pablo Garcia-Rovés, Elisa Balboa, Silvana Zanlungo, Gemma Fabrías, Josefina Casas, Carlos Enrich, Carmen Garcia-Ruiz, José C. Fernández-Checa
      Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1 -/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1 -/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1 -/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1 -/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.
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      PubDate: 2016-11-26T09:01:10Z
      DOI: 10.1016/j.redox.2016.11.010
      Issue No: Vol. 11 (2016)
       
  • Increased mitochondrial superoxide in the brain, but not periphery,
           sensitizes mice to angiotensin II-mediated hypertension

    • Authors: Adam J. Case; Jun Tian; Matthew C. Zimmerman
      Pages: 82 - 90
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Adam J. Case, Jun Tian, Matthew C. Zimmerman
      Angiotensin II (AngII) elicits the production of superoxide (O2 •−) from mitochondria in numerous cell types within peripheral organs and in the brain suggesting a role for mitochondrial-produced O2 •− in the pathogenesis of hypertension. However, it remains unclear if mitochondrial O2 •− is causal in the development of AngII-induced hypertension, or if mitochondrial O2 •− in the absence of elevated AngII is sufficient to increase blood pressure. Further, the tissue specific (i.e. central versus peripheral) redox regulation of AngII hypertension remains elusive. Herein, we hypothesized that increased mitochondrial O2 •− in the absence of pro-hypertensive stimuli, such as AngII, elevates baseline systemic mean arterial pressure (MAP), and that AngII-mediated hypertension is exacerbated in animals with increased mitochondrial O2 •− levels. To address this hypothesis, we generated novel inducible knock-down mouse models of manganese superoxide dismutase (MnSOD), the O2 •− scavenging antioxidant enzyme specifically localized to mitochondria, targeted to either the brain subfornical organ (SFO) or peripheral tissues. Contrary to our hypothesis, knock-down of MnSOD either in the SFO or in peripheral tissues was not sufficient to alter baseline systemic MAP. Interestingly, when mice were challenged with chronic, peripheral infusion of AngII, only the MnSOD knock-down confined to the SFO, and not the periphery, demonstrated an increased sensitization and potentiated hypertension. In complementary experiments, over-expressing MnSOD in the SFO significantly decreased blood pressure in response to chronic AngII. Overall, these studies indicate that mitochondrial O2 •− in the brain SFO works in concert with other AngII-dependent factors to drive an increase in MAP, as elevated mitochondrial O2 •− alone, either in the SFO or peripheral tissues, failed to raise baseline blood pressure.
      Graphical abstract image

      PubDate: 2016-11-26T09:01:10Z
      DOI: 10.1016/j.redox.2016.11.011
      Issue No: Vol. 11 (2016)
       
  • Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission

    • Authors: Gary B. O'Mealey; William L. Berry; Scott M. Plafker
      Pages: 103 - 110
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Gary B. O'Mealey, William L. Berry, Scott M. Plafker
      The KEAP1-Nrf2-ARE antioxidant system is a principal means by which cells respond to oxidative and xenobiotic stresses. Sulforaphane (SFN), an electrophilic isothiocyanate derived from cruciferous vegetables, activates the KEAP1-Nrf2-ARE pathway and has become a molecule-of-interest in the treatment of diseases in which chronic oxidative stress plays a major etiological role. We demonstrate here that the mitochondria of cultured, human retinal pigment epithelial (RPE-1) cells treated with SFN undergo hyperfusion that is independent of both Nrf2 and its cytoplasmic inhibitor KEAP1. Mitochondrial fusion has been reported to be cytoprotective by inhibiting pore formation in mitochondria during apoptosis, and consistent with this, we show Nrf2-independent, cytoprotection of SFN-treated cells exposed to the apoptosis-inducer, staurosporine. Mechanistically, SFN mitigates the recruitment and/or retention of the soluble fission factor Drp1 to mitochondria and to peroxisomes but does not affect overall Drp1 abundance. These data demonstrate that the beneficial properties of SFN extend beyond activation of the KEAP1-Nrf2-ARE system and warrant further interrogation given the current use of this agent in multiple clinical trials.

      PubDate: 2016-11-26T09:01:10Z
      DOI: 10.1016/j.redox.2016.11.007
      Issue No: Vol. 11 (2016)
       
  • Advanced Oxidation Protein Products Sensitized the Transient Receptor
           Potential Vanilloid 1 via NADPH Oxidase 1 and 4 to Cause Mechanical
           Hyperalgesia

    • Authors: Ruoting Ding; Hui Jiang; Baihui Sun; Xiaoliang Wu; Wei Li; Siyuan Zhu; Congrui Liao; Zhaoming Zhong; Jianting Chen
      Pages: 1 - 11
      Abstract: Publication date: Available online 17 September 2016
      Source:Redox Biology
      Author(s): Ruoting Ding, Hui Jiang, Baihui Sun, Xiaoliang Wu, Wei Li, Siyuan Zhu, Congrui Liao, Zhaoming Zhong, Jianting Chen
      Oxidative stress is a possible pathogenesis of hyperalgesia. Advanced oxidation protein products (AOPPs), a new family of oxidized protein compounds, have been considered as a novel marker of oxidative stress. However, the role of AOPPs in the mechanism of hyperalgesia remains unknown. Our study aims to investigate whether AOPPs have an effect on hyperalgesia and the possible underlying mechanisms. To identify the AOPPs involved, we induced hyperalgesia in rats by injecting complete Freund’s adjuvant (CFA) in hindpaw. The level of plasma AOPPs in CFA-induced rats was 1.6-fold in comparison with what in normal rats (P<0.05). After intravenous injection of AOPPs-modified rat serum albumin (AOPPs-RSA) in Sprague-Dawley rats, the paw mechanical thresholds, measured by the electronic von Frey system, significantly declined. Immunofluorescence staining indicated that AOPPs increased expressions of NADPH oxidase 1 (Nox1), NADPH oxidase 4 (Nox4), transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in the dorsal root ganglia (DRG) tissues. In-vitro studies were performed on primary DRG neurons which were obtained from both thoracic and lumbar DRG of rats. Results indicated that AOPPs triggered reactive oxygen species (ROS) production in DRG neurons, which were significantly abolished by ROS scavenger N-acetyl-l-cysteine (NAC) and small-interfering RNA (siRNA) silencing of Nox1 or Nox4. The expressions of Nox1, Nox4, TRPV1 and CGRP were significantly increased in AOPPs-induced DRG neurons. And relevant siRNA or inhibitors notably suppressed the expressions of these proteins and the calcium influxes in AOPPs-induced DRG neurons. In conclusion, AOPPs increased significantly in CFA-induced hyperalgesia rats and they activated Nox1/Nox4-ROS to sensitize TRPV1-dependent Ca2+ influx and CGRP release which led to inducing mechanical hyperalgesia.
      Graphical abstract image

      PubDate: 2016-09-20T08:25:02Z
      DOI: 10.1016/j.redox.2016.09.004
      Issue No: Vol. 10 (2016)
       
  • Autocrine IL-10 Functions as a Rheostat for M1 Macrophage Glycolytic
           Commitment by Tuning Nitric Oxide Production

    • Authors: Walter A. Baseler; Luke C. Davies; Laura Quigley; Lisa A. Ridnour; Jonathan M. Weiss; S. Perwez Hussain; David A. Wink; Daniel W. McVicar
      Pages: 12 - 23
      Abstract: Publication date: Available online 16 September 2016
      Source:Redox Biology
      Author(s): Walter A. Baseler, Luke C. Davies, Laura Quigley, Lisa A. Ridnour, Jonathan M. Weiss, S. Perwez Hussain, David A. Wink, Daniel W. McVicar
      Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, “alternatively activated” macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments. Here we provide evidence that the immunosuppressive cytokine IL-10 defines a metabolic regulatory loop. Our data show for the first time that lipopolysaccharide (LPS)-induced glycolytic flux controls IL-10-production via regulation of mammalian target of rapamycin (mTOR) and that autocrine IL-10 in turn regulates macrophage nitric oxide (NO) production. Genetic and pharmacological manipulation of IL-10 and nitric oxide (NO) establish that metabolically regulated autocrine IL-10 controls glycolytic commitment by limiting NO-mediated suppression of OXPHOS. Together these data support a model where autocine IL-10 production is controlled by glycolytic flux in turn regulating glycolytic commitment by preserving OXPHOS via suppression of NO. We propose that this IL-10-driven metabolic rheostat maintains metabolic equilibrium during M1 macrophage differentiation and that perturbation of this regulatory loop, either directly by exogenous cellular sources of IL-10 or indirectly via limitations in glucose availability, skews the cellular metabolic program altering the balance between inflammatory and immunosuppressive phenotypes.
      Graphical abstract image

      PubDate: 2016-09-20T08:25:02Z
      DOI: 10.1016/j.redox.2016.09.005
      Issue No: Vol. 10 (2016)
       
  • Changes in brain oxysterols at different stages of Alzheimer's disease:
           their involvement in neuroinflammation

    • Authors: Gabriella Testa; Erica Staurenghi; Chiara Zerbinati; Simona Gargiulo; Luigi Iuliano; Giorgio Giaccone; Fausto Fantò; Giuseppe Poli; Gabriella Leonarduzzi; Paola Gamba
      Pages: 24 - 33
      Abstract: Publication date: Available online 16 September 2016
      Source:Redox Biology
      Author(s): Gabriella Testa, Erica Staurenghi, Chiara Zerbinati, Simona Gargiulo, Luigi Iuliano, Giorgio Giaccone, Fausto Fantò, Giuseppe Poli, Gabriella Leonarduzzi, Paola Gamba
      Alzheimer's disease (AD) is a gradually debilitating disease that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers are available for the early diagnosis. In the last several years, together with oxidative stress and neuroinflammation, altered cholesterol metabolism in the brain has become increasingly implicated in AD progression. A significant body of evidence indicates that oxidized cholesterol, in the form of oxysterols, is one of the main triggers of AD. The oxysterols potentially most closely involved in the pathogenesis of AD are 24-hydroxycholesterol and 27-hydroxycholesterol, respectively deriving from cholesterol oxidation by the enzymes CYP46A1 and CYP27A1. However, the possible involvement of oxysterols resulting from cholesterol autooxidation, including 7-ketocholesterol and 7β-hydroxycholesterol, is now emerging. In a systematic analysis of oxysterols in post-mortem human AD brains, classified by the Braak staging system of neurofibrillary pathology, alongside the two oxysterols of enzymatic origin, a variety of oxysterols deriving from cholesterol autoxidation were identified; these included 7-ketocholesterol, 7α-hydroxycholesterol, 4β-hydroxycholesterol, 5α,6α-epoxycholesterol, and 5β,6β-epoxycholesterol. Their levels were quantified and compared across the disease stages. Some inflammatory mediators, and the proteolytic enzyme matrix metalloprotease-9, were also found to be enhanced in the brains, depending on disease progression. This highlights the pathogenic association between the trends of inflammatory molecules and oxysterol levels during the evolution of AD. Conversely, sirtuin 1, an enzyme that regulates several pathways involved in the anti-inflammatory response, was reduced markedly with the progression of AD, supporting the hypothesis that the loss of sirtuin 1 might play a key role in AD. Taken together, these results strongly support the association between changes in oxysterol levels and AD progression.

      PubDate: 2016-09-20T08:25:02Z
      DOI: 10.1016/j.redox.2016.09.001
      Issue No: Vol. 10 (2016)
       
  • Resistance Training And Redox Homeostasis: Correlation With Age-Associated
           Genomic Changes

    • Authors: Dimauro Ivan; Scalabrin Mattia; Fantini Cristina; Grazioli Elisa; Beltran Valls Maria Reyes; Mercatelli Neri; Parisi Attilio; Sabatini Stefania; Di Luigi Luigi; Caporossi Daniela
      Pages: 34 - 44
      Abstract: Publication date: Available online 21 September 2016
      Source:Redox Biology
      Author(s): Dimauro Ivan, Scalabrin Mattia, Fantini Cristina, Grazioli Elisa, Beltran Valls Maria Reyes, Neri Mercatelli, Parisi Attilio, Sabatini Stefania, Di Luigi Luigi, Caporossi Daniela
      Regular physical activity is effective as prevention and treatment for different chronic conditions related to the ageing processes. In fact, a sedentary lifestyle has been linked to a worsening of cellular ageing biomarkers such as telomere length (TL) and/or specific epigenetic changes (e.g. DNA methylation), with increase of the propensity to aging-related diseases and premature death. Extending our previous findings, we aimed to test the hypothesis that 12 weeks of low frequency, moderate intensity, explosive-type resistance training (EMRT) may attenuate age-associated genomic changes. To this aim, TL, global DNA methylation, TRF2, Ku80, SIRT1, SIRT2 and global protein acetylation, as well as other proteins involved in apoptotic pathway (Bcl-2, Bax and Caspase-3), antioxidant response (TrxR1 and MnSOD) and oxidative damage (myeloperoxidase) were evaluated before and after EMRT in whole blood or peripheral mononuclear cells (PBMCs) of elderly subjects. Our findings confirm the potential of EMRT to induce an adaptive change in the antioxidant protein systems at systemic level and suggest a putative role of resistance training in the reduction of global DNA methylation. Moreover, we observed that EMRT counteracts the telomeres’ shortening in a manner that proved to be directly correlated with the amelioration of redox homeostasis and efficacy of training regime, evaluated as improvement of both muscle's power/strength and functional parameters.

      PubDate: 2016-09-24T09:13:47Z
      DOI: 10.1016/j.redox.2016.09.008
      Issue No: Vol. 10 (2016)
       
  • Glutathione Maintenance Mitigates Age Related Susceptibility to Redox
           Cycling Agents

    • Authors: Nicholas O. Thomas; Kate P. Shay; Amanda R. Kelley; Judy A. Butler; Tory M. Hagen
      Pages: 45 - 52
      Abstract: Publication date: Available online 22 September 2016
      Source:Redox Biology
      Author(s): Nicholas O. Thomas, Kate P. Shay, Amanda R. Kelley, Judy A. Butler, Tory M. Hagen
      Isolated hepatocytes from young (4-6 mo) and old (24-26 mo) F344 rats were exposed to increasing concentrations of menadione, a vitamin K derivative and redox cycling agent, to determine whether the age-related decline in Nrf2-mediated detoxification defenses resulted in heightened susceptibility to xenobiotic insult. An LC50 for each age group was established, which showed that aging resulted in a nearly 2-fold increase in susceptibility to menadione (LC50 for young: 405μM; LC50 for old: 275μM). Examination of the known Nrf2-regulated pathways associated with menadione detoxification revealed, surprisingly, that NAD(P)H:quinone oxido-reductase 1 (NQO1) protein levels and activity were induced 9-fold and 4-fold with age, respectively (p=0.0019 and p=0.018; N=3), but glutathione peroxidase 4 (GPX4) declined by 70% (p=0.0043; N=3). These results indicate toxicity may stem from vulnerability to lipid peroxidation instead of inadequate reduction of menadione semi-quinone. Lipid peroxidation was 2-fold higher, and GSH declined by a 3-fold greater margin in old versus young rat cells given 300µM menadione (p<0.05 and p≤0.01 respectively; N=3). We therefore provided 400µM N-acetyl-cysteine (NAC) to hepatocytes from old rats before menadione exposure to alleviate limits in cysteine substrate availability for GSH synthesis during challenge. NAC pretreatment resulted in a >2-fold reduction in cell death, suggesting that the age-related increase in menadione susceptibility likely stems from attenuated GSH-dependent defenses. This data identifies cellular targets for intervention in order to limit age-related toxicological insults to menadione and potentially other redox cycling compounds.
      Graphical abstract image

      PubDate: 2016-09-24T09:13:47Z
      DOI: 10.1016/j.redox.2016.09.010
      Issue No: Vol. 10 (2016)
       
  • Salinity stress from the perspective of the energy-redox axis: lessons
           from a marine intertidal flatworm

    • Authors: Georgina A. Rivera-Ingraham; Aude Nommick; Eva Blondeau-Bidet; Peter Ladurner; Jehan-Hervé Lignot
      Pages: 53 - 64
      Abstract: Publication date: Available online 22 September 2016
      Source:Redox Biology
      Author(s): Georgina A. rivera-Ingraham, Aude Nommick, Eva Blondeau-Bidet, Peter Ladurner, Jehan-Hervé Lignot
      In the context of global change, there is an urgent need for researchers in conservation physiology to understand the physiological mechanisms leading to the acquisition of stress acclimation phenotypes. Intertidal organisms continuously cope with drastic changes in their environmental conditions, making themoutstanding models for the study of physiological acclimation. As the implementation of such processes usually comes at a high bioenergetic cost, a mitochondrial/oxidative stress approach emerges as the most relevant approach when seeking to analyze whole-animal responses. Here we use the intertidal flatworm Macrostomum lignano to analyze the bioenergetics of salinity acclimation and its consequences in terms of reactive oxygen/nitrogen species formation and physiological response to counteract redox imbalance. Measures of water fluxes and body volume suggest that M. lignano is a hyper-/iso-regulator. Higher salinities were revealed to be the most energetically expensive conditions, with an increase in mitochondrial density accompanied by increased respiration rates. Such modifications came at the price of enhanced superoxide anion production, likely associated with a high caspase 3 upregulation. These animals nevertheless managed to live at high levels of environmental salinity through the upregulation of several mitochondrial antioxidant enzymes such as superoxide dismutase. Contrarily, animals at low salinities decreased their respiration rates, reduced their activity and increased nitric oxide formation, suggesting a certain degree of metabolic arrest. A contradictory increase in dichlorofluorescein fluorescence and an upregulation of pi-gluthathione-S-transferase (GST-pi) expression were observed in these individuals. If animals at low salinity are indeed facing metabolic depression, the return to seawater may result in an oxidative burst. We hypothesize that this increase in GST-pi could be a “preparation for oxidative stress”, i.e. a mechanism to counteract the production of free radicals upon returning to seawater. The results of the present study shed new light on how tolerant organisms carry out subcellular adaptations to withstand environmental change.
      Graphical abstract image

      PubDate: 2016-09-24T09:13:47Z
      DOI: 10.1016/j.redox.2016.09.012
      Issue No: Vol. 10 (2016)
       
  • Blood Cell Respirometry is Associated with Skeletal and Cardiac Muscle
           Bioenergetics: Implications For a Minimally Invasive Biomarker of
           Mitochondrial Health

    • Authors: Daniel J. Tyrrell; Manish S. Bharadwaj; Matthew J. Jorgensen; Thomas C. Register; Anthony J.A. Molina
      Pages: 65 - 77
      Abstract: Publication date: Available online 21 September 2016
      Source:Redox Biology
      Author(s): Daniel J. Tyrrell, Manish S. Bharadwaj, Matthew J. Jorgensen, Thomas C. Register, Anthony J.A. Molina
      Blood based bioenergetic profiling strategies are emerging as potential reporters of systemic mitochondrial function; however, the extent to which these measures reflect the bioenergetic capacity of other tissues is not known. The premise of this work is that highly metabolically active tissues, such as skeletal and cardiac muscle, are susceptible to differences in systemic bioenergetic capacity. Therefore, we tested whether the respiratory capacity of blood cells, monocytes and platelets, are related to contemporaneous respirometric assessments of skeletal and cardiac muscle mitochondria. 18 female vervet/African green monkeys (Chlorocebus aethiops sabaeus) of varying age and metabolic status were examined for this study. Monocyte and platelet maximal capacity correlated with maximal oxidative phosphorylation capacity of permeabilized skeletal muscle (R=0.75, 95% confidence interval [CI]: 0.38-0.97; R=0.51, 95%CI: 0.05-0.81; respectively), isolated skeletal muscle mitochondrial respiratory control ratio (RCR; R=0.70, 95%CI: 0.35-0.89; R=0.64, 95%CI: 0.23-0.98; respectively), and isolated cardiac muscle mitochondrial RCR (R=0.55, 95%CI: 0.22-0.86; R=0.58, 95%CI: 0.22-0.85; respectively). These results suggest that blood based bioenergetic profiling may be used to report on the bioenergetic capacity of muscle tissues. Blood cell respirometry represents an attractive alternative to tissue based assessments of mitochondrial function in human studies based on ease of access and the minimal participant burden required by these measures.
      Graphical abstract image

      PubDate: 2016-09-24T09:13:47Z
      DOI: 10.1016/j.redox.2016.09.009
      Issue No: Vol. 10 (2016)
       
  • Synergistic antitumor activity of Rapamycin and EF24 via increasing ROS
           for the treatment of gastric cancer

    • Authors: Weiqian Chen; Peng Zou; Zhongwei Zhao; Xi Chen; Xiaoxi Fan; Rajamanickam Vinothkumar; Ri Cui; Fazong Wu; Qianqian Zhang; Guang Liang; Jiansong Ji
      Pages: 78 - 89
      Abstract: Publication date: Available online 21 September 2016
      Source:Redox Biology
      Author(s): Weiqian Chen, Peng Zou, Zhongwei Zhao, Xi Chen, Xiaoxi Fan, Rajamanickam Vinothkumar, Ri Cui, Fazong Wu, Qianqian Zhang, Guang Liang, Jiansong Ji
      Mechanistic/mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. Rapamycin and rapamycin analogs are undergoing clinical trials and have produced clinical responses in a subgroup of cancer patients. However, monotherapy with rapamycin at safe dosage fails to induce cell apoptosis and tumor regression which has hampered its clinical application. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of rapamycin. In our present study, we have investigated the combination of rapamycin and a reactive oxygen species (ROS) inducer EF24 in gastric cancer. We show that rapamycin increases intracellular ROS levels and displays selective synergistic antitumor activity with EF24 in gastric cancer cells. This activity was mediated through the activation of c-Jun N terminal kinase and endoplasmic reticulum stress (ER) pathways in cancer cells. We also show that inhibiting ROS accumulation reverses ER stress and prevents apoptosis induced by the combination of rapamycin and EF24. These mechanisms were confirmed using human gastric cancer xenografts in immunodeficient mice. Taken together, our work provides a novel therapeutic strategy for the treatment of gastric cancer. The work reveals that ROS generation could be an important target for the development of new combination therapies for cancer treatment.
      Graphical abstract image

      PubDate: 2016-09-24T09:13:47Z
      DOI: 10.1016/j.redox.2016.09.006
      Issue No: Vol. 10 (2016)
       
  • Hyperglycemia induced damage to mitochondrial respiration in renal
           mesangial and tubular cells: implications for diabetic nephropathy

    • Authors: Anna Czajka; Afshan N. Malik
      Pages: 100 - 107
      Abstract: Publication date: Available online 17 September 2016
      Source:Redox Biology
      Author(s): Anna Czajka, Afshan N. Malik
      Damage to renal tubular and mesangial cells is central to the development of diabetic nephropathy (DN), a complication of diabetes which can lead renal failure. Mitochondria are the site of cellular respiration and produce energy in the form of ATP via oxidative phosphorylation, and mitochondrial dysfunction has been implicated in DN. Since the kidney is an organ with high bioenergetic needs, we postulated that hyperglycemia causes damage to renal mitochondria resulting in bioenergetic deficit. The bioenergetic profiles and the effect of hyperglycemia on cellular respiration of human primary mesangial (HMCs) and proximal tubular cells (HK-2) were compared in normoglycemic and hyperglycemic conditions using the seahorse bio-analyser. In normoglycemia, HK-2 had significantly lower basal, ATP-linked and maximal respiration rates, and lower reserve capacity compared to HMCs. Hyperglycemia caused a down-regulation of all respiratory parameters within 4 days in HK-2 but not in HMCs. After 8 days of hyperglycemia, down-regulation of respiratory parameters persisted in tubular cells with compensatory up-regulated glycolysis. HMCs had reduced maximal respiration and reserve capacity at 8 days, and by 12 days had compromised mitochondrial respiration despite which they did not enhance glycolysis. These data suggest that diabetes is likely to lead to a cellular deficit in ATP production in both cell types, although with different sensitivities, and this mechanism could significantly contribute to the cellular damage seen in the diabetic kidney. Prevention of diabetes induced damage to renal mitochondrial respiration may be a novel therapeutic approach for the prevention/treatment of DN.
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      PubDate: 2016-09-20T08:25:02Z
      DOI: 10.1016/j.redox.2016.09.007
      Issue No: Vol. 10 (2016)
       
  • Signaling pathways involved in HSP32 induction by hyperbaric oxygen in rat
           spinal neurons

    • Authors: Guoyang Huang; Jiale Diao; Hongjie Yi; Li Xu; Jiajun Xu; Weigang Xu
      Pages: 108 - 118
      Abstract: Publication date: Available online 24 September 2016
      Source:Redox Biology
      Author(s): Guoyang Huang, Jiale Diao, Hongjie Yi, Li Xu, Jiajun Xu, Weigang Xu
      Spinal cord injury (SCI) is a debilitating disease, effective prevention measures are in desperate need. Our previous work found that hyperbaric oxygen (HBO) preconditioning significantly protected rats from SCI after stimulated diving, and in vitro study further testified that HBO protected primary cultured rat spinal neurons from oxidative insult and oxygen glucose deprivation injury via heat shock protein (HSP) 32 induction. In this study, underlying molecular mechanisms were further investigated. The results showed that a single exposure to HBO significantly increased intracellular levels of reactive oxygen species (ROS) and nitric oxide (NO) and activated MEK1/2, ERK1/2, p38 MAPK, CREB, Bach1 and Nrf2. The induction of HSP32 by HBO was significantly reversed by pretreatment neurons with ROS scavenger N-Acetyl-l-cysteine, p38 MAPK inhibitor or Nrf2 gene knockdown, enhanced by MEK1/2 inhibitors or gene knockdown but not by ERK1/2 inhibitor. CREB knockdown did not change the expression of HSP32 induced by HBO. N-Acetyl-l-cysteine significantly inhibited the activation of MEK1/2, ERK1/2, p38 MAPK, and Nrf2. Activation of Nrf2 was significantly inhibited by p38 MAPK inhibitor and the nuclear export of Bach1 was significantly enhanced by MEK1/2 inhibitor. The results demonstrated that HBO induces HSP32 expression through a ROS/p38 MAPK/Nrf2 pathway and the MEK1/2/Bach1 pathway contributes to negative regulation in the process. More importantly, as we know, this is the first study to delineate that ERK1/2 is not the only physiological substrates of MEK1/2.
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      PubDate: 2016-09-24T09:13:47Z
      DOI: 10.1016/j.redox.2016.09.011
      Issue No: Vol. 10 (2016)
       
  • Nitrite-mediated reduction of macrophage NADPH oxidase activity is
           dependent on xanthine oxidoreductase-derived nitric oxide but independent
           of S-nitrosation

    • Authors: Christa Zollbrecht; A. Erik G. Persson; Jon O. Lundberg; Eddie Weitzberg; Mattias Carlström
      Pages: 119 - 127
      Abstract: Publication date: Available online 28 September 2016
      Source:Redox Biology
      Author(s): Christa Zollbrecht, A. Erik G. Persson, Jon O. Lundberg, Eddie Weitzberg, Mattias Carlström
      Background Inorganic nitrite has shown beneficial effects in cardiovascular and metabolic diseases partly via attenuation of NADPH-oxidase (NOX)-mediated oxidative stress. However, the exact mechanisms are still unclear. Here we investigated the role of S-nitrosation or altered expression of NOX subunits, and the role of xanthine oxidoreductase (XOR) in nitrite-derived nitric oxide (NO) production. Methods Mouse macrophages were activated with LPS in the presence or absence of nitrite. NOX activity was measured by lucigenin-dependent chemiluminescence. Gene and protein expression of NOX2 subunits and XOR were investigated using qPCR and Western Blot. S-nitrosation of Nox2 and p22phox was studied with a Biotin Switch assay. Uric acid levels in cell culture medium were analyzed as a measure of XOR activity, and NO production was assessed by DAF-FM fluorescence. Results NOX activity in activated macrophages was significantly reduced by nitrite. Reduced NOX activity was not attributed to decreased NOX gene expression. However, protein levels of p47phox and p67phox subunits were reduced by nitrite in activated macrophages. Protein expression of Nox2 and p22phox was not influenced by this treatment and neither was their S-nitrosation status. Increased uric acid levels after nitrite and diminished NO production during XOR-inhibition with febuxostat suggest that XOR is more active during nitrite-treatment of activated macrophages and plays an important role in the bioactivation of nitrite. Conclusions Our findings contribute to the mechanistic understanding about the therapeutic effects associated with nitrite supplementation in many diseases. We show that nitrite-mediated inhibition of NOX activity cannot be explained by S-nitrosation of the NOX enzyme, but that changes in NOX2 expression and XOR function may contribute.
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      PubDate: 2016-09-30T14:51:02Z
      DOI: 10.1016/j.redox.2016.09.015
      Issue No: Vol. 10 (2016)
       
  • The synthetic progestin norgestrel modulates Nrf2 signaling and acts as an
           antioxidant in a model of retinal degeneration

    • Authors: Ashleigh M. Byrne; Ana M. Ruiz-Lopez; Sarah L. Roche; Jennifer N. Moloney; Alice C. Wyse -Jackson; Thomas G. Cotter
      Pages: 128 - 139
      Abstract: Publication date: Available online 4 October 2016
      Source:Redox Biology
      Author(s): Ashleigh M. Byrne, Ana M. Ruiz-Lopez, Sarah L. Roche, Jennifer N. Moloney, Alice C. Wyse Jackson, Thomas G. Cotter
      Retinitis pigmentosa (RP) is one of the most common retinal degenerative conditions affecting people worldwide, and is currently incurable. It is characterized by the progressive loss of photoreceptors, in which the death of rod cells leads to the secondary death of cone cells; the cause of eventual blindness. As rod cells die, retinal-oxygen metabolism becomes perturbed, leading to increased levels of reactive oxygen species (ROS) and thus oxidative stress; a key factor in the secondary death of cones. In this study, norgestrel, an FDA-approved synthetic analog of progesterone, was found to be a powerful neuroprotective antioxidant, preventing light-induced ROS in photoreceptor cells, and subsequent cell death. Norgestrel also prevented light-induced photoreceptor morphological changes that were associated with ROS production, and that are characteristic of RP. Further investigation showed that norgestrel acts via post-translational modulation of the major antioxidant transcription factor Nrf2; bringing about its phosphorylation, subsequent nuclear translocation, and increased levels of its effector protein superoxide dismutase 2 (SOD2). In summary, these results demonstrate significant protection of photoreceptor cells from oxidative stress, and underscore the potential of norgestrel as a therapeutic option for RP.
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      PubDate: 2016-10-08T11:51:09Z
      DOI: 10.1016/j.redox.2016.10.002
      Issue No: Vol. 10 (2016)
       
  • Impaired vascular function in sepsis-surviving rats mediated by oxidative
           stress and Rho-Kinase pathway

    • Authors: Priscila de Souza; Karla Lorena Guarido; Karin Scheschowitsch; Luísa Mota da Silva; Maria Fernanda Werner; Jamil Assreuy; José Eduardo da Silva-Santos
      Pages: 140 - 147
      Abstract: Publication date: Available online 30 September 2016
      Source:Redox Biology
      Author(s): Priscila de Souza, Karla Lorena Guarido, Karin Scheschowitsch, Luísa Mota da Silva, Maria Fernanda Werner, Jamil Assreuy, José Eduardo da Silva-Santos
      We investigated long-lasting changes in endothelial and vascular function in adult rat survivors of severe sepsis induced by cecal ligation and puncture (CLP) model. For this, male Wistar rats (200–350g) had their cecum punctured once (non-transfixing hole) with a 14-gauge needle. Performed in this way, a mortality rate around 30% was achieved in the first 72h. The survivors, together with age-matched control rats (not subjected to CLP), were maintained in our holding room for 60 days (S60 group) and had the descending thoracic aorta processed for functional, histological, biochemical or molecular analyses. Endothelium-intact aortic rings obtained from sepsis-surviving S60 group displayed increased angiotensin II-induced contraction, accompanied by decreased activity of the endogenous superoxide dismutase, augmented reactive oxygen species generation, and increased levels of tyrosine nitration compared with vessels from control group. The superoxide scavengers superoxide dismutase and tempol, and the antioxidant apocynin, were able to avoid this enhanced contractility to angiotensin II in aortic rings from the S60 group. In addition, aortic rings from the S60 group presented reduced sensitivity to Y-27632, a Rho-kinase (ROCK) inhibitor. Immunoblot analyses revealed augmented RhoA and ROCK II, and high levels of phosphorylation of myosin phosphatase target subunit 1 in vessels from S60 rats. In conclusion, aortic rings from sepsis-surviving rats display endothelial dysfunction mediated by the increased production of reactive oxygen species, which in turn reduces the bioavailability of nitric oxide and increases the formation of peroxynitrite, and enhances RhoA-ROCK-mediated calcium sensitization, leading to augmented contractile responses to angiotensin II. Notably, this is the first study demonstrating long-term dysfunction in the vasculature of sepsis-surviving rats, which take place or remain beyond the acute septic insult.
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      PubDate: 2016-09-30T14:51:02Z
      DOI: 10.1016/j.redox.2016.09.016
      Issue No: Vol. 10 (2016)
       
  • Oxidative Stress during Acetaminophen Hepatotoxicity: Sources,
           Pathophysiological Role and Therapeutic Potential

    • Authors: Kuo Du; Anup Ramachandran; Hartmut Jaeschke
      Pages: 148 - 156
      Abstract: Publication date: Available online 4 October 2016
      Source:Redox Biology
      Author(s): Kuo Du, Anup Ramachandran, Hartmut Jaeschke
      Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death. Although immune cells can be a source of ROS in other models, no reliable evidence exists to support a role for immune cell-derived ROS in APAP hepatotoxicity. Recent studies suggest that mitochondrial targeted antioxidants can be viable therapeutic agents against hepatotoxicity induced by APAP overdose, and re-purposing existing drugs to target oxidative stress and other concurrent signaling events can be a promising strategy to increase its potential application in patients with APAP overdose.
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      PubDate: 2016-10-08T11:51:09Z
      DOI: 10.1016/j.redox.2016.10.001
      Issue No: Vol. 10 (2016)
       
  • S-propargyl-cysteine attenuates inflammatory response in rheumatoid
           arthritis by modulating the Nrf2-ARE signaling pathway

    • Authors: Wei-Jun Wu; Wan-Wan Jia; Xin-Hua Liu; Li-Long Pan; Qiu-Yan Zhang; Di Yang; Xiao-Yan Shen; Liang Liu; Yi Zhun Zhu
      Pages: 157 - 167
      Abstract: Publication date: Available online 6 October 2016
      Source:Redox Biology
      Author(s): Wei-Jun Wu, Wan-Wan Jia, Xin-Hua Liu, Li-Long Pan, Qiu-Yan Zhang, Di Yang, Xiao-Yan Shen, Liang Liu, Yi Zhun Zhu
      Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder. Hydrogen sulfide (H2S), the third physiological gasotransmitter, is well recognized as an anti-inflammatory mediator in various inflammatory conditions. Herein, we explored the protective effects of S-propargyl-cysteine (SPRC, also known as ZYZ-802), an endogenous H2S modulator, on RA and determined the underlying mechanisms. In the present study, SPRC concentration-dependently attenuated inflammatory mediator expression, reactive oxidase species generation, and the expression and activity of matrix metalloproteinases (MMP)−9 in interleukin (IL)−1β-induced human rheumatoid fibroblast-like synoviocytes MH7A. In addition, SPRC blocked IL-1β-mediated migration and invasion of MH7A cells. As expected, the protective effects of SPRC were partially abrogated by DL-propargylglycine (PAG, a H2S biosynthesis inhibitor). In vivo study also demonstrated that SPRC treatment markedly ameliorated the severity of RA in adjuvant-induced arthritis rats, and this effect was associated with the inhibition of inflammatory response. We further identified that SPRC remarkably induced heme oxygenase-1 expression associated with the degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2); this effect was attributed to the sulfhydrylation of the cysteine residue of Keap1. Our data demonstrated for the first time that SPRC, an endogenous H2S modulator, exerted anti-inflammatory properties in RA by upregulating the Nrf2-antioxidant response element (ARE) signaling pathway.
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      PubDate: 2016-10-08T11:51:09Z
      DOI: 10.1016/j.redox.2016.08.011
      Issue No: Vol. 10 (2016)
       
  • Metabolomics insights into activated redox signaling and lipid metabolism
           dysfunction in chronic kidney disease progression

    • Authors: Hua Chen; Gang Cao; Dan-Qian Chen; Ming Wang; Nosratola D. Vaziri; Zhi-Hao Zhang; Jia-Rong Mao; Xu Bai; Ying-Yong Zhao
      Pages: 168 - 178
      Abstract: Publication date: December 2016
      Source:Redox Biology, Volume 10
      Author(s): Hua Chen, Gang Cao, Dan-Qian Chen, Ming Wang, Nosratola D. Vaziri, Zhi-Hao Zhang, Jia-Rong Mao, Xu Bai, Ying-Yong Zhao
      Early detection is critical in prevention and treatment of kidney disease. However currently clinical laboratory and histopathological tests do not provide region-specific and accurate biomarkers for early detection of kidney disease. The present study was conducted to identify sensitive biomarkers for early detection and progression of tubulo-interstitial nephropathy in aristolochic acid I-induced rats at weeks 4, 8 and 12. Biomarkers were validated using aristolochic acid nephropathy (AAN) rats at week 24, adenine-induced chronic kidney disease (CKD) rats and CKD patients. Compared with control rats, AAN rats showed anemia, increased serum urea and creatinine, progressive renal interstitial fibrosis, activation of nuclear factor-kappa B, and up-regulation of pro-inflammatory, pro-oxidant, and pro-fibrotic proteins at weeks 8 and 12. However, no significant difference was found at week 4. Metabolomics identified 12-ketodeoxycholic acid, taurochenodesoxycholic acid, LPC(15:0) and docosahexaenoic acid as biomarkers for early detection of tubulo-interstitial nephropathy. With prolonging aristolochic acid I exposure, LPE(20:2), cholic acid, chenodeoxycholic acid and LPC(17:0) were identified as biomarkers for progression from early to advanced AAN and lysoPE(22:5), indoxyl sulfate, uric acid and creatinine as biomarkers of advanced AAN. These biomarkers were reversed by treatment of irbesartan and ergone in AAN rats at week 24 and adenine-induced CKD rats. In addition, these biomarkers were also reversed by irbesartan treatment in CKD patients.
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      PubDate: 2016-10-16T14:24:47Z
      DOI: 10.1016/j.redox.2016.09.014
      Issue No: Vol. 10 (2016)
       
  • The mitochondria-targeted antioxidant MitoQ modulates oxidative stress,
           inflammation and leukocyte-endothelium interactions in leukocytes isolated
           from type 2 diabetic patients

    • Authors: Irene Escribano-Lopez; Noelia Diaz-Morales; Susana Rovira-Llopis; Arantxa Martinez de Marañon; Samuel Orden; Angeles Alvarez; Celia Bañuls; Milagros Rocha; Michael P. Murphy; Antonio Hernandez-Mijares; Victor M. Victor
      Pages: 200 - 205
      Abstract: Publication date: Available online 27 October 2016
      Source:Redox Biology
      Author(s): Irene Escribano-Lopez, Noelia Diaz-Morales, Susana Rovira-Llopis, Arantxa Martinez de Marañon, Samuel Orden, Angeles Alvarez, Celia Bañuls, Milagros Rocha, Michael P. Murphy, Antonio Hernandez-Mijares, Victor M. Victor
      It is not known if the mitochondria-targeted antioxidants such as mitoquinone (MitoQ) can modulate oxidative stress and leukocyte-endothelium interactions in T2D patients. We aimed to evaluate the beneficial effect of MitoQ on oxidative stress parameters and leukocyte-endothelium interactions in leukocytes of T2D patients. The study population consisted of 98 T2D patients and 71 control subjects. We assessed metabolic and anthropometric parameters, mitochondrial reactive oxygen species (ROS) production, glutathione peroxidase 1 (GPX-1), NFκB-p65, TNFα and leukocyte-endothelium interactions. Diabetic patients exhibited higher weight, BMI, waist circumference, SBP, DBP, glucose, insulin, HOMA-IR, HbA1c, triglycerides, hs-CRP and lower HDL-c with respect to controls. Mitochondrial ROS production was enhanced in T2D patients and decreased by MitoQ. The antioxidant also increased GPX-1 levels and PMN rolling velocity and decreased PMN rolling flux and PMN adhesion in T2D patients. NFκB-p65 and TNFα were augmented in T2D and were both reduced by MitoQ treatment. Our findings support that the antioxidant MitoQ has an anti-inflammatory and antioxidant action in T2D patients by decreasing ROS production, leukocyte-endothelium interactions and TNFα through the action of NFκB. These data suggest that mitochondria-targeted antioxidants such as MitoQ should be investigated as a novel means of preventing cardiovascular events in T2D patients.
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      PubDate: 2016-10-28T17:01:38Z
      DOI: 10.1016/j.redox.2016.10.017
      Issue No: Vol. 10 (2016)
       
  • Profound differences between humans and rodents in the ability to
           concentrate salivary nitrate: Implications for translational research

    • Authors: Marcelo F Montenegro; Michaela L Sundqvist; Carina Nihlén; Michael Hezel; Mattias Carlström; Eddie Weitzberg; Jon O Lundberg
      Pages: 206 - 210
      Abstract: Publication date: Available online 25 October 2016
      Source:Redox Biology
      Author(s): Marcelo F Montenegro, Michaela L Sundqvist, Carina Nihlén, Michael Hezel, Mattias Carlström, Eddie Weitzberg, Jon O Lundberg
      In humans dietary circulating nitrate accumulates rapidly in saliva through active transport in the salivary glands. By this mechanism resulting salivary nitrate concentrations are 10–20 times higher than in plasma. In the oral cavity nitrate is reduced by commensal bacteria to nitrite, which is subsequently swallowed and further metabolized to nitric oxide (NO) and other bioactive nitrogen oxides in blood and tissues. This entero-salivary circulation of nitrate is central in the various NO-like effects observed after ingestion of inorganic nitrate. The very same system has also been the focus of toxicologists studying potential carcinogenic effects of nitrite-dependent nitrosamine formation. Whether active transport of nitrate and accumulation in saliva occurs also in rodents is not entirely clear. Here we measured salivary and plasma levels of nitrate and nitrite in humans, rats and mice after administration of a standardized dose of nitrate. After oral (humans) or intraperitoneal (rodents) sodium nitrate administration (0.1mmol/kg), plasma nitrate levels increased markedly reaching ~300µM in all three species. In humans ingestion of nitrate was followed by a rapid increase in salivary nitrate to >6000µM, ie 20 times higher than those found in plasma. In contrast, in rats and mice salivary nitrate concentrations never exceeded the levels in plasma. Nitrite levels in saliva and plasma followed a similar pattern, ie marked increases in humans but modest elevations in rodents. In mice there was also no accumulation of nitrate in the salivary glands as measured directly in whole glands obtained after acute administration of nitrate. This study suggests that in contrast to humans, rats and mice do not actively concentrate circulating nitrate in saliva. These apparent species differences should be taken into consideration when studying the nitrate-nitrite-nitric oxide pathway in rodents, when calculating doses, exploring physiological, therapeutic and toxicological effects and comparing with human data.
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      PubDate: 2016-10-28T17:01:38Z
      DOI: 10.1016/j.redox.2016.10.011
      Issue No: Vol. 10 (2016)
       
  • Oxalomalate reduces expression and secretion of vascular endothelial
           growth factor in the retinal pigment epithelium and inhibits angiogenesis:
           Implications for age-related macular degeneration

    • Authors: Sung Hwan Kim; Hyunjin Kim; Hyeong Jun Ku; Jung Hyun Park; Hanvit Cha; Seoyoon Lee; Jin Hyup Lee; Jeen-Woo Park
      Pages: 211 - 220
      Abstract: Publication date: Available online 24 October 2016
      Source:Redox Biology
      Author(s): Sung Hwan Kim, Hyunjin Kim, Hyeong Jun Ku, Jung Hyun Park, Hanvit Cha, Seoyoon Lee, Jin Hyup Lee, Jeen-Woo Park
      Clinical and experimental observations indicate a critical role for vascular endothelial growth factor (VEGF), secreted by the retinal pigment epithelium (RPE), in pathological angiogenesis and the development of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). RPE-mediated VEGF expression, leading to angiogenesis, is a major signaling mechanism underlying ocular neovascular disease. Inhibiting this signaling pathway with a therapeutic molecule is a promising anti-angiogenic strategy to treat this disease with potentially fewer side effects. Oxalomalate (OMA) is a competitive inhibitor of NADP+-dependent isocitrate dehydrogenase (IDH), which plays an important role in cellular signaling pathways regulated by reactive oxygen species (ROS). Here, we have investigated the inhibitory effect of OMA on the expression of VEGF, and the associated underlying mechanism of action, using in vitro and in vivo RPE cell models of AMD. We found that OMA reduced the expression and secretion of VEGF in RPE cells, and consequently inhibited CNV formation. This function of OMA was linked to its capacity to activate the pVHL-mediated HIF-1α degradation in these cells, partly via a ROS-dependent ATM signaling axis, through inhibition of IDH enzymes. These findings reveal a novel role for OMA in inhibiting RPE-derived VEGF expression and angiogenesis, and suggest unique therapeutic strategies for treating pathological angiogenesis and AMD development.
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      PubDate: 2016-10-28T17:01:38Z
      DOI: 10.1016/j.redox.2016.10.008
      Issue No: Vol. 10 (2016)
       
  • Epigallocatechin-3-gallate enhances key enzymatic activities of hepatic
           thioredoxin and glutathione systems in selenium-optimal mice but activates
           hepatic Nrf2 responses in selenium-deficient mice

    • Authors: Ruixia Dong; Dongxu Wang; Xiaoxiao Wang; Ke Zhang; Pingping Chen; Chung S. Yang; Jinsong Zhang
      Pages: 221 - 232
      Abstract: Publication date: Available online 24 October 2016
      Source:Redox Biology
      Author(s): Ruixia Dong, Dongxu Wang, Xiaoxiao Wang, Ke Zhang, Pingping Chen, Chung S. Yang, Jinsong Zhang
      Selenium participates in the antioxidant defense mainly through a class of selenoproteins, including thioredoxin reductase. Epigallocatechin-3-gallate (EGCG) is the most abundant and biologically active catechin in green tea. Depending upon the dose and biological systems, EGCG may function either as an antioxidant or as an inducer of antioxidant defense via its pro-oxidant action or other unidentified mechanisms. By manipulating the selenium status, the present study investigated the interactions of EGCG with antioxidant defense systems including the thioredoxin system comprising of thioredoxin and thioredoxin reductase, the glutathione system comprising of glutathione and glutathione reductase coupled with glutaredoxin, and the Nrf2 system. In selenium-optimal mice, EGCG increased hepatic activities of thioredoxin reductase, glutathione reductase and glutaredoxin. These effects of EGCG appeared to be not due to overt pro-oxidant action because melatonin, a powerful antioxidant, did not influence the increase. However, in selenium-deficient mice, with low basal levels of thioredoxin reductase 1, the same dose of EGCG did not elevate the above-mentioned enzymes; intriguingly EGCG in turn activated hepatic Nrf2 response, leading to increased heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1 protein levels and thioredoxin activity. Overall, the present work reveals that EGCG is a robust inducer of the Nrf2 system only in selenium-deficient conditions. Under normal physiological conditions, in selenium-optimal mice, thioredoxin and glutathione systems serve as the first line defense systems against the stress induced by high doses of EGCG, sparing the activation of the Nrf2 system.
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      PubDate: 2016-10-28T17:01:38Z
      DOI: 10.1016/j.redox.2016.10.009
      Issue No: Vol. 10 (2016)
       
  • Targeting nitrative stress for attenuating cisplatin-induced
           downregulation of cochlear LIM domain only 4 and ototoxicity

    • Authors: Samson Jamesdaniel; Rajamani Rathinam; William L. Neumann
      Pages: 257 - 265
      Abstract: Publication date: Available online 31 October 2016
      Source:Redox Biology
      Author(s): Samson Jamesdaniel, Rajamani Rathinam, William L. Neumann
      Cisplatin-induced ototoxicity remains a primary dose-limiting adverse effect of this highly effective anticancer drug. The clinical utility of cisplatin could be enhanced if the signaling pathways that regulate the toxic side-effects are delineated. In previous studies, we reported cisplatin-induced nitration of cochlear proteins and provided the first evidence for nitration and downregulation of cochlear LIM domain only 4 (LMO4) in cisplatin ototoxicity. Here, we extend these findings to define the critical role of nitrative stress in cisplatin-induced downregulation of LMO4 and its consequent ototoxic effects in UBOC1 cell cultures derived from sensory epithelial cells of the inner ear and in CBA/J mice. Cisplatin treatment increased the levels of nitrotyrosine and active caspase 3 in UBOC1 cells, which was detected by immunocytochemical and flow cytometry analysis, respectively. The cisplatin-induced nitrative stress and apoptosis were attenuated by co-treatment with SRI110, a peroxynitrite decomposition catalyst (PNDC), which also attenuated the cisplatin-induced downregulation of LMO4 in a dose-dependent manner. Furthermore, transient overexpression of LMO4 in UBOC1 cells prevented cisplatin-induced cytotoxicity while repression of LMO4 exacerbated cisplatin-induced cell death, indicating a direct link between LMO4 protein levels and cisplatin ototoxicity. Finally, auditory brainstem responses (ABR) recorded from CBA/J mice indicated that co-treatment with SRI110 mitigated cisplatin-induced hearing loss. Together, these results suggest that cisplatin-induced nitrative stress leads to a decrease in the levels of LMO4, downregulation of LMO4 is a critical determinant in cisplatin-induced ototoxicity, and targeting peroxynitrite could be a promising strategy for mitigating cisplatin-induced hearing loss.
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      PubDate: 2016-11-04T17:27:58Z
      DOI: 10.1016/j.redox.2016.10.016
      Issue No: Vol. 10 (2016)
       
  • Rac1-NADPH Oxidase Signaling Promotes CD36 Activation under Glucotoxic
           Conditions in Pancreatic Beta Cells

    • Authors: Suma Elumalai; Udayakumar Karunakaran; In Kyu Lee; Jun Sung Moon; Kyu Chang Won
      Abstract: Publication date: Available online 23 November 2016
      Source:Redox Biology
      Author(s): Suma Elumalai, Udayakumar Karunakaran, In Kyu Lee, Jun Sung Moon, Kyu Chang Won
      We recently reported that cluster determinant 36 (CD36), a fatty acid transporter, plays a pivotal role in glucotoxicity-induced β-cell dysfunction. However, little is known about how glucotoxicity influences CD36 expression. Emerging evidence suggests that the small GTPase Rac1 is involved in the pathogenesis of beta cell dysfunction in type 2 diabetes (T2D). The primary objective of the current study was to determine the role of Rac1 in CD36 activation and its impact on β-cell dysfunction in diabetes mellitus. To address this question, we subjected INS-1 cells and human beta cells (1.1B4) to high glucose conditions (30mM) in the presence or absence of Rac1 inhibition either by NSC23766 (Rac1 GTPase inhibitor) or small interfering RNA. High glucose exposure in INS-1 and human beta cells (1.1b4) resulted in the activation of Rac1 and induced cell apoptosis. Rac1 activation mediates NADPH oxidase (NOX) activation leading to elevated ROS production in both cells. Activation of the Rac1-NOX complex by high glucose levels enhanced CD36 expression in INS-1 and human 1.1b4 beta cell membrane fractions. The inhibition of Rac1 by NSC23766 inhibited NADPH oxidase activity and ROS generation induced by high glucose concentrations in INS-1 & human 1.1b4 beta cells. Inhibition of Rac1-NOX complex activation by NSC23766 significantly reduced CD36 expression in INS-1 and human 1.1b4 beta cell membrane fractions. In addition, Rac1 inhibition by NSC23766 significantly reduced high glucose-induced mitochondrial dysfunction. Furthermore, NADPH oxidase inhibition by VAS2870 also attenuated high glucose-induced ROS generation and cell apoptosis. These results suggest that Rac1-NADPH oxidase dependent CD36 expression contributes to high glucose-induced beta cell dysfunction and cell death.
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      PubDate: 2016-11-26T09:01:10Z
      DOI: 10.1016/j.redox.2016.11.009
       
  • Mass spectrometry profiling of oxysterols in human sperm identifies
           25-hydroxycholesterol as a marker of sperm function

    • Authors: Chiara Zerbinati; Luisa Caponecchia; Rosa Puca; Marco Ciacciarelli; Pietro Salacone; Annalisa Sebastianelli; Antonio Pastore; Giovanni Palleschi; Vincenzo Petrozza; Natale Porta; Rocco Rago; Antonio Carbone; Luigi Iuliano
      Abstract: Publication date: Available online 22 November 2016
      Source:Redox Biology
      Author(s): Chiara Zerbinati, Luisa Caponecchia, Rosa Puca, Marco Ciacciarelli, Pietro Salacone, Annalisa Sebastianelli, Antonio Pastore, Giovanni Palleschi, Vincenzo Petrozza, Natale Porta, Rocco Rago, Antonio Carbone, Luigi Iuliano
      Cholesterol is a main lipid component of sperm cell that is essential for sperm membrane fluidity, capacitation, and acrosomal reaction. Recent data obtained in bovine sperm showed that sperm capacitation is associated to the formation of oxysterols, oxidized products of cholesterol. The aim of this study was to profile oxysterol content in human semen, and to investigate their potential role in sperm pathophysiology. Among the 12 oxysterols analyzed, 25 -hydroxycholesterol (25-HCCh) resulted the most represented in normozoospermic samples, and its concentration positively correlated with spermatozoa number. We detected Cholesterol 25-hydroxylase, the enzyme responsible for 25-HC production, in human spermatozoa at the level of the neck and the post acrosomal area. Upon incubation with spermatozoa, 25-HC induced calcium and cholesterol transients in connection with the acrosomal reaction. Our results support a role for 25-HC in sperm function.

      PubDate: 2016-11-26T09:01:10Z
      DOI: 10.1016/j.redox.2016.11.008
       
  • Deficiency in Duox2 activity alleviates ileitis in GPx1- and GPx2-knockout
           mice without affecting apoptosis incidence in the crypt epithelium

    • Authors: Fong-Fong Chu; R. Steven Esworthy; James H. Doroshow; Helmut Grasberger; Agnes Donko; Thomas L. Leto; Qiang Gao; Binghui Shen
      Abstract: Publication date: Available online 22 November 2016
      Source:Redox Biology
      Author(s): Fong-Fong Chu, R. Steven Esworthy, James H. Doroshow, Helmut Grasberger, Agnes Donko, Thomas L. Leto, Qiang Gao, Binghui Shen
      Mice deficient in glutathione peroxidase (GPx)-1 and -2 (GPx1-/-GPx2-/- double knockout or DKO mice) develop very-early-onset (VEO) ileocolitis, suggesting that lack of defense against reactive oxygen species (ROS) renders susceptibility to intestinal inflammation. Two members of ROS-generating NADPH oxidase family, NOX1 and DUOX2, are highly inducible in the intestinal epithelium. Previously, we reported that Nox1 deficiency ameliorated the pathology in DKO mice (Nox1-TKO). The role of Duox2 in ileocolitis of the DKO mice is evaluated here in Duoxa-TKO mice by breeding DKO mice with Duoxa-/- mice (Duoxa-TKO), which do not have Duox2 activity. Similar to Nox1-TKO mice, Duoxa-TKO mice no longer have growth retardation, shortened intestine, exfoliation of crypt epithelium, crypt abscesses and depletion of goblet cells manifested in DKO mice by 35 days of age. Unlike Nox1-TKO mice, Duoxa-TKO mice still have rampant crypt apoptosis, elevated proliferation, partial loss of Paneth cells and diminished crypt density. Treating DKO mice with NOX inhibitors (di-2-thienyliodonium/DTI and thioridazine/THZ) and an antioxidant (mitoquinone/MitoQ) significantly reduced gut pathology. Furthermore, in the inflamed human colon, DUOX protein expression is highly elevated in the apical, lateral and perinuclear membrane along the whole length of gland. Taken together, we conclude that exfoliation of crypt epithelium, but not crypt apoptosis, is a major contributor to inflammation. Both Nox1 and Duox2 induce exfoliation of crypt epithelium, but only Nox1 induces apoptosis. NOX1 and DUOX2 may be potential therapeutic targets for treating ileocolitis in human patients suffering inflammatory bowel disease (IBD).

      PubDate: 2016-11-26T09:01:10Z
      DOI: 10.1016/j.redox.2016.11.001
       
  • NOX Isoforms in the Development of Abdominal Aortic Aneurysm

    • Authors: Kin Lung Siu; Qiang Li; Yixuan Zhang; Jun Guo; Ji Youn Youn; Du Jie; Hua Cai
      Abstract: Publication date: Available online 19 November 2016
      Source:Redox Biology
      Author(s): Kin Lung Siu, Qiang Li, Yixuan Zhang, Jun Guo, Ji Youn Youn, Du Jie, Hua Cai
      Oxidative stress plays an important role in the formation of abdominal aortic aneurysm (AAA), and we have recently established a causal role of uncoupled eNOS in this severe human disease. We have also shown that activation of NADPH oxidase (NOX) lies upstream of uncoupled eNOS. Therefore, identification of the specific NOX isoforms that are required for eNOS uncoupling and AAA formation would ultimately lead to novel therapies for AAA. In the present study, we used the Ang II infused hph-1 mice to examine the roles of NOX isoforms in the development of AAA. We generated double mutants of hph-1-NOX1, hph-1-NOX2, hph-1-p47phox, and hph-1-NOX4. After two weeks of Ang II infusion, the incidence rate of AAA substantially dropped from 76.5% in Ang II infused hph-1 mice (n=34) to 11.1%, 15.0%, 9.5% and 0% in hph-1-NOX1 (n=27), hph-1-NOX2 (n=40), hph-1-p47phox (n=21), and hph-1-NOX4 (n=33) double mutant mice, respectively. The size of abdominal aortas of the four double mutant mice, determined by ultrasound analyses, was significantly smaller than the hph-1 mice. Aortic nitric oxide and H4B bioavailabilities were markedly improved in the double mutants, while superoxide production and eNOS uncoupling activity were substantially diminished. These effects seemed attributed to an endothelial specific restoration of dihydrofolate reductase expression and activity, deficiency of which has been shown to induce eNOS uncoupling and AAA formation in both Ang II-infused hph-1 and apoE null animals. In addition, over-expression of human NOX4 N129S or T555S mutant newly identified in aneurysm patients increased hydrogen peroxide production, further implicating a relationship between NOX and human aneurysm. Taken together, these data indicate that NOX isoforms 1, 2 or 4 lies upstream of dihydrofolate reductase deficiency and eNOS uncoupling to induce AAA formation. These findings may promote development of novel therapeutics for the treatment of the disease by inhibiting NOX signaling.
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      PubDate: 2016-11-26T09:01:10Z
      DOI: 10.1016/j.redox.2016.11.002
       
  • Inhibition of autophagy with bafilomycin and chloroquine decreases
           mitochondrial quality and bioenergetic function in primary neurons

    • Authors: Matthew Redmann; Gloria A. Benavides; Taylor F. Berryhill; Willayat Y. Wani; Xiaosen Ouyang; Michelle S. Johnson; Saranya Ravi; Stephen Barnes; Victor M. Darley-Usmar; Jianhua Zhang
      Abstract: Publication date: Available online 18 November 2016
      Source:Redox Biology
      Author(s): Matthew Redmann, Gloria A. Benavides, Taylor F. Berryhill, Willayat Y. Wani, Xiaosen Ouyang, Michelle S. Johnson, Saranya Ravi, Stephen Barnes, Victor M. Darley-Usmar, Jianhua Zhang
      Autophagy is an important cell recycling program responsible for the clearance of damaged or long-lived proteins and organelles. Pharmacological modulators of this pathway have been extensively utilized in a wide range of basic research and pre-clinical studies. Bafilomycin A1 and chloroquine are commonly used compounds that inhibit autophagy by targeting the lysosomes but through distinct mechanisms. Since it is now clear that mitochondrial quality control, particularly in neurons, is dependent on autophagy, it is important to determine whether these compounds modify cellular bioenergetics. To address this, we cultured primary rat cortical neurons from E18 embryos and used the Seahorse XF96 analyzer and a targeted metabolomics approach to measure the effects of bafilomycin A1 and chloroquine on bioenergetics and metabolism. We found that both bafilomycin and chloroquine could significantly increase the autophagosome marker LC3-II and inhibit key parameters of mitochondrial function, and increase mtDNA damage. Furthermore, we observed significant alterations in TCA cycle intermediates, particularly those downstream of citrate synthase and those linked to glutaminolysis. Taken together, these data demonstrate a significant impact of bafilomycin and chloroquine on cellular bioenergetics and metabolism consistent with decreased mitochondrial quality associated with inhibition of autophagy.
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      PubDate: 2016-11-18T20:15:58Z
      DOI: 10.1016/j.redox.2016.11.004
       
  • Reactive oxygen species signaling and stomatal movement: current updates
           and future perspectives

    • Authors: Rachana Singh; Parul Parihar; Samiksha Singh; Rohit Kumar Mishra; Vijay Pratap Singh; Sheo Mohan Prasad
      Abstract: Publication date: Available online 17 November 2016
      Source:Redox Biology
      Author(s): Rachana Singh, Parul Parihar, Samiksha Singh, Rohit Kumar Mishra, Vijay Pratap Singh, Sheo Mohan Prasad
      Reactive oxygen species (ROS), a by-product of aerobic metabolism were initially studied in context to their damaging effect but recent decades witnessed significant advancements in understanding the role of ROS as signaling molecules. Contrary to earlier views, it is becoming evident that ROS production is not necessarily a symptom of cellular dysfunction but it might represent a necessary signal in adjusting the cellular machinery according to the altered conditions. Stomatal movement is controlled by multifaceted signaling network in response to endogenous and environmental signals. Furthermore, the stomatal aperture is regulated by a coordinated action of signaling proteins, ROS-generating enzymes, and downstream executors like transporters, ion pumps, plasma membrane channels which control the turgor pressure of the guard cell. The earliest hallmarks of stomatal closure are ROS accumulation in the apoplast and chloroplasts and thereafter, there is a successive increase in cytoplasmic Ca2+ level which rules the multiple kinases activity that in turn regulates the activity of ROS-generating enzymes and various ion channels. In addition, ROS also regulate the action of multiple proteins directly by oxidative post translational modifications to adjust guard cell signaling. Notwithstanding an active progress has been made with ROS signaling mechanism but the regulatory action for ROS signaling processes in stomatal movement is still fragmentary. Therefore, keeping in view the above facts, in this mini review the basic concepts and role of ROS signaling in the stomatal movement have been presented comprehensively along with recent highlights.

      PubDate: 2016-11-18T20:15:58Z
      DOI: 10.1016/j.redox.2016.11.006
       
  • Redox imbalance and mitochondrial abnormalities in the diabetic lung

    • Authors: Jinzi Wu; Zhen Jin; Liang-Jun Yan
      Abstract: Publication date: Available online 17 November 2016
      Source:Redox Biology
      Author(s): Jinzi Wu, Zhen Jin, Liang-Jun Yan
      Although the lung is one of the least studied organs in diabetes, increasing evidence indicates that it is an inevitable target of diabetic complications. Nevertheless, the underlying biochemical mechanisms of lung injury in diabetes remain largely unexplored. Given that redox imbalance, oxidative stress, and mitochondrial dysfunction have been implicated in diabetic tissue injury, we set out to investigate mechanisms of lung injury in diabetes. The objective of this study was to evaluate NADH/NAD+ redox status, oxidative stress, and mitochondrial abnormalities in the diabetic lung. Using STZ induced diabetes in rat as a model, we measured redox-imbalance related parameters including aldose reductase activity, level of poly ADP ribose polymerase (PAPR-1), NAD+ content, NADPH content, reduced form of glutathione (GSH), and glucose 6-phophate dehydrogenase (G6PD) activity. For assessment of mitochondrial abnormalities in the diabetic lung, we measured the activities of mitochondrial electron transport chain complexes I to IV and complex V as well as dihydrolipoamide dehydrogenase (DLDH) content and activity. We also measured the protein content of NAD+ dependent enzymes such as sirtuin3 (sirt3) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Our results demonstrate that NADH/NAD+ redox imbalance occurs in the diabetic lung. This redox imbalance upregulates the activities of complexes I to IV, but not complex V; and this upregulation is likely the source of increased mitochondrial ROS production, oxidative stress, and cell death in the diabetic lung. These results, together with the findings that the protein contents of DLDH, sirt3, and NQO1 all are decreased in the diabetic lung, demonstrate that redox imbalance, mitochondrial abnormality, and oxidative stress contribute to lung injury in diabetes.

      PubDate: 2016-11-18T20:15:58Z
      DOI: 10.1016/j.redox.2016.11.003
       
  • Redox control of senescence and age-related disease

    • Authors: Akshaya Chandrasekaran; Maria del Pilar Sosa Idelchik; J. Andrés Melendez
      Abstract: Publication date: Available online 16 November 2016
      Source:Redox Biology
      Author(s): Akshaya Chandrasekaran, Maria del Pilar Sosa Idelchik, J. Andrés Melendez
      The signaling networks that drive the aging process, associated functional deterioration, and pathologies has captured the scientific community's attention for decades. While many theories exist to explain the aging process, the production of reactive oxygen species (ROS) provides a signaling link between engagement of cellular senescence and several age-associated pathologies. Cellular senescence has evolved to restrict tumor progression but the accompanying senescence-associated secretory phenotype (SASP) promotes pathogenic pathways. Here, we review known biological theories of aging and how ROS mechanistically control senescence and the aging process. We also describe the redox-regulated signaling networks controlling the SASP and its important role in driving age-related diseases. Finally, we discuss progress in designing therapeutic strategies that manipulate the cellular redox environment to restrict age-associated pathology.
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      PubDate: 2016-11-18T20:15:58Z
      DOI: 10.1016/j.redox.2016.11.005
       
  • Degenerate cysteine patterns mediate two redox sensing mechanisms in the
           papillomavirus E7 oncoprotein

    • Authors: Gabriela Camporeale; Juan R. Lorenzo; Maria G. Thomas; Edgardo Salvatierra; Silvia S. Borkosky; Marikena G. Risso; Ignacio E. Sánchez; Gonzalo de Prat Gay; Leonardo G. Alonso
      Abstract: Publication date: Available online 12 November 2016
      Source:Redox Biology
      Author(s): Gabriela Camporeale, Juan R. Lorenzo, Maria G. Thomas, Edgardo Salvatierra, Silvia S. Borkosky, Marikena G. Risso, Ignacio E. Sánchez, Gonzalo de Prat Gay, Leonardo G. Alonso
      Infection with oncogenic human papillomavirus induces deregulation of cellular redox homeostasis. Virus replication and papillomavirus-induced cell transformation require persistent expression of viral oncoproteins E7 and E6 that must retain their functionality in a persistent oxidative environment. Here, we dissected the molecular mechanisms by which E7 oncoprotein can sense and manage the potentially harmful oxidative environment of the papillomavirus-infected cell. The carboxy terminal domain of E7 protein from most of the 79 papillomavirus viral types of alpha genus, which encloses all the tumorigenic viral types, is a cysteine rich domain that contains two classes of cysteines: strictly conserved low reactive Zn+2 binding and degenerate reactive cysteine residues that can sense reactive oxygen species (ROS). Based on experimental data obtained from E7 proteins from the prototypical viral types 16, 18 and 11, we identified a couple of low pKa nucleophilic cysteines that can form a disulfide bridge upon the exposure to ROS and regulate the cytoplasm to nucleus transport. From sequence analysis and phylogenetic reconstruction of redox sensing states we propose that reactive cysteine acquisition through evolution leads to three separate E7s protein families that differ in the ROS sensing mechanism: non ROS-sensitive E7s; ROS-sensitive E7s using only a single or multiple reactive cysteine sensing mechanisms and ROS-sensitive E7s using a reactive-resolutive cysteine couple sensing mechanism.
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      PubDate: 2016-11-12T12:27:21Z
      DOI: 10.1016/j.redox.2016.10.020
       
  • A New Role for Oxidative Stress in Aging: The accelerated aging phenotype
           in Sod1-/- mice is correlated to increased cellular senescence

    • Authors: Yiqiang Zhang; Archana Unnikrishnan; Sathyaseelan S Deepa; Yuhong Liu; Yan Li; Yuji Ikeno; Danuta Sosnowska; Holly Van Remmen; Arlan Richardson
      Abstract: Publication date: Available online 2 November 2016
      Source:Redox Biology
      Author(s): Yiqiang Zhang, Archana Unnikrishnan, Sathyaseelan S Deepa, Yuhong Liu, Yan Li, Yuji Ikeno, Danuta Sosnowska, Holly Van Remmen, Arlan Richardson
      In contrast to other mouse models that are deficient in antioxidant enzymes, mice null for Cu/Zn-superoxide dismutase (Sod1 -/- mice) show a major decrease in lifespan and several accelerated aging phenotypes. The goal of this study was to determine if cell senescence might be a contributing factor in the accelerated aging phenotype observed in the Sod1 -/- mice. We focused on kidney because it is a tissue that has been shown to a significant increase in senescent cells with age. The Sod1 -/- mice are characterized by high levels of DNA oxidation in the kidney, which is attenuated by DR. The kidney of the Sod1 -/- mice also have higher levels of double strand DNA breaks than wild type (WT) mice. Expression (mRNA and protein) of p16 and p21, two of the markers of cellular senescence, which increased with age, are increased significantly in the kidney of Sod1 -/- mice as is β-gal staining cells. In addition, the senescence associated secretory phenotype was also increased significantly in the kidney of Sod1 -/- mice compared to WT mice as measured by the expression of transcripts for IL-6 and IL-1β. Dietary restriction of the Sod1 -/- mice attenuated the increase in DNA damage, cellular senescence, and expression of IL-6 and IL-1β. Interestingly, the Sod1 -/- mice showed higher levels of circulating cytokines than WT mice, suggesting that the accelerated aging phenotype shown by the Sod1 -/- mice could result from increased inflammation arising from an accelerated accumulation of senescent cells. Based on our data with Sod1 -/- mice, we propose that various bouts of increased oxidative stress over the lifespan of an animal leads to the accumulation of senescent cells. The accumulation of senescent cells in turn leads to increased inflammation, which plays a major role in the loss of function and increased pathology that are hallmark features of aging.
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      PubDate: 2016-11-04T17:27:58Z
      DOI: 10.1016/j.redox.2016.10.014
       
  • Vitamin B12 deficiency results in severe oxidative stress, leading to
           memory retention impairment in Caenorhabditis elegans

    • Authors: Tomohiro Bito; Taihei Misaki; Yukinori Yabuta; Takahiro Ishikawa; Tsuyoshi Kawano; Fumio Watanabe
      Abstract: Publication date: Available online 3 November 2016
      Source:Redox Biology
      Author(s): Tomohiro Bito, Taihei Misaki, Yukinori Yabuta, Takahiro Ishikawa, Tsuyoshi Kawano, Fumio Watanabe
      Oxidative stress is implicated in various human diseases and conditions, such as a neurodegeneration, which is the major symptom of vitamin B12 deficiency, although the underlying disease mechanisms associated with vitamin deficiency are poorly understood. Vitamin B12 deficiency was found to significantly increase cellular H2O2 and NO content in Caenorhabditis elegans and significantly decrease low molecular antioxidant [reduced glutathione (GSH) and l-ascorbic acid] levels and antioxidant enzyme (superoxide dismutase and catalase) activities, indicating that vitamin B12 deficiency induces severe oxidative stress leading to oxidative damage of various cellular components in worms. An NaCl chemotaxis associative learning assay indicated that vitamin B12 deficiency did not affect learning ability but impaired memory retention ability, which decreased to approximately 58% of the control value. When worms were treated with 1mmol/L GSH, l-ascorbic acid, or vitamin E for three generations during vitamin B12 deficiency, cellular malondialdehyde content as an index of oxidative stress decreased to the control level, but the impairment of memory retention ability was not completely reversed (up to approximately 50%). These results suggest that memory retention impairment formed during B12 deficiency is partially attributable to oxidative stress.
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      PubDate: 2016-11-04T17:27:58Z
      DOI: 10.1016/j.redox.2016.10.013
       
  • Brain adaptation to hypoxia and hyperoxia in mice

    • Authors: Laura Terraneo; Rita Paroni; Paola Bianciardi; Toniella Giallongo; Stephana Carelli; Alfredo Gorio; Michele Samaja
      Abstract: Publication date: Available online 4 November 2016
      Source:Redox Biology
      Author(s): Laura Terraneo, Rita Paroni, Paola Bianciardi, Toniella Giallongo, Stephana Carelli, Alfredo Gorio, Michele Samaja
      Aims Hyperoxic breathing might lead to redox imbalance and signaling changes that affect cerebral function. Paradoxically, hypoxic breathing is also believed to cause oxidative stress. Our aim is to dissect the cerebral tissue responses to altered O2 fractions in breathed air by assessing the redox imbalance and the recruitment of the hypoxia signaling pathways. Results Mice were exposed to mild hypoxia (10%O2), normoxia (21%O2) or mild hyperoxia (30%O2) for 28 days, sacrificed and brain tissue excised and analyzed. Although one might expect linear responses to %O2, only few of the examined variables exhibited this pattern, including neuroprotective phospho- protein kinase B and the erythropoietin receptor. The major reactive oxygen species (ROS) source in brain, NADPH oxidase subunit 4 increased in hypoxia but not in hyperoxia, whereas neither affected nuclear factor (erythroid-derived 2)-like 2, a transcription factor that regulates the expression of antioxidant proteins. As a result of the delicate equilibrium between ROS generation and antioxidant defense, neuron apoptosis and cerebral tissue hydroperoxides increased in both 10%O2 and 30%O2, as compared with 21%O2. Remarkably, the expression level of hypoxia-inducible factor (HIF)-2α (but not HIF-1α) was higher in both 10%O2 and 30%O2 with respect to 21%O2 Innovation Comparing the in vivo effects driven by mild hypoxia with those driven by mild hyperoxia helps addressing whether clinically relevant situations of O2 excess and scarcity are toxic for the organism. Conclusion Prolonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.
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      PubDate: 2016-11-04T17:27:58Z
      DOI: 10.1016/j.redox.2016.10.018
       
  • Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and
           zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and
           Nrf2/HO-1 pathways

    • Authors: Chao Zhang; Chuwen Li; Shenghui Chen; Zhiping Li; Xuejing Jia; Kai Wang; Jiaolin Bao; Yeer Liang; Xiaotong Wang; Meiwan Chen; Peng Li; Huanxing Su; Jian-Bo Wan; Simon Ming Yuen Lee; Kechun Liu; Chengwei He
      Abstract: Publication date: Available online 4 November 2016
      Source:Redox Biology
      Author(s): Chao Zhang, Chuwen Li, Shenghui Chen, Zhiping Li, Xuejing Jia, Kai Wang, Jiaolin Bao, Yeer Liang, Xiaotong Wang, Meiwan Chen, Peng Li, Huanxing Su, Jian-Bo Wan, Simon Ming Yuen Lee, Kechun Liu, Chengwei He
      Berberine (BBR) is a renowned natural compound that exhibits potent neuroprotective activities. However, the cellular and molecular mechanisms are still unclear. Hormesis is an adaptive mechanism generally activated by mild oxidative stress to protect the cells from further damage. Many phytochemicals have been shown to induce hormesis. This study aims to investigate whether the neuroprotective activity of BBR is mediated by hormesis and the related signaling pathways in 6-OHDA-induced PC12 cells and zebrafish neurotoxic models. Our results demonstrated that BBR induced a typical hormetic response in PC12 cells, i.e. low dose BBR significantly increased the cell viability, while high dose BBR inhibited the cell viability. Moreover, low dose BBR protected the PC12 cells from 6-OHDA-induced cytotoxicity and apoptosis, whereas relatively high dose BBR did not show neuroprotective activity. The hormetic and neuroprotective effects of BBR were confirmed to be mediated by up-regulated PI3K/AKT/Bcl-2 cell survival and Nrf2/HO-1 antioxidative signaling pathways. In addition, low dose BBR markedly mitigated the 6-OHDA-induced dopaminergic neuron loss and behavior movement deficiency in zebrafish, while high dose BBR only slightly exhibited neuroprotective activities. These results strongly suggested that the neuroprotection of BBR were attributable to the hormetic mechanisms via activating cell survival and antioxidative signaling pathways.

      PubDate: 2016-11-04T17:27:58Z
      DOI: 10.1016/j.redox.2016.10.019
       
  • Macroautophagy is impaired in old murine brain tissue as well as in
           senescent human fibroblasts

    • Authors: Christiane Ott; Jeannette König; Annika Höhn; Tobias Jung; Tilman Grune
      Abstract: Publication date: Available online 26 October 2016
      Source:Redox Biology
      Author(s): Christiane Ott, Jeannette König, Annika Höhn, Tobias Jung, Tilman Grune
      The overall decrease in proteolytic activity in aging can promote and accelerate protein accumulation and metabolic disturbances. To specifically analyze changes in macroautophagy (MA) we quantified different autophagy-related proteins (ATGs) in young, adult and old murine tissue as well as in young and senescent human fibroblasts. Thus, we revealed significantly reduced levels of ATG5-ATG12, LC3-II/LC3-I ratio, Beclin-1 and p62 in old brain tissue and senescent human fibroblasts. To investigate the role of mTOR, the protein itself and its target proteins p70S6 kinase and 4E-BP1 were quantified. Significant increased mTOR protein levels were determined in old tissue and cells. Determination of phosphorylated and basal amount of both proteins suggested higher mTOR activity in old murine tissue and senescent human fibroblasts. Besides the reduced levels of ATGs, mTOR can additionally reduce MA, promoting further acceleration of protein accumulation and metabolic disturbances during aging.

      PubDate: 2016-10-28T17:01:38Z
      DOI: 10.1016/j.redox.2016.10.015
       
  • Prevailing vitamin D status influences mitochondrial and glycolytic
           bioenergetics in peripheral blood mononuclear cells obtained from adults

    • Authors: Emily K. Calton; Kevin N. Keane; Mario J. Soares; Jordan Rowlands; Philip Newsholme
      Abstract: Publication date: Available online 20 October 2016
      Source:Redox Biology
      Author(s): Emily K. Calton, Kevin N. Keane, Mario J. Soares, Jordan Rowlands, Philip Newsholme
      Background Circulating peripheral blood mononuclear cells (PBMCs) are exposed to metabolic and immunological stimuli that influence their functionality. We hypothesized that prevailing vitamin D status [25(OH)D] would modulate the bioenergetic profile of PBMCs derived from humans. Materials and methods 38 participants (16 males, 22 females) ranging in body fat from 14% to 51% were studied. PBMCs were isolated from whole blood, counted and freshly seeded for bioenergetic analysis using the Seahorse XFe96 flux analyser. Whole body energy metabolism via indirect calorimetry, body composition by dual-energy X-ray absorptiometry, and relevant clinical biochemistry were measured. Data was analysed based on 25(OH)D cut-offs of <50nmol/L (Group 1, n=12), 50–75 nmol/L (Group 2, n=15) and ≥75nmol/L (Group 3, n=11). A multivariate general linear model adjusting for age, fat mass, fat-free mass, parathyroid hormone and insulin sensitivity was used. Results There were significant differences in cellular mitochondrial function between groups. Group 1 had significantly higher basal respiration (p=0.001), non-mitochondrial respiration (p=0.009), ATP production (p=0.001), proton leak (p=0.018), background glycolysis (p=0.023) and glycolytic reserve (p=0.039) relative to either Group 2 or Group 3; the latter two did not differ on any measures. There were no differences in bioenergetic health index (BHI), resting metabolic rates and systemic inflammatory markers between groups. Conclusions Inadequate vitamin D status adversely influenced bioenergetic parameters of PBMCs obtained from adults, in a pattern consistent with increased oxidative metabolism and activation of these cells.

      PubDate: 2016-10-28T17:01:38Z
      DOI: 10.1016/j.redox.2016.10.007
       
  • Effects of Transgenic Methionine Sulfoxide Reductase A (MsrA) Expression
           on Lifespan and Age-Dependent Changes in Metabolic Function in Mice

    • Authors: Adam B. Salmon; Geumsoo Kim; Chengyu Liu; Jonathan D. Wren; Constantin Georgescu; Arlan Richardson; Rodney L. Levine
      Abstract: Publication date: Available online 25 October 2016
      Source:Redox Biology
      Author(s): Adam B. Salmon, Geumsoo Kim, Chengyu Liu, Jonathan D. Wren, Constantin Georgescu, Arlan Richardson, Rodney L. Levine
      Mechanisms that preserve and maintain the cellular proteome are associated with long life and healthy aging. Oxidative damage is a significant contributor to perturbation of proteostasis and is dealt with by the cell through regulation of antioxidants, protein degradation, and repair of oxidized amino acids. Methionine sulfoxide reductase A (MsrA) repairs oxidation of free- and protein-bound methionine residues through enzymatic reduction and is found in both the cytosol and the mitochondria. Previous studies in Drosophila have shown that increasing expression of MsrA can extend longevity. Here we test the effects of increasing MsrA on longevity and healthy aging in two transgenic mouse models. We show that elevated expression of MsrA targeted specifically to the cytosol reduces the rate of age-related death in female mice when assessed by Gompertz analysis. However, neither cytosolic nor mitochondrial MsrA overexpression extends lifespan when measured by Log Rank analysis. In mice with MsrA overexpression targeted to the mitochondria, we see no effect on longevity but evidence for improved insulin sensitivity in aged female mice. With these and our previous data, we conclude that the increasing MsrA expression in mice has differential effects on aging and healthy aging that are dependent on the target of its subcellular localization.
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      PubDate: 2016-10-28T17:01:38Z
      DOI: 10.1016/j.redox.2016.10.012
       
  • Tumor cells have decreased ability to metabolize H2O2: Implications for
           pharmacological ascorbate in cancer therapy

    • Authors: Claire M. Doskey; Visarut Buranasudja; Brett A. Wagner; Justin G. Wilkes; Juan Du; Joseph J. Cullen; Garry R. Buettner
      Abstract: Publication date: Available online 28 October 2016
      Source:Redox Biology
      Author(s): Claire M. Doskey, Visarut Buranasudja, Brett A. Wagner, Justin G. Wilkes, Juan Du, Joseph J. Cullen, Garry R. Buettner
      Ascorbate (AscH-) functions as a versatile reducing agent. At pharmacological doses (P-AscH-; [plasma AscH-] ≥ ≈20mM), achievable through intravenous delivery, oxidation of P-AscH- can produce a high flux of H2O2 in tumors. Catalase is the major enzyme for detoxifying high concentrations of H2O2. We hypothesize that sensitivity of tumor cells to P-AscH- compared to normal cells is due to their lower capacity to metabolize H2O2. Rate constants for removal of H2O2 (k cell) and catalase activities were determined for 15 tumor and 10 normal cell lines of various tissue types. A differential in the capacity of cells to remove H2O2 was revealed, with the average k cell for normal cells being twice that of tumor cells. The ED50 (50% clonogenic survival) of P-AscH- correlated directly with k cell and catalase activity. Catalase activity could present a promising indicator of which tumors may respond to P-AscH-.
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      PubDate: 2016-10-28T17:01:38Z
      DOI: 10.1016/j.redox.2016.10.010
       
  • Hydroxytyrosol inhibits hydrogen peroxide-induced apoptotic signaling via
           labile iron chelation

    • Authors: Natalia Kitsati; Michalis D. Mantzaris; Dimitrios Galaris
      Abstract: Publication date: Available online 15 October 2016
      Source:Redox Biology
      Author(s): Natalia Kitsati, Michalis D. Mantzaris, Dimitrios Galaris
      Although it is known that Mediterranean diet plays an important role in maintaining human health, the underlying molecular mechanisms remain largely unknown. The aim of this investigation was to elucidate the potential role of ortho-dihydroxy group containing natural compounds in H2O2-induced DNA damage and apoptosis. For this purpose, the main phenolic alcohols of olive oil, namely hydroxytyrosol and tyrosol, were examined for their ability to protect cultured cells under conditions of oxidative stress. A strong correlation was observed between the ability of hydroxytyrosol to mitigate intracellular labile iron level and the protection offered against H2O2-induced DNA damage and apoptosis. On the other hand, tyrosol, which lacks the ortho-dihydroxy group, was ineffective. Moreover, hydroxytyrosol (but not tyrosol), was able to diminish the late sustained phase of H2O2-induced JNK and p38 phosphorylation. The derangement of intracellular iron homeostasis, following exposure of cells to H2O2, played pivotal role both in the induction of DNA damage and the initiation of apoptotic signaling. The presented results suggest that the protective effects exerted by ortho-dihydroxy group containing dietary compounds against oxidative stress-induced cell damage are linked to their ability to influence changes in the intracellular labile iron homeostasis.
      Graphical abstract image

      PubDate: 2016-10-16T14:24:47Z
      DOI: 10.1016/j.redox.2016.10.006
       
  • Nrf2 Mediates Redox Adaptations to Exercise

    • Authors: Aaron Tinna
      Abstract: Publication date: Available online 14 October 2016
      Source:Redox Biology
      Author(s): Aaron J. Done, Tinna Traustadóttir
      The primary aim of this review is to summarize the current literature on the effects of acute exercise and regular exercise on nuclear factor erythroid 2-related factor 2 (Nrf2) activity and downstream targets of Nrf2 signaling. Nrf2 (encoded in humans by the NFE2L2 gene) is the master regulator of antioxidant defenses, a transcription factor that regulates expression of more than 200 cytoprotective genes. Increasing evidence indicates that Nrf2 signaling plays a key role in how oxidative stress mediates the beneficial effects of exercise. Episodic increases in oxidative stress induced through bouts of acute exercise stimulate Nrf2 activation and when applied repeatedly, as with regular exercise, leads to upregulation of endogenous antioxidant defenses and overall greater ability to counteract the damaging effects of oxidative stress. The evidence of Nrf2 activation in response to exercise across variety of tissues may be an important mechanism of how exercise exerts its well-known systemic effects that are not limited to skeletal muscle and myocardium. Additionally there are emerging data that results from animal studies translate to humans.
      Graphical abstract image

      PubDate: 2016-10-14T14:17:53Z
       
  • Taurine promotes cognitive function in prenatally stressed juvenile rats
           via activating the Akt-CREB-PGC1α pathway

    • Authors: Ning Jia; Qinru Sun Qian Shaokang Dang Guomin Chen
      Abstract: Publication date: Available online 13 October 2016
      Source:Redox Biology
      Author(s): Ning Jia, Qinru Sun, Qian Su, Shaokang Dang, Guomin Chen
      Substantial evidence has shown that the oxidative damage of hippocampal neurons is associated with the cognitive impairment induced by adverse stimuli during gestation named prenatal stress (PS). Taurine, a conditionally essential amino acid, possesses multiple roles in the brain as a neuromodulator or antioxidant. In this study, to explore the roles of taurine in PS-induced learning and memory impairment, prenatal restraint stress was set up and Morris water maze (MWM) was employed for testing the cognitive function in the one-month-old rat offspring. The mitochondrial reactive oxygen species (ROS) level,mitochondrial membrane potential (MMP), ATP and cytochrome c oxidase (CcO) activity and apoptosis-related proteins in the hippocampus were detected. The activity of the Akt-cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor –γ coactivator-1α (PGC1α) pathway in the hippocampus was measured. The results showed that high dosage of taurine administration in the early postnatal period attenuated impairment of spatial learning and memory induced by PS. Meanwhile, taurine administration diminished the increase of mitochondrial ROS, reduction of MMP, ATP level and the activities of CcO, superoxide dismutase 2 (SOD2) and catalase induced by PS in the hippocampus. In addition, taurine administration recovered PS-suppressed SOD2 expression level. Taurine administration blocked PS-induced decrease of the ratio of Bcl-2/Bax and increase of the ratio of cleaved caspase-3/full-length caspase-3. Notably, taurine inhibited PS-decreased phosphorylation of Akt (pAkt) and phosphorylation of CREB (pCREB), which consequently enhanced the mRNA and protein levels of PGC1α. Taken together, these results suggest that high dosage of taurine administration during the early postnatal period can significantly improve the cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1α pathway. Therefore, taurine has therapeutic potential for prenatal stressed offspring rats in future.
      Graphical abstract image

      PubDate: 2016-10-14T14:17:53Z
       
  • Autophagy and The Redox Connection: Virtual Collection Vol 2

    • Authors: Jianhua Zhang; Victor Darley-Usmar
      Abstract: Publication date: Available online 13 October 2016
      Source:Redox Biology
      Author(s): Jianhua Zhang, Victor Darley-Usmar


      PubDate: 2016-10-14T14:17:53Z
       
  • Albendazole as a promising molecule for tumor control

    • Authors: L.S.E.W. Castro; M.R. Kviecinski Ourique E.B. Parisotto V.M.A.S. Grienevicius J.F.G.
      Abstract: Publication date: Available online 22 September 2016
      Source:Redox Biology
      Author(s): L.S.E.W. Castro, M.R. Kviecinski, F. Ourique, E.B. Parisotto, V.M.A.S. Grienevicius, J.F.G. Correia, D. Wilhelm Filho, R.C. Pedrosa
      This work evaluated the antitumor effects of albendazole (ABZ) and its relationship with modulation of oxidative stress and induction of DNA damage. The present results showed that ABZ causes oxidative cleavage on calf-Thymus DNA suggesting that this compound can break DNA. ABZ treatment decreased MCF-7 cell viability (EC50 = 44.9 for 24h) and inhibited MCF-7 colony formation (~67.5% at 5μM). Intracellular ROS levels increased with ABZ treatment (~123%). The antioxidant NAC is able to revert the cytotoxic effects, ROS generation and loss of mitochondrial membrane potential of MCF-7 cells treated with ABZ. Ehrlich carcinoma growth was inhibited (~32%) and survival time was elongated (~50%) in animals treated with ABZ. Oxidative biomarkers (TBARS and protein carbonyl levels) and activity of antioxidant enzymes (CAT, SOD and GR) increased, and reduced glutathione (GSH) was depleted in animals treated with ABZ, indicating an oxidative stress condition, leading to a DNA damage causing phosphorylation of histone H2A and triggering apoptosis signaling, which was confirmed by increasing Bax/Bcl-xL rate, p53 and Bax expression. We propose that ABZ induces oxidative stress promoting DNA fragmentation and triggering apoptosis and inducing cell death, making this drug a promising leader molecule for development of new antitumor drugs.
      Graphical abstract image

      PubDate: 2016-09-24T09:13:47Z
       
 
 
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