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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  [3039 journals]
  • Angiogenesis in the atherosclerotic plaque

    • Authors: Caroline Camaré; Mélanie Pucelle; Anne Nègre-Salvayre; Robert Salvayre
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Caroline Camaré, Mélanie Pucelle, Anne Nègre-Salvayre, Robert Salvayre
      Atherosclerosis is a multifocal alteration of the vascular wall of medium and large arteries characterized by a local accumulation of cholesterol and non-resolving inflammation. Atherothrombotic complications are the leading cause of disability and mortality in western countries. Neovascularization in atherosclerotic lesions plays a major role in plaque growth and instability. The angiogenic process is mediated by classical angiogenic factors and by additional factors specific to atherosclerotic angiogenesis. In addition to its role in plaque progression, neovascularization may take part in plaque destabilization and thromboembolic events. Anti-angiogenic agents are effective to reduce atherosclerosis progression in various animal models. However, clinical trials with anti-angiogenic drugs, mainly anti-VEGF/VEGFR, used in anti-cancer therapy show cardiovascular adverse effects, and require additional investigations.
      Graphical abstract image

      PubDate: 2017-02-14T12:51:47Z
      DOI: 10.1016/j.redox.2017.01.007
      Issue No: Vol. 12 (2017)
       
  • Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain
           neurons promotes cognitive impairment and neurodegeneration

    • Authors: William Sealy Hambright; Rene Solano Fonseca; Liuji Chen; Ren Na; Qitao Ran
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): William Sealy Hambright, Rene Solano Fonseca, Liuji Chen, Ren Na, Qitao Ran
      Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD); however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus) that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4), a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD.
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      PubDate: 2017-02-14T12:51:47Z
      DOI: 10.1016/j.redox.2017.01.021
      Issue No: Vol. 12 (2017)
       
  • Plasma metabolite score correlates with Hypoxia time in a newly born
           piglet model for asphyxia

    • Authors: Julia Kuligowski; Rønnaug Solberg; Ángel Sánchez-Illana; Leonid Pankratov; Anna Parra-Llorca; Guillermo Quintás; Ola Didrik Saugstad; Máximo Vento
      Pages: 1 - 7
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Julia Kuligowski, Rønnaug Solberg, Ángel Sánchez-Illana, Leonid Pankratov, Anna Parra-Llorca, Guillermo Quintás, Ola Didrik Saugstad, Máximo Vento
      Hypoxic-ischemic encephalopathy (HIE) secondary to perinatal asphyxia is a leading cause of mortality and acquired long-term neurologic co-morbidities in the neonate. The most successful intervention for the treatment of moderate to severe HIE is moderate whole body hypothermia initiated within 6h from birth. The objective and prompt identification of infants who are at risk of developing moderate to severe HIE in the critical first hours still remains a challenge. This work proposes a metabolite score calculated based on the relative intensities of three metabolites (choline, 6,8-dihydroxypurine and hypoxanthine) that showed maximum correlation with hypoxia time in a consolidated piglet model for neonatal hypoxia-ischemia. The metabolite score's performance as a biomarker for perinatal hypoxia and its usefulness for clinical grading and decision making have been assessed and compared to the performance of lactate which is currently considered the gold standard. For plasma samples withdrawn before and directly after a hypoxic insult, the metabolite score performed similar to lactate. However, it provided an enhanced predictive capacity at 2h after resuscitation. The present study evidences the usefulness of the metabolite score for improving the early assessment of the severity of the hypoxic insult based on serial determinations in a minimally invasive biofluid. The applicability of the metabolite score for clinical diagnosis and patient stratification for hypothermia treatment has to be confirmed in multicenter trials involving newborns suffering from HIE.
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      PubDate: 2017-02-13T12:51:44Z
      DOI: 10.1016/j.redox.2017.02.002
      Issue No: Vol. 12 (2017)
       
  • Taking up the cudgels for the traditional reactive oxygen and nitrogen
           species detection assays and their use in the cardiovascular system

    • Authors: Andreas Daiber; Matthias Oelze; Sebastian Steven; Swenja Kröller-Schön; Thomas Münzel
      Pages: 35 - 49
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Andreas Daiber, Matthias Oelze, Sebastian Steven, Swenja Kröller-Schön, Thomas Münzel
      Reactive oxygen and nitrogen species (RONS such as H2O2, nitric oxide) confer redox regulation of essential cellular functions (e.g. differentiation, proliferation, migration, apoptosis), initiate and catalyze adaptive stress responses. In contrast, excessive formation of RONS caused by impaired break-down by cellular antioxidant systems and/or insufficient repair of the resulting oxidative damage of biomolecules may lead to appreciable impairment of cellular function and in the worst case to cell death, organ dysfunction and severe disease phenotypes of the entire organism. Therefore, the knowledge of the severity of oxidative stress and tissue specific localization is of great biological and clinical importance. However, at this level of investigation quantitative information may be enough. For the development of specific drugs, the cellular and subcellular localization of the sources of RONS or even the nature of the reactive species may be of great importance, and accordingly, more qualitative information is required. These two different philosophies currently compete with each other and their different needs (also reflected by different detection assays) often lead to controversial discussions within the redox research community. With the present review we want to shed some light on these different philosophies and needs (based on our personal views), but also to defend some of the traditional assays for the detection of RONS that work very well in our hands and to provide some guidelines how to use and interpret the results of these assays. We will also provide an overview on the “new assays” with a brief discussion on their strengths but also weaknesses and limitations.

      PubDate: 2017-02-20T13:22:20Z
      DOI: 10.1016/j.redox.2017.02.001
      Issue No: Vol. 12 (2017)
       
  • Redox regulation in metabolic programming and inflammation

    • Authors: Helen R. Griffiths; Dan Gao; Chathyan Pararasa
      Pages: 50 - 57
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Helen R. Griffiths, Dan Gao, Chathyan Pararasa
      Energy metabolism and redox state are intrinsically linked. In order to mount an adequate immune response, cells must have an adequate and rapidly available energy resource to migrate to the inflammatory site, to generate reactive oxygen species using NADPH as a cofactor and to engulf bacteria or damaged tissue. The first responder cells of the innate immune response, neutrophils, are largely dependent on glycolysis. Neutrophils are relatively short-lived, dying via apoptosis in the process of bacterial killing through production of hypochlorous acid and release of extracellular NETs. Later on, the most prevalent recruited innate immune cells are monocytes. Their role is to complete a damage limitation exercise initiated by neutrophils and then, as re-programmed M2 macrophages, to resolve the inflammatory event. Almost twenty five years ago, it was noted that macrophages lose their glycolytic capacity and become anti-inflammatory after treatment with corticosteroids. In support of this we now understand that, in contrast to early responders, M2 macrophages are predominantly dependent on oxidative phosphorylation for energy. During early inflammation, polarisation towards M1 macrophages is dependent on NOX2 activation which, via protein tyrosine phosphatase oxidation and AKT activation, increases trafficking of glucose transporters to the membrane and consequently increases glucose uptake for glycolysis. In parallel, mitochondrial efficiency is likely to be compromised via nitrosylation of the electron transport chain. Resolution of inflammation is triggered by encounter with apoptotic membranes exposing oxidised phosphatidylserine that interact with the scavenger receptor, CD36. Downstream of CD36, activation of AMPK and PPARγ elicits mitochondrial biogenesis, arginase expression and a switch towards oxidative phosphorylation in the M2 macrophage. Proinflammatory cytokine production by M2 cells decreases, but anti-inflammatory and wound healing growth factor production is maintained to support restoration of normal function.
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      PubDate: 2017-02-20T13:22:20Z
      DOI: 10.1016/j.redox.2017.01.023
      Issue No: Vol. 12 (2017)
       
  • Role of Nrf2 and protective effects of Metformin against tobacco
           smoke-induced cerebrovascular toxicity

    • Authors: Shikha Prasad; Ravi K. Sajja; Mohammad Abul Kaisar; Jee Hyun Park; Heidi Villalba; Taylor Liles; Thomas Abbruscato; Luca Cucullo
      Pages: 58 - 69
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Shikha Prasad, Ravi K. Sajja, Mohammad Abul Kaisar, Jee Hyun Park, Heidi Villalba, Taylor Liles, Thomas Abbruscato, Luca Cucullo
      Cigarette smoking (CS) is associated with vascular endothelial dysfunction in a causative way primarily related to the TS content of reactive oxygen species (ROS), nicotine, and inflammation. TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and blood-brain barrier (BBB) impairment. Herein we provide evidence of the role played by nuclear factor erythroid 2-related factor (Nrf2) in CS-induced cerebrobvascular/BBB impairments and how these cerebrovascular harmful effects can be circumvented by the use of metformin (MF; a widely prescribed, firstline anti-diabetic drug) treatment. Our data in fact revealed that MF activates counteractive mechanisms primarily associated with the Nrf2 pathway which drastically reduce CS toxicity at the cerebrovascular level. These include the suppression of tight junction (TJ) protein downregulation and loss of BBB integrity induced by CS, reduction of inflammation and oxidative stress, renormalization of the expression levels of the major BBB glucose transporter Glut-1 and that of the anticoagulant factor thrombomodulin. Further, we provide additional insights on the controversial interplay between Nrf2 and AMPK.
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      PubDate: 2017-02-20T13:22:20Z
      DOI: 10.1016/j.redox.2017.02.007
      Issue No: Vol. 12 (2017)
       
  • Reciprocal regulation of eNOS, H2S and CO-synthesizing enzymes in human
           atheroma: Correlation with plaque stability and effects of simvastatin

    • Authors: Fragiska Sigala; Panagiotis Efentakis; Dimitra Karageorgiadi; Konstadinos Filis; Paraskevas Zampas; Efstathios K. Iliodromitis; George Zografos; Andreas Papapetropoulos; Ioanna Andreadou
      Pages: 70 - 81
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Fragiska Sigala, Panagiotis Efentakis, Dimitra Karageorgiadi, Konstadinos Filis, Paraskevas Zampas, Efstathios K. Iliodromitis, George Zografos, Andreas Papapetropoulos, Ioanna Andreadou
      The molecular and cellular mechanisms underlying plaque destabilization remain obscure. We sought to elucidate the correlation between NO, H2S and CO-generating enzymes, nitro-oxidative stress and plaque stability in carotid arteries. Carotid atherosclerotic plaques were collected from 62 patients who had undergone endarterectomy due to internal artery stenosis. Following histological evaluation the plaques were divided into stable and unstable ones. To investigate the impact of simvastatin we divided patients with stable plaques, into those receiving and to those not receiving simvastatin. Expression and/or levels of p-eNOS/eNOS, pAkt/t-Akt, iNOS, cystathionine beta synthase (CBS), cystathionine gamma lyase (CSE), heme oxygenase-1(HO-1), soluble guanyl cyclase sGCα1, sGCβ1, NOX-4 and HIF-1α were evaluated. Oxidative stress biomarkers malondialdehyde (MDA) and nitrotyrosine (NT) were measured. NT levels were decreased in stable plaques with a concomitant increase of eNOS phosphorylation and expression and Akt activation compared to unstable lesions. An increase in HIF-1α, NOX-4, HO-1, iNOS, CBS and CSE expression was observed only in unstable plaques. 78% of patients under simvastatin were diagnosed with stable plaques whereas 23% of those not receiving simvastatin exhibited unstable plaques. Simvastatin decreased iNOS, HO-1, HIF-1α and CSE whilst it increased eNOS phosphorylation. In conclusion, enhanced eNOS and reduced iNOS and NOX-4 were observed in stable plaques; CBS and CSE positively correlated with plaque vulnerability. Simvastatin, besides its known effect on eNOS upregulation, reduced the HIF-1α and its downstream targets. The observed changes might be useful in developing biomarkers of plaque stability or could be targets for pharmacothepary against plaque vulnerability.

      PubDate: 2017-02-20T13:22:20Z
      DOI: 10.1016/j.redox.2017.02.006
      Issue No: Vol. 12 (2017)
       
  • Shortcuts to a functional adipose tissue: The role of small non-coding
           RNAs

    • Authors: Bruna B. Brandão; Beatriz A. Guerra; Marcelo A. Mori
      Pages: 82 - 102
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Bruna B. Brandão, Beatriz A. Guerra, Marcelo A. Mori
      Metabolic diseases such as type 2 diabetes are a major public health issue worldwide. These diseases are often linked to a dysfunctional adipose tissue. Fat is a large, heterogenic, pleiotropic and rather complex tissue. It is found in virtually all cavities of the human body, shows unique plasticity among tissues, and harbors many cell types in addition to its main functional unit – the adipocyte. Adipose tissue function varies depending on the localization of the fat depot, the cell composition of the tissue and the energy status of the organism. While the white adipose tissue (WAT) serves as the main site for triglyceride storage and acts as an important endocrine organ, the brown adipose tissue (BAT) is responsible for thermogenesis. Beige adipocytes can also appear in WAT depots to sustain heat production upon certain conditions, and it is becoming clear that adipose tissue depots can switch phenotypes depending on cell autonomous and non-autonomous stimuli. To maintain such degree of plasticity and respond adequately to changes in the energy balance, three basic processes need to be properly functioning in the adipose tissue: i) adipogenesis and adipocyte turnover, ii) metabolism, and iii) signaling. Here we review the fundamental role of small non-coding RNAs (sncRNAs) in these processes, with focus on microRNAs, and demonstrate their importance in adipose tissue function and whole body metabolic control in mammals.
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      PubDate: 2017-02-20T13:22:20Z
      DOI: 10.1016/j.redox.2017.01.020
      Issue No: Vol. 12 (2017)
       
  • Influence of oxygen partial pressure on the characteristics of human
           hepatocarcinoma cells

    • Authors: Jenifer Trepiana; Susana Meijide; Rosaura Navarro; M. Luisa Hernández; José Ignacio Ruiz-Sanz; M. Begoña Ruiz-Larrea
      Pages: 103 - 113
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Jenifer Trepiana, Susana Meijide, Rosaura Navarro, M. Luisa Hernández, José Ignacio Ruiz-Sanz, M. Begoña Ruiz-Larrea
      Most of the in vitro studies using liver cell lines have been performed under atmospheric oxygen partial pressure (21% O2). However, the oxygen concentrations in the liver and cancer cells are far from this value. In the present study, we have evaluated the influence of oxygen on 1) the tumor cell lines features (growth, steady-state ROS levels, GSH content, activities of antioxidant enzymes, p66 Shc and SOD expressions, metalloproteinases secretion, migration, invasion, and adhesion) of human hepatocellular carcinoma cell lines, and b) the response of the cells to an oxidant stimulus (aqueous leaf extract of the V. baccifera plant species). For this purpose, three hepatocarcinoma cell lines with different p53 status, HepG2 (wild-type), Huh7 (mutated), and Hep3B (deleted), were cultured (6–30 days) under atmospheric (21%) and more physiological (8%) pO2. Results showed that after long-term culturing at 8% versus 21% O2, the cellular proliferation rate and the steady-state levels of mitochondrial O2 - were unaffected. However, the intracellular basal ROS levels were higher independently of the characteristics of the cell line. Moreover, the lower pO2 was associated with lower glutathione content, the induction of p66 Shc and Mn-SOD proteins, and increased SOD activity only in HepG2. This cell line also showed a higher migration rate, secretion of active metalloproteinases, and a faster invasion. HepG2 cells were more resistant to the oxidative stress induced by V. baccifera. Results suggest that the long-term culturing of human hepatoma cells at a low, more physiological pO2 induces antioxidant adaptations that could be mediated by p53, and may alter the cellular response to a subsequent oxidant challenge. Data support the necessity of validating outcomes from studies performed with hepatoma cell cultures under ambient O2.
      Graphical abstract image

      PubDate: 2017-02-20T13:22:20Z
      DOI: 10.1016/j.redox.2017.02.004
      Issue No: Vol. 12 (2017)
       
  • Increased static and decreased capacity oxidation-reduction potentials in
           plasma are predictive of metabolic syndrome

    • Authors: Gerd Bobe; Tora J. Cobb; Scott W. Leonard; Savinda Aponso; Christopher B. Bahro; Dipankar Koley; Eunice Mah; Richard S. Bruno; Maret G. Traber
      Pages: 121 - 128
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Gerd Bobe, Tora J. Cobb, Scott W. Leonard, Savinda Aponso, Christopher B. Bahro, Dipankar Koley, Eunice Mah, Richard S. Bruno, Maret G. Traber
      Electric conductivity in plasma is the balance between oxidized and reduced molecules (static Oxidation-Reduction Potential, sORP) and the amount of readily oxidizable molecules (capacity ORP, cORP). Adults with metabolic syndrome (MetS) have increased inflammation, dyslipidemia and oxidative stress; therefore, participants with MetS were hypothesized to have higher plasma sORP and lower cORP than those measures in healthy adults. Heparin-anticoagulated plasma from healthy and age- and gender-matched individuals with MetS (BMI: 22.6±0.7 vs. 37.7±3.0kg/m2, respectively) was collected in the fasting state at 0, 24, 48, and 72h during each of four separate interventions in a clinical trial. At baseline, plasma sORP was 12.4% higher (P=0.007), while cORP values were less than half (41.1%, P=0.001) in those with MetS compared with healthy participants. An sORP >140mV detected MetS with 90% sensitivity and 80% specificity, while a cORP <0.50μC detected MetS with 80% sensitivity and 100% specificity. sORP and cORP values in participants with MetS compared with healthy adults were linked to differences in waist circumference and BMI; in plasma markers of dyslipidemia (triglycerides, HDL-cholesterol, and oxidized LDL-cholesterol) and inflammation (C-reactive protein, IL-10); as well as with urinary markers of lipid peroxidation (e.g., 2,3-dinor-5,6-dihydro-8-iso-PGF2α; 2,3-dinor-8-iso-PGF2α). Higher sORP values are a robust indicator of metabolic stress, while lower cORP values act as an indicator of decreased metabolic resilience.
      Graphical abstract image

      PubDate: 2017-02-20T13:22:20Z
      DOI: 10.1016/j.redox.2017.02.010
      Issue No: Vol. 12 (2017)
       
  • Plant peroxisomes: A nitro-oxidative cocktail

    • Authors: Francisco J. Corpas; Juan B. Barroso; José M. Palma; Marta Rodriguez-Ruiz
      Pages: 535 - 542
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Francisco J. Corpas, Juan B. Barroso, José M. Palma, Marta Rodriguez-Ruiz
      Although peroxisomes are very simple organelles, research on different species has provided us with an understanding of their importance in terms of cell viability. In addition to the significant role played by plant peroxisomes in the metabolism of reactive oxygen species (ROS), data gathered over the last two decades show that these organelles are an endogenous source of nitric oxide (NO) and related molecules called reactive nitrogen species (RNS). Molecules such as NO and H2O2 act as retrograde signals among the different cellular compartments, thus facilitating integral cellular adaptation to physiological and environmental changes. However, under nitro-oxidative conditions, part of this network can be overloaded, possibly leading to cellular damage and even cell death. This review aims to update our knowledge of the ROS/RNS metabolism, whose important role in plant peroxisomes is still underestimated. However, this pioneering approach, in which key elements such as β-oxidation, superoxide dismutase (SOD) and NO have been mainly described in relation to plant peroxisomes, could also be used to explore peroxisomes from other organisms.
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      PubDate: 2017-01-19T17:53:04Z
      DOI: 10.1016/j.redox.2016.12.033
      Issue No: Vol. 11 (2017)
       
  • Nitro-fatty acids in plant signaling: New key mediators of nitric oxide
           metabolism

    • Authors: Capilla Mata-Pérez; Beatriz Sánchez-Calvo; María N. Padilla; Juan C. Begara-Morales; Raquel Valderrama; Francisco J. Corpas; Juan B. Barroso
      Pages: 554 - 561
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Capilla Mata-Pérez, Beatriz Sánchez-Calvo, María N. Padilla, Juan C. Begara-Morales, Raquel Valderrama, Francisco J. Corpas, Juan B. Barroso
      Recent studies in animal systems have shown that NO can interact with fatty acids to generate nitro-fatty acids (NO2-FAs). They are the product of the reaction between reactive nitrogen species and unsaturated fatty acids, and are considered novel mediators of cell signaling based mainly on a proven anti-inflammatory response. Although these signaling mediators have been described widely in animal systems, NO2-FAs have scarcely been studied in plants. Preliminary data have revealed the endogenous presence of free and protein-adducted NO2-FAs in extra-virgin olive oil (EVOO), which appear to be contributing to the cardiovascular benefits associated with the Mediterranean diet. Importantly, new findings have displayed the endogenous occurrence of nitro-linolenic acid (NO2-Ln) in the model plant Arabidopsis thaliana and the modulation of NO2-Ln levels throughout this plant's development. Furthermore, a transcriptomic analysis by RNA-seq technology established a clear signaling role for this molecule, demonstrating that NO2-Ln was involved in plant-defense response against different abiotic-stress conditions, mainly by inducing the chaperone network and supporting a conserved mechanism of action in both animal and plant defense processes. Thus, NO2-Ln levels significantly rose under several abiotic-stress conditions, highlighting the strong signaling role of these molecules in the plant-protection mechanism. Finally, the potential of NO2-Ln as a NO donor has recently been described both in vitro and in vivo. Jointly, this ability gives NO2-Ln the potential to act as a signaling molecule by the direct release of NO, due to its capacity to induce different changes mediated by NO or NO-related molecules such as nitration and S-nitrosylation, or by the electrophilic capacity of these molecules through a nitroalkylation mechanism. Here, we describe the current state of the art regarding the advances performed in the field of NO2-FAs in plants and their implication in plant physiology.
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      PubDate: 2017-01-19T17:53:04Z
      DOI: 10.1016/j.redox.2017.01.002
      Issue No: Vol. 11 (2017)
       
  • Hydrogen peroxide as a central redox signaling molecule in physiological
           oxidative stress: Oxidative eustress

    • Authors: Helmut Sies
      Pages: 613 - 619
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Helmut Sies
      Hydrogen peroxide emerged as major redox metabolite operative in redox sensing, signaling and redox regulation. Generation, transport and capture of H2O2 in biological settings as well as their biological consequences can now be addressed. The present overview focuses on recent progress on metabolic sources and sinks of H2O2 and on the role of H2O2 in redox signaling under physiological conditions (1–10nM), denoted as oxidative eustress. Higher concentrations lead to adaptive stress responses via master switches such as Nrf2/Keap1 or NF-κB. Supraphysiological concentrations of H2O2 (>100nM) lead to damage of biomolecules, denoted as oxidative distress. Three questions are addressed: How can H2O2 be assayed in the biological setting? What are the metabolic sources and sinks of H2O2? What is the role of H2O2 in redox signaling and oxidative stress?
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      PubDate: 2017-01-25T18:18:46Z
      DOI: 10.1016/j.redox.2016.12.035
      Issue No: Vol. 11 (2017)
       
  • Autophagy and the redox connection: Virtual collection Vol 2

    • Authors: Jianhua Zhang; Victor Darley-Usmar
      Pages: 620 - 621
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Jianhua Zhang, Victor Darley-Usmar


      PubDate: 2017-01-25T18:18:46Z
      DOI: 10.1016/j.redox.2016.10.005
      Issue No: Vol. 11 (2017)
       
  • Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications

    • Authors: Susana Rovira-Llopis; Celia Bañuls; Noelia Diaz-Morales; Antonio Hernandez-Mijares; Milagros Rocha; Victor M. Victor
      Pages: 637 - 645
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Susana Rovira-Llopis, Celia Bañuls, Noelia Diaz-Morales, Antonio Hernandez-Mijares, Milagros Rocha, Victor M. Victor
      Mitochondria play a key role in maintaining cellular metabolic homeostasis. These organelles have a high plasticity and are involved in dynamic processes such as mitochondrial fusion and fission, mitophagy and mitochondrial biogenesis. Type 2 diabetes is characterised by mitochondrial dysfunction, high production of reactive oxygen species (ROS) and low levels of ATP. Mitochondrial fusion is modulated by different proteins, including mitofusin-1 (MFN1), mitofusin-2 (MFN2) and optic atrophy (OPA-1), while fission is controlled by mitochondrial fission 1 (FIS1), dynamin-related protein 1 (DRP1) and mitochondrial fission factor (MFF). PARKIN and (PTEN)-induced putative kinase 1 (PINK1) participate in the process of mitophagy, for which mitochondrial fission is necessary. In this review, we discuss the molecular pathways of mitochondrial dynamics, their impairment under type 2 diabetes, and pharmaceutical approaches for targeting mitochondrial dynamics, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110 and 15-oxospiramilactone. Furthermore, we discuss the pathophysiological implications of impaired mitochondrial dynamics, especially in type 2 diabetes.

      PubDate: 2017-02-02T10:20:57Z
      DOI: 10.1016/j.redox.2017.01.013
      Issue No: Vol. 11 (2017)
       
  • Modulation of proteostasis by transcription factor NRF2 and impact in
           neurodegenerative diseases

    • Authors: Marta Pajares; Antonio Cuadrado; Ana I. Rojo
      Abstract: Publication date: Available online 10 January 2017
      Source:Redox Biology
      Author(s): Marta Pajares, Antonio Cuadrado, Ana I. Rojo
      Neurodegenerative diseases are linked to the accumulation of specific protein aggregates, suggesting an intimate connection between injured brain and loss of proteostasis. Proteostasis refers to all the processes by which cells control the abundance and folding of the proteome thanks to a wide network that integrates the regulation of signaling pathways, gene expression and protein degradation systems. This review attempts to summarize the most relevant findings about the transcriptional modulation of proteostasis exerted by the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2). NRF2 has been classically considered as the master regulator of the antioxidant cell response, although it is currently emerging as a key component of the transduction machinery to maintain proteostasis. As we will discuss, NRF2 could be envisioned as a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and perdurable transcriptional response. This is achieved by functions of NRF2 related to the control of genes involved in the maintenance of the endoplasmic reticulum physiology, the proteasome and autophagy.

      PubDate: 2017-01-11T16:49:06Z
      DOI: 10.1016/j.redox.2017.01.006
       
  • Oxidative stress, mitochondrial abnormalities and antioxidant defense in
           Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

    • Authors: Mateusz Maciejczyk; Bozena Mikoluc; Barbara Pietrucha; Edyta Heropolitanska - Pliszka; Malgorzata Pac; Radosław Motkowski; Halina Car
      Abstract: Publication date: Available online 28 December 2016
      Source:Redox Biology
      Author(s): Mateusz Maciejczyk, Bozena Mikoluc, Barbara Pietrucha, Edyta Heropolitanska - Pliszka, Malgorzata Pac, Radosław Motkowski, Halina Car
      Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP). Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS), and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model.
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      PubDate: 2017-01-01T07:48:50Z
      DOI: 10.1016/j.redox.2016.12.030
       
  • Oxidative stress in cancer and fibrosis: Opportunity for therapeutic
           intervention with antioxidant compounds, enzymes, and nanoparticles

    • Authors: Worapol Ngamcherdtrakul; David J. Castro; Shenda Gu; Jingga Morry; Moataz Reda; Joe W. Gray; Wassana Yantasee
      Pages: 19 - 29
      Abstract: Publication date: Available online 16 December 2016
      Source:Redox Biology
      Author(s): Jingga Morry, Worapol Ngamcherdtrakul, Wassana Yantasee
      Oxidative stress, mainly contributed by reactive oxygen species (ROS), has been implicated in pathogenesis of several diseases. We review two primary examples; fibrosis and cancer. In fibrosis, ROS promote activation and proliferation of fibroblasts and myofibroblasts, activating TGF-β pathway in an autocrine manner. In cancer, ROS account for its genomic instability, resistance to apoptosis, proliferation, and angiogenesis. Importantly, ROS trigger cancer cell invasion through invadopodia formation as well as extravasation into a distant metastasis site. Use of antioxidant supplements, enzymes, and inhibitors for ROS-generating NADPH oxidases (NOX) is a logical therapeutic intervention for fibrosis and cancer. We review such attempts, progress, and challenges. Lastly, we review how nanoparticles with inherent antioxidant activity can also be a promising therapeutic option, considering their additional feature as a delivery platform for drugs, genes, and imaging agents.
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      PubDate: 2016-12-16T13:24:35Z
      DOI: 10.1016/j.ctrv.2016.02.005
      Issue No: Vol. 45 (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.
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      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)
       
  • Specificity protein 1-zinc finger protein 179 pathway is involved in the
           attenuation of oxidative stress following brain injury

    • Authors: Jian-Ying Chuang; Tzu-Jen Kao; Shu-Hui Lin; An-Chih Wu; Pin-Tse Lee; Tsung-Ping Su; Shiu-Hwa Yeh; Yi-Chao Lee; Chung-Che Wu; Wen-Chang Chang
      Pages: 135 - 143
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Jian-Ying Chuang, Tzu-Jen Kao, Shu-Hui Lin, An-Chih Wu, Pin-Tse Lee, Tsung-Ping Su, Shiu-Hwa Yeh, Yi-Chao Lee, Chung-Che Wu, Wen-Chang Chang
      After sudden traumatic brain injuries, secondary injuries may occur during the following days or weeks, which leads to the accumulation of reactive oxygen species (ROS). Since ROS exacerbate brain damage, it is important to protect neurons against their activity. Zinc finger protein 179 (Znf179) was shown to act as a neuroprotective factor, but the regulation of gene expression under oxidative stress remains unknown. In this study, we demonstrated an increase in Znf179 protein levels in both in vitro model of hydrogen peroxide (H2O2)-induced ROS accumulation and animal models of traumatic brain injury. Additionally, we examined the sub-cellular localization of Znf179, and demonstrated that oxidative stress increases Znf179 nuclear shuttling and its interaction with specificity protein 1 (Sp1). Subsequently, the positive autoregulation of Znf179 expression, which is Sp1-dependent, was further demonstrated using luciferase reporter assay and green fluorescent protein (GFP)-Znf179-expressing cells and transgenic mice. The upregulation of Sp1 transcriptional activity induced by the treatment with nerve growth factor (NGF) led to an increase in Znf179 levels, which further protected cells against H2O2-induced damage. However, Sp1 inhibitor, mithramycin A, was shown to inhibit NGF effects, leading to a decrease in Znf179 expression and lower cellular protection. In conclusion, the results obtained in this study show that Znf179 autoregulation through Sp1-dependent mechanism plays an important role in neuroprotection, and NGF-induced Sp1 signaling may help attenuate more extensive (ROS-induced) damage following brain injury.
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      PubDate: 2016-12-03T12:49:41Z
      DOI: 10.1016/j.redox.2016.11.012
      Issue No: Vol. 11 (2016)
       
  • The timing of caffeic acid treatment with cisplatin determines
           sensitization or resistance of ovarian carcinoma cell lines

    • Authors: R. Sirota; D. Gibson; R. Kohen
      Pages: 170 - 175
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): R. Sirota, D. Gibson, R. Kohen
      Cisplatin is a widely used chemotherapeutic drug showing high efficiency in the treatment of primary tumors such as ovarian, testicular and cervical cancers. The major drawback of cisplatin is tumor resistance either acquired or intrinsic. Many mechanisms are involved in the resistance, among them is the Nrf2 pathway which regulates glutathione related enzymes. Caffeic acid, a non-toxic polyphenol which is abundant in many foods modulates glutathione S-transferase (GST) and glutathione reductase (GSR) activity, these enzymes were shown to be involved in resistance of cells towards cisplatin. Caffeic acid induces the Nrf2 pathway and can also inhibit the activity of GST and GSR. Our findings demonstrate that the co-treatment of cancer cells with cisplatin and caffeic acid can enhance cisplatin cytotoxicity and increases the amount of platinum bound to nuclear DNA. However, 6h of pre incubation with caffeic acid prior to cisplatin treatment led to acquired resistance to cisplatin and reduced DNA binding. In conclusion, the enzyme inhibitory action of caffeic acid is dominant when the two agents are co-administered leading to increased cytotoxicity, and the Nrf2 induction is dominant when the cells are treated with caffeic acid prior to cisplatin treatment leading to resistance. The use of caffeic acid as adjuvant for cisplatin should be carefully examined due to different pharmacokinetic profiles of caffeic acid and cisplatin. Thus, it is questionable if the two agents can reach the tumors at the right time frame in vivo.
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      PubDate: 2016-12-10T13:03:59Z
      DOI: 10.1016/j.redox.2016.12.006
      Issue No: Vol. 11 (2016)
       
  • Autophagy deficient keratinocytes display increased DNA damage, senescence
           and aberrant lipid composition after oxidative stress in vitro and in vivo
           

    • Authors: Xiuzu Song; Marie Sophie Narzt; Ionela Mariana Nagelreiter; Philipp Hohensinner; Lucia Terlecki-Zaniewicz; Erwin Tschachler; Johannes Grillari; Florian Gruber
      Pages: 219 - 230
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Xiuzu Song, Marie Sophie Narzt, Ionela Mariana Nagelreiter, Philipp Hohensinner, Lucia Terlecki-Zaniewicz, Erwin Tschachler, Johannes Grillari, Florian Gruber
      Autophagy allows cells fundamental adaptations to metabolic needs and to stress. Using autophagic bulk degradation cells can clear crosslinked macromolecules and damaged organelles that arise under redox stress. Accumulation of such debris results in cellular dysfunction and is observed in aged tissue and senescent cells. Conversely, promising anti-aging strategies aim at inhibiting the mTOR pathway and thereby activating autophagy, to counteract aging associated damage. We have inactivated autophagy related 7 (Atg7), an essential autophagy gene, in murine keratinocytes (KC) and have found in an earlier study that this resulted in increased baseline oxidative stress and reduced capacity to degrade crosslinked proteins after oxidative ultraviolet stress. To investigate whether autophagy deficiency would promote cellular aging, we studied how Atg7 deficient (KO) and Atg7 bearing cells (WT) would respond to stress induced by paraquat (PQ), an oxidant drug commonly used to induce cellular senescence. Atg7 deficient KC displayed increased prostanoid signaling and a pro- mitotic gene expression signature as compared to the WT. After exposure to PQ, both WT and KO cells showed an inflammatory and stress-related transcriptomic response. However, the Atg7 deficient cells additionally showed drastic DNA damage- and cell cycle arrest signaling. Indeed, DNA fragmentation and –oxidation were strongly increased in the stressed Atg7 deficient cells upon PQ stress but also after oxidizing ultraviolet A irradiation. Damage associated phosphorylated histone H2AX (γH2AX) foci were increased in the nuclei, whereas expression of the nuclear lamina protein lamin B1 was strongly decreased. Similarly, in both, PQ treated mouse tail skin explants and in UVA irradiated mouse tail skin, we found a strong increase in γH2AX positive nuclei within the basal layer of Atg7 deficient epidermis. Atg7 deficiency significantly affected expression of lipid metabolic genes. Therefore we performed lipid profiling of keratinocytes which demonstrated a major dysregulation of cellular lipid metabolism. We found accumulation of autophagy agonisitic free fatty acids, whereas triglyceride levels were strongly decreased. Together, our data show that in absence of Atg7/autophagy the resistance of keratinocytes to intrinsic and environmental oxidative stress was severely impaired and resulted in DNA damage, cell cycle arrest and a disturbed lipid phenotype, all typical for premature cell aging.
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      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.015
      Issue No: Vol. 11 (2016)
       
  • Nrf2 inhibition reverses the resistance of cisplatin-resistant head and
           neck cancer cells to artesunate-induced ferroptosis

    • Authors: Jong-Lyel Roh; Eun Hye Kim; Hyejin Jang; Daiha Shin
      Pages: 254 - 262
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Jong-Lyel Roh, Eun Hye Kim, Hyejin Jang, Daiha Shin
      Artesunate, an anti-malarial drug, has been repurposed as an anticancer drug due to its induction of cell death via reactive oxygen species (ROS) production. However, the molecular mechanisms regulating cancer cell death and the resistance of cells to artesunate remain unclear. We investigated the molecular mechanisms behind the antitumor effects of artesunate and an approach to overcome artesunate resistance in head and neck cancer (HNC). The effects of artesunate and trigonelline were tested in different HNC cell lines, including three cisplatin-resistant HNC cell lines. The effects of these drugs as well as the inhibition of Keap1, Nrf2, and HO-1 were assessed by cell viability, cell death, glutathione (GSH) and ROS production, protein expression, and mouse tumor xenograft models. Artesunate selectively killed HNC cells but not normal cells. The artesunate sensitivity was relatively low in cisplatin-resistant HNC cells. Artesunate induced ferroptosis in HNC cells by decreasing cellular GSH levels and increasing lipid ROS levels. This effect was blocked by co-incubation with ferrostatin-1 and a trolox pretreatment. Artesunate activated the Nrf2–antioxidant response element (ARE) pathway in HNC cells, which contributed to ferroptosis resistance. The silencing of Keap1, a negative regulator of Nrf2, decreased artesunate sensitivity in HNC cells. Nrf2 genetic silencing or trigonelline reversed the ferroptosis resistance of Keap1-silenced and cisplatin-resistant HNC cells to artesunate in vitro and in vivo. Nrf2–ARE pathway activation contributes to the artesunate resistance of HNC cells, and inhibition of this pathway abolishes ferroptosis-resistant HNC. Condensed abstract Our results show the effectiveness and molecular mechanism of artesunate treatment on head and neck cancer (HNC). Artesunate selectively killed HNC cells but not normal cells by inducing an iron-dependent, ROS-accumulated ferroptosis. However, this effect may be suboptimal in some cisplatin-resistant HNCs because of Nrf2–antioxidant response element (ARE) pathway activation. Inhibition of the Nrf2–ARE pathway increased artesunate sensitivity and reversed the ferroptosis resistance in resistant HNC cells.
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      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.010
      Issue No: Vol. 11 (2016)
       
  • Ugonin U stimulates NLRP3 inflammasome activation and enhances
           inflammasome-mediated pathogen clearance

    • Authors: Chun-Yu Chen; Chuan-Hui Yang; Yung-Fong Tsai; Chih-Chuang Liaw; Wen-Yi Chang; Tsong-Long Hwang
      Pages: 263 - 274
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Chun-Yu Chen, Chuan-Hui Yang, Yung-Fong Tsai, Chih-Chuang Liaw, Wen-Yi Chang, Tsong-Long Hwang
      The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1β processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1β and caspase-1 activation. UgU induced Ca2+ mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IP3R). Blocking Ca2+ mobilization, PLC, or IP3R diminished UgU-induced IL-1β release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca2+ mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases.
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      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.018
      Issue No: Vol. 11 (2016)
       
  • A capture method based on the VC1 domain reveals new binding properties of
           the human receptor for advanced glycation end products (RAGE)

    • Authors: Genny Degani; Alessandra A. Altomare; Mara Colzani; Caterina Martino; Angelica Mazzolari; Guenter Fritz; Giulio Vistoli; Laura Popolo; Giancarlo Aldini
      Pages: 275 - 285
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Genny Degani, Alessandra A. Altomare, Mara Colzani, Caterina Martino, Angelica Mazzolari, Guenter Fritz, Giulio Vistoli, Laura Popolo, Giancarlo Aldini
      The Advanced Glycation and Lipoxidation End products (AGEs and ALEs) are a heterogeneous class of compounds derived from the non-enzymatic glycation or protein adduction by lipoxidation break-down products. The receptor for AGEs (RAGE) is involved in the progression of chronic diseases based on persistent inflammatory state and oxidative stress. RAGE is a pattern recognition receptor (PRR) and the inhibition of the interaction with its ligands or of the ligand accumulation have a potential therapeutic effect. The N-terminal domain of RAGE, the V domain, is the major site of AGEs binding and is stabilized by the adjacent C1 domain. In this study, we set up an affinity assay relying on the extremely specific biological interaction AGEs ligands have for the VC1 domain. A glycosylated form of VC1, produced in the yeast Pichia pastoris, was attached to magnetic beads and used as insoluble affinity matrix (VC1-resin). The VC1 interaction assay was employed to isolate specific VC1 binding partners from in vitro generated AGE-albumins and modifications were identified/localized by mass spectrometry analysis. Interestingly, this method also led to the isolation of ALEs produced by malondialdehyde treatment of albumins. Computational studies provided a rational-based interpretation of the contacts established by specific modified residues and amino acids of the V domain. The validation of VC1-resin in capturing AGE-albumins from complex biological mixtures such as plasma and milk, may lead to the identification of new RAGE ligands potentially involved in pro-inflammatory and pro-fibrotic responses, independently of their structures or physical properties, and without the use of any covalent derivatization process. In addition, the method can be applied to the identification of antagonists of RAGE-ligand interaction.
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      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.017
      Issue No: Vol. 11 (2016)
       
  • Aldehyde dehydrogenase 2 protects against oxidative stress associated with
           pulmonary arterial hypertension

    • Authors: Tao Xu; Shuangyue Liu; Tingting Ma; Ziyi Jia; Zhifei Zhang; Aimei Wang
      Pages: 286 - 296
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Tao Xu, Shuangyue Liu, Tingting Ma, Ziyi Jia, Zhifei Zhang, Aimei Wang
      The cardioprotective benefits of aldehyde dehydrogenase 2 (ALDH2) are well established, although the regulatory role of ALDH2 in vascular remodeling in pulmonary arterial hypertension (PAH) is largely unknown. ALDH2 potently regulates the metabolism of aldehydes such as 4-hydroxynonenal (4-HNE), the endogenous product of lipid peroxidation. Thus, we hypothesized that ALDH2 ameliorates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting 4-HNE accumulation and regulating downstream signaling pathways, thereby ameliorating pulmonary vascular remodeling. We found that low concentrations of 4-HNE (0.1 and 1μM) stimulated cell proliferation by enhancing cyclin D1 and c-Myc expression in primary HPASMCs. Low 4-HNE concentrations also enhanced cell migration by activating the nuclear factor kappa B (NF-κB) signaling pathway, thereby regulating matrix metalloprotein (MMP)-9 and MMP2 expression in vitro. In vivo, Alda-1, an ALDH2 agonist, significantly stimulated ALDH2 activity, reducing elevated 4-HNE and malondialdehyde levels and right ventricular systolic pressure in a monocrotaline-induced PAH animal model to the level of control animals. Our findings indicate that 4-HNE plays an important role in the abnormal proliferation and migration of HPASMCs, and that ALDH2 activation can attenuate 4-HNE-induced PASMC proliferation and migration, possibly by regulating NF-κB activation, in turn ameliorating vascular remodeling in PAH. This mechanism might reflect a new molecular target for treating PAH.
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      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.019
      Issue No: Vol. 11 (2016)
       
  • Fibroblast growth factor 21 and its novel association with oxidative
           stress

    • Authors: Miguel Ángel Gómez-Sámano; Mariana Grajales-Gómez; Julia María Zuarth-Vázquez; Ma. Fernanda Navarro-Flores; Mayela Martínez-Saavedra; Óscar Alfredo Juárez-León; Mariana G. Morales-García; Víctor Manuel Enríquez-Estrada; Francisco J. Gómez-Pérez; Daniel Cuevas-Ramos
      Abstract: Publication date: Available online 22 December 2016
      Source:Redox Biology
      Author(s): Miguel Ángel Gómez-Sámano, Mariana Grajales-Gómez, Julia María Zuarth-Vázquez, Ma. Fernanda Navarro-Flores, Mayela Martínez-Saavedra, Óscar Alfredo Juárez-León, Mariana G. Morales-García, Víctor Manuel Enríquez-Estrada, Francisco J. Gómez-Pérez, Daniel Cuevas-Ramos
      Fibroblast growth factor 21 (FGF21) is an endocrine-member of the FGF family. It is synthesized mainly in the liver, but it is also expressed in adipose tissue, skeletal muscle, and many other organs. It has a key role in glucose and lipid metabolism, as well as in energy balance. FGF21 concentration in plasma is increased in patients with obesity, insulin resistance, and metabolic syndrome. Recent findings suggest that such increment protects tissue from an increased oxidative stress environment. Different types of physical stress, such as strenuous exercising, lactation, diabetic nephropathy, cardiovascular disease, and critical illnesses, also increase FGF21 circulating concentration. FGF21 is now considered a stress-responsive hormone in humans. The discovery of an essential response element in the FGF21 gene, for the activating transcription factor 4 (ATF4), involved in the regulation of oxidative stress, and its relation with genes such as NRF2, TBP-2, UCP3, SOD2, ERK, and p38, places FGF21 as a key regulator of the oxidative stress cell response. Its role in chronic diseases and its involvement in the treatment and follow-up of these diseases has been recently the target of new studies. The diminished oxidative stress through FGF21 pathways observed with anti-diabetic therapy is another clue of the new insights of this hormone.

      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.024
       
  • Knock out of the NADPH oxidase Nox4 has no impact on life span in mice

    • Authors: Flavia Rezende; Christoph Schürmann; Susanne Schütz; Sabine Harenkamp; Eva Herrmann; Michael Seimetz; Norbert Weißmann; Katrin Schröder
      Abstract: Publication date: Available online 22 December 2016
      Source:Redox Biology
      Author(s): Flavia Rezende, Christoph Schürmann, Susanne Schütz, Sabine Harenkamp, Eva Herrmann, Michael Seimetz, Norbert Weißmann, Katrin Schröder
      The free radical theory of aging suggests reactive oxygen species as a main reason for accumulation of damage events eventually leading to aging. Nox4, a member of the family of NADPH oxidases constitutively produces ROS and therefore has the potential to be a main driver of aging. Herein we analyzed the life span of Nox4 deficient mice and found no difference when compared to their wildtype littermates. Accordingly neither Tert expression nor telomere length was different in cells isolated from those animals. In fact, Nox4 mRNA expression in lungs of wildtype mice dropped with age. We conclude that Nox4 has no influence on lifespan of healthy mice.
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      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.012
       
  • The Mitochondria-targeted Antioxidant MitoQ Ameliorated Tubular Injury
           Mediated by Mitophagy in Diabetic Kidney Disease via Nrf2/PINK1

    • Authors: Li Xiao; Xiaoxuan Xu; Fan Zhang; Ming Wang; Yan Xu; Dan Tang; Jiahui Wang; Yan Qin; Yu Liu; Chengyuan Tang; Liyu He; Anna Greka; Zhiguang Zhou; Fuyou Liu; Dong Zeng; Lin Sun
      Abstract: Publication date: Available online 21 December 2016
      Source:Redox Biology
      Author(s): Li Xiao, Xiaoxuan Xu, Fan Zhang, Ming Wang, Yan Xu, Dan Tang, Jiahui Wang, Yan Qin, Yu Liu, Chengyuan Tang, Liyu He, Anna Greka, Zhiguang Zhou, Fuyou Liu, Dong Zeng, Lin Sun
      Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, changes accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.

      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.022
       
  • Oxidized epigallocatechin gallate inhibited lysozyme fibrillation more
           strongly than the native form

    • Authors: Ting-Ting An; Shuang Feng; Cheng-Ming Zeng
      Abstract: Publication date: Available online 21 December 2016
      Source:Redox Biology
      Author(s): Ting-Ting An, Shuang Feng, Cheng-Ming Zeng
      Epigallocatechin gallate (EGCG), the most abundant flavanoid in green tea, is currently being evaluated in the clinic due to its benefits in the treatment of amyloid disorders. Its anti-amyloidogenic effect has been attributed to direct interaction of the intact molecule with misfolded polypeptides. In addition, antioxidant activity is also involved in the anti-amyloidogenic role. The detailed molecular mechanism is still unclear and requires further investigation. In the present study, the kinetics of EGCG oxidation and the anti-amyloidogenic effect of the resultant oxidation substances have been examined. The results indicate that EGCG degrades in a medium at pH 8.0 with a half-life less than 2h. By utilizing lysozyme as an in vitro model, the oxidized EGCG demonstrates a more potent anti-amyloidogenic capacity than the intact molecule, as shown by ThT and ANS fluorescence, TEM determination, and hemolytic assay. The oxidized EGCG also has a stronger disruptive effect on preformed fibrils than the native form. Ascorbic acid eliminates the disruptive role of native EGCG on the fibrils, suggesting that oxidation is a prerequisite in fibril disruption. The results of this work demonstrate that oxidized EGCG plays a more important role than the intact molecule in anti-amyloidogenic activity. These insights into the action of EGCG may provide a novel route to understand the anti-amyloidogenic activity of natural polyphenols.
      Graphical abstract image

      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.016
       
  • On the nature of the Cu-rich aggregates in brain astrocytes

    • Authors: Brendan Sullivan; Gregory Robison; Jenna Osborn; Martin Kay; Peter Thompson; Katherine Davis; Taisiya Zakharova; Olga Antipova; Yulia Pushkar
      Abstract: Publication date: Available online 9 December 2016
      Source:Redox Biology
      Author(s): Brendan Sullivan, Gregory Robison, Jenna Osborn, Martin Kay, Peter Thompson, Katherine Davis, Taisiya Zakharova, Olga Antipova, Yulia Pushkar
      Fulfilling a bevy of biological roles, copper is an essential metal for healthy brain function. Cu dyshomeostasis has been demonstrated to be involved in some neurological conditions including Menkes and Alzheimer's diseases. We have previously reported localized Cu-rich aggregates in astrocytes of the subventricular zone (SVZ) in rodent brains with Cu concentrations in the hundreds of millimolar. Metallothionein, a cysteine-rich protein critical to metal homeostasis and known to participate in a variety of neuroprotective and neuroregenerative processes, was proposed as a binding protein. Here, we present an analysis of metallothionein(1,2) knockout (MTKO) mice and age-matched controls using X-ray fluorescence microscopy. In large structures such as the corpus callosum, cortex, and striatum, there is no significant difference in Cu, Fe, or Zn concentrations in MTKO mice compared to age-matched controls. In the astrocyte-rich subventricular zone where Cu-rich aggregates reside, approximately 1/3 as many Cu-rich aggregates persist in MTKO mice resulting in a decrease in periventricular Cu concentration. Aggregates in both wild-type and MTKO mice show XANES spectra characteristic of CuxSy multimetallic clusters and have similar [S]/[Cu] ratios. Consistent with assignment as a CuxSy multimetallic cluster, the astrocyte-rich SVZ of both MTKO and wild-type mice exhibit autofluorescent bodies, though MTKO mice exhibit fewer. Furthermore, XRF imaging of Au-labeled lysosomes and ubiquitin demonstrates a lack of co-localization with Cu-rich aggregates suggesting they are not involved in a degradation pathway. Overall, these data suggest that Cu in aggregates is bound by either metallothionein-3 or a yet unknown protein similar to metallothionein.
      Graphical abstract image

      PubDate: 2016-12-10T13:03:59Z
      DOI: 10.1016/j.redox.2016.12.007
       
  • New insights into the effects of onion consumption on lipid mediators
           using a diet-induced model of hypercholesterolemia

    • Authors: Diana González-Peña; Antonio Checa; Begoña de Ancos; Craig E. Wheelock; Concepción Sánchez-Moreno
      Abstract: Publication date: Available online 9 December 2016
      Source:Redox Biology
      Author(s): Diana González-Peña, Antonio Checa, Begoña de Ancos, Craig E. Wheelock, Concepción Sánchez-Moreno
      The levels and roles of lipid mediators can be modified in response to nutritional stimuli. The aim of this study was to investigate shifts in oxylipin and sphingolipid profiles stimulated by a hypercholesterolemic (HC) diet along with the modulating effects of onion introduced as an antioxidant functional ingredient characterized in the diet (HCO). Oxylipin and sphingolipid profiles were determined in plasma and tissues from Wistar rats using LC-MS/MS. Plasma ω-3 and ω-6 PUFA-derived oxylipins decreased in rats after 7 weeks of HC feeding, but did not evidence a further shift with HCO diet. Onion ingredient supplementation modulated the hepatic concentrations of prostaglandins and enhanced ω-3 oxylipins in the liver of HCO-fed rats relative to the HC group. The HC diet induced shifts in plasma sphingolipids, increasing sphingoid bases, dihydroceramides and ceramides, whilst the sphingomyelin, hexosylceramide and lactosylceramide families decreased. The HCO diet modified some HC diet-induced changes in sphingolipids in liver and spleen tissue. Onion supplementation effected changes in lipid mediator levels in diet-induced hypercholesterolemic Wistar rats. The potential of onion as regulator of pro-inflammatory mediators, and possible enhancer of pro-resolution pathways, warrants further study of the interaction of functional ingredients with bioactive lipid mediators and their potential impact on inflammation, oxidative stress and organ dysfunction.
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      PubDate: 2016-12-10T13:03:59Z
      DOI: 10.1016/j.redox.2016.12.002
       
  • A Review of Redox Signaling and the Control of MAP Kinase Pathway in
           Plants

    • Authors: Yukun Liu; Chengzhong He
      Abstract: Publication date: Available online 9 December 2016
      Source:Redox Biology
      Author(s): Yukun Liu, Chengzhong He
      Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved modules among eukaryotic species that range from yeast, plants, flies to mammals. In eukaryotic cells, reactive oxygen species (ROS) has both physiological and toxic effects. Both MAPK cascades and ROS signaling are involved in plant response to various biotic and abiotic stresses. It has been observed that not only can ROS induce MAPK activation, but also that disturbing MAPK cascades can modulate ROS production and responses. This review will discuss the potential mechanisms by which ROS may activate and/or regulate MAPK cascades in plants. The role of MAPK cascades and ROS signaling in regulating gene expression, stomatal function, and programmed cell death (PCD) is also discussed. In addition, the relationship between Rboh-dependent ROS production and MAPK activation in PAMP-triggered immunity will be reviewed.

      PubDate: 2016-12-10T13:03:59Z
      DOI: 10.1016/j.redox.2016.12.009
       
  • mberHappily (n)ever after: Aging in the context of oxidative stress,
           proteostasis loss and cellular senescence

    • Authors: Annika Höhn; Daniela Weber; Tobias Jung; Christiane Ott; Martin Hugo; Bastian Kochlik; Richard Kehm; Jeannette König; Tilman Grune; José Pedro Castro
      Abstract: Publication date: Available online 7 December 2016
      Source:Redox Biology
      Author(s): Annika Höhn, Daniela Weber, Tobias Jung, Christiane Ott, Martin Hugo, Bastian Kochlik, Richard Kehm, Jeannette König, Tilman Grune, José Pedro Castro
      Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies) by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset.
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      PubDate: 2016-12-10T13:03:59Z
      DOI: 10.1016/j.redox.2016.12.001
       
  • Redox-guided axonal regrowth requires cyclic GMP dependent protein kinase
           1: implication for neuropathic pain

    • Authors: Lucie Valek; Annett Häussler; Stefan Dröse; Philipp Eaton; Katrin Schröder; Irmgard Tegeder
      Abstract: Publication date: Available online 7 December 2016
      Source:Redox Biology
      Author(s): Lucie Valek, Annett Häussler, Stefan Dröse, Philipp Eaton, Katrin Schröder, Irmgard Tegeder
      Cyclic GMP-dependent protein kinase 1 (PKG1) mediates presynaptic nociceptive long-term potentiation (LTP) in the spinal cord and contributes to inflammatory pain in rodents but the present study revealed opposite effects in the context of neuropathic pain. We used a set of loss-of-function models for in vivo and in vitro studies to address this controversy: peripheral neuron specific deletion (SNS-PKG1-/-), inducible deletion in subsets of neurons (SLICK-PKG1-/-) and redox-dead PKG1 mutants. In contrast to inflammatory pain, SNS-PKG1-/- mice developed stronger neuropathic hyperalgesia associated with an impairment of nerve regeneration, suggesting specific repair functions of PKG1. Although PKG1 accumulated at the site of injury, its activity was lost in the proximal nerve due to a reduction of oxidation-dependent dimerization, which was a consequence of mitochondrial damage in injured axons. In vitro, PKG1 deficiency or its redox-insensitivity resulted in enhanced outgrowth and reduction of growth cone collapse in response to redox signals, which presented as oxidative hotspots in growing cones. At the molecular level, PKG1 deficiency caused a depletion of phosphorylated cofilin, which is essential for growth cone collapse and guidance. Hence, redox-mediated guidance required PKG1 and consequently, its deficiency in vivo resulted in defective repair and enhanced neuropathic pain after nerve injury. PKG1-dependent repair functions will outweigh its signaling functions in spinal nociceptive LTP, so that inhibition of PKG1 is no option for neuropathic pain.
      Graphical abstract image

      PubDate: 2016-12-10T13:03:59Z
      DOI: 10.1016/j.redox.2016.12.004
       
  • Genetic disruption of NRF2 promotes the development of necroinflammation
           and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis

    • Authors: Tiago L. Duarte; Carolina Caldas; Ana G. Santos; Sandro Silva-Gomes; Andreia Santos-Gonçalves; Maria João Martins; Graça Porto; José Manuel Lopes
      Abstract: Publication date: Available online 1 December 2016
      Source:Redox Biology
      Author(s): Tiago L. Duarte, Carolina Caldas, Ana G. Santos, Sandro Silva-Gomes, Andreia Santos-Gonçalves, Maria João Martins, Graça Porto, José Manuel Lopes
      Background & Aims In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe -/- mice (an established model of human HFE-hemochromatosis). Methods Wild-type, Nrf2 -/-, Hfe -/- and double knockout (Hfe/Nrf2 -/-) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12–18 (middle-aged) or 24 months (old) for evaluation of liver pathology. Results Despite the parenchymal iron accumulation, Hfe -/- mice presented no liver injury. The combination of iron overload (Hfe -/-) and defective antioxidant defences (Nrf2 -/-) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. Conclusions The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe -/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron.
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      PubDate: 2016-12-03T12:49:41Z
      DOI: 10.1016/j.redox.2016.11.013
       
  • 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
       
  • 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.
      Graphical abstract image

      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
       
  • 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
       
  • 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.
      Graphical abstract image

      PubDate: 2016-11-04T17:27:58Z
      DOI: 10.1016/j.redox.2016.10.018
       
  • 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.
      Graphical abstract image

      PubDate: 2016-11-04T17:27:58Z
      DOI: 10.1016/j.redox.2016.10.013
       
  • 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.
      Graphical abstract image

      PubDate: 2016-11-04T17:27:58Z
      DOI: 10.1016/j.redox.2016.10.014
       
 
 
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