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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  [3031 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.
      Graphical abstract image

      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)
       
  • Fetal hemoglobin is much less prone to DNA cleavage compared to the adult
           protein

    • Authors: Sandeep Chakane; Tiago Matos; Karin Kettisen; Leif Bulow
      Pages: 114 - 120
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Sandeep Chakane, Tiago Matos, Karin Kettisen, Leif Bulow
      Hemoglobin (Hb) is well protected inside the red blood cells (RBCs). Upon hemolysis and when free in circulation, Hb can be involved in a range of radical generating reactions and may thereby attack several different biomolecules. In this study, we have examined the potential damaging effects of cell-free Hb on plasmid DNA (pDNA). Hb induced cleavage of supercoiled pDNA (sc pDNA) which was proportional to the concentration of Hb applied. Almost 70% of sc pDNA was converted to open circular or linear DNA using 10µM of Hb in 12h. Hb can be present in several different forms. The oxy (HbO2) and met forms are most reactive, while the carboxy-protein shows only low hydrolytic activity. Hemoglobin A (HbA) could easily induce complete pDNA cleavage while fetal hemoglobin (HbF) was three-fold less reactive. By inserting, a redox active cysteine residue on the surface of the alpha chain of HbF by site-directed mutagenesis, the DNA cleavage reaction was enhanced by 82%. Reactive oxygen species were not directly involved in the reaction since addition of superoxide dismutase and catalase did not prevent pDNA cleavage. The reactivity of Hb with pDNA can rather be associated with the formation of protein based radicals.

      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.008
      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)
       
  • A novel redox regulator, MnTnBuOE-2-PyP5+, enhances normal hematopoietic
           stem/progenitor cell function

    • Authors: Y. Zhao; D.W. Carroll; Y. You; L. Chaiswing; R. Wen; I. Batinic-Haberle; S. Bondada; Y. Liang; D.K. St. Clair
      Pages: 129 - 138
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Y. Zhao, D.W. Carroll, Y. You, L. Chaiswing, R. Wen, I. Batinic-Haberle, S. Bondada, Y. Liang, D.K. St. Clair
      The signaling of reactive oxygen species (ROS) is essential for the maintenance of normal cellular function. However, whether and how ROS regulate stem cells are unclear. Here, we demonstrate that, in transgenic mice expressing the human manganese superoxide dismutase (MnSOD) gene, a scavenger of ROS in mitochondria, the number and function of mouse hematopoietic stem/progenitor cells (HSPC) under physiological conditions are enhanced. Importantly, giving MnTnBuOE-2-PyP5+(MnP), a redox- active MnSOD mimetic, to mouse primary bone marrow cells or to C57B/L6 mice significantly enhances the number of HSPCs. Mechanistically, MnP reduces superoxide to hydrogen peroxide, which activates intracellular Nrf2 signaling leading to the induction of antioxidant enzymes, including MnSOD and catalase, and mitochondrial uncoupling protein 3. The results reveal a novel role of ROS signaling in regulating stem cell function, and suggest a possible beneficial effect of MnP in treating pathological bone marrow cell loss and in increasing stem cell population for bone marrow transplantation.

      PubDate: 2017-02-26T13:55:44Z
      DOI: 10.1016/j.redox.2017.02.005
      Issue No: Vol. 12 (2017)
       
  • Oxidative stress, metabolomics profiling, and mechanism of local
           anesthetic induced cell death in yeast

    • Authors: Cory H.T. Boone; Ryan A. Grove; Dana Adamcova; Javier Seravalli; Jiri Adamec
      Pages: 139 - 149
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Cory H.T. Boone, Ryan A. Grove, Dana Adamcova, Javier Seravalli, Jiri Adamec
      The World Health Organization designates lidocaine as an essential medicine in healthcare, greatly increasing the probability of human exposure. Its use has been associated with ROS generation and neurotoxicity. Physiological and metabolomic alterations, and genetics leading to the clinically observed adverse effects have not been temporally characterized. To study alterations that may lead to these undesirable effects, Saccharomyces cerevisiae grown on aerobic carbon sources to stationary phase was assessed over 6h. Exposure of an LC50 dose of lidocaine, increased mitochondrial depolarization and ROS/RNS generation assessed using JC-1, ROS/RNS specific probes, and FACS. Intracellular calcium also increased, assessed by ICP-MS. Measurement of the relative ATP and ADP concentrations indicates an initial 3-fold depletion of ATP suggesting an alteration in the ATP:ADP ratio. At the 6h time point the lidocaine exposed population contained ATP concentrations roughly 85% that of the negative control suggesting the surviving population adapted its metabolic pathways to, at least partially restore cellular bioenergetics. Metabolite analysis indicates an increase of intermediates in the pentose phosphate pathway, the preparatory phase of glycolysis, and NADPH. Oxidative stress produced by lidocaine exposure targets aconitase decreasing its activity with an observed decrease in isocitrate and an increase citrate. Similarly, increases in α-ketoglutarate, malate, and oxaloacetate imply activation of anaplerotic reactions. Antioxidant molecule glutathione and its precursor amino acids, cysteine and glutamate were greatly increased at later time points. Phosphatidylserine externalization suggestive of early phase apoptosis was also observed. Genetic studies using metacaspase null strains showed resistance to lidocaine induced cell death. These data suggest lidocaine induces perpetual mitochondrial depolarization, ROS/RNS generation along with increased glutathione to combat the oxidative cellular environment, glycolytic to PPP cycling of carbon generating NADPH, obstruction of carbon flow through the TCA cycle, decreased ATP generation, and metacaspase dependent apoptotic cell death.
      Graphical abstract image

      PubDate: 2017-02-26T13:55:44Z
      DOI: 10.1016/j.redox.2017.01.025
      Issue No: Vol. 12 (2017)
       
  • Triggering autophagic cell death with a di-manganese(II) developmental
           therapeutic

    • Authors: Creina Slator; Zara Molphy; Vickie McKee; Andrew Kellett
      Pages: 150 - 161
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Creina Slator, Zara Molphy, Vickie McKee, Andrew Kellett
      There is an unmet need for novel metal-based chemotherapeutics with alternative modes of action compared to clinical agents such as cisplatin and metallo-bleomycin. Recent attention in this field has focused on designing intracellular ROS-mediators as powerful cytotoxins of human cancers and identifying potentially unique toxic mechanisms underpinning their utility. Herein, we report the developmental di-manganese(II) therapeutic [Mn2(μ-oda)(phen)4(H2O)2][Mn2(μ-oda)(phen)4(oda)2]·4H2O (Mn-Oda) induces autophagy-promoted apoptosis in human ovarian cancer cells (SKOV3). The complex was initially identified to intercalate DNA by topoisomerase I unwinding and circular dichroism spectroscopy. Intracellular DNA damage, detected by γH2AX and the COMET assay, however, is not linked to direct Mn-Oda free radical generation, but is instead mediated through the promotion of intracellular reactive oxygen species (ROS) leading to autophagic vacuole formation and downstream nuclear degradation. To elucidate the cytotoxic profile of Mn-Oda, a wide range of biomarkers specific to apoptosis and autophagy including caspase release, mitochondrial membrane integrity, fluorogenic probe localisation, and cell cycle analysis were employed. Through these techniques, the activity of Mn-Oda was compared directly to i.) the pro-apoptotic clinical anticancer drug doxorubicin, ii.) the multimodal histone deacetylase inhibitor suberoyanilide hydroxamic acid, and iii.) the autophagy inducer rapamycin. In conjunction with ROS-specific trapping agents and established inhibitors of autophagy, we have identified autophagy-induction linked to mitochondrial superoxide production, with confocal image analysis of SKOV3 cells further supporting autophagosome formation.

      PubDate: 2017-02-26T13:55:44Z
      DOI: 10.1016/j.redox.2017.01.024
      Issue No: Vol. 12 (2017)
       
  • NADPH oxidase-derived H2O2 mediates the regulatory effects of microglia on
           astrogliosis in experimental models of Parkinson's disease

    • Authors: Liyan Hou; Xueying Zhou; Cong Zhang; Ke Wang; Xiaofang Liu; Yuning Che; Fuqiang Sun; Huihua Li; Qingshan Wang; Dan Zhang; Jau-Shyong Hong
      Pages: 162 - 170
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Liyan Hou, Xueying Zhou, Cong Zhang, Ke Wang, Xiaofang Liu, Yuning Che, Fuqiang Sun, Huihua Li, Qingshan Wang, Dan Zhang, Jau-Shyong Hong
      Astrogliosis has long been recognized in Parkinson's disease (PD), the most common neurodegenerative movement disorder. However, the mechanisms of how astroglia become activated remain unclear. Reciprocal interactions between microglia and astroglia play a pivotal role in regulating the activities of astroglia. The purpose of this study is to investigate the mechanism by which microglia regulate astrogliosis by using lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD models. We found that the activation of microglia preceded astroglia in the substantia nigra of mice treated with either LPS or MPTP. Furthermore, suppression of microglial activation by pharmacological inhibition or genetic deletion of NADPH oxidase (NOX2) in mice attenuated astrogliosis. The important role of NOX2 in microglial regulation of astrogliosis was further mirrored in a mixed-glia culture system. Mechanistically, H2O2, a product of microglial NOX2 activation, serves as a direct signal to regulate astrogliosis. Astrogliosis was induced by H2O2 through a process in which extracellularly generated H2O2 diffused into the cytoplasm and subsequently stimulated activation of transcription factors, STAT1 and STAT3. STAT1/3 activation regulated the immunological functions of H2O2-induced astrogliosis since AG490, an inhibitor of STAT1/3, attenuated the gene expressions of both proinflammatory and neurotrophic factors in H2O2-treated astrocyte. Our findings indicate that microglial NOX2-generated H2O2 is able to regulate the immunological functions of astroglia via a STAT1/3-dependent manner, providing additional evidence for the immune pathogenesis and therapeutic studies of PD.

      PubDate: 2017-02-26T13:55:44Z
      DOI: 10.1016/j.redox.2017.02.016
      Issue No: Vol. 12 (2017)
       
  • Characterization of the galactono-1,4-lactone dehydrogenase from pepper
           fruits and its modulation in the ascorbate biosynthesis. Role of nitric
           oxide

    • Authors: Marta Rodríguez-Ruiz; Rosa M. Mateos; Verónica Codesido; Francisco J. Corpas; José M. Palma
      Pages: 171 - 181
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Marta Rodríguez-Ruiz, Rosa M. Mateos, Verónica Codesido, Francisco J. Corpas, José M. Palma
      Pepper fruit is one of the highest vitamin C sources of plant origin for our diet. In plants, ascorbic acid is mainly synthesized through the L-galactose pathway, being the L-galactono-1,4-lactone dehydrogenase (GalLDH) the last step. Using pepper fruits, the full GalLDH gene was cloned and the protein molecular characterization accomplished. GalLDH protein sequence (586 residues) showed a 37 amino acids signal peptide at the N-terminus, characteristic of mitochondria. The hydrophobic analysis of the mature protein displayed one transmembrane helix comprising 20 amino acids at the N-terminus. By using a polyclonal antibody raised against a GalLDH internal sequence and immunoblotting analysis, a 56kDa polypeptide cross-reacted with pepper fruit samples. Using leaves, flowers, stems and fruits, the expression of GalLDH by qRT-PCR and the enzyme activity were analyzed, and results indicate that GalLDH is a key player in the physiology of pepper plants, being possibly involved in the processes which undertake the transport of ascorbate among different organs. We also report that an NO (nitric oxide)-enriched atmosphere enhanced ascorbate content in pepper fruits about 40% parallel to increased GalLDH gene expression and enzyme activity. This is the first report on the stimulating effect of NO treatment on the vitamin C concentration in plants. Accordingly, the modulation by NO of GalLDH was addressed. In vitro enzymatic assays of GalLDH were performed in the presence of SIN-1 (peroxynitrite donor) and S-nitrosoglutahione (NO donor). Combined results of in vivo NO treatment and in vitro assays showed that NO provoked the regulation of GalLDH at transcriptional and post-transcriptional levels, but not post-translational modifications through nitration or S-nitrosylation events promoted by reactive nitrogen species (RNS) took place. These results suggest that this modulation point of the ascorbate biosynthesis could be potentially used for biotechnological purposes to increase the vitamin C levels in pepper fruits.
      Graphical abstract image

      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.009
      Issue No: Vol. 12 (2017)
       
  • Probes for protein adduction in cholesterol biosynthesis disorders:
           Alkynyl lanosterol as a viable sterol precursor

    • Authors: Keri A. Tallman; Hye-Young H. Kim; Zeljka Korade; Thiago C. Genaro-Mattos; Phillip A. Wages; Wei Liu; Ned A. Porter
      Pages: 182 - 190
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Keri A. Tallman, Hye-Young H. Kim, Zeljka Korade, Thiago C. Genaro-Mattos, Phillip A. Wages, Wei Liu, Ned A. Porter
      The formation of lipid electrophile-protein adducts is associated with many disorders that involve perturbations of cellular redox status. The identities of adducted proteins and the effects of adduction on protein function are mostly unknown and an increased understanding of these factors may help to define the pathogenesis of various human disorders involving oxidative stress. 7-Dehydrocholesterol (7-DHC), the immediate biosynthetic precursor to cholesterol, is highly oxidizable and gives electrophilic oxysterols that adduct proteins readily, a sequence of events proposed to occur in Smith-Lemli-Opitz syndrome (SLOS), a human disorder resulting from an error in cholesterol biosynthesis. Alkynyl lanosterol (a-Lan) was synthesized and studied in Neuro2a cells, Dhcr7-deficient Neuro2a cells and human fibroblasts. When incubated in control Neuro2a cells and control human fibroblasts, a-Lan completed the sequence of steps involved in cholesterol biosynthesis and alkynyl-cholesterol (a-Chol) was the major product formed. In Dhcr7-deficient Neuro2a cells or fibroblasts from SLOS patients, the biosynthetic transformation was interrupted at the penultimate step and alkynyl-7-DHC (a-7-DHC) was the major product formed. When a-Lan was incubated in Dhcr7-deficient Neuro2a cells and the alkynyl tag was used to ligate a biotin group to alkyne-containing products, protein-sterol adducts were isolated and identified. In parallel experiments with a-Lan and a-7-DHC in Dhcr7-deficient Neuro2a cells, a-7-DHC was found to adduct to a larger set of proteins (799) than a-Lan (457) with most of the a-Lan protein adducts (423) being common to the larger a-7-DHC set. Of the 423 proteins found common to both experiments, those formed from a-7-DHC were more highly enriched compared to a DMSO control than were those derived from a-Lan. The 423 common proteins were ranked according to the enrichment determined for each protein in the a-Lan and a-7-DHC experiments and there was a very strong correlation of protein ranks for the adducts formed in the parallel experiments.
      Graphical abstract image

      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.013
      Issue No: Vol. 12 (2017)
       
  • The diverse roles of glutathione-associated cell resistance against
           hypericin photodynamic therapy

    • Authors: Theodossis A. Theodossiou; Cathrine E. Olsen; Marte Jonsson; Andreas Kubin; John S. Hothersall; Kristian Berg
      Pages: 191 - 197
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Theodossis A. Theodossiou, Cathrine E. Olsen, Marte Jonsson, Andreas Kubin, John S. Hothersall, Kristian Berg
      The diverse responses of different cancers to treatments such as photodynamic therapy of cancer (PDT) have fueled a growing need for reliable predictive markers for treatment outcome. In the present work we have studied the differential response of two phenotypically and genotypically different breast adenocarcinoma cell lines, MCF7 and MDA-MB-231, to hypericin PDT (HYP-PDT). MDA-MB-231 cells were 70% more sensitive to HYP PDT than MCF7 cells at LD50. MCF7 were found to express a substantially higher level of glutathione peroxidase (GPX4) than MDA-MB-231, while MDA-MB-231 differentially expressed glutathione-S-transferase (GSTP1), mainly used for xenobiotic detoxification. Eighty % reduction of intracellular glutathione (GSH) by buthionine sulfoximine (BSO), largely enhanced the sensitivity of the GSTP1 expressing MDA-MB-231 cells to HYP-PDT, but not in MCF7 cells. Further inhibition of the GSH reduction however by carmustine (BCNU) resulted in an enhanced sensitivity of MCF7 to HYP-PDT. HYP loading studies suggested that HYP can be a substrate of GSTP for GSH conjugation as BSO enhanced the cellular HYP accumulation by 20% in MDA-MB-231 cells, but not in MCF7 cells. Studies in solutions showed that L-cysteine can bind the GSTP substrate CDNB in the absence of GSTP. This means that the GSTP-lacking MCF7 may use L-cysteine for xenobiotic detoxification, especially during GSH synthesis inhibition, which leads to L-cysteine build-up. This was confirmed by the lowered accumulation of HYP in both cell lines in the presence of BSO and the L-cysteine source NAC. NAC reduced the sensitivity of MCF7, but not MDA-MB-231, cells to HYP PDT which is in accordance with the antioxidant effects of L-cysteine and its potential as a GSTP substrate. As a conclusion we have herein shown that the different GSH based cell defense mechanisms can be utilized as predictive markers for the outcome of PDT and as a guide for selecting optimal combination strategies.
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      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.018
      Issue No: Vol. 12 (2017)
       
  • Importance of ROS-mediated autophagy in determining apoptotic cell death
           induced by physapubescin B

    • Authors: Jian Xu; Yihua Wu; Guang Lu; Shujun Xie; Zhongjun Ma; Zhe Chen; Han-Ming Shen; Dajing Xia
      Pages: 198 - 207
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Jian Xu, Yihua Wu, Guang Lu, Shujun Xie, Zhongjun Ma, Zhe Chen, Han-Ming Shen, Dajing Xia
      Physapubescin B, a steroidal compound extracted from the plant Physalis pubescens L. (Solanaceae), has been reported to possess anti-cancer potential, whereas the molecular mechanism remains elusive. In this study, we first demonstrated that physapubescin B induced autophagy in human cancer cells based on the evidence that physapubescin B increased lipidation of microtubule-associated protein 1 light chain 3 (LC3) as well as number of GFP-LC3 puncta. We further examined the molecular mechanisms and found that physapubescin B enhanced the autophagic flux through promotion of reactive oxygen species (ROS)-mediated suppression of mammalian target of rapamycin complex I (mTORC1), the key negative regulator of autophagy. Additionally, excessive ROS caused by physapubescin B also induced p53-dependent apoptotic cell death. Furthermore, we provided evidence that inhibition of autophagy either by a chemical inhibitor or gene silencing promoted physapubescin B-induced apoptotic cell death, indicating that autophagy serves as a cell survival mechanism to protect cell death. Thus, our data provide a clue that inhibition of autophagy would serve as a novel strategy for enhancing the anti-cancer potential of physapubescin B.
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      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.017
      Issue No: Vol. 12 (2017)
       
  • Mitochondrial composition and function under the control of hypoxia

    • Authors: Dominik C. Fuhrmann; Bernhard Brüne
      Pages: 208 - 215
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Dominik C. Fuhrmann, Bernhard Brüne
      Hypoxia triggers several mechanisms to adapt cells to a low oxygen environment. Mitochondria are major consumers of oxygen and a potential source of reactive oxygen species (ROS). In response to hypoxia they exchange or modify distinct subunits of the respiratory chain and adjust their metabolism, especially lowering the citric acid cycle. Intermediates of the citric acid cycle participate in regulating hypoxia inducible factors (HIF), the key mediators of adaptation to hypoxia. Here we summarize how hypoxia conditions mitochondria with consequences for ROS-production and the HIF-pathway.
      Graphical abstract image

      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.012
      Issue No: Vol. 12 (2017)
       
  • Oxidative stress and apoptosis after acute respiratory hypoxia and
           reoxygenation in rat brain

    • Authors: Debora Coimbra-Costa; Norma Alva; Mónica Duran; Teresa Carbonell; Ramón Rama
      Pages: 216 - 225
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Debora Coimbra-Costa, Norma Alva, Mónica Duran, Teresa Carbonell, Ramón Rama
      Acute hypoxia increases the formation of reactive oxygen species (ROS) in the brain. However, the effect of reoxygenation, unavoidable to achieve full recovery of the hypoxic organ, has not been clearly established. The aim of the present study was to evaluate the effects of exposition to acute severe respiratory hypoxia followed by reoxygenation on the evolution of oxidative stress and apoptosis in the brain. We investigated the effect of in vivo acute severe normobaric hypoxia (rats exposed to 7% O2 for 6h) and reoxygenation in normoxia (21% O2 for 24h or 48h) on oxidative stress markers, the antioxidant system and apoptosis in the brain. After respiratory hypoxia we found increased levels of HIF-1α expression, lipid peroxidation, protein oxidation and nitric oxide in brain extracts. Antioxidant defence systems such as superoxide dismutase (SOD), reduced glutathione (GSH) and glutathione peroxidase (GPx) and the reduced/oxidized glutathione (GSH/GSSG) ratio were significantly decreased in the brain. After 24h of reoxygenation, oxidative stress parameters and the anti-oxidant system returned to control values. Regarding the apoptosis parameters, acute hypoxia increased cytochrome c, AIF and caspase 3 activity in the brain. The apoptotic effect is greatest after 24h of reoxygenation. Immunohistochemistry suggests that CA3 and dentate gyrus in the hippocampus seem more susceptible to hypoxia than the cortex. Severe acute hypoxia increases oxidative damage, which in turn could activate apoptotic mechanisms. Our work is the first to demonstrate that after 24h of reoxygenation oxidative stress is attenuated, while apoptosis is maintained mainly in the hippocampus, which may, in fact, be the cause of impaired brain function.

      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.014
      Issue No: Vol. 12 (2017)
       
  • Critical role of vascular peroxidase 1 in regulating endothelial nitric
           oxide synthase

    • Authors: Zhaoya Liu; Yanbo Liu; Qian Xu; Haiyang Peng; Yixin Tang; Tianlun Yang; Zaixin Yu; Guangjie Cheng; Guogang Zhang; Ruizheng Shi
      Pages: 226 - 232
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Zhaoya Liu, Yanbo Liu, Qian Xu, Haiyang Peng, Yixin Tang, Tianlun Yang, Zaixin Yu, Guangjie Cheng, Guogang Zhang, Ruizheng Shi
      Vascular peroxidase 1 (VPO1) is a member of the peroxidase family which aggravates oxidative stress by producing hypochlorous acid (HOCl). Our previous study demonstrated that VPO1 plays a critical role in endothelial dysfunction through dimethylarginine dimethylaminohydrolase2 (DDAH2)/asymmetric Dimethylarginine (ADMA) pathway. Hereby we describe the regulatory role of VPO1 on endothelial nitric oxide synthase (eNOS) expression and activity in human umbilical vein endothelial cells (HUVECs). In HUVECs AngiotensinII (100nM) treatment reduced Nitric Oxide (NO) production, decreased eNOS expression and activity, which were reversed by VPO1 siRNA. Knockdown of VPO1 also attenuated ADMA production and eNOS uncoupling while enhancing phosphorylated ser1177 eNOS expression level. Furthermore, HOCl stimulation was shown to directly induce ADMA production and eNOS uncoupling, decrease phosphorylated ser1177 eNOS expression. It also significantly suppressed eNOS expression and activity together with NO production. Therefore, VPO1 plays a vital role in regulating eNOS expression and activity via hydrogen peroxide (H2O2)-VPO1-HOCl pathway.

      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.022
      Issue No: Vol. 12 (2017)
       
  • Localized redox relays as a privileged mode of cytoplasmic hydrogen
           peroxide signaling

    • Authors: Rui D.M. Travasso; Fernando Sampaio dos Aidos; Anahita Bayani; Pedro Abranches; Armindo Salvador
      Pages: 233 - 245
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Rui D.M. Travasso, Fernando Sampaio dos Aidos, Anahita Bayani, Pedro Abranches, Armindo Salvador
      Hydrogen peroxide (H2O2) is a key signaling agent. Its best characterized signaling actions in mammalian cells involve the early oxidation of thiols in cytoplasmic phosphatases, kinases and transcription factors. However, these redox targets are orders of magnitude less H2O2-reactive and abundant than cytoplasmic peroxiredoxins. How can they be oxidized in a signaling time frame? Here we investigate this question using computational reaction-diffusion models of H2O2 signaling. The results show that at H2O2 supply rates commensurate with mitogenic signaling a H2O2 concentration gradient with a length scale of a few tenths of μm is established. Even near the supply sites H2O2 concentrations are far too low to oxidize typical targets in an early mitogenic signaling time frame. Furthermore, any inhibition of the peroxiredoxin or increase in H2O2 supply able to drastically increase the local H2O2 concentration would collapse the concentration gradient and/or cause an extensive oxidation of the peroxiredoxins I and II, inconsistent with experimental observations. In turn, the local concentrations of peroxiredoxin sulfenate and disulfide forms exceed those of H2O2 by several orders of magnitude. Redox targets reacting with these forms at rate constants much lower than that for, say, thioredoxin could be oxidized within seconds. Moreover, the spatial distribution of the concentrations of these peroxiredoxin forms allows them to reach targets within 1 μm from the H2O2 sites while maintaining signaling localized. The recruitment of peroxiredoxins to specific sites such as caveolae can dramatically increase the local concentrations of the sulfenic and disulfide forms, thus further helping these species to outcompete H2O2 for the oxidation of redox targets. Altogether, these results suggest that H2O2 signaling is mediated by localized redox relays whereby peroxiredoxins are oxidized to sulfenate and disulfide forms at H2O2 supply sites and these forms in turn oxidize the redox targets near these sites.
      Graphical abstract image Highlights fx1

      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.01.003
      Issue No: Vol. 12 (2017)
       
  • Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases
           - important players in mitochondrial metabolism and metabolic health

    • Authors: Riikka Jokinen; Sini Pirnes-Karhu; Kirsi H. Pietiläinen; Eija Pirinen
      Pages: 246 - 263
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Riikka Jokinen, Sini Pirnes-Karhu, Kirsi H. Pietiläinen, Eija Pirinen
      Obesity, a chronic state of energy overload, is characterized by adipose tissue dysfunction that is considered to be the major driver for obesity associated metabolic complications. The reasons for adipose tissue dysfunction are incompletely understood, but one potential contributing factor is adipose tissue mitochondrial dysfunction. Derangements of adipose tissue mitochondrial biogenesis and pathways associate with obesity and metabolic diseases. Mitochondria are central organelles in energy metabolism through their role in energy derivation through catabolic oxidative reactions. The mitochondrial processes are dependent on the proper NAD+/NADH redox balance and NAD+ is essential for reactions catalyzed by the key regulators of mitochondrial metabolism, sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). Notably, obesity is associated with disturbed adipose tissue NAD+ homeostasis and the balance of SIRT and PARP activities. In this review we aim to summarize existing literature on the maintenance of intracellular NAD+ pools and the function of SIRTs and PARPs in adipose tissue during normal and obese conditions, with the purpose of comprehending their potential role in mitochondrial derangements and obesity associated metabolic complications. Understanding the molecular mechanisms that are the root cause of the adipose tissue mitochondrial derangements is crucial for developing new effective strategies to reverse obesity associated metabolic complications.
      Graphical abstract image

      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.011
      Issue No: Vol. 12 (2017)
       
  • Inhibition of Drp1 protects against senecionine-induced
           mitochondria-mediated apoptosis in primary hepatocytes and in mice

    • Authors: Xiao Yang; Hua Wang; Hong-Min Ni; Aizhen Xiong; Zhengtao Wang; Hiromi Sesaki; Wen-Xing Ding; Li Yang
      Pages: 264 - 273
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Xiao Yang, Hua Wang, Hong-Min Ni, Aizhen Xiong, Zhengtao Wang, Hiromi Sesaki, Wen-Xing Ding, Li Yang
      Pyrrolizidine alkaloids (PAs) are a group of compounds found in various plants and some of them are widely consumed in the world as herbal medicines and food supplements. PAs are potent hepatotoxins that cause irreversible liver injury in animals and humans. However, the mechanisms by which PAs induce liver injury are not clear. In the present study, we determined the hepatotoxicity and molecular mechanisms of senecionine, one of the most common toxic PAs, in primary cultured mouse and human hepatocytes as well as in mice. We found that senecionine administration increased serum alanine aminotransferase levels in mice. H&E and TUNEL staining of liver tissues revealed increased hemorrhage and hepatocyte apoptosis in liver zone 2 areas. Mechanistically, senecionine induced loss of mitochondrial membrane potential, release of mitochondrial cytochrome c as well as mitochondrial JNK translocation and activation prior to the increased DNA fragmentation and caspase-3 activation in primary cultured mouse and human hepatocytes. SP600125, a specific JNK inhibitor, and ZVAD-fmk, a general caspase inhibitor, alleviated senecionine-induced apoptosis in primary hepatocytes. Interestingly, senecionine also caused marked mitochondria fragmentation in hepatocytes. Pharmacological inhibition of dynamin-related protein1 (Drp1), a protein that is critical to regulate mitochondrial fission, blocked senecionine-induced mitochondrial fragmentation and mitochondrial release of cytochrome c and apoptosis. More importantly, hepatocyte-specific Drp1 knockout mice were resistant to senecionine-induced liver injury due to decreased mitochondrial damage and apoptosis. In conclusion, our results uncovered a novel mechanism of Drp1-mediated mitochondrial fragmentation in senecionine-induced liver injury. Targeting Drp1-mediated mitochondrial fragmentation and apoptosis may be a potential avenue to prevent and treat hepatotoxicity induced by PAs.
      Graphical abstract image

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.02.020
      Issue No: Vol. 12 (2017)
       
  • MLN64 induces mitochondrial dysfunction associated with increased
           mitochondrial cholesterol content

    • Authors: Elisa Balboa; Juan Castro; María-José Pinochet; Gonzalo I. Cancino; Nuria Matías; Pablo José Sáez; Alexis Martínez; Alejandra R. Álvarez; Carmen Garcia-Ruiz; José C. Fernandez-Checa; Silvana Zanlungo
      Pages: 274 - 284
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Elisa Balboa, Juan Castro, María-José Pinochet, Gonzalo I. Cancino, Nuria Matías, Pablo José Sáez, Alexis Martínez, Alejandra R. Álvarez, Carmen Garcia-Ruiz, José C. Fernandez-Checa, Silvana Zanlungo
      MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria, in toxin-induced resistance, and in mitochondrial dysfunction. Down-regulation of MLN64 in Niemann-Pick C1 deficient cells decreased mitochondrial cholesterol content, suggesting that MLN64 functions independently of NPC1. However, the role of MLN64 in the maintenance of endosomal cholesterol flow and intracellular cholesterol homeostasis remains unclear. We have previously described that hepatic MLN64 overexpression increases liver cholesterol content and induces liver damage. Here, we studied the function of MLN64 in normal and NPC1-deficient cells and we evaluated whether MLN64 overexpressing cells exhibit alterations in mitochondrial function. We used recombinant-adenovirus-mediated MLN64 gene transfer to overexpress MLN64 in mouse liver and hepatic cells; and RNA interference to down-regulate MLN64 in NPC1-deficient cells. In MLN64-overexpressing cells, we found increased mitochondrial cholesterol content and decreased glutathione (GSH) levels and ATPase activity. Furthermore, we found decreased mitochondrial membrane potential and mitochondrial fragmentation and increased mitochondrial superoxide levels in MLN64-overexpressing cells and in NPC1-deficient cells. Consequently, MLN64 expression was increased in NPC1-deficient cells and reduction of its expression restore mitochondrial membrane potential and mitochondrial superoxide levels. Our findings suggest that MLN64 overexpression induces an increase in mitochondrial cholesterol content and consequently a decrease in mitochondrial GSH content leading to mitochondrial dysfunction. In addition, we demonstrate that MLN64 expression is increased in NPC cells and plays a key role in cholesterol transport into the mitochondria.
      Graphical abstract image

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.02.024
      Issue No: Vol. 12 (2017)
       
  • Nitrate decreases xanthine oxidoreductase-mediated nitrite reductase
           activity and attenuates vascular and blood pressure responses to nitrite

    • Authors: Célio Damacena-Angelis; Gustavo H. Oliveira-Paula; Lucas C. Pinheiro; Eduardo J. Crevelin; Rafael L. Portella; Luiz Alberto B. Moraes; Jose E. Tanus-Santos
      Pages: 291 - 299
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Célio Damacena-Angelis, Gustavo H. Oliveira-Paula, Lucas C. Pinheiro, Eduardo J. Crevelin, Rafael L. Portella, Luiz Alberto B. Moraes, Jose E. Tanus-Santos
      Nitrite and nitrate restore deficient endogenous nitric oxide (NO) production as they are converted back to NO, and therefore complement the classic enzymatic NO synthesis. Circulating nitrate and nitrite must cross membrane barriers to produce their effects and increased nitrate concentrations may attenuate the nitrite influx into cells, decreasing NO generation from nitrite. Moreover, xanthine oxidoreductase (XOR) mediates NO formation from nitrite and nitrate. However, no study has examined whether nitrate attenuates XOR-mediated NO generation from nitrite. We hypothesized that nitrate attenuates the vascular and blood pressure responses to nitrite either by interfering with nitrite influx into vascular tissue, or by competing with nitrite for XOR, thus inhibiting XOR-mediated NO generation. We used two independent vascular function assays in rats (aortic ring preparations and isolated mesenteric arterial bed perfusion) to examine the effects of sodium nitrate on the concentration-dependent responses to sodium nitrite. Both assays showed that nitrate attenuated the vascular responses to nitrite. Conversely, the aortic responses to the NO donor DETANONOate were not affected by sodium nitrate. Further confirming these results, we found that nitrate attenuated the acute blood pressure lowering effects of increasing doses of nitrite infused intravenously in freely moving rats. The possibility that nitrate could compete with nitrite and decrease nitrite influx into cells was tested by measuring the accumulation of nitrogen-15-labeled nitrite (15N-nitrite) by aortic rings using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS). Nitrate exerted no effect on aortic accumulation of 15N-nitrite. Next, we used chemiluminescence-based NO detection to examine whether nitrate attenuates XOR-mediated nitrite reductase activity. Nitrate significantly shifted the Michaelis Menten saturation curve to the right, with a 3-fold increase in the Michaelis constant. Together, our results show that nitrate inhibits XOR-mediated NO production from nitrite, and this mechanism may explain how nitrate attenuates the vascular and blood pressure responses to nitrite.

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.03.003
      Issue No: Vol. 12 (2017)
       
  • Polychlorinated biphenyls-153 induces metabolic dysfunction through
           activation of ROS/NF-κB signaling via downregulation of HNF1b

    • Authors: Hao Wu; Weihua Yu; Fansen Meng; Jie Mi; Jie Peng; Jiangzheng Liu; Xiaodi Zhang; Chunxu Hai; Xin Wang
      Pages: 300 - 310
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Hao Wu, Weihua Yu, Fansen Meng, Jie Mi, Jie Peng, Jiangzheng Liu, Xiaodi Zhang, Chunxu Hai, Xin Wang
      Polychlorinated biphenyls (PCB) is a major type of persistent organic pollutants (POPs) that act as endocrine-disrupting chemicals. In the current study, we examined the mechanism underlying the effect of PCB-153 on glucose and lipid metabolism in vivo and in vitro. We found that PCB-153 induced per se and worsened high fat diet (HFD)-resulted increase of blood glucose level and glucose and insulin intolerance. In addition, PCB-153 induced per se and worsened HFD-resulted increase of triglyceride content and adipose mass. Moreover, PCB-153 concentration-dependently inhibited insulin-dependent glucose uptake and lipid accumulation in cultured hepatocytes and adipocytes. PCB-153 induced the expression and nuclear translocation of p65 NF-κB and the expression of its downstream inflammatory markers, and worsened HFD-resulted increase of those inflammatory markers. Inhibition of NF-κB significantly suppressed PCB-153-induced inflammation, lipid accumulation and decrease of glucose uptake. PCB-153 induced oxidative stress and decreased hepatocyte nuclear factor 1b (HNF1b) and glutathione peroxidase 1 (GPx1) expression in vivo and in vitro. Overexpression of HNF1b increased GPx1 expression, decreased ROS level, decreased Srebp1, ACC and FAS expression, and inhibited PCB-153-resulted oxidative stress, NF-κB-mediated inflammation, and final glucose/lipid metabolic disorder. Our results suggest that dysregulation of HNF1b/ROS/NF-κB plays an important role in PCB-153-induced glucose/lipid metabolic disorder.

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.02.026
      Issue No: Vol. 12 (2017)
       
  • Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury
           via induction of AMPK/GSK3β-Nrf2 signal axis

    • Authors: Hongming Lv; Qinmei Liu; Zhongmei Wen; Haihua Feng; Xuming Deng; Xinxin Ci
      Pages: 311 - 324
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Hongming Lv, Qinmei Liu, Zhongmei Wen, Haihua Feng, Xuming Deng, Xinxin Ci
      Abundant natural flavonoids can induce nuclear factor-erythroid 2 related factor 2 (Nrf2) and/or AMP-activated protein kinase (AMPK) activation, which play crucial roles in the amelioration of various inflammation- and oxidative stress-induced diseases, including acute lung injury (ALI). Xanthohumol (Xn), a principal prenylflavonoid, possesses anti-inflammation and anti-oxidant activities. However, whether Xn could protect from LPS-induced ALI through inducing AMPK/Nrf2 activation and its downstream signals, are still poorly elucidated. Accordingly, we focused on exploring the protective effect of Xn in the context of ALI and the involvement of underlying molecular mechanisms. Our findings indicated that Xn effectively alleviated lung injury by reduction of lung W/D ratio and protein levels, neutrophil infiltration, MDA and MPO formation, and SOD and GSH depletion. Meanwhile, Xn significantly lessened histopathological changes, reactive oxygen species (ROS) generation, several cytokines secretion, and iNOS and HMGB1 expression, and inhibited Txnip/NLRP3 inflammasome and NF-κB signaling pathway activation. Additionally, Xn evidently decreased t-BHP-stimulated cell apoptosis, ROS generation and GSH depletion but increased various anti-oxidative enzymes expression regulated by Keap1-Nrf2/ARE activation, which may be associated with AMPK and GSK3β phosphorylation. However, Xn-mediated inflammatory cytokines and ROS production, histopathological changes, Txnip/NLRP3 inflammasome and NF-κB signaling pathway in WT mice were remarkably abrogated in Nrf2-/- mice. Our experimental results firstly provided a support that Xn effectively protected LPS-induced ALI against oxidative stress and inflammation damage which are largely dependent upon upregulation of the Nrf2 pathway via activation of AMPK/GSK3β, thereby suppressing LPS-activated Txnip/NLRP3 inflammasome and NF-κB signaling pathway.
      Graphical abstract image

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.03.001
      Issue No: Vol. 12 (2017)
       
  • Catalase as a sulfide-sulfur oxido-reductase: An ancient (and modern?)
           regulator of reactive sulfur species (RSS)

    • Authors: Kenneth R. Olson; Yan Gao; Eric R. DeLeon; Maaz Arif; Faihaan Arif; Nitin Arora; Karl D. Straub
      Pages: 325 - 339
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Kenneth R. Olson, Yan Gao, Eric R. DeLeon, Maaz Arif, Faihaan Arif, Nitin Arora, Karl D. Straub
      Catalase is well-known as an antioxidant dismutating H2O2 to O2 and H2O. However, catalases evolved when metabolism was largely sulfur-based, long before O2 and reactive oxygen species (ROS) became abundant, suggesting catalase metabolizes reactive sulfide species (RSS). Here we examine catalase metabolism of H2Sn, the sulfur analog of H2O2, hydrogen sulfide (H2S) and other sulfur-bearing molecules using H2S-specific amperometric electrodes and fluorophores to measure polysulfides (H2Sn; SSP4) and ROS (dichlorofluorescein, DCF). Catalase eliminated H2Sn, but did not anaerobically generate H2S, the expected product of dismutation. Instead, catalase concentration- and oxygen-dependently metabolized H2S and in so doing acted as a sulfide oxidase with a P50 of 20mmHg. H2O2 had little effect on catalase-mediated H2S metabolism but in the presence of the catalase inhibitor, sodium azide (Az), H2O2 rapidly and efficiently expedited H2S metabolism in both normoxia and hypoxia suggesting H2O2 is an effective electron acceptor in this reaction. Unexpectedly, catalase concentration-dependently generated H2S from dithiothreitol (DTT) in both normoxia and hypoxia, concomitantly oxidizing H2S in the presence of O2. H2S production from DTT was inhibited by carbon monoxide and augmented by NADPH suggesting that catalase heme-iron is the catalytic site and that NADPH provides reducing equivalents. Catalase also generated H2S from garlic oil, diallyltrisulfide, thioredoxin and sulfur dioxide, but not from sulfite, metabisulfite, carbonyl sulfide, cysteine, cystine, glutathione or oxidized glutathione. Oxidase activity was also present in catalase from Aspergillus niger. These results show that catalase can act as either a sulfide oxidase or sulfur reductase and they suggest that these activities likely played a prominent role in sulfur metabolism during evolution and may continue do so in modern cells as well. This also appears to be the first observation of catalase reductase activity independent of peroxide dismutation.
      Graphical abstract image

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.02.021
      Issue No: Vol. 12 (2017)
       
  • Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1
           pathway in hepatic cancer cells

    • Authors: Kishor Pant; Ajay K. Yadav; Parul Gupta; Rakibul Islam; Anoop Saraya; Senthil K. Venugopal
      Pages: 340 - 349
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Kishor Pant, Ajay K. Yadav, Parul Gupta, Rakibul Islam, Anoop Saraya, Senthil K. Venugopal
      Butyrate is one of the short chain fatty acids, produced by the gut microbiota during anaerobic fermentation of dietary fibres. It has been shown that it can inhibit tumor progression via suppressing histone deacetylase and can induce apoptosis in cancer cells. However, the comprehensive pathway by which butyrate mediates apoptosis and growth arrest in cancer cells still remains unclear. In this study, the role of miR-22 in butyrate-mediated ROS release and induction of apoptosis was determined in hepatic cells. Intracellular expression of miR-22 was increased when the Huh 7 cells were incubated with sodium butyrate. Over-expression of miR-22 or addition of sodium butyrate inhibited SIRT-1 expression and enhanced the ROS production. Incubation of cells with anti-miR-22 reversed the effects of butyrate. Butyrate induced apoptosis via ROS production, cytochrome c release and activation of caspase-3, whereas addition of N-acetyl cysteine or anti-miR-22 reversed these butyrate-induced effects. Furthermore, sodium butyrate inhibited cell growth and proliferation, whereas anti-miR-22 inhibited these butyrate-mediated changes. The expression of PTEN and gsk-3 was found to be increased while p-akt and β-catenin expression was decreased significantly by butyrate. These data showed that butyrate modulated both apoptosis and proliferation via miR-22 expression in hepatic cells.

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.03.006
      Issue No: Vol. 12 (2017)
       
  • Deciphering the interplay between cysteine synthase and thiol cascade
           proteins in modulating Amphotericin B resistance and survival of
           Leishmania donovani under oxidative stress

    • Authors: Kuljit Singh; Vahab Ali; Krishn Pratap Singh; Parool Gupta; Shashi S. Suman; Ayan K. Ghosh; Sanjiva Bimal; Krishna Pandey; Pradeep Das
      Pages: 350 - 366
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Kuljit Singh, Vahab Ali, Krishn Pratap Singh, Parool Gupta, Shashi S. Suman, Ayan K. Ghosh, Sanjiva Bimal, Krishna Pandey, Pradeep Das
      Leishmania donovani is the causative organism of the neglected human disease known as visceral leishmaniasis which is often fatal, if left untreated. The cysteine biosynthesis pathway of Leishmania may serve as a potential drug target because it is different from human host and regulates downstream components of redox metabolism of the parasites; essential for their survival, pathogenicity and drug resistance. However, despite the apparent dependency of redox metabolism of cysteine biosynthesis pathway, the role of L. donovani cysteine synthase (LdCS) in drug resistance and redox homeostasis has been unexplored. Herein, we report that over-expression of LdCS in Amphotericin B (Amp B) sensitive strain (S1-OE) modulates resistance towards oxidative stress and drug pressure. We observed that antioxidant enzyme activities were up-regulated in S1-OE parasites and these parasites alleviate intracellular reactive oxygen species (ROS) efficiently by maintaining the reduced thiol pool. In contrast to S1-OE parasites, Amp B sensitive strain (S1) showed higher levels of ROS which was positively correlated with the protein carbonylation levels and negatively correlated with cell viability. Moreover, further investigations showed that LdCS over-expression also augments the ROS-primed induction of LdCS-GFP as well as endogenous LdCS and thiol pathway proteins (LdTryS, LdTryR and LdcTXN) in L. donovani parasites; which probably aids in stress tolerance and drug resistance. In addition, the expression of LdCS was found to be up-regulated in Amp B resistant isolates and during infective stationary stages of growth and consistent with these observations, our ex vivo infectivity studies confirmed that LdCS over-expression enhances the infectivity of L. donovani parasites. Our results reveal a novel crosstalk between LdCS and thiol metabolic pathway proteins and demonstrate the crucial role of LdCS in drug resistance and redox homeostasis of Leishmania.

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.03.004
      Issue No: Vol. 12 (2017)
       
  • Induction of reactive oxygen species-stimulated distinctive autophagy by
           chelerythrine in non-small cell lung cancer cells

    • Authors: Zheng-Hai Tang; Wen-Xiang Cao; Zhao-Yu Wang; Jia-Hong Lu; Bo Liu; Xiuping Chen; Jin-Jian Lu
      Pages: 367 - 376
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Zheng-Hai Tang, Wen-Xiang Cao, Zhao-Yu Wang, Jia-Hong Lu, Bo Liu, Xiuping Chen, Jin-Jian Lu
      Chelerythrine (CHE), a natural benzo[c]phenanthridine alkaloid, shows anti-cancer effect through a number of mechanisms. Herein, the effect and mechanism of the CHE-induced autophagy, a type II programmed cell death, in non-small cell lung cancer (NSCLC) cells were studied for the first time. CHE induced cell viability decrease, colony formation inhibition, and apoptosis in a concentration-dependent manner in NSCLC A549 and NCI-H1299 cells. In addition, CHE triggered the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II). The CHE-induced expression of LC3-II was further increased in the combination treatment with chloroquine (CQ), an autophagy inhibitor, and large amounts of red-puncta were observed in the CHE-treated A549 cells with stable expression of mRFP-EGFP-LC3, indicating that CHE induces autophagy flux. Silence of beclin 1 reversed the CHE-induced expression of LC3-II. Inhibition of autophagy remarkably reversed the CHE-induced cell viability decrease and apoptosis in NCI-H1299 cells but not in A549 cells. Furthermore, CHE triggered reactive oxygen species (ROS) generation in both cell lines. A decreased level of ROS through pretreatment with N-acetyl-L-cysteine reversed the CHE-induced cell viability decrease, apoptosis, and autophagy. Taken together, CHE induced distinctive autophagy in A549 (accompanied autophagy) and NCI-H1299 (pro-death autophagy) cells and a decreased level of ROS reversed the effect of CHE in NSCLC cells in terms of cell viability, apoptosis, and autophagy.

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.03.009
      Issue No: Vol. 12 (2017)
       
  • CO-releasing molecules CORM2 attenuates angiotensin II-induced human
           aortic smooth muscle cell migration through inhibition of ROS/IL-6
           generation and matrix metalloproteinases-9 expression

    • Authors: Ming-Horng Tsai; Chiang-Wen Lee; Lee-Fen Hsu; Shu-Yu Li; Yao-Chang Chiang; Ming-Hsueh Lee; Chun-Han Chen; Hwey-Fang Liang; Jia-Mei How; Pey-Jium Chang; Ching-Mei Wu; I-Ta Lee
      Pages: 377 - 388
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Ming-Horng Tsai, Chiang-Wen Lee, Lee-Fen Hsu, Shu-Yu Li, Yao-Chang Chiang, Ming-Hsueh Lee, Chun-Han Chen, Hwey-Fang Liang, Jia-Mei How, Pey-Jium Chang, Ching-Mei Wu, I-Ta Lee
      Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47phox, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed.
      Graphical abstract image

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.02.019
      Issue No: Vol. 12 (2017)
       
  • One-year follow-up of clinical, metabolic and oxidative stress profile of
           morbid obese patients after laparoscopic sleeve gastrectomy. 8-oxo-dG as a
           clinical marker

    • Authors: Lidia Monzo-Beltran; Antonio Vazquez-Tarragón; Concha Cerdà; Paula Garcia-Perez; Antonio Iradi; Carlos Sánchez; Benjamin Climent; Carmen Tormos; Antonio Vázquez-Prado; Javier Girbés; Nuria Estáñ; Sebastián Blesa; Raquel Cortés; Felipe J. Chaves; Guillermo T. Sáez
      Pages: 389 - 402
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Lidia Monzo-Beltran, Antonio Vazquez-Tarragón, Concha Cerdà, Paula Garcia-Perez, Antonio Iradi, Carlos Sánchez, Benjamin Climent, Carmen Tormos, Antonio Vázquez-Prado, Javier Girbés, Nuria Estáñ, Sebastián Blesa, Raquel Cortés, Felipe J. Chaves, Guillermo T. Sáez
      Obesity has grown worldwide over the last few decades. In its different degrees, obesity is accompanied by many clinical and biochemical alterations reflecting the pathological condition of various body tissues. Among the mechanisms underlying the pathogenesis of obesity and associated complications, oxidative stress (OS) may be playing an important role. In the present study, we have characterized at systemic level the degree of OS status in a group of morbid obese patients (BMI>40kg/m2) at basal sate and its modulation during one year after bariatric surgery using the laparoscopic sleeve gastrectomy (LSG) technique. As compared with normal weight subjects matched in age, peripheral blood mononuclear cells (PBMc) of obese patients present a significant reduction of the antioxidant enzyme activities superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) as well as a significant increase of the oxidized/reduced glutathione ratio (GSSG/GSH) in these cells. Lipid peroxidation is significantly increased in the patient group as shown by the increased levels of malondialdehyde (MDA) in PBMc and the amount of F2-Isoprostanes (F2-IsoPs) released in urine. In addition, the DNA damage product 8-oxo-7,8-2′-deoxyguanosine (8-oxo-dG) was also observed to be increased in serum and urine of morbid obese patients as compared with the control group. After LSG, an improvement of their ponderal and metabolic profile was accompanied by a progressive recovery of antioxidant enzyme activities and the decline of oxidative byproducts both in PBMc and biological fluids. The observed changes of urinary 8-oxo-dG levels correlate positively with its serum concentration, the lipid peroxidation products MDA and F2-IsoPs, triglycerides, glucose, insulin, HOMA index and body weight and negatively with the percentage of weight and BMI loss and antioxidant activities. We conclude that the analysis of urinary 8-oxo-dG could be validated as a useful marker for the monitoring of ponderal and metabolic status of morbid obese patients.
      Graphical abstract image

      PubDate: 2017-03-18T01:09:55Z
      DOI: 10.1016/j.redox.2017.02.003
      Issue No: Vol. 12 (2017)
       
  • Time- and cell-resolved dynamics of redox-sensitive Nrf2, HIF and NF-κB
           activities in 3D spheroids enriched for cancer stem cells

    • Authors: Anna P. Kipp; Stefanie Deubel; Elias S.J. Arnér; Katarina Johansson
      Pages: 403 - 409
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Anna P. Kipp, Stefanie Deubel, Elias S.J. Arnér, Katarina Johansson
      Cancer cells have an altered redox status, with changes in intracellular signaling pathways. The knowledge of how such processes are regulated in 3D spheroids, being well-established tumor models, is limited. To approach this question we stably transfected HCT116 cells with a pTRAF reporter that enabled time- and cell-resolved activity monitoring of three redox-regulated transcription factors Nrf2, HIF and NF-κB in spheroids enriched for cancer stem cells. At the first day of spheroid formation, these transcription factors were activated and thereafter became repressed. After about a week, both HIF and Nrf2 were reactivated within the spheroid cores. Further amplifying HIF activation in spheroids by treatment with DMOG resulted in a dominant quiescent stem-cell-like phenotype, with high resistance to stress-inducing treatments. Auranofin, triggering oxidative stress and Nrf2 activation, had opposite effects with increased differentiation and proliferation. These novel high-resolution insights into spatiotemporal activation patterns demonstrate a striking coordination of redox regulated transcription factors within spheroids not occurring in conventional cell culture models.
      Graphical abstract image

      PubDate: 2017-03-18T01:09:55Z
      DOI: 10.1016/j.redox.2017.03.013
      Issue No: Vol. 12 (2017)
       
  • Mitochondrial hyperpolarization in iPSC-derived neurons from patients of
           FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and
           neurodegeneration

    • Authors: Noemí Esteras; Jonathan D. Rohrer; John Hardy; Selina Wray; Andrey Y. Abramov
      Pages: 410 - 422
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Noemí Esteras, Jonathan D. Rohrer, John Hardy, Selina Wray, Andrey Y. Abramov
      Tau protein inclusions are a frequent hallmark of a variety of neurodegenerative disorders. The 10+16 intronic mutation in MAPT gene, encoding tau, causes frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), by altering the splicing of the gene and inducing an increase in the production of 4R tau isoforms, which are more prone to aggregation. However, the molecular mechanisms linking increased 4R tau to neurodegeneration are not well understood. Here, we have used iPSC-derived neurons from patients of FTDP-17 carrying the 10+16 mutation to study the molecular mechanisms underlying neurodegeneration. We show that mitochondrial function is altered in the neurons of the patients. We found that FTDP-17 neurons present an increased mitochondrial membrane potential, which is partially maintained by the F1Fo ATPase working in reverse mode. The 10+16 MAPT mutation is also associated with lower mitochondrial NADH levels, partially supressed complex I-driven respiration, and lower ATP production by oxidative phosphorylation, with cells relying on glycolysis to maintain ATP levels. Increased mitochondrial membrane potential in FTDP-17 neurons leads to overproduction of the ROS in mitochondria, which in turn causes oxidative stress and cell death. Mitochondrial ROS overproduction in these cells is a major trigger for neuronal cell death and can be prevented by mitochondrial antioxidants
      Graphical abstract image

      PubDate: 2017-03-18T01:09:55Z
      DOI: 10.1016/j.redox.2017.03.008
      Issue No: Vol. 12 (2017)
       
  • Role of macrophages in age-related oxidative stress and lipofuscin
           accumulation in mice

    • Authors: Carmen Vida; Irene Martínez de Toda; Julia Cruces; Antonio Garrido; Mónica Gonzalez-Sanchez; Mónica De la Fuente
      Pages: 423 - 437
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Carmen Vida, Irene Martínez de Toda, Julia Cruces, Antonio Garrido, Mónica Gonzalez-Sanchez, Mónica De la Fuente
      The age-related changes in the immune functions (immunosenescence) may be mediated by an increase of oxidative stress and damage affecting leukocytes. Although the “oxidation-inflammation” theory of aging proposes that phagocytes are the main immune cells contributing to “oxi-inflamm-aging”, this idea has not been corroborated. The aim of this work was to characterize the age-related changes in several parameters of oxidative stress and immune function, as well as in lipofuscin accumulation (“a hallmark of aging”), in both total peritoneal leukocyte population and isolated peritoneal macrophages. Adult, mature, old and long-lived mice (7, 13, 18 and 30 months of age, respectively) were used. The xanthine oxidase (XO) activity-expression, basal levels of superoxide anion and ROS, catalase activity, oxidized (GSSG) and reduced (GSH) glutathione content and lipofuscin levels, as well as both phagocytosis and digestion capacity were evaluated. The results showed an age-related increase of oxidative stress and lipofuscin accumulation in murine peritoneal leukocytes, but especially in macrophages. Macrophages from old mice showed lower antioxidant defenses (catalase activity and GSH levels), higher oxidizing compounds (XO activity/expression and superoxide, ROS and GSSG levels) and lipofuscin levels, together with an impaired macrophage functions, in comparison to adults. In contrast, long-lived mice showed in their peritoneal leukocytes, and especially in macrophages, a well-preserved redox state and maintenance of their immune functions, all which could account for their high longevity. Interestingly, macrophages showed higher XO activity and lipofuscin accumulation than lymphocytes in all the ages analyzed. Our results support that macrophages play a central role in the chronic oxidative stress associated with aging, and the fact that phagocytes are key cells contributing to immunosenescence and “oxi-inflamm-aging”. Moreover, the determination of oxidative stress and immune function parameters, together with the lipofuscin quantification, in macrophages, can be used as useful markers of the rate of aging and longevity.
      Graphical abstract image

      PubDate: 2017-03-18T01:09:55Z
      DOI: 10.1016/j.redox.2017.03.005
      Issue No: Vol. 12 (2017)
       
  • Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects
           endothelial adherens junction integrity and barrier function

    • Authors: Rima Chattopadhyay; Somasundaram Raghavan; Gadiparthi N. Rao
      Pages: 438 - 455
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Rima Chattopadhyay, Somasundaram Raghavan, Gadiparthi N. Rao
      Resolvins are a novel class of lipid mediators that play an important role in the resolution of inflammation, although the underlying mechanisms are not very clear. To explore the anti-inflammatory mechanisms of resolvins, we have studied the effects of resolvin D1 (RvD1) on lipopolysaccharide (LPS)-induced endothelial barrier disruption as it is linked to propagation of inflammation. We found that LPS induces endothelial cell (EC) barrier disruption via xanthine oxidase (XO)-mediated reactive oxygen species (ROS) production, protein tyrosine phosphatase SHP2 inactivation and Fyn-related kinase (Frk) activation leading to tyrosine phosphorylation of α-catenin and VE-cadherin and their dissociation from each other affecting adherens junction (AJ) integrity and thereby increasing endothelial barrier permeability. RvD1 attenuated LPS-induced AJ disassembly and endothelial barrier permeability by arresting tyrosine phosphorylation of α-catenin and VE-cadherin and their dislocation from AJ via blockade of XO-mediated ROS production and thereby suppression of SHP2 inhibition and Frk activation. We have also found that the protective effects of RvD1 on EC barrier function involve ALX/FPR2 and GPR32 as inhibition or neutralization of these receptors negates its protective effects. LPS also increased XO activity, SHP2 cysteine oxidation and its inactivation, Frk activation, α-catenin and VE-cadherin tyrosine phosphorylation and their dissociation from each other leading to AJ disruption with increased vascular permeability in mice arteries and RvD1 blocked all these effects. Thus, RvD1 protects endothelial AJ and its barrier function from disruption by inflammatory mediators such as LPS via a mechanism involving the suppression of XO-mediated ROS production and blocking SHP2 inactivation.
      Graphical abstract image

      PubDate: 2017-03-24T01:35:29Z
      DOI: 10.1016/j.redox.2017.02.023
      Issue No: Vol. 12 (2017)
       
  • Impact of high cholesterol and endoplasmic reticulum stress on metabolic
           diseases: An updated mini-review

    • Authors: Erdi Sozen; Nesrin Kartal Ozer
      Pages: 456 - 461
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Erdi Sozen, Nesrin Kartal Ozer
      Endoplasmic reticulum (ER) is the major site of protein folding and calcium storage. Beside the role of ER in protein homeostasis, it controls the cholesterol production and lipid-membrane biosynthesis as well as surviving and cell death signaling mechanisms in the cell. It is well-documented that elevated plasma cholesterol induces adverse effects in cardiovascular diseases (CVDs), liver disorders, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatosis hepatitis (NASH), and metabolic diseases which are associated with oxidative and ER stress. Recent animal model and human studies have showed high cholesterol and ER stress as an emerging factors involved in the development of many metabolic diseases. In this review, we will summarize the crucial effects of hypercholesterolemia and ER stress response in the pathogenesis of CVDs, NAFLD/NASH, diabetes and obesity which are major health problems in western countries.
      Graphical abstract image

      PubDate: 2017-03-18T01:09:55Z
      DOI: 10.1016/j.redox.2017.02.025
      Issue No: Vol. 12 (2017)
       
  • Fluorescent proteins such as eGFP lead to catalytic oxidative stress in
           cells

    • Authors: Douglas Ganini; Fabian Leinisch; Ashutosh Kumar; JinJie Jiang; Erik J. Tokar; Christine C. Malone; Robert M. Petrovich; Ronald P. Mason
      Pages: 462 - 468
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Douglas Ganini, Fabian Leinisch, Ashutosh Kumar, JinJie Jiang, Erik J. Tokar, Christine C. Malone, Robert M. Petrovich, Ronald P. Mason
      Fluorescent proteins are an important tool that has become omnipresent in life sciences research. They are frequently used for localization of proteins and monitoring of cells [1,2]. Green fluorescent protein (GFP) was the first and has been the most used fluorescent protein. Enhanced GFP (eGFP) was optimized from wild-type GFP for increased fluorescence yield and improved expression in mammalian systems [3]. Many GFP-like fluorescent proteins have been discovered, optimized or created, such as the red fluorescent protein TagRFP [4]. Fluorescent proteins are expressed colorless and immature and, for eGFP, the conversion to the fluorescent form, mature, is known to produce one equivalent of hydrogen peroxide (H2O2) per molecule of chromophore [5,6]. Even though it has been proposed that this process is non-catalytic and generates nontoxic levels of H2O2 [6], this study investigates the role of fluorescent proteins in generating free radicals and inducing oxidative stress in biological systems. Immature eGFP and TagRFP catalytically generate the free radical superoxide anion (O2 •–) and H2O2 in the presence of NADH. Generation of the free radical O2 •– and H2O2 by eGFP in the presence of NADH affects the gene expression of cells. Many biological pathways are altered, such as a decrease in HIF1α stabilization and activity. The biological pathways altered by eGFP are known to be implicated in the pathophysiology of many diseases associated with oxidative stress; therefore, it is critical that such experiments using fluorescent proteins are validated with alternative methodologies and the results are carefully interpreted. Since cells inevitably experience oxidative stress when fluorescent proteins are expressed, the use of this tool for cell labeling and in vivo cell tracing also requires validation using alternative methodologies.
      Graphical abstract image

      PubDate: 2017-03-24T01:35:29Z
      DOI: 10.1016/j.redox.2017.03.002
      Issue No: Vol. 12 (2017)
       
  • Phytochemical-induced nucleolar stress results in the inhibition of breast
           cancer cell proliferation

    • Authors: Anna Lewinska; Diana Bednarz; Jagoda Adamczyk-Grochala; Maciej Wnuk
      Pages: 469 - 482
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Anna Lewinska, Diana Bednarz, Jagoda Adamczyk-Grochala, Maciej Wnuk
      The nucleolus is a stress sensor and compromised nucleolar activity may be considered as an attractive anticancer strategy. In the present study, the effects of three plant-derived natural compounds, i.e., sulforaphane (SFN), ursolic acid (UA) and betulinic acid (BA) on nucleolar state were investigated in breast cancer cell lines of different receptor status, namely MCF-7, MDA-MB-231 and SK-BR-3 cells. Cytostatic action of phytochemicals against breast cancer cells was observed at low micromolar concentration window (5–20µM) and mediated by elevated p21 levels, and cell proliferation of SFN-, UA- and BA-treated normal human mammary epithelial cells (HMEC) was unaffected. Phytochemical-mediated inhibition of cell proliferation was accompanied by increased levels of superoxide and protein carbonylation that lead to disorganization of A- and B-type lamin networks and alterations in the nuclear architecture. Phytochemicals promoted nucleolar stress as judged by the nucleoplasmic translocation of RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA, inhibition of new rRNA synthesis and decrease in number of nucleoli. Phytochemicals also decreased the levels of NOP2, proliferation-associated nucleolar protein p120, and WDR12 required for maturation of 28S and 5.8S ribosomal RNAs and formation of the 60S ribosome, and phosphorylation of S6 ribosomal protein that may result in diminished translation and inhibition of cell proliferation. In summary, three novel ribotoxic stress stimuli were revealed with a potential to be used in nucleolus-focused anticancer therapy.

      PubDate: 2017-03-24T01:35:29Z
      DOI: 10.1016/j.redox.2017.03.014
      Issue No: Vol. 12 (2017)
       
  • Combined metformin and insulin treatment reverses metabolically impaired
           omental adipogenesis and accumulation of 4-hydroxynonenal in obese
           diabetic patients

    • Authors: Morana Jaganjac; Shamma Almuraikhy; Fatima Al-Khelaifi; Mashael Al-Jaber; Moataz Bashah; Nayef A. Mazloum; Kamelija Zarkovic; Neven Zarkovic; Georg Waeg; Wael Kafienah; Mohamed A. Elrayess
      Pages: 483 - 490
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Morana Jaganjac, Shamma Almuraikhy, Fatima Al-Khelaifi, Mashael Al-Jaber, Moataz Bashah, Nayef A. Mazloum, Kamelija Zarkovic, Neven Zarkovic, Georg Waeg, Wael Kafienah, Mohamed A. Elrayess
      Objective Obesity-associated impaired fat accumulation in the visceral adipose tissue can lead to ectopic fat deposition and increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). This study investigated whether impaired adipogenesis of omental (OM) adipose tissues and elevated 4-hydroxynonenal (4-HNE) accumulation contribute to this process, and if combined metformin and insulin treatment in T2DM patients could rescue this phenotype. Methods OM adipose tissues were obtained from forty clinically well characterized obese individuals during weight reduction surgery. Levels of 4-HNE protein adducts, adipocyte size and number of macrophages were determined within these tissues by immunohistochemistry. Adipogenic capacity and gene expression profiles were assessed in preadipocytes derived from these tissues in relation to insulin resistance and in response to 4-HNE, metformin or combined metformin and insulin treatment. Results Preadipocytes isolated from insulin resistant (IR) and T2DM individuals exhibited lower adipogenesis, marked by upregulation of anti-adipogenic genes, compared to preadipocytes derived from insulin sensitive (IS) individuals. Impaired adipogenesis was also associated with increased 4-HNE levels, smaller adipocytes and greater macrophage presence in the adipose tissues. Within the T2DM group, preadipocytes from combined metformin and insulin treated subset showed better in vitro adipogenesis compared to metformin alone, which was associated with less presence of macrophages and 4-HNE in the adipose tissues. Treatment of preadipocytes in vitro with 4-HNE reduced their adipogenesis and increased proliferation, even in the presence of metformin, which was partially rescued by the presence of insulin. Conclusion This study reveals involvement of 4-HNE in the impaired OM adipogenesis-associated with insulin resistance and T2DM and provides a proof of concept that this impairment can be reversed by the synergistic action of insulin and metformin. Further studies are needed to evaluate involvement of 4-HNE in metabolically impaired abdominal adipogenesis and to confirm benefits of combined metformin-insulin therapy in T2DM patients.

      PubDate: 2017-03-24T01:35:29Z
      DOI: 10.1016/j.redox.2017.03.012
      Issue No: Vol. 12 (2017)
       
  • Biochemical signaling by remote ischemic conditioning of the arm versus
           thigh: Is one raise of the cuff enough'

    • Authors: Cameron Dezfulian; Maia Taft; Catherine Corey; Gabrielle Hill; Nicholas Krehel; Jon C. Rittenberger; Frank X. Guyette; Sruti Shiva
      Pages: 491 - 498
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Cameron Dezfulian, Maia Taft, Catherine Corey, Gabrielle Hill, Nicholas Krehel, Jon C. Rittenberger, Frank X. Guyette, Sruti Shiva
      Remote Ischemic Conditioning (RIC), induced by brief cycles of ischemia and reperfusion, protects vital organs from a prolonged ischemic insult. While several biochemical mediators have been implicated in RIC's mechanism of action, it remains unclear whether the localization or “dose” of RIC affects the extent of protective signaling. In this randomized crossover study of healthy individuals, we tested whether the number of cycles of RIC and its localization (arm versus thigh) determines biochemical signaling and cytoprotection. Subjects received either arm or thigh RIC and then were crossed over to receive RIC in the other extremity. Blood flow, tissue perfusion, concentrations of the circulating protective mediator nitrite, and platelet mitochondrial function were measured after each RIC cycle. We found that plasma nitrite concentration peaked after the first RIC cycle and remained elevated throughout RIC. This plasma nitrite conferred cytoprotection in an in vitro myocyte model of hypoxia/reoxygenation. Notably, though plasma nitrite returned to baseline at 24h, RIC conditioned plasma still mediated protection. Additionally, no difference in endpoints between RIC in thigh versus arm was found. These data demonstrate that localization and “dose” of RIC does not affect cytoprotection and further elucidate the mechanisms by which nitrite contributes to RIC-dependent protection.

      PubDate: 2017-03-24T01:35:29Z
      DOI: 10.1016/j.redox.2017.03.010
      Issue No: Vol. 12 (2017)
       
  • Hypoxia and hydrogen sulfide differentially affect normal and
           tumor-derived vascular endothelium

    • Authors: Serena Bianco; Daniele Mancardi; Annalisa Merlino; Benedetta Bussolati; Luca Munaron
      Pages: 499 - 504
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Serena Bianco, Daniele Mancardi, Annalisa Merlino, Benedetta Bussolati, Luca Munaron
      Background endothelial cells play a key role in vessels formation both under physiological and pathological conditions. Their behavior is influenced by blood components including gasotransmitters (H2S, NO and CO). Tumor cells are subjected to a cyclic shift between pro-oxidative and hypoxic state and, in this scenario, H2S can be both cytoprotective and detrimental depending on its concentration. H2S effects on tumors onset and development is scarcely studied, particularly concerning tumor angiogenesis. We previously demonstrated that H2S is proangiogenic for tumoral but not for normal endothelium and this may represent a target for antiangiogenic therapeutical strategies. Methods in this work, we investigate cell viability, migration and tubulogenesis on human EC derived from two different tumors, breast and renal carcinoma (BTEC and RTEC), compared to normal microvascular endothelium (HMEC) under oxidative stress, hypoxia and treatment with exogenous H2S. Results all EC types are similarly sensitive to oxidative stress induced by hydrogen peroxide; chemical hypoxia differentially affects endothelial viability, that results unaltered by real hypoxia. H2S neither affects cell viability nor prevents hypoxia and H2O2-induced damage. Endothelial migration is enhanced by hypoxia, while tubulogenesis is inhibited for all EC types. H2S acts differentially on EC migration and tubulogenesis. Conclusions these data provide evidence for a great variability of normal and altered endothelium in response to the environmental conditions.
      Graphical abstract image

      PubDate: 2017-03-24T01:35:29Z
      DOI: 10.1016/j.redox.2017.03.015
      Issue No: Vol. 12 (2017)
       
  • Gene and protein expressions and metabolomics exhibit activated redox
           signaling and wnt/β-catenin pathway are associated with metabolite
           dysfunction in patients with chronic kidney disease

    • Authors: Dan-Qian Chen; Gang Cao; Hua Chen; Dan Liu; Wei Su; Xiao-Yong Yu; Nosratola D. Vaziri; Xiu-Hua Liu; Xu Bai; Li Zhang; Ying-Yong Zhao
      Pages: 505 - 521
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Dan-Qian Chen, Gang Cao, Hua Chen, Dan Liu, Wei Su, Xiao-Yong Yu, Nosratola D. Vaziri, Xiu-Hua Liu, Xu Bai, Li Zhang, Ying-Yong Zhao
      Changes in plasma concentration of small organic metabolites could be due to their altered production or urinary excretion and changes in their urine concentration may be due to the changes in their filtered load, tubular reabsorption, and/or altered urine volume. Therefore, these factors should be considered in interpretation of the changes observed in plasma or urine of the target metabolite(s). Fasting plasma and urine samples from 180 CKD patients and 120 age-matched healthy controls were determined by UPLC-HDMS-metabolomics and quantitative real-time RT-PCR techniques. Compared with healthy controls, patients with CKD showed activation of NF-κB and up-regulation of pro-inflammatory and pro-oxidant mRNA and protein expression as well as down-regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression, accompanied by activated canonical Wnt/β-catenin signaling. 124 plasma and 128 urine metabolites were identified and 40 metabolites were significantly altered in both plasma and urine. Plasma concentration and urine excretion of 25 metabolites were distinctly different between CKD and controls. They were related to amino acid, methylamine, purine and lipid metabolisms. Logistic regression identified four plasma and five urine metabolites. Parts of them were good correlated with eGFR or serum creatinine. 5-Methoxytryptophan and homocystine and citrulline were good correlated with both eGFR and creatinine. Clinical factors were incorporated to establish predictive models. The enhanced metabolite model showed 5-methoxytryptophan, homocystine and citrulline have satisfactory accuracy, sensitivity and specificity for predictive CKD. The dysregulation of CKD was related to amino acid, methylamine, purine and lipid metabolisms. 5-methoxytryptophan, homocystine and citrulline could be considered as additional GFR-associated biomarker candidates and for indicating advanced renal injury. CKD caused dysregulation of the plasma and urine metabolome, activation of inflammatory/oxidative pathway and Wnt/β-catenin signaling and suppression of antioxidant pathway.
      Graphical abstract image

      PubDate: 2017-03-31T02:51:54Z
      DOI: 10.1016/j.redox.2017.03.017
      Issue No: Vol. 12 (2017)
       
  • Inhibition of herpes simplex-1 virus replication by 25-hydroxycholesterol
           and 27-hydroxycholesterol

    • Authors: Valeria Cagno; Andrea Civra; Daniela Rossin; Simone Calfapietra; Claudio Caccia; Valerio Leoni; Nicholas Dorma; Fiorella Biasi; Giuseppe Poli; David Lembo
      Pages: 522 - 527
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Valeria Cagno, Andrea Civra, Daniela Rossin, Simone Calfapietra, Claudio Caccia, Valerio Leoni, Nicholas Dorma, Fiorella Biasi, Giuseppe Poli, David Lembo
      Oxysterols are known pleiotropic molecules whose antiviral action has been recently discovered. Here reported is the activity of a panel of oxysterols against HSV-1 with the identification of a new mechanism of action. A marked antiviral activity not only of 25HC but also of 27HC against HSV-1 was observed either if the oxysterols were added before or after infection, suggesting an activity unrelated to the viral entry inhibition as proposed by previous literature. Therefore, the relation between the pro-inflammatory activity of oxysterols and the activation of NF-kB and IL-6 induced by HSV-1 in the host cell was investigated. Indeed, cell pre-incubation with oxysterols further potentiated IL-6 production as induced by HSV-1 infection with a consequent boost of the interleukin's total cell secretion. Further, a direct antiviral effect of IL-6 administration to HSV-1 infected cells was demonstrated, disclosing an additional mechanism of antiviral action by both 25HC and 27HC.
      Graphical abstract image

      PubDate: 2017-03-31T02:51:54Z
      DOI: 10.1016/j.redox.2017.03.016
      Issue No: Vol. 12 (2017)
       
  • Catalase as a regulator of reactive sulfur metabolism; a new
           interpretation beyond hydrogen peroxide✩

    • Authors: Christopher G. Kevil
      Pages: 528 - 529
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Christopher G. Kevil
      Graphical abstract image

      PubDate: 2017-03-31T02:51:54Z
      DOI: 10.1016/j.redox.2017.03.018
      Issue No: Vol. 12 (2017)
       
  • Cysteine persulfides and polysulfides produced by exchange reactions with
           H2S protect SH-SY5Y cells from methylglyoxal-induced toxicity through Nrf2
           activation

    • Authors: Shin Koike; Shoichi Nishimoto; Yuki Ogasawara
      Pages: 530 - 539
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Shin Koike, Shoichi Nishimoto, Yuki Ogasawara
      Many physiological functions of hydrogen sulfide (H2S) have been reported in mammalian cells over the last 20 years. These physiological effects have been ascertained through in vitro treatment of cells with Na2S or NaHS, both of which are precursors of H2S. Since H2S exists as HS− in a neutral solution, a disulfide compound such as cystine could react with HS− in culture medium as well as in the cell. This study demonstrated that after the addition of Na2S solution into culture medium, HS− was transiently generated and disappeared immediately through the reaction between HS− and cystine to form cysteine persulfides and polysulfides in the culture medium (bound sulfur mixture: BS-Mix). Furthermore, we found that the addition of Na2S solution resulted in an increase of intracellular cysteine persulfide levels in SH-SY5Y cells. This alteration in intracellular persulfide was also observed in cystine-free medium. Considering this reaction of HS− as a precursor of BS-Mix, we highlighted the cytoprotective effect of Na2S on human neuroblastoma SH-SY5Y cells against methylglyoxal (MG)-induced toxicity. BS-Mix produced with Na2S in cystine-containing medium provided SH-SY5Y cells significant protective effect against MG-induced toxicity. However, the protective effect was attenuated in cystine-free medium. Moreover, we observed that Na2S or BS-Mix activated the Keap1/Nrf2 system and increased glutathione (GSH) levels in the cell. In addition, the activation of Nrf2 is significantly attenuated in cystine-free medium. These results suggested that Na2S protects SH-SY5Y cells from MG cytotoxicity through the activation of Nrf2, mediated by cysteine persulfides and polysulfides that were generated by Na2S addition.
      Graphical abstract image

      PubDate: 2017-04-07T04:24:44Z
      DOI: 10.1016/j.redox.2017.03.020
      Issue No: Vol. 12 (2017)
       
  • Oxygen and oxidative stress in the perinatal period

    • Authors: Isabel Torres-Cuevas; Anna Parra-Llorca; Angel Sánchez-Illana; Antonio Nuñez-Ramiro; Julia Kuligowski; Consuelo Cháfer-Pericás; María Cernada; Justo Escobar; Máximo Vento
      Pages: 674 - 681
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Isabel Torres-Cuevas, Anna Parra-Llorca, Angel Sánchez-Illana, Antonio Nuñez-Ramiro, Julia Kuligowski, Consuelo Cháfer-Pericás, María Cernada, Justo Escobar, Máximo Vento
      Fetal life evolves in a hypoxic environment. Changes in the oxygen content in utero caused by conditions such as pre-eclampsia or type I diabetes or by oxygen supplementation to the mother lead to increased free radical production and correlate with perinatal outcomes. In the fetal-to-neonatal transition asphyxia is characterized by intermittent periods of hypoxia ischemia that may evolve to hypoxic ischemic encephalopathy associated with neurocognitive, motor, and neurosensorial impairment. Free radicals generated upon reoxygenation may notably increase brain damage. Hence, clinical trials have shown that the use of 100% oxygen given with positive pressure in the airways of the newborn infant during resuscitation causes more oxidative stress than using air, and increases mortality. Preterm infants are endowed with an immature lung and antioxidant system. Clinical stabilization of preterm infants after birth frequently requires positive pressure ventilation with a gas admixture that contains oxygen to achieve a normal heart rate and arterial oxygen saturation. In randomized controlled trials the use high oxygen concentrations (90% to 100%) has caused more oxidative stress and clinical complications that the use of lower oxygen concentrations (30–60%). A correlation between the amount of oxygen received during resuscitation and the level of biomarkers of oxidative stress and clinical outcomes was established. Thus, based on clinical outcomes and analytical results of oxidative stress biomarkers relevant changes were introduced in the resuscitation policies. However, it should be underscored that analysis of oxidative stress biomarkers in biofluids has only been used in experimental and clinical research but not in clinical routine. The complexity of the technical procedures, lack of automation, and cost of these determinations have hindered the routine use of biomarkers in the clinical setting. Overcoming these technical and economical difficulties constitutes a challenge for the immediate future since accurate evaluation of oxidative stress would contribute to improve the quality of care of our neonatal patients.
      Graphical abstract image

      PubDate: 2017-04-12T15:30:22Z
      DOI: 10.1016/j.redox.2017.03.011
      Issue No: Vol. 12 (2017)
       
 
 
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