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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  [3041 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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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)
       
  • Exercise, oxidants, and antioxidants change the shape of the bell-shaped
           hormesis curve

    • Authors: Zsolt Radak; Kazunari Ishihara; Eva Tekus; Csaba Varga; Aniko Posa; Laszlo Balogh; Istvan Boldogh; Erika Koltai
      Pages: 285 - 290
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Zsolt Radak, Kazunari Ishihara, Eva Tekus, Csaba Varga, Aniko Posa, Laszlo Balogh, Istvan Boldogh, Erika Koltai
      It is debated whether exercise-induced ROS production is obligatory to cause adaptive response. It is also claimed that antioxidant treatment could eliminate the adaptive response, which appears to be systemic and reportedly reduces the incidence of a wide range of diseases. Here we suggest that if the antioxidant treatment occurs before the physiological function-ROS dose-response curve reaches peak level, the antioxidants can attenuate function. On the other hand, if the antioxidant treatment takes place after the summit of the bell-shaped dose response curve, antioxidant treatment would have beneficial effects on function. We suggest that the effects of antioxidant treatment are dependent on the intensity of exercise, since the adaptive response, which is multi pathway dependent, is strongly influenced by exercise intensity. It is further suggested that levels of ROS concentration are associated with peak physiological function and can be extended by physical fitness level and this could be the basis for exercise pre-conditioning. Physical inactivity, aging or pathological disorders increase the sensitivity to oxidative stress by altering the bell-shaped dose response curve.
      Graphical abstract image

      PubDate: 2017-03-11T15:25:32Z
      DOI: 10.1016/j.redox.2017.02.015
      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
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      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)
       
  • 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)
       
  • Plant peroxisomes: A nitro-oxidative cocktail

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

      PubDate: 2017-01-19T17:53:04Z
      DOI: 10.1016/j.redox.2016.12.033
      Issue No: Vol. 11 (2017)
       
  • Nitro-fatty acids in plant signaling: New key mediators of nitric oxide
           metabolism

    • Authors: Capilla Mata-Pérez; Beatriz Sánchez-Calvo; María N. Padilla; Juan C. Begara-Morales; Raquel Valderrama; Francisco J. Corpas; Juan B. Barroso
      Pages: 554 - 561
      Abstract: Publication date: April 2017
      Source:Redox Biology, Volume 11
      Author(s): Capilla Mata-Pérez, Beatriz Sánchez-Calvo, María N. Padilla, Juan C. Begara-Morales, Raquel Valderrama, Francisco J. Corpas, Juan B. Barroso
      Recent studies in animal systems have shown that NO can interact with fatty acids to generate nitro-fatty acids (NO2-FAs). They are the product of the reaction between reactive nitrogen species and unsaturated fatty acids, and are considered novel mediators of cell signaling based mainly on a proven anti-inflammatory response. Although these signaling mediators have been described widely in animal systems, NO2-FAs have scarcely been studied in plants. Preliminary data have revealed the endogenous presence of free and protein-adducted NO2-FAs in extra-virgin olive oil (EVOO), which appear to be contributing to the cardiovascular benefits associated with the Mediterranean diet. Importantly, new findings have displayed the endogenous occurrence of nitro-linolenic acid (NO2-Ln) in the model plant Arabidopsis thaliana and the modulation of NO2-Ln levels throughout this plant's development. Furthermore, a transcriptomic analysis by RNA-seq technology established a clear signaling role for this molecule, demonstrating that NO2-Ln was involved in plant-defense response against different abiotic-stress conditions, mainly by inducing the chaperone network and supporting a conserved mechanism of action in both animal and plant defense processes. Thus, NO2-Ln levels significantly rose under several abiotic-stress conditions, highlighting the strong signaling role of these molecules in the plant-protection mechanism. Finally, the potential of NO2-Ln as a NO donor has recently been described both in vitro and in vivo. Jointly, this ability gives NO2-Ln the potential to act as a signaling molecule by the direct release of NO, due to its capacity to induce different changes mediated by NO or NO-related molecules such as nitration and S-nitrosylation, or by the electrophilic capacity of these molecules through a nitroalkylation mechanism. Here, we describe the current state of the art regarding the advances performed in the field of NO2-FAs in plants and their implication in plant physiology.
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      PubDate: 2017-01-19T17:53:04Z
      DOI: 10.1016/j.redox.2017.01.002
      Issue No: Vol. 11 (2017)
       
  • Autophagy and the redox connection: Virtual collection Vol 2

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


      PubDate: 2017-01-25T18:18:46Z
      DOI: 10.1016/j.redox.2016.10.005
      Issue No: Vol. 11 (2017)
       
  • Modulation of proteostasis by transcription factor NRF2 and impact in
           neurodegenerative diseases

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

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

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

      PubDate: 2017-01-01T07:48:50Z
      DOI: 10.1016/j.redox.2016.12.030
       
  • Oxidative stress in cancer and fibrosis: Opportunity for therapeutic
           intervention with antioxidant compounds, enzymes, and nanoparticles

    • Authors: Worapol Ngamcherdtrakul; David J. Castro; Shenda Gu; Jingga Morry; Moataz Reda; Joe W. Gray; Wassana Yantasee
      Pages: 19 - 29
      Abstract: Publication date: Available online 16 December 2016
      Source:Redox Biology
      Author(s): Jingga Morry, Worapol Ngamcherdtrakul, Wassana Yantasee
      Oxidative stress, mainly contributed by reactive oxygen species (ROS), has been implicated in pathogenesis of several diseases. We review two primary examples; fibrosis and cancer. In fibrosis, ROS promote activation and proliferation of fibroblasts and myofibroblasts, activating TGF-β pathway in an autocrine manner. In cancer, ROS account for its genomic instability, resistance to apoptosis, proliferation, and angiogenesis. Importantly, ROS trigger cancer cell invasion through invadopodia formation as well as extravasation into a distant metastasis site. Use of antioxidant supplements, enzymes, and inhibitors for ROS-generating NADPH oxidases (NOX) is a logical therapeutic intervention for fibrosis and cancer. We review such attempts, progress, and challenges. Lastly, we review how nanoparticles with inherent antioxidant activity can also be a promising therapeutic option, considering their additional feature as a delivery platform for drugs, genes, and imaging agents.
      Graphical abstract image

      PubDate: 2016-12-16T13:24:35Z
      DOI: 10.1016/j.ctrv.2016.02.005
      Issue No: Vol. 45 (2016)
       
  • Fibroblast growth factor 21 and its novel association with oxidative
           stress

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

      PubDate: 2016-12-25T14:48:22Z
      DOI: 10.1016/j.redox.2016.12.024
       
  • A Review of Redox Signaling and the Control of MAP Kinase Pathway in
           Plants

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

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

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

      PubDate: 2016-12-10T13:03:59Z
      DOI: 10.1016/j.redox.2016.12.001
       
  • Redox control of senescence and age-related disease

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

      PubDate: 2016-11-18T20:15:58Z
      DOI: 10.1016/j.redox.2016.11.005
       
 
 
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