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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  [3043 journals]
  • Does hypoxia play a role in the development of sarcopenia in humans?
           Mechanistic insights from the Caudwell Xtreme Everest Expedition

    • Authors: Liesl Wandrag; Mario Siervo; Heather L. Riley; Maryam Khosravi; Bernadette O. Fernandez; Carl A. Leckstrom; Daniel S. Martin; Kay Mitchell; Denny Z.H. Levett; Hugh E. Montgomery; Monty G. Mythen; Michael A. Stroud; Michael P.W. Grocott; Martin Feelisch
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Liesl Wandrag, Mario Siervo, Heather L. Riley, Maryam Khosravi, Bernadette O. Fernandez, Carl A. Leckstrom, Daniel S. Martin, Kay Mitchell, Denny Z.H. Levett, Hugh E. Montgomery, Monty G. Mythen, Michael A. Stroud, Michael P.W. Grocott, Martin Feelisch
      Objectives Sarcopenia refers to the involuntary loss of skeletal muscle and is a predictor of physical disability/mortality. Its pathogenesis is poorly understood, although roles for altered hypoxic signaling, oxidative stress, adipokines and inflammatory mediators have been suggested. Sarcopenia also occurs upon exposure to the hypoxia of high altitude. Using data from the Caudwell Xtreme Everest expedition we therefore sought to analyze the extent of hypoxia-induced body composition changes and identify putative pathways associated with fat-free mass (FFM) and fat mass (FM) loss. Methods After baseline testing in London (75m), 24 investigators ascended from Kathmandu (1300m) to Everest base camp (EBC 5300m) over 13 days. Fourteen investigators climbed above EBC, eight of whom reached the summit (8848m). Assessments were conducted at baseline, during ascent and after one, six and eight week(s) of arrival at EBC. Changes in body composition (FM, FFM, total body water, intra- and extra-cellular water) were measured by bioelectrical impedance. Biomarkers of nitric oxide and oxidative stress were measured together with adipokines, inflammatory, metabolic and vascular markers. Results Participants lost a substantial, but variable, amount of body weight (7.3±4.9kg by expedition end; p<0.001). A progressive loss of both FM and FFM was observed, and after eight weeks, the proportion of FFM loss was 48% greater than FM loss (p<0.008). Changes in protein carbonyls (p<0.001) were associated with a decline in FM whereas 4-hydroxynonenal (p<0.001) and IL-6 (p<0.001) correlated with FFM loss. GLP-1 (r=−0.45, p<0.001) and nitrite (r=−0.29, p<0.001) concentration changes were associated with FFM loss. In a multivariate model, GLP-1, insulin and nitrite were significant predictors of FFM loss while protein carbonyls were predicted FM loss. Conclusions The putative role of GLP-1 and nitrite as mediators of the effects of hypoxia on FFM is an intriguing finding. If confirmed, nutritional and pharmacological interventions targeting these pathways may offer new avenues for prevention and treatment of sarcopenia.

      PubDate: 2017-05-30T07:10:02Z
      DOI: 10.1016/j.redox.2017.05.004
      Issue No: Vol. 13 (2017)
       
  • Quantitative biology of hydrogen peroxide signaling

    • Authors: Fernando Antunes; Paula Matos Brito
      Pages: 1 - 7
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Fernando Antunes, Paula Matos Brito
      Hydrogen peroxide (H2O2) controls signaling pathways in cells by oxidative modulation of the activity of redox sensitive proteins denominated redox switches. Here, quantitative biology concepts are applied to review how H2O2 fulfills a key role in information transmission. Equations described lay the foundation of H2O2 signaling, give new insights on H2O2 signaling mechanisms, and help to learn new information from common redox signaling experiments. A key characteristic of H2O2 signaling is that the ratio between reduction and oxidation of redox switches determines the range of H2O2 concentrations to which they respond. Thus, a redox switch with low H2O2-dependent oxidability and slow reduction rate responds to the same range of H2O2 concentrations as a redox switch with high H2O2-dependent oxidability, but that is rapidly reduced. Yet, in the first case the response time is slow while in the second case is rapid. H2O2 sensing and transmission of information can be done directly or by complex mechanisms in which oxidation is relayed between proteins before oxidizing the final regulatory redox target. In spite of being a very simple molecule, H2O2 has a key role in cellular signaling, with the reliability of the information transmitted depending on the inherent chemical reactivity of redox switches, on the presence of localized H2O2 pools, and on the molecular recognition between redox switches and their partners.
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      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.039
      Issue No: Vol. 13 (2017)
       
  • HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like
           inflammation in murine nonalcoholic fatty liver disease

    • Authors: Varun Chandrashekaran; Ratanesh K. Seth; Diptadip Dattaroy; Firas Alhasson; Jacek Ziolenka; James Carson; Franklin G. Berger; Balaraman Kalyanaraman; Anna Mae Diehl; Saurabh Chatterjee
      Pages: 8 - 19
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Varun Chandrashekaran, Ratanesh K. Seth, Diptadip Dattaroy, Firas Alhasson, Jacek Ziolenka, James Carson, Franklin G. Berger, Balaraman Kalyanaraman, Anna Mae Diehl, Saurabh Chatterjee
      Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD)-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD) yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1) as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4) activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA), AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE) as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.

      PubDate: 2017-05-30T07:10:02Z
      DOI: 10.1016/j.redox.2017.05.005
      Issue No: Vol. 13 (2017)
       
  • Bi-directionally protective communication between neurons and astrocytes
           under ischemia

    • Authors: Xiao-Mei Wu; Christopher Qian; Yu-Fu Zhou; Yick-Chun Yan; Qian-Qian Luo; Wing-Ho Yung; Fa-Li Zhang; Li-Rong Jiang; Zhong Ming Qian; Ya Ke
      Pages: 20 - 31
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Xiao-Mei Wu, Christopher Qian, Yu-Fu Zhou, Yick-Chun Yan, Qian-Qian Luo, Wing-Ho Yung, Fa-Li Zhang, Li-Rong Jiang, Zhong Ming Qian, Ya Ke
      The extensive existing knowledge on bi-directional communication between astrocytes and neurons led us to hypothesize that not only ischemia-preconditioned (IP) astrocytes can protect neurons but also IP neurons protect astrocytes from lethal ischemic injury. Here, we demonstrated for the first time that neurons have a significant role in protecting astrocytes from ischemic injury. The cultured medium from IP neurons (IPcNCM) induced a remarkable reduction in LDH and an increase in cell viability in ischemic astrocytes in vitro. Selective neuronal loss by kainic acid injection induced a significant increase in apoptotic astrocyte numbers in the brain of ischemic rats in vivo. Furthermore, TUNEL analysis, DNA ladder assay, and the measurements of ROS, GSH, pro- and anti-apoptotic factors, anti-oxidant enzymes and signal molecules in vitro and/or in vivo demonstrated that IP neurons protect astrocytes by an EPO-mediated inhibition of pro-apoptotic signals, activation of anti-apoptotic proteins via the P13K/ERK/STAT5 pathways and activation of anti-oxidant proteins via up-regulation of anti-oxidant enzymes. We demonstrated the existence of astro-protection by IP neurons under ischemia and proposed that the bi-directionally protective communications between cells might be a common activity in the brain or peripheral organs under most if not all pathological conditions.

      PubDate: 2017-05-30T07:10:02Z
      DOI: 10.1016/j.redox.2017.05.010
      Issue No: Vol. 13 (2017)
       
  • Increased susceptibility of IDH2-deficient mice to dextran sodium
           sulfate-induced colitis

    • Authors: Hanvit Cha; Seoyoon Lee; Sung Hwan Kim; Hyunjin Kim; Dong-Seok Lee; Hyun-Shik Lee; Jin Hyup Lee; Jeen-Woo Park
      Pages: 32 - 38
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Hanvit Cha, Seoyoon Lee, Sung Hwan Kim, Hyunjin Kim, Dong-Seok Lee, Hyun-Shik Lee, Jin Hyup Lee, Jeen-Woo Park
      Inflammatory bowel disease (IBD) is a group of chronic, relapsing, immunological, inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease (CD). It has been reported that UC, which is studied using a dextran sodium sulfate (DSS)-induced colitis model, is associated with the production of reactive oxygen species (ROS) and the apoptosis of intestine epithelial cells (IEC). Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) has been reported as an essential enzyme in the mitochondrial antioxidant system via generation of NADPH. Therefore, we evaluated the role of IDH2 in DSS-induced colitis using IDH2-deficient (IDH2-/-) mice. We observed that DSS-induced colitis in IDH2-/- mice was more severe than that in wild-type IDH2+/+ mice. Our results also suggest that IDH2 deficiency exacerbates PUMA-mediated apoptosis, resulting from NF-κB activation regulated by histone deacetylase (HDAC) activity. In addition, DSS-induced colitis is ameliorated by an antioxidant N-acetylcysteine (NAC) through attenuation of oxidative stress, resulting from deficiency of the IDH2 gene. In conclusion, deficiency of IDH2 leads to increased mitochondrial ROS levels, which inhibits HDAC activity, and the activation of NF-κB via acetylation is enhanced by attenuated HDAC activity, which causes PUMA-mediated apoptosis of IEC in DSS-induced colitis. The present study supported the rationale for targeting IDH2 as an important cancer chemoprevention strategy, particularly in the prevention of colorectal cancer.
      Graphical abstract image

      PubDate: 2017-05-30T07:10:02Z
      DOI: 10.1016/j.redox.2017.05.009
      Issue No: Vol. 13 (2017)
       
  • IGF-II promotes neuroprotection and neuroplasticity recovery in a
           long-lasting model of oxidative damage induced by glucocorticoids

    • Authors: E. Martín-Montañez; C. Millon; F. Boraldi; F. Garcia-Guirado; C. Pedraza; E. Lara; L.J. Santin; J. Pavia; M. Garcia-Fernandez
      Pages: 69 - 81
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): E. Martín-Montañez, C. Millon, F. Boraldi, F. Garcia-Guirado, C. Pedraza, E. Lara, L.J. Santin, J. Pavia, M. Garcia-Fernandez
      Insulin-like growth factor-II (IGF-II) is a naturally occurring hormone that exerts neurotrophic and neuroprotective properties in a wide range of neurodegenerative diseases and ageing. Accumulating evidence suggests that the effects of IGF-II in the brain may be explained by its binding to the specific transmembrane receptor, IGFII/M6P receptor (IGF-IIR). However, relatively little is known regarding the role of IGF-II through IGF-IIR in neuroprotection. Here, using adult cortical neuronal cultures, we investigated whether IGF-II exhibits long-term antioxidant effects and neuroprotection at the synaptic level after oxidative damage induced by high and transient levels of corticosterone (CORT). Furthermore, the involvement of the IGF-IIR was also studied to elucidate its role in the neuroprotective actions of IGF-II. We found that neurons treated with IGF-II after CORT incubation showed reduced oxidative stress damage and recovered antioxidant status (normalized total antioxidant status, lipid hydroperoxides and NAD(P) H:quinone oxidoreductase activity). Similar results were obtained when mitochondria function was analysed (cytochrome c oxidase activity, mitochondrial membrane potential and subcellular mitochondrial distribution). Furthermore, neuronal impairment and degeneration were also assessed (synaptophysin and PSD-95 expression, presynaptic function and FluoroJade B® stain). IGF-II was also able to recover the long-lasting neuronal cell damage. Finally, the effects of IGF-II were not blocked by an IGF-IR antagonist, suggesting the involvement of IGF-IIR. Altogether these results suggest that, in or model, IGF-II through IGF-IIR is able to revert the oxidative damage induced by CORT. In accordance with the neuroprotective role of the IGF-II/IGF-IIR reported in our study, pharmacotherapy approaches targeting this pathway may be useful for the treatment of diseases associated with cognitive deficits (i.e., neurodegenerative disorders, depression, etc.).
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      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.012
      Issue No: Vol. 13 (2017)
       
  • Decreased neural precursor cell pool in NADPH oxidase 2-deficiency: From
           mouse brain to neural differentiation of patient derived iPSC

    • Authors: Zeynab Nayernia; Marilena Colaianna; Natalia Robledinos-Antón; Eveline Gutzwiller; Frédérique Sloan-Béna; Elisavet Stathaki; Yousef Hibaoui; Antonio Cuadrado; Jürgen Hescheler; Marie José Stasia; Tomo Saric; Vincent Jaquet; Karl-Heinz Krause
      Pages: 82 - 93
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Zeynab Nayernia, Marilena Colaianna, Natalia Robledinos-Antón, Eveline Gutzwiller, Frédérique Sloan-Béna, Elisavet Stathaki, Yousef Hibaoui, Antonio Cuadrado, Jürgen Hescheler, Marie José Stasia, Tomo Saric, Vincent Jaquet, Karl-Heinz Krause
      There is emerging evidence for the involvement of reactive oxygen species (ROS) in the regulation of stem cells and cellular differentiation. Absence of the ROS-generating NADPH oxidase NOX2 in chronic granulomatous disease (CGD) patients, predominantly manifests as immune deficiency, but has also been associated with decreased cognition. Here, we investigate the role of NOX enzymes in neuronal homeostasis in adult mouse brain and in neural cells derived from human induced pluripotent stem cells (iPSC). High levels of NOX2 were found in mouse adult neurogenic regions. In NOX2-deficient mice, neurogenic regions showed diminished redox modifications, as well as decrease in neuroprecursor numbers and in expression of genes involved in neural differentiation including NES, BDNF and OTX2. iPSC from healthy subjects and patients with CGD were used to study the role of NOX2 in human in vitro neuronal development. Expression of NOX2 was low in undifferentiated iPSC, upregulated upon neural induction, and disappeared during neuronal differentiation. In human neurospheres, NOX2 protein and ROS generation were polarized within the inner cell layer of rosette structures. NOX2 deficiency in CGD-iPSCs resulted in an abnormal neural induction in vitro, as revealed by a reduced expression of neuroprogenitor markers (NES, BDNF, OTX2, NRSF/REST), and a decreased generation of mature neurons. Vector-mediated NOX2 expression in NOX2-deficient iPSCs rescued neurogenesis. Taken together, our study provides novel evidence for a regulatory role of NOX2 during early stages of neurogenesis in mouse and human.

      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.04.026
      Issue No: Vol. 13 (2017)
       
  • European contribution to the study of ROS: A summary of the findings and
           prospects for the future from the COST action BM1203 (EU-ROS)

    • Authors: Javier Egea; Isabel Fabregat; Yves M. Frapart; Pietro Ghezzi; Agnes Görlach; Thomas Kietzmann; Kateryna Kubaichuk; Ulla G. Knaus; Manuela G. Lopez; Gloria Olaso-Gonzalez; Andreas Petry; Rainer Schulz; Jose Vina; Paul Winyard; Kahina Abbas; Opeyemi S. Ademowo; Catarina B. Afonso; Ioanna Andreadou; Haike Antelmann; Fernando Antunes; Mutay Aslan; Markus M. Bachschmid; Rui M. Barbosa; Vsevolod Belousov; Carsten Berndt; David Bernlohr; Esther Bertrán; Alberto Bindoli; Serge P. Bottari; Paula M. Brito; Guia Carrara; Ana I. Casas; Afroditi Chatzi; Niki Chondrogianni; Marcus Conrad; Marcus S. Cooke; João G. Costa; Antonio Cuadrado; Pham My-Chan Dang; Barbara De Smet; Bilge Debelec–Butuner; Irundika H.K. Dias; Joe Dan Dunn; Amanda J. Edson; Mariam El Assar; Jamel El-Benna; Péter Ferdinandy; Ana S. Fernandes; Kari E. Fladmark; Ulrich Förstermann; Rashid Giniatullin; Zoltán Giricz; Anikó Görbe; Helen Griffiths; Vaclav Hampl; Alina Hanf; Jan Herget; Pablo Hernansanz-Agustín; Melanie Hillion; Jingjing Huang; Serap Ilikay; Pidder Jansen-Dürr; Vincent Jaquet; Jaap A. Joles; Balaraman Kalyanaraman; Danylo Kaminskyy; Mahsa Karbaschi; Marina Kleanthous; Lars-Oliver Klotz; Bato Korac; Kemal Sami Korkmaz; Rafal Koziel; Damir Kračun; Karl-Heinz Krause; Vladimír Křen; Thomas Krieg; João Laranjinha; Antigone Lazou; Huige Li; Antonio Martínez-Ruiz; Reiko Matsui; Gethin J. McBean; Stuart P. Meredith; Joris Messens; Verónica Miguel; Yuliya Mikhed; Irina Milisav; Lidija Milković; Antonio Miranda-Vizuete; Miloš Mojović; María Monsalve; Pierre-Alexis Mouthuy; John Mulvey; Thomas Münzel; Vladimir Muzykantov; Isabel T.N. Nguyen; Matthias Oelze; Nuno G. Oliveira; Carlos M. Palmeira; Nikoletta Papaevgeniou; Aleksandra Pavićević; Brandán Pedre; Fabienne Peyrot; Marios Phylactides; Gratiela G. Pircalabioru; Andrew R. Pitt; Henrik E. Poulsen; Ignacio Prieto; Maria Pia Rigobello; Natalia Robledinos-Antón; Leocadio Rodríguez-Mañas; Anabela P. Rolo; Francis Rousset; Tatjana Ruskovska; Nuno Saraiva; Shlomo Sasson; Katrin Schröder; Khrystyna Semen; Tamara Seredenina; Anastasia Shakirzyanova; Geoffrey L. Smith; Thierry Soldati; Bebiana C. Sousa; Corinne M. Spickett; Ana Stancic; Marie José Stasia; Holger Steinbrenner; Višnja Stepanić; Sebastian Steven; Kostas Tokatlidis; Erkan Tuncay; Belma Turan; Fulvio Ursini; Jan Vacek; Olga Vajnerova; Kateřina Valentová; Frank Van Breusegem; Lokman Varisli; Elizabeth A. Veal; A. Suha Yalçın; Olha Yelisyeyeva; Neven Žarković; Martina Zatloukalová; Jacek Zielonka; Rhian M. Touyz; Andreas Papapetropoulos; Tilman Grune; Santiago Lamas; Harald H.H.W. Schmidt; Fabio Di Lisa; Andreas Daiber
      Pages: 94 - 162
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Javier Egea, Isabel Fabregat, Yves M. Frapart, Pietro Ghezzi, Agnes Görlach, Thomas Kietzmann, Kateryna Kubaichuk, Ulla G. Knaus, Manuela G. Lopez, Gloria Olaso-Gonzalez, Andreas Petry, Rainer Schulz, Jose Vina, Paul Winyard, Kahina Abbas, Opeyemi S. Ademowo, Catarina B. Afonso, Ioanna Andreadou, Haike Antelmann, Fernando Antunes, Mutay Aslan, Markus M. Bachschmid, Rui M. Barbosa, Vsevolod Belousov, Carsten Berndt, David Bernlohr, Esther Bertrán, Alberto Bindoli, Serge P. Bottari, Paula M. Brito, Guia Carrara, Ana I. Casas, Afroditi Chatzi, Niki Chondrogianni, Marcus Conrad, Marcus S. Cooke, João G. Costa, Antonio Cuadrado, Pham My-Chan Dang, Barbara De Smet, Bilge Debelec–Butuner, Irundika H.K. Dias, Joe Dan Dunn, Amanda J. Edson, Mariam El Assar, Jamel El-Benna, Péter Ferdinandy, Ana S. Fernandes, Kari E. Fladmark, Ulrich Förstermann, Rashid Giniatullin, Zoltán Giricz, Anikó Görbe, Helen Griffiths, Vaclav Hampl, Alina Hanf, Jan Herget, Pablo Hernansanz-Agustín, Melanie Hillion, Jingjing Huang, Serap Ilikay, Pidder Jansen-Dürr, Vincent Jaquet, Jaap A. Joles, Balaraman Kalyanaraman, Danylo Kaminskyy, Mahsa Karbaschi, Marina Kleanthous, Lars-Oliver Klotz, Bato Korac, Kemal Sami Korkmaz, Rafal Koziel, Damir Kračun, Karl-Heinz Krause, Vladimír Křen, Thomas Krieg, João Laranjinha, Antigone Lazou, Huige Li, Antonio Martínez-Ruiz, Reiko Matsui, Gethin J. McBean, Stuart P. Meredith, Joris Messens, Verónica Miguel, Yuliya Mikhed, Irina Milisav, Lidija Milković, Antonio Miranda-Vizuete, Miloš Mojović, María Monsalve, Pierre-Alexis Mouthuy, John Mulvey, Thomas Münzel, Vladimir Muzykantov, Isabel T.N. Nguyen, Matthias Oelze, Nuno G. Oliveira, Carlos M. Palmeira, Nikoletta Papaevgeniou, Aleksandra Pavićević, Brandán Pedre, Fabienne Peyrot, Marios Phylactides, Gratiela G. Pircalabioru, Andrew R. Pitt, Henrik E. Poulsen, Ignacio Prieto, Maria Pia Rigobello, Natalia Robledinos-Antón, Leocadio Rodríguez-Mañas, Anabela P. Rolo, Francis Rousset, Tatjana Ruskovska, Nuno Saraiva, Shlomo Sasson, Katrin Schröder, Khrystyna Semen, Tamara Seredenina, Anastasia Shakirzyanova, Geoffrey L. Smith, Thierry Soldati, Bebiana C. Sousa, Corinne M. Spickett, Ana Stancic, Marie José Stasia, Holger Steinbrenner, Višnja Stepanić, Sebastian Steven, Kostas Tokatlidis, Erkan Tuncay, Belma Turan, Fulvio Ursini, Jan Vacek, Olga Vajnerova, Kateřina Valentová, Frank Van Breusegem, Lokman Varisli, Elizabeth A. Veal, A. Suha Yalçın, Olha Yelisyeyeva, Neven Žarković, Martina Zatloukalová, Jacek Zielonka, Rhian M. Touyz, Andreas Papapetropoulos, Tilman Grune, Santiago Lamas, Harald H.H.W. Schmidt, Fabio Di Lisa, Andreas Daiber
      The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.
      Graphical abstract image

      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.007
      Issue No: Vol. 13 (2017)
       
  • Synthesis and characterization of a novel organic nitrate NDHP: Role of
           xanthine oxidoreductase-mediated nitric oxide formation

    • Authors: Zhengbing Zhuge; Luciano L. Paulo; Arghavan Jahandideh; Maria C.R. Brandão; Petrônio F. Athayde-Filho; Jon O. Lundberg; Valdir A. Braga; Mattias Carlström; Marcelo F. Montenegro
      Pages: 163 - 169
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Zhengbing Zhuge, Luciano L. Paulo, Arghavan Jahandideh, Maria C.R. Brandão, Petrônio F. Athayde-Filho, Jon O. Lundberg, Valdir A. Braga, Mattias Carlström, Marcelo F. Montenegro
      In this report, we describe the synthesis and characterization of 1,3-bis(hexyloxy)propan-2-yl nitrate (NDHP), a novel organic mono nitrate. Using purified xanthine oxidoreductase (XOR), chemiluminescence and electron paramagnetic resonance (EPR) spectroscopy, we found that XOR catalyzes nitric oxide (NO) generation from NDHP under anaerobic conditions, and that thiols are not involved or required in this process. Further mechanistic studies revealed that NDHP could be reduced to NO at both the FAD and the molybdenum sites of XOR, but that the FAD site required an unoccupied molybdenum site. Conversely, the molybdenum site was able to reduce NDHP independently of an active FAD site. Moreover, using isolated vessels in a myograph, we demonstrate that NDHP dilates pre-constricted mesenteric arteries from rats and mice. These effects were diminished when XOR was blocked using the selective inhibitor febuxostat. Finally, we demonstrate that NDHP, in contrast to glyceryl trinitrate (GTN), is not subject to development of tolerance in isolated mesenteric arteries.

      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.014
      Issue No: Vol. 13 (2017)
       
  • Mitochondria-meditated pathways of organ failure upon inflammation

    • Authors: Andrey V. Kozlov; Jack R. Lancaster; Andras T. Meszaros; Adelheid Weidinger
      Pages: 170 - 181
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Andrey V. Kozlov, Jack R. Lancaster, Andras T. Meszaros, Adelheid Weidinger
      Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca2+ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca++ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca2+ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.
      Graphical abstract image

      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.017
      Issue No: Vol. 13 (2017)
       
  • Decoding NADPH oxidase 4 expression in human tumors

    • Authors: Jennifer L. Meitzler; Hala R. Makhlouf; Smitha Antony; Yongzhong Wu; Donna Butcher; Guojian Jiang; Agnes Juhasz; Jiamo Lu; Iris Dahan; Pidder Jansen-Dürr; Haymo Pircher; Ajay M. Shah; Krishnendu Roy; James H. Doroshow
      Pages: 182 - 195
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Jennifer L. Meitzler, Hala R. Makhlouf, Smitha Antony, Yongzhong Wu, Donna Butcher, Guojian Jiang, Agnes Juhasz, Jiamo Lu, Iris Dahan, Pidder Jansen-Dürr, Haymo Pircher, Ajay M. Shah, Krishnendu Roy, James H. Doroshow
      NADPH oxidase 4 (NOX4) is a redox active, membrane-associated protein that contributes to genomic instability, redox signaling, and radiation sensitivity in human cancers based on its capacity to generate H2O2 constitutively. Most studies of NOX4 in malignancy have focused on the evaluation of a small number of tumor cell lines and not on human tumor specimens themselves; furthermore, these studies have often employed immunological tools that have not been well characterized. To determine the prevalence of NOX4 expression across a broad range of solid tumors, we developed a novel monoclonal antibody that recognizes a specific extracellular region of the human NOX4 protein, and that does not cross-react with any of the other six members of the NOX gene family. Evaluation of 20 sets of epithelial tumors revealed, for the first time, high levels of NOX4 expression in carcinomas of the head and neck (15/19 patients), esophagus (12/18 patients), bladder (10/19 patients), ovary (6/17 patients), and prostate (7/19 patients), as well as malignant melanoma (7/15 patients) when these tumors were compared to histologically-uninvolved specimens from the same organs. Detection of NOX4 protein upregulation by low levels of TGF-β1 demonstrated the sensitivity of this new probe; and immunofluorescence experiments found that high levels of endogenous NOX4 expression in ovarian cancer cells were only demonstrable associated with perinuclear membranes. These studies suggest that NOX4 expression is upregulated, compared to normal tissues, in a well-defined, and specific group of human carcinomas, and that its expression is localized on intracellular membranes in a fashion that could modulate oxidative DNA damage.
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      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.016
      Issue No: Vol. 13 (2017)
       
  • Mitochondrial aldehyde dehydrogenase-2 deficiency compromises therapeutic
           effect of ALDH bright cell on peripheral ischemia

    • Authors: Xiaolei Sun; Hong Zhu; Zhen Dong; Xiangwei Liu; Xin Ma; Shasha Han; Fei Lu; Peng Wang; Sanli Qian; Cong Wang; Cheng Shen; Xiaona Zhao; Yunzeng Zou; Junbo Ge; Aijun Sun
      Pages: 196 - 206
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Xiaolei Sun, Hong Zhu, Zhen Dong, Xiangwei Liu, Xin Ma, Shasha Han, Fei Lu, Peng Wang, Sanli Qian, Cong Wang, Cheng Shen, Xiaona Zhao, Yunzeng Zou, Junbo Ge, Aijun Sun
      The autologous ALDH bright (ALDHbr) cell therapy for ischemic injury is clinically safe and effective, while the underlying mechanism remains elusive. Here, we demonstrated that the glycolysis dominant metabolism of ALDHbr cells is permissive to restore blood flow in an ischemic hind limb model compared with bone marrow mononuclear cells (BMNCs). PCR array analysis showed overtly elevated Aldh2 expression of ALDHbr cells following hypoxic challenge. Notably, ALDHbr cells therapy induced blood flow recovery in this model was reduced in case of ALDH2 deficiency. Moreover, significantly reduced glycolysis flux and increased reactive oxygen species (ROS) levels were detected in ALDHbr cell from Aldh2-/- mice. Compromised effect on blood flow recovery was also noticed post transplanting the human ALDHbr cell from ALDH2 deficient patients (GA or AA genotypes) in this ischemic hindlimb mice model. Taken together, our findings illustrate the indispensable role of ALDH2 in maintaining glycolysis dominant metabolism of ALDHbr cell and advocate that patient's Aldh2 genotype is a prerequisite for the efficacy of ALDHbr cell therapy for peripheral ischemia.
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      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.018
      Issue No: Vol. 13 (2017)
       
  • The role of Nrf1 and Nrf2 in the regulation of glutathione and redox
           dynamics in the developing zebrafish embryo

    • Authors: Karilyn E. Sant; Jason M. Hansen; Larissa M. Williams; Nancy L. Tran; Jared V. Goldstone; John J. Stegeman; Mark E. Hahn; Alicia Timme-Laragy
      Pages: 207 - 218
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Karilyn E. Sant, Jason M. Hansen, Larissa M. Williams, Nancy L. Tran, Jared V. Goldstone, John J. Stegeman, Mark E. Hahn, Alicia Timme-Laragy
      Redox signaling is important for embryogenesis, guiding pathways that govern processes crucial for embryo patterning, including cell polarization, proliferation, and apoptosis. Exposure to pro-oxidants during this period can be deleterious, resulting in altered physiology, teratogenesis, later-life diseases, or lethality. We previously reported that the glutathione antioxidant defense system becomes increasingly robust, including a doubling of total glutathione and dynamic shifts in the glutathione redox potential at specific stages during embryonic development in the zebrafish, Danio rerio. However, the mechanisms underlying these changes are unclear, as is the effectiveness of the glutathione system in ameliorating oxidative insults to the embryo at different stages. Here, we examine how the glutathione system responds to the model pro-oxidants tert-butylhydroperoxide and tert-butylhydroquinone at different developmental stages, and the role of Nuclear factor erythroid 2-related factor (Nrf) proteins in regulating developmental glutathione redox status. Embryos became increasingly sensitive to pro-oxidants after 72h post-fertilization (hpf), after which the duration of the recovery period for the glutathione redox potential was increased. To determine whether the doubling of glutathione or the dynamic changes in glutathione redox potential are mediated by zebrafish paralogs of Nrf transcription factors, morpholino oligonucleotides were used to knock down translation of Nrf1 and Nrf2 (nrf1a, nrf1b, nrf2a, nrf2b). Knockdown of Nrf1a or Nrf1b perturbed glutathione redox state until 72 hpf. Knockdown of Nrf2 paralogs also perturbed glutathione redox state but did not significantly affect the response of glutathione to pro-oxidants. Nrf1b morphants had decreased gene expression of glutathione synthesis enzymes, while hsp70 increased in Nrf2b morphants. This work demonstrates that despite having a more robust glutathione system, embryos become more sensitive to oxidative stress later in development, and that neither Nrf1 nor Nrf2 alone appear to be essential for the response and recovery of glutathione to oxidative insults.

      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.023
      Issue No: Vol. 13 (2017)
       
  • RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via
           dual inhibition of autophagy and antioxidant systems

    • Authors: Daiha Shin; Eun Hye Kim; Jaewang Lee; Jong-Lyel Roh
      Pages: 219 - 227
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Daiha Shin, Eun Hye Kim, Jaewang Lee, Jong-Lyel Roh
      Reactivation of p53 and induction of tumor cell apoptosis (RITA) is a small molecule that blocks p53–MDM2 interaction, thereby reactivating p53 in tumors. RITA can induce exclusive apoptosis in cancer cells independently of the p53 pathway; however, the resistance of cancer cells remains a major drawback. Here, we found a novel resistance mechanism of RITA treatment and an effective combined treatment to overcome RITA resistance in head and neck cancer (HNC) cells. The effects of RITA and 3-methyladenine (3-MA) were tested in different HNC cell lines, including cisplatin-resistant and acquired RITA-resistant HNC cells. The effects of each drug alone and in combination were assessed by measuring cell viability, apoptosis, cell cycle, glutathione, reactive oxygen species, protein expression, genetic inhibition of p62 and Nrf2, and a mouse xenograft model of cisplatin-resistant HNC. RITA induced apoptosis of HNC cells at different levels without significantly inhibiting normal cell viability. Following RITA treatment, RITA-resistant HNC cells exhibited a sustained expression of other autophagy-related proteins, overexpressed p62, and displayed activation of the Keap1-Nrf2 antioxidant pathway. The autophagy inhibitor 3-MA sensitized resistant HNC cells to RITA treatment via the dual inhibition of molecules related to the autophagy and antioxidant systems. Silencing of the p62 gene augmented the combined effects. The effective antitumor activity of RITA plus 3-MA was also confirmed in vivo in mouse xenograft models transplanted with resistant HNC cells, showing increased oxidative stress and DNA damage. The results indicate that RITA plus 3-MA can help overcome RITA resistance in HNC cells. Condensed abstract This study revealed a novel RITA resistant mechanism associated with the sustained induction of autophagy, p62 overexpression, and Keap1-Nrf2 antioxidant system activation. The combined treatment of RITA with the autophagy inhibitor 3-methyladenine overcomes RITA resistance via dual inhibition of autophagy and antioxidant systems in vitro and in vivo.

      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.025
      Issue No: Vol. 13 (2017)
       
  • Redox signaling during hypoxia in mammalian cells

    • Authors: Kimberly A. Smith; Gregory B. Waypa; Paul T. Schumacker
      Pages: 228 - 234
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Kimberly A. Smith, Gregory B. Waypa, Paul T. Schumacker
      Hypoxia triggers a wide range of protective responses in mammalian cells, which are mediated through transcriptional and post-translational mechanisms. Redox signaling in cells by reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) occurs through the reversible oxidation of cysteine thiol groups, resulting in structural modifications that can change protein function profoundly. Mitochondria are an important source of ROS generation, and studies reveal that superoxide generation by the electron transport chain increases during hypoxia. Other sources of ROS, such as the NAD(P)H oxidases, may also generate oxidant signals in hypoxia. This review considers the growing body of work indicating that increased ROS signals during hypoxia are responsible for regulating the activation of protective mechanisms in diverse cell types.
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      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.020
      Issue No: Vol. 13 (2017)
       
  • Non-linear actions of physiological agents: Finite disarrangements elicit
           fitness benefits

    • Authors: Filip Sedlic; Zdenko Kovac
      Pages: 235 - 243
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Filip Sedlic, Zdenko Kovac
      Finite disarrangements of important (vital) physiological agents and nutrients can induce plethora of beneficial effects, exceeding mere attenuation of the specific stress. Such response to disrupted homeostasis appears to be universally conserved among species. The underlying mechanism of improved fitness and longevity, when physiological agents act outside their normal range is similar to hormesis, a phenomenon whereby toxins elicit beneficial effects at low doses. Due to similarity with such non-linear response to toxins described with J-shaped curve, we have coined a new term “mirror J-shaped curves” for non-linear response to finite disarrangement of physiological agents. Examples from the clinical trials and basic research are provided, along with the unifying mechanisms that tie classical non-linear response to toxins with the non-linear response to physiological agents (glucose, oxygen, osmolarity, thermal energy, calcium, body mass, calorie intake and exercise). Reactive oxygen species and cytosolic calcium seem to be common triggers of signaling pathways that result in these beneficial effects. Awareness of such phenomena and exploring underlying mechanisms can help physicians in their everyday practice. It can also benefit researchers when designing studies and interpreting growing number of scientific data showing non-linear responses to physiological agents.

      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.008
      Issue No: Vol. 13 (2017)
       
  • Pharmacologic concentrations of linezolid modify oxidative phosphorylation
           function and adipocyte secretome

    • Authors: Laura Llobet; M. Pilar Bayona-Bafaluy; David Pacheu-Grau; Elena Torres-Pérez; José M. Arbones-Mainar; M. Ángeles Navarro; Covadonga Gómez-Díaz; Julio Montoya; Ester López-Gallardo; Eduardo Ruiz-Pesini
      Pages: 244 - 254
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Laura Llobet, M. Pilar Bayona-Bafaluy, David Pacheu-Grau, Elena Torres-Pérez, José M. Arbones-Mainar, M. Ángeles Navarro, Covadonga Gómez-Díaz, Julio Montoya, Ester López-Gallardo, Eduardo Ruiz-Pesini
      The oxidative phosphorylation system is important for adipocyte differentiation. Therefore, xenobiotics inhibitors of the oxidative phosphorylation system could affect adipocyte differentiation and adipokine secretion. As adipokines impact the overall health status, these xenobiotics may have wide effects on human health. Some of these xenobiotics are widely used therapeutic drugs, such as ribosomal antibiotics. Because of its similarity to the bacterial one, mitochondrial translation system is an off-target for these compounds. To study the influence of the ribosomal antibiotic linezolid on adipokine production, we analyzed its effects on adipocyte secretome. Linezolid, at therapeutic concentrations, modifies the levels of apolipoprotein E and several adipokines and proteins related with the extracellular matrix. This antibiotic also alters the global methylation status of human adipose tissue-derived stem cells and, therefore, its effects are not limited to the exposure period. Besides their consequences on other tissues, xenobiotics acting on the adipocyte oxidative phosphorylation system alter apolipoprotein E and adipokine production, secondarily contributing to their systemic effects.
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      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.026
      Issue No: Vol. 13 (2017)
       
  • Altered bioenergetics and enhanced resistance to oxidative stress in human
           retinal pigment epithelial cells from donors with age-related macular
           degeneration

    • Authors: Deborah A. Ferrington; Mara C. Ebeling; Rebecca J. Kapphahn; Marcia R. Terluk; Cody R. Fisher; Jorge R. Polanco; Heidi Roehrich; Michaela M. Leary; Zhaohui Geng; James R. Dutton; Sandra R. Montezuma
      Pages: 255 - 265
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Deborah A. Ferrington, Mara C. Ebeling, Rebecca J. Kapphahn, Marcia R. Terluk, Cody R. Fisher, Jorge R. Polanco, Heidi Roehrich, Michaela M. Leary, Zhaohui Geng, James R. Dutton, Sandra R. Montezuma
      Age-related macular degeneration (AMD) is the leading cause of blindness among older adults. It has been suggested that mitochondrial defects in the retinal pigment epithelium (RPE) underlies AMD pathology. To test this idea, we developed primary cultures of RPE to ask whether RPE from donors with AMD differ in their metabolic profile compared with healthy age-matched donors. Analysis of gene expression, protein content, and RPE function showed that these cultured cells replicated many of the cardinal features of RPE in vivo. Using the Seahorse Extracellular Flux Analyzer to measure bioenergetics, we observed RPE from donors with AMD exhibited reduced mitochondrial and glycolytic function compared with healthy donors. RPE from AMD donors were also more resistant to oxidative inactivation of these two energy-producing pathways and were less susceptible to oxidation-induced cell death compared with cells from healthy donors. Investigation of the potential mechanism responsible for differences in bioenergetics and resistance to oxidative stress showed RPE from AMD donors had increased PGC1α protein as well as differential expression of multiple genes in response to an oxidative challenge. Based on our data, we propose that cultured RPE from donors phenotyped for the presence or absence of AMD provides an excellent model system for studying “AMD in a dish”. Our results are consistent with the ideas that (i) a bioenergetics crisis in the RPE contributes to AMD pathology, and (ii) the diseased environment in vivo causes changes in the cellular profile that are retained in vitro.
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      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.015
      Issue No: Vol. 13 (2017)
       
  • HPW-RX40 prevents human platelet activation by attenuating cell surface
           protein disulfide isomerases

    • Authors: Po-Hsiung Kung; Pei-Wen Hsieh; Ying-Ting Lin; Jia-Hau Lee; I-Hua Chen; Chin-Chung Wu
      Pages: 266 - 277
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Po-Hsiung Kung, Pei-Wen Hsieh, Ying-Ting Lin, Jia-Hau Lee, I-Hua Chen, Chin-Chung Wu
      Protein disulfide isomerase (PDI) present at platelet surfaces has been considered to play an important role in the conformational change and activation of the integrin glycoprotein IIb/IIIa (GPIIb/IIIa) and thus enhances platelet aggregation. Growing evidences indicated that platelet surface PDI may serve as a potential target for developing of a new class of antithrombotic agents. In the present study, we investigated the effects of HPW-RX40, a chemical derivative of β-nitrostyrene, on platelet activation and PDI activity. HPW-RX40 inhibited platelet aggregation, GPIIb/IIIa activation, and P-selectin expression in human platelets. Moreover, HPW-RX40 reduced thrombus formation in human whole blood under flow conditions, and protects mice from FeCl3-induced carotid artery occlusion. HPW-RX40 inhibited the activity of recombinant PDI family proteins (PDI, ERp57, and ERp5) as well as suppressed cell surface PDI activity of platelets in a reversible manner. Exogenous addition of PDI attenuated the inhibitory effect of HPW-RX40 on GPIIb/IIIa activation. Structure-based molecular docking simulations indicated that HPW-RX40 binds to the active site of PDI by forming hydrogen bonds. In addition, HPW-RX40 neither affected the cell viability nor induced endoplasmic reticulum stress in human cancer A549 and MDA-MB-231 cells. Taken together, our results suggest that HPW-RX40 is a reversible and non-cytotoxic PDI inhibitor with antiplatelet effects, and it may have a potential for development of novel antithrombotic agents.
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      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.019
      Issue No: Vol. 13 (2017)
       
  • Impaired cross-talk between the thioredoxin and glutathione systems is
           related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury

    • Authors: Vasco Branco; Lucia Coppo; Susana Solá; Jun Lu; Cecília M.P. Rodrigues; Arne Holmgren; Cristina Carvalho
      Pages: 278 - 287
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Vasco Branco, Lucia Coppo, Susana Solá, Jun Lu, Cecília M.P. Rodrigues, Arne Holmgren, Cristina Carvalho
      Mercury (Hg) compounds target both cysteine (Cys) and selenocysteine (Sec) residues in peptides and proteins. Thus, the components of the two major cellular antioxidant systems – glutathione (GSH) and thioredoxin (Trx) systems – are likely targets for mercurials. Hg exposure results in GSH depletion and Trx and thioredoxin reductase (TrxR) are prime targets for mercury. These systems have a wide-range of common functions and interaction between their components has been reported. However, toxic effects over both systems are normally treated as isolated events. To study how the interaction between the glutathione and thioredoxin systems is affected by Hg, human neuroblastoma (SH-SY5Y) cells were exposed to 1 and 5μM of inorganic mercury (Hg2+), methylmercury (MeHg) or ethylmercury (EtHg) and examined for TrxR, GSH and Grx levels and activities, as well as for Trx redox state. Phosphorylation of apoptosis signalling kinase 1 (ASK1), caspase-3 activity and the number of apoptotic cells were evaluated to investigate the induction of Trx-mediated apoptotic cell death. Additionally, primary cerebellar neurons from mice depleted of mitochondrial Grx2 (mGrx2D) were used to examine the link between Grx activity and Trx function. Results showed that Trx was affected at higher exposure levels than TrxR, especially for EtHg. GSH levels were only significantly affected by exposure to a high concentration of EtHg. Depletion of GSH with buthionine sulfoximine (BSO) severely increased Trx oxidation by Hg. Notably, EtHg-induced oxidation of Trx was significantly enhanced in primary neurons of mGrx2D mice. Our results suggest that GSH/Grx acts as backups for TrxR in neuronal cells to maintain Trx turnover during Hg exposure, thus linking different mechanisms of molecular and cellular toxicity. Finally, Trx oxidation by Hg compounds was associated to apoptotic hallmarks, including increased ASK-1 phosphorylation, caspase-3 activation and increased number of apoptotic cells.
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      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.024
      Issue No: Vol. 13 (2017)
       
  • Nox2 contributes to hyperinsulinemia-induced redox imbalance and impaired
           vascular function

    • Authors: Abeer M. Mahmoud; Mohamed M. Ali; Edwin R. Miranda; Jacob T. Mey; Brian K. Blackburn; Jacob M. Haus; Shane A. Phillips
      Pages: 288 - 300
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Abeer M. Mahmoud, Mohamed M. Ali, Edwin R. Miranda, Jacob T. Mey, Brian K. Blackburn, Jacob M. Haus, Shane A. Phillips
      Insulin resistance promotes vascular endothelial dysfunction and subsequent development of cardiovascular disease. Previously we found that skeletal muscle arteriolar flow-induced dilation (FID) was reduced following a hyperinsulinemic clamp in healthy adults. Therefore, we hypothesized that hyperinsulinemia, a hallmark of insulin resistance, contributes to microvascular endothelial cell dysfunction via inducing oxidative stress that is mediated by NADPH oxidase (Nox) system. We examined the effect of insulin, at levels that are comparable with human hyperinsulinemia on 1) FID of isolated arterioles from human skeletal muscle tissue in the presence and absence of Nox inhibitors and 2) human adipose microvascular endothelial cell (HAMECs) expression of nitric oxide (NO), endothelial NO synthase (eNOS), and Nox-mediated oxidative stress. In six lean healthy participants (mean age 25.5±1.6 y, BMI 21.8±0.9), reactive oxygen species (ROS) were increased while NO and arteriolar FID were reduced following 60min of ex vivo insulin incubation. These changes were reversed after co-incubation with the Nox isoform 2 (Nox2) inhibitor, VAS2870. In HAMECs, insulin-induced time-dependent increases in Nox2 expression and P47phox phosphorylation were echoed by elevations of superoxide production. In contrast, phosphorylation of eNOS and expression of superoxide dismutase (SOD2 and SOD3) isoforms showed a biphasic response with an increased expression at earlier time points followed by a steep reduction phase. Insulin induced eNOS uncoupling that was synchronized with a drop of NO and a surge of ROS production. These effects were reversed by Tempol (SOD mimetic), Tetrahydrobiopterin (BH4; eNOS cofactor), and VAS2870. Finally, insulin induced nitrotyrosine formation which was reversed by inhibiting NO or superoxide generation. In conclusions, hyperinsulinemia may reduce FID via inducing Nox2-mediated superoxide production in microvascular endothelial cells which reduce the availability of NO and enhances peroxynitrite formation. Therefore, the Nox2 pathway should be considered as a target for the prevention of oxidative stress-associated endothelial dysfunction during hyperinsulinemia.
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      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.06.001
      Issue No: Vol. 13 (2017)
       
  • SIRT1 inhibition causes oxidative stress and inflammation in patients with
           coronary artery disease

    • Authors: Shih-Hung Chan; Ching-Hsia Hung; Jhih-Yuan Shih; Pei-Ming Chu; Yung-Hsin Cheng; Huei-Chen Lin; Kun-Ling Tsai
      Pages: 301 - 309
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Shih-Hung Chan, Ching-Hsia Hung, Jhih-Yuan Shih, Pei-Ming Chu, Yung-Hsin Cheng, Huei-Chen Lin, Kun-Ling Tsai
      Coronary artery disease (CAD) is the primary critical cardiovascular event. Endothelial cell and monocyte dysfunction with subsequent extravagant inflammation are the main causes of vessel damage in CAD. Thus, strategies that repress cell death and manage unsuitable pro-inflammatory responses in CAD are potential therapeutic strategies for improving the clinical prognosis of patients with CAD. SIRT1 (Sirtuin 1) plays an important role in regulating cellular physiological processes. SIRT1 is also thought to protect the cardiovascular system by means of its antioxidant, anti-inflammation and anti-apoptosis activities. In the present study, we found that the SIRT1 expression levels were repressed and the acetylated p53 expression levels were enhanced in the monocytes of patients with CAD. LOX-1/oxidative stress was also up-regulated in the monocytes of patients with CAD, thereby increasing pro-apoptotic events and pro-inflammatory responses. We also demonstrated that monocytes from CAD patients caused endothelial adhesion molecule activation and the adherence of monocytes and endothelial cells. Our findings may explain why CAD patients remain at an increased risk of long-term recurrent ischemic events and provide new knowledge regarding the management of clinical CAD patients.

      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.027
      Issue No: Vol. 13 (2017)
       
  • Cysteine residues 244 and 458–459 within the catalytic subunit of
           Na,K-ATPase control the enzyme's hydrolytic and signaling function under
           hypoxic conditions

    • Authors: Irina Yu. Petrushanko; Vladimir A. Mitkevich; Valentina A. Lakunina; Anastasia A. Anashkina; Pavel V. Spirin; Peter M. Rubtsov; Vladimir S. Prassolov; Nikolay B. Bogdanov; Pascal Hänggi; William Fuller; Alexander A. Makarov; Anna Bogdanova
      Pages: 310 - 319
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Irina Yu. Petrushanko, Vladimir A. Mitkevich, Valentina A. Lakunina, Anastasia A. Anashkina, Pavel V. Spirin, Peter M. Rubtsov, Vladimir S. Prassolov, Nikolay B. Bogdanov, Pascal Hänggi, William Fuller, Alexander A. Makarov, Anna Bogdanova
      Our previous findings suggested that reversible thiol modifications of cysteine residues within the actuator (AD) and nucleotide binding domain (NBD) of the Na,K-ATPase may represent a powerful regulatory mechanism conveying redox- and oxygen-sensitivity of this multifunctional enzyme. S-glutathionylation of Cys244 in the AD and Cys 454-458-459 in the NBD inhibited the enzyme and protected cysteines’ thiol groups from irreversible oxidation under hypoxic conditions. In this study mutagenesis approach was used to assess the role these cysteines play in regulation of the Na,K-ATPase hydrolytic and signaling functions. Several constructs of mouse α1 subunit of the Na,K-ATPase were produced in which Cys244, Cys 454-458-459 or Cys 244-454-458-459 were replaced by alanine. These constructs were expressed in human HEK293 cells. Non-transfected cells and those expressing murine α1 subunit were exposed to hypoxia or treated with oxidized glutathione (GSSG). Both conditions induced inhibition of the wild type Na,K-ATPase. Enzymes containing mutated mouse α1 lacking Cys244 or all four cysteines (Cys 244-454-458-459) were insensitive to hypoxia. Inhibitory effect of GSSG was observed for wild type murine Na,K-ATPase, but was less pronounced in Cys454-458-459Ala mutant and completely absent in the Cys244Ala and Cys 244-454-458-459Ala mutants. In cells, expressing wild type enzyme, ouabain induced activation of Src and Erk kinases under normoxic conditions, whereas under hypoxic conditions this effect was inversed. Cys454-458-459Ala substitution abolished Src kinase activation in response to ouabain treatment, uncoupled Src from Erk signaling, and interfered with O2-sensitivity of Na,K-ATPase signaling function. Moreover, modeling predicted that S-glutathionylation of Cys 458 and 459 should prevent inhibitory binding of Src to NBD. Our data indicate for the first time that cysteine residues within the AD and NBD influence hydrolytic as well as receptor function of the Na,K-ATPase and alter responses of the enzyme to hypoxia or upon treatment with cardiotonic steroids.
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      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.021
      Issue No: Vol. 13 (2017)
       
  • Dietary nitrate attenuates renal ischemia-reperfusion injuries by
           modulation of immune responses and reduction of oxidative stress

    • Authors: Ting Yang; Xing-Mei Zhang; Laura Tarnawski; Maria Peleli; Zhengbing Zhuge; Niccolo Terrando; Robert A. Harris; Peder S. Olofsson; Erik Larsson; A. Erik G. Persson; Jon O. Lundberg; Eddie Weitzberg; Mattias Carlstrom
      Pages: 320 - 330
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Ting Yang, Xing-Mei Zhang, Laura Tarnawski, Maria Peleli, Zhengbing Zhuge, Niccolo Terrando, Robert A. Harris, Peder S. Olofsson, Erik Larsson, A. Erik G. Persson, Jon O. Lundberg, Eddie Weitzberg, Mattias Carlstrom
      Ischemia-reperfusion (IR) injury involves complex pathological processes in which reduction of nitric oxide (NO) bioavailability is suggested as a key factor. Inorganic nitrate can form NO in vivo via NO synthase-independent pathways and may thus provide beneficial effects during IR. Herein we evaluated the effects of dietary nitrate supplementation in a renal IR model. Male mice (C57BL/6J) were fed nitrate-supplemented chow (1.0mmol/kg/day) or standard chow for two weeks prior to 30min ischemia and during the reperfusion period. Unilateral renal IR caused profound tubular and glomerular damage in the ischemic kidney. Renal function, assessed by plasma creatinine levels, glomerular filtration rate and renal plasma flow, was also impaired after IR. All these pathologies were significantly improved by nitrate. Mechanistically, nitrate treatment reduced renal superoxide generation, pro-inflammatory cytokines (IL-1β, IL-6 and IL-12 p70) and macrophage infiltration in the kidney. Moreover, nitrate reduced mRNA expression of pro-inflammatory cytokines and chemo attractors, while increasing anti-inflammatory cytokines in the injured kidney. In another cohort of mice, two weeks of nitrate supplementation lowered superoxide generation and IL-6 expression in bone marrow-derived macrophages. Our study demonstrates protective effect of dietary nitrate in renal IR injury that may be mediated via modulation of oxidative stress and inflammatory responses. These novel findings suggest that nitrate supplementation deserve further exploration as a potential treatment in patients at high risk of renal IR injury.
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      PubDate: 2017-06-18T17:06:38Z
      DOI: 10.1016/j.redox.2017.06.002
      Issue No: Vol. 13 (2017)
       
  • Maintenance of redox homeostasis by hypoxia-inducible factors

    • Authors: Debangshu Samanta; Gregg L. Semenza
      Pages: 331 - 335
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Debangshu Samanta, Gregg L. Semenza
      Oxidative phosphorylation enables cells to generate the large amounts of ATP required for development and maintenance of multicellular organisms. However, under conditions of reduced O2 availability, electron transport becomes less efficient, leading to increased generation of superoxide anions. Hypoxia-inducible factors switch cells from oxidative to glycolytic metabolism, to reduce mitochondrial superoxide generation, and increase the synthesis of NADPH and glutathione, in order to maintain redox homeostasis under hypoxic conditions.

      PubDate: 2017-06-18T17:06:38Z
      DOI: 10.1016/j.redox.2017.05.022
      Issue No: Vol. 13 (2017)
       
  • Endothelial NLRP3 inflammasome activation and arterial neointima formation
           associated with acid sphingomyelinase during hypercholesterolemia

    • Authors: Saisudha Koka; Min Xia; Yang Chen; Owais M. Bhat; Xinxu Yuan; Krishna M. Boini; Pin-Lan Li
      Pages: 336 - 344
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Saisudha Koka, Min Xia, Yang Chen, Owais M. Bhat, Xinxu Yuan, Krishna M. Boini, Pin-Lan Li
      The NLRP3 inflammasome has been reported to be activated by atherogenic factors, whereby endothelial injury and consequent atherosclerotic lesions are triggered in the arterial wall. However, the mechanisms activating and regulating NLRP3 inflammasomes remain poorly understood. The present study tested whether acid sphingomyelinase (ASM) and ceramide associated membrane raft (MR) signaling platforms contribute to the activation of NLRP3 inflammasomes and atherosclerotic lesions during hypercholesterolemia. We found that 7-ketocholesterol (7-Keto) or cholesterol crystal (ChC) markedly increased the formation and activation of NLRP3 inflammasomes in mouse carotid arterial endothelial cells (CAECs), as shown by increased colocalization of NLRP3 with ASC or caspase-1, enhanced caspase-1 activity and elevated IL-1β levels, which were markedly attenuated by mouse Asm siRNA, ASM inhibitor- amitriptyline, and deletion of mouse Asm gene. In CAECs with NLRP3 inflammasome formation, membrane raft (MR) clustering with NADPH oxidase subunits was found remarkably increased as shown by CTXB (MR marker) and gp91 phox aggregation indicating the formation of MR redox signaling platforms. This MR clustering was blocked by MR disruptor (MCD), ROS scavenger (Tempol) and TXNIP inhibitor (verapamil), accompanied by attenuation of 7-Keto or ChC-induced increase in caspase-1 activity. In animal experiments, Western diet fed mice with partially ligated left carotid artery (PLCA) were found to have significantly increased neointimal formation, which was associated with increased NLRP3 inflammasome formation and IL-1β production in the intima of Asm +/+ mice but not in Asm -/- mice. These results suggest that Asm gene and ceramide associated MR clustering are essential to endothelial inflammasome activation and dysfunction in the carotid arteries, ultimately determining the extent of atherosclerotic lesions.

      PubDate: 2017-06-23T17:31:41Z
      DOI: 10.1016/j.redox.2017.06.004
      Issue No: Vol. 13 (2017)
       
  • Dexibuprofen prevents neurodegeneration and cognitive decline in
           APPswe/PS1dE9 through multiple signaling pathways

    • Authors: Miren Ettcheto; Elena Sánchez-López; Laura Pons; Oriol Busquets; Jordi Olloquequi; Carlos Beas-Zarate; Merce Pallas; Maria Luisa García; Carme Auladell; Jaume Folch; Antoni Camins
      Pages: 345 - 352
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Miren Ettcheto, Elena Sánchez-López, Laura Pons, Oriol Busquets, Jordi Olloquequi, Carlos Beas-Zarate, Merce Pallas, Maria Luisa García, Carme Auladell, Jaume Folch, Antoni Camins
      The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks.
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      PubDate: 2017-06-23T17:31:41Z
      DOI: 10.1016/j.redox.2017.06.003
      Issue No: Vol. 13 (2017)
       
  • Offsetting the impact of smoking and e-cigarette vaping on the
           cerebrovascular system and stroke injury: Is Metformin a viable
           countermeasure'

    • Authors: Mohammad A. Kaisar; Heidi Villalba; Shikha Prasad; Taylor Liles; Ali Ehsan Sifat; Ravi K. Sajja; Thomas J. Abbruscato; Luca Cucullo
      Pages: 353 - 362
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Mohammad A. Kaisar, Heidi Villalba, Shikha Prasad, Taylor Liles, Ali Ehsan Sifat, Ravi K. Sajja, Thomas J. Abbruscato, Luca Cucullo
      Recently published in vitro and in vivo findings strongly suggest that BBB impairment and increased risk for stroke by tobacco smoke (TS) closely resemble that of type-2 diabetes (2DM) and develop largely in response to common key modulators such oxidative stress (OS), inflammation and alterations of the endogenous antioxidative response system (ARE) regulated by the nuclear factor erythroid 2-related factor (Nrf2). Preclinical studies have also shown that nicotine (the principal e-liquid's ingredient used in e-cigarettes) can also cause OS, exacerbation of cerebral ischemia and secondary brain injury. Herein we provide evidence that likewise to TS, chronic e-Cigarette (e-Cig) vaping can be prodromal to the loss of blood-brain barrier (BBB) integrity and vascular inflammation as well as act as a promoting factor for the onset of stroke and worsening of post-ischemic brain injury. In addition, recent reports have shown that Metformin (MF) treatment before and after ischemic injury reduces stress and inhibits inflammatory responses. Recent published data by our group revealead that MF promotes the activation of counteractive mechanisms mediated by the activation of Nrf2 which drastically reduce TS toxicity at the brain and cerebrovascular levels and protect BBB integrity. In this study we provide additional in vivo evidence showing that MF can effectively reduce the oxidative and inflammatory risk for stroke and attenuate post-ischemic brain injury promoted by TS and e-Cig vaping. Our data also suggest that MF administration could be extended as prophylactic care during the time window required for the renormalization of the risk levels of stroke following smoking cessation thus further studies in that direction are warrated.
      Graphical abstract image

      PubDate: 2017-06-23T17:31:41Z
      DOI: 10.1016/j.redox.2017.06.006
      Issue No: Vol. 13 (2017)
       
  • Urinary albumin and 8-oxo-7,8-dihydroguanosine as markers of mortality and
           cardiovascular disease during 19 years after diagnosis of type 2 diabetes
           – A comparative study of two markers to identify high risk patients

    • Authors: Kasper Broedbaek; Rasmus Køster-Rasmussen; Volkert Siersma; Frederik Persson; Henrik E. Poulsen; Niels de Fine Olivarius
      Pages: 363 - 369
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Kasper Broedbaek, Rasmus Køster-Rasmussen, Volkert Siersma, Frederik Persson, Henrik E. Poulsen, Niels de Fine Olivarius
      Urinary albumin is an important biomarker used to identify high risk patients with diabetes, but there is a need for new biomarkers that alone or in combination with urinary albumin could give an even better prediction of clinical patient outcomes. One promising biomarker is 8-oxo-7,8-dihydroguanosine (8-oxoGuo) that represents intracellular oxidative stress. We investigated the ability of microalbuminuria (MA) and urinary 8-oxoGuo, alone and in combination, to predict mortality and cardiovascular disease (CVD) in patients with type 2 diabetes. We used data from 1381 newly diagnosed diabetes patients, and urinary albumin and 8-oxoGuo were assessed in morning urine collected at the time of diabetes diagnosis and at a follow-up visit 6 years later. Associations between the urinary markers and mortality and CVD were assessed in Cox proportional hazards regression models. Test performance was assessed using sensitivity, specificity, positive predictive value and negative predictive value for 10-year mortality and 10-year incidence of CVD. Both 8-oxoGuo and urinary albumin were statistically significantly associated with all-cause mortality at diagnosis as well as at 6-year follow-up. At diagnosis only urinary albumin was associated with CVD. In contrast, only 8-oxoGuo was associated with CVD at 6-year follow-up. When investigating test performance, we found that by combining information from MA and 8-oxoGuo the ability to correctly identify patients at risk could be improved. The findings suggest that measurement of urinary 8-oxoGuo provides additional information about risk to that obtained from urinary albumin, and that the combined use of 8-oxoGuo and urinary albumin could be useful for a better identification of patients at risk of CVD and death.

      PubDate: 2017-07-04T20:32:43Z
      DOI: 10.1016/j.redox.2017.06.005
      Issue No: Vol. 13 (2017)
       
  • The SGLT2 inhibitor empagliflozin improves the primary diabetic
           complications in ZDF rats

    • Authors: Sebastian Steven; Matthias Oelze; Alina Hanf; Swenja Kröller-Schön; Fatemeh Kashani; Siyer Roohani; Philipp Welschof; Maximilian Kopp; Ute Gödtel-Armbrust; Ning Xia; Huige Li; Eberhard Schulz; Karl J. Lackner; Leszek Wojnowski; Serge P. Bottari; Philip Wenzel; Eric Mayoux; Thomas Münzel; Andreas Daiber
      Pages: 370 - 385
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Sebastian Steven, Matthias Oelze, Alina Hanf, Swenja Kröller-Schön, Fatemeh Kashani, Siyer Roohani, Philipp Welschof, Maximilian Kopp, Ute Gödtel-Armbrust, Ning Xia, Huige Li, Eberhard Schulz, Karl J. Lackner, Leszek Wojnowski, Serge P. Bottari, Philip Wenzel, Eric Mayoux, Thomas Münzel, Andreas Daiber
      Hyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance®), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF‐Leprfa/fa and 16 ZDF-Lepr+/+ controls). Empagliflozin (10 and 30mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial).
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      PubDate: 2017-07-04T20:32:43Z
      DOI: 10.1016/j.redox.2017.06.009
      Issue No: Vol. 13 (2017)
       
  • Transcription factor NRF2 controls the fate of neural stem cells in the
           subgranular zone of the hippocampus

    • Authors: Natalia Robledinos-Antón; Ana I. Rojo; Elisabete Ferreiro; Ángel Núñez; Karl-Heinz Krause; Vincent Jaquet; Antonio Cuadrado
      Pages: 393 - 401
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Natalia Robledinos-Antón, Ana I. Rojo, Elisabete Ferreiro, Ángel Núñez, Karl-Heinz Krause, Vincent Jaquet, Antonio Cuadrado
      Neural stem/progenitor cells (NSPCs) located at the subgranular zone (SGZ) of the hippocampus participate in the maintenance of synaptic networks that ensure cognitive functions during life. Although it is known that this neurogenic niche losses activity with oxidative stress and ageing, the molecular events involved in its regulation are largely unknown. Here, we studied the role of transcription factor Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) in the control of NSPCs destinies in the SGZ. We first describe that NRF2-knockout (Nrf2 -/-) mice exhibit impaired long term potentiation, a function that requires integrity of the SGZ, therefore suggesting a cognitive deficit that might be linked to hippocampal neurogenesis. Then, we found a reduction in NSCs from birth to adulthood that was exacerbated in Nrf2 -/- vs. Nrf2 +/+ mice. The clonogenic and proliferative capacity of SGZ-derived NSPCs from newborn and 3-month-old Nrf2 -/- mice was severely reduced as determined in neurosphere cultures. Nrf2-deficiency also impaired neuronal differentiation both the SGZ, and in neurosphere differentiation assays, leading to an abnormal production of astrocytes and oligodendrocytes vs. neurons. Rescue of Nrf2 -/- NSPCs by ectopic expression of NRF2 attenuated the alterations in clonogenic, proliferative and differentiating capacity of hippocampal NSPCs. In turn, knockdown of the NRF2 gene in wild type NSPCs reproduced the data obtained with Nrf2 -/- NSPCs. Our findings demonstrate the importance of NRF2 in the maintenance of proper proliferation and differentiation rates of hippocampal NSPCs and suggest that interventions to up-regulate NRF2 might provide a mechanism to preserve the neurogenic functionality of the hippocampus.
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      PubDate: 2017-07-04T20:32:43Z
      DOI: 10.1016/j.redox.2017.06.010
      Issue No: Vol. 13 (2017)
       
  • Graphical review: The redox dark side of e-cigarettes; exposure to
           oxidants and public health concerns

    • Authors: Hua Cai; Chen Wang
      Pages: 402 - 406
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Hua Cai, Chen Wang
      Since the initial marketing in 2005, the use of e-cigarettes has increased exponentially. Nonetheless, accumulating evidence has demonstrated the ineffectiveness of e-cigarettes in leading to smoking cessation, and decreasing the adverse health impacts of cigarette smoking. The number of adolescents adapted to e-cigarettes has been increasing substantially each year, and this adaptation has promoted openness to tobacco smoking. The present review discusses controversies regarding the smoking cessation effects of e-cigarettes, recent governmental policies and regulations of e-cigarette use, toxic components and vaporization products of e-cigarettes, and the novel molecular mechanisms underlying the adverse health impacts of e-cigarettes leading to oxidative stress in target tissues, and consequent development of cardiopulmonary diseases (i.e. COPD), neurodegenerative disorders (i.e. Alzheimer's’ disease), and cancer. Health warning signs on the packaging and professional consultation to avoid adaptation in risk groups might be helpful solutions to control negative impacts of e-cigarettes. It is also recommended to further expand basic and clinical investigations to reveal more detailed oxidative stress mechanisms of e-cigarette induced damages, which would ultimately result in more effective protective strategies.
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      PubDate: 2017-07-04T20:32:43Z
      DOI: 10.1016/j.redox.2017.05.013
      Issue No: Vol. 13 (2017)
       
  • Azidothymidine-triphosphate impairs mitochondrial dynamics by disrupting
           the quality control system

    • Authors: Ryosuke Nomura; Takeya Sato; Yuka Sato; Jeffrey A. Medin; Shigeki Kushimoto; Teruyuki Yanagisawa
      Pages: 407 - 417
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Ryosuke Nomura, Takeya Sato, Yuka Sato, Jeffrey A. Medin, Shigeki Kushimoto, Teruyuki Yanagisawa
      Highly active anti-retrovirus therapy (HAART) has been used to block the progression and symptoms of human immunodeficiency virus infection. Although it decreases morbidity and mortality, clinical use of HAART has also been linked to various adverse effects such as severe cardiomyopathy resulting from compromised mitochondrial functioning. However, the mechanistic basis for these effects remains unclear. Here, we demonstrate that a key component of HAART, 3ꞌ-azido-3ꞌ-deoxythymidine (AZT), particularly, its active metabolite AZT-triphosphate (AZT-TP), caused mitochondrial dysfunction, leading to induction of cell death in H9c2 cells derived from rat embryonic myoblasts, which serve as a model for cardiomyopathy. Specifically, treatment with 100µM AZT for 48h disrupted the mitochondrial tubular network via accumulation of AZT-TP. The mRNA expression of dynamin-related protein (Drp)1 and the Drp1 receptor mitochondrial fission factor (Mff) was upregulated whereas that of optic atrophy 1 (Opa1) was downregulated following AZT treatment. Increased mitochondrial translocation of Drp1, Mff upregulation, and decreased functional Opa1 expression induced by AZT impaired the balance of mitochondrial fission vs. fusion. These data demonstrate that AZT-TP causes cell death by altering mitochondrial dynamics.

      PubDate: 2017-07-04T20:32:43Z
      DOI: 10.1016/j.redox.2017.06.011
      Issue No: Vol. 13 (2017)
       
  • Blood-based bioenergetic profiling: A readout of systemic bioenergetic
           capacity that is related to differences in body composition

    • Authors: Anthony J.A. Molina
      Pages: 418 - 420
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Anthony J.A. Molina


      PubDate: 2017-07-13T16:28:00Z
      DOI: 10.1016/j.redox.2017.06.012
      Issue No: Vol. 13 (2017)
       
  • BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid
           production enhancing therapeutic potential of umbilical cord blood-derived
           human mesenchymal stem cells

    • Authors: Hyun Jik Lee; Young Hyun Jung; Gee Euhn Choi; So Hee Ko; Sei-Jung Lee; Sang Hun Lee; Ho Jae Han
      Pages: 426 - 443
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Hyun Jik Lee, Young Hyun Jung, Gee Euhn Choi, So Hee Ko, Sei-Jung Lee, Sang Hun Lee, Ho Jae Han
      Mitophagy under hypoxia is an important factor for maintaining and regulating stem cell functions. We previously demonstrated that fatty acid synthase (FASN) induced by hypoxia is a critical lipid metabolic factor determining the therapeutic efficacy of umbilical cord blood-derived human mesenchymal stem cells (UCB-hMSCs). Therefore, we investigated the mechanism of a major mitophagy regulator controlling lipid metabolism and therapeutic potential of UCB-hMSCs. This study revealed that Bcl2/adenovirus E1B 19kDa protein-interacting protein 3 (BNIP3)-dependent mitophagy is important for reducing mitochondrial reactive oxygen species accumulation, anti-apoptosis, and migration under hypoxia. And, BNIP3 expression was regulated by CREB binding protein-mediated transcriptional actions of HIF-1α and FOXO3. Silencing of BNIP3 suppressed free fatty acid (FFA) synthesis regulated by SREBP1/FASN pathway, which is involved in UCB-hMSC apoptosis via caspases cleavage and migration via cofilin-1-mediated F-actin reorganization in hypoxia. Moreover, reduced mouse skin wound-healing capacity of UCB-hMSC with hypoxia pretreatment by BNIP3 silencing was recovered by palmitic acid. Collectively, our findings suggest that BNIP3-mediated mitophagy under hypoxia leads to FASN-induced FFA synthesis, which is critical for therapeutic potential of UCB-hMSCs with hypoxia pretreatment.
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      PubDate: 2017-07-13T16:28:00Z
      DOI: 10.1016/j.redox.2017.07.004
      Issue No: Vol. 13 (2017)
       
  • NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients
           and worsens APP and TAU pathology

    • Authors: Ana I. Rojo; Marta Pajares; Patricia Rada; Angel Nuñez; Alejo J. Nevado-Holgado; Richard Killik; Fred Van Leuven; Elena Ribe; Simon Lovestone; Masayuki Yamamoto; Antonio Cuadrado
      Pages: 444 - 451
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Ana I. Rojo, Marta Pajares, Patricia Rada, Angel Nuñez, Alejo J. Nevado-Holgado, Richard Killik, Fred Van Leuven, Elena Ribe, Simon Lovestone, Masayuki Yamamoto, Antonio Cuadrado
      Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.
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      PubDate: 2017-07-13T16:28:00Z
      DOI: 10.1016/j.redox.2017.07.006
      Issue No: Vol. 13 (2017)
       
  • Metabolomics analysis reveals that benzo[a]pyrene, a component of PM2.5,
           promotes pulmonary injury by modifying lipid metabolism in a phospholipase
           A2-dependent manner in vivo and in vitro

    • Authors: Song-Yang Zhang; Danqing Shao; Huiying Liu; Juan Feng; Baihuan Feng; Xiaoming Song; Qian Zhao; Ming Chu; Changtao Jiang; Wei Huang; Xian Wang
      Pages: 459 - 469
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Song-Yang Zhang, Danqing Shao, Huiying Liu, Juan Feng, Baihuan Feng, Xiaoming Song, Qian Zhao, Ming Chu, Changtao Jiang, Wei Huang, Xian Wang
      Particulate matter with an aerodynamic diameter less than 2.5μM (PM2.5) is one of the major environmental pollutants in China. In this study, we carried out a metabolomics profile study on PM2.5-induced inflammation. PM2.5 from Beijing, China, was collected and given to rats through intra-tracheal instillation in vivo. Acute pulmonary injury were observed by pulmonary function assessment and H.E. staining. The lipid metabolic profile was also altered with increased phospholipid and sphingolipid metabolites in broncho-alveolar lavage fluid (BALF) after PM2.5 instillation. Organic component analysis revealed that benzo[a]pyrene (BaP) is one of the most abundant and toxic components in the PM2.5 collected on the fiber filter. In vitro, BaP was used to treat A549 cells, an alveolar type II cell line. BaP (4μM, 24h) induced inflammation in the cells. Metabolomics analysis revealed that BaP (4μM, 6h) treatment altered the cellular lipid metabolic profile with increased phospholipid metabolites and reduced sphingolipid metabolites and free fatty acids (FFAs). The proportion of ω–3 polyunsaturated fatty acid (PUFA) was also decreased. Mechanically, BaP (4μM) increased the phospholipase A2 (PLA2) activity at 4h as well as the mRNA level of Pla2g2a at 12h. The pro-inflammatory effect of BaP was reversed by the cytosolic PLA2 (cPLA2) inhibitor and chelator of intracellular Ca2+. This study revealed that BaP, as a component of PM2.5, induces pulmonary injury by activating PLA2 and elevating lysophosphatidylcholine (LPC) in a Ca2+-dependent manner in the alveolar type II cells.
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      PubDate: 2017-07-24T20:11:59Z
      DOI: 10.1016/j.redox.2017.07.001
      Issue No: Vol. 13 (2017)
       
  • Proteasome inhibitor-induced cleavage of HSP90 is mediated by ROS
           generation and caspase 10-activation in human leukemic cells

    • Authors: Sangkyu Park; Jeong-A Park; Hwanmin Yoo; Han-Bum Park; Younghee Lee
      Pages: 470 - 476
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Sangkyu Park, Jeong-A Park, Hwanmin Yoo, Han-Bum Park, Younghee Lee
      Heat shock protein 90 (HSP90) is a molecular chaperone that supports the stability of client proteins. The proteasome is one of the targets for cancer therapy, and studies are underway to use proteasome inhibitors as anti-cancer drugs. In this study, we found that HSP90 was cleaved to a 55kDa protein after treatment with proteasome inhibitors including MG132 in leukemia cells but was not cleaved in other tissue-derived cells. HSP90 has two major isoforms (HSP90α and HSP90β), and both were cleaved by MG132 treatment. MG132 treatment also induced a decrease in HSP90 client proteins. MG132 treatment generated ROS, and the cleavage of HSP90 was blocked by a ROS scavenger, N-acetylcysteine (NAC). MG132 activated several caspases, and the activation was reduced by pretreatment with NAC. Based on an inhibitor study, the cleavage of HSP90 induced by MG132 was dependent on caspase 10 activation. Furthermore, active recombinant caspase 10 induced HSP90 cleavage in vitro. MG132 upregulated VDUP-1 expression and reduced the GSH levels implying that the regulation of redox-related proteins is involved. Taken all together, our results suggest that the cleavage of HSP90 by MG132 treatment is mediated by ROS generation and caspase 10 activation. HSP90 cleavage may provide an additional mechanism involved in the anti-cancer effects of proteasome inhibitors.
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      PubDate: 2017-07-24T20:11:59Z
      DOI: 10.1016/j.redox.2017.07.010
      Issue No: Vol. 13 (2017)
       
  • Probucol ameliorates renal injury in diabetic nephropathy by inhibiting
           the expression of the redox enzyme p66Shc

    • Authors: Shikun Yang; Li Zhao; Yachun Han; Yu Liu; Chao Chen; Ming Zhan; Xiaofen Xiong; Xuejing Zhu; Li Xiao; Chun Hu; Fuyou Liu; Zhiguang Zhou; Yashpal S. Kanwar; Lin Sun
      Pages: 482 - 497
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Shikun Yang, Li Zhao, Yachun Han, Yu Liu, Chao Chen, Ming Zhan, Xiaofen Xiong, Xuejing Zhu, Li Xiao, Chun Hu, Fuyou Liu, Zhiguang Zhou, Yashpal S. Kanwar, Lin Sun
      Aims Probucol is an anti-hyperlipidemic agent and a potent antioxidant drug that can delay progression of diabetic nephropathy (DN) and reverses renal oxidative stress in diabetic animal models; however, the mechanisms underlying these effects remain unclear. p66Shc is a newly recognized mediator of mitochondrial ROS production in renal cells under high-glucose (HG) ambience. We previously showed that p66Shc can serve as a biomarker for renal oxidative injury in DN patients and that p66Shc up-regulation is correlated with renal damage in vivo and in vitro. Here, we determined whether probucol ameliorates renal injury in DN by inhibiting p66Shc expression. Results We found that the expression of SIRT1, Ac-H3 and p66Shc in kidneys of DN patients was altered. Also, probucol reduced the levels of serum creatinine, urine protein and LDL-c and attenuated renal oxidative injury and fibrosis in STZ induced diabetic mice. In addition, probucol reversed p-AMPK, SIRT1, Ac-H3 and p66Shc expression. Correlation analyses showed that p66Shc expression was correlated with p-AMPK and Sirt1 expression and severity of renal injury. In vitro pretreatment of HK-2 cells with p-AMPK and SIRT1 siRNA negated the beneficial effects of probucol. Furthermore, we noted that probucol activates p-AMPK and Sirt1 and inhibits p66shc mRNA transcription by facilitating the binding of Sirt1 to the p66Shc promoter and modulation of Ac-H3 expression in HK-2 cells under HG ambience. Innovation and conclusion Our results suggest for the first time that probucol ameliorates renal damage in DN by epigenetically suppressing p66Shc expression via the AMPK-SIRT1-AcH3 pathway.

      PubDate: 2017-07-24T20:11:59Z
      DOI: 10.1016/j.redox.2017.07.002
      Issue No: Vol. 13 (2017)
       
  • Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy
           in cardiac IR injury

    • Authors: Hao Zhou; Pingjun Zhu; Jun Guo; Nan Hu; Shuyi Wang; Dandan Li; Shunying Hu; Jun Ren; Feng Cao; Yundai Chen
      Pages: 498 - 507
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Hao Zhou, Pingjun Zhu, Jun Guo, Nan Hu, Shuyi Wang, Dandan Li, Shunying Hu, Jun Ren, Feng Cao, Yundai Chen
      Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI). Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3-/-) mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria-mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI.
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      PubDate: 2017-07-24T20:11:59Z
      DOI: 10.1016/j.redox.2017.07.007
      Issue No: Vol. 13 (2017)
       
  • Caveolin 1-related autophagy initiated by aldosterone-induced oxidation
           promotes liver sinusoidal endothelial cells defenestration

    • Authors: Xiaoying Luo; Dan Wang; Xuan Luo; Xintao Zhu; Guozhen Wang; Zuowei Ning; Yang Li; Xiaoxin Ma; Renqiang Yang; Siyi Jin; Yun Huang; Ying Meng; Xu Li
      Pages: 508 - 521
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Xiaoying Luo, Dan Wang, Xuan Luo, Xintao Zhu, Guozhen Wang, Zuowei Ning, Yang Li, Xiaoxin Ma, Renqiang Yang, Siyi Jin, Yun Huang, Ying Meng, Xu Li
      Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models. In vitro, fenestrae of primary LSECs gradually shrank, along with the down-regulation of the NO-dependent pathway and the augment of the AMPK-dependent autophagy; these effects were aggravated by rapamycin (an autophagy activator) or aldosterone treatment. Additionally, aldosterone increased oxidation mediated by Cav1, reduced ATP generation, and subsequently induced the AMPK-dependent autophagy, leading to the down-regulation of the NO-dependent pathway and LSECs defenestration. These effects were reversed by MR antagonist spironolactone, antioxidants or autophagy inhibitors. Besides, aldosterone enhanced the co-immunoprecipitation of Cav1 with p62 and ubiquitin, and induced Cav1 co-immunofluorescence staining with LC3, ubiquitin, and F-actin in the perinuclear area of LSECs. Furthermore, aldosterone treatment increased the membrane protein level of Cav1, whereas decrease the cytoplasmic protein level of Cav1, indicating that aldosterone induced Cav1-related selective autophagy and F-actin remodeling to promote defenestration. Consequently, Cav1-related selective autophagy initiated by aldosterone-induced oxidation promotes LSECs defenestration via activating the AMPK-ULK1 pathway and inhibiting the NO-dependent pathway.

      PubDate: 2017-07-24T20:11:59Z
      DOI: 10.1016/j.redox.2017.07.011
      Issue No: Vol. 13 (2017)
       
  • Therapeutic effects of L-Cysteine in newborn mice subjected to
           hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative
           stress and endoplasmic reticulum stress

    • Authors: Song Liu; Danqing Xin; Lingxiao Wang; Tiantian Zhang; Xuemei Bai; Tong Li; Yunkai Xie; Hao Xue; Shishi Bo; Dexiang Liu; Zhen Wang
      Pages: 528 - 540
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Song Liu, Danqing Xin, Lingxiao Wang, Tiantian Zhang, Xuemei Bai, Tong Li, Yunkai Xie, Hao Xue, Shishi Bo, Dexiang Liu, Zhen Wang
      Neonatal hypoxic-ischemic (HI) injury is a major cause of neonatal death and neurological dysfunction. H2S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-β-synthase (CBS) in the brain and sequentially produces endogenous H2S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H2S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72h after HI. Additionally, L-Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER) stress-associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long-term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H2S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI.
      Graphical abstract image

      PubDate: 2017-07-24T20:11:59Z
      DOI: 10.1016/j.redox.2017.06.007
      Issue No: Vol. 13 (2017)
       
  • Upregulation of UCP2 in beta-cells confers partial protection against both
           oxidative stress and glucotoxicity

    • Authors: Ning Li; Melis Karaca; Pierre Maechler
      Pages: 541 - 549
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Ning Li, Melis Karaca, Pierre Maechler
      Deterioration of pancreatic beta-cells plays a critical role in the development of type 2 diabetes. Among the various stressors contributing to these deleterious effects, glucotoxicity and superoxides have been proposed as major players. In this context, the mitochondrial uncoupling protein UCP2 is regularly associated with the stress response. In the present study, we tested the effects of UCP2 upregulation in mouse islets with beta-cell specific overexpression of UCP2 (RIP-UCP2). Islets were subjected to both chronic glucotoxicity (7 days at 30mM glucose) and acute oxidative stress (200µM H2O2 for 10min). Increased UCP2 expression did not alter mitochondrial potential and ATP generation but protected against glucotoxic effects. Glucose-stimulated insulin secretion was altered by both glucotoxicity and oxidative stress, in particular through higher basal insulin release at non-stimulatory glucose concentrations. The secretory response to glucose stimulation was partially preserved in beta-cells overexpressing UCP2. The higher rate of cell death induced by chronic high glucose exposure was lower in RIP-UCP2 islets. Finally, superoxide production was reduced by high glucose, both under acute and chronic conditions, and not modified by UCP2 overexpression. In conclusion, upregulation of UCP2 conferred protective effects to the stressed beta-cell through mechanisms not directly associated with superoxide production.
      Graphical abstract image

      PubDate: 2017-07-31T09:57:33Z
      DOI: 10.1016/j.redox.2017.07.012
      Issue No: Vol. 13 (2017)
       
  • Proteostasis, oxidative stress and aging

    • Authors: Ioanna Korovila; Martín Hugo; José Pedro Castro; Daniela Weber; Annika Höhn; Tilman Grune; Tobias Jung
      Pages: 550 - 567
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Ioanna Korovila, Martín Hugo, José Pedro Castro, Daniela Weber, Annika Höhn, Tilman Grune, Tobias Jung
      The production of reactive species is an inevitable by-product of metabolism and thus, life itself. Since reactive species are able to damage cellular structures, especially proteins, as the most abundant macromolecule of mammalian cells, systems are necessary which regulate and preserve a functional cellular protein pool, in a process termed “proteostasis”. Not only the mammalian protein pool is subject of a constant turnover, organelles are also degraded and rebuild. The most important systems for these removal processes are the “ubiquitin-proteasomal system” (UPS), the central proteolytic machinery of mammalian cells, mainly responsible for proteostasis, as well as the “autophagy-lysosomal system”, which mediates the turnover of organelles and large aggregates. Many age-related pathologies and the aging process itself are accompanied by a dysregulation of UPS, autophagy and the cross-talk between both systems. This review will describe the sources and effects of oxidative stress, preservation of cellular protein- and organelle-homeostasis and the effects of aging on proteostasis in mammalian cells.
      Graphical abstract image

      PubDate: 2017-07-31T09:57:33Z
      DOI: 10.1016/j.redox.2017.07.008
      Issue No: Vol. 13 (2017)
       
  • Identification of transcriptome signature for myocardial reductive stress

    • Authors: Justin M. Quiles; Madhusudhanan Narasimhan; Timothy Mosbruger; Gobinath Shanmugam; David Crossman; Namakkal S. Rajasekaran
      Pages: 568 - 580
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Justin M. Quiles, Madhusudhanan Narasimhan, Timothy Mosbruger, Gobinath Shanmugam, David Crossman, Namakkal S. Rajasekaran
      The nuclear factor erythroid 2 like 2 (Nfe2l2/Nrf2) is a master regulator of antioxidant gene transcription. We recently identified that constitutive activation of Nrf2 (CaNrf2) caused reductive stress (RS) in the myocardium. Here we investigate how chronic Nrf2 activation alters myocardial mRNA transcriptome in the hearts of CaNrf2 transgenic (TG-low and TG-high) mice using an unbiased integrated systems approach and next generation RNA sequencing followed by qRT-PCR methods. A total of 246 and 1031 differentially expressed genes (DEGs) were identified in the heart of TGL and TGH in relation to NTG littermates at ~ 6 months of age. Notably, the expression and validation of the transcripts were gene-dosage dependent and statistically significant. Ingenuity Pathway Analysis identified enriched biological processes and canonical pathways associated with myocardial RS in the CaNrf2-TG mice. In addition, an overrepresentation of xenobiotic metabolic signaling, glutathione-mediated detoxification, unfolded protein response, and protein ubiquitination was observed. Other, non-canonical signaling pathways identified include: eNOS, integrin-linked kinase, glucocorticoid receptor, PI3/AKT, actin cytoskeleton, cardiac hypertrophy, and the endoplasmic reticulum stress response. In conclusion, this mRNA profiling identified a "biosignature" for pro-reductive (TGL) and reductive stress (TGH) that can predict the onset, rate of progression, and clinical outcome of Nrf2-dependent myocardial complications. We anticipate that this global sequencing analysis will illuminate the undesirable effect of chronic Nrf2 signaling leading to RS-mediated pathogenesis besides providing important guidance for the application of Nrf2 activation-based cytoprotective strategies.
      Graphical abstract image

      PubDate: 2017-07-31T09:57:33Z
      DOI: 10.1016/j.redox.2017.07.013
      Issue No: Vol. 13 (2017)
       
  • Endothelial cells, endoplasmic reticulum stress and oxysterols

    • Authors: F. Luchetti; R. Crinelli; E. Cesarini; B. Canonico; L. Guidi; C. Zerbinati; G. Di Sario; L. Zamai; M. Magnani; S. Papa; L. Iuliano
      Pages: 581 - 587
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): F. Luchetti, R. Crinelli, E. Cesarini, B. Canonico, L. Guidi, C. Zerbinati, G. Di Sario, L. Zamai, M. Magnani, S. Papa, L. Iuliano
      Oxysterols are bioactive lipids that act as regulators of lipid metabolism, inflammation, cell viability and are involved in several diseases, including atherosclerosis. Mounting evidence linked the atherosclerosis to endothelium dysfunction; in fact, the endothelium regulates the vascular system with roles in processes such as hemostasis, cell cholesterol, hormone trafficking, signal transduction and inflammation. Several papers shed light the ability of oxysterols to induce apoptosis in different cell lines including endothelial cells. Apoptotic endothelial cell and endothelial denudation may constitute a critical step in the transition to plaque erosion and vessel thrombosis, so preventing the endothelial damaged has garnered considerable attention as a novel means of treating atherosclerosis. Endoplasmic reticulum (ER) is the site where the proteins are synthetized and folded and is necessary for most cellular activity; perturbations of ER homeostasis leads to a condition known as endoplasmic reticulum stress. This condition evokes the unfolded protein response (UPR) an adaptive pathway that aims to restore ER homeostasis. Mounting evidence suggests that chronic activation of UPR leads to cell dysfunction and death and recently has been implicated in pathogenesis of endothelial dysfunction. Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation, maintaining basal levels of autophagic activity it is critical for cell survival. Several evidence suggests that persistent ER stress often results in stimulation of autophagic activities, likely as a compensatory mechanism to relieve ER stress and consequently cell death. In this review, we summarize evidence for the effect of oxysterols on endothelial cells, especially focusing on oxysterols-mediated induction of endoplasmic reticulum stress.
      Graphical abstract image

      PubDate: 2017-08-09T11:09:37Z
      DOI: 10.1016/j.redox.2017.07.014
      Issue No: Vol. 13 (2017)
       
  • Carnosine attenuates cyclophosphamide-induced bone marrow suppression by
           reducing oxidative DNA damage

    • Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Jie Deng, Yi-Fei Zhong, Yan-Ping Wu, Zhuo Luo, Yuan-Ming Sun, Guo-En Wang, Hiroshi Kurihara, Yi-Fang Li, Rong-Rong He
      Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX). However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (β-alanyl-l-histidine), a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200mg/kg, i.p.) significantly inhibited the generation of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-oxo-dG), and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20mg/kg, i.v., 24h). Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity.
      Graphical abstract image

      PubDate: 2017-08-18T21:44:36Z
       
  • Tetrahydrobiopterin in antenatal brain hypoxia-ischemia-induced motor
           impairments and cerebral palsy

    • Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Jeannette Vasquez-Vivar, Zhongjie Shi, Kehuan Luo, Karthikeyan Thirugnanam, Sidhartha Tan
      Antenatal brain hypoxia-ischemia, which occurs in cerebral palsy, is considered a significant cause of motor impairments in children. The mechanisms by which antenatal hypoxia-ischemia causes brain injury and motor deficits still need to be elucidated. Tetrahydrobiopterin is an important enzyme cofactor that is necessary to produce neurotransmitters and to maintain the redox status of the brain. A genetic deficiency of this cofactor from mutations of biosynthetic or recycling enzymes is a well-recognized factor in the development of childhood neurological disorders characterized by motor impairments, developmental delay, and encephalopathy. Experimental hypoxia-ischemia causes a decline in the availability of tetrahydrobiopterin in the immature brain. This decline coincides with the loss of brain function, suggesting this occurrence contributes to neuronal dysfunction and motor impairments. One possible mechanism linking tetrahydrobiopterin deficiency, hypoxia-ischemia, and neuronal injury is oxidative injury. Evidence of the central role of the developmental biology of tetrahydrobiopterin in response to hypoxic ischemic brain injury, especially the development of motor deficits, is discussed.
      Graphical abstract image

      PubDate: 2017-08-18T21:44:36Z
       
  • Direct antioxidant properties of methotrexate: Inhibition of
           malondialdehyde-acetaldehyde-protein adduct formation and superoxide
           scavenging

    • Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Matthew C. Zimmerman, Dahn L. Clemens, Michael J. Duryee, Cleofes Sarmiento, Andrew Chiou, Carlos D. Hunter, Jun Tian, Lynell W. Klassen, James R. O’Dell, Geoffrey M. Thiele, Ted R. Mikuls, Daniel R. Anderson
      Methotrexate (MTX) is an immunosuppressant commonly used for the treatment of autoimmune diseases. Recent observations have shown that patients treated with MTX also exhibit a reduced risk for the development of cardiovascular disease (CVD). Although MTX reduces systemic inflammation and tissue damage, the mechanisms by which MTX exerts these beneficial effects are not entirely known. We have previously demonstrated that protein adducts formed by the interaction of malondialdehyde (MDA) and acetaldehyde (AA), known as MAA-protein adducts, are present in diseased tissues of individuals with rheumatoid arthritis (RA) or CVD. In previously reported studies, MAA-adducts were shown to be highly immunogenic, supporting the concept that MAA-adducts not only serve as markers of oxidative stress but may have a direct role in the pathogenesis of inflammatory diseases. Because MAA-adducts are commonly detected in diseased tissues and are proposed to mitigate disease progression in both RA and CVD, we tested the hypothesis that MTX inhibits the generation of MAA-protein adducts by scavenging reactive oxygen species. Using a cell free system, we found that MTX reduces MAA-adduct formation by approximately 6-fold, and scavenges free radicals produced during MAA-adduct formation. Further investigation revealed that MTX directly scavenges superoxide, but not hydrogen peroxide. Additionally, using the Nrf2/ARE luciferase reporter cell line, which responds to intracellular redox changes, we observed that MTX inhibits the activation of Nrf2 in cells treated with MDA and AA. These studies define previously unrecognized mechanisms by which MTX can reduce inflammation and subsequent tissue damage, namely, scavenging free radicals, reducing oxidative stress, and inhibiting MAA-adduct formation.
      Graphical abstract image

      PubDate: 2017-08-18T21:44:36Z
       
  • Direct 1O2 optical excitation: A tool for redox biology

    • Authors: Alfonso
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Alfonso Blázquez-Castro
      Molecular oxygen (O2) displays very interesting properties. Its first excited state, commonly known as singlet oxygen (1O2), is one of the so-called Reactive Oxygen Species (ROS). It has been implicated in many redox processes in biological systems. For many decades its role has been that of a deleterious chemical species, although very positive clinical applications in the Photodynamic Therapy of cancer (PDT) have been reported. More recently, many ROS, and also 1O2, are in the spotlight because of their role in physiological signaling, like cell proliferation or tissue regeneration. However, there are methodological shortcomings to properly assess the role of 1O2 in redox biology with classical generation procedures. In this review the direct optical excitation of O2 to produce 1O2 will be introduced, in order to present its main advantages and drawbacks for biological studies. This photonic approach can provide with many interesting possibilities to understand and put to use ROS in redox signaling and in the biomedical field.
      Graphical abstract image

      PubDate: 2017-05-30T07:10:02Z
       
 
 
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