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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  [3034 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)
       
  • Angiogenesis in the atherosclerotic plaque

    • Authors: Caroline Camaré; Mélanie Pucelle; Anne Nègre-Salvayre; Robert Salvayre
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Caroline Camaré, Mélanie Pucelle, Anne Nègre-Salvayre, Robert Salvayre
      Atherosclerosis is a multifocal alteration of the vascular wall of medium and large arteries characterized by a local accumulation of cholesterol and non-resolving inflammation. Atherothrombotic complications are the leading cause of disability and mortality in western countries. Neovascularization in atherosclerotic lesions plays a major role in plaque growth and instability. The angiogenic process is mediated by classical angiogenic factors and by additional factors specific to atherosclerotic angiogenesis. In addition to its role in plaque progression, neovascularization may take part in plaque destabilization and thromboembolic events. Anti-angiogenic agents are effective to reduce atherosclerosis progression in various animal models. However, clinical trials with anti-angiogenic drugs, mainly anti-VEGF/VEGFR, used in anti-cancer therapy show cardiovascular adverse effects, and require additional investigations.
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      PubDate: 2017-02-14T12:51:47Z
      DOI: 10.1016/j.redox.2017.01.007
      Issue No: Vol. 12 (2017)
       
  • Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain
           neurons promotes cognitive impairment and neurodegeneration

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

    • Authors: Julia Kuligowski; Rønnaug Solberg; Ángel Sánchez-Illana; Leonid Pankratov; Anna Parra-Llorca; Guillermo Quintás; Ola Didrik Saugstad; Máximo Vento
      Pages: 1 - 7
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Julia Kuligowski, Rønnaug Solberg, Ángel Sánchez-Illana, Leonid Pankratov, Anna Parra-Llorca, Guillermo Quintás, Ola Didrik Saugstad, Máximo Vento
      Hypoxic-ischemic encephalopathy (HIE) secondary to perinatal asphyxia is a leading cause of mortality and acquired long-term neurologic co-morbidities in the neonate. The most successful intervention for the treatment of moderate to severe HIE is moderate whole body hypothermia initiated within 6h from birth. The objective and prompt identification of infants who are at risk of developing moderate to severe HIE in the critical first hours still remains a challenge. This work proposes a metabolite score calculated based on the relative intensities of three metabolites (choline, 6,8-dihydroxypurine and hypoxanthine) that showed maximum correlation with hypoxia time in a consolidated piglet model for neonatal hypoxia-ischemia. The metabolite score's performance as a biomarker for perinatal hypoxia and its usefulness for clinical grading and decision making have been assessed and compared to the performance of lactate which is currently considered the gold standard. For plasma samples withdrawn before and directly after a hypoxic insult, the metabolite score performed similar to lactate. However, it provided an enhanced predictive capacity at 2h after resuscitation. The present study evidences the usefulness of the metabolite score for improving the early assessment of the severity of the hypoxic insult based on serial determinations in a minimally invasive biofluid. The applicability of the metabolite score for clinical diagnosis and patient stratification for hypothermia treatment has to be confirmed in multicenter trials involving newborns suffering from HIE.
      Graphical abstract image

      PubDate: 2017-02-13T12:51:44Z
      DOI: 10.1016/j.redox.2017.02.002
      Issue No: Vol. 12 (2017)
       
  • Taking up the cudgels for the traditional reactive oxygen and nitrogen
           species detection assays and their use in the cardiovascular system

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

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

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

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

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

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

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

    • Authors: Jenifer Trepiana; Susana Meijide; Rosaura Navarro; M. Luisa Hernández; José Ignacio Ruiz-Sanz; M. Begoña Ruiz-Larrea
      Pages: 103 - 113
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Jenifer Trepiana, Susana Meijide, Rosaura Navarro, M. Luisa Hernández, José Ignacio Ruiz-Sanz, M. Begoña Ruiz-Larrea
      Most of the in vitro studies using liver cell lines have been performed under atmospheric oxygen partial pressure (21% O2). However, the oxygen concentrations in the liver and cancer cells are far from this value. In the present study, we have evaluated the influence of oxygen on 1) the tumor cell lines features (growth, steady-state ROS levels, GSH content, activities of antioxidant enzymes, p66 Shc and SOD expressions, metalloproteinases secretion, migration, invasion, and adhesion) of human hepatocellular carcinoma cell lines, and b) the response of the cells to an oxidant stimulus (aqueous leaf extract of the V. baccifera plant species). For this purpose, three hepatocarcinoma cell lines with different p53 status, HepG2 (wild-type), Huh7 (mutated), and Hep3B (deleted), were cultured (6–30 days) under atmospheric (21%) and more physiological (8%) pO2. Results showed that after long-term culturing at 8% versus 21% O2, the cellular proliferation rate and the steady-state levels of mitochondrial O2 - were unaffected. However, the intracellular basal ROS levels were higher independently of the characteristics of the cell line. Moreover, the lower pO2 was associated with lower glutathione content, the induction of p66 Shc and Mn-SOD proteins, and increased SOD activity only in HepG2. This cell line also showed a higher migration rate, secretion of active metalloproteinases, and a faster invasion. HepG2 cells were more resistant to the oxidative stress induced by V. baccifera. Results suggest that the long-term culturing of human hepatoma cells at a low, more physiological pO2 induces antioxidant adaptations that could be mediated by p53, and may alter the cellular response to a subsequent oxidant challenge. Data support the necessity of validating outcomes from studies performed with hepatoma cell cultures under ambient O2.
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      PubDate: 2017-02-20T13:22:20Z
      DOI: 10.1016/j.redox.2017.02.004
      Issue No: Vol. 12 (2017)
       
  • Mitochondrial composition and function under the control of hypoxia

    • Authors: Dominik C. Fuhrmann; Bernhard Brüne
      Pages: 208 - 215
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Dominik C. Fuhrmann, Bernhard Brüne
      Hypoxia triggers several mechanisms to adapt cells to a low oxygen environment. Mitochondria are major consumers of oxygen and a potential source of reactive oxygen species (ROS). In response to hypoxia they exchange or modify distinct subunits of the respiratory chain and adjust their metabolism, especially lowering the citric acid cycle. Intermediates of the citric acid cycle participate in regulating hypoxia inducible factors (HIF), the key mediators of adaptation to hypoxia. Here we summarize how hypoxia conditions mitochondria with consequences for ROS-production and the HIF-pathway.
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      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.012
      Issue No: Vol. 12 (2017)
       
  • Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases
           - important players in mitochondrial metabolism and metabolic health

    • Authors: Riikka Jokinen; Sini Pirnes-Karhu; Kirsi H. Pietiläinen; Eija Pirinen
      Pages: 246 - 263
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Riikka Jokinen, Sini Pirnes-Karhu, Kirsi H. Pietiläinen, Eija Pirinen
      Obesity, a chronic state of energy overload, is characterized by adipose tissue dysfunction that is considered to be the major driver for obesity associated metabolic complications. The reasons for adipose tissue dysfunction are incompletely understood, but one potential contributing factor is adipose tissue mitochondrial dysfunction. Derangements of adipose tissue mitochondrial biogenesis and pathways associate with obesity and metabolic diseases. Mitochondria are central organelles in energy metabolism through their role in energy derivation through catabolic oxidative reactions. The mitochondrial processes are dependent on the proper NAD+/NADH redox balance and NAD+ is essential for reactions catalyzed by the key regulators of mitochondrial metabolism, sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). Notably, obesity is associated with disturbed adipose tissue NAD+ homeostasis and the balance of SIRT and PARP activities. In this review we aim to summarize existing literature on the maintenance of intracellular NAD+ pools and the function of SIRTs and PARPs in adipose tissue during normal and obese conditions, with the purpose of comprehending their potential role in mitochondrial derangements and obesity associated metabolic complications. Understanding the molecular mechanisms that are the root cause of the adipose tissue mitochondrial derangements is crucial for developing new effective strategies to reverse obesity associated metabolic complications.
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      PubDate: 2017-03-06T14:33:00Z
      DOI: 10.1016/j.redox.2017.02.011
      Issue No: Vol. 12 (2017)
       
  • Impact of high cholesterol and endoplasmic reticulum stress on metabolic
           diseases: An updated mini-review

    • Authors: Erdi Sozen; Nesrin Kartal Ozer
      Pages: 456 - 461
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Erdi Sozen, Nesrin Kartal Ozer
      Endoplasmic reticulum (ER) is the major site of protein folding and calcium storage. Beside the role of ER in protein homeostasis, it controls the cholesterol production and lipid-membrane biosynthesis as well as surviving and cell death signaling mechanisms in the cell. It is well-documented that elevated plasma cholesterol induces adverse effects in cardiovascular diseases (CVDs), liver disorders, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatosis hepatitis (NASH), and metabolic diseases which are associated with oxidative and ER stress. Recent animal model and human studies have showed high cholesterol and ER stress as an emerging factors involved in the development of many metabolic diseases. In this review, we will summarize the crucial effects of hypercholesterolemia and ER stress response in the pathogenesis of CVDs, NAFLD/NASH, diabetes and obesity which are major health problems in western countries.
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      PubDate: 2017-03-18T01:09:55Z
      DOI: 10.1016/j.redox.2017.02.025
      Issue No: Vol. 12 (2017)
       
  • Catalase as a regulator of reactive sulfur metabolism; a new
           interpretation beyond hydrogen peroxide✩

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

      PubDate: 2017-03-31T02:51:54Z
      DOI: 10.1016/j.redox.2017.03.018
      Issue No: Vol. 12 (2017)
       
  • Oxygen and oxidative stress in the perinatal period

    • Authors: Isabel Torres-Cuevas; Anna Parra-Llorca; Angel Sánchez-Illana; Antonio Nuñez-Ramiro; Julia Kuligowski; Consuelo Cháfer-Pericás; María Cernada; Justo Escobar; Máximo Vento
      Pages: 674 - 681
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Isabel Torres-Cuevas, Anna Parra-Llorca, Angel Sánchez-Illana, Antonio Nuñez-Ramiro, Julia Kuligowski, Consuelo Cháfer-Pericás, María Cernada, Justo Escobar, Máximo Vento
      Fetal life evolves in a hypoxic environment. Changes in the oxygen content in utero caused by conditions such as pre-eclampsia or type I diabetes or by oxygen supplementation to the mother lead to increased free radical production and correlate with perinatal outcomes. In the fetal-to-neonatal transition asphyxia is characterized by intermittent periods of hypoxia ischemia that may evolve to hypoxic ischemic encephalopathy associated with neurocognitive, motor, and neurosensorial impairment. Free radicals generated upon reoxygenation may notably increase brain damage. Hence, clinical trials have shown that the use of 100% oxygen given with positive pressure in the airways of the newborn infant during resuscitation causes more oxidative stress than using air, and increases mortality. Preterm infants are endowed with an immature lung and antioxidant system. Clinical stabilization of preterm infants after birth frequently requires positive pressure ventilation with a gas admixture that contains oxygen to achieve a normal heart rate and arterial oxygen saturation. In randomized controlled trials the use high oxygen concentrations (90% to 100%) has caused more oxidative stress and clinical complications that the use of lower oxygen concentrations (30–60%). A correlation between the amount of oxygen received during resuscitation and the level of biomarkers of oxidative stress and clinical outcomes was established. Thus, based on clinical outcomes and analytical results of oxidative stress biomarkers relevant changes were introduced in the resuscitation policies. However, it should be underscored that analysis of oxidative stress biomarkers in biofluids has only been used in experimental and clinical research but not in clinical routine. The complexity of the technical procedures, lack of automation, and cost of these determinations have hindered the routine use of biomarkers in the clinical setting. Overcoming these technical and economical difficulties constitutes a challenge for the immediate future since accurate evaluation of oxidative stress would contribute to improve the quality of care of our neonatal patients.
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      PubDate: 2017-04-12T15:30:22Z
      DOI: 10.1016/j.redox.2017.03.011
      Issue No: Vol. 12 (2017)
       
  • Controversy about pharmacological modulation of Nrf2 for cancer therapy

    • Authors: Lidija Milkovic; Neven Zarkovic; Luciano Saso
      Pages: 727 - 732
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Lidija Milkovic, Neven Zarkovic, Luciano Saso
      Conventional anticancer therapies such as radiotherapy and chemotherapies are associated with oxidative stress generating reactive oxygen species (ROS) and reactive aldehydes like 4-hydroxynonenal in cancer cells that govern them to die. The main mechanism activated due to exposure of the cell to these reactive species is the Nrf2-Keap1 pathway. Although Nrf2 was firstly perceived as a tumor suppressor that inhibits tumor initiation and cancer metastasis, more recent data reveal its role also as a pro-oncogenic factor. Discovery of the upregulation of Nrf2 in different types of cancer supports such undesirable pathophysiological roles of Nrf2. The upregulation of Nrf2 leads to activation of cytoprotective genes thus helping malignant cells to withstand high levels of ROS and to avoid apoptosis, eventually becoming resistant to conventional anticancer therapy. Therefore, new treatment strategies are needed for eradication of cancer and in this review, we will explore two opposing approaches for modulation of Nrf2 in cancer treatments.
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      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.013
      Issue No: Vol. 12 (2017)
       
  • Metabolic regulation and the anti-obesity perspectives of human brown fat

    • Authors: Camilla Scheele; Søren Nielsen
      Pages: 770 - 775
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Camilla Scheele, Søren Nielsen
      Activation of brown adipose tissue (BAT) in adult humans increase glucose and fatty acid clearance as well as resting metabolic rate, whereas a prolonged elevation of BAT activity improves insulin sensitivity. However, substantial reductions in body weight following BAT activation has not yet been shown in humans. This observation raise the possibility for feedback mechanisms in adult humans in terms of a brown fat-brain crosstalk, possibly mediated by batokines, factors produced by and secreted from brown fat. Batokines also seems to be involved in BAT recruitment by stimulating proliferation and differentiation of brown fat progenitors. Increasing human BAT capacity could thus include inducing brown fat biogenesis as well as identifying novel batokines. Another attractive approach would be to induce a brown fat phenotype, the so-called brite or beige fat, within the white fat depots. In adult humans, white fat tissue transformation into beige has been observed in patients with pheochromocytoma, a norepinephrine-producing tumor. Interestingly, human beige fat is predominantly induced in regions that were BAT during early childhood, possibly reflecting that a presence of human beige progenitors is depot specific and originating from BAT. In conclusion, to utilize the anti-obesity potential of human BAT focus should be directed towards identifying novel regulators of brown and beige fat progenitor cells, as well as feedback mechanisms of BAT activation. This would allow for identification of novel anti-obesity targets.
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      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.011
      Issue No: Vol. 12 (2017)
       
  • Peripheral artery disease, redox signaling, oxidative stress – Basic
           and clinical aspects

    • Authors: Sebastian Steven; Andreas Daiber; Jörn F. Dopheide; Thomas Münzel; Christine Espinola-Klein
      Pages: 787 - 797
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Sebastian Steven, Andreas Daiber, Jörn F. Dopheide, Thomas Münzel, Christine Espinola-Klein
      Reactive oxygen and nitrogen species (ROS and RNS, e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. At higher concentrations, ROS and RNS lead to oxidative stress and oxidative damage of biomolecules (e.g. via formation of peroxynitrite, fenton chemistry). Peripheral artery disease (PAD) is characterized by severe ischemic conditions in the periphery leading to intermittent claudication and critical limb ischemia (end stage). It is well known that redox biology and oxidative stress play an important role in this setting. We here discuss the major pathways of oxidative stress and redox signaling underlying the disease progression with special emphasis on the contribution of inflammatory processes. We also highlight therapeutic strategies comprising pharmacological (e.g. statins, angiotensin-converting enzyme inhibitors, phosphodiesterase inhibition) and non-pharmacological (e.g. exercise) interventions. Both of these strategies induce potent indirect antioxidant and anti-inflammatory mechanisms that may contribute to an improvement of PAD associated complications and disease progression by removing excess formation of ROS and RNS (e.g. by ameliorating primary complications such as hyperlipidemia and hypertension) as well as the normalization of the inflammatory phenotype suppressing the progression of atherosclerosis.

      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.017
      Issue No: Vol. 12 (2017)
       
  • Sex matters: The effects of biological sex on adipose tissue biology and
           energy metabolism

    • Authors: Teresa G. Valencak; Anne Osterrieder; Tim J. Schulz
      Pages: 806 - 813
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Teresa G. Valencak, Anne Osterrieder, Tim J. Schulz
      Adipose tissue is a complex and multi-faceted organ. It responds dynamically to internal and external stimuli, depending on the developmental stage and activity of the organism. The most common functional subunits of adipose tissue, white and brown adipocytes, regulate and respond to endocrine processes, which then determine metabolic rate as well as adipose tissue functions. While the molecular aspects of white and brown adipose biology have become clearer in the recent past, much less is known about sex-specific differences in regulation and deposition of adipose tissue, and the specific role of the so-called pink adipocytes during lactation in females. This review summarises the current understanding of adipose tissue dynamics with a focus on sex-specific differences in adipose tissue energy metabolism and endocrine functions, focussing on mammalian model organisms as well as human-derived data. In females, pink adipocytes trans-differentiate during pregnancy from subcutaneous white adipocytes and are responsible for milk-secretion in mammary glands. Overlooking biological sex variation may ultimately hamper clinical treatments of many aspects of metabolic disorders.
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      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.012
      Issue No: Vol. 12 (2017)
       
  • Mitochondria in endothelial cells: Sensors and integrators of
           environmental cues

    • Authors: Sergio Caja; Jose Antonio Enríquez
      Pages: 821 - 827
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Sergio Caja, Jose Antonio Enríquez
      The involvement of angiogenesis in disease and its potential as a therapeutic target have been firmly established over recent decades. Endothelial cells (ECs) are central elements in vessel homeostasis and regulate the passage of material and cells into and out of the bloodstream. EC proliferation and migration are modified by alterations to mitochondrial biogenesis and dynamics resulting from several signals and environmental cues, such as oxygen, hemodynamics, and nutrients. As intermediary signals, mitochondrial ROS are released as important downstream modulators of the expression of angiogenesis-related genes. In this review, we discuss the physiological actions of these signals and aberrant responses during vascular disorders.

      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.021
      Issue No: Vol. 12 (2017)
       
  • Teaching the basics of cancer metabolism: Developing antitumor strategies
           by exploiting the differences between normal and cancer cell metabolism

    • Authors: Balaraman Kalyanaraman
      Pages: 833 - 842
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Balaraman Kalyanaraman
      This review of the basics of cancer metabolism focuses on exploiting the metabolic differences between normal and cancer cells. The first part of the review covers the different metabolic pathways utilized in normal cells to generate cellular energy, or ATP, and the glycolytic intermediates required to build the cellular machinery. The second part of the review discusses aerobic glycolysis, or the Warburg effect, and the metabolic reprogramming involving glycolysis, tricarboxylic acid cycle, and glutaminolysis in the context of developing targeted inhibitors in cancer cells. Finally, the selective targeting of cancer mitochondrial metabolism using positively charged lipophilic compounds as potential therapeutics and their ability to mitigate the toxic side effects of conventional chemotherapeutics in normal cells are discussed. I hope this graphical review will be useful in helping undergraduate, graduate, and medical students understand how investigating the basics of cancer cell metabolism could provide new insight in developing potentially new anticancer treatment strategies.

      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.018
      Issue No: Vol. 12 (2017)
       
  • Traveling from the hypothalamus to the adipose tissue: The thermogenic
           pathway

    • Authors: Cristina Contreras; Rubén Nogueiras; Carlos Diéguez; Kamal Rahmouni; Miguel López
      Pages: 854 - 863
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Cristina Contreras, Rubén Nogueiras, Carlos Diéguez, Kamal Rahmouni, Miguel López
      Brown adipose tissue (BAT) is a specialized tissue critical for non-shivering thermogenesis producing heat through mitochondrial uncoupling; whereas white adipose tissue (WAT) is responsible of energy storage in the form of triglycerides. Another type of fat has been described, the beige adipose tissue; this tissue emerges in existing WAT depots but with thermogenic ability, a phenomenon known as browning. Several peripheral signals relaying information about energy status act in the brain, particularly the hypothalamus, to regulate thermogenesis in BAT and browning of WAT. Different hypothalamic areas have the capacity to regulate the thermogenic process in brown and beige adipocytes through the sympathetic nervous system (SNS). This review discusses important concepts and discoveries about the central control of thermogenesis as a trip that starts in the hypothalamus, and taking the sympathetic roads to reach brown and beige fat to modulate thermogenic functions.

      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.019
      Issue No: Vol. 12 (2017)
       
  • Redox signaling in acute oxygen sensing

    • Authors: Lin Gao; Patricia González-Rodríguez; Patricia Ortega-Sáenz; José López-Barneo
      Pages: 908 - 915
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Lin Gao, Patricia González-Rodríguez, Patricia Ortega-Sáenz, José López-Barneo
      Acute oxygen (O2) sensing is essential for individuals to survive under hypoxic conditions. The carotid body (CB) is the main peripheral chemoreceptor, which contains excitable and O2-sensitive glomus cells with O2-regulated ion channels. Upon exposure to acute hypoxia, inhibition of K+ channels is the signal that triggers cell depolarization, transmitter release and activation of sensory fibers that stimulate the brainstem respiratory center to produce hyperventilation. The molecular mechanisms underlying O2 sensing by glomus cells have, however, remained elusive. Here we discuss recent data demonstrating that ablation of mitochondrial Ndufs2 gene selectively abolishes sensitivity of glomus cells to hypoxia, maintaining responsiveness to hypercapnia or hypoglycemia. These data suggest that reactive oxygen species and NADH generated in mitochondrial complex I during hypoxia are signaling molecules that modulate membrane K+ channels. We propose that the structural substrates for acute O2 sensing in CB glomus cells are “O2-sensing microdomains” formed by mitochondria and neighboring K+ channels in the plasma membrane.
      Graphical abstract image

      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.033
      Issue No: Vol. 12 (2017)
       
  • Shotgun lipidomics in substantiating lipid peroxidation in redox biology:
           Methods and applications

    • Authors: Changfeng Hu; Miao Wang; Xianlin Han
      Pages: 946 - 955
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Changfeng Hu, Miao Wang, Xianlin Han
      Multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) has made profound advances for comprehensive analysis of cellular lipids. It represents one of the most powerful tools in analyzing lipids directly from lipid extracts of biological samples. It enables the analysis of nearly 50 lipid classes and thousands of individual lipid species with high accuracy/precision. The redox imbalance causes oxidative stress, resulting in lipid peroxidation, and alterations in lipid metabolism and homeostasis. Some lipid classes such as oxidized fatty acids, 4-hydroxyalkenal species, and plasmalogen are sensitive to oxidative stress or generated corresponding to redox imbalance. Therefore, accurate assessment of these lipid classes can provide not only the redox states, but also molecular insights into the pathogenesis of diseases. This review focuses on the advances of MDMS-SL in analysis of these lipid classes and molecular species, and summarizes their recent representative applications in biomedical/biological research. We believe that MDMS-SL can make great contributions to redox biology through substantiating the aberrant lipid metabolism, signaling, trafficking, and homeostasis under oxidative stress-related condition.
      Graphical abstract image

      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.030
      Issue No: Vol. 12 (2017)
       
  • Redox regulation of ischemic limb neovascularization – What we have
           learned from animal studies

    • Authors: Reiko Matsui; Yosuke Watanabe; Colin E. Murdoch
      Pages: 1011 - 1019
      Abstract: Publication date: August 2017
      Source:Redox Biology, Volume 12
      Author(s): Reiko Matsui, Yosuke Watanabe, Colin E. Murdoch
      Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts), is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx) is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization.

      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.040
      Issue No: Vol. 12 (2017)
       
  • 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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