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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  [3118 journals]
  • Novel H2S-NO hybrid molecule (ZYZ-803) promoted synergistic effects
           against heart failure

    • Authors: Dan Wu; Qingxun Hu; Ying Xiong; Deqiu Zhu; Yicheng Mao; Yi Zhun Zhu
      Pages: 243 - 252
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Dan Wu, Qingxun Hu, Ying Xiong, Deqiu Zhu, Yicheng Mao, Yi Zhun Zhu
      Therapeutic strategies that increase hydrogen sulfide (H2S) or nitric oxide (NO) are cytoprotective in various models of cardiovascular injury. However, the nature of interaction between H2S and NO in heart failure and the underlying mechanisms for the protective effects remain undefined. The present study tested the cardioprotective effect of ZYZ-803, a novel synthetic H2S-NO hybrid molecule that decomposed to release H2S and NO. ZYZ-803 dose dependently improved left ventricular remodeling and preserved left ventricular function in the setting of isoprenaline-induced heart failure. The cardioprotective effect of ZYZ-803 is significantly more potent than that of H2S and/or NO donor alone. ZYZ-803 stimulated the expression of cystathionine γ-lyase (CSE) for H2S generation and the activity of endothelial NO synthase (eNOS) for NO production. Blocking CSE and/or eNOS suppressed ZYZ-803-induced H2S and NO production and cardioprotection. ZYZ-803 increased vascular endothelial growth factor (VEGF) concentration and cyclic guanosine 5′-monophosphate (cGMP) level. Moreover, ZYZ-803 upregulated the endogenous antioxidants, glutathione peroxidase (GPx) and heme oxygenase 1 (HO-1). These findings indicate that H2S and NO cooperatively attenuates left ventricular remodeling and dysfunction during the development of heart failure through VEGF/cGMP pathway and ZYZ-803 provide expanding insight into strategies for treatment of heart failure.
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      PubDate: 2018-01-03T13:39:04Z
      DOI: 10.1016/j.redox.2017.11.020
      Issue No: Vol. 15 (2018)
       
  • Impaired pentose phosphate pathway in the development of 3D MCF-7 cells
           mediated intracellular redox disturbance and multi-cellular resistance
           without drug induction

    • Authors: Wenjie Wang; Qingyun Cai; Fang Zhou; Jiali Liu; Xiaoliang Jin; Ping Ni; Meng Lu; Guangji Wang; Jingwei Zhang
      Pages: 253 - 265
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Wenjie Wang, Qingyun Cai, Fang Zhou, Jiali Liu, Xiaoliang Jin, Ping Ni, Meng Lu, Guangji Wang, Jingwei Zhang
      Although metabolic reprogramming and redox imbalance are widely reported to be involved in chemo-resistance in cancer treatment, much more attention was paid to anti-cancer drug induced effect. Our previous studies showed that cancer cells can develop P-gp overexpression-mediated intrinsic drug resistance in the formation of 3D MCF-7 multi-cellular layers (MCLs) without any drug induction. However, whether metabolic reprogramming and redox imbalance functioned during this progress remained unrevealed. In our present study, LC-Q/TOF-MS and GC-MS were used in combination for analysing intracellular metabolites. The contribution of pentose phosphate pathway (PPP) and its related redox status were checked by chemical interfering and silencing/over-expression of glucose-6-phosphate dehydrogenase (G6PD). The downstream products of G6PD were assayed by quantitative real-time PCR, western blot and flow cytometry. Results showed that not only G6PD expression but also G6PD activity was significantly lowered along with 3D MCF-7 cells culture time. Impaired PPP disturbed redox-cycling, generated reactive oxygen species (ROS), which triggered cell cycle arrest and caused the switch to Chk2/p53/NF-κB pathway-mediated P-gp induction. Our results provided a new attempt to associate intrinsic small molecule metabolites (impaired PPP) communicating with cell signalling pathways through disturbed intracellular redox status to elucidate multi-cellular resistance (MCR) in 3D MCF-7 cells, which improved the understanding of the mechanisms of P-gp up-regulation in MCR with metabolomic and related redox status support.

      PubDate: 2018-01-03T13:39:04Z
      DOI: 10.1016/j.redox.2017.12.009
      Issue No: Vol. 15 (2018)
       
  • TiO2 nanoparticles cause mitochondrial dysfunction, activate inflammatory
           responses, and attenuate phagocytosis in macrophages: A proteomic and
           metabolomic insight

    • Authors: Qun Chen; Ningning Wang; Mingjiang Zhu; Jianhong Lu; Huiqin Zhong; Xinli Xue; Shuoyuan Guo; Min Li; Xinben Wei; Yongzhen Tao; Huiyong Yin
      Pages: 266 - 276
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Qun Chen, Ningning Wang, Mingjiang Zhu, Jianhong Lu, Huiqin Zhong, Xinli Xue, Shuoyuan Guo, Min Li, Xinben Wei, Yongzhen Tao, Huiyong Yin
      Titanium dioxide nanoparticles (TiO2 NPs) are widely used in food and cosmetics but the health impact of human exposure remains poorly defined. Emerging evidence suggests that TiO2 NPs may elicit immune responses by acting on macrophages. Our proteomic study showed that treatment of macrophages with TiO2 NPs led to significant re-organization of cell membrane and activation of inflammation. These observations were further corroborated with transmission electron microscopy (TEM) experiments, which demonstrated that TiO2 NPs were trapped inside of multi-vesicular bodies (MVB) through endocytotic pathways. TiO2 NP caused significant mitochondrial dysfunction by increasing levels of mitochondrial reactive oxygen species (ROS), decreasing ATP generation, and decreasing metabolic flux in tricarboxylic acid (TCA) cycle from 13C-labelled glutamine using GC-MS-based metabolic flux analysis. Further lipidomic analysis showed that TiO2 NPs significantly decreased levels of cardiolipins, an important class of mitochondrial phospholipids for maintaining proper function of electron transport chains. Furthermore, TiO2 NP exposure activates inflammatory responses by increasing mRNA levels of TNF-α, iNOS, and COX-2. Consistently, our targeted metabolomic analysis showed significantly increased production of COX-2 metabolites including PGD2, PGE2, and 15d-PGJ2. In addition, TiO2 NP also caused significant attenuation of phagocytotic function of macrophages. In summary, our studies utilizing multiple powerful omic techniques suggest that human exposure of TiO2 NPs may have profound impact on macrophage function through activating inflammatory responses and causing mitochondrial dysfunction without physical presence in mitochondria.
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      PubDate: 2018-01-03T13:39:04Z
      DOI: 10.1016/j.redox.2017.12.011
      Issue No: Vol. 15 (2018)
       
  • Differential mitochondrial dinitrosyliron complex formation by nitrite and
           nitric oxide

    • Authors: Douglas D. Thomas; Catherine Corey; Jason Hickok; Yinna Wang; Sruti Shiva
      Pages: 277 - 283
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Douglas D. Thomas, Catherine Corey, Jason Hickok, Yinna Wang, Sruti Shiva
      Nitrite represents an endocrine reserve of bioavailable nitric oxide (NO) that mediates a number of physiological responses including conferral of cytoprotection after ischemia/reperfusion (I/R). It has long been known that nitrite can react with non-heme iron to form dinitrosyliron complexes (DNIC). However, it remains unclear how quickly nitrite-dependent DNIC form in vivo, whether formation kinetics differ from that of NO-dependent DNIC, and whether DNIC play a role in the cytoprotective effects of nitrite. Here we demonstrate that chronic but not acute nitrite supplementation increases DNIC concentration in the liver and kidney of mice. Although DNIC have been purported to have antioxidant properties, we show that the accumulation of DNIC in vivo is not associated with nitrite-dependent cytoprotection after hepatic I/R. Further, our data in an isolated mitochondrial model of anoxia/reoxygenation show that while NO and nitrite demonstrate similar S-nitrosothiol formation kinetics, DNIC formation is significantly greater with NO and associated with mitochondrial dysfunction as well as inhibition of aconitase activity. These data are the first to directly compare mitochondrial DNIC formation by NO and nitrite. This study suggests that nitrite-dependent DNIC formation is a physiological consequence of dietary nitrite. The data presented herein implicate mitochondrial DNIC formation as a potential mechanism underlying the differential cytoprotective effects of nitrite and NO after I/R, and suggest that DNIC formation is potentially responsible for the cytotoxic effects observed at high NO concentrations.
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      PubDate: 2018-01-03T13:39:04Z
      DOI: 10.1016/j.redox.2017.12.007
      Issue No: Vol. 15 (2018)
       
  • MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting
           myocardial oxidative stress via targeting Nrf2 and Sirt2

    • Authors: Lisha Zhao; Yan Qi; Lina Xu; Xufeng Tao; Xu Han; Lianhong Yin; Jinyong Peng
      Pages: 284 - 296
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Lisha Zhao, Yan Qi, Lina Xu, Xufeng Tao, Xu Han, Lianhong Yin, Jinyong Peng
      Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px. Total of 18 differentially expressed microRNAs in rat heart tissue caused by DOX were screened out using microRNA microarray assay, especially showing that miR-140-5p was significantly increased by DOX which was selected as the target miRNA. Double-luciferase reporter assay showed that miR-140-5p directly targeted Nrf2 and Sirt2, as a result of affecting the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a, and thereby increasing DOX-caused myocardial oxidative damage. In addition, the levels of intracellular ROS were significantly increased or decreased in H9C2 cells treated with DOX after miR-140-5p mimic or miR-140-5p inhibitor transfection, respectively, as well as the changed expression levels of Nrf2 and Sirt2. Furthermore, DOX- induced myocardial oxidative damage was worsened in mice treated with miR-140-5p agomir, and however the injury was alleviated in the mice administrated with miR-140-5p antagomir. Therefore, miR-140-5p plays an important role in DOX-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Our data provide novel insights for investigating DOX-induced heart injury. In addition, miR-140-5p/ Nrf2 and miR-140-5p/Sirt2 may be the new targets to treat DOX-induced cardiotoxicity.
      Graphical abstract image

      PubDate: 2018-01-03T13:39:04Z
      DOI: 10.1016/j.redox.2017.12.013
      Issue No: Vol. 15 (2018)
       
  • Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin
           – Thioredoxin system. 1. Understanding commonalities and differences
           among cell types

    • Authors: Gianluca Selvaggio; Pedro M.B.M. Coelho; Armindo Salvador
      Pages: 297 - 315
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Gianluca Selvaggio, Pedro M.B.M. Coelho, Armindo Salvador
      The system (PTTRS) formed by typical 2-Cys peroxiredoxins (Prx), thioredoxin (Trx), Trx reductase (TrxR), and sulfiredoxin (Srx) is central in antioxidant protection and redox signaling in the cytoplasm of eukaryotic cells. Understanding how the PTTRS integrates these functions requires tracing phenotypes to molecular properties, which is non-trivial. Here we analyze this problem based on a model that captures the PTTRS’ conserved features. We have mapped the conditions that generate each distinct response to H2O2 supply rates (v sup), and estimated the parameters for thirteen human cell types and for Saccharomyces cerevisiae. The resulting composition-to-phenotype map yielded the following experimentally testable predictions. The PTTRS permits many distinct responses including ultra-sensitivity and hysteresis. However, nearly all tumor cell lines showed a similar response characterized by limited Trx-S- depletion and a substantial but self-limited gradual accumulation of hyperoxidized Prx at high v sup. This similarity ensues from strong correlations between the TrxR, Srx and Prx activities over cell lines, which contribute to maintain the Prx-SS reduction capacity in slight excess over the maximal steady state Prx-SS production. In turn, in erythrocytes, hepatocytes and HepG2 cells high v sup depletes Trx-S- and oxidizes Prx mainly to Prx-SS. In all nucleated human cells the Prx-SS reduction capacity defined a threshold separating two different regimes. At sub-threshold v sup the cytoplasmic H2O2 concentration is determined by Prx, nM-range and spatially localized, whereas at supra-threshold v sup it is determined by much less active alternative sinks and μM-range throughout the cytoplasm. The yeast shows a distinct response where the Prx Tsa1 accumulates in sulfenate form at high v sup. This is mainly due to an exceptional stability of Tsa1's sulfenate. The implications of these findings for thiol redox regulation and cell physiology are discussed. All estimates were thoroughly documented and provided, together with analytical approximations for system properties, as a resource for quantitative redox biology.
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      PubDate: 2018-01-03T13:39:04Z
      DOI: 10.1016/j.redox.2017.12.008
      Issue No: Vol. 15 (2018)
       
  • Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes
           human lung cancer cells to anticancer drug-induced death by impairing
           OGG1-dependent base excision repair

    • Authors: Dominika Tempka; Paulina Tokarz; Kinga Chmielewska; Magdalena Kluska; Julita Pietrzak; Żaneta Rygielska; László Virág; Agnieszka Robaszkiewicz
      Pages: 316 - 326
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Dominika Tempka, Paulina Tokarz, Kinga Chmielewska, Magdalena Kluska, Julita Pietrzak, Żaneta Rygielska, László Virág, Agnieszka Robaszkiewicz
      Hallmarks of cancer cells include uncontrolled growth and rapid proliferation; thus, cyclin-dependent kinases are a therapeutic target for cancer treatment. Treating non-small lung cancer cells with sublethal concentrations of the CDK4/6 inhibitors, ribociclib (LEE011) and palbociclib (PD0332991), which are approved by the FDA for anticancer therapies, caused cell cycle arrest in the G1 phase and suppression of poly(ADP-ribose) polymerase 1 (PARP1) transcription by inducing recruitment of the RB1-E2F1-HDAC1-EZH2 repressive complex to the PARP1 promoter. Downregulation of PARP1 made cancer cells vulnerable to death triggered by the anticancer drugs (WP631 and etoposide) and H2O2. All agents brought about redox imbalance and DNA strand breaks. The lack of PARP1 and poly(ADP-ribosyl)ation impaired the 8-oxoguanine glycosylase (OGG1)-dependent base excision DNA repair pathway, which is critical for maintaining the viability of cells treated with CDK4/6 inhibitors during oxidative stress. Upon G1 arrest of PARP1 overexpressing cells, OGG1 formed an immunoprecipitable complex with PARP1. Similar to cells with downregulated PARP1 expression, inhibition of PARP1 or OGG1 in PARP1 overexpressing cells resulted in DNA damage and decreased viability. Thus, PARP1 and OGG1 act in the same regulatory pathway, and PARP1 activity is required for OGG1-mediated repair of oxidative DNA damage in G1-arrested cells. In conclusion, the action of CDK4/6 inhibitors is not limited to the inhibition of cell growth. CDK4/6 inhibitors also lead to accumulation of DNA damage by repressing PARP1 in oxidatively stressed cells. Thus, CDK4/6 inhibitors sensitize G1-arrested cells to anticancer drugs, since these cells require PARP1-OGG1 functional interaction for cell survival.
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      PubDate: 2018-01-03T13:39:04Z
      DOI: 10.1016/j.redox.2017.12.017
      Issue No: Vol. 15 (2018)
       
  • Sulfite-induced protein radical formation in LPS aerosol-challenged mice:
           Implications for sulfite sensitivity in human lung disease

    • Authors: Ashutosh Kumar; Mathilde Triquigneaux; Jennifer Madenspacher; Kalina Ranguelova; John J. Bang; Michael B. Fessler; Ronald P. Mason
      Pages: 327 - 334
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Ashutosh Kumar, Mathilde Triquigneaux, Jennifer Madenspacher, Kalina Ranguelova, John J. Bang, Michael B. Fessler, Ronald P. Mason
      Exposure to (bi)sulfite (HSO3 –) and sulfite (SO3 2–) has been shown to induce a wide range of adverse reactions in sensitive individuals. Studies have shown that peroxidase-catalyzed oxidation of (bi)sulfite leads to formation of several reactive free radicals, such as sulfur trioxide anion (.SO3 –), peroxymonosulfate (–O3SOO.), and especially the sulfate (SO4 . –) anion radicals. One such peroxidase in neutrophils is myeloperoxidase (MPO), which has been shown to form protein radicals. Although formation of (bi)sulfite-derived protein radicals is documented in isolated neutrophils, its involvement and role in in vivo inflammatory processes, has not been demonstrated. Therefore, we aimed to investigate (bi)sulfite-derived protein radical formation and its mechanism in LPS aerosol-challenged mice, a model of non-atopic asthma. Using immuno-spin trapping to detect protein radical formation, we show that, in the presence of (bi)sulfite, neutrophils present in bronchoalveolar lavage and in the lung parenchyma exhibit, MPO-catalyzed oxidation of MPO to a protein radical. The absence of radical formation in LPS-challenged MPO- or NADPH oxidase-knockout mice indicates that sulfite-derived radical formation is dependent on both MPO and NADPH oxidase activity. In addition to its oxidation by the MPO-catalyzed pathway, (bi)sulfite is efficiently detoxified to sulfate by the sulfite oxidase (SOX) pathway, which forms sulfate in a two-electron oxidation reaction. Since SOX activity in rodents is much higher than in humans, to better model sulfite toxicity in humans, we induced SOX deficiency in mice by feeding them a low molybdenum diet with tungstate. We found that mice treated with the SOX deficiency diet prior to exposure to (bi)sulfite had much higher protein radical formation than mice with normal SOX activity. Altogether, these results demonstrate the role of MPO and NADPH oxidase in (bi)sulfite-derived protein radical formation and show the involvement of protein radicals in a mouse model of human lung disease.

      PubDate: 2018-01-10T13:44:16Z
      DOI: 10.1016/j.redox.2017.12.014
      Issue No: Vol. 15 (2018)
       
  • Empagliflozin rescues diabetic myocardial microvascular injury via
           AMPK-mediated inhibition of mitochondrial fission

    • Authors: Hao Zhou; Shuyi Wang; Pingjun Zhu; Shunying Hu; Yundai Chen; Jun Ren
      Pages: 335 - 346
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Hao Zhou, Shuyi Wang, Pingjun Zhu, Shunying Hu, Yundai Chen, Jun Ren
      Impaired cardiac microvascular function contributes to diabetic cardiovascular complications although effective therapy remains elusive. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor recently approved for treatment of type 2 diabetes, promotes glycosuria excretion and offers cardioprotective actions beyond its glucose-lowering effects. This study was designed to evaluate the effect of empagliflozin on cardiac microvascular injury in diabetes and the underlying mechanism involved with a focus on mitochondria. Our data revealed that empagliflozin improved diabetic myocardial structure and function, preserved cardiac microvascular barrier function and integrity, sustained eNOS phosphorylation and endothelium-dependent relaxation, as well as improved microvessel density and perfusion. Further study suggested that empagliflozin exerted its effects through inhibition of mitochondrial fission in an adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent manner. Empagliflozin restored AMP-to-ATP ratio to trigger AMPK activation, suppressed Drp1S616 phosphorylation, and increased Drp1S637 phosphorylation, ultimately leading to inhibition of mitochondrial fission. The empagliflozin-induced inhibition of mitochondrial fission preserved cardiac microvascular endothelial cell (CMEC) barrier function through suppressed mitochondrial reactive oxygen species (mtROS) production and subsequently oxidative stress to impede CMEC senescence. Empagliflozin-induced fission loss also favored angiogenesis by promoting CMEC migration through amelioration of F-actin depolymerization. Taken together, these results indicated the therapeutic promises of empagliflozin in the treatment of pathological microvascular changes in diabetes.

      PubDate: 2018-01-10T13:44:16Z
      DOI: 10.1016/j.redox.2017.12.019
      Issue No: Vol. 15 (2018)
       
  • Teaching the basics of reactive oxygen species and their relevance to
           cancer biology: Mitochondrial reactive oxygen species detection, redox
           signaling, and targeted therapies

    • Authors: Balaraman Kalyanaraman; Gang Cheng; Micael Hardy; Olivier Ouari; Brian Bennett; Jacek Zielonka
      Pages: 347 - 362
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Balaraman Kalyanaraman, Gang Cheng, Micael Hardy, Olivier Ouari, Brian Bennett, Jacek Zielonka
      Reactive oxygen species (ROS) have been implicated in tumorigenesis (tumor initiation, tumor progression, and metastasis). Of the many cellular sources of ROS generation, the mitochondria and the NADPH oxidase family of enzymes are possibly the most prevalent intracellular sources. In this article, we discuss the methodologies to detect mitochondria-derived superoxide and hydrogen peroxide using conventional probes as well as newly developed assays and probes, and the necessity of characterizing the diagnostic marker products with HPLC and LC-MS in order to rigorously identify the oxidizing species. The redox signaling roles of mitochondrial ROS, mitochondrial thiol peroxidases, and transcription factors in response to mitochondria-targeted drugs are highlighted. ROS generation and ROS detoxification in drug-resistant cancer cells and the relationship to metabolic reprogramming are discussed. Understanding the subtle role of ROS in redox signaling and in tumor proliferation, progression, and metastasis as well as the molecular and cellular mechanisms (e.g., autophagy) could help in the development of combination therapies. The paradoxical aspects of antioxidants in cancer treatment are highlighted in relation to the ROS mechanisms in normal and cancer cells. Finally, the potential uses of newly synthesized exomarker probes for in vivo superoxide and hydrogen peroxide detection and the low-temperature electron paramagnetic resonance technique for monitoring oxidant production in tumor tissues are discussed.

      PubDate: 2018-01-10T13:44:16Z
      DOI: 10.1016/j.redox.2017.12.012
      Issue No: Vol. 15 (2018)
       
  • A single-cysteine mutant and chimeras of essential Leishmania Erv can
           complement the loss of Erv1 but not of Mia40 in yeast

    • Authors: Sandra Specht; Linda Liedgens; Margarida Duarte; Alexandra Stiegler; Ulrike Wirth; Maike Eberhardt; Ana Tomás; Kai Hell; Marcel Deponte
      Pages: 363 - 374
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Sandra Specht, Linda Liedgens, Margarida Duarte, Alexandra Stiegler, Ulrike Wirth, Maike Eberhardt, Ana Tomás, Kai Hell, Marcel Deponte
      Mia40/CHCHD4 and Erv1/ALR are essential for oxidative protein folding in the mitochondrial intermembrane space of yeast and mammals. In contrast, many protists, including important apicomplexan and kinetoplastid parasites, lack Mia40. Furthermore, the Erv homolog of the model parasite Leishmania tarentolae (LtErv) was shown to be incompatible with Saccharomyces cerevisiae Mia40 (ScMia40). Here we addressed structure-function relationships of ScErv1 and LtErv as well as their compatibility with the oxidative protein folding system in yeast using chimeric, truncated, and mutant Erv constructs. Chimeras between the N-terminal arm of ScErv1 and a variety of truncated LtErv constructs were able to rescue yeast cells that lack ScErv1. Yeast cells were also viable when only a single cysteine residue was replaced in LtErvC17S. Thus, the presence and position of the C-terminal arm and the kinetoplastida-specific second (KISS) domain of LtErv did not interfere with its functionality in the yeast system, whereas a relatively conserved cysteine residue before the flavodomain rendered LtErv incompatible with ScMia40. The question whether parasite Erv homologs might also exert the function of Mia40 was addressed in another set of complementation assays. However, neither the KISS domain nor other truncated or mutant LtErv constructs were able to rescue yeast cells that lack ScMia40. The general relevance of Erv and its candidate substrate small Tim1 was analyzed for the related parasite L. infantum. Repeated unsuccessful knockout attempts suggest that both genes are essential in this human pathogen and underline the potential of mitochondrial protein import pathways for future intervention strategies.
      Graphical abstract image

      PubDate: 2018-01-10T13:44:16Z
      DOI: 10.1016/j.redox.2017.12.010
      Issue No: Vol. 15 (2018)
       
  • Administration of exercise-conditioned plasma alters muscle catalase
           kinetics in rat: An argument for in vivo-like Km instead of in vitro-like
           Vmax

    • Authors: Aristidis S. Veskoukis; Vassilis Paschalis; Antonios Kyparos; Michalis G. Nikolaidis
      Pages: 375 - 379
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Aristidis S. Veskoukis, Vassilis Paschalis, Antonios Kyparos, Michalis G. Nikolaidis
      Maximal velocity (Vmax) is a well established biomarker for the assessment of tissue redox status. There is scarce evidence, though, that it does not probably reflect sufficiently in vivo tissue redox profile. Instead, the Michaelis constant (Km) could more adequately image tissue oxidative stress and, thus, be a more physiologically relevant redox biomarker. Therefore, the aim of the present study was to side-by-side compare Vmax and Km of an antioxidant enzyme after implementing an in vivo set up that induces alterations in tissue redox status. Forty rats were divided into two groups including rats injected with blood plasma originating from rats that had previously swam until exhaustion and rats injected with blood plasma originating from sedentary rats. Tail-vein injections were performed daily for 21 days. Catalase Vmax and Km measured in gastrocnemius muscle were increased after administration of the exercise-conditioned plasma, denoting enhancement of the enzyme activity but impairment of its affinity for the substrate, respectively. These alterations are potential adaptations stimulated by the administered plasma pointing out that blood is an active fluid capable of regulating tissue homeostasis. Our findings suggest that Km adequately reflects in vivo modifications of skeletal muscle catalase and seems to surpass Vmax regarding its physiological relevance and biological interpretation. In conclusion, Km can be regarded as an in vivo-like biomarker that satisfactorily images the intracellular environment, as compared to Vmax that could be aptly parallelized with a biomarker that describes tissue oxidative stress in an in vitro manner.

      PubDate: 2018-01-10T13:44:16Z
      DOI: 10.1016/j.redox.2018.01.001
      Issue No: Vol. 15 (2018)
       
  • Blocking LPA-dependent signaling increases ovarian cancer cell death in
           response to chemotherapy

    • Authors: LeAnn C. Rogers; Ryan R. Davis; Naveen Said; Thomas Hollis; Larry W. Daniel
      Pages: 380 - 386
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): LeAnn C. Rogers, Ryan R. Davis, Naveen Said, Thomas Hollis, Larry W. Daniel
      The paradoxical role of reactive oxygen species in cell death versus cell survival establishes a delicate balance between chemotherapy efficacy and management of detrimental side effects. Normal proliferative signaling requires that cells remain inside a redox range that allows reversible protein oxidation to occur. Shifting the redox environment toward highly reducing or oxidizing states leads to cellular stress and cell death. Reactive oxygen species produced in response to Taxol and cisplatin treatment are necessary for effective cancer cell killing but the same ROS leads to damaging side effects in normal tissues. Combining antioxidants with chemotherapeutics to alleviate the unwanted side effects produces variable and often undesirable effects on cancer treatment. Here, we describe a more targeted method to improve ovarian cancer cell killing without the need for antioxidants. In ovarian cancer cells, lysophosphatidic acid (LPA) is a prominent growth factor that contributes to tumor survival and proliferation. We find that blocking LPA-dependent signaling with a specific receptor antagonist consistently increases cell death in response to both Taxol and cisplatin. We propose that inhibiting the upregulated growth factor-dependent signaling in cancer cells will target chemo-insensitivity, potentially lowering the necessary dose of the drugs and preventing harmful side effects.
      Graphical abstract image

      PubDate: 2018-01-10T13:44:16Z
      DOI: 10.1016/j.redox.2018.01.002
      Issue No: Vol. 15 (2018)
       
  • Oxidized LDL triggers changes in oxidative stress and inflammatory
           biomarkers in human macrophages

    • Authors: Oscar J. Lara-Guzmán; Ángel Gil-Izquierdo; Sonia Medina; Edison Osorio; Rafael Álvarez-Quintero; Natalia Zuluaga; Camille Oger; Jean-Marie Galano; Thierry Durand; Katalina Muñoz-Durango
      Pages: 1 - 11
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Oscar J. Lara-Guzmán, Ángel Gil-Izquierdo, Sonia Medina, Edison Osorio, Rafael Álvarez-Quintero, Natalia Zuluaga, Camille Oger, Jean-Marie Galano, Thierry Durand, Katalina Muñoz-Durango
      Oxidized low-density lipoprotein (oxLDL) is a well-recognized proatherogenic particle that functions in atherosclerosis. In this study, we established conditions to generate human oxLDL, characterized according to the grade of lipid and protein oxidation, particle size and oxylipin content. The induction effect of the cellular proatherogenic response was assessed in foam cells by using an oxLDL-macrophage interaction model. Uptake of oxLDL, reactive oxygen species production and expression of oxLDL receptors (CD36, SR-A and LOX-1) were significantly increased in THP-1 macrophages. Analyses of 35 oxylipins revealed that isoprostanes (IsoP) and prostaglandins (PGs) derived from the oxidation of arachidonic, dihomo gamma-linolenic and eicosapentaenoic acids were strongly and significantly induced in macrophages stimulated with oxLDL. Importantly, the main metabolites responsible for the THP1-macrophage response to oxLDL exposure were the oxidative stress markers 5-epi-5-F2t-IsoP, 15-E1t-IsoP, 8-F3t-IsoP and 15-keto-15-F2t-IsoP as well as inflammatory markers PGDM, 17-trans-PGF3α, and 11β-PGF2α, all of which are reported here, for the first time, to function in the interaction of oxLDL with THP-1 macrophages. By contrast, a salvage pathway mediated by anti-inflammatory PGs (PGE1 and 17-trans-PGF3α) was also identified, suggesting a response to oxLDL-induced injury. In conclusion, when THP-1 macrophages were treated with oxLDL, a specific induction of biomarkers related to oxidative stress and inflammation was triggered. This work contributes to our understanding of initial atherogenic events mediated by oxLDL-macrophage interactions and helps to generate new approaches for their modulation.
      Graphical abstract image

      PubDate: 2017-11-30T03:59:41Z
      DOI: 10.1016/j.redox.2017.11.017
      Issue No: Vol. 15 (2017)
       
  • The NADPH organizers NoxO1 and p47phox are both mediators of
           diabetes-induced vascular dysfunction in mice

    • Authors: Flávia Rezende; Franziska Moll; Maria Walter; Valeska Helfinger; Fabian Hahner; Patrick Janetzko; Christian Ringel; Andreas Weigert; Ingrid Fleming; Norbert Weissmann; Carsten Kuenne; Mario Looso; Michael A. Rieger; Peter Nawroth; Thomas Fleming; Ralf P. Brandes; Katrin Schröder
      Pages: 12 - 21
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Flávia Rezende, Franziska Moll, Maria Walter, Valeska Helfinger, Fabian Hahner, Patrick Janetzko, Christian Ringel, Andreas Weigert, Ingrid Fleming, Norbert Weissmann, Carsten Kuenne, Mario Looso, Michael A. Rieger, Peter Nawroth, Thomas Fleming, Ralf P. Brandes, Katrin Schröder
      Aim NADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes. Results In the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice. Innovation and conclusion ROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.
      Graphical abstract image

      PubDate: 2017-11-30T03:59:41Z
      DOI: 10.1016/j.redox.2017.11.014
      Issue No: Vol. 15 (2017)
       
  • Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by
           suppressing inflammation and oxidative stress

    • Authors: Dong-Jie Li; Hui Fu; Jie Tong; Yong-Hua Li; Le-Feng Qu; Pei Wang; Fu-Ming Shen
      Pages: 22 - 33
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Dong-Jie Li, Hui Fu, Jie Tong, Yong-Hua Li, Le-Feng Qu, Pei Wang, Fu-Ming Shen
      Neointimal hyperplasia as a consequence of vascular injury is aggravated by inflammatory reaction and oxidative stress. The α7 nicotinic acetylcholine receptor (α7nAChR) is a orchestrator of cholinergic anti-inflammatory pathway (CAP), which refers to a physiological neuro-immune mechanism that restricts inflammation. Here, we investigated the potential role of CAP in neointimal hyperplasia using α7nAChR knockout (KO) mice. Male α7nAChR-KO mice and their wild-type control mice (WT) were subjected to wire injury in left common carotid artery. At 4 weeks post injury, the injured aortae were isolated for examination. The neointimal hyperplasia after wire injury was significantly aggravated in α7nAChR-KO mice compared with WT mice. The α7nAChR-KO mice had increased collagen contents and vascular smooth muscle cells (VSMCs) amount. Moreover, the inflammation was significantly enhanced in the neointima of α7nAChR-KO mice relative to WT mice, evidenced by the increased expression of tumor necrosis factor-α/interleukin-1β, and macrophage infiltration. Meanwhile, the chemokines chemokine (C-C motif) ligand 2 and chemokine (CXC motif) ligand 2 expression was also augmented in the neointima of α7nAChR-KO mice compared with WT mice. Additionally, the depletion of superoxide dismutase (SOD) and reduced glutathione (GSH), and the upregulation of 3-nitrotyrosine, malondialdehyde and myeloperoxidase were more pronounced in neointima of α7nAChR-KO mice compared with WT mice. Accordingly, the protein expression of NADPH oxidase 1 (Nox1), Nox2 and Nox4, was also higher in neointima of α7nAChR-KO mice compared with WT mice. Finally, pharmacologically activation of CAP with a selective α7nAChR agonist PNU-282987, significantly reduced neointima formation, arterial inflammation and oxidative stress after vascular injury in C57BL/6 mice. In conclusion, our results demonstrate that α7nAChR-mediated CAP is a neuro-physiological mechanism that inhibits neointima formation after vascular injury via suppressing arterial inflammation and oxidative stress. Further, these results imply that targeting α7nAChR may be a promising interventional strategy for in-stent stenosis.

      PubDate: 2017-11-30T03:59:41Z
      DOI: 10.1016/j.redox.2017.11.013
      Issue No: Vol. 15 (2017)
       
  • Developing the next generation of graphene-based platforms for cancer
           therapeutics: The potential role of reactive oxygen species

    • Authors: Tanveer A. Tabish; Shaowei Zhang; Paul G. Winyard
      Pages: 34 - 40
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Tanveer A. Tabish, Shaowei Zhang, Paul G. Winyard
      Graphene has a promising future in applications such as disease diagnosis, cancer therapy, drug/gene delivery, bio-imaging and antibacterial approaches owing to graphene's unique physical, chemical and mechanical properties alongside minimal toxicity to normal cells, and photo-stability. However, these unique features and bioavailability of graphene are fraught with uncertainties and concerns for environmental and occupational exposure. Changes in the physicochemical properties of graphene affect biological responses including reactive oxygen species (ROS) production. Lower production of ROS by currently available theranostic agents, e.g. magnetic nanoparticles, carbon nanotubes, gold nanostructures or polymeric nanoparticles, restricts their clinical application in cancer therapy. Oxidative stress induced by graphene accumulated in living organs is due to acellular factors which may affect physiological interactions between graphene and target tissues and cells. Acellular factors include particle size, shape, surface charge, surface containing functional groups, and light activation. Cellular responses such as mitochondrial respiration, graphene-cell interactions and pH of the medium are also determinants of ROS production. The mechanisms of ROS production by graphene and the role of ROS for cancer treatment, are poorly understood. The aim of this review is to set the theoretical basis for further research in developing graphene-based theranostic platforms.

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.11.018
      Issue No: Vol. 15 (2017)
       
  • Redox system and phospholipid metabolism in the kidney of hypertensive
           rats after FAAH inhibitor URB597 administration

    • Authors: Michał Biernacki; Ewa Ambrożewicz; Agnieszka Gęgotek; Marek Toczek; Katarzyna Bielawska; Elżbieta Skrzydlewska
      Pages: 41 - 50
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Michał Biernacki, Ewa Ambrożewicz, Agnieszka Gęgotek, Marek Toczek, Katarzyna Bielawska, Elżbieta Skrzydlewska
      Primary and secondary hypertension is associated with kidney redox imbalance resulting in enhanced reactive oxygen species (ROS) and enzymes dependent phospholipid metabolism. The fatty acid amide hydrolase inhibitor, URB597, modulates the levels of endocannabinoids, particularly of anandamide, which is responsible for controlling blood pressure and regulating redox balance. Therefore, this study aimed to compare the effects of chronic URB597 administration to spontaneously hypertensive rats (SHR) and rats with secondary hypertension (DOCA-salt rats) on the kidney metabolism associated with the redox and endocannabinoid systems. It was shown fatty acid amide hydrolase (FAAH) inhibitor decreased the activity of ROS-generated enzymes what resulted in a reduction of ROS level. Moreover varied changes in antioxidant parameters were observed with tendency to improve antioxidant defense in SHR kidney. Moreover, URB597 administration to hypertensive rats decreased pro-inflammatory response, particularly in the kidneys of DOCA-salt hypertensive rats. URB597 had tendency to enhance ROS-dependent phospholipid oxidation, estimated by changes in neuroprostanes in the kidney of SHR and reactive aldehydes (4-hydroxynonenal and malondialdehyde) in DOCA-salt rats, in particular. The administration of FAAH inhibitor resulted in increased level of endocannabinoids in kidney of both groups of hypertensive rats led to enhanced expression of the cannabinoid receptors type 1 and 2 in SHR as well as vanilloid receptor 1 receptors in DOCA-salt rats. URB597 given to normotensive rats also affected kidney oxidative metabolism, resulting in enhanced level of neuroprostanes in Wistar Kyoto rats and reactive aldehydes in Wistar rats. Moreover, the level of endocannabinoids and cannabinoid receptors were significantly higher in both control groups of rats after URB597 administration. In conclusion, because URB597 disturbed the kidney redox system and phospholipid ROS-dependent and enzymatic-dependent metabolism, the administration of this inhibitor may enhance kidney disorders depending on model of hypertension, but may also cause kidney disturbances in control rats. Therefore, further studies are warranted.
      Graphical abstract image

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.11.022
      Issue No: Vol. 15 (2017)
       
  • Loss of heme oxygenase-1 accelerates mesodermal gene expressions during
           embryoid body development from mouse embryonic stem cells

    • Authors: Yan-Liang Lai; Chen-Yu Lin; Wei-Cheng Jiang; Yen-Chun Ho; Chung-Huang Chen; Shaw-Fang Yet
      Pages: 51 - 61
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Yan-Liang Lai, Chen-Yu Lin, Wei-Cheng Jiang, Yen-Chun Ho, Chung-Huang Chen, Shaw-Fang Yet
      Heme oxygenase (HO)-1 is an inducible stress response protein and well known to protect cells and tissues against injury. Despite its important function in cytoprotection against physiological stress, the role of HO-1 in embryonic stem cell (ESC) differentiation remains largely unknown. We showed previously that induced pluripotent stem (iPS) cells that lack HO-1 are more sensitive to oxidant stress-induced cell death and more prone to lose pluripotent markers upon LIF withdrawal. To elucidate the role of HO-1 in ESC differentiation and to rule out the controversy of potential gene flaws in iPS cells, we derived and established mouse HO-1 knockout ESC lines from HO-1 knockout blastocysts. Using wild type D3 and HO-1 knockout ESCs in the 3-dimensional embryoid body (EB) differentiation model, we showed that at an early time point during EB development, an absence of HO-1 led to enhanced ROS level, concomitant with increased expressions of master mesodermal regulator brachyury and endodermal marker GATA6. In addition, critical smooth muscle cell (SMC) transcription factor serum response factor and its coactivator myocardin were enhanced. Furthermore, HO-1 deficiency increased Smad2 in ESCs and EBs, revealing a role of HO-1 in controlling Smad2 level. Smad2 not only mediates mesendoderm differentiation of mouse ESCs but also SMC development. Collectively, loss of HO-1 resulted in higher level of mesodermal and SMC regulators, leading to accelerated and enhanced SMC marker SM α-actin expression. Our results reveal a previously unrecognized function of HO-1 in regulating SMC gene expressions during ESC-EB development. More importantly, our findings may provide a novel strategy in enhancing ESC differentiation toward SMC lineage.
      Graphical abstract image

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.11.019
      Issue No: Vol. 15 (2017)
       
  • Cardioprotection of CAPE-oNO2 against myocardial ischemia/reperfusion
           induced ROS generation via regulating the SIRT1/eNOS/NF-κB pathway in
           vivo and in vitro

    • Authors: Dejuan Li; Xiaoling Wang; Qin Huang; Sai Li; You Zhou; Zhubo Li
      Pages: 62 - 73
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Dejuan Li, Xiaoling Wang, Qin Huang, Sai Li, You Zhou, Zhubo Li
      Caffeic acid phenethyl ester (CAPE) could ameliorate myocardial ischemia/reperfusion injury (MIRI) by various mechanisms, but there hadn’t been any reports on that CAPE could regulate silent information regulator 1 (SIRT1) and endothelial nitric oxide synthase (eNOS) to exert cardioprotective effect. The present study aimed to investigate the cardioprotective potential of caffeic acid o-nitro phenethyl ester (CAPE-oNO2) on MIRI and the possible mechanism based on the positive control of CAPE. The SD rats were subjected to left coronary artery ischemia /reperfusion (IR) and the H9c2 cell cultured in hypoxia/reoxygenation (HR) to induce the MIRI model. Prior to the procedure, vehicle, CAPE or CAPE-oNO2 were treated in the absence or presence of a SIRT1 inhibitor nicotinamide (NAM) and an eNOS inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). In vivo, CAPE and CAPE-oNO2 conferred a cardioprotective effect as shown by reduced myocardial infarct size, cardiac marker enzymes and structural abnormalities. From immunohistochemical and sirius red staining, above two compounds ameliorated the TNF-α release and collagen deposition of IR rat hearts. They could agitate SIRT1 and eNOS expression, and consequently enhance NO release and suppress NF-κB signaling, to reduce the malondialdehyde content and cell necrosis. In vitro, they could inhibit HR-induced H9c2 cell apoptosis and ROS generation by activating SIRT1/eNOS pathway and inhabiting NF-κB expression. Emphatically, CAPE-oNO2 presented the stronger cardioprotection than CAPE both in vivo and in vitro. However, NAM and L-NAME eliminated the CAPE-oNO2-mediated cardioprotection by restraining SIRT1 and eNOS expression, respectively. It suggested that CAPE-oNO2 ameliorated MIRI by suppressing the oxidative stress, inflammatory response, fibrosis and necrocytosis via the SIRT1/eNOS/NF-κB pathway.
      Graphical abstract image

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.11.023
      Issue No: Vol. 15 (2017)
       
  • Metabolism of hydrogen sulfide (H2S) and Production of Reactive Sulfur
           Species (RSS) by superoxide dismutase

    • Authors: Kenneth R. Olson; Yan Gao; Faihaan Arif; Kanika Arora; Shivali Patel; Eric. R. DeLeon; Thomas R. Sutton; Martin Feelisch; Miriam M. Cortese-Krott; Karl D. Straub
      Pages: 74 - 85
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Kenneth R. Olson, Yan Gao, Faihaan Arif, Kanika Arora, Shivali Patel, Eric. R. DeLeon, Thomas R. Sutton, Martin Feelisch, Miriam M. Cortese-Krott, Karl D. Straub
      Reactive sulfur species (RSS) such as H2S, HS•, H2Sn, (n = 2–7) and HS2 •- are chemically similar to H2O and the reactive oxygen species (ROS) HO•, H2O2, O2 •- and act on common biological effectors. RSS were present in evolution long before ROS, and because both are metabolized by catalase it has been suggested that “antioxidant” enzymes originally evolved to regulate RSS and may continue to do so today. Here we examined RSS metabolism by Cu/Zn superoxide dismutase (SOD) using amperometric electrodes for dissolved H2S, a polysulfide-specific fluorescent probe (SSP4), and mass spectrometry to identify specific polysulfides (H2S2-H2S5). H2S was concentration- and oxygen-dependently oxidized by 1μM SOD to polysulfides (mainly H2S2, and to a lesser extent H2S3 and H2S5) with an EC50 of approximately 380μM H2S. H2S concentrations > 750μM inhibited SOD oxidation (IC50 = 1.25mM) with complete inhibition when H2S > 1.75mM. Polysulfides were not metabolized by SOD. SOD oxidation preferred dissolved H2S over hydrosulfide anion (HS-), whereas HS- inhibited polysulfide production. In hypoxia, other possible electron donors such as nitrate, nitrite, sulfite, sulfate, thiosulfate and metabisulfite were ineffective. Manganese SOD also catalyzed H2S oxidation to form polysulfides, but did not metabolize polysulfides indicating common attributes of these SODs. These experiments suggest that, unlike the well-known SOD-mediated dismutation of two O2 •- to form H2O2 and O2 , SOD catalyzes a reaction using H2S and O2 to form persulfide. These can then combine in various ways to form polysulfides and sulfur oxides. It is also possible that H2S (or polysulfides) interact/react with SOD cysteines to affect catalytic activity or to directly contribute to sulfide metabolism. Our studies suggest that H2S metabolism by SOD may have been an ancient mechanism to detoxify sulfide or to regulate RSS and along with catalase may continue to do so in contemporary organisms.

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.11.009
      Issue No: Vol. 15 (2017)
       
  • Synergistic interaction of fatty acids and oxysterols impairs
           mitochondrial function and limits liver adaptation during nafld
           progression

    • Authors: Francesco Bellanti; Rosanna Villani; Rosanna Tamborra; Maria Blonda; Giuseppina Iannelli; Giorgia di Bello; Antonio Facciorusso; Giuseppe Poli; Luigi Iuliano; Carlo Avolio; Gianluigi Vendemiale; Gaetano Serviddio
      Pages: 86 - 96
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Francesco Bellanti, Rosanna Villani, Rosanna Tamborra, Maria Blonda, Giuseppina Iannelli, Giorgia di Bello, Antonio Facciorusso, Giuseppe Poli, Luigi Iuliano, Carlo Avolio, Gianluigi Vendemiale, Gaetano Serviddio
      The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury.
      Graphical abstract image

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.11.016
      Issue No: Vol. 15 (2017)
       
  • HIV-1 Tat protein induces DNA damage in human peripheral blood
           B-lymphocytes via mitochondrial ROS production

    • Authors: Rawan El-Amine; Diego Germini; Vlada V. Zakharova; Tatyana Tsfasman; Eugene V. Sheval; Ruy A.N. Louzada; Corinne Dupuy; Chrystèle Bilhou-Nabera; Aline Hamade; Fadia Najjar; Eric Oksenhendler; Marс Lipinski; Boris V. Chernyak; Yegor S. Vassetzky
      Pages: 97 - 108
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Rawan El-Amine, Diego Germini, Vlada V. Zakharova, Tatyana Tsfasman, Eugene V. Sheval, Ruy A.N. Louzada, Corinne Dupuy, Chrystèle Bilhou-Nabera, Aline Hamade, Fadia Najjar, Eric Oksenhendler, Marс Lipinski, Boris V. Chernyak, Yegor S. Vassetzky
      Human immunodeficiency virus (HIV) infection is associated with B-cell malignancies in patients though HIV-1 is not able to infect B-cells. The rate of B-cell lymphomas in HIV-infected individuals remains high even under the combined antiretroviral therapy (cART) that reconstitutes the immune function. Thus, the contribution of HIV-1 to B-cell oncogenesis remains enigmatic. HIV-1 induces oxidative stress and DNA damage in infected cells via multiple mechanisms, including viral Tat protein. We have detected elevated levels of reactive oxygen species (ROS) and DNA damage in B-cells of HIV-infected individuals. As Tat is present in blood of infected individuals and is able to transduce cells, we hypothesized that it could induce oxidative DNA damage in B-cells promoting genetic instability and malignant transformation. Indeed, incubation of B-cells isolated from healthy donors with purified Tat protein led to oxidative stress, a decrease in the glutathione (GSH) levels, DNA damage and appearance of chromosomal aberrations. The effects of Tat relied on its transcriptional activity and were mediated by NF-κB activation. Tat stimulated oxidative stress in B-cells mostly via mitochondrial ROS production which depended on the reverse electron flow in Complex I of respiratory chain. We propose that Tat-induced oxidative stress, DNA damage and chromosomal aberrations are novel oncogenic factors favoring B-cell lymphomas in HIV-1 infected individuals.
      Graphical abstract image

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.11.024
      Issue No: Vol. 15 (2017)
       
  • Cytochrome b5 reductase is the component from neuronal synaptic plasma
           membrane vesicles that generates superoxide anion upon stimulation by
           cytochrome c

    • Authors: Alejandro K. Samhan-Arias; Sofia Fortalezas; Cristina M. Cordas; Isabel Moura; José J.G. Moura; Carlos Gutierrez-Merino
      Pages: 109 - 114
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Alejandro K. Samhan-Arias, Sofia Fortalezas, Cristina M. Cordas, Isabel Moura, José J.G. Moura, Carlos Gutierrez-Merino
      In this work, we measured the effect of cytochrome c on the NADH-dependent superoxide anion production by synaptic plasma membrane vesicles from rat brain. In these membranes, the cytochrome c stimulated NADH-dependent superoxide anion production was inhibited by antibodies against cytochrome b 5 reductase linking the production to this enzyme. Measurement of the superoxide anion radical generated by purified recombinant soluble and membrane cytochrome b 5 reductase corroborates the production of the radical by different enzyme isoforms. In the presence of cytochrome c, a burst of superoxide anion as well as the reduction of cytochrome c by cytochrome b 5 reductase was measured. Complex formation between both proteins suggests that cytochrome b 5 reductase is one of the major partners of cytochrome c upon its release from mitochondria to the cytosol during apoptosis. Superoxide anion production and cytochrome c reduction are the consequences of the stimulated NADH consumption by cytochrome b 5 reductase upon complex formation with cytochrome c and suggest a major role of this enzyme as an anti-apoptotic protein during cell death.

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.11.021
      Issue No: Vol. 15 (2017)
       
  • Trehalose protects against oxidative stress by regulating the Keap1–Nrf2
           and autophagy pathways

    • Authors: Yuhei Mizunoe; Masaki Kobayashi; Yuka Sudo; Shukoh Watanabe; Hiromine Yasukawa; Daiki Natori; Ayana Hoshino; Arisa Negishi; Naoyuki Okita; Masaaki Komatsu; Yoshikazu Higami
      Pages: 115 - 124
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Yuhei Mizunoe, Masaki Kobayashi, Yuka Sudo, Shukoh Watanabe, Hiromine Yasukawa, Daiki Natori, Ayana Hoshino, Arisa Negishi, Naoyuki Okita, Masaaki Komatsu, Yoshikazu Higami
      Dysfunction of autophagy, which regulates cellular homeostasis by degrading organelles and proteins, is associated with pathogenesis of various diseases such as cancer, neurodegeneration and metabolic disease. Trehalose, a naturally occurring nontoxic disaccharide found in plants, insects, microorganisms and invertebrates, but not in mammals, was reported to function as a mechanistic target of the rapamycin (mTOR)-independent inducer of autophagy. In addition, trehalose functions as an antioxidant though its underlying molecular mechanisms remain unclear. In this study, we showed that trehalose not only promoted autophagy, but also increased p62 protein expression, in an autophagy-independent manner. In addition, trehalose increased nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in a p62-dependent manner and enhance expression of its downstream antioxidant factors, heme oxygenase-1 (Ho-1) and nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (Nqo1). Moreover, treatment with trehalose significantly reduced amount of reactive oxygen species. Collectively, these results suggested that trehalose can function as a novel activator of the p62–Keap1/Nrf2 pathway, in addition to inducing autophagy. Therefore, trehalose may be useful to treat many chronic diseases involving oxidative stress and dysfunction of autophagy.

      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.09.007
      Issue No: Vol. 15 (2017)
       
  • Small Maf functions in the maintenance of germline stem cells in the
           Drosophila testis

    • Authors: Sharon Wui Sing Tan; George W. Yip; Toshio Suda; Gyeong Hun Baeg
      Pages: 125 - 134
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Sharon Wui Sing Tan, George W. Yip, Toshio Suda, Gyeong Hun Baeg
      Reactive oxygen species (ROS) are byproducts generated during normal cellular metabolism, and redox states have been shown to influence stem cell self-renewal and lineage commitment across phyla. However, the downstream effectors of ROS signaling that control stem cell behavior remain largely unexplored. Here, we used the Drosophila testis as an in vivo model to identify ROS-induced effectors that are involved in the differentiation process of germline stem cells (GSCs). In the Affymetrix microarray analysis, 152 genes were either upregulated or downregulated during GSC differentiation induced by elevated levels of ROS, and a follow-up validation of the gene expression by qRT-PCR showed a Spearman's rho of 0.9173 (P<0.0001). Notably, 47 (31%) of the identified genes had no predicted molecular function or recognizable protein domain. These suggest the robustness of this microarray analysis, which identified many uncharacterized genes, possibly with an essential role in ROS-induced GSC differentiation. We also showed that maf-S is transcriptionally downregulated by oxidative stress, and that maf-S knockdown promotes GSC differentiation but Maf-S overexpression conversely results in an over-growth of GSC-like cells by promoting the mitotic activity of germ cell lineage. Together with the facts that Maf-S regulates ROS levels and genetically interacts with Keap1/Nrf2 in GSC maintenance, our study suggests that Maf-S plays an important role in the Drosophila testis GSC maintenance by participating in the regulation of redox homeostasis.
      Graphical abstract image

      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.12.002
      Issue No: Vol. 15 (2017)
       
  • Post-translational regulation of macrophage migration inhibitory factor:
           Basis for functional fine-tuning

    • Authors: Lisa Schindler; Nina Dickerhof; Mark B. Hampton; Jürgen Bernhagen
      Pages: 135 - 142
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Lisa Schindler, Nina Dickerhof, Mark B. Hampton, Jürgen Bernhagen
      Macrophage migration inhibitory factor (MIF) is a chemokine-like protein and an important mediator in the inflammatory response. Unlike most other pro-inflammatory cytokines, a number of cell types constitutively express MIF and secretion occurs from preformed stores. MIF is an evolutionarily conserved protein that shows a remarkable functional diversity, including specific binding to surface CD74 and chemokine receptors and the presence of two intrinsic tautomerase and oxidoreductase activities. Several studies have shown that MIF is subject to post-translational modification, particularly redox-dependent modification of the catalytic proline and cysteine residues. In this review, we summarize and discuss MIF post-translational modifications and their effects on the biological properties of this protein. We propose that the redox-sensitive residues in MIF will be modified at sites of inflammation and that this will add further depth to the functional diversity of this intriguing cytokine.

      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.11.028
      Issue No: Vol. 15 (2017)
       
  • Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers
           protection against brain ischemia by modifying blood Tf saturation and
           subsequent neuronal damage

    • Authors: Nuria DeGregorio-Rocasolano; Octavi Martí-Sistac; Jovita Ponce; María Castelló-Ruiz; Mònica Millán; Verónica Guirao; Isaac García-Yébenes; Juan B. Salom; Pedro Ramos-Cabrer; Enrique Alborch; Ignacio Lizasoain; José Castillo; Antoni Dávalos; Teresa Gasull
      Pages: 143 - 158
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Nuria DeGregorio-Rocasolano, Octavi Martí-Sistac, Jovita Ponce, María Castelló-Ruiz, Mònica Millán, Verónica Guirao, Isaac García-Yébenes, Juan B. Salom, Pedro Ramos-Cabrer, Enrique Alborch, Ignacio Lizasoain, José Castillo, Antoni Dávalos, Teresa Gasull
      Despite transferrin being the main circulating carrier of iron in body fluids, and iron overload conditions being known to worsen stroke outcome through reactive oxygen species (ROS)-induced damage, the contribution of blood transferrin saturation (TSAT) to stroke brain damage is unknown. The objective of this study was to obtain evidence on whether TSAT determines the impact of experimental ischemic stroke on brain damage and whether iron-free transferrin (apotransferrin, ATf)-induced reduction of TSAT is neuroprotective. We found that experimental ischemic stroke promoted an early extravasation of circulating iron-loaded transferrin (holotransferrin, HTf) to the ischemic brain parenchyma. In vitro, HTf was found to boost ROS production and to be harmful to primary neuronal cultures exposed to oxygen and glucose deprivation. In stroked rats, whereas increasing TSAT with exogenous HTf was detrimental, administration of exogenous ATf and the subsequent reduction of TSAT was neuroprotective. Mechanistically, ATf did not prevent extravasation of HTf to the brain parenchyma in rats exposed to ischemic stroke. However, ATf in vitro reduced NMDA-induced neuronal uptake of HTf and also both the NMDA-mediated lipid peroxidation derived 4-HNE and the resulting neuronal death without altering Ca2+-calcineurin signaling downstream the NMDA receptor. Removal of transferrin from the culture media or blockade of transferrin receptors reduced neuronal death. Together, our data establish that blood TSAT exerts a critical role in experimental stroke-induced brain damage. In addition, our findings suggest that the protective effect of ATf at the neuronal level resides in preventing NMDA-induced HTf uptake and ROS production, which in turn reduces neuronal damage.

      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.11.026
      Issue No: Vol. 15 (2017)
       
  • miR-200a-5p regulates myocardial necroptosis induced by Se deficiency via
           targeting RNF11

    • Authors: Tianshu Yang; Changyu Cao; Jie Yang; Tianqi Liu; Xin Gen Lei; Ziwei Zhang; Shiwen Xu
      Pages: 159 - 169
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Tianshu Yang, Changyu Cao, Jie Yang, Tianqi Liu, Xin Gen Lei, Ziwei Zhang, Shiwen Xu
      Necroptosis has been discovered as a new paradigm of cell death and may play a key role in heart disease and selenium (Se) deficiency. Hence, we detected the specific microRNA (miRNA) in response to Se-deficient heart using microRNAome analysis. For high-throughput sequencing using Se-deficient chicken cardiac tissue, we selected miR-200a-5p and its target gene ring finger protein 11 (RNF11) based on differential expression in cardiac tissue and confirmed the relationship between miR-200a-5p and RNF11 by dual luciferase reporter assay and real-time quantitative PCR (qRT-PCR) in cardiomyocytes. We further explored the function of miR-200a-5p and observed that overexpression of miR-200a-5p spark the receptor interacting serine/threonine kinase 3 (RIP3)-dependent necroptosis in vivo and in vitro. To understand whether miR-200a-5p and RNF11 are involved in the RIP3-dependent necroptosis pathway, we presumed that oxidative stress, inflammation response and the mitogen-activated protein kinase (MAPK) pathway might trigger necroptosis. Interestingly, necroptosis trigger, z-VAD-fmk, failed to induce necroptosis but enhanced cell survival against necrosis in cardiomyocytes with knockdown of miR-200a-5p. Our present study provides a new insight that the modulation of miR-200a-5p and its target gene might block necroptosis in the heart, revealing a novel myocardial necrosis regulation model in heart disease.
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      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.11.025
      Issue No: Vol. 15 (2017)
       
  • Short-term sustained hyperglycaemia fosters an archetypal
           senescence-associated secretory phenotype in endothelial cells and
           macrophages

    • Authors: Francesco Prattichizzo; Valeria De Nigris; Elettra Mancuso; Rosangela Spiga; Angelica Giuliani; Giulia Matacchione; Raffaella Lazzarini; Fiorella Marcheselli; Rina Recchioni; Roberto Testa; Lucia La Sala; Maria Rita Rippo; Antonio Domenico Procopio; Fabiola Olivieri; Antonio Ceriello
      Pages: 170 - 181
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Francesco Prattichizzo, Valeria De Nigris, Elettra Mancuso, Rosangela Spiga, Angelica Giuliani, Giulia Matacchione, Raffaella Lazzarini, Fiorella Marcheselli, Rina Recchioni, Roberto Testa, Lucia La Sala, Maria Rita Rippo, Antonio Domenico Procopio, Fabiola Olivieri, Antonio Ceriello
      Diabetic status is characterized by chronic low-grade inflammation and an increased burden of senescent cells. Recently, the senescence-associated secretory phenotype (SASP) has been suggested as a possible source of inflammatory factors in obesity-induced type 2 diabetes. However, while senescence is a known consequence of hyperglycaemia, evidences of SASP as a result of the glycaemic insult are missing. In addition, few data are available regarding which cell types are the main SASP-spreading cells in vivo. Adopting a four-pronged approach we demonstrated that: i) an archetypal SASP response that was at least partly attributable to endothelial cells and macrophages is induced in mouse kidney after in vivo exposure to sustained hyperglycaemia; ii) reproducing a similar condition in vitro in endothelial cells and macrophages, hyperglycaemic stimulus largely phenocopies the SASP acquired during replicative senescence; iii) in endothelial cells, hyperglycaemia-induced senescence and SASP could be prevented by SOD-1 overexpression; and iiii) ex vivo circulating angiogenic cells derived from peripheral blood mononuclear cells from diabetic patients displayed features consistent with the SASP. Overall, the present findings document a direct link between hyperglycaemia and the SASP in endothelial cells and macrophages, making the SASP a highly likely contributor to the fuelling of low-grade inflammation in diabetes.

      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.12.001
      Issue No: Vol. 15 (2017)
       
  • The novel organic mononitrate NDHP attenuates hypertension and endothelial
           dysfunction in hypertensive rats

    • Authors: Luciano L. Paulo; Josiane Campos Cruz; Zhengbing Zhuge; Alynne Carvalho-Galvão; Maria C.R. Brandão; Thiago F. Diniz; Sarah McCann Haworth; Petrônio F. Athayde-Filho; Virginia S. Lemos; Jon O. Lundberg; Marcelo F. Montenegro; Valdir A. Braga; Mattias Carlström
      Pages: 182 - 191
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Luciano L. Paulo, Josiane Campos Cruz, Zhengbing Zhuge, Alynne Carvalho-Galvão, Maria C.R. Brandão, Thiago F. Diniz, Sarah McCann Haworth, Petrônio F. Athayde-Filho, Virginia S. Lemos, Jon O. Lundberg, Marcelo F. Montenegro, Valdir A. Braga, Mattias Carlström
      Rationale Development and progression of cardiovascular diseases, including hypertension, are often associated with impaired nitric oxide synthase (NOS) function and nitric oxide (NO) deficiency. Current treatment strategies to restore NO bioavailability with organic nitrates are hampered by undesirable side effects and development of tolerance. In this study, we evaluated NO release capability and cardiovascular effects of the newly synthesized organic nitrate 1, 3-bis (hexyloxy) propan-2-yl nitrate (NDHP). Methods A combination of in vitro and in vivo approaches was utilized to assess acute effects of NDHP on NO release, vascular reactivity and blood pressure. The therapeutic value of chronic NDHP treatment was assessed in an experimental model of angiotensin II-induced hypertension in combination with NOS inhibition. Results NDHP mediates NO formation in both cell-free system and small resistance arteries, a process which is catalyzed by xanthine oxidoreductase. NDHP-induced vasorelaxation is endothelium independent and mediated by NO release and modulation of potassium channels. Reduction of blood pressure following acute intravenous infusion of NDHP was more pronounced in hypertensive rats (two-kidney-one-clip model) than in normotensive sham-operated rats. Toxicological tests did not reveal any harmful effects following treatment with high doses of NDHP. Finally, chronic treatment with NDHP significantly attenuated the development of hypertension and endothelial dysfunction in rats with chronic NOS inhibition and angiotensin II infusion. Conclusion Acute treatment with the novel organic nitrate NDHP increases NO formation, which is associated with vasorelaxation and a significant reduction of blood pressure in hypertensive animals. Chronic NDHP treatment attenuates the progression of hypertension and endothelial dysfunction, suggesting a potential for therapeutic applications in cardiovascular disease.
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      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.12.004
      Issue No: Vol. 15 (2017)
       
  • iNOS polymorphism modulates iNOS/NO expression via impaired antioxidant
           and ROS content in P. vivax and P. falciparum infection

    • Authors: Amod Kumar; Krishn Pratap Singh; Prerna Bali; Shadab Anwar; Asha Kaul; Om P. Singh; Birendra Kumar Gupta; Nutan Kumari; Md. Noor Alam; Mohammad Raziuddin; Manoranjan Prasad Sinha; Ajay Kumar Sharma; Mohammad Sohail
      Pages: 192 - 206
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Amod Kumar, Krishn Pratap Singh, Prerna Bali, Shadab Anwar, Asha Kaul, Om P. Singh, Birendra Kumar Gupta, Nutan Kumari, Md. Noor Alam, Mohammad Raziuddin, Manoranjan Prasad Sinha, Ajay Kumar Sharma, Mohammad Sohail
      Nitric oxide (NO) has dicotomic influence on modulating host-parasite interplay, synchronizing physiological orchestrations and diagnostic potential; instigated us to investigate the plausible association and genetic regulation among NO level, components of oxidative stress, iNOS polymorphisms and risk of malaria. Here, we experimentally elucidate that iNOS promoter polymorphisms are associated with risk of malaria; employing mutation specific genotyping, functional interplay using western blot and RT-PCR, quantitative estimation of NO, total antioxidant content (TAC) and reactive oxygen species (ROS). Genotyping revealed significantly associated risk of P. vivax (adjusted OR = 1.92 and 1.72) and P. falciparum (adjusted OR = 1.68 and 1.75) infection with SNP at iNOS-954G/C and iNOS-1173C/T positions, respectively; though vivax showed higher risk of infection. Intriguingly, mutation and infection specific differential upregulation of iNOS expression/NO level was observed and found to be significantly associated with mutant genotypes. Moreover, P. vivax showed pronounced iNOS protein (2.4 fold) and mRNA (2.5 fold) expression relative to healthy subjects. Furthermore, TAC and ROS were significantly decreased in infection; and differentially decreased in mutant genotypes. Our findings endorse polymorphic regulation of iNOS expression, altered oxidant-antioxidant components and evidences of risk association as the hallmark of malaria pathogenesis. iNOS/NO may serve as potential diagnostic marker in assessing clinical malaria.
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      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.12.005
      Issue No: Vol. 15 (2017)
       
  • Oxalate induces mitochondrial dysfunction and disrupts redox homeostasis
           in a human monocyte derived cell line

    • Authors: Mikita Patel; Vidhush Yarlagadda; Oreoluwa Adedoyin; Vikram Saini; Dean G. Assimos; Ross P. Holmes; Tanecia Mitchell
      Pages: 207 - 215
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Mikita Patel, Vidhush Yarlagadda, Oreoluwa Adedoyin, Vikram Saini, Dean G. Assimos, Ross P. Holmes, Tanecia Mitchell
      Monocytes/macrophages are thought to be recruited to the renal interstitium during calcium oxalate (CaOx) kidney stone disease for crystal clearance. Mitochondria play an important role in monocyte function during the immune response. We recently determined that monocytes in patients with CaOx kidney stones have decreased mitochondrial function compared to healthy subjects. The objective of this study was to determine whether oxalate, a major constituent found in CaOx kidney stones, alters cell viability, mitochondrial function, and redox homeostasis in THP-1 cells, a human derived monocyte cell line. THP-1 cells were treated with varying concentrations of CaOx crystals (insoluble form) or sodium oxalate (NaOx; soluble form) for 24h. In addition, the effect of calcium phosphate (CaP) and cystine crystals was tested. CaOx crystals decreased cell viability and induced mitochondrial dysfunction and redox imbalance in THP-1 cells compared to control cells. However, NaOx only caused mitochondrial damage and redox imbalance in THP-1 cells. In contrast, both CaP and cystine crystals did not affect THP-1 cells. Separate experiments showed that elevated oxalate also induced mitochondrial dysfunction in primary monocytes from healthy subjects. These findings suggest that oxalate may play an important role in monocyte mitochondrial dysfunction in CaOx kidney stone disease.
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      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.12.003
      Issue No: Vol. 15 (2017)
       
  • Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on
           superoxide/hydrogen peroxide release from cardiac and liver mitochondria

    • Authors: Julia Chalker; Danielle Gardiner; Nidhi Kuksal; Ryan J. Mailloux
      Pages: 216 - 227
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Julia Chalker, Danielle Gardiner, Nidhi Kuksal, Ryan J. Mailloux
      Mitochondria are critical sources of hydrogen peroxide (H2O2), an important secondary messenger in mammalian cells. Recent work has shown that O2 •-/H2O2 emission from individual sites of production in mitochondria is regulated by protein S-glutathionylation. Here, we conducted the first examination of O2 •-/H2O2 release rates from cardiac and liver mitochondria isolated from mice deficient for glutaredoxin-2 (GRX2), a matrix-associated thiol oxidoreductase that facilitates the S-glutathionylation and deglutathionylation of proteins. Liver mitochondria isolated from mice heterozygous (GRX2+/-) and homozygous (GRX2-/-) for glutaredoxin-2 displayed a significant decrease in O2 •-/H2O2 release when oxidizing pyruvate or 2-oxoglutarate. The genetic deletion of the Grx2 gene was associated with increased protein expression of pyruvate dehydrogenase (PDH) but not 2-oxoglutarate dehydrogenase (OGDH). By contrast, O2 •-/H2O2 production was augmented in cardiac mitochondria from GRX2+/- and GRX2-/- mice metabolizing pyruvate or 2-oxoglutarate which was associated with decreased PDH and OGDH protein levels. ROS production was augmented in liver and cardiac mitochondria metabolizing succinate. Inhibitor studies revealed that OGDH and Complex III served as high capacity ROS release sites in liver mitochondria. By contrast, Complex I and Complex III were found to be the chief O2 •-/H2O2 emitters in cardiac mitochondria. These findings identify an essential role for GRX2 in regulating O2 •-/H2O2 release from mitochondria in liver and cardiac tissue. Our results demonstrate that the GRX2-mediated regulation of O2 •-/H2O2 release through the S-glutathionylation of mitochondrial proteins may play an integral role in controlling cellular ROS signaling.

      PubDate: 2017-12-21T13:29:38Z
      DOI: 10.1016/j.redox.2017.12.006
      Issue No: Vol. 15 (2017)
       
  • Apolipoprotein A-1 mimetic peptide 4F promotes endothelial repairing and
           compromises reendothelialization impaired by oxidized HDL through SR-B1

    • Authors: Dan He; Mingming Zhao; Congying Wu; Wenjing Zhang; Chenguang Niu; Baoqi Yu; Jingru Jin; Liang Ji; Belinda Willard; Anna V. Mathew; Y. Eugene Chen; Subramaniam Pennathur; Huiyong Yin; Yuan He; Bing Pan; Lemin Zheng
      Pages: 228 - 242
      Abstract: Publication date: May 2018
      Source:Redox Biology, Volume 15
      Author(s): Dan He, Mingming Zhao, Congying Wu, Wenjing Zhang, Chenguang Niu, Baoqi Yu, Jingru Jin, Liang Ji, Belinda Willard, Anna V. Mathew, Y. Eugene Chen, Subramaniam Pennathur, Huiyong Yin, Yuan He, Bing Pan, Lemin Zheng
      Disruption of endothelial monolayer integrity is the primary instigating factor for many cardiovascular diseases. High density lipoprotein (HDL) oxidized by heme enzyme myeloperoxidase (MPO) is dysfunctional in promoting endothelial repair. Apolipoprotein A-1 mimetic 4F with its pleiotropic benefits has been proven effective in many in vivo models. In this study we investigated whether 4F promotes endothelial repair and restores the impaired function of oxidized HDL (Cl/NO2-HDL) in promoting re-endothelialization. We demonstrate that 4F and Cl/NO2-HDL act on scavenger receptor type I (SR-B1) using human aorta endothelial cells (HAEC) and SR-B1 (-/-) mouse aortic endothelial cells. Wound healing, transwell migration, lamellipodia formation and single cell migration assay experiments show that 4F treatment is associated with a recovery of endothelial cell migration and associated with significantly increased endothelial nitric oxide synthase (eNOS) activity, Akt phosphorylation and SR-B1 expression. 4F increases NO generation and diminishes oxidative stress. In vivo, 4F can stimulate cell proliferation and re-endothelialization in the carotid artery after treatment with Cl/NO2-HDL in a carotid artery electric injury model but fails to do so in SR-B1(-/-) mice. These findings demonstrate that 4F promotes endothelial cell migration and has a potential therapeutic benefit against early endothelial injury in cardiovascular diseases.

      PubDate: 2017-12-27T13:34:23Z
      DOI: 10.1016/j.redox.2017.11.027
      Issue No: Vol. 15 (2017)
       
  • A reciprocal relationship between reactive oxygen species and
           mitochondrial dynamics in neurodegeneration

    • Authors: Clara Hiu-Ling Hung; Sally Shuk-Yee Cheng; Yuen-Ting Cheung; Suthicha Wuwongse; Natalie Qishan Zhang; Yuen-Shan Ho; Simon Ming-Yuen Lee; Raymond Chuen-Chung Chang
      Pages: 7 - 19
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Clara Hiu-Ling Hung, Sally Shuk-Yee Cheng, Yuen-Ting Cheung, Suthicha Wuwongse, Natalie Qishan Zhang, Yuen-Shan Ho, Simon Ming-Yuen Lee, Raymond Chuen-Chung Chang
      Mitochondrial fragmentation due to fission/fusion imbalance has often been linked to mitochondrial dysfunction and apoptosis in neurodegeneration. Conventionally, it is believed that once mitochondrial morphology shifts away from its physiological tubular form, mitochondria become defective and downstream apoptotic signaling pathways are triggered. However, our study shows that beta-amyloid (Aβ) induces morphological changes in mitochondria where they become granular-shaped and are distinct from fragmented mitochondria in terms of both morphology and functions. Accumulation of mitochondrial reactive oxygen species triggers granular mitochondria formation, while mitoTEMPO (a mitochondria-targeted superoxide scavenger) restores tubular mitochondrial morphology within Aβ-treated neurons. Interestingly, modulations of mitochondria fission and fusion by genetic and pharmacological tools attenuated not only the induction of granular mitochondria, but also mitochondrial superoxide levels in Aβ−treated neurons. Our study shows a reciprocal relationship between mitochondrial dynamics and reactive oxygen species and provides a new potential therapeutic target at early stages of neurodegenerative disease pathogenesis.
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      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.010
      Issue No: Vol. 14 (2017)
       
  • Reduced levels of methyltransferase DNMT2 sensitize human fibroblasts to
           oxidative stress and DNA damage that is accompanied by changes in
           proliferation-related miRNA expression

    • Authors: Anna Lewinska; Jagoda Adamczyk-Grochala; Ewa Kwasniewicz; Anna Deregowska; Ewelina Semik; Tomasz Zabek; Maciej Wnuk
      Pages: 20 - 34
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Anna Lewinska, Jagoda Adamczyk-Grochala, Ewa Kwasniewicz, Anna Deregowska, Ewelina Semik, Tomasz Zabek, Maciej Wnuk
      Methyltransferase DNMT2 is suggested to be involved in the regulation of numerous processes, however its biological significance and underlying molecular mechanisms remain elusive. In the present study, we have used WI-38 and BJ human fibroblasts as an in vitro model system to investigate the effects of siRNA-based DNMT2 silencing. DNMT2-depleted cells were found to be sensitive to oxidative stress conditions as judged by increased production of reactive oxygen species and susceptible to DNA damage that resulted in the inhibition of cell proliferation. DNMT2 silencing promoted upregulation of proliferation-related and tumor suppressor miRNAs, namely miR-28-3p, miR-34a-3p, miR-30b-5p, miR-29b-3p, miR-200c-3p, miR-28-5p, miR-379-5p, miR-382-5p, miR-194-5p, miR-193b-3p and miR-409-3p. Moreover, DNMT2 silencing induced cellular senescence and DNMT2 levels were elevated in replicatively senescent cells. Taken together, we found that DNMT2 may take part in the regulation of cell proliferation and longevity in human fibroblasts and speculate that the manipulation of DNMT2 levels that limits cell proliferation may be potentially useful anticancer strategy.

      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.012
      Issue No: Vol. 14 (2017)
       
  • Aging-related decline in the induction of Nrf2-regulated antioxidant genes
           in human bronchial epithelial cells

    • Authors: Lulu Zhou; Hongqiao Zhang; Kelvin J.A. Davies; Henry Jay Forman
      Pages: 35 - 40
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Lulu Zhou, Hongqiao Zhang, Kelvin J.A. Davies, Henry Jay Forman
      Evidence from animal studies suggests that stress-induced increases in Nrf2-regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE) cells from subjects of young adult (21–29 years) and older (60–69 years) non-smokers, and explored factors affecting expresion. The basal expression of three representative Nrf2-regulated genes, the catalytic and modulator subunits of glutamate cysteine ligase (GCLC and GCLM, respectively), and NAD(P)H quinone oxidoreductase 1 (NQO1), was higher in cells from the older donors compared with cells from the young adult donors. Upon exposure to the Nrf2 activator, sulforaphane (SF), the expression of these antioxidant genes was increased in cells from both the young adults and the older donors; however, the induction by SF in older donor cells was significantly less than that seen in young adult cells. In addition, the activation of an EpRE-driven reporter by SF was lower in cells from older donors compared to cells from young adults. The basal expression of Nrf2 protein was also lower in cells from older donors than cells from young adults. Furthermore, we found that the basal expression of both Bach1 and c-Myc, two Nrf2 suppressors, was higher in cells from older adults than from young adult donors. In summary, our data suggest that, as in other species, basal expression of Nrf2-regulated genes increases with aging, while inducibility declines with aging. The increased expression of Nrf2 suppressors such as Bach1 and c-Myc may contribute to the impaired inducibility of the Nrf2-regulated antioxidant genes with aging in human bronchial epithelial cells.

      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.014
      Issue No: Vol. 14 (2017)
       
  • Peroxiredoxin 6 phospholipid hydroperoxidase activity in the repair of
           peroxidized cell membranes

    • Authors: Aron B. Fisher; Jose P. Vasquez-Medina; Chandra Dodia; Elena M. Sorokina; Jian-Qin Tao; Sheldon I. Feinstein
      Pages: 41 - 46
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Aron B. Fisher, Jose P. Vasquez-Medina, Chandra Dodia, Elena M. Sorokina, Jian-Qin Tao, Sheldon I. Feinstein
      Although lipid peroxidation associated with oxidative stress can result in cellular death, sub-lethal lipid peroxidation can gradually resolve with return to the pre-exposure state. We have shown that resolution of lipid peroxidation is greatly delayed in lungs or cells that are null for peroxiredoxin 6 (Prdx6) and that both the phospholipase A2 and the GSH peroxidase activities of Prdx6 are required for a maximal rate of recovery. Like other peroxiredoxins, Prdx6 can reduce H2O2 and short chain hydroperoxides, but in addition can directly reduce phospholipid hydroperoxides. This study evaluated the relative role of these two different peroxidase activities of Prdx6 in the repair of peroxidized cell membranes. The His26 residue in Prdx6 is an important component of the binding site for phospholipids. Thus, we evaluated the lungs from H26A-Prdx6 expressing mice and generated H26A-Prdx6 expressing pulmonary microvascular endothelial cells (PMVEC) by lentiviral infection of Prdx6 null cells to compare with wild type in the repair of lipid peroxidation. Isolated lungs and PMVEC were exposed to tert-butyl hydroperoxide and mice were exposed to hyperoxia (> 95% O2). Assays for lipid peroxidation in wild type control and mutant lungs and cells showed ~4-fold increase at end-exposure. Control lungs and cells showed gradual resolution during a post-exposure recovery period. However, there was no recovery from lipid peroxidation by H26A-Prdx6 lungs or PMVEC. These studies confirm an important role for Prdx6 in recovery from membrane lipid peroxidation and indicate that reduction of H2O2 or short chain hydroperoxides does not play a role in the recovery process.
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      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.008
      Issue No: Vol. 14 (2017)
       
  • Short overview on metabolomics approach to study pathophysiology of
           oxidative stress in cancer

    • Authors: Luka Andrisic; Danuta Dudzik; Coral Barbas; Lidija Milkovic; Tilman Grune; Neven Zarkovic
      Pages: 47 - 58
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Luka Andrisic, Danuta Dudzik, Coral Barbas, Lidija Milkovic, Tilman Grune, Neven Zarkovic
      Association of oxidative stress with carcinogenesis is well known, but not understood well, as is pathophysiology of oxidative stress generated during different types of anti-cancer treatments. Moreover, recent findings indicate that cancer associated lipid peroxidation might eventually help defending adjacent nonmalignant cells from cancer invasion. Therefore, untargeted metabolomics studies designed for advanced translational and clinical studies are needed to understand the existing paradoxes in oncology, including those related to controversial usage of antioxidants aiming to prevent or treat cancer. In this short review we have tried to put emphasis on the importance of pathophysiology of oxidative stress and lipid peroxidation in cancer development in relation to metabolic adaptation of particular types of cancer allowing us to conclude that adaptation to oxidative stress is one of the main driving forces of cancer pathophysiology. With the help of metabolomics many novel findings are being achieved thus encouraging further scientific breakthroughs. Combined with targeted qualitative and quantitative methods, especially immunochemistry, further research might reveal bio-signatures of individual patients and respective malignant diseases, leading to individualized treatment approach, according to the concepts of modern integrative medicine.

      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.009
      Issue No: Vol. 14 (2017)
       
  • Yap promotes hepatocellular carcinoma metastasis and mobilization via
           governing cofilin/F-actin/lamellipodium axis by regulation of
           JNK/Bnip3/SERCA/CaMKII pathways

    • Authors: Chen Shi; Yong Cai; Yongheng Li; Ye Li; Nan Hu; Sai Ma; Shunying Hu; Pingjun Zhu; Weihu Wang; Hao Zhou
      Pages: 59 - 71
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Chen Shi, Yong Cai, Yongheng Li, Ye Li, Nan Hu, Sai Ma, Shunying Hu, Pingjun Zhu, Weihu Wang, Hao Zhou
      Despite the increasingly important role of Hippo-Yap in hepatocellular carcinoma (HCC) development and progression, little insight is available at the time regarding the specifics interaction of Yap and cancer cells migration. Here, we identified the mechanism by which tumor-intrinsic Yap deletion resulted in HCC migratory inhibition. Yap was greatly upregulated in HCC and its expression promoted the cells migration. Functional studies found that knockdown of Yap induced JNK phosphorylation which closely bound to the Bnip3 promoter and contributed to Bnip3 expression. Higher Bnip3 employed excessive mitophagy leading to mitochondrial dysfunction and ATP shortage. The insufficient ATP inactivated SERCA and consequently triggered intracellular calcium overload. As the consequence of calcium oscillation, Ca/calmodulin-dependent protein kinases II (CaMKII) was signaled and subsequently inhibited cofilin activity via phosphorylated modification. The phosphorylated cofilin failed to manipulate F-actin polymerization and lamellipodium formation, resulting into the impairment of lamellipodium-based migration. Collectively, our results identified Hippo-Yap as the tumor promoter in hepatocellular carcinoma that mediated via activation of cofilin/F-actin/lamellipodium axis by limiting JNK-Bnip3-SERCA-CaMKII pathways, with potential application to HCC therapy involving cancer metastasis.
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      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.013
      Issue No: Vol. 14 (2017)
       
  • PKR activation causes inflammation and MMP-13 secretion in human
           degenerated articular chondrocytes

    • Authors: Ching-Hou Ma; Chin-Hsien Wu; I.-Ming Jou; Yuan-Kun Tu; Ching-Hsia Hung; Pei-Ling Hsieh; Kun-Ling Tsai
      Pages: 72 - 81
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Ching-Hou Ma, Chin-Hsien Wu, I.-Ming Jou, Yuan-Kun Tu, Ching-Hsia Hung, Pei-Ling Hsieh, Kun-Ling Tsai
      Osteoarthritis (OA) is a degenerative joint disease affecting a large population of people. Although the elevated expression of PKR (double stranded RNA-dependent protein kinase) and MMP-13 (collagenase-3) have been indicated to play pivotal roles in the pathogenesis of OA, the exact mechanism underlying the regulation of MMP-13 by PKR following inflammatory stimulation was relatively unknown. The purpose of this study was to determine the signaling pathway involved in the PKR-mediated induction of MMP-13 after TNF-α-stimulation. In this study, cartilages of knee joint were obtained from OA subjects who underwent arthroplastic knee surgery. Cartilages were used for tissue analysis or for chondrocytes isolation. In results, the upregulated expression of PKR was observed in damaged OA cartilages as well as in TNF-α-stimulated chondrocytes. Phosphorylation of PKC (protein kinase C) was found after TNF-α administration or PKR activation using poly(I:C), indicating PKC was regulated by PKR. The subsequent increased activity of NADPH oxidase led to oxidative stress accumulation and antioxidant capacity downregulation followed by an exaggerated inflammatory response with elevated levels of COX-2 and IL-8 via ERK/NF-κB pathway. Activated ERK pathway also impeded the inhibition of MMP-13 by PPAR-γ. These findings demonstrated that TNF-α-induced PKR activation triggered oxidative stress-mediated inflammation and MMP-13 in human chondrocytes. Unraveling these deregulated signaling cascades will deepen our knowledge of OA pathophysiology and provide aid in the development of novel therapies.
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      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.011
      Issue No: Vol. 14 (2017)
       
  • Augmentation of intracellular iron using iron sucrose enhances the
           toxicity of pharmacological ascorbate in colon cancer cells

    • Authors: Kristin E. Brandt; Kelly C. Falls; Joshua D. Schoenfeld; Samuel N. Rodman; Zhimin Gu; Fenghuang Zhan; Joseph J. Cullen; Brett A. Wagner; Garry R. Buettner; Bryan G. Allen; Daniel J. Berg; Douglas R. Spitz; Melissa A. Fath
      Pages: 82 - 87
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Kristin E. Brandt, Kelly C. Falls, Joshua D. Schoenfeld, Samuel N. Rodman, Zhimin Gu, Fenghuang Zhan, Joseph J. Cullen, Brett A. Wagner, Garry R. Buettner, Bryan G. Allen, Daniel J. Berg, Douglas R. Spitz, Melissa A. Fath
      Pharmacological doses (> 1mM) of ascorbate (a.k.a., vitamin C) have been shown to selectively kill cancer cells through a mechanism that is dependent on the generation of H2O2 at doses that are safely achievable in humans using intravenous administration. The process by which ascorbate oxidizes to form H2O2 is thought to be mediated catalytically by redox active metal ions such as iron (Fe). Because intravenous iron sucrose is often administered to colon cancer patients to help mitigate anemia, the current study assessed the ability of pharmacological ascorbate to kill colon cancer cells in the presence and absence of iron sucrose. In vitro survival assays showed that 10mM ascorbate exposure (2h) clonogenically inactivated 40–80% of exponentially growing colon cancer cell lines (HCT116 and HT29). When the H2O2 scavenging enzyme, catalase, was added to the media, or conditionally over-expressed using a doxycycline inducible vector, the toxicity of pharmacological ascorbate was significantly blunted. When colon cancer cells were treated in the presence or absence of 250µM iron sucrose, then rinsed, and treated with 10mM ascorbate, the cells demonstrated increased levels of labile iron that resulted in significantly increased clonogenic cell killing, compared to pharmacological ascorbate alone. Interestingly, when colon cancer cells were treated with iron sucrose for 1h and then 10mM ascorbate was added to the media in the continued presence of iron sucrose, there was no enhancement of toxicity despite similar increases in intracellular labile iron. The combination of iron chelators, deferoxamine and diethylenetriaminepentaacetic acid, significantly inhibited the toxicity of either ascorbate alone or ascorbate following iron sucrose. These observations support the hypothesis that increasing intracellular labile iron pools, using iron sucrose, can be used to increase the toxicity of pharmacological ascorbate in human colon cancer cells by a mechanism involving increased generation of H2O2.

      PubDate: 2017-09-11T23:57:42Z
      DOI: 10.1016/j.redox.2017.08.017
      Issue No: Vol. 14 (2017)
       
  • Role of glutathione biosynthesis in endothelial dysfunction and fibrosis

    • Authors: Cristina Espinosa-Díez; Verónica Miguel; Susana Vallejo; Francisco J. Sánchez; Elena Sandoval; Eva Blanco; Pablo Cannata; Concepción Peiró; Carlos F. Sánchez-Ferrer; Santiago Lamas
      Pages: 88 - 99
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Cristina Espinosa-Díez, Verónica Miguel, Susana Vallejo, Francisco J. Sánchez, Elena Sandoval, Eva Blanco, Pablo Cannata, Concepción Peiró, Carlos F. Sánchez-Ferrer, Santiago Lamas
      Glutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH4. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses.
      Graphical abstract image

      PubDate: 2017-09-11T23:57:42Z
      DOI: 10.1016/j.redox.2017.08.019
      Issue No: Vol. 14 (2017)
       
  • Iron accumulation in senescent cells is coupled with impaired
           ferritinophagy and inhibition of ferroptosis

    • Authors: Shashank Masaldan; Sharnel A.S. Clatworthy; Cristina Gamell; Peter M. Meggyesy; Antonia-Tonia Rigopoulos; Sue Haupt; Ygal Haupt; Delphine Denoyer; Paul A. Adlard; Ashley I. Bush; Michael A. Cater
      Pages: 100 - 115
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Shashank Masaldan, Sharnel A.S. Clatworthy, Cristina Gamell, Peter M. Meggyesy, Antonia-Tonia Rigopoulos, Sue Haupt, Ygal Haupt, Delphine Denoyer, Paul A. Adlard, Ashley I. Bush, Michael A. Cater
      Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity. Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone). Iron accumulation in senescent cells was driven by impaired ferritinophagy, a lysosomal process that promotes ferritin degradation and ferroptosis. Lysosomal dysfunction in senescent cells was confirmed through several markers, including the build-up of microtubule-associated protein light chain 3 (LC3-II) in autophagosomes. Impaired ferritin degradation explains the iron accumulation phenotype of senescent cells, whereby iron is effectively trapped in ferritin creating a perceived cellular deficiency. Accordingly, senescent cells were highly resistant to ferroptosis. Promoting ferritin degradation by using the autophagy activator rapamycin averted the iron accumulation phenotype of senescent cells, preventing the increase of TfR1, ferritin and intracellular iron, but failed to re-sensitize these cells to ferroptosis. Finally, the enrichment of senescent cells in mouse ageing hepatic tissue was found to accompany iron accumulation, an elevation in ferritin and mirrored our observations using cultured senescent cells.
      Graphical abstract image

      PubDate: 2017-09-11T23:57:42Z
      DOI: 10.1016/j.redox.2017.08.015
      Issue No: Vol. 14 (2017)
       
  • Cytoprotective mechanisms of DJ-1 against oxidative stress through
           modulating ERK1/2 and ASK1 signal transduction

    • Authors: Stephanie E. Oh; M. Maral Mouradian
      Pages: 211 - 217
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Stephanie E. Oh, M. Maral Mouradian
      DJ-1 is a highly conserved multifunctional protein linked to both neurodegeneration and neoplasia. Among its various activities is an antioxidant property leading to cytoprotection under oxidative stress conditions. This is associated with the ability to modulate signal transduction events that determine how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy in order to adapt to environmental stimuli and stresses. Alterations in DJ-1 expression or function can disrupt homeostatic signaling networks and initiate cascades that play a role in the pathogenesis of conditions such as Parkinson's disease and cancer. DJ-1 plays a major role in various signaling pathways. Related to its anti-oxidant properties, it mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and attenuates cell death signaling by inhibiting apoptosis signal-regulating kinase 1 (ASK1) activation. Here, we review the ways through which DJ-1 regulates these pathways, focusing on how its regulation of signal transduction contributes to cellular homeostasis and the pathologic states that result from their dysregulation.

      PubDate: 2017-09-30T16:03:23Z
      DOI: 10.1016/j.redox.2017.09.008
      Issue No: Vol. 14 (2017)
       
  • A review of the basics of mitochondrial bioenergetics, metabolism, and
           related signaling pathways in cancer cells: Therapeutic targeting of tumor
           mitochondria with lipophilic cationic compounds

    • Authors: Balaraman Kalyanaraman; Gang Cheng; Micael Hardy; Olivier Ouari; Marcos Lopez; Joy Joseph; Jacek Zielonka; Michael B. Dwinell
      Pages: 316 - 327
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Balaraman Kalyanaraman, Gang Cheng, Micael Hardy, Olivier Ouari, Marcos Lopez, Joy Joseph, Jacek Zielonka, Michael B. Dwinell
      The present review is a sequel to the previous review on cancer metabolism published in this journal. This review focuses on the selective antiproliferative and cytotoxic effects of mitochondria-targeted therapeutics (MTTs) in cancer cells. Emerging research reveals a key role of mitochondrial respiration on tumor proliferation. Previously, a mitochondria-targeted nitroxide was shown to selectively inhibit colon cancer cell proliferation at submicromolar levels. This review is centered on the therapeutic use of MTTs and their bioenergetic profiling in cancer cells. Triphenylphosphonium cation conjugated to a parent molecule (e.g., vitamin-E or chromanol, ubiquinone, and metformin) via a linker alkyl chain is considered an MTT. MTTs selectively and potently inhibit proliferation of cancer cells and, in some cases, induce cytotoxicity. MTTs inhibit mitochondrial complex I activity and induce mitochondrial stress in cancer cells through generation of reactive oxygen species. MTTs in combination with glycolytic inhibitors synergistically inhibit tumor cell proliferation. This review discusses how signaling molecules traditionally linked to tumor cell proliferation affect tumor metabolism and bioenergetics (glycolysis, TCA cycle, and glutaminolysis).

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.09.020
      Issue No: Vol. 14 (2017)
       
  • Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

    • Authors: C. Cheignon; M. Tomas; D. Bonnefont-Rousselot; P. Faller; C. Hureau; F. Collin
      Pages: 450 - 464
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): C. Cheignon, M. Tomas, D. Bonnefont-Rousselot, P. Faller, C. Hureau, F. Collin
      Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.
      Graphical abstract image

      PubDate: 2017-11-11T14:46:44Z
      DOI: 10.1016/j.redox.2017.10.014
      Issue No: Vol. 14 (2017)
       
  • Fundamentals on the biochemistry of peroxynitrite and protein tyrosine
           nitration

    • Authors: Silvina Bartesaghi; Rafael Radi
      Pages: 618 - 625
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Silvina Bartesaghi, Rafael Radi
      In this review we provide an analysis of the biochemistry of peroxynitrite and tyrosine nitration. Peroxynitrite is the product of the diffusion-controlled reaction between superoxide (O2 • -) and nitric oxide (•NO). This process is in competition with the enzymatic dismutation of O2 •- and the diffusion of •NO across cells and tissues and its reaction with molecular targets (e.g. guanylate cyclase). Understanding the kinetics and compartmentalization of the O2 •- / •NO interplay is critical to rationalize the shift of •NO from a physiological mediator to a cytotoxic intermediate. Once formed, peroxynitrite (ONOO- and ONOOH; pKa = 6,8) behaves as a strong one and two-electron oxidant towards a series of biomolecules including transition metal centers and thiols. In addition, peroxynitrite anion can secondarily evolve to secondary radicals either via its fast reaction with CO2 or through proton-catalyzed homolysis. Thus, peroxynitrite can participate in direct (bimolecular) and indirect (through secondary radical intermediates) oxidation reactions; through these processes peroxynitrite can participate as cytotoxic effector molecule against invading pathogens and/or as an endogenous pathogenic mediator. Peroxynitrite can cause protein tyrosine nitration in vitro and in vivo. Indeed, tyrosine nitration is a hallmark of the reactions of •NO-derived oxidants in cells and tissues and serves as a biomarker of oxidative damage. Protein tyrosine nitration can mediate changes in protein structure and function that affect cell homeostasis. Tyrosine nitration in biological systems is a free radical process that can be promoted either by peroxynitrite-derived radicals or by other related •NO-dependent oxidative processes. Recently, mechanisms responsible of tyrosine nitration in hydrophobic biostructures such as membranes and lipoproteins have been assessed and involve the parallel occurrence and connection with lipid peroxidation. Experimental strategies to reveal the proximal oxidizing mechanism during tyrosine nitration in given pathophysiologically-relevant conditions include mapping and identification of the tyrosine nitration sites in specific proteins.
      Graphical abstract image

      PubDate: 2017-12-10T21:22:26Z
      DOI: 10.1016/j.redox.2017.09.009
      Issue No: Vol. 14 (2017)
       
  • 8-Oxoguanine DNA glycosylase 1: Beyond repair of the oxidatively modified
           base lesions

    • Authors: Xueqing Ba; lstvan Boldogh
      Pages: 669 - 678
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Xueqing Ba, lstvan Boldogh
      Oxidative stress and the resulting damage to genomic DNA are inevitable consequences of endogenous physiological processes, and they are amplified by cellular responses to environmental exposures. One of the most frequent reactions of reactive oxygen species with DNA is the oxidation of guanine to pre-mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG). Despite the vulnerability of guanine to oxidation, vertebrate genes are primarily embedded in GC-rich genomic regions, and over 72% of the promoters of human genes belong to a class with a high GC content. In the promoter, 8-oxoG may serve as an epigenetic mark, and when complexed with the oxidatively inactivated repair enzyme 8-oxoguanine DNA glycosylase 1, provide a platform for the coordination of the initial steps of DNA repair and the assembly of the transcriptional machinery to launch the prompt and preferential expression of redox-regulated genes. Deviations/variations from this artful coordination may be the etiological links between guanine oxidation and various cellular pathologies and diseases during ageing processes.
      Graphical abstract image

      PubDate: 2017-11-30T03:59:41Z
      DOI: 10.1016/j.redox.2017.11.008
      Issue No: Vol. 14 (2017)
       
 
 
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