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Journal Cover   Redox Biology
  [1 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2213-2317
   Published by Elsevier Homepage  [2812 journals]
  • Protein lipoxidation: detection strategies and challenges

    • Abstract: Publication date: Available online 21 May 2015
      Source:Redox Biology
      Author(s): Giancarlo Aldini , M. Rosário Domingues , Corinne M. Spickett , Pedro Domingues , Alessandra Altomare , Francisco J. Sánchez-Gómez , Clara L. Oeste , Dolores Pérez-Sala
      Enzymatic and non-enzymatic lipid metabolism can give rise to reactive species that may covalently modify cellular or plasma proteins through a process known as lipoxidation. Under basal conditions, protein lipoxidation can contribute to normal cell homeostasis and participate in signaling or adaptive mechanisms, as exemplified by lipoxidation of Ras proteins or of the cytoskeletal protein vimentin, both of which behave as sensors of electrophilic species. Nevertheless, increased lipoxidation under pathological conditions may lead to deleterious effects on protein structure or aggregation. This can result in impaired degradation and accumulation of abnormally folded proteins contributing to pathophysiology, as may occur in neurodegenerative diseases. Identification of the protein targets of lipoxidation and its functional consequences under pathophysiological situations can unveil the modification patterns associated with the various outcomes, as well as preventive strategies or potential therapeutic targets. Given the wide structural variability of lipid moieties involved in lipoxidation, highly sensitive and specific methods for its detection are required. Derivatization of reactive carbonyl species is instrumental in the detection of adducts retaining carbonyl groups. In addition, use of tagged derivatives of electrophilic lipids enables enrichment of lipoxidized proteins or peptides. Ultimate confirmation of lipoxidation requires high resolution mass spectrometry approaches to unequivocally identify the adduct and the targeted residue. Moreover, rigorous validation of the targets identified and assessment of the functional consequences of these modifications are essential. Here we present an update on methods to approach the complex field of lipoxidation along with validation strategies and functional assays illustrated with well-studied lipoxidation targets.
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      PubDate: 2015-05-22T12:14:54Z
       
  • Can nitric oxide synthase activity be unequivocally measured in red blood
           cells and platelets' If yes, by which assay'

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Dimitrios Tsikas



      PubDate: 2015-05-22T12:14:54Z
       
  • Response to commentary

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Miriam M. Cortese-Krott , Malte Kelm



      PubDate: 2015-05-22T12:14:54Z
       
  • Editors' Forum Discussion of controversies in the measurement of
           nitric oxide metabolites in biological matrices

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Santiago Lamas



      PubDate: 2015-05-22T12:14:54Z
       
  • Thiol redox homeostasis in neurodegenerative disease

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Gethin J. McBean , Mutay Aslan , Helen R. Griffiths , Rita C. Torrão
      This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc − cystine–glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Fetal–maternal interface impedance parallels local NADPH oxidase
           related superoxide production

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): L. Guedes-Martins , E. Silva , A.R. Gaio , J. Saraiva , A.I. Soares , J. Afonso , F. Macedo , H. Almeida
      Blood flow assessment employing Doppler techniques is a useful procedure in pregnancy evaluation, as it may predict pregnancy disorders coursing with increased uterine vascular impedance, as pre-eclampsia. While the local causes are unknown, emphasis has been put on reactive oxygen species (ROS) excessive production. As NADPH oxidase (NOX) is a ROS generator, it is hypothesized that combining Doppler assessment with NOX activity might provide useful knowledge on placental bed disorders underlying mechanisms. A prospective longitudinal study was performed in 19 normal course, singleton pregnancies. Fetal aortic isthmus (AoI) and maternal uterine arteries (UtA) pulsatility index (PI) were recorded at two time points: 20–22 and 40–41 weeks, just before elective Cesarean section. In addition, placenta and placental bed biopsies were performed immediately after fetal extraction. NOX activity was evaluated using a dihydroethidium-based fluorescence method and associations to PI values were studied with Spearman correlations. A clustering of pregnancies coursing with higher and lower PI values was shown, which correlated strongly with placental bed NOX activity, but less consistently with placental tissue. The study provides evidence favoring that placental bed NOX activity parallels UtA PI enhancement and suggests that an excess in oxidation underlies the development of pregnancy disorders coursing with enhanced UtA impedance.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Standardization and quality control in quantifying non-enzymatic oxidative
           protein modifications in relation to ageing and disease: Why is it
           important and why is it hard?

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Olgica Nedić , Adelina Rogowska-Wrzesinska , Suresh I.S. Rattan
      Post-translational modifications (PTM) of proteins determine the activity, stability, specificity, transportability and lifespan of a protein. Some PTM are highly specific and regulated involving various enzymatic pathways, but there are other non-enzymatic PTM (nePTM), which occur stochastically, depend on the ternary structure of proteins and can be damaging. It is often observed that inactive and abnormal proteins accumulate in old cells and tissues. The nature, site and extent of nePTM give rise to a population of that specific protein with alterations in structure and function ranging from being fully active to totally inactive molecules. Determination of the type and the amount (abundance) of nePTM is essential for establishing connection between specific protein structure and specific biological role. This article summarizes analytical demands for reliable quantification of nePTM, including requirements for the assay performance, standardization and quality control, and points to the difficulties, uncertainties and un-resolved issues.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Neuron specific reduction in CuZnSOD is not sufficient to initiate a full
           sarcopenia phenotype

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Kavithalakshmi Sataranatarajan , Rizwan Qaisar , Carol Davis , Giorgos K. Sakellariou , Aphrodite Vasilaki , Yiqiang Zhang , Yuhong Liu , Shylesh Bhaskaran , Anne McArdle , Malcolm Jackson , Susan V. Brooks , Arlan Richardson , Holly Van Remmen
      Our previous studies showed that adult (8 month) mice lacking CuZn-superoxide dismutase (CuZnSOD, Sod1KO mice) have neuromuscular changes resulting in dramatic accelerated muscle atrophy and weakness that mimics age-related sarcopenia. We have further shown that loss of CuZnSOD targeted to skeletal muscle alone results in only mild weakness and no muscle atrophy. In this study, we targeted deletion of CuZnSOD specifically to neurons (nSod1KO mice) and determined the effect on muscle mass and weakness. The nSod1KO mice show a significant loss of CuZnSOD activity and protein level in brain and spinal cord but not in muscle tissue. The masses of the gastrocnemius, tibialis anterior and extensor digitorum longus (EDL) muscles were not reduced in nSod1KO compared to wild type mice, even at 20 months of age, although the quadriceps and soleus muscles showed small but statistically significant reductions in mass in the nSod1KO mice. Maximum isometric specific force was reduced by 8–10% in the gastrocnemius and EDL muscle of nSod1KO mice, while soleus was not affected. Muscle mitochondrial ROS generation and oxidative stress measured by levels of reactive oxygen/nitrogen species (RONS) regulatory enzymes, protein nitration and F2-isoprostane levels were not increased in muscle from the nSod1KO mice. Although we did not find evidence of denervation in the nSod1KO mice, neuromuscular junction morphology was altered and the expression of genes associated with denervation acetylcholine receptor subunit alpha (AChRα), the transcription factor, Runx1 and GADD45α) was increased, supporting a role for neuronal loss of CuZnSOD initiating alterations at the neuromuscular junction. These results and our previous studies support the concept that CuZnSOD deficits in either the motor neuron or muscle alone are not sufficient to initiate a full sarcopenic phenotype and that deficits in both tissues are required to recapitulate the loss of muscle observed in Sod1KO mice.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Oxidative stress triggered by naturally occurring flavone apigenin results
           in senescence and chemotherapeutic effect in human colorectal cancer cells
           

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Kacoli Banerjee , Mahitosh Mandal
      Recent studies involving phytochemical polyphenolic compounds have suggested flavones often exert pro-oxidative effect in vitro against wide array of cancer cell lines. The aim of this study was to evaluate the in-vitro pro-oxidative activity of apigenin, a plant based flavone against colorectal cancer cell lines and investigate cumulative effect on long term exposure. In the present study, treatment of colorectal cell lines HT-29 and HCT-15 with apigenin resulted in anti-proliferative and apoptotic effects characterized by biochemical and morphological changes, including loss of mitochondrial membrane potential which aided in reversing the impaired apoptotic machinery leading to negative implications in cancer pathogenesis. Apigenin induces rapid free radical species production and the level of oxidative damage was assessed by qualitative and quantitative estimation of biochemical markers of oxidative stress. Increased level of mitochondrial superoxide suggested dose dependent mitochondrial oxidative damage which was generated by disruption in anti-apoptotic and pro-apoptotic protein balance. Continuous and persistent oxidative stress induced by apigenin at growth suppressive doses over extended treatment time period was observed to induce senescence which is a natural cellular mechanism to attenuate tumor formation. Senescence phenotype inducted by apigenin was attributed to changes in key molecules involved in p16-Rb and p53 independent p21 signaling pathways. Phosphorylation of retinoblastoma was inhibited and significant up-regulation of p21 led to simultaneous suppression of cyclins D1 and E which indicated the onset of senescence. Pro-oxidative stress induced premature senescence mediated by apigenin makes this treatment regimen a potential chemopreventive strategy and an in vitro model for aging research.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Protection against renal ischemia–reperfusion injury in vivo by the
           mitochondria targeted antioxidant MitoQ

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Anna J. Dare , Eleanor A. Bolton , Gavin J. Pettigrew , J. Andrew Bradley , Kourosh Saeb-Parsy , Michael P. Murphy
      Ischemia–reperfusion (IR) injury to the kidney occurs in a range of clinically important scenarios including hypotension, sepsis and in surgical procedures such as cardiac bypass surgery and kidney transplantation, leading to acute kidney injury (AKI). Mitochondrial oxidative damage is a significant contributor to the early phases of IR injury and may initiate a damaging inflammatory response. Here we assessed whether the mitochondria targeted antioxidant MitoQ could decrease oxidative damage during IR injury and thereby protect kidney function. To do this we exposed kidneys in mice to in vivo ischemia by bilaterally occluding the renal vessels followed by reperfusion for up to 24h. This caused renal dysfunction, measured by decreased creatinine clearance, and increased markers of oxidative damage. Administering MitoQ to the mice intravenously 15min prior to ischemia protected the kidney from damage and dysfunction. These data indicate that mitochondrial oxidative damage contributes to kidney IR injury and that mitochondria targeted antioxidants such as MitoQ are potential therapies for renal dysfunction due to IR injury.


      PubDate: 2015-05-17T11:42:38Z
       
  • Dimethyl fumarate modulates antioxidant and lipid metabolism in
           oligodendrocytes

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): He Huang , Alexandra Taraboletti , Leah P. Shriver
      Oxidative stress contributes to pathology associated with inflammatory brain disorders and therapies that upregulate antioxidant pathways may be neuroprotective in diseases such as multiple sclerosis. Dimethyl fumarate, a small molecule therapeutic for multiple sclerosis, activates cellular antioxidant signaling pathways and may promote myelin preservation. However, it is still unclear what mechanisms may underlie this neuroprotection and whether dimethyl fumarate affects oligodendrocyte responses to oxidative stress. Here, we examine metabolic alterations in oligodendrocytes treated with dimethyl fumarate by using a global metabolomic platform that employs both hydrophilic interaction liquid chromatography–mass spectrometry and shotgun lipidomics. Prolonged treatment of oligodendrocytes with dimethyl fumarate induces changes in citric acid cycle intermediates, glutathione, and lipids, indicating that this compound can directly impact oligodendrocyte metabolism. These metabolic alterations are also associated with protection from oxidant challenge. This study provides insight into the mechanisms by which dimethyl fumarate could preserve myelin integrity in patients with multiple sclerosis.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Hyperoxia activates ATM independent from mitochondrial ROS and dysfunction

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Emily A. Resseguie , Rhonda J. Staversky , Paul S. Brookes , Michael A. O’Reilly
      High levels of oxygen (hyperoxia) are often used to treat individuals with respiratory distress, yet prolonged hyperoxia causes mitochondrial dysfunction and excessive reactive oxygen species (ROS) that can damage molecules such as DNA. Ataxia telangiectasia mutated (ATM) kinase is activated by nuclear DNA double strand breaks and delays hyperoxia-induced cell death through downstream targets p53 and p21. Evidence for its role in regulating mitochondrial function is emerging, yet it has not been determined if mitochondrial dysfunction or ROS activates ATM. Because ATM maintains mitochondrial homeostasis, we hypothesized that hyperoxia induces both mitochondrial dysfunction and ROS that activate ATM. In A549 lung epithelial cells, hyperoxia decreased mitochondrial respiratory reserve capacity at 12h and basal respiration by 48h. ROS were significantly increased at 24h, yet mitochondrial DNA double strand breaks were not detected. ATM was not required for activating p53 when mitochondrial respiration was inhibited by chronic exposure to antimycin A. Also, ATM was not further activated by mitochondrial ROS, which were enhanced by depleting manganese superoxide dismutase (SOD2). In contrast, ATM dampened the accumulation of mitochondrial ROS during exposure to hyperoxia. Our findings suggest that hyperoxia-induced mitochondrial dysfunction and ROS do not activate ATM. ATM more likely carries out its canonical response to nuclear DNA damage and may function to attenuate mitochondrial ROS that contribute to oxygen toxicity.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Fluorescence labeling of carbonylated lipids and proteins in cells using
           coumarin-hydrazide

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Venukumar Vemula , Zhixu Ni , Maria Fedorova
      Carbonylation is a generic term which refers to reactive carbonyl groups present in biomolecules due to oxidative reactions induced by reactive oxygen species. Carbonylated proteins, lipids and nucleic acids have been intensively studied and often associated with onset or progression of oxidative stress related disorders. In order to reveal underlying carbonylation pathways and biological relevance, it is crucial to study their intracellular formation and spatial distribution. Carbonylated species are usually identified and quantified in cell lysates and body fluids after derivatization using specific chemical probes. However, spatial cellular and tissue distribution have been less often investigated. Here, we report coumarin-hydrazide, a fluorescent chemical probe for time- and cost-efficient labeling of cellular carbonyls followed by fluorescence microscopy to evaluate their intracellular formation both in time and space. The specificity of coumarin-hydrazide was confirmed in time- and dose-dependent experiments using human primary fibroblasts stressed with paraquat and compared with conventional DNPH-based immunocytochemistry. Both techniques stained carbonylated species accumulated in cytoplasm with strong perinuclear clustering. Using a complimentary array of analytical methods specificity of coumarin-hydrazide probe towards both protein- and lipid-bound carbonyls has been shown. Additionally, co-distribution of carbonylated species and oxidized phospholipids was demonstrated.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Hexapeptide-11 is a novel modulator of the proteostasis network in human
           diploid fibroblasts

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Aimilia D. Sklirou , Marianna Ralli , Maria Dominguez , Issidora Papassideri , Alexios-Leandros Skaltsounis , Ioannis P. Trougakos
      Despite the fact that several natural products (e.g. crude extracts or purified compounds) have been found to activate cell antioxidant responses and/or delay cellular senescence the effect(s) of small peptides on cell viability and/or modulation of protective mechanisms (e.g. the proteostasis network) remain largely elusive. We have thus studied a hexapeptide (Hexapeptide-11) of structure Phe–Val–Ala–Pro–Phe–Pro (FVAPFP) originally isolated from yeast extracts and later synthesized by solid state synthesis to high purity. We show herein that Hexapeptide-11 exhibits no significant toxicity in normal human diploid lung or skin fibroblasts. Exposure of fibroblasts to Hexapeptide-11 promoted dose and time-dependent activation of proteasome, autophagy, chaperones and antioxidant responses related genes. Moreover, it promoted increased nuclear accumulation of Nrf2; higher expression levels of proteasomal protein subunits and increased proteasome peptidase activities. In line with these findings we noted that Hexapeptide-11 conferred significant protection in fibroblasts against oxidative-stress-mediated premature cellular senescence, while at in vivo skin deformation assays in human subjects it improved skin elasticity. Finally, Hexapeptide-11 was found to induce the activity of extracellular MMPs and it also suppressed cell migration. Our presented findings indicate that Hexapeptide-11 is a promising anti-ageing agent.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Differentiating between apparent and actual rates of H2O2 metabolism by
           isolated rat muscle mitochondria to test a simple model of mitochondria as
           regulators of H2O2 concentration

    • Abstract: Publication date: Available online 7 May 2015
      Source:Redox Biology
      Author(s): Jason R. Treberg , Daniel Munro , Sheena Banh , Pamela Zacharias , Emianka Sotiri
      Mitochondria are often regarded as a major source of reactive oxygen species (ROS) in animal cells, with H2O2 being the predominant ROS released from mitochondria; however, it has been recently demonstrated that energized brain mitochondria may act as stabilizers of H2O2 concentration (Starkov et al. [1]) based on the balance between production and the consumption of H2O2, the later of which is a function of [H2O2] and follows first order kinetics. Here we test the hypothesis that isolated skeletal muscle mitochondria, from the rat, are able to modulate [H2O2] based upon the interaction between the production of ROS, as superoxide/H2O2, and the H2O2 decomposition capacity. The compartmentalization of detection systems for H2O2 and the intramitochondrial metabolism of H2O2 leads to spacial separation between these two components of the assay system. This results in an underestimation of rates when relying solely on extramitochondrial H2O2 detection. We find that differentiating between these apparent rates found when using extramitochondrial H2O2 detection and the actual rates of metabolism is important to determining the rate constant for H2O2 consumption by mitochondria in kinetic experiments. Using the high rate of ROS production by mitochondria respiring on succinate, we demonstrate that net H2O2 metabolism by mitochondria can approach a stable steady-state of extramitochondrial [H2O2]. Importantly, the rate constant determined by extrapolation of kinetic experiments is similar to the rate constant determined as the [H2O2] approaches a steady state.
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      PubDate: 2015-05-17T11:42:38Z
       
  • Oxygen in human health from life to death – an approach to teaching
           redox biology and signaling to graduate and medical students

    • Abstract: Publication date: Available online 11 April 2015
      Source:Redox Biology
      Author(s): Margaret M. Briehl
      In the absence of oxygen human life is measured in minutes. In the presence of oxygen, normal metabolism generates reactive species (ROS) that have the potential to cause cell injury contributing to human aging and disease. Between these extremes, organisms have developed means for sensing oxygen and ROS and regulating their cellular processes in response. Redox signaling contributes to the control of cell proliferation and death. Aberrant redox signaling underlies many human diseases. The attributes acquired by altered redox homeostasis in cancer cells illustrate this particularly well. This teaching review and the accompanying illustrations provide an introduction to redox biology and signaling aimed at instructors of graduate and medical students.
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      PubDate: 2015-04-12T23:48:00Z
       
  • A potential role for endogenous proteins as sacrificial sunscreens and
           antioxidants in human tissues

    • Abstract: Publication date: Available online 11 April 2015
      Source:Redox Biology
      Author(s): Sarah A. Hibbert , Rachel E.B. Watson , Neil K. Gibbs , Patrick Costello , Clair Baldock , Anthony S. Weiss , Christopher E.M. Griffiths , Michael J. Sherratt
      Excessive ultraviolet radiation (UVR) exposure of the skin is associated with adverse clinical outcomes. Although both exogenous sunscreens and endogenous tissue components (including melanins and tryptophan-derived compounds) reduce UVR penetration, the role of endogenous proteins in absorbing environmental UV wavelengths is poorly defined. Having previously demonstrated that proteins which are rich in UVR-absorbing amino acid residues are readily degraded by broadband UVB-radiation (which contains UVA, UVB and UVC wavelengths) here we hypothesised that UV chromophore (Cys, Trp and Tyr) content can predict the susceptibility of structural proteins in skin and the eye to damage by physiologically relevant doses (up to 15.4 J/cm2) of solar UVR (95% UVA, 5% UVB). We show that: i) purified suspensions of UV-chromophore-rich fibronectin dimers, fibrillin microfibrils and β- and γ-lens crystallins undergo solar simulated radiation (SSR)-induced aggregation and/or decomposition and ii) exposure to identical doses of SSR has minimal effect on the size or ultrastructure of UV chromophore-poor tropoelastin, collagen I, collagen VI microfibrils and α-crystallin. If UV chromophore content is a factor in determining protein stability in vivo, we would expect that the tissue distribution of Cys, Trp and Tyr-rich proteins would correlate with regional UVR exposure. From bioinformatic analysis of 244 key structural proteins we identified several biochemically distinct, yet UV chromophore-rich, protein families. The majority of these putative UV-absorbing proteins (including the late cornified envelope proteins, keratin associated proteins, elastic fibre-associated components and β- and γ-crystallins) are localised and/or particularly abundant in tissues that are exposed to the highest doses of environmental UVR, specifically the stratum corneum, hair, papillary dermis and lens. We therefore propose that UV chromophore-rich proteins are localised in regions of high UVR exposure as a consequence of an evolutionary pressure to express sacrificial protein sunscreens which reduce UVR penetration and hence mitigate tissue damage.
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      PubDate: 2015-04-12T23:48:00Z
       
  • Redox theory of aging

    • Abstract: Publication date: August 2015
      Source:Redox Biology, Volume 5
      Author(s): Dean P. Jones
      Metazoan genomes encode exposure memory systems to enhance survival and reproductive potential by providing mechanisms for an individual to adjust during lifespan to environmental resources and challenges. These systems are inherently redox networks, arising during evolution of complex systems with O2 as a major determinant of bioenergetics, metabolic and structural organization, defense, and reproduction. The network structure decreases flexibility from conception onward due to differentiation and cumulative responses to environment (exposome). The redox theory of aging is that aging is a decline in plasticity of genome–exposome interaction that occurs as a consequence of execution of differentiation and exposure memory systems. This includes compromised mitochondrial and bioenergetic flexibility, impaired food utilization and metabolic homeostasis, decreased barrier and defense capabilities and loss of reproductive fidelity and fecundity. This theory accounts for hallmarks of aging, including failure to maintain oxidative or xenobiotic defenses, mitochondrial integrity, proteostasis, barrier structures, DNA repair, telomeres, immune function, metabolic regulation and regenerative capacity.
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      PubDate: 2015-04-03T23:03:31Z
       
  • High glucose, glucose fluctuation and carbonyl stress enhance brain
           microvascular endothelial barrier dysfunction: Implications for diabetic
           cerebral microvasculature

    • Abstract: Publication date: Available online 2 April 2015
      Source:Redox Biology
      Author(s): Wei Li , Ronald E. Maloney , Tak Yee Aw
      We previously demonstrated that in normal glucose (5 mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6 h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and western analysis confirmed an increase in MG-occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG-occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes.
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      PubDate: 2015-04-03T23:03:31Z
       
  • Lyme: inflammation, oxidative stress, and mitochondrial dysfunction

    • Abstract: Publication date: Available online 16 March 2015
      Source:Redox Biology
      Author(s): Brandon N. Peacock , Teshome B. Gherezghiher , Jennifer D. Hilario , Gottfried H. Kellermann
      Lyme borreliosis is transmitted through the bite of a tick that is infected by the bacterial spirochete Borrelia burgdorferi. Clinical manifestation of the disease can lead to heart conditions, neurological disorders, and inflammatory disorders. Oxidative stress has been implicated in the pathogenesis of many human diseases. The aim of this study was to investigate the mechanisms of oxidative stress and intracellular communication in Lyme borreliosis patients. Mitochondrial superoxide and cytosolic ionized calcium was measured in peripheral blood mononuclear cells (PBMCs) of Lyme borreliosis patients and healthy controls. Mitochondrial superoxide levels were significantly higher (p < 0.0001) in Lyme borreliosis patients (n = 32) as compared to healthy controls (n = 30). Significantly low (p < 0.0001) levels of cytosolic ionized calcium were also observed in Lyme borreliosis patients (n = 11) when compared to healthy controls (n = 11). These results indicate that there is an imbalance of reactive oxygen species and cytosolic calcium in Lyme borreliosis patients. The results further suggest that oxidative stress and interrupted intracellular communication may ultimately contribute to a condition of mitochondrial dysfunction in the immune cells of Lyme borreliosis patients.
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      PubDate: 2015-03-18T21:42:16Z
       
  • Expression of xCT and activity of system xc− are regulated by NRF2
           in human breast cancer cells in response to oxidative stress

    • Abstract: Publication date: Available online 18 March 2015
      Source:Redox Biology
      Author(s): Eric Habib , Katja Linher-Melville , Han-Xin Lin , Gurmit Singh
      Cancer cells adapt to high levels of oxidative stress in order to survive and proliferate by activating key transcription factors. One such master regulator, the redox sensitive transcription factor NF E2 Related Factor 2 (NRF2), controls the expression of cellular defense genes including those encoding intracellular redox-balancing proteins involved in glutathione (GSH) synthesis. Under basal conditions, Kelch-like ECH-associated protein 1 (KEAP1) targets NRF2 for ubiquitination. In response to oxidative stress, NRF2 dissociates from KEAP1, entering the nucleus and binding to the antioxidant response element (ARE) in the promoter of its target genes. Elevated reactive oxygen species (ROS) production may deplete GSH levels within cancer cells. System xc −, an antiporter that exports glutamate while importing cystine to be converted into cysteine for GSH synthesis, is upregulated in cancer cells in response to oxidative stress. Here, we provided evidence that the expression of xCT, the light chain subunit of system xc −, is regulated by NRF2 in representative human breast cancer cells. Hydrogen peroxide (H2O2) treatment increased nuclear translocation of NRF2, also increasing levels of xCT mRNA and protein and extracellular glutamate release. Overexpression of NRF2 up-regulated the activity of the xCT promoter, which contains a proximal ARE. In contrast, overexpression of KEAP1 repressed promoter activity and decreased xCT protein levels, while siRNA knockdown of KEAP1 up-regulated xCT protein levels and transporter activity. These results demonstrate the importance of the KEAP1/NRF2 pathway in balancing oxidative stress in breast cancer cells through system xc −. We have previously shown that xCT is upregulated in various cancer cell lines under oxidative stress. In the current investigation, we focused on MCF-7 cells as a model for mechanistic studies.
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      PubDate: 2015-03-18T21:42:16Z
       
  • Persistent oxidative stress in human neural stem cells exposed to low
           fluences of charged particles

    • Abstract: Publication date: Available online 11 March 2015
      Source:Redox Biology
      Author(s): Janet E. Baulch , Brianna M. Craver , Katherine K. Tran , Liping Yu , Nicole Chmielewski , Barrett D. Allen , Charles L. Limoli
      Exposure to the space radiation environment poses risks for a range of deleterious health effects due to the unique types of radiation encountered. Galactic cosmic rays are comprised of a spectrum of highly energetic nuclei that deposit densely ionizing tracks of damage along the particle trajectory. These tracks are distinct from those generated by the more sparsely ionizing terrestrial radiations, and elicit complex cellular damage when charged particles traverse the tissues of the body. The exquisite radiosensitivity of multipotent neural stem and progenitor cells found within the neurogenic regions of the brain predispose the central nervous system to elevated risks for radiation induced sequelae. Here we show that human neural stem cells (hNSC) exposed to different charged particles at space relevant fluences exhibit significant and persistent oxidative stress. Radiation induced oxidative stress was found to be most dependent on total dose rather than on the linear energy transfer of the incident particle. The use of redox sensitive fluorogenic dyes possessing relative specificity for hydroxyl radicals, peroxynitrite, nitric oxide (NO) and mitochondrial superoxide confirmed that most irradiation paradigms elevated reactive oxygen and nitrogen species (ROS and RNS, respectively) in hNSC over a 1 week interval following exposure. Nitric oxide synthase (NOS) was not the major source of elevated nitric oxides, as the use of NOS inhibitors had little effect on NO dependent fluorescence. Our data provide extensive evidence for the capability of low doses of charged particles to elicit marked changes in the metabolic profile of irradiated hNSC. Radiation induced changes in redox state may render the brain more susceptible to the development of neurocognitive deficits that could affect an astronaut’s ability to perform complex tasks during extended missions in deep space.
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      PubDate: 2015-03-14T21:25:22Z
       
  • Advancing age increases sperm chromatin damage and impairs fertility in
           peroxiredoxin 6 null mice

    • Abstract: Publication date: Available online 25 February 2015
      Source:Redox Biology
      Author(s): Burak Ozkosem , Sheldon I. Feinstein , Aron B. Fisher , Cristian O’Flaherty
      Due to socioeconomic factors, more couples are choosing to delay conception than ever. Increasing average maternal and paternal age in developed countries over the past 40 years has raised the question of how aging affects reproductive success of males and females. Since oxidative stress in the male reproductive tract increases with age, we investigated the impact of advanced paternal age on the integrity of sperm nucleus and reproductive success of males by using a Prdx6−/− mouse model. We compared sperm motility, cytoplasmic droplet retention sperm chromatin quality and reproductive outcomes of young (2-month-old), adult (8-month-old), and old (20-month-old) Prdx6−/− males with their age-matched wild type (WT) controls. Absence of PRDX6 caused age-dependent impairment of sperm motility and sperm maturation and increased sperm DNA fragmentation and oxidation as well as decreased sperm DNA compaction and protamination. Litter size, total number of litters and total number of pups per male were significantly lower in Prdx6−/− males compared to WT controls. These abnormal reproductive outcomes were severely affected by age in Prdx6−/− males. In conclusion, the advanced paternal age affects sperm chromatin integrity and fertility more severely in the absence of PRDX6, suggesting a protective role of PRDX6 in age-associated decline in the sperm quality and fertility in mice.
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      PubDate: 2015-02-27T22:52:43Z
       
  • An educational overview of the chemistry, biochemistry and therapeutic
           aspects of Mn porphyrins – from superoxide dismutation to
           H2O2-driven pathways

    • Abstract: Publication date: Available online 7 February 2015
      Source:Redox Biology
      Author(s): Ines Batinic-Haberle , Artak Tovmasyan , Ivan Spasojevic
      SOD mimics thus far developed belong to the classes of Mn-(MnPs) and Fe porphyrins(FePs), Mn(III) salens, Mn(II) cyclic polyamines and metal salts. Due to their remarkable stability we have predominantly explored Mn porphyrins, aiming initially at mimicking kinetics and thermodynamics of the catalysis of O2 . dismutation by SOD enzymes. Several MnPs are of potency similar to SOD enzymes. The in vivo bioavailability and toxicity of MnPs have been addressed also. Numerous in vitro and in vivo studies indicate their impressive therapeutic efficacy. Increasing insight into complex cellular redox biology has been accompanied by increasing awareness of complex redox chemistry of MnPs. During O2 •− dismutation process, the most powerful Mn porphyrin-based SOD mimics reduce and oxidize O2 •− with close to identical rate constants. Therefore MnPs reduce and oxidize other reactive species also (none of them appear specific to MnPs), acting as reductants (antioxidant) and pro-oxidants. Distinction must be made between the type of reactions of MnPs and the favorable therapeutic effects, we observe, which may be of either anti- or pro-oxidative nature. H2O2/MnP mediated oxidation of protein thiols and its impact on cellular transcription seems to dominate redox biology of MnPs. It has been thus far demonstrated that the ability of MnPs to catalyze O2 •− dismutation parallels all other reactivities (such as ONOO−) and in turn their therapeutic efficacies. Assuming safely that all diseases have in common the perturbation of cellular redox environment, developing SOD mimics still seems to be the most appropriate strategy for the design of potent redox-active therapeutics.
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      PubDate: 2015-02-23T05:01:51Z
       
  • Teaching the fundamentals of electron transfer reactions in mitochondria
           and the production and detection of reactive oxygen species

    • Abstract: Publication date: Available online 7 February 2015
      Source:Redox Biology
      Author(s): Ryan J. Mailloux
      Mitochondria fulfill a number of biological functions which inherently depend on ATP and O2 −•/H2O2 production. Both ATP and O2 −•/H2O2 are generated by electron transfer reactions. ATP is the product of oxidative phosphorylation whereas O2 −• is generated by singlet electron reduction of di-oxygen (O2). O2 −• is then rapidly dismutated by superoxide dismutase (SOD) producing H2O2. O2 −•/H2O2 were once viewed as unfortunately by-products of aerobic respiration. This characterization is fitting considering over production of O2 −•/H2O2 by mitochondria is associated with range of pathological conditions and aging. However, O2 −•/H2O2 are only dangerous in large quantities. If produced in a controlled fashion and maintained at a low concentration, cells can benefit greatly from the redox properties of O2 −•/H2O2. Indeed, low rates of O2 −•/H2O2 production are required for intrinsic mitochondrial signaling (e.g. modulation of mitochondrial processes) and communication with the rest of the cell. O2 −•/H2O2 levels are kept in check by anti-oxidant defense systems that sequester O2 −•/H2O2 with extreme efficiency. Given the importance of O2 −•/H2O2 in cellular function, it is imperative to consider how mitochondria produce O2 −•/H2O2 and how O2 −•/H2O2 genesis is regulated in conjunction with fluctuations in nutritional and redox states. Here, I discuss the fundamentals of electron transfer reactions in mitochondria and emerging knowledge on the 11 potential sources of mitochondrial O2 −•/H2O2 in tandem with their significance in contributing to overall O2 −•/H2O2 emission in health and disease. The potential for classifying these different sites in isopotential groups, which is essentially defined by the redox properties of electron donator involved in O2 −•/H2O2 production, as originally suggested by Brand and colleagues is also surveyed in detail. In addition, redox signaling mechanisms that control O2 −•/H2O2 genesis from these sites are discussed. Finally, the current methodologies utilized for measuring O2 −•/H2O2 in isolated mitochondria, cell culture and in vivo are reviewed.
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      PubDate: 2015-02-23T05:01:51Z
       
  • Redox signaling in acute pancreatitis

    • Abstract: Publication date: Available online 27 January 2015
      Source:Redox Biology
      Author(s): Salvador Pérez , Javier Pereda , Luis Sabater , Juan Sastre
      Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling modulator in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF-VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis.


      PubDate: 2015-01-29T15:32:56Z
       
  • The shifting perception on antioxidants: the case of vitamin E and
           β-carotene

    • Abstract: Publication date: Available online 16 January 2015
      Source:Redox Biology
      Author(s): Misha F. Vrolijk , Antoon Opperhuizen , Eugène H.J.M. Jansen , Roger W. Godschalk , Frederik J. Van Schooten , Aalt Bast , Guido R.M.M. Haenen
      Antioxidants are vital for aerobic life, and for decades the expectations of antioxidants as health promoting agents were very high. However, relatively recent meta-analyses of clinical studies show that supplementation of antioxidants does not result in the presumed health benefit, but is associated with increased mortality. The dilemma that still needs to be solved is: what are antioxidants in the end, healthy or toxic? We have evaluated this dilemma by examining the presumed health effects of two individual antioxidants with opposite images i.e. the “poisonous” β-carotene and the “wholesome” vitamin E and focused on one aspect, namely their role in inducing BPDE-DNA adducts. It appears that both antioxidants promote DNA adduct formation indirectly by inhibition of the protective enzyme glutathione-S-transferase π (GST π). Despite their opposite image, both antioxidants display a similar type of toxicity. It is concluded that, in the appreciation of antioxidants, first their benefits should be identified and substantiated by elucidating their molecular mechanism. Subsequently, the risks should be identified including the molecular mechanism. The optimal benefit–risk ratio has to be determined for each antioxidant and each individual separately, also considering the dose.
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      PubDate: 2015-01-21T14:53:12Z
       
  • Interdependence of tetrapyrrole metabolism, the generation of oxidative
           stress and the mitigative oxidative stress response

    • Abstract: Publication date: Available online 16 January 2015
      Source:Redox Biology
      Author(s): Andrea W.U. Busch , Beronda L. Montgomery
      Tetrapyrroles are involved in light harvesting and light perception, electron-transfer reactions, and as co-factors for key enzymes and sensory proteins. Under conditions in which cells exhibit stress-induced imbalances of photosynthetic reactions, or light absorption exceeds the ability of the cell to use photoexcitation energy in synthesis reactions, redox imbalance can occur in photosynthetic cells. Such conditions can lead to the generation of reactive oxygen species (ROS) associated with alterations in tetrapyrrole homeostasis. ROS accumulation can result in cellular damage and detrimental effects on organismal fitness, or ROS molecules can serve as signals to induce a protective or damage-mitigating oxidative stress signaling response in cells. Induced oxidative stress responses include tetrapyrrole-dependent and -independent mechanisms for mitigating ROS generation and/or accumulation. Thus, tetrapyrroles can be contributors to oxidative stress, but are also essential in the oxidative stress response to protect cells by contributing to detoxification of ROS. In this review, we highlight the interconnection and interdependence of tetrapyrrole metabolism with the occurrence of oxidative stress and protective oxidative stress signaling responses in photosynthetic organisms.
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      PubDate: 2015-01-21T14:53:12Z
       
  • Teaching the basics of autophagy and mitophagy to redox biologists
           − mechanisms and experimental approaches

    • Abstract: Publication date: Available online 13 January 2015
      Source:Redox Biology
      Author(s): Jianhua Zhang
      Autophagy is a lysosomal mediated degradation activity providing an essential mechanism for recycling cellular constituents, and clearance of excess or damaged lipids, proteins and organelles. Autophagy involves more than 30 proteins and is regulated by nutrient availability, and various stress sensing signaling pathways. This article provides an overview of the mechanisms and regulation of autophagy, its role in health and diseases, and methods for its measurement. Hopefully this teaching review together with the graphic illustrations will be helpful for instructors teaching graduate students who are interested in grasping the concepts and major research areas and introducing recent developments in the field.
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      PubDate: 2015-01-16T14:31:29Z
       
  • NLRP3 inflammasome: from a danger signal sensor to a regulatory node of
           oxidative stress and inflammatory diseases

    • Abstract: Publication date: Available online 13 January 2015
      Source:Redox Biology
      Author(s): Amna Abderrazak , Tatiana Syrovets , Dominique Couchie , Khadija El Hadri , Bertrand Friguet , Thomas Simmet , Mustapha Rouis
      IL-1β production is critically regulated by cytosolic molecular complexes, termed inflammasomes. Different inflammasome complexes have been described to date. While all inflammasomes recognize certain pathogen, it is the distinctive feature of NLRP3 inflammasome to be activated by many and diverse stimuli making NLRP3 the most versatile, and importantly also the most clinically implicated inflammasome. However, NLRP3 activation has remained the most enigmatic. It is not plausible that the intracellular NLRP3 receptor is able to detect all of its many and diverse triggers through direct interactions; instead, it is discussed that NLRP3 is responding to certain generic cellular stress-signals induced by the multitude of molecules that trigger its activation. An ever increasing number of studies link the sensing of cellular stress signals to a direct pathophysiological role of NLRP3 activation in a wide range of autoinflammatory and autoimmune disorders, and thus provide a novel mechanistic rational, on how molecules trigger and support sterile inflammatory diseases. A vast interest has created to unravel how NLRP3 becomes activated, since mechanistic insight is the prerequisite for a knowledge-based development of therapeutic intervention strategies that specifically target the NLRP3 triggered IL-1β production. In this review, we have updated knowledge on NLRP3 inflammasome assembly and activation and on the pyrin domain in NLRP3 that could represent a drug target to treat sterile inflammatory diseases. In addition, we have reported mutations in NLRP3 that were found to be associated with certain diseases. In addition, we have reviewed the functional link between NLRP3 inflammasome, the regulator of cellular redox status Trx/Txnip complex, endoplasmic reticulum stress and the pathogenesis of diseases such as diabetes type 2. Finally, we have provided data on NLRP3 inflammasome, as a critical regulator involved in the pathogenesis of obesity and cardiovascular diseases. Highlights • We review recently described knowledge that have been proposed to be involved in NLRP3 inflammasome assembly and activation. • We have updated knowledge on the pyrin domain in NLRP3 that could represent a drug target to treat sterile inflammatory diseases. • We have reported mutations in NLRP3 that were found to be associated with certain diseases. • We reviewed the functional link between NLRP3 inflammasome, the regulator of cellular redox status Trx/Txnip complex, endoplasmic reticulum stress and the pathogenesis of diseases such as diabetes type 2. • We have provided data on NLRP3, as a critical regulator, involved in the pathogenesis of obesity and cardiovascular diseases.


      PubDate: 2015-01-16T14:31:29Z
       
  • Border between natural product and drug: comparison of the related
           benzoquinones idebenone and coenzyme Q10

    • Abstract: Publication date: Available online 14 January 2015
      Source:Redox Biology
      Author(s): Nuri Gueven , Krystel Woolley , Jason Smith
      CoenzymeQ10 is a ubiquitous component of cellular membranes and belongs to the class of benzoquinones that mainly differ with regards to the length and composition of their hydrophobic tail. The characteristic quinone group can accept electrons from various biological sources and is converted by a one electron transfer to the unstable semiquinone or by a two electron transfer to the more stable hydroquinone. This feature makes CoQ10 the bona fide cellular electron transfer molecule within the mitochondrial respiratory chain and also makes it a potent cellular antioxidant. These activities serve as justification for its popular use as food supplement. Another quinone with similarities to the naturally occurring CoQ10 is the idebenone, which shares its quinone moiety with CoQ10, but at the same time differs from CoQ10 by the presence of a much shorter, less lipophilic tail. However, despite its similarity to CoQ10, idebenone cannot be isolated from any natural sources but instead was synthesized and selected as a pharmacologically active compound in the 1980s by Takeda Pharmaceuticals purely based on its pharmacological properties. Several recent clinical trials demonstrated some therapeutic efficacy of idebenone in different indications and as a consequence, many practitioners question if the freely available CoQ10 could not be used instead. Here, we describe the molecular and pharmacological features of both molecules that arise from their structural differences to answer the question if idebenone is merely a CoQ10 analogue as frequently perpetuated in the literature or a pharmaceutical drug with entirely different features.
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      PubDate: 2015-01-16T14:31:29Z
       
  • Oxidative stress in severe acute illness

    • Abstract: Publication date: Available online 13 January 2015
      Source:Redox Biology
      Author(s): David Bar-Or , Raphael Bar-Or , Leonard T. Rael , Edward N. Brody
      The overall redox potential of a cell is primarily determined by oxidizable/reducible chemical pairs, including glutathione-glutathione disulfide, reduced thioredoxin-oxidized thioredoxin, and NAD+ − NADH (and NADP-NADPH). Current methods for evaluating oxidative stress rely on detecting levels of individual byproducts of oxidative damage or by determining the total levels or activity of individual antioxidant enzymes. Oxidation-reduction potential (ORP), on the other hand, is an integrated, comprehensive measure of the balance between total (known and unknown) pro-oxidant and antioxidant components in a biological system. Much emphasis has been placed on the role of oxidative stress in chronic diseases, such as Alzheimer’s disease and atherosclerosis. The role of oxidative stress in acute diseases often seen in the emergency room and intensive care unit is considerable. New tools for the rapid, inexpensive measurement of both redox potential and total redox capacity should aid in introducing a new body of literature on the role of oxidative stress in acute illness and how to screen and monitor for potentially beneficial pharmacologic agents.


      PubDate: 2015-01-16T14:31:29Z
       
  • Autophagy in lung disease pathogenesis and therapeutics

    • Abstract: Publication date: Available online 2 January 2015
      Source:Redox Biology
      Author(s): Stefan W. Ryter , Augustine M.K. Choi
      Autophagy, a cellular pathway for the degradation of damaged organelles and proteins, has gained increasing importance in human pulmonary diseases, both as a modulator of pathogenesis and as a potential therapeutic target. In this pathway, cytosolic cargos are sequestered into autophagosomes, which are delivered to the lysosomes where they are enzymatically degraded and then recycled as metabolic precursors. Autophagy exerts an important effector function in the regulation of inflammation, and immune system functions. Selective pathways for autophagic degradation of cargoes may have variable significance in disease pathogenesis. Among these, the autophagic clearance of bacteria (xenophagy) may represent a crucial host defense mechanism in the pathogenesis of sepsis and inflammatory diseases. Our recent studies indicate that the autophagic clearance of mitochondria, a potentially protective program, may aggravate the pathogenesis of chronic obstructive pulmonary disease by activating cell death programs. We report similar findings with respect to the autophagic clearance of cilia components, which can contribute to airways dysfunction in chronic lung disease. In certain diseases such as pulmonary hypertension, autophagy may confer protection by modulating proliferation and cell death. In other disorders, such as idiopathic pulmonary fibrosis and cystic fibrosis, impaired autophagy may contribute to pathogenesis. In lung cancer, autophagy has multiple consequences by limiting carcinogenesis, modulating therapeutic effectiveness, and promoting tumor cell survival. In this review we highlight the multiple functions of autophagy and its selective autophagy subtypes that may be of significance to the pathogenesis of human disease, with an emphasis on lung disease and therapeutics.
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      PubDate: 2015-01-07T13:46:51Z
       
  • Oxidative stress: a concept in redox biology and medicine

    • Abstract: Publication date: Available online 2 January 2015
      Source:Redox Biology
      Author(s): Helmut Sies
      “Oxidative stress” as a concept in redox biology and medicine has been formulated in 1985; at the beginning of 2015, approx. 140,000 PubMed entries show for this term. This concept has its merits and its pitfalls. Among the merits is the notion, elicited by the combined two terms of (i) aerobic metabolism as a steady-state redox balance, and (ii) the associated potential strains in the balance as denoted by the term, stress, evoking biological stress responses. Current research on molecular redox switches governing oxidative stress responses is in full bloom. The fundamental importance of linking redox shifts to phosphorylation/dephosphorylation signaling is being more fully appreciated, thanks to major advances in methodology. Among the pitfalls is the fact that the underlying molecular details are to be worked out in each particular case, which is bvious for a global concept, but which is sometimes overlooked. This can lead to indiscriminate use of the term, oxidative stress, without clear relation to redox chemistry. The major role in antioxidant defense is fulfilled by antioxidant enzymes, not by small-molecule antioxidant compounds. The field of oxidative stress research embraces chemistry, biochemistry, cell biology, physiology and pathophysiology, all the way to medicine and health and disease research.


      PubDate: 2015-01-07T13:46:51Z
       
  • Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer:
           focusing on mitochondria

    • Abstract: Publication date: Available online 29 December 2014
      Source:Redox Biology
      Author(s): Huiqin Zhong , Huiyong Yin
      Oxidative stress − induced lipid peroxidation has been associated with human physiology and diseases including cancer. Overwhelming data suggest that reactive lipid mediators generated from this process, such as 4-hydroxynonenal (4-HNE), are biomarkers for oxidative stress and important players for mediating a number of signaling pathways. The biological effects of 4-HNE are primarily due to covalent modification of important biomolecules including proteins, DNA, and phospholipids containing amino group. In this review, we summarize recent progress on the role of 4-HNE in pathogenesis of cancer and focus on the involvement of mitochondria: generation of 4-HNE from oxidation of mitochondria-specific phospholipid cardiolipin; covalent modification of mitochondrial proteins, lipids, and DNA; potential therapeutic strategies for targeting mitochondrial ROS generation, lipid peroxidation, and 4-HNE.


      PubDate: 2015-01-02T11:17:18Z
       
  • Elastin aging and lipid oxidation products in human aorta

    • Abstract: Publication date: Available online 18 December 2014
      Source:Redox Biology
      Author(s): Kamelija Zarkovic , Pauline Larroque-Cardoso , Mélanie Pucelle , Robert Salvayre , Georg Waeg , Anne Nègre-Salvayre , Neven Zarkovic
      Vascular aging is associated with structural and functional modifications of the arteries, and by an increase in arterial wall thickening in the intima and the media, mainly resulting from structural modifications of the extracellular matrix (ECM) components. Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA), (4-hydroxynonenal, malondialdehyde, acrolein), form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging. The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that 4-HNE-histidine-adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by 4-HNE. These data indicate a complex role for lipid peroxidation and in particular for 4-HNE in elastin homeostasis, in the vascular wall remodeling during aging and atherosclerosis development.
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      PubDate: 2014-12-22T09:39:42Z
       
  • Redox regulated peroxisome homeostasis

    • Abstract: Publication date: Available online 18 December 2014
      Source:Redox Biology
      Author(s): Xiaofeng Wang , Shuo Li , Yu Liu , Changle Ma
      Peroxisomes are ubiquitous organelles present in nearly all eukaryotic cells. Conserved functions of peroxisomes encompass beta-oxidation of fatty acids and scavenging of reactive oxygen species generated from diverse peroxisomal metabolic pathways. Peroxisome content, number, and size can change quickly in response to environmental and/or developmental cues. To achieve efficient peroxisome homeostasis, peroxisome biogenesis and degradation must be orchestrated. We review the current knowledge on redox regulated peroxisome biogenesis and degradation with an emphasis on yeasts and plants.
      Graphical abstract image

      PubDate: 2014-12-22T09:39:42Z
       
  • Autophagic regulation of smooth muscle cell biology

    • Abstract: Publication date: Available online 18 December 2014
      Source:Redox Biology
      Author(s): Joshua K. Salabei , Bradford G. Hill
      Autophagy is a process that regulates the metabolism, survival, and function of numerous cell types, including those comprising the cardiovascular system. In the vasculature, changes in autophagy have been documented in atherosclerotic and restenotic lesions and in hypertensive vessels. The biology of vascular smooth muscle cells appears particularly sensitive to changes in the autophagic program. Recent evidence indicates that stimuli or stressors evoked during the course of vascular disease can regulate autophagic activity, resulting in modulation of VSMC phenotype and viability. In particular, certain growth factors and cytokines, oxygen tension, and pharmacological drugs have been shown to trigger autophagy in smooth muscle cells. Importantly, each of these stimuli has a redox component, typically associated with changes in the abundance of reactive oxygen, nitrogen, or lipid species. Collective findings support the hypothesis that autophagy plays a critical role in vascular remodeling by regulating smooth muscle cell phenotype transitions and by influencing the cellular response to stress. In this graphical review, we summarize current knowledge on the role of autophagy in the biology of the smooth muscle cell in (patho)physiology.


      PubDate: 2014-12-22T09:39:42Z
       
  • Hyaluronan synthase-2 upregulation protects smpd3-deficient fibroblasts
           against cell death induced by nutrient deprivation, but not against
           apoptosis evoked by oxidized LDL

    • Abstract: Publication date: Available online 16 December 2014
      Source:Redox Biology
      Author(s): Sandra Garoby-Salom , Myriam Rouahi , Elodie Mucher , Nathalie Auge , Robert Salvayre , Anne Negre-Salvayre
      The neutral type 2 sphingomyelinase (nSMase2) hydrolyzes sphingomyelin and generates ceramide, a major bioactive sphingolipid mediator, involved in growth arrest and apoptosis. The role of nSMase2 in apoptosis is debated, and apparently contradictory results have been observed on fibroblasts isolated from nSMase2-deficient fragilitas ossium (homozygous fro/fro) mice. These mice exhibit a severe neonatal dysplasia, a lack of long bone mineralization and delayed apoptosis patterns of hypertrophic chondrocytes in the growth plate. We hypothesized that apoptosis induced by nutrient deprivation, which mimics the environmental modifications of the growth plate, requires nSMase2 activation. In this study, we have compared the resistance of fro/fro fibroblasts to different death inducers (oxidized LDL, hydrogen peroxide and nutrient starvation). The data show that nSMase2-deficient fro/fro cells resist to apoptosis evoked by nutrient starvation (fetal calf serum/glucose/pyruvate-free DMEM), whereas wt fibroblasts die after 48 h incubation in this medium. In contrast, oxidized LDL and hydrogen peroxide are similarly toxic to fro/fro and wt fibroblasts, indicating that nSMase2 is not involved in the mechanism of toxicity evoked by these agents. Interestingly, wt fibroblasts treated with the SMase inhibitor GW4869 were more resistant to starvation-induced apoptosis. The resistance of fro/fro cells to starvation-induced apoptosis is associated with an increased expression of hyaluronan synthase 2 (HAS2) mRNAs and protein, which is inhibited by ceramide. In wt fibroblasts, this HAS2 rise and its protective effect did not occur, but exogenously added HA exhibited a protective effect against starvation-induced apoptosis. The protective mechanism of HAS2 involves an increased expression of the heat-shock protein Hsp72, a chaperone with antiapoptotic activity. Taken together, these results highlight the role of nSMase2 in apoptosis evoked by nutrient starvation that could contribute to the delayed apoptosis of hypertrophic chondrocytes in the growth plate, and emphasize the antiapoptotic properties of HAS2.
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      PubDate: 2014-12-18T09:24:20Z
       
  • Molecular mechanisms of the microsomal mixed function oxidases and
           biological and pathological implications

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): Arthur I. Cederbaum
      The cytochrome P450 mixed function oxidase enzymes play a major role in the metabolism of important endogenous substrates as well as in the biotransformation of xenobiotics. The liver P450 system is the most active in metabolism of exogenous substrates. This review briefly describes the liver P450 (CYP) mixed function oxidase system with respect to its enzymatic components and functions. Electron transfer by the NADPH-P450 oxidoreductase is required for reduction of the heme of P450, necessary for binding of molecular oxygen. Binding of substrates to P450 produce substrate binding spectra. The P450 catalytic cycle is complex and rate-limiting steps are not clear. Many types of chemical reactions can be catalyzed by P450 enzymes, making this family among the most diverse catalysts known. There are multiple forms of P450s arranged into families based on structural homology. The major drug metabolizing CYPs are discussed with respect to typical substrates, inducers and inhibitors and their polymorphic forms. The composition of CYPs in humans varies considerably among individuals because of sex and age differences, the influence of diet, liver disease, presence of potential inducers and/or inhibitors. Because of such factors and CYP polymorphisms, and overlapping drug specificity, there is a large variability in the content and composition of P450 enzymes among individuals. This can result in large variations in drug metabolism by humans and often can contribute to drug–drug interactions and adverse drug reactions. Because of many of the above factors, especially CYP polymorphisms, there has been much interest in personalized medicine especially with respect to which CYPs and which of their polymorphic forms are present in order to attempt to determine what drug therapy and what dosage would reflect the best therapeutic strategy in treating individual patients.
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      PubDate: 2014-12-14T09:04:46Z
       
  • Urinary markers of nucleic acid oxidation and cancer in type 2 diabetes

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): Kasper Broedbaek , Volkert Siersma , Trine Henriksen , Allan Weimann , Morten Petersen , Jon T. Andersen , Espen Jimenez-Solem , Lars J. Hansen , Jan Erik Henriksen , Steen J. Bonnema , Niels de Fine Olivarius , Søren Friis , Henrik E. Poulsen
      Aims/hypothesis We investigated whether urinary markers of nucleic acid oxidation are associated with an increased risk of cancer in type 2 diabetes patients. Methods Urine samples from 1381 newly diagnosed diabetes patients were assayed for the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo). Cox proportional hazards regression was used to examine the relationship between the urinary markers and cancer incidence. Results The crude analyses showed an association between overall cancer and urinary excretion of the RNA oxidation marker 8-oxoGuo (unadjusted hazard ratio for cancer per natural log increase in 8-oxoGuo 1.35 [95% CI, 1.01–1.81]), however, in the adjusted analyses, no significant associations between 8-oxodG or 8-oxoGuo and overall cancer were found. For site-specific cancers 8-oxodG was associated with breast cancer in the crude analyses (unadjusted hazard ratio for breast cancer per natural log increase in 8-oxodG was 2.37 [95% CI, 1.07–5.26]), although the association was attenuated in the adjusted analyses (sex- and age-adjusted hazard ratio 2.15 [95% CI, 0.92–5.02] and multivariate adjusted hazard ratio1.98 [95% CI, 0.95–4.10]). Conclusions Urinary excretion of the nucleic acid oxidation markers 8-oxodG and 8-oxoGuo at the time of diagnosis was not associated with cancer overall in type 2 diabetes patients. For site-specific cancers, risk elevations were seen for breast cancer (8-oxodG). These findings should be examined in future and larger studies.


      PubDate: 2014-12-14T09:04:46Z
       
  • The role of the catecholic and the electrophilic moieties of caffeic acid
           in Nrf2/Keap1 pathway activation in ovarian carcinoma cell lines

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): R. Sirota , D. Gibson , R. Kohen
      In recent years, numerous studies have demonstrated the health benefits of polyphenols. A major portion of polyphenols in western diet are derived from coffee, which is one of the most consumed beverages in the world. It has been shown that many polyphenols gain their beneficial properties (e.g. cancer prevention) through the activation of the Nrf2/Keap1 pathway as well as their direct antioxidant activity. However, activation of Nrf2 in cancer cells might lead to resistance towards therapy through induction of phase II enzymes. In the present work we hypothesize that caffeic acid (CA), a coffee polyphenol, might act as an electrophile in addition to its nucleophilic properties and is capable of inducing the Nrf2/EpRE pathway in cancer cells. The results indicate that CA induces Nrf2 translocation into the nucleus and consequently its transcription. It has been demonstrated that generated hydrogen peroxide is involved in the induction process. It has also been found that this process is induced predominantly via the double bond in CA (Michael acceptor). However, surprisingly the presence of both nucleophilic and electrophilic moieties in CA resulted in a synergetic activation of Nrf2 and phase II enzymes. We also found that CA possesses a dual activity, although inducing GSTP1 and GSR, it inhibiting their enzymatic activity. In conclusion, the mechanism of induction of Nrf2 pathway and phase II enzymes by CA has been elucidated. The electrophilic moiety in CA is essential for the oxidation of the Keap1 protein. It should be noted that while the nucleophilic moiety (the catechol/quinone moiety) can provide scavenging ability, it cannot contribute directly to Nrf2 induction. It was found that this process may be induced by H2O2 produced by the catechol group. On the whole, it appears that CA might play a major role in the cancer cells by enhancing their resistance to treatment.
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      PubDate: 2014-12-14T09:04:46Z
       
  • A novel role for 12/15-lipoxygenase in regulating autophagy

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): Alwena H. Morgan , Victoria J. Hammond , Machiko Sakoh-Nakatogawa , Yoshinori Ohsumi , Christopher P. Thomas , Fabien Blanchet , Vincent Piguet , Kirill Kiselyov , Valerie B. O’Donnell
      12/15-Lipoxygenase (LOX) enzymatically generates oxidized phospholipids in monocytes and macrophages. Herein, we show that cells deficient in 12/15-LOX contain defective mitochondria and numerous cytoplasmic vacuoles containing electron dense material, indicating defects in autophagy or membrane processing, However, both LC3 expression and lipidation were normal both basally and on chloroquine treatment. A LOX-derived oxidized phospholipid, 12-hydroxyeicosatetraenoic acid-phosphatidylethanolamine (12-HETE-PE) was found to be a preferred substrate for yeast Atg8 lipidation, versus native PE, while both native and oxidized PE were effective substrates for LC3 lipidation. Last, phospholipidomics demonstrated altered levels of several phospholipid classes. Thus, we show that oxidized phospholipids generated by 12/15-LOX can act as substrates for key proteins required for effective autophagy and that cells deficient in this enzyme show evidence of autophagic dysfunction. The data functionally link phospholipid oxidation with autophagy for the first time.
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      PubDate: 2014-12-14T09:04:46Z
       
  • Copper–zinc superoxide dismutase-mediated redox regulation of
           bortezomib resistance in multiple myeloma

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): Kelley Salem , Michael L. McCormick , Erik Wendlandt , Fenghuang Zhan , Apollina Goel
      Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper–zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity.
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      PubDate: 2014-12-14T09:04:46Z
       
  • Uncoupling protein-2 attenuates palmitoleate protection against the
           cytotoxic production of mitochondrial reactive oxygen species in INS-1E
           insulinoma cells

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): Jonathan Barlow , Verena Hirschberg Jensen , Charles Affourtit
      High glucose and fatty acid levels impair pancreatic beta cell function. We have recently shown that palmitate-induced loss of INS-1E insulinoma cells is related to increased reactive oxygen species (ROS) production as both toxic effects are prevented by palmitoleate. Here we show that palmitate-induced ROS are mostly mitochondrial: oxidation of MitoSOX, a mitochondria-targeted superoxide probe, is increased by palmitate, whilst oxidation of the equivalent non-targeted probe is unaffected. Moreover, mitochondrial respiratory inhibition with antimycin A stimulates palmitate-induced MitoSOX oxidation. We also show that palmitate does not change the level of mitochondrial uncoupling protein-2 (UCP2) and that UCP2 knockdown does not affect palmitate-induced MitoSOX oxidation. Palmitoleate does not influence MitoSOX oxidation in INS-1E cells ±UCP2 and largely prevents the palmitate-induced effects. Importantly, UCP2 knockdown amplifies the preventive effect of palmitoleate on palmitate-induced ROS. Consistently, viability effects of palmitate and palmitoleate are similar between cells ±UCP2, but UCP2 knockdown significantly augments the palmitoleate protection against palmitate-induced cell loss at high glucose. We conclude that UCP2 neither mediates palmitate-induced mitochondrial ROS generation and the associated cell loss, nor protects against these deleterious effects. Instead, UCP2 dampens palmitoleate protection against palmitate toxicity.
      Graphical abstract image Highlights

      PubDate: 2014-12-14T09:04:46Z
       
  • Redox-active cerium oxide nanoparticles protect human dermal fibroblasts
           from PQ-induced damage

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): Claudia von Montfort , Lirija Alili , Sarah Teuber-Hanselmann , Peter Brenneisen
      Recently, it has been published that cerium (Ce) oxide nanoparticles (CNP; nanoceria) are able to downregulate tumor invasion in cancer cell lines. Redox-active CNP exhibit both selective pro-oxidative and antioxidative properties, the first being responsible for impairment of tumor growth and invasion. A non-toxic and even protective effect of CNP in human dermal fibroblasts (HDF) has already been observed. However, the effect on important parameters such as cell death, proliferation and redox state of the cells needs further clarification. Here, we present that nanoceria prevent HDF from reactive oxygen species (ROS)-induced cell death and stimulate proliferation due to the antioxidative property of these particles.
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      PubDate: 2014-12-14T09:04:46Z
       
  • Mitochondrial dynamics and mitochondrial quality control

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): Hong-Min Ni , Jessica A. Williams , Wen-Xing Ding
      Mitochondria are cellular energy powerhouses that play important roles in maintaining cell survival, cell death and cellular metabolic homeostasis. Timely removal of damaged mitochondria via autophagy (mitophagy) is thus critical for cellular homeostasis and function. Mitochondria are reticular organelles that have high plasticity for their dynamic structures and constantly undergo fission and fusion as well as movement through the cytoskeleton. In this review, we discuss the most recent progress on the molecular mechanisms and roles of mitochondrial fission/fusion and mitochondrial motility in mitophagy. We also discuss multiple pathways leading to the quality control of mitochondria in addition to the traditional mitophagy pathway under different conditions.
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      PubDate: 2014-12-14T09:04:46Z
       
  • Functional interaction between cyclooxygenase-2 and p53 in response to an
           endogenous electrophile

    • Abstract: Publication date: April 2015
      Source:Redox Biology, Volume 4
      Author(s): Takeshi Kumagai , Hiroko Usami , Nao Matsukawa , Fumie Nakashima , Miho Chikazawa , Takahiro Shibata , Noriko Noguchi , Koji Uchida
      Cyclooxygenase-2 (Cox-2) is rapidly expressed by various stimuli and plays a key role in conversion of free arachidonic acid to prostaglandins. We have previously identified 4-hydroxy-2-nonenal (HNE), a lipid peroxidation-derived electrophile, as the potent Cox-2 inducer in rat epithelial RL34 cells and revealed that the HNE-induced Cox-2 expression resulted from the stabilization of Cox-2 mRNA that is mediated by the p38 mitogen-activated protein kinase signaling pathway. In the present study, we investigated an alternative regulatory mechanism of Cox-2 expression mediated by a transcription factor p53. In addition, to characterize the causal role for Cox-2, we examined the effects of Cox-2 overexpression in RL34 cells. To examine whether the HNE-induced Cox-2 expression was mechanistically linked to the p53 expression, we analyzed changes in Cox-2 and p53 expression levels in response to HNE and observed that the Cox-2 levels were inversely correlated with the p53 levels. Down-regulation of p53 followed by the activation of a transcription factor Sp1 was suggested to be involved in the HNE-induced Cox-2 gene expression. To characterize the effect of Cox-2 expression in the cells, we established the Cox-2-overexpressing derivatives of RL34 cells by stable transfection with Cox-2 cDNA. An oligonucleotide microarray analysis revealed a dramatic down-regulation of the proteasome subunit RC1 in the Cox-2 overexpressed cells compared to the empty-vector transfected control cells. Consistent with the Cox-2-mediated down-regulation of proteasome, a moderate reduction of the proteasome activities was observed. This proteasome dysfunction mediated by the Cox-2 overproduction was associated with the enhanced accumulation of p53 and ubiquitinated proteins, leading to the enhanced sensitivity toward electrophiles. These results suggest the existence of a causal link between Cox-2 and p53, which may represent a toxic mechanism of electrophilic lipid peroxidation products.


      PubDate: 2014-12-14T09:04:46Z
       
  • Interplay between ROS and autophagy in cancer cells, from tumor initiation
           to cancer therapy

    • Abstract: Publication date: Available online 10 December 2014
      Source:Redox Biology
      Author(s): Laura Poillet-Perez , Gilles Despouy , Régis Delage-Mourroux , Michaël Boyer-Guittaut
      Cancer formation is a complex and highly regulated multi-step process which is highly dependent of its environment, from the tissue to the patient. This complexity implies the development of specific treatments adapted to each type of tumor. The initial step of cancer formation requires the transformation of a healthy cell to a cancer cell, a process regulated by multiple intracellular and extracellular stimuli. The further steps, from the anarchic proliferation of cancer cells to form a primary tumor to the migration of cancer cells to distant organs to form metastasis, are also highly dependent of the tumor environment but of intracellular molecules and pathways as well. In this review, we will focus on the regulatory role of ROS (reactive oxygen species) and autophagy levels during the course of cancer development, from cellular transformation to the formation of metastasis. These data will allow us to discuss the potential of these molecule or pathway as putative future therapeutic targets.
      Graphical abstract image

      PubDate: 2014-12-14T09:04:46Z
       
  • Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by
           stimulating Nrf2 pathway in endothelial cells

    • Abstract: Publication date: Available online 10 December 2014
      Source:Redox Biology
      Author(s): Kaori Yama , Keisuke Sato , Natsuki Abe , Yu Murao , Ryosuke Tatsunami , Yoshiko Tampo
      Epalrestat (EPS) is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH plays a crucial role in protecting endothelial cells from oxidative stress, thereby preventing vascular diseases. Here we show that EPS increases GSH levels in not only Schwann cells but also endothelial cells. Treatment of bovine aortic endothelial cells (BAECs), an in vitro model of the vascular endothelium, with EPS caused a dramatic increase in intracellular GSH levels. This was concomitant with the up-regulation of glutamate cysteine ligase, an enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Moreover, EPS stimulated the expression of thioredoxin and heme oxygenase-1, which have important redox regulatory functions in endothelial cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of antioxidant genes. EPS increased nuclear Nrf2 levels in BAECs. Nrf2 knockdown by siRNA suppressed the EPS-induced glutamate cysteine ligase, thioredoxin-1, and heme oxygenase-1 expression. Interestingly, LY294002, an inhibitor of phosphatidylinositol 3-kinase, abolished the EPS-stimulated GSH synthesis, suggesting that the kinase is associated with Nrf2 activation induced by EPS. Furthermore, EPS reduced the cytotoxicity induced by H2O2 and tert-butylhydroperoxide, indicating that EPS plays a role in protecting cells from oxidative stress. Taken together, the results provide evidence that EPS exerts new beneficial effects on endothelial cells by increasing GSH, thioredoxin, and heme oxygenase-1 levels through the activation of Nrf2. We suggest that EPS has the potential to prevent several vascular diseases caused by oxidative stress.
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      PubDate: 2014-12-14T09:04:46Z
       
 
 
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