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Free Radical Biology and Medicine (FRBM)

Enhanced plasma protein carbonylation in patients with myelodysplastic syndromes

Publication date: July 2017 Source:Free Radical Biology and Medicine, Volume 108 Author(s): Alžběta Hlaváčková, Jana Štikarová, Kristýna Pimková, Leona Chrastinová, Pavel Májek, Roman Kotlín, Jaroslav Čermák, Jiří Suttnar, Jan Evangelista Dyr Myelodysplastic syndromes (MDS) represent a heterogeneous group of pre-leukemic disorders, characterized by ineffective hematopoiesis and the abnormal blood cell development of one or more lineages. Oxidative stress, as an important factor in the carcinogenesis of onco-hematological diseases, is also one of the known factors involved in the pathogenesis of MDS. An increase of reactive oxygen species (ROS) may lead to the oxidation of DNA, lipids, and proteins, thereby causing cell damage. Protein carbonylation caused by ROS is defined as an irreversible post-translational oxidative modification of amino acid side chains, and could play an important role in signaling processes. The detection of protein carbonyl groups is a specific useful marker of oxidative stress. In this study, we examined 32 patients divided into three different subtypes of MDS according to the World Health Organization (WHO) classification criteria as refractory anemia with ringed sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia with excess blasts-1,2 (RAEB-1,2). We found significant differences in protein carbonylation between the group of all MDS patients and healthy controls (P=0.0078). Furthermore, carbonylated protein levels were significantly elevated in RARS patients compared to healthy donors (P=0.0013) and to RCMD patients (P=0.0277). We also found a significant difference in the total iron binding capacity (TIBC) between individual subgroups of MDS patients (P=0.0263). Moreover, TIBC was decreased in RARS patients compared to RCMD patients (P=0.0203). TIBC moderately negatively correlated with carbonyl levels (r=−0.5978, P=0.0054) in the MDS patients as a whole. Additionally we observed changes in the carbonylated proteins

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Ergothioneine products derived by superoxide oxidation in endothelial cells exposed to high-glucose

Publication date: July 2017 Source:Free Radical Biology and Medicine, Volume 108 Author(s): Luigi Servillo, Nunzia D’Onofrio, Rosario Casale, Domenico Cautela, Alfonso Giovane, Domenico Castaldo, Maria Luisa Balestrieri Ergothioneine (Egt), 2-mercapto-L-histidine betaine (ESH), is a dietary component acting as antioxidant and cytoprotectant. In vitro studies demonstrated that Egt, a powerful scavenger of hydroxyl radicals, superoxide anion, hypochlorous acid and peroxynitrite, protects vascular function against oxidative damages, thus preventing endothelial dysfunction. In order to delve the peculiar oxidative behavior of Egt, firstly identified in cell free-systems, experiments were designed to identify the Egt oxidation products when endothelial cells (EC) benefit of its protection against high-glucose (hGluc). HPLC-ESI-MS/MS analyses revealed a decrease in the intracellular GSH levels and an increase in the ophthalmic acid (OPH) levels during hGluc treatment. Interestingly, in the presence of Egt, the decrease of the GSH levels was lower than in cells treated with hGluc alone, and this effect was paralleled by lower OPH levels. Egt was also effective in reducing the cytotoxicity of H2O2 and paraquat (PQT), an inducer of superoxide anion production, showing a similar time-dependent pattern of GSH and OPH levels, although with peaks occurring at different times. Importantly, Egt oxidation generated not only hercynine (EH) but also the sulfonic acid derivative (ESO3H) whose amounts were dependent on the oxidative stress employed. Furthermore, cell-free experiments confirmed the formation of both EH and ESO3H when Egt was reacted with superoxide anion. In summary, these data, by identifying the EH and ESO3H formation in EC exposed to hGluc, highlight the cellular antioxidant properties of Egt, whose peculiar redox behavior makes it an attractive candidate for the prevention of oxidative stress-associated endothelial dysfunction during hyperglycemia. Graphical abstract

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Redox regulation of gasotransmission in the vascular system: A focus on angiogenesis

Publication date: July 2017 Source:Free Radical Biology and Medicine, Volume 108 Author(s): Rajesh K. Mistry, Alison C. Brewer Reactive oxygen species have emerged as key participants in a broad range of physiological and pathophysiological processes, not least within the vascular system. Diverse cellular functions which have been attributed to some of these pro-oxidants within the vasculature include the regulation of blood pressure, neovascularisation and vascular inflammation. We here highlight the emerging roles of the enzymatically-generated reaction oxygen species, O2 - and H2O2, in the regulation of the functions of the gaseous signalling molecules: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulphide (H2S). These gasotransmitters are produced on demand from distinct enzymatic sources and in recent years it has become apparent that they are capable of mediating a number of homeostatic processes within the cardiovascular system including enhanced vasodilation, angiogenesis, wound healing and improved cardiac function following myocardial infarction. In common with O2 - and/or H2O2 they signal by altering the functions of target proteins, either by the covalent modification of thiol groups or by direct binding to metal centres within metalloproteins, most notably haem proteins. The regulation of the enzymes which generate NO, CO and H2S have been shown to be influenced at both the transcriptional and post-translational levels by redox-dependent mechanisms, while the activity and bioavailability of the gasotransmitters themselves are also subject to oxidative modification. Within vascular cells, the family of nicotinamide adenine dinucleotide phosphate oxidases (NAPDH oxidases/Noxs) have emerged as functionally significant sources of regulated O2 - and H2O2 production and accordingly, direct associations between Nox-generated oxidants and the functions of specific gasotransmitters are beginning to be identified. This review focuses on the current knowledge of the redox-dependent mechanism

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RelB attenuates cigarette smoke extract-induced apoptosis in association with transcriptional regulation of the aryl hydrocarbon receptor

Publication date: July 2017 Source:Free Radical Biology and Medicine, Volume 108 Author(s): Matthew Iu, Michela Zago, Angela Rico de Souza, Manuella Bouttier, Swati Pareek, John H. White, Qutayba Hamid, David H. Eidelman, Carolyn J. Baglole Chronic obstructive pulmonary disease (COPD) is a chronic and prevalent respiratory disease caused primarily by long term inhalation of cigarette smoke. A major hallmark of COPD is elevated apoptosis of structural lung cells including fibroblasts. The NF-κB member RelB may suppress apoptosis in response to cigarette smoke, but its role in lung cell survival is not known. RelB may act as a pro-survival factor by controlling the expression of superoxide dismutase 2 (SOD2). SOD2 is also regulated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that suppresses cigarette smoke-induced apoptosis. As the AhR is also a binding partner for RelB, we speculate that RelB suppresses cigarette smoke-induced apoptosis by regulating the AhR. Using an in vitro model of cigarette smoke exposure (cigarette smoke extract [CSE]), we found that CSE down-regulated RelB expression in mouse lung fibroblasts, which was associated with elevated levels of cleaved PARP. Genetic ablation of RelB elevated CSE-induced apoptosis, including chromatin condensation, and reduced mitochondrial function. There was also more reactive oxygen species production in RelB-/- cells exposed to CSE. While there was no alteration in Nrf2 expression or localization between RelB-/- and wild type cells in response to CSE, RelB-/- cells displayed significantly decreased AhR mRNA and protein expression, concomitant with loss of AhR target gene expression (Cyp1a1, Cyp1b1, Nqo1). Finally, we found that RelB binds to the Ahr gene at 3 sites to potentially increase its expression via transcriptional induction. These data support that RelB suppresses cigarette smoke-induced apoptosis, potentially by increasing the AhR. Together, these two proteins may comprise an important cell

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Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis

Publication date: July 2017 Source:Free Radical Biology and Medicine, Volume 108 Author(s): Shinya Toyokuni, Fumiya Ito, Kyoko Yamashita, Yasumasa Okazaki, Shinya Akatsuka Epidemiological data indicate a constant worldwide increase in cancer mortality, although the age of onset is increasing. Recent accumulation of genomic data on human cancer via next-generation sequencing confirmed that cancer is a disease of genome alteration. In many cancers, the Nrf2 transcription system is activated via mutations either in Nrf2 or Keap1 ubiquitin ligase, leading to persistent activation of the genes with antioxidative functions. Furthermore, deep sequencing of passenger mutations is clarifying responsible cancer causative agent(s) in each case, including aging, APOBEC activation, smoking and UV. Therefore, it is most likely that oxidative stress is the principal initiating factor in carcinogenesis, with the involvement of two essential molecules for life, iron and oxygen. There is evidence based on epidemiological and animal studies that excess iron is a major risk for carcinogenesis, suggesting the importance of ferroptosis-resistance. Microscopic visualization of catalytic Fe(II) has recently become available. Although catalytic Fe(II) is largely present in lysosomes, proliferating cells harbor catalytic Fe(II) also in the cytosol and mitochondria. Oxidative stress catalyzed by Fe(II) is counteracted by thiol systems at different functional levels. Nitric oxide, carbon monoxide and hydrogen (per)sulfide modulate these reactions. Mitochondria generate not only energy but also heme/iron sulfur cluster cofactors and remain mostly dysfunctional in cancer cells, leading to Warburg effects. Cancer cells are under persistent oxidative stress with a delicate balance between catalytic iron and thiols, thereby escaping ferroptosis. Thus, high-dose L-ascorbate and non-thermal plasma as well as glucose/glutamine deprivation may provide additional benefits as cancer therapies over preexisting therapeutics. Graphical

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Redox Biology

Catalase as a regulator of reactive sulfur metabolism; a new interpretation beyond hydrogen peroxide✩

Publication date: August 2017 Source:Redox Biology, Volume 12 Author(s): Christopher G. Kevil Graphical abstract

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Angiogenesis in the atherosclerotic plaque

Publication date: August 2017 Source:Redox Biology, Volume 12 Author(s): Caroline Camaré, Mélanie Pucelle, Anne Nègre-Salvayre, Robert Salvayre Atherosclerosis is a multifocal alteration of the vascular wall of medium and large arteries characterized by a local accumulation of cholesterol and non-resolving inflammation. Atherothrombotic complications are the leading cause of disability and mortality in western countries. Neovascularization in atherosclerotic lesions plays a major role in plaque growth and instability. The angiogenic process is mediated by classical angiogenic factors and by additional factors specific to atherosclerotic angiogenesis. In addition to its role in plaque progression, neovascularization may take part in plaque destabilization and thromboembolic events. Anti-angiogenic agents are effective to reduce atherosclerosis progression in various animal models. However, clinical trials with anti-angiogenic drugs, mainly anti-VEGF/VEGFR, used in anti-cancer therapy show cardiovascular adverse effects, and require additional investigations. Graphical abstract

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Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

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

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Redox regulation in metabolic programming and inflammation

Publication date: August 2017 Source:Redox Biology, Volume 12 Author(s): Helen R. Griffiths, Dan Gao, Chathyan Pararasa Energy metabolism and redox state are intrinsically linked. In order to mount an adequate immune response, cells must have an adequate and rapidly available energy resource to migrate to the inflammatory site, to generate reactive oxygen species using NADPH as a cofactor and to engulf bacteria or damaged tissue. The first responder cells of the innate immune response, neutrophils, are largely dependent on glycolysis. Neutrophils are relatively short-lived, dying via apoptosis in the process of bacterial killing through production of hypochlorous acid and release of extracellular NETs. Later on, the most prevalent recruited innate immune cells are monocytes. Their role is to complete a damage limitation exercise initiated by neutrophils and then, as re-programmed M2 macrophages, to resolve the inflammatory event. Almost twenty five years ago, it was noted that macrophages lose their glycolytic capacity and become anti-inflammatory after treatment with corticosteroids. In support of this we now understand that, in contrast to early responders, M2 macrophages are predominantly dependent on oxidative phosphorylation for energy. During early inflammation, polarisation towards M1 macrophages is dependent on NOX2 activation which, via protein tyrosine phosphatase oxidation and AKT activation, increases trafficking of glucose transporters to the membrane and consequently increases glucose uptake for glycolysis. In parallel, mitochondrial efficiency is likely to be compromised via nitrosylation of the electron transport chain. Resolution of inflammation is triggered by encounter with apoptotic membranes exposing oxidised phosphatidylserine that interact with the scavenger receptor, CD36. Downstream of CD36, activation of AMPK and PPARγ elicits mitochondrial biogenesis, arginase expression and a switch towards oxidative phosphorylation in the M2 macrophage. Proinflammatory cytokine production

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Shortcuts to a functional adipose tissue: The role of small non-coding RNAs

Publication date: August 2017 Source:Redox Biology, Volume 12 Author(s): Bruna B. Brandão, Beatriz A. Guerra, Marcelo A. Mori Metabolic diseases such as type 2 diabetes are a major public health issue worldwide. These diseases are often linked to a dysfunctional adipose tissue. Fat is a large, heterogenic, pleiotropic and rather complex tissue. It is found in virtually all cavities of the human body, shows unique plasticity among tissues, and harbors many cell types in addition to its main functional unit – the adipocyte. Adipose tissue function varies depending on the localization of the fat depot, the cell composition of the tissue and the energy status of the organism. While the white adipose tissue (WAT) serves as the main site for triglyceride storage and acts as an important endocrine organ, the brown adipose tissue (BAT) is responsible for thermogenesis. Beige adipocytes can also appear in WAT depots to sustain heat production upon certain conditions, and it is becoming clear that adipose tissue depots can switch phenotypes depending on cell autonomous and non-autonomous stimuli. To maintain such degree of plasticity and respond adequately to changes in the energy balance, three basic processes need to be properly functioning in the adipose tissue: i) adipogenesis and adipocyte turnover, ii) metabolism, and iii) signaling. Here we review the fundamental role of small non-coding RNAs (sncRNAs) in these processes, with focus on microRNAs, and demonstrate their importance in adipose tissue function and whole body metabolic control in mammals. Graphical abstract

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