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Free Radical Biology and Medicine (FRBM)

Aging and Parkinson's Disease: Inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis

Publication date: 1 February 2018 Source:Free Radical Biology and Medicine, Volume 115 Author(s): Vittorio Calabrese, Aurelia Santoro, Daniela Monti, Rosalia Crupi, Rosanna Di Paola, Saverio Latteri, Salvatore Cuzzocrea, Mario Zappia, James Giordano, Edward J. Calabrese, Claudio Franceschi In order to better understand the pathogenesis of Parkinson's Disease (PD) it is important to consider possible contributory factors inherent to the aging process, as age-related changes in a number of physiological systems (perhaps incurred within particular environments) appear to influence the onset and progression of neurodegenerative disorders. Accordingly, we posit that a principal mechanism underlying PD is inflammaging, i.e. the chronic inflammatory process characterized by an imbalance of pro- and anti-inflammatory mechanisms which has been recognized as operative in several age-related, and notably neurodegenerative diseases. Recent conceptualization suggests that inflammaging is part of the complex adaptive mechanisms (“re-modeling”) that are ongoing through the lifespan, and which function to prevent or mitigate endogenous processes of tissue disruption and degenerative change(s). The absence of an adequate anti-inflammatory response can fuel inflammaging, which propagates on both local (i.e.- from cell to cell) and systemic levels (e.g.- via exosomes and other molecules present in the blood). In general, this scenario is compatible with the hypothesis that inflammaging represents a hormetic or hormetic-like effect, in which low levels of inflammatory stress may prompt induction of anti-inflammatory mediators and mechanisms, while sustained pro-inflammatory stress incurs higher and more durable levels of inflammatory substances, which, in turn prompt a local-to-systemic effect and more diverse inflammatory response(s). Given this perspective, new treatments of PD may be envisioned that strategically are aimed at exerting hormetic effects to sustain anti-inflammatory responses, inclusive

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F2-isoprostanes can mediate bleomycin-induced lung fibrosis

Publication date: 1 February 2018 Source:Free Radical Biology and Medicine, Volume 115 Author(s): Beatrice Arezzini, Daniela Vecchio, Cinzia Signorini, Blerta Stringa, Concetta Gardi F2-isoprostanes (F2-IsoPs) have been considered markers of oxidative stress in various pulmonary diseases, but little is known about their possible role in pulmonary fibrosis. In this study, we have investigated the potential key role of F2-IsoPs as markers and mediators of bleomycin (BLM)-induced pulmonary fibrosis in rats. During the in vivo study, plasma F2-IsoPs showed a peak at 7 days and remained elevated for the entire experimental period. Lung F2-IsoP content nearly tripled 7 days following the intratracheal instillation of BLM, and by 28 days, the value increased about fivefold compared to the controls. Collagen deposition correlated with F2-IsoP content in the lung. Furthermore, from day 21 onwards, lung sections from BLM-treated animals showed α-smooth muscle actin (α-SMA) positive cells, which were mostly evident at 28 days. In vitro studies performed in rat lung fibroblasts (RLF) demonstrated that either BLM or F2-IsoPs stimulated both cell proliferation and collagen synthesis. Moreover, RLF treated with F2-IsoPs showed a significant increase of α-SMA expression compared to control, indicating that F2-IsoPs can readily activate fibroblasts to myofibroblasts. Our data demonstrated that F2-IsoPs can be mediators of key events for the onset and development of lung fibrosis, such as cell proliferation, collagen synthesis and fibroblast activation. Immunocytochemistry analysis, inhibition and binding studies demonstrated the presence of the thromboxane A2 receptor (TP receptor) on lung fibroblasts and suggested that the observed effects may be elicited through the binding to this receptor. Our data added a new perspective on the role of F2-IsoPs in lung fibrosis by providing evidence of a profibrotic role for these mediators in the pathogenesis of pulmonary fibrosis. Graphical abstract

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Angiotensin converting enzyme inhibitors enhance the hypotensive effects of propofol by increasing nitric oxide production

Publication date: 1 February 2018 Source:Free Radical Biology and Medicine, Volume 115 Author(s): Gustavo H. Oliveira-Paula, Lucas C. Pinheiro, Graziele C. Ferreira, Waynice N.P. Garcia, Riccardo Lacchini, Luis V. Garcia, Jose E. Tanus-Santos Propofol anesthesia is usually accompanied by hypotension. Studies have shown that the hypotensive effects of propofol increase in patients treated with angiotensin-converting enzyme inhibitors (ACEi). Given that both propofol and ACEi affect nitric oxide (NO) signaling, the present study tested the hypothesis that ACEi treatment induces pronounced hypotensive responses to propofol by increasing NO bioavailability. In this study we evaluated 65 patients, divided into three groups: hypertensive patients chronically treated with ACEi (HT-ACEi; n = 21), hypertensive patients treated with other antihypertensive drugs instead of ACEi, such as angiotensin II receptor blockers, β-blockers or diuretics (HT; n = 21) and healthy normotensive subjects (NT; n = 23). Venous blood samples were collected at baseline and after 10min of anesthesia with propofol 2mg/kg administrated intravenously by bolus injection. Hemodynamic parameters were recorded at each blood sample collection. Nitrite levels were determined by using an ozone-based chemiluminescence assay, while NOx (nitrites+nitrates) levels were measured by using the Griess reaction. Additionally, experimental approaches were used to validate our clinical findings. Higher decreases in blood pressure after propofol anesthesia were observed in HT-ACEi group as compared with those found in NT and HT groups. Consistently, rats treated with the ACEi enalapril showed more intense hypotensive responses to propofol. The hypotensive effects of propofol were associated with increased NO production in both clinical and experimental approaches. Enhanced increases in nitrite levels after propofol anesthesia were observed in HT-ACEi patients compared with NT and HT groups. Accordingly, rats treated with enalapril showed increa

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SIRT6 protects against hepatic ischemia/reperfusion injury by inhibiting apoptosis and autophagy related cell death

Publication date: 1 February 2018 Source:Free Radical Biology and Medicine, Volume 115 Author(s): Song Zhang, Shuai Jiang, Haiping Wang, Wencheng Di, Chao Deng, Zhenxiao Jin, Wei Yi, Xiao Xiao, Yongzhan Nie, Yang Yang Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice. In vitro studies in SIRT6-KO hepatocytes exhibited similar results. In contrast, SIRT6 upregulation alleviated liver damage during hepatic I/R injury. Our study demonstrated for the first time that SIRT6 upregulation effectively protects against hepatic I/R injury. The underlying mechanisms involve the maintenance of oxidative homeostasis and mitochondrial function, which subsequently inhibit the inflammatory responses and MAPK signaling, and finally attenuate apoptosis and autophagy related hepatocyte death. These results suggest that the activation of SIRT6 exerts multifaceted protective effects during hepatic I/R injury, which can provide a novel therapeutic target for hepatic I/R injury. Graphical abstract

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Topical electrophilic nitro-fatty acids potentiate cutaneous inflammation

Publication date: 1 February 2018 Source:Free Radical Biology and Medicine, Volume 115 Author(s): Alicia R. Mathers, Cara D. Carey, Meaghan E. Killeen, Sonia R. Salvatore, Laura K. Ferris, Bruce A. Freeman, Francisco J. Schopfer, Louis D. Falo Endogenous electrophilic fatty acids mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction and gene expression. Nitro-fatty acids and other electrophilic fatty acids may thus be useful for the prevention and treatment of immune-mediated diseases, including inflammatory skin disorders. In this regard, subcutaneous (SC) injections of nitro oleic acid (OA-NO2), an exemplary nitro-fatty acid, inhibit skin inflammation in a model of allergic contact dermatitis (ACD). Given the nitration of unsaturated fatty acids during metabolic and inflammatory processes and the growing use of fatty acids in topical formulations, we sought to further study the effect of nitro-fatty acids on cutaneous inflammation. To accomplish this, the effect of topically applied OA-NO2 on skin inflammation was evaluated using established murine models of contact hypersensitivity (CHS). In contrast to the effects of subcutaneously injected OA-NO2, topical OA-NO2 potentiated hapten-dependent inflammation inducing a sustained neutrophil-dependent inflammatory response characterized by psoriasiform histological features, increased angiogenesis, and an inflammatory infiltrate that included neutrophils, inflammatory monocytes, and γδ T cells. Consistent with these results, HPLC-MS/MS analysis of skin from psoriasis patients displayed a 56% increase in nitro-conjugated linoleic acid (CLA-NO2) levels in lesional skin compared to non-lesional skin. These results suggest that nitro-fatty acids in the skin microenvironment are products of cutaneous inflammatory responses and, in high local concentrations, may exacerbate inflammatory skin diseases. Graphical abstract

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Redox Biology

Developing the next generation of graphene-based platforms for cancer therapeutics: The potential role of reactive oxygen species

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

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Oxidized LDL triggers changes in oxidative stress and inflammatory biomarkers in human macrophages

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

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The NADPH organizers NoxO1 and p47phox are both mediators of diabetes-induced vascular dysfunction in mice

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

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Post-translational regulation of macrophage migration inhibitory factor: Basis for functional fine-tuning

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

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Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress

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

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