1,720,987 research outputs found
Peroxiredoxin 2 Plays a Pivotal Role Against Oxidation in the Early Phase of Pulmonary Artery Hypertension
Full text linkBackground. Peroxiredoxin 2 (Prx2) is a typical 2-cysteine (Cys) peroxiredoxin ubiquitously expressed. Prx2 is able to efficiently scavenge H2O2 and other hydro-peroxides to maintain intracellular redox balance. Prx2 has been largely studied in red cells, where it acts as antioxidant system and chaperone-like molecule. Although growing evidences indicate the important role of Prx2 in different cell models, much still remains to be investigated in complex disease scenario such as chronic lung disease or stress erythropoiesis. Aim. The major aim of my work is to understand the functional role of Peroxiredoxin 2 in a mouse model of pulmonary artery hypertension. Section 1. I focus on the functional role of peroxiredoxin-2 (Prx2) in lung homeostasis. Here, I studied the events related to the generation of pulmonary artery hypertension (PAH), a life threatening and highly invalidating chronic disorder. Hypoxia was used as trigger factor. I found that Prx2-/- mice displayed chronic lung inflammatory disease associated with (i) abnormal pulmonary vascular dysfunction; and (ii) increased markers of extracellular-matrix remodelling. Rescue experiments with in vivo the administration of fused-recombinant-PEP-Prx2 to hypoxic mice show a reduction in pulmonary inflammatory vasculopathy and down-regulation of autophagy. Thus, we propose Prx2 plays a pivotal role in the early stage of PAH as multimodal anti-oxidant system targeting oxidation, inflammatory vasculopathy and indirectly autophagy. Section 2. I have studied the effect of iron-overload (IO) diet on Prx2-/- mouse erythropoiesis and its link with iron homeostasis. In Prx2-/- mice, IO displayed a potent cytotoxic effect on erythropoiesis and it was associated with lacking in liver STAT3 activation. This results in low hepcidin expression. Treatment with PEP Prx2 ameliorates IO-induced anemia and restored liver STAT3 activation, with adequate hepcidin expression in relation to IO. The importance of Prx2 on the axis between erythropoiesis and iron metabolism is also supported by the beneficial effects of PEP Prx2 on hepcidin levels a mouse model of β-thalassemia. Section 3. I have studied a humanized mouse model for sickle cell disease (SCD, Tim Townes mouse model). Based on the revision of the literature, SCD and healthy mice were supplemented with ω-3 fatty acids. Hypoxia/reoxygenation stress was used to mimic SCD acute vaso-occlusive crisis. We found that ω-3 fatty supplementation reduces: (i) sickle cell related oxidative stress, (ii) systemic and local (lung and liver) inflammatory response, (iii) vascular endothelial activation and (iv) vascular dysfunction. Our data generate a rationale for ω-3 fatty supplementation in clinical management of SCD patients
Emerging drugs in randomized controlled trials for sickle cell disease: are we on the brink of a new era in research and treatment?
Full text linkABSTRACT Introduction: Sickle cell disease (SCD) is caused by a mutation in the HBB gene which is key for making a component of hemoglobin. The mutation leads to the formation of an abnormal hemoglobin molecule called sickle hemoglobin (HbS). SCD is a chronic, complex disease with a multiplicity of pathophysiological targets; it has high morbidity and mortality. Hydroxyurea has for many years been the only approved drug for SCD; hence, the development of new therapeutics is critical. Areas covered: This article offers an overview of the key studies of new therapeutic options for SCD. We searched the PubMed database and Cochrane Database of Systemic Reviews for agents in early phase clinic trials and preclinical development. Expert opinion: Although knowledge of SCD has progressed, patient survival and quality of life must be improved. Phase II and phase III clinical trials investigating pathophysiology-based novel agents show promising results in the clinical management of SCD acute events. The design of longterm clinical studies is necessary to fully understand the clinical impact of these new therapeutics on the natural history of the disease. Furthermore, the building of global collaborations will enhance the clinical management of SCD and the design of primary outcomes of future clinical trials
Resolvin D1 and Resolvin D2 Protect Against Hypoxia/Reoxygenation Induced Lung and Kidney Damage in a Sickle Cell Mouse Model of Acute Vaso-Occlusive Crisis
No full textSickle cell disease (SCD) is characterized by hemolytic anemia in association with acute and chronic life-threatening clinical complications. Acute vaso-occlusive crisis (VOCs) are the main cause of hospitalization for SCD patients. In VOCs, amplified inflammatory response plays a key role in acute organ damage. Pro-Resolving lipid mediators such as resolvins (Rv) accelerate resolution of acute inflammation in different models, indicating that stimulation of endogenous resolution of inflammatory processes may be an additional strategy in limiting tissue damage. Recent data suggest beneficial effects of Rvs in hypoxia/reoxygenation (H/R) related tissue injury. Here, we study the effects of Rvs on a model of acute VOCs using humanized SCD mice (Hbatm1(HBA)Tow Hbbtm2(HBG1,HBB*)Tow). We treated SCD and control healthy mice (AA, Hbatm1(HBA)Tow Hbbtm3(HBG1,HBB)Tow) (n =6-7 animals in each group) with RvD1, 7S, 8R, 17S- trihydroxy-docosa-4Z, 9E, 11E, 13Z, 15E, 19Z-hexaenoic acid, 17R- RvD1, 7S, 8R, 17R- trihydroxy-docosa-4Z, 9E, 11E, 13Z, 15E, 19Z-hexaenoic acid; RvD2, 7S, 16R, 17S-trihydroxy-docosa-4Z, 8E, 10Z, 12E, 14E, 19Z-hexaenoic acid. Mice were treated with RvD1 and RvD2 at the dose of 2.5 ug/Kg by gavage 1 hour (hr) before H/R stress (10 hrs 8% oxygen followed by 3 hrs reoxygenation), which we have used in the past to mimic acute VOCs. We found that RvD1 and RvD2 significantly reduced the H/R-induced (i) increase in neutrophil count; (ii) lung inflammatory cell infiltrate, mucus and thrombi formation; (iii) glomerular inflammatory cell infiltration, glomerular sclerosis and thrombi formation. In the lung of H/R SCD mice, RvD1 prevented the H/R induced up-regulation of (i) cytokines such as MCP2, IL-6 and ET-1; (ii) vascular endothelial activation markers (VCAM-1 and ICAM-1; (iii) cytoprotective systems such as Prx6 and HO-1. In the kidney of H/R SCD mice, RvD1 significantly reduced H/R induced expression of IL-6 and ET-1 as well as HO-1. Our data indicate that RvD1 and RvD2 modulating inflammatory responses related to H/R in SCD, protect sickle cell target organs, and foster resolution. Thus, RvD1 and RvD2 might represent a novel therapeutic approach for acute VOCs in SCD
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Dietary w-3 fatty acids protect against vasculopathy in a transgenic mouse model for sickle cell disease.
No full textThe anemia of sickle cell disease is associated with a severe inflammatory vasculopathy and endothelial dysfunction,which leads to painful and life-threatening clinical complications. Growing evidence supports the anti-inflammatoryproperties of ω-3 fatty acids in clinical models of endothelial dysfunction. Promising but limited studiesshow potential therapeutic effects of ω-3 fatty acid supplementation in sickle cell disease. Here, we treated humanizedhealthy and sickle cell mice for 6 weeks with ω-3 fatty acid diet (fish-oil diet). We found that a ω-3 fatty aciddiet: (i) normalizes red cell membrane ω-6/ ω-3 ratio; (ii) reduces neutrophil count; (iii) decreases endothelial activationby targeting endothelin-1 and (iv) improves left ventricular outflow tract dimensions. In a hypoxia-reoxygenationmodel of acute vaso-occlusive crisis, a ω-3 fatty acid diet reduced systemic and local inflammation andprotected against sickle cell-related end-organ injury. Using isolated aortas from sickle cell mice exposed to hypoxia-reoxygenation, we demonstrated a direct impact of a ω-3 fatty acid diet on vascular activation, inflammation,and anti-oxidant systems. Our data provide the rationale for ω-3 dietary supplementation as a therapeutic interventionto reduce vascular dysfunction in sickle cell disease
A Selective Oral GLYT1 Inhibitor, Improves Anemia and Red Cell Survival in a Mouse Model of Beta-Thalassemia
No full textThe unbalanced hemoglobin chain synthesis in beta-thalassemias leads to hemichrome-induced damage that contributes to ineffective erythropoiesis, hemolysis and reduced red cell survival. Iron overload related to ineffective erythropoiesis and abnormally low Hepcidin (Hamp), combined with the cytotoxic effects of free heme with free-alpha-chains play a key role in the increased generation of reactive oxygen species (ROS) in beta thalassemias. Here we used a specific and selective inhibitor of the plasma membrane expressed glycine transporter GlyT1 (Ro4917838). Use of Ro4917838 has been associated with a dose-dependent decrease in MCH, Hb, soluble transferrin receptor, and increase in absolute reticulocytes and RBC counts in several animal species, attributed to reduce glycine bioavailability in erythroblasts and decreased heme synthesis. In rats, Ro4917838 reduces heme synthesis, and down-regulates erythroid transferrin receptor, but does not interfere with hepcidin regulation and systemic iron homeostasis. We aimed to determine if reduced cellular availability of glycine in erythroblasts may reduce heme synthesis, and impact pathologic erythropoiesis in a mouse model for b-thalassemia. Wild-type control (WT) C57B6/2J, and beta-thalassemia Hbbth3/+ mice were treated with either vehicle or Ro4917838 at dosages of 3, 10, 30 mg/kg/d administered over 4 weeks once daily by gavage. RO4917838 administration was associated with significant improvements of central hallmarks of the b-thalassemia pathology. Reduced erythrocyte destruction was seen bydemonstrated a significant improvements in erythrocyte morphology and amelioration of hemoglobin reduction in reticulocytes. We also observed an impressively quick reduction of the circulating erythroblast count within 1 week of initiating treatment. This was also associated with decreased hemolysis biomarkers. Ro4917838 induced a significant reduction in extramedullary erythropoiesis and reduction in orthochromatic erythroblasts as well as insoluble alpha chain aggregates in circulating red cells. Red cell survival of b-thal mice treated with 30 mg/kg/day Ro4917838 significantly increased by more than 50%. CD71+ erythroid precursors significantly decreased in WT mice treated with Ro4917838 at 30 mg/kg and in b-thal mice at the dosage of 30 mg/kg/ d. These data suggest that Ro4917838 ameliorates anemia in a b-thalassemia mouse model and positively affects ineffective erythropoiesis and red cell survival in peripheral circulation. Ro4917838 may represent a novel therapeutic approach for the treatment of anemia in b-thalassemia patients
Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders
No full textThe dynamic coordination between kinases and phosphatases is crucial for cell homeostasis, in response to different stresses. The functional connection between oxidation and the intracellular signaling machinery still remains to be investigated. In the last decade, several studies have highlighted the role of reactive oxygen species (ROS) as modulators directly targeting kinases, phosphatases, and downstream modulators, or indirectly acting on cysteine residues on kinases/phosphatases resulting in protein conformational changes with modulation of intracellular signaling pathway(s). Translational studies have revealed the important link between oxidation and signal transduction pathways in hematological disorders. The intricate nature of intracellular signal transduction mechanisms, based on the generation of complex networks of different types of signaling proteins, revealed the novel and important role of phosphatases together with kinases in disease mechanisms. Thus, therapeutic approaches to abnormal signal transduction pathways should consider either inhibition of overactivated/accumulated kinases or homeostatic signaling resetting through the activation of phosphatases. This review discusses the progress in the knowledge of the interplay between oxidation and cell signaling, involving phosphatase/kinase systems in models of globally distributed hematological disorders
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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