126 research outputs found
Transferrin gene ChIP-seq data
No full textChIP-seq Peak-calling data to support the supplementary information to:
In severe alcoholic hepatitis, serum transferrin constitutes an independent mortality predictor indicating an impaired HNF4αsignaling. Stephen R. Atkinson, MD*; Karim Hamesch, MD*; Igor Spivak, MD; Nurdan Guldiken, PhD; Joaquín Cabezas, PhD3; Josepmaria Argemi, PhD; Igor Theurl, MD, Heinz Zoller, MD; Sheng Cao, MD; Philippe Mathurin, MD; Vijay H. Shah, MD; Christian Trautwein, MD; Ramon Bataller, MD; Mark R. Thursz, MD+; Pavel Strnad, MD
Nramp1 functionality increases inducible nitric oxide synthase transcription via stimulation of IFN regulatory factor 1 expression
No full textNatural-resistance associated macrophage protein 1 (Nramp1) encodes a transmembrane phagolysosomal protein exerting resistance toward infections with intracellular pathogens by a mechanism not fully elucidated so far. We used the murine macrophagecell line RAW264.7, stably transfected with functional (RAW-37) or nonfunctional (RAW-21) Nramp1, to study for differences in the expression of NO, a central antimicrobial effector molecule of macrophages. Following stimulation with IFN- and LPS, Nramp1-expressing cells exhibit higher enzymatic activity of inducible NO synthase (iNOS) and increased cytoplasmic iNOS-mRNA levels than RAW-21 cells. Time-course experiments showed that iNOS-mRNA levels remain increased in RAW-37 cells after prolonged cytokine stimulation while they decrease in RAW-21 cells. Reporter gene assays with iNOS-promoter luciferase constructs demonstrated an increased and prolonged promoter activity in Nramp1-resistant vs susceptible cells. This was paralleled by increased IFN regulatory factor 1 (IRF-1) expression and binding affinity to the iNOS promoter in RAW-37 cells, which may be related to enhanced STAT-1 binding affinity in these cells. A point mutation within the IRF-1 binding site of the iNOS promoter abolished the differences in iNOS transcription between RAW-21 and RAW-37 cells. Cells carrying functional Nramp1express increased amounts of NO, which may be related to STAT-1-mediated stimulation of IRF-1 expression with subsequent prolonged activation of iNOS transcription. Enhanced NO expression may partly underlie the protection against infection with intracellular pathogens by Nramp1 functionality
Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1
No full textHereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues, leading to eventual organ failure. We have discovered a new mechanism to reverse iron overload-pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Its additional functions in iron handling in the kidney and liver are less well understood. We show that the L-type calcium channel blocker nifedipine increases DMT-1-mediated cellular iron transport 10- to 100-fold at concentrations between 1 and 100 muM. Mechanistically, nifedipine causes this effect by prolonging the iron-transporting activity of DMT-1. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium channel blockers emerges as a new pharmacological therapy for the treatment of iron overload disorders
Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression
No full textHepcidin, a small cationic liver derived peptide, is a master regulator of body iron homeostasis. Cytokines and iron availability have so far been identified as regulators of hepcidin expression. Herein, we investigated the functional role of Kupffer cells for hepcidin expression because of their vicinity to the hepatocytes and their importance for iron recycling via erythrophagocytosis. We investigated C57Bl6 mice and littermates, in which Kupffer cells were eliminated in vivo upon intravenous injection of liposome-encapsulated clodronate. Primary cultures of hepatocytes and Kupffer cells were used to study direct regulatory effects ex vivo. The in vivo depletion of Kupffer cells resulted in a significant increase in liver hepcidin expression, which was paralleled by a significant reduction in serum iron levels. The same pattern of regulation by Kupffer cell depletion was observed upon injection of bacterial lipopolysaccharide into mice and in primary (Hfe −/−) and in secondary iron-overloaded mice. Accordingly, the messenger ribonucleic acid (mRNA) concentrations of the hepcidin iron-sensing molecule hemojuvelin were not significantly changed upon Kupffer cell depletion. When primary hepatocytes were cocultivated with Kupffer cells or stimulated with a Kupffer cell-conditioned medium ex vivo, a significant reduction in hepatocyte hepcidin mRNA expression was observed. Our data suggest that Kupffer cells control body iron homeostasis by exerting negative regulatory signals toward hepcidin expression, which may be primarily referred to the secretion of yet unidentified hepcidin-suppressing molecules by Kupffer cells
Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease
No full textBACKGROUND ; AIMS: Iron perturbations are frequently observed in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate a potential association of copper status with disturbances of iron homeostasis in NAFLD. METHODS: We retrospectively studied 140 NAFLD patients and 25 control subjects. Biochemical and hepatic iron and copper parameters were analyzed. Hepatic expression of iron regulatory molecules was investigated in liver biopsy specimens by reverse-transcription polymerase chain reaction and Western blot analysis. RESULTS: NAFLD patients had lower hepatic copper concentrations than control subjects (21.9 +/- 9.8 vs 29.6 +/- 5.1 microg/g; P = .002). NAFLD patients with low serum and liver copper concentrations presented with higher serum ferritin levels (606.7 +/- 265.8 vs 224.2 +/- 176.0 mg/L; P < .001), increased prevalence of siderosis in liver biopsy specimens (36/46 vs 10/47 patients; P < .001), and with elevated hepatic iron concentrations (1184.4 +/- 842.7 vs 319.9 +/- 451.3 microg/g; P = .020). Lower serum concentrations of the copper-dependent ferroxidase ceruloplasmin (21.7 +/- 4.1 vs 30.4 +/- 6.4 mg/dL; P < .001) and decreased liver ferroportin (FP-1; P = .009) messenger RNA expression were found in these patients compared with NAFLD patients with high liver or serum copper concentrations. Accordingly, in rats, a reduced dietary copper intake was paralleled by a decreased hepatic FP-1 protein expression. CONCLUSIONS: A significant proportion of NAFLD patients should be considered copper deficient. Our results indicate that copper status is linked to iron homeostasis in NAFLD, suggesting that low copper bioavailability causes increased hepatic iron stores via decreased FP-1 expression and ceruloplasmin ferroxidase activity thus blocking liver iron export in copper-deficient subjects
Rezension: "Erzählen im Imperativ. Zur strukturellen Agonalität von Rollenspielen und mittelhochdeutschen Epen" von Franziska Ascher
No full textDie zeitliche und mediale Kluft zwischen mittelhochdeutschen Epen auf der einen und Computerrollenspielen auf der anderen Seite lässt einen Vergleich beider Gegenstände auf den ersten Blick schwierig erscheinen. Dafür, dass ein zweiter Blick sich lohnen könnte, plädiert Franziska Ascher – derzeit Dozentin an der Universität Innsbruck und Mitherausgeberin der Zeitschrift für Computerspielforschung PAIDA – in ihrer neu erschienen Dissertationsschrift. In Erzählen im Imperativ beleuchtet die Autorin aus medien- und kulturwissenschaftlicher Perspektive strukturelle Ähnlichkeiten zwischen Computerrollenspielen und mittelalterlicher Heldenepik.At first glance, a comparison of Middle High German epics and computer role-playing games seems, to say the least, hardly feasible. In her newly published dissertation, Franziska Ascher – currently lecturer at the University of Innsbruck and co-editor of the magazine for computer game research PAIDA – argues that a second look might be worthwhile. In Erzählen im Imperativ, the author illuminates structural similarities between computer role-playing games and medieval heroic epics from a media and cultural studies perspective
Transferrin gene ChIP-seq data
No full text<p>ChIP-seq Peak-calling data to support the supplementary information to:</p>
<p><strong>In severe alcoholic hepatitis, serum transferrin constitutes an independent mortality predictor indicating an impaired HNF4</strong><strong>αsignaling. </strong>Stephen R. Atkinson, MD<sup>*</sup>; Karim Hamesch, MD<sup>*</sup>; Igor Spivak, MD; Nurdan Guldiken, PhD; Joaquín Cabezas, PhD<sup>3</sup>; Josepmaria Argemi, PhD; Igor Theurl, MD, Heinz Zoller, MD; Sheng Cao, MD; Philippe Mathurin, MD; Vijay H. Shah, MD; Christian Trautwein, MD; Ramon Bataller, MD; Mark R. Thursz, MD<sup>+</sup>; Pavel Strnad, MD<sup>+</sup></p>These datasets include 2 ChIP-seq peak-calling result files: one in .csv format, which variables are described in TF_PeakCalling_results_metadata.txt file and the other one in .bed format to be used for peak range visualization in its genomic context. Methods are included in TF_PeakCalling_results_metadata.txt file.
Peak calling data are limited to Transferrin (TF) genomic region.
Raw data of ChIP-seq are available upon request to Dr. Vijay Shah (Mayo Clinic, Rochester, MN, USA, [email protected])
Anemia at older age: etiologies, clinical implications, and management
No full textAbstract
Anemia is quite frequently diagnosed in older individuals and is a key indicator of various reactive and clonal conditions. Many underlying diseases, like myelodysplastic syndrome (MDS), develop preferentially in elderly individuals. The prevalence of anemia at older age is increasing, and this is mainly attributable to more frequently applied diagnostics and demographic changes in our societies. The etiology of anemia at older age is complex and ranges from bone marrow failure syndromes to chronic kidney disease, and from nutritional deficiencies to inflammatory processes including inflammaging in immunosenescence. In a smaller number of cases, no clear-cut etiology is identified. These patients are referred to as unexplained anemia or idiopathic cytopenia of unknown significance. In others, somatic mutations in leukocytes are found, but diagnostic criteria for MDS or other hematologic diseases are not fulfilled, a condition termed clonal cytopenia of undetermined significance. Management of anemias at older age depends on (1) the severity of the anemia, (2) underlying condition(s), and (3) patient-related factors, including comorbidities. Even a mild anemia may substantially affect physical and cognitive capacities and quality of life. An underestimated aspect is that because of age-related changes, organ function such as erythropoietin production in the kidney may become suboptimal. Management and treatment of anemia in older patients often require a multidisciplinary approach and detailed investigations of organ function. In this article, we review current concepts around anemias at older age, with special emphasis on etiologies, clinical implications, and innovative concepts in the management of these patients.</jats:p
Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases
No full textInflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution strategies. Deeper insights into the pathophysiology of AI has led to the development of new therapeutics targeting inflammatory cytokines and the introduction of new iron formulations. Moreover, the discovery that the hormone, hepcidin, plays a key regulatory role in AI has stimulated the development of several therapeutic approaches targeting the function of this peptide. Hence, inflammation-driven hepcidin elevation causes iron retention in cells and tissues. Besides pathophysiological concepts and diagnostic approaches for AI, this review discusses current guidelines for iron replacement therapies with special emphasis on benefits, limitations, and unresolved questions concerning oral versus parenteral iron supplementation in chronic inflammatory diseases. Furthermore, the review explores how therapies aiming at curing the disease underlying AI can also affect anemia and discusses emerging hepcidin antagonizing drugs, which are currently under preclinical or clinical investigation
- …
