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Transcriptional profiling of chronic clinical hepatic schistosomiasis japonica indicates reduced metabolism and immune responses
- GEOFFREY N. GOBERT, MELISSA L. BURKE, DONALD P. MCMANUS, MAGDA K. ELLIS, CANDY CHUAH, GRANT A. RAMM, YUANYUAN WANG, YUESHENG LI
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- Journal:
- Parasitology / Volume 142 / Issue 12 / October 2015
- Published online by Cambridge University Press:
- 28 July 2015, pp. 1453-1468
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- Article
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Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wide transcriptional survey of liver biopsies obtained from Chinese patients with chronic schistosomiasis only, or chronic schistosomiasis with a current or past history of viral hepatitis B. Both disease groups were compared with patients with no prior history or indicators of any liver disease. Analysis showed in the main, downregulation in gene expression, particularly those involved in signal transduction via EIF2 signalling and mTOR signalling, as were genes associated with cellular remodelling. Focusing on immune associated pathways, genes were generally downregulated. However, a set of three genes associated with granulocytes, MMP7, CLDN7, CXCL6 were upregulated. Differential gene profiles unique to schistosomiasis included the gene Granulin which was decreased despite being generally considered a marker for liver disease, and IGBP2 which is associated with increased liver size, and was the most upregulated gene in schistosomiasis only patients, all of which presented with hepatomegaly. The unique features of gene expression, in conjunction with previous reports in the murine model of the cellular composition of granulomas, granuloma formation and recovery, provide an increased understanding of the molecular immunopathology and general physiological processes underlying hepatic schistosomiasis.
48 - Animal models of iron overload based on excess exogenous iron
- from Part X - Animal models of hemochromatosis and iron overload
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- By Grant A. Ramm, Joint Clinical Sciences Program, The Queensland Institute of Medical Research and The University of Queensland Department of Medicine, Brisbane, Queensland, Australia
- Edited by James C. Barton, Southern Iron Disorders Center, Alabama, Corwin Q. Edwards, University of Utah
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- Book:
- Hemochromatosis
- Published online:
- 05 August 2011
- Print publication:
- 13 January 2000, pp 494-507
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- Chapter
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Summary
Introduction
The purpose of an animal model of iron overload is to mimic hemochromatosis in humans. In hemochromatosis, excess iron accumulation in parenchymal cells of the liver results in toxicity, hepatic fibrosis and ultimately cirrhosis. Characteristically, the excess iron is initially deposited in periportal hepatocytes in hemochromatosis; with progression, hepatocytes across the entire acinus become heavily iron loaded. Although there is some Kupffer cell iron overload late in the course of iron loading, hemochromatosis is an iron overload disorder in which parenchymal cells are predominantly affected.
There are many models of iron overload, and they can be categorized into two main groups according to the route of iron administration. The first are enteral or dietary iron overload models in which carbonyl iron, ferrocene, and ferric ammonium citrate are administered to experimental animals. The second are parenteral iron overload models that involve administration of iron chelates such as iron–dextran, iron–sorbitol, or ferric nitrilotriacetate. Some have been proposed to represent the clinical and physiological manifestations of hemochromatosis. Some mimic the pattern of iron accumulation of hemochromatosis. A few induce hepatic fibrosis. Most do not faithfully reproduce all of the pathophysiologic characteristics of hemochromatosis. However, they provide experimental systems in which to examine the pathways of iron metabolism and to study the toxic effects of excess iron on normal physiology. This chapter discusses the pathophysiologic consequences of excess hepatic iron and outlines the different animal model systems used to study the pathophysiology of iron overload and its relationship to hemochromatosis.
13 - Ferritin metabolism in hemochromatosis
- from Part III - Metal absorption and metabolism in hemochromatosis
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- By Gregory J. Anderson, Joint Clinical Sciences Program, Queensland Intitute of Medical Research and the University of Queensland, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia, Grant A. Ramm, Joint Clinical Sciences Program, Queensland Intitute of Medical Research and the University of Queensland, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia, June W. Halliday, Joint Clinical Sciences Program, Queensland Intitute of Medical Research and the University of Queensland, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia, Lawrie W. Powell, Joint Clinical Sciences Program, Queensland Intitute of Medical Research and the University of Queensland, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia
- Edited by James C. Barton, Southern Iron Disorders Center, Alabama, Corwin Q. Edwards, University of Utah
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- Book:
- Hemochromatosis
- Published online:
- 05 August 2011
- Print publication:
- 13 January 2000, pp 145-156
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- Chapter
- Export citation
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Summary
Introduction
In all mammalian cells, iron in excess of current metabolic requirements is incorporated into ferritin. Effective iron storage is an essential component of cellular iron homeostasis, because iron not sequestered within the cell can catalyze potentially cytotoxic free radical-generating reactions. Although all cells can store iron in ferritin, macrophages and hepatocytes are particularly adapted for this function and retain excess iron as a reserve for times of increased body iron needs. The hepatocyte can take up iron in a variety of different forms and act as a major site of available iron stores, and thus has a central ‘buffering’ role in internal iron exchange.
Because hemochromatosis is an iron storage disorder, ferritin, the principal iron storage protein, plays an important role in the disease. Ferritin sequesters the iron distributed throughout the body as a consequence of elevated intestinal iron absorption. The serum ferritin concentration accurately reflects the body iron load and provides a valuable diagnostic tool. The iron in ferritin is not biologically inert but can be utilized readily for various cellular functions. The ability of ferritin to release iron in times of demand is essential physiologically but also underlies the treatment of hemochromatosis by phlebotomy therapy.
Aspects of ferritin metabolism relevant to hemochromatosis will be discussed in this chapter. The areas covered include a brief overview of ferritin biochemistry, a discussion of ferritin synthesis and its regulation in the intestinal mucosa, the liver and the reticuloendothelial (RE) system, and the role played by the serum ferritin concentration in the diagnosis of hemochromatosis.