Insulin resistance and adipose tissue inflammation induced by a high-fat diet are attenuated in the absence of hepcidin.

Increased body iron stores and inflammation in adipose tissue have been implicated in the pathogenesis of insulin resistance (IR) and type 2 diabetes mellitus. However, the underlying basis of these associations is unclear. To attempt to investigate this, we studied the development of IR and associated inflammation in adipose tissue in the presence of increased body iron stores.

Enhanced insulin signaling and its downstream effects in iron-overloaded primary hepatocytes from hepcidin knock-out mice.

Background: Increased body iron stores have been implicated in the pathogenesis of diabetes mellitus. However, the molecular mechanisms involved are unclear. The liver plays a central role in homeostasis of iron and glucose in the body.

Increased intracellular iron in mouse primary hepatocytes in vitro causes activation of the Akt pathway but decreases its response to insulin.

Background: An iron-overloaded state has been reported to be associated with insulin resistance. On the other hand, conditions such as classical hemochromatosis (where iron overload occurs primarily in the liver) have been reported to be associated with increased insulin sensitivity. The reasons for these contradictory findings are unclear.

Hepcidin suppression in β-thalassemia is associated with the down-regulation of atonal homolog 8.

Atonal homolog 8 (ATOH8) is defined as a positive regulator of hepcidin transcription, which links erythropoietic activity with iron-sensing molecules. In the present study, we investigated the association between hepcidin and ATOH8 expression in β-thalassemia. We found that inhibition of hepcidin expression in β-thalassemia is correlated with reduced ATOH8 expression.

Iron and oxygen sensing: a tale of 2 interacting elements?

Iron and oxygen metabolism are intimately linked with one another. A change in the level of either metabolite results in activation of common pathways. At the heart of these responses lies a group of iron and oxygen dependent enzymes called prolyl hydroxylases.

Expression of ABCG2 (BCRP) in mouse models with enhanced erythropoiesis.

Haem is a structural component of numerous cellular proteins which contributes significantly to iron metabolic processes in mammals but its toxicity demands that cellular levels must be tightly regulated. Breast Cancer Resistance Protein (BCRP/ABCG2), an ATP Binding Cassette G-member protein has been shown to possess porphyrin/haem efflux function. The current study evaluated the expression and regulation of Abcg2 mRNA and protein levels in mouse tissues involved in erythropoiesis.

The transcription factor ATOH8 is regulated by erythropoietic activity and regulates HAMP transcription and cellular pSMAD1,5,8 levels.

ATOH8 has previously been shown to be an iron-regulated transcription factor, however its role in iron metabolism is not known. ATOH8 expression in HEK293 cells resulted in increased endogenous HAMP mRNA levels as well as HAMP promoter activity. Mutation of the E-box or SMAD response elements within the HAMP promoter significantly reduced the effects of ATOH8, indicating that ATOH8 activates HAMP transcription directly as well as through bone morphogenic protein (BMP) signalling.

Duodenal reductase activity and spleen iron stores are reduced and erythropoiesis is abnormal in Dcytb knockout mice exposed to hypoxic conditions.

Duodenal cytochrome b (Dcytb, Cybrd1) is a ferric reductase localized in the duodenum that is highly upregulated in circumstances of increased iron absorption. To address the contribution of Dcytb to total duodenal ferric reductase activity as well as its wider role in iron metabolism, we first measured duodenal ferric reductase activity in wild-type (WT) and Dcytb knockout (Dcytb(-/-)) mice under 3 conditions known to induce gut ferric reductase: dietary iron deficiency, hypoxia, and pregnancy. Dcytb(-/-) and WT mice were randomly assigned to control (iron deficiency experiment, 48 mg/kg dietary iron; hypoxia experiment, normal atmospheric pressure; pregnancy experiment, nonpregnant animals) or treatment (iron deficiency experiment, 2-3 mg/kg dietary iron; hypoxia experiment, 53.

Iron metabolism in hepcidin1 knockout mice in response to phenylhydrazine-induced hemolysis.

Hepcidin, an iron regulatory peptide, plays a central role in the maintenance of systemic iron homeostasis by inducing the internalization and degradation of the iron exporter, ferroportin. Hepcidin expression in the liver is regulated in response to several stimuli including iron status, erythropoietic activity, hypoxia and inflammation. Hepcidin expression has been shown to be reduced in phenylhydrazine-treated mice, a mouse model of acute hemolysis.

Using the arts and humanities to promote a liberal nursing education: strengths and weaknesses.

Background: The requirement that all student nurses in the United Kingdom will be educated to degree level from 2013 permits a review of the current state of nursing education in university contexts. Recent educational standards for these new programmes (NMC, 2010) allow a liberal, or broad-based, education, with its features of breadth of knowledge, formativity, critical thinking and working with others, to be considered.

Objective: Select narratives from a PhD study featuring student nurses and nurse teachers exploring the relationship between reading literature and poetry and ethical practice are presented to critically support the place of liberal education within these programmes.

Exploring clinical wisdom in nursing education.

The recent interest in wisdom in professional health care practice is explored in this article. Key features of wisdom are identified via consideration of certain classical, ancient and modern sources. Common themes are discussed in terms of their contribution to 'clinical wisdom' itself and this is reviewed against the nature of contemporary nursing education.

Effects of acute and chronic inflammation on proteins involved in duodenal iron absorption in mice: a time-course study.

In order to understand better the molecular mechanisms involved in the pathogenesis of anaemia of inflammation, we carried out a time-course study on the effects of turpentine-induced acute and chronic inflammation on duodenal proteins involved in Fe absorption in mice. Expression levels of these proteins and hepatic hepcidin and serum Fe levels were determined in inflamed mice. In acutely inflamed mice, significantly increased expression of ferritin was the earliest change observed, followed by decreased divalent metal transporter 1 expression in the duodenum and increased hepcidin expression in the liver.

Regulation of iron metabolism in Hamp (-/-) mice in response to iron-deficient diet.

Background: Hepcidin, the liver-secreted iron regulatory peptide, maintains systemic iron homeostasis in response to several stimuli including dietary iron levels and body iron status. In addition, iron metabolism is controlled by several local regulatory mechanisms including IRP and Hif-2α activities independently of hepcidin. However, the roles of these mechanisms and their interaction particularly in hepcidin-deficient individuals are not yet fully understood.

BMPER protein is a negative regulator of hepcidin and is up-regulated in hypotransferrinemic mice.

The BMP/SMAD4 pathway has major effects on liver hepcidin levels. Bone morphogenetic protein-binding endothelial cell precursor-derived regulator (Bmper), a known regulator of BMP signaling, was found to be overexpressed at the mRNA and protein levels in liver of genetically hypotransferrinemic mice (Trf(hpx/hpx)). Soluble BMPER peptide inhibited BMP2- and BMP6-dependent hepcidin promoter activity in both HepG2 and HuH7 cells.

Duodenal cytochrome b (Cybrd 1) and HIF-2α expression during acute hypoxic exposure in mice.

Background: Recent evidence suggests that the duodenum can regulate iron absorption independently of hepcidin via the transcription factor Hif-2α acting directly on the transcription of the proteins involved in the iron transport. The current study investigates the temporal relationship between Dcytb and Hif-2α during early hypoxic stimulus in the enterocyte in vivo.

Methods: Duodenal Dcytb and Hif-2α protein expression was analysed by Western blot technique while gene regulation was determined by quantitative PCR.

Iron absorption in hepcidin1 knockout mice.

Hepcidin, the Fe-regulatory peptide, has been shown to inhibit Fe absorption and reticuloendothelial Fe recycling. The present study was conducted to explore the mechanism of in vivo Fe regulation through genetic disruption of hepcidin1 and acute effects of hepcidin treatment in hepcidin1 knockout (Hepc1-/-) and heterozygous mice. Hepcidin1 disruption resulted in significantly increased intestinal Fe uptake.

Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling.

Hepcidin negatively regulates systemic iron homeostasis in response to inflammation and elevated serum iron. Conversely, hepcidin expression is diminished in response to hypoxia, oxidative stress, and increased erythropoietic demand, though the molecular intermediates involved are incompletely understood. To address this, we have investigated hypoxic hepcidin regulation in HuH7 hepatoma cells either cultured alone or cocultured with activated THP-1 macrophages.

Are nurses empowered to make decisions about levels of patient observation in mental health?

Background: The Clinical Resource and Audit Group (2002) guidelines emphasise that local policies should make the procedure for deciding and maintaining patient observation levels clear.

Aim: To investigate the views of nurses, doctors and other members of the multidisciplinary team on patient observation.

Method: A postal survey of all acute adultinpatient facilities and intensive patient care units in Scotland was carried out, followed by 38 interviews, 37 with staff members and one with a service user.

Characterization of the transition-metal-binding properties of hepcidin.

Accumulating evidence suggests that hepcidin, a 25-residue peptide hormone, is the master regulator of iron metabolism. Further evidence suggests that the five N-terminal amino acids are crucial for mediating its biological function. With a histidine residue at position 3, this region also has the potential to bind bivalent metal ions.

A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis.

There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample, stratified by HFE genotype, of 863 from a cohort of 31 192 people of northern European descent provided blood samples for genotyping of 476 single nucleotide polymorphisms (SNPs) in 44 genes involved in iron metabolism. Single SNP association testing, using linear regression models adjusted for sex, menopause and HFE genotype, was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron.

Regulation of intestinal iron absorption: the mucosa takes control?

Two studies (Shah et al., 2009; Mastrogiannaki et al., 2009) show that the hypoxia inducible factor HIF-2alpha is a major player in regulating iron absorption by directly controlling the transcription of iron transporters in the intestine in response to changes in mucosal iron or oxygen levels.

Activated macrophages induce hepcidin expression in HuH7 hepatoma cells.

Background: Hepcidin is an iron regulatory peptide produced by the liver in response to inflammation and elevated systemic iron. Recent studies suggest that circulating monocytes and resident liver macrophages--Küpffer cells--may influence both basal and inflammatory expression of hepcidin.

Design And Methods: We used an in vitro co-culture model to investigate hepatocyte hepcidin regulation in the presence of activated THP1 macrophages.

The role of Dcytb in iron metabolism: an update.

Dcytb (duodenal cytochrome b) is an iron-regulated ferric reductase highly expressed in duodenal enterocytes. Its location and strong regulation by iron has indicated it plays an important role in iron absorption. Expression of Dcytb in cells (Caco-2 and MDCK) was found to increase both ferric reductase activity and stimulate uptake of (59)Fe.

Identification of a Steap3 endosomal targeting motif essential for normal iron metabolism.

Hereditary forms of iron-deficiency anemia, including animal models, have taught us much about the normal physiologic control of iron metabolism. However, the discovery of new informative mutants is limited by the natural mutation frequency. To address this limitation, we have developed a screen for heritable abnormalities of red blood cell morphology in mice with single-nucleotide changes induced by the chemical mutagen ethylnitrosourea (ENU).