ORCID Profile
0000-0002-8814-5866
Current Organisations
The University of Newcastle
,
QIMR Berghofer Medical Research Institute
,
McMaster University
,
University of Queensland
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Related Links
Publications
Hephaestin and ceruloplasmin facilitate iron metabolism in the mouse kidney
Publisher: Springer Science and Business Media LLC
Date: 19-12-2016
DOI: 10.1038/SREP39470
Abstract: Multicopper ferroxidases (MCFs) play an important role in cellular iron homeostasis. However, the role of MCFs in renal metabolism remains unclear. We used Hephaestin ( Heph ) and Ceruloplasmin ( Cp ) single or double ( Heph / Cp ) knockout (KO) mice to study the roles of MCFs in the kidney. Renal iron levels and the expression of iron metabolism genes were examined. The non-heme iron content both in the renal cortex and medulla of Heph / Cp KO mice was significantly increased. Perls’ Prussian blue staining showed iron accumulation on the apical side of renal tubular cells in Heph / Cp KO mice. A significant increase in ferritin protein expression was also observed in the renal medulla and cortex of Heph / Cp KO mice. Both DMT1 and TfR1 protein expression were significantly decreased in the renal medulla of Heph / Cp KO mice, while the expression of DMT1 protein was significantly increased in the renal cortex of these animals. Significant increase in proteinuria and total urinary iron was observed in the double knockout mice, and this was associated with compromised structural integrity. These results suggest that KO of both the HEPH and CP genes leads to kidney iron deposition and toxicity, MCFs could protect kidney against a damage from iron excess.
Identification of two novel PBGD mutations in acute intermittent porphyria patients accompanying anemia in mainland China
Publisher: Elsevier BV
Date: 08-2011
Dietary iron depletion at weaning imprints low microbiome diversity and this is not recovered with oral nano Fe(III)
Publisher: Wiley
Date: 02-12-2014
DOI: 10.1002/MBO3.213
Cell‐specific location of Hfe: It is the 'cyte that matters
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2008
DOI: 10.1002/HEP.22427
Transferrin receptors in hemochromatosis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1987
Abstract: Peripheral leukocytes can exacerbate brain damage by release of cytotoxic mediators that disrupt blood-brain barrier (BBB) function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl) formed via the myeloperoxidase (MPO)-H2O2-Cl(-) system. In the present study we examined the role of leukocyte activation, leukocyte-derived MPO and MPO-generated oxidants on BBB function in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS)-induced systemic inflammation, neutrophils that had become adherent released MPO into the cerebrovasculature. In vivo, LPS-induced BBB dysfunction was significantly lower in MPO-deficient mice as compared to wild-type littermates. Both, fMLP-activated leukocytes and the MPO-H2O2-Cl(-) system inflicted barrier dysfunction of primary brain microvascular endothelial cells (BMVEC) that was partially rescued with the MPO inhibitor 4-aminobenzoic acid hydrazide. BMVEC treatment with the MPO-H2O2-Cl(-) system or activated neutrophils resulted in the formation of plasmalogen-derived chlorinated fatty aldehydes. 2-chlorohexadecanal (2-ClHDA) severely compromised BMVEC barrier function and induced morphological alterations in tight and adherens junctions. In situ perfusion of rat brain with 2-ClHDA increased BBB permeability in vivo. 2-ClHDA potently activated the MAPK cascade at physiological concentrations. An ERK1/2 and JNK antagonist (PD098059 and SP600125, respectively) protected against 2-ClHDA-induced barrier dysfunction in vitro. The current data provide evidence that interference with the MPO pathway could protect against BBB dysfunction under (neuro)inflammatory conditions.
Effects of gestational age and surface modification on materno-fetal transfer of nanoparticles in murine pregnancy
Publisher: Springer Science and Business Media LLC
Date: 13-11-2012
DOI: 10.1038/SREP00847
A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.BIOMATERIALS.2013.11.083
Abstract: Targeted drug delivery vehicles with low immunogenicity and toxicity are needed for cancer therapy. Here we show that exosomes, endogenous nano-sized membrane vesicles secreted by most cell types, can deliver chemotherapeutics such as doxorubicin (Dox) to tumor tissue in BALB/c nude mice. To reduce immunogenicity and toxicity, mouse immature dendritic cells (imDCs) were used for exosome production. Tumor targeting was facilitated by engineering the imDCs to express a well-characterized exosomal membrane protein (L 2b) fused to αv integrin-specific iRGD peptide (CRGDKGPDC). Purified exosomes from imDCs were loaded with Dox via electroporation, with an encapsulation efficiency of up to 20%. iRGD exosomes showed highly efficient targeting and Dox delivery to αv integrin-positive breast cancer cells in vitro as demonstrated by confocal imaging and flow cytometry. Intravenously injected targeted exosomes delivered Dox specifically to tumor tissues, leading to inhibition of tumor growth without overt toxicity. Our results suggest that exosomes modified by targeting ligands can be used therapeutically for the delivery of Dox to tumors, thus having great potential value for clinical applications.
The regulation of iron transport.
Publisher: Wiley
Date: 17-10-2013
DOI: 10.1002/BIOF.1148
Abstract: Iron is an essential nutrient, but its concentration and distribution in the body must be tightly controlled due to its inherent toxicity and insolubility in aqueous solution. Living systems have successfully overcome these potential limitations by evolving a range of iron binding proteins and transport systems that effectively maintain iron in a nontoxic and soluble form for much, if not all, of its time within the body. In the circulation, iron is transported to target organs bound to the serum iron binding protein transferrin. In idual cells modulate their uptake of transferrin-bound iron depending on their iron requirements, using both transferrin receptor 1-dependent and independent pathways. Once inside the cell, iron can be chaperoned to sites of need or, if in excess, stored within ferritin. Iron is released from cells by the iron export protein ferroportin1, which requires the ferroxidase activity of ceruloplasmin or hephestin to load iron safely onto transferrin. The regulation of iron export is controlled predominantly at the systemic level by the master regulator of iron homeostasis hepcidin. Hepcidin, in turn, responds to changes in body iron demand, making use of a range of regulatory mechanisms that center on the bone morphogenetic protein signaling pathway. This review provides an overview of recent advances in the field of iron metabolism and outlines the key components of the iron transport and regulation systems.
Direct evidence for catalase and peroxidase activities of ferritin–platinum nanoparticles
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.BIOMATERIALS.2010.11.004
Abstract: Using apoferritin (apoFt) as a nucleation substrate, we have successfully synthesized 1-2 nm platinum nanoparticles (Pt-Ft) which are highly stable. By directly measuring the products of Pt-Ft-catalyzed reactions, we showed, with no doubt, Pt-Ft possesses both catalase and peroxidase activities. With hydrogen peroxide as substrate, we observed oxygen gas bubbles were generated from hydrogen peroxide decomposed by Pt-Ft the generation of oxygen gas strongly supports Pt-Ft reacts as catalase, other than peroxidase. While with organic dyes and hydrogen peroxide as substrates, distinctive color products were formed catalyzed by Pt-Ft, which indicates a peroxidase-like activity. Interestingly, these biomimetic properties showed differential response to pH and temperature for different reaction substrates. Pt-Ft showed a significant increase in catalase activity with increasing pH and temperature. The HRP-like activity of Pt-Ft was optimal at physiological temperature and slightly acidic conditions. Our current study demonstrates that Pt-Ft possesses both catalase and peroxidase activities for different substrates under different conditions.
Nanoparticulate iron(III) oxo-hydroxide delivers safe iron that is well absorbed and utilised in humans
Publisher: Elsevier BV
Date: 11-2014
Sustained expression of heme oxygenase-1 alters iron homeostasis in nonerythroid cells
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.FREERADBIOMED.2012.03.007
Abstract: Heme oxygenases initiate the catabolism of heme, releasing carbon monoxide, iron, and biliverdin. Sustained induction of heme oxygenase-1 (HO-1) in nonerythroid cells plays a key role in many pathological processes, yet the effect of long-term HO-1 expression on cellular iron metabolism in the absence of exogenous heme is poorly understood. Here we report that in a model nonerythroid cell, both transient and stable HO-1 expression increased heme oxygenase activity, but total cellular heme content was decreased only with transient enzyme expression. Sustained HO-1 activity increased the expression of both the mitochondrial iron importer mitoferrin-2 and the rate-limiting enzyme in heme synthesis, aminolevulinate synthase-1, and it augmented the mitochondrial content of heme. Also, the expression of transferrin receptor-1 and the activities of iron-regulatory proteins 1 and 2 decreased, whereas total labile iron and the regulatory activity of the heme-binding transcription factor Bach1 were unaltered. In addition, stable, but not transient, HO-1 expression decreased the activities of aconitase, as well as increasing proteasomal degradation of ferritin. Together, our results reveal a novel and coordinated adaptive response of nonerythroid cells to sustained HO-1 induction that has an impact on cellular iron homeostasis.
Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-10-2009
DOI: 10.1002/HEP.23198
Abstract: Hepcidin is a central regulator of iron homeostasis. HFE and transferrin receptor 2 (TFR2) are mutated in adult-onset forms of hereditary hemochromatosis and regulate the expression of hepcidin in response to iron. Whether they act through the same or parallel pathways is unclear. To investigate this, we generated a mouse model with deletion of both Hfe and Tfr2 genes by crossing Hfe and Tfr2 null mice on a genetically identical background. Tissue and serum from wildtype, single-, and double-null mice were analyzed. Serum transferrin saturation and hepatic iron concentrations were determined. The expression of iron-related messenger RNA (mRNA) transcripts was analyzed by real-time polymerase chain reaction (PCR). Levels of the iron-related proteins Tfr1, Tfr2, ferritin, and prohepcidin, and the phosphorylation status of the cell signaling proteins extracellular signal-regulated kinase 1/2 (Erk1/2) and Smad1/5/8, were analyzed by immunoblotting. Double-null mice had more severe iron loading than mice lacking either Hfe or Tfr2 Tfr2 null mice had a greater iron burden than Hfe-null mice. Hepcidin expression relative to iron stores was reduced in the Hfe-null mice, with significantly lower values in the Tfr2-null mice. In the absence of both Hfe and Tfr2, hepcidin expression was reduced even further. A significant decrease in phospho-Erk1/2 in the livers of null mice and a reduction in phospho-Smad1/5/8 suggest that both the mitogen-activated protein kinase (MAPK) and bone morphogenetic protein / mothers against decapentaplegic homolog (BMP/SMAD) signaling pathways may be involved in Hfe- and Tfr2-mediated regulation of hepcidin. These studies demonstrate that iron overload due to deletion of Tfr2 is more severe than that due to Hfe, and that loss of both molecules results in pronounced iron overload. Analysis of Hfe/Tfr2 double-null mice suggests that Hfe and Tfr2 regulate hepcidin through parallel pathways involving Erk1/2 and Smad1/5/8.
High Dietary Iron Disrupts Iron Homeostasis and Induces Amyloid-β and Phospho-τ Expression in the Hippocampus of Adult Wild-Type and APP/PS1 Transgenic Mice
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1093/JN/NXZ168
Intestinal hephaestin potentiates iron absorption in weanling, adult, and pregnant mice under physiological conditions
Publisher: American Society of Hematology
Date: 25-07-2017
DOI: 10.1182/BLOODADVANCES.2017008359
Abstract: Intestinal Heph may be required to potentiate iron absorption during rapid growth and pregnancy, or when hypoxia stimulates erythropoiesis. Here, the physiological conditions in which Heph is required are defined and other, complementary, intestinal ferroxidases are identified.
Screening for Hemochromatosis in Asymptomatic Subjects With or Without a Family History
Publisher: American Medical Association (AMA)
Date: 13-02-2006
DOI: 10.1001/ARCHINTE.166.3.294
Abstract: Hemochromatosis in white subjects is mostly due to homozygosity for the common C282Y substitution in HFE. Although clinical symptoms are preventable by early detection of the genetic predisposition and prophylactic treatment, population screening is not currently advocated because of the discrepancy between the common mutation prevalence and apparently lower frequency of clinical disease. This study compared screening for hemochromatosis in subjects with or without a family history. We assessed disease expression by clinical evaluation and liver biopsy in 672 essentially asymptomatic C282Y homozygous subjects identified by either family screening or health checks. We also observed a subgroup of untreated homozygotes with normal serum ferritin levels for up to 24 years. Prevalence of hepatic iron overload and fibrosis were comparable between the 2 groups. Disease-related conditions were more common in male subjects identified by health checks, but they were older. Hepatic iron overload (grades 2-4) was present in 56% and 34.5% of male and female subjects, respectively hepatic fibrosis (stages 2-4) in 18.4% and 5.4% and cirrhosis in 5.6% and 1.9%. Hepatic fibrosis and cirrhosis correlated significantly with the hepatic iron concentration, and except in cases of cirrhosis, there was a 7.5-fold reduction in the mean fibrosis score after phlebotomy. All subjects with cirrhosis were asymptomatic. Screening for hemochromatosis in apparently healthy subjects homozygous for the C282Y mutation with or without a family history reveals comparable levels of hepatic iron overload and disease. Significant hepatic fibrosis is frequently found in asymptomatic subjects with hemochromatosis and, except when cirrhosis is present, is reversed by iron removal.
Molecular and Functional Roles of Duodenal Cytochrome B (Dcytb) in Iron Metabolism
Publisher: Elsevier BV
Date: 11-2002
Abstract: Dcytb has been identified as the mammalian transplasma ferric reductase that catalyzes the reduction of ferric to ferrous iron in the process of iron absorption. Its mRNA and protein levels are up-regulated by several independent stimulators of iron absorption. Furthermore, its cDNA encodes putative binding sites for heme and ascorbic acid. Using Northern and Western blots, RT-PCR and confocal microscopy, we studied the expression and localisation of Dcytb in cell lines and tissues of CD1 mice. Dcytb expression and function were modulated by iron. Dcytb and DMT1, both predominantly localised in the apical region of the duodenum were up-regulated in iron deficiency. Dcytb, the iron regulated ferric reductase may also utilize cytoplasmic ascorbate as electron donor for transmembrane reduction of iron. Dcytb expression was found in other tissues apart from the duodenum and its regulation and functions at these other sites are of interest in iron metabolism.
The Ceruloplasmin Homolog Hephaestin and the Control of Intestinal Iron Absorption
Publisher: Elsevier BV
Date: 11-2002
Abstract: Hephaestin is the gene affected in the sex-linked anemic (sla) mouse. These animals have a defect in the export of iron from intestinal enterocytes into the circulation and this implicates hephaestin in the basolateral transfer step of iron absorption. Hephaestin is homologous to the plasma copper-containing protein ceruloplasmin, and all residues involved in copper binding and disulfide bond formation in ceruloplasmin are conserved in hephaestin. Unlike ceruloplasmin, hephaestin is an integral membrane protein with a single trans-membrane domain. It is highly expressed throughout the small intestine, to a lesser extent in the colon, and at low levels in several other tissues. Surprisingly, most hephaestin appears to be located intracellularly in a perinuclear distribution. Like ceruloplasmin, hephaestin has a ferroxidase activity which is predicted to underlie its biological function. In addition, its expression is stimulated under iron deficient conditions. Analysis of the sla mouse has supported our model for the regulation of intestinal iron absorption whereby changes in systemic iron requirements alter the levels of basolateral transport components with subsequent regulation of brush border transport.
HFE gene and hemochromatosis
Publisher: Wiley
Date: 18-05-2004
A Corn Oil–Based Diet Protects Against Combined Ethanol and Iron‐Induced Liver Injury in a Mouse Model of Hemochromatosis
Publisher: Wiley
Date: 06-06-2013
DOI: 10.1111/ACER.12155
Abstract: Combined iron overload and alcohol may promote synergistic chronic liver injury and toxicity. The role of specific dietary fats in influencing the development of co-toxic alcoholic liver disease needs further evaluation and is investigated in this study. Wild-type (WT) and the iron-loaded Hfe-null (Hfe(-/-) ) mice were fed chow (CC), a AIN-93G standard control (SC), or a corn oil-modified, AIN-93G-based (CO) diet with or without the addition of 20% ethanol (EtOH) in the drinking water for 8 weeks and assessed for liver injury. WT mice on CC, SC, and CO diets had no liver injury, although mild steatosis developed in the SC and CO groups. The addition of EtOH resulted in mild steatohepatitis in WT mice fed SC but not those on a CO diet. EtOH administration in Hfe(-/-) animals on the CC and SC diets caused marked oxidative stress, inflammatory activity, and subsinusoidal and portal-portal tract linkage fibrosis with significant up-regulation of genes involved in cellular stress signaling and fibrogenic pathways. These effects were abrogated in the CO-fed mice, despite elevated serum EtOH levels and hepatic iron concentrations, reduced hepatic glutathione and mitochondrial superoxide dismutase activities. Feeding with the CO diet led to increased hepatic glutathione peroxidase and catalase activities and attenuated alcohol-induced hepatic steatosis in the Hfe(-/-) animals. Iron and EtOH feeding markedly reduced p-STAT3 and p-AMPK protein levels, but this effect was significantly attenuated when a CO diet was consumed. A CO-based diet is protective against combined EtOH- and iron-induced liver toxicity, likely via attenuation of hepatic steatosis and oxidative stress and may have a role in the prevention of fibrosis development in chronic liver disease.
Multi-copper ferroxidase deficiency leads to iron accumulation and oxidative damage in astrocytes and oligodendrocytes
Publisher: Springer Science and Business Media LLC
Date: 07-2019
DOI: 10.1038/S41598-019-46019-9
Abstract: Accumulation of iron has been associated with the pathobiology of various disorders of the central nervous system. Our previous work has shown that hephaestin ( Heph ) and ceruloplasmin ( Cp ) double knockout (KO) mice induced iron accumulation in multiple brain regions and that this was paralleled by increased oxidative damage and deficits in cognition and memory. In this study, we enriched astrocytes and oligodendrocytes from the cerebral cortex of neonatal wild-type (WT), Heph KO and Cp KO mice. We demonstrated that Heph is highly expressed in oligodendrocytes, while Cp is mainly expressed in astrocytes. Iron efflux was impaired in Cp KO astrocytes and Heph KO oligodendrocytes and was associated with increased oxidative stress. The expression of Heph , Cp , and other iron-related genes was examined in astrocytes and oligodendrocytes both with and without iron treatment. Interestingly, we found that the expression of the mRNA encoding ferroportin 1, a transmembrane protein that cooperates with CP and HEPH to export iron from cells, was positively correlated with Cp expression in astrocytes, and with Heph expression in oligodendrocytes. Our findings collectively demonstrate that HEPH and CP are important for the prevention of glial iron accumulation and thus may be protective against oxidative damage.
Severe Iron Metabolism Defects in Mice With Double Knockout of the Multicopper Ferroxidases Hephaestin and Ceruloplasmin
Publisher: Elsevier BV
Date: 2018
Biallelic HEPHL1 variants impair ferroxidase activity and cause an abnormal hair phenotype
Publisher: Public Library of Science (PLoS)
Date: 24-05-2019
An Extendable Star-Like Nanoplatform for Functional and Anatomical Imaging-Guided Photothermal Oncotherapy
Publisher: American Chemical Society (ACS)
Date: 22-03-2019
Abstract: Combining informative imaging methodologies with effective treatments to destroy tumors is of great importance for oncotherapy. Versatile nanotheranostic agents that inherently possess both diagnostic imaging and therapeutic capabilities are highly desirable to meet these requirements. Here, a simple but powerful nanoplatform based on polydopamine-coated gold nanostar (GNS@PDA), which can be easily ersified to achieve various function extensions, is designed to realize functional and anatomical imaging-guided photothermal oncotherapy. This nanoplatform intrinsically enables computed tomography hotoacoustic/two-photon luminescence/infrared thermal tetramodal imaging and can further incorporate fibroblast activation protein (FAP, a protease highly expressed in most of tumors) activatable near-infrared fluorescence imaging and Fe
Lactate as a regulator of iron homeostasis
Publisher: Oxford University Press (OUP)
Date: 27-07-2023
Nanopore film based enrichment and quantification of low abundance hepcidin from human bodily fluids
Publisher: Elsevier BV
Date: 07-2014
pHLIP-mediated targeting of truncated tissue factor to tumor vessels causes vascular occlusion and impairs tumor growth
Publisher: Impact Journals, LLC
Date: 25-06-2015
Things that go BMP in the liver: bone morphogenetic protein 6 and the control of body iron homeostasis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-05-2009
DOI: 10.1002/HEP.23106
Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis
Publisher: BMJ
Date: 10-2004
Serum hyaluronic acid with serum ferritin accurately predicts cirrhosis and reduces the need for liver biopsy in C282Y hemochromatosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-09-2008
DOI: 10.1002/HEP.22650
Abstract: Diagnosing the presence of cirrhosis is crucial for the management of patients with C282Y hereditary hemochromatosis (HH). HH patients with serum ferritin >1,000 microg/L are at risk of cirrhosis however, the majority of these patients do not have cirrhosis. Noninvasive markers of hepatic fibrosis may assist in determining which patients with a serum ferritin >1,000 microg/L have cirrhosis and require liver biopsy. This study evaluated the utility of current diagnostic algorithms for detecting cirrhosis, including serum ferritin concentration, platelet counts, and aspartate aminotransferase (AST) levels, in combination with serum markers of fibrosis, hyaluronic acid and collagen type IV (CLIV), in predicting cirrhosis in HH patients. Stage of fibrosis, serum hyaluronic acid and CLIV levels, were measured in 56 patients with HH. No patient with a serum ferritin 1,000 microg/L were cirrhotic. A combination of platelet count ( 1,000 microg/L did not detect 30% of cirrhotic subjects. Serum hyaluronic acid was increased in HH compared with controls (42.0 +/- 9.8 ng/mL versus 19.3 +/- 1.8 ng/mL P = 0.02). A hyaluronic acid concentration >46.5 ng/mL was 100% sensitive and 100% specific in identifying patients with cirrhosis. In patients with serum ferritin >1,000 microg/L, hyaluronic acid levels were significantly elevated in patients with cirrhosis versus those without cirrhosis (137 +/- 34.4 ng/mL versus 18.6 +/- 1.5 ng/mL, respectively P = 0.006). CLIV >113 ng/mL was 100% sensitive but only 56% specific for cirrhosis (area under the curve = 0.78 P = 0.01). In HH, the measurement of hyaluronic acid in patients with serum ferritin >1,000 microg/L is a noninvasive, accurate, and cost-effective method for the diagnosis of cirrhosis. (HEPATOLOGY 2009 :418-425.).
Pumping iron: a potential target for novel therapeutics against schistosomes
Publisher: Elsevier BV
Date: 12-2007
The Natural History of Serum Iron Indices for HFE C282Y Homozygosity Associated With Hereditary Hemochromatosis
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1053/J.GASTRO.2008.08.056
Abstract: There are few longitudinal studies of serum ferritin (SF) and transferrin saturation (TS) levels in in iduals homozygous for the C282Y mutation. We characterized the development of elevated iron measures in C282Y homozygotes followed for 12 years. From 31,192 people aged 40-69 years at baseline, we identified 203 C282Y homozygotes (95 males), of whom 116 had SF and fasting TS levels measured at baseline (mean age, 55 years) and 86 were untreated and had iron measures at follow-up (mean, 12 years later). The probabilities of SF at follow-up exceeding clinical thresholds were predicted from baseline SF and TS under a multivariate normal model. For C282Y homozygotes, at baseline, 84% of males and 65% of females had elevated SF and 37% of males and 3% of females had SF >1000 microg/L. For males with SF 300-1000 microg/L at baseline, the predicted probability of progressing to SF >1000 microg/L at follow-up was between 13% and 35% and, for females, between 16% and 22%. For C282Y homozygotes with normal baseline SF, 1000 microg/L if left untreated. The majority of C282Y homozygotes who are likely to develop SF levels sufficient to place them at risk of iron overload-related disease will have done so by mean age 55 years. TS >95% at mean age 55 years in males increases the likelihood that SF levels will be elevated at mean age 65 years, but this effect is absent in females, most likely because of physiologic blood loss associated with menstruation.
Iron Wars - The host strikes back.
Publisher: Massachusetts Medical Society
Date: 22-11-2018
Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-12-2015
DOI: 10.1002/HEP.28260
Cystic fibrosis: ironing out the problem of infection?
Publisher: American Physiological Society
Date: 07-2008
Changes in the expression of intestinal iron transport and hepatic regulatory molecules explain the enhanced iron absorption associated with pregnancy in the rat.
Publisher: BMJ
Date: 05-2004
Abstract: Iron absorption increases during pregnancy to cater for the increased iron requirements of the growing fetus. To investigate the role of the duodenal iron transport molecules and hepatic regulatory molecules in coordinating the changes in iron absorption observed during pregnancy. Rats at various days of gestation and 24-48 hours post-partum were examined for hepatic expression of hepcidin, transferrin receptors 1 and 2, and HFE (the gene mutated in the most prevalent form of hereditary haemochromatosis), and duodenal expression of alent metal transporter 1 (DMT1), duodenal cytochrome b (Dcytb), iron regulated mRNA (Ireg1), and hephaestin (Hp) by ribonuclease protection assay, western blotting, and immunohistochemistry. Decreased hepatic non-haem iron and transferrin saturation and increased expression of transferrin receptor 1 in the liver indicated a progressive reduction in maternal body iron stores during pregnancy. Duodenal expression of the iron transport molecules DMT1, Dcytb, and Ireg1 increased during pregnancy, and this corresponded with a reduction in hepcidin, HFE, and transferrin receptor 2 expression in the liver. Expression of all molecules returned towards control values by 24-48 hours post-partum. These data indicate that increased expression of key iron transport molecules is responsible for the elevated iron absorption associated with pregnancy, and implicate hepcidin, HFE, and transferrin receptor 2 in determining how the maternal iron homeostatic machinery responds to the increased iron demands accompanying gestation.
Iron absorption and metabolism.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Dihydrolipoic Acid–Gold Nanoclusters Regulate Microglial Polarization and Have the Potential To Alter Neurogenesis
Publisher: American Chemical Society (ACS)
Date: 30-11-2019
DOI: 10.1021/ACS.NANOLETT.9B04216
Abstract: Microglia-mediated neuroinflammation is one of the most significant features in a variety of central nervous system (CNS) disorders such as traumatic brain injury, stroke, and many neurodegenerative diseases. Microglia become polarized upon stimulation. The two extremes of the polarization are the neuron-destructive proinflammatory M1-like and the neuron-regenerative M2-like phenotypes. Thus, manipulating microglial polarization toward the M2 phenotype is a promising therapeutic approach for CNS repair and regeneration. It has been reported that nanoparticles are potential tools for regulating microglial polarization. Gold nanoclusters (AuNCs) could penetrate the blood-brain barrier and have neuroprotective effects, suggesting the possibility of utilizing AuNCs to regulate microglial polarization and improve neuronal regeneration in CNS. In the current study, AuNCs functionalized with dihydrolipoic acid (DHLA-AuNCs), an antioxidant with demonstrated neuroprotective roles, were prepared, and their effects on polarization of a microglial cell line (BV2) were examined. DHLA-AuNCs effectively suppressed proinflammatory processes in BV2 cells by inducing polarization toward the M2-like phenotype. This was associated with a decrease in reactive oxygen species and reduced NF-kB signaling and an improvement in cell survival coupled with enhanced autophagy and inhibited apoptosis. Conditioned medium from DHLA-AuNC-treated BV2 cells was able to enhance neurogenesis in both the neuronal cell line N2a and in an ex vivo brain slice stroke model. The direct treatment of brain slices with DHLA-AuNCs also ameliorated stroke-related tissue injury and reduced astrocyte activation (astrogliosis). This study suggests that by regulating neuroinflammation to improve neuronal regeneration, DHLA-AuNCs could be a potential therapeutic agent in CNS disorders.
Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-06-2015
DOI: 10.1002/HEP.27851
Increased hepcidin expression and hypoferraemia associated with an acute phase response are not affected by inactivation of HFE
Publisher: Wiley
Date: 30-06-2004
Interrelationships between circulating gastrin and iron status in mice and humans
Publisher: American Physiological Society
Date: 10-2008
Abstract: The observations that the peptide hormone gastrin interacts with transferrin in vitro and that circulating gastrin concentrations are increased in the iron-loading disorder hemochromatosis suggest a possible link between gastrin and iron homeostasis. This study tested the hypothesis that gastrin and iron status are interrelated by measurement of iron homeostasis in mice and humans with abnormal circulating gastrin concentrations. Intestinal iron absorption was determined by 59 Fe uptake following oral gavage, and concentrations of duodenal alent metal transporter-1 (DMT-1) and hepatic hepcidin mRNAs were determined by quantitative real-time PCR in agastrinemic (GasKO), hypergastrinemic cholecystokinin 2 receptor-deficient (CCK2RKO), or wild-type mice. Iron status was measured by standard methods in the same mice and in hypergastrinemic humans with multiple endocrine neoplasia type 1 (MEN-1). Iron absorption was increased sixfold and DMT-1 mRNA concentration fourfold, and transferrin saturation was reduced 0.8-fold and hepcidin mRNA expression 0.5-fold in juvenile GasKO mice compared with age-matched wild-type mice. In mature mice, few differences were observed between the strains. Juvenile CCK2RKO mice were hypergastrinemic and had a 5.4-fold higher DMT-1 mRNA concentration than wild-type mice without any increase in iron absorption. In contrast to juvenile GasKO mice, juvenile CCK2RKO mice had a 1.5-fold greater transferrin saturation, which was reflected in a twofold increase in liver iron deposition at maturity compared with wild-type mice. The correlation between transferrin saturation and circulating gastrin concentration observed in mutant mice was also observed in human patients with MEN, in whom hypergastrinemia correlated positively ( P = 0.004) with an increased transferrin saturation. Our data indicate that, in juvenile animals when iron demand is high, circulating gastrin concentrations may alter iron status by a CCK2R-independent mechanism.
A novel mutation in ferroportin implicated in iron overload
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.JHEP.2007.01.033
Abstract: Hereditary iron overload is associated with mutations in a number of genes involved in the regulation of iron metabolism. In this study we examined the molecular basis of iron overload in an in idual from New Zealand and characterised the molecular and cellular defect. We analysed the ferroportin gene and a control population was screened using allele-specific PCR and denaturation analysis. Molecular characterisation was performed by immunofluorescence microscopy analysis of transfected cells. We analysed the ferritin levels of cells expressing wild-type and mutant ferroportin to define the nature of the molecular defect on iron transport. We identified a novel nucleotide substitution (c. 1014T>G) in the ferroportin gene leading to the S338R mutation. This mutation is not a common polymorphism. Cellular analysis of the mutant protein indicates that this amino acid change does not affect the localisation of the protein or its ability to transport iron. The S338R mutation results in a mutated ferroportin associated with iron overload and is predicted insensitive to regulation by the iron regulatory hormone hepcidin.
Double-edge sword roles of iron in driving energy production versus instigating ferroptosis
Publisher: Springer Science and Business Media LLC
Date: 10-01-2022
DOI: 10.1038/S41419-021-04490-1
Abstract: Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to erse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.
Desialylated transferrin as a serological marker of chronic excessive alcohol ingestion.
Publisher: Elsevier BV
Date: 06-1987
DOI: 10.1016/S0140-6736(87)90544-7
Abstract: Partly desialylated transferrin was measured in the serum of subjects with chronic alcoholism, of patients with non-alcoholic-related steatohepatitis, diabetes, and other non-alcoholic liver diseases, and of healthy controls. In non-alcoholic patients and controls the maximum desialylated transferrin expressed in relation to total transferrin was 1.5%. This value was exceeded in 18 (90%) of the 20 alcoholics. By contrast, gamma-glutamyl transferase was within the reference range in 9 of the alcoholics.
Reduction of body iron in HFE -related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial
Publisher: Elsevier BV
Date: 12-2017
Should HFE p.C282Y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi-iron)
Publisher: BMJ
Date: 08-2015
Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice
Publisher: Wiley
Date: 05-04-2019
DOI: 10.1096/FJ.14-251520
Hepcidin independent iron recycling in a mouse model of β-thalassaemia intermedia.
Publisher: Wiley
Date: 13-07-2016
DOI: 10.1111/BJH.14206
Abstract: In conditions such as β-thalassaemia, stimulated erythropoiesis can reduce the expression of the iron regulatory hormone hepcidin, increasing both macrophage iron release and intestinal iron absorption and leading to iron loading. However, in certain conditions, sustained elevation of erythropoiesis can occur without an increase in body iron load. To investigate this in more detail, we made use of a novel mouse strain (RBC14), which exhibits mild β-thalassaemia intermedia with minimal iron loading. We compared iron homeostasis in RBC14 mice to that of Hbb
Circulating iron levels influence the regulation of hepcidin following stimulated erythropoiesis
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 14-06-2018
Targeting iron uptake to controlPseudomonas aeruginosainfections in cystic fibrosis
Publisher: European Respiratory Society (ERS)
Date: 08-11-2012
DOI: 10.1183/09031936.00124012
Abstract: The aerobic Gram-negative bacterium Pseudomonas aeruginosa is an opportunistic pathogen responsible for life-threatening acute and chronic infections in humans. As part of chronic infection P. aeruginosa forms biofilms, which shield the encased bacteria from host immune clearance and provide an impermeable and protective barrier against currently available antimicrobial agents. P. aeruginosa has an absolute requirement for iron for infection success. By influencing cell-cell communication (quorum sensing) and virulence factor expression, iron is a powerful regulator of P. aeruginosa behaviour. Consequently, the imposed perturbation of iron acquisition systems has been proposed as a novel therapeutic approach to the treatment of P. aeruginosa biofilm infection. In this review, we explore the influence of iron availability on P. aeruginosa infection in the lungs of the people with the autosomal recessive condition cystic fibrosis as an archetypal model of chronic P. aeruginosa biofilm infection. Novel therapeutics aimed at disrupting P. aeruginosa are discussed, with an emphasis placed on identifying the barriers that need to be overcome in order to translate these promising in vitro agents into effective therapies in human pulmonary infections.
Natural history of HFE simple heterozygosity for C 282Y and H 63D : A prospective 12‐year study
Publisher: Wiley
Date: 16-03-2015
DOI: 10.1111/JGH.12804
Large scale expression and purification of secreted mouse hephaestin
Publisher: Public Library of Science (PLoS)
Date: 07-09-2017
Modulation of iron transport proteins in human colorectal carcinogenesis
Publisher: BMJ
Date: 10-2006
Mechanisms of Haem and Non-Haem Iron Absorption: Lessons from Inherited Disorders of Iron Metabolism
Publisher: Springer Science and Business Media LLC
Date: 08-2005
DOI: 10.1007/S10534-005-3708-8
Abstract: Our current state of knowledge of the mechanism and regulation of intestinal iron absorption has been critically dependent on the analysis of inherited disorders of iron homeostasis in both humans and other animal species. Mutations in DMT1 and Ireg1 have revealed that these molecules are major mediators of iron transport across the brush border and basolateral membranes of the enterocyte, respectively. Similarly, the iron oxidase hephaestin has been shown to play an important role in basolateral iron efflux. The analysis of a range of human iron loading disorders has provided very strong evidence that the products of the HFE, TfR2, hepcidin and hemojuvelin genes comprise integral components of the machinery that regulates iron absorption and iron traffic around the body. Engineered mouse strains have already proved very effective in helping to dissect pathways of iron homeostasis, and in the future they will continue to provide important insights into the absorption of both inorganic and haem iron by the gut.
Controlling Assembly of Paired Gold Clusters within Apoferritin Nanoreactor for in Vivo Kidney Targeting and Biomedical Imaging
Publisher: American Chemical Society (ACS)
Date: 17-05-2011
DOI: 10.1021/JA200746P
Abstract: Functional nanostructures with high biocompatibility and stability, low toxicity, and specificity of targeting to desired organs or cells are of great interest in nanobiology and medicine. However, the challenge is to integrate all of these desired features into a single nanobiostructure, which can be applied to biomedical applications and eventually in clinical settings. In this context, we designed a strategy to assemble two gold nanoclusters at the ferroxidase active sites of ferritin heavy chain. Our studies showed that the resulting nanostructures (Au-Ft) retain not only the intrinsic fluorescence properties of noble metal, but gain enhanced intensity, show a red-shift, and exhibit tunable emissions due to the coupling interaction between the paired Au clusters. Furthermore, Au-Ft possessed the well-defined nanostructure of native ferritin, showed organ-specific targeting ability, high biocompatibility, and low cytotoxicity. The current study demonstrates that an integrated multimodal assembly strategy is able to generate stable and effective biomolecule-noble metal complexes of controllable size and with desirable fluorescence emission characteristics. Such agents are ideal for targeted in vitro and in vivo imaging. These results thus open new opportunities for biomolecule-guided nanostructure assembly with great potential for biomedical applications.
Severe iron deficiency blunts the response of the iron regulatory gene Hamp and pro-inflammatory cytokines to lipopolysaccharide
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 29-05-2010
A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis
Publisher: Wiley
Date: 14-09-2009
Emerging nanomedicines for anti-stromal therapy against desmoplastic tumors
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.BIOMATERIALS.2019.119745
Abstract: Solid tumors, especially desmoplastic tumors, are characterized by a dense fibrotic stroma composed of abundant cancer-associated fibroblasts and excessive extracellular matrix. These physical barriers seriously compromise drug delivery to tumor cells, leading to suboptimal treatment efficacy and resistance to current tumor-centric therapeutics. The need to overcome these problems has driven extensive investigations and sparked the flourish of anti-stromal therapy, particularly in the field of nanomedicines. In this paper, we firstly review the major components of the tumor stroma and discuss their impact on drug delivery. Then, according to the different stromal targets, we summarize the current status of anti-stromal therapy and highlight recent advances in anti-stromal nanomedicines. We further examine the potential of nano-enabled anti-stromal therapy to enhance the anti-tumor efficacy of other therapeutic modalities, including chemotherapy, immunotherapy, phototherapy and radiotherapy. Finally, the potential concerns and future developments of anti-stromal nanomedicines are discussed.
Dietary iron absorption during early postnatal life
Publisher: Springer Science and Business Media LLC
Date: 23-02-2019
DOI: 10.1007/S10534-019-00181-9
Abstract: Inadequate iron levels during early life can have adverse consequences for the developing infant. Iron deficiency during this critical period of growth can affect brain development and cognitive function, problems that can be lifelong despite subsequent correction of the iron deficit. Therefore, it is critical that the suckling infant has sufficient iron for their developmental needs. Much of the iron used in the immediate post-natal period is stored iron that was acquired from the mother in the final trimester of pregnancy, however, despite having low iron levels, breast milk can also make a significant contribution to infant iron needs. This reflects the ability of the suckling infant to absorb dietary iron far more efficiently than is possible after weaning. The mechanisms underlying this enhanced iron absorption are poorly understood. The iron export protein ferroportin is essential for this process, as it is in adults, however, the role of other molecules normally involved in iron absorption following weaning is less clear. The composition and distribution of iron in breast milk may be important, as could the contribution of more distal parts of the gastrointestinal tract. This review discusses the potential role of each of the above components in intestinal iron absorption during suckling and highlights the need for further research into this important process.
Multi-Copper Ferroxidase–Deficient Mice Have Increased Brain Iron Concentrations and Learning and Memory Deficits
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1093/JN/NXY012
Abstract: The accumulation of iron occurs in the central nervous system (CNS) in several neurodegenerative diseases. Although multi-copper ferroxidases (MCFs) play an important role in cellular iron metabolism and homeostasis, the mechanism of MCFs in the CNS remains unclear. The aim was to study the role of MCFs in CNS iron metabolism and homeostasis by using hephaestin/ceruloplasmin (Heph/Cp) double knockout (KO) mice. Heph/Cp double KO male mice were generated by crossing both single KO mice. In Heph/Cp KO and wild-type (WT) control mice at 4 wk and 6 mo of age, iron concentrations of selected brain regions were measured by atomic absorption spectrophotometry, and gene expressions of Heph, Cp, ferroportin 1 (Fpn1) [+ iron responsive element (IRE)], L-ferritin, H-ferritin, transferrin receptor 1 (Tfrc), and alent metal transporter 1 (Dmt1) (+IRE) were quantitated by quantitative reverse transcriptase-polymerase chain reaction. Brain region L-ferritin protein concentration, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities and malondialdehyde (MDA) concentration were also determined. Learning and memory abilities in Heph/Cp KO and WT control mice at 6 mo of age were tested by the IntelliCage system (New Behavior). Iron concentration was significantly higher in Heph/Cp KO mice than in WT control mice at 4 wk of age in the cortex (50%), hippoc us (120%), brainstem (35%), and cerebellum (220%) and at 6 mo of age in the cortex (140%), hippoc us (420%), brainstem (560%), and cerebellum (340%). L-Ferritin and MDA concentrations were significantly higher and SOD and GPx activities were significantly lower in the cortex, hippoc us, brainstem, and cerebellum of KO mice than in those of WT controls at both 4 wk and 6 mo of age. Iron-related gene expressions also differed significantly between groups. Learning and memory deficits occurred in Heph/Cp KO mice at 6 mo of age. Mutation of both MCFs in mice induces iron accumulation in brain regions, oxidative damage, and learning and memory defects.
Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency
Publisher: American Society of Hematology
Date: 30-06-2005
DOI: 10.1182/BLOOD-2003-02-0347
Abstract: Hephaestin is a membrane-bound multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation. Mice with sex-linked anemia (sla) have a mutant form of Hephaestin and a defect in intestinal basolateral iron transport, which results in iron deficiency and anemia. Ireg1 (SLC11A3, also known as Ferroportin1 or Mtp1) is the putative intestinal basolateral iron transporter. We compared iron levels and expression of genes involved in iron uptake and storage in sla mice and C57BL/6J mice fed iron-deficient, iron-overload, or control diets. Both iron-deficient wild-type mice and sla mice showed increased expression of Heph and Ireg1 mRNA, compared to controls, whereas only iron-deficient wild-type mice had increased expression of the brush border transporter Dmt1. Unlike iron-deficient mice, sla mouse enterocytes accumulated nonheme iron and ferritin. These results indicate that Dmt1 can be modulated by the enterocyte iron level, whereas Hephaestin and Ireg1 expression respond to systemic rather than local signals of iron status. Thus, the basolateral transport step appears to be the primary site at which the small intestine responds to alterations in body iron requirements.
The biology of mammalian multi-copper ferroxidases
Publisher: Springer Science and Business Media LLC
Date: 15-02-2022
Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem
Publisher: Springer Science and Business Media LLC
Date: 23-08-2018
DOI: 10.1038/S41467-018-05906-X
Abstract: Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all- trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.
Copper ions and coordination complexes as novel carbapenem adjuvants
Publisher: American Society for Microbiology
Date: 02-2018
DOI: 10.1128/AAC.02280-17
Abstract: Carbapenem-resistant Enterobacteriaceae are urgent threats to global human health. These organisms produce β-lactamases with carbapenemase activity, such as the metallo-β-lactamase NDM-1, which is notable due to its association with mobile genetic elements and the lack of a clinically useful inhibitor. Here we examined the ability of copper to inhibit the activity of NDM-1 and explored the potential of a copper coordination complex as a mechanism to efficiently deliver copper as an adjuvant in clinical therapeutics. An NDM-positive Escherichia coli isolate, MS6192, was cultured from the urine of a patient with a urinary tract infection. MS6192 was resistant to antibiotics from multiple classes, including erse β-lactams (penicillins, cephalosporins, and carbapenems), aminoglycosides, and fluoroquinolones. In the presence of copper (range, 0 to 2 mM), however, the susceptibility of MS6192 to the carbapenems ertapenem and meropenem increased markedly. In standard checkerboard assays, copper decreased the MICs of ertapenem and meropenem against MS6192 in a dose-dependent manner, suggesting a synergistic mode of action. To examine the inhibitory effect of copper in the absence of other β-lactamases, the bla NDM-1 gene from MS6192 was cloned and expressed in a recombinant E. coli K-12 strain. Analysis of cell extracts prepared from this strain revealed that copper directly inhibited NDM-1 activity, which was confirmed using purified recombinant NDM-1. Finally, delivery of copper at a low concentration of 10 μM by using the FDA-approved coordination complex copper-pyrithione sensitized MS6192 to ertapenem and meropenem in a synergistic manner. Overall, this work demonstrates the potential use of copper coordination complexes as novel carbapenemase adjuvants.
Role of lung iron in determining the bacterial and host struggle in cystic fibrosis
Publisher: American Physiological Society
Date: 11-2009
DOI: 10.1152/AJPLUNG.00132.2009
Abstract: Cystic fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations. It is a multiorgan system disease that affects the lungs, gastrointestinal tract, liver, and pancreas. The majority of morbidity and mortality in CF relates to chronic airway infection with a variety of bacterial species, commencing in very early infancy, which results in lung destruction and ultimately organ failure ( 41 , 43 ). This review focuses on iron homeostasis in the CF lung and its role in determining the success and chronicity of Pseudomonas aeruginosa infection. There have been previous excellent reviews regarding iron metabolism in the lower respiratory tract and mechanisms of P. aeruginosa iron acquisition, and we direct readers to these articles for further background reading ( 31 , 53 , 58 , 77 , 96 ). In this review, we have brought the “two sides of the coin” together to provide a holistic overview of the relationship between host and bacterial iron homeostasis and put this information into the context of current understanding on infection in the CF lung.
Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy
Publisher: American Chemical Society (ACS)
Date: 23-04-2018
DOI: 10.1021/ACS.NANOLETT.8B01071
Abstract: Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (
Reply:
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-02-2017
DOI: 10.1002/HEP.29002
A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption
Publisher: BMJ
Date: 03-2003
DOI: 10.1136/GUT.52.3.340
Abstract: A large oral dose of iron will reduce the absorption of a subsequent smaller dose of iron in a phenomenon known as mucosal block. Molecular analysis of this process may provide insights into the regulation of intestinal iron absorption. To determine the effect of an oral bolus of iron on duodenal expression of molecules associated with intestinal iron transport in rats and to relate this to changes in iron absorption. Rats were given an oral dose of iron and duodenal expression of alent metal transporter 1 (DMT1), Dcytb, Ireg1, and hephaestin (Hp) was determined using the ribonuclease protection assay, western blotting, and immunofluorescence. Iron absorption was measured using radioactive (59)Fe. A decrease in intestinal iron absorption occurred following an oral dose of iron and this was associated with increased enterocyte iron levels, as assessed by iron regulatory protein activity and immunoblotting for ferritin. Reduced absorption was also accompanied by a rapid decrease in expression of the mRNAs encoding the brush border iron transport molecules Dcytb and the iron responsive element (IRE) containing the splice variant of DMT1. No such change was seen in expression of the non-IRE splice variant of DMT1 or the basolateral iron transport molecules Ireg1 and Hp. Similar changes were observed at the protein level. These data indicate that brush border, but not basolateral, iron transport components are regulated locally by enterocyte iron levels and support the hypothesis that systemic stimuli exert their primary effect on basolateral transport molecules.
Two Isoforms of a Divalent Metal Transporter (DMT1) in Schistosoma mansoni Suggest a Surface-associated Pathway for Iron Absorption in Schistosomes
Publisher: Elsevier BV
Date: 2006
Characterization of putative erythroid regulators of hepcidin in mouse models of anemia.
Publisher: Public Library of Science (PLoS)
Date: 30-01-2017
Identification of an Intestinal Heme Transporter
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.CELL.2005.06.025
Abstract: Dietary heme iron is an important nutritional source of iron in carnivores and omnivores that is more readily absorbed than non-heme iron derived from vegetables and grain. Most heme is absorbed in the proximal intestine, with absorptive capacity decreasing distally. We utilized a subtractive hybridization approach to isolate a heme transporter from duodenum by taking advantage of the intestinal gradient for heme absorption. Here we show a membrane protein named HCP 1 (heme carrier protein 1), with homology to bacterial metal-tetracycline transporters, mediates heme uptake by cells in a temperature-dependent and saturable manner. HCP 1 mRNA was highly expressed in duodenum and regulated by hypoxia. HCP 1 protein was iron regulated and localized to the brush-border membrane of duodenal enterocytes in iron deficiency. Our data indicate that HCP 1 is the long-sought intestinal heme transporter.
Disrupted hepcidin regulation in HFE -associated haemochromatosis and the liver as a regulator of body iron homoeostasis
Publisher: Elsevier BV
Date: 02-2003
Role of iron in the pathogenesis of cysteamine-induced duodenal ulceration in rats.
Publisher: American Physiological Society
Date: 06-2009
Abstract: Cysteamine induces perforating duodenal ulcers in rats within 24–48 h. This reducing aminothiol generates hydrogen peroxide in the presence of transition metals (e.g., ferric iron), producing oxidative stress, which may contribute to organ-specific tissue damage. Since most intestinal iron absorption takes place in the proximal duodenum, we hypothesized that cysteamine may disrupt regulation of mucosal iron transport, and iron may facilitate cysteamine-induced duodenal ulceration. We show here that cysteamine-induced ulceration was aggravated by pretreatment of rats with Fe 3+ or Fe 2+ compounds, which elevated iron concentration in the duodenal mucosa. In contrast, feeding rats an iron-deficient diet was associated with a 4.6-fold decrease in ulcer formation, accompanied by a 34% decrease ( P 0.05) in the duodenal mucosal iron concentration. Administration of deferoxamine inhibited ulceration by 65%. We also observed that the antiulcer effect of H2 receptor antagonist cimetidine included a 35% decrease in iron concentration in the duodenal mucosa. Cysteamine-induced duodenal ulcers were also decreased in iron-deficient Belgrade rats ( P 0.05). In normal rats, cysteamine administration increased the iron concentration in the proximal duodenal mucosa by 33% in the preulcerogenic stage but at the same time decreased serum iron ( P 0.05). Cysteamine also enhanced activation of mucosal iron regulatory protein 1 and increased the expression of alent metal transporter 1 mRNA and protein. Transferrin receptor 1 protein expression was also increased, although mucosal ferroportin and ferritin remained almost unchanged. These results indicate an expansion of the intracellular labile iron pool in the duodenal mucosa, increasing its susceptibility to oxidative stress, and suggest a role for iron in the pathogenesis of organ-specific tissue injury such as duodenal ulcers.
Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse
Publisher: Springer Science and Business Media LLC
Date: 02-1999
DOI: 10.1038/5979
Abstract: Iron is essential for many cellular functions consequently, disturbances of iron homeostasis, leading to either iron deficiency or iron overload, can have significant clinical consequences. Despite the clinical prevalence of these disorders, the mechanism by which dietary iron is absorbed into the body is poorly understood. We have identified a key component in intestinal iron transport by study of the sex-linked anaemia (sla) mouse, which has a block in intestinal iron transport. Mice carrying the sla mutation develop moderate to severe microcytic hypochromic anaemia. Although these mice take up iron from the intestinal lumen into mature epithelial cells normally, the subsequent exit of iron into the circulation is diminished. As a result, iron accumulates in enterocytes and is lost during turnover of the intestinal epithelium. Biochemical studies have failed to identify the underlying difference between sla and normal mice, therefore, we used a genetic approach to identify the gene mutant in sla mice. We describe here a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine. We suggest that the hephaestin protein is a multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it is an important link between copper and iron metabolism in mammals.
Gastrin-deficient mice have disturbed hematopoiesis in response to iron deficiency
Publisher: The Endocrine Society
Date: 07-06-2011
DOI: 10.1210/EN.2010-1474
Abstract: Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. Here we report the effect of long-term dietary iron modification on gastrin-deficient (Gas−/−) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r−/−) mice, both of which have reduced basal gastric acid secretion. Iron homeostasis in both strains appeared normal unless the animals were challenged by iron deficiency. When fed an iron-deficient diet, Gas−/− mice, but not Cck2r−/−mice, developed severe anemia. In iron-deficient Gas−/−mice, massive splenomegaly was also apparent with an increased number of splenic megakaryocytes accompanied by thrombocytosis. The expression of the mRNA encoding the iron-regulatory peptide hepcidin, H , was down-regulated in both Cck2r−/− and Gas−/−mice on a low-iron diet, but, interestingly, the reduction was greater in Cck2r−/− mice and smaller in Gas−/− mice than in the corresponding wild-type strains. These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in hematopoiesis under conditions of iron deficiency.
HFE C282Y homozygotes are at increased risk of breast and colorectal cancer
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-11-2009
DOI: 10.1002/HEP.23448
How much iron is too much?
Publisher: Informa UK Limited
Date: 06-2008
Ferric reductase of Saccharomyces cerevisiae: molecular characterization, role in iron uptake, and transcriptional control by iron.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-1992
Abstract: The principal iron uptake system of Saccharomyces cerevisiae utilizes a reductase activity that acts on ferric iron chelates external to the cell. The FRE1 gene product is required for this activity. The deduced amino acid sequence of the FRE1 protein exhibits hydrophobic regions compatible with transmembrane domains and has significant similarity to the sequence of the plasma membrane cytochrome b558 (the X-CGD protein), a critical component of a human phagocyte oxidoreductase, suggesting that FRE1 is a structural component of the yeast ferric reductase. FRE1 mRNA levels are repressed by iron. Fusion of 977 base pairs of FRE1 DNA upstream from the translation start site of an Escherichia coli lacZ reporter gene confers iron-dependent regulation on expression of beta-galactosidase in yeast. An 85-base-pair segment of FRE1 5' noncoding sequence contains a RAP1 binding site and a repeated sequence, TTTTTGCTCAYC this segment is sufficient to confer iron-repressible transcriptional activity on heterologous downstream promoter elements.
Notes on the ant-mimic genus Anatea Berland (Araneae: Theridiidae) and two new species from tropical Australia
Publisher: Australian Museum
Date: 31-05-2017
Hepcidin compared with prohepcidin: an absorbing story.
Publisher: Elsevier BV
Date: 02-2008
GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes
Publisher: Elsevier BV
Date: 03-2017
Pyrosequencing reveals transient cystic fibrosis lung microbiome changes with intravenous antibiotics
Publisher: European Respiratory Society (ERS)
Date: 17-07-2014
DOI: 10.1183/09031936.00203013
Abstract: Chronic airway infection in adults with cystic fibrosis (CF) is polymicrobial and the impact of intravenous antibiotics on the bacterial community composition is poorly understood. We employed culture-independent molecular techniques to explore the early effects of i.v. antibiotics on the CF airway microbiome. DNA was extracted from sputum s les collected from adult subjects with CF at three time-points (before starting treatment, and at day 3 and day 8–10 of i.v. antibiotics) during treatment of an infective pulmonary exacerbation. Microbial community profiles were derived through analysis of bacterial-derived 16S ribosomal RNA by pyrosequencing and changes over time were compared. 59 sputum s les were collected during 24 pulmonary exacerbations from 23 subjects. Between treatment onset and day 3 there was a significant reduction in the relative abundance of Pseudomonas and increased microbial ersity. By day 8–10, bacterial community composition was similar to pre-treatment. Changes in community composition did not predict improvements in lung function. The relative abundance of Pseudomonas falls rapidly in subjects with CF receiving i.v. antibiotic treatment for a pulmonary exacerbation and is accompanied by an increase in overall microbial ersity. However, this effect is not maintained beyond the first week of treatment.
Regulation of systemic iron homeostasis: how the body responds to changes in iron demand
Publisher: Springer Science and Business Media LLC
Date: 02-02-2007
DOI: 10.1007/S10534-006-9030-2
Abstract: The iron that is required to meet the metabolic needs of cells and tissues is derived from the plasma. Plasma iron in turn reflects the release of iron from various body cells, principally the macrophages of the reticuloendothelial system, and the absorption of dietary iron by the proximal small intestine. This iron donation is highly regulated and the liver-derived peptide hepcidin has emerged as the key modulator of cellular iron export. Following its synthesis and secretion from the liver, circulating hepcidin reduces iron export into the plasma by binding to the iron efflux protein ferroportin1 on the surface of enterocytes, macrophages and other cell types and causing its internalization. The level of hepatic hepcidin expression is influenced by HFE, transferrin receptor 2 and hemojuvelin, and the signal transduction pathway(s) linking these proteins to hepcidin are only beginning to be revealed. Hemojuvelin has recently been shown to signal through the bone morphogenetic protein pathway, ultimately activating receptor SMAD/SMAD4 complexes to alter hepcidin transcription. Circulating differic transferrin has emerged as a possible upstream regulator of the liver-based hepcidin regulatory pathway. In addition to being regulated by body iron requirements, hepcidin expression can be modulated by pro-inflammatory cytokines such as interleukin-6. The continuing analysis of inherited disorders of iron metabolism combined with biochemical analysis of signal transduction pathways is essential to fully define this important regulatory system.
Calcitonin increases hepatic hepcidin expression through the BMP6 of kidney in mice
Publisher: Elsevier BV
Date: 12-2021
The Clinical Relevance of Compound Heterozygosity for the C282Y and H63D Substitutions in Hemochromatosis
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1016/J.CGH.2006.07.009
Abstract: Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y substitution have been well characterized, the clinical significance of the C282Y/H63D state remains unclear. This study assessed the phenotypic expression in C282Y/H63D subjects as compared with C282Y homozygotes. Data were obtained from 91 C282Y/H63D probands, 158 C282Y/H63D subjects identified through family screening, and 483 C282Y homozygotes. Subjects underwent clinical evaluation, genotyping, biochemical assessment, and liver biopsy examination where clinically indicated. C282Y/H63D probands had significantly less clinical and biochemical expression than C282Y homozygotes. Biochemical expression was higher in C282Y/H63D probands than in C282Y/H63D subjects identified through family screening (P < .001). Of the C282Y/H63D subjects with serum ferritin levels greater than 1000 mug/L, all had known comorbid factors that could have contributed to the increased ferritin level. Of the 51 C282Y/H63D subjects who underwent liver biopsy examination, significantly increased iron stores were present in 9 subjects and hepatic fibrosis was present in 13. Twelve of the 13 had evidence of hepatic steatosis, excess alcohol consumption, or diabetes. The mobilizable iron level was significantly higher in C282Y homozygous males than in compound heterozygous males (P < .001). Genetic screening of C282Y/H63D first-degree relatives detected 5 C282Y homozygotes. C282Y/H63D subjects referred for assessment had a high prevalence of increased iron indices but did not develop progressive clinical disease without comorbid factors such as steatosis, diabetes, or excess alcohol consumption. When fibrosis was seen, 1 or more comorbid factors almost always were present. Thus, phlebotomy therapy is warranted and cascade screening of relatives should be performed because expressing C282Y homozygotes may be detected.
HFE p.C282Y homozygosity predisposes to rapid serum ferritin rise after menopause: A genotype‐stratified cohort study of hemochromatosis in Australian women
Publisher: Wiley
Date: 24-03-2017
DOI: 10.1111/JGH.13621
A Chinese family carrying novel mutations in SEC23B and HFE2, the genes responsible for congenital dyserythropoietic anaemia II (CDA II) and primary iron overload, respectively
Publisher: Wiley
Date: 20-03-2012
HFE and non-HFE hemochromatosis.
Publisher: Springer Science and Business Media LLC
Date: 10-2002
DOI: 10.1007/BF02982788
Hepcidin Regulation in Wild‐Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol‐Induced Hypoxic Response
Publisher: Wiley
Date: 27-07-2009
DOI: 10.1111/J.1530-0277.2009.00969.X
Abstract: Expression of H 1, the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE-associated hereditary hemochromatosis and Hfe knockout mice (Hfe(-/-)). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe(-/-) mice. Hfe(-/-) and C57BL/6 (wild-type) mice were pair-fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT-PCR and protein expression of hypoxia inducible factor-1 alpha (HIF-1alpha) was measured by western blot. H 1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol-fed wild-type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, H 1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe(-/-) mice fed on the control diet compared with wild-type animals and alcohol further exacerbated these effects. HIF-1alpha protein levels were elevated in alcohol-fed wild-type animals compared with controls. Alcohol may decrease H 1 gene expression independently of the HFE pathway possibly via alcohol-induced hypoxia.
Ceruloplasmin and hephaestin jointly protect the exocrine pancreas against oxidative damage by facilitating iron efflux
Publisher: Elsevier BV
Date: 07-2018
Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice
Publisher: American Society of Hematology
Date: 15-05-2004
Iron metabolism in the hemoglobin-deficit mouse: correlation of diferric transferrin with hepcidin expression.
Publisher: American Society of Hematology
Date: 15-02-2005
DOI: 10.1182/BLOOD-2005-07-2614
Abstract: The iron requirements of the erythroid compartment modulate the expression of hepcidin in the liver, which in turn alters intestinal iron absorption and iron release from the reticuloendothelial system. We have taken advantage of an inherited anemia of the mouse (hemoglobin deficit, or hbd) to gain insights into the factors regulating hepcidin expression. hbd mice showed a significant anemia but, surprisingly, their iron absorption was not increased as it was in wild-type animals made anemic to a similar degree by dietary iron depletion. In wild-type mice hepatic hepcidin levels were decreased but in hbd animals a significant and unexpected increase was observed. The level of absorption was appropriate for the expression of hepcidin in each case, but in hbd mice did not reflect the degree of anemia. However, this apparent inappropriate regulation of hepcidin correlated with increased transferrin saturation and levels of diferric transferrin in the plasma, which in turn resulted from the reduced capacity of hbd animals to effectively use transferrin-bound iron. These data strengthen the proposal that diferric transferrin is a key indicator of body iron requirements.
Iron homeostasis: transport, metabolism, and regulation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2016
Identification of H‐ and L‐ferritin subunit binding sites on human T and B lymphoid cells
Publisher: Wiley
Date: 10-1989
DOI: 10.1111/J.1365-2141.1989.TB00262.X
Abstract: Monoclonal antibodies to the H and L subunits of ferritin were used in indirect immunofluorescent studies to investigate the subunit specificity of ferritin binding to transformed T and B lymphoid cell lines. Pre-incubation of cells with recombinant H ferritin followed by antibodies to the H subunit produced a labelling pattern in which all cells showed strong fluorescent stippling. Corresponding experiments with liver ferritin and an antibody to the L subunit revealed that most cells were lightly stippled, but 3-5% of the cells were intensely labelled. These two labelling patterns were distinct as assessed by cross-blocking experiments with recombinant H and liver ferritins. These results imply that different binding sites exist for each subunit.
Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases
Publisher: Elsevier BV
Date: 04-2016
DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients.
Publisher: Hindawi Limited
Date: 19-11-2002
DOI: 10.1002/HUMU.9095
Abstract: Alagille syndrome (AGS) is an autosomal dominant disorder characterized by abnormal development of the liver, heart, skeleton, eye, and face. Mutations in the Jagged1 gene have been found to result in the AGS phenotype. Using denaturing high performance liquid chromatography (DHPLC) mutation analysis we have screened 20 in iduals with symptoms of AGS from 14 families for mutations within Jagged1. Eleven distinct Jagged1 mutations, six of which are novel, were identified in the 14 probands and affected family members. The mutations include four small deletions (36.6%), one small insertion (9.1%), three missense mutations (27.3%), one nonsense mutation (9.1%) and two splice donor site mutations (18.2%). The two newly identified splice site mutations were shown to cause the aberrant splicing of Jagged1 mRNA resulting in premature truncation of JAG1. A splice acceptor site mutation previously identified by our group in intron 13 was also shown to cause multiple splicing abnormalities of Jagged1 mRNA, consequently removing exons 14 and 15. The results of this study are consistent with the proposal that either haploinsufficiency for wild-type JAG1 and/or dominant negative effects produced by mutated JAG1 are responsible for the AGS phenotype.
Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency.
Publisher: Elsevier BV
Date: 05-2006
Abstract: Copper and iron metabolism intersect in mammals. Copper deficiency simultaneously leads to decreased iron levels in some tissues and iron deficiency anemia, whereas it results in iron overload in other tissues such as the intestine and liver. The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals. We investigated the effect of in vivo and in vitro copper deficiency on hephaestin (Heph) expression and activity. C57BL/6J mice were separated into 2 groups on the day of parturition. One group was fed a copper-deficient diet and another was fed a control diet for 6 wk. Copper-deficient mice had significantly lower hephaestin and ceruloplasmin (approximately 50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (approximately 60% of controls), and enterocyte mRNA and protein levels of ferroportin1 were increased to 2.5 and 10 times, respectively, relative to controls, by copper deficiency, indicating a systemic iron deficiency in the copper-deficient mice. Interestingly, hephaestin protein levels were significantly decreased to approximately 40% of control, suggesting that decreased enterocyte copper content leads to decreased hephaestin synthesis and/or stability. We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity. Both in vivo and in vitro studies indicate that copper is required for the proper processing and/or stability of hephaestin.
Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with β-thalassemia major: A longitudinal study
Publisher: American Society of Hematology
Date: 04-07-2013
DOI: 10.1182/BLOOD-2012-12-471441
Abstract: In β-thalassemia major, hepcidin levels are simultaneously associated with erythropoiesis and iron loading pre- and posttransfusion. Transfusion improves anemia, suppressing erythropoiesis and in turn increasing hepcidin in patients with β-thalassemia major.
Duodenal expression of iron transport molecules in untreated haemochromatosis subjects
Publisher: BMJ
Date: 07-2003
DOI: 10.1136/GUT.52.7.953
Abstract: In HFE associated hereditary haemochromatosis, the duodenal enterocyte behaves as if iron deficient and previous reports have shown increased duodenal expression of alent metal transporter 1 (DMT1) and iron regulated gene 1 (Ireg1) in affected subjects. In those studies, many patients had undergone venesection, which is a potent stimulus of iron absorption. Our study investigated duodenal expression of DMT1 (IRE and non-IRE), Ireg1, hephaestin, and duodenal cytochrome-b (Dyctb) in untreated C282Y homozygous haemochromatosis patients, iron deficient patients, and iron replete subjects. Total RNA was extracted from duodenal biopsies and expression of the iron transport genes was assessed by ribonuclease protection assay. Expression of DMT1 (IRE) and Ireg1 was increased 3-5-fold in iron deficient subjects compared with iron replete subjects. Duodenal expression of DMT1 (IRE) and Ireg1 was similar in haemochromatosis patients and iron replete subjects but in haemochromatosis patients with elevated serum ferritin concentrations, both DMT1 (IRE) and Ireg1 expression were inappropriately increased relative to serum ferritin concentration. Hephaestin and Dcytb levels were not upregulated in haemochromatosis. DMT1 (IRE) and Ireg1 levels showed significant inverse correlations with serum ferritin concentration in each group of patients. These findings are consistent with DMT1 (IRE) and Ireg1 playing primary roles in the adaptive response to iron deficiency. Untreated haemochromatosis patients showed inappropriate increases in DMT1 (IRE) and Ireg1 expression for a given level of serum ferritin concentration, although the actual level of expression of these iron transport genes was not significantly different from that of normal subjects.
Polymeric Nanoparticles Enhance the Ability of Deferoxamine To Deplete Hepatic and Systemic Iron
Publisher: American Chemical Society (ACS)
Date: 07-08-2018
DOI: 10.1021/ACS.NANOLETT.8B02428
Abstract: Chelators are commonly used to remove excess iron in iron-loading disorders. Deferoxamine (DFO) is an effective and safe iron chelator but an onerous parenteral administration regimen limits its routine use. To develop more effective methods for delivering iron chelators, we examined whether hiphilic copolymer nanoparticles (NPs) could deliver DFO more efficiently. Physical characterization showed a uniform and stable preparation of DFO nanoparticles (DFO-NPs) with an average diameter of 105.3 nm. In macrophage (RAW264.7) and hepatoma (HepG2) cell lines, DFO-NPs proved more effective at depleting iron than free DFO. In wild-type mice previously loaded with iron dextran, as well as Hbb
Iron-Overload–Related Disease inHFEHereditary Hemochromatosis
Publisher: Massachusetts Medical Society
Date: 17-01-2008
DOI: 10.1056/NEJMOA073286
Cloning and gastrointestinal expression of rat hephaestin: relationship to other iron transport proteins.
Publisher: American Physiological Society
Date: 10-2001
DOI: 10.1152/AJPGI.2001.281.4.G931
Abstract: The membrane-bound ceruloplasmin homolog hephaestin plays a critical role in intestinal iron absorption. The aims of this study were to clone the rat hephaestin gene and to examine its expression in the gastrointestinal tract in relation to other genes encoding iron transport proteins. The rat hephaestin gene was isolated from intestinal mRNA and was found to encode a protein 96% identical to mouse hephaestin. Analysis by ribonuclease protection assay and Western blotting showed that hephaestin was expressed at high levels throughout the small intestine and colon. Immunofluorescence localized the hephaestin protein to the mature villus enterocytes with little or no expression in the crypts. Variations in iron status had a small but nonsignificant effect on hephaestin expression in the duodenum. The high sequence conservation between rat and mouse hephaestin is consistent with this protein playing a central role in intestinal iron absorption, although its precise function remains to be determined.
Intestinal Iron Transport and its Regulation.
Publisher: Informa UK Limited
Date: 2001
DOI: 10.1080/10245332.2001.11746572
Abstract: In recent years, a number of components of the iron absorption pathway have been identified, greatly increasing our understanding of this important process. These include two molecules involved in brush border iron uptake, the ferric reductase DcytB and the iron transporter DMT1, and two mediating iron transfer to the body, the iron transporter Ireg1 and the ferroxidase hephaestin (Hp). Analysis of the regulation of these molecules has provided us with valuable insights into how the body responds to changes in iron requirements, and has enabled us to re-examine how iron absorption is controlled, and in particular the mucosal block phenomenon. Evidence suggests that the block to absorption that follows a priming dose of iron is the result of elevated intracellular iron levels decreasing the expression of the brush border iron transporter DMT1. Based on these observations, it is possible to propose a general model for the regulation of iron absorption whereby the basolateral transfer step involving Ireg1 and Hp controls the rate of absorption. In this model, DMT1 expression, and hence, brush border uptake, is regulated by local iron levels that are, in turn, determined by the rate of basolateral transfer.
Hepatic iron metabolism.
Publisher: Georg Thieme Verlag KG
Date: 2005
Abstract: The liver performs three main functions in iron homeostasis. It is the major site of iron storage, it regulates iron traffic into and around the body through its production of the peptide hepcidin, and it is the site of synthesis of major proteins of iron metabolism such as transferrin and ceruloplasmin. Most of the iron that enters the liver is derived from plasma transferrin under normal circumstances, and transferrin receptors 1 and 2 play important roles in this process. In pathological situations, non-transferrin-bound iron, ferritin, and hemoglobin/haptoglobin and heme/hemopexin complexes assume greater importance in iron delivery to the organ. Iron is stored in the liver as ferritin and, with heavy iron loading, as hemosiderin. The liver can est itself of iron through the plasma membrane iron exporter ferroportin 1, a process that also requires ceruloplasmin. Hepcidin can regulate this iron release through its interaction with ferroportin.
Tissue-specific changes in iron metabolism genes in mice following phenylhydrazine-induced haemolysis
Publisher: Elsevier BV
Date: 10-2004
DOI: 10.1016/J.BBADIS.2004.06.011
Abstract: Iron metabolism in animals is altered by haemolytic anaemia induced by phenylhydrazine (PHZ). In common with a number of other modulators of iron metabolism, the mode and the mechanisms of this response are yet to be determined. However, recent studies have shown increased expression of the ferrous transporter DMT1 in the duodenum and other tissues of mice administered PHZ. We examined the expression of the ferric reductase Dcytb, DMT1 and some other genes involved in Fe metabolism in tissues of mice dosed with PHZ. The expression of iron-related genes in the duodenum, liver, and spleen of the mice were evaluated using Northern blot analyses, RT-PCR and immunocytochemistry. Dcytb, and DMT1 mRNA and protein increased markedly in the duodenum of mice given PHZ. The efflux protein Ireg1 also increased in the duodenum of the treated mice. These changes correlated with a decrease in hepatic hepcidin expression. Dcytb, DMT1, Ireg1 and transferrin receptor 1 mRNA expression in the spleen and liver of mice treated with PHZ responded to the enhanced iron demand associated with the resulting stimulation of erythropoiesis. Enhanced iron absorption observed in PHZ-treated animals is facilitated by the up-regulation of the genes involved in iron transport and recycling. The probable association of the erythroid and the store regulators of iron homeostasis and absorption in the mice is discussed.
Mechanistic and regulatory aspects of intestinal iron absorption
Publisher: American Physiological Society
Date: 15-08-2014
Abstract: Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands.
Improved purification of the human placental transferrin receptor and a novel immunoradiometric assay for receptor protein.
Publisher: Elsevier BV
Date: 11-1986
DOI: 10.1016/0304-4165(86)90167-4
Abstract: A simplified method for the purification of human placental transferrin receptor is described. The procedure involves chromatography of a detergent extract of placenta on immobilized iron-loaded transferrin. Knowledge of the physiology of the interaction between transferrin and its receptor is applied to enable bound receptor to be eluted under mild conditions and essentially free of containing transferrin. Purified transferrin receptor and a monoclonal antibody to the receptor were used to develop a novel immunoradiometric assay for the receptor in which the monoclonal antibody is the radiolabelled species. A competition between two populations of receptor, one immobilized on a particulate support and the other in solution, provides the basis for the assay. Using this assay we have measured transferrin receptor levels in placental and hepatic tissue and in three cell lines during both the logarithmic and stationary phases of cell growth.
The Expression and Regulation of the Iron Transport Molecules Hephaestin and IREG1
Publisher: Springer Science and Business Media LLC
Date: 2002
Food deprivation increases hepatic hepcidin expression and can overcome the effect of Hfe deletion in male mice
Publisher: Wiley
Date: 25-05-2018
Gastrins, iron homeostasis and colorectal cancer
Publisher: Elsevier BV
Date: 05-2011
Intestinal transferrin receptors and iron absorption in the neonatal rat.
Publisher: Wiley
Date: 02-1991
DOI: 10.1111/J.1365-2141.1991.TB07982.X
Abstract: The transferrin receptor is a major protein found on the basolateral membranes of intestinal epithelial cells, yet its possible role in intestinal iron metabolism and also in iron absorption is unclear. We have studied intestinal transferrin receptor expression during the peri- and postnatal development of the small intestine of the rat using immunohistochemistry with a monoclonal antibody to the rat receptor. Two major changes in transferrin receptor expression in the developing small intestine were found, a decrease in receptor expression associated with birth, and an increase at the time of weaning. Around the time of weaning there was a large decrease in iron absorption, but there was no direct correlation between absorption and transferrin receptor expression. However, at both birth and weaning there were major changes in intestinal cell kinetics, and the distribution of receptor correlated well with the distribution of proliferating cell populations. In addition, as the intestinal epithelial cells differentiated and stopped iding, there was a redistribution of transferrin receptors from the cell surface to intracellular sites. These data suggest that the most likely role of the transferrin receptor in the neonatal intestine is in the supply of iron to the developing epithelial cells in the crypts, and that the receptor does not play a direct role in iron transit across the intestinal epithelium.
Ferric iron reduction and iron assimilation in Saccharomyces cerevisiae.
Publisher: Elsevier BV
Date: 08-1992
DOI: 10.1016/0162-0134(92)84070-4
Abstract: We have used the yeast Saccharomyces cerevisiae as a model organism to study the role of ferric iron reduction in eucaryotic iron uptake. S. cerevisiae is able to utilize ferric chelates as an iron source by reducing the ferric iron to the ferrous form, which is subsequently internalized by the cells. A gene (FRE1) was identified which encodes a protein required for both ferric iron reduction and efficient ferric iron assimilation, thus linking these two activities. The predicted FRE1 protein appears to be a membrane protein and shows homology to the beta-subunit of the human respiratory burst oxidase. These data suggest that FRE1 is a structural component of the ferric reductase. Subcellular fractionation studies showed that the ferric reductase activity of isolated plasma membranes did not reflect the activity of the intact cells, implying that cellular integrity was necessary for function of the major S. cerevisiae ferric reductase. An NADPH-dependent plasma membrane ferric reductase was partially purified from plasma membranes. Preliminary evidence suggests that the cell surface ferric reductase may, in addition to mediating cellular iron uptake, help modulate the intracellular redox potential of the yeast cell.
Targeted Brain Delivery of Rabies Virus Glycoprotein 29-Modified Deferoxamine-Loaded Nanoparticles Reverses Functional Deficits in Parkinsonian Mice
Publisher: American Chemical Society (ACS)
Date: 04-04-2018
Abstract: Excess iron deposition in the brain often causes oxidative stress-related damage and necrosis of dopaminergic neurons in the substantia nigra and has been reported to be one of the major vulnerability factors in Parkinson's disease (PD). Iron chelation therapy using deferoxamine (DFO) may inhibit this nigrostriatal degeneration and prevent the progress of PD. However, DFO shows very short half-life in vivo and hardly penetrates the blood brain barrier (BBB). Hence, it is of great interest to develop DFO formulations for safe and efficient intracerebral drug delivery. Herein, we report a polymeric nanoparticle system modified with brain-targeting peptide rabies virus glycoprotein (RVG) 29 that can intracerebrally deliver DFO. The nanoparticle system penetrates the BBB possibly through specific receptor-mediated endocytosis triggered by the RVG29 peptide. Administration of these nanoparticles significantly decreased iron content and oxidative stress levels in the substantia nigra and striatum of PD mice and effectively reduced their dopaminergic neuron damage and as reversed their neurobehavioral deficits, without causing any overt adverse effects in the brain or other organs. This DFO-based nanoformulation holds great promise for delivery of DFO into the brain and for realizing iron chelation therapy in PD treatment.
Correlation of serum hepcidin levels with disease progression in hepatitis B virus-related disease assessed by nanopore film based assay
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/SREP34252
Abstract: Chronic hepatitis B virus (HBV) infection often develop into cirrhosis, and both are major risk factors of hepatocellular carcinoma. However, effective approaches for the monitoring of HBV-related disease progress are still in need. Increased iron storage has an important role in HBV-related diseases. Hepcidin is a key regulator of iron homeostasis whose expression changes are often indicative of abnormal iron metabolism. There are few reports of hepcidin levels in patients with HBV infections, and the available results are inconsistent. In this study, using a recently validated nanopore silica film based method, we measured serum hepcidin levels in 46 HBV-related patients and 20 healthy controls. Patients were ided into three groups: chronic hepatitis B without cirrhosis HBV-related cirrhosis and HBV-related cirrhosis with hepatocellular carcinoma. Compared to healthy controls, the mean serum hepcidin level was significantly higher in CHB patients without cirrhosis, and in those with hepatocellular carcinoma, but not in those with cirrhosis. Iron-loading, viral infection and liver dysfunction are determined to be the major regulators of hepcidin in these patients. These observations suggest correlations between serum hepcidin and progression of chronic HBV infection, and may shed a new light on the development of biomarkers for HBV-related disease surveillance.
Bacterial Outer Membrane Vesicles Presenting Programmed Death 1 for Improved Cancer Immunotherapy via Immune Activation and Checkpoint Inhibition
Publisher: American Chemical Society (ACS)
Date: 11-11-2032
Abstract: Natural, extracellular membrane vesicles secreted by Gram-negative bacteria, outer membrane vesicles (OMVs), contain numerous pathogen-associated molecular patterns which can activate systemic immune responses. Previous studies have shown that OMVs induce strong IFN-γ- and T cell-mediated anti-tumor effects in mice. However, IFN-γ is known to upregulate immunosuppressive factors in the tumor microenvironment, especially the immune checkpoint programmed death 1 ligand 1 (PD-L1), which may h er T cell function and limit immunotherapeutic effectiveness. Here, we report the development of genetically engineered OMVs whose surface has been modified by insertion of the ectodomain of programmed death 1 (PD1). This genetic modification does not affect the ability of OMVs to trigger immune activation. More importantly, the engineered OMV-PD1 can bind to PD-L1 on the tumor cell surface and facilitate its internalization and reduction, thereby protecting T cells from the PD1/PD-L1 immune inhibitory axis. Through the combined effects of immune activation and checkpoint suppression, the engineered OMVs drive the accumulation of effector T cells in the tumor, which, in turn, leads to a greater impairment of tumor growth, compared with not only native OMVs but also the commonly used PD-L1 antibody. In conclusion, this work demonstrates the potential of bioengineered OMVs as effective immunotherapeutic agents that can comprehensively regulate the tumor immune microenvironment to effect markedly increased anti-tumor efficacy.
Control of iron absorption.
Publisher: Wiley
Date: 11-1996
DOI: 10.1111/J.1440-1746.1996.TB00029.X
Abstract: Intestinal iron absorption plays an essential role in body iron homeostasis, although the mechanism by which iron moves across the cells of the intestinal epithelium and the way in which this process is regulated are poorly understood. Signals to alter iron absorption are received from the body by cells of the intestinal crypt and these signals are translated into an absorption response after the cells have migrated up the villus and differentiated into mature absorptive enterocytes. The intracellular iron concentration of the crypt cell may play an important role in the regulation of this process. Biochemical investigations on the mechanism of iron absorption have met with only limited success and a molecular understanding of this mechanism appears most likely to come from the identification of the genes affected in various inherited disturbances of iron absorption in several mammalian species.
Essential but toxic: Controlling the flux of iron in the body
Publisher: Wiley
Date: 25-07-2012
DOI: 10.1111/J.1440-1681.2011.05661.X
Abstract: Iron is an essential nutrient, but, because it is toxic when present in excess, its levels in the body are tightly controlled. This regulation is affected by controlling the release of iron into the plasma. Most iron enters the plasma from macrophages, which recycle iron from senescent erythrocytes, but dietary iron absorption and the release of hepatocyte storage iron are other major sources. Cellular iron export is mediated by the membrane iron transporter ferroportin 1, in conjunction with an iron oxidase. Hephaestin provides this oxidase activity in the intestine, whereas ceruloplasmin is the oxidase used by most other tissues. The liver-derived peptide hepcidin binds to ferroportin 1 and removes it from the cell surface, thus reducing iron donation to the plasma. The levels of hepcidin, in turn, reflect body iron requirements. At the cellular level, ferroportin 1 can also be regulated independently of hepcidin by hypoxia-inducible factors and the iron regulatory proteins. The hepcidin-ferroportin axis plays a critical role in regulating body iron homeostasis.
Circulating gastrin is increased in hemochromatosis
Publisher: Wiley
Date: 18-10-2006
Is there a better way to set population iron recommendations?
Publisher: Elsevier BV
Date: 06-2017
Hephaestin and Ceruloplasmin Play Distinct but Interrelated Roles in Iron Homeostasis in Mouse Brain
Publisher: Elsevier BV
Date: 05-2015
Abstract: Iron accumulation in the central nervous system (CNS) is a common feature of many neurodegenerative diseases. Multicopper ferroxidases (MCFs) play an important role in cellular iron metabolism. However, the role of MCFs in the CNS in health and disease remains poorly characterized. The aim was to study the role of hephaestin (HEPH) and ceruloplasmin (CP) in CNS iron metabolism and homeostasis. Iron concentrations and L-ferritin protein levels of selected brain regions were determined in global hephaestin knockout (Heph KO), global ceruloplasmin knockout (Cp KO), and wild-type (WT) male mice at 6-7 mo of age. Gene expression of alent metal transporter 1 (Dmt1), ferroportin 1 (Fpn1), Heph, Cp, and transferrin receptor 1 (Tfrc) and HEPH protein level was quantitated in the same brain regions. Iron and L-ferritin protein levels were significantly increased in Heph KO mouse brain cortex (iron: 30%, P < 0.05 L-ferritin: 200%, P < 0.05), hippoc us (iron: 80%, P < 0.05 L-ferritin: 300%, P < 0.05), brainstem (iron: 20%, P < 0.05 L-ferritin: 150%, P < 0.05), and cerebellum (iron: 20%, P < 0.05 L-ferritin: 100%, P < 0.05) regions than in WT and Cp KO mouse brain regions at 6 mo of age. Expression of the Heph gene was significantly increased in the Cp KO mouse cortex (100% P < 0.01), hippoc us (350% P < 0.001), brainstem (30% P < 0.01), and cerebellum (150% P < 0.001) than in WT controls, and Cp gene expression was significantly decreased in the Heph KO mouse hippoc us (20% P < 0.05) than in WT control mice at 6 mo of age. Ablation of HEPH or CP results in disordered brain iron homeostasis in mice. Heph KO may provide a novel model for neurodegenerative disorders.
SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 20-03-2008
The fission yeast ferric reductase gene frp1+ is required for ferric iron uptake and encodes a protein that is homologous to the gp91-phox subunit of the human NADPH phagocyte oxidoreductase.
Publisher: Informa UK Limited
Date: 07-1993
Abstract: We have identified a cell surface ferric reductase activity in the fission yeast Schizosaccharomyces pombe. A mutant strain deficient in this activity was also deficient in ferric iron uptake, while ferrous iron uptake was not impaired. Therefore, reduction is a required step in cellular ferric iron acquisition. We have cloned frp1+, the wild-type allele of the mutant gene. frp1+ mRNA levels were repressed by iron addition to the growth medium. Fusion of 138 nucleotides of frp1+ promoter sequences to a reporter gene, the bacterial chlor henicol acetyltransferase gene, conferred iron-dependent regulation upon the latter when introduced into S. pombe. The predicted amino acid sequence of the frp1+ gene exhibits hydrophobic regions compatible with transmembrane domains. It shows similarity to the Saccharomyces cerevisiae FRE1 gene product and the gp91-phox protein, a component of the human NADPH phagocyte oxidoreductase that is deficient in X-linked chronic granulomatous disease.
Heterozygous missense mutations in the GLRX5 gene cause sideroblastic anemia in a Chinese patient
Publisher: American Society of Hematology
Date: 23-10-2014
Elevated metal concentrations in the CF airway correlate with cellular injury and disease severity
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JCF.2013.12.001
Abstract: Bio-active trace metals have been identified in respiratory tract secretions of subjects with lung disease and may potentially influence bacterial virulence, inflammation and disease severity. We measured a erse range of metal ions in sputum s les from subjects with CF and non-CF bronchiectasis (NCFB) compared to healthy controls and examined their relationship to airway inflammation, disease severity and the presence of bacterial pathogens. We studied 45 subjects with CF, 8 with NCFB and 8 healthy controls. Metal concentrations were measured in sputum supernatant by inductively-coupled plasma mass spectrometry and correlated with sputum inflammatory cell counts, lactate dehydrogenase (LDH) and interleukin (IL)-8 concentrations, atmospheric particulate matter, lung function, clinical status and participant demographics. Sputum from subjects with CF and NCFB contained increased concentrations of magnesium, calcium, iron and zinc. Metal ion concentrations correlated positively with LDH levels. The concentrations of magnesium, iron and zinc positively correlated with IL-8. A sub-group of CF subjects with severe lung disease demonstrated increased sputum molybdenum concentrations. Elevated concentrations of sputum metal ions appear to be associated with cell/tissue necrosis and inflammation in subjects with CF and NCFB. Sputum molybdenum concentrations may be a biomarker of severe CF airway disease.
Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2004
DOI: 10.1002/HEP.20038
Abstract: Hepatic hemosiderosis and increased iron absorption are common findings in cirrhosis. It has been proposed that a positive relation exists between intestinal iron absorption and the development of hepatic hemosiderosis. The current study investigated the duodenal expression of the iron transport molecules alent metal transporter 1 (DMT1 [IRE]), iron-regulated gene 1 (Ireg1 [ferroportin]), hephaestin, and duodenal cytochrome b (Dyctb) in 46 patients with cirrhosis and 20 control subjects. Total RNA s les were extracted from duodenal biopsy s les and the expression of the iron transport genes was assessed by ribonuclease protection assays. Expression of DMT1 and Ireg1 was increased 1.5 to 3-fold in subjects with cirrhosis compared with iron-replete control subjects. The presence of cirrhosis per se and serum ferritin (SF) concentration were independent factors that influenced the expression of DMT1. However, only SF concentration was independently associated with Ireg1 expression. In cirrhosis, the expression of DMT1 and Ireg1 was not related to the severity of liver disease or cirrhosis type. There was no correlation between the duodenal expression of DMT1 and Ireg1 and the degree of hepatic siderosis. In conclusion, the presence of cirrhosis is an independent factor associated with increased expression of DMT1 but not Ireg1. The mechanism by which cirrhosis mediates this change in DMT1 expression has yet to be determined. Increased expression of DMT1 may play an important role in the pathogenesis of cirrhosis-associated hepatic iron overload.
The Multicopper Ferroxidase Hephaestin Enhances Intestinal Iron Absorption in Mice
Publisher: Public Library of Science (PLoS)
Date: 04-06-2014
HFEC282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-03-2009
DOI: 10.1002/HEP.22972
Mice overexpressing hepcidin suggest ferroportin does not play a major role in Mn homeostasis
Publisher: Oxford University Press (OUP)
Date: 13-03-2019
DOI: 10.1039/C8MT00370J
Abstract: Manganese is an essential metal that is required for a wide range of biological functions. Ferroportin (FPN), the only known cellular exporter of iron, has also been proposed to play a role in manganese export, but this relationship is incompletely understood. To investigate this in more detail in vivo, we examined the relative distributions of manganese and iron in TMPRSS6 deficient mice, which are characterized by constitutively high expression of the iron regulatory hormone hepcidin and, consequently, very low FPN levels in their tissues. Tmprss6−/− mice showed frank iron deficiency and reduced iron levels in most tissues, consistent with FPN playing an important role in the distribution of this metal, but manganese levels were largely unaffected. Associated studies using intestine-specific FPN knockout mice showed that loss of FPN significantly reduced the dietary absorption of iron, but had no effect on manganese intake. Taken together, our data suggest that FPN does not play a major role in Mn transport in vivo. They do not exclude a minor role for FPN in manganese homeostasis, nor the possibility that the transporter may be relevant at high Mn levels, but at physiological levels of this metal, other transport proteins appear to be more important.
HFECys282Tyr homozygotes with serum ferritin concentrations below 1000 μg/L are at low risk of hemochromatosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2010
DOI: 10.1002/HEP.23786
Suppression of Tumor Energy Supply by Liposomal Nanoparticle-Mediated Inhibition of Aerobic Glycolysis
Publisher: American Chemical Society (ACS)
Date: 09-01-2018
Abstract: Aerobic glycolysis enables cancer cells to rapidly take up nutrients (e.g., nucleotides, amino acids, and lipids) and incorporate them into the biomass needed to produce a new cell. In contrast to existing chemotherapy/radiotherapy strategies, inhibiting aerobic glycolysis to limit the adenosine 5'-triphosphate (ATP) yield is a highly efficient approach for suppressing tumor cell proliferation. However, most, if not all, current inhibitors of aerobic glycolysis cause significant adverse effects because of their nonspecific delivery and distribution to nondiseased organs, low bioavailability, and a narrow therapeutic window. New strategies to enhance the biosafety and efficacy of these inhibitors are needed for moving them into clinical applications. To address this need, we developed a liposomal nanocarrier functionalized with a well-validated tumor-targeting peptide to specifically deliver the aerobic glycolysis inhibitor 3-bromopyruvate (3-BP) into the tumor tissue. The nanoparticles effectively targeted tumors after systemic administration into tumor-bearing mice and suppressed tumor growth by locally releasing 3-BP to inhibit the ATP production of the tumor cells. No overt side effects were observed in the major organs. This report demonstrates the potential utility of the nanoparticle-enabled delivery of an aerobic glycolysis inhibitor as an anticancer therapeutic agent.
Ironing out disease: inherited disorders of iron homeostasis.
Publisher: Wiley
Date: 2001
Abstract: Iron presents us with a paradox. Without it, cells simply cannot survive because iron is an essential cofactor for many enzymes in critical biochemical pathways. However, when iron is present in excess, it can be highly cytotoxic due to its propensity to catalyze the formation of reactive oxygen radicals. To cater for this dual nature, cells and organisms have developed elaborate mechanisms for regulating iron intake and efflux. When these mechanisms are disrupted, as is the case in a number of inherited disorders of iron metabolism, the pathological consequences can be severe. Many of these disorders are characterized by iron overload and include relatively common diseases such as hereditary hemochromatosis, rare abnormalities of plasma protein synthesis (atransferrinemia and aceruloplasminemia), and the neuromuscular disease Friedreich ataxia. The few described inherited anemias in humans have yet to yield to molecular dissection, but the investigation of several rodent anemias has proved highly rewarding. This review will provide a summary of some of these disorders and describe how their analysis has provided important new insights into iron trafficking pathways and their regulation.
Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats
Publisher: Elsevier BV
Date: 09-2002
Abstract: Hepcidin is an antimicrobial peptide thought to be involved in the regulation of intestinal iron absorption. To further investigate its role in this process, we examined hepatic and duodenal gene expression in rats after the switch from a control diet to an iron-deficient diet. Adult rats on an iron-replete diet were switched to an iron-deficient diet and the expression of iron homeostasis molecules in duodenal and liver tissue was studied over 14 days. Intestinal iron absorption was determined at these same time-points by measuring the retention of an oral dose of (59)Fe. Iron absorption increased 2.7-fold within 6 days of switching to an iron-deficient diet and was accompanied by an increase in the duodenal expression of Dcytb, alent metal transporter 1, and Ireg1. These changes precisely correlated with decreases in hepatic hepcidin expression and transferrin saturation. No change in iron stores or hematologic parameters was detected. This study showed a close relationship between the expression of hepcidin, duodenal iron transporters, and iron absorption. Both hepcidin expression and iron absorption can be regulated before iron stores and erythropoiesis are affected, and transferrin saturation may signal such changes.
5-Aza-2′-deoxycytidine Activates Iron Uptake and Heme Biosynthesis by Increasing c-Myc Nuclear Localization and Binding to the E-boxes of Transferrin Receptor 1 (TfR1) and Ferrochelatase (Fech) Genes
Publisher: Elsevier BV
Date: 10-2011
Supplementation with Sucrosomial® iron leads to favourable changes in the intestinal microbiome when compared to ferrous sulfate in mice
Publisher: Springer Science and Business Media LLC
Date: 25-10-2021
DOI: 10.1007/S10534-021-00348-3
Abstract: Iron deficiency is one of the most common nutritional deficiencies worldwide and is often treated with oral iron supplements. However, commonly used supplements, including those based on ferrous iron salts, are associated with gastrointestinal side effects and unfavorable changes in the intestinal microbiome. Sucrosomial® iron is a novel iron formulation that is effective at treating iron deficiency, and with fewer gastrointestinal side effects, yet its effect on the gut microbiome has not been examined previously. Thus, we treated mice for two weeks with diets containing either Sucrosomial® iron or ferrous sulfate as the sole iron source and examined bacterial communities in the intestine using 16S Microbial Profiling of DNA extracted from feces collected both prior to and following dietary treatment. Mice treated with Sucrosomial® iron showed an increase in Shannon ersity over the course of the study. This was associated with a decrease in the abundance of the phylum Proteobacteria, which contains many pathogenic species, and an increase in short chain fatty acid producing bacteria such as Lachnospiraceae , Oscillibacter and Faecalibaculum . None of these changes were observed in mice treated with ferrous sulfate. These results suggest that Sucrosomial® iron may have a beneficial effect on the intestinal microbiome when compared to ferrous sulfate and that this form of iron is a promising alternative to ferrous iron salts for the treatment of iron deficiency.
The orchestration of body iron intake: how and where do enterocytes receive their cues?
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S1079-9796(03)00039-1
Abstract: Our understanding of how iron transverses the intestinal epithelium has improved greatly in recent years, although the mechanism by which body iron demands regulate this process remains poorly understood. By critically examining the earlier literature in this field and considering it in combination with recent advances we have formulated a model explaining how iron absorption could be regulated by body iron requirements. In particular, this analysis suggests that signals to alter absorption exert a direct effect on mature enterocytes rather than influencing the intestinal crypt cells. We propose that the liver plays a central role in the maintenance of iron homeostasis by regulating the expression of hepcidin in response to changes in the ratio of diferric transferrin in the circulation to the level of transferrin receptor 1. Such changes are detected by transferrin receptor 2 and the HFE/transferrin receptor 1 complex. Circulating hepcidin then directly influences the expression of Ireg1 in the mature villus enterocytes of the duodenum, thereby regulating iron absorption in response to body iron requirements. In this manner, the body can rapidly and appropriately respond to changes in iron demands by adjusting the release of iron from the duodenal enterocytes and, possibly, the macrophages of the reticuloendothelial system. This model can explain the regulation of iron absorption under normal conditions and also the inappropriate absorption seen in pathological states such as hemochromatosis and thalassemia.
A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo
Publisher: Springer Science and Business Media LLC
Date: 12-02-2018
DOI: 10.1038/NBT.4071
Abstract: Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.
Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis
Publisher: American Physiological Society
Date: 11-2011
Abstract: The HFE protein plays a crucial role in the control of cellular iron homeostasis. Steatosis is commonly observed in HFE-related iron-overload disorders, and current evidence suggests a causal link between iron and steatosis. Here, we investigated the potential contribution of HFE mutations to hepatic lipid metabolism and its role in the pathogenesis of nonalcoholic fatty liver disease. Wild-type (WT) and Hfe knockout mice ( Hfe −/− ) were fed either standard chow, a monounsaturated low fat, or a high-fat, high-carbohydrate diet (HFD) and assessed for liver injury, body iron status, and markers of lipid metabolism. Despite hepatic iron concentrations and body weights similar to WT controls, Hfe −/− mice fed the HFD developed severe hypoxia-related steatohepatitis, Tnf-α activation, and mitochondrial respiratory complex and antioxidant dysfunction with early fibrogenesis. These features were associated with an upregulation in the expression of genes involved in intracellular lipid synthesis and trafficking, while transcripts for mitochondrial fatty acid β-oxidation and adiponectin signaling-related genes were significantly attenuated. In contrast, HFD-fed WT mice developed bland steatosis only, with no inflammation or fibrosis and no upregulation of lipogenesis-related genes. A HFD led to reduced hepatic iron in Hfe −/− mice compared with chow-fed mice, despite higher serum iron, decreased hepcidin expression, and increased duodenal ferroportin mRNA . In conclusion, our results demonstrate that Hfe −/− mice show defective hepatic-intestinal iron and lipid signaling, which predispose them toward diet-induced hepatic lipotoxicity, accompanied by an accelerated progression of injury to fibrosis.
In silico QTL mapping of basal liver iron levels in inbred mouse strains
Publisher: American Physiological Society
Date: 02-2011
DOI: 10.1152/PHYSIOLGENOMICS.00025.2010
Abstract: Both iron deficiency and iron excess are detrimental in many organisms, and previous studies in both mice and humans suggest that genetic variation may influence iron status in mammals. However, these genetic factors are not well defined. To address this issue, we measured basal liver iron levels in 18 inbred strains of mice of both sexes on a defined iron diet and found ∼4-fold variation in liver iron in males (lowest 153 μg/g, highest 661 μg/g) and ∼3-fold variation in females (lowest 222 μg/g, highest 658 μg/g). We carried out a genome-wide association mapping to identify haplotypes underlying differences in liver iron and three other related traits (copper and zinc liver levels, and plasma diferric transferrin levels) in a subset of 14 inbred strains for which genotype information was available. We identified two putative quantitative trait loci (QTL) that contain genes with a known role in iron metabolism: Eif2ak1 and Igf2r. We also identified four putative QTL that reside in previously identified iron-related QTL and 22 novel putative QTL. The most promising putative QTL include a 0.22 Mb region on Chromosome 7 and a 0.32 Mb region on Chromosome 11 that both contain only one candidate gene, Adam12 and Gria1, respectively. Identified putative QTL are good candidates for further refinement and subsequent functional studies.
Specific tissue factor delivery using a tumor-homing peptide for inducing tumor infarction.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.BCP.2018.09.020
Abstract: Targeting the human blood coagulation-inducing protein tissue factor (TF) to the tumor vasculature to induce infarction and disrupt the blood vessels has proven to be an effective approach for tumor therapy. In this study, we investigated the thrombogenic activity and anti-tumor potential of a novel fusion protein (tTF-CREKA) comprising the extracellular domain of human tissue factor (truncated TF, tTF) and a tumor targeting pentapeptide, Cys-Arg-Glu-Lys-Ala (CREKA). tTF is soluble and inactive in its free state, but when it is targeted to the plasma membrane of both tumor vessel endothelial cells and stromal cells by the CREKA peptide, its native coagulation-inducing activity is restored. Systemic administration of the tTF-CREKA fusion protein into tumor-bearing mice induced tumor-selective intravascular thrombosis and reduced tumor blood perfusion, consequently inhibiting tumor growth. The development of tTF-CREKA introduces a new method for treating a wide spectrum of solid tumors by selectively blocking tumor blood supply.
Iron metabolism meets signal transduction.
Publisher: Springer Science and Business Media LLC
Date: 05-2006
DOI: 10.1038/NG0506-503
Nasal delivery of nanoliposome-encapsulated ferric ammonium citrate can increase the iron content of rat brain.
Publisher: Springer Science and Business Media LLC
Date: 02-06-2017
Liver-gut axis in the regulation of iron homeostasis
Publisher: Baishideng Publishing Group Inc.
Date: 2007
Abstract: The human body requires about 1-2 mg of iron per day for its normal functioning, and dietary iron is the only source for this essential metal. Since humans do not possess a mechanism for the active excretion of iron, the amount of iron in the body is determined by the amount absorbed across the proximal small intestine and, consequently, intestinal iron absorption is a highly regulated process. In recent years, the liver has emerged as a central regulator of both iron absorption and iron release from other tissues. It achieves this by secreting a peptide hormone called hepcidin that acts on the small intestinal epithelium and other cells to limit iron delivery to the plasma. Hepcidin itself is regulated in response to various systemic stimuli including variations in body iron stores, the rate of erythropoiesis, inflammation and hypoxia, the same stimuli that have been known for many years to modulate iron absorption. This review will summarize recent findings on the role played by the liver and hepcidin in the regulation of body iron absorption.
Recent advances in intestinal iron transport.
Publisher: Springer Science and Business Media LLC
Date: 09-2005
DOI: 10.1007/S11894-005-0005-1
Abstract: Our understanding of intestinal iron absorption and its regulation has expanded enormously in recent years. Dietary iron crosses the enterocyte brush border membrane through the transporter DMT1 after first being reduced by the ferric reductase Dcytb. The subsequent movement of iron across the basolateral membrane and into the circulation is mediated by ferroportin1 in conjunction with the iron oxidase hephaestin. The activity of ferroportin1 is controlled by the liver-derived peptide hepcidin, and the expression of hepcidin in turn is influenced by plasma transferrin saturation via a pathway that involves HFE, TfR2, and hemojuvelin. Future studies investigating how these molecules interact will provide a comprehensive understanding of this essential physiologic process.
Mammalian iron transport
Publisher: Springer Science and Business Media LLC
Date: 31-05-2009
DOI: 10.1007/S00018-009-0051-1
Abstract: Iron is essential for basic cellular processes but is toxic when present in excess. Consequently, iron transport into and out of cells is tightly regulated. Most iron is delivered to cells bound to plasma transferrin via a process that involves transferrin receptor 1, alent metal-ion transporter 1 and several other proteins. Non-transferrin-bound iron can also be taken up efficiently by cells, although the mechanism is poorly understood. Cells can est themselves of iron via the iron export protein ferroportin in conjunction with an iron oxidase. The linking of an oxidoreductase to a membrane permease is a common theme in membrane iron transport. At the systemic level, iron transport is regulated by the liver-derived peptide hepcidin which acts on ferroportin to control iron release to the plasma.
A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient
Publisher: BMJ
Date: 08-2003
Abstract: A severe form of iron overload with the clinicopathological features of haemochromatosis inherited in an autosomal dominant manner has been described in the Solomon Islands. The genetic basis of the disorder has not been identified. The disorder has similarities to type 4 haemochromatosis, which is caused by mutations in ferroportin1. The aims of this study were to identify the genetic basis of iron overload in a patient from the Solomon Islands. Genomic DNA was isolated from peripheral blood leucocytes of a Solomon Islands man with severe iron overload. The entire coding region and splice sites of the ferroportin1 gene was sequenced. A novel missense mutation (431A>C N144T) was identified in exon 5 of the ferroportin1 gene. A novel restriction endonuclease based assay which identifies both the N144T and N144H mutations was developed which will simplify the diagnosis and screening of patients for iron overload in the Solomon Islands and other populations. This is the first identified mutation associated with haemochromatosis in the Solomon Islands population.
Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1038/LABINVEST.2013.121
Abstract: Endoplasmic reticulum (ER) stress is an important pathogenic mechanism for alcoholic (ALD) and nonalcoholic fatty liver disease (NAFLD). Iron overload is an important cofactor for liver injury in ALD and NAFLD, but its role in ER stress and associated stress signaling pathways is unclear. To investigate this, we developed a murine model of combined liver injury by co-feeding the mildly iron overloaded, the hemochromatosis gene-null (Hfe(-/)) mouse ad libitum with ethanol and a high-fat diet (HFD) for 8 weeks. This co-feeding led to profound steatohepatitis, significant fibrosis, and increased apoptosis in the Hfe(-/-) mice as compared with wild-type (WT) controls. Iron overload also led to induction of unfolded protein response (XBP1 splicing, activation of IRE-1α and PERK, as well as sequestration of GRP78) and ER stress (increased CHOP protein expression) following HFD and ethanol. This is associated with a muted autophagic response including reduced LC3-I expression and impaired conjugation to LC3-II, reduced beclin-1 protein, and failure of induction of autophagy-related proteins (Atg) 3, 5, 7, and 12. As a result of the impaired autophagy, levels of the sequestosome protein p62 were most elevated in the Hfe(-/-) group co-fed ethanol and HFD. Iron overload reduces the activation of adenosine monophosphate protein kinase associated with ethanol and HFD feeding. We conclude that iron toxicity may modulate hepatic stress signaling pathways by impairing adaptive cellular compensatory mechanisms in alcohol- and obesity-induced liver injury.
Intestinal iron absorption during suckling in mammals
Publisher: Springer Science and Business Media LLC
Date: 26-02-2011
DOI: 10.1007/S10534-011-9429-2
Abstract: The maintenance of appropriate iron levels is important for mammalian health, particularly during the rapid growth period following birth. Too little iron can lead to irreversible damage to the developing central nervous system and too much iron at this point can have adverse long term consequences, possibly due to excessive free radical production. In order to maintain iron levels, intestinal iron absorption is very efficient in young mammals, such that almost all of the iron in breast milk is utilized. However this high level of absorption is unable to be down regulated in response to excess iron as it can be in adults, implying that different regulatory processes are involved during suckling. Various mechanisms have been proposed to explain this high absorption, including enhanced expression of the proteins involved in iron absorption in adults (particularly DMT1 and ferroportin), non-specific uptake via pinocytosis, and the uptake of lactoferrin bound iron by the lactoferrin receptor. However, at present the precise mechanism is unclear. It is possible that all of these components contribute to the high intestinal iron absorption seen during suckling, or a novel, as yet undescribed, mechanism could be involved. This review summarises the evidence for and against each of the mechanisms described above and highlights how little is known about iron homeostasis in this vital stage of development.
Targeted Co-delivery of the Iron Chelator Deferoxamine and a HIF1α Inhibitor Impairs Pancreatic Tumor Growth
Publisher: American Chemical Society (ACS)
Date: 28-01-2019
Abstract: Rapidly growing cancer cells exhibit a strong dependence on iron for their survival. Thus, iron-removing drugs, iron chelators, have potential applications in cancer treatment. Deferoxamine (DFO) is an efficient iron chelator, but its short circulation half-life and ability to induce hypoxia-inducible factor 1α (HIF1α) overexpression restricts its use as an antitumor agent. In the present study, we first found that a pattern of iron-related protein expression favoring higher intracellular iron closely correlates with shorter overall and relapse-free survival in pancreatic cancer patients. We subsequently found that a combination of DFO and the HIF1α inhibitor, lificiguat (also named YC1), significantly enhanced the antitumor efficacy of DFO in vitro. We then employed transferrin receptor 1 (TFR1) targeting liposomes to codeliver DFO and YC1 to pancreatic tumors in a mouse model. The encapsulation of DFO prolonged its circulation time, improved its accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect, and facilitated efficient uptake by cancer cells, which express high level of TFR1. After entering the tumor cells, the encapsulated DFO and YC1 were released to elicit a synergistic antitumor effect in subcutaneous and orthotopic pancreatic cancer xenografts. In summary, our work overcame two major obstacles in DFO-based cancer treatment through a simple liposome-based drug delivery system. This nanoencapsulation and targeting paradigm lays the foundation for future application of iron chelation in cancer therapy.
Mutations in the HFE gene can be associated with increased lung disease severity in cystic fibrosis
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.GENE.2018.10.002
Abstract: Genetic modifiers contribute to variable disease phenotype in cystic fibrosis (CF). We explored the association between mutations in the hemochromatosis (HFE) gene and disease severity in adults with CF. HFE genotyping was performed in 163 adults with CF attending a single centre. Results were correlated with lung disease severity, prevalence of CF-related diabetes (CFRD) and history of meconium ileus (MI) or distal intestinal obstruction syndrome (DIOS). Subjects with the C282Y substitution in the HFE protein (C282Y mutation) had a lower FEV In subjects with CF, the C282Y HFE substitution was associated with worse lung function, and increased rates of CFRD and gastrointestinal complications. The H63D HFE substitution also impacted on disease phenotype, but to a lesser extent. The results support a role for HFE gene mutations as modifiers of CF phenotype.
Genetics of Hemochromatosis
Publisher: Annual Reviews
Date: 02-1999
DOI: 10.1146/ANNUREV.MED.50.1.87
Abstract: Hereditary hemochromatosis (HHC) is a common autosomal recessive disorder of iron metabolism that results in progressive iron overload and can be fatal if untreated. The hemochromatosis gene (HFE) was identified by positional cloning in 1996. Two missense mutations have been described in HFE. The majority of HHC patients are homozygous for a cysteine-to-tyrosine substitution (C282Y) however, a small number are homozygous for a histidine-to-aspartic-acid substitution (H63D) or are heterozygous for both of these mutations. Mechanisms by which C282Y and H63D may disrupt the normal functioning of HFE have been suggested, but the role of HFE in the process of normal iron metabolism has yet to be clearly defined.
Non-transferrin-bound iron and cellular toxicity.
Publisher: Wiley
Date: 02-1999
Epidermal Growth Factor Receptor-Targeting Peptide Nanoparticles Simultaneously Deliver Gemcitabine and Olaparib To Treat Pancreatic Cancer with Breast Cancer 2 (BRCA2) Mutation
Publisher: American Chemical Society (ACS)
Date: 08-11-2018
Abstract: Pancreatic cancer (PCa) is one of the most lethal malignancies, with a 5 year survival rate of less than 8%. Current treatment regiments have a low response rate in unselected patients. However, the subgroup of PCa patients with BRCA mutations may benefit from poly-ADP-ribose polymerase inhibitors (PARPi) due to their biological properties in DNA repair. Dose-limiting toxicity in normal tissues is frequently observed when PARPi are combined with other chemotherapies, and the co-delivery of two drugs to tumor sites at an adequate concentration is challenging. To address this issue, we have engineered an epidermal growth factor receptor (EGFR) targeting (with GE11 peptide) self-assembly hiphilic peptide nanoparticle (GENP) to co-deliver gemcitabine and the PARPi olaparib to treat BRCA mutant PCa. The GENP was relatively stable, exhibited high encapsulation efficiency, and could coordinately release the two drugs in tumor milieu. Gemcitabine and olaparib showed strong synergistic actions in optimized conditions in vitro. The nanoparticle prolonged the half-life of both drugs and resulted in their tumor accumulation at the optimal therapeutic ratio in vivo. The drug-loaded nanoparticles were able to significantly suppress tumor growth in a murine PCa model with minimal side effects. Drug co-delivery of DNA damaging agents and PARP inhibitors via the GENP represents a promising approach for treatment of pancreatic cancers with molecular defects in the DNA repair pathway.
Ferroportin Is Essential for Iron Absorption During Suckling, But Is Hyporesponsive to the Regulatory Hormone Hepcidin
Publisher: Elsevier BV
Date: 05-2017
Haemochromatosis and control of intestinal iron absorption.
Publisher: Elsevier BV
Date: 06-1999
Impaired Iron Transport Activity of Ferroportin 1 in Hereditary Iron Overload
Publisher: Springer Science and Business Media LLC
Date: 07-2005
DOI: 10.1007/S00232-005-0768-1
Abstract: To investigate the functional significance of mutations in Ferroportin that cause hereditary iron overload, we directly measured the iron efflux activity of the proteins expressed in Xenopus oocytes. We found that wild type and mutant Ferroportin molecules (A77D, N144H, Q248H and V162Delta) were all expressed at the plasma membrane at similar levels. All mutations caused significant reductions in (59)Fe efflux compared to wild type but all retained some residual transport activity. A77D had the strongest effect on (59)Fe efflux (remaining activity 9% of wild-type control), whereas the N144H mutation retained the highest efflux activity (42% of control). The Q248H and V162Delta mutations were intermediate between these values. Co-injection of mutant and wild-type mRNAs revealed that the A77D and N144H mutations had a dominant negative effect on the function of the WT protein.
Current understanding of iron homeostasis.
Publisher: Elsevier BV
Date: 12-2017
Modularly Designed Peptide Nanoprodrug Augments Antitumor Immunity of PD-L1 Checkpoint Blockade by Targeting Indoleamine 2,3-Dioxygenase
Publisher: American Chemical Society (ACS)
Date: 16-01-2020
DOI: 10.1021/JACS.9B12232
Abstract: The limited efficacy of single-agent immune checkpoint inhibitors in treating tumors has prompted investigations on their combination partners. Here, a tumor-homing indoleamine 2,3-dioxygenase (IDO) nanoinhibitor is reported to selectively inhibit immunosuppressive IDO pathway in the tumor microenvironment. It is self-assembled from a modularly designed peptide-drug conjugate containing a hydrophilic targeting motif (arginyl-glycyl-aspartic acid RGD), two protonatable histidines, and an ester bond-linked hydrophobic IDO inhibitor, which exhibits pH-responsive disassembly and esterase-catalyzed drug release. Markedly, it achieved potent and persistent inhibition of intratumoral IDO activity with a reduced systemic toxicity, which greatly enhanced the therapeutic efficacy of programmed cell death-ligand 1 blockade
Mechanisms of iron loading and toxicity.
Publisher: Wiley
Date: 12-2007
DOI: 10.1002/AJH.21075
Abstract: Normal iron homeostasis is a finely balanced system that reflects iron absorption, loss and utilization. The body has no mechanism for the active excretion of iron, so body iron levels are controlled at the point of absorption in the small intestine. Disturbances in this equilibrium, such as those leading to enhanced absorption, can have significant clinical consequences. Continued excessive iron uptake is followed by iron deposition in various tissues, ultimately leading to tissue damage, and possibly end-organ failure. In this review, current concepts in normal iron homeostasis, and iron loading are explained. The clinical consequences as well as the differences between primary and secondary iron loading are also reviewed, and some future research priorities are discussed.
Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses
Publisher: American Society of Hematology
Date: 18-08-2011
DOI: 10.1182/BLOOD-2011-01-330324
Abstract: Systemic iron requirements are met predominantly through the recycling of iron from senescent erythrocytes by macrophages, a process in which the iron exporter ferroportin (Fpn1) is considered to be essential. Yet the role of Fpn1 in macrophage iron recycling and whether it influences innate immune responses are poorly understood in vivo. We inactivated Fpn1 in macrophages by crossing Fpn1-floxed animals with macrophage-targeted LysM-Cre or F4/80-Cre transgenic mice. Macrophage Fpn1 deletion mice were overtly normal however, they displayed a mild anemia and iron accumulation in splenic, hepatic, and bone marrow macrophages when fed a standard diet. Iron loading was exacerbated after the administration of iron dextran or phenylhydrazine. When Fpn1LysM/LysM mice were challenged with an iron-deficient diet, they developed a more severe anemia and strikingly higher splenic iron levels than control mice, indicating significantly impaired iron mobilization from macrophages. Because immune responses can be altered by modulating iron status, we also examined the expression of proinflammatory cytokines. We found that expression levels of TNF-α and IL-6 were significantly enhanced in Fpn1LysM/LysM macrophages lacking Fpn1. These studies demonstrate that Fpn1 plays important roles in macrophage iron release in vivo and in modulating innate immune responses.
Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2016
DOI: 10.1002/HEP.28479
The role of duodenal cytochrome b in intestinal iron absorption remains unclear
Publisher: American Society of Hematology
Date: 15-12-2005
Mapping the gene for sex-linked anemia: an inherited defect of intestinal iron absorption in the mouse.
Publisher: Elsevier BV
Date: 02-1998
Abstract: The sex-linked anemic (sla) mouse carries an anemia that results from an inherited defect of intestinal iron absorption and provides an ideal model with which to investigate this poorly understood yet clinically important process. We have precisely mapped the sla locus within the central region of the X chromosome in relation to a panel of microsatellite markers. Analysis of over 500 progeny from an intraspecific intercross and a smaller intraspecific backcross segregating sla established the following locus order in the sla region: DXMit45-sla- (DXMit16, DXMit96)-DXMit41-DXMit169-DXMit170- DXMit148-(DXMit18, DXMit171)-DXMit84-DXMit64. The two microsatellites DXMit16 and DXMit96 are located 0.60 +/- 0.35cM from sla and form the telomeric limit of the sla region. The mapping of the sla locus is an important first step to identifying the gene itself.
Molecular basis of iron-loading disorders
Publisher: Cambridge University Press (CUP)
Date: 11-2010
DOI: 10.1017/S1462399410001687
Abstract: Iron-loading disorders (haemochromatosis) represent an important class of human diseases. Primary iron loading results from inherited disturbances in the mechanisms regulating intestinal iron absorption, such that excess iron is taken up from the diet. Body iron load can also be increased by repeated blood transfusions (secondary iron loading), usually as part of the treatment for various haematological disorders. In these syndromes, an element of enhanced iron absorption is also often involved. The central regulator of body iron trafficking is the liver-derived peptide hepcidin. Hepcidin limits iron entry into the plasma from macrophages, intestinal enterocytes and other cells by binding to the sole iron-export protein ferroportin, and facilitating its removal from the plasma membrane. Mutations in hepcidin or its upstream regulators (HFE, TFR2, HFE2 and BMP6) lead to reduced or absent hepcidin expression and a concomitant increase in iron absorption. Mutations in ferroportin that prevent hepcidin binding produce a similar result. Increased ineffective erythropoiesis, which often characterises erythrocyte disorders, also leads to reduced hepcidin expression and increased absorption. Recent advances in our understanding of hepcidin and body iron homeostasis provide the potential for a range of new diagnostic and therapeutic tools for haemochromatosis and related conditions.
Of metals, mice, and men: what animal models can teach us about body iron loading.
Publisher: American Society for Clinical Investigation
Date: 05-2000
DOI: 10.1172/JCI9972
Functional Analysis of GLRX5 Mutants Reveals Distinct Functionalities of GLRX5 Protein
Publisher: Wiley
Date: 19-11-2015
DOI: 10.1002/JCB.25267
Abstract: Glutaredoxin 5 (GLRX5) is a 156 amino acid mitochondrial protein that plays an essential role in mitochondrial iron-sulfur cluster transfer. Mutations in this protein were reported to result in sideroblastic anemia and variant nonketotic hyperglycinemia in human. Recently, we have characterized a Chinese congenital sideroblastic anemia patient who has two compound heterozygous missense mutations (c. 301 A>C and c. 443 T>C) in his GLRX5 gene. Herein, we developed a GLRX5 knockout K562 cell line and studied the biochemical functions of the identified pathogenic mutations and other conserved amino acids with predicted essential functions. We observed that the K101Q mutation (due to c. 301 A>C mutation) may prevent the binding of [Fe-S] to GLRX5 protein, while L148S (due to c. 443 T>C mutation) may interfere with [Fe-S] transfer from GLRX5 to iron regulatory protein 1 (IRP1), mitochondrial aconitase (m-aconitase) and ferrochelatase. We also demonstrated that L148S is functionally complementary to the K51del mutant with respect to Fe/S-ferrochelatase, Fe/S-IRP1, Fe/S-succinate dehydrogenase, and Fe/S-m-aconitase biosynthesis and lipoylation of pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex. Furthermore, we demonstrated that the mutations of highly conserved amino acid residues in GLRX5 protein can have different effects on downstream Fe/S proteins. Collectively, our current work demonstrates that GLRX5 protein is multifunctional in [Fe-S] protein synthesis and maturation and defects of the different amino acids of the protein will lead to distinct effects on downstream Fe/S biosynthesis.
Small-molecule dissection of BMP signaling
Publisher: Springer Science and Business Media LLC
Date: 2008
Inhibition of platelet function using liposomal nanoparticles blocks tumor metastasis.
Publisher: Ivyspring International Publisher
Date: 2017
DOI: 10.7150/THNO.17908
Elevated iron absorption in the neonatal rat reflects high expression of iron transport genes in the distal alimentary tract.
Publisher: American Physiological Society
Date: 09-2007
Abstract: Intestinal iron absorption is extremely high in neonatal mammals but falls rapidly to adult levels following weaning. The aim of this study was to investigate the molecular basis of this elevated neonatal absorption using the rat as an experimental model. RNA was extracted from various sections of the intestine of 10-, 15-, 20-, 25-, and 300-day-old rats and the expression of the genes encoding DMT1 ( Slc11a2), ferroportin ( Slc40a1), Cybrd1 ( Cybrd1), and hephaestin ( heph) determined by ribonuclease protection assay. The hepatic expression of H was studied at the same ages. Iron absorption was examined by following 59 Fe uptake in both whole animals and in isolated intestinal loops. Slc11a2, Slc40a1, and Cybrd1 mRNAs were highly expressed in all regions of the small intestine and colon studied in suckling rats. However, after weaning, when iron absorption declined significantly, strong expression was retained only in the duodenum. No change in hephaestin mRNA occurred in any part of the digestive tract. In the distal small intestine and colon, Slc40a1 expression most closely followed the change in absorption that occurred after weaning. H expression was low during the neonatal period and increased to adult levels following weaning. Our results suggest that the distal small intestine and colon contribute significantly to the high intestinal iron absorption seen in neonatal animals and that this reflects increased expression of the iron transporters, particularly Slc40a1.
Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease.
Publisher: Wiley
Date: 2006
DOI: 10.1111/J.1530-0277.2006.00002.X
Abstract: Alcoholic liver disease is known to be associated with abnormal iron homeostasis, and iron metabolism itself is regulated by the liver-derived peptide hepcidin. Both CCAAT enhancer binding protein alpha (C/EBPalpha) and interleukin 6 (IL-6) have been shown to regulate hepcidin gene transcription. To investigate mechanisms underlying alcohol-induced disturbances in iron homeostasis by measuring the expression of hepcidin and C/EBPalpha mRNA using in vivo and in vitro models of alcoholic liver injury. Male rats were pair-fed an alcoholic liquid diet for 12 weeks. RT-PCR was performed on liver tissue using specific primers for hepcidin and C/EBPalpha. The effect of alcohol on hepcidin and C/EBPalpha gene expression was also determined in isolated hepatocytes, HuH-7 cells and HepG2 cells treated with 50 mM ethanol, 200 microM acetaldehyde, and/or 20 ng/ml IL-6. Hepcidin and C/EBPalpha mRNA expression were significantly decreased in alcohol-fed rats compared with pair-fed controls (6-fold p < 0.001 and 2.2-fold p < 0.0002 reduction, respectively) and hepatic lipid peroxidation was increased by 32.5% (p < 0.05) in alcohol-fed rats compared with controls. Hepcidin gene expression was not altered significantly in cells cultured in the presence of 50 mM ethanol. Following 24 hour stimulation by IL-6, there was a 4-fold increase in hepcidin expression in hepatocytes and a 9-fold increase in HuH-7 cells. Ethanol (50 mM) attenuated the IL-6-induced increase in hepcidin expression in HuH-7 cells (9-fold to a 4-fold increase) but not in hepatocytes. Acetaldehyde had no effect on hepcidin gene expression in cells in culture. The down-regulation of hepcidin and C/EBPalpha gene expression shown in vivo implies disturbed iron sensing contributing to the hepatosiderosis seen in alcoholic liver disease, possibly by mechanisms involving the IL-6 signaling cascade.
Mislocalisation of hephaestin, a multicopper ferroxidase involved in basolateral intestinal iron transport, in the sex linked anaemia mouse
Publisher: BMJ
Date: 02-2004
Abstract: Hephaestin is a multicopper ferroxidase required for basolateral transport of iron from enterocytes. Sex linked anaemia (sla) mice have a defect in the release of iron from intestinal enterocytes into the circulation due to an interstitial deletion in the hephaestin gene (heph). We have demonstrated that hephaestin is primarily localised to a supranuclear compartment in both intestinal enterocytes and in cultured cells. In normal intestinal enterocytes, hephaestin was also present on the basolateral surface. In sla mice, hephaestin was present only in the supranuclear compartment. In contrast, the iron permease Ireg1 localised to the basolateral membrane in both control and sla mice. We suggest that mislocalisation of hephaestin likely contributes to the functional defect in sla intestinal epithelium.
Interacting signals in the control of hepcidin expression
Publisher: Springer Science and Business Media LLC
Date: 08-01-2009
DOI: 10.1007/S10534-008-9187-Y
Abstract: The amount of iron in the plasma is determined by the regulated release of iron from most body cells, but macrophages, intestinal enterocytes and hepatocytes play a particularly important role in this process. This cellular iron efflux is modulated by the liver-derived peptide hepcidin, and this peptide is now regarded as the central regulator of body iron homeostasis. Hepcidin expression is influenced by systemic stimuli such as iron stores, the rate of erythropoiesis, inflammation, hypoxia and oxidative stress. These stimuli control hepcidin levels by acting through hepatocyte cell surface proteins including HFE, transferrin receptor 2, hemojuvelin, TMPRSS6 and the IL-6R. The surface proteins activate various cell signal transduction pathways, including the BMP-SMAD, JAK-STAT and HIF1 pathways, to alter transcription of HAMP, the gene which encodes hepcidin. It is becoming increasingly apparent that various stimuli can signal through multiple pathways to regulate hepcidin expression, and the interplay between positive and negative stimuli is critical in determining the net hepcidin level. The BMP-SMAD pathway appears to be particularly important and disruption of this pathway will abrogate the response of hepcidin to many stimuli.
Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.BBAMCR.2016.01.026
Abstract: Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics.
Reduced mortality due to phlebotomy in moderately iron-loaded HFE haemochromatosis? The need for clinical trials
Publisher: Elsevier BV
Date: 07-2015
Iron imports. I. Intestinal iron absorption and its regulation.
Publisher: American Physiological Society
Date: 10-2005
Abstract: Our knowledge of how the body absorbs iron from the diet and how this process is controlled has increased at a rapid rate in recent years. The identification of key molecules, including the iron regulatory peptide hepcidin, and the analysis of how they are regulated and interact have led to the development of an integrated model for the control of iron absorption by body iron requirements. Research now focuses on the role of the liver as the primary regulator of iron absorption, and this review considers some of the recent highlights and controversies in this area.
Transferrin receptor distribution and regulation in the rat small intestine. Effect of iron stores and erythropoiesis.
Publisher: Elsevier BV
Date: 03-1990
DOI: 10.1016/0016-5085(90)90276-7
Abstract: A combination of biochemical quantitation and immunohistochemistry has been used to examine in detail transferrin receptor distribution and expression in the rat small intestine and its relationship to iron absorption. Receptor numbers were quantitated by transferrin binding to preparations of basolateral or brush-border membranes. Receptors were demonstrated on the basolateral membranes of the gut cells, but not on the brush-border fraction. Apotransferrin demonstrated little binding to basolateral membranes at physiological pH. Dietary or parenteral iron loading of animals produced a significant decline in transferrin binding, whereas binding was increased in iron deficiency. These data were confirmed by immunohistochemical studies using a monoclonal antibody to the transferrin receptor. When iron absorption was increased threefold following acute hemolysis and without a decrease in body iron stores, there was no change in transferrin receptor number. These data indicate that intestinal transferrin receptors may be regulated by body iron stores but suggest that they are not directly involved in iron absorption.
Injectable Hexapeptide Hydrogel for Localized Chemotherapy Prevents Breast Cancer Recurrence
Publisher: American Chemical Society (ACS)
Date: 19-02-2018
Abstract: Although postsurgical chemotherapy is frequently used for the treatment of breast cancer, tumor recurrence is still a frequent event. Enhancing the efficacy of chemotherapy via localized drug delivery may help to prevent breast cancer recurrence. To achieve this goal, we designed a hydrogel nanocarrier that could be injected at the tumor site by coassembly of tailor-made hexapeptide and doxorubicin. Evidently, on the basis of our findings, the sustained release of drug from the hydrogel led to a reduction in cancer recurrence, including the suppression of primary regrowth and distant metastasis. This localized chemotherapy strategy did not show any obvious side effects in vivo and represents a promising adjuvant therapeutic strategy for breast cancer recurrence.
Systemic regulation of intestinal iron absorption.
Publisher: Wiley
Date: 07-2005
DOI: 10.1080/15216540500149904
Abstract: The intestinal absorption of the essential trace element iron and its mobilization from storage sites in the body are controlled by systemic signals that reflect tissue iron requirements. Recent advances have indicated that the liver-derived peptide hepcidin plays a central role in this process by repressing iron release from intestinal enterocytes, macrophages and other body cells. When iron requirements are increased, hepcidin levels decline and more iron enters the plasma. It has been proposed that the level of circulating diferric transferrin, which reflects tissue iron levels, acts as a signal to alter hepcidin expression. In the liver, the proteins HFE, transferrin receptor 2 and hemojuvelin may be involved in mediating this signal as disruption of each of these molecules decreases hepcidin expression. Patients carrying mutations in these molecules or in hepcidin itself develop systemic iron loading (or hemochromatosis) due to their inability to down regulate iron absorption. Hepcidin is also responsible for the decreased plasma iron or hypoferremia that accompanies inflammation and various chronic diseases as its expression is stimulated by pro-inflammatory cytokines such as interleukin 6. The mechanisms underlying the regulation of hepcidin expression and how it acts on cells to control iron release are key areas of ongoing research.
Age-dependent expression of hephaestin in the brain of ceruloplasmin-deficient mice.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.JTEMB.2009.05.004
Abstract: Aceruloplasminemia is an autosomal recessive disorder caused by mutations in the ceruloplasmin (CP) gene. It is characterized by iron accumulation in the brain and in visceral organs. However, little is known about the mechanism of iron transport in these regions. Adult CP null (CP(-/-)) mice show increased iron deposition in several regions of brain, such as the cerebellum and brainstem. In this study, we investigated the expression of the ceruloplasmin homolog hephaestin (Heph) in the brain of CP(-/-) mice as a function of age. In the cerebral cortex and caudate putamen of 80-week-old CP(-/-) mice, the expression of Heph increased significantly whilst iron levels remain normal [Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, David S. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J Neurosci 2002 (15):6578-6], indicating that Heph might compensate for the loss of CP. In contrast, the substantia nigra and cerebellum of 80-week-old CP(-/-) mice accumulate iron but do not express high levels or significant decrease of Heph, suggesting that Heph does not replace CP in these regions. These data suggest that Heph may compensate for the loss of CP in a region-specific manner.
Stimulated erythropoiesis with secondary iron loading leads to a decrease in hepcidin despite an increase in bone morphogenetic protein 6 expression
Publisher: Wiley
Date: 26-03-2012
DOI: 10.1111/J.1365-2141.2012.09104.X
Abstract: The BMP/SMAD signalling pathway plays an important role in iron homeostasis, regulating hepcidin expression in response to body iron levels. However, the role of this pathway in the reduction in hepcidin associated with increased erythropoiesis (and secondary iron loading) is unclear. To investigate this, we established a mouse model of chronic stimulated erythropoiesis with secondary iron loading using the haemolytic agent phenylhydrazine. We then examined the expression of components of the BMP6/SMAD signalling pathway in these animals. We also examined this pathway in the Hbb(th3/+) mouse, a model of the iron loading anaemia β-thalassaemia intermedia. Increasing doses of phenylhydrazine led to a progressive increase in both liver iron levels and Bmp6 mRNA expression, but, in contrast, hepatic H expression declined. The increase in Bmp6 expression was not associated with a corresponding change in the phosphorylation of hepatic SMAD1/5/8, indicating that stimulated erythropoiesis decreases the ability of BMP6 to alter SMAD phosphorylation. Increased erythropoiesis also reduces the capacity of phosphorylated SMAD (pSMAD) to induce hepcidin, as H levels declined despite no changes in pSMAD1/5/8. Similar results were seen in Hbb(th3/+) mice. Thus the erythroid signal probably affects some components of BMP/SMAD signalling, but also may exert some independent effects.
Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-07-2021
DOI: 10.1126/SCITRANSLMED.ABC2816
Abstract: A nanovaccine based on bacterial cytoplasmic membranes and cell membranes from resected tumor tissue prevents tumor recurrence in mice.
Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours
Publisher: Springer Science and Business Media LLC
Date: 24-07-2017
DOI: 10.1038/S41551-017-0115-8
Abstract: Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer-lipid-peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid-peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.
Iron supplementation has minor effects on gut microbiota composition in overweight and obese women in early pregnancy
Publisher: Cambridge University Press (CUP)
Date: 23-05-2018
DOI: 10.1017/S0007114518001149
Abstract: Fe is an essential nutrient for many bacteria, and Fe supplementation has been reported to affect the composition of the gut microbiota in both Fe-deficient and Fe-replete in iduals outside pregnancy. This study examined whether the dose of Fe in pregnancy multivitamin supplements affects the overall composition of the gut microbiota in overweight and obese pregnant women in early pregnancy. Women participating in the SPRING study with a faecal s le obtained at 16 weeks’ gestation were included in this substudy. For each subject, the brand of multivitamin used was recorded. Faecal microbiome composition was assessed by 16S rRNA sequencing and analysed with the QIIME software suite. Dietary intake of Fe was assessed using a FFQ at 16 weeks’ gestation. Women were grouped as receiving low ( mg/d, n 94) or high (≥60 mg/d n 65) Fe supplementation. The median supplementary Fe intake in the low group was 10 (interquartile range (IQR) 5–10) v . 60 (IQR 60–60) mg/d in the high group ( P ·001). Dietary Fe intake did not differ between the groups (10·0 (IQR 7·4–13·3) v . 9·8 (IQR 8·2–13·2) mg/d). Fe supplementation did not significantly affect the composition of the faecal microbiome at any taxonomic level. Network analysis showed that the gut microbiota in the low Fe supplementation group had a higher predominance of SCFA producers. Pregnancy multivitamin Fe content has a minor effect on the overall composition of the gut microbiota of overweight and obese pregnant women at 16 weeks’ gestation.
Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-03-2015
DOI: 10.1002/HEP.27711
Abstract: To identify polymorphisms associated with variability of iron overload severity in HFE ‐associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22 cases) or with normal or mildly increased iron stores (n = 13 controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single‐nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload ( P = 3 × 10 −6 P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty‐two participants with severe iron overload had glyceronephosphate O‐acyltransferase ( GNPAT ) polymorphism p.D519G (rs11558492 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA–based knockdown of GNPAT in the human liver‐derived cell line, HepG2/C3A. This knockdown resulted in a ‐fold decrease in expression of the messenger RNA encoding the iron‐regulatory hormone, hepcidin. Conclusion: GNPAT p.D519G is associated with a high‐iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation. (H epatology 2015 :429–439
A comparison of self‐reported and record‐linked blood donation history in an Australian cohort
Publisher: Wiley
Date: 19-04-2011
DOI: 10.1111/J.1537-2995.2011.03141.X
Abstract: Questionnaire-based studies investigating blood donation history rely on the accurate recall of information from participants for results to be valid. This study aimed to retrieve electronic records from a national blood donation service and link them to self-reported history of donation to assess agreement between the two sources. Between 2004 and 2006, a s le of participants of northern European descent was selected from the Melbourne Collaborative Cohort Study (n = 31,192) to participate in the "HealthIron" study (n = 1438). A total of 1052 participants completed questionnaires that included questions about blood donation history. In 2009, consenting participants' records were linked to the Australian Red Cross Blood Service (ARCBS) to provide information on blood donations made between 1980 and follow-up (2004-2006). Those who commenced blood donation before 1980 were excluded. A total of 718 participants were available for analysis. Of these, 394 (55%) provided signed consent, including 182 (82%) of the 227 participants who self-reported ever donating blood. The two data sources were concordant for 331 (87%) of participants, with a κ statistic of 0.74 (SE, 0.05) indicating a high level of agreement. Participants tended to overstate by a factor of 2.0 (95% confidence interval, 1.7-2.2) the number of donations they had made when compared with ARCBS records. Participants in studies assessing self-reported blood donation history are likely to correctly indicate whether or not they have ever donated blood. Quantitative estimates are potentially inaccurate and could benefit from validating a s le of records to quantify the bias.
Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population
Publisher: Elsevier BV
Date: 03-2012
Abstract: Transmembrane protease serine 6 (TMPRSS6) regulates iron homeostasis by inhibiting the expression of hepcidin. Multiple common variants in TMPRSS6 were significantly associated with serum iron in recent genome-wide association studies, but their effects in the Chinese remain to be elucidated. The objective was to determine whether the TMPRSS6 single nucleotide polymorphisms (SNPs) rs855791(V736A) and rs4820268(D521D) were associated with blood hemoglobin and plasma ferritin concentrations and risk of type 2 diabetes in Chinese in iduals. The SNPs rs855791(V736A) and rs4820268(D521D) in the TMPRSS6 gene were genotyped and tested for their associations with plasma iron and type 2 diabetes risk in 1574 unrelated Chinese Hans from Beijing. The 2 TMPRSS6 SNPs rs855791(V736A) and rs4820268(D521D) were both significantly associated with plasma ferritin (P ≤ 0.0058), hemoglobin (P ≤ 0.0013), iron overload risk (P ≤ 0.0068), and type 2 diabetes risk (P ≤ 0.0314). None of the associations with hemoglobin or plasma ferritin remained significant (P ≥ 0.1229) when the 2 variants were both included in one linear regression model. A haplotype carrying both iron-lowering alleles from the 2 TMPRSS SNPs showed significant associations with lower hemoglobin (P = 0.0014), lower plasma ferritin (P = 0.0027), and a reduced risk of iron overload (P = 0.0017) and of type 2 diabetes (P = 0.0277). These findings suggest that TMPRSS6 variants were significantly associated with plasma ferritin, hemoglobin, risk of iron overload, and type 2 diabetes in Chinese Hans. The type 2 diabetes risk conferred by the TMPRSS6 SNPs is possibly mediated by plasma ferritin.
Reduced Expression of Ferroportin-1 Mediates Hyporesponsiveness of Suckling Rats to Stimuli That Reduce Iron Absorption
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1053/J.GASTRO.2011.04.012
Abstract: Suckling mammals absorb high levels of iron to support their rapid growth. In adults, iron absorption is controlled by systemic signals that alter expression of the iron-regulatory hormone hepcidin. We investigated whether hepcidin and absorption respond appropriately to systemic stimuli during suckling. In Sprague-Dawley rats, iron levels increased following administration of iron dextran, and inflammation was induced with lipopolysaccharide. Gene expression was measured by quantitative reverse-transcription polymerase chain reaction protein levels were measured by immunoblot analyses. Iron absorption was determined based on retention of an oral dose of 59Fe. Iron absorption was high during suckling and reduced to adult levels upon weaning. In response to iron dextran or lipopolysaccharide, iron absorption in adults decreased substantially, but, in suckling animals, the changes were minimal. Despite this, expression of hepcidin messenger RNA was strongly induced by each agent, before and after weaning. The hyporesponsiveness of iron absorption to increased levels of hepcidin during suckling correlated with reduced or absent duodenal expression of ferroportin 1 (Fpn1), normally a hepcidin target. Fpn1 expression was robust in adults. Predominance of the Fpn1A splice variant, which is under iron-dependent translational control, accounts for the low level of Fpn1 in the iron-deficient intestine of suckling rats. Iron absorption during suckling is largely refractory to changes in expression of the systemic iron regulator hepcidin, and this in turn reflects limited expression of Fpn1 protein in the small intestine. Iron absorption is therefore not always controlled by hepcidin.
Pyocyanin-induced toxicity in A549 respiratory cells is causally linked to oxidative stress
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.TIV.2011.05.004
Abstract: Pyocyanin, a virulence factor produced by Pseudomonas aeruginosa, has many damaging effects on mammalian cells. Several lines of evidence suggest that this damage is primarily mediated by its ability to generate ROS and deplete host antioxidant defence mechanisms. However, a causal role for oxidative stress has not yet been demonstrated conclusively. Parallel measures of ROS production, antioxidant levels and cytotoxicity provide convincing evidence that pyocyanin-induced cytotoxicity in A549 respiratory cells is mediated by acute ROS production and subsequent oxidative stress. Pyocyanin increased ROS levels in A549 cells as measured by the fluorescent H(2)O(2) probes Amplex Red and DCFH-DA. These effects were attenuated by the antioxidant N-acetylcysteine. Furthermore, pyocyanin-induced depletion of intracellular GSH levels 24h after exposure was also prevented by pre-treatment of cells with NAC. Under these conditions, NAC protected cells against pyocyanin-induced cytotoxicity as measured by resazurin reduction to resorufin and viable cell counts, strongly supporting a causal role for oxidative stress. Finally, we also show that pyocyanin-induced activation of the immune and inflammatory transcription factor NF-κB in A549 cells is likely mediated by increased ROS. This increased understanding of mechanisms underlying pyocyanin-induced cytotoxicity may ultimately lead to better strategies for reducing the virulence associated with chronic P. aeruginosa infection.
Postnatal growth restriction and gene expression changes in a mouse model of fetal alcohol syndrome.
Publisher: Wiley
Date: 28-09-2010
DOI: 10.1002/BDRA.20729
Abstract: Growth restriction, craniofacial dysmorphology, and central nervous system defects are the main diagnostic features of fetal alcohol syndrome. Studies in humans and mice have reported that the growth restriction can be prenatal or postnatal, but the underlying mechanisms remain unknown.We recently described a mouse model of moderate gestational ethanol exposure that produces measurable phenotypes in line with fetal alcohol syndrome (e.g., craniofacial changes and growth restriction in adolescent mice). In this study, we characterize in detail the growth restriction phenotype by measuring body weight at gestational day 16.5, cross-fostering from birth to weaning, and by extending our observations into adulthood. Furthermore, in an attempt to unravel the molecular events contributing to the growth phenotype, we have compared gene expression patterns in the liver and kidney of nonfostered, ethanol-exposed and control mice at postnatal day 28.We find that the ethanol-induced growth phenotype is not detectable prior to birth, but is present at weaning, even in mice that have been cross-fostered to unexposed dams. This finding suggests a postnatal growth restriction phenotype that is not due to deficient postpartum care by dams that drank ethanol, but rather a physiologic result of ethanol exposure in utero. We also find that, despite some catch-up growth after 5 weeks of age, the effect extends into adulthood, which is consistent with longitudinal studies in humans.Genome-wide gene expression analysis revealed interesting ethanol-induced changes in the liver, including genes involved in the metabolism of exogenous and endogenous compounds, iron homeostasis, and lipid metabolism.
Intestinal iron absorption
Publisher: Elsevier BV
Date: 06-2201
DOI: 10.1016/J.JTEMB.2012.03.015
Abstract: Intestinal iron absorption is a critical process for maintaining body iron levels within the optimal physiological range. Iron in the diet is found in a wide variety of forms, but the absorption of non-heme iron is best understood. Most of this iron is moved across the enterocyte brush border membrane by the iron transporter alent metal-ion transporter 1, a process enhanced by the prior reduction of the iron by duodenal cytochrome B and possibly other reductases. Enterocyte iron is exported to the blood via ferroportin 1 on the basolateral membrane. This transporter acts in partnership with the ferroxidase hephaestin that oxidizes exported ferrous iron to facilitate its binding to plasma transferrin. Iron absorption is controlled by a complex network of systemic and local influences. The liver-derived peptide hepcidin binds to ferroportin, leading to its internalization and a reduction in absorption. Hepcidin expression in turn responds to body iron demands and the BMP-SMAD signaling pathway plays a key role in this process. The levels of iron and oxygen in the enterocyte also exert important influences on iron absorption. Disturbances in the regulation of iron absorption are responsible for both iron loading and iron deficiency disorders in humans.
Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes
Publisher: Elsevier BV
Date: 09-2018
Accurate assessment of systemic iron status in cystic fibrosis will avoid the hazards of inappropriate iron supplementation
Publisher: Elsevier BV
Date: 05-2013
Related Organisations
Related Funding Activities
No related grants have been discovered for Gregory Anderson.