Media for study of growth kinetics and envelope properties of iron-deprived bacteria.

Ion-exchange chromatography was used to remove iron from complex and chemically defined laboratory media. The kinetics of metal cation removal from the media was investigated by using atomic absorption spectrophotometry, and the results indicated that over 90% of the iron could be eliminated from certain complex media by this treatment. The treated medium was used for growth studies in a gram-positive and a number of gram-negative organisms that were isolated from infections in humans. High-molecular-weight outer membrane proteins that are known to be induced under iron-depleted growth conditions (iron-regulated membrane proteins) were observed when a number of gram-negative pathogens were cultivated in the treated media. Iron uptake by Staphylococcus aureus varied, depending on the iron content of the medium.     

Recent advance in the understanding of iron metabolism and its role on host defense]

Iron is an essential trace element for human beings, but at the same time, it is toxic for us to generate free radicals because of its high reactivity to molecular oxygen. Therefore, iron metabolism is tightly regulated. Recently, hepcidin, a peptide hormone secreted by hepatocytes in response to iron overload and inflammation, has been identified to be a predominant negative regulator of iron absorption in the duodenum and iron release from tissue macrophages. The discovery of hepcidin unexpectedly revealed the link between iron metabolism and host defense. Here we describe recent advance in our understanding on the regulation of iron metabolism, including our findings and discuss its relationship to various diseases.     

Intracellular iron transport and storage: from molecular mechanisms to health implications

Maintenance of proper "labile iron" levels is a critical component in preserving homeostasis. Iron is a vital element that is a constituent of a number of important macromolecules, including those involved in energy production, respiration, DNA synthesis, and metabolism; however, excess "labile iron" is potentially detrimental to the cell or organism or both because of its propensity to participate in oxidation-reduction reactions that generate harmful free radicals. Because of this dual nature, elaborate systems tightly control the concentration of available iron. Perturbation of normal physiologic iron concentrations may be both a cause and a consequence of cellular damage and disease states. This review highlights the molecular mechanisms responsible for regulation of iron absorption, transport, and storage through the roles of key regulatory proteins, including ferroportin, hepcidin, ferritin, and frataxin. In addition, we present an overview of the relation between iron regulation and oxidative stress and we discuss the role of functional iron overload in the pathogenesis of hemochromatosis, neurodegeneration, and inflammation.     

Carence en fer et troubles digestifs

Iron deficiency anemia still remains problematic worldwide. Iron deficiency without anemia is often undiagnosed. We reviewed, in this study, symptoms and syndromes associated with iron deficiency with or without anemia: fatigue, cognitive functions, restless legs syndrome, hair loss, and chronic heart failure. Iron is absorbed through the digestive tract. Hepcidin and ferroportin are the main proteins of iron regulation. Pathogenic micro-organisms or intestinal dysbiosis are suspected to influence iron absorption.     

Iron metabolism: State of the art

Iron homeostasis relies on the amount of its absorption by the intestine and its release from storage sites, the macrophages. Iron homeostasis is also dependent on the amount of iron used for the erythropoiesis. Hepcidin, which is synthesized predominantly by the liver, is the main regulator of iron metabolism. Hepcidin reduces serum iron by inhibiting the iron exporter, ferroportin expressed both tissues, the intestine and the macrophages. In addition, in the enterocytes, hepcidin inhibits the iron influx by acting on the apical transporter, DMT1. A defect of hepcidin expression leading to the appearance of a parenchymal iron overload may be genetic or secondary to dyserythropoiesis. The exploration of genetic hemochromatosis has revealed the involvement of several genes, including the recently described BMP6. Non-transfusional secondary hemochromatosis is due to hepcidin repression by cytokines, in particular the erythroferone factor that is produced directly by the erythroid precursors. Iron overload is correlated with the appearance of a free form of iron called NTBI. The influx of NTBI seems to be mediated by ZIP14 transporter in the liver and by calcium channels in the cardiomyocytes. Beside the liver, hepcidin is expressed at lesser extent in several extrahepatic tissues where it plays its ancestral role of antimicrobial peptide. In the kidney, hepcidin modulates defense barriers against urinary tract infections. In the heart, hepcidin maintains tissue iron homeostasis by an autocrine regulation of ferroprotine expression on the surface of cardiomyocytes. In conclusion, hepcidin remains a promising therapeutic tool in various iron pathologies.     

DMT1在小肠吸收细胞的摄铁机制

铁是生物体最丰富的微量金属元素之一,小肠是机体铁吸收和铁稳态调节最关键结构,小肠吸收细胞对非血红素铁的吸收摄取主要由二价金属离子转运体(divalent metal transporter1,DMT1)介导的。DMT1对铁的吸收转运主要通过囊泡运输和载体运输实现的。囊泡运输主要包括DMT1形成吸收铁的囊泡、与apo-Tf囊泡融合、分离、分选转运完成的;载体运输则是在肠表面H+电化学梯度的驱动下将铁转入细胞内的。本文着重介绍了最近国内外关于DMT1在小肠非血红素铁吸收转运中的作用机制的最新研究进展。     

Iron metabolism, overview and recent insights

The paper is an up to date overview of knowledge on iron metabolism that integrate recent findings in this field. Significant advances were made in understanding the implication of protein factors (transporters, enzymes and regulation factors) in iron metabolism, as well as related genetic abnormalities. The research highlighted the complexity of mechanisms in charge of maintaining equilibrium of Fe in the body. The iron is vital to the life of cells, but its presence in excess is rather toxic. Iron is mostly required for hemoglobin synthesis. It is recycled between reticulo-endothelial macrophages and bone marrow that is the main user of iron. Intestinal absorption is a key step in determining iron capital in the body. Its rate is tightly controlled by several factors that act under influence of signals of unknown nature, which indicate iron needs and storage. The IRP/IRE (iron regulatory protein/iron responsive element) system controls cellular uptake, stores and exportation of iron, and heme synthesis. Mitochondrion is a dynamo of iron metabolism, being vital for heme synthesis and iron sulphur cluster genesis. The recent discovery of several mitochondrial proteins involved in iron metabolism resulted in better understanding mitochondrial iron movement, storage and exchange. Nevertheless, much remains to be known on the role of some actors such as HFE protein, hepcidin, hemojuvelin and transferrin receptor 2, and to determine the nature and mechanisms of signals regulating iron level in the body.     

Ironing-out mechanisms of neuronal injury under hypoxic-ischemic conditions and potential role of iron chelators as neuroprotective agents

Iron is the most abundant transition metal in the brain, where it functions as an important cofactor in a host of vital metabolic processes and plays an absolutely essential role in cell viability. Free iron is also very toxic when present in high concentrations, thus placing this essential metal at the core of neurotoxic injury in a number of neurological disorders. The pivotal role of iron in cellular homeostasis, including its latent toxicity, necessitates a tight regulation of iron metabolism. Oxygen and iron appear to play an important role in iron homeostasis. They appear to exert their homeostatic role by modulating the proteins involved in a complex interplay between iron sensing, transport, and storage. These key regulatory proteins include ferritin (intracellular storage), transferrin (extracellular transport), transferrin receptor, and iron regulatory protein (sensor of intracellular iron concentration). The interplay of iron and oxygen is most intriguing in the setting of stroke, where hypoxia and free iron appear to interact in causing the subsequent neuronal death.     

Turnover in the transferrin iron pool during the hypoferremic phase of experimental Neisseria meningitidis infection in mice.

Mouse transferrin was used to specifically label the plasma transferrin iron pool for studies of iron kinetics in normal mice and infected mice during the hypoferremic phase of experimental meningococcal infection. The plasma transferrin iron pool of normal mice was found to be very dynamic, with a half-life of iron in the pool of 0.7 h. Iron left the plasma pool, entered the bone marrow, and was released into the blood in erythrocytes. Iron from the transferrin pool also entered the liver and spleen and was presumably in the reticuloendothelial system components of these organs. Most of the iron that had been supplied as transferrin iron was found in erythrocytes by 48 h after injection. Studies with mice infected with Neisseria meningitidis strain M1011 revealed similar kinetics for transferrin iron. There was no redistribution of iron within the various iron pools as a result of infection. Iron turnover in the plasma transferrin pool during the hypoferremic phase was similar to control rates, and iron leaving the pool entered its normal erythroid compartments. The lack of accelerated turnover of plasma iron and the finding that plasma iron was not rerouted to storage compartments during the hypoferremic phase provided good evidence that lactoferrin and leukocytic endogenous mediator were not directly involved in redirecting transferrin iron. Our evidence has implicated an impaired return of reticuloendothelial system-processed iron to the transferrin pool during the hypoferremic response. This appears to be a logical point in the erythroid iron cycle for host-mediated iron sequestration, as the reticuloendothelial system is involved in iron storage and may regulate iron levels in the plasma transferrin pool under normal conditions.     

Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis

IRON FUNCTIONS: Iron is an essential micronutrient, as it is required for satisfactory erythropoietic function, oxidative metabolism and cellular immune response. IRON PHYSIOLOGY: Absorption of dietary iron (1-2 mg/day) is tightly regulated and just balanced against iron loss because there are no active iron excretory mechanisms. Dietary iron is found in haem (10%) and non-haem (ionic, 90%) forms, and their absorption occurs at the apical surface of duodenal enterocytes via different mechanisms. Iron is exported by ferroportin 1 (the only putative iron exporter) across the basolateral membrane of the enterocyte into the circulation (absorbed iron), where it binds to transferrin and is transported to sites of use and storage. Transferrin-bound iron enters target cells-mainly erythroid cells, but also immune and hepatic cells-via receptor-mediated endocytosis. Senescent erythrocytes are phagocytosed by reticuloendothelial system macrophages, haem is metabolised by haem oxygenase, and the released iron is stored as ferritin. Iron will be later exported from macrophages to transferrin. This internal turnover of iron is essential to meet the requirements of erythropoiesis (20-30 mg/day). As transferrin becomes saturated in iron-overload states, excess iron is transported to the liver, the other main storage organ for iron, carrying the risk of free radical formation and tissue damage. REGULATION OF IRON HOMOEOSTASIS: Hepcidin, synthesised by hepatocytes in response to iron concentrations, inflammation, hypoxia and erythropoiesis, is the main iron-regulatory hormone. It binds ferroportin on enterocytes, macrophages and hepatocytes triggering its internalisation and lysosomal degradation. Inappropriate hepcidin secretion may lead to either iron deficiency or iron overload.     

Iron overload induces changes of pancreatic and duodenal divalent metal transporter 1 and prohepcidin expression in mice

It is well known that the iron content of the body is tightly regulated. Iron excess induces adaptive changes that are differentially regulated in each tissue. The pancreas is particularly susceptible to iron-related disorders. We studied the expression and regulation of key iron proteins in the pancreas, duodenum and liver, using an animal model of iron overload (female CF1 mice injected i.p. with iron saccharate, colloidal iron form). Divalent metal transporter 1, prohepcidin and ferritin (pancreas, duodenum, liver) were assessed by immunohistochemistry; divalent metal transporter 1 (pancreas, duodenum) by Western blot. In the iron overloaded mice, prohepcidin expression increased in islets of Langerhans and hepatocytes, and divalent metal transporter 1 expression decreased in cells of islets and in enterocytes. In the iron overloaded mice, ferritin expression decreased in islets of Langerhans and increased in acinar cells; hemosiderin was localized in connective tissue cells. The inverse relationship between divalent metal transporter 1 and prohepcidin may indicate a negative regulation by hepcidin, and hence reduction of iron stores in islets of Langerhans. Our data showed that in iron overloaded mice model, induced by colloidal iron form, a coordinated expression of key iron proteins in the pancreas, duodenum and liver may occur. Further research will be necessary to determine the adaptive responses induced by iron in the pancreas.     

Iron accumulation during development and ageing of Drosophila

We examined Drosophila melanogaster fruit flies to determine whether iron accumulates with ageing as it does in mice. Iron concentrations were measured by atomic absorption for flies maintained at 11, 20, 25 and 30 degrees C where the average lifespans were 152, 81, 62 and 25 days, respectively. Iron was found to accumulate with ageing during both the adult and developmental stages with an overall increase of 186% at 25 degrees C. A similar increase was found at 20 degrees C and 30 degrees C. At 11 degrees C the increase was less than half that at 25 degrees C. The rate of iron accumulation also varied with environmental temperature with the logarithm of the rate proportional to temperature (log R = 0.0509T-0.384). The rate of iron accumulation with ageing was, thus, found to be proportional to the rate of ageing, suggesting that excess dietary iron may be an initiator of senescence.     

Proteomic response of Streptococcus pneumoniae to iron limitation

Iron is an essential trace element and involved in various key metabolic pathways in bacterial lifestyle. Within the human host, iron is extremely limited. Hence, the ability of bacteria to acquire iron from the environment is critical for a successful infection. Streptococcus pneumoniae (the pneumococcus) is a human pathobiont colonizing symptomless the human respiratory tract, but can also cause various local and invasive infections. To survive and proliferate pneumococci have therefore to adapt their metabolism and virulence factor repertoire to different host compartments. In this study, the response of S. pneumoniae to iron limitation as infection-relevant condition was investigated on the proteome level. The iron limitation was induced by application of the iron chelator 2,2′-bipyridine (BIP) in two different media mimicking different physiological traits. Under these conditions, the influence of the initial iron concentration on pneumococcal protein expression in response to limited iron availability was analyzed. Interestingly, one major difference between these two iron limitation experiments is the regulation of proteins involved in pneumococcal pathogenesis. In iron-poor medium several proteins of this group were downregulated whereas these proteins are upregulated in iron-rich medium. However, iron limitation in both environments led to a strong upregulation of the iron uptake protein PiuA and the significant downregulation of the non-heme iron-containing ferritin Dpr. Based on the results, it is shown that the pneumococcal proteome response to iron limitation is strongly dependent on the initial iron concentration in the medium or the environment.     

Manipulation of iron to determine survival

Iron is an essential nutrient that can determine cellular survival. Many organisms have evolved sophisticated mechanisms for iron uptake and transport to support their growth. The dual dependence on iron of both the host and invading pathogen initiates a competition for this nutrient following infection. Microorganisms have developed various strategies to acquire iron from the host. These are counter-balanced by an iron-withholding strategy that the host deploys as part of its defense system. This strategy, involving many iron-regulatory proteins, mediates iron depletion at the mucosal surfaces, in the extracellular environment, and within the cells. Iron is sequestered into storage by the host in order to deprive the pathogens of this factor and to prevent their proliferation. This system can be compromised. In particular, new evidence is emerging that suggests that viruses are able to specifically target and regulate proteins involved in iron homeostasis. This review focuses on the procedures employed by the host and viruses to regulate iron as a means of defense and survival, respectively.     

海帕西啶与铁代谢

铁是人体必需的微量元素,在体内的含量受着精确的调节以保证机体的正常功能。最近发现的一种含有25个氨基酸的多肽激素海帕西啶是体内铁代谢的重要调节因素之一,在小肠铁吸收、巨噬细胞的铁释放、铁跨胎盘运输等过程中发挥着重要的作用。海帕西啶的过量和不足都会影响铁的内稳态,而发生一系列疾病,随着对海帕西啶调节机制的研究将出现针对一些铁代谢紊乱疾病,如血色素沉着、炎症性贫血等的新治疗方法。     

Regulation of iron metabolism and its involvement in diseases

Iron is an essential nutrient virtually almost all organisms including human, but at the same time, it is toxic because its high reactivity to molecular oxygen generates free radicals. Therefore, iron metabolism is tightly regulated. Recently, knowledge of roles that iron plays in our body as well as regulatory mechanism of iron metabolism in human body has been drastically expanded. Here I describe recent advance in our understanding on the regulation of iron metabolism and discuss its relationship to various diseases.     

The battle for iron in enteric infections

Iron is an essential element for almost all living organisms, but can be extremely toxic in high concentrations. All organisms must therefore employ homeostatic mechanisms to finely regulate iron uptake, usage and storage in the face of dynamic environmental conditions. The critical step in mammalian systemic iron homeostasis is the fine regulation of dietary iron absorption. However, as the gastrointestinal system is also home to >10¹⁴ bacteria, all of which engage in their own programmes of iron homeostasis, the gut represents an anatomical location where the inter-kingdom fight for iron is never-ending. Here, we explore the molecular mechanisms of, and interactions between, host and bacterial iron homeostasis in the gastrointestinal tract. We first detail how mammalian systemic and cellular iron homeostasis influences gastrointestinal iron availability. We then focus on two important human pathogens, Salmonella and Clostridia; despite their differences, they exemplify how a bacterial pathogen must navigate and exploit this web of iron homeostasis interactions to avoid host nutritional immunity and replicate successfully. We then reciprocally explore how iron availability interacts with the gastrointestinal microbiota, and the consequences of this on mammalian physiology and pathogen iron acquisition. Finally, we address how understanding the battle for iron in the gastrointestinal tract might inform clinical practice and inspire new treatments for important diseases.     

Non haematological effects of iron deficiency - a perspective

Iron deficiency is a continuum beginning from lowering of tissue stores to the phase of exhausted tissue stores, interference with iron driven biochemical reactions in the body, microcytosis, hypochromia, increasing severity of anaemia with all its attendant consequences. Iron deficiency anaemia is a very well known concept but what is often not appreciated is the effect of broad canvas of iron deficiency on various tissues, organs and systems in our body in addition to iron deficiency anaemia leading to concept of "Iron deficiency disease". In this condition not only tissue delivery of oxygen is compromised but proliferation, growth, differentiation, myelinogenesis, immunofunction, energy metabolism, absorption and biotransformation are compromised leading to abnormal growth and behaviour, mental retardation, reduced cardiac performance and work efficiency, infection etc which ultimately leads to the concept that "iron deficiency not only breaks the machine but also wrecks the machinery."