Iron, infection, and neoplasia

In nearly all forms of life, the number and diversity of enzymes that contain iron or that depend on the presence of this metal for activity are impressive. Not surprisingly, chemical mechanisms have been evolved by many organisms that permit them to solubilize and acquire iron while at the same time depriving their competitors or their pathogens of this element. Proteins such as transferrin and lactoferrin that are employed by vertebrate hosts for iron transport and acquisition can, to some extent, withhold the metal from the siderophores of invading bacteria and fungi. Attempts also are made by animal hosts to withhold iron from protozoa and neoplastic cells. Unfortunately, pathogenic microorganisms have developed a variety of counter measures that are especially dangerous in hosts stressed by iron overload in specific fluids, tissues, or cells. In recent years, however, a number of possible methods and agents for strengthening iron-withholding defense have become apparent. Nearly 3,000 papers on various aspects of iron withholding are contained in the 18-year Medline Database and numerous reviews have been published since 1966. The present paper will focus on developments that have been reported within the past 2 1/2 years.     

Effects of Iron Chelators,Iron Salts,and Iron Oxide Nanoparticles on the Proliferation and the Iron Content of Oligodendroglial OLN-93 Cells

The oligodendroglial cell line OLN-93 was used as model system to investigate the consequences of iron deprivation or iron excess on cell proliferation. Presence of ferric or ferrous iron chelators inhibited the proliferation of OLN-93 cells in a time and concentration dependent manner, while the application of a molar excess of ferric ammonium citrate (FAC) prevented the inhibition of proliferation by the chelator deferoxamine. Proliferation of OLN-93 cells was not affected by incubation with 300 μM iron that was applied in the form of FAC, FeCl₂, ferrous ammonium sulfate or iron oxide nanoparticles, although the cells efficiently accumulated iron during exposure to each of these iron sources. The highest specific iron content was observed for cells that were exposed to the nanoparticles. These data demonstrate that the proliferation of OLN-93 cells depends strongly on the availability of iron and that these cells efficiently accumulate iron from various extracellular iron sources.     

Total Iron,Heme Iron,Zinc, and Copper Content in Rabbit Meat and Viscera

The aim of this study is to determine the content of total iron (TFe), heme iron (HeFe), zinc (Zn), and copper (Cu) in different cuts of meat and viscera from rabbit. Five young New Zealand rabbits were used in the study. Samples in triplicate were obtained from three meat cuts (foreleg, hind leg, and loin) and from main viscera. TFe, Zn, and Cu concentrations from samples were determined by wet acid digestion followed by atomic absorption spectrophotometry (AAS), while HeFe was determined by acid extraction followed by AAS. Mean TFe, HeFe, Zn, and Cu in meat was 0.83 ± 0.09, 0.56 ± 0.11, 0.95 ± 0.35, and 0.08 ± 0.01 mg/100 g, respectively. TFe content was less than 1 mg/100 g in all meat cuts. Sixty-seven percent of iron content was HeFe. The cut of meat with highest Zn concentrations was the foreleg with 1.33 ± 0.12 mg/100 g. Cu content was low for all meat cuts. TFe, HeFe, Zn, and Cu content in viscera varied greatly. The spleen was the organ with the highest TFe and Zn concentrations (82.79 ± 9.22 mg/100 g and 3.49 ± 0.63 mg/100 g, respectively). Nevertheless, the lungs had the highest concentration of HeFe (5.79 ± 0.90 mg/100 g), accounting for 91% of the total iron. The liver had the highest Cu content (3.89 ± 0.89 mg/100 g). Rabbit meat has low TFe concentration, similar to that of poultry, and most of the iron is HeFe. The amount of minerals in viscera closely depends on their function.     

Morphological and Physiological Differences in Synechococcus elongatus during Continuous Cultivation at High Iron,Low Iron,and Iron Deficient Medium

Thermophilic unicellular cyanobacterium Synechococcus elongatus Näg. var. thermalis Geitl. strain Kovrov 1972/8 was cultivated in continuous flow reactor to simulate conditions occurring in nature in regions with low iron concentration. Two degrees of iron deprivation were established: (a) low iron (LI) conditions (9.0 µM Fe) when cells still maintained maximal growth rate but already exhibited changes in photosynthetic apparatus, and (b) iron deficient (ID) conditions (0.9 µM Fe) when cell growth rate decreased and extensive morphological and functional changes were observed. A decrease in the cellular content of phycobilin antenna was observed in both ID and LI cells and an increase of carotenoid concentration only in the ID culture. Morphologically, ID cells showed a decrease in the amount of phycobilins and in the number of thylakoid membranes. This suggests that S. elongatus responds to decrease in iron availability by substitution of the phycobilisomes by antennae containing chlorophyll (Chl) and carotenoids. Photochemical activity of photosystem (PS) 2, determined as F_v/F_m ratio was similar in high iron (HI) and LI cultures and approximately five times lower in ID culture. On the other hand, the activity of the whole electron transport chain showed the opposite tendency: the relative rates of the CO₂-dependent oxygen evolution in HI : LI : ID cultures were approximately 1 : 2 : 4. Thus in nutrient stress the photosynthetic apparatus preserved its activity despite the decrease in the amount of both Chl-binding complexes and thylakoid membranes.     

Iron mobilization from ultraviolet-irradiated,iron-saturated,transferrin

SUMMARY

Transferrin is the major iron transport protein of mammalian plasma. The ultraviolet-B irradiation of 1.4 mg/ml iron saturated transferrin solutions (~32 μM Fe³⁺) induces a Fe³⁺ loss accompanied by Fe²⁺ formation. The initial quantum yield of Fe³⁺ loss is wavelength dependent (φ(313 nm)~1.3×10^?3) and oxygen independent suggesting an intramolecular electron transfer from one of the Fe³⁺ ligands. A photolysis of tryptophan residues parallels this photoreduction.     

Iron, infection, and the role of bicarbonate

Ferric iron will not saturate transferrin in Tris buffer, and its use in experimental infections has been criticized. However, in the presence of bicarbonate, as in plasma, saturation occurs rapidly. This is comparable to natural iron overload, and infections.     

Iron metabolism: microbes,mouse, and man

Recent advances in research on iron metabolism have revealed the identity of a number of genes, signal transduction pathways, and proteins involved in iron regulation in mammals. The emerging paradigm is a coordination of homeostasis within a network of classical iron metabolic pathways and other cellular processes such as cell differentiation, growth, inflammation, immunity, and a host of physiologic and pathologic conditions. Iron, immunity, and infection are intricately linked and their regulation is fundamental to the survival of mammals. The mutual dependence on iron by the host and invading pathogenic organisms elicits competition for the element during infection. While the host maintains mechanisms to utilize iron for its own metabolism exclusively, pathogenic organisms are armed with a myriad of strategies to circumvent these measures. This review explores iron metabolism in mammalian host, defense mechanisms against pathogenic microbes and the competitive devices of microbes for access to iron.     

铁代谢与铁调素hepcidin

铁是机体必需的营养元素。然而,铁过载则导致细胞的损伤。由于生物体缺少排泄铁的机制,因而,肠铁吸收的调控便成为维持机体铁稳态的关键。新近研究发现hepcidin对机体铁稳态的调节起着至关重要的作用,被人们称为铁调节激素。Hepcidin主要在肝细胞中合成,之后分泌至血液将体内铁需要的信号传至小肠,调控肠铁的吸收。这一过程主要通过调节小肠铁转运相关蛋白的表达而实现。任何影响hepcidin表达的因素都可能破坏体内的铁平衡,造成铁代谢相关疾病。     

Iron, metalloenzymes and cytotoxic reactions.

There is considerable evidence implicating iron and other redox-active transition metals as progenitors of reactive intermediates of oxygen (ROI), molecules which lead to oxidative stress and contribute to various neurodegenerative processes. An important aspect of such metal-mediated damage to biomolecules is the site-specific nature of such pathological activity. Iron sequestering molecules, such as ferritin, transferrin, lactotransferrin, melanotransferrin, hemosiderin and heme can serve as cytoprotectants against metal-mediated oxidant damage. Metalloenzymes also constitute an important group of iron sequestering molecules. Metalloenzyme-catalyzed reactions in which metal ions at the enzyme active site undergo redox-cycling in association with O2 are site-specific in nature, and may represent a potential source of ROI-mediated damage to biomolecules. Dysregulation of brain iron and alterations in the levels of metalloenzymes involved in reactions with O2 derived molecules can contribute to neuronal damage. Iron may increase the cytotoxicity of neuronal dopamine by increasing its rate of oxidation to quinones and semiquinones, thereby reducing the level of this neurotransmitter. Interestingly, dopamine also may play an important role in the maintenance of transition-metal homeostasis as an iron chelator, since it can form both catecholate and hydroxamate groups, molecules employed by many microorganisms to sequester iron.     

Iron, brain ageing and neurodegenerative disorders

There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases. Conditions such as neuroferritinopathy and Friedreich ataxia are associated with mutations in genes that encode proteins that are involved in iron metabolism, and as the brain ages, iron accumulates in regions that are affected by Alzheimer's disease and Parkinson's disease. High concentrations of reactive iron can increase oxidative-stress induced neuronal vulnerability, and iron accumulation might increase the toxicity of environmental or endogenous toxins. By studying the accumulation and cellular distribution of iron during ageing, we should be able to increase our understanding of these neurodegenerative disorders and develop new therapeutic strategies.     

Iron, oxidative stress and human health

The amount of iron within the cell is carefully regulated in order to provide an adequate level of the micronutrient while preventing its accumulation to toxic levels. Iron excess is believed to generate oxidative stress, understood as an increase in the steady state concentration of oxygen radical intermediates. The main aspects of cellular metabolism of iron, with special emphasis on the role of iron with respect to oxidative damage to lipid membranes, are briefly reviewed here. Both in vitro and in vivo models are examined. Finally, a discussion of iron overload and its impact on human health is included. Overall, further studies are required to assess more effective means to limit iron-dependent damage, by minimizing the formation and release of free radicals in tissues when the cellular iron steady state concentration is increased either as a consequence of disease or by therapeutic iron supplementation.     

Ferrous Iron and Sulfur Oxidation and Ferric Iron Reduction Activities of Thiobacillus ferrooxidans Are Affected by Growth on Ferrous Iron, Sulfur, or a Sulfide Ore

Eight strains of Thiobacillus ferrooxidans (laboratory strains Tf-1 [= ATCC 13661] and Tf-2 [= ATCC 19859] and mine isolates SM-1, SM-2, SM-3, SM-4, SM-5, and SM-8) and three strains of Thiobacillus thiooxidans (laboratory strain Tt [= ATCC 8085] and mine isolates SM-6 and SM-7) were grown on ferrous iron (Fe²⁺), elemental sulfur (S⁰), or sulfide ore (Fe, Cu, and Zn). The cells were studied for their aerobic Fe²⁺ - and S⁰-oxidizing activities (O₂ consumption) and anaerobic S⁰-oxidizing activity with ferric iron (Fe³⁺) (Fe²⁺ formation). Fe²⁺-grown T. ferrooxidans cells oxidized S⁰ aerobically at a rate of 2 to 4% of the Fe²⁺ oxidation rate. The rate of anaerobic S⁰ oxidation with Fe³⁺ was equal to the aerobic oxidation rate in SM-1, SM-3, SM-4, and SM-5, but was only one-half or less that in Tf-1, Tf-2, SM-2, and SM-8. Transition from growth on Fe²⁺ to that on S⁰ produced cells with relatively undiminished Fe²⁺ oxidation activities and increased S⁰ oxidation (both aerobic and anaerobic) activities in Tf-2, SM-4, and SM-5, whereas it produced cells with dramatically reduced Fe²⁺ oxidation and anaerobic S⁰ oxidation activities in Tf-1, SM-1, SM-2, SM-3, and SM-8. Growth on ore 1 of metal-leaching Fe²⁺-grown strains and on ore 2 of all Fe²⁺-grown strains resulted in very high yields of cells with high Fe²⁺ and S⁰ oxidation (both aerobic and anaerobic) activities with similar ratios of various activities. Sulfur-grown Tf-2, SM-1, SM-4, SM-6, SM-7, and SM-8 cultures leached metals from ore 3, and Tf-2 and SM-4 cells recovered showed activity ratios similar to those of other ore-grown cells. It is concluded that all the T. ferrooxidans strains studied have the ability to produce cells with Fe²⁺ and S⁰ oxidation and Fe³⁺ reduction activities, but their levels are influenced by growth substrates and strain differences.     

Iron, Nitric Oxide, and Myeloperoxidase in Asthmatic Patients

Plasma nitric oxide (NO), myeloperoxidase (MPO), and iron (Fe) levels were determined in bronchial asthma. The relations among these parameters in different stages of asthma were interpreted. Their association with airway inflammation observed in patients with bronchial asthma as well as the roles and the contributions to the pathological processes were evaluated. A total of 62 individuals, 32 asthmatics and 30 controls, were included into the scope of this study. Plasma nitric oxide metabolites (NOx) and MPO and Fe levels were determined by the Griess reaction, ELISA, and the automated TPTZ (2,4,6-tri[2-pyridyl]-5-triazine) method, respectively. In the asthmatic individuals, plasma NOx, MPO, and Fe concentrations were 133 +/- 13 microM, 95 +/- 20 ng/ml, and 159 +/- 20 microg/dl, respectively; in the control group these values were 82 +/- 11 microM, 62 +/- 11 ng/ml, and 96 +/- 9 microg/dl. Increased values were detected for plasma MPO (p > 0.05), NOx (p < 0.01), and Fe (p < 0.01) concentrations in asthmatic individuals. Considering the facts that NO modulates the catalytic activity of MPO and induces the expression of heme oxygenase as important contributors to the mechanisms causing free Fe release, it is concluded that elevated NOx, MPO, and Fe levels observed in the asthmatic group act in a concerted manner and appear to be involved in the pathogenesis of asthma.     

Redox Cycling in Iron Uptake,Efflux, and Trafficking

Aerobic organisms are faced with a dilemma. Environmental iron is found primarily in the relatively inert Fe(III) form, whereas the more metabolically active ferrous form is a strong pro-oxidant. This conundrum is solved by the redox cycling of iron between Fe(III) and Fe(II) at every step in the iron metabolic pathway. As a transition metal ion, iron can be “metabolized” only by this redox cycling, which is catalyzed in aerobes by the coupled activities of ferric iron reductases (ferrireductases) and ferrous iron oxidases (ferroxidases).