Insensitivity of the ferritin iron core to heat treatment.

To test whether the reactivity of ferritin iron is affected by the heat treatment used in ferritin isolation, we prepared ferritin from the same horse spleen with or without heating. Both samples exhibited similar reactivity upon reduction or chelation of iron.     

Cellular regulation and molecular interactions of the ferritins

Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA (mRNA) structures, signaling pathways and protein catalysts. Ferritin, a protein nanocage around an iron/oxy mineral, centralizes the control. Complementary DNA (antioxidant responsive element/Maf recognition element) and mRNA (iron responsive element) responses regulate ferritin synthesis rates. Multiple iron-protein interactions control iron and oxygen substrate movement through the protein cage, from dynamic gated pores to catalytic sites related to di-iron oxygenase cofactor sites. Maxi-ferritins concentrate iron for the bio-synthesis of iron/heme proteins, trapping oxygen; bacterial mini-ferritins, DNA protection during starvation proteins, reverse the substrate roles, destroying oxidants, trapping iron and protecting DNA. Ferritin is nature’s unique and conserved approach to controlled, safe use of iron and oxygen, with protein synthesis in animals adjusted by dual, genetic DNA and mRNA sequences that selectively respond to iron or oxidant signals and link ferritin to proteins of iron, oxygen and antioxidant metabolism. Received 25 June 2005; received after revision 17 October 2005; accepted 25 November 2005     

Effects of CO2 exposure on distribution of various forms of iron and copper in guinea-pig tissues

The effects on iron and copper distribution and metabolism of exposure to high levels of CO2 were studied in the guinea-pig. Mature, male animals were placed in an atmosphere of 15% CO2, 21% O2 (balance N2), and sacrificed from 1 h to 1 week thereafter. Total iron and copper concentrations of blood, liver, spleen and bone, as well as concentrations of heme and ferritin iron, were measured together with blood hematocrit, reticulocytes, plasma hemoglobin, plasma ceruloplasmin and copper concentrations. The results show clearly that rapid and sustained red cell damage or hemolysis ensued several h from the start of CO2 treatment. This resulted in loss of iron and copper from the blood, an influx of both elements into liver, spleen and bone, and a rise in plasma ceruloplasmin. Influx of iron into liver and spleen caused an accumulation of ferritin, the main site for iron storage in cells. Following the effect on red cells, there was an accumulation of heme iron, and a decreased hematocrit, best explained by a depressed activity of the reticuloendothelial and erythropoietic systems. A period of adaptation succeeded these events, in which all blood parameters and most tissue values returned to normal, despite the continuing presence of high CO2. The only changes not reversed were the elevations in liver, spleen and bone iron stores. These remained high, with a net accumulation of greater than 2 mg iron, or 3-4 times more than originally present. The results indicate that at least in the guinea-pig, high CO2 exposure results in red cell damage and other events leading to an accumulation of additional iron in the body; also, that iron accumulated as ferritin and hemosiderin in liver and spleen may not be readily available to restore blood hemoglobin concentrations on an acute basis.     

Effects of CO2 exposure on distribution of various forms of iron and copper in guinea-pig tissues

Summary The effects on iron and copper distribution and metabolism of exposure to high levels of CO₂ were studied in the guinea-pig. Mature, male animals were placed in an atmosphere of 15% CO₂, 21% O₂ (balance N₂), and sacrificed from 1 h to 1 week thereafter. Total iron and copper concentrations of blood, liver, spleen and bone, as well as concentrations of heme and ferritin iron, were measured together with blood hematocrit, reticulocytes, plasma hemoglobin, plasma ceruloplasmin and copper concentrations. The results show clearly that rapid and sustained red cell damage or hemolysis ensued several h from the start of CO₂ treatment. This resulted in loss of iron and copper from the blood, an influx of both elements into liver, spleen and bone, and a rise in plasma ceruloplasmin. Influx of iron into liver and spleen caused an accumulation of ferritin, the main site for iron storage in cells. Following the effect on red cells, there was an accumulation of heme iron, and a decreased hematocrit, best explained by a depressed activity of the reticuloendothelial and erythropoietic systems. A period of adaptation succeeded these events, in which all blood parameters and most tissue values returned to normal, despite the continuing presence of high CO₂. The only changes not reversed were the elevations in liver, spleen and bone iron stores. These remained high, with a net accumulation of >2 mg iron, or 3–4 times more than originally present. The results indicate that at least in the guinea-pig, high CO₂ exposure results in red cell damage and other events leading to an accumulation of additional iron in the body; also, that iron accumulated as ferritin and hemosiderin in liver and spleen may not be readily available to restore blood hemoglobin concentrations on an acute basis.Acknowledgments. We gratefully acknowledge the technical assistance of Joan R. Moor and Lakshmi Vulimiri with these studies, and the support of Grants No. 17249 and HL22410 from the U.S. Public Health Service.     

Molecular weight of human alpha2-H-ferroglobulin subunits. Comparison with molecular weight of ferritin subunits]

alpha2 H globulin, a glycoferroprotein, was first demonstrated in the sera of patients with malignant diseases. This protein was isolated from cancerous human liver, and compared with ferritin, a ferroprotein showing some identical properties (presence of iron, high molecular weight, common antigenic determinants). However, physicochemical differences were observed between these two proteins. The study of protein dissociation was performed by polyacrylamide gel electrophoresis in sodium dodecyl sulfate after reduction by mercaptoethanol. A similar molecular weight of 19 000 is obtained for subunits of these two proteins. This value agrees well with the results obtained by other authors for ferritin.     

On the turnover of exogenous ferritin in the cephalopod optic gland. A microprobe study

Summary X-ray energy emission spectra of iron show that horse spleen ferritin, after injection into the blood of the octopus, is taken up, accumulated and disposed of again by lysosomes of the optic gland.Part of this work is supported by the Swiss National Foundation.     

Hemoglobin as a source of iron overload in multiple sclerosis: does multiple sclerosis share risk factors with vascular disorders?

Although iron is known to be essential for the normal development and health of the central nervous system, abnormal iron deposits are found in and around multiple sclerosis (MS) lesions that themselves are closely associated with the cerebral vasculature. However, the origin of this excess iron is unknown, and it is not clear whether this is one of the primary causative events in the pathogenesis of MS, or simply another consequence of the long-lasting inflammatory conditions. Here, applying a systems biology approach, we propose an additional way for understanding the neurodegenerative component of the disease caused by chronic subclinical extravasation of hemoglobin, in combination with multiple other factors including, but not limited to, dysfunction of different cellular protective mechanisms against extracellular hemoglobin reactivity and oxidative stress. Moreover, such considerations could also shed light on and explain the higher susceptibility of MS patients to a wide range of cardiovascular disorders.     

Biologische und chemische Wege zur Anreicherung von Spurenelementen

Summary Using as examples hemovanadin, the vanadium-containing blood pigment of the ascidianPhallusia mamillata, and ferritin, the protein for iron storage in mammals, pathways for the concentration of vanadium and of iron are described: These have been realizedin vitro and may occurin vivo. The uptake and concentration of heavy metals in nature seems to occur by means of complexing agents.High molecular weight, insoluble chelating substances which are able to bind metal ions, especially uranium and copper selectively, have been synthesized. Recovery of the metals is possible without destruction of the chelating groups, and, as in the case of ion-exchange resins, repeated cycles can be carried out without diminishing the metal-binding capacity.     

Molecular evidence for increased hematopoietic proliferation in the spleen of the b/b laboratory rat

The splenomegaly and the appearance of a significant number of CFU-E (erythroid colony-forming units) and BFU-E¹ (erythroid burst-forming units) in the Belgrade laboratory rat (b/b) spleen prompted us to analyse further the molecular evidence for increased hematopoietic proliferation in the b/b spleen. Messenger RNAs (mRNAs) specific for globins, proteins for iron transport and deposition and the band 3 protein were used in rat erythropoietic tissues as markers for proliferation and erythroid differentiation. In the b/b spleen, all mRNAs analysed display an erythroid-specific pattern of expression. This analysis also revealed an enhanced level of mRNA for ferritin in the +/b spleen, whereas erythrocyte-specific mRNA production was normal.     

Uptake of ferritin from the medium byTokophrya infusionum

Summary Tokophrya infusionum, a suctorian, is deprived of a mouth opening. The uptake of ferritin from the medium is accomplished through pits, invaginations of the plasma membrane which are permanent structures. From the pits containing ferritin, flat vesicles are pinched off transporting the ferritin to the cytoplasm.Supported by grant AI-08989 US Public Health Service.The author acknowledges gratefully the excellent technical assistance of Mrs Sondra Lewengrub.     

Ferritin synthesis by splenic tumor tissue of Hodgkin's disease.

Increased ferritin synthesis by Hodgkin's disease splenic tumor tissue was demonstrated by incorporation of 14C-leucine and radioautography. This suggests that elevated tumor and serum ferritin concentrations found in patients with Hodgkin's disease is derived from tumor tissue per se.     

Morphological evidence for tracer uptake at the active zones of stimulated frog neuromuscular junction

Lanthanum or ferritin added to the fixative were found in small and non-coated vesicles located at active zones in nerve-muscle preparations stimulated by potassium during cold aldehyde fixation. The presence of labeled vesicles at active zones supports the hypothesis that a double process of exo-endocytosis might occur under moderate stimulation conditions.     

Liver ferritin synthesis following chronic alcohol administration to rats: Modulation by propylthiouracil

Summary Liver ferritin synthesis was inhibited by 22.3% in rats treated with alcohol (2 g/kg) for 45 days. This inhibition was prevented by simultaneous administration (5 mg/kg) of propylthiouracil during the last 15 days. There was no significant effect on liver ferritin concentration.     

Uptake of ferritin from the medium by Tokophrya infusionum.

Tokophrya infusionum, a suctorian, is deprived of a mouth opening. The uptake of ferritin from the medium is accomplished through pits, invaginations of the plasma membrane which are permanent structures. From the pits containing ferritin, flat vesicles are pinched off transporting the ferritin to the cytoplasm.     

Time and theophylline influence on the quantitative variations of the glomerular basement membrane ferritin pathway (author's transl)

A fine quantitative evaluation of ferritin aggregates in rat GBM permits to counts 5.08 +/- 1.51 and 18.30 +/- 3.21 g/cm2, respectively 30 and 60 min after ferritin injection; likewise, 30 min after ferritin administration, 5.08 +/- 1.51 and 17.11 +/- 3.9 g/cm2, respectively in normal and theophylline-treated animals.     

Effect of blood pH on anionic ferritin transport through rat aortic endothelium.

Acute lowering of blood pH between 7.4 and 6.9 in rats by ventilation with 10 or 20% CO2 does not increase the passage of ferritin molecules across the aortic endothelium. These results do not rule out alteration of endothelial permeability to anionic macromolecules in local circulatory disturbances when blood pH drops to levels much lower than 6.9.     

Études des variations quantitatives du passage de la ferritine au niveau de la membrane basale glomérulaire en fonction du temps et sous l'influence de la théophylline

Summary A fine quantitative evaluation of ferritin aggregates in rat GBM permits to counts 5.08±1.51 and 18.30±3.21 g/cm², respectively 30 and 60 min after ferritin injection; likewise, 30 min after ferritin administration, 5.08±1.51 and 17.11±3.9 g/cm², respectively in normal and theophylline-treated animals.     

The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen

The life of aerobes is dependent on iron and oxygen for efficient bioenergetics. Due to potential risks associated with iron/oxygen chemistry, iron acquisition, concentration, storage, utilization, and efflux are tightly regulated in the cell. A central role in regulating iron/oxygen chemistry in animals is played by mRNA translation or turnover via the iron responsive element (IRE)/iron regulatory protein (IRP) system. The IRE family is composed of three-dimensional RNA structures located in 3′ or 5′ untranslated regions of mRNA. To date, there are 11 different IRE mRNAs in the family, regulated through translation initiation or mRNA stability. Iron or oxidant stimuli induce a set of graded responses related to mRNA-specific IRE substructures, indicated by differential responses to iron in vivo and binding IRPs in vitro. Molecular effects of phosphorylation, iron and oxygen remain to be added to the structural information of the IRE-RNA and IRP repressor in the regulatory complex. Received 21 April 2007; received after revision 13 July 2007; accepted 2 August 2007     

Altered hyperemic response of the coronary arterial bed in alloxan-diabetes

Reactive hyperemic responses of the coronary arterial bed, provoked by asphyxia or clamping of the coronary artery, were compared in alloxan-diabetic and metabolically healthy dogs. In alloxan-diabetic dogs the response of the coronary arterial bed lasted longer, and its reactivity to hypoxia was lower. Treatment with adenosine caused less vasodilation in diabetic animals than in controls. These changes may be due to the altered reactivity of diabetic vascular smooth muscle.