Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms involved and the potentially useful therapeutic strategies in the prevention of acute renal failure (ARF) are briefly reviewed. Factors mentioned are the role of calcium channel blockers, the antioxidant agents, heme oxygenase induction, and ferritin synthesis; and of substances with hemodynamic actions in ARF; such as endothelin, atrial natriuretic peptide, urodilatin, PAF antagonist, prostaglandins, diuretics, and dopamine. The loss of tubular epithelium polarity, the mechanisms involved in this process, and the usefulness of arginine-glycine-aspartic acid peptide and anti-ICAM antibodies in the prevention of tubular obstruction are also reviewed.
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PMID:Therapeutic strategies in the prevention of acute renal failure. 910 98

Calculations to determine the electrostatic potential of the iron storage protein ferritin, using the human H-chain homopolymer (HuHF), reveal novel aspects of the protein. Some of the charge density correlates well with regions previously identified as active sites in the protein. The three-fold channels, the putative ferroxidase sites, and the nucleation sites all show expectedly negative values of the electrostatic potential. However, the outer entrance to the three-fold channels are surrounded by regions of positive potential, creating an electrostatic field directed toward the interior cavity. This electrostatic gradient provides a guidance mechanism for cations entering the protein cavity, indicating the three-fold channel as the major entrance to the protein. Pathways from the three-fold channels, indicated by electrostatic gradients on the inner surface, lead to the ferroxidase center, the nucleation center and to the interior entrance to the four-fold channel. Six glutamic acid residues at the nucleation site give rise to a region of very negative potential, surrounding a small positively charged center due to the presence of two conserved arginine residues, R63, in close proximity (4.9 A), suggesting that electrostatic fields could also play a role in the nucleation process. A large gradient in the electrostatic potential at the 4-fold channel gives rise to a field directed outward from the internal cavity, indicating the possibility that this channel functions to expel cations from inside the protein. The 4-fold channel could therefore provide an exit pathway for protons during mineralization, or iron leaving the protein cavity during de-mineralization.
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PMID:Calculated electrostatic gradients in recombinant human H-chain ferritin. 960 13

Articles published during the past year on the ocular manifestations of metabolic disorders and related issues are reviewed. Fewer articles on this topic were available this year than previous years. Ornithine-delta-amino transferase-deficient mice were produced by gene targeting in the hope of creating an animal model for gyrate atrophy. The mice developed unexpected hypoornithinemia in the neonatal period and died 24 to 48 hours after birth. One human infant also had hypoornithnemia without serious symptoms. Both mice and human develop hyperornithinemia later. Arginine supplementation rescued the mice, but they developed central retinal degeneration by 7 months. Coexistence of autosomal dominant congenital or early onset cataract and hyperferritinemia, not related to iron overload, was discovered in three pedigrees, two Italian and one not mentioned, by two different groups. Mutations of the ferritin L-subunit gene in the iron-responsive element were identified, with autosomal dominant inherited cataract associated with hyperferritinemia.
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PMID:Ocular manifestations of metabolic disorders. 1016 58

Human iron regulatory protein-1 (IRP-1) is a bifunctional protein that regulates iron metabolism by binding to mRNAs encoding proteins involved in iron uptake, storage, and utilization. Intracellular iron accumulation regulates IRP-1 function by promoting the assembly of an iron-sulfur cluster, conferring aconitase activity to IRP-1, and hindering RNA binding. Using protein footprinting, we have studied the structure of the two functional forms of IRP-1 and have mapped the surface of the iron-responsive element (IRE) binding site. Binding of the ferritin IRE or of the minimal regulatory region of transferrin receptor mRNA induced strong protections against proteolysis in the region spanning amino acids 80 to 187, which are located in the putative cleft thought to be involved in RNA binding. In addition, IRE-induced protections were also found in the C-terminal domain at Arg-721 and Arg-728. These data implicate a bipartite IRE binding site located in the putative cleft of IRP-1. The aconitase form of IRP-1 adopts a more compact structure because strong reductions of cleavage were detected in two defined areas encompassing residues 149 to 187 and 721 to 735. Thus both ligands of apo-IRP-1, the IRE and the 4Fe-4S cluster, induce distinct but overlapping alterations in protease accessibility. These data provide evidences for structural changes in IRP-1 upon cluster formation that affect the accessibility of residues constituting the RNA binding site.
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PMID:Ligand-induced structural alterations in human iron regulatory protein-1 revealed by protein footprinting. 1032 9

Ferritin from the liver of fresh, salt and brackish water fishes was purified by thermal denaturation of liver homogenate followed by ammonium sulphate fractionation and Sephacryl S-300 gel filtration. Yield and iron content of purified fish ferritins were 0.016-0.026 mg/g of wet tissue and 4-14%, respectively. The iron content of ferritins from marine and brackish species was higher than from fresh water species. The phosphate/iron ratio ranged from 0.5 to 1.8 and was higher than mammalian ferritins. The fish ferritins have 5-6% neutral carbohydrate. Native gel electrophoresis and molecular weight analysis revealed the presence of a monomeric ferritin. SDS-gel electrophoresis and immunoblotting showed a single protein band of 21 kDa suggesting the presence of similar sized subunits in the native structure of fish ferritins. Isoelectric focusing revealed microheterogeneity with five to seven bands of pI values between 4.1 and 7.0. Variations in the amino acid composition were observed. Proline and arginine were not detected in murrel and salmon species, respectively. High proline and low tyrosine contents were recorded for perch ferritin. Immunological studies by non-competitive indirect ELISA revealed varying degrees of cross-reactivity. Mammalian ferritins exhibited a moderate cross-reactivity with anti-fish ferritin. On the contrary, very low or no cross-reactivity was observed between fish ferritin and anti-mammalian ferritin. Ferritins from bony fishes such as murrel and rohu exhibited a high degree of cross-reactivity with anti-shark ferritin. However, a moderate cross-reactivity was observed between shark and anti-murrel ferritin. Ferritin from marine bony fishes, salmon and mackerel and perch (brackish) showed a low to very low cross-reactivity with both the antisera.
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PMID:Purification and characterization of fish liver ferritins. 1048 Dec 57

To elucidate the pathways by which nitric oxide (NO) influences macrophage iron metabolism, the uptake, release, and intracellular distribution of iron in the murine macrophage cell line J774 has been investigated, together with transferrin receptor (TfR) expression and iron-regulatory protein (IRP1 and IRP2) activity. Stimulation of macrophages with interferon-gamma (IFN-gamma) and/or lipopolysaccharide (LPS) decreased Fe uptake from transferrin (Tf), and there was a concomitant downregulation of TfR expression. These effects were mediated by NO-dependent and NO-independent mechanisms. Addition of the NO synthase (NOS) inhibitor N-monomethyl arginine (NMMA) partially restored Fe uptake but either had no effect on or downregulated TfR expression, which suggests that NO by itself is able to affect iron availability. Analysis of the intracellular distribution of incorporated iron revealed that in IFN-gamma/LPS-activated macrophages there was a decreased amount and proportion of ferritin-bound iron and a compensatory increase in insoluble iron, which probably consists mainly of iron bound to intracellular organelles. Finally, although NO released by IFN-gamma/LPS-activated macrophages increased the iron-responsive element (IRE)-binding activity of both IRP1 and IRP2, IFN-gamma treatment decreased IRP2 activity in an NO-independent manner. This study demonstrates that the effect of IFN-gamma and/or LPS on macrophage iron metabolism is complex, and is not entirely due to either NO-or to IRP-mediated mechanisms. The overall effect is to decrease iron uptake, but not its utilization.
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PMID:Regulation of iron metabolism in murine J774 macrophages: role of nitric oxide-dependent and -independent pathways following activation with gamma interferon and lipopolysaccharide. 1049 10

Camel kidney ferritin was isolated from a tissue homogenate by thermal denaturation, ammonium sulphate fractionation, Sephacryl S-300 gel filtration and DEAE-blue gel affinity chromatography. The yield and the iron and neutral carbohydrate contents were 0.012 mg/g wet tissue, 4.0% and 2.7%, respectively. The phosphate:iron ratio was 0.13, twofold lower than that reported for camel liver ferritin. Native gel electrophoresis revealed the presence of a monomeric ferritin. SDS gel electrophoresis and immunoblotting showed two types of subunits, heavy and light, contrary to the extensive heterogeneity observed in camel liver ferritin. In general, the tissue ferritins shared a similar amino acid composition. However, a twofold lower glycine and an eightfold higher arginine content were recorded for camel kidney ferritin. In addition, kidney ferritin had a relatively high content of glutamic acid. Cross-reactivity studies by Ouchterlony double diffusion and noncompetitive indirect ELISA revealed a distinct cross-reactivity between buffalo ferritin antiserum and camel liver ferritin, but camel liver ferritin showed only weak cross-reactivity.
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PMID:Camel kidney ferritin: isolation and partial characterization. 1086 47

Chronic nitric oxide (NO) inhibition causes hypertension and renal injury. Concomitant salt overload promotes massive albuminuria. We investigated the mechanisms whereby these treatments impair glomerular permselectivity. Adult male Munich-Wistar rats received either a standard-salt (SS; 0.5% Na) or high-salt (HS; 3.1% Na) diet and either no treatment or the NO inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). At 30 days, albuminuria was moderate, the density of fixed anionic sites at the glomerular basement membrane (GBM), estimated by cationic ferritin binding, declined by approximately 35%, and the fractional clearance of 70-kDa neutral dextran (phi) rose moderately in rats receiving L-NAME and SS. Rats given L-NAME and HS exhibited massive albuminuria, whereas phi was nearly tripled. Depletion of GBM anionic sites was also seen in these rats. The GBM was thickened in both L-NAME-treated groups. These abnormalities were largely reversed after cessation of treatments. These results indicate that chronic L-NAME treatment promotes reversible albuminuria by impairing both glomerular size and charge selectivity. These effects likely reflect functional rather than structural disruption of the glomerular wall.
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PMID:Mechanisms of albuminuria in the chronic nitric oxide inhibition model. 1109 24

Substrates for CYP2C9 include fluoxetine, phenytoin, warfarin, losartam and numerous nonsteroidal anti-inflammatory drugs. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino-acid residues 144 Arg/Cys and 359 Ile/Leu of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, the frequency of this allele is, however, rather low. Consistently with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. The polymorphic enzyme CYP2C9 takes part in the metabolism of alkylating agents and polycyclic aromatic hydrocarbons like benzo(a)pyrene, a carcinogen present in tobacco smoke. Although the impact of impaired enzyme activity in metabolism of carcinogens and procarcinogens has not been fully defined, an association of CYP2C9 variant alleles to DNA adduct levels in lung tissues as well as to lung cancer risk have been reported. In this study 64 healthy subjects (44M/22F) were analysed for CYP2C9 genotype with PCR-RFLP and for serum carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), CA 19-9, CA 15-3, ferritin, IL-6, IL-8 concentrations by chemiluminescence or electrochemiluminescence methods. CYP2C9*1 was found to be the most prevalent allele and CYP2C9*1/CYP2C9*1 was the most frequent genotype represented in 64% of the population in southeastern Anatolia (Gaziantep). Although slight differences in serum tumour marker and cytokine concentrations were observed for CYP2C9 genotypes the differences were statistically insignificant (P > 0.05). This could be due to the complexity of the role of CYP2C9 in benzo(a)pyrene metabolism as well as from other contributing factors like interindividual variability of diverse enzymes participating in the same metabolic pathway, unequal expression of the variant alleles and differences in exposure to carcinogens. However, determination of CYP2C9 phenotypes in a larger group of subjects might clarify these slight differences.
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PMID:Cytochrome P4502C9 genotype in Southeast Anatolia and possible relation with some serum tumour markers and cytokines. 1183 86

The biological significance of the heme oxygenase (HO) system's response to stress reflects functions of its products-CO and bile pigments. CO is a messenger molecule, whereas bile pigments are antioxidants and modulators of cell signaling. Presently, an unexpected mechanism for sustained suprainduction of renal HO-1 following ischemia/reperfusion injury is described. Inhibition of nitric-oxide synthase (NOS) activity by Nomega-nitro-l-arginine methyl ester (l-NAME) at the resumption of reperfusion of rat kidney subjected to bilateral ischemia (30 min) was as effective as the most potent HO-1 inducer, the spin trap agent n-tert-butyl-alpha-phenyl nitrone (PBN), in causing sustained suprainduction of HO-1 mRNA. PBN forms stable radicals of oxygen and nitrogen. Twenty-four hours after reperfusion, HO-1 mRNA measured approximately 30-fold that of the control in the presence of l-NAME treatment; in its absence, the transcript increased to only approximately 5-fold. At 4 h in the presence or absence of the l-NAME HO-1, mRNA was increased by approximately 30-fold. The transcript was translated to active protein as indicated by Western blotting, immunohistochemistry, and activity analyses. l-NAME was not effective given 1 h after resumption of reperfusion. Suprainduction was restricted to the kidney and not detected in the heart and aorta; ferritin expression in the kidney was not effected. It is reasoned that in tissue directly insulted by ischemia/reperfusion, increased production of NO radicals promotes the loss of HO-1 transcript. Because the absence of NO radicals and presence of PBN had a similar effect on HO-1, we propose that suprainduction of the gene is mainly caused by O2 radicals formed on reperfusion. Inhibition of NOS is potentially useful for sustained induction of HO-1 in organs that will be subjected to oxidative-stress insult.
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PMID:Nitric oxide inhibitor N omega -nitro-l-arginine methyl ester potentiates induction of heme oxygenase-1 in kidney ischemia/reperfusion model: a novel mechanism for regulation of the oxygenase. 1267 88


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