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)

Biosynthesis of nitric oxide (NO) from L-arginine modulates activity of iron-dependent enzymes, including mitochondrial acontiase, an [Fe-S] protein. We examined the effect of NO on the activity of iron regulatory factor (IRF), a cytoplasmic protein which modulates both ferritin mRNA translation and transferrin receptor mRNA stability by binding to specific mRNA sequences called iron responsive elements (IREs). Murine macrophages were activated with interferon-gamma and lipopolysaccharide to induce NO synthase activity and cultured in the presence or absence of NG-substituted analogues of L-arginine which served as selective inhibitors of NO synthesis. Measurement of the nitrite concentration in the culture medium was taken as an index of NO production. Mitochondria-free cytosols were then prepared and aconitase activity as well as IRE binding activity and induction of IRE binding activity were correlated and depended on NO synthesis after IFN-gamma and/or LPS stimulation. Authentic NO gas as well as the NO-generating compound 3-morpholinosydnonimine (SIN-1) also conversely modulated aconitase and IRE binding activities of purified recombinant IRF. These results provide evidence that endogenously produced NO may modulate the post-transcriptional regulation of genes involved in iron homeostasis and support the hypothesis that the [Fe-S] cluster of IRF mediates iron-dependent regulation.
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PMID:Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. 750 26

Recently, it was reported that nitric oxide (NO) directly controls intracellular iron metabolism by activating iron regulatory protein (IRP), a cytoplasmic protein that regulates ferritin translation. To determine whether intracellular iron levels themselves affect NO synthase (NOS), we studied the effect of iron on cytokine-inducible NOS activity and mRNA expression in the murine macrophage cell line J774A.1. We show here that NOS activity is decreased by about 50% in homogenates obtained from cells treated with interferon gamma plus lipopolysaccharide (IFN-gamma/LPS) in the presence of 50 microM ferric iron [Fe(3+)] as compared with extracts from cells treated with IFN-gamma/LPS alone. Conversely, addition of the iron chelator desferrioxamine (100 microM) at the time of stimulation with IFN-gamma/LPS increases NOS activity up to 2.5-fold in J774 cells. These effects of changing the cellular iron state cannot be attributed to a general alteration of the IFN-gamma/LPS signal, since IFN-gamma/LPS-mediated major histocompatibility complex class II antigen expression is unaffected. Furthermore, neither was the intracellular availability of the NOS cofactor tetrahydrobiopterin altered by treatment with Fe(3+) or desferrioxamine, nor do these compounds interfere with the activity of the hemoprotein NOS in vitro. We demonstrate that the mRNA levels for NOS are profoundly increased by treatment with desferrioxamine and reduced by Fe(3+). The half-life of NOS mRNA appeared not to be significantly altered by administration of ferric ion, and NOS mRNA stability was only slightly prolonged by desferrioxamine treatment. Nuclear run-off experiments demonstrate that nuclear transcription of cytokine-inducible NOS mRNA is strongly increased by desferrioxamine whereas it is decreased by Fe(3+). Thus, this transcriptional response appears to account quantitatively for the changes in enzyme activity. Our results suggest the existence of a regulatory loop between iron metabolism and the NO/NOS pathway.
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PMID:Iron regulates nitric oxide synthase activity by controlling nuclear transcription. 752 Apr 77

Iron-regulatory protein (IRP) is a master regulator of cellular iron homeostasis. Expression of several genes involved in iron uptake, storage, and utilization is regulated by binding of IRP to iron-responsive elements (IREs), structural motifs within the untranslated regions of their mRNAs. IRP-binding to IREs is controlled by cellular iron availability. Recent work revealed that nitric oxide (NO) can mimic the effect of iron chelation on IRP and on ferritin mRNA translation, whereas the stabilization of transferrin receptor mRNA following NO-mediated IRP activation could not be observed in gamma-interferon/lipopolysaccharide-stimulated murine macrophages. In this study, we establish the function of NO as a signaling molecule to IRP and as a regulator of mRNA translation and stabilization. Fibroblasts with undetectable levels of endogenous NO synthase activity were stably transfected with a cDNA encoding murine macrophage inducible NO synthase. Synthesis of NO activates IRE binding, which in turn represses ferritin mRNA translation and stabilizes transferrin receptor mRNA against targeted degradation. Furthermore, iron starvation and NO release are shown to be independent signals to IRP. The posttranscriptional control of iron metabolism is thus intimately connected with the NO pathways.
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PMID:Nitric oxide signaling to iron-regulatory protein: direct control of ferritin mRNA translation and transferrin receptor mRNA stability in transfected fibroblasts. 753 89

Macrophage effector functions are influenced by their iron status and by shifts in the balance between type 1 Th1 and Th2 cells. To elucidate the influence of the Th2 cytokines IL-4 and IL-13 on macrophage iron metabolism, we investigated activated primary mouse macrophages and the murine macrophage cell line J774. Stimulation of J774 cells and primary macrophages with IFN-gamma/LPS activates the RNA binding affinities of iron regulatory protein-1 (IRP-1) and IRP-2 for iron-responsive elements, leading to translational repression of the iron storage protein ferritin. Activation of IRP-1 and IRP-2 is caused by increased formation of nitric oxide (NO) via stimulation of the inducible NO synthase by IFN-gamma/LPS. Treatment of macrophages with IL-4 and/or IL-13 before stimulation with IFN-gamma/LPS suppresses NO formation and IRP activation, with concomitantly enhanced ferritin synthesis despite a small reduction in ferritin heavy chain mRNA levels. The mRNA levels for the membrane receptor for iron uptake, transferrin receptor (TfR), decrease following stimulation with IFN-gamma/LPS, although IRP-mediated stabilization of the TfR mRNA would have been expected. This as yet unidentified proximal inhibitory signal by IFN-gamma/LPS is antagonized by IL-4 and/or IL-13, which leads to increased TfR mRNA expression in an IRP-independent manner. Thus, IL-4 and IL-13 regulate the iron metabolism of activated macrophages by at least two different pathways: first, by opposing NO-mediated IRP activation, thereby increasing ferritin translation; and second, by an IRP-independent augmentation of TfR mRNA expression. We suggest that IL-4 and IL-13 may enhance iron uptake and storage in activated macrophages and thereby contribute to down-regulation of macrophage effector functions.
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PMID:Pathways for the regulation of macrophage iron metabolism by the anti-inflammatory cytokines IL-4 and IL-13. 897 18

Heme oxygenase (HO) proteins are members of the HSP30 family and consist of 2 isozymes identified to date, termed HO-1 and HO-2. Separate genes encode the isozymes and protein products which are immunochemically distinct, share less than 50% similarity at the amino acid sequence level. Each form, however, shows greater than 90% similarity among species, including human and the rat (reviewed in ref.). Furthermore, these isozymes function in a well-defined role to carry out oxidation of the heme molecule (Fe-protoporphyrin IX) in concert with NADPH-cytochrome P450 reductase. The oxidation of heme is isomer specific and results in the formation of bile pigments, carbon monoxide, and iron. The heme molecule constitutes the prosthetic moiety of hemoproteins, such as hemoglobin, myoglobin, catalase, soluble guanylate cyclase, cytochrome b5, cytochromes P450 and NO synthase. HO-1 also known as heat shock protein (HSP) 32 is encoded by a gene which is exquisitely stress-responsive and a host of stimuli that mediate oxidative stress cause induction of the protein both in vivo and in vitro. The HO-2 form shows a unique pattern of regulation from that of HO-1. HO-2 is a constitutive protein and its expression is not affected by the inducers of HO-1 tested to date; rather, the only known regulator of HO-2 yet identified is adrenal glucocorticoids. The two isozymes display vast differences in tissue distribution and under normal conditions HO-1 is present in the whole brain at the limit of immunodetection and is discreetly localized in select neuronal populations. HO-1 protein (approximately 32 kDa) and its approximately 1.8 kb transcript are increased, however, in response to stressful stimuli primarily in non-neuronal cell populations. The heme oxygenase system serves in both a catabolic and anabolic capacity in the cell. In the former capacity, it down-regulates cellular heme and hemoprotein levels. And, as such it inactivates the most effective catalyst for formation of free radicals, the heme molecule. In its anabolic role, as noted above, heme oxygenase produces bile pigments, carbon monoxide, and iron, all of which are biologically active: bile pigments function as antioxidants; the carbon monoxide generated by HO activity has been correlated with the generation of cGMP; and iron regulates expression of various genes, including that of HO-1 itself, as well as transferrin receptors, ferritin, and NO synthase. We used rabbit anti-rat HO-2 polyclonal antibody and HO-2 cDNA to localize HO-2 immunoreactive protein and the 1.3- and 1.9 kb homologous transcripts, respectively, in rodent brain as visualized by histochemical staining procedures. These protocols provide the first detailed description of methodologies successfully used to define the pattern of HO-2 expression at the transcriptional and translational levels in the adult rat brain and glucocorticoid-treated newborn rats. The procedures described herein have the virtue of being non-radioactive, as well as applicability to the systemic organs, such as the cardiovascular system and the male reproductive organs. Visualization of cellular HO-2 expression aids in assessment of potential sites of carbon monoxide, iron, and bilirubin production within the nervous system.
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PMID:Histochemical localization of heme oxygenase-2 protein and mRNA expression in rat brain. 938 81

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

Dry cough is the most common limiting factor of ACE inhibitor (ACEI) use. Generation of NO, a proinflammatory substance on bronchial epithelial cells, is increased by ACEI. Using a randomized, double-blind, placebo-controlled trial, we tested the hypothesis that supplementing iron, an inhibitor of NO synthase, may reduce the cough associated with ACEI use. The subjects were 19 patients who had developed ACEI-induced cough. After a 2-week observation period, they were randomized to a daily morning dose of either 256-mg ferrous sulfate as a tablet or placebo for a treatment period of 4 weeks. The subjects were requested to fill out a cough diary by scoring the daily severity of the cough on a scale of 0 to 4. Mean daily cough scores for the last week of the observation and treatment period were compared. Changes in blood cell count and serum iron and ferritin concentration between the 2 periods were evaluated. Mean daily cough scores during the observation and treatment periods were 3.07+/-0.70 and 1.69+/-1.10, respectively, for the iron group and 2.57+/-0.80 and 2.35+/-1.22, respectively, for the placebo group, showing a significant reduction in cough scores with iron supplementation (P<0.01) but not with placebo. Three subjects in the iron group showed almost complete cough abolition. No significant changes in laboratory data were observed in either group. In conclusion, iron supplementation successfully decreases ACEI-induced cough. This effect may be related to the decrease of NO generation associated with the inhibition of NO synthase activity in bronchial epithelial cells.
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PMID:Iron supplementation inhibits cough associated with ACE inhibitors. 1175 45

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

To explore the role of nitric oxide (NO) in the pathogenesis and effect on regulation of iron metabolism in anemia of chronic disease (ACD) and provide experimental evidence for prevention and treatment of ACD. On the basis of traditional animal model of rheumatoid arthritis, an ACD rat model was established by repeated injection of Freund's complete adjuvant. The relationship between NO concentration and iron metabolism was observed in ACD rats with and without NO synthase inhibitor, L-NAME, (N omega-nitro-L-arginine methyl ester L-NAME). The results showed that anemia was induced in the rat model. In the ACD group, NO concentration and NO synthase activity in serum increased; iron, total iron binding capacity (TIBC) and transferrin saturation (TS) in serum and ferritin in erythrocytes (rFn) decreased; transferrin receptor (TfR) and iron in bone marrow cells decreased; ferritin in serum and iron in liver increased and meanwhile the acotinase activity in liver decreased. After administration of L-NAME, anemia was improved, when NO, NO-synthase activity, liver iron and serum ferritin decreased, but serum iron, TS, TIBC, rFn, TfR, iron in marrow cells and liver acotinase activity elevated. The levels of parameters for iron metabolism in ACD + L-NAME group were situated between ACD and control groups. It is concluded that NO plays an important role in pathogenesis of ACD and influences the regulation of iron in ACD. Decrease of NO level as early as possible will benefit to block the development of anemia, that will provide a new strategy of therapy for ACD.
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PMID:[Effect of nitric oxide on iron metabolism in rats with anemia of chronic disease]. 1296 68

Heme oxygenase-1 (HO-1) is part of the integrated response to oxidative stress. This enzyme may exert anti-inflammatory effects in some animal models, although the precise mechanisms are not fully understood. We have examined the role of HO-1 in the inflammatory response induced by zymosan in the mouse air pouch. Zymosan administration induced HO-1 protein expression in leukocytes migrating to exudates, with maximal levels in the late phase of this response (24-48 h). This was accompanied by ferritin induction and bilirubin accumulation, indicating that this enzyme is active in our model. HO-1 expression by zymosan treatment was partly reduced by aminoguanidine, suggesting the participation of endogenous nitric oxide in the mechanisms leading to HO-1 synthesis in the zymosan-injected mouse air pouch. Up-regulation of HO-1 by hemin administration resulted in inhibition of nitric-oxide synthase-2 activity, cellular infiltration into the air pouch exudate, and plasmatic exudation. Leukotriene B4 levels in exudates were significantly decreased in the early phase of this response (4 h), whereas interleukin-1beta and tumor necrosis factor-alpha were inhibited at all time points. Inhibition of HO-1 activity by zinc protoporphyrin IX prevented most of the effects caused by hemin administration. Our results indicate that HO-1 exerts anti-inflammatory effects on the response to zymosan in the mouse air pouch and support a role for this enzyme in the modulation of inflammatory processes.
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PMID:Beneficial effects of heme oxygenase-1 up-regulation in the development of experimental inflammation induced by zymosan. 1456 52


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