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 Nrf2/anti-oxidant response element (ARE) pathway plays an important role in regulating cellular anti-oxidants, including haem oxygenase-1 (HO-1). Various kinases have been implicated in the pathways leading to Nrf2 activation. Here, we investigated the effect of epigallocatechin (EGC) on ARE-mediated gene expression in human monocytic cells. EGC time and dose dependently increased HO-1 mRNA and protein expression but had minimal effect on expression of other ARE-regulated genes, including NAD(P)H:quinone oxidoreductase 1, glutathione cysteine ligase and ferritin. siRNA knock down of Nrf2 significantly inhibited EGC-induced HO-1 expression. Furthermore, inhibition of PKC by Ro-31-8220 dose dependently decreased EGC-induced HO-1 mRNA expression, whereas MAP kinase and phosphatidylinositol-3-kinase pathway inhibitors had no significant effect. EGC stimulated phosphorylation of PKCalphabeta and delta in THP-1 cells. PKCdelta inhibition significantly decreased EGC-induced HO-1 mRNA expression, whereas PKCalpha- and beta-specific inhibitors had no significant effect. These results demonstrate for the first time that EGC-induced HO-1 expression occurs via PKCdelta and Nrf2.
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PMID:Epigallocatechin activates haem oxygenase-1 expression via protein kinase Cdelta and Nrf2. 1858 7

Entamoeba histolytica is a parasitic protozoan that produces dysentery and often reaches the liver, leading to abscess formation. Ferritin is an iron-storage protein that is mainly found in liver and spleen in mammals. The liver contains a plentiful source of iron for amoebae multiplying in that organ, making it a prime target for infection since iron is essential for the growth of this parasite. The aim of this study was to determine whether trophozoites are able to take up ferritin and internalise this protein for their growth in axenic culture. Interaction between the amoebae and ferritin was studied by flow cytometry, confocal laser-scanning microscopy and transmission electron microscopy. Amoebae were viable in iron supplied by ferritin. Trophozoites quickly internalised ferritin via clathrin-coated vesicles, a process that was initiated within the first 2 min of incubation. In 30 min, ferritin was found colocalizing with the LAMP-2 protein at vesicles in the cytosol. The uptake of ferritin was time- temperature- and concentration-dependent, specific and saturated at 46 nM of ferritin. Haemoglobin and holo-transferrin did not compete with ferritin for binding to amoebae. Amoebae cleaved ferritin leading to the production of several different sized fragments. Cysteine proteases of 100, 75 and 50 kDa from amoeba extracts were observed in gels copolymerised with ferritin. For a pathogen such as E. histolytica, the capacity to utilise ferritin as an iron source may well explain its high pathogenic potential in the liver.
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PMID:Entamoeba histolytica uses ferritin as an iron source and internalises this protein by means of clathrin-coated vesicles. 1884 48

Ferritin heavy chain (FHC) protein was significantly reduced in murine failing hearts following left coronary ligation or thoracic transverse aortic constriction. The mRNA expression of FHC was not significantly altered in failing hearts, compared to that in control sham-operated hearts. Prussian blue staining revealed spotty iron depositions in myocardial infarct failing hearts. Oxidative stress was enhanced in the myocardial infarct failing hearts, as evidenced by increases in 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine immunoreactivity. To clarify the functional significance of FHC downregulation in hearts, we infected rat neonatal cardiomyocytes with adenoviral vector expressing short hairpin RNA targeted to FHC (Ad-FHC-RNAi). The downregulation of FHC induced a reduction in the viability of cardiomyocytes. The relative number of iron deposition-, 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cardiomyocytes was significantly higher in Ad-FHC-RNAi-infected cardiomyocytes than in control vector-infected cardiomyocytes. Treatment of Ad-FHC-RNAi-infected cardiomyocytes with desferrioxamine, an iron chelator, significantly reduced the number of iron, 4-hydroxy-2-nonenal or 8-hydroxy-2'-deoxyguanosine-positive cells, and increased viability. In addition, treatment with N-acetyl cysteine, an antioxidant, significantly reduced the number of 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cells. Reduced viability in Ad-FHC-RNAi-infected cardiomyocytes was significantly improved with N-acetyl cysteine treatment. These findings indicate that excessive free iron and the resultant enhanced oxidative stress caused by downregulation of FHC lead to cardiomyocyte death. The decrease in FHC expression in failing hearts may play an important role in the pathogenesis of heart failure.
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PMID:Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes. 1899 54

Parkinson's disease (PD) is characterized by early glutathione depletion in the substantia nigra (SN). Among its various functions in the cell, glutathione acts as a substrate for the mitochondrial enzyme glutaredoxin 2 (Grx2). Grx2 is involved in glutathionylation of protein cysteine sulfhydryl residues in the mitochondria. Although monothiol glutathione-dependent oxidoreductases (Grxs) have previously been demonstrated to be involved in iron-sulfur (Fe-S) center biogenesis, including that in yeast, here we report data suggesting the involvement of mitochondrial Grx2, a dithiol Grx, in iron-sulfur biogenesis in a mammalian dopaminergic cell line. Given that mitochondrial dysfunction and increased cellular iron levels are two important hallmarks of PD, this suggests a novel potential mechanism by which glutathione depletion may affect these processes in dopaminergic neurons. We report that depletion of glutathione as substrate results in a dose-dependent Grx2 inhibition and decreased iron incorporation into a mitochondrial complex I (CI) and aconitase (m-aconitase). Mitochondrial Grx2 inhibition through siRNA results in a corresponding decrease in CI and m-aconitase activities. It also results in significant increases in iron-regulatory protein (IRP) binding, likely as a consequence of conversion of Fe-S-containing cellular aconitase to its non-Fe-S-containing IRP1 form. This is accompanied by increased transferrin receptor, decreased ferritin, and subsequent increases in mitochondrial iron levels. This suggests that glutathione depletion may affect important pathologic cellular events associated with PD through its effects on Grx2 activity and mitochondrial Fe-S biogenesis.
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PMID:A disruption in iron-sulfur center biogenesis via inhibition of mitochondrial dithiol glutaredoxin 2 may contribute to mitochondrial and cellular iron dysregulation in mammalian glutathione-depleted dopaminergic cells: implications for Parkinson's disease. 1929 Jul 77

Neonatal hemochromatosis is a rare disease of iron metabolism, characterized by the excess accumulation of iron in the tissues. This occurs in utero and can lead to fetal demise or an infant who presents with advanced liver disease in the neonatal period. A case of neonatal hemochromatosis is reported in a 37-week infant who presented at birth with thrombocytopenia, coagulopathy, and abnormal liver imaging studies. The diagnoses of infection and metabolic errors were excluded before the confirmation of neonatal hemochromatosis was made. This diagnosis was confirmed by elevated ferritin levels and extrahepatic siderosis excluding the reticuloendothelial system. Anti-oxidant therapy was initiated with N-acetyl cysteine, selenium, vitamins C and E and intravenous immunoglobulin. The infant demonstrated a positive response and was discharged home with outpatient follow up. The clinical presentation of neonatal hemochromatosis is reviewed as well as diagnosis and treatment strategies.
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PMID:Neonatal hemochromatosis: a case report. 1936 27

Iron bioavailability from supplements and fortificants varies depending upon the form of the iron and the presence or absence of iron absorption enhancers and inhibitors. Our objectives were to compare the effects of pH and selected enhancers and inhibitors and food matrices on the bioavailability of iron in soluble ferric pyrophosphate (SFP) to other iron fortificants using a Caco-2 cell culture model with or without the combination of in vitro digestion. Ferritin formation was the highest in cells treated with SFP compared to those treated with other iron compounds or chelates. Exposure to pH 2 followed by adjustment to pH 7 markedly decreased FeSO(4) bioavailability but had a smaller effect on bioavailabilities from SFP and sodium iron(III) ethylenediaminetetraacetate (NaFeEDTA), suggesting that chelating agents minimize the effects of pH on iron bioavailability. Adding ascorbic acid (AA) and cysteine to SFP in a 20:1 molar ratio increased ferritin formation by 3- and 2-fold, respectively, whereas adding citrate had no significant effect on the bioavailability of SFP. Adding phytic acid (10:1) and tannic acid (1:1) to iron decreased iron bioavailability from SFP by 91 and 99%, respectively. The addition of zinc had a marked inhibitory effect on iron bioavailability. Calcium and magnesium also inhibited iron bioavailability but to a lesser extent. Incorporating SFP in rice greatly reduced iron bioavailability from SFP, but this effect can be partially reversed with the addition of AA. SFP and FeSO(4) were taken up similarly when added to nonfat dry milk. Our results suggest that dietary factors known to enhance and inhibit iron bioavailability from various iron sources affect iron bioavailability from SFP in similar directions. However, the magnitude of the effects of iron absorption inhibitors on SFP iron appears to be smaller than on iron salts, such as FeSO(4) and FeCl(3). This supports the hypothesis that SFP is a promising iron source for food fortification and dietary supplements.
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PMID:Comparing soluble ferric pyrophosphate to common iron salts and chelates as sources of bioavailable iron in a Caco-2 cell culture model. 1944 7

Iron is essential for nearly all organisms; in mammals, it is part of proteins such as haemoglobin, and it is captured by transferrin and lactoferrin. Transferrin is present in serum, and lactoferrin is secreted by the mucosa and by neutrophils at infection sites, as a host iron-withholding response, sequestering iron away from invading microorganisms. Additionally, all cells contain ferritin, which sequesters iron when its intracellular levels are increased, detoxifying and preventing damage. Liver ferritin contains 50% of iron corporal reserves. During evolution, pathogens have evolved diverse strategies to obtain iron from their hosts in order to survive. The protozoan Entamoeba histolytica invades the intestinal mucosa, causing dysentery, and the trophozoites often travel to the liver producing hepatic abscesses; thus, intestine and liver proteins could be important iron supplies for E. histolytica. We found that E. histolytica trophozoites can grow in both ferrous and ferric iron, and that they can use haemoglobin, holo-transferrin, holo-lactoferrin, and ferritin as in vitro iron sources. These proteins supported the amoeba growth throughout consecutive passages, similarly to ferric citrate. By confocal microscopy and immunoblotting, iron-binding proteins were observed specifically bound to the amoeba surface, and they were endocytosed, trafficked through the endosomal/lysosomal route, and degraded by neutral and acidic cysteine-proteases. Transferrin and ferritin were mainly internalized through clathrin-coated vesicles, and holo-lactoferrin was mainly internalized by caveola-like structures. In contrast, apo-lactoferrin bound to membrane lipids and cholesterol, inducing cell death. The results suggest that in vivo trophozoites secrete products that can destroy enterocytes, erythrocytes, and hepatocytes, releasing transferrin, haemoglobin, ferritin, and other iron-containing proteins, which, together with lactoferrin derived from neutrophils and acinar cells, could be used as abundant iron supplies by amoebas.
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PMID:Use and endocytosis of iron-containing proteins by Entamoeba histolytica trophozoites. 1953 57

We used the muscle creatine kinase (MCK) conditional frataxin knockout mouse to elucidate how frataxin deficiency alters iron metabolism. This is of significance because frataxin deficiency leads to Friedreich's ataxia, a disease marked by neurologic and cardiologic degeneration. Using cardiac tissues, we demonstrate that frataxin deficiency leads to down-regulation of key molecules involved in 3 mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase Nfs1), mitochondrial iron storage (mitochondrial ferritin), and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, and ferrochelatase). This marked decrease in mitochondrial iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excessive mitochondrial iron observed. This effect is compounded by increased iron availability for mitochondrial uptake through (i) transferrin receptor1 up-regulation, increasing iron uptake from transferrin; (ii) decreased ferroportin1 expression, limiting iron export; (iii) increased expression of the heme catabolism enzyme heme oxygenase1 and down-regulation of ferritin-H and -L, both likely leading to increased "free iron" for mitochondrial uptake; and (iv) increased expression of the mammalian exocyst protein Sec15l1 and the mitochondrial iron importer mitoferrin-2 (Mfrn2), which facilitate cellular iron uptake and mitochondrial iron influx, respectively. Our results enable the construction of a model explaining the cytosolic iron deficiency and mitochondrial iron loading in the absence of frataxin, which is important for understanding the pathogenesis of Friedreich's ataxia.
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PMID:Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant. 1980 8

Gold nanoshells around 26 nm in diameter with a 7 nm thick wall were fabricated in an aqueous solution using pre-reconstituted ferritin proteins as a removable bio-template. The synthesis of gold nanoshells was initiated by planting gold nanoparticle seeds in the hydrophilic three-fold channels of the ferritin protein. The process was facilitated by the energetically favorable gold-sulfur bonds formed at the cysteine residues lining these channels.
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PMID:Gold nanoshell assembly on a ferritin protein employed as a bio-template. 2035 72

Apo-ferritin (apo-Fr) mutants are used as scaffolds to accommodate palladium (allyl) complexes. Various coordination arrangements of the Pd complexes are achieved by adjusting the positions of cysteine and histidine residues on the interior surface of the apo-Fr cage.
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PMID:Definite coordination arrangement of organometallic palladium complexes accumulated on the designed interior surface of apo-ferritin. 2073 Feb 33


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