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 iron storage protein, ferritin, represents a possible source of iron for oxidative reactions in biological systems. It has been shown that superoxide and several xenobiotic free radicals can release iron from ferritin by a reductive mechanism. Tetravalent vanadium (vanadyl) reacts with oxygen to generate superoxide and pentavalent vanadium (vanadate). This led to the hypothesis that vanadyl causes the release of iron from ferritin. Therefore, the ability of vanadyl and vanadate to release iron from ferritin was investigated. Iron release was measured by monitoring the generation of the Fe(2+)-ferrozine complex. It was found that vanadyl but not vanadate was able to mobilize ferritin iron in a concentration dependent fashion. Initial rates, and iron release over 30 minutes, were unaffected by the addition of superoxide dismutase. Glutathione or vanadate added in relative excess to the concentration of vanadyl, inhibited iron release up to 45%. Addition of ferritin at the concentration used for measuring iron release prevented vanadyl-induced NADH oxidation. Vanadyl promoted lipid peroxidation in phospholipid liposomes. Addition of ferritin to the system stimulated lipid peroxidation up to 50% above that with vanadyl alone. Ferritin alone did not promote significant levels of lipid peroxidation.
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PMID:Tetravalent vanadium releases ferritin iron which stimulates vanadium-dependent lipid peroxidation. 164 80

Reduction of iron is important in promoting xenobiotic-enhanced, microsomal lipid peroxidation, yet there is little evidence that Fe3+ chelates that promote lipid peroxidation can be reduced by the microsomal system. We have shown that rat liver microsomes catalyse NADPH-dependent reduction of Fe3+ without chelator, as well as Fe3+(ADP), Fe3+(ATP), Fe3+(citrate), Fe3+(EDTA), and ferrioxamine in N2. The NADPH oxidation that accompanied Fe3+ reduction was inhibited by CO for all chelates, except Fe3+ (EDTA). This implies that, except for Fe3+ (EDTA), cytochrome P450 was involved in reduction of the complexes. Adriamycin, paraquat, and anthraquinone 2-sulfonate (AQS) enhanced reduction of all the Fe3+ chelates, whereas menadione enhanced reduction only of Fe3+(ADP) and Fe3+(citrate). All the compounds enhanced oxidation of NADPH in the presence or absence of iron. This was not inhibited by CO, and the results are compatible with Fe3+ reduction occurring via the xenobiotic radicals produced by cytochrome P450 reductase. Microsomal reduction of the xenobiotics, except menadione, enabled the reduction and release of iron from ferritin. Fe3+ chelate reduction, both with and without xenobiotic, was inhibited by O2, although it still proceeded in air at 10-20% of the rate in N2. Iron-dependent lipid peroxidation was promoted by ADP and ATP, inhibited 50% by citrate, and completely inhibited by EDTA and desferrioxamine. Of the xenobiotics, only Adriamycin enhanced microsomal lipid peroxidation. These results indicate that the effects of chelators and xenobiotics on Fe3+ reduction do not correlate with lipid peroxidation and, although reduction is necessary, there must be other factors involved.
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PMID:Microsomal reduction of low-molecular-weight Fe3+ chelates and ferritin: enhancement by adriamycin, paraquat, menadione, and anthraquinone 2-sulfonate and inhibition by oxygen. 285 Jul 67

Electrophiles formed during metabolic activation of chemical carcinogens and reactive oxygen species generated from endogenous and exogenous sources play a significant role in carcinogenesis. Cancer chemoprevention by induction of phase 2 proteins to counteract the insults of these reactive intermediates has gained considerable attention. Nuclear factor E2 p45-related factor 2 (Nrf2), a bZIP transcription factor, plays a central role in the regulation (basal and or inducible expression) of phase 2 genes by binding to the "antioxidant response element" in their promoters. Identification of novel Nrf2-regulated genes is likely to provide insight into cellular defense systems against the toxicities of electrophiles and oxidants and may define effective targets for achieving cancer chemoprevention. Sulforaphane is a promising chemopreventive agent that exerts its effect by strong induction of phase 2 enzymes via activation of Nrf2. In the present study, a transcriptional profile of small intestine of wild-type (nrf2 +/+) and knock out (nrf2 -/-) mice treated with vehicle or sulforaphane (9 micromol/day for 1 week, p.o.) was generated using the Murine Genome U74Av2 oligonucleotide array (representing approximately 6000 well-characterized genes and nearly 6000 expressed sequence tags). Comparative analysis of gene expression changes between different treatment groups of wild-type and nrf2-deficient mice facilitated identification of numerous genes regulated by Nrf2 including previously reported Nrf2-regulated genes such as NAD(P)H:quinone reductase (NQO1), glutathione S-transferase (GST), gamma-glutamylcysteine synthetase (GCS), UDP-glucuronosyltransferases (UGT),epoxide hydrolase, as well as a number of new genes. Also identified were genes encoding for cellular NADPH regenerating enzymes (glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme), various xenobiotic metabolizing enzymes, antioxidants (glutathione peroxidase, glutathione reductase, ferritin, and haptaglobin), and biosynthetic enzymes of the glutathione and glucuronidation conjugation pathways. The data were validated by Northern blot analysis and enzyme assays of selected genes. This investigation expands the horizon of Nrf2-regulated genes, highlights the cross-talk between various metabolic pathways, and divulges the pivotal role played by Nrf2 in regulating cellular defenses against carcinogens and other toxins.
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PMID:Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. 1223 84

Ferritin is a ubiquitous intracellular iron storage protein that consists of 24 subunits of the H and L type. The ability to sequester iron from participation in oxygen free radical formation is consistent with a cytoprotective role for ferritin. Here we demonstrate that ferritins H and L are induced in cells treated with beta-napthoflavone (beta-NF) and chemopreventive dithiolethiones. Induction of ferritin H by beta-NF and the dithiolethiones oltipraz and 1,2-dithiole-3-thione (D3T) occurs via a transcriptional mechanism that is mediated by the ferritin H electrophile/antioxidant-responsive element (EpRE/ARE). The murine ferritin H gene contains five potential xenobiotic-responsive element (XRE) sequences in its 5'-promoter region. However, deletion analysis demonstrates that these XRE sequences are not functional in inducing ferritin H in response to beta-NF. Electrophoretic mobility shift assays demonstrate that the ferritin H EpRE/ARE binds Nrf2. Transfection of chimeric ferritin H reporter genes with Nrf2 expression vectors and Nrf2 dominant-negative mutants indicate that Nrf2 functions at the EpRE/ARE to mediate transcriptional activation of ferritin H. Induction of ferritin H and L was not seen in Nrf2 knockout cells, demonstrating that this transcription factor is required for the induction of ferritin in response to polycyclic aromatic xenobiotics and chemopreventive agents. Nrf2 may also play a role in basal transcription of both ferritin H and L. These results provide a mechanistic link between regulation of the iron storage protein ferritin and the cancer chemopreventive response.
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PMID:Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones. 1243 35

Glutathione plays an essential role in maintaining cellular redox balance, protecting cells from oxidative stress and detoxifying xenobiotic compounds. Glutathione depletion has been implicated in neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Cells of neuronal origin are acutely sensitive to glutathione depletion, providing an avenue for studying the mechanisms invoked for neuronal survival in response to oxidant challenge. We investigated the changes in mRNA profile in HT22 hippocampal cells following administration of homocysteic acid (HCA), a glutathione-depleting drug. We report that HCA treatment of HT22 murine hippocampal cells increases the levels of the mRNAs encoding at least three proteins involved in protection from oxidant injury, the mRNAs encoding heavy (H) and light (L) ferritin and glutathione S-transferase (GST).
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PMID:Glutathione depletion in hippocampal cells increases levels of H and L ferritin and glutathione S-transferase mRNAs. 1753 47

The use of animal models in pharmaceutical research is a costly and sometimes misleading method of generating toxicity data and hence predicting human safety. Therefore, in vitro test systems, such as primary rat hepatocytes, and the developing genomics and proteomics technologies, are playing an increasingly important role in toxicological research. Gene and protein expression analysis were investigated in a time series (up to 5 days) of primary rat hepatocytes cultured on collagen coated dishes. Especially after 24h, a significant down-regulation of many important Phase I and Phase II enzymes (e.g., cytochrome P450's, glutathione-S-transferases, sulfotransferases) involved in xenobiotic metabolism, and antioxidative enzymes (e.g., catalase, superoxide dismutase, glutathione peroxidase) was observed. Acute-phase-response enzymes were frequently up-regulated (e.g., LPS binding protein, alpha-2-macro-globulin, ferritin, serine proteinase inhibitor B, haptoglobin), which is likely to be a result of cellular stress caused by the cell isolation procedure (perfusion) itself. A parallel observation was the increased expression of several structural genes (e.g., beta-actin, alpha-tubulin, vimentin), possibly caused by other proliferating cell types in the culture, such as fibroblasts or alternatively by hepatocyte dedifferentiation. In conclusion, the careful interpretation of data derived from this in vitro system indicates that primary hepatocytes can be successfully used for short-term toxicity studies up to 24h. However, culturing conditions need to be further optimized to reduce the massive changes of gene and protein expression of long-term cultured hepatocytes to allow practical applications as a long-term toxicity test system.
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PMID:Genomics and proteomics analysis of cultured primary rat hepatocytes. 1776 30

Recent advances in proteomics have provided an excellent opportunity to understand biological adaptation under complex environmental stress at the protein level. Gaobeidian Lake, located in Beijing, China, is characterized by complex environmental stresses by serving as both the effluent of a wastewater treatment plant and a coolant of a nearby thermal power plant. Liver is the primary organ of energy metabolism and xenobiotic detoxification. To further our understanding of how organisms that live in Gaobeidian Lake acclimatize themselves to these complex environmental stresses, hepatic protein expression patterns were examined in goldfish Carassius auratus that inhabit the lake. Huairou Reservoir, a drinking water source, was used as a reference site. Twenty four protein spots, which were differently expressed in the two sites, were further digested with trypsin and analyzed by matrix-assisted laser desorption/ionization (MALDI) tandem time of flight mass spectrometry (TOF/TOF). The expression of several energy metabolism and oxidative stress proteins, such as glutathione peroxidase (GPx), ferritin H3, and liver basic fatty acid-binding protein (Lb-FABP) were found to be altered in this stressful environment. In addition to the up-regulation of GPx translation, both the mRNA levels and enzymatic activity of GPx protein were elevated in goldfish living in Gaobeidian Lake. The expression of both peroxisome proliferator activated receptor (PPAR), one of the most important metabolism and stress regulation genes as well as cytochrome P450 1A1 (CYP1A1), a detoxification gene, was also detected by real-time PCR at the two sites. Increased expression levels of both PPAR-beta and CYP1A1 (P < 0.1) were observed in Gaobeidian Lake. Our study provides an integrative view of the expression levels of hepatic proteins and genes in goldfish under complex environmental stress that live in Gaobeidian Lake. Our results showed that anthropogenic environmental stresses in Gaobeidian Lake activated the regulation gene of lipid metabolism PPAR, elevated the lipid metabolism levels, and activated the anti-oxidative adaptation mechanism of organisms in the lake.
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PMID:Proteomic study of the effects of complex environmental stresses in the livers of goldfish (Carassius auratus) that inhabit Gaobeidian Lake in Beijing, China. 1808 Jul 50

Microorganisms control the redox cycling of manganese in the natural environment. Although the homogeneous oxidation of Mn(II) to form manganese oxide minerals is slow, solid MnO(2) is the stable form of manganese in the oxygenated portion of the biosphere. Diverse bacteria and fungi have evolved the ability to catalyze this process, producing the manganese oxides found in soils and sediments. Other bacteria have evolved to utilize MnO(2) as a terminal electron acceptor in respiration. This Account summarizes the properties of Mn oxides produced by bacteria (bacteriogenic MnO(2)) and our current thinking about the biochemical mechanisms of bacterial Mn(II) oxidation. According to X-ray absorption spectroscopy and X-ray scattering studies, the MnO(2) produced by bacteria consists of stacked hexagonal sheets of MnO(6) octahedra, but these particles are extremely small and have numerous structural defects, particularly cation vacancies. The defects provide coordination sites for binding exogenous metal ions, which can be adsorbed to a high loading. As a result, bacterial production of MnO(2) influences the bioavailability of these metals in the natural environment. Because of its high surface area and oxidizing power, bacteriogenic MnO(2) efficiently degrades biologically recalcitrant organic molecules to lower-molecular-mass compounds, spurring interest in using these properties in the bioremediation of xenobiotic organic compounds. Finally, bacteriogenic MnO(2) is reduced to soluble Mn(II) rapidly in the presence of exogenous ligands or sunlight. It can therefore help to regulate the bioavailability of Mn(II), which is known to protect organisms from superoxide radicals and is required to assemble the water-splitting complex in photosynthetic organisms. Bioinorganic chemists and microbiologists have long been interested in the biochemical mechanism of Mn(IV) oxide production. The reaction requires a two-electron oxidation of Mn(II), but genetic and biochemical evidence for several bacteria implicate multicopper oxidases (MCOs), which are only known to engage one-electron transfers from substrate to O(2). In experiments with the exosporium of a Mn(II)-oxidizing Bacillus species, we could trap the one-electron oxidation product, Mn(III), as a pyrophosphate complex in an oxygen-dependent reaction inhibited by azide, consistent with MCO catalysis. The Mn(III) pyrophosphate complex can further act as a substrate, reacting in the presence of the exosporium to produce Mn(IV) oxide. Although this process appears to be unprecedented in biology, it is reminiscent of the oxidation of Fe(II) to form Fe(2)O(3) in the ferritin iron storage protein. However, it includes a critical additional step of Mn(III) oxidation or disproportionation. We shall continue to investigate this biochemically unique process with purified enzymes.
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PMID:Bacteriogenic manganese oxides. 1977 36

The aryl hydrocarbon receptor (AhR) belongs to the basic-helix-loop helix (bHLH) Per-Arnt-Sim (PAS) family of transcription factors. AhR has been known primarily for its role in the regulation of several drug and xenobiotic metabolizing enzymes, as well as the mediation of the toxicity of certain xenobiotics, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Although the AhR is well-studied as a mediator of the toxicity of certain xenobiotics in marine bivalves, the normal physiological function remains unknown. In order to explore the function of the AhR, the bait protein expression plasmid pGBKT7-CfAhR and the cDNA library of gill from Chlamys farreri were constructed. By yeast two hybrid system, after multiple screening with the high screening rate medium, rotary verification, sequencing and bioinformatics analysis, the interactions of the CfAhR with receptor for activated protein kinase C 1 (RACK1), thyroid peroxidase-like protein (TPO), Toll-like receptor 4(TLR 4), androglobin-like, store-operated Ca(2+) entry (SocE), ADP/ATP carrier protein, cytochrome b, thioesterase, actin, ferritin subunit 1, poly-ubiquitin, short-chain collagen C4-like and one hypothetical protein in gill cells were identified. This study suggests that the CfAhR played fundamental roles in immune system homeostasis, oxidative stress response, and in grow and development of C. farreri. The elucidation of these protein interactions is of much importance both in understanding the normal physiological function of AhR, and as potential targets for further research on protein function in AhR interactions.
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PMID:Identification of interacting proteins with aryl hydrocarbon receptor in scallop Chlamys farreri by yeast two hybrid screening. 2749 85