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

Hepcidin has been implicated as the iron stores regulator: a hepatic signaling molecule that regulates intestinal iron absorption by undefined mechanisms. The possibility that hepcidin regulates the expression of ferroportin 1 (FPT1), the basolateral iron transporter, was examined in rats after administration of LPS, an iron chelator, or His-tagged recombinant hepcidin (His-rHepc). In the liver, LPS stimulated a biphasic increase of hepcidin mRNA with peaks of mRNA at 6 and 36 h. Concurrently, hepatic FPT1 mRNA expression decreased to minimal level at 6 h and then increased with a peak at 24-36 h. LPS also induced biphasic changes in intestinal FPT1 mRNA expression, with decreased levels at 6 h and increased expression at 48 h. Whereas the initial decrease of FPT1 coincides with an LPS-induced decrease in serum iron, both intestinal and hepatic FPT1 expression recovered, whereas serum iron concentration continued to decrease for at least 24 h. Dietary iron ingestion increased intestinal ferritin protein production but did not reduce intestinal FPT1 mRNA expression. The iron chelator pyrrolidinedithiocarbamate (PDTC) stimulated hepatic hepcidin without suppressing intestinal FPT1 expression. In PDTC-treated rats, LPS stimulated no additional hepatic hepcidin expression but did increase intestinal FPT1 expression. Administration of HisrHepc induced significant reduction of intestinal FPT1 expression. Taken together, these data suggest that hepcidin mediates LPS-induced downregulation of intestinal FPT1 expression and that the hepcidin signaling pathway involves a PDTC-sensitive step.
 ...
PMID:Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat. 1459 44

Iron regulatory protein-1 (IRP-1) is a bifunctional [4Fe-4S] protein that functions as a cytosolic aconitase or as a trans-regulatory factor controlling iron homeostasis at a post-transcriptional level. Because IRP-1 is a sensitive target protein for nitric oxide (NO), we investigated whether this protein is nitrated in inflammatory macrophages and whether this post-transcriptional modification changes its activities. RAW 264.7 macrophages were first stimulated with interferon-gamma and lipopolysaccharide (IFN-gamma/LPS) and then triggered by phorbol 12-myristate 13-acetate (PMA) in order to promote co-generation of NO* and O*2-.. IRP-1 was isolated by immunoprecipitation and analyzed for protein-bound nitrotyrosine by Western blotting. We show that nitration of endogenous IRP-1 in NO-producing macrophages boosted to produce O*2- was accompanied by aconitase inhibition and impairment of its capacity to bind the iron-responsive element (IRE) of ferritin mRNA. Lost IRE-binding activity was not recovered by exposure of IRP-1 to 2% 2-mercaptoethanol and was not due to protein degradation. Inclusion of cis-aconitate with cell extract to stabilize the [4Fe-4S] cluster of holo-IRP-1 rendered protein insensitive to nitration by peroxynitrite, suggesting that loss of [Fe-S] cluster and subsequent change of conformation are prerequisites for tyrosine nitration. IRP-1 nitration was strongly reduced when IFN-gamma/LPS/PMA-stimulated cells were incubated with myeloperoxidase inhibitors, which points to the contribution of the nitrite/H2O2/peroxidase pathway to IRP-1 nitration in vivo. Interestingly, under these conditions, IRP-1 recovered full IRE binding as assessed by treatment with 2% 2-mercaptoethanol. Peroxidase-mediated nitration of critical tyrosine residues, by holding IRP-1 in an inactive state, may constitute, in activated macrophages, a self-protecting mechanism against iron-induced toxicity.
 ...
PMID:Endogenous nitration of iron regulatory protein-1 (IRP-1) in nitric oxide-producing murine macrophages: further insight into the mechanism of nitration in vivo and its impact on IRP-1 functions. 1525 60

We have suggested that renal tubular synthesis of C3 and its activation in the cortical interstitium is a mechanism for the progression of glomerulonephritis to interstitial injury. To test this hypothesis, immune complex glomerulonephritis was induced in C57BL/6 mice by intraperitoneal injections of horse spleen apoferritin and lipopolysaccharide (HSA/LPS). When compared to wild-type (WT) animals, C3 knockout (C3KO) mice had glomerular changes that were identical. Morphometric analysis of the cortical interstitium, however, showed marked differences. WT mice had more interstitial inflammation, edema, and tubular atrophy, when compared to C3KO mice. At the end of the experiment, WT animals also had significantly more proteinuria than did C3KOs. These experiments provide further evidence of a role of locally synthesized complement in the progression of glomerular disease.
 ...
PMID:C3 is central to the interstitial component of experimental immune complex glomerulonephritis. 1587 25

Skeletal demineralization is a frequent accompaniment of chronic renal disease and is likely multifactorial. We studied the role of inflammation in stimulating bone resorption in a rat model of glomerulonephritis (GN). Three-week-old Sprague-Dawley rats received either saline (n = 8) or horse spleen apoferritin and lipopolysaccharide (HSA/LPS, n = 8) by intraperitoneal injection, for 6 weeks; afterward, they were observed for either an additional 3 weeks (9 weeks total; n = 4 from each group) or 14 weeks (20 weeks total; n = 4 from each group). Kidneys were analyzed by histomorphometry, and blood and urine samples were obtained to assess bone resorption. Whole-body and isolated femur Dual-Energy X-ray Absorptiometry (DEXA) scans were performed at the end of each study. HSA/LPS-treated animals developed a proliferative GN by 9 weeks, which is associated with proteinuria but no change in renal function. Between 9 and 20 weeks, there was evidence of an increasing interstitial inflammation (1381 +/- 67 interstitial cells/mm(2) at 9 weeks and 1818 +/- 28 interstitial cells/mm(2) at 20 weeks.) There was also evidence of bone resorbing activity as assessed by experimental/control (E/C) < 1.0 at 9 (E/C plasma = 0.66 +/- 0.05) and 20 (E/C plasma = 0.52 +/- 0.04) weeks. Parathyroid hormone (PTH) levels were normal at all time points, and no differences in bone mineral density were found. This model produces not only an immune glomerular/tubular injury, but also a stimulus for bone resorption that is related to objective measures of inflammation severity. The bone resorption is not caused by renal insufficiency, hyperparathyroidism, or steroid therapy. This model will prove useful in other studies of the role of renal inflammation in skeletal disorders.
 ...
PMID:Nonparathyroid hormone-mediated calcium resorption in a rat model of immune glomerulonephritis. 1613 56

Increasing evidence suggests that abnormal iron handling may be involved in the pathogenesis of Parkinson's disease. The present study investigates the role of iron and the iron-storage protein ferritin in inflammation-induced degeneration of dopaminergic neurons of the substantia nigra pars compacta. Injection of lipopolysaccharide into the globus pallidus of young and middle-aged rats substantially decreased tyrosine hydroxylase immunostaining in substantia nigra pars compacta four weeks after injection. Loss of tyrosine hydroxylase expression was accompanied by increased iron and ferritin levels in glial cells of the substantia nigra pars reticulata. Despite greater increases in nigral iron levels, ferritin induction was less pronounced in older rats, suggesting the regulation of ferritin was compromised with age. Automated movement tracking analyses showed that young rats recovered from LPS-induced locomotor deficits within four weeks, yet older rats failed to improve on measures of speed and total distance moved. Intrapallidal lipopolysaccharide injection also increased expression of alpha-synuclein and ubiquitin in tyrosine hydroxylase-positive neurons of the substantia nigra pars compacta. These results suggest that pallidal inflammation significantly increases stress on dopamine-containing neurons in the substantia nigra pars compacta. Alterations in nigral iron levels and protein handing may increase the vulnerability of nigral neurons to degenerative processes.
 ...
PMID:Intrapallidal lipopolysaccharide injection increases iron and ferritin levels in glia of the rat substantia nigra and induces locomotor deficits. 1616 92

Iron is one of the trace elements playing a key role in the normal cellular metabolism. Since an excess of free iron is catalyzing the Fenton reaction, most of the intracellular iron is sequestered in the iron storage protein ferritin. The binding of iron into ferritin is well described for physiological conditions, however, under certain pathophysiological situations, the efficiency of this process is unknown. In the brain, microglial cells are among others the cell population most importantly responsible for the maintenance of the extracellular environment. These cells might undergo activation, and little is known about the expression of ferritin during activation of microglial cells. Therefore, we tested the microglial model cell line RAW264.7 for the expression of ferritin after LPS activation. A significant decrease in the levels of the ferritin H-chain during activation and a significant increase in the early recovery phase were found. We were able to demonstrate that reactive oxygen species are responsible for a suppression of the H-chain of ferritin, whereas iNOS expression and NO synthesis are counteracting the reactive oxygen species effect. The balance of reactive oxygen species and NO production are, therefore, determining expression levels of the ferritin H-chain during activation of microglial cells.
 ...
PMID:Ferritin levels in microglia depend upon activation: modulation by reactive oxygen species. 1677 45

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.
 ...
PMID:Genomics and proteomics analysis of cultured primary rat hepatocytes. 1776 30

Ferritin plays a key role in cellular iron metabolism including iron storage and detoxification, which has been identified in a wide range of organisms including bacteria, fungi, plants and animals. However, little information is available regarding ferritin in the protochordates to date. Here we demonstrate the presence of a ferritin gene homolog, BbFRT, in amphioxus Branchiostoma belcheri. Analysis of the BbFRT 5'-UTR indicated the existence of a putative iron-responsive element (IRE) with a predicated stem-loop structure. BbFRT encoded a deduced protein of 172 amino acids with the conserved motif for ferroxidase center typical of heavy chains of vertebrate ferritins. Sequence comparison showed that BbFRT shared more identity to H-chains (68%) of vertebrate ferritins than to the L-chains (46-51%). Both in situ hybridization histochemistry and immunohistochemical staining revealed that BbFRT was ubiquitously expressed in B. belcheri. In addition, BbFRT expression was up-regulated by 1.6-fold and 1.5-fold, respectively, following exposure to LPS at both transcriptional and translational levels. Similarly, exposure to iron resulted in about 1.6-fold increase in BbFRT in the humoral fluids. These suggest that BbFRT seems a protein with a dual function functioning in both immune response and iron metabolism.
 ...
PMID:Identification and expression of a ferritin homolog in amphioxus Branchiostoma belcheri: evidence for its dual role in immune response and iron metabolism. 1845 69

Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions, mimicked by the combined action of LPS and IFN-gamma (M1 polarization). However, macrophages can undergo an alternative type of activation stimulated by Th2 cytokines, and acquire a role in cell growth and tissue repair control (M2 polarization). We characterized the expression of genes related to iron homeostasis in fully differentiated unpolarized (M0), M1 and M2 human macrophages. The molecular signature of the M1 macrophages showed changes in gene expression (ferroportin repression and H ferritin induction) that favour iron sequestration in the reticuloendothelial system, a hallmark of inflammatory disorders, whereas the M2 macrophages had an expression profile (ferroportin upregulation and the downregulation of H ferritin and heme oxygenase) that enhanced iron release. The conditioned media from M2 macrophages promoted cell proliferation more efficiently than those of M1 cells and the effect was blunted by iron chelation. The role of ferroportin-mediated iron release was demonstrated by the absence of differences from the media of macrophages of a patient with loss of function ferroportin mutation. The distinct regulation of iron homeostasis in M2 macrophages provides insights into their role under pathophysiological conditions.
 ...
PMID:Differential regulation of iron homeostasis during human macrophage polarized activation. 2003 3

The clinical significance of serum ferritin in monitoring the iron status of patients on maintenance hemodialysis (MHD) has become suspected. In this review, we reassess the interpretation of high serum ferritin values in such patients, with the goal of treating their anemia in a safe way. From the observations that (1) H-ferritin gene transcription is predominantly active in inflammatory conditions, whereas L-ferritin is induced only after exposure to very high iron concentrations and is preferentially secreted to plasma from hepatocytes; (2) the expression of both types of ferritin proteins are exclusively dependent on intracellular free iron, which is often sequestered by LPS or cytokines in several cell types, and (3) splenic iron is depleted and serum ferritin does not increase in the combined conditions of both inflammation and iron deficiency, it is deduced that elevated serum ferritin levels are caused by the accumulation of intracellular iron, especially reticuloendothelial cells or macrophages, hepatocytes, and other cells, while cytokines or inflammation might modulate the relative ratio of ferritin to body iron storage. Therefore, high levels of serum ferritin in patients on MHD can be used to indicate iron deposition in most cells, including vascular and immunocompetent cells, and is still a reliable indicator of the need to withhold iron administration.
 ...
PMID:Importance of ferritin for optimizing anemia therapy in chronic kidney disease. 2088 81


<< Previous 1 2 3 4 Next >>