Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.16.3.1 (ceruloplasmin)
5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The leakage of different serum proteins, including immunoglobulins, into human cerebral gliomas was studied by use of the unlabeled peroxidase-antiperoxidase (PAP) method on cryostat and paraffin sections. Our series of 50 tumour biopsies included 21 isomorphic astrocytomas and oligodendrogliomas (grade II), 19 anaplastic astrocytomas and oligodendrogliomas (grade III), and 10 glioblastomas (grade IV). The immunohistochemical staining of the serum proteins was similar on paraffin and cryostat sections and graded with respect to occurrence, distribution, and intensity. Serum proteins of a small hydrodynamic radius with a low serum concentration (prealbumin) or with a high serum concentration (albumin) were diffusely present in the interstitial spaces of all glioma types. Serum proteins with a medium molecular size and variable serum concentrations, i.e. IgG, IgA, and ceruloplasmin, were detected preferentially in anaplastic gliomas and in glioblastomas (grade III and IV) displaying comparable distribution patterns but different intensities. Alpha-2-macroglobulin a serum protein with a large hydrodynamic radius was also demonstrated in grade III and IV gliomas, whereas IgM and beta-lipoprotein being the largest serum proteins tested were almost restricted to blood vessels and tumour necroses. In addition, most serum proteins occurred with high intensities in those areas of isomorphic grade II gliomas that showed a macro- or microcystic or mucinous tissue degeneration. The varying immunohistochemical staining results for the serum proteins studied indicate that the blood-brain barrier within isomorphic and anaplastic gliomas is not completely disturbed. It appears that the vascular permeability is preferentially increased for small-sized serum proteins, whereas the leakage of larger serum proteins into the glioma interstitium seems to depend on the tumour type and on increasing malignancy.
...
PMID:Immunohistochemical demonstration of serum proteins in human cerebral gliomas. 244 Feb 23

Erythrocyte antioxidant enzymes were analysed in 100 patients with intracranial neoplasm and in 47 controls. There was a significant decrease in RBC glutathione reductase (GRx) and superoxide dismutase (SOD) activity in most types of brain tumor cases. Patients with acoustic neurinoma showed a significant reduction in selenium-dependent glutathione peroxidase (Se-GPx) activity. A decrease in catalase (CT) activity was seen in most of the brain tumor patients but remained statistically insignificant when compared to controls. A significant increase in plasma ceruloplasmin concentration was observed in patients with glioma. These enzymes were also studied in 27 post-treatment cases. GRx activity returned to normal levels in these patients. RBC SOD and plasma ceruloplasmin levels showed a tendency to return to normal. Hence, a marked decrease in the antioxidant enzymes may have a role in the genesis of considerable oxidative stress in patients with brain tumors.
...
PMID:Role of antioxidant enzymes in brain tumours. 1080 83

In a previous study, we found that human ceruloplasmin (hCP) promotes iron uptake rather than release in BT325 cells, a human glioma cell line. In this study, we investigated the effect of ferroxidase activity of hCP and different species of ceruloplasmins on CP-mediated iron uptake by the cells. The cells were incubated for 30 min at 37 degrees C with 1 microM 59Fe2+ with or without 150 microg/ml of the untreated and the ferroxidase-defective hCPs (apohCP and heat-inactivated hCP) or different species of ceruloplasmins (human CP, rabbit CP and bovine CP). The untreated hCP induced a significant increase in iron uptake by BT325 cells, while ferroxidase-defective hCPs with (heat-inactivated hCP) or without cooper ions (apohCP) had no such role. The untreated hCP increases significantly internalized iron but not membrane-bound iron, implying that hCP stimulated iron entry into the cell rather than increased extracellular binding of iron to the cell surface. All species of ceruloplasmins could promote iron uptake by the cells and the difference in degree of stimulatory effect among them was insignificant. These results suggested that ferroxidase activity of hCP is essential for the hCP-mediated iron uptake process and also that CP-stimulated iron uptake is not associated with copper ions in the protein, and that the effect of ceruloplasmin on iron uptake by BT325 cells is not species specific.
...
PMID:Effects of ferroxidase activity and species on ceruloplasmin mediated iron uptake by BT325 cells. 1186 3

The core protein of glypican-1, a glycosylphosphatidylinositol-linked heparan sulfate proteoglycan, can bind Cu(II) or Zn(II) ions and undergo S-nitrosylation in the presence of nitric oxide. Cu(II)-to-Cu(I)-reduction supports extensive and permanent nitrosothiol formation, whereas Zn(II) ions appear to support a more limited, possibly transient one. Ascorbate induces release of nitric oxide, which catalyzes deaminative degradation of the heparan sulfate chains on the same core protein. Although free Zn(II) ions support a more limited degradation, Cu(II) ions support a more extensive self-pruning process. Here, we have investigated processing of glypican-1 in rat C6 glioma cells and the possible participation of the copper-containing glycosylphosphatidylinositol-linked splice variant of ceruloplasmin in nitrosothiol formation. Confocal microscopy demonstrated colocalization of glypican-1 and ceruloplasmin in endosomal compartments. Ascorbate induced extensive, Zn(II)-supported heparan sulfate degradation, which could be demonstrated using a specific zinc probe. RNA interference silencing of ceruloplasmin expression reduced the extent of Zn(II)-supported degradation. In cell-free experiments, the presence of free Zn(II) ions prevented free Cu(II) ion from binding to glypican-1 and precluded extensive heparan sulfate autodegradation. However, in the presence of Cu(II)-loaded ceruloplasmin, heparan sulfate in Zn(II)-loaded glypican-1 underwent extensive, ascorbate-induced degradation. We propose that the Cu(II)-to-Cu(I)-reduction that is required for S-nitrosylation of glypican-1 can take place on ceruloplasmin and thereby ensure extensive glypican-1 processing in the presence of free Zn(II) ions.
...
PMID:Involvement of glycosylphosphatidylinositol-linked ceruloplasmin in the copper/zinc-nitric oxide-dependent degradation of glypican-1 heparan sulfate in rat C6 glioma cells. 1470 33

Cp is an acute phase reactant protein that also acts as a ferroxidase, and thus indirectly decreases the production of the reactive oxygen species hydroxyl radical. Ceruloplasmin (Cp) expression is induced by a variety of central nervous system injuries, but the mechanism by which this occurs is unclear. Based on the fact that peripheral nerve injury induces interleukin-6 (IL-6) expression and that there are three IL-6 response elements in the upstream region of the Cp gene, we studied their role in transcriptional regulation of Cp in astrocytic C6 glioma cells, using transfection of a rat Cp-luciferase construct, followed by sequential and simultaneous mutation of the IL-6 response elements. We found that 0.8 kb of sequence upstream to the rat ceruloplasmin start site was sufficient to drive luciferase expression in C6 glioma cells. Cells transfected with Cp-luc and treated with 100 ng/ml rat IL-6 induced 216.8% +/- 4.6% of control activity. Mutagenesis of the IL-6 response elements decreased luciferase activity, with the maximal decline (9.7 +/- 0.7% of wild-type) after mutation of the second site. Mutagenesis of multiple sites decreased activity beyond mutagenesis of single sites with mutation of all three sites decreasing activity to 5.3 +/- 0.4% of wild-type. Gel shift and supershift assays indicated that activation of Cp in these cells was not via STAT-3. These results are consistent with a signaling process via IL-6 response elements for Cp upregulation.
...
PMID:Transcriptional regulation of ceruloplasmin by an IL-6 response element pathway. 1597 98

Ceruloplasmin (glycosylphosphatidylinositol-linked ferroxidase associated with normal astrocytes) can also be secreted by glioma cells, where its function is unknown. Ceruloplasmin is not only present in glioma cells and in human glioma specimens but also is enriched in highly malignant glioma stem-like cells. Hyaluronan is a large extracellular glycosaminoglycan that enhances malignant glioma behaviors by interacting with CD44 receptors and by downstream activation of signaling proteins and transporters associated with malignancy. We examined the relationship between hyaluronan and ceruloplasmin expression in glioma stem-like cells. Antagonism of hyaluronan interactions with short-fragment hyaluronan oligomers decreased ceruloplasmin expression in parental and stem-like glioma cells in vivo and in cell culture, implying that hyaluronan regulates ceruloplasmin expression. Further gain and loss-of-function studies are needed to fully define the relationship between hyaluronan and ceruloplasmin, and ceruloplasmin's effect on malignant behaviors.
...
PMID:Hyaluronan regulates ceruloplasmin production by gliomas and their treatment-resistant multipotent progenitors. 1895 89

The multicopper oxidase ceruloplasmin plays a key role in iron homeostasis, and its ferroxidase activity is required to stabilize cell surface ferroportin, the only known mammalian iron exporter. Missense mutations causing the rare autosomal neurodegenerative disease aceruloplasminemia were investigated by testing their ability to prevent ferroportin degradation in rat glioma C6 cells silenced for endogenous ceruloplasmin. Most of the mutants did not complement (i.e. did not stabilize ferroportin) because of the irreversible loss of copper binding ability. Mutant R701W, which was found in a heterozygous very young patient with severe neurological problems, was unable to complement per se but did so in the presence of copper-glutathione or when the yeast copper ATPase Ccc2p was co-expressed, indicating that the protein was structurally able to bind copper but that metal loading involving the mammalian copper ATPase ATP7B was impaired. Notably, R701W exerted a dominant negative effect on wild type, and it induced the subcellular relocalization of ATP7B. Our results constitute the first evidence of "functional silencing" of ATP7B as a novel molecular defect in aceruloplasminemia. The possibility to reverse the deleterious effects of some aceruloplasminemia mutations may disclose new possible therapeutic strategies.
...
PMID:Dominant mutants of ceruloplasmin impair the copper loading machinery in aceruloplasminemia. 1909 59

Ceruloplasmin plays an essential role in cellular iron efflux by oxidizing ferrous iron exported from ferroportin. Ferroportin is posttranslationally regulated through internalization triggered by hepcidin binding. Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis resulting from mutations in the ceruloplasmin gene. The present study investigated the biological effects of glycosylphosphatidylinositol (GPI)-linked ceruloplasmin on the hepcidin-mediated internalization of ferroportin. The prevention of hepcidin-mediated ferroportin internalization was observed in the glioma cells lines expressing endogenous ceruloplasmin as well as in the cells transfected with GPI-linked ceruloplasmin under low levels of hepcidin. A decrease in the extracellular ferrous iron by an iron chelator and incubation with purified ceruloplasmin in the culture medium prevented hepcidin-mediated ferroportin internalization, while the reconstitution of apo-ceruloplasmin was not able to prevent ferroportin internalization. The effect of ceruloplasmin on the ferroportin stability was impaired due to three distinct properties of the mutant ceruloplasmin: namely, a decreased ferroxidase activity, the mislocalization in the endoplasmic reticulum, and the failure of copper incorporation into apo-ceruloplasmin. Patients with aceruloplasminemia exhibited low serum hepcidin levels and a decreased ferroportin protein expression in the liver. The in vivo findings supported the notion that under low levels of hepcidin, mutant ceruloplasmin cannot stabilize ferroportin because of a loss-of-function in the ferroxidase activity, which has been reported to play an important role in the stability of ferroportin. The properties of mutant ceruloplasmin regarding the regulation of ferroportin may therefore provide a therapeutic strategy for aceruloplasminemia patients.
...
PMID:Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin. 2065 81

Polyphenol epigallocatechin-3-gallate (EGCG) induced apoptosis in glioma cells by elevating oxidative stress through increased reactive oxygen species (ROS) generation. Signs of apoptosis included altered mitochondrial membrane potential and elevated expression of caspase-3 and cytochrome c. The increase in ROS was concomitant with the decrease in expression of thioredoxin (TRX-1) and ceruloplasmin (CP), mediators associated with protection against oxidative stress. EGCG downregulated the levels of pro-inflammatory cytokine interleukin (IL)-6 and chemokines IL-8, monocyte-chemoattractant protein (MCP)-1 and RANTES. EGCG also decreased the invasive potential of gliomas, possibly by affecting the urokinase plasminogen activator (uPA) and cytoskeletal architecture. Our study indicates that EGCG might serve as an effective therapeutic strategy against glioma as it not only promotes cell death through redox perturbation, but also downregulates the release of pro-inflammatory mediators while concomitantly decreasing the invasive potential of glioma cells.
...
PMID:Epigallocatechin-3-gallate exhibits anti-tumor effect by perturbing redox homeostasis, modulating the release of pro-inflammatory mediators and decreasing the invasiveness of glioblastoma cells. 2147 41

We have used an in vitro model system to probe the iron transport pathway across the brain microvascular endothelial cells (BMVEC) of the blood-brain barrier (BBB). This model consists of human BMVEC (hBMVEC) and C6 glioma cells (as an astrocytic cell line) grown in a transwell, a cell culture system commonly used to quantify metabolite flux across a cell-derived barrier. We found that iron efflux from hBMVEC through the ferrous iron permease ferroportin (Fpn) was stimulated by secretion of the soluble form of the multi-copper ferroxidase, ceruloplasmin (sCp) from the co-cultured C6 cells. Reciprocally, expression of sCp mRNA in the C6 cells was increased by neighboring hBMVEC. In addition, data indicate that C6 cell-secreted hepcidin stimulates internalization of hBMVEC Fpn but only when the end-feet projections characteristic of this glia-derived cell line are proximal to the endothelial cells. This hepcidin-dependent loss of Fpn correlated with knock-down of iron efflux from the hBMVEC; this result was consistent with the mechanism by which hepcidin regulates iron efflux in mammalian cells. In summary, the data support a model of iron trafficking across the BBB in which the capillary endothelium induce the underlying astrocytes to produce the ferroxidase activity needed to support Fpn-mediated iron efflux. Reciprocally, astrocyte proximity modulates the effective concentration of hepcidin at the endothelial cell membrane and thus the surface expression of hBMVEC Fpn. These results are independent of the source of hBMVEC iron (transferrin or non-transferrin bound) indicating that the model developed here is broadly applicable to brain iron homeostasis.
...
PMID:Glial cell ceruloplasmin and hepcidin differentially regulate iron efflux from brain microvascular endothelial cells. 2453 65


1

---