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Neuropathology : Official Journal of... Feb 2015Aceruloplasminemia is characterized by progressive neurodegeneration with brain iron accumulation due to the complete lack of ceruloplasmin ferroxidase activity caused...
Aceruloplasminemia is characterized by progressive neurodegeneration with brain iron accumulation due to the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. Redox-active iron accumulation was found to be more prominent in the astrocytes than in the neurons. The most characteristic findings were abnormal or deformed astrocytes and globular structures of astrocytes. The lack of ceruloplasmin may primarily damage astrocytes in the aceruloplasminemic brains as a result of lipid peroxidation due to massive iron deposition. In the normal brain, iron may be continuously recycled between astrocytes and neurons, with transferrin acting as a shuttle. The glycosylphosphatidylinositol (GPI)-linked ceruloplasmin on astrocytes functions as a ferroxidase, mediating the oxidation of ferrous iron transported from the cytosol by ferroportin and its subsequent transfer to transferrin. In cases with aceruloplasminemia, neurons take up the iron from alternative sources of non-transferrin-bound iron, because astrocytes without GPI-linked ceruloplasmin cannot transport iron to transferrin. The excess iron in astrocytes could result in oxidative damage to these cells, and the neuronal cell protection offered by astrocytes would thus be disrupted. Neuronal cell loss may result from iron starvation in the early stage and from iron-mediated oxidation in the late stage. Ceruloplasmin may therefore play an essential role in neuronal survival in the central nervous system.
Topics: Astrocytes; Brain Diseases, Metabolic, Inborn; Ceruloplasmin; Humans; Iron; Iron Metabolism Disorders; Neurodegenerative Diseases; Neurons
PubMed: 25168455
DOI: 10.1111/neup.12149 -
Circulation Research May 2014
Topics: Ceruloplasmin; Cysteine; Female; Heart Failure; Humans; Male; Peroxynitrous Acid; Tyrosine
PubMed: 24855197
DOI: 10.1161/CIRCRESAHA.114.304091 -
Nutrients Oct 2020Several studies indicate that oxidative stress might play a central role in the initiation and maintenance of cardiovascular diseases. It remains unclear whether...
Several studies indicate that oxidative stress might play a central role in the initiation and maintenance of cardiovascular diseases. It remains unclear whether ceruloplasmin acts as a passive marker of inflammation or as a causal mediator. To better understand the impact of ceruloplasmin blood levels on the risk of cardiovascular disease, and paying special attention to coronary heart disease, we conducted a search on the two most commonly used electronic databases (Medline via PubMed and EMBASE) to analyze current assessment using observational studies in the general adult population. Each study was quality rated using criteria developed by the US Preventive Services Task Force. Most of 18 eligible studies reviewed support a direct relationship between ceruloplasmin elevated levels and incidence of coronary heart disease. Our results highlight the importance of promoting clinical trials that determine the functions of ceruloplasmin as a mediator in the development of coronary heart disease and evaluate whether the treatment of elevated ceruloplasmin levels has a role in the prognosis or prevention of this condition.
Topics: Aged; Ceruloplasmin; Coronary Disease; Female; Heart Disease Risk Factors; Humans; Incidence; Inflammation; Male; Middle Aged
PubMed: 33096845
DOI: 10.3390/nu12103219 -
Biometals : An International Journal on... Apr 2023The mammalian multicopper ferroxidases (MCFs) ceruloplasmin (CP), hephaestin (HEPH) and zyklopen (ZP) comprise a family of conserved enzymes that are essential for body... (Review)
Review
The mammalian multicopper ferroxidases (MCFs) ceruloplasmin (CP), hephaestin (HEPH) and zyklopen (ZP) comprise a family of conserved enzymes that are essential for body iron homeostasis. Each of these enzymes contains six biosynthetically incorporated copper atoms which act as intermediate electron acceptors, and the oxidation of iron is associated with the four electron reduction of dioxygen to generate two water molecules. CP occurs in both a secreted and GPI-linked (membrane-bound) form, while HEPH and ZP each contain a single C-terminal transmembrane domain. These enzymes function to ensure the efficient oxidation of iron so that it can be effectively released from tissues via the iron export protein ferroportin and subsequently bound to the iron carrier protein transferrin in the blood. CP is particularly important in facilitating iron release from the liver and central nervous system, HEPH is the major MCF in the small intestine and is critical for dietary iron absorption, and ZP is important for normal hair development. CP and HEPH (and possibly ZP) function in multiple tissues. These proteins also play other (non-iron-related) physiological roles, but many of these are ill-defined. In addition to disrupting iron homeostasis, MCF dysfunction perturbs neurological and immune function, alters cancer susceptibility, and causes hair loss, but, despite their importance, how MCFs co-ordinately maintain body iron homeostasis and perform other functions remains incompletely understood.
Topics: Animals; Mice; Copper; Ceruloplasmin; Mice, Knockout; Oxidation-Reduction; Biology; Mammals
PubMed: 35167013
DOI: 10.1007/s10534-022-00370-z -
Aging Aug 2021Breast-invasive carcinoma (BRCA) is the most frequent and malignant tumor in females. Ceruloplasmin (CP) is a multifunctional molecule involved in iron metabolism, but...
Breast-invasive carcinoma (BRCA) is the most frequent and malignant tumor in females. Ceruloplasmin (CP) is a multifunctional molecule involved in iron metabolism, but its expression profile, prognostic potential and relationship with immune cell infiltration in BRCA are unknown. Ceruloplasmin mRNA and protein expression was significantly decreased in BRCA patients according to the Oncomine, UALCAN, GEPIA and TCGA databases. Ceruloplasmin expression was strongly correlated with various clinicopathological features of BRCA patients. BRCA patients with high ceruloplasmin expression exhibited shorter survival times than those with low ceruloplasmin expression based on the Kaplan-Meier plotter and PrognoScan databases. GO and KEGG analyses and GSEA revealed a strong correlation between ceruloplasmin and various immune-related pathways. Ceruloplasmin expression was significantly associated with the infiltration of immune cells into tumor sites by analyzing the TIMER and CIBERSORT. Additionally, ceruloplasmin was positively correlated with immune checkpoints in BRCA. These findings suggest that low ceruloplasmin expression correlates with a favorable prognosis and tumor immune cell infiltration in BRCA patients. Ceruloplasmin may serve as a therapeutic target and predict the efficacy of immunotherapy for BRCA.
Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Ceruloplasmin; Databases, Genetic; Female; Gene Expression Regulation, Neoplastic; Humans; Immune System; Middle Aged; Prognosis
PubMed: 34413268
DOI: 10.18632/aging.203427 -
Current Neuropharmacology 2019Ceruloplasmin (CP) is the major copper transport protein in plasma, mainly produced by the liver. Glycosylphosphatidylinositol-linked CP (GPI-CP) is the predominant form... (Review)
Review
Ceruloplasmin (CP) is the major copper transport protein in plasma, mainly produced by the liver. Glycosylphosphatidylinositol-linked CP (GPI-CP) is the predominant form expressed in astrocytes of the brain. A growing body of evidence has demonstrated that CP is an essential protein in the body with multiple functions such as regulating the homeostasis of copper and iron ions, ferroxidase activity, oxidizing organic amines, and preventing the formation of free radicals. In addition, as an acute-phase protein, CP is induced during inflammation and infection. The fact that patients with genetic disorder aceruloplasminemia do not suffer from tissue copper deficiency, but rather from disruptions in iron metabolism shows essential roles of CP in iron metabolism rather than copper. Furthermore, abnormal metabolism of metal ions and oxidative stress are found in other neurodegenerative diseases, such as Wilson's disease, Alzheimer's disease and Parkinson's disease. Brain iron accumulation and decreased activity of CP have been shown to be associated with neurodegeneration. We hypothesize that CP may play a protective role in neurodegenerative diseases. However, whether iron accumulation is a cause or a result of neurodegeneration remains unclear. Further research on molecular mechanisms is required before a consensus can be reached regarding a neuroprotective role for CP in neurodegeneration. This review article summarizes the main physiological functions of CP and the current knowledge of its role in neurodegenerative diseases.
Topics: Animals; Ceruloplasmin; Humans; Neurodegenerative Diseases; Neuroprotection
PubMed: 29737252
DOI: 10.2174/1570159X16666180508113025 -
Arquivos de Gastroenterologia 2020Copper deficiency has been linked to alterations in lipid metabolism and hepatic steatosis. Oxidative stress plays a role in the pathogenesis of non-alcoholic fatty...
BACKGROUND
Copper deficiency has been linked to alterations in lipid metabolism and hepatic steatosis. Oxidative stress plays a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). One of the enzymes that neutralize oxidative stress is Cu/Zn superoxide dismutase, which depends on the availability of adequate amounts of copper.
OBJECTIVE
Correlate the levels of ceruloplasmin and of non-ceruloplasmin-bound copper (NCBC) with clinical, biochemical and histological parameters of non-alcoholic fatty liver disease (NAFLD) patients.
METHODS
Data from 95 consecutively admitted NAFLD patients who underwent liver biopsy composed the groups based on ceruloplasmin levels lower than 25 mg/dL and on negative NCBC. The risk factors for NAFLD in each group were compared.
RESULTS
Body mass index was lower in patients with ceruloplasmin <25 mg/dL (29.1±3.47 vs 32.8±6.24 kg/m2; P=0.005) as were the levels of LDL, HDL and total cholesterol, when compared with their counterparts with ceruloplasmin >25 mg/dL (101±38 vs 116±35 mg/dL, P=0.05; 43±9 vs 51±16 mg/dL, P=0.01; 174±43 vs 197±39 mg/dL, P=0.01, respectively). Mean serum ferritin levels were higher in the ceruloplasmin <25 mg/dL group (343±327 vs 197±190 ng/mL; P=0.02). Otherwise, patients with negative NCBC had higher HOMA-IR (8.2±14.7 vs 4.6±3.7; P=0.03). Age, gender, hypertension and diabetes showed no statistical difference.
CONCLUSION
Patients with NAFLD had different clinical and biochemical markers according to the levels of NCBC and ceruloplasmin.
Topics: Body Mass Index; Ceruloplasmin; Copper; Humans; Non-alcoholic Fatty Liver Disease; Phenotype
PubMed: 32935743
DOI: 10.1590/S0004-2803.202000000-47 -
Journal of Clinical Pathology Apr 2007Investigation of copper status can be a diagnostic challenge. The non-caeruloplasmin-bound copper (NCC) has deficiencies; accordingly, the copper:caeruloplasmin ratio...
Investigation of copper status can be a diagnostic challenge. The non-caeruloplasmin-bound copper (NCC) has deficiencies; accordingly, the copper:caeruloplasmin ratio has been suggested as an alternative index of copper status. A reference interval for this index was derived. In addition to making the interpretation of copper easier, the copper:caeruloplasmin ratio should also enable adjustment for relatively high caeruloplasmin concentrations without recourse to producing gender- and age-derived intervals. The copper:caeruloplasmin ratio has weaknesses similar to those identified for NCC in that immunological methods used for caeruloplasmin can cross react with apocaeruloplasmin and there is no standardised method for caeruloplasmin. Caeruloplasmin assays also have uncertainty from precision, bias and specificity and, accordingly, method-related differences may have a large effect on the copper:caeruloplasmin ratio in a manner similar to the NCC.
Topics: Biomarkers; Ceruloplasmin; Copper; Hepatolenticular Degeneration; Humans; Predictive Value of Tests; Reference Values
PubMed: 17405985
DOI: 10.1136/jcp.2006.041756 -
Mediators of Inflammation 2013Ceruloplasmin was elevated in patients with coronary heart disease, but the relationship between ceruloplasmin and heart failure was still unknown. We aimed to evaluate...
OBJECTIVE
Ceruloplasmin was elevated in patients with coronary heart disease, but the relationship between ceruloplasmin and heart failure was still unknown. We aimed to evaluate ceruloplasmin in heart failure patients and assess association between ceruloplasmin and the extent of heart failure.
METHODS AND RESULTS
202 heart failure patients were divided into ischemic (78 with coronary stenosis) and nonischemic groups (124 without coronary stenosis). 94 subjects without heart failure were included as controls. The extent of heart failure was defined according to NYHA classification. Ceruloplasmin levels in ischemic (P < 0.001) and nonischemic groups (P < 0.001) were higher than those in control group. Ceruloplasmin had a positive linear correlation with C-reactive protein (P < 0.01) and a negative linear correlation with LVEF (P < 0.05). In nonischemic group, CP levels were significantly different among different NYHA subgroups (P < 0.05). The correlation between ceruloplasmin and extent of heart failure was calculated by binary logistic regression. Ceruloplasmin showed an independent association with the extent of heart failure in nonischemic cardiomyopathy patients (P < 0.05).
CONCLUSIONS
Ceruloplasmin was significantly elevated in patients with ischemic or nonischemic cardiomyopathy and had linear correlation with C-reactive protein and LVEF. In nonischemic cardiomyopathy patients, the ceruloplasmin value was an independent biomarker associated with the extent of heart failure.
Topics: Adult; C-Reactive Protein; Cardiomyopathies; Ceruloplasmin; Coronary Stenosis; Female; Heart Failure; Humans; Logistic Models; Male; Middle Aged
PubMed: 23781119
DOI: 10.1155/2013/348145 -
Journal of Thrombosis and Haemostasis :... May 2019Essentials Ceruloplasmin (CP) is an acute-phase reactant and a potential biomarker of atherothrombotic risk. We assessed associations between CP and venous...
Essentials Ceruloplasmin (CP) is an acute-phase reactant and a potential biomarker of atherothrombotic risk. We assessed associations between CP and venous thromboembolism (VTE) risk in 9933 individuals. Higher circulating CP but not CP-related genes were associated with greater incident VTE rates. Circulating CP could be considered a non-causal biomarker of VTE risk in the community. SUMMARY: Background Ceruloplasmin (CP) is an acute-phase reactant and a potential biomarker of atherothrombotic risk. We assessed the associations between CP, CP-associated genetic variants and incident venous thomboembolism (VTE) in the Atherosclerosis Risk in Communities study. Methods and results In an observational study, 9933 men and women aged 53-75 years without prevalent VTE were included in 1996-1998 and followed through 2011. Circulating CP was measured in stored blood samples obtained in 1996-1998. Polymorphisms rs11708215 and rs13072552, which have been previously associated with CP concentrations, were measured in 8439 participants. VTEs were identified from hospital discharge codes and validated by physician review of medical records and imaging reports. Over a mean of 10.5 years of follow-up, 376 cases of VTE were identified. The association between circulating CP, CP-associated polymorphisms and the incidence of VTE was estimated. After adjustment for traditional risk factors and biomarkers, higher concentrations of circulating CP were associated with greater incident VTE rates (hazard ratio 1.82, 95% confidence interval 1.12-2.95, comparing the 87.5-100th percentile with the bottom quartile). Both rs11708215 and rs13072552 were associated with CP concentrations but not with VTE risk. Conclusions Even though high CP concentrations were associated with an increased VTE risk, CP-associated genetic variants were not associated with a higher risk of VTE. Our results suggest that circulating CP concentrations may not be causally related to the risk of incident VTE.
Topics: Black or African American; Aged; Alleles; Atherosclerosis; Biomarkers; Ceruloplasmin; Female; Humans; Incidence; Male; Middle Aged; Polymorphism, Genetic; Proportional Hazards Models; Prospective Studies; Risk Factors; Venous Thromboembolism; White People
PubMed: 30803124
DOI: 10.1111/jth.14420