Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer.

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.

Integrated Proteome and Cytokine Profiles Reveal Ceruloplasmin Eliciting Liver Allograft Tolerance via Antioxidant Cascades.

Acute rejection (AR) and spontaneous tolerance may occur after allograft orthotopic liver transplants (OLT) performed in certain combinations of donor and recipient rat strains, yet the underlying molecular cascades involved in these conditions remain poorly understood. Comprehensive analysis with proteomic tools revealed that ceruloplasmin was highly expressed during the tolerant period on day 63 post-OLT (POD 63) compared to the rejected samples on POD 14. Meanwhile, cytokine expression profiles implied that the inflammation was significantly stimulated in the AR subjects. Again, protein carbonylation was dramatically upregulated in the rejected subject within the tolerant group. Knockdown of ceruloplasmin would elicit more severe ROS damage, leading to cell death in the presence of H2O2, which induced Nrf2 cascade and the recovery of ceruloplasmin to mediate spontaneous tolerance. In summary, ceruloplasmin may contribute to amending the oxidative stress that eventually causes cell apoptosis and to maintaining the survival of hepatocytes in a drug-free tolerance OLT model.

Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion vs. open mini-laparotomy cystectomy: evaluation of surgical inflammatory response and immunosuppressive ability of CO2-pneumoperitoneum in an experimental porcine study.

OBJECTS: To compare surgical inflammatory response (SIR) after radical cystectomy (RC) in a porcine model using minimal invasive techniques. Additionally we aimed to investigate the potential immunosuppressive ability of preoperative CO2-pneumoperitoneum (CO2P). MATERIALS AND METHODS: Forty female landrace pigs were randomized to five groups: Three intervention groups all having a cystectomy and an ileal conduit either done by robot-assisted laparoscopic technique with intracorporeal urinary diversion (RALC) or an open mini-laparotomy with or without prior CO2P (OMC ± CO2P). Two control sham groups with or without prior CO2P (S ± CO2P). Serum samples were obtained preoperatively, immediately postoperative, 24, 48 and 72 hours postoperatively, and the inflammatory mediators CRP, Haptoglobin, Ceruloplasmin, Albumin, Cortisol, IL-4, IL-6, IL-12 and IFN-α were measured. RESULTS: Operative time was significantly longer in RALC compared to open groups (OMC ± CO2P) (p's < .0001). CRP and Haptoglobin levels were significantly higher for surgical intervention groups (SIG) compared to controls 24, 48 and 72 hours postoperatively (p's < .001). At 48 hours, CRP was higher for RALC vs OMC + CO2P (p = .029). At 72 hours, Haptoglobin was higher for RALC vs open groups (p's < .024). Ceruloplasmin, cortisol, albumin, IL-4, IL-6, IL-12 and IFN-α, revealed no significant differences between SIG. CONCLUSIONS: No major differences were found between RALC and OMC regarding the degree of tissue trauma quantified by inflammatory markers. Thirty minutes of CO2-insufflation preoperative appears to have a transient immunosuppressive effect of the innate postoperative SIR, whereas prolonged CO2P apparently diminishes this effect.

Serum Proteomics Analysis in Rats of Immunosuppression Induced by Chronic Stress.

The immune system can be damaged by chronic stress. However, for this process, the involved molecular alterations and their regulatory roles played in immunosuppression still remain unclear. This study was aimed to identify the differences in serum protein expressions that are closely associated with the effect of chronic stress on immune function. Serum protein levels of rats in control group and chronic stress group were measured by iTRAQ analysis. Subsequently, among the 121 differentially expressed proteins screened between the two groups, 46 proteins were upregulated (>1.5-fold, P < 0.05), while 75 proteins were downregulated (<0.67-fold, P < 0.05). Bioinformatics analysis revealed that most of the differentially expressed proteins were in relation with the metabolic, cellular, response stimulus and immune system processes. The significantly differential expression of ceruloplasmin, haptoglobin, catalase and peroxiredoxin-1 were picked out for reconfirmation by ELISA analysis. The results were consistent with those obtained by iTRAQ. What is more, the roles of above-mentioned four proteins, apolipoprotein B-100 and heat-shock protein 90 in immunosuppression induced by chronic stress were discussed. Taken together, these findings may provide a new insight into better understanding the molecular mechanisms of immunosuppression induced by chronic stress.

Systemic effects of unspecific inflammatory reaction at traumatic brain injury.

To determine the role of systemic effects of inflammation at traumatic brain disease caused by severe traumatic brain injury. The study is performed on 65 white outbred male rats. TBI is applied with one blow on animal's cranial vaults with blow energy of 0.52 J. The rate of mortality within the first 5 days after the injury is 87%. Experimental animals have got severe closed TBI. Blood contents of circulating immune complexes, C-reactive protein, ceruloplasmin, proinflammatory - interleukins(IL-1b, IL-6, IL-8 and tumor necrosis factor a -TNF-a) are investigated. The circulating immune complexes levels are increased 3.1 times in 24 hours and 4.4 times on the 5th days of trauma reflecting the progressive accumulation of metabolites and toxins in brain tissue and in the blood of injured animals. Blood levels of C-reactive protein are markedly increased in all periods of observation exceeding the control levels 3.5 times in 3 hours and 21.3 times after 5th day of trauma. Thus the study results suggest that the acute phase of systemic inflammation sets at the end of the 1st day after the trauma and it progresses in the course of traumatic brain disease. Blood contents of IL-1b increases continuously: 4.7 times in 3 hours; 7.6 times in 24 hours; and 17.4 times on the 5th day after trauma. The other interleukins levels are also increased but to a lesser extent. The coherence of changes in levels of circulating immune complexes, acute-phase proteins and interleukins indicates a pathogenic pattern of the acute period of traumatic disease at traumatic brain injury: spreading of damage processes with the involvement of body organs and tissues and the establishment of a systemic inflammatory reaction stage from the second day of posttraumatic period.

Amperometric immunosensor for the determination of ceruloplasmin in human serum and urine based on covalent binding to carbon nanotubes-modified screen-printed electrodes.

A novel electrochemical immunosensor for the determination of ceruloplasmin (Cp) in human serum and urine is reported. The immunosensor configuration involves an indirect competitive immunoassay implying covalent immobilization of Cp on activated carboxylic groups at carbon nanotubes-modified screen-printed electrodes (CNTs/SPE). After Cp immobilization and reaction between the target analyte and anti-ceruloplasmin antibodies in solution, the remaining non-conjugated antibody is attached on the Cp-CNTs modified electrode. Monitoring of Cp is performed by means of a secondary antibody labeled with peroxidase (HRP-anti-IgG) and measurement of the amperometric current resulting from the addition of hydrogen peroxide in the presence of hydroquinone as the redox mediator. The experimental variables affecting the analytical performance of the immunosensor were optimized. Calibration curves for Cp provided a linear range between 0.07 and 250 µg/mL (r=0.997). The limit of detection achieved was 21 ng/mL. These analytical characteristics allow the immunosensor to be successfully used for the determination of Cp in spiked human serum and urine at various concentration levels.

Characterization of the ceruloplasmin gene and its potential role as an indirect marker for selection to Aeromonas hydrophila resistance in rohu, Labeo rohita.

Ceruloplasmin is an acute phase protein found to be activated by the host immune system during stress conditions. The ceruloplasmin gene has been reported in several teleosts and here we characterize the gene and test its association with resistance to Aeromonas hydrophila in rohu, Labeo rohita. A ceruloplasmin mRNA sequence of 3355 base pairs (bp) was derived (GenBank ID: JX010736). The coding sequence (CDS) comprised of 3276 bp that coded for 1092 amino acids. Alignment results showed the greatest similarity with zebrafish followed by channel catfish sequence, and a phylogenetic tree constructed on the basis of amino acid sequences showed that rohu shares a common clade with these two species. In the ontogeny study, the expression of ceruloplasmin was detected at 9 h post-fertilization onwards, and a strong level of expression was detected at 24 h (38-fold) and 15 days (34-fold) post-fertilization. The ceruloplasmin transcripts were evident in liver, spleen, stomach and heart. Expression was undetectable in gill, brain, eye, skin, muscle, intestine, anterior and posterior kidney tissues. Expression of ceruloplasmin after A. hydrophila infection was up-regulated 6 h post-challenge and was modulated until 15 days post-challenge. The level of ceruloplasmin was also compared in rohu selectively bred for higher growth and disease resistance. The gene showed a 4.58-fold higher level of expression in resistant line over susceptible line rohu selected based on family challenge test survival to A. hydrophila. Serum ceruloplasmin levels in three year classes of rohu selected for higher growth showed a positive correlation (0.49 ± 1.11) with survival against challenge with A. hydrophila. The estimated heritability was also found to be quite high (0.50 ± 0.22) for this parameter. Thus, ceruloplasmin could be one of the useful marker traits for selection against A. hydrophila resistance in fish.

Ontogenetic expression and 17ß-estradiol regulation of immune-related genes in early life stages of Japanese medaka (Oryzias latipes).

Accumulating evidence suggests that environmental endocrine disrupting chemicals (EDCs) may exert adverse effects on aquatic organisms via the modulation of immune competence in addition to the endocrine system. However, to date, most studies have been undertaken only on biochemical and histopathological endpoints, and few studies have addressed the role of immune response gene transcript abundance in response to estrogen. In the present study, the ontogenetic expression of immune-related genes, including three complement components (C3-1, C3-2 and Bf/C2), two cytokines (IL-21 and type I IFN [IFN]), lysozyme (LZM), novel immune-type receptor (NITR-18), Ikaros (IK) and ceruloplasmin (CP) were characterized during different developmental periods (from 0 to 28 d post-hatch [dph]) in Japanese medaka. Furthermore, the responses of these genes to natural estrogen (i.e., 17ß-estradiol [E2]) were evaluated. E2 exposure at sublethal concentrations (0.1-10 µg/L) down-regulated the gene expression of C3-1, C3-2, Bf/C2, LZM and CP, while up-regulating the expression of IL-21, IFN, NITR-18 and IK. The results demonstrate a very different trend in gene expression in fish larvae exposed to E2 when compared with the ontogenetic changes in control, suggesting that exposure to environmental chemicals with estrogenic activities may interfere with immune-related genes and thus potentially influence the susceptibility of fish to opportunistic infections. These findings confirm the ability of exogenous estrogens to elicit changes in immune-related gene expression, and broaden our understanding about the mechanisms underlying the actions of EDCs. In addition, the expression profiles of immune-related genes can be developed for use as biomarkers for future immunotoxicological studies.

Molecular responses of ceruloplasmin to Edwardsiella ictaluri infection and iron overload in channel catfish (Ictalurus punctatus).

Ceruloplasmin is a serum ferroxidase that carries more than 90% of the copper in plasma and has documented roles in iron homeostasis as well as antioxidative functions. In our previous studies, it has been shown that the ceruloplasmin gene is strongly up-regulated in catfish during challenge with Edwardsiella ictaluri. However, little is known about the function of this gene in teleost fish. The objective of this study, therefore, was to characterize the ceruloplasmin gene from channel catfish, determine its genomic organization, profile its patterns of tissue expression, and establish its potential for physiological antioxidant responses in catfish after bacterial infection with E. ictaluri and iron treatment. The genomic organization suggested that the catfish ceruloplasmin gene had 20 exons and 19 introns, encoding 1074 amino acids. Exon sizes of the catfish ceruloplasmin gene were close to or identical with mammalian and zebrafish homologs. Further phylogenetic analyses suggested that the gene was highly conserved through evolution. The catfish ceruloplasmin gene was mapped to both the catfish physical map and linkage map. The catfish ceruloplasmin gene was mainly expressed in liver with limited expression in other tissues, and it was significantly up-regulated in the liver after bacterial infection alone or after co-injection with bacteria and iron-dextran, while expression was not significantly induced with iron-dextran treatment alone.

Copper and ceruloplasmin abnormalities in Alzheimer's disease.

The idea that copper may play a role in the pathogenesis of Alzheimer's disease is gaining momentum. Serum copper and ceruloplasmin were measured by both enzymatic (eCp) and immunologic (iCp) methods in 28 patients with Alzheimer's disease and 29 age-matched controls. ''Free copper'' was determined by subtracting copper accounted for in the eCp assay from total serum copper. Percentage free copper, that is the proportion of serum copper not bound to ceruloplasmin, was significantly elevated in patients with Alzheimer's compared to controls. There was significantly more ''defective'' ceruloplasmin, which is apoceruloplamin lacking its copper, in Alzheimer's disease than in normal controls. This abnormality may precede the clinical onset of the disease and help predict risk of disease onset. Increased exposure to environmental copper (eg, the spread of copper plumbing and the use of copper in supplements) and/or defective ceruloplasmin function may play a role in the current epidemic of Alzheimer's disease.

Human hephaestin expression is not limited to enterocytes of the gastrointestinal tract but is also found in the antrum, the enteric nervous system, and pancreatic {beta}-cells.

Hephaestin (Hp) is a membrane protein with ferroxidase activity that converts Fe(II) to Fe(III) during the absorption of nutritional iron in the gut. Using anti-peptide antibodies to predicted immunogenic regions of rodent Hp, previous immunocytochemical studies in rat, mouse, and human gut tissues localized Hp to the basolateral membranes of the duodenal enterocytes where the Hp was predicted to aid in the transfer of Fe(III) to transferrin in the blood. We used a recombinant soluble form of human Hp to obtain a high-titer polyclonal antibody to Hp. This antibody was used to identify the intracellular location of Hp in human gut tissue. Our immunocytochemical studies confirmed the previous localization of Hp in human enterocytes. However, we also localized Hp to the entire length of the gastrointestinal tract, the antral portion of the stomach, and to the enteric nervous system (both the myenteric and submucous plexi). Hp was also localized to human pancreatic beta-cells. In addition to its expression in the same cells as Hp, ferroportin was also localized to the ductal cells of the exocrine pancreas. The localization of the ferroxidase Hp to the neuronal plexi and the pancreatic beta cells suggests a role for the enzymatic function of Hp in the protection of these specialized cell types from oxidative damage.

[Investigation of relation between LPO, AOD and some immune parameters in patients with chronic kidney disease].

Time course of lipid peroxidation and the state of antioxidant system of patients with chronic kidney disease were studied. Increases of conjugated dienes, malonic dialdehyde, lipid peroxidation degree were found. Alterations in ceruloplasmin activity, observed in blood of patients depended on the stage of the disease. Content of lipid peroxidation products was also dissimilar during the first and the second stage of disease. Estimation of ceruloplasmin activity and content of conjugated dienes were the most suitable parameters for monitoring treatment of chronic renal disease.

Japanese encephalitis virus differentially modulates the induction of multiple pro-inflammatory mediators in human astrocytoma and astroglioma cell-lines.

Astrocytes become activated in response to many CNS pathologies. The process of astrocyte activation remains rather enigmatic and results in so-called reactive gliosis, a reaction with specific structural and functional characteristics. Astrocytes play a vital role in regulating aspects of inflammation and in the homeostatic maintenance of the CNS. However, the responses of different human astroglial cell-lines in viral encephalitis mediated inflammation are not well documented. We have shown that Japanese encephalitis virus (JEV) infection causes morphological and functional changes in astrocytic cell-lines. We have demonstrated that besides reactive oxygen species (ROS) JEV infection differentially regulated the induction pattern of IL-6, IL-1 beta and IL-8. IP-10, MCP-1, MIG and RANTES secretions in different astroglial cell-lines. The expression of different proteins such as astrocyte-specific glial fibrillary acidic protein (GFAP), the glutamate aspartate transporter/essential amino acid transporter-1 (GLAST/EAAT-1), glutamate transporter-1/essential amino acid transporter-2 (GLT-1/EAAT-2), Ceruloplasmin and Thioredoxin (TRX) expression level also differ in different human astrocyte cell-lines following infection.

Immunological changes after a single bout of moderate-intensity exercise in a hot environment

This study was aimed to evaluate the possible changes caused by a single bout ofmoderate-intensity exercise in a hot environmental temperature on the immune functionand on inflammatory markers. A total of 22 young male adults (VO2max, 55.4 ¡¾3.6 ml¡¤kg-1¡¤min-1) volunteered to participate in an exercise session of 60 minutes on atreadmill ergometer at moderate speed (60% of the maximum aerobic speed) in hotenvironmental conditions (35 ¨¬C and humidity 60%). Total leukocyte numbers, lymphocytesubsets (CD8+, CD4+, CD3+, NK and CD19+), cytokine productioncapacity by peripheral blood mononuclear cells (PBMCs) (IL-2, IL-4, IL-5, IL-10,IFN-¥ã and TNF-¥á) as well as the concentration of several inflammation related proteins(ceruloplasmin, C-reactive protein (CRP), complement factors C3 and C4)were evaluated before and after exercise. The results show that leukocyte and neutrophilabsolute values increased (P<0.001) after the exercise period. In contrast,eosinophil values decreased (P<0.05) after the exercise. In addition, ceruloplasmin,C3 and C4 values (P<0.05) increased after exercise. No changes in T lymphocyte subsets,cytokine production, or CRP were observed. These data confirm previous studiessuggesting that a 60 min exercise in a hot environment is enough to cause a physiologicadaptation to these special conditions leading to an increase of non-specificimmune cells and promoting inflammatory processes. On the other hand, PCR values, lymphocyte subsets and the capacity of cytokine production by PBMC were notchanged in a relatively short bout of exercise under these conditions in contrast withprevious studies (AU)

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Immunological changes after a single bout of moderate-intensity exercise in a hot environment.

This study was aimed to evaluate the possible changes caused by a single bout of moderate-intensity exercise in a hot environmental temperature on the immune function and on inflammatory markers. A total of 22 young male adults (VO2(max), 55.4 +/- 3.6 ml x kg(-1) x min(-1)) volunteered to participate in an exercise session of 60 minutes on a treadmill ergometer at moderate speed (60% of the maximum aerobic speed) in hot environmental conditions (35 degrees C and humidity 60%). Total leukocyte numbers, lymphocyte subsets (CD8+, CD4+, CD3+, NK and CD19+), cytokine production capacity by peripheral blood mononuclear cells (PBMCs) (IL-2, IL-4, IL-5, IL-10, IFN-gamma and TNF-alpha) as well as the concentration of several inflammation related proteins (ceruloplasmin, C-reactive protein (CRP), complement factors C3 and C4) were evaluated before and after exercise. The results show that leukocyte and neutrophil absolute values increased (P < 0.001) after the exercise period. In contrast, eosinophil values decreased (P < 0.05) after the exercise. In addition, ceruloplasmin, C3 and C4 values (P < 0.05) increased after exercise. No changes in T lymphocyte subsets, cytokine production, or CRP were observed. These data confirm previous studies suggesting that a 60 min exercise in a hot environment is enough to cause a physiologic adaptation to these special conditions leading to an increase of non-specific immune cells and promoting inflammatory processes. On the other hand, PCR values, lymphocyte subsets and the capacity of cytokine production by PBMC were not changed in a relatively short bout of exercise under these conditions in contrast with previous studies.

[The role of ceruloplasmin in neoplastic processes].

Ceruloplasmin (CP) is a copper containing oxidase of human plasma alpha 2-globulin fraction. The review summarizes literature data on biological role of CP under normal conditions and during development of malignant tumor. This protein may be involved both into antitumor deference and also into metastasizing process. Although CP has already been employed into intensive therapy of oncologic patients all mechanisms underlying its biological activity remain to be clarified.

Production and characterization of monoclonal antibodies against human ceruloplasmin.

Ceruloplasmin (CP) is the major plasma antioxidant and copper transport protein. Monoclonal antibodies (mAbs) against human CP were produced and characterized. A total of five hybridoma cell lines were established (CP2, CP10, CP20, CP25, CP30). From the epitope mapping analysis, two subgroups of mAbs recognize different peptide fragments were identified. When the purified CP was incubated with the mAbs, the ferroxidase activity of CP was inhibited up to a maximum 57 %. Immunoblotting with various tissue homogenates indicated that all the mAbs specifically recognize a single protein band of 130 kDa. They also appear to be extensively cross-reactive among different mammalian including human and avian sources. These results demonstrated that only one type of immunologically similar CP is present in all of the mammalian tissues including human. The CP mAbs could be of great benefit to design the diagnostic kit for CP-related diseases such as Wilson's disease.

Ceruloplasmin immunoreactivity in neurodegenerative disorders.

Ceruloplasmin (CP) is a 132 kd cuproprotein which, together with transferrin, provides the majority of anti-oxidant capacity in serum. Increased iron deposition and lipid peroxidation in the basal ganglia of subjects with hereditary CP deficiency suggest that CP may serve as an anti-oxidant in the brain as well. The present study compared CP immunoreactivity in brain specimens from normal controls and subjects with neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], progressive supranuclear palsy [PSP], and Huntington's disease [HD]) (n = 5 per group). The relative intensity of neuronal CP staining and the numbers of CP-stained neurons per 25x microscope field were determined in hippocampus (CA1, subiculum, and parahippocampal gyrus), parietal cortex, frontal cortex, substantia nigra, and caudate. CP was detected in both neurons and astrocytes in all specimens, and in senile plaques and occasional neurofibrillary tangles in AD brain. Neuronal CP staining intensity tended to increase in most AD brain regions, but was statistically significant vs controls only in the CA1 region of hippocampus (p = .016). Neuronal CP staining in brain specimens from other neurodegenerative disorders showed a slight but nonsignificant increase vs controls. The numbers of CP-stained neurons per field did not differ between the various neurodegenerative disorders and controls. These results suggest that a modest increase in neuronal CP content is present in the AD brain, and lesser elevations in neuronal CP occur in the other neurodegenerative disorders in this study. Though CP functions as both an acute phase protein and an anti-oxidant in peripheral tissues, whether it does so in the brain remains to be determined.

Antioxidant binding of caeruloplasmin to myeloperoxidase: myeloperoxidase is inhibited, but oxidase, peroxidase and immunoreactive properties of caeruloplasmin remain intact.

The neutrophil enzyme myeloperoxidase (MPO) purposefully makes hypochlorous acid (HOCl) as part of the cells defence against microbial infections. During cell lysis, however, MPO will be released into the extracellular environment where production of HOCl, a powerful oxidant, will lead to molecular damage. Extracellular MPO binds to the copper-containing protein caeruloplasmin (Cp) and prevents MPO making HOCl. Cp has several important antioxidant functions in extracellular fluids associated with its ability to catalyse oxidation of ferrous ions and to remove peroxides. The binding of MPO to Cp did not inhibit these important extracellular antioxidant activities of Cp, but in so doing it provided additional antioxidant protection against formation of HOCl.

[Effects of infant formula feeding on the distribution of copper in the body of 8-day-old rats]. / Vliianie iskusstvennogo vskarmlivaniia na raspredelenie medi v organizme 8-dnevnykh krysiat.

The oxidase activity of ceruloplasmin (Cp, EC 1.16.3.1), the content of immunoreactive Cp and copper ion concentration were measured in the serum of eight day-old rats receiving either breast feeding (control group) or commercial nutritive mixture which has been recommended for the newborn children beginning from zero age (experimental group). It was shown that the artificial feeding caused almost 3-fold increase of Cp oxidase activity and copper content in the serum when compared to age-matched controls. No changes in the copper content per Cp molecule were observed. Dot-hybridization of the total liver polyribosomal RNA with Cp [32P]cDNA showed that the increased Cp level in the blood of the rats of experimental group correlated well with the level of expression of Cp gene. The copper content in the liver of experimental rats was two times lower that in control animals while no differences was found in the brain copper content between two groups of rats. The role of the regulation of Cp gene expression in the lactating mammary gland and of milk Cp in the copper homeostasis in the newborn body is discussed.