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It has been reported that Cu(II) ions in human blood are bound mainly to serum albumin (HSA), ceruloplasmin (CP), alpha-2-macroglobulin (α2M) and His, however, data for α2M are very limited and the thermodynamics and kinetics of the copper distribution are not known. We have applied a new LC-ICP MS-based approach for direct determination of Cu(II)-binding affinities of HSA, CP and α2M in the presence of competing Cu(II)-binding reference ligands including His. The ligands affected both the rate of metal release from Cu•HSA complex and the value of K D . Slow release and K D  = 0.90 pM was observed with nitrilotriacetic acid (NTA), whereas His showed fast release and substantially lower K D  = 34.7 fM (50 mM HEPES, 50 mM NaCl, pH 7.4), which was explained with formation of ternary His•Cu•HSA complex. High mM concentrations of EDTA were not able to elicit metal release from metallated CP at pH 7.4 and therefore it was impossible to determine the K D value for CP. In contrast to earlier inconclusive evidence, we show that α2M does not bind Cu(II) ions. In the human blood serum ~75% of Cu(II) ions are in a nonexchangeable manner bound to CP and the rest exchangeable copper is in an equilibrium between HSA (~25%) and Cu(II)-His-Xaa ternary complexes (~0.2%).

Significance In cancer, the metabolism of copper and sulfur are dysregulated, leading to deleterious side effects. These issues are commonly addressed by studying the variations of concentrations of the elements, but here we have used, for the first time to our knowledge, copper and sulfur stable isotope compositions variations, using methods widespread in Earth sciences. We show that in hepatocellular carcinomas patients, blood copper and sulfur are enriched in light isotopes compared with control subjects. These isotopic signatures are not compatible with a dietary origin, but rather reflect the massive reallocation in the body of copper immobilized within cysteine-rich proteins such as metallothioneins. We also propose that sulfur isotope compositions could serve to track sulfur originating from tumor-derived sulfides. The widespread hypoxic conditions of the tumor microenvironment can impair the metabolism of bioessential elements such as copper and sulfur, notably by changing their redox state and, as a consequence, their ability to bind specific molecules. Because competing redox state is known to drive isotopic fractionation, we have used here the stable isotope compositions of copper ( ⁶⁵Cu/ ⁶³Cu) and sulfur ( ³⁴S/ ³²S) in the blood of patients with hepatocellular carcinoma (HCC) as a tool to explore the cancer-driven copper and sulfur imbalances. We report that copper is ⁶³Cu-enriched by ∼0.4‰ and sulfur is ³²S-enriched by ∼1.5‰ in the blood of patients compared with that of control subjects. As expected, HCC patients have more copper in red blood cells and serum compared with control subjects. However, the isotopic signature of this blood extra copper burden is not in favor of a dietary origin but rather suggests a reallocation in the body of copper bound to cysteine-rich proteins such as metallothioneins. The magnitude of the sulfur isotope effect is similar in red blood cells and serum of HCC patients, implying that sulfur fractionation is systemic. The ³²S-enrichment of sulfur in the blood of HCC patients is compatible with the notion that sulfur partly originates from tumor-derived sulfides. The measurement of natural variations of stable isotope compositions, using techniques developed in the field of Earth sciences, can provide new means to detect and quantify cancer metabolic changes and provide insights into underlying mechanisms.

Circulating mineral concentrations are used to assess nutritional status or as markers for clinical conditions, but the quality of these measurements depends on the methods used for blood processing. Since the procedures for measuring mineral levels in blood are not standardized, discrepancies in sampling may influence the analytical results. We previously reported that zinc content in blood samples showed significant variation depending on several pre-analytical variables selected during blood collection and processing. In this study, we extend our analysis to determine how other mineral levels might be affected by different blood draw sites (capillary or venous) or sample matrices (plasma or serum). Sequential capillary and venous blood samples were collected from a diverse cohort of sixty healthy adults and analyzed for multiple minerals using inductively coupled plasma-optical emission spectrometry. Calcium, copper, iron, and magnesium were the only minerals that were detected in all samples and were free from contamination in the blood collection tubes used for the study. When assessing different blood draw sites, the concentrations of calcium, copper, iron, and magnesium were 2-11% higher from capillary compared to the venous plasma. When assessing different blood sample matrices, the concentrations of calcium, copper, and magnesium were 2-5% higher in serum compared to plasma samples, whereas the concentration of iron was 7% higher in plasma compared to serum samples. The differences observed in these four essential minerals from discrepant draw sites and blood matrices demonstrate the importance of controlling key pre-analytic variables when assessing mineral levels in blood.

The prevalence of obesity has increased at an alarming rate worldwide. Metallic elements are involved in the pathogenesis of obesity and related diseases. To date, whether environmental exposure to metallic elements has effects on obesity in children and adolescents is still unclear. The aim of the current study was to investigate the association of blood metallic elements with obesity in U.S. children and adolescents. This cross-sectional study was performed with 5404 children and adolescents (6–19 years, 2745 males and 2659 females) who participated in the US National Health and Nutrition Examination Survey 2011–2014. Blood lead, mercury, selenium, manganese, copper, and zinc, as well as biochemical parameters including triglyceride (TG), cholesterol, low-density lipoprotein (LDL), and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed for all subjects. Multivariate logistic regression and linear regression were applied to assess associations of metallic elements and overweight, obesity status, and serum metabolites as distinct outcomes adjusted for age, gender, ethnicity, and the poverty income ratio. When stratified by age and sex, significant associations were found between the highest quartile of copper concentrations in blood with obesity status (OR = 9.27, 95% CI: 5.43, 15.82, pfor trend < 0.001) and cholesterol (OR = 3.08, 95% CI: 1.43, 6.63, pfor trend < 0.001). The highest concentrations of manganese in the blood was associated with obesity in those aged 6–19 years (OR = 2.29, 95% CI: 1.74, 3.02, pfor trend < 0.001). Moreover, blood mercury and selenium showed positive relationships with cholesterol. Further, a negative association existed between blood zinc and obesity. The National Health and Nutrition Examination Survey data provide epidemiological evidence that blood metallic elements are positively associated with obesity in children and adolescents. However, the underlying mechanisms still need further exploration.

Angiogenesis critically sustains the progression of both physiological and pathological processes. Copper behaves as an obligatory co-factor throughout the angiogenic signalling cascades, so much so that a deficiency causes neovascularization to abate. Moreover, the progress of several angiogenic pathologies (e.g. diabetes, cardiac hypertrophy and ischaemia) can be tracked by measuring serum copper levels, which are being increasingly investigated as a useful prognostic marker. Accordingly, the therapeutic modulation of body copper has been proven effective in rescuing the pathological angiogenic dysfunctions underlying several disease states. Vascular copper transport systems profoundly influence the activation and execution of angiogenesis, acting as multi-functional regulators of apparently discrete pro-angiogenic pathways. This review concerns the complex relationship among copper-dependent angiogenic factors, copper transporters and common pathological conditions, with an unusual accent on the multi-faceted involvement of the proteins handling vascular copper. Functions regulated by the major copper transport proteins (CTR1 importer, ATP7A efflux pump and metallo-chaperones) include the modulation of endothelial migration and vascular superoxide, known to activate angiogenesis within a narrow concentration range. The potential contribution of prion protein, a controversial regulator of copper homeostasis, is discussed, even though its angiogenic involvement seems to be mainly associated with the modulation of endothelial motility and permeability.

The aim of the present study was to evaluate serum concentrations of copper (Cu) and zinc (Zn), in relation with metabolic profile and clinicopathologic features of patients with endometrial cancer. A total of 47 women with endometrial cancer and 45 controls were eligible for the study. Clinicopathologic features and metabolic profile as well as serum copper and zinc levels were evaluated in each subject. Patients with endometrial cancer (Cu mean 3.72 ± 2.15 mg/L, median 3.54 [0.41–9.16] mg/L and Zn mean 1.83 ± 0.71 mg/L, median 1.77 [0.71–4.02] mg/L) exhibited lower Cu and Zn levels than those of controls (Cu mean 6.06 ± 1.79 mg/L, median 6.32 [2.95–9.05] mg/L and Zn mean 2.48 ± 0.89 mg/L, median 2.23 [1.23–4.54] mg/L) (p < 0.001). Cu/Zn ratio was also higher (0.85 ± 1.96 vs. 2.57 ± 0.73) in controls as compared with patients with endometrial cancer. While Cu levels showed no significant correlation with age, body mass index, gravidity, and parity, a positive correlation was found between Zn levels and parity. When cancer patients were evaluated on their own, both Cu and Zn levels showed positive correlation with age. Additionally, the cancer patients with myometrial invasion > 1/2 exhibited lower Cu levels compared with the cancer patients with myometrial invasion < 1/2. The data of the present study suggested that women with endometrial cancer are characterized by altered serum Cu and Zn levels as compared with controls. Imbalance of these trace element levels might be associated with endometrial cancer among Turkish patients.

Some correlations between serum Cu, Zn and Se and cytokines have been reported in humans. Especially, the Cu:Zn ratio corresponded with inflammation. To date, relationships between microelements and proinflammatory proteins are poorly understood in horses. The aim of the study was to evaluate whether Cu, Zn and Se may influence turnover of IL-6, IL-8 and tissue factor (TF) in breeding and working horses. Blood samples obtained from 66 horses were analysed. There were 37 pregnant broodmares of different breeds, 13 barren broodmares and 16 race Thoroughbred horses. Serum Cu, Zn and Se concentration was determined using the gas flame atomic absorption spectrometry (GFAAS) method. Plasma IL-6, IL-8 and TF concentration was determined by the ELISA method. A coefficient correlation was carried out to compare the values of microelements studied with IL-6, IL-8 and TF using Pearson’s test. The values of IL-6 correlated significantly positively with Se and Cu:Zn ratio, IL-8 correlated positively with Cu and Cu:Zn ratio and negatively with Zn, and TF correlated positively with Cu, Cu:Zn ratio and Se. The Cu:Zn ratio varies significantly between horses, with high values occurring in horses with high levels of proinflammatory proteins, which may indicate the presence of a subclinical inflammatory process. The high variability of TF in the studied groups gives hope for the use of its determination in laboratory diagnostics of horses.

The trace element copper (Cu) is part of our nutrition and essentially needed for several cuproenzymes that control redox status and support the immune system. In blood, the ferroxidase ceruloplasmin (CP) accounts for the majority of circulating Cu and serves as transport protein. Both Cu and CP behave as positive, whereas serum selenium (Se) and its transporter selenoprotein P (SELENOP) behave as negative acute phase reactants. In view that coronavirus disease (COVID-19) causes systemic inflammation, we hypothesized that biomarkers of Cu and Se status are regulated inversely, in relation to disease severity and mortality risk. Serum samples from COVID-19 patients were analysed for Cu by total reflection X-ray fluorescence and CP was quantified by a validated sandwich ELISA. The two Cu biomarkers correlated positively in serum from patients with COVID-19 (R = 0.42, p < 0.001). Surviving patients showed higher mean serum Cu and CP concentrations in comparison to non-survivors ([mean+/−SEM], Cu; 1475.9+/−22.7 vs. 1317.9+/−43.9 µg/L; p < 0.001, CP; 547.2.5+/−19.5 vs. 438.8+/−32.9 mg/L, p = 0.086). In contrast to expectations, total serum Cu and Se concentrations displayed a positive linear correlation in the patient samples analysed (R = 0.23, p = 0.003). Serum CP and SELENOP levels were not interrelated. Applying receiver operating characteristics (ROC) curve analysis, the combination of Cu and SELENOP with age outperformed other combinations of parameters for predicting risk of death, yielding an AUC of 95.0%. We conclude that the alterations in serum biomarkers of Cu and Se status in COVID-19 are not compatible with a simple acute phase response, and that serum Cu and SELENOP levels contribute to a good prediction of survival. Adjuvant supplementation in patients with diagnostically proven deficits in Cu or Se may positively influence disease course, as both increase in survivors and are of crucial importance for the immune response and antioxidative defence systems.

Objective To evaluate the association between serum copper levels and lung cancer risk. Methods We searched the electronic PubMed, WanFang, CNKI, and SinoMed databases to identify studies including information on serum copper levels and lung cancer. Standard mean differences and corresponding 95% confidence intervals were calculated using Stata 12.0 software. We performed a meta-analysis on the identified studies overall and according to geographic location. We also evaluated heterogeneity among the studies and the occurrence of publication bias. Results Thirty-three articles including 3026 cases and 9439 controls were included in our study. The combined results showed that serum copper levels were higher in patients with lung cancer compared with controls without lung cancer, though the results showed high heterogeneity. In a subgroup analysis according to geographic location, significant associations between copper levels and lung cancer were found for both Asian and European populations. No publication bias was detected in this meta-analysis. Conclusions High serum copper levels could increase the risk of lung cancer, suggesting that environmental copper exposure may be a risk factor for the development of lung cancer.

While in vitro and animal studies of osteoblastic and osteoclastic activity as well as bone resistance for copper are numerous, and the results encouraging in terms of regulation, human studies are scarce. The aim of this narrative review was to investigate the correlation of blood copper, daily copper intake, and copper supplementation with bone mineral density. This review included 10 eligible studies: five studies concerned copper blood levels, one study concerned daily copper intake, and four studies concerned copper supplementation. Blood copper levels did not show statistically significant differences in four of the studies analyzed, while only one study showed differences between osteoporotic and healthy women, although only with women between 45 and 59 years of age and not between 60 and 80 years of age. The dietary copper intake among women with or without osteoporosis did not show any differences. Only one study with a small sample of subjects carried out these assessments; therefore, it is a topic that the literature must deepen with further studies. The two studies that analyzed the integration of copper (2.5–3 mg/day) only showed good results in terms of slowing down bone mineral loss and reducing resorption markers, confirming the effectiveness of copper supplementation on bone metabolism.