Adequate Copper Research Articles

Analysis of zinc and copper levels in very low birth weight infants using human milk additives: phase 1 trial findings

ObjectiveThe aim of this study was to assess whether the micronutrients zinc and copper, provided by human milk additives, are sufficient for very low birth weight preterm infants. MethodA phase 1 randomized double-blind controlled trial was conducted with very low birth weight preterm infants. This is a secondary analysis of copper and zinc. Sixty-six newborns were part of the initial sample, with forty participating and reaching the final stage of the study. Inclusion criteria were: gestational age less than 37 weeks, birth weight greater than or equal to 750 g and less than or equal to 1500 g, small or appropriate for gestational age, exclusively receiving human milk at a volume greater than or equal to 100 mL per kilogram per day, and hemodynamically stable. Participants were randomly assigned to two groups: intervention, Lioneo (received human milk with additive based on lyophilized human milk), n = 20, and control, HMCA (received human milk with commercial additive based on cow's milk protein), n = 20, and their serum levels of zinc and copper were measured on the first and twenty-first days. ResultsThere was a reduction in intragroup zinc serum levels from the first to the twenty-first day of the study (p < 0.01). There was no intergroup difference. No difference was found in serum copper levels. ConclusionHuman milk additives were not sufficient to maintain adequate zinc serum levels in very low birth weight newborns. It was not possible to affirm whether human milk additives were sufficient to maintain adequate serum copper levels in the studied sample. UTN: U1111–1220–0550.

Clinical experience on switching trientine tetrahydrochloride to trientine dihydrochloride in Wilson disease patients.

This study evaluates the effectiveness and safety of trientine dihydrochloride (TETA 2-HCl) in patients with Wilson disease (WD) following a switch from trientine tetrahydrochloride (TETA 4-HCl). A total of 30 WD patients with stable copper metabolism were identified for treatment with TETA 2-HCl (Cufence™) after prior use of TETA 4-HCl (Cuprior™). Biochemical markers including urinary copper, non-ceruloplasmin bound copper (NCC) and liver function were analyzed at baseline and followed up over 12 months. Safety was assessed based on reported adverse events (AEs). Urinary copper levels and NCC remained stable across all follow-ups, indicating adequate copper metabolism control. Reported AEs during TETA 2-HCl treatment were mostly gastrointestinal discomfort (n = 6). In two patients, progressive elevation of transaminases occurred (despite stable copper metabolism). AEs led to discontinuation of treatment in five cases. Median baseline dose per day was 10.2 mg TETA 4-HCl/kg bodyweight, whereas median baseline dose after therapeutic switch to TETA 2-HCl was 12.8 mg/kg bodyweight. Median daily dose at 12 months did not differ significantly from TETA 2-HCl dose at switching timepoint, with stable biochemical markers and markers of copper metabolism in most (25/30) of the patients. Transitioning from TETA 4-HCl to TETA 2-HCl maintained stable copper parameters and liver function in most of analyzed patients. TETA 2-HCl treatment was generally well tolerated, suggesting that switching medications is safe and effective. In our real-life cohort, adjustment factor of ~1.25× for the switch of TETA 4-HCl to TETA 2-HCl resulted in adequate copper metabolism control.

Associations between APOE genotypes, urine 8-isoprostane and blood trace elements in middle-aged mothers (CROME study)

BackgroundThere is almost no data on the combined associations between apolipoprotein E gene (APOE) genotypes, trace elements (TEs), and lipid peroxidation in vivo. The aim of our study was to evaluate the association between APOE genotypes and TE levels in blood (B-TEs) and erythrocytes (E-TEs), and 8-isoprostane in urine (U-8-isoprostane) in women with low exposure to potentially toxic TEs and with adequate supply of essential TEs. MethodsB-TEs, E-TEs and U-8-isoprostane were determined in 172 healthy women of childbearing age (30.1–51.4 years) using ICP-MS and ELISA competitive assay, respectively. All women were divided into three APOE genotype groups according to the presence of the ɛ4 allele, ɛ2 allele or ɛ3 homozygotic allele. The associations between B-TEs, E-TE, U-8-isoprostane, and the APOE genotype groups were estimated by multiple variable linear regression models with relevant explanatory variables (e.g., age, BMI, and seafood). ResultsAll TE and U-8-isoprostane levels were inside the reference ranges for the healthy population. In the multiple variable linear regression models, our results showed that urine 8-isoprostane levels increased by up to 43.3% in the APOE4 group compared to the APOE3 group and a negligible negative modifying effect for essential TEs. However, the APOE genotype groups were associated also with some TEs. A clear positive association was found between the APOE2 and APOE4 groups (vs. APOE3) with B-molybdenum. ConclusionsOur study suggests that the APOE4 genotype played an important role in 8-isoprostane variability in a population with an adequate supply of essential and with low exposure to potentially toxic TEs. Adequate copper, zinc and selenium status seemed to be protective against, while the levels of nonessential TEs were probably too low to play a decisive role in 8-isoprostane formation. The observed impact of the APOE2 and APOE4 groups on increased B-molybdenum opens a new research topic.

Intermittent hypoxia exacerbates metabolic dysfunction-associated fatty liver disease by aggravating hepatic copper deficiency-induced ferroptosis.

Intermittent hypoxia (IH) is an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Copper deficiency can disrupt redox homeostasis, iron, and lipid metabolism. Here, we investigated whether hepatic copper deficiency plays a role in IH-associated MAFLD and explored the underlying mechanism(s). Male C57BL/6 mice were fed a western-type diet with adequate copper (CuA) or marginally deficient copper (CuD) and were exposed separately to room air (RA) or IH. Hepatic histology, plasma biomarkers, copper-iron status, and oxidative stress were assessed. An in vitro HepG2 cell lipotoxicity model and proteomic analysis were used to elucidate the specific targets involved. We observed that there were no differences in hepatic phenotypes between CuA-fed and CuD-fed mice under RA. However, in IH exposure, CuD-fed mice showed more pronounced hepatic steatosis, liver injury, and oxidative stress than CuA-fed mice. IH induced copper accumulation in the brain and heart and exacerbated hepatic copper deficiency and secondary iron deposition. In vitro, CuD-treated cells with IH exposure showed elevated levels of lipid accumulation, oxidative stress, and ferroptosis susceptibility. Proteomic analysis identified 360 upregulated and 359 downregulated differentially expressed proteins between CuA and CuD groups under IH; these proteins were mainly enriched in citrate cycle, oxidative phosphorylation, fatty acid metabolism, the peroxisome proliferator-activated receptor (PPAR)α pathway, and ferroptosis. In IH exposure, CuD significantly upregulated the ferroptosis-promoting factor arachidonyl-CoA synthetase long chain family member (ACSL)4. ACSL4 knockdown markedly eliminated CuD-induced ferroptosis and lipid accumulation in IH exposure. In conculsion, IH can lead to reduced hepatic copper reserves and secondary iron deposition, thereby inducing ferroptosis and subsequent MAFLD progression. Insufficient dietary copper may worsen IH-associated MAFLD.

Association Between Maternal Copper/Zinc Intake and the Risk of Preterm Birth

Background: The relationship between maternal copper and zinc intake and the risk of preterm birth is unclear Objectives: This study was designed to investigate the effects of daily copper and zinc intake before and during pregnancy on the risk of preterm birth and to assess whether there is an interaction between copper and zinc intake and the risk of preterm birth Methods: A nested case - control study was conducted in Lanzhou, involving 880 cases and 8017 controls. Eligible participants were interviewed about their diet and characteristics during pregnancy. Unconditional logistic regression was used to determine the association between dietary copper and zinc intake and the risk of preterm birth, including its clinical subtypes. A multivariate adjusted restricted cubic spline (RCS) model was used to investigate the nonlinear relationship between dietary copper and zinc intake and the risk of preterm birth. Results: The study revealed that compared to pregnant women with the highest dietary copper intake before and during pregnancy, those with copper intake in the lower three quartiles (quartiles 1, 2, and 3) had increased risks of preterm birth, with adjusted odds ratios (ORs) of 1.05 (0.96 - 1.14), 1.05 (0.93 - 1.18), and 1.04 (0.82 - 1.32), respectively. The trend test yielded significant results (P = 0.013), particularly in late pregnancy, indicating an association between lower copper intake and increased risks of preterm and spontaneous preterm birth. Maternal dietary zinc intake during pregnancy was positively associated with the risk of preterm birth. The adjusted ORs for quartile 2 compared to quartile 4 were 1.29 (1.09 - 1.52), 1.55 (1.13 - 2.12), and 1.20 (1.00 - 1.46) throughout pregnancy, indicating significantly increased risks in the mid to late stages of pregnancy. No significant association was found between zinc intake and medically induced preterm birth. Zinc intake below the nutritional reference value in late pregnancy was significantly associated with an increased risk of preterm birth (P &lt; 0.05). A nonlinear relationship was observed between copper/zinc intake and the risk of preterm birth (P Nonlinear &lt; 0.05). A synergistic effect of low copper and zinc intake on the risk of preterm birth was found (OR: 2.23, 95% CI: 1.64 - 3.04, P &lt; 0.001). Conclusions: Efforts to promote adequate copper and zinc intake before and during pregnancy need to be intensified to reduce the incidence of preterm birth.

Ileum Proteomics Identifies Distinct Pathways Associated with Different Dietary Doses of Copper-Fructose Interactions: Implications for the Gut-Liver Axis and MASLD.

The interactions of different dietary doses of copper with fructose contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) via the gut-liver axis. The underlying mechanisms remain elusive. The aim of this study was to identify the specific pathways leading to gut barrier dysfunction in the ileum using a proteomics approach in a rat model. Male weanling Sprague Dawley rats were fed diets with adequate copper (CuA), marginal copper (CuM), or supplemented copper (CuS) in the absence or presence of fructose supplementation (CuAF, CuMF, and CuSF) for 4 weeks. Ileum protein was extracted and analyzed with an LC-MS. A total of 2847 differentially expressed proteins (DEPs) were identified and submitted to functional enrichment analysis. As a result, the ileum proteome and signaling pathways that were differentially altered were revealed. Of note, the CuAF is characterized by the enrichment of oxidative phosphorylation and ribosome as analyzed with the KEGG; the CuMF is characterized by an enriched arachidonic acid metabolism pathway; and focal adhesion, the regulation of the actin cytoskeleton, and tight junction were significantly enriched by the CuSF. In conclusion, our proteomics analysis identified the specific pathways in the ileum related to the different dietary doses of copper-fructose interactions, suggesting that distinct mechanisms in the gut are involved in the development of MASLD.

Copper Deficiency Associated with Glycemic Control in Individuals with Type 2 Diabetes Mellitus.

Adequate copper (Cu) status has been associated with improved glycemic control, partly because of its role in reducing oxidative stress through superoxide dismutase (SOD) activity. Thus, the aim was to investigate the relationship between plasma Cu concentration and markers associated with glycemic control in individuals with type 2 diabetes mellitus (T2DM). This observational and cross-sectional study was conducted in individuals with T2DM of both sexes, aged between 19 and 59years. Plasma Cu levels were analyzed using inductively coupled plasma optical emission spectrometry (ICP-OES). Fasting glucose and insulin concentrations, C-peptide levels, SOD activity, and glycated hemoglobin (%HbA1c) were measured. Homeostatic model assessments (HOMA%B, HOMA%S, and HOMA-IR) were also performed. Additionally, %body fat and waist circumference were measured, and body mass index was calculated. Participants were categorized based on their plasma Cu concentrations (< 70µg/dL and ≥ 70µg/dL). The associations between variables were analyzed using chi-squared or Fisher's test and binary logistic regression models. Statistical significance was set at P < 0.05. Of the 97 participants (74.2% women), 85.5% had Cu deficiency. Cu-deficient individuals showed elevated C-peptide concentrations and HOMA%B values compared to those with adequate Cu levels (2.8ng/mL vs. 1.8ng/mL, P = 0.011; and 71.4 vs. 31.0, P = 0.003), respectively. Cu deficiency was associated with insulin resistance (P = 0.044) and decreased likelihood of exceeding the target serum glucose level (OR = 0.147, P = 0.013). However, no significant association was found between SOD activity and plasma Cu concentration. Consequently, Cu deficiency was linked to improved glycemic control, although it was not associated with the other markers.

Update on copper and selenium in Canadian cow-calf herds: regional differences and estimation of serum reference values.

Trace mineral supplementation of beef cattle is essential for efficient reproduction and herd health. Understanding regional differences in cow trace mineral status could inform decisions about risks of deficiencies and supplementation management. Cow-calf surveillance projects provided three opportunities to evaluate the trace mineral status of Canadian beef cow herds. Blood samples were collected at pregnancy testing in 2014 from 102 cow-calf herds and in 2016 from 86 cow-calf herds in Western Canada. In 2019, blood samples were collected at pregnancy testing from cows in 163 cow-calf herds from Eastern and Western Canada. Serum samples were analyzed for copper, selenium, and molybdenum concentrations using a plasma mass spectrometer. The prevalence of copper deficient cows sampled from the Western provinces ranged from 24% to 43% across the three periods, and was 20% from Eastern Canada in 2019. The prevalence of selenium deficient cows ranged from 0.2% to 0.4% across the three projects in Western Canada, but was higher in Eastern Canada at 4.6% in 2019. High serum molybdenum was identified in 9.4% to 14% of cows across the three periods in Western Canada and in 15% of cows sampled in Eastern Canada in 2019. Serum copper, selenium, and molybdenum concentrations varied by cow age and month of sample collection. Serum selenium and molybdenum concentrations, but not copper, varied by soil type associated with the location of the farm. A subsample of samples from cows from Western Canadian herds provided body condition score (BCS) data, pregnancy status, and calf survival data and were used to estimate updated serum reference values for adequate concentrations. Age-specific values were required for selenium and molybdenum. Reference intervals (80%) were estimated from 2,406 pregnant beef cows from 99 herds with each cow having a BCS ≥ 2.5/5 and a live calf at 3 wk with no retained placenta: copper for all cows (0.379 to 0.717 ppm), selenium for cows <4 yr (0.052 to 0.152 ppm), and selenium for cows ≥4 yr (0.064 to 0.184 ppm). Upper 90% reference limits were also estimated for serum molybdenum for cows <4 yr (>0.104 ppm) and cows ≥4 yr (>0.110 ppm). The lower limits for the reference intervals for adequate copper and selenium are below those previously reported; nevertheless, they represent a large sample that was specifically applicable to extensively managed beef animals in western Canada.

Potential Role of Copper in Diabetes and Diabetic Kidney Disease.

Copper is a fundamental element for the homeostasis of the body. It is the third most abundant essential transition metal in humans. Changes in the concentration of copper in the blood are responsible for numerous diseases affecting various organs, including the heart, brain, kidneys, and liver. Even small copper deficiencies can lead to the development and progression of several pathologies. On the other hand, excessive exposure to copper can cause toxicity in many human organs, leading to various systemic alterations. In the kidney, increased copper concentration in the blood can cause deposition of this element in the kidneys, leading to nephrotoxicity. One of the most interesting aspects of copper balance is its influence on diabetes and the progression of its complications, such as Diabetic Kidney Disease (DKD). Several studies have shown a close relationship between copper serum levels and altered glycemic control. An imbalance of copper can lead to the progression of diabetes-related complications and impaired antioxidant homeostasis. A high Zinc/Copper (Zn/Cu) ratio is associated with improved renal function and reduced risk of poor glycemic control in patients with type two diabetes mellitus (T2DM). Furthermore, the progression of DKD appears to be related to the extent of urinary copper excretion, while regulation of adequate serum copper concentration appears to prevent and treat DKD. The aim of this review is to evaluate the possible role of copper in DKD patients.

Osteoporosis is the cause of spontaneous humeral fracture in dairy cows from New Zealand.

Outbreaks of humeral fractures in dairy cows have been reported in New Zealand for several years. Gross, histologic, and histomorphometric findings in the humerus from primiparous cows with spontaneous humeral fracture were compared to age-matched control cows. Affected cows had a complete nonarticular spiral fracture of the humerus. Histologically affected humeri had a thicker growth plate with abnormal architecture, thinner cortex with increased abnormal resorption, increased resorption in the distal humerus, decreased trabecular density, abnormal trabecular architecture, presence of growth arrest lines and woven bone formation. Histomorphometry showed reduction in bone volume, trabecular perimeter, and trabecular width. Cows grazed on fodder beet had thicker growth plates with an abnormal appearance compared with cows grazed on pasture, and cows with low/marginal liver copper concentration had more resorption cavities in the distal humerus and thinner cortical bone compared with cows with adequate liver copper concentration. Decreased trabecular density (OR = 249.5), abnormal cortical resorption (OR = 54.2), presence of woven bone formation in the proximal metaphysis (OR = 37.2), and the number of resorption cavities in the distal humerus were significantly associated with a high probability of fracture. Ribs had enlargement of the costochondral junction with fractures in different stages of healing. Histology of the ribs revealed abnormal growth plate appearance, presence of fracture lines, callus tissue, fibrosis, and microfractures. Cows with humeral fracture have osteoporosis due to decreased bone formation and increased bone resorption, likely associated with inadequate feed quality and perhaps copper deficiency leading to a reduction in bone strength and fracture.

Novel closed-cycle reaction mode for totally green production of Cu1.8Se nanoparticles based on laser-generated Se colloidal solution

Non-stoichiometric copper selenide (Cu2 – x Se, x = 0.18 ∼ 0.25) nanomaterials have attracted extensive attentions due to their excellent thermoelectric, optoelectronic and photocatalytic performances. However, efficient production of Cu2 – x Se nanoparticles (NPs) through a green and convenient way is still hindered by the inevitable non-environmentally friendly operations in common chemical synthesis. Herein, we initially reveal the coexistence of seleninic acid content and elemental selenium (Se) NPs in pulsed laser-generated Se colloidal solution. Consequently, we put forward firstly a closed-cycle reaction mode for totally green production of Cu1.8Se NPs to exclude traditional requirements of high temperature and toxic precursors by using Se colloidal solution. In such closed-cycle reaction, seleninic acid works as the initiator to oxidize copper sheet to release cuprous ions which can catalyze the disproportion of Se NPs to form and Se2– ions and further produce Cu2 – x Se NPs, and the by-product ions promote subsequent formation of cuprous from the excessive Cu sheet. In experiments, the adequate copper (Cu) sheet was simply dipped into such Se colloidal solution at 70 °C, and then the stream of Cu1.8Se NPs could be produced until the exhaustion of selenium source. The conversion rate of Se element reaches to more than 75% when the size of Se NPs in weakly acidic colloidal solution is limited between 1 nm and 50 nm. The laser irradiation duration shows negative correlation with the size of Se NPs and unobvious impact to the pH of the solution which both are essential to the high yield of Cu1.8Se NPs. Before Cu sheet is exhausted, Se colloidal solution can be successively added without influences to the product quality and the Se conversion rate. Such green methodology positively showcases a brand-new and potential strategy for mass production of Cu2 – x Se nanomaterials.

A new method for calculating copper content and determining appropriate copper levels in foods

Since the amount of food can affect the copper content, the copper content of different amounts of food (except foods without copper) is different. The copper content of some foods is inappropriately calculated per 100 kcal, 100 g or 100 mL, or the reference amount customarily consumed (RACC). Thus, making some food choices based on these calculations to achieve adequate copper intake may increase the risk of some chronic diseases. Calculating the copper content and determining appropriate copper levels (to achieve adequate copper intake) based on U.S. Food and Drug Administration (FDA), Codex Alimentarius Commission (CAC), and the proposed method were performed in 7,379 food items. Making some food choices based on the FDA and CAC per serving (the serving is derived from the RACC) or CAC per 100 g or 100 mL to achieve adequate copper intake exceeded energy needs, which could lead to overweight or obesity. Making some food choices based on the CAC per 100 kcal or CAC per 100 g or 100 mL to achieve adequate copper intake did not meet copper requirements, which could lead to copper deficiency. Some foods that met copper requirements were not appropriate food choices based on the CAC per 100 g or 100 mL or CAC per serving to achieve adequate copper intake. On the basis of the proposed method, calculating the copper content and determining appropriate copper levels in foods are performed by considering RACCs and the energy content of foods. Thus, making food choices based on the proposed method met copper requirements and did not exceed energy needs.

Exogenous copper exposure causing clinical wilson disease in a patient with copper deficiency

BackgroundHuman Swayback is a disease characterized by acquired copper deficiency which primarily manifests as myeloneuropathy. Common causes include malabsorptive disorders, gastric surgery, total parenteral nutrition and excessive zinc intake. In contrast, copper supplementation should be closely monitored as excessive doses can lead to acute intoxication and in chronic cases, cirrhosis. Copper derangements are rare, however it is important to consider them due to potential severe complications.Case presentationWe present a middle-aged man who had been previously diagnosed with Human Swayback after presenting with various neurological symptoms. The patient was subsequently placed on copper supplementation. A decade later, he was referred to our hospital for liver transplant evaluation due to new diagnosis of decompensated end-stage liver disease after an abdominal surgery. His initial workup was suggestive of Wilson disease—subsequent ATP7B gene was negative. Ultimately, the patient underwent liver transplantation; liver explant was significant for a copper dry weight concentration of 5436 mcg/g.ConclusionsHuman Swayback is a very rare copper-related disease which deserves awareness due to its potential irreversible health effects in the human body. Additionally, in patients who require copper supplementation, serial levels should be monitored to ensure adequate copper levels.

Biosynthesis of copper nanoparticles from copper tailings ore – An approach to the ‘Bionanomining’

Nanotechnology is a discipline that studies the behavior of materials on a nanometric scale. These materials are known to have a wide range of applications due to the outstanding optoelectronic, magnetic, and thermal properties that their scale provides. However, one of the current challenges associated with nanotechnology lies in how nanomaterials are generated. Within the new synthesis trends, biological routes have been proposed as an alternative that requires less polluting organic solvents and less energy consumption.The biosynthesis of metallic nanoparticles is a Bottom-up method that requires precursors, which have mostly been described as pure solutions. However, in the present work and approaching the concept of ‘Bionanomining’, the use of a real effluent obtained from the leaching of sulfide ore tailings is studied for the biosynthesis of copper nanoparticles. For this purpose, the bacterial biomass of Pseudomonas stutzeri was used as a bioreducing agent.The leaching of the chalcopyrite-bearing tailings achieved a copper recovery of 50% in 8 h, thanks to sodium nitrate that acted as an oxidizing agent. The copper concentration was increased by solvent extraction, allowing a solution of 700 mg/L of copper to be achieved.In the biosynthesis of nanoparticles, the experiments were carried out at room temperature and pressure for 48 h, using two different copper precursor solutions. In the first stage, a pure solution was used to determine an adequate copper concentration and biomass dosage, which were 381 mg/L and 1050 mg, respectively. In an advanced approach, the solution obtained from the treated tailings was employed for the biosynthesis, obtaining nanoparticles in the two resulting streams: a solid dead biomass and sodium sulfate solution with 2.7% and 0.27% copper nanoparticles, respectively. These nanoparticles are spherical and with a size between 1 and 2 nm.

Cyanide-free environment-friendly alternative to copper electroplating for zinc die-cast alloys.

In this paper, a cyanide-free electroplating bath containing glutamate as a complexing agent is investigated as an environment-friendly alternative for copper plating on zinc die-cast alloys. Glutamate reacts with copper in an aqueous solution that exhibits similar copper cyanide properties by forming complexes. The electroplating bath pH is chosen from equilibrium diagrams to avoid the formation of insoluble complexes and oxides at varying copper-to-glutamate molar ratio. The plating bath's electrochemical response on a stationary electrode confirms that a 1:3 molar ratio between copper and glutamate at pH 8 exhibits better copper deposition onto the substrate, with its morphology characterized using SEM. The results suggest that the copper glutamate electroplating bath can be suitable for copper cyanide bath replacement without additives, allowing a one-step electroplating process. Moreover, the polarization and electrochemical impedance measurements suggest inhibition of the substrate's corrosion when copper was electroplated at a 1:3 copper-to-glutamate molar ratio. With the careful control of the concentration ratio, the process can provide adequate copper deposition and anti-corrosion capability suitable for green nanocoating applications.

Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis

BackgroundInadequate copper intake and increased fructose consumption represent two important nutritional problems in the USA. Dietary copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis.MethodsMale and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6 mg/kg and 1.5 mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma alanine aminotransferase, aspartate aminotransferase, and liver histology as well as liver triglyceride were evaluated. Fecal microbial contents were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Fecal and cecal short-chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS).ResultsMale and female rats exhibit similar trends of changes in the body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in the CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF diets. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis.ConclusionsOur data demonstrated sex differences in the alterations of gut microbial abundance, activities, and hepatic steatosis in response to dietary copper-fructose interaction in rats. The correlation between sex differences in metabolic phenotypes and alterations of gut microbial activities remains elusive.

Copper Supplementation, A Challenge in Cattle.

Simple SummaryCopper supplementation in ruminants deserves special attention because of the narrow margin between deficiency and toxicity, both of which ruminants are susceptible to suffering from. Supplementation of copper above requirements to prevent deficiency has led to an increased number of outbreaks of copper toxicity being reported in recent years, particularly in dairy cattle. In this paper we describe the key points of copper metabolism in cattle that should be taken into consideration to guarantee an adequate copper supply while preventing toxic effects.Ensuring adequate copper supplementation in ruminants is a challenging task due to the complexity of copper metabolism in these animals. The three-way interaction between copper, molybdenum and sulphur (Cu-Mo-S) in the rumen makes ruminants, particularly cattle, very susceptible to suffering from secondary copper deficiency. Paradoxically, excessive copper storage in the liver to prevent deficiency becomes a hazard when ruminants are fed copper-supplemented diets even slightly above requirements. While cattle were traditionally thought to be relatively tolerant of copper accumulation, and reports of copper poisoning were until recently somewhat rare, in recent years an increased number of episodes/outbreaks of copper toxicity in cattle, particularly in dairy cattle, have been reported worldwide. The growing number of lethal cases reported seems to indicate that copper intoxication is spreading silently in dairy herds, urging the development of strategies to monitor herd copper status and improve farmers’ awareness of copper toxicity. In fact, monitoring studies carried out on numerous samples collected from culled animals in slaughterhouses and/or diagnostic laboratories have demonstrated that large numbers of animals have hepatic copper concentrations well above adequate levels in many different countries. These trends are undoubtedly due to copper supplementation aimed at preventing copper deficiency, as dietary copper intake from pasture alone is unlikely to cause such high levels of accumulation in liver tissue. The reasons behind the copper overfeeding in cattle are related both to a poor understanding of copper metabolism and the theory of “if adding a little produces a response, then adding a lot will produce a better response”. Contrary to most trace elements, copper in ruminants has narrow margins of safety, which must also be formulated considering the concentrations of copper antagonists in the diet. This review paper aims to provide nutritionists/veterinary practitioners with the key points about copper metabolism in cattle to guarantee an adequate copper supply while preventing excessive hepatic copper loading, which requires à la carte copper supplementation for each herd.

Effect of the nature of copper species on methanol synthesis from CO2 hydrogenation reaction over CuO/Ce0.4Zr0.6O2 catalyst

A series of x wt.% CuO/Ce0.4Zr0.6O2 (x = 2, 5, 15, 25, 35 and 40) catalysts obtained by oxalate co-precipitation method are characterized by XRD, BET, SEM, Raman, EPR, H2-TPR, CO2/H2-TPD and high pressure (3 MPa) in situ DRITFS techniques in order to elucidate the effect of CuO loading on the catalytic activity of CO2 hydrogenation to methanol. Catalytic activity results demonstrate that CO2 conversion and methanol selectivity enhance with an increase of the CuO loading until it reaches the maximum values at a CuO loading of 35 wt.%, while further addition of CuO inhibits the catalytic performance. The higher CO2 conversion of 7.0 % (13.2 %) and methanol selectivity of 96.4 % (71.8 %) are obtained over 35 wt.% CuO/Ce0.4Zr0.6O2 catalyst at 220 °C (280 °C) and 3 MPa. The excellent performance of 35 wt.% CuO/Ce0.4Zr0.6O2 is attributed to the presence of adequate copper species with higher copper surface area and larger number of Cu-Ce-Zr solid solution. These two features are benefit to provide larger number of activated hydrogen atom and promote CO2 adsorption, respectively, which are the key to the hydrogenation reaction related to the hydrogen dissociation and the activation of the carbon dioxide.

Copper Deficiency: An Overlooked Cause of Anemia and Leucopenia

Copper deficiency (hypocupremia) is an acknowledged but often overlooked cause of anemia and leukopenia (1-4). It is recognized as a frequent cause of hypochromic microcytic anemia, leukopenia, and neuropathy. Copper deficiency anemia has been reported after gastric resection (e.g., Roux-en-Y) (1, 5, 6), excessive zinc consumption (1, 6-9), and in patients with short bowel syndrome receiving total parenteral or enteral nutrition lacking adequate copper supplementation (1, 2). We report a case of vitamin B12, and iron refractory severe anemia and leucopenia with history of Roux-en-Y surgery. Myelodysplastic syndrome was suspected. Bone marrow biopsy was consistent with copper deficiency and serum copper levels were undetectable. The patient experienced complete hematological recovery after copper replacement therapy.

Dietary copper‐fructose interactions alter gut microbiome in a sex‐differential manner likely contributes to the sex differences in the metabolic phenotype

ObjectiveInadequate copper intake and increased fructose consumption represent two important nutritional problems in the US. Dietary copper‐fructose interactions alter gut microbial activity and contribute to the development of metabolic phenotype. The aim of this study is to determine whether dietary copper‐fructose interactions alter gut microbiome in a sex‐differential manner, which may contribute to the sex differences in the metabolic phenotype.MethodsMale and female weanling Sprague‐Dawley (SD) rats were fed (ad lib) with a modified AIN‐93G purified rodent diet with defined copper content in the form of cupric carbonate for 8 weeks. The copper content is 6mg/kg and 1.6mg/kg in adequate copper diet (CuA) and marginal copper deficient diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (w/v) as the only drink during the experiment. Body weight gain, plasma ALT, AST and liver histology were evaluated. Fecal and cecal microbiome were analyzed by 16S rDNA sequencing. Fecal and cecal Short chain fatty acids were analyzed by GC‐MS.ResultsRats fed with CuA or CuM with or without fructose (CuAF or CuMF) did not gain body weight in both male and female. No obvious liver injury was observed in both male and female rats in terms of plasma ALT and AST. A few of female rats developed very mild steatosis, whereas no obvious steatosis was observed in male rats fed with CuAF or CuMF. 16S rDNA sequencing analysis of fecal and cecal DNA showed that Firmicutes was significantly decreased, whereas Bacteroidetes and Proteobacteria were significantly increased in CuAF and CuMF fed female rats compared to controls, suggesting gut microbiota dysbiosis. The significant alterations of gut microbiota composition in phylum level in female rats attribute to the effect of dietary fructose as shown by two‐way ANOVA. However, this effect was not obvious in male rats. In parallel, fecal and cecal short chain fatty acid, butyrate was significantly decreased in female rats fed with CuMF and to a less extent in male rats compared to controls. This effect was due to dietary factors of both copper and fructose in female rats, and copper in male rats.ConclusionFemale rats exhibit more sensitivity to dietary copper and fructose‐induced metabolic phenotypes and gut microbiota dysbiosis compared to male rats. The metabolic phenotypes are closely associated with the alterations of gut microbiome. These results are different with previous reports, likely due to the factors, such as the dose of copper and fructose as well as species and location.Support or Funding InformationThis study was supported in part by NIH Grants U01AA021901, U01AA022489, R01AA023681, P20GM113226, P50AA024337 and the Jewish Heritage Fund for Excellence Pilot Grant Program at the University of Louisville School of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (C.J.M.); the Veterans Administration (C.J.M.); and the Uof L Clinical and Translational Pilot Program (C.J.M.).