Copper plays an important role in many metabolic activities in the human body. Copper level in the human body is in a state of dynamic equilibrium. Recent research on copper metabolism has revealed that copper dyshomeostasis can cause cell damage and induce or aggravate some diseases by affecting oxidative stress, proteasome, cuprotosis, and angiogenesis. The liver plays a central role in copper metabolism in the human body. Research conducted in recent years has unraveled the relationship between copper homeostasis and liver diseases. In this paper, we review the available evidence of the mechanism by which copper dyshomeostasis promotes cell damage and the development of liver diseases, and identify the future research priorities.
Humans ; Copper/metabolism* ; Homeostasis ; Oxidative Stress ; Liver Diseases

Antibiotics are playing an increasingly important role in clinical antibacterial applications. However, their abuse has also brought toxic and side effects, drug-resistant pathogens, decreased immunity and other problems. New antibacterial schemes in clinic are urgently needed. In recent years, nano-metals and their oxides have attracted wide attention due to their broad-spectrum antibacterial activity. Nano-silver, nano-copper, nano-zinc and their oxides are gradually applied in biomedical field. In this study, the classification and basic properties of nano-metallic materials such as conductivity, superplasticity, catalysis, and antibacterial activities were firstly introduced. Secondly, the common preparation techniques, including physical, chemical and biological methods, were summarized. Subsequently, four main antibacterial mechanisms, such as cell membrane, oxidative stress, DNA destruction and cell respiration reduction, were summarized. Finally, the effect of size, shape, concentration and surface chemical characteristics of nano-metals and their oxides on antibacterial effectiveness and the research status of biological safety such as cytotoxicity, genotoxicity and reproductive toxicity were reviewed. At present, although nano-metals and their oxides have been applied in medical antibacterial, cancer treatment and other clinical fields, some issues such as the development of green preparation technology, the understanding of antibacterial mechanism, the improvement of biosafety, and the expansion of application fields, require further exploration.
Oxides/chemistry* ; Metal Nanoparticles/chemistry* ; Anti-Bacterial Agents/chemistry* ; Zinc ; Copper

OBJECTIVE: To explore the clinical characteristics and genetic etiology of three children with Menkes disease. METHODS: Three children who had presented at the Children's Medical Center, the Affiliated Hospital of Guangdong Medical University from January 2020 to July 2022 were selected as the study subjects. Clinical data of the children were reviewed. Genomic DNA was extracted from peripheral blood samples of the children, their parents and sister of child 1. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing, copy number variation sequencing (CNV-seq), and bioinformatic analysis. RESULTS: Child 1 was a 1-year-and-4-month male, and children 2 and 3 were monozygotic twin males aged 1-year-and-10-month. The clinical manifestations of the three children have included developmental delay and seizures. WES showed that child 1 has harbored a c.3294+1G>A variant of the ATP7A gene. Sanger sequencing confirmed that his parents and sister did not carry the same variant, suggesting that it was de novo. Children 2 and 3 had carried a c.77266650_77267178del copy number variation. CNV-seq results showed that their mother has carried the same variant. By searching the HGMD, OMIM and ClinVar databases, the c.3294+1G>A was known to be pathogenic. No carrier frequency has been recorded in the 1000 Genomes, ESP, ExAC and gnomAD databases. Based on the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics (ACMG), the ATP7A gene c.3294+1G>A variant was predicted to be pathogenic. The c.77266650_77267178del variant has involved exons 8 to 9 of the ATP7A gene. ClinGen online system score for it was 1.8, which was also considered to be pathogenic. CONCLUSION The c.3294+1G>A and c.77266650_ 77267178del variants of the ATP7A gene probably underlay the Menkes disease in the three children. Above finding has enriched the mutational spectrum of Menkes disease and provided a basis for clinical diagnosis and genetic counseling.
Humans ; Male ; Computational Biology ; Copper-Transporting ATPases/genetics* ; DNA Copy Number Variations ; Exons ; Menkes Kinky Hair Syndrome/genetics* ; Mutation ; Peptide Fragments ; Seizures ; Infant

OBJECTIVES: To study the efficacy of a low-copper diet guidance based on food exchange portions in children with hepatolenticular degeneration. METHODS: A self-controlled study was conducted from July 2021 to June 2022, including 30 children under the age of 18 who were diagnosed with hepatolenticular degeneration and poorly controlled with a low-copper diet. During the medical visit, personalized low-copper diet guidance was provided to the children and their parents using a copper-containing food exchange table and a copper food exchange chart. During home care, compliance with the low-copper diet of the children was improved by recording dietary diaries and conducting regular follow-ups. The changes in 24-hour urine copper level, liver function indicators, and the low-copper diet knowledge of the children's parents were observed before and after the intervention, with no change in the original drug treatment. RESULTS: After 8, 16, and 24 weeks of intervention, the 24-hour urine copper level decreased significantly compared to before intervention (P<0.05). When compared to 8-week intervention, the urine copper level decreased significantly after 16 and 24 weeks of intervention. The 24-hour urine copper level after 24 weeks of intervention decreased significantly compared to 16 weeks of intervention (P<0.05).After 24 weeks of intervention, the alanine aminotransferase and aspartate aminotransferase levels decreased significantly compared to before intervention (P<0.05). Additionally, in 16 of the cases (53%), alanine aminotransferase and aspartate aminotransferase returned to normal levels. Following 8 weeks of intervention, the low-copper diet knowledge of the children's parents increased significantly (P<0.05). CONCLUSIONS A low-copper diet guidance based on food exchange portions can effectively decrease the urine copper level and improve liver function in children with hepatolenticular degeneration. Furthermore, it can increase the low-copper diet knowledge of the children's parents.
Humans ; Child ; Hepatolenticular Degeneration/therapy* ; Alanine Transaminase ; Copper ; Food ; Aspartate Aminotransferases

OBJECTIVES: To construct a prognosis risk model based on long noncoding RNAs (lncRNAs) related to cuproptosis and to evaluate its application in assessing prognosis risk of bladder cancer patients. METHODS: RNA sequence data and clinical data of bladder cancer patients were downloaded from the Cancer Genome Atlas database. The correlation between lncRNAs related to cuproptosis and bladder cancer prognosis was analyzed with Pearson correlation analysis, univariate Cox regression, Lasso regression, and multivariate Cox regression. Then a cuproptosis-related lncRNA prognostic risk scoring equation was constructed. Patients were divided into high-risk and low-risk groups based on the median risk score, and the immune cell abundance between the two groups were compared. The accuracy of the risk scoring equation was evaluated using Kaplan-Meier survival curves, and the application of the risk scoring equation in predicting 1, 3 and 5-year survival rates was evaluated using receiver operating characteristic (ROC) curves. Univariate and multivariate Cox regression were used to screen for prognostic factors related to bladder cancer patients, and a prognostic risk assessment nomogram was constructed, the accuracy of which was evaluated with calibration curves. RESULTS: A prognostic risk scoring equation for bladder cancer patients was constructed based on nine cuproptosis-related lncRNAs. Immune infiltration analysis showed that the abundances of M0 macrophages, M1 macrophages, M2 macrophages, resting mast cells and neutrophils in the high-risk group were significantly higher than those in the low-risk group, while the abundances of CD8⁺ T cells, helper T cells, regulatory T cells and plasma cells in the low-risk group were significantly higher than those in the high-risk group (all P<0.05). Kaplan-Meier survival curve analysis showed that the total survival and progression-free survival of the low-risk group were longer than those of the high-risk group (both P<0.01). Univariate and multivariate Cox analysis showed that the risk score, age and tumor stage were independent factors for patient prognosis. The ROC curve analysis showed that the area under the curve (AUC) of the risk score in predicting 1, 3 and 5-year survival was 0.716, 0.697 and 0.717, respectively. When combined with age and tumor stage, the AUC for predicting 1-year prognosis increased to 0.725. The prognostic risk assessment nomogram for bladder cancer patients constructed based on patient age, tumor stage, and risk score had a prediction value that was consistent with the actual value. CONCLUSIONS A bladder cancer patient prognosis risk assessment model based on cuproptosis-related lncRNA has been successfully constructed in this study. The model can predict the prognosis of bladder cancer patients and their immune infiltration status, which may also provide a reference for tumor immunotherapy.
Humans ; CD8-Positive T-Lymphocytes ; Prognosis ; RNA, Long Noncoding/genetics* ; Urinary Bladder ; Urinary Bladder Neoplasms/genetics* ; Copper ; Apoptosis

INTRODUCTION: The diagnosis of Wilson disease (WD) is plagued by biochemical and clinical uncertainties. Thus, calculated parameters have been proposed. This study aimed to: (a) compare the diagnostic values of non-caeruloplasmin copper (NCC), NCC percentage (NCC%), copper-caeruloplasmin ratio (CCR) and adjusted copper in WD; and (b) derive and evaluate a discriminant function in diagnosing WD. METHODS: A total of 213 subjects across all ages who were investigated for WD were recruited. WD was confirmed in 55 patients, and the rest were WD free. Based on serum copper and caeruloplasmin values, NCC, NCC%, CCR and adjusted copper were calculated for each subject. A function was derived using discriminant analysis, and the cut-off value was determined through receiver operating characteristic analysis. Classification accuracy was found by cross-tabulation. RESULTS: Caeruloplasmin, total copper, NCC, NCC%, CCR, adjusted copper and discriminant function were significantly lower in WD compared to non-WD. Discriminant function showed the best diagnostic specificity (99.4%), sensitivity (98.2%) and classification accuracy (99.1%). Caeruloplasmin levels <0.14 g/L showed higher accuracy than the recommended 0.20 g/L cut-off value (97.7% vs. 87.8%). Similarly, molar NCC below the European cut-off of 1.6 umol/L showed higher accuracy than the American cut-off of 3.9 umol/L (80.3% vs. 59.6%) (P < 0.001). NCC%, mass NCC, CCR and adjusted copper showed poorer performances. CONCLUSION Discriminant function differentiates WD from non-WD with excellent specificity, sensitivity and accuracy. Performance of serum caeruloplasmin <0.14 g/L was better than that of <0.20 g/L. NCC, NCC%, CCR and adjusted copper are not helpful in diagnosing WD.
Humans ; Hepatolenticular Degeneration/diagnosis* ; Copper/analysis* ; Ceruloplasmin/metabolism* ; Repressor Proteins

Objective: To investigate the relationship between the levels of selenium, iron and copper in cord blood of neonates and the risk of congenital heart disease (CHD), and analyze their interaction effects. Methods: The subjects were obtained from the birth cohort in Lanzhou area established from 2010 to 2012. A baseline survey was conducted in the first trimester, and the follow-up was conducted in the second trimester, third trimester and 42 days after delivery. The umbilical vein blood was collected from newborns at delivery, and information on their birth outcomes was extracted from medical records. A nested case-control study was used to select 97 neonates with CHD newly diagnosed by echocardiography as the case group, and 194 neonates were selected as the control group by 1∶2 matching according to their mother's age, block and CHD onset time. Inductively coupled ion mass spectrometry was used to detect the concentrations of selenium, iron and copper in neonatal cord blood. The element exposure was categorized into three groups, the low, medium and high concentrations, according to the quartiles Q₁ and Q₃ of selenium, iron and copper concentrations in the control group. The association between cord blood selenium, iron and copper concentrations and CHD was analyzed by conditional logistic regression model using medium concentration as the reference standard. The association of their interactions with CHD was analyzed by a phase multiplication model. Results: The M (Q₁, Q₃) concentration of neonatal cord blood copper was 746.12 (467.48, 759.74) μg/L in the case group and 535.69 (425.21, 587.79) μg/L in the control group, with a statistically significant difference between the two groups (P<0.05). After adjustment for confounders, logistic regression models showed that the risk of CHD development was increased in neonates with either high copper in cord blood (OR=4.062, 95%CI: 2.013-8.199) or high copper combined with high iron (OR=3.226, 95%CI: 1.343-7.750). No correlation was observed between selenium and iron concentrations and the development of CHD in neonates. There was a multiplicative interaction between copper and iron in cord blood on the risk of developing CHD (OR=1.303, 95%CI: 1.056-1.608). Conclusion: There is a multiplicative interaction between iron and copper elements. The high copper and the high copper combined with high iron in umbilical cord blood are risk factors for neonatal CHD.
Humans ; Infant, Newborn ; Copper/analysis* ; Selenium ; Iron/analysis* ; Fetal Blood/chemistry* ; Case-Control Studies ; Heart Defects, Congenital

Phytoremediation plays an important role in the treatment of heavy metal pollution in soil. In order to elucidate the mechanism of salicylic acid (SA) on copper absorption, seedlings from Xuzhou (with strong Cu-tolerance) and Weifang Helianthus tuberosus cultivars (with weak Cu-tolerance) were selected for pot culture experiments. 1 mmol/L SA was sprayed upon 300 mg/kg soil copper stress, and the photosynthesis, leaf antioxidant system, several essential mineral nutrients and the changes of root upon copper stress were analyzed to explore the mechanism of copper resistance. The results showed that Pn, Tr, Gs and Ci upon copper stress decreased significantly compared to the control group. Meanwhile, chlorophyll a, chlorophyll b and carotenoid decreased with significant increase in initial fluorescence (F₀), maximum photochemical quantum yield of PSⅡ (Fv/Fm), electron transfer rate (ETR) and photochemical quenching coefficient (qP) content all decreased. The ascorbic acid (AsA) content was decreased, the glutathione (GSH) value was increased, the superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) activity in the leaves were decreased, and the peroxidase (POD) activity was significantly increased. SA increased the Cu content in the ground and root system, and weakened the nutrient uptake capacity of K, Ca, Mg, and Zn in the root stem and leaves. Spray of exogenous SA can maintain the opening of leaf stomata, improve the adverse effect of copper on photosynthetic pigment and PSⅡ reaction center. Mediating the SOD and APX activity started the AsA-GSH cycle process, effectively regulated the antioxidant enzyme system in chrysanthemum taro, significantly reduced the copper content of all parts of the plant, and improved the ion exchange capacity in the body. External SA increased the content of the negative electric group on the root by changing the proportion of components in the root, promoted the absorption of mineral nutrient elements and the accumulation of osmoregulatory substances, strengthened the fixation effect of the root on metal copper, and avoided its massive accumulation in the H. tuberosus body, so as to alleviate the inhibitory effect of copper on plant growth. The study revealed the physiological regulation of SA upon copper stress, and provided a theoretical basis for planting H. tuberosus to repair soil copper pollution.
Antioxidants ; Copper ; Helianthus/metabolism* ; Salicylic Acid/pharmacology* ; Chlorophyll A/pharmacology* ; Spectroscopy, Fourier Transform Infrared ; Chlorophyll/pharmacology* ; Ascorbic Acid ; Superoxide Dismutase/metabolism* ; Photosynthesis ; Glutathione ; Plant Leaves ; Stress, Physiological ; Seedlings

Background Kidney renal clear cell carcinoma (KIRC) is one of the most common renal malignancies with a high mortality rate. Cuproptosis, a novel form of cell death, is strongly linked to mitochondrial metabolism and is mediated by protein lipoylation, leading to a proteotoxic stress response and cell death. To date, few studies have ellucidated the holistic role of cuproptosis-related genes (CRGs) in the pathogenesis of KIRC.Methods We comprehensively and completely analyzed the RNA sequencing data and corresponding clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We screened for differentially expressed CRGs and constructed a prognostic risk model using univariate and multivariate Cox proportional regression analyses. Kaplan-Meier analysis was performed and receiver operating characteristic (ROC) curves were plotted to predict the prognosis of KIRC patients. Functional enrichment analysis was utilized to explore the internal mechanisms. Immune-related functions were analyzed using single-sample gene set enrichment analysis (ssGSEA), tumour immune dysfunction and exclusion (TIDE) scores, and drug sensitivity analysis.Results We established a concise prognostic risk model consisting of four CRGs (DBT, DLAT, LIAS and PDHB) to predict the overall survival (OS) in KIRC patients. The results of the survival analysis indicated a significantly lower OS in the high-risk group as compared to the patients in the low-risk group. The area under the time-dependent ROC curve (AUC) at 1, 3, and 5 year was 0.691, 0.618, and 0.614 in KIRC. Functional enrichment analysis demonstrated that CRGs were significantly enriched in tricarboxylic acid (TCA) cycle-related processes and metabolism-related pathways. Sorafenib, doxorubicin, embelin, and vinorelbine were more sensitive in the high-risk group.Conclusions We constructed a concise CRGs risk model to evaluate the prognosis of KIRC patients and this may be a new direction for the diagnosis and treatment of KIRC.
Humans ; Carcinoma, Renal Cell/genetics* ; Immunotherapy ; Kidney ; Kidney Neoplasms/genetics* ; Prognosis ; Copper ; Apoptosis

OBJECTIVE: To explore the clinical characteristics and variants of ATP7A gene in a child with Menkes disease. METHODS: A child with Menkes disease diagnosed at the West China Second Hospital of Sichuan University and its family members in March 2022 was selected as the study subjects. Clinical manifestations and results of laboratory tests and genetic testing were summarized. RESULTS: The main manifestations of the child included seizures, global development delay, facial dysmorphism, sparse and curly hair, increased lactate and pyruvate, and significantly decreased cuprin. EEG showed frequent issuance of multifocal spikes, spines, polyspines (slow) and polymorphic slow waves. Multiple tortuous vascular shadows were observed on cranial MRI. Whole exome sequencing revealed that the child has harbored a hemizygous c.3076delA (p.ile1026*) variant of the ATP7A gene, which was inherited from his mother. The variant may lead to premature termination of protein translation. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as pathogenic (PVS1+PM2+PP4). CONCLUSION The c.3076delA (p.Ile1026*) variant of the ATP7A gene probably underlay the Menkes disease in this child. Above finding has provided evidence for clinical diagnosis. The significantly increased lactic acid and pyruvate can be used as a reference for the diagnosis and management of Menkes disease. Microscopic abnormalities in the hair of the carriers may also facilitate their diagnosis.
Child ; Humans ; Copper-Transporting ATPases/genetics* ; East Asian People ; Menkes Kinky Hair Syndrome/genetics* ; Mutation ; Pedigree ; Peptide Fragments ; Pyruvic Acid