Excess Copper Research Articles

Heavy Metals in Water and Sediments and Their Impact on Water Quality in Andean Micro-watersheds: A Study of the Colorado and Alajua Rivers in the Ambato River Watershed, Tungurahua, Ecuador

The present study aims to characterize the water and sediment quality of the Colorado and Alajua rivers within Ecuador’s Ambato River watershed, with a specific focus on the presence of heavy metals. Measurements were conducted at five sampling points along the upper and lower zones of each river, where both physicochemical and microbiological parameters, as well as concentrations of heavy metals in water and sediments, were analyzed. Most parameters exhibited statistically significant differences, as determined by the analysis of variance (ANOVA), between the values observed in the upper and lower zones of the micro-watersheds. Water quality in the mentioned rivers was assessed using specific water quality indices, WQI, namely the NSF-WQI and Dinius WQI. Additionally, the impact of heavy metal presence in the water and sediments was evaluated using the Heavy Metal Evaluation Index (HEI). While most parameters met the Ecuadorian quality standards for water sources intended for human consumption, concerns emerged regarding elevated levels of total and fecal coliforms along both rivers, which could limit the suitability of these rivers as a water source for human use and consumption. At various sampling points, water quality criteria for the preservation of aquatic life were not met for several heavy metals. For example, the Colorado River exhibited elevated levels of zinc (59-76 μg.L-1), copper (12-47 μg.L-1), lead (1.2-3.9 μg.L-1 ), iron (0.33-0.37 mg.L-1 ), and manganese (0.37-0.47 mg.L-1), while the Alajua River showed excess copper (11 μg.L-1), iron (0.61-0.72 mg.L-1), and manganese (0.62-0.98 mg.L-1). Geological factors likely contribute to the concentration of heavy metals in the upper segments of the rivers, while agricultural runoff may contribute to concentrations in the lower segments. Sediments exhibited higher average values of the Heavy Metal Evaluation Index (HEI) (20.6-26.7) compared to water samples (13.9-15.4), indicating a potential accumulation of heavy metals in the river sediments. Overall, both rivers exhibited contamination levels ranging from regular to moderate, as indicated by the calculated average Water Quality Indices (WQI), with certain areas showing slight contamination or meeting acceptable standards. These results highlight the influence of anthropogenic activities on water quality, emphasizing the necessity of continuous monitoring to assess and control their impact.

Highly efficient narrow bandgap Cu(In,Ga)Se2 solar cells with enhanced open circuit voltage for tandem application

Although an ideal bandgap matching with 0.96 eV and 1.62 eV for a double-junction tandem is hard to realize practically, among all mature photovoltaic systems, Cu(In,Ga)Se2 (CIGSe) can provide the closest bandgap of 1.00 eV for the bottom sub-cell by adjusting its composition. However, pure CuInSe2 (CISe) solar cell suffers strong interfacial carrier recombination. We hereby present approaches to introduce appropriate Ga gradients in both the back and front parts of absorber while maintaining the absorption spectrum close to CISe. With an appropriate front Ga gradient, the open circuit voltage can be enhanced by ~30 mV. With a pre-deposited CIGSe layer and a high copper excess deposition during absorber growth, the Ga diffusion can be well suppressed and a wide U-shaped Ga grading with a minimum bandgap of 1.01 eV has been created. Our optimized narrow-bandgap CIGSe solar cell has achieved a certified record PCE of 20.26%, with a record-low open circuit voltage deficit of 368 mV and a record-high contribution of 10% absolute efficiency to a four-terminal tandem. This work demonstrates the potential of controlling gallium diffusion to improve the performance of narrow bandgap CIGSe solar cells for tandem applications.

When Metal Complexes Evolve, and a Minor Species is the Most Active: the Case of Bis(Phenanthroline)Copper in the Catalysis of Glutathione Oxidation and Hydroxyl Radical Generation

AbstractSeveral copper‐ligands, including 1,10‐phenanthroline (Phen), have been investigated for anticancer purposes based on their capacity to bind excess copper (Cu) in cancer tissues and form redox active complexes able to catalyse the formation of reactive oxygen species (ROS), ultimately leading to oxidative stress and cell death. Glutathione (GSH) is a critical compound as it is highly concentrated intracellularly and can reduce and dissociate copper(II) from the ligand forming poorly redox‐active copper(I)‐thiolate clusters. Here we report that Cu‐Phen2 speciation evolves in physiologically relevant GSH concentrations. Experimental and computational experiments suggest that at pH 7.4 mostly copper(I)‐GSH clusters are formed, but a minor species of copper(I) bound to one Phen and forming ternary complexes with GSH (GS−Cu‐Phen) is the redox active species, oxidizing quite efficiently GSH to GSSG and forming HO⋅ radicals. This minor active species becomes more populated at lower pH, such as typical lysosomal pH 5, resulting in faster GSH oxidation and HO⋅ production. Consistently, cell culture studies showed lower toxicity of Cu‐Phen2 upon inhibition of lysosomal acidification. Overall, this study underscores that sub‐cellular localisation can considerably influence the speciation of Cu‐based drugs and that minor species can be the most redox‐ and biologically‐active.

When Metal Complexes Evolve, and a Minor Species is the Most Active: the Case of Bis(Phenanthroline)Copper in the Catalysis of Glutathione Oxidation and Hydroxyl Radical Generation.

Several copper-ligands, including 1,10-phenanthroline (Phen), have been investigated for anticancer purposes based on their capacity to bind excess copper (Cu) in cancer tissues and form redox active complexes able to catalyse the formation of reactive oxygen species (ROS), ultimately leading to oxidative stress and cell death. Glutathione (GSH) is a critical compound as it is highly concentrated intracellularly and can reduce and dissociate copper(II) from the ligand forming poorly redox-active copper(I)-thiolate clusters. Here we report that Cu-Phen2 speciation evolves in physiologically relevant GSH concentrations. Experimental and computational experiments suggest that at pH7.4 mostly copper(I)-GSH clusters are formed, but a minor species of copper(I) bound to one Phen and forming ternary complexes with GSH (GS-Cu-Phen) is the redox active species, oxidizing quite efficiently GSH to GSSG and forming HO⋅ radicals. This minor active species becomes more populated at lower pH, such as typical lysosomal pH5, resulting in faster GSH oxidation and HO⋅ production. Consistently, cell culture studies showed lower toxicity of Cu-Phen2 upon inhibition of lysosomal acidification. Overall, this study underscores that sub-cellular localisation can considerably influence the speciation of Cu-based drugs and that minor species can be the most redox- and biologically-active.

Cuproptosis: A Copper-Mediated Programmed Cell Death.

It has been found that various heavy metals can initiate different types of regulated cell deaths. Among these metals, copper, an essential trace micronutrient that plays a major role in a lot of physiological processes, also can initiate cell death. It can act as a constituent of metalloenzymes, and can act as a mediator for signaling pathways to regulate proliferation and metastasis of tumor. It is also an integral part of some metal-based anticancer drugs. Recent studies have revealed that excessive intracellular copper accumulation leads to the aggregation of mitochondrial lipoylated proteins, causing proteotoxic stress and ultimately resulting in cell death. This newly discovered copper-induced cell death is termed as cuproptosis. In the last few, a lot of research has been done to understand the mechanism of copper-mediated cell death, and attempts have also been made to identify the relationship between cuproptosis and the development of cancer. In this review, we provide a comprehensive overview on the significance of copper, its regulation inside the body, the possible mechanism of cuproptosis, and how this cuproptosis can be employed as a therapeutic tool for cancer ablation.

Assessing antioxidant responses in C6 and U-87 MG cell lines exposed to high copper levels

Copper excess has been tested as an anticancer therapy, due to its properties to generate oxidative stress resulting in tumoral cell death. Thus, this study aimed to evaluate the impact of copper excess on oxidative stress and antioxidant responses in glioma cells, establishing the antioxidant system as a target of copper toxicity in tumoral cells. C6 and U-87 MG cells were exposed to CuSO4 (0–600 μM) for 24-48 h. SOD, CAT, GPx, GR, and CK activities, protein and non-protein thiol levels (PSH and NPSH), and O2− production were assessed, alongside SOD1, GPx1, and GR gene expression. Results revealed a decrease in GPx, GR, and CAT activity after CuSO4 exposure in both cell lines over 24-48 h, while SOD activity initially increased, then declined after 48 h. CK activity was also decreased in C6 cells. NPSH and PSH levels dropped after 24 h, and O2− production was observed in all CuSO4 concentrations. GR mRNA was reduced in both cell lines, contrasting with increased GPx1 mRNA in C6. U-87 MG cells exhibited higher levels of SOD1 mRNA, while C6 cells displayed lower expression. Our findings suggest that copper excess limits antioxidant enzyme activity and thiol levels, particularly in the C6 cells, likely attributable to oxidative stress or direct copper-enzyme interactions. Moreover, our results imply differences in copper toxicity regarding the cell lineage used, highlighting the importance of analyzing high copper levels effects in different models. Moreover, it could be proposed that the antioxidant system is a target of copper toxicity, contributing to glioma cell death.

The Role of Heat Shock Factor 1 in Preserving Proteomic Integrity During Copper-Induced Cellular Toxicity.

Copper is crucial for many physiological processes across mammalian cells, including energy metabolism, neurotransmitter synthesis, and antioxidant defense mechanisms. However, excessive copper levels can lead to cellular toxicity and "cuproptosis", a form of programmed cell death characterized by the accumulation of copper within mitochondria. Tumor cells are less sensitive to this toxicity than normal cells, the mechanism for which remains unclear. We address this important issue by exploring the role of heat shock factor 1 (HSF1), a transcription factor that is highly expressed across several types of cancer and has a crucial role in tumor survival, in protecting against copper-mediated cytotoxicity. Using pancreatic ductal adenocarcinoma cells, we show that excessive copper triggers a proteotoxic stress response (PSR), activating HSF1 and that overexpressing HSF1 diminishes intracellular copper accumulation and prevents excessive copper-induced cell death and amyloid fibrils formation, highlighting HSF1's role in preserving proteasomal integrity. Copper treatment decreases the lipoylation of dihydrolipoamide S-acetyltransferase (DLAT), an enzyme necessary for cuproptosis, induces DLAT oligomerization, and induces insoluble DLAT formation, which is suppressed by overexpressing HSF1, in addition to enhancing the interaction between HSF1 and DLAT. Our findings uncover how HSF1 protects against copper-induced damage in cancer cells and thus represents a novel therapeutic target for enhancing copper-mediated cancer cell death.

U-shaped nonlinear relationship between dietary copper intake and peripheral neuropathy

Background: Dietary copper intake is a promising predictor of peripheral neuropathy. There is no research exploring the potential link between dietary copper intake and peripheral neuropathy. Methods: The information utilized in our research was collected from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004. The relationship between dietary copper intake and peripheral neuropathy was analyzed using a multivariate logistic regression model and restricted cubic spline (RCS). Results: The RCS analysis results showed a U-shaped nonlinear relationship between dietary copper intake and peripheral neuropathy (P for nonlinearity < 0.001). The threshold effect analysis results indicated that when dietary copper intake was less than 0.889 mg/d, the risk of peripheral neuropathy decreased with increasing copper intake (OR: 0.388, 95% CI: 0.200-0.753). When dietary copper intake was ≥ 0.889 mg/d, the risk of peripheral neuropathy increased with increasing copper intake (OR: 1.129, 95% CI: 1.006–1.266). And the incidence rate of peripheral neuropathy in the first quantile (OR: 1.421, 95% CI: 1.143–1.766), the third quantile (OR: 1.358, 95% CI: 1.057–1.744), and the fourth quantile (OR: 1.676, 95% CI: 1.250–2.248) of dietary copper intake were significantly higher than that in the second quantile (where the inflection point was located). Conclusion: Our study suggests that both insufficient and excessive dietary copper intake may be associated with an increased incidence of peripheral neuropathy. However, further research is needed to provide definitive evidence and confirm these findings.

Copper as the driver of the lncRNA-TCONS-6251/miR-novel-100/TC2N axis: Unraveling ferroptosis in duck kidney

Ferroptosis is an iron-dependent form of oxidative cell death. Competitive endogenous RNAs diminish the inhibitory impact of microRNAs on other transcripts by chelating effects, which affects ferroptosis and reactive oxygen species (ROS) levels. However, the role of ferroptosis in excessive copper (Cu)-induced renal injury via the ceRNA axis has not been fully illustrated yet. Herein, we found that Cu induced ferroptosis in duck renal tubular epithelial cells, as indicated by the increase in intracellular iron levels and lipid peroxidation, upregulation of PTGS2 and ACSL4 levels, reduced GPX4 and GSH levels. In addition, knockdown miR-novel-100 could effectively decreased ferroptosis induced by Cu. Overexpression of miR-novel-100 or TC2N knockdown resulted in the stimulation of ROS and the upregulation of ferroptosis indicators. However, butylated hydroxyanisole (BHA) decreased the stimulation of ROS and the ferroptosis effect caused by miR-novel-100 overexpression. In conclusion, Cu induced ferroptosis by activating the lncRNA-TCONS-6251/miR-novel-100/TC2N axis to cause ROS accumulation.

Uncovering mechanism of excessive copper ion-activated depressed-sphalerite under moderate alkaline conditions: A combined experimental and DFT investigation

Currently, extensive research exists on the activation mechanisms of sphalerite, yet there is a notable absence of studies on the mechanisms behind the activation of depressed sphalerite. This paper investigates the mechanism through which moderate or excessive copper ions activate depressed sphalerite under conditions (pH 9–10) of moderate alkalinity, employing a comprehensive approach that includes pure mineral flotation experiments, contact angle measurements, FESEM-EDS, XPS, and density functional theory simulations.The results from pure mineral flotation experiments reveal that, at a copper ion concentration of 1 × 10−4 mol/L, sphalerite, previously depressed by zinc sulfate, is activated by copper ions, achieving a recovery rate of 91.46 % with butyl xanthate as the collector. However, when more cooper ions are added, the recovery of sphalerite decreases. Contact angle measurements and FESEM-EDS data indicate that under conditions of moderate alkalinity, zinc sulfate undergoes hydrolysis to form hydrophilic colloidal substances (hydroxylated zinc) that adhere to the surface of sphalerite, rendering it hydrophilic and thereby depressed. Following the introduction of copper ions, a dense striated material forms on the surface of sphalerite previously inhibited by zinc sulfate, enhancing its hydrophobicity, but if more copper ions were added, the hydrophobicity of activated sphalerite will be weakened. XPS findings further suggest that activated sphalerite by copper is capable of forming polysulfides, which then act on the sphalerite. DFT simulations verify that under moderate alkalinity conditions, copper ions first undergo a hydroxylation reaction in the solution before adsorbing or precipitating on the mineral surface as hydroxylated substances, which subsequently interact with sulfur on the surface of sphalerite. The analysis of the density of states indicates that following the addition of butyl xanthate, the strongest 3p orbital electron peak of the sulfur atom bound to butyl xanthate and the strongest 3d orbital electron peak of zinc are at distinct energy levels, suggesting that the overlap of the electronic density of states is minimal, indicating a weak and unstable interaction between the sulfur and zinc atoms bonded with butyl xanthate. Conversely, the strongest 3p orbital electron peak of the sulfur atom bonded with butyl xanthate overlaps with the strongest 3d orbital electron peak of copper and is positioned near the Fermi level, signifying a strong reactivity and more stable interaction between the sulfur and copper atoms.

The balance between alleviating copper damage and maintaining root function during root pruning with excessive copper.

Coating high concentrations of copper (Cu) on the inner wall of containers can efficiently inhibit root entanglement of container-grown seedlings. However, how the protective and defensive responses of roots maintain root structure and function during Cu-root pruning is still unclear. Here, Duranta erecta seedlings were planted in the containers coated with 40 (T1), 80 (T2), 100 (T3), 120 (T4), 140 (T5), and 160 (T6) g L-1 Cu(OH)2 with containers without Cu(OH)2 as the control. Although T5 and T6 produced the best inhibitory effect on root entanglement, root anatomy structure was damaged. T1 and T2 not only failed to completely control root circling, but also led to decreased root activity and stunted growth. Cu(OH)2 treatments significantly increased lignin concentration of roots with the highest values at T3 and T4. Compared with T3, seedlings at T4 had higher height, biomass, and root activity and no significant root entanglement. Excessive Cu accumulation in Cu(OH)2 treatments changed the absorption of other mineral nutrients and their allocation in the roots, stems, and leaves. Overall, Ca was decreased while Mg, Mn, Fe, and K were increased, especially K and Mn at T4 which is related to defense capacity. The results indicate that there is a Cu threshold to balance root entanglement control, defense capacity, and nutrient uptake function under excessive Cu for container-grown D. erecta seedlings.

Review to Elucidate the Correlation between Cuproptosis-Related Genes and Immune Infiltration for Enhancing the Detection and Treatment of Cervical Cancer.

Copper is a vital trace element in oxidized and reduced forms. It plays crucial roles in numerous biological events such as redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy, and immune modulation. Maintaining the balance of copper in the body is essential because its deficiency and excess can be harmful. Abnormal copper metabolism has a two-fold impact on the development of tumors and cancer treatment. Cuproptosis is a form of cell death that occurs when there is excessive copper in the body, leading to proteotoxic stress and the activation of a specific pathway in the mitochondria. Research has been conducted on the advantageous role of copper ionophores and chelators in cancer management. This review presents recent progress in understanding copper metabolism, cuproptosis, and the molecular mechanisms involved in using copper for targeted therapy in cervical cancer. Integrating trace metals and minerals into nanoparticulate systems is a promising approach for controlling invasive tumors. Therefore, we have also included a concise overview of copper nanoformulations targeting cervical cancer cells. This review offers comprehensive insights into the correlation between cuproptosis-related genes and immune infiltration, as well as the prognosis of cervical cancer. These findings can be valuable for developing advanced clinical tools to enhance the detection and treatment of cervical cancer.

Alleviation of Copper-Induced Hepatotoxicity by Bergenin: Diminution of Oxidative Stress, Inflammation, and Apoptosis via Targeting SIRT1/FOXO3a/NF-κB Axes and p38 MAPK Signaling.

Despite its biological importance, excess copper induces organ damage, especially to the liver. Disruption of critical signaling cascades that control redox status, inflammatory responses, and cellular apoptosis significantly contributes to the copper-induced hepatotoxicity. The present work explored the hepatoprotective ability of bergenin against the copper-induced hepatotoxicity using male Wistar rats as a mammalian model. The results revealed that bergenin suppressed the copper-evoked histopathological changes and hepatocellular necrosis as indicated by decreased activity of the liver enzymes ALT and AST in the sera of the copper-intoxicated rats. It decreased hepatic copper content and the copper-induced oxidative stress as revealed by reduced lipid peroxidation and improved activity of the antioxidant enzymes thioredoxin reductase, glutathione peroxidase, catalase, and superoxide dismutase. Bergenin downregulated the inflammatory cytokines TNF-α and IL-6, and the inflammatory cell infiltration to the liver tissues. Additionally, it inhibited the copper-induced apoptosis as indicated by significant reduction in caspase-3 activity. At the molecular level, bergenin activated the antioxidant transcription factor FOXO3a, inhibited the nuclear translocation of the inflammatory transcription factor NF-κB, and suppressed the inflammatory signaling molecules p38 MAPK and c-Fos. Interestingly, bergenin improved the expression of the anti-apoptotic protein Bcl2 and reduced the pro-apoptotic protein BAX. Bergenin markedly enhanced the expression of the histone deacetylase protein SIRT1 that regulates activity of NF-κB and FOXO3a. Collectively, these findings highlight the alleviating activity of bergenin against the copper-induced hepatotoxicity via controlling oxidative stress, inflammation, and apoptosis potentially through upregulation of SIRT1, activation of FOXO3a along with suppression of NF-κB and p38 MAPK signaling.

Copper Dyshomeostasis And Diabetic Complications: Chelation Strategies For Management.

Cuproptosis, An Emerging Concept In The Field Of Diabetes Research, Presents A Novel And Promising Perspective For The Effective Management Of Diabetes Mellitus And Its Associated Complications. Diabetes, Characterized By Chronic Hyperglycemia, Poses A Substantial Global Health Burden, With An Increasing Prevalence Worldwide. Despite Significant Progress In Our Understanding Of This Complex Metabolic Disorder, Optimal Therapeutic Strategies Still Remain Elusive. The Advent Of Cuproptosis, A Term Coined To Describe Copper-Induced Cellular Cell Death And Its Pivotal Role In Diabetes Pathogenesis, Opens New Avenues For Innovative Interventions. Copper, An Indispensable Trace Element, Plays A Pivotal Role In A Myriad Of Vital Biological Processes, Encompassing Energy Production, Bolstering Antioxidant Defenses, And Altered Cellular Signaling. However, In The Context Of Diabetes, This Copper Homeostasis Is Perturbed, Driven By A Combination Of Genetic Predisposition, Dietary Patterns, And Environmental Factors. Excessive Copper Levels Act As Catalysts For Oxidative Stress, Sparking Intricate Intracellular Signaling Cascades That Further Exacerbate Metabolic Dysfunction. In This Review, We Aim To Explore The Interrelationship Between Copper And Diabetes Comprehensively, Shedding Light On The Intricate Mechanisms Underpinning Cuproptosis. By Unraveling The Roles Of Copper Transporters, Copper-Dependent Enzymes, And Cuproptotic Signaling Pathways, We Seek To Elucidate Potential Therapeutic Strategies That Harness The Power Of Copper Modulation In Diabetes Management. This Insight Sets The Stage For A Targeted Approach To Challenge The Complex Hurdles Posed By Diabetes, Potentially Transforming Our Therapeutic Strategies In The Ongoing Fight Against This Pervasive Global Health Concern.

A Case Series of Atypical Neuroimaging Phenotypes in Wilson’s Disease

Abstract Wilson’s disease (WD) is an inherited disorder of copper metabolism that leads to excessive copper deposition, predominantly involving the hepatic and neural parenchyma. The clinical presentation may vary from being completely asymptomatic to hepatic cirrhosis with or without frank extrapyramidal symptoms. Neuroimaging plays a crucial role in diagnosis and follow-up among these patients. The myriad neuroimaging features in WD depend on the chronicity of the disease and are also associated with the extent of hepatolenticular degeneration. Here, we present various atypical imaging phenotypes encountered in a cohort of 13 patients with the expected clinical presentation. All of them are proven cases of WD either based on genetic/ceruloplasmin levels. Asymmetry of the bilateral hyperintensities, involvement of the parahippocampal gyri, lingual gyri, insular necrosis, preferential affliction of the thalamus, and brainstem sparing the neostriatum were some of the observed atypical neuroimaging phenotypes which are hitherto undescribed to the best of our knowledge. Timely recognition of the atypical imaging findings and apt clinical correlation results in effective and early management decisions.

Role of copper during microglial inflammation.

Copper plays crucial roles in various physiological functions of the nervous and immune systems. Dysregulation of copper homeostasis is linked to several diseases, including neurodegenerative diseases. Since dysfunctional microglial immunity can contribute to such diseases, we investigated the role of copper in microglial immunity. We found that both increased and decreased copper levels induced by chemical treatments suppresses lipopolysaccharide (LPS)-mediated inflammation in microglial cells, as determined by RT-qPCR analysis. RNA sequencing (RNA-seq) analysis confirmed that increased copper level reduces the inflammatory response to LPS; however, it also showed that decreased copper level affects genes involved in cell proliferation, transcription, and autophagosome regulation. These findings suggest that copper is vital for maintaining normal immune function in microglia, and both copper excess and deficiency can disrupt microglial immunity.

Copper ions: The invisible killer of cardiovascular disease (Review).

Copper, a vital trace element, is indispensable for the maintenance of physiological functioning, particularly in the cardiac system. Unlike other forms of cell death such as iron death and apoptosis, copper‑induced cell death has gained increasing recognition as a significant process influencing the development of cardiovascular diseases. The present review highlights the significance of maintaining copper homeostasis in addressing cardiovascular diseases. This review delves into the crucial roles of copper in physiology, including the metabolic pathways and its absorption, transport and excretion. It provides detailed insights into the mechanisms underlying cardiovascular diseases resulting from both excess and deficient copper levels. Additionally, it summarizes strategies for treating copper imbalances through approaches such as copper chelators and ion carriers while discussing their limitations and future prospects.

Copper homeostasis and cuproptosis in health and disease.

Copper is a vital trace element in human physiology, essential for the synthesis of numerous crucial metabolic enzymes and facilitation of various biological processes. Regulation of copper levels within a narrow range is imperative for maintaining metabolic homeostasis. Numerous studies have demonstrated the significant roles of copper homeostasis and cuproptosis in health and disease pathogenesis. However, a comprehensive and up-to-date systematic review in this domain remains absent. This review aims to consolidate recent advancements in understanding the roles of cuproptosis and copper homeostasis in health and disease, focusing on the underlying mechanisms and potential therapeutic interventions. Dysregulation of copper homeostasis, manifesting as either copper excess or deficiency, is implicated in the etiology of various diseases. Cuproptosis, a recently identified form of cell death, is characterized by intracellular copper overload. This phenomenon mediates a diverse array of evolutionary processes in organisms, spanning from health to disease, and is implicated in genetic disorders, liver diseases, neurodegenerative disorders, and various cancers. This review provides a comprehensive summary of the pathogenic mechanisms underlying cuproptosis and copper homeostasis, along with associated targeted therapeutic agents. Furthermore, it explores future research directions with the potential to yield significant advancements in disease treatment, health management, and disease prevention.

Copper excess in psychiatric disorders: a focus on mood spectrum disorders and sex

BackgroundMeta-analyses show increased copper (Cu) levels in major depression disorder. However, the association of Cu biomarkers with clinical classification in other mental health disorders has not been fully explored. MethodsTo this aim, we compared an extensive panel of Cu biomarkers, composed of Cu, ceruloplasmin (Cp) Cp activity, Cp specific activity, Cu not bound to ceruloplasmin (non-Cp Cu, also known as ‘free’ copper) in 171 consecutive patients affected by psychiatric disorders and in 61 healthy controls (HC) using MANOVA adjusting for the effect of sex and age, and studied their association with the clinical scale outcomes at psychiatric examination, namely Global Assessment of Functioning, Clinical Global Impression, and Brief Psychiatric Rating Scale. Resultsindividuals with psychiatric disorders were classified as 109 patients affected by mood spectrum disorders (MSD), 20 patients with schizophrenia spectrum disorders (SSD), and 42 with personality disorders (PD). Cu and non-Cp Cu were increased in psychiatric individuals than in HC, which also differed among the patients stratified per the clinical classification, being higher in the MSD individuals. The analysis stratified for sex revealed that women from the patient group, and specifically from the MSD group, had increased levels of Cu and non-Cp Cu than healthy women, while no difference was revealed in men. A logistic regression model considering the effect of sex and age revealed that non-Cp Cu could explain 26 % increased odds of having MSD per µmol/L unit increase (OR = 1.26; p = 0.0008; 95 % CI 1.099–1.436), that reached 40 % when considering only women. This result was driven by non-Cp Cu that correctly classified 64.1 % MSD (70 % in women) individuals vs. HC in a decision tree model, with values higher than 2.1 µmol/L which could distinguish the majority of MSD patients (86.3 % MSD vs. 13.7 % HC in women). None of the biological variables under study correlated with outcomes of the clinical scales, substances, or alcohol abuse. ConclusionCurrent results suggest mild Cu toxicity in women with MSD, as revealed by a value of non-Cp Cu higher than 2.1 µmol/L, which can be further investigated to assess its potential diagnostic accuracy in bigger and longitudinal cohorts.

Copper Homeostasis and Its Impact on Innate Immunity in Crustaceans

ABSTRACTCopper, an essential micronutrient in crustaceans, plays vital roles in enzymatic processes, oxygen transport, pigmentation, and structural protein synthesis, including collagen and elastin. Recent research has elucidated its pivotal role in innate immunity of crustaceans, enhancing the immune response by promoting phagocytic activity, antimicrobial peptide production, and modulation of immune gene expression. Copper ions exhibit antimicrobial effects by disrupting cell membranes and inhibiting microbial proliferation. Furthermore, copper governs antioxidant defense mechanisms, protecting crustaceans against oxidative stress and infection. However, excessive copper can lead to toxicity, highlighting the need for strict maintenance of copper homeostasis. This review explores the complex processes of copper homeostasis in crustaceans, detailing transport mechanisms, storage proteins, and detoxification pathways. It emphasizes copper's critical physiological and immunological functions, contributing to a comprehensive understanding of its multifaceted roles in crustaceans and laying groundwork for further exploration of copper homeostasis as a strategy for boosting crustacean immunity. Aquaculture practices significantly influence copper levels in crustaceans. Effective copper management, including monitoring techniques, water treatment strategies, and regulatory frameworks, is crucial for both crustacean welfare and environmental sustainability.