Copper homeostasis and neurodegenerative diseases

Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Role of copper chelating agents: between old applications and new perspectives in neuroscience

The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays an important role in the central nervous system, where it is associated with glutamatergic signaling, and it is widely involved in inflammatory processes. Thus, diseases involving copper(Ⅱ) dyshomeostasis often have neurological symptoms, as exemplified by Alzheimer's and other diseases(such as Parkinson's and Wilson's diseases). Moreover, imbalanced copper ion concentrations have also been associated with diabetes and certain types of cancer, including glioma. In this paper, we propose a comprehensive overview of recent results that show the importance of these metal ions in several pathologies, mainly Alzheimer's disease, through the lens of the development and use of copper chelators as research compounds and potential therapeutics if included in multi-target hybrid drugs. Seeing how copper homeostasis is important for the well-being of animals as well as humans, we shortly describe the state of the art regarding the effects of copper and its chelators in agriculture, livestock rearing, and aquaculture, as ingredients for the formulation of feed supplements as well as to prevent the effects of pollution on animal productions.

Role of copper in central nervous system physiology and pathology

Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

Optimization of copper extraction for bioleaching of complex Cu-polymetallic concentrate by moderate thermophiles

Effects of initial pH, temperature, liquid volume, rotation speed, galvanic interaction （pyrite ratio） and pulp density on bioleaching of complex Cu-polymetallic concentrate were investigated. The results indicated that the copper extraction at pH 1.5 was 1.5 and 1.4 times that at pH 1.0 and pH 2.0 respectively. The copper extraction obtained at 45 ℃ was 1236.8%higher than that at 50 ℃. With the increase of rotation speed or the decrease of liquid volume, copper extraction was improved obviously. Copper extraction was improved gradually with the increase of pyrite ratio. However, when the ratio was higher than 20.0%, no further increase in copper extraction was observed. And the statistically significant interactive effects on copper extraction were found between temperature and pH, and temperature and pyrite ratio.

Leaching Behavior of Complex Copper Sulphide Concentrate with Ferric Chloride by Microwave Irradiation

Microwave assisted leaching of complex copper sulphide concentrate with ferric chloride was investigated, and its mechanism was analyzed. The results show that the leaching rate by microwave irradiation heating is much faster than that by conventional heating.

Leaching of a copper flotation concentrate with ammonium persulfate in an autoclave system

The leaching behavior of a copper flotation concentrate was investigated using ammonium persulfate （APS） in an autoclave systee. The decomposition products of APS, active oxygen, and acidic medium were used to extract metals from the concentrate. Leaching experiments were performed to compare the availability of APS as an oxidizing agent for leaching of the concentrate under atmospheric conditions and in an autoclave system. Leaching temperature and APS concentration were found to be important parameters in both leaching systems. Atmospheric leaching studies showed that the metal extractions increased with the increase in APS concentration and temperature （up to 333 K）. A similar tendency was determined in the autoclave studies up to 423 K. It was also determined that the metal extractions decreased at temperatures above 423 K due to the passivation of the particle surface by molten elemental sulfur. The results showed that higher copper extractions could be achieved using an autoclave system.

Removal of copper from molybdenite concentrate by mesophilic and extreme thermophilic microorganisms

Mixed mesophilic and extreme thermophilic bioleaching were evaluated to remove copper from the molybdenite concentrate.Bioleaching tests were carried out in shake flasks and in a 50-L bioreactor.The shake flask tests were performed with different inoculum size,solids density,pH.and temperature in order to identify optimum conditions.The highest amount of copper elimination,75%was obtained with extreme thermophilic microorganisms(at 12%inoculation,10%solids,65℃and a pH of 1.5).The highest copper elimination by mesophilic microorganisms was 55%(at 12%inoculation,5%solids,30℃at pH 2).The optimum conditions in shake flask tests were applied to 7 days batch tests in a50-L bioreactor.Extreme thermophilic experiment gave the best copper elimination of 60%(at 12%inoculation,10%solids,65℃and pH 1.5).Mesophilic test removed 50%of the copper(at 12%inoculation,10%solids,35℃at pH 2).

Molybdenum removal from copper ore concentrate by sodium hypochlorite leaching

The removal of molybdenum from a copper ore concentrate by sodium hypochlorite leaching was investigated. The results show that leaching time,liquid to solid ratio,leaching temperature,agitation speed,and sodium hypochlorite and sodium hydroxide concentrations all have a significant effect on the removal of molybdenum.The optimum process operating parameters were found to be：time,4 h;sodium hydroxide concentration,10%;sodium hypochlorite concentration,8%;liquid to solid ratio,10：1;temperature,50℃;and, agitation speed,500 r/min.Under these conditions the extraction of molybdenum is greater than 99,9%and the extraction of copper is less than 0.01%.A shrinking particle model could be used to describe the leaching process.The apparent activation energy of the dissolution reaction was found to be approximately 8.8 kJ/mol.

Occurrence mechanism of silicate and aluminosilicate minerals in Sarcheshmeh copper flotation concentrate

The Sarcheshmeh copper flotation circuit is producing 5× 10^4 t copper concentrate per month with an averaging grade of 28% Cu in rougher, cleaner and recleaner stages. In recent years, with the increase in the open pit depth, the content of aluminosilicate minerals increased in plant feed and subsequently in flotation concentrate. It can motivate some problems, such as unwanted consumption of reagents, decreasing of the copper concentrate grade, increasing of Al2O3 and SiO2 in the copper concentrate, and needing a higher temperature in the smelting process. The evaluation of the composite samples related to the most critical working period of the plant shows that quartz, illite, biotite, chlorite, orthoclase, albeit, muscovite, and kaolinite are the major Al2O3 and SiO2 beating minerals that accompany chalcopyrite, chalcocite, and covellite minerals in the plant feed. The severe alteration to clay minerals was a general rule in all thin sections that were prepared from the plant feed. Sieve analysis of the flotation concentrate shows that Al2O3 and SiO2 bearing minerals in the flotation concentrate can be decreased by promoting the size reduction from 53 to 38 μm. Interlocking of the Al2O3 and SiO2 bearing minerals with chalcopyrite and chalcocite is the occurrence mechanism of silicate and aluminosilicate minerals in the flotation concentrate. The dispersed form of interlocking is predominant.

Structural, compositional and mineralogical characterization of carbonatitic copper sulfide: Run of mine, concentrate and tailings

The aim of this study was to determine the structural, compositional, and mineralogical composition of carbonatitic copper sulfide concentrator plant streams. Three samples, each from a different stream(run of mine(ROM), concentrate, and tailings) of a copper concentrator were characterized using various techniques, including stereomicroscopy, X-ray fluorescence, X-ray diffraction, Fourier transform infrared(FTIR) spectroscopy, scanning electron microscopy(SEM) in conjunction with energy-dispersive X-ray spectroscopy(EDS), and optical microscopy. The results reveal that each stream possesses its own unique compositional features. Carbonate minerals associated with calcite and dolomite, followed by quartz, remain the major minerals in both the ROM and tails streams. In the ROM stream, chalcopyrite appears to occur as veins within the carbonatite-hosting ore body. Mineral phase mutation was discovered in the tails stream because magnetite formerly identified in the ROM as the primary iron oxide had evolved into hematite. This metamorphosis was likely promoted by the concentration process. The concentration process was effective, upgrading the chalcopyrite content from 2 wt% in the ROM stream to 58 wt% in the concentrate stream; it was accompanied by bornite(4 wt%), anilite(3 wt%), and digenite(2.5 wt%). In addition, the concentrate stream exhibited properties distinctive from those of the other streams. The FTIR analysis showed the existence of a sulfide group related to the chalcopyrite mineral. Free chalcopyrite grains were observed in the concentrate by SEM analysis, and their mineral presence was supported by the EDS analysis results. All characterization techniques corresponded well with each other regarding the structure, chemistry, and composition of the samples.

Water model experiments of multiphase mixing in the top-blown smelting process of copper concentrate

We constructed a 1：10 cold water experimental model by geometrically scaling down an Isa smelting furnace. The mixing processes at different liquid heights, lance diameters, lance submersion depths, and gas flow rates were subsequently measured using the conductivity method. A new criterion was proposed to determine the mixing time. On this basis, the quasi-equations of the mixing time as a function of different parameters were established. The parameters of the top-blown smelting process were optimized using high-speed photography. An excessively high gas flow rate or excessively low liquid height would enhance the fluctuation and splashing of liquid in the bath, which is unfavorable for material mixing. Simultaneously increasing the lance diameter and the lance submersion depth would promote the mixing in the bath, thereby improving the smelting efficiency.

SELECTIVE COPPER REMOVAL FROM CUPRIFEROUS GOLD CONCENTRATE

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Copper,zinc,and iron bioleaching from polymetallic sulphide concentrate

Bioleaching of low-grade complex Cu&ndash;Zn&ndash;Pb&ndash;Fe&ndash;Ag&ndash;Au sulphide concentrate (of Majdanpek ore body, RTB Bor, Serbia) was carried out in an aerated bioleach reactor in the presence of mesophilic mixed bacterial culture of Acidithiobacillus ferrooxidans, Acidithiobacillus thiooxidans, and Leptospirillum ferrooxidans. A mesophilic acidophiles culture was isolated from the acidic solution of the underground copper mine of Bor, Serbia. The nutrient medium was 9K at pH 1.6. 87% of the particles were <10 &micro;m in size, with a pulp density of 8% (w/v). Bioleaching efficiencies of 89% for zinc, 83% for copper, and 68% for iron can be achieved in the examined conditions. Kinetic analysis shows that the change in leaching corresponds to the Spencer-Topley kinetic model for diffusion-controlled topochemical reactions.

Removal of Metallic Impurities from Off-Grade Copper Concentrate in Alkaline Solution

The removal of metallic impurities from off-grade copper concentrate was investigated in alkaline solution with H2O2. The analysis results of XRD and SEM-EDS revealed the oxidative mechanisms of all sulfides. The influence of various parameters of alkaline leaching were investigated including concentrations of sodium hydroxide and hydrogen peroxide, liquid to solid ratio, leaching time and temperature. The results showed that the removal rate of Mo, As and Zn were increased with increasing leaching time and H2O2 concentration, and that the removal rate of Mo, As and Zn were firstly increased and then slightly decreased with increasing liquid to solid ratio, temperature and NaOH concentration, respectively. More than 95% Mo, 94% As, and 94 % Zn are removed from the off-grade concentrate under the optimum conditions, while only 1.7% Cu is dissolved. These optimum conditions were sodium hydroxide 1.5 mol/L, hydrogen peroxide 1.0 mol/L, temperature 50&deg;C, liquid to solid ratio 5/1 mL/g and leaching time 5 h.

Influence of Ferric and Ferrous Iron on Chemical and Bacterial Leaching of Copper Flotation Concentrates

The effects of ferrous and ferric iron as well as redox potential on copper and iron extraction from the copper flotation concentrate of Sarcheshmeh, Kerman, Iran, were evaluated using shake flask leaching examinations. Experiments were carried out in the presence and absence of a mixed culture of moderately thermophile microorganisms at 50?C. Chemical leaching experiments were performed in the absence and presence of 0.15 M iron (ferric added medium, ferrous added medium and a mixture medium regulated at 420 mV, Pt. vs. Ag/AgCl). In addition, bioleaching experiments were carried out in the presence and absence of 0.1 M iron (ferric and ferrous added mediua) at pulp density 10% (w/v), inoculated bacteria 20% (v/v), initial pH 1.6, nutrient medium Norris and yeast extract addition 0.02% (w/w). Abiotic leaching tests showed that the addition of iron at low solution redox potentials significantly increased the rate and extent of copper dissolution but when ferric iron was added, despite a higher initial rate of copper dissolution, leaching process stopped. Addition of both ferrous and ferric iron to the bioleaching medium levelled off the copper extraction and had an inhibitory effect which decreased the final redox potential. The monitoring of ferrous iron, ferric iron and copper extraction in leach solutions gave helpful results to understand the behaviour of iron cations during chemical and bacterial leaching processes.

Effect of Flotation Reagents on the Cake Moisture of Copper Concentrate

The effect of reagents used in separating chalcopyrite from pyrite on the cake moisture of the copper concentrate at Daye Iron Mine Mineral Processing Plant was investigated. The results showed that the dosage of lime used for depressing pyrite was the main factor that increased the filter cake moisture of copper concentrate. With increasing the dosage of lime, the cake moisture of copper concentrate increased sharply. The cause was concluded to be the addition of lime to the pulp, which resulted in the formation of floc and a high pH value. The collector Z-200#, used for collecting chalcopyrite, had, as well, an adverse effect on the cake moisture of copper concentrate, but its effect was inferior in respect to that of lime. The cake moisture of copper concentrate can be decreased by changing the method with which lime is added and the pH value of pulp is regulated. The experiment results showed that the sulfuric acid was the best regulator. When the clarified liquor of lime was used as a depressant and the pH value of the pulp was regulated to 6.5€*7.0 by adding sulfuric acid, the cake moisture of copper concentrate was reduced from 15.49% to 13.13%. The examination of chalcopyrite surface by using ESCA (Electron Spectroscopy for Chemical Analysis) showed that calcium sulfate and iron hydroxide had formed on the surface of chalcopyrite when lime was added to the pulp. The formation of calcium sulfate and iron hydroxide on its surface increased the hydrophilicity of chalcopyrite so that its cake moisture increased. The addition of sulfuric acid to the pulp not only removed the calcium sulfate, but also reduced the concentration of iron hydroxide on the surface of chalcopyrite so that the cake moisture of copper concentrate was decreased.

Optimization of selective copper extraction from chalcopyrite concentrate in presence of ammonium persulfate and ammonium hydroxide

The dissolution of copper and iron from chalcopyrite concentrate in the presence of ammonium persulfate(APS)and ammonium hydroxide was investigated under atmospheric leaching conditions.Experiments were designed by central composite design(CCD).Under the optimum leaching conditions((NH4)2S2O8 concentration=328 g/L;NH4OH addition=16vol%;leaching temperature=321 K(48℃);leaching time=120 min;liquid-to-solid ratio=16;stirring speed=400 r/min),selective leaching was achieved.98.14%of the copper was leached,whereas iron did not pass into the solution.X-ray diffraction analysis of the leaching residue showed that iron compounds were predominant.Given the leaching results,the fact that the leaching process does not include uneconomical leaching stages such as extended milling/mechanical activation or high pressures/temperatures,and the low copper dissolution conditions,the attained selective leaching yield may be remarkable.

Effect of Roasting Temperature for Copper Leaching of Sulfide Concentrate by Combined Methods

This study was undertaken to develop a cost-effective method of copper leaching in sulfide concentrate involving minerals as chalcopyrite and pyrite. The combined methods involving low temperature roasting of sulfide copper minerals with potassium chlorides without the formation of sulfurous gases and their evolution into the atmosphere is suggested. The effect of experi-mental parameters such as a roasting temperature and time has been pre-sented and discussed in detail. This study was carried out in the roasting temperature range 400&#176C - 600&#176C and roasting time ranges 1 - 4 h with potas-sium chloride. The obtained cake is leached by an aqueous sulfuric acid 60 g/l concentrated at pH = 2 - 2.5 and 4 h. The concentrate, a roasting cake and after leaching solid residue were analyzed by chemical analysis, XRD and SEM-EDX. At temperature ranges 450&#176C - 550&#176C and 3 h of roasting, the pro-cess is activated. The recovery of copper into the solution at optimal roasting condition (500&#176C, roasting time 3 h) is 93.2%. The advantage of the devel-oped method is that, it not requires high roasting temperature and the use of autoclave for leaching. The method gives possibility to leach the concentrate at room temperature and atmospheric pressure, which gives possibility to reduce cost of the process.

Leaching of copper from chalcopyrite concentrate by using ammonium persulphate in an autoclave:Determination of most suitable impeller type by using response surface methodology

Some effective parameters on the copper extraction from Kiire chalcopyrite concentrate were optimized by using response surface methodology （RSM）. Experiments designed by RSM were carried out in the presence of ammonium persulfate （APS） and different types of impeller in an autoclave system. Ammonium persulfate concentration and leaching temperature were defined numerically and three types of impellers were defined categorically as independent variables using experimental design software. The optimum condition for copper extraction from the chalcopyrite concentrate is found to be ammonium persulfate concentration of 277.77 kg/m3, leaching temperature of 389.98 K and wheel type of impeller. The proposed model equation using RSM has shown good agreement with the experimental data, with correlation coefficients R2 and RaZaj for the model as 0.89 and 0.84, respectively.

Copper Metabolism and Cuproptosis:Molecular Mechanisms and Therapeutic Perspectives in Neurodegenerative Diseases

Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess can adversely affect cellular function.Therefore,copper homeostasis is stringently regulated.Recent studies suggest that copper can trigger a specific form of cell death,namely,cuproptosis,which is triggered by excessive levels of intracellular copper.Cuproptosis induces the aggregation of mitochondrial lipoylated proteins,and the loss of iron-sulfur cluster proteins.In neurodegenerative diseases,the pathogenesis and progression of neurological disorders are linked to copper homeostasis.This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases.This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.