Role Of Copper Research Articles

Molecular Analysis of Trace Elements in Oral Submucous Fibrosis and Future Perspectives

Context: Several studies have linked micronutrients with various forms of precancer and cancer but with many limitations and inconclusive outcomes. There is a need to work on the limitations of existing studies and develop guidelines for future perspectives. Aims: Our research is an attempt to search, at molecular level, the reasons for alterations in trace metals occurring and their role, if any, in the etiopathogenesis of OSMF and carcinogenesis, with an aim to improve prognosis. Also to evaluate the role of copper (Cu) and zinc (Zn) along with cadmium (Cd), chromium (Cr), and nickel (Ni) which may have a role in carcinogenesis. Settings and Design: It was an observational cross-sectional study. Subjects and Methods: The study comprised 50 patients each in group-A with oral submucous fibrosis, group B (chewing habit without oral submucous fibrosis), and group C (healthy individuals without chewing habit). The serum levels of Cu, Zn, Cd, Cr, and Ni were analyzed from venous blood using atomic absorption spectrometry. Statistical Analysis: The data were analyzed by Student's unpaired '' t '- test and one-way analysis of variance Bonferroni post-hoc test using SPSS software. Results: Groups A and B showed a highly significant statistical difference in serum values of Cu, Zn, and Cd ( P Conclusion: The altered values of serum observed may be a reflection of the tissue levels. Copper's role in pathogenesis of OSMF is reestablished with proposed role of Zn, Cd, Cr, and Ni in carcinogenesis.

Changes in copper concentrations affect the protein levels but not the mRNA levels of copper chaperones in human umbilical vein endothelial cells

Copper chaperones are critical regulators of intracellular copper metabolism and distribution. The present study was undertaken to investigate the effects of changes in copper concentrations on the abundance of copper chaperones. Human umbilical vein endothelial cells (HUVECs) were treated with siRNA targeting copper transporter 1 (CTR1) or tetraethylenepentamine (TEPA) to decrease, or with copper sulfide to increase, intracellular copper concentrations, assayed using an atomic absorption spectrophotometer. Western blot analyses showed that CTR1 silencing or TEPA treatment increased the protein levels of copper chaperone ATOX1 and copper chaperone for superoxide dismutase 1 (CCS-1), but decreased copper chaperone for cytochrome c oxidase (COX17). In contrast, copper supplementation decreased the protein levels of ATOX1 and CCS-1 and increased COX17. Real-time RT-PCR analyses found no difference in the mRNA levels of the copper chaperones examined under the conditions defined above. This study thus demonstrated that changes in copper concentrations alter the protein levels, but not the mRNA levels, of copper chaperones, suggesting a role of copper in the post-translational modification of these proteins.

Growth and characterization of bamboo-like carbon nanotubes synthesized on Fe-Co-Cu catalysts prepared by high-energy ball milling

Bamboo-like carbon nanotubes (BCNTs) are special nanotubes with unique morphology and properties. Until now BCNTs could be fabricated mostly by nitrogen doping, but the use of nitrogen-containing organic compound is toxic and it makes the synthesis more complicated. Here, we present a simple method for the selective growth of bamboo-like CNTs. We employed high energy ball milling method for preparing Fe–Co–Cu (2.5–2.5–1 wt%) catalysts on Al2O3 support to synthesize bamboo-like CNTs by hydrogen-assisted catalytic chemical vapor deposition (CCVD) from acetylene at 720 °C. The effect of milling time on the growth of bamboo-like CNTs was investigated. Morphology and structure of the carbon deposits were characterized by transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM), and Raman spectroscopy. The growth mechanism of the as-prepared bamboo-like CNTs, and the role of copper containing catalyst were studied. Their properties theoretically make them ideal for gas storage and can be used as matrix fillers in composite materials, where the improved electrical conductivity with the mechanical properties of the tubes are the novel factor. HRTEM image of bamboo-like carbon nanotube (the scalebar is 50 nm).

Copper induces – and copper chelation by tetrathiomolybdate inhibits – endothelial activation in vitro

Endothelial activation with increased expression of cellular adhesion molecules and chemokines critically contributes to vascular inflammation and atherogenesis. Redox-active transition metal ions play an important role in vascular oxidative stress and inflammation. Therefore, the goal of the present study was to investigate the role of copper in endothelial activation and the potential anti-inflammatory effects of copper chelation by tetrathiomolybdate (TTM) in human aortic endothelial cells (HAECs). Incubating HAECs with cupric sulfate dose- and time-dependently increased mRNA and protein expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1). Copper also activated the redox-sensitive transcription factors, nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1), which was inhibited by pretreatment of the cells with TTM. Furthermore, TTM dose-dependently inhibited tumor necrosis factor α (TNFα)-induced activation of NF-κB and AP-1, as well as mRNA and protein expression of VCAM-1, ICAM-1, and MCP-1, which was abolished by preincubating the cells with 5 µM TTM and 15 µM cupric sulfate. The inhibitory effect of TTM on TNFα-induced NF-κB activation was associated with decreased phosphorylation and degradation of IκBα. These data suggest that intracellular copper causes activation of redox-sensitive transcription factors and upregulation of inflammatory mediators in endothelial cells. Copper chelation by TTM may attenuate TNFα-induced endothelial activation and, hence, inhibit vascular inflammation and atherosclerosis.

Micromolar copper modifies electrical properties and spontaneous discharges of nodose ganglion neurons in vitro

Copper plays a key role in aerobic cell physiology mainly related to mitochondrial metabolism. This element is also present at higher than basal levels in some central nuclei and indeed, current evidence support copper's role as a neuromodulator in the central nervous system. More recent data indicate that copper may also affect peripheral neuronal activity, but so far, there are not detailed descriptions of what peripheral neuronal characteristics are targeted by copper. Here, we studied the effect of physiological concentration of CuCl2 (μM range) on the activity of peripheral neurons using a preparation of nodose ganglion in vitro. By mean of conventional intracellular recordings passive and active electrical membrane properties were studied. Extracellular copper modified (in a redox-independent manner) the resting membrane potential and the input resistance of the nodose ganglion neurons, increasing the excitability in most of the tested neurons. These results suggest that Cu(2+) modulates the activity of nodose ganglion neurons and support nodose ganglion in vitro preparation as a simple model to study the subcellular mechanisms involved in the Cu(2+) effects on neuron electrical properties.

Structural Diversity of Copper(I)–N‐Heterocyclic Carbene Complexes; Ligand Tuning Facilitates Isolation of the First Structurally Characterised Copper(I)–NHC Containing a Copper(I)–Alkene Interaction

The preparation of a series of imidazolium salts bearing N-allyl substituents, and a range of substituents on the second nitrogen atom that have varying electronic and steric properties, is reported. The ligands have been coordinated to a copper(I) centre and the resulting copper(I)-NHC (NHC=N-heterocyclic carbene) complexes have been thoroughly examined, both in solution and in the solid-state. The solid-state structures are highly diverse and exhibit a range of unusual geometries and cuprophilic interactions. The first structurally characterised copper(I)-NHC complex containing a copper(I)-alkene interaction is reported. An N-pyridyl substituent, which forms a dative bond with the copper(I) centre, stabilises an interaction between the metal centre and the allyl substituent of a neighbouring ligand, to form a 1D coordination polymer. The stabilisation is attributed to the pyridyl substituent increasing the electron density at the copper(I) centre, and thus enhancing the metal(d)-to-alkene(π*) back-bonding. In addition, components other than charge transfer appear to have a role in copper(I)-alkene stabilisation because further increases in the Lewis basicity of the ligand disfavours copper(I)-alkene binding.

New Issues for Copper-64: from Precursor to Innovative Pet Tracers in Clinical Oncology

The role of copper in the metabolism of human cancer cells has been largely investigated in the last 20 years and a strong relationship between copper levels and cancer progression has been demonstrated. Moreover copper is involved in tumor angiogenesis as well as in non-neoplastic conditions like neurodegenerative diseases. The main mechanism of action is related to a cellular transporter (CTR1) that plays a pivotal role in preserving the intra-cellular homeostasis, allowing at the same time the anti- tumor activity of platinum based therapies. Copper-64, emitting positrons and β- radiations, is suitable for the labeling of a large number of molecules that could be used for radionuclide imaging, being also usable in radionuclide therapy. Nevertheless few data are at present available on radiotracers labeled with radiocopper and in particular on the use of (64)Cu-Cl2 in cancer patients. In this paper we analyze the potential applications for Copper-64 as PET agent in the clinical oncological scenario.

Potent and long-lasting inhibition of human P2X2 receptors by copper

P2X receptors are ion channels gated by ATP. In rodents these channels are modulated by zinc and copper. Zinc is co-released with neurotransmitter at some synapses and can modulate neuronal activity, but the role of copper in the brain is unclear. Rat P2X2 receptors show potentiation by 2–100 μM zinc or copper in the presence of a submaximal concentration of ATP but are inhibited by zinc or copper at concentrations above 100 μM. In contrast, human P2X2 (hP2X2) receptors show no potentiation and are strongly inhibited by zinc over the range of 2–100 μM. The effect of copper on hP2X2 is of interest because there are human brain disorders in which copper concentration is altered.We found that hP2X2 receptors are potently inhibited by copper (IC50 = 40 nM). ATP responsiveness recovered extremely slowly after copper washout, with full recovery requiring over 1 h. ATP binding facilitated copper binding but not unbinding from this inhibitory site. A mutant receptor in which the first six extracellular cysteines were deleted, C(1–6)S, showed normal copper inhibition, however reducing agents dramatically accelerated recovery from copper inhibition in wild type hP2X2 and the C(1–6)S mutant, indicating that the final two disulfide bonds are required to maintain the high affinity copper binding site. Three histidine residues required for normal zinc inhibition were also required for normal copper inhibition. Humans with untreated Wilson's disease have excess amounts of copper in the brain. The high copper sensitivity of hP2X2 receptors suggests that they are non-functional in these patients.

Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth, Normalizes Vessels and Promotes T Cell Infiltration

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes.

Investigation into Structural Changes of the Copper Binding Site in Lysyl Oxidase upon Substrate and Inhibitor Docking

The present paper reports a computational investigation of potential communication between the lysine tyrosylquinone (LTQ) and copper cofactors within lysyl oxidase (LOX). Various substrates and inhibitors of LOX were docked into the active site in our computer generated model of the enzyme. Conformational changes in the vicinity of the copper site as well as changes in the electrostatic environment were identified. The appearance of a canal-like structure involving tyrosine 35 (TYR35) and glutamine 104 (GLN104) residues was shown to be consistent upon docking of a variety of different compounds. Interactions between LOX and its natural substrate, collagen, were also explored through molecular dynamic simulations. The possibility of communication between the organic and inorganic cofactors in LOX was proposed, aiding the ongoing debate regarding the role of copper in the catalytic mechanism of this important enzyme.

The Early Cretaceous Weilasituo Zn–Cu–Ag vein deposit in the southern Great Xing'an Range, northeast China: Fluid inclusions, H, O, S, Pb isotope geochemistry and genetic implications

The Weilasituo vein-type deposit hosted in Hercynian (Middle to Late Paleozoic) quartz diorite and Palaeozoic gneiss occurs on the western slopes of the southern Great Xing'an Range. In this paper, we present results from fluid inclusion and isotope (H, O, S, Pb) investigations on the Weilasituo deposit. We identify three stages during the ore formation: a barren pre-ore stage (stage 1), a main-ore stage with economic grade Cu–Zn–Ag mineralization (stage 2), and a barren post-ore stage (stage 3). Fluid inclusion and mineral thermometry constrain temperature intervals of approximately 243 to 333°C, 192 to 425°C, and 141 to 261°C, for the three stages, respectively. Fluids in the main-ore stage are characterized by complex NaCl–H2O–CH4–CO2 low-salinity (3.55 to 8.68wt.% NaCl equiv.) with isotopic signatures consistent with a magmatic source. These fluids evolved by mixing with local meteoric water (δ18Ofluid=1.15 to 5.15‰, δDfluid=−139.4 to −88.2‰). Measured and calculated sulfur isotope compositions of hydrothermal fluids (δ34Sfluid=−3.0 to 3.4‰) indicate that the ore sulfur was derived mainly from a magmatic source. The lead isotope ratios from the ores show mean values of 18.326, 15.553, and 38.242 for 206Pb/204Pb, 207Pb/204Pb, and 208Pb/204Pb, respectively, indicating a mantle source. Our study shows that fluid mixing and/or dilution played an important role in copper, zinc, and silver mineralization in the Weilasituo deposit. The Weilasituo and Bairendaba deposits represent a linked ore system genetically related to the late Mesozoic magmatism. The ore-forming fluids associated with the Early Cretaceous mineralization in the southern Great Xing'an Range are of magmatic in origin, and evolved by mixing with local meteoric water. These deposits preserve the signature of a mantle source for lead. However, the deposits formed at ca. 177–160Ma possess a dominantly magmatic signature with less radiogenic lead.

The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells

Disulfiram has been used for several decades in the treatment of alcoholism. It now shows promise as an anticancer drug and radiosensitizer. Proposed mechanisms of action include the induction of oxidative stress and inhibition of proteasome activity. Our purpose was to determine the potential of disulfiram to enhance the antitumor efficacy of external-beam γ-irradiation and (131)I-metaiodobenzylguanidine ((131)I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. The role of copper in disulfiram-induced toxicity was investigated by clonogenic assay after treatment of human SK-N-BE(2c) neuroblastoma and UVW/noradrenaline transporter (NAT) glioma cells. The synergistic interaction between disulfiram and radiotherapy was evaluated by combination-index analysis. Tumor growth delay was determined in vitro using multicellular tumor spheroids and in vivo using human tumor xenografts in athymic mice. Escalating the disulfiram dosage caused a biphasic reduction in the surviving fraction of clonogens. Clonogenic cell kill after treatment with disulfiram concentrations less than 4 μM was copper-dependent, whereas cytotoxicity at concentrations greater than 10 μM was caused by oxidative stress. The cytotoxic effect of disulfiram was maximal when administered with equimolar copper. Likewise, disulfiram radiosensitization of tumor cells was copper-dependent. Furthermore, disulfiram treatment enhanced the toxicity of (131)I-MIBG to spheroids and xenografts expressing the noradrenaline transporter. The results demonstrate that the cytotoxicity of disulfiram was copper-dependent, the molar excess of disulfiram relative to copper resulted in attenuation of disulfiram-mediated cytotoxicity, copper was required for the radiosensitizing activity of disulfiram, and copper-complexed disulfiram enhanced the efficacy not only of external-beam radiation but also of targeted radionuclide therapy in the form of (131)I-MIBG. Therefore, disulfiram may have anticancer potential in combination with radiotherapy.

Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1

Copper is an essential micronutrient. Following entry via the human copper transporter 1 (hCTR1), copper is delivered to several copper chaperones, which subsequently transfer the metal to specific targets via protein:protein interactions. It is has been assumed, but not demonstrated, that chaperones acquire copper directly from hCTR1. However, some reports have pointed to an intermediary role for glutathione (GSH), an abundant copper-binding tri-peptide. To address the issue of how transported copper is acquired by the copper chaperones in vivo, we measured the initial rate of (64)Cu uptake in cells in which the cellular levels of copper chaperones or GSH were substantially depleted or elevated. Knockdown or overexpression of copper chaperones ATOX1, CCS, or both had no effect on the initial rate of (64)Cu entry into HEK293 cells having endogenous or overexpressed hCTR1. In contrast, depleting cellular GSH using L-buthionine-sulfoximine (BSO) caused a 50% decrease in the initial rate of (64)Cu entry in HEK293 cells and other cell types. This decrease was reversed by washout of BSO or GSH replenishment with a permeable ester. BSO treatment under our experimental conditions had no significant effects on the viability, ATP levels, or metal content of the cells. Attenuated (64)Cu uptake in BSO was not due to oxidation of the cysteine in the putative metal-binding motif (HCH) at the intracellular hCTR1 COOH terminus, because a mutant lacking this motif was fully active, and (64)Cu uptake was still reduced by BSO treatment. Our data suggest that GSH plays an important role in copper handling at the entry step.

Position of Serbian copper production complex on the world market

This paper presents the status, importance and role of copper in development the modern world economy. The main features of the world copper market are analyzed, such as: trends in consumption - cumulative and per capita, trends in production, exploitation reserves of copper - cumulative and by exploitation period, and finally the impact of new mining projects to projection of balance and imbalance of supply and demand on the world copper market. An analysis of the Serbian copper complex position on the world market is presented, along with comparison of copper resources between Serbia and the world. Also, the cost curve and position of the Serbian copper production complex are presented, accompanied by analysis of influencing factors that define the position of the Serbian copper production on the global market, as well as comparison with copper mining and processing companies in the world. Finally, a suggestion for possible routes of strategic activities is introduced, aiming to improve the existing position of the Serbian copper production on global market.

Role of Copper and Cholesterol Association in the Neurodegenerative Process

Age is one of the main factors involved in the development of neurological illnesses, in particular, Alzheimer, and it is widely held that the rapid aging of the world population is accompanied by a rise in the prevalence and incidence of Alzheimer disease. However, evidence from recent decades indicates that Cu and Cho overload are emerging causative factors in neurodegeneration, a hypothesis that has been partially investigated in experimental models. The link between these two variables and the onset of Alzheimer disease has opened up interesting new possibilities requiring more in-depth analysis. The aim of the present study was therefore to investigate the effect of the association of Cu + Cho (CuCho) as a possible synergistic factor in the development of an Alzheimer-like pathology in Wistar rats. We measured total- and nonceruloplasmin-bound Cu and Cho (free and sterified) contents in plasma and brain zones (cortex and hippocampus), markers of oxidative stress damage, inflammation, and programmed cell death (caspase-3 and calpain isoforms). The ratio beta-amyloid (1-42)/(1-40) was determined in plasma and brain as neurodegenerative biomarker. An evaluation of visuospatial memory (Barnes maze test) was also performed. The results demonstrate the establishment of a prooxidative and proinflammatory environment after CuCho treatment, hallmarked by increased TBARS, protein carbonyls, and nitrite plus nitrate levels in plasma and brain zones (cortex and hippocampus) with a consequent increase in the activity of calpains and no significant changes in caspase-3. A simultaneous increase in the plasma Aβ1-42/Aβ1-40 ratio was found. Furthermore, a slight but noticeable change in visuospatial memory was observed in rats treated with CuCho. We conclude that our model could reflect an initial stage of neurodegeneration in which Cu and Cho interact with one another to exacerbate neurological damage.

The role of copper in catalytic performance of a Fe–Cu–Al–O catalyst for water gas shift reaction

A Fe-Cu-Al-O water gas shift catalyst with a Fe : Cu atomic ratio of 4 : 1 upon pretreatment at 350 °C in H2 exhibits a conversion higher than a physical mixture of Fe-Al-O and Cu-Al-O by ~40% over a temperature range of 300 °C-450 °C. In situ ambient pressure X-ray photoelectron spectroscopy studies suggest that the surface region of Fe-Cu-Al-O was restructured into a double-layer structure consisting of a surface layer of Fe3O4 and a metallic Cu layer below it upon pretreatment at 350 °C. The strong metal (Cu)-oxide (Fe3O4) interface effect of this double layer structure enhances the catalytic activity of Fe3O4 in WGS.

Transition metals in plant photosynthesis

Transition metals are involved in essential biological processes in plants since they are cofactors of metalloproteins and also act as regulator elements. Particularly, plant chloroplasts are organelles with high transition metal ion demand because metalloproteins are involved in the photosynthetic electron transport chain. The transition metal requirement of photosynthetic organisms greatly exceeds that of non-photosynthetic organisms, and either metal deficiency or metal excess strongly impacts photosynthetic functions. In chloroplasts, the transition metal ion requirement needs a homeostasis network that strictly regulates metal uptake, chelation, trafficking and storage since under some conditions metals cause toxicity. This review gives an overview of the current understanding of main features concerning the role of copper (Cu), iron (Fe), manganese (Mn) and zinc (Zn) in plant photosynthesis as well as the mechanisms involved in their homeostasis within chloroplasts. The metalloproteins functioning in photosynthetic proteins of plants as well as those proteins participating in the metal transport and metal binding assembly are reviewed. Furthermore, the role of nickel (Ni) in artificial photosynthesis will be discussed.

On the Role of Copper and Cooling Rates on the Microstructure, Defect Formations and Mechanical Properties of Al-Si-Mg Alloys

This paper aims to assess the role of Cu on Al-Si-Mg alloys, in a range of 0 - 5 wt%, qualitatively on microstructure, defect formation, in terms of porosity, and strength in the as-cast conditions. The ternary system of Al-Si-Mg, using the A356 alloy as a base material, were cast using the gradient solidification technique; applying three different solidification rates to produce directional solidified samples with a variety of microstructure coarsenesses. Microstructural observations reveal that as the Cu levels in the alloys are increased, the amounts of intermetallic compounds as well as the Cu concentration in the α-Al matrix are increased. Furthermore, the level of porosity is unaffected and the tensile strength is improved at the expense of ductility.

Cholesterol and Copper Affect Learning and Memory in the Rabbit

A rabbit model of Alzheimer's disease based on feeding a cholesterol diet for eight weeks shows sixteen hallmarks of the disease including beta amyloid accumulation and learning and memory changes. Although we have shown that feeding 2% cholesterol and adding copper to the drinking water can retard learning, other studies have shown that feeding dietary cholesterol before learning can improve acquisition and feeding cholesterol after learning can degrade long-term memory. We explore the development of this model, the issues surrounding the role of copper, and the particular contributions of the late D. Larry Sparks.

Novel macro metallomesogens derived from simple dihydroxy benzenes

A series of tetradentate Schiff base metallomesogenic diols and their model compounds were synthesized from two simple dihydroxy benzenes. The metallomesogenic diol was constructed from three ring containing mesogen linked through ester and azomethine with terminal hydroxy group. This upon complexation with copper(II) formed metallomesogenic diol with varing terminal chain length. The related model metallomesogenic compounds were also synthesized with varying chain length with terminal methyl group and compared the properties with metallomesogenic diols. Extensive characterization of all metallomesogenic compounds and intermediates were carried out by FT-IR, 1H &13C NMR, EPR, VSM, Mass (EI and FAB) and UV–Vis spectroscopy. Hot stage polarizing microscope, Differential scanning calorimetry was used to ensure the phase characteristics such as nature of phase, melting and clearing temperatures and phase range. The appearance of enantiotropic smectic A phases indicated high molecular polarizability of the core due to the metal ion. The role of copper(II) ion on mesogens were discussed.