Cycling Of Cu Research Articles

Cu(II)-coumestrol interaction leads to ROS-mediated DNA damage and cell death: a putative mechanism for anticancer activity

Phytoestrogens have attracted considerable interest as natural alternatives to hormone replacement therapy and their potential as cancer therapeutic agents. Among phytoestrogens, coumestrol has shown multipharmacological properties such as antiinflammatory, neuroprotective, osteoblastic differentiation and anticancer. Though several studies have described anticancer effects of coumestrol, a clear underlying molecular mechanism has not been elucidated. Unlike normal cells, cancer cells contain elevated copper levels that play an integral role in angiogenesis. Copper is an important metal ion associated with the chromatin DNA, particularly with guanine. Thus, targeting copper in cancer cells can serve as effective anticancer strategy. Using human peripheral lymphocytes, we assessed lipid peroxidation, protein carbonylation, reactive oxygen species (ROS) generation, DNA damage and apoptosis by coumestrol in the presence of exogenously added Cu(II) in cells to simulate malignancy-like condition. Results showed that Cu(II)-coumestrol interaction leads to lipid peroxidation and protein carbonylation (markers of oxidative stress), DNA fragmentation and apoptosis in treated lymphocytes. Further, incubation of lymphocytes with ROS scavengers and membrane-permeant copper chelator, neocuproine, resulted in inhibition of DNA damage and apoptosis. This suggests that coumestrol engages in redox cycling of Cu(II) to generate ROS that leads to DNA fragmentation and apoptosis. In conclusion, this is the first report showing that coumestrol targets cellular copper to induce prooxidant death in malignant cells. We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of coumestrol. These findings will provide significant insights into the development of new chemical molecules with better copper-chelating and prooxidant properties against cancer cells.

Copper and zinc isotope fractionation during deposition and weathering of highly metalliferous black shales in central China

Black shales represent one of the main reservoirs of metals released to hydrosphere via chemical weathering and play an important role in geochemical cycling of metals in the ocean. The stable isotope systematics of transitional metals (e.g., Cu and Zn) may be used as a proxy for evaluating their geochemical cycling. To investigate the behaviors of Cu and Zn isotopes during metal enrichment of black shales and the migration during weathering, in this study we reported Cu and Zn concentration and isotope data for unweathered and weathered metalliferous shales and siliceous interbeds from the Maokou Formation in central China. The unweathered shales and cherts have moderately enriched Cu and Zn concentrations with silicate-like δ65Cu (+0.14±0.09‰, 1σ) but heavy δ66Zn (0.51±0.11‰, 1σ). The elevated δ66Zn values reflect an important contribution from seawater via sulfide precipitation and/or organic matter (OM) adsorption. The Zn isotopic compositions of these metalliferous shales are different from those of the ‘normal’ shales, highlighting the potential of Zn isotopes as a tracer for metal enrichment in natural systems.The weathered shales and cherts have an extreme δ65Cu range from −6.42‰ to +19.73‰ and a modest δ66Zn range of +0.25‰ to +0.78‰. The strongly weathered samples have lower Cu and Zn concentrations and lighter isotopic compositions compared to the weakly weathered samples. The leaching of Cu- and Zn-rich sulfides in shallow depths and their downward transport and refixation by Fe-sulfide account for the Cu and Zn isotope fractionation, with the huge Cu isotope variation generated by multistage redox leaching. In general, δ66Zn values of the weathered shales shift towards light values compared to the unweathered protoliths, suggesting that shale weathering releases Zn which is isotopically heavier than igneous rocks and the global riverine average (+0.33‰). Our results therefore indicate that Cu isotopes can be extremely fractionated during weathering of Cu-rich shales and both heavy Cu and Zn isotopes are preferentially released into fluids during shale weathering. These results should be considered when evaluating geochemical cycling of Cu and Zn in the modern or past oceans.

Cysteine Enhances Bioavailability of Copper to Marine Phytoplankton.

Emiliania huxleyi, a ubiquitous marine algae, was cultured under replete and Cu-limiting conditions to investigate Cu uptake strategies involving thiols and associated redox reactions; comparisons to a model diatom, Thalassiosira pseudonana, were also drawn. Cu-limitation increased rates of cell surface reduction of Cu(II) to Cu(I) in E. huxleyi but not in T. pseudonana. Furthermore, Cu-limited E. huxleyi cells took up more Cu when cysteine was present compared to when no ligand was added, although a dependence on cysteine concentration was not observed. In contrast, Cu uptake by replete cells was dependent upon the relative abundance of inorganic species [Cu(I)']. We also show that cysteine can increase the bioavailability of Cu to Cu-limited cells, of both species, through the reductive release of Cu(I) from fairly strong Cu(II) ligands such as EDTA. Finally, support for a mechanism involving uptake of a Cys-Cu complex in E. huxleyi is drawn from the observation that Cu-limitation significantly enhances cysteine uptake by transporters that exhibit Michaelis-Menten kinetics. These Cu uptake strategies help explain the presence and distribution of dissolved thiols in surface seawater and have implications for the biogeochemical cycling of Cu in low Cu environments.

Isotopic constraints on biogeochemical cycling of copper in the ocean.

Trace elements and their isotopes are being actively studied as powerful tracers in the modern ocean and as proxies for the palaeocean. Although distributions and fractionations have been reported for stable isotopes of dissolved Fe, Cu, Zn and Cd in the ocean, the data remain limited and only preliminary explanations have been given. Copper is of great interest because it is either essential or toxic to organisms and because its distribution reflects both biological recycling and scavenging. Here we present new isotopic composition data for dissolved Cu (δ(65)Cu) in seawater and rainwater. The Cu isotopic composition in surface seawater can be explained by the mixing of rain, river and deep seawater. In deep seawater, δ(65)Cu becomes heavier with oceanic circulation because of preferential scavenging of the lighter isotope ((63)Cu). In addition, we constrain the marine biogeochemical cycling of Cu using a new box model based on Cu concentrations and δ(65)Cu.

Redox cycling of Cu(II) by 6-mercaptopurine leads to ROS generation and DNA breakage: possible mechanism of anticancer activity.

6-Mercaptopurine (6MP) is a well-known purine antimetabolite used to treat childhood acute lymphoblastic leukemia and other diseases. Cancer cells as compared to normal cells are under increased oxidative stress and show high copper level. These differences between cancer cells and normal cells can be targeted to develop effective cancer therapy. Pro-oxidant property of 6MP in the presence of metal ions is not well documented. Redox cycling of Cu(II) to Cu(I) was found to be efficiently mediated by 6MP. We have performed a series of in vitro experiments to demonstrate the pro-oxidant property of 6MP in the presence of Cu(II). Studies on human lymphocytes confirmed the DNA damaging ability of 6MP in the presence of Cu(II). Since 6MP possesses DNA damaging ability by producing reactive oxygen species (ROS) in the presence of Cu(II), it may also possess apoptosis-inducing activity by involving endogenous copper ions. Essentially, this would be an alternative and copper-dependent pathway for anticancer activity of 6MP.

Anthropogenic sources and biogeochemical reactivity of particulate and dissolved Cu isotopes in the turbidity gradient of the Garonne River (France)

High precision MC-ICP-MS Cu isotope measurements were performed on suspended particulate matter (SPM) and filtered water sampled along the turbidity gradient of the fluvial Gironde Estuary (Garonne Branch), following a summer lasting period of low freshwater discharge. High Cu concentrations (up to ~200μg/g) in particulate organic carbon (POC)-rich (up to ~14%) particles upstream from the Maximum Turbidity Zone (MTZ) coincide with the most negative δ65Cu values (down to −0.39‰). This suggests the preferential uptake of light Cu isotopes by phytoplankton or anthropogenic contamination from CuSO4 fungicides related to intensive wine farming in the area (δ65Cu=−0.37‰ for vineyard soils). Suspended particulate matter samples in the MTZ exhibit lower Cu concentrations (~35μg/g) and heavier isotopic compositions (δ65Cu=−0.20‰ in average), as recorded by other samples from the Gironde Watershed. Along the fluvial estuary, dissolved Cu is mostly enriched in heavy isotopes (up to δ65Cu=+0.21‰), but negative signatures down to δ65Cu=−0.66‰ occur near the city of Bordeaux. Release of dissolved Cu was attributed to the mineralization of organic matter with a total addition of ~600ng/L in the fluvial estuary. Continuously decreasing amounts of dissolved Cu added with distance suggest that the observed Cu release evolved towards completion in the MTZ and contributed to negative values for dissolved Cu isotopes, as modeled by a Rayleigh process. Urban wastewater effluents probably also contribute to both (i) the dissolved Cu addition (10–20%) in the MTZ and (ii) negative Cu isotope signatures. Further work is necessary to assess the respective roles of anthropogenic sources and biogeochemical fractionation processes. Accordingly, the present study provides new insights into the potential of Cu isotopes for fingerprinting sources and mechanisms involved in the biogeochemical cycle of Cu in temperate aquatic environments impacted by anthropogenic activities.

Copper ionic liquids: Tunable ligand and anion chemistries to control electrochemistry and deposition morphology

A multi-technique investigation was performed on three copper-based ionic liquids to elucidate the influence of coordinating ligands and charge-balancing anions on the electrochemical properties of the materials. Galvanostatic cycling of Cu(OHCH2CH2NH2)6(BF4)2 (Cu1) in 1-butyl-3-methyl-imidazolium hexafluorophosphate gave partially reversible plating of copper that was consistent with cyclic voltammetry data (collected using an ionic liquid-based reference electrode verified with measurements of ferrocene, cobaltocene, and lithium). Scanning electron microscopy also showed pitting in the copper-coated surface of the electrode that was consistent with the stripping wave observed by cyclic voltammetry. Potentiostatic deposition in neat Cu1 showed significant dendrite formation. The substitution of the OHCH2CH2NH2 ligands of Cu1 with stronger coordinating NH(CH2CH2OH)2 in Cu(NH(CH2CH2OH)2)6(BF4)2 (Cu2) resulted in the complete suppression of both copper stripping and dendrite formation. Substitution of the BF4- anions of Cu2 with CF3SO3- in Cu(NH(CH2CH2OH)2)6(CF3SO3)2 (Cu3) shifted the copper deposition 0.1V more negative and produced slightly larger spherical particles (1.5μm versus 5μm). The results suggested that while the anion composition influenced particle size, and the metal–ligand bond strength helped control particle morphology, both factors affected the electrochemical properties including the plating and stripping of copper.

Determination of isotopic composition of dissolved copper in seawater by multi-collector inductively coupled plasma mass spectrometry after pre-concentration using an ethylenediaminetriacetic acid chelating resin

Copper is an essential trace metal that shows a vertical recycled-scavenged profile in the ocean. To help elucidate the biogeochemical cycling of Cu in the present and past oceans, it is important to determine the distribution of Cu isotopes in seawater. However, precise isotopic analysis of Cu has been impaired by the low concentrations of Cu as well as co-existing elements that interfere with measurements by multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). The objective of this study is to develop a simple Cu pre-concentration method using Nobias-chelate PA1 resin (Hitachi High Technologies). This extraction followed by anion exchange, allows precise analysis of the Cu isotopic composition in seawater. Using this method, Cu was quantitatively concentrated from seawater and >99.9999% of the alkali and alkaline earth metals were removed. The technique has a low procedural blank of 0.70ng for Cu for a 2L sample and the precision of the Cu isotopic analysis was ±0.07‰ (±2SD, n=6). We applied this method to seawater reference materials (i.e., CASS-5 and NASS-6) and seawater samples obtained from the northwestern Pacific Ocean. The range of dissolved δ65Cu was 0.40–0.68‰.

On role of atomic migration in amnesia occurrence during complex thermal cycling of Cu–Zn–Al shape memory alloy

The reproducibility of thermally induced reversible martensitic transformation, occurring in a Cu–15Zn–6Al (mass-%) shape memory alloy during heating, was studied on three different fragments of martensitic alloy subjected to complex thermal cycling comprising four series of five heating–cooling cycles, applied on a differential scanning calorimetry (DSC) device, between room temperature (RT) and three maximum temperatures: 453, 463 and 473 K respectively. After each series of heating–cooling cycles the fragments were naturally aged at RT for 37 days (∼3·2 Ms). Thermograms of DSC revealed a gradual diminution in the magnitude of martensite reversion to parent phase, accompanied by decreasing tendencies of both critical temperatures and transformation rates, which reflect a gradual loss of thermal memory, associated with ‘amnesia’ occurrence. Scanning electron microscopy observations coupled with energy dispersive X-ray spectroscopy performed at the end of complex thermal cycling revealed that ‘amnesia’ occurrence was associated with changes in the morphology of martensite plates, from parallel plate-like to interblocking needle-like, and with an increase of chemical fluctuations, as an effect of the intensification of atomic migration.

Electrodeposition of CuInSe2(CIS) via Electrochemical Atomic Layer Deposition (E-ALD)

The growth of stoichiometric CuInSe(2) (CIS) on Au substrates using electrochemical atomic layer deposition (E-ALD) is reported here. Parameters for a ternary E-ALD cycle were investigated and included potentials, step sequence, solution compositions and timing. CIS was also grown by combining cycles for two binary compounds, InSe and Cu(2)Se, using a superlattice sequence. The formation, composition, and crystal structure of each are discussed. Stoichiometric CIS samples were formed using the superlattice sequence by performing 25 periods, each consisting of 3 cycles of InSe and 1 cycle of Cu(2)Se. The deposits were grown using 0.14, -0.7, and -0.65 V for Cu, In, and Se precursor solutions, respectively. XRD patterns displayed peaks consistent with the chalcopyrite phase of CIS, for the as-deposited samples, with the (112) reflection as the most prominent. AFM images of deposits suggested conformal deposition, when compared with corresponding image of the Au on glass substrate.

Low absorption vitreous carbon reactors for operandoXAS: a case study on Cu/Zeolites for selective catalytic reduction of NOxby NH3

We describe the use of vitreous carbon as an improved reactor material for an operando X-ray absorption spectroscopy (XAS) plug-flow reactor. These tubes significantly broaden the operating range for operando experiments. Using selective catalytic reduction (SCR) of NO(x) by NH(3) on Cu/Zeolites (SSZ-13, SAPO-34 and ZSM-5) as an example reaction, we illustrate the high-quality XAS data achievable with these reactors. The operando experiments showed that in Standard SCR conditions of 300 ppm NO, 300 ppm NH(3), 5% O(2), 5% H(2)O, 5% CO(2) and balance He at 200 °C, the Cu was a mixture of Cu(I) and Cu(II) oxidation states. XANES and EXAFS fitting found the percent of Cu(I) to be 15%, 45% and 65% for SSZ-13, SAPO-34 and ZSM-5, respectively. For Standard SCR, the catalytic rates per mole of Cu for Cu/SSZ-13 and Cu/SAPO-34 were about one third of the rate per mole of Cu on Cu/ZSM-5. Based on the apparent lack of correlation of rate with the presence of Cu(I), we propose that the reaction occurs via a redox cycle of Cu(I) and Cu(II). Cu(I) was not found in in situ SCR experiments on Cu/Zeolites under the same conditions, demonstrating a possible pitfall of in situ measurements. A Cu/SiO(2) catalyst, reduced in H(2) at 300 °C, was also used to demonstrate the reactor's operando capabilities using a bending magnet beamline. Analysis of the EXAFS data showed the Cu/SiO(2) catalyst to be in a partially reduced Cu metal-Cu(I) state. In addition to improvements in data quality, the reactors are superior in temperature, stability, strength and ease of use compared to previously proposed borosilicate glass, polyimide tubing, beryllium and capillary reactors. The solid carbon tubes are non-porous, machinable, can be operated at high pressure (tested at 25 bar), are inert, have high material purity and high X-ray transmittance.

Abstract 2093: Elesclomol-Cu chelate selectively targets mitochondria to induce oxidative stress

Abstract Introduction: Elesclomol is a first-in-class investigational drug that exerts anticancer activity through the elevation of reactive oxygen species (ROS) and oxidative damage. We recently reported that elesclomol selectively chelates Cu(II) in plasma, which causes a change in conformation that enables its uptake into cells. A cell-free assay system showed that elesclomol-Cu(II) was capable of efficient generation of ROS via the reduction of Cu(II) to Cu(I). A correlation has been observed between redox potential and anticancer activity for Cu chelates of elesclomol and its analogs, suggesting that the ability to promote redox cycling of Cu(II) to Cu(I) is necessary for the anticancer activity. Here, we demonstrate that elesclomol-Cu carries copper to mitochondria, leading to an increase in oxidative stress and apoptosis due to mitochondrial stress. Results: First we attempted to track subcellular distribution of elesclomol-Cu. Cytosol, nuclear and mitochondrial fractions of HL60 cells were prepared from cells treated with elesclomol-Cu, and total copper levels were determined for each cellular fraction. Increased copper was only observed in the mitochondrial fraction, suggesting that elesclomol-Cu selectively carried copper to the mitochondria. To verify that the copper increased in mitochondria was from elesclomol-Cu, a copper complex of elesclomol was preformed with 65Cu, and this elesclomol-65Cu complex was incubated for 2h with HL60 cells that were previously enriched with 63Cu using 63Cu-supplemented media and subcellular distributions of 63Cu and 65Cu were determined by ICP-MS. Neither 63Cu nor 65Cu was detected in any fractions in DMSO-treated control cells. 65Cu was selectively detected in mitochondrial fraction of elesclomol-65Cu treated cells but not in cytosol and nuclear fractions, demonstrating a selective mitochondrial uptake of copper with elesclomol-Cu. Next we compared the mitochondrial uptake of elesclomol-Cu and disulfiram(DSF)-Cu using isolated mitochondria. DSF is a Cu chelator, and Cu has been shown to enhance DSF-mediated growth inhibition and apoptosis in cancer cells through the generation of ROS. As expected, an increase in the copper level was observed in mitochondria treated with elesclomol-Cu, while there was no increase in copper in the mitochondria treated with DSF-Cu at its cytotoxic concentration, emphasizing the novel mitochondria selectivity of elesclomol-Cu. Lastly, to identify whether the mitochondrial entry of elesclomol-Cu triggers the generation of ROS, ROS in isolated mitochondria was measured. Mitochondrial ROS was immediately increased by adding elesclomol-Cu while no change in mitochondrial ROS was seen using DSF-Cu or free Cu2+. These results indicate that elesclomol-Cu selectively permeates mitochondria and induces mitochondrial ROS, which likely leads to apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2093. doi:10.1158/1538-7445.AM2011-2093

Copper isotope fractionation by desert shrubs

Copper has two naturally occurring stable isotopes of masses 63 and 65 which can undergo mass dependent fractionation during various biotic and abiotic chemical reactions. These interactions and their resulting Cu isotope fractionations can be used to determine the mechanisms involved in the cycling of Cu in natural systems. In this study, Cu isotope changes were investigated at the organismal level in the metal-accumulating desert plant, Prosopis pubescens. Initial results suggest that the lighter Cu isotope was preferentially incorporated into the leaves of the plant, which may suggest that Cu was actively transported via intracellular proteins. The roots and stems show a smaller degree of Cu isotope fractionation and the direction and magnitude of the fractionations was dependent upon the levels of Cu exposure. Based on this and previous work with bacteria and yeast, a trend is emerging that suggests the lighter Cu isotope is preferentially incorporated into biological components, while the heavier Cu isotope tends to become enriched in aqueous solutions. In bacteria, plants and animals, intracellular Cu concentrations are strictly regulated via dozens of enzymes that can bind, transport, and store Cu. Many of these enzymes reduce Cu(II) to Cu(I). These initial results seem to fit into a broader picture of Cu isotope cycling in natural systems where oxidation/reduction reactions are fundamental in controlling the distributions of Cu isotopes.

Pleistocene recycling of copper at a porphyry system, Atacama Desert, Chile: Cu isotope evidence

We present Cu isotope data of hypogene and supergene minerals from the Late Paleocene Spence Cu-Mo porphyry in the Atacama Desert of northern Chile. Chalcopyrite displays a restricted range of δ65Cu values within the values reported for primary porphyry Cu sulfides (+ 0.28‰ to + 0.34‰, n = 6). Supergene chalcocite samples show heavier and remarkably homogeneous δ65Cu values, between + 3.91‰ and + 3.95‰ (n = 6), consistent with previous models of Cu leaching and enrichment in porphyry systems. Secondary Cu minerals from the oxide zone show a wider range of composition, varying from + 1.28‰ and + 1.37‰ for chrysocolla (n = 6) to very light Cu isotope signatures reported for atacamite between -5.72‰ to -6.77‰ (n = 17). These data suggest redox cycling of Cu during supergene enrichment of the Spence Cu deposit, characterized by a first stage of supergene chalcocite formation from acidic, isotopically-heavy leach fluids of meteoric origin down-flowing in a semi-arid climate (44 to ~ 15-9 Ma). Reworking of the initial supergene copper assemblage, during the Pleistocene, by rising neutral and chlorine-rich deep formation waters under well-established hyper-arid climate conditions lead to the formation of atacamite with extremely fractionated Cu compositions. Essentially coeval chrysocolla formed by dissolution of atacamite during short episodes of wetter climatic conditions occurring in the latest Pleistocene.

E-ALD of Cu Nanofilms on Ru/Ta Wafers Using Surface Limited Redox Replacement

This paper describes the formation of Cu nanofilms on a Ru/Ta-coated wafer using electrochemical atomic layer deposition (E-ALD). The initial steps involved cleaning and oxide removal from the Ru/Ta substrate using ultrahigh vacuum electrochemical system. Auger spectroscopy was used to follow the relative amounts of oxygen, Ru, and Cu on the wafer: as-received, after electrochemical treatment, after ion bombardment, and after Cu deposition. An automated flow cell electrodeposition system was employed to grow Cu nanofilms with up to 200 cycles using surface limited redox replacement (SLRR) reaction. The open-circuit potential was used to follow the exchange of Pb for Cu in the SLRR reaction. Electron probe microanalysis was used to determine the homogeneity of the Cu films. The use of a complexing agent (citrate) greatly improved the homogeneity. Different concentrations of citrate were investigated, containing 2 or 4 mM citrate. Atomic force microscopy images of the Cu films showed the ingress morphology to be the same as the egress when 4 mM citrate was used. A prominent Cu(111) peak was displayed in the X-ray diffraction pattern for 200 cycles of Cu grown on the Ru/Ta-coated wafer.

Abstract C11: The oxidative stress inducer elesclomol requires copper chelation for its anticancer activity

Abstract Introduction: Elesclomol [N-malonyl-bis (N′-methyl-N′-thiobenzoyl hydrazide)] is a first-in-class investigational drug, believed to exert anticancer activity through the elevation of reactive oxygen species (ROS) levels leading to the activation of the mitochondrial apoptosis pathway. The mechanism of ROS induction by elesclomol was previously unknown. Data presented here shows that ROS is generated via chelation and redox cycling of copper. Methods: Formation of a Cu chelate of elesclomol was analyzed by LCMS and single crystal X-ray diffraction. ROS was measured using DCF-DA and cytotoxicity assessed using a WST-8 assay primarily in Ramos human B cell lymphoma and M14 human melanoma cell lines. Cellular levels of free elesclomol and elesclomol-Cu were determined by LCMS. Redox potential was analyzed by cyclic voltammetry. Results: Elesclomol readily formed a Cu chelate and strongly preferred Cu over zinc, iron or manganese in competition assays. Cu bound elesclomol in a 1:1 molar ratio and the chelate formed a flat rigid structure. The donation of four lone-pair electrons from elesclomol to Cu(II) yields higher hydrophobicity, which may facilitate greater cell permeability relative to free elesclomol. We evaluated the effect of Cu on both cellular uptake and cytotoxic activity of elesclomol on cultured cancer cells. Elesclomol lost cytotoxicity when applied to cells under Cu-starved conditions. The presence of Cu was required for elesclomol entry into cells. The cell membrane impermeable Cu chelator BCP blocked both uptake of elesclomol and cytotoxicity, indicating that elesclomol obtains Cu outside the cell and requires it for cellular entry and cytotoxicity. Elesclomol was able to obtain Cu from serum as well as from purified ceruloplasmin, the primary Cu-binding protein in blood. Elesclomol had poor activity against densely-plated cancer cells in culture, but became highly potent when extra Cu was added to the medium, indicating that Cu may be limiting under dense culture conditions. We next evaluated the impact of Cu on ROS generation. A cellfree assay system showed that elesclomol-Cu(II) was capable of efficient generation of ROS via the reduction of Cu(II) to Cu(I). A correlation was observed between redox potential and ROS production for Cu chelates of elesclomol and its analogs. Elesclomol also chelated nickel. However, while elesclomol-Ni was highly cell permeable, it was inactive for ROS production and cancer cell cytotoxicity. The lack of activity of elesclomol-Ni can be explained by its low redox potential. The redox potential of elesclomol-Cu(II) was −333mV, while that of elesclomol-Ni was −1100mV. Conclusion: Elesclomol chelates Cu outside of cells and enters cells as elesclomol-Cu(II). At present, our data support the hypothesis that elesclomol generates ROS by redox cycling of Cu(II) to Cu(I), and that this process is necessary for its anticancer activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C11.

Anthropogenic versus natural control on trace element and Sr–Nd–Pb isotope stratigraphy in peat sediments of southeast Florida (USA), ∼1500 AD to present

Analysis of a well-dated peat core from Blue Cypress Marsh (BCM) provides a detailed record of natural and anthropogenic factors that controlled the geochemical cycles of a number of trace elements in Florida over the last five centuries. The trace elements were divided into “natural” and “anthropogenic” groups using concentration trends from the bottom to the top of the core. The “natural” group includes Li, Sc, Cr, Co, Ga, Ge, Zr, Nb, Cs, Ba, Hf, Y, Ta, Th, and REE (Rare Earth Elements). These elements show similar concentrations throughout the core, indicating that changes in human activities after European arrival in the “New World” did not affect their geochemical cycles. The “anthropogenic” group includes Pb, Cu, Zn, V, Sb, Sn, Bi, and Cd. Upcore enrichment of these elements indicates enhancement by anthropogenic activities. From the early 1500s to present, fluxes of the “anthropogenic” metals to the marsh increased significantly, with modern accumulation rates several-fold (e.g., V) to hundreds of times (e.g., Zn) greater than pre-colonial rates. The dominant input mechanism for trace elements from both groups to the marsh has been atmospheric deposition. Atmospheric input of a number of the elements, including the anthropogenic metals, was dominated by local sources during the last century. For several elements, long-distant transport may be important. For instance, REE and Nd isotopes provide evidence for long-range atmospheric transport dominated by Saharan dust. The greatest increase in flux of the “anthropogenic” metals occurred during the 20th century and was caused by changes in the chemical composition of atmospheric deposition entering the marsh. Increased atmospheric inputs were a consequence of several anthropogenic activities, including fossil fuel combustion (coal and oil), agricultural activities, and quarrying and mining operations. Pb and V exhibit similar trends, with peak accumulation rates in 1970. The principal anthropogenic source of V is oil combustion. The decline in V accumulation after 1970 in the BCM peat corresponds to the introduction of low-sulfur fuels and the change from heavy to distilled oils since the 1970s. After the 1920s, Pb distribution in the peat follows closely the history of alkyl lead consumption in the US, which peaked in the 1970s. Pb isotopes support this inference and furthermore, record changes in the ore sources used to produce leaded gasoline. Idaho ores dominated the peat Pb isotope record until the 1960s, followed by Pb from Mississippi Valley Type deposits from the 1960s to the 1980s. Enhanced fluxes of Cu, Zn, Cd, Sn, Sb, Bi, and to some extent Ni during the last century are likely also related to fossil fuel combustion. Local agricultural activities may also have influenced the geochemical cycles of Cu and Zn. The peat record shows enhanced U accumulation during the last century, possibly related to phosphate mining in western Florida. Sr isotopes in the peat core also reflect anthropogenic influence. The 87Sr/ 86Sr ratio decreases from natural background values in the basal part of the core to lower values in the upper part of the core. The Sr isotope shift is probably related to quarrying operations in Florida, and marks the first time an anthropogenic signal has been detected using the Sr isotope record in a peat core.

Theoretical studies on the reaction mechanism of oxidation of primary alcohols by Zn/Cu(ii)-phenoxyl radical catalyst

The catalytic mechanism for the oxidation of primary alcohols catalyzed by the two functional models of galactose oxidase (GOase), M(II) L (M = Cu, Zn; L = N,N'-bis(3,5-di-tert-butyl-2-hydroxyphenyl)-1-2-diiminoquinone)), has been studied by use of the density functional method B3LYP. The catalytic cycle of Cu- and Zn-catalysts consists of two parts, namely, substrate oxidation (primary alcohol oxidation) and O(2) reduction (catalyst regeneration). The catalytic mechanisms have been studied for the two reaction pathways (route 1 and route 2). The calculations indicate that the hydrogen atom transfer within the substrate oxidation part is the rate-determining step for both catalysts, in agreement with the experimental observation. The calculated overall reaction barrier for Cu-catalyst is 16.74 kcal mol(-1), smaller than 22.96 kcal mol(-1) for the Zn-catalyst. This is consistent with the experimental result that the Zn-catalyst is less efficient when compared with the Cu-catalyst. The importance of the solvent effect is demonstrated. Insights into the hydrogen atom transfer process are discussed.

Phase quantification during pseudoelastic cycling of Cu–13.1Al–4.0Ni (wt.%) single-crystal shape memory alloys using neutron diffraction

This paper reports on the pseudoelastic, isothermal mechanical cycling of copper–aluminium–nickel single-crystals. It was found that stress-free transformation temperatures at the end of 1000 stress cycles did not change, whereas the transformation stresses decreased by about 10%; otherwise, the overall strain of 7% imposed during a loading cycle was completely recovered at the end of 1000 cycles. Non-contact multi-video extensometry uncovered a significant spatial non-uniformity in the maximum strains attained in different sections of the wire. At the end of the 1000th cycle, the top and bottom sections demonstrated very similar maximum strains while the midsection demonstrated lower strain. Phase quantification of the midsection of the wire using neutron diffraction demonstrated an increase in the stabilization of austenite from 0% in the first cycle to about 60% in the 1000th cycle. The specific nature of the tests required by neutron diffraction also uncovered a creep-like response of the SMA. Preliminary investigation suggests that this “pseudo-creep” is due to the motion of phase fronts during the phase transformation. Neutron diffraction has also confirmed that while the single crystallinity of the SMA is excellent at 175 °C, there is a spread in orientation of the cubic phase at 200 °C with respect to the axis of the wire that is estimated at 2.17°. This spread disappears/reappears on mechanical loading/unloading, but decreases permanently on cyclic loading.

Fine Root Decomposition and Cycling of Cu, Ni, Pb, and Zn at Forest Sites Near Smelters in Sudbury, ON, and Rouyn-Noranda, QU, Canada

ABSTRACT This study determined rates of in situ fine root decomposition and changes in trace metals concentration during decomposition at sites in Sudbury, ON, and Rouyn-Noranda, QU, with elevated or background concentrations of Cu, Ni, Pb, and/or Zn in the soil, and correlated the depth gradients of Cu, Ni, Pb, and Zn for soils and roots at the same sites. Fine roots were extracted from soil cores within root traps several times over 12 months; biomass and metal concentrations were measured. Live roots were collected from 30-cm soil cores, separated into three depths. Elevated soil metal concentrations did not necessarily reduce fine root decomposition, and effects on decomposition were similar to those previously reported for surface foliar litter at the same sites. Decomposing roots at only the high metal sites demonstrated increased metal concentrations with time. Root tissue concentrations of Cu, Ni, and Zn, but not Pb, at lower soil depths were generally higher than expected from soil metal concentrations. This could be explained by reallocation of essential metals, although these metals were likely also more available for uptake at depth due to lower DOC concentrations. This study means that for risk assessment, separate determinations of altered decomposition for roots and leaf litter are likely not necessary for predicting ecosystem effects, a pragmatically useful conclusion given the labor intensity of the fine root studies. This study also suggests that for risk assessment of plant community exposure to metals, prediction of exposure to metals should probably consider soil layers that do not have substantially elevated metal concentrations, as their soil characteristics, or plant processes, may result in unexpected exposure.