Elevated Copper Levels Research Articles

Responsively Aggregatable Sub-6 nm Nanochelators Induce Simultaneous Antiangiogenesis and Vascular Obstruction for Enhanced Tumor Vasculature Targeted Therapy.

Inhibiting the formation of new tumor blood vessels (so-called antiangiogenesis) and obstructing the established ones are two primary strategies in tumor vasculature targeted therapy. However, the therapeutic outcome of conventional methodologies relying on only one mechanism is rather limited. Herein, the first example of ultrasmall responsively aggregatable nanochelators that can intrinsically fulfill both antivasculature functions as well as high renal clearable efficiency is introduced. The nanochelators with sub-6 nm sizes exhibit not only systemic copper depletion activity for tumor antiangiogenesis but also, more surprisingly, the capability to transform from a "dispersed" state to an "aggregated" state to form large secondary particles in responsetotumor microenvironment with elevated copper and phosphate levels for blood vessel obstruction. Compared to a benchmark antiangiogenic agent that can only inhibit the formation of tumor blood vessels, the nanochelators with unprecedented synergistic functions demonstrate significantly enhanced tumor inhibition activity in both breast cancer and colon cancer tumor models. Moreover, these ultrasmall nanochelators are noncytotoxic and renal clearable, ensuring superior biocompatibility. It is envisaged that the design of nanomaterials with ground-breaking properties and the synergistic antivasculature functions would offer a substantial conceptual advance for tumor vasculature targeted therapy and may provide vast opportunities for developing advanced nanomedicines.

Ammonia Oxidizers as Biological Health Indicators of Elevated Zn and Cu in Poultry Litter Amended Soil

Ammonia-oxidixing bacteria (AOB) and archaea (AOA) mediate the first and rate-limiting step of nitrification and are responsive to agricultural management practices. These two attributes make them ideal indicators of biological soil health. We conducted a laboratory incubation study to determine their response to elevated levels of zinc (Zn) and copper (Cu) in poultry litter treated soil at three substrate concentrations: 0 (low), 50 (medium) and 100 (high) mg ammonium ($$ {\mathrm{NH}}_4^{+} $$-N) kg−1 soil. Nitrification potential (NP) was measured to characterize changes in their function in which 1-octyne was used to separate their contributions. Quantitative polymerase chain reaction was used to measure their abundance by targeting amoA. Increasing Zn from 21 to 250 mg kg−1 resulted in large reductions in AOB (78%) and AOA (85%) abundance at the high $$ {\mathrm{NH}}_4^{+} $$ level over 28 days. Likewise, increasing Cu from 20 to 120 mg kg−1 significantly reduced AOB (92%) and AOA (63%) abundance at the high $$ {\mathrm{NH}}_4^{+} $$ level over 28 days. The relative contribution of AOB to NP was significantly higher than that of AOA in both Zn (~60%) and Cu (~70%) treated soils despite the numerical dominance of AOA over AOB. Overall, results indicate that elevated levels of Zn and Cu depressed AOB and AOA abundance and function and that their effect was dependent on availability of $$ {\mathrm{NH}}_4^{+} $$. The results also indicated that AOB are functionally more important than AOA under elevated Zn and Cu concentrations and that management practices to improve N use efficiency should focus on AOB under this condition.

Microbial community response to environmental changes in a technosol historically contaminated by the burning of chemical ammunitions

The burning of chemical weapons in the 1926–1928 period produced polluted technosols with elevated levels of arsenic, zinc, lead and copper. During an eight-month mesocosm experiment, these soils were submitted to two controlled environmental changes, namely the alternation of dry and water-saturated conditions and the addition of fragmented organic forest litter to the surface soil. We investigated, by sequencing the gene coding 16S rRNA and 18S rRNA, (1) the structure of the prokaryotic and eukaryotic community in this polluted technosol and (2) their response to the simulated environmental changes, in the four distinct layers of the mesocosm. In spite of the high concentrations of toxic elements, microbial diversity was found to be similar to that of non-polluted soils. The bacterial community was dominated by Proteobacteria, Acidobacteria and Bacteroidetes, while the fungal community was dominated by Ascomicota. Amongst the most abundant bacterial Operational Taxonomic Units (OTUs), including Sphingomonas as a major genus, some were common to soil environments in general whereas a few, such as organisms related to Leptospirillum and Acidiferrobacter, seemed to be more specific to the geochemical context. Evolution of the microbial abundance and community structures shed light on modifications induced by water saturation and the addition of forest litter to the soil surface. Co-inertia analysis suggests a relationship between the physico-chemical parameters total organic carbon, Zn, NH4+ and As(III) concentrations and the bacterial community structure. Both these results imply that microbial community dynamics linked to environmental changes should be considered as factors influencing the behavior of toxic elements on former ammunition burning sites.

Predicting copper toxicosis: relationship between the ATP7A and ATP7B gene mutations and hepatic copper quantification in dogs.

This preliminary study summarizes the genotypes of 42 Labrador Retrievers and Labrador Retriever-Golden Retriever crosses and phenotypes a subset of ten of these dogs that are homozygous mutant, heterozygous, or homozygous normal for mutations in the ATP7A and ATP7B genes that have been associated with the development of copper toxicosis in Labrador Retrievers. The purpose of this study is to evaluate whether there is a correlation between ATP7A and ATP7B genotypes and clinical evidence of hepatic pathology in young, asymptomatic Labrador Retrievers. We evaluated serum ALT levels, hepatic copper concentrations, and hepatic histopathology from ten offspring where both parents had a least one copy of the ATP7B mutation. Five were homozygous mutant, four were heterozygous, and one was homozygous normal for comparison. None had increased serum ALT activity. All dogs homozygous for the ATP7B mutation had elevated hepatic copper concentrations compared to dogs heterozygous for the ATP7B mutation regardless of sex or presence of an ATP7A mutation with the mean hepatic copper concentration being 1464ppm (reference range 100-330ppm). Mean hepatic copper concentration in homozygous normal and heterozygous dogs was 328ppm. In this preliminary analysis, we found that dogs that carry two copies of the ATP7B mutation have abnormally elevated hepatic copper levels despite having normal serum ALT activity. Our findings support the hypothesis that the ATP7B DNA test can predict defects in hepatic copper metabolism. Veterinarians can test for the ATP7B gene mutation to identify Labrador Retrievers at risk for copper toxicosis so that they can take steps to prevent development of copper-associated chronic hepatitis in their patients.

Interaction of C20-substituted derivative of pregnenolone acetate with copper (II) leads to ROS generation, DNA cleavage and apoptosis in cervical cancer cells: Therapeutic potential of copper chelation for cancer treatment

Cervical cancer is a leading cause of cancer-related deaths among women in developing countries. Therefore, development of new chemotherapeutic agents is required. Unlike normal cells, cancer cells contain elevated copper levels which play an integral role in angiogenesis. Thus, targeting copper via copper-specific chelators in cancer cells can serve as effective anticancer strategy. In this work, a copper chelator pregnenolone acetate nucleus-based tetrazole derivative (ligand-L) was synthesized and characterized by elemental analysis, ESI-MS, 1H NMR and 13C NMR. DNA binding ability of ligand-L was studied using UV–Vis and fluorescence spectroscopy. Fluorescence spectroscopy studies reveal that quenching constant of ligand-l-DNA and ligand-L-Cu(II) were found to be 7.4 × 103 M−1 and 8.8 × 103 M−1, respectively. In vitro toxicity of ligand-L was studied on human cervical cancer C33A cancer cells. Results showed that ligand-L exhibit significant cytotoxic activity against cervical cancer C33A cells with IC50 value 5.0 ± 1.8 µM. Further, it was found that ligand-L cytotoxicity is due to redox cycling of copper to generate ROS which leads to DNA damage and apoptosis. In conclusion, this is the report where we synthesized pregnenolone acetate-based tetrazole derivative against C33A cells that targets cellular copper to induce pro-oxidant death in cancer cells. These findings will provide significant insights into the development of new chemical molecules with better copper chelating and pro-oxidant properties against cancer cells.

Copper as the Target for Anticancer Nanomedicine

AbstractMicroelements such as copper are essential and involved in various biological processes and under strict homeostatic regulation. Compared to healthy individuals, cancer patients have aberrantly elevated intratumoral and systemic copper levels, which promote tumorigenesis, angiogenesis, tumor metastasis, and recurrence of diverse human cancers. Two copper‐based anticancer strategies—copper depletion therapy and copper‐based cytotoxin—have been developed for the treatment of cancers. In this review, the authors summarize the roles of copper related to cancer progression and provide the recent therapeutic advances using the copper‐based anticancer strategies and copper‐based nanomedicines. The authors also present their perspectives for further developing antitumor copper‐targeting nanomedicines for enhanced therapeutics and mitigated side effects.

Application of multistate modeling to estimate salmonid survival and movement in relation to spatial and temporal variation in metal exposure in a mining-impacted river

Multistate modeling was used to estimate survival and movement of brown trout (Salmo trutta) and westslope cutthroat trout (Oncorhynchus clarkii lewisi) in relation to copper concentrations in the mining-impacted Clark Fork River, Montana. Survival probability in the uppermost river segment, where dissolved copper concentrations frequently exceeded acute criteria for aquatic life (range: 31–60 days > 13.4 μg·L–1), was 2.1 times lower for brown trout and 122 times lower for westslope cutthroat trout compared with survival rates in the lowermost segment that had relatively low dissolved copper (0 days exceedance of acute concentration). Lowest survival for both species occurred in the spring–summer period when dissolved copper concentrations were elevated coincident with higher discharge. Movement among study segments was generally low, and cutthroat trout showed low movement into the uppermost river segment with the most elevated copper levels. Both species showed high rates of movement into tributaries, which coincided with their respective spawning migrations rather than as an apparent avoidance of elevated copper levels. The linkage between survival rate and level of copper exposure for both trout species suggests that additional removal of tailings deposits could improve survival rates.

Copper accumulation in the brain of Down syndrome model mice and its pathophysiological significance

Down syndrome caused by triplication of human chromosome 21 (HSA21) is the most frequent aneuploidy, resulting in mental retardation, intellectual disability and accelerated aging. Individuals with DS are at an increased risk of developing Alzheimer's disease (AD)-like dementia, with up to 75% of DS people in their 60s developing dementia. Oxidative stress is widely accepted as a mechanism underlying a number of DS symptoms, such as accelerated aging and cognitive decline. Superoxide disumutase 1 (Sod1) and amiloyd precursor protein (App) genes are suggested as the candidate genes in HSA21 underlying the enhanced oxidative stress in individuals with DS. However, we previously demonstrated that the Ts1Cje mouse model, which has a normal copy number of both candidate genes, also shows enhanced oxidative stress, suggesting that triplicated genes other than Sod1 and App likely enhance oxidative stress in the brain of DS people. To identify the molecules with enhanced oxidative stress in Ts1Cje mice, we performed several -omics analyses. Recently, we showed that copper was accumulated in the brain of adult Ts1Cje mice in an analysis using inductively coupled plasma mass spectrometry (ICP-MS), and a low-copper diet was able to improve the elevated levels of copper. The low-copper diet also resolved some anomalies, such as the enhanced oxidative stress, accumulation of phosphorylated tau and low anxiety. These findings suggest that the accumulation of copper in the DS brain may be a therapeutic target for ameliorating a number of abnormal phenotypes in individuals with DS.

Assessing Compliance of European Fresh Waters for Copper: Accounting for Bioavailability

This study determines the levels of compliance of European fresh waters with a bioavailability-based copper Environmental Quality Standard (EQS). A tiered approach for compliance assessment is used at which the first tier compares the dissolved metal concentration to a threshold, estimated using either regional or continental water chemistry data. At the second tier, the bioavailable metal concentration is calculated using the chemistry of the water body, and compared to the EQSbioavailable for copper. The thresholds at Tier 1 must be set at a level to ensure adequate protection of sensitive environments and to ensure efficient use of regulatory resources. Compliance of 99.3% is observed where bioavailability-based thresholds are used for the implementation derived from regionally relevant water chemistry data. Sites where elevated ambient background levels of copper are combined with high bioavailability (waters with low dissolved organic carbon) are those most likely to be at risk from copper exposures.

Assessment of potentially toxic trace element contamination in urban allotment soils and their uptake by onions: A preliminary case study from Sheffield, England

Toxic trace element (TTE) contamination in urban soils may pose potential health risks, especially in cities with previous industrial activities. This study aimed to investigate soil contamination in urban allotments in Sheffield, the uptake of TTEs in autumn and spring sown onions (Allium cepa), and their potential risks on human health via consumption of the crops. Paired soil and plant samples were taken in triplicates from four private allotments to assess potentially elevated levels of lead (Pb), zinc (Zn), copper (Cu), arsenic (As), and chromium (Cr). These elements in soils exceeded the ambient background levels for England. Both Pb and As exceeded some UK and EU soil tolerable limits. Concentration factors (CF) were calculated as the ratio of trace element in the plant as compared to that in the soil, and uptake rates were in the order Zn>Cu>Cr>Pb>As. Concentrations were higher for most TTEs in spring sown onions (SSO), and had significantly higher CF (p < 0.05) for Pb and Cr than autumn sown onions (ASO), whereas the opposite was true for As. Toxic elements in plants did not exceed FAO/WHO intake limits when considering TTE content per plant and consumption rates. Human health risk assessment calculations using target hazard quotients (THQ) and hazard indexes (HI) indicated that consuming onions alone did not pose an immediate health risk.

Redox-Dependent Copper Carrier Promotes Cellular Copper Uptake and Oxidative Stress-Mediated Apoptosis of Cancer Cells.

Transportation of exogenous copper ions into cancer cells by copper carriers has gained increasing interest for cancer chemotherapy. We disclosed herein a redox-dependent copper carrier, 2,2'-dithiodipyridine (DPy), which binds copper ions and carries the cargo into cells. The cellular reducing environment cleaved the disulfide bond in DPy to facilitate unloading copper ions. The elevated copper level then elicits oxidative stress and subsequently promotes the reformation of DPy. Further mechanistic studies revealed that the DPy/copper combination predominantly targets the cellular redox-regulating systems, including the thioredoxin system and the glutathione system, to induce the oxidative stress-mediated death of tumor cells. The discovery of DPy as a cleavable and recyclable copper shuttle provides a proof of concept for designing novel biomaterials for copper transportation as potential anticancer agents.

Detection of particles of metals in the shell casing for a partial species identification of weapons with the use of x-ray function-spectral analysis

One of the current in the examination of gunshot injuries is to determine the combustion charge or factors that accompany the shot. At the same time, the question remains about the use of a scapegoat or non-narrative short-barrel weapon. Therefore, by detecting particles of metal balls membrane formed passing through the bore rifle, their visual, stereomikroskopichnoho research and using infrared rays and renthenfluorestsentnoho spectral analysis was possible species of partial identification of said weapons. The archival material of the department of the word-medical criminology of the Kiev city clinic bureau of a forensic medicine was used in the work. The obtained results were processed by standard methods of variation statistics. The study in the thickness of the lower edge of the input gunshot wounds were found strips of metal density yellow color with a high content of copper (Cu), zinc (Zn) and lead (Pb), which indicates the characteristics of the membrane balls outside covered with red brass (an alloy of copper and zinc). The main metal of bullets of 4 mm caliber, provided for examination, was lead. In the study of the surface of the globe №1, facing the canal weapons found four areas of wiping material shell formed from the action fields rifling firearms is the rifling on the surface membrane of the globe, the bottom of which is parallel to the rolls and grooves alternating with one another . Thus, the detection of metallic strips of yellow density, resulting from passing through the channel rifle, gave reason to identify it as the weapon used in isolation. Elevated levels of copper (Cu), zinc (Zn) and lead (Pb) indicates that the outside shell of the balls were coated red brass (an alloy of copper and zinc). So the ball was shell.

Potential role of peroxisome proliferator activated receptor gamma activation on serum visfatin and trace elements in high fat diet induced type 2 diabetes mellitus

AimsElectrolytes and trace elements dysregulation play an important role in the progression of obesity and diabetes complications. The present study was designed to evaluate the insulin sensitizing effects of peroxisomes proliferators activated receptor gamma (PPAR-γ) agonist on trace elements in obesity induced type 2 diabetes mellitus and correlate with serum visfatin. Materials and methodsWistar rats were categorized into five groups. Group I served as control; Group II fed on high fat diet (HFD); Group III fed on HFD and treated with rosiglitazone (3 mg/kg) for 7 days; Group IV were T2DM rats induce by HFD and low dose of streptozotocin (i.p. 35 mg/kg); Group V was T2DM rats treated with rosiglitazone (3 mg/kg) for 7 days. Serum and tissues electrolytes levels and renal, hepatic and cardiac tissues trace elements were estimated by flame photometer and atomic absorption spectroscopy. Serum visfatin was estimated by ELISA. Pearson correlations were analyzed among fasting blood glucose (FBG), serum visfatin and tissues trace elements. Key findingsResults of the current study showed hyponatremia, hyperkalemia, hypomagnesemia and hypercalcemia in HFD and T2DM groups. HFD and T2DM also showed elevated copper and iron levels; however, zinc and selenium levels were decreased. Rosiglitazone treatment increased the insulin sensitization and altered these changes. A Strong association was observed among FBG, serum visfatin and trace elements levels of HFD and T2DM. SignificanceObesity and diabetes mellitus disturbed visfatin, electrolytes and trace elements homeostasis. Rosiglitazone treatment restored these changes. The results of the study could serve as a basis for further studies for the prevention of diabetic complications.

Restrained management of copper level enhances the antineoplastic activity of imatinib in vitro and in vivo

The present study was designed to investigate if elevated copper level can be targeted to enhance the efficacy of a significant anticancer drug, imatinib (ITB). The antineoplastic activity of this drug was assessed in the HepG2, HEK-293, MCF-7 and MDA-MD-231 cells targeting elevated copper level as their common drug target. The cell lines were treated with the different doses of copper chloride (Cu II) and disulfiram (DSF) alone as well as in their combinations with the drug for 24 h in standard culture medium and conditions. The treated cells were subjected to various assays including MTT, PARP, p-53, caspase-7, caspase-3, LDH and single cell electrophoresis. The study shows that DSF and Cu (II) synergizes the anticancer activity of ITB to a significant extent in a dose-specific way as evidenced by the combinations treated groups. Furthermore, the same treatment strategy was employed in cancer-induced rats in which the combinations of ITB-DSF and ITB-Cu II showed enhanced antineoplastic activity as compared to ITB alone. However, DSF was more effective than Cu (II) as an adjuvant to the drug. Hence, restrained manipulation of copper level in tumor cells can orchestrate the redox and molecular dispositions inside the cells favoring the induction of apoptosis.

The Divalent Elements Changes in Early Stages of Chronic Kidney Disease.

As the glomerular filtration rate (GFR) decreases, it can cause imbalance in some divalent elements. These imbalances can cause increased oxidative stress in patients with renal impairment. The aim of present study was to investigate the changes of these divalent elements with CKD progression. One hundred and ninety-four patients with chronic kidney diseases (CKD) were divided into five stages, stage 1, 2, 3a, 3b, 4, and were recruited into this study. The divalent elements, calcium, magnesium, phosphorus, as well as iron, zinc, and copper were determined in clinical chemistry analyzer. Higher CKD stages were found to be associated with increased levels of phosphorus and copper; Ptrend values were 0.002 and 0.004, respectively. Also, higher CKD stages were associated with decreased levels of zinc; Ptrend value was 0.002, after adjustment for age, gender, smoke, education, diabetes, hypertension, and BMI. Decreased levels of zinc and elevated levels of phosphorus and copper might increase the oxidative stress and complications in CKD patients. Future randomized studies are needed to show whether adjusting dietary intake of phosphorus, copper, and zinc might affect the progression of CKD.

Copper and zinc content in wild game shot with lead or non-lead ammunition - implications for consumer health protection.

The aim of this study was to examine the contamination of game meat with copper and zinc and establish whether the use of alternative (non-lead) ammunition can lead to higher or unsafe levels of copper and zinc in the meat of roe deer, wild boar and red deer. The research project “Safety of game meat obtained through hunting” (LEMISI) was conducted in Germany with the purpose of examining the entry of lead as well as copper and zinc into the meat of hunted game when using either lead or non-lead ammunition.The outcome of this study shows that the usage of both lead-based ammunition and alternative non-lead ammunition results in the entry of copper and zinc into the edible parts of the game. Using non-lead ammunition does not entail dangerously elevated levels of copper and zinc, so replacing lead ammunition with alternative ammunition does not introduce a further health problem with regard to these metals. The levels of copper and zinc in game meat found in this study are in the range found in previous studies of game. The content of copper and zinc in game meat is also comparable to those regularly detected in meat and its products from livestock (pig, cattle, sheep) for which the mean human consumption rate is much higher. From the viewpoint of consumer health protection, the use of non-lead ammunition does not pose an additional hazard through copper and zinc contamination. A health risk due to the presence of copper and zinc in game meat at typical levels of consumer exposure is unlikely for both types of ammunition.

Abstract 3552: Selective inhibition of copper metabolism as a novel approach to treat triple-negative breast cancer

Abstract Rationale: Treatment of patients with triple-negative breast cancer (TNBC) remains challenging due to unpredictable disease progression and acquired resistance to chemotherapy. Finding novel targets in TNBC is important for the development of anticancer therapy. Cancer cells frequently adapt to cytotoxicity of existing pharmacological agents by exploiting metabolic pathways. Elevated copper metabolism and adaptations to oxidative stress have been linked to cancer progression. Copper chelation with tetrathiomolybdate (TM) was reported to control disease progression, especially in patients with TNBC. However, long-term consequences of global copper depletion are still under investigation. An alternative strategy is provided by a recently developed small molecule DCAC50 that blocks the copper transfer interface of two major copper chaperons, ATOX-1 and CCS. Protein levels of ATOX-1 and CCS are elevated in TNBC cells compared to normal cells. Thus, we hypothesized that disrupting copper transport by targeting ATOX-1 and CCS with DCAC50 may suppress TNBC progression. Results: We investigated efficacy and potency of novel small molecule DCAC50 to induce cytotoxicity in a panel of TNBC cells lines. DCAC50 reduced cell proliferation in dose-dependent manner, measured by MTS assay. IC50 doses ranged from 3-10uM. Most importantly, DCAC50 induced apoptosis in TNBC cells, detected by Caspase 3/7 activity and Annexin V/PI staining. As expected, DCAC50 elevated intracellular copper levels. Moreover, TNBC cells treated with DCAC50 had significantly higher levels of oxidized glutathione (GSSG) and caused increased oxidation of DCF-DA reagent, demonstrating elevated oxidative stress. Surprisingly, activity of CCS downstream target, SOD1, was not affected by selective inhibition of copper transport with DCAC50; suggesting that intracellular copper accumulation and oxidative stress is mediated by ATOX-1 inhibition. Interestingly, copper depletion with TM inhibited SOD1 activity but failed to significantly impact oxidative stress in TNBC cells. Recognizing DCAC50 generates oxidative stress triggering apoptosis in TNBC cells we evaluated benefits of combining DCAC50 treatment with paclitaxel. Multi-drug combination dose-response analysis revealed that co-treatment induced synergistic cytotoxicity and resulted in favorable dose reduction of both drugs. Conclusions: Selective inhibition of copper metabolism with novel small molecule DCAC50 elevates oxidative stress triggering apoptosis in TNBC cells. This approach may be valuable in combination with chemotherapy especially when tumor cells acquire resistance to first line therapy in TNBC. Ongoing studies comparing selective inhibition of copper transport to global copper chelation, and investigating efficacy and biological activity of DCAC50 in vivo will help further estimate benefits and clinical relevance of this approach for treatment of TNBC patients. Citation Format: Olga Karginova, Claire Weekley, Akila Raoul, Alhareth Alsayed, Tong Wu, Chuan He, Olufunmilayo I. Olopade. Selective inhibition of copper metabolism as a novel approach to treat triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3552. doi:10.1158/1538-7445.AM2017-3552

РАЗГРУЗКА ПОДЗЕМНЫХ ВОД ВЕНДСКОГО ВОДОНОСНОГО КОМПЛЕКСА В ФИНСКОМ ЗАЛИВЕ

Цель работы состояла в оценке влияния разгрузки подземных вод на состав морской воды и донных отложений в Финском заливе. Рассмотрены собственные данные и материалы ряда геологических организаций (ОАО Севзапгеология, ВСЕГЕИ и ВНИИ Океангеология), относящиеся к побережью Курортного района Санкт-Петербурга и к Невской губе. Пробы поверхностных вод и донных отложений проанализированы в лаборатории геоэкологического мониторинга СПбГУ на содержание металлов методом атомно-абсорбционной спектрометрии и нефтепродуктов методом ИК-спектрометрии. Пробы подземных вод проанализированы в аккредитованных лабораториях ОАО «Севзапгеология». Отмечены повышенные концентрации меди, бария, железа, алюминия, свинца, никеля в воде и донных отложениях Невской губы, а также прибрежной части Курортного района. Проведено сравнение составов морских вод в районе кратерообразных донных образований (покмарков) в Копорской губе и подземных вод вендского водоносного горизонта. Результаты свидетельствуют о существовании в Финском заливе участков, подверженных существенному влиянию сосредоточенной подводной разгрузки подземных вод.

The Relationship Between Copper, Iron, and Selenium Levels and Alzheimer Disease.

This study aimed to evaluate the concentrations of copper, iron, and selenium in elderly people with Alzheimer disease (AD), comparing the same parameters in a paired group of healthy people, in order to verify if the amount of these metals may influence the cognitive impairment progression. Patients' cognitive impairment was evaluated by Clinical Dementia Rating (CDR). The elementary quantification of erythrocytes was performed by inductively coupled plasma mass spectrometry technique. The statistical analyses were carried out by SPSS software 20.0 version, employing Shapiro-Wilk, Wilcoxon, Kruskall-Wallis, and Spearman correlation tests, considering significant results of p<0.05. The sample was composed of 34% (n=11) of women and 66% (n=21) of men in each group. The AD group was characterized by a higher concentration of copper (p<0.0001) and iron (p<0.0001); however, there is no significant difference in selenium level. The analyses of the metal levels in different stages of AD were not significant in CDR-1, however in CDR-2 and CDR-3, elevated levels of copper and iron were observed; in CDR-3 patients, the level of selenium was lower (p<0.008) compared to that of healthy controls. Patients with Alzheimer disease studied present increase in biometal blood levels, especially of copper and iron, and such increase can be different according to the disease stage and can cause more impairment cognitive functions in AD.

CD147 functions as the signaling receptor for extracellular divalent copper in hepatocellular carcinoma cells.

Elevated copper levels in tumor microenvironment are directly correlated to cancer progression in a variety of malignancies. Copper is required in angiogenesis, and promotes the proliferation and metastasis of cancer cells. However, the molecular mechanism of copper in promoting cancer progression remains elusive. Here we report that CD147 serves as a signaling receptor for extracellular Cu2+ in hepatocellular carcinoma (HCC) cells. Cu2+ binds to the extracellular membrane-proximal domain of CD147 and mediates its self-association. Cu2+-mediated self-association of CD147 activates PI3K/Akt signaling pathway leading to the up-regulation of matrix metalloproteinase MMP-2 and MMP-14 in HCC cells. Cu2+-induced CD147 self-association also enhances the ability of HCC cells to stimulate MMP-2 expression from neighboring fibroblasts, as well as increases the invasiveness of HCC cells which is abolished by the copper chelator tetrathiomolybdate. We have mapped the interfaces and identified the key residues of CD147 involved in the Cu2+ induced self-association. The Cu2+ binding deficient CD147 mutant abolishes the stimulating effects of Cu2+ on HCC cells. Our study reveals a novel extracellular signaling role of copper in promoting cancer cell metastasis, which implies that targeting the Cu2+-induced self-association of CD147 is a new strategy for cancer treatment.