Free Copper Levels Research Articles

Prediction of fetal growth restriction in obese women

Objective. To develop a way of prediction of fetal growth restriction in the first trimester of pregnancy in obese women. Materials and methods. 85 obese pregnant women at 6–9 weeks of gestation took part in the study. Obesity was determined by body mass index, as squared height (m)-to-weight (kg) ratio, with a BMI 30 kg/m2. In the blood serum of all patients the level of total copper (Cuvol.) was determined by the colorimetric method, and ceruloplasmin (CP) by of V.S. Kamyshnikov`s method and the percentage of free copper (Cufree) was calculated. The free copper index was calculated using the formula: Cufree = (Cuvol. – (ceruloplasmin · 3)) / Cuvol. · 100, where Cufree is the percentage of free copper in the blood serum, %; Cuob. – content of total copper in blood serum, µmol/l; CP – content of ceruloplasmin in blood serum, mg/l; 3 – conversion factor. All pregnant women were divided into two groups depending on the percentage of free copper: group A – pregnant women with obesity and free copper content 25 % (n = 26); group B – obese pregnant women with a percentage of free copper 25 %, (n = 59). The control group consisted of 20 pregnant women with normal body weight. Results. Among the studied groups, in pregnant women with obesity statistically significant differences in the content of total copper (p = 0.013), and the percentage of free copper (p = 0.041) were revealed. In the group of pregnant women with a free copper content 25 % chronic placental insufficiency occurred 1.5 times more frequently and fetal growth restriction syndrome was 6.4 times more frequent than in the group of patients with a free copper content of 25 %. Conclusion. The free copper level, determined in the first trimester of pregnancy equal to 25% or more, can be considered as a predictor of fetal growth restriction in obese pregnant women.

Copper and cuproptosis: new therapeutic approaches for Alzheimer's disease.

Copper (Cu) plays a crucial role as a trace element in various physiological processes in humans. Nonetheless, free copper ions accumulate in the brain over time, resulting in a range of pathological changes. Compelling evidence indicates that excessive free copper deposition contributes to cognitive decline in individuals with Alzheimer's disease (AD). Free copper levels in the serum and brain of AD patients are notably elevated, leading to reduced antioxidant defenses and mitochondrial dysfunction. Moreover, free copper accumulation triggers a specific form of cell death, namely copper-dependent cell death (cuproptosis). This article aimed to review the correlation between copper dysregulation and the pathogenesis of AD, along with the primary pathways regulating copper homoeostasis and copper-induced death in AD. Additionally, the efficacy and safety of natural and synthetic agents, including copper chelators, lipid peroxidation inhibitors, and antioxidants, were examined. These treatments can restore copper equilibrium and prevent copper-induced cell death in AD cases. Another aim of this review was to highlight the significance of copper dysregulation and promote the development of pharmaceutical interventions to address it.

Are high copper levels related to Alzheimer's and Parkinson's diseases? A systematic review and meta-analysis of articles published between 2011 and 2022.

Copper performs an important role in the brain, but in high levels it can be neurotoxic. Further, some authors have described that copper dyshomeostasis could be related with neurodegenerative diseases. Thus, this review was performed to observe whether high copper levels are related to Alzheimer's and Parkinson's diseases (AD and PD), using the literature published recently. Articles that measured copper levels in AD or PD patients was included, as well as they that measured copper levels in models used to mimic these diseases. Also, results about high copper levels effects and its relationship with AD and PD observed in laboratory animals are considered. In summary, 38 and 24 articles with AD and PD patients were included, respectively. Despite of the heterogeneity between the studies in humans, meta-analysis has demonstrated that there is an increase in free and total copper levels in the blood of AD patients compared to controls, and a decrease in copper levels in PD patients. A decrease in the metal content in postmortem brain tissue was observed in AD and PD. In manuscripts using animal models that mimic AD and PD, it was included seven and three articles, respectively. Two of them have reported an increase in copper concentrations in AD model, and one in PD model. Finally, studies with laboratory animals have concluded that high copper levels are related to oxidative stress, neuroinflammation, mitochondrial dysfunction, changes in neurotransmitter levels, cell death, and reduced both cognitive and locomotor activity, which are also described in AD or PD.

Shift to remote learning degrades water quality in buildings

AbstractCommercial and institutional buildings now experience weeks and even months with below‐normal occupancy due to remote work/learning, which results in reduced water use and has the potential to adversely impact water quality. This study monitored the variations in water quality in multiple university buildings during several months of below‐normal occupancy followed by several months of normal occupancy. The levels of free chlorine, copper, and cellular ATP in water varied within buildings and between buildings. Using Wi‐Fi activity as a surrogate for building occupancy, the free chlorine concentration in water increased as Wi‐Fi counts increased. The copper concentration in building water was higher when the occupancy was below‐normal compared with normal occupancy, and the copper concentration decreased as Wi‐Fi counts increased. Throughout the study, flushing a fixture at the time of use decreased the concentrations of copper and cellular ATP and increased the concentration of free chlorine.

Application of coconut fiber and shell in the bleaching of soybean oil

The bleaching process is an important stage in the edible oil refining operation, and is carried out by using acid-activated bleaching earths. The aim of this study was to evaluate the efficiency of coconut fiber ash, shell ash, acid-activated fiber ash and acid-activated shell ash as compared to the commercial bleaching earth in the bleaching of neutralized soybean oil. Bleaching materials were added to neutralized oil at the concentration of 1% (w/v) with agitation under vacuum at 110 °C for 30 minutes. The values for red and yellow colors, carotenoids, chlorophylls, peroxide value, p-anisidine value, free fatty acid contents, copper and iron levels of the bleached samples were determined. The results indicated that all coconut-based adsorbents have been significantly more effective than commercial bleaching earth in reducing color and the greatest reductions in carotenoid (84.25%) and chlorophyll (82.30%) contents were obtained by using acid-activated fiber ash. The peroxide value for all treatments decreased. The amounts of iron and copper as peroxide compounds decreased considerably (44.59% and 23.53%) by using acid-activated fiber ash and acid-activated shell ash, respectively. Therefore, coconut fiber and shell as agricultural wastes which have been ignored in the past might be employed as effective agents to bleach crude oils, particularly soybean oil, in refining operations.

CtpB Facilitates Mycobacterium tuberculosis Growth in Copper-Limited Niches.

Copper is required for aerobic respiration by Mycobacterium tuberculosis and its human host, but this essential element is toxic in abundance. Copper nutritional immunity refers to host processes that modulate levels of free copper to alternately starve and intoxicate invading microbes. Bacteria engulfed by macrophages are initially contained within copper-limited phagosomes, which fuse with ATP7A vesicles that pump in toxic levels of copper. In this report, we examine how CtpB, a P-type ATPase in M. tuberculosis, aids in response to nutritional immunity. In vitro, the induced expression of ctpB in copper-replete medium inhibited mycobacterial growth, while deletion of the gene impaired growth only in copper-starved medium and within copper-limited host cells, suggesting a role for CtpB in copper acquisition or export to the copper-dependent respiration supercomplex. Unexpectedly, the absence of ctpB resulted in hypervirulence in the DBA/2 mouse infection model. As ctpB null strains exhibit diminished growth only in copper-starved conditions, reduced copper transport may have enabled the mutant to acquire a “Goldilocks” amount of the metal during transit through copper-intoxicating environments within this model system. This work reveals CtpB as a component of the M. tuberculosis toolkit to counter host nutritional immunity and underscores the importance of elucidating copper-uptake mechanisms in pathogenic mycobacteria.

Impact of a particular diet on the nutritional status and glycemic response of noninsulin-dependent diabetes mellitus patients – An analytical study

BACKGROUND: Diabetes mellitus is a heterogeneous primary disorder of carbohydrate metabolism with multiple etiological factors that generally involve absolute or relative insulin deficiency or insulin resistance or both. All causes of diabetes ultimately lead to hyperglycemia, which is the hall mark of this disease syndrome. Nutrition and diet play a critical role in the course of disease, in the controlling hyperglycemia in addition to drugs in diabetes mellitus patients.OBJECTIVES: To assess nutritional status of noninsulin-dependent diabetes mellitus (NIDDM) patients and glycemic response to the given type of food as compared to normal individuals.MATERIALS AND METHODS: Out of 40 cases of NIDDM patients, 15 normal subjects belonging to the same age and socioeconomic group were selected for the study on glycemic response to dextrose load and given test food (idly). In another six of NIDDM subjects, glycemic response to test food chapati was studied. In 13 cases of diabetes with hypertension, 12 cases of diabetes without hypertension, and 16 cases of normal subjects, a wide range of biochemical parameters like lipid profile, free fatty acid (FFA) levels, serum, and erythrocyte copper and malondialdehyde levels were estimated among them.DISCUSSION: The results of the study showed that in NIDDM patients, body mass index is significantly lower than the normal, showing that obesity is not a predisposing condition in these subjects. The glycemic response to food (idly) is much higher than the response observed in normal subjects. The extent of suppression and FFA levels in the serum that was brought out by the food for glucose is lower than that observed in normal subjects.CONCLUSION: High lipid profile values and low copper levels can favor the generation of lipid-derived free radicals, which further predispose to the vascular changes and hypertensive states observed in the NIDDM patients.

Mix-and-read bioluminescent copper detection platform using a caged coelenterazine analogue.

Serum copper levels are biomarkers for copper-related diseases. Quantification of levels of free copper (not bound to proteins) in serum is important for diagnosing Wilson's disease, in which the free copper concentration is elevated. Bioluminescence is commonly used in point-of-care diagnostics, but these assays require genetically engineered luciferase. Here, we developed a luciferase-independent copper detection platform. A luminogenic caged coelenterazine analogue (TPA-H1) was designed and synthesized to detect copper ions in human serum. TPA-H1 was developed by introducing a tris[(2-pyridyl)-methyl]amine (TPA) ligand, which is a Cu+ cleavable caging group, to the carbonyl group at the C-3 position of the imidazopyrazinone scaffold. The luciferin, named HuLumino1, is the product of the cleavage reaction of TPA-H1 with a copper ion and displays "turn-on" bioluminescence signals specifically with human serum albumin, which can be used to quantitatively analyse copper ions. TPA-H1 exhibited a fast cleavage of the protective group, high specificity, and high sensitivity for copper over other metal ions. This novel caged coelenterazine derivative, TPA-H1, can detect free copper ions in serum in a simple "mix-and-read" manner.

Clinical characteristics of the Wilson disease carrier

Objective: To study the clinical symptoms, copper metabolism and imaging characteristics of Wilson disease (WD) carriers and to explore the treatment strategy of WD carriers. Methods: Forty WD carriers, 40 WD patients and 20 normal controls from the First Affiliated Hospital of Sun Yat-sen University from July 2007 to May 2018 were included. The modified Young scale was used for neural symptom scoring, and Child grading of liver function, mental symptoms rating scale, magnetic resonance imaging (MRI) scan, susceptibility weighted imaging (SWI) inspection, metal metabolism tests were also applied to all the included subjects. Corrected phase (CP) was measured by SWI. WD carriers were divided into symptomatic group and asymptomatic group. Symptomatic WD carriers were treated with penicillamine for 2 weeks and zinc gluconate for 3 months, then their neurological symptoms, liver function grade, metal metabolism index were rechecked. Results: Six WD carriers presented with some clinical symptoms, including 5 with neurological symptoms and 4 with liver dysfunction. The score of Hamilton anxiety (HAMA) scale of symptomatic WD carriers was higher than that of normal control group (P=0.021). 85% of carriers had ceruloplasmin level less than 0.26 g/L. 80% of carriers had serum copper between normal controls and WD patients. The free copper level of WD carriers was lower than that of WD patients (P=0.012, 0.019). Urinary copper in symptomatic WD carriers was higher than normal controls (P=0.047). The CP values of thalamus, globus pallidus and putamen in symptomatic WD carriers were lower than those in normal control group. After treatment with penicillamine in symptomatic WD carriers, urinary copper was higher than that before treatment (P=0.036). After treatment, the liver enzymes of symptomatic WD carriers returned to normal, and the score of modified Young scale was lower than before treatment (P=0.031). Conclusions: Mild copper metabolism abnormality is seen in WD carriers. A few carriers have neurological symptoms such as limb tremors, or liver symptoms such as abnormal liver enzymes. Abnormal copper metabolism is more serious in symptomatic WD carriers than in asymptomatic WD carriers. Symptomatic WD carriers can be treated with zinc gluconate.

Targeting the Mitochondrial Metallochaperone Cox17 Reduces DNA Methylation and Promotes AML Differentiation through a Copper Dependent Mechanism

The majority of mitochondrial proteins are encoded in the nucleus, translated in the cytoplasm and imported into the mitochondria. A subset of cysteine-rich proteins destined for the mitochondrial intermembrane space are oxidized and folded by the Mitochondrial IMS Assembly (MIA) pathway. We found that genes encoding substrates of the MIA pathway are over-expressed in leukemic stem cells compared to bulk AML cells. Therefore, we assessed the effects of inhibiting the MIA pathway in AML by targeting the FAD linked sulfhydryl oxidase ALR, an integral part of the MIA machinery.Knockdown of ALR with shRNA reduced the growth and viability of OCI-AML2, TEX and NB4 leukemia cells. In addition, ALR knockdown reduced engraftment of TEX cells into mouse marrow, demonstrating an effect on the leukemia initiating cells. The small molecule selective ALR inhibitor, MitoBloCK-6 killed AML cells (IC50 of 5-10 mM) and preferentially reduced the clonogenic growth of primary AML cells over normal hematopoietic cells. MitoBloCK-6 treatment (80 mg/kg i.p. 5 of 7 days x 2 weeks) of mice engrafted with primary AML cells strongly reduced the leukemic burden without changing mouse body weight, serum chemistries, or organ histology. In contrast, MitoBloCK-6 did not change engraftment of normal cord blood in similar experiments. As evidenced by secondary transplants, MitoBloCK-6 also targeted leukemic stem cells.As expression levels of ALR substrates are increased in AML stem cells we assessed the effects of ALR inhibition on differentiation in AML. Genetic or chemical inhibition of ALR induced the differentiation of AML cells as evidenced by changes in gene expression, increased differentiation associated CD surface marker expression and increased non-specific esterase.Interrogation of the effects of ALR inhibition on its substrates identified the mitochondrial copper chaperone, Cox17 as the primary downstream target in leukemic cells. Genetic or chemical inhibition of ALR selectively reduced levels of Cox17 protein. Validating the functional importance of these findings, knockdown of Cox17 phenocopied ALR inhibition and reduced AML proliferation and induced AML differentiation.Cox17 is a copper metallochaperone that promotes respiratory chain complex IV assembly by loading copper into the respiratory complex. COX17 knockdown slightly reduced the complex IV enzymatic activity, but did not change basal oxygen consumption or ROS production. However, COX17 knockdown increased intracellular levels of free copper 16-fold as measured by atomic mass spectrometry. Copper is a known inhibitor of adenosylhomocysteinase, a key enzyme involved in the preservation of S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio in cells. SAM is a global methyl donor and is critical for DNA methylation. Knockdown of COX17 or ALR inhibition with MitoBloCK-6 decreased levels of SAM and reduced DNA methylation in AML cells. Likewise, the enzymatic activity of adenosylhomocysteinase was reduced in OCI-AML2 cells after MitoBloCK-6 treatment. Importantly, co-treatment with the copper chelator, penicillamine, rescued reductions in SAM, DNA methylation, and cell viability after COX17 knockdown or MitoBloCK-6 treatment.Thus, we have discovered a novel copper-dependent mechanism by which mitochondrial pathways regulate epigenetics and stemness in AML. Moreover, inhibitors of ALR or COX17 may be a novel therapeutic strategy to promote the differentiation of AML cells and stem cells. DisclosuresSchimmer:Otsuka Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medivir AB: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Biochemical and molecular characterisation of neurological Wilson disease

BackgroundTo identify biochemical and genetic features that characterise neurological Wilson disease as a distinct disease subgroup.MethodsDetailed biochemical profiles and genotypic characteristics of neurological (86 patients) and hepatic subgroups (233 patients)...

Difficulties in managing patients with hepatolenticular degeneration

In this paper, we present some typical problems of managing patients with hepatolenticular degeneration (HLD), a severe hereditary disorder of cupper metabolism requiring permanent cupper-eliminating therapy. Special attention should be paid the following questions: choice of combined treatment with D-penicillamine (D-PAM) and zinc vs. monotherapy with either of these medications; the possibility of temporary worsening of neurologic symptoms induced by massive increase in free copper level in the blood following therapy with D-PAM ; the need for special psychological support of patients and their relatives; strict adherence to a regimen prohibiting physical exercises and the need for following a special diet. Two clinical cases have been described: a fatal case of many-year compensated HLD after a physical load during a travel to the seaside, and a case of an infected foot wound in a HLD patient with the development of septicopyaemia (lower leg phlegmon and osteomyelitis of the lumbar vertebrae) following a physical activity and violation of the dietary pattern.

Copper and ceruloplasmin dyshomeostasis in serum and cerebrospinal fluid of multiple sclerosis subjects

Although many studies have been carried out in order to understand the implication of copper (Cu) in the pathogenesis of multiple sclerosis (MS), the exact role that this metal plays in the disease is not still clear. Because of the lack of information in this subject, the present study compared the serum and cerebrospinal (CSF) levels of copper in MS patients in respect to a control group, matched for age and sex, finding a significant increase of metal concentrations, in both biological fluids of MS subjects. To confirm the possible impairment of Cu metabolism, we analyzed ceruloplasmin (Cp) level and activity, seeing as this protein is an established peripheral marker in diseases associated with Cu imbalance. By comparing these two parameters between control and MS subjects, we found an increase of Cp levels, associated with a decrease in Cp activity, in the second group. By analysing these data, free copper levels were calculated, significantly increased in serum of MS subjects; the increase in free copper could be one of the predisposing factors responsible for the Cu altered levels in CSF of MS patients. At the same time, this alteration could be attributable to the inability to incorporate Cu by Cp, probably due to the high oxidative environment found in serum of MS patients. Overall, all these copper alterations may play a role in MS pathogenesis.

Estimation of Trace Elements in Mixed Saliva of Caries Free and Caries Active Children.

Composition of saliva plays an important role in defining the dental caries risk for an individual. The role of trace elements present in saliva on dental caries is still not clear. Thus this study was designed to evaluate the effect of certain salivary trace elements like copper, potassium, fluoride, selenium and lead on the caries experience of children. 60 subjects in the age group of 3-15 years were selected and divided into two groups, caries active and caries free. 5 ml of unstimulated saliva from each subject was collected and analyzed for the levels of trace elements using Induced Couple Plasma Spectrophotometer (ICP-OES). Copper and Fluoride levels were significantly higher in caries free as compared to caries active individuals whereas Lead was significantly higher in caries active as compared to caries free children (p-value<0.05). Potassium and Selenium though present in appreciable amounts did not show any significant difference between the two groups (p-value>0.05). In caries free subjects, copper and fluoride levels were significantly higher while the level of lead was lower as compared to caries-active children. Potassium and selenium did not show any significant differences within the two groups.

Utility of Serum Copper Level Estimation in Patients Suffering from Alzheimer’s Disease

Background: Alzheimer’s disease is the most common cause of dementia. Metals such as zinc , copper, iron are likely involved in the neurodegeneration of Alzheimer’s disease . Copper can catalyze a flux of reactive oxygen species that can damage functional and structural macromolecules in brain. Most studies found association of high serum copper level with Alzheimer’s disease but also some studies did not.&#x0D; Methods: Total 48 patients of Alzheimer’s disease who were diagnosed according to NIA-AA ( National institute of Aging – Alzheimer’s Association) recommendation ( revised NINCDS-ADRDA) criteria were taken as study population purposively and 42 age and sex matched control were selected. Fasting serum copper level were done for both groups. Comparison of serum copper level of Alzheimer’s patients with that of the control group were done to see association.&#x0D; Results : A total of 28 male and 20 female with mean age of 66.20 ± 9.42 (mean±SD) years, 22 male and 20 female with mean age of 63.54 ± 9.74 (mean±SD) years constituted as case and control groups, respectively. The mean of serum copper in case and control groups were 0.95 ± 0.37 versus 0.92 ± 0.25 mg/L (P &gt; 0.05). The present study found that serum copper levels are non-significantly higher in patients with AD than control group, however it did not show a significant relationship with severity of dementia.&#x0D; Conclusion: So our suggestion was to perform a study work including total serum copper level , serum ceruloplasmin level and free serum copper level comparing between a large Alzheimer’s Disease patients group and age , sex matched apparently healthy control group to understand the copper dyshomeostasis in Alzheimer’ Disease.&#x0D; Bangladesh Journal of Neuroscience 2017; Vol. 33 (2): 96-102

Effect of Copper on l-Cysteine/l-Cystine Influx in Normal Human Erythrocytes and Erythrocytes of Wilson's Disease.

Wilson's disease is a disease of abnormal copper metabolism in which free serum copper level is raised. The objective of the study was to determine, whether in Wilson disease, l-cysteine/l-cystine influx into RBC was decreased or not and the specific amino acid transporter affected by copper in normal human RBC. For l-cysteine/l-cystine influx, ten untreated cases, ten treated cases and ten age and sex matched healthy controls were recruited. To study the effect of copper on l-cysteine/l-cystine influx in RBC, 15 healthy subjects were selected. RBC GSH and l-cysteine/l-cystine influx were estimated by Beautler's and Yildiz's method respectively. In untreated cases, l-cysteine/l-cystine influx and erythrocyte GSH level were decreased showing that elevated level of free copper in serum or media decreased l-cysteine/l-cystine influx in human RBC. Copper treatment inhibited L amino acid transporter in normal RBC specifically.

Response of plasma copper, ceruloplasmin, iron and ions in carp, Cyprinus carpio to waterborne copper ion and nanoparticle exposure

In this study, Cyprinus carpio was exposed to 0.25mgL−1 copper as either copper sulfate (CuSO4) or copper oxide nanoparticles (nano-Cu), and 25mgL−1 copper as nano-Cu for 14days. CuSO4 and high concentration of nano-Cu led to a significant increase in plasma total copper levels. Plasma free copper levels increased significantly in all copper-exposed treatments. Except for low concentration of nano-Cu after 7 and 14days, copper exposure generally led to a significant decrease in plasma ceruloplasmin levels. Plasma iron levels increased significantly in CuSO4 (all times) and nano-Cu (7th and 14th days) treatments. A significant elevation in plasma total iron binding capacity (TIBC) was observed after 3days in the fish exposed to low concentration nano-Cu, and after 14days in all copper-exposed treatments. Transferrin saturation (TSA) ratio showed significant increase in CuSO4 (3rd and 7th days) and the high concentration nano-Cu (7th day) treatments. Decrease in plasma chloride (7th and 14th days) and sodium (14th days) was observed in CuSO4 treatment. In conclusion, the results suggest that ionic copper is mainly absorbed via fish gill, whereas, nano-copper are more likely absorbed via gut. Also, data suggest that ionic copper has more adverse effects on the examined plasma biochemical characteristics compared to the equivalent nano-copper concentration, which may be due to the lower copper absorption by fish in the nano-copper suspension.

Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons.

Extracellular and intracellular copper and zinc regulate synaptic activity and plasticity, which may impact brain functionality and human behavior. We have found that a metal coordinating molecule, Neocuproine, transiently increases free intracellular copper and zinc levels (i.e., min) in hippocampal neurons as monitored by Phen Green and FluoZin-3 fluorescence, respectively. The changes in free intracellular zinc induced by Neocuproine were abolished by the presence of a non-permeant copper chelator, Bathocuproine (BC), indicating that copper influx is needed for the action of Neocuproine on intracellular Zn levels. Moreover, Neocuproine decreased the mRNA levels of Synapsin and Dynamin, and did not affect the expression of Bassoon, tubulin or superoxide dismutase (SOD). Western blot analysis showed that protein levels of synapsin and dynamin were also down regulated in the presence of Neocuproine and that these changes were accompanied by a decrease in calcium transients and neuronal activity. Furthermore, Neocuproine decreased the number of active neurons, effect that was blocked by the presence of BC, indicating that copper influx is needed for the action of Neocuproine. We finally show that Neocuproine blocks the epileptiform-like activity induced by bicuculline in hippocampal neurons. Collectively, our data indicates that presynaptic protein configuration and function of primary hippocampal neurons is sensitive to transient changes in transition metal homeostasis. Therefore, small molecules able to coordinate transition metals and penetrate the blood-brain barrier might modify neurotransmission at the Central Nervous System (CNS). This might be useful to establish therapeutic approaches to control the neuronal hyperexcitabiltity observed in brain conditions that are associated to copper dyshomeotasis such as Alzheimer’s and Menkes diseases. Our work also opens a new avenue to find novel and effective antiepilepsy drugs based in metal coordinating molecules.

Elevated copper ion levels as potential cause of impaired kinesin-dependent transport processes.

Copper is a trace element required to maintain essential life processes. In healthy organisms, copper metabolism is well balanced. If this balance is destroyed, the cellular level of free copper might increase and cause toxic effects. So far, the molecular mechanisms of copper intoxication are understood only partly. The present study revealed that the kinesin-dependent transport system is strongly affected by copper(II) ions. Both the microtubules, along which kinesin moves, and the kinesin itself were found to be the target structures of copper ions: Microtubule formation was suppressed by copper ions (IC50 26-70 µM) apparently chiefly by inhibition of binding of microtubule-associated proteins to tubulin. This inhibition could be widely compensated by the microtubule-stabilising agent paclitaxel. In addition, copper ions strongly inhibited the ATPase activity of neuron-specific kinesin KIF5A. At final KIF5A concentration of 112 nM, an IC50 of 1.3 µM was determined. Correspondingly, the motility activity of KIF5A, measured as velocity of microtubules gliding across a kinesin-covered surface, was blocked. The effects of copper ions on microtubules and on KIF5A are suggested to contribute to impaired transport processes within brain and other organs in cases of copper ion surplus.

Disorder of copper homeostasis induced by lead exposure among mice and intervention effect of quercetin

To investigate the effect of lead exposure on copper and copper metalloenzyme and the intervention effect of quercetin. Twenty-four specific pathogen-free male Sprague-Dawley rats of good health were randomly divided into control group (n = 8), lead acetate group (n = 8), and lead acetate + quercetin group (n = 8). The rats in lead acetate group were poisoned by drinking water with 1 g/L lead acetate for 8 weeks, while the rats in control group were fed by drinking water with sodium acetate of the same volume for 8 weeks; the rats in lead acetate+quercetin group were intraperitoneally injected with quercetin (30 mg × kg-1 × d-1) for 8 weeks while drinking water with lead acetate. The Morris water maze was used to test the learning and memory abilities of rats. The lead and copper levels in the serum, hippocampus, cortex, and bone were measured by graphite furnace atomic absorption spectrometry. The level of advanced glycation end products, activity of Cu/Zn superoxide dismutase (SOD), and content and activity of ceruloplasmin (CP) in the hippocampus and serum were measured using a test kit. HE staining was performed to observe the pathological changes in the hippocampus. The Morris water maze test showed that the latency in lead acetate group (52.50±12.04 s) was significantly longer than that in control group (28.08±7.31 s) (P<0.05), and the number of platform crossings was significantly lower in the lead acetate group than in the control group. Compared with those in the control group, the lead levels in the cortex and hippocampus in lead acetate group increased 2.72-fold and 3.79-fold, and the copper in the cortex and hippocampus, and serum free copper levels in lead acetate group increased 1.15-fold, 1.48-fold, and 6.44-fold. Compared with the control group, the lead acetate group had a lower content of CP in the hippocampus (1.23±0.40 U/mg provs0.78±0.08 U/mg pro) and 31.81%and 19.49%decreases in CP content and Cu/Zn SOD activity. Free copper level in serum was positively correlated with the latency and lead levels in the serum, cortex, and hippocampus. The escape latency of rats in lead acetate + quercetin group was decreased by 42.15% (P<0.05). The lead levels in the cortex and hippocampus in lead acetate + quercetin group (0.246 ± 0.58 µg/g and 0.202±0.049 µg/g) were significantly lower than those in lead acetate group (0.391±0.49 µg/g and 0.546±0.120 µg/g), but the free copper and copper levels in the hippocampus and cortex were not significantly reduced. The lead acetate + quercetin group had higher Cu/Zn SOD activity and CP content in the hippocampus than the lead acetate group (P < 0.05). The light microscope observation showed that the number of cells in the hippocampus was reduced with disordered arrangement in the lead acetate group; with quercetin intervention, the hippocampus damage was reduced. Lead exposure results in disorder of copper homeostasis, while quercetin may alleviate the damage induced by lead to some extent.