Case Report: Copper sulphate related hemophagocytosis with lymphohistiocytosis.

The accidental, suicidal, and homicidal toxicities of copper sulfate have been extensively documented. The later stages of the disease demonstrate signs of systemic toxicity, characterized by intravascular hemolysis, oliguric renal failure, convulsions, and circulatory collapse. Despite the extensive description of life-threatening intravascular hemolysis, Hemophagocytic Lymphohistiocytosis (HLH) related to copper sulfate poisoning has not been described. A 45-year-old male presented with accidental consumption of copper sulfate. Laboratory evaluation revealed leukocytosis, intravascular hemolysis, acute liver injury, acute kidney injury, severe metabolic acidosis, and hyperkalemia. The patient was shifted to the Intensive Care Unit and hemodialysis was initiated. On the 9 th day, he developed high-grade fever with chills. With the suspicion of a central line-associated bloodstream infection, empirical antibiotic therapy was initiated, and the lines were revised. On the 19 th day, the high-grade fever recurred. Investigations revealed trilineage cytopenias. With a high degree of suspicion for HLH, further investigations revealed increased ferritin levels. Bone marrow aspiration cytology showed evidence of reactive marrow with haemophagocytic lymphohistiocytosis. The patient was initiated on corticosteroid therapy, after which symptomatic and laboratory recovery was noted. Although copper sulfate poisoning is potentially fatal in large quantities, few studies have examined the possible immune-mediated abnormalities in individuals. Owing to the direct membranolytic effect of copper sulfate, it is not unreasonable to have immune-mediated organ damage. To the best of our knowledge, this is the first report of Hemophagocytic Lymphohistiocytosis attributed to copper sulfate intoxication. The present case demonstrates that the diagnosis of HLH must be considered when treating a case of copper sulfate poisoning; however, the exclusion of the most common complications must be first established.

Copper-induced oxidative stress inhibits asexual reproduction of Aurelia coerulea polyps.

OBJECTIVE: Our research aims to investigate the specific mechanisms by which copper inhibits the asexual proliferation of Aurelia coerulea polyps. METHODS: Aurelia coerulea polyps were exposed to various CuSO4 concentrations to study metamorphosis and budding proliferation. Oxidative stress markers (ROS, MDA, CAT, H2O2, T-AOC, SOD) were measured in polyps and early strobilae. Transcriptomic analysis were used to compare differences in gene expression and enrichment pathways between untreated and copper-exposed polyps. Additionally, RT-qPCR was used to analyze the expression of key molecules. Antioxidant L-Ascorbic acid was applied to determine the role of oxidative stress in asexual reproduction of Aurelia coerulea polyps when exposed to copper. RESULTS: Copper inhibited strobilization and budding of Aurelia coerulea polyps in a dose-dependent manner, in which oxidative stress was involved. Transcriptomic data suggested that the DNA replication pathway was significantly enriched in early strobilae compared to polyps. However, copper treatment repealed the difference of DNA replication pathway between early strobilae compared and polyps. Transcriptomic data suggested that alanine, aspartate, and glutamate metabolism pathways were enriched in untreated budding polyps compared to copper-exposed polyps. After applying the antioxidant L-Ascorbic acid to copper-exposed polyps, various oxidative indicators changed to different extents, with increases in ROS, MDA, CAT, H2O2, and SOD and a decrease in T-AOC. Further more, the time required for polyps to develop into early strobila was shortened, indicating that the delay in metamorphosis caused by copper exposure was effectively alleviated. And the budding rate increased, indicating that the inhibition of budding proliferation caused by copper exposure was effectively alleviated. The expression of key genes were consist with the transcriptomic sequencing results. CONCLUSION: Copper exposure causes oxidative stress resulting in the inhibition of asexual reproduction in Aurelia coerulea polyps, including metamorphosis and budding.

An intense cathodic electrochemiluminescence from carbon-nanosheets in situ grown on glassy carbon electrode and application in immunoanalysis via biometallization strategy.

An intense cathodic electrochemiluminescence (ECL) is reported from a polarized glassy carbon electrode (GCE) in peroxydisulfate solution. After the polarization in 1 M Na2SO4 at the potential of - 3.7 V for 3 s, carbon nanosheets (C-NSs) were in situ grown on the surface of the GCE. Measured in 100 mM K2S2O8 solution, the ECL intensity of the GCE/C-NSs is 112-fold that of a bare GCE. The ECL spectrum revealed that the true ECL luminophore in the GCE/C-NSs-peroxydisulfate system is O2/S2O82- which is promoted by C-NSs. When Cu2+ was electrochemically enriched and reduced to Cu(0) on the catalytic sites of C-NSs, the ECL from GCE/C-NSs/Cu in K2S2O8 solution was decreased with increasing logarithmic concentration of Cu2+ in the range from 10 pM to 1 µM, with a limit of detection (LOD) of 3 pM. An immunoanalysis method is proposed via a biometallization strategy using CuS nanoparticles as the tags and carcinoembryonic antigen (CEA) as the model analyte. After the immune recognition in the microplate, the CuS tags in the immunocomplex were dissolved and the resultant Cu2+ was electrochemically enriched and reduced on the catalytic sites of C-NSs, quenching the ECL intensity of GCE/C-NSs-O2/S2O82- system. The proposed ECL immunoanalysis method was used to quantify CEA in actual serum samples with an LOD of 1.0 fg mL-1, possessing the advantages of simple electrode modification, high sensitivity and good reproducibility.

Copper exposure induces mitochondrial dysfunction and hepatotoxicity via the induction of oxidative stress and PERK/ATF4 -mediated endoplasmic reticulum stress.

Copper is an essential trace element, and excessive exposure could result in hepatoxicity, however, the underlying molecular mechanisms remain incompletely understood. The present study is aimed to investigate the molecular mechanisms of copper sulfate (CuSO4) exposure-induced hepatoxicity both in vivo and in vitro. In vitro, HepG2 and L02 cells were exposed to various doses of CuSO4 for 24 h. Cell viability, ROS production, oxidative stress biomarkers, mitochondrial functions, ultrastructure, intracellular calcium (Ca2+) concentration, and the expression of proteins related to mitochondrial apoptosis and endoplasmic reticulum (ER) stress were assessed. In vivo, C57BL/6 mice were treated with CuSO4 at doses of 10 and 30 mg/kg BW/day and co-treated with 4-PBA at 100 mg/kg BW/day for 35 days. Subsequently, liver function, histopathological features, and protein expression were evaluated. Results found that exposure to CuSO4 at concentrations of 100-400 µM for 24 h significantly decreased the viabilities of HepG2 and L02 cells and it was in a dose-dependent manner. Additionally, CuSO4 exposure induced significant oxidative stress and mitochondrial dysfunction in HepG2 cells, which were partially ameliorated by the antioxidant N-acetylcysteine (NAC). Furthermore, CuSO4 exposure prominently triggered ER stress, as evidenced by the upregulation of GRP94, GRP78, phosphorylated forms of PERK and eIF2α, and CHOP proteins in livers of mice and HepG2 cells. NAC treatment significantly inhibited CuSO4 exposure -induced ER stress in HepG2 cells. Pharmacological inhibition of ER stress through co-treatment with 4-PBA and the PERK inhibitor GSK2606414, as well as genetic knockdown of ATF4, partially mitigated CuSO4-induced cytotoxicity in HepG2 cells by reducing mitochondrial dysfunction and inhibiting the mitochondrial apoptotic pathway. Moreover, 4-PBA treatment significantly attenuated CuSO4-induced caspase activation and hepatoxicity in mice. In conclusion, these results reveal that CuSO4-induced hepatotoxicity involves mitochondrial dysfunction and ER stress by activating oxidative stress induction and PERK/ATF4 pathway.

Comparative efficacy of stannous fluoride and zinc sulfate solution to copper sulfate footbath solutions for the treatment and prevention of digital dermatitis in lactating dairy cows.

The objective of this study was to determine whether a novel footbath solution containing stannous fluoride (SnF2) was superior to 5% copper sulfate solution for the treatment and prevention of digital dermatitis (DD) in dairy cattle. Study 1 was conducted over 4 wk in Missouri and involved 34 lactating Holstein-Friesian cows with hind feet DD lesions. Cows in group SF walked through a footbath containing a proprietary formulation of SnF2 once weekly, whereas cows in group CS walked through a 5% CuSO4 footbath once daily for 5 d each week. Study 2 was conducted over 8 wk in California and involved 40 lactating Holstein-Friesian cows with hind feet DD lesions. Cows in group SF walked through a SnF2 footbath for 3 consecutive days and then once a week for the following 7 wk. Cows in group CS walked through a 5% CuSO4 footbath 3 times each week for 8 wk. Data collection included lesion type, lesion area, locomotion score, and pain score. Digital dermatitis was actively transmitted in study 1, and lesion area and locomotion scores were lower in group SF than group CS. In contrast, DD was not actively transmitted in study 2, and lesion area and locomotion scores were similar in groups SF and CS. Stannous fluoride delayed the development of active DD lesions in study 1 compared with copper sulfate, with a lower relative risk (0.57) of a hind foot developing an active DD lesion over 28 d. However, SnF2 decreased the rate that active DD lesions transitioned to M3, M4, or M0 lesions compared with 5% copper sulfate in both studies, with the relative risk of a hind foot with an active DD lesion transitioning to M3, M4, or M0 in group SF being slightly lower in study 1 (0.83) and study 2 (0.90) than in group CS. Our findings demonstrated that walking cows through a stannous fluoride footbath once per week in a herd undergoing active transmission of infection was more effective in preventing active DD lesions, but less effective in treating active DD lesions, than walking cows through a copper sulfate footbath 4 times per week. The novel SnF2 footbath solution shows promise for controlling DD in dairy herds that want an alternative footbath solution to CuSO4 and are interested in limiting the environmental accumulation of copper.

High copper levels induce premature senescence in 3T3-L1 preadipocytes.

Copper (Cu) dyshomeostasis has been linked to obesity and related morbidities and also to aging. Cu levels are higher in older or obese individuals, and adipose tissue (AT) Cu levels correlate with body mass index. Aging and obesity induce similar AT functional and structural changes, including an accumulation of senescent cells. To study the effect of Cu-mediated stress-induced premature senescent (Cu-SIPS) on preadipocytes, 3T3-L1 cell line was exposed to a subcytotoxic concentration of copper sulfate. After Cu treatment, preadipocytes acquired typical senescence characteristics including diminished cell proliferation, cell and nuclei enlargement and increased lysosomal mass (higher Lamp2 expression and a slight increased number of cells positive for ß-galactosidase associated with senescence (SA-ß-Gal)). Cell cycle arrest was due to upregulation of p16Ink4aInk4a and p21Waf1/Cip1. Accordingly, protein levels of the proliferation marker KI67 were reduced. Cu-SIPS relates with oxidative stress and, in this context, an increase of SOD1 and HO-1 expression was detected in Cu-treated cells. The mRNA expression of senescence-associated secretory phenotype factors, such as Mmp3, Il-6 and Tnf-α, increased in Cu-SIPS 3T3-L1 cells but no effect was observed on the expression of heterochromatin-associated protein 1(HP1). Although the downregulation of Lamin B1 expression is considered a hallmark of senescence, Cu-SIPS cells presented higher levels of Lamin B1. The dysregulation of nuclear lamina was accompanied by an increase of nuclear blebbing, but not of micronuclei number. To conclude, a Cu-SIPS model in 3T3-L1 preadipocytes is here described, which may be an asset to the study of AT dysregulation observed in obesity and aging.

Cuproptosis mediates copper-induced testicular spermatogenic cell death.

Cuproptosis, a novel mechanism of programmed cell death, has not been fully explored in the context of spermatogenic cells. This study investigated the potential involvement of cuproptosis in spermatogenic cell death using a mouse model of copper overload. Sixty male Institute of Cancer Research (ICR) mice were randomly divided into four groups that received daily oral gavage with sodium chloride (control) or copper sulfate (CuSO 4 ) at 50 mg kg -1 , 100 mg kg -1 , or 200 mg kg -1 , for 42 consecutive days. Mice subjected to copper overload exhibited a disruption in copper homeostasis. Additionally, significant upregulated expression of key cuproptosis factors was accompanied by a significant rise in the rates of testicular tissue cell apoptosis. Immunohistochemical analysis revealed the presence of ferredoxin 1 (Fdx1) in Sertoli cells, Leydig cells, and spermatogenic cells at various stages of testicular development, and the Fdx1-positive staining area was significantly increased in copper-overloaded mice. Mitochondrial dysfunction and decreased adenosine triphosphate levels were also observed, further implicating mitochondrial damage under cuproptosis. Further analyses revealed pathological lesions and blood-testis barrier destruction in the testicular tissue, accompanied by decreased sperm concentration and motility, in copper-overloaded mice. In summary, our results indicate that copper-overloaded mice exhibit copper homeostasis disorder in the testicular tissue and that cuproptosis participates in spermatogenic cell death. These findings provide novel insights into the pathogenic mechanisms underlying spermatogenic cell death and provide initial experimental evidence for the occurrence of cuproptosis in the testis.

Reduced toxic effects of nano­copper sulfate in comparison of bulk CuSO4 on biochemical parameters in the Rohu (Labeo rohita).

Considering the wide application of nanoparticles in various fields of life and growing concern regarding their toxic effects, the present study was designed with the aim to evaluate the potential risks of using copper sulfate nanoparticles (CuSO4-NPs) in comparison to bulk form. Nanoparticles of CuSO4, having mean size of 73 nm were prepared by ball milling method, and fingerlings of Labeo rohita were exposed to two levels, 20 and 100 µg L-1 of CuSO4 in both bulk and nano forms for 28 days and their comparative effects on the metallothioneins (MTs), heat shock proteins 70 (HSP 70), lipid profile, cholesterol (CHOL) and triglyceraldehyde (TG) levels, activities of some metabolic enzymes Alanine transaminase (ALT), Aspartate transaminase (AST) Akaline phosphatase (ALP), and genes expressions of HSP-70, TNF-α and IL1-ß were investigated. CuSO4 showed the concentration and particle type dependent effects. The over expression of HSPs and MTs, significant decreases in CHOL, TG, low density lipid (LDL) levels and ALP activity, while significant increases in high density lipid (HDL)level as well as ALT and AST activities and HSP-70, TNF-α and IL1-ß expressions were observed in response to higher concentration of both bulk and nano form of copper sulfate. At lower concentration (20 µg L-1), however, only bulk form showed toxicity. Thus, low concentrations of CuSO4-NPs pose negligible threat to freshwater fish.

Pentoxifylline as Add-On Treatment to Donepezil in Copper Sulphate-Induced Alzheimer's Disease-Like Neurodegeneration in Rats.

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by behavioral, cognitive, and progressive memory impairments. Extensive neuronal loss, extracellular accumulation of insoluble senile amyloid-ß (Aß) plaques, and intracellular neurofibrillary tangles (NFTs) are the major pathological features. The present study aimed to investigate the therapeutic effect of donepezil (DON) and pentoxifylline (PTX) in combination to combat the neurodegenerative disorders (experimental AD) induced by CuSO4 intake in experimental rats. Thirty adult male Wistar rats (140-160 g) were used in this study. AD was first induced in rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. The AD group received no further treatment. Oral treatment with DON (10 mg/kg/day), PTX (100 mg/kg/day), or DON + PTX for the other three groups was started from the 10th week of CuSO4 intake for 4 weeks. Cortex markers like acetylcholine (ACh), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) and hippocampus markers like ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), Clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 were measured. The histopathology studies were done by using hematoxylin and eosin and Congo red stains as well as immunohistochemistry for neurofilament. CuSO4 induced adverse histological and biochemical changes. The histological injury in the hippocampus was inhibited following the administration of the DON and PTX. The brain tissue levels of AChE, MDA, BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α were significantly increased, while brain tissue levels of ACh, TAC, and Bcl-2 were significantly decreased in CuSO4-treated rats as compared with the untreated control group. The effects induced by either DON or PTX on most studied parameters were comparable. Combined treatment of DON and PTX induced remarkable results compared with their individual use. However, more clinical and preclinical studies are still required to further confirm and prove the long-term efficacy of such combination.

Biochemical Responses to the Long-Term Impact of Copper Sulfate (CuSO4) in Tobacco Plants.

Metabolic changes under stress are often studied in short-term experiments, revealing rapid responses in gene expression, enzyme activity, and the amount of antioxidants. In a long-term experiment, it is possible to identify adaptive changes in both primary and secondary metabolism. In this study, we characterized the physiological state of tobacco plants and assessed the amount and spectrum of phenolic compounds and the lignification of axial organs under excess copper stress in a long-term experiment (40 days). Plants were treated with 100 and 300 µM CuSO4, as well as a control (Knop solution). Copper accumulation, the size and anatomical structure of organs, stress markers, and the activity of antioxidant enzymes were studied. Lignin content was determined with the cysteine-assisted sulfuric method (CASA), and the metabolite profile and phenolic spectrum were determined with UHPLC-MS and thin-layer chromatography (TLC). Cu2+ mainly accumulated in the roots and, to a lesser extent, in the shoots. Copper sulfate (100 µM) slightly stimulated stem and leaf growth. A higher concentration (300 µM) caused oxidative stress; H2O2 content, superoxide dismutase (SOD), and guaiacol peroxidase (GPOX) activity increased in roots, and malondialdehyde (MDA) increased in all organs. The deposition of lignin increased in the roots and stems compared with the control. The content of free phenolics, which could be used as substrates for lignification, declined. The proportions of ferulic, cinnamic, and p-coumaric acids in the hydrolysate of bound phenolics were higher, and they tended toward additional lignification. The metabolic profile changed in both roots and stems at both concentrations, and changed in leaves only at a concentration of 300 µM. Thus, changes in the phenolic spectrum and the enhanced lignification of cell walls in the metaxylem of axial (root and stem) organs in tobacco can be considered important metabolic responses to stress caused by excess CuSO4.

Conversion of senescent cartilage into a pro-chondrogenic microenvironment with antibody-functionalized copper sulfate nanoparticles for efficient osteoarthritis therapy.

The development of osteoarthritis (OA) correlates with the expansion of senescent cells in cartilage, which contributes to an inflammatory microenvironment that accelerates matrix degradation and hampers cartilage generation. To address OA, we synthesized small copper sulfide nanoparticles functionalized with anti-beta-2-microglobulin antibodies (B2M-CuS NPs) that catalyze the formation of toxic •OH from H2O2 via peroxidase-like activity. These B2M-CuS NPs are specifically targeted to induce apoptosis in senescent chondrocytes while showing no toxicity toward normal chondrocytes. Furthermore, B2M-CuS NPs enhance the chondrogenesis of normal chondrocytes. Thus, B2M-CuS NPs can effectively treat OA by clearing senescent chondrocytes and promoting cartilage regeneration after intra-articular injection into the knee joints of surgery-induced OA mice. This study uses smart nanomaterials to treat OA with a synergistic strategy that both remodels senescent cartilage and creates a pro-chondrogenic microenvironment.

Photothermal and Acid-Responsive Fucoidan-CuS Bubble Pump Microneedles for Combined CDT/PTT/CT Treatment of Melanoma.

Transdermal cancer therapy faces great challenges in clinical practice due to the low drug transdermal efficiency and the unsatisfactory effect of monotherapy. Herein, we develop a novel bubble pump microneedle system (BPMN-CuS/DOX) by embedding sodium bicarbonate (NaHCO3) into hyaluronic acid microneedles (MNs) loaded with fucoidan-based copper sulfide nanoparticles (Fuc-CuS NPs) and doxorubicin (DOX). BPMN-CuS/DOX can generate CO2 bubbles triggered by an acidic tumor microenvironment for deep and rapid intradermal drug delivery. Fuc-CuS NPs exhibit excellent photothermal effect and Fenton-like catalytic activity, producing more reactive oxygen species (ROS) by photothermal therapy (PTT) and chemodynamic therapy (CDT), which enhances the antitumor efficacy of DOX and reduces the dosage of its chemotherapy (CT). Simultaneously, DOX increases intracellular hydrogen peroxide (H2O2) supplementation and promotes the sustained production of ROS. BPMN-CuS/DOX significantly inhibits melanoma both in vitro and in vivo by the combination of CDT, PTT, and CT. In short, our study significantly enhances the effectiveness of transdermal drug delivery by constructing BPMNs and provides a promising novel strategy for transdermal cancer treatment with multiple therapies.

Trace identification of cysteine enantiomers based on an electrochemical sensor assembled from CuxS@SOD zeolite.

The nonchiral sensor concept based on a sodalite (SOD) zeolite loaded CuxS (CuxS@SOD) catalyst is proposed as a sensing platform for chiral cysteine (Cys) determination. Chiral Cys is analyzed by the difference of binding capacity between CuxS catalysts. The observed current in amperometric i-t curve (A i-t C) is always positive for the L-cysteine (L-Cys), while it is negative for the D-cysteine (D-Cys). Under differential pulse voltammetry (DPV) method, the characteristic current peak for the CuxS@SOD moves to right (positive potential position) with the addition of L-Cys while it moves to left (negative potential direction) with the addition of D-Cys, respectively. Cyclic voltammetry (CV) is consistent with DPV and discusses the diffusion control mechanism. In this work, the ultra-trace determination of cysteine enantiomers reaches the limit of detection (LOD) of 0.70 fM and 0.60 fM by the highly efficient CuxS catalyst restrained in the nanosized SOD zeolite cages of the opening window pores, respectively. The sensor opens up a novel potential prospect for achiral composite in the field of chiral recognition through electrochemical methods with extra-low concentration.

Variation of the rate of pesticides decomposition used together in the process of agricultural production.

The use of tank mixtures of pesticides makes it possible to increase the efficiency of chemical treatment. The aim of the study was to establish the relationship between the joint use of pesticides and the rate of decomposition of active substances. The study was carried out on the crops of spring wheat, spring barley, peas, spring rapeseed, seed potato. Chemical treatments were carried out with insecticides and fungicides - the insecticide (imidacloprid and λ-cyhalothrin), suspension concentrate; the fungicide (propiconazole), emulsifiable concentrate; the insecticide (imidacloprid), soluble concentrate; the fungicide (copper sulfate tribasic), suspension concentrate. Determination of residual amounts of active substances of pesticides was carried out using methods of gas-liquid chromatography and high-performance liquid chromatography. The acceleration of decomposition of the active substance - imidacloprid on pea crops and spring rapeseed was caused by the combined use of the insecticide (imidacloprid) and the fungicide (propiconazole). The use of the fungicide (copper sulfate tribasic) in a tank mixture with the insecticide (imidacloprid and λ-cyhalothrin) on potatoes caused a slowdown in the decomposition of the active substances imidacloprid and λ-cyhalothrin. Also, there was a change in the level of intake by plant of active substances in the first three hours after spraying, when using tank mixtures, in comparison with the separate use of compounds. The data obtained on the change in the rate of decomposition of active substances of pesticides, when they are used together in mixtures, indicate the need to continue research in this area. In this regard, it is important to study the dynamics of the decomposition of individual active substances of pesticides in plant tissues when they are used in tank mixtures, it is also necessary to conduct research using compounds most commonly used in agricultural production.

Oral iron supplementation ameliorated alterations in iron uptake and utilization in copper-toxic female Wistar rats.

OBJECTIVE: Women are more susceptible to both iron deficiency and copper toxicity due to monthly flow and estrogen action, respectively. Oral iron is beneficial for menstruating women and enhances erythropoiesis, but both deficiency and excess of copper impact iron absorption and mobilization. The aim of this study was to investigate the possibility of mitigating copper toxicity in female Wistar rats while supplementing with iron. METHODS: 20 female rats (160-180g) were grouped into four: Groups 1 (Control) received 0.3mls normal saline, 2- copper-toxic (100m mg/kg Copper sulphate), 3- Copper-toxic+Iron (100 mg/kg Copper sulphate + 1 mg/kg Ferrous sulphate) and 4- Iron (1 mg/kg Ferrous sulphate). All treatment was administered orally for 5 weeks. Blood was collected retro-orbitally after light anesthesia into EDTA and plain bottles for hematological, serum copper, iron, ferritin and total iron binding capacity (TIBC) analysis. Liver was excised for copper and iron levels while bone marrow was harvested for myeloid/erythroid ratio. The data were analyzed by one-Way ANOVA and statistical significance was considered at p<0.05. RESULTS: Iron supplementation significantly increased packed cell volume, hemoglobin concentration, red blood cell count and myeloid/erythroid ratio, compared to the copper-toxic group. Serum iron and TIBC were significantly increased while liver copper and iron levels reduced significantly in iron supplemented group compared to the copper-toxic group. CONCLUSIONS: Oral iron supplementation mitigated alterations in iron absorption and mobilization following copper toxicity.

Involvement of oxidative stress and pro-inflammatory cytokines in copper sulfate-induced depression-like disorders and abnormal neuronal morphology in mice.

Epidemiological studies have implicated copper as one of the key environmental risk factors for the pathogenesis of depression. However, the precise mechanism by which copper contribute to the genesis of depression particularly the involvement of oxidative stress-driven neuroinflammation is yet to be fully investigated. Thus, this study was designed to evaluate the effects of copper sulfate (CuSO4) on depression-like behaviors and the role of oxidative stress and pro-inflammatory cytokines in mice. Forty male Swiss mice were distributed into control and three test groups (n = 10), and were treated orally with distilled water (10 mL/kg) or CuSO4 (25, 50 and 100 mg/kg) daily for 28 days. Afterwards, the tail suspension, forced swim, and sucrose splash tests were used for the detection of depression-like effects. The animals were then euthanized and the brains were processed for the estimation of biomarkers of oxidative stress and pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6). The histomorphological features and neuronal viability of the prefrontal cortex, hippocampus and striatum were also determined. Mice exposed to CuSO4 displayed depression-like features when compared with controls. The brain concentrations of malondialdehyde, nitrite and pro-inflammatory cytokines were elevated in CuSO4-treated mice. Mice exposed to CuSO4 also had reduced brain antioxidant status (glutathione, glutathione-s-transferase, total thiols, superoxide-dismutase and catalase), as well as altered histomorphological features, and decreased population of viable neuronal cells. These findings suggest that CuSO4 increases oxidative stress and pro-inflammatory cytokines to elicit depression-like effects in mice.

Anti-inflammatory and antioxidant properties of rice bran oil extract in copper sulfate-induced inflammation in zebrafish (Danio rerio).

Tocotrienols have strong antioxidant properties; however, tocotrienol has not been investigated in detail in aquatic products. In this study, the anti-inflammatory and antioxidant activities of the tocotrienol-rich fraction from rice bran oil and its potential mechanism were verified in a zebrafish CuSO4 inflammation model. The in vitro antioxidant activity was evaluated using the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) stable radical method. The copper chelating activity was determined using the pyrocatechol violet method. Intracellular reactive oxygen species in zebrafish were detected using a fluorescent ROS probe. Transgenic Tg (lyz: DsRed2) zebrafish were used for neutrophil transmigration assays. The mRNA expression levels of antioxidant and pro-inflammatory factor genes were measured using quantitative real-time reverse transcription PCR. In the concentration range tested, 100 µg/mL TRF had the highest copper chelating activity (10%). TRF showed DPPH-free radical scavenging ability, which was 53% at 100 µg/mL TRF. TRF effectively repressed ROS generation and inhibited neutrophil migration to the inflamed site. Moreover, TRF upregulated the expression of antioxidant genes sod and gpx4b, inhibited the expression of pro-inflammatory factors tnfa and il8, and suppressed CuSO4-induced inflammation. In conclusion, TRF has significant anti-inflammatory and antioxidant properties, which supports the use of TRF as an aquatic feed additive to improve the anti-inflammatory and antioxidant capacity of aquatic products.

Vitamin D alleviates cognitive dysfunction and brain damage induced by copper sulfate intake in experimental rats: focus on its combination with donepezil.

This study aimed to demonstrate the potential benefits of donepezil (DPZ) and vitamin D (Vit D) in combination to counteract the neurodegenerative disorders induced by CuSO4 intake in experimental rats. Neurodegeneration (Alzheimer-like) was induced in twenty-four male Wistar albino rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. AD rats were divided into four groups: untreated AD group (Cu-AD) and three treated AD groups; orally treated for 4 weeks with either DPZ (10 mg/kg/day), Vit D (500 IU/kg/day), or DPZ + Vit D starting from the 10th week of CuSO4 intake. Another six rats were used as normal control (NC) group. The hippocampal tissue content of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 and the cortical content of acetylcholine (Ach), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Cognitive function tests (Y-maze) and histopathology studies (hematoxylin and eosin and Congo red stains) and immunohistochemistry for neurofilament. Vit D supplementation alleviated CuSO4-induced memory deficits including significant reduction hippocampal BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α and cortical AChE and MDA. Vit D remarkably increased cortical Ach, TAC, and hippocampal Bcl-2. It also improved neurobehavioral and histological abnormalities. The effects attained by Vit D treatment were better than those attained by DPZ. Furthermore, Vit D boosted the therapeutic potential of DPZ in almost all AD associated behavioral and pathological changes. Vit D is suggested as a potential therapy to retard neurodegeneration.

Modulation of quorum sensing activity by copper sulfate, potassium dichromate, and cadmium chloride in biosensor strains.

Beyond their biological roles, metals have a strong impact on the environment. It has been reported that metals are also inhibitory of Quorum Sensing (QS) mechanisms, ones of the best characterized signaling systems in bacteria and fungi. We analyzed the effect of CuSO4, CdCl2, and K2Cr2O7, on QS systems sharing or differing in the bacterial host or the QS signal. The results in this study show that CuSO4 can not only be inhibitory, but also stimulatory of QS activity: at 0.2 mM increased six fold the activity in Chromobacterium subtsugae CV026. This behavior is related to the concentration of the metal and the particular QS system: E. coli MT102 (pJBA132) was no affected, but CuSO4 decreased the QS activity of Pseudomonas putida F117 (pKR-C12) to half its control values. K2Cr2O7 increased four and three folds the QS activities of E. coli MT102 (pJBA132) and P. putida F117 (pAS-C8), respectively, but without effect when combined with CuSO4 or CdCl2. CdCl2 only showed a positive effect in CV026 when combined with CuSO4. Results suggest that factors related with the culture conditions impact on the influence of the metals, and reinforce the importance of the environment in the modulation of QS activity.

Ionomics-metabolome association analysis as a new approach to the impact of dietary copper levels in suckling piglets model.

Ionomics-metabolomics association analysis is a novel method to elucidating the potential mechanisms underlying the effects of dietary copper on the overall health parameters of suckling piglets model. Few studies have elucidated the relationship between the changes of ionic and metabolic homeostasis responses to dietary copper level. The growth performance data was obtained from 180 suckling piglets which access to different copper levels: 6 (low copper diet, LC), 20 (control diet, CON), and 300 (high copper diet, HC) mg·kg-1 copper (based on diet, supplementation from CuSO4), and offered ad libitum from d 14 until weaning at 40 d of age. Dietary high level copper (300 mg·kg-1) increased the ADG and ADFI during d 14 to 28 of piglets. Six elements (Mg, Na, K, P, Cu, and Mn) concentrations significantly changes in hair among the three treatment diets. The significant increased concentrations of Na and K, and decreased concentration of Mg and Mn in 300 mg·kg-1 than 20 mg·kg-1 copper diet was observed. In current study, with the increase in copper level from 20 to 300 mg·kg-1 in diet, the correlation between hair Na, K and Cu, Mn, Zn vanish. Hair Na and K were positively correlated with serum total antioxidant capacity (T-AOC) and negatively correlated with tumor necrosis factor-α (TNF-α). The hair Cu was negatively correlated with serum malondialdehyde (MDA), total bile acid (TBA). The fecal Cu was positively correlated with serum growth hormone (GH). The results suggested that the average daily gain (ADG) in 6 mg·kg-1 copper diet and the average daily feed intake (ADFI) in 20 mg·kg-1 copper diet were decreased than 300 mg·kg-1 copper diet during d 14 to 28 and the ADG was decreased in 6 and 20 mg·kg-1 copper diets in d 29 to 40 of piglets. Dietary 20 mg·kg-1 copper maintain ion homeostasis due to increase the number of positive correlations between macroelements-microelements in hair and serum. Significantly changed Na, K, Mg, Mn and Cu concentrations in hair can reflect the adverse effects of dietary 300 mg·kg-1 copper of suckling piglets. We believe our results may benefit people to gain a better understanding of the ion interactions and metabolic homeostasis of heavy metal elements that are critical to human and animal health.