Influence of culinary treatment on the concentration and on the bioavailability of cadmium, chromium, copper, and lead in seafood.

BACKGROUND: Seafood present important advantages for human nutrition, but it can also accumulate high levels of toxic and potentially toxic elements. Culinary treatments could influence seafood chemical element content and element bioavailability. In this study, the influence of culinary treatments on the total concentration and on the bioavailability of Cd, Cr, Cu and Pb in shark, shrimp, squid, oyster, and scallop was assessed. METHODS: Boiling, frying, and sautéing with or without seasonings (salt, lemon juice and garlic) were evaluated. Total concentration and bioavailability of Cd, Cr, Cu and Pb in seafood after all these culinary treatments were compared with those in uncooked samples. Analytes were determined by triple-quadrupole inductively coupled plasma mass spectrometry (ICP-MS/MS). An alternative to express the results avoiding underestimated or overestimated values was proposed. RESULTS: The analytes concentration in seafood without culinary treatment varied from 0.0030 µg g-1 (shrimp) to 0.338 µg g-1 (oyster) for Cd; 0.010 µg g-1 (squid) to 0.036 µg g-1 (oyster) for Cr; 0.088 µg g-1 (scallop) to 8.63 µg g-1 (oyster) for Cu, and < 0.005 µg g-1 (shrimp, squid and oyster) to 0.020 µg g-1 (shark) for Pb. Only Cd (in scallop) was influenced by culinary treatments (reduction from 37 to 53 % after boiling, frying, and sautéing). Bioavailability percentage varied from 11% (oyster) for Cd; 18% (oyster) to 41% (shark) for Cr; 6% (shark) for Cu, and 8% (oyster) for Pb. Bioavailability percentage was not influenced by culinary treatments. CONCLUSION: Cadmium concentration was reduced in scallop after some culinary treatments (reduction o 37-53% after boiling, frying, and sautéing), but bioavailability percentage was not influenced. The employed analytical method was adequate for the purpose, presenting import results for food safety assessment about the influence of culinary treatments on metals concentration and bioavailability in seafood.

Assessing the toxicity and accumulation of bulk- and nano-CuO in Hordeum sativum L.

The effects of bulk- and nano-CuO were monitored on barley (Hordeum sativum L.) in hydroponic conditions. The anatomical and cyto-/morphometric parameters of plants, exposed to both types of CuO in different doses (300 and 2000 mg/L) were recorded. The germination rate, root and shoot lengths decreased in a dose-dependent manner. Exposure to nano-CuO significantly increased Cu content in the H. sativum roots; however, the translocation rates of dissolved Cu were low and showed less accumulation in above-ground tissues. The differences between nano- and bulk-CuO treated plants were sufficiently evident, but at lower concentrations, these differences were non-significant. The relative seed germination inhibition was noted up to 11% and 22% under the high dose of bulk- and nano-CuO, respectively; however, at low dose, it was non-significant. The relative root length was reduced 3.6 fold by bulk- and 1.5 fold by nano-CuO, and shoot lengths decreased 1.6 fold by bulk- and 1.4 fold by nano-CuO under the high dose after growth of 30 days. It indicated more morphological effects on H. sativum caused by bulk- than the nano-CuO. The cytomorphometric analysis indicated the average cortex cell, total cortex, and total central cylinder areas of root cells and the average areas of chlorenchyma leaf cells were increased as compared to control in both bulk- and nano-CuO treated plants. It showed destructive effects of nano- and bulk-CuO on cellular organizations of H. sativum anatomy. Thus, at the low dose, the minimal effects of nano-CuO were observed than the bulk. Therefore, the finding could be interest for the safe application of nano-CuO.

Marriage of black phosphorus and Cu2+ as effective photothermal agents for PET-guided combination cancer therapy.

The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu2+-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu2+ into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing 64Cu2+, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an "ideal" PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.

Coupling phytoremediation efficiency and detoxification to assess the role of P in the Cu tolerant Ricinus communis L.

Phosphorous (P) fertilization is an important agronomic practice, but its role in enhancing phytoremediation efficacy and mediating detoxification has rarely been reported in environmental remediation studies. In this study, a pot experiment was undertaken to assess: firstly, the effect of P on phytoextraction of Cu by Ricinus communis L.; secondly, the potential mechanisms by differentiating the effects of the plant from that of P fertilizer (Ca(H2PO4)2); and thirdly, the role of P in physiological detoxification. Results showed that the application of P fertilizer significantly (p ≤ 0.05) increased the plant biomass as well as the Cu concentrations in plant tissues. This enhanced the phytoremediation efficiency represented by the total Cu extraction (up to 121.3 µg Cu plant-1). Phosphorous (P) fertilizer led to a negligible decline in soil pH (0.2 units) but significantly (p ≤ 0.05) reduced the concentrations of soil available in Cu and Fe, due to the formation of insoluble Cu/Fe-phosphate precipitates. Nevertheless, P fertilizer still improved the accumulation and extraction of Cu by R. communis, most likely attributable to the Fe-deficiency induced by applied P fertilizer. Moreover, the application of P fertilizer revealed a significant reduction in MDA, and a profound (p ≤ 0.05) elevation in the amount of photosynthetic pigments, GSH and AsA, along with the enhanced activities of antioxidative enzymes (SOD, POD, and CAT). In this way, Cu toxicity was alleviated. P fertilizers not only enhance the phytoremediation efficiency of Cu-contaminated soils by R. communis, but they also facilitate detoxification, which improves our understanding of the role of P in phytoremediation technologies.

Photothermal Therapy Nanomaterials Boosting Transformation of Fe(III) into Fe(II) in Tumor Cells for Highly Improving Chemodynamic Therapy.

Chemodynamic therapy based on Fe2+-catalyzed Fenton reaction holds great promise in cancer treatment. However, low-produced hydroxyl radicals in tumor cells constitute its severe challenges because of the fact that Fe2+ with high catalytic activity could be easily oxidized into Fe3+ with low catalytic activity, greatly lowering Fenton reaction efficacy. Here, we codeliver CuS with the iron-containing prodrug into tumor cells. In tumor cells, the overproduced esterase could cleave the phenolic ester bond in the prodrug to release Fe2+, activating Fenton reaction to produce the hydroxyl radical. Meanwhile, CuS could act as a nanocatalyst for continuously catalyzing the regeneration of high-active Fe2+ from low-active Fe3+ to produce enough hydroxyl radicals to efficiently kill tumor cells as well as a photothermal therapy agent for generating hyperthermia for thermal ablation of tumor cells upon NIR irradiation. The results have exhibited that the approach of photothermal therapy nanomaterials boosting transformation of Fe3+ into Fe2+ in tumor cells can highly improve Fenton reaction for efficient chemodynamic therapy. This strategy was demonstrated to have an excellent antitumor activity both in vitro and in vivo, which provides an innovative perspective to Fenton reaction-based chemodynamic therapy.

Multifunctional Magnetic Copper Ferrite Nanoparticles as Fenton-like Reaction and Near-Infrared Photothermal Agents for Synergetic Antibacterial Therapy.

Synergistic therapeutic strategies for bacterial infection have attracted extensive attentions owing to their enhanced therapeutic effects and less adverse effects compared with monotherapy. Herein, we report a novel synergistic antibacterial platform that integrates the nanocatalytic antibacterial therapy and photothermal therapy (PTT) by hemoglobin-functionalized copper ferrite nanoparticles (Hb-CFNPs). In the presence of a low concentration of hydrogen peroxide (H2O2), the excellent Fenton and Fenton-like reaction activity of Hb-CFNPs can effectively catalyze the decomposition of H2O2 to produce hydroxyl radicals (·OH), rendering an increase in the permeability of the bacterial cell membrane and the sensitivity to heat. With the assistance of NIR irradiation, hyperthermia generated by Hb-CFNPs can induce the death of the damaged bacteria. Additionally, owing to the outstanding magnetic property of Hb-CFNPs, it can improve the photothermal efficiency by about 20 times via magnetic enrichment, which facilitates to realize excellent bactericidal efficacy at a very low experimental dose (20 µg/mL). In vitro antibacterial experiment shows that this synergistic antibacterial strategy has a broad-spectrum antibacterial property against Gram-negative Escherichia coli (E. coli, 100%) and Gram-positive Staphylococcus aureus (S. aureus, 96.4%). More importantly, in vivo S. aureus-infected abscess treatment studies indicate that Hb-CFNPs can serve as an antibacterial candidate with negligible toxicity to realize synergistic treatment of bacterial infections through catalytic and photothermal effects. Accordingly, this study proposes a novel, high-efficiency, and multifunctional therapeutic system for the treatment of bacterial infection, which will open up a new avenue for the design of synergistic antibacterial systems in the future.

Clearable Theranostic Platform with a pH-Independent Chemodynamic Therapy Enhancement Strategy for Synergetic Photothermal Tumor Therapy.

Chemodynamic therapy (CDT) is an emerging field, which utilizes intratumoral iron-mediated Fenton chemistry for cancer therapy. However, the slightly acidic tumor environment is improper for the classical Fenton reaction, which is generally energetic in a narrow pH range (e.g., pH = 3-4). Herein, a kind of ultrasmall bovine serum albumin (BSA)-modified chalcopyrite nanoparticles (BSA-CuFeS2 NPs) was synthesized via a facile aqueous biomineralization strategy, which shows high dispersity and biocompatibility. Interestingly, the obtained BSA-CuFeS2 shows a pH-independent Fenton-like reaction, which could exert Fenton-like activity to efficiently generate •OH under a weak acidic tumor environment. Combined with the extraordinarily high photothermal conversion (38.8%), BSA-CuFeS2 shows the synergistic function of high photothermal therapy (PTT) and enhanced CDT, that is, PTT/CDT. Importantly, such ultrasmall BSA-CuFeS2 NPs measuring around 4.9 nm can be quickly cleared out of the body through kidneys and liver, thus effectively avoiding long-term toxicity and systemic toxicity. Moreover, BSA-CuFeS2 NPs can act as an efficient T2-weighted magnetic resonance imaging (MRI) contrast agent to guide tumor ablation in vivo. This work offers a universal approach to boost production •OH by a pH-independent Fenton-like reaction strategy and achieves MRI-guided synergistic enhanced photothermal-CDT for highly efficient tumor treatment.

The combined effects of Cr(III) propionate complex supplementation and iron excess on copper and zinc status in rats.

It is suggested that both iron overload and chromium(III) deficiency may be risk factors of diabetes. It seems that both Fe and Cr(III) metabolism as well as copper and zinc metabolism are interrelated. However, the direction of these changes may depend on mutual proportions of these elements in the diet and organism. The aim of the study was to evaluate the combined effects of Cr(III) supplementation with Fe excess on the Cu and Zn status in female rats. Thirty-six healthy rats were divided into 6 experimental groups with different Fe levels in the diet. Groups marked with C (control) contained Fe at the recommended level (45 mg kg-1). The excess groups (E) contained Fe at 180 mg kg-1. At the same time the animals were supplemented with Cr(III) of doses 1, 50 and 500 mg kg-1 of diet. The Cr, Fe, Cu and Zn dietary and tissular contents were measured with the AAS method.The excess Fe in the diet significantly decreased the Cu content in the liver and kidneys, but it increased the spleen Cu level. The Cr(III) supplementary did not affect the tissular Cu levels, regardless of Fe supply with diet. The experimental factors did not have significant interactional effect on the Cu status parameters under study.The Fe excess in the diet reduced the renal and splenic Zn content, but increased the heart Zn content. The Cr(III) supplementation decreased the Zn content in the kidneys. The Zn content in the liver and spleen tended to decrease as the Cr(III) supply in the diet increased. There was no significant interactional effect of Cr(III) supplementation and the Fe excessive supply in diet on the parameters of Zn metabolism in Wistar rats. Iron oversupply disturbed the rat's Cu and Zn status. However, Cr(III) supplementation did not affect the tissular levels of these elements, except the kidney Zn content. Simultaneous supplementation with the Cr(III) propionate complex did not deepen changes in tissular Cu and Zn levels caused by the Fe excess in the diet.

Copper complexes for biomedical applications: Structural insights, antioxidant activity and neuron compatibility.

Copper coordinated with amino acid residues is essential for the function of many proteins. In addition, copper complexed to free l-Histidine, as [Cu(His)2], is used in the treatment of the neurodegenerative Menkes disease and of cardioencephalomyopathy. This study was aimed to coordinate copper(II) with four small ligands (l-Serine, l-Histidine, Urea and Biuret) and to evaluate structural features, stability, antioxidant activity and neuronal compatibility of the resulting complexes. All complexes were synthesized with CuCl2 and purified by precipitation in alcohol. Elemental composition, X-rays diffraction and FTIR indicated that the complexes were in form of [Cu(ligand)2] and exhibited tridentate (l-Histidine), bidentate (l-Serine and Biuret) or monodentate (Urea) coordination with copper. UV-Vis absorbance profiles in physiologically relevant solutions and cyclic voltammetry revealed that, contrarily to [Cu(Urea)2Cl2] and [Cu(Biuret)2Cl2], the [Cu(Ser)2] and [Cu(His)2Cl2] complexes were stable in different media including water, physiological saline and intestinal-like solutions. All complexes and their ligands had antioxidant capacity as evaluated by DPPH (1,1-diphenyl-2,2-picrylhydrazyl) and DPD (N,N-diethyl-p-phenylenediamine) methods, and the [Cu(His)2Cl2] complex was the most potent. Neuronal compatibility was assessed through cell viability measurements using cultured neurons derived from mouse P19 stem cells. Although only [Cu(His)2Cl2] showed a good neurocompatibility (about 90% at concentrations up to 200 µM), the cytotoxicity of the other copper complexes was lower compared to equivalent concentrations of CuCl2. These findings open new perspectives for the use of these copper complexes as antioxidants and possibly as therapeutic agents for neurodegenerative diseases. Furthermore, study of these complexes may help to improve chelation therapy for copper dysfunctions.

Relative bioavailability of organic and hydroxy copper sources in growing steers fed a high antagonist diet1.

To assess relative bioavailability (RBV) of hydroxy and organic Cu sources compared with CuSO4 in steers fed a high Cu antagonist diet, 84 steers were stratified by BW to pens randomly assigned to dietary treatments for 90 d. Steers received a common corn silage-based diet supplemented with Cu antagonists (diet analyzed 0.25% S; 6.8 mg Mo/kg DM). Supplemental (SUPP) Cu treatments included: control (CON; no SUPP Cu), low or high inorganic (ING5 or ING10; 5 or 10 mg Cu/kg DM from CuSO4; Old Bridge Chemical Inc., Old Bridge, NJ, USA), low or high organic (ORG5 or ORG10; 5 or 10 mg Cu/kg DM from Cu lysine; CuPlex 100, ZinPro Corp., Eden Prairie, MN), and low or high hydroxy (HYD5 or HYD10; 5 or 10 mg Cu/kg DM; IntelliBond CII, Micronutrients USA LLC, Indianapolis, IN). Body weights were recorded on days -7, -6, 28, 56, 84, and 85, and plasma samples collected on days -7, 28, 56, and 85. Liver samples were collected to start and end the trial. Data were analyzed using the mixed procedure of SAS and the model included treatment with initial liver Cu values used as a covariate in analysis of final liver Cu. Contrast statements were used to separate treatment means: 0 vs. 5 mg SUPP Cu/kg DM, 0 vs. 10 mg SUPP Cu/kg DM, 5 vs. 10 mg SUPP Cu/kg DM, HYD vs. ORG, HYD vs. ING, and ORG vs. ING. Initial liver Cu concentrations were similar across all treatment comparisons (P ≥ 0.22). Final liver Cu concentrations were lesser in CON compared with either 5 or 10 mg Cu/kg DM (P ≤ 0.001). Final liver concentrations were lesser in ORG compared with HYD and ING (P ≤ 0.009), but HYD was similar to ING (P = 0.14). There was a treatment × time interaction (P ≤ 0.001) for plasma Cu concentrations where CON exhibited a rapid decline in plasma Cu, steers receiving 5 mg SUPP Cu/kg DM were decreased to a greater extent in ORG, and steers supplemented with 10 mg Cu/kg DM did not differ at the end of the trial. Assessment of RBV was conducted for liver and plasma Cu concentrations using a slope-ratio assay in the GLM procedure. The RBV of Cu tended (P = 0.07) to be increased in HYD (112%) compared with ING (100%) for liver Cu values, but RBV was similar for all other source comparisons based on liver and plasma Cu values (P ≥ 0.22). These data suggest in steers fed high antagonist diets hydroxy Cu may be more available. Based on plasma and liver Cu concentrations, supplementation of 10 mg Cu/kg DM is needed to maintain Cu status in cattle fed diets high in S and Mo.

Hollow CuS nanocube as nanocarrier for synergetic chemo/photothermal/photodynamic therapy.

Here, hollow CuS nanocubes about 250-300 nm in size were synthesized based on the Kirkendall effect by using CuO nanocubeas precursor and template. The reactant concentration and reaction time could be adopted to adjust the final composition and hollow structure. The as-synthetic CuS nanocube was assembled by a great deal of nanoparticles (15-20 nm), making abundant porous structure in the shell layer. The localized surface plasmon resonance and the novel porous hollow structure (improve light reflex) further make sure the enhanced Near-infrared (NIR) light absorption as well as photothermal conversion efficiency (30.3%). Moreover, the mechanism of reactive oxygen species (ROS) generation was investigated in detail, revealing that the released Cu+ ion and the oxygen are the determined factors. To further improve the monodispersity and biocompatibility, PEG-NH2 modified nanostructure (CuS@PEG) was prepared and it possessed high loading efficiency to doxorubicin hydrochloride (DOX). Moreover, DOX-CuS@PEG reveals the acid and NIR sensitive-release performance. The synergistic effect of chemotherapy associated with photothermal therapy (PTT) and photodynamic therapy (PDT) display the enhanced specific cytotoxicity to cancer cells.

Phase-Change Material Packaged within Hollow Copper Sulfide Nanoparticles Carrying Doxorubicin and Chlorin e6 for Fluorescence-Guided Trimodal Therapy of Cancer.

Environmental stimuli, including pH, light, and temperature, have been utilized for activating controlled drug delivery to achieve efficient antitumor therapeutics while minimizing undesirable side effects. In this study, a multifunctional nanoplatform based on hollow mesoporous copper sulfide nanoparticles (H-CuS NPs) was developed by loading the interior cavity of the NPs with a drug-loaded phase-change material (PCM, 1-tetradecanol). Doxorubicin (DOX) and chlorin e6 (Ce6) were selected as the model chemotherapeutic drug and photosensitizer, respectively, which were encapsulated in H-CuS NPs via the PCM to form H-CuS@PCM/DOX/Ce6 (HPDC) NPs. When exposed to near infrared laser irradiation, this nanocomplex could produce a strong photothermic effect and thus induce the controlled release of DOX and Ce6 from the melting PCM. Subsequently, the DOX-mediated chemotherapeutic effect and Ce6-mediated photodynamic effect further contributed to enhanced tumor eradication. The efficacy of this multimodal cancer treatment combining chemo-, photothermal, and photodynamic therapies was systematically evaluated both in vitro and in vivo using a 4T1 mouse mammary tumor cell line and a mouse model bearing breast cancer. Moreover, this nanoplatform exhibited minimal systemic toxicity and good hemocompatibility and may provide an effective strategy for the delivery of multiple therapeutic agents and application of multimodal cancer treatments.

Polydopamine-mediated bio-inspired synthesis of copper sulfide nanoparticles for T1-weighted magnetic resonance imaging guided photothermal cancer therapy.

Copper sulfide nanoparticles(CuS NPs) have attracted considerable interest in the field of photothermal therapy(PTT) due to its low cost, easy preparation and favorable photothermal effect. However, lack of reliable visualization and relatively poor biocompatibility restrict its further bio-application. To overcome these limitations, polydopamine(PDA, a melanin-like biopolymer) stabilized CuS NPs and further chelated with iron ions (denoted as CuPDF) were designed as a versatile nanoplatform for T1-weighted MR imaging-guided PTT. In this system, PDA served as both bio-template to synthesis CuS NPs and an active platform to give MRI diagnostic capability. The as-prepared CuPDF NPs demonstrated strong absorption at NIR region, nearly three times higher than that of pure PDA NPs at 808 nm. Moreover, toxicity studies and histology evalution verified that CuPDF NPs possess excellent biocompatibility. In addition, CuPDF NPs showed significant MRI signal enhancement with high longitudinal relaxivity (r1 = 4.59 mM-1 s-1). In vivo MRI and biodistribution test confirmed the efficient accumulation of CuPDF NPs in the tumor region. After intravenous injection of CuPDF, irreversible tumor ablation was successfully achieved without inducing any obvious side effects by using 808-nm laser irradiation. All in all, these results indicated that the developed CuPDF NPs hold great potential as an effective theranostic agent for MR imaging guided PTT in vivo.

Cu-Fe-Se Ternary Nanosheet-Based Drug Delivery Carrier for Multimodal Imaging and Combined Chemo/Photothermal Therapy of Cancer.

Ternary transition-metal chalcogenide nanosheets have shown great potential in diverse applications owing to their intrinsically amazing properties with a broad tunable window. Direct preparation of water-soluble and biocompatible ternary chalcogenide nanosheets for theranostic application remains a challenge. In this article, we prepared Cu-Fe-Se nanosheets (CFS NSs) in an aqueous solution under ambient conditions by a sequential coprecipitation method. They were functionalized with anticancer drug doxorubin (CFS@DOX) through electrostatic interactions and labeled with radioactive isotope 99mTc through surface coordination effect. The resulting nanosheets have a size of 70 nm and a thickness of 5 nm, and can be well dispersed in water, phosphate-buffered saline, 10% fetal bovine serum, and 0.9% NaCl with an excellent colloidal stability. They also exhibit a high photothermal conversion efficiency of 78.9% for in vitro and in vivo photoacoustic imaging and photothermal therapy. The isotope-labeled nanosheets (99mTc-CFS NSs) were used for single photon emission computed tomography/computed tomography imaging to quantify their blood circulation time (∼4.7 h) and biodistributions in major organs, which follow an order of liver > bladder > lung > spleen > heart > kidney. The DOX-functionalized nanosheets (CFS@DOX) were used for chemotherapy of cancer and exhibited excellent anticancer efficacy. Our research shows the great promise of ternary metal chalcogenide nanosheets for combined imaging and therapy of cancer.

A Modular Ionophore Platform for Liver-Directed Copper Supplementation in Cells and Animals.

Copper deficiency is implicated in a variety of genetic, neurological, cardiovascular, and metabolic diseases. Current approaches for addressing copper deficiency rely on generic copper supplementation, which can potentially lead to detrimental off-target metal accumulation in unwanted tissues and subsequently trigger oxidative stress and damage cascades. Here we present a new modular platform for delivering metal ions in a tissue-specific manner and demonstrate liver-targeted copper supplementation as a proof of concept of this strategy. Specifically, we designed and synthesized an N-acetylgalactosamine-functionalized ionophore, Gal-Cu(gtsm), to serve as a copper-carrying "Trojan Horse" that targets liver-localized asialoglycoprotein receptors (ASGPRs) and releases copper only after being taken up by cells, where the reducing intracellular environment triggers copper release from the ionophore. We utilized a combination of bioluminescence imaging and inductively coupled plasma mass spectrometry assays to establish ASGPR-dependent copper accumulation with this reagent in both liver cell culture and mouse models with minimal toxicity. The modular nature of our synthetic approach presages that this platform can be expanded to deliver a broader range of metals to specific cells, tissues, and organs in a more directed manner to treat metal deficiency in disease.

CuS@MOF-Based Well-Designed Quercetin Delivery System for Chemo-Photothermal Therapy.

Quercetin (QT) is one promising candidate for the treatment of various cancers with virtually no toxic side effects. However, its anticancer effect is severely restricted by its poor bioavailability, low water solubility, and chemical instability in the neutral and alkaline medium. Herein, zeolitic imidazolate framework-8 (ZIF-8) is first reported as the multifunctional nanoplatform to the codelivery of quercetin as an anticancer agent and CuS nanoparticles as a photothermal therapy (PTT) agent for synergistic combination of chemotherapy and PTT as well as overcoming the drawbacks of quercetin. Moreover, folic acid-bovine serum albumin (FA-BSA) conjugates are applied to stabilize the CuS@ZIF-8-QT to promote the bioavailability of quercetin and realize active-targeting drug delivery. Near-infrared (NIR) fluorescent imaging demonstrated the highly increased drug accumulations of FA-BSA/CuS@ZIF-8-QT in tumors, resulting from efficient internalization via FA-receptors-mediated endocytosis. The results of in vivo and in vitro anticancer experiments demonstrate that quercetin and PTT agent can work together efficiently under NIR irradiation, thus remarkably improving the anticancer effect. Therefore, our newly designed FA-BSA/CuS@ZIF-8-QT multifunctional drug delivery system might be a promising nanoplatform for cancer treatment.

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse.

BACKGROUND: Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (MoMl/y) mice, a mouse model of Menkes disease. METHODS: CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed. RESULTS: CuGTSM treatment extended the lifespan of MoMl/y mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling MoMl/y mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum. CONCLUSION: Oral administration of CuGTSM extended the lifespan of MoMl/y mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.

Copper supplementation reverses dietary iron overload-induced pathologies in mice.

Dietary iron overload in rodents impairs growth and causes cardiac hypertrophy, serum and tissue copper depletion, depression of serum ceruloplasmin (Cp) activity and anemia. Notably, increasing dietary copper content to ~25-fold above requirements prevents the development of these physiological perturbations. Whether copper supplementation can reverse these high-iron-related abnormalities has, however, not been established. The current investigation was thus undertaken to test the hypothesis that supplemental copper will mitigate negative outcomes associated with dietary iron loading. Weanling mice were thus fed AIN-93G-based diets with high (>100-fold in excess) or adequate (~80 ppm) iron content. To establish the optimal experimental conditions, we first defined the time course of iron loading, and assessed the impact of supplemental copper (provided in drinking water) on the development of high-iron-related pathologies. Copper supplementation (20 mg/L) for the last 3 weeks of a 7-week high-iron feeding period reversed the anemia, normalized serum copper levels and Cp activity, and restored tissue copper concentrations. Growth rates, cardiac copper concentrations and heart size, however, were only partially normalized by copper supplementation. Furthermore, high dietary iron intake reduced intestinal 64Cu absorption (~60%) from a transport solution provided to mice by oral, intragastric gavage. Copper supplementation of iron-loaded mice enhanced intestinal 64Cu transport, thus allowing sufficient assimilation of dietary copper to correct many of the noted high-iron-related physiological perturbations. We therefore conclude that high- iron intake increases the requirement for dietary copper (to overcome the inhibition of intestinal copper absorption).

Tumor-targeting CuS nanoparticles for multimodal imaging and guided photothermal therapy of lymph node metastasis.

Precise diagnosis of lymph node metastasis to guide lymphadenectomy is highly important for gastric cancer therapy in clinics. Though surgical dissection of regional metastatic lymph nodes remains the only way for gastric cancer therapy, the extended dissection may cause unavoidable postoperative risk of complications. It is still lack of effective method enabling the accurate removal of metastatic gastric cancer cells in lymph nodes with minimum injuries to normal tissue. Herein, we report a new fluorescent copper sulfide (CuS) nanoparticle (RGD-CuS-Cy5.5) enabling both non-invasive multimodality imaging and targeting photothermal therapy (PTT) of metastatic gastric cancer cells in lymph nodes. We demonstrate that RGD-CuS-Cy5.5 can easily drain into sentinel lymph nodes (SLN) after injection into primary tumors, and selectively enter into metastatic gastric MNK45 tumor cells via αvß3 integrin-mediated endocytosis. The resulting strong near-infrared (NIR) fluorescence and computed tomography (CT) contrast in metastatic SLN compared to normal SLN can precisely differentiate SLN metastasis of gastric cancers. Guided by the imaging, localized PTT with RGD-CuS-Cy5.5 is conducted upon irradiation with an 808 nm laser, resulting in complete removal of metastatic gastric tumor cells in SLN without obvious toxicity. Moreover, RGD-CuS-Cy5.5 can also allow for the rapid and non-invasive self-monitoring of PTT efficacy against metastatic SLNs in living mice. This study highlights the potential of using RGD-CuS-Cy5.5 for imaging-guided and targeting PTT of SLN metastasis in vivo, which may be applicable for the metastatic gastric cancer therapy in clinics. STATEMENT OF SIGNIFICANCE: RGD-CuS-Cy5.5 nanoparticles possess NIR fluorescence and CT signals for in vivo bimodality imaging of lymph node metastasis. Strong photothermal property under irradiation at 808 nm for efficient PTT. Easy drain into sentinel lymph nodes and selective enter metastatic gastric cancer cells via αvß3 integrin-mediated endocytosis. Rapid and non-invasive monitoring of therapeutic efficacy against lymph node metastasis.

Serum and dietary zinc and copper in Iranian girls.

OBJECTIVE: Girls with micronutrient deficiencies may have impaired growth and development, and furthermore this may also impact on their childbearing. We have investigated the relationship between serum zinc and copper concentrations, dietary zinc and copper intake and anthropometric and demographic parameters, and cardiovascular risk factors, in 408 girls living in northeastern Iran. METHODS: A total of 408 healthy girls, aged 12-18 years old, were included in our study. Serum zinc and copper concentrations were measured by flame atomic absorption (Varian AA240FS) and zinc and copper intake were assessed using a 3-day dietary record. RESULTS: There was a weak correlation between serum and dietary zinc intake (r = 0.117, p = 0.018). The correlation between serum and dietary copper approached significance (r = -0.094, p = 0.056). The mean serum zinc and copper concentrations were 14.61 ±â€¯2.71 µmol/L and 19.48 ±â€¯8.01 µmol/L respectively. Height, total cholesterol (TC) and low-density lipoprotein (LDL) were positively correlated with serum copper concentration. Subjects with high serum copper concentrations (>24 µmol/L) were found to have a significantly higher fasting blood glucose (FBG) compared to subjects with normal, or low serum copper concentrations (p = 0.033). Girls who were in the 5th percentile or greater for height were found to have higher serum copper concentrations than girls in other height categories. CONCLUSION: There was a weak relationship between dietary and serum concentrations of zinc. Copper status was associated with anthropometric and biochemical parameters, including FBG and lipid profile. Further studies are required to define the role of copper in metabolic health.