Association between dietary copper intake and bone mineral density in children and adolescents aged 8-19 years: A cross-sectional study.

PURPOSE: Some studies showed the possible role of copper intake on bone mineral density (BMD) in adults or the elderly, but the association remained uncertain in children and adolescents. Our research explored the association between copper intake and BMD in individuals aged 8-19 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2016. METHODS: In the present study, 6,965 individuals aged 8-19 (mean age 13.18 ± 3.38 years) were enrolled from the NHANES 2011-2016. Copper intake was evaluated by averaging two 24-hour copper dietary intake recalls. Multivariate linear regression analyses were used to explore the association between copper intake and total BMD, subtotal BMD, and total spine BMD in children and adolescents. Stratified analyses and interaction tests were performed by age, gender, and race. RESULTS: Participants of the higher quartile of copper intake were more likely to be older, men, Non-Hispanic White, and Other Hispanic. They have higher values of poverty income ratio (PIR), serum phosphorus, blood urea nitrogen, serum vitamin D, and BMD and lower values of body mass index (BMI), cholesterol, total protein, and serum cotinine. In the fully adjusted model, we found positive associations between copper intake and total BMD (ß = 0.013, 95CI: 0.006, 0.019)), subtotal BMD (ß = 0.020, 95CI: 0.015, 0.024), and total spine BMD (ß = 0.014, 95CI: 0.009, 0.019). Stratified analyses showed that the association was stronger in men, individuals aged 14-19, Non-Hispanic White, and Other Hispanic. CONCLUSIONS: Our study suggests that copper intake is positively associated with BMD in U.S. children and adolescents. The study emphasizes the role of copper intake on bone health in the early stages of life. However, more investigations are needed to verify our findings and their underlying mechanisms.

Prolonged Copper Supplementation Modified Minerals in the Kidney, Liver and Blood, and Potentiated Oxidative Stress and Vasodilation of Isolated Aortic Rings in Young Wistar Rats.

BACKGROUND: Previous studies have highlighted that copper supplementation at 200% of the recommended daily dietary allowance modified vascular contraction and relaxation through increased reactive oxygen species (ROS) and prostaglandin formation, which modified the antioxidant status of middle-aged Wistar rats. METHODS: In this study, young (1 month old) male Wistar rats (n/group = 10) received a diet supplemented with 6.45 mg copper/kg (100% of daily recommendation-Group A) for 8 weeks. The experimental group received 12.9 mg copper/kg of diet (200% of the daily recommendation-Group B). RESULTS: Experimental supplementation with 200% copper modified the copper concentration in the blood (1.21-fold, p = 0.04), liver (1.15-fold, p = 0.032), and kidneys (1.23-fold, p = 0.045), potentiated the ROS formation in the aortic rings, and enhanced the sensitivity of the aortic rings to the vasodilator acetylcholine. We observed an increased participation of nitric oxide (NO) derived from inducible NO synthase (iNOS) in vascular contraction and a decreased net effect of vasodilator prostanoids derived from cyclooxygenase-2 in vascular relaxation. In rat kidneys, the concentrations of potassium (1.08-fold, p = 0.001) and iron (1.13-fold, p = 0.046) were higher, while, calcium (0.88-fold, p = 0.001) and chromium (0.77-fold, p = 0.005) concentrations were lower. In the rat liver, magnesium (1.06-fold, p = 0.012) was higher. No differences were observed in the concentrations of sodium, zinc, manganese, selenium, cobalt, molybdenum, and vanadium. The antioxidant activity of water- and lipid-soluble compounds; total antioxidant status in the blood; and superoxide dismutase, catalase, and malondialdehyde levels in the heart did not change. CONCLUSIONS: In young rats, prolonged supplementation with 200% copper had a lesser effect than anticipated on oxidative stress and vascular reactivity. Detailed data on the status of trace elements and their interactions in patients of different age groups are strongly required for effective nutritional and therapeutic intervention.

U-shaped nonlinear relationship between dietary copper intake and peripheral neuropathy.

BACKGROUND: Dietary copper intake is a promising predictor of peripheral neuropathy. There is no research exploring the potential link between dietary copper intake and peripheral neuropathy. METHODS: The information utilized in our research was collected from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004. The relationship between dietary copper intake and peripheral neuropathy was analyzed using a multivariate logistic regression model and restricted cubic spline (RCS). RESULTS: The RCS analysis results showed a U-shaped nonlinear relationship between dietary copper intake and peripheral neuropathy (P for nonlinearity < 0.001). The threshold effect analysis results indicated that when dietary copper intake was less than 0.889 mg/d, the risk of peripheral neuropathy decreased with increasing copper intake (OR: 0.388, 95% CI: 0.200-0.753). When dietary copper intake was ≥ 0.889 mg/d, the risk of peripheral neuropathy increased with increasing copper intake (OR: 1.129, 95% CI: 1.006-1.266). And the incidence rate of peripheral neuropathy in the first quantile (OR: 1.421, 95% CI: 1.143-1.766), the third quantile (OR: 1.358, 95% CI: 1.057-1.744), and the fourth quantile (OR: 1.676, 95% CI: 1.250-2.248) of dietary copper intake were significantly higher than that in the second quantile (where the inflection point was located). CONCLUSION: Our study suggests that both insufficient and excessive dietary copper intake may be associated with an increased incidence of peripheral neuropathy. However, further research is needed to provide definitive evidence and confirm these findings.

Effects of reducing copper and zinc supplementation on the performance and mineral status of fattening pigs.

Pig manure with high copper (Cu) and zinc (Zn) concentration is applied to the soil, and these trace minerals can accumulate in the topsoil and decrease its fertility. Thus, adjusting concentrations of Cu and Zn in pig diets below current maximum allowance can prevent this risk. Reduction of dietary concentrations of Cu and Zn reduces their faecal excretion since only a small portion is retained in the pig's body. The aim of this study was to evaluate the effects of reducing concentration of dietary Cu and Zn or withdrawing their supplementation on the performance and mineral status of fattening pigs. Four dietary treatments were compared: a basal diet (WS; withdraw supplementation), with no Cu or Zn supplementation (5 and 29 mg/kg of native Cu and Zn, respectively); intermediate concentration (OINT), supplemented with Cu and Zn oxides to obtain mean dietary concentration of 7.4 and 47.5 mg/kg of Cu and Zn, respectively; and two diets supplemented with oxides (OREG) or sulphates (SREG) at concentration similar to European Union limits (i.e. 25 and 120 mg/kg of total Cu and Zn, respectively), as commonly used on commercial farms. Ninety-six pigs (24.3 ± 3.3 kg BW) were each assigned to one of the four treatments and reared in individual pens for 14 weeks (up to 110.3 ± 8.9 kg BW). Animal performances were measured, and samples of plasma (on day 1 and day 41 of experimentation and at slaughter), bones and the liver (at slaughter) were collected from all pigs. Faecal samples were collected from all pigs every 3 weeks to determine the Cu and Zn excretion. Over the entire experiment, neither the concentration nor the source of Cu and Zn influenced feed intake, BW or the feed conversion ratio. Plasma Cu and Zn concentrations were not influenced by the treatment but increased as the age of the pigs increased. Liver Cu concentration increased (P < 0.05) as dietary concentrations increased (OREG> WS). Neither the concentration nor the source of Cu and Zn influenced bone Cu and Zn concentration or physical bone parameters. However, SREG had a higher maximum load until bone breaking (P < 0.05) than OREG. As expected, faecal excretion of Cu and Zn decreased (P < 0.01) as dietary concentration decreased. Dietary Cu and Zn can be reduced without decreasing the performance or mineral status of pigs, and these results should be validated on commercial farms that have more challenging health conditions.

Biofilm-camouflaged Prussian blue synergistic mitochondrial mass enhancement for Alzheimer's disease based on Cu2+ chelation and photothermal therapy.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases characterized by cognitive and memory impairment. Metal ion imbalance and Mitochondrial dysfunction, leading to abnormal aggregation of ß-amyloid protein (Aß), are key factors in the pathogenesis of AD. Therefore, we designed a composite nanometer system of red blood cell (RBC) membranes-encapsulated Prussian blue nanoparticles (PB/RBC). Prussian blue nanoparticles (PBNPs) can chelate Cu2+ and reduce reactive oxygen species (ROS). The RBC membranes are a kind of natural long-lasting circulating carrier. At the same time, through NIR irradiation, the excellent photothermal ability of PBNPs can also temporarily open the blood-brain barrier (BBB), enhance the transmission efficiency of PB/RBC across the BBB, and depolymerize the formed Aß deposits, thereby achieving the optimal therapeutic effect. In vitro and in vivo studies demonstrated that PB/RBC could inhibit Cu2+-induced Aß monomers aggregation, eliminate the deposition of Aß plaques, improve the quality of mitochondria, restore the phagocytic function of microglia, alleviate neuroinflammation in APP/PS1 mice, and repair memory damage. In conclusion, our biofilm-camouflaged nano-delivery system provides significant neuroprotection by inhibiting Cu2+-induced Aß monomers aggregation, photothermally depolymerizing Aß fibrils and reducing the level of ROS, thus effectively ameliorating and treating AD.

NIR-triggered and Thermoresponsive Core-shell nanoparticles for synergistic anticancer therapy.

Recent advancements in cancer treatment have underscored the inadequacy of conventional monotherapies in addressing complex malignant tumors. Consequently, there is a growing interest in synergistic therapies capable of overcoming the limitations of monotherapies, leading to more personalized and effective approaches. Among these, the combination of photothermal therapy (PTT) and chemotherapy has emerged as a promising avenue for tumor management. In this study, we present a novel approach utilizing thermoresponsive mesoporous silica nanoparticles (MSN) as a delivery system for the chemotherapeutic drug doxorubicin. By incorporating photothermal agent copper sulfide (CuS) nanoparticles into the MSN, the resulting composite material exhibits potent photothermal properties. Furthermore, the integration of an upper critical solution temperature (UCST) polymer within the silica outer layer serves as a "gatekeeper", enabling precise control over drug release kinetics. This innovative nanomaterial effectively merges thermoresponsive behavior with PTT, thereby minimizing the collateral damage associated with traditional chemotherapy on healthy tissues. Moreover, in both in vitro studies using mouse breast carcinoma cells (4 T1) and in vivo experiments utilizing a 4 T1 tumor-bearing mouse model, our nanomaterials demonstrated synergistic effects, enhancing the anti-tumor efficacy of combined PTT and chemotherapy. With its remarkable photothermal conversion efficiency, robust stability, and biocompatibility, the UCST-responsive nanoplatform holds immense potential for clinical applications.

Dietary Intakes of Copper and Selenium in Association with Bone Mineral Density.

The important trace elements, copper and selenium, have diverse effects on human health. As well as other important roles in living tissues, these trace elements are toxic at high levels but are key constituents of various enzymes and proteins essential for maintaining physiological health. However, links between dietary intakes of these elements, particularly copper, and bone mineral density (BMD) in humans remain uncertain. This study aimed to investigate whether dietary intakes of copper and selenium are associated with BMD in women. Dietary intakes of copper and selenium were assessed for 575 women in the Geelong Osteoporosis Study, using a detailed semi-quantitative food frequency questionnaire in conjunction with nutrition composition databases. Participants taking oral multivitamin preparations were excluded from analyses; 522 participants (ages 20-88 y) met the eligibility criteria. BMD at multiple skeletal sites was measured by dual energy X-ray absorptiometry (Lunar DPX-L). Separate multivariable regression models were developed to identify associations between copper and selenium intakes and BMD, after adjustments for age, anthropometry, other dietary factors, medication use, and lifestyle factors. Median (interquartile range) daily intake for copper was 1.5 mg (1.2-1.9) and for selenium, 72 µg (57-90). Low intakes (lowest tertile versus pooled upper tertiles) of copper and selenium were consistently associated with lower BMD at multiple skeletal sites. Fully adjusted models identified small but statistically significant differences in BMD, ranging from 1.8% to 4.0% for low copper intakes and 1.4% to 4.0% for low selenium intakes. Low dietary intakes of copper and selenium were both independently associated with lower BMD, at least in this sample of women. The results contribute to the evidence base for informing dietary recommendations for these trace elements with respect to their contributions to optimal bone health.

Association between dietary copper intake and constipation in US adults.

Dietary micronutrients are integral to the development and progression of constipation; however, the specific relationship between dietary copper intake and constipation has not been thoroughly investigated. This study aims to examine the correlation between dietary copper intake and constipation among U.S. adults, thereby offering novel insights and recommendations for the clinical management and prevention of constipation. Bowel health data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2010 were analyzed. Subjects' dietary information was collected through questionnaire records. Multivariate logistic regression analysis, subgroup analysis, and curve fitting analysis were used to assess the correlation between dietary copper intake and chronic constipation. After adjusting for all possible confounders, each unit increase in dietary copper intake (converted to natural logarithms) was associated with a 20% reduction in the prevalence of constipation (OR = 0.80; 95% CI 0.65-0.98; P = 0.037). The interaction P-values for all subgroups were greater than 0.05, indicating that the findings were stable and consistent across subgroups. The present study showed a significant negative association between dietary copper intake and chronic constipation in adults. This finding raises clinical and healthcare professionals' awareness of the impact of dietary trace elements on intestinal health and has important implications for the development of personalized meal plans and rational supplementation of trace copper in patients with constipation.

Dietary supplementation with copper nanoparticles enhances broiler performance by improving growth, immunity, digestive enzymes, and gut microbiota.

The aim of this work is to measure the influence of copper nanoparticles (CuNPs) on growth performance, carcass traits, renal and hepatic indices, immunity, lipid profile, antioxidant status, blood minerals, digestive enzymes, and cecal microbiota in broilers. 300 unsexed one-week-old Arbor Acre broiler chicks in total were randomly assigned into 5 treatment groups of 60 chicks per eachwhich were divided into 5 replicates of 12 chicks. The 1st group (G1) was given basal diet (only); the 2nd group (G2), the 3rd group (G3), the 4th group (G4) and the 5th group (G5) were given basal diet treated with CuNPs at a rate of 5, 10, 15, and 20 mg/kg diet, respectively. The result revealed a significant improvement (P < 0.01) in performance paramters where the best values of body weight, weight gain, and feed conversion ratio were achieved at 15 mg/kg diet (CuNPs). Moreover, CuNPs supplementation significantly (P < 0.05) improved carcass traits specially carcass, dressing, giblets, and liver percentage, particularly at 15 mg/kg diet which revealed the best results. Furthermore, CuNPs supplementation at all tested levels increased the immune organ's weight (spleen and thymus). Plasma total protein and globulin were increased with CuNPs supplementation at levels 10 to 20 mg/kg diet. CuNPs supplementation (10-20 mg/kg diet) significantly improved liver and renal function by lowering the levels of AST, creatinine and uric acid. Moreover, CuNPs supplementation significantly (P < 0.05) improved lipid profile indicated by decreased the levels of cholesterol, triglyceride, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol as well as malondialdehyde (MDA). CuNP supplementation significantly improved broiler immunity indicated by increased IgA, IgM, complement (C3) and lysozyme, where CuNPs at 15 and 20 mg/kg diet revealed the best results. CuNPs supplementation increased reduced glutathione (GSH), total antioxidant capacity (TAC), and superoxide dismutase (SOD) as well as increased blood minerals (Cu, Fe, P, and Ca). Also, the digestive enzymes of broiler chicks treated with CuNPs significantly increased (P < 0.05), such as lipase, protease, and amylase enzymes. The findings revealed a significant elevation in total bacterial count (TBC) and lactic acid bacteria and significantly decreased total yeast and mold count (TYMC), E. coli, Salmonella and Coliform. In conclusion, CuNPs supplementation significantly improves performance, carcass yield, renal and hepatic indices, lipid profile, immunity, antioxidants, blood minerals, digestive enzymes, and cecal microbiota of broiler chicks.

Targeted doxorubicin-loaded core-shell copper peroxide-mesoporous silica nanoparticles for combination of ferroptosis and chemotherapy of metastatic breast cancer.

In the current study, a tumor microenvironment responsive (TME-responsive) copper peroxide-mesoporous silica core-shell structure with H2O2 self-supplying ability was fabricated for targeted ferroptosis/chemotherapy against metastatic breast cancer. At the first stage, copper peroxide nanodot was synthesized and subsequently coated with mesoporous organosilica shell. After (3-Aminopropyl) triethoxysilane (APTMS) functionalization of the organosilica shell, doxorubicin (DOX) was loaded in the mesoporous structure of the nanoparticles and then, heterofunctional COOH-PEG-Maleimide was decorated on the surface through EDC/NHS chemistry. Afterward, thiol-functionalized AS1411 aptamer was conjugated to the maleimide groups of the PEGylated nanoparticles. In vitro study illustrated ROS generation of the system in the treated 4 T1 cell. Cellular uptake and cytotoxicity experiments showed enhanced internalization and cytotoxicity of the targeted system comparing to non-targeted one. The in vivo study on ectopic 4 T1 tumor induced in Female BALB/c mice showed ideal therapeutic effect of Apt-PEG-Silica-DOT@DOX with approximately 90 % tumor suppression in comparison with 50 % and 25 % tumor suppression for PEG-Silica-DOT@DOX and PEG-Silica-DOT. Moreover, Apt-PEG-Silica-DOT@DOX provide favorable characteristics for biosafety issues concerning the rate of survival and loss of body weight. The prepared platform could serve as a multifunctional system with smart behavior in drug release, tumor accumulation and capable for ferroptosis/chemotherapy against breast cancer.

Enhanced diabetic wound healing with injectable hydrogel containing self-assembling nanozymes.

To build a smart system in response to the variable microenvironment in infected diabetic wounds, a multifunctional wound dressing was constructed by co-incorporating glucose oxidase (GOx) and a pH-responsive self-assembly Cu2-xSe-BSA nanozyme into a dual-dynamic bond cross-linked hydrogel (OBG). This composite hydrogel (OBG@CG) can adhere to the wound site and respond to the acidic inflammatory environment, initiating the GOx-catalyzed generation of H2O2 and the self-assembly activated peroxidase-like property of Cu2-xSe-BSA nanozymes, resulting in significant hydroxyl radical production to attack the biofilm during the acute infection period and alleviate the high-glucose microenvironment for better wound healing. During the wound recovery phase, Cu2-xSe-BSA aggregates disassembled owing to the elevated pH, terminating catalytic reactive oxygen species generation. Simultaneously, Cu2+ released from the Cu2-xSe-BSA not only promotes the production of mature collagen but also enhances the migration and proliferation of endothelial cells. RNA-seq analysis demonstrated that OBG@CG exerted its antibacterial property by damaging the integrity of the biofilm by inducing radicals and interfering with the energy supply, along with destroying the defense system by disturbing thiol metabolism and reducing transporter activities. This work proposes an innovative glucose consumption strategy for infected diabetic wound management, which may inspire new ideas in the exploration of smart wound dressing.

Nano copper in the diet of laying quails: productive performance, metabolism, and tissue concentration.

The study evaluated the use of nano copper in semi-purified diets for laying quails and its effect on performance, metabolic state, and bioavailability. A total of 160 (180-days-old) quails were distributed in a completely randomized design, in a 3x3+1 factorial. The copper sources used were copper sulfate, copper oxide, and nano copper oxide, at levels of 200, 400, and 800 ppm each, totaling nine treatments plus a negative control (with no copper inclusion). The following variables were determined: weight gain, feed intake, egg production, egg weight, hemoglobin, hematocrit, Cu in the tissues and Cu bioavailability. Data were subjected to analysis of variance at 5% probability. The effect of sources and levels, as well as the interaction between the factors were evaluated. When interaction was observed, the effect of sources was evaluated separately by the Tukey's test and the effect of levels by regression, both at 5% probability. Copper nano oxide can be used at up to 800 ppm in the diet of laying quails without altering the productive performance, and with higher bioavailability than conventional copper oxide. Hemoglobin increases with the inclusion of 200 and 400 ppm of nano copper oxide and the hematocrit with 400 ppm.

Chitosan-copper microparticles as doxorubicin microcarriers for bone tumor therapy.

Doxorubicin (DOX) is a chemotherapeutic drug used in osteosarcoma treatments, usually administrated in very high dosages. This study proposes novel DOX microcarriers based on chitosan (CHT) physically crosslinked with copper(II) ions that will act synergically to inhibit tumor growth at lower drug dosage without affecting the healthy cells. Spherical CHT-Cu microparticles with a smooth surface and an average size of 30.1 ± 9.1 µm were obtained by emulsion. The release of Cu2+ ions from the CHT-Cu microparticles showed that 99.4 % of added cupric ions were released in 72 h of incubation in a complete cell culture medium (CCM). DOX entrapment in microparticles was conducted in a phosphate buffer solution (pH 6), utilizing the pH sensitivity of the polymer. The successful drug-loading process was confirmed by DOX emitting red fluorescence from drug-loaded microcarriers (DOX@CHT-Cu). The drug release in CCM showed an initial burst release, followed by sustained release. Biological assays indicated mild toxicity of CHT-Cu microparticles on the MG-63 osteosarcoma cell line, without affecting the viability of human mesenchymal stem cells (hMSCs). The DOX@CHT-Cu microparticles at concentration of 0.5 mg mL‒1 showed selective toxicity toward MG-63 cells.

Glycyrrhizin functionalized CuS Nanoprobes for NIR Light-based therapeutic mitigation of acne vulgaris.

Acne Vulgaris or Acne is a multifactorial bacterial infection caused by Propionibacterium acne, leading to inflammation and decreased quality of life, especially in adolescence. Currently, antibiotics and retinoids are preferred for treating acne. However, their continuous usage may lead to anti-microbial resistance and other side effects. Therefore, research on developing effective strategies to reduce antimicrobial resistance and improve acne healing is ongoing. The current work reports the synthesis and evaluation of near-infrared light-absorbing copper sulfide (CuS) nanoparticles loaded with a biomolecule, Glycyrrhizin (Ga). The photothermal efficacy studies, and in-vitro and in-vivo experiments indicated that the Ga-CuS NPs generated localized hyperthermia in acne-causing bacteria, leading to their complete growth inhibition. The results indicated that the Ga-Cus NPs possess excellent antibacterial and anti-inflammatory properties in the acne and inflammatory models. This could be from the synergistic effect of CuS NPs mediated mild Photothermal effect and inherent pharmacological properties of Ga. Further detailed studies of the formulations can pave the way for application in cosmetic clinics for the effective and minimally invasive management of Acne-like conditions.

Biodegradable pyroptosis inducer with multienzyme-mimic activity kicks up reactive oxygen species storm for sensitizing immunotherapy.

Triggering pyroptosis is a major new weathervane for activating tumor immune response. However, biodegradable pyroptosis inducers for the safe and efficient treatment of tumors are still scarce. Herein, a novel tumor microenvironment (TME)-responsive activation nanoneedle for pyroptosis induction, copper-tannic acid (CuTA), was synthesized and combined with the sonosensitizer Chlorin e6 (Ce6) to form a pyroptosis amplifier (CuTA-Ce6) for dual activation and amplification of pyroptosis by exogenous ultrasound (US) and TME. It was demonstrated that Ce6-triggered sonodynamic therapy (SDT) further enhanced the cellular pyroptosis caused by CuTA, activating the body to develop a powerful anti-tumor immune response. Concretely, CuTA nanoneedles with quadruple mimetic enzyme activity could be activated to an "active" state in the TME, destroying the antioxidant defense system of the tumor cells through self-destructive degradation, breaking the "immunosilent" TME, and thus realizing the pyroptosis-mediated immunotherapy with fewer systemic side effects. Considering the outstanding oxygen-producing capacity of CuTA and the distinctive advantages of US, the sonosensitizer Ce6 was attached to CuTA via an amide reaction, which further amplified the pyroptosis and sensitized pyroptosis-induced immunotherapy with the two-pronged strategy of CuTA enzyme-catalyzed cascade and US-driven SDT pathway to generate a "reactive oxygen species (ROS) storm". Conclusively, this work provided a representative paradigm for achieving safe, reliable and efficient pyroptosis, which was further enhanced by SDT for more robust immunotherapy.

Enhanced localized therapeutic precision: A face-to-face folate-targeted Cu2+-mediated nanotherapy with thermosensitive sustained-release system.

Safe and effective Cu2+ supplementation in local lesion is crucial for minimizing toxicity of DSF-based chemotherapy. Targeted delivery of Cu2+ appears more promising. Intraperitoneal chemotherapy for peritoneal carcinoma (PC) establishes "face-to-face" contact between targeted nanocarriers and tumor tissue. Herein, this study developed a biodegradable, injectable thermosensitive hydrogel that coencapsulating DSF submicroemulsion (DSF-SE) and folate-modified liposome loading glycyrrhizic acid-Cu (FCDL). FCDL acted as 'beneficial horse' to target the tumor-localized folate receptor, thus liberating Cu2+ in tumor nidus. The prepared FCDL and DSF-SE were found with uniform sizes (160.2 nm, 175.4 nm), low surface charge (-25.77 mV, -16.40 mV) and high encapsulation efficiency (97.93 %, 90.08 %). In vitro drug release profile of FCDL, DSF-SE and FCDL＆DSF-SE@G followed a sustained release pattern. And the release behavior of Cu2+ from FCDL was pH-related, i.e., Cu2+ was released faster under acidic condition. When FCDL and DSF-SE were loaded into an PLGA-PEG-PLGA-based hydrogel system, FCDL＆DSF-SE@G was formed to ensure separated delivery of Cu2+ and DSF in space but synchronized release over time. The rheology experiment showed a satisfactory gelling temperature of 32.7 °C. In vitro cytotoxicity study demonstrated that FCDL＆DSF-SE@G significantly lowered the IC50 of free Cu2+/DSF, Cu2+/DSF hydrogel and non-targeted analogue by almost 70 %, 65 % and 32 %, respectively. Accordingly, in tumor-bearing mice, FCDL＆DSF-SE@G augmented the tumor inhibition rates for the same formulations by 352 %, 145 % and 44 %, respectively. The main mechanism was attributed to higher uptake of FCDL and DSF-SE, resulting in increased Cu(DDTC)2 formation, ROS production and cell apoptosis. In conclusion, this targeted nanotherapy approach with dual-nanocarriers loaded hydrogel system, with its focus on face-to-face contact between nanocarriers and tumor tissues in the peritoneal cavity, holds significant promise for intraperitoneal chemotherapy in PC.

Novel feed additive delivers antimicrobial copper and influences fecal microbiota in pigs.

Dehydrated alginate beads formulated with copper were synthesized and tested as a feed additive to influence the microbiota in finishing pigs and potentially use them as a preharvest intervention to reduce fecal pathogen shedding. The efficacy of the copper beads was tested in vitro and in vivo. In vitro, Salmonella was significantly (P < 0.05) reduced when in contact with the copper beads solution for up to 6 h, with a 5.4 log CFU/mL reduction over the first hour. Chemical analysis of the soak solutions demonstrated the beads delivered their copper payload gradually over the same period the bactericidal effect was observed. For the in vivo experiments, pigs (n = 48) supplemented with the copper beads experienced significant shifts in their microbiota. Enterobacteriaceae (EB) increased by 1.07 log CFU/g (P < 0.05), while lactic acid bacteria (LAB) decreased by 1.22 log CFU/g (P < 0.05) during the treatment period. When beads were removed from the feed, EB and LAB concentrations returned to baseline, indicating copper beads led to measurable and significant changes in microbial loads. Fecal microbiome analysis conducted to explore additional changes by copper bead supplementation demonstrated that, at the phylum level, there was an increase in Firmicutes, Euryarchaeota, and Acidobacteriota, while at the genus level, an increase in Methanosphaera and Pseudomonas was observed. Measures of copper in swine feces showed values ~20 times higher in the treatment group than in the control group during the treatment period, suggesting that dehydrated alginate copper beads were effective in delivering antimicrobial copper to the animal hindgut.IMPORTANCECopper has long been known to have antimicrobial properties. However, when water-soluble salts are fed to livestock, the copper may rapidly dissolve in gastric contents and fail to reach the gut. Here, specially formulated copper beads are seamlessly incorporated into feed and allow copper to remain longer in the gastrointestinal tract of animals, reach deep into both the foregut and hindgut, and shift microbial populations. The technology delivers antimicrobial copper to the animal hindgut and potentially reduces pathogenic microorganisms before animal slaughter.

Healing with precision: A multi-functional hydrogel-bioactive glass dressing boosts infected wound recovery and enhances neurogenesis in the wound bed.

Chronic skin wounds, especially infected ones, pose a significant clinical challenge due to their increasing incidence and poor outcomes. The deteriorative microenvironment in such wounds, characterized by reduced extracellular matrix, impaired angiogenesis, insufficient neurogenesis, and persistent bacterial infection, has prompted the exploration of novel therapeutic strategies. In this study, we developed an injectable multifunctional hydrogel (GEL/BG@Cu + Mg) incorporating Gelatin-Tannic acid/ N-hydroxysuccinimide functionalized polyethylene glycol and Bioactive glass doped with copper and magnesium ions to accelerate the healing of infected wounds. The GEL/BG@Cu + Mg hydrogel composite demonstrates good biocompatibility, degradability, and rapid formation of a protective barrier to stop bleeding. Synergistic bactericidal effects are achieved through the photothermal properties of BG@Cu + Mg and sustained copper ions release, with the latter further promoting angiogenesis. Furthermore, the hydrogel enhances neurogenesis by stimulating axons and Schwann cells in the wound bed through the beneficial effects of magnesium ions. Our results demonstrate that the designed novel multifunctional hydrogel holds tremendous promise for treating infected wounds and allowing regenerative neurogenesis at the wound site, which provides a viable alternative for further improving clinical outcomes.

Dietary intake of copper and gastric cancer: a pooled analysis within the Stomach cancer Pooling (StoP) Project.

BACKGROUND: Evidence on the potential association between dietary copper intake and gastric cancer (GC) is lacking. Thus, we aimed to evaluate this association within the Stomach cancer Pooling (StoP) Project-an international consortium of epidemiological studies on GC. METHODS: Data from five case-control studies within the StoP Project were included (2448 cases, 4350 controls). We estimated adjusted odds ratios (ORs) and 95% CIs for the association between dietary copper intake and GC using multivariable mixed-effects logistic regression models. We also modelled the dose-response relationship between copper intake and GC using a logistic mixed-effects model with fractional polynomial. RESULTS: The OR for the highest quartile of copper intake compared with the lowest one was 0.78 (95% CI: 0.63-0.95; P for trend = 0.013). Results were similar for non-cardia-type (OR: 0.72; 95% CI: 0.57-0.91), intestinal-type (OR: 0.75; 95% CI: 0.56-0.99) and other histological-type GC (OR: 0.65; 95% CI: 0.44-0.96). The dose-response analysis showed a steep decrease in ORs for modest intakes (<1 mg/day), which were subsequently steady for ≤3 mg/day (OR: 0.09; 95% CI: 0.02-0.41) and slowly increased for higher intakes. CONCLUSIONS: The findings of our large study suggest that copper intake might be inversely associated with GC, although their confirmation by prospective studies is required.

ROS mediated Cu[Fe(CN)5NO] nanoparticles for triple negative breast cancer: A detailed study in preclinical mouse model.

Triple negative breast cancer (TNBC) is an aggressive form of tumor, more prevalent in younger women resulting in poor survival rate (2nd in cancer deaths) because of its asymptomatic existence. The most popular and convenient approach for the treatment of TNBC is chemotherapy which is associated with several limitations. Considering the importance of nanotechnology in health care system, in the present manuscript, we have designed and developed a simple, efficient, cost effective, and ecofriendly method for the synthesis of copper nitroprusside analogue nanoparticles (Cu[Fe(CN)5NO] which is abbreviated as CuNPANP that may be the potential anti-cancer nanomedicine for the treatment of TNBC. Copper (present in CuNPANP) is used because of its affordability, nutritional value and various biomedical applications. The CuNPANP are thoroughly characterized using several analytical techniques. The in vitro cell viability (in normal cells) and the ex vivo hemolysis assay reveal the biocompatible nature of CuNPANP. The anti-cancer activity of the CuNPANP is established in TNBC cells (MDA-MB-231 and 4T1) through several in vitro assays along with plausible mechanisms. The intraperitoneal administration of CuNPANP in orthotopic breast tumor model by transplanting 4T1 cells into the mammary fat pad of BALB/c mouse significantly inhibits the growth of breast carcinoma as well as increases the survival time of tumor-bearing mice. These results altogether potentiate the anti-cancer efficacy of CuNPANP as a smart therapeutic nanomedicine for treating TNBC in near future after bio-safety evaluation in large animals.