Nutritional Approaches as a Treatment for Impaired Bone Growth and Quality Following the Consumption of Ultra-Processed Food.

The severe impairment of bone development and quality was recently described as a new target for unbalanced ultra-processed food (UPF). Here, we describe nutritional approaches to repair this skeletal impairment in rats: supplementation with micro-nutrients and a rescue approach and switching the UPF to balanced nutrition during the growth period. The positive effect of supplementation with multi-vitamins and minerals on bone growth and quality was followed by the formation of mineral deposits on the rats' kidneys and modifications in the expression of genes involved in inflammation and vitamin-D metabolism, demonstrating the cost of supplementation. Short and prolonged rescue improved trabecular parameters but incompletely improved the cortical parameters and the mechanical performance of the femur. Cortical porosity and cartilaginous lesions in the growth-plate were still detected one week after rescue and were reduced to normal levels 3 weeks after rescue. These findings highlight bone as a target for the effect of UPF and emphasize the importance of a balanced diet, especially during growth.

U-shaped association between dietary copper intake and new-onset hypertension.

AIMS: To investigate the relationship of dietary copper intake with new-onset hypertension among Chinese adults. METHODS: A total of 12,245 participants who were free of hypertension at baseline from the China Health and Nutrition Survey (CHNS) were included. Dietary intake was measured by 3 consecutive 24-h dietary recalls combined with a household food inventory. New-onset hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or diagnosed by a physician or under antihypertensive treatment during the follow-up. RESULTS: During a median follow-up of 6.1 years, 4304 participants developed new-onset hypertension. Overall, the associations between dietary copper intake and new-onset hypertension followed a U-shape (P for nonlinearity <0.001). The risk of new-onset hypertension significantly decreased with the increment of dietary copper intake (per SD increment: HR, 0.71; 95% CI, 0.57-0.88) in participants with copper intake <1.57 mg/day, and increased with the increment of dietary copper intake (per SD increment: HR, 1.09; 95% CI: 1.07-1.12) in participants with copper intake ≥1.57 mg/day. CONCLUSIONS: There was a U-shaped association between dietary copper intake and new-onset hypertension in general Chinese adults, with an inflection point at about 1.57 mg/day. Our results emphasized the importance of maintaining optimal copper intake levels for the primary prevention of hypertension.

Evaluation of transcriptional biomarkers using a high-resolution regression approach: Concentration-dependence of selected transcripts in copper-exposed freshwater mussels (Anodonta anatina).

We tested concentration-dependence of selected gene transcripts (cat, gst, hsp70, hsp90, mt and sod) for evaluation as biomarkers of chemical stress. Contrary to the common approach of factorial designs and few exposure concentrations, we used regression across a high-resolution concentration series. Specifically, freshwater mussels (Anodonta anatina) were acutely (96 h) exposed to Cu (13 nominal concentrations, measuring 0.13-1 600 µg/L), and transcripts were measured by RT-qPCR. In digestive glands, cat, hsp90 and mt decreased with water Cu (p < 0.05), but response magnitudes saturated at < 2-fold decreases. In gills, gst, hsp70, hsp90 and mt increased with water Cu (p < 0.05). While hsp70, hsp90 and mt exceeded 2-fold increases within the exposure range, high Cu concentrations were required (38-160 µg/L). Although gill responses were generally more robust compared to digestive glands, overall small response magnitudes and moderate sensitivity may set limit for potential application as general biomarkers of chemical stress.

Collagen Peptides, in Association with Vitamin C, Sodium Hyaluronate, Manganese and Copper, as Part of the Rehabilitation Project in the Treatment of Chronic Low Back Pain.

BACKGROUND AND OBJECTIVE: Low back pain (LBP) is a frequent symptom. Among the causes that can determine it, lumbar osteoarthritis plays an important role. Therapeutic exercise, according to McKenzie method, has been shown to be effective in the treatment of LBP. Oral supplementation with collagen peptides represents a new therapeutic possibility in osteoarthritis. The aim of this study is to evaluate the combined efficacy of therapeutic exercise and oral administered viscosupplements in the treatment of osteoarthritis-related chronic LBP. METHODS: Sixty patients were recruited and randomly divided into two groups (Group A and B). Group A performed only kinesitherapy, Group B carried out the same kinesitherapy combined with the daily administration of food supplements such as Fortigel®, Vitamin C, sodium hyaluronate, manganese and copper, during the whole treatment period. Patients were evaluated at the time of recruitment (T0), at the end of the treatment (T1 - 3 weeks after T0) and 6 weeks after T1 (T2). The outcome measures used were: Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Short Form-12 (SF-12). RESULTS: All the outcomes improved significantly at T1 in both groups, but more markedly in group B. Furthermore, in group A at T2, there was a statistically significant worsening in the scores of VAS, ODI and physical component of the SF-12, while in group B, this variation has not been detected. CONCLUSION: The combination of rehabilitation based on McKenzie back exercises and oral viscosupplementation with Fortigel®, Vitamin C, sodium hyaluronate, manganese and copper represents a valid option in patients with chronic LBP, as it ensures pain relief and improvement in the quality of life and in lumbar spine functionality. These therapeutic benefits are more evident and long-lasting compared to those obtained with rehabilitation alone.

Copper (Cu) induced changes of lipid metabolism through oxidative stress-mediated autophagy and Nrf2/PPARγ pathways.

Oxidative stress can induce occurrence of non-alcoholic fatty liver disease (NAFLD). Nrf2 is a central regulator of cellular oxidative stress and also participates in the control of lipid deposition and metabolism. Here, we hypothesize that oxidative stress-mediated Nrf2 activation participates in the regulation of the Cu-induced lipid deposition. We found that Cu excess activated oxidative stress and autophagy, up-regulated lipogenesis and lipid metabolism, suppressed Keap1 expression and activated Nrf2 signaling. Moreover, Cu induced lipid deposition via oxidative stress and the mitochondrial dysfunction. Oxidative stress mediated Cu-induced activation of Nrf2 and autophagy. The activation of autophagy helps to alleviate Cu-induced lipid deposition and accordingly provided a protective role against Cu-induced NAFLD. Meantime, Cu-induced oxidative stress promoted Nrf2 recruitment to the PPARγ promoter, inducing target gene transcription, and subsequent lipogenesis. Our findings, for the first time, provide direct evidences for Nrf2 function in the modulation of lipogenic metabolism via the transcriptional activation of PPARγ, and elucidate the mechanisms by which Nrf2 functions as the central regulator of lipogenic genes and highlights the significance of Nrf2 as potential therapeutic targets for oxidative stress-associated obesity and NAFLD for fish and human beings.

Polyurethane Foam Incorporated with Nanosized Copper-Based Metal-Organic Framework: Its Antibacterial Properties and Biocompatibility.

Polyurethane foams (PUFs) have attracted attention as biomaterials because of their low adhesion to the wound area and suitability as biodegradable or bioactive materials. The composition of the building blocks for PUFs can be controlled with additives, which provide excellent anti-drug resistance and biocompatibility. Herein, nanosized Cu-BTC (copper(II)-benzene-1,3,5-tricarboxylate) was incorporated into a PUF via the crosslinking reaction of castor oil and chitosan with toluene-2,4-diisocyanate, to enhance therapeutic efficiency through the modification of the surface of PUF. The physical and thermal properties of the nanosized Cu-BTC-incorporated PUF (PUF@Cu-BTC), e.g., swelling ratio, phase transition, thermal gravity loss, and cell morphology, were compared with those of the control PUF. The bactericidal activities of PUF@Cu-BTC and control PUF were evaluated against Pseudomonas aeruginosa, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus. PUF@Cu-BTC exhibited selective and significant antibacterial activity toward the tested bacteria and lower cytotoxicity for mouse embryonic fibroblasts compared with the control PUF at a dose of 2 mg mL-1. The Cu(II) ions release test showed that PUF@Cu-BTC was stable in phosphate buffered saline (PBS) for 24 h. The selective bactericidal activity and low cytotoxicity of PUF@Cu-BTC ensure it is a candidate for therapeutic applications for the drug delivery, treatment of skin disease, and wound healing.

Validation of a Short Food Frequency Questionnaire to Measure Dietary Intake of a Selection of Micronutrients in Oncology Patients Undergoing Systemic Therapy.

Dietary intake, specifically consumption of anti-inflammatory micronutrients, can play a role in both cancer initiation as well as the treatment-related outcomes experienced by patients receiving systemic cancer therapy. Increasing research is being conducted to determine whether micronutrient supplementation can aid in altering the tumor microenvironment (TME), reducing inflammatory side effects and immune-related adverse events (irAEs). However, further research pertaining to the adequacy of dietary micronutrient intake is indicated in the oncology cohort. Currently, no tool measuring dietary intakes of various micronutrients exists in the oncology population. In this study, a 21-item food frequency questionnaire (FFQ) measuring intakes of 14 different micronutrients was validated using diet history as the reference method in 112 oncology patients. Bland Altman plot and Passing Bablok regression analysis were conducted to determine agreement between the two methods. The results showed adequate agreement between FFQ and diet history for 12 nutrients including copper, iron, vitamins A, E, and D, alpha linolenic acid (ALA), long-chain omega 3 fatty acids (LC n3-FA), arginine, glutamic acid, isoleucine, leucine, and valine. This 21-item FFQ, which takes an average of 10 min to complete, can be utilized as a quick screening tool to determine adequacy for 12 different micronutrients in place of a diet history.

The Role of 20-HETE, COX, Thromboxane Receptors, and Blood Plasma Antioxidant Status in Vascular Relaxation of Copper-Nanoparticle-Fed WKY Rats.

Recently, the addition of copper nanoparticles (NPs) in a daily diet (6.5 mg/kg) was studied in different animal models as a possible alternative to ionic forms. Male Wistar-Kyoto rats (24-week-old, n = 11) were fed with copper, either in the form of carbonate salt (Cu6.5) or metal-based copper NPs (NP6.5), for 8 weeks. The third group was fed with a half dose of each (NP3.25 + Cu3.25). The thoracic aorta and blood plasma was studied. Supplementation with NP6.5 decreased the Cu (×0.7), Cu/Zn-ratio (×0.6) and catalase (CAT, ×0.7), and increased Zn (×1.2) and superoxide dismutase (SOD, ×1.4). Meanwhile, NP3.25 + Cu3.25 decreased the Cu/Zn-ratio (×0.7), and CAT (×0.7), and increased the daily feed intake (×1.06). Preincubation with either the selective cyclooxygenase (COX)-2 inhibitor, or the non-selective COX-1/2 inhibitor attenuated vasodilation of rat thoracic aorta in the NP6.5 group exclusively. However, an increased vasodilator response was observed in the NP6.5 and NP3.25 + Cu3.25 group of rats after preincubation with an inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) formation, and the thromboxane receptor (TP) antagonist. Significant differences were observed between the NP6.5 and NP3.25 + Cu3.25 groups of rats in: dietary intake, acetylcholine-induced vasodilation, and response to COX-inhibitors. Copper NPs in a standard daily dose had more significant effects on the mechanism(s) responsible for the utilization of reactive oxygen species in the blood plasma with the participation of prostanoids derived from COX-2 in the vascular relaxation. Dietary copper NPs in both doses modified vasodilation through the vasoconstrictor 20-HETE and the TP receptors.

Integrated in silico analysis for the identification of key genes and signaling pathways in copper oxide nanoparticles toxicity.

Copper oxide nanoparticles (CuO-NPs) are used in various industrial and commercial products due to their enhanced physicochemical properties. The vast consumption increases their exposure in the environment, thereby affecting the ecosystem. Even with the rise in research towards understanding their toxicity, the major signaling cascades and key genes involved in CuO-NPs remain elusive due to the various attributes involved (size, shape, charge, coating in terms of nanoparticles, and dose, duration, and species used in the experiment). The focus of the study is to identify the key signaling cascades and genes involved in CuO-NPs toxicity irrespective of these attributes. CuO-NPs related microarray expression profiles were screened from GEO database and were subjected to toxicogenomic analysis to elucidate the toxicity mechanism. In silico tools were used to obtain the DEGs, followed by GO and KEGG functional enrichment analysis. The identified DEGs were then analyzed to determine major signaling pathways and key genes. Module and centrality parameter analysis was performed to identify the key genes. Further, the miRNAs and transcription factors involved in regulating the genes were predicted, and their interactive pathways were constructed. A total of 44 DEGs were commonly present in all the analysed datasets and all of them were downregulated. GO analysis reveals that most of the genes were enriched in functions related to cell division and chemotaxis. Cell-cycle, chemokine, cytokine-cytokine receptor interaction, and p53 signaling pathways were the key pathways with Cdk1 as the major biomarker altered irrespective of the variables (dosage, duration, species used, and surface coating). Overall, our integrated toxicogenomic analysis reveal that Cdk1 regulated cell cycle and cytokine-cytokine signaling cascades might be responsible for CuO-NPs toxicity. These findings will help us in understanding the mechanisms involved in NPs toxicity.

Liposomal formulations of anticancer copper(II) thiosemicarbazone complexes.

α-N-Heterocyclic thiosemicarbazones such as triapine and COTI-2 are currently investigated as anticancer therapeutics in clinical trials. However, triapine was widely inactive against solid tumor types. A likely explanation is the short plasma half-life time and fast metabolism. One promising approach to overcome these drawbacks is the encapsulation of the drug into nanoparticles (passive drug-targeting). In a previous work we showed that it was not possible to stably encapsulate free triapine into liposomes. Hence, in this manuscript we present the successful preparation of liposomal formulations of the copper(II) complexes of triapine and COTI-2. To this end, various drug-loading strategies were examined and the resulting liposomes were physico-chemically characterized. Especially for liposomal Cu-triapine, a decent encapsulation efficacy and a slow drug release behavior could be observed. In contrast, for COTI-2 and its copper(II) complex no stable loading could be achieved. Subsequent in vitro studies in different cell lines with liposomal Cu-triapine showed the expected strongly reduced cytotoxicity and DNA damage induction. Also in vivo distinctly higher copper plasma levels and a continuous release could be observed for the liposomal formulation compared to free Cu-triapine. Taken together, the here presented nanoformulation of Cu-triapine is an important step further to increase the plasma half-life time and tumor targeting properties of anticancer thiosemicarbazones.

Atherosclerotic lesion-specific copper delivery suppresses atherosclerosis in high-cholesterol-fed rabbits.

Dietary cholesterol supplements cause hypercholesterolemia and atherosclerosis along with a reduction of copper concentrations in the atherosclerotic wall in animal models. This study was to determine if target-specific copper delivery to the copper-deficient atherosclerotic wall can block the pathogenesis of atherosclerosis. Male New Zealand white rabbits, 10-weeks-old and averaged 2.0 kg, were fed a diet containing 1% (w/w) cholesterol or the same diet without cholesterol as control. Twelve weeks after the feeding, the animals were injected with copper-albumin microbubbles and subjected to ultrasound sonication specifically directed at the atherosclerotic lesions (Cu-MB-US) for target-specific copper delivery, twice a week for four weeks. This regiment was repeated 3 times with a gap of two weeks in between. Two weeks after the last treatment, the animals were harvested for analyses of serum and aortic pathological changes. Compared to controls, rabbits fed cholesterol-rich diet developed atherosclerotic lesion with a reduction in copper concentrations in the lesion tissue. Cu-MB-US treatment significantly increased copper concentrations in the lesion, and reduced the size of the lesion. Furthermore, copper repletion reduced the number of apoptotic cells as well as the content of cholesterol and phospholipids in the atherosclerotic lesion without a disturbance of the stability of the lesion. The results thus demonstrate that target-specific copper supplementation suppresses the progression of atherosclerosis at least in part through preventing endothelial cell death, thus reducing lipid infiltration in the atherosclerotic lesion.

Effects of Zinc Acetate Hydrate Treatment on Serum Oxidative Stress Markers in Patients with Macular Drusen.

Purpose: To measure the serum levels of the oxidative stress markers superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GPx) and compare them before and after zinc supplementation in patients with early age-related macular degeneration (AMD). Methods: We measured serum zinc levels in 65 patients with early AMD. Of these, 29 patients with macular drusen and a serum zinc level <80 µg/dL received oral zinc acetate dihydrate (50 mg/day). Serum trace metal levels (zinc and copper) and oxidative stress marker levels (SOD, MDA, and GPx) were measured at baseline and 12 weeks after the treatment. The macular drusen areas and best-corrected visual acuity were evaluated in 24 participants who attended the 3-month follow-up. Results: MDA level was significantly decreased from baseline to 12 weeks after zinc administration (170.5 ± 100.9 vs. 148.3 ± 57.9 pmol/mL, P = 0.03), while SOD was significantly increased from baseline to 12 weeks after zinc intake (4.2 ± 0.9 vs. 4.6 ± 0.9 U/mL, P = 0.03). The serum zinc level was significantly correlated with the MDA level (P = 0.03, ρ = -0.26). The area of soft drusen was significantly decreased after zinc treatment (1,936,654.9 ± 1,348,267.6 vs. 966,883.9 ± 719,938.1 µmm2, P = 0.04). Conclusions: The levels of oxidative stress markers MDA and SOD decreased and increased, respectively, after oral zinc administration to 24 patients with AMD. The therapeutic effect of zinc treatment on drusen area might differ depending on the drusen phenotype in early AMD.

Copper as Dietary Supplement for Bone Metabolism: A Review.

While in vitro and animal studies of osteoblastic and osteoclastic activity as well as bone resistance for copper are numerous, and the results encouraging in terms of regulation, human studies are scarce. The aim of this narrative review was to investigate the correlation of blood copper, daily copper intake, and copper supplementation with bone mineral density. This review included 10 eligible studies: five studies concerned copper blood levels, one study concerned daily copper intake, and four studies concerned copper supplementation. Blood copper levels did not show statistically significant differences in four of the studies analyzed, while only one study showed differences between osteoporotic and healthy women, although only with women between 45 and 59 years of age and not between 60 and 80 years of age. The dietary copper intake among women with or without osteoporosis did not show any differences. Only one study with a small sample of subjects carried out these assessments; therefore, it is a topic that the literature must deepen with further studies. The two studies that analyzed the integration of copper (2.5-3 mg/day) only showed good results in terms of slowing down bone mineral loss and reducing resorption markers, confirming the effectiveness of copper supplementation on bone metabolism.

Organic mineral supplementation on differential protein profile of Osmanabadi bucks (Capra hircus).

The present study aimed to determine the differential protein profile of seminal plasma proteins of bucks supplemented with trace minerals. Forty bucks of uniform size and body weight were assigned as ten groups (n = 4). The control group (T1) was fed with the control diet (concentration mixture and roughages) whereas the remaining groups were supplemented the control diet with Zn20 mg (T2), Zn40 mg (T3), Zn60 mg (T4), Cu12.5 mg (T5), Cu25 mg (T6), Cu37.5 mg (T7), Zn20 mg + Cu12.5 mg (T8), Zn40 mg + Cu25 mg (T9), and Zn60 mg + Cu37.5 mg (T10) for eight months. Seminal plasma proteins from each group were subjected to two-dimensional electrophoresis and fifteen differential proteins were selected based on differential expression, subjected to identification using Nano-LC-MS/MS (LTQ-Qrbitrap-MS). The identified proteins were Triacylglycerol lipase, EGF like repeats and discoidin domains 3, Lipocalin, Iodothyronine deiodinase, Transcription factor AP2-delta, 60S ribosomal protein L13, IST1 factor associated with ESCRT-III, Lysozyme, Uncharacterized protein (BRI3-binding protein), Uncharacterized protein, Histone deacetylase 11, General transcription factor IIF subunit 2, Nudix hydrolase 6, Protein kinase cAMP-activated catalytic subunit beta and Elongin C. The organic Cu supplemented group is the better than the organic Zn and organic Zn + Cu supplemented groups.

Threshold Effects of Total Copper Intake on Cognitive Function in US Older Adults and the Moderating Effect of Fat and Saturated Fatty Acid Intake.

BACKGROUND: Evidence for a relationship between total copper intake and cognition is lacking, and few studies have assessed the moderating effect of dietary fat and saturated fatty acid (SFA) intake on this relationship. OBJECTIVE: Our aim was to explore the curvilinear association between total copper intake and cognitive function in older adults, and to clarify the moderating effect of dietary fat and SFA intake on the association. DESIGN: This was a cross-sectional analysis of data from National Health and Nutrition Examination Surveys 2011-2014. PARTICIPANTS: The analysis included 2,483 participants aged 60 years and older. MAIN OUTCOME MEASURES: Cognitive function was evaluated by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning subtest, the Animal Fluency Test, and the Digit Symbol Substitution Test (DSST). STATISTICAL ANALYSES PERFORMED: Smooth curve fitting and two-piecewise linear regression models were performed to address the nonlinear association between total copper intake and cognitive function. Multivariable quadratic regression models and analyses stratified by total fat or SFA intake were used to assess the effects of the interaction between copper and fat intake and between copper and SFA intake on cognitive function. RESULTS: There was a nonlinear association between total copper intake and cognitive test scores. The inflection point of copper was 0.8 mg/d for the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest and 1.4 mg/d for both the Animal Fluency test and the DSST. When copper intake was below the inflection point, positive associations were apparent for copper intake and Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest scores (ß = 3.9; 95% CI 1.2 to 6.5), Animal Fluency test scores (ß = 1.7, 95% CI .9 to 2.6), and DSST scores (ß = 6.0, 95% CI 3.8 to 8.3). When copper intake was above the inflection point, a nonsignificant downward trend was found. Interactive effects between total copper and total fat intake (P interaction = .000) and between total copper and SFA intake (P interaction = .011) on the DSST scores were observed. In the low fat intake and low SFA intake groups, DSST scores first increased and then decreased with increasing copper. However, in the high fat intake and high SFA intake groups, DSST scores first increased and then flattened with increasing copper. CONCLUSIONS: The present study suggests a nonlinear association between copper intake and cognitive function and identifies threshold effects of copper intake on cognitive function. Copper intake below the inflection point was positively and independently associated with cognitive function. High fat and high SFA intake may protect older adults against a decline in DSST scores related to high copper intake.

Glucose oxidase loaded Cu2+ based metal-organic framework for glutathione depletion/reactive oxygen species elevation enhanced chemotherapy.

INTRODUCTION: The development of multidrug resistance (MDR) is a major cause for the failure of chemotherapy, which requires the aid of nanomedicine. METHODS: Here in our study, a Cu2+ based metal-organic framework (COF) was firstly developed and employed as a carrier for the delivery of glucose oxidase (GOx) and doxorubicin (Dox) (COF/GOx/Dox) for the therapy of MDR lung cancers. RESULTS: Our results showed that the GOx can catalyze glucose and produce H2O2. In the mean time, the Cu2+ can react with GSH and then transform into Cu+, which resulted in GSH depletion. Afterwards, the produced Cu+ and H2O2 trigger Fenton reaction to generate ROS to damage the redox equilibrium of cancer cells. Both effects contributed to the reverse of MDR in A549/Dox cells and finally resulted in significantly enhanced in vitro/in vivo anticancer performance. DISCUSSION: The combination of glutathione depletion/reactive oxygen species elevation might be a promising strategy to enhance the efficacy of chemotherapy and reverse MDR in cancers.

Dual Size/Charge-Switchable Nanocatalytic Medicine for Deep Tumor Therapy.

Elevating intratumoral levels of highly toxic reactive oxygen species (ROS) by nanocatalytic medicine for tumor-specific therapy without using conventional toxic chemodrugs is recently of considerable interest, which, however, still suffers from less satisfactory therapeutic efficacy due to the relatively poor accumulation at the tumor site and largely blocked intratumoral infiltration of nanomedicines. Herein, an ultrasound (US)-triggered dual size/charge-switchable nanocatalytic medicine, designated as Cu-LDH/HMME@Lips, is constructed for deep solid tumor therapy via catalytic ROS generations. The negatively charged liposome outer-layer of the nanomedicine enables much-prolonged blood circulation for significantly enhanced tumoral accumulation, while the positively charged Fenton-like catalyst Cu-LDH released from the liposome under the US stimulation demonstrates much enhanced intratumoral penetration via transcytosis. In the meantime, the co-released sonosensitizer hematoporphyrin monomethyl ether (HMME) catalyze the singlet oxygen (1O2) generation upon the US irradiation, and deep-tumoral infiltrated Cu-LDH catalyzes the H2O2 decomposition to produce highly toxic hydroxyl radical (·OH) specifically within the mildly acidic tumor microenvironment (TME). The efficient intratumoral accumulation and penetration via the dual size/charge switching mechanism, and the ROS generations by both sonosensitization and Fenton-like reactions, ensures the high therapeutic efficacy for the deep tumor therapy by the nanocatalytic medicine.

Pulmonary Exposure to Copper Oxide Nanoparticles Leads to Neurotoxicity via Oxidative Damage and Mitochondrial Dysfunction.

Copper oxide nanoparticles (CuONPs) are widely used in pharmaceutical, food, and textile industries. They have been shown to cause lung, liver, and kidney damage. However, whether an intratracheal instillation of CuONPs would affect the brain and its underlying mechanisms remain poorly studied. In this study, healthy C57BL/6J male mice were equally subdivided into control group, low-dose (30 µg/animal), medium-dose (50 µg/animal), and high-dose (100 µg/animal) CuONPs-treated groups. Mice were subjected to acute exposure of CuONPs via intratracheal instillation. Brain histopathology, inflammatory factors, oxidative stress markers, and mitochondrial function-related protein expression were determined. Our results demonstrated that CuONPs caused a dose-dependent brain damage in mice. Histopathological changes in the brain, elevation of inflammatory factors (Tnf, Il-6), and significant alterations in oxidative stress markers were also observed after treatment with CuONPs. Intriguingly, we did not observe infiltration of macrophage cell. Moreover, Tim23, TFAM, and MFN2 protein expression levels showed the decreasing trend after treatment with CuONPs. Taken together, these results indicate that pulmonary exposure to CuONPs induces pathological damage, inflammation, oxidative stress, and mitochondrial dysfunction in the cerebral cortex, suggesting that neurotoxicity caused by pulmonary exposure of CuONPs needs more attention from the public and relevant departments.

Low-Dose Copper Exposure Exacerbates Depression-Like Behavior in ApoE4 Transgenic Mice.

Depression is one of the most common neuropsychiatric disorders. Although the pathogenesis of depression is still unknown, environmental risk factors and genetics are implicated. Copper (Cu), a cofactor of multiple enzymes, is involved in regulating depression-related processes. Depressed patients carrying the apolipoprotein ε4 allele display more severe depressive symptoms, indicating that ApoE4 is closely associated with an increased risk of depression. The study explored the effect of low-dose Cu exposure and ApoE4 on depression-like behavior of mice and further investigates the possible mechanisms. The ApoE4 mice and wild-type (WT) mice were treated with 0.13 ppm CuCl2 for 4 months. After the treatment, ApoE4 mice displayed obvious depression-like behavior compared with the WT mice, and Cu exposure further exacerbated the depression-like behavior of ApoE4 mice. There was no significant difference in anxiety behavior and memory behavior. Proteomic analysis revealed that the differentially expressed proteins between Cu-exposed and nonexposed ApoE4 mice were mainly involved in the Ras signaling pathway, protein export, axon guidance, serotonergic synapse, GABAergic synapse, and dopaminergic synapse. Among these differentially expressed proteins, immune response and synaptic function are highly correlated. Representative protein expression changes are quantified by western blot, showing consistent results as determined by proteomic analysis. Hippocampal astrocytes and microglia were increased in Cu-exposed ApoE4 mice, suggesting that neuroglial cells played an important role in the pathogenesis of depression. Taken together, our study demonstrated that Cu exposure exacerbates depression-like behavior of ApoE4 mice and the mechanisms may involve the dysregulation of synaptic function and immune response and overactivation of neuroinflammation.

Biogenic copper nanoparticles from Avicennia marina leaves: Impact on seed germination, detoxification enzymes, chlorophyll content and uptake by wheat seedlings.

Biogenic copper nanoparticles (Cu NPs) were synthesized using the aqueous crude extract of mangrove leaves, Avicennia marina (CE). GC-MS metabolite profiling of CE showed that their carbohydrates are mainly composed of D-mannose (29.21%), D-fructose, (18.51%), L-sorbose (12.91%), D-galactose (5.47%) and D-Talose (5.21%). Ultra-fine nanoparticles of 11.60 ±4.65 nm comprising Cu2O and Cu(OH)2 species were obtained with a carbohydrate and phenolic content of 35.6±3.2% and 3.13±0.05 mgGA/g, respectively. The impact of the biogenic Cu NPs on wheat seedling growth was dose-dependent. Upon treatment with 0.06 mg/mL of Cu NPs, the growth was promoted by 172.78 ± 23.11 and 215.94 ± 37.76% for wheat root and shoot, respectively. However, the lowest relative growth % of 81.94 ± 11.70 and 72.46 ± 18.78% were recorded for wheat root and shoot, respectively when applying 0.43 mg/mL of Cu NPs. At this concentration, peroxidase activity (POX) of the germinated wheat seeds also decreased, while ascorbic acid oxidase (AAO) and polyphenol oxidase (PPO) activities increased. Higher uptake of copper was observed in the root relative to the shoot implying the accumulation of the nanoparticles in the former. The uptake was also higher than that of the commercial Cu NPs, which showed an insignificant effect on the seedling growth. By treating the wheat leaves in foliar application with 0.06 mg/mL of Cu NPs, their contents of Chlorophyll a, Chlorophyll b, and total chlorophyll were enhanced after 21 days of application. Meanwhile, the high concentration (0.43 mg/mL) of Cu NPs was the most effective in reducing the leaf content of chlorophyll (a, b, and total) after the same time of application. The findings of this study manifest the potential of utilizing controlled doses of the prepared biogenic Cu NPs for inhibition or stimulation of seedling growth.