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Disturbances in zinc (Zn) and copper (Cu) homeostasis have emerged as reproducible biochemical features of autism spectrum disorder (ASD). This study presents an integrative reanalysis of six investigations (2014-2025) encompassing serum, whole-blood, and plasma measurements in ASD cases and controls, and one supplementation trial. Three case-control studies reporting mean ± SD values in circulating matrices were meta-analyzed. Circulating Zn levels were significantly lower in ASD (fixed-effect Hedges' g = -0.95; 95% CI -1.22 to -0.68; Q = 1.72, p = 0.42; I2 = 0%; Egger intercept = 4.86, one-sided p = 0.044). The Zn/Cu ratio showed greater dispersion (random-effects g = -1.28; 95% CI -2.59 to 0.03; Q = 39.5, p < 0.001; I2 = 95%), driven primarily by one cohort (leave-one-out g = -0.63; 95% CI -0.99 to -0.26). In Brazilian subjects, plasma Zn and Cu fell within reference ranges, consistent with short-term plasma buffering of marginal deficits. In an Egyptian 12-week oral elemental Zn intervention in children with ASD, serum Cu fell by ~8%, circulating metallothionein (MT) protein increased, and CARS and TGMD-2 motor scores improved. MT-1A gene expression changed with Zn. Taken together, the evidence indicates that Zn insufficiency and altered Cu homeostasis are recurring features of ASD and that oral elemental Zn lowers serum Cu and increases MT. © 2025. The Author(s), under exclusive licence to Springer Nature B.V.

The effects of dietary zinc (Zn) supplementation on lambs fed diets without added Zn remain controversial, and the precise nature and extent of the associations between Zn administration and lamb responses are not fully understood. To address this, a comprehensive systematic review and dose-response meta-analysis was conducted to explore the effects of Zn supplementation on growth performance, mineral metabolism, and nutrient digestibility. Initially, 3169 studies were identified through comprehensive database searches using relevant keywords. Following a two-stage screening process, 30 eligible articles were selected based on predefined criteria and used in the current meta-analysis. The one-stage random-effects model was utilized in this meta-analysis, with sensitivity analyses conducted to evaluate the robustness of the derived effect sizes. The results showed nonlinear relationships between Zn supplementation and performance parameters. Optimal Zn levels were identified: approximately 28.51 mg/kg DM for maximum dry matter intake, 37.84 mg/kg DM for highest weight gain, and 42.00 mg/kg DM for best feed conversion ratio. Linear increases in fecal and urinary Zn, and a decrease in apparent Zn absorption, were observed with increasing Zn supplementation (P < 0.05). Zinc supplementation up to 53 mg/kg DM enhanced Zn retention, and up to 107 mg/kg DM, increased liver Zn concentration, with the highest concentration at 50.59 mg/kg DM. Zinc supplementation also affected copper and iron concentrations in various tissues. Specifically, it decreased pancreatic copper up to 22 mg/kg DM but increased it above 50 mg/kg DM. In kidney tissue, copper concentration increased linearly with Zn supplementation from 76 to 150 mg/kg DM, while in liver tissue, it decreased from 42 to 150 mg/kg DM. Heart tissue iron concentration increased up to 24 mg/kg DM but decreased from 41 to 150 mg/kg DM, with the highest concentration at 16.31 mg/kg DM. Zinc supplementation at 28.28 and 20.88 mg/kg DM increased total concentration of rumen volatile fatty acids and dry matter digestibility, respectively. However, final weight, carcass weight, nitrogen metabolism, Zn levels in heart, pancreas,

Copper is an essential trace element for fish, yet defining its optimal dietary levels remains a challenge in aquaculture nutrition. This meta-analysis quantitatively evaluated the effects of dietary copper supplementation on fish growth performance, superoxide dismutase activity, tissue copper levels, and body composition. Significant benefits in terms of fish survival, weight gain, hepatic Cu-Zn superoxide dismutase activity, and copper concentrations in the whole body, liver, and intestine were observed following supplementation with varying levels of copper, while excessive copper intake (> 25 mg/Kg) led to trade-offs in feed conversion, protein efficiency, and condition factor. Meta-regression identified that dietary copper levels, source of copper, feeding duration, and main protein content in the diet significantly moderated effect sizes of weight gain. Piecewise regression showed that the optimal dietary copper concentration determined to be 5.7 mg/kg. Structural equation models revealed that increased dietary protein and feeding duration enhance effect sizes of weight gain through elevated copper and crude protein levels in the body. This study provides a nuanced understanding of dietary copper supplementation effects on fish physiology, offering valuable insights for formulating diets that enhance aquaculture productivity while maintaining fish health. © 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

BACKGROUND: Alopecia areata (AA) is a prevalent autoimmune disorder in dermatology, impacting 0.5%-2% of the general population worldwide. More and more scholars are focusing on the important role of micronutrients in the occurrence and development of AA. AIMS: This research aimed to thoroughly and systematically assess the relationship between serum trace element levels and AA. METHODS: The PubMed, Web of Science, EMBASE, and Cochrane Library databases were searched up to May 12, 2024. Two researchers independently screened and identified eligible studies. Depending on the heterogeneity assessed by the I2 statistic, either a random-effects model or a fixed-effects model was used to combine the effect estimates. RESULTS: 34 papers, including 4931 participants from 16 countries, were analyzed. The results of meta-analysis demonstrated patients with AA had a lower serum level of vitamin D (SMD = -0.93 ng/mL, 95% CI = 0.168-0.747, p < 0.05) and serum zinc (SMD = -0.69 μg/dL, 95% CI = -0.99 to -0.39, p < 0.05) than the healthy controls. Vitamin D deficiency was strongly associated to an elevated risk of AA (OR = 2.48, 95% CI = 1.47-4.17, p < 0.05). However, there is no significant difference in serum copper levels between AA patients and the control group. CONCLUSIONS: Our research provided evidence that the levels of serum VD and zinc were associated with the risk of AA. Supplementation with VD and zinc may become a potential treatment for AA. © 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

BACKGROUND: The treatment of vitiligo is complex, and providing guidance based on lifestyle habits is a good option that has not been summarized or analyzed. OBJECTIVE: To elucidate the relationship between vitiligo and lifestyle factors. METHODS: Four databases (PubMed, Embase, Cochrane, and China National Knowledge Internet) were searched for articles published between 1980 and December 2022. Keywords such as smoking, drinking, exercise, diet, and sleep were used. RESULTS: Based on the search strategy, 875 relevant studies were retrieved, and 73 were included in this study, of which 41 studies with 8,542 patients with vitiligo were included in the meta-analysis. Vitamin C [mean difference (MD), -0.342; 95% confidence interval (CI), -1.090-0.407; p >0.05), folic acid (MD, -1.463; 95% CI, -7.133-4.208; p >0.05), and selenium (MD, 0.350; 95% CI, -0.687-1.387; p >0.05) levels did not differ between the groups. Vitamin E (MD, -1.408; 95% CI, -2.611--0.206; p <0.05), vitamin B12 (MD, -0.951; 95% CI, -1.672--0.275; p <0.05), copper (MD, -0.719; 95% CI, -1.185--0.252, p <0.005), and zinc (MD, -0.642; 95% CI, -0.731--0.554; p <0.001) levels were lower in the vitiligo group than in the control group. The serum iron level of the vitiligo group was significantly higher than that of the control group (MD, 1.181; 95% CI, 0.390-1.972; p <0.005). Finally, more participants in the vitiligo group smoked and drank alcohol than those in the control group. LIMITATIONS: Most studies are from Eastern countries; thus, extrapolating these results to Western populations is questionable. The significant heterogeneity may be attributed to the different stages, types, duration, center settings, population registries, etc., which seriously impair the validity of the results. CONCLUSIONS: Patients with vitiligo should reduce smoking and alcohol consumption and take appropriate vitamin E, B12, copper, and zinc supplements. However, vitamin C, vitamin D, selenium, iron, and folic acid supplements are unnecessary. Moreover, they should consider sun protection and avoid permanent hair dye use. Patients with vitiligo may experience sleep disturbances and sexual dysfunction, and these patients sh

AIMS: Previous studies have investigated the relationship between heart failure (HF) and levels of zinc and copper, but conflicting results have been reported. This meta-analysis aims to clarify the role of zinc and copper in HF progression by examining the associations between HF and concentrations of these minerals. METHODS AND RESULTS: We utilized STATA 12.0 software to calculate the standard mean difference (SMD) and 95% confidence interval (CI) for serum zinc and copper levels in patients with HF compared with healthy controls (HCs). The meta-analysis indicated a lower serum zinc level in patients with HF compared with HCs, using a random effects model (SMD = -0.77; 95% CI: -1.01, -0.54; I2 = 61.9%, the P-value for Q test = 0.002). Additionally, the meta-analysis showed an increased serum copper level in patients with HF compared with HCs, using a random effects model (SMD = 0.66; 95% CI: 0.09, 1.23; I2 = 93.8%, the P-value for Q test < 0.001). Meta-regression analysis indicated that publication year, age, and gender were not responsible for heterogeneity across studies. CONCLUSIONS: This meta-analysis demonstrates that patients with HF have lower serum zinc and higher copper concentrations compared with healthy subjects. However, the potential of zinc supplementation as a therapy for HF should be approached with caution. The heterogeneity among the included studies was found to be high. It is recommended that further well-designed large sample studies be conducted to validate these findings. © 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

BACKGROUND AND OBJECTIVE: Given the potential association between oxidative stress, periodontitis and dental caries, whether dietary supplementation with antioxidants is beneficial for periodontitis and dental caries has been widely reported, but remains controversial. This study aims to clarify these relationships through two-sample Mendelian randomization (MR) analysis. METHODS: Circulating antioxidants (copper, selenium, zinc, ascorbate, β-carotene, lycopene, retinol and vitamin E) were derived from absolute circulating antioxidants and circulating antioxidant metabolites. Summary data of periodontitis and dental caries were obtained from two separate databases, respectively. We performed inverse-variance weighted (IVW) analysis separately in different databases, followed by meta-analysis. The robustness of results was examined by sensitivity analyses, including three complementary MR methods, heterogeneity and pleiotropy tests, and PhenoScanner query. RESULTS: IVW analysis showed that elevated levels of absolute circulating retinol reduced the risk of periodontitis (GLIDE: OR = 0.41, 95% CI = 0.18-0.95, p = .038, power = 100%; FinnGen: OR = 0.15, 95% CI = 0.04-0.54, p = .004, power = 100%). The pooled OR for periodontitis risk per unit increase of retinol is 0.30 (95% CI = 0.15-0.61, p = .001, I2 = 40.3%, power = 100%). No significant associations were noted for genetically predicted circulating antioxidants and dental caries risk. The sensitivity analyses yielded similar estimates. CONCLUSION: This study demonstrates that a negative causality between circulating retinol and periodontitis risk, and null linkage between circulating antioxidants and dental caries risk, suggesting potential strategies for the prevention and control of periodontitis. © 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

BACKGROUND: The risk of protein and vitamin deficiencies after bariatric surgery has been well studied, but the change in mineral status has not gotten enough attention. This study aimed to perform a meta-analysis regarding the change in mineral levels after bariatric surgery and the prevalence of postoperative mineral deficiency, with subgroup analyses of different surgical procedures, study regions, and follow-up time. METHODS: CENTRAL, PubMed, and EMBASE were searched for related articles. Meta-analysis, subgroup analysis, and sensitivity analysis were performed if necessary. RESULTS: A total of 107 articles with 47,432 patients were included. The most severe mineral deficiency after bariatric surgery was iron (20.1%), followed by zinc (18.3%), copper (14.4%), chlorine (12.2%), phosphorus (7.5%), and calcium (7.4%). Serum concentrations of potassium, sodium, selenium, manganese, and molybdenum showed no significant change before and after surgery. Subgroup analyses revealed that SG had fewer deficiencies in serum iron, calcium, zinc, magnesium, phosphorus, copper, and selenium than RYGB. OAGB showed a higher incidence of serum iron and zinc deficiencies than RYGB. Studies conducted in different regions also found various mineral statuses after surgery. Studies with follow-up ≥ 5 years had a lower prevalence of zinc, copper, and selenium deficiencies than follow-up < 5 years. CONCLUSION: A high deficiency rate of serum iron, zinc, copper, chlorine, phosphorus, and calcium was seen after bariatric surgery. The difference in surgical procedures, study regions, and follow-up time may affect postoperative mineral status; more targeted mineral supplement programs are needed considering these influencing factors. © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

BACKGROUND: Down syndrome (DS) is the most common genetic disorder. To date, the scientific literature regarding micronutrient status in children and adolescents with DS has not been systematically reviewed. Therefore, our aim was to provide a systematic review and meta-analysis on this topic. METHODS: We identified all relevant case-control studies published by 1 January 2022, by searching the PubMed and Scopus databases for original English-language articles analysing the micronutrient status of individuals with DS. Forty studies were included in the systematic review and 31 in the meta-analysis. RESULTS: Statistically significant differences between individuals with DS (cases) and non-DS (controls) (P ≤ 0.05) were obtained for zinc, selenium, copper, vitamin B12, sodium and calcium. Serum, plasma and whole blood analyses showed lower zinc levels in cases than controls {standardised mean difference [SMD] serum [95% confidence interval (CI)] = -2.32 [-3.22, -1.41], P < 0.00001; SMD plasma [95% CI] = -1.29 [-2.26, -0.31], P < 0.01; SMD blood [95% CI] = -1.59 [-2.29, -0.89], P < 0.00001}. Similarly, plasma and blood selenium concentrations were significantly lower in cases than controls (SMD plasma [95% CI] = -1.39 [-2.26, -0.51], P = 0.002; SMD blood [95% CI] = -1.86 [-2.59, -1.13], P < 0.00001). Intraerythrocytic copper and serum B12 were higher in cases than controls (SMD Cu [95% CI] = 3.33 [2.19, 4.46], P < 0.00001; SMD B12 [95% CI] = 0.89 [0.01, 1.77], P = 0.048). Blood calcium was lower in cases than controls (SMD Ca [95% CI] = -0.77 [-1.34, -0.21], P = 0.007). CONCLUSIONS: This study provides the first systematic overview of micronutrient status in children and adolescents with DS and has shown that relatively little consistent research has been executed in this field. There is a clear need for more well-designed, clinical trials to study the micronutrient status and effects of dietary supplements in children and adolescents with DS. © 2023 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd. The association between micronutrient levels and diabetic foot ulcer: A systematic

BACKGROUND: Diabetic foot ulcers (DFU) are a major complication of diabetes mellitus (DM). Nutrient deficiencies are among the major risk factors in DFU development and healing. In this context, we aimed to investigate the possible association between micronutrient status and risk of DFU. METHODS: A systematic review (Prospero registration: CRD42021259817) of articles, published in PubMed, Web of Science, Scopus, CINAHL Complete, and Embase, that measured the status of micronutrients in DFU patients was performed. RESULTS: Thirty-seven studies were considered, of which thirty were included for meta-analysis. These studies reported levels of 11 micronutrients: vitamins B9, B12, C, D, E, calcium, magnesium, iron, selenium, copper, and zinc. DFU, compared to healthy controls (HC) had significantly lower vitamin D (MD: -10.82 14 ng/ml, 95% CI: -20.47, -1.16), magnesium (MD: -0.45 mg/dL, 95% CI: -0.78, -0.12) and selenium (MD: -0.33 µmol/L, 95% CI: -0.34, -0.32) levels. DFU, compared to DM patients without DFU, had significantly lower vitamin D (MD: -5.41 ng/ml, 95% CI: -8.06, -2.76), and magnesium (MD: -0.20 mg/dL, 95% CI: -0.25, -0.15) levels. The overall analysis showed lower levels of vitamin D [15.55ng/ml (95% CI:13.44, 17.65)], vitamin C [4.99µmol/L (95% CI:3.16, 6.83)], magnesium [1.53mg/dL (95% CI:1.28, 1.78)] and selenium [0.54µmol/L (95% CI:0.45, 0.64)]. CONCLUSION: This review provides evidence that micronutrient levels significantly differ in DFU patients, suggesting an association between micronutrient status and risk of DFU. Therefore, routine monitoring and supplementations are warranted in DFU patients. We suggest that personalized nutrition therapy may be considered in the DFU management guidelines. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=259817, identifier CRD42021259817.

OBJECTIVE: The objective of this trial was to compare the clinical performance and safety of a novel wound dressing containing silver and copper nanoparticles (Nanordica; Nanordica Medical OÜ, Estonia) (Ag/Cu) with the ionic silver-based dressing Aquacel Ag+ Extra (Convatec Group, UK) (Ag+) for the treatment of infected diabetic foot ulcers (DFUs). METHOD: This study was a single-blinded, randomised, active-controlled pilot trial involving patients with infected DFUs who were randomly assigned to receive either the Ag/Cu or Ag+ dressing. Patients were treated over a one-week active phase with dressing changes every other day, followed by a two-week follow-up phase using a non-antibacterial dressing. Efficacy was measured by wound area size (WAS) reduction, bacterial load control and quality of life (QoL) scores. Safety outcomes were based on adverse events and blood Ag levels. RESULTS: The experimental cohort included 30 patients. Consistently better results were observed in nearly all efficacy and safety endpoints for patients treated with the Ag/Cu dressing compared with those treated with the Ag+ dressing. Although WAS decreased in both groups, the WAS in the Ag/Cu dressing group had already decreased by 31% after the first dressing change. By the end of the active phase, the WAS had decreased by 43% in the Ag/Cu dressing group, compared with a 13% reduction in the Ag+ dressing group. The mean total bacterial load in the wound bed did not change significantly in the Ag/Cu dressing group but increased in the Ag+ dressing group. The QoL score increased more in the Ag/Cu dressing group, but this difference did not reach statistical significance. CONCLUSION: The findings of this clinical study indicated that the Ag/Cu dressing is a safe and effective way to treat infected DFUs, demonstrating faster WAS reduction, enhanced bacterial control, and higher QoL scores compared with traditional Ag+ dressings.

The menstrual cycle (MC), characterized by hormonal fluctuations, may impact skeletal muscle oxygenation (SMO) during high-intensity interval training (HIIT). SMO measured around HIIT in eumenorrheic (EUM) or hormonal contraceptive (HC) users can inform exercise and recovery practices. Females who were EUM (no hormonal contraceptive n = 21; copper intrauterine device n = 5) or using HC (oral n = 5; hormonal intrauterine n = 6) completed two HIIT protocols (HIIT1:1: 10 × 60 s work/60 s rest; HIIT2:1: 20 × 20 s work/10 s rest) during both low-hormone (LHP) and high-hormone phases (HHP) of the MC, in randomized order. SMO (tissue saturation index (TSI) and total hemoglobin (THb) were measured at rest, during HIIT, and during 15 min recovery using near-infrared spectroscopy. Data were analyzed as repeated measures ANOVA. During HIIT1:1, TSI desaturation was greater in LHP (-8.30 ± 3.30%) compared to HHP (-6.77 ± 4.55%; MC phase p < 0.001). During HIIT2:1, TSI desaturation was greater in HHP (-6.98 ± 3.54%) compared to LHP (-6.71 ± 3.61%; MC phase p < 0.001). During HIIT2:1, TSI resaturation was greater in LHP (-5.05 ± 3.31%) compared to HHP (-5.33 ± 3.31%; MC phase p = 0.004). During recovery from HIIT1:1, THb was greater in LHP (16.25 ± 6.32 µmol/L) compared to HHP (15.91 ± 6.46 µmol/L; MC phase p = 0.039). During HIIT2:1 recovery, THb was higher in HHP (15.92 ± 5.47 µmol/L) compared to LHP (14.08 ± 5.05 µmol/L; MC phase p = 0.039). During HIIT2:1, HC demonstrated greater TSI desaturation and resaturation in HHP compared to LHP (p < 0.001). These data suggest MC influences SMO during HIIT, with HHP favoring longer work/rest intervals (HIIT1:1), while recovery remains unaffected; HC demonstrated greater SMO fluctuations during HIIT2:1 in HHP.

PURPOSE: Trientine dihydrochloride (TETA-2HCl) is an established treatment for Wilson disease. We assessed different dissolution profiles of TETA-2HCl capsules on the pharmacokinetics (PK) of trientine (TETA) and on direct copper (Cu) parameters. METHODS: In this open-label, randomized, two way cross-over study, 24 healthy subjects received two single oral doses of 600 mg TETA-2HCl with a washout of at least one week; one dose with a fast and one dose with a slow dissolution profile. Blood and urine samples were collected up to 48 h for analysis of plasma TETA and its metabolites, N1-acetyltriethylenetetramine (MAT) and N1-N10-diacetyltriethylenetetramine (DAT), serum Cu, ceruloplasmin (Cp) and urinary Cu excretion (UCE). The effect of dissolution profile on the PK was assessed through the ratio of geometric mean ratios (GMRs) and two-sided 90%-confidence intervals (CI) of the fast vs. slow dissolution profile. RESULTS: The Cmax of TETA was comparable for the two products (GMR 95.81%; CI 83.87-109.46%) while AUC0 - inf was slightly lower for the capsules with fast dissolution profile (GMR 90.65; 90% CI 78.32-104.91%). PK parameters were similar for the metabolites of TETA. Additionally, serum Cu and Cp concentrations remained stable over the 12 h period after dosing and were comparable between the two products, as was UCE. CONCLUSION: The pharmacokinetic profiles of TETA after administration of TETA-2HCl capsules with fast and slow dissolution characteristics were similar. Though the lower 90%-CI for AUC0-inf was outside the formal bioequivalence ranges, differences were small (9%) and not considered clinically relevant. A difference in dissolution profile did not affect copper parameters and tolerability. © 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

BACKGROUND: Limited high-quality evidence exists from controlled trials on the impact of avocado-containing diets on cardiometabolic risk factors. OBJECTIVES: The purpose of this randomized, double-blind, free-living, controlled feeding, crossover study in adults with increased cardiometabolic risk was to assess the effects of replacing energy from solid fats and added sugars with equivalent energy from 1 avocado daily on cardiometabolic risk factors. METHODS: For two 3-wk periods, separated by a 2-wk washout, healthy adults with elevated triglycerides (TG, 135-499 mg/dL) consumed an average American diet or a diet in which 1 avocado (∼180 g/d, ∼300 kcal/d) replaced energy from saturated fatty acids and added sugars. The same study products (muffins, granola bites, dressing, salsa, marinade, and pesto) delivered the avocado or control ingredients. Green food dye was added to the control study products to facilitate double blinding. Non-high-density lipoprotein (non-HDL) cholesterol (primary outcome), other lipoprotein lipids, fasting glucose and insulin, and fasting and postprandial blood pressures were measured at baseline and end of condition. Linear mixed models were used to generate estimates for percentage changes. RESULTS: Of 42 randomly assigned participants, 37 completed the avocado condition and 39 completed the control condition. An intention-to-treat analysis showed significantly larger percentage changes, 95% confidence intervals (CIs), from baseline after the avocado condition, compared with after the control condition, for non-HDL cholesterol (-4.65%; 95% CI: -9.01%, -0.08%; P = 0.047), very-low-density lipoprotein cholesterol (-9.30%; 95% CI: -15.3%, -2.82%; P = 0.007); TG (-17.4%; 95% CI: -25.0%, -8.99%; P < 0.001), small low-density lipoprotein subfraction cholesterol (-13.9%; 95% CI: -23.2%, -3.49%; P = 0.012), and total cholesterol:HDL cholesterol ratio (-6.56%; 95% CI: -12.0%, -0.79%; P = 0.028). Percentage changes for other lipoprotein lipids, glucose, insulin, and blood pressures did not significantly differ (P > 0.05) between conditions. CONCLUSIONS: Replacing solid fats and added sugars with avocado in a typical American diet improves the

Dysregulation contributes to Alzheimer's disease (AD) pathophysiology. Zinc therapy promotes enterocyte copper sequestration, potentially reducing systemic copper. Individual biological responses may vary. METHODS: ZINCAiD was a 24-week, randomized, double-blind, placebo-controlled phase II trial assessing zinc therapy in individuals with mild cognitive impairment (MCI) due to AD (EudraCT No.: 2019-000604-15; registered on 26 March 2020). Participants were randomized 2:1 to receive elemental zinc (135 mg/day for 12 weeks, then 65 mg/day) or placebo. Ceruloplasmin was measured at predefined intervals for safety monitoring, blinded to the investigators. Post hoc, "Zinc Responders" were defined by ≥20% reduction in ceruloplasmin at week 12. The primary cognitive endpoint was the Cognitive Composite 2 scale (CC2); secondary endpoints included MMSE and CDR-Sob. FINDINGS: Of the 48 participants randomized, 9 discontinued, primarily due to unrelated clinical deterioration; 39 had complete ceruloplasmin data. Two serious adverse events occurred in the Placebo group. Mild gastrointestinal symptoms occurred in eight participants, with only four leading to dropout. In the primary zinc vs. placebo analysis, no significant differences emerged in cognitive outcomes. A post hoc exploratory analysis stratified participants by pharmacodynamic response: 12 individuals with MCI due to AD (31%) met the criteria for "Zinc Responder," defined by ≥20% reduction in serum ceruloplasmin at week 12. Only Zinc Responders maintained cognitive stability over 24 weeks, whereas the combined group of Zinc Non-Responders and placebo-treated participants showed a significant decline. For the composite cognitive score (CC2), the interaction between visit and response group was significant (p = 0.030), with deterioration observed only in the Non-Responder + Placebo group (Δ = -2.72, p < 0.0001 vs. -0.71, p = 0.35 in Responders). Similar patterns were observed for CDR-Sob (interaction p = 0.017) and MMSE (trend p = 0.09). INTERPRETATION: Zinc therapy stabilized cognition in a pharmacodynamically defined MCI subgroup. These exploratory findings suggest serum ceruloplasmin as a feasible biomarker of t

BACKGROUND: There is a scarcity of prospective data on the impact of available vaccinations against respiratory viruses on hard clinical endpoints in patients with heart failure (HF). AIMS: We investigated whether, in the population of high-risk HF patients, simultaneous vaccination against influenza and respiratory syncytial virus (RSV) improves outcomes during the subsequent infection season. METHODS: We conducted a prospective, randomized, single-centre, open-label study in which patients with high-risk HF were randomized 1:1 to simultaneous influenza and RSV vaccination or standard of care (SOC). The primary composite endpoint comprised all-cause death, HF hospitalization (HFH) or clinical signs/symptoms of infection within a 6 month follow-up period (regular structured telephone interview). Secondary endpoints were components of the composite primary endpoint. RESULTS: Two hundred twenty patients were randomized. During the follow-up period, the primary endpoint occurred in 59% of patients in the vaccination group versus 75% in the SOC group [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.48-0.92, P = 0.01]. Regarding the secondary endpoint analyses, during 6 month follow-up, 3% in the vaccination group died compared with 5% of patients in the SOC arm (HR 0.50, 95% CI 0.12 1.99, P = 0.32), and 18% versus 16% of study participants were hospitalized for HF in the two study arms, respectively (HR 0.86, 95% CI 0.45-1.62, P = 0.64). Infection occurred in 53% of vaccinated patients compared with 68% in SOC (HR 0.68, 95% CI 0.48-0.96, P = 0.03). CONCLUSIONS: In the population of high-risk HF, simultaneous vaccination against influenza and RSV reduced the incidence of the primary outcome. The effect was driven by a significant reduction in infections. © 2025 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

BACKGROUND: Intrauterine devices (IUDs) are highly effective, yet acceptability and continuation differ by user and device characteristics. We evaluated the efficacy of the NTCu380 Mini, a 380-mm2 copper IUD available in Europe and Canada, and compared safety and continuation with the TCu380A IUD, the 380-mm2 copper IUD available in the United States. METHODS: We randomly assigned participants between 16 and 40 years of age in a 4:1 ratio to the NTCu380 Mini or TCu380A and assessed over 37 months. The primary outcome was NTCu380 Mini efficacy measured by the Pearl Index (defined as the number of pregnancies per 100 woman-years) in participants 35 years of age and under. Additional outcomes included NTCu380 Mini time to pregnancy by survival analysis, and comparative adverse events (AEs) and continuation rates of NTCu380 Mini versus TCu380A. RESULTS: We randomly assigned 887 participants to NTCu380 Mini (744 [83.9%] nulliparous) and 218 to TCu380A (183 [83.9%] nulliparous), of whom 875 (98.6%) and 213 (97.7%), respectively, had successful placement. The NTCu380 Mini IUD 3-year cumulative Pearl Index was 1.86 (95% confidence interval [CI], 1.20 to 2.74) pregnancies per 100 women-years; the cumulative rate of pregnancy through year 3 was 4.8% (95% CI, 2.8 to 6.9%). Serious AEs occurred in 31 (3.5%) NTCu380 Mini and 4 (1.9%) TCu380A users (P=0.28). Discontinuation occurred in 449 (51.3%) NTCu380 Mini and 122 (57.3%) TCu380A users (P=0.07). AEs led to discontinuation less frequently among NTCu380 Mini (152 [20.8%]) than TCu380A users (57 [33.2%]) (P=0.001), particularly bleeding or pelvic pain AEs (103 [14.5%] vs. 46 [27.3%], respectively; P<0.001). CONCLUSIONS: In this predominantly nulliparous population, the NTCu380 Mini IUD had an approximate 5% pregnancy rate over 3 years, with fewer side effects leading to discontinuation than observed among TCu380A users. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03124160.) The findings and conclusions in this article are those of the authors and do not necessarily reflect the views of the Planned Parenthood Federation of America, Inc.

OBJECTIVES: This study compares the expulsion rate of the postplacental copper intrauterine device (IUD) based on the insertion technique: manual versus ring forceps. Pain, perforation, infection, and increased bleeding were assessed as secondary outcomes. METHOD: The study consisted of a randomized clinical trial involving 210 women (with 105 in each group) admitted for vaginal delivery at a teaching hospital who wanted to use an IUD and had no contraindications to use an IUD. Patient recruitment occurred between December 2021 and June 2024. Pain was evaluated using the visual analog scale immediately after insertion. Descriptive statistics and bivariate analysis were performed. The Cochran-Armitage test was used to assess the temporal trend of expulsion. Participants were followed up between 6 and 12 weeks postpartum. RESULTS: The complete IUD expulsion rate was 20.5%, with no significant difference between forceps and manual insertion (25% vs. 16.7%, P = 0.168). Expulsions were easily perceived by the women and occurred early. Notably, in this teaching hospital setting, the turnover of new medical residents (P = 0.057) performing insertions did not affect the expulsion rates throughout the year. Manual insertion was associated with greater discomfort compared to forceps (P = 0.001), even with epidural anesthesia (P = 0.002). There were no cases of uterine perforation or infection. CONCLUSION: The postplacental IUD expulsion rate was lower with manual insertion, although not statistically significant. Insertion discomfort was lower in the forceps group, regardless of analgesia. Postplacental IUD insertion was well tolerated, safe, and easily reproducible by junior doctors. TRIAL REGISTRATION: This study was approved by the Ethics and Research Commission of the University of Campinas (UNICAMP) and the Brazilian Registry of Clinical Trials (REBEC): https://ensaiosclinicos.gov.br/rg/RBR-4j62jv6, (number RBR-4j62jv6). © 2025 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.

Chronic inflammation and gut barrier breakdown contribute to the progression of metabolic syndrome and affect the development of cardiometabolic diseases, especially in persons consuming low-quality diets with limited bioactive compounds. Almonds are a rich source of bioactive compounds with antioxidant and anti-inflammatory properties. We hypothesize almond consumption can help disrupt metabolic syndrome progression by improving gut and cardiometabolic health and decreasing inflammation and oxidative stress. To test this hypothesis, adults with metabolic syndrome were randomized to consume either almonds (2 oz, whole, dry roasted, n = 38) or crackers (control, equal caloric content, n = 39), as a daily snack for 12 weeks, and samples were collected (0, 4, and 12 weeks). Compared with participants consuming crackers, almond consumption resulted in lower plasma total and low-density lipoprotein-cholesterol concentrations, a modest improvement in waist circumference (week 4), and improved dietary intakes of α-tocopherol, soluble fiber, copper, biotin, magnesium, polyunsaturated fatty acids, and monounsaturated fatty acids. Almond consumption raised plasma α-tocopherol concentrations (relative to cholesterol concentrations) and increased excretion of a vitamin E biomarker (α-CEHC). Almond consumption improved biomarkers of gut barrier function and intestinal inflammation (fecal calprotectin, myeloperoxidase) in participants with elevated inflammation at baseline. Total body weight, caloric intake, and markers of carbohydrate metabolism (glucose, insulin), systemic inflammation (plasma interleukin-6, C-reactive protein, lipopolysaccharide-binding protein, CD14), and oxidative damage (malondialdehyde) were not altered by almond consumption. In conclusion, daily almond snacking improves nutrient intake and decreases gut inflammation in participants with metabolic syndrome. These beneficial dietary and inflammatory changes may contribute to the improvements in cardiovascular health observed.

OBJECTIVES: This study aimed to determine observed vs expected pregnancy risk among levonorgestrel 52 mg and copper T380A intrauterine device (IUD) emergency contraception (EC) users. STUDY DESIGN: This is a secondary analysis of participants seeking EC randomly assigned to a levonorgestrel 52 mg or copper T380A IUD. Participants had at least one episode of unprotected intercourse (UPI) in the 5 days preceding enrollment and reported all episodes in the preceding 5 days. We report the proportion of pregnancies prevented of those expected at 1 month following IUD insertion using an established approach that assigns pregnancy risk by menstrual cycle day of intercourse. We calculated proportion of pregnancies prevented using both the day of most recent UPI and all reported UPIs within 5 days of presentation. RESULTS: One pregnancy occurred among the 312 participants who received the levonorgestrel 52 mg IUD, with 137 (43.9%) reporting multiple episodes of UPI. No pregnancies occurred among the 318 participants who received the copper IUD, of whom 142 (44.6%) reported multiple episodes. In the levonorgestrel 52 mg IUD group, 14.8 pregnancies were expected using the most recent episode of UPI, and 22.0 pregnancies were expected using all episodes within 5 days of presentation. In the copper IUD group, we calculated 15.0 and 23.1 expected pregnancies, respectively. Levonorgestrel 52 mg IUDs prevented 93.2% to 95.7% of expected pregnancies, and copper IUDs prevented 100% of expected pregnancies. CONCLUSIONS: The results of this analysis provide additional data quantifying the pregnancy risk reduction for both the levonorgestrel 52 mg IUD and copper IUD in a realistic population of EC users. IMPLICATIONS: The levonorgestrel 52 mg IUD for emergency contraception prevented 93% to 96% of expected pregnancies using an established pregnancy risk method, while copper IUD users experienced 100% pregnancy prevention.

BACKGROUND: Paclitaxel is a cornerstone of breast cancer treatment, but its efficacy is often limited by low response rates and drug resistance. To address this, we developed MEVs@CuET, a novel therapeutic approach combining cuproptosis-inducing copper(II) complex (CuET) with macrophage-derived extracellular vesicles (MEVs), aiming to enhance paclitaxel's antitumor effects. METHODS: The tumor-targeting capability of MEVs@CuET was evaluated through cellular uptake and in vivo distribution studies. In vitro synergy was assessed using the ZIP model, while transcriptome sequencing analyzed gene expression changes. In vivo antitumor activity and immune modulation were examined in breast cancer models, with tumor growth inhibition, apoptosis, and Th17 lymphocyte levels measured. RESULTS: MEVs@CuET demonstrated efficient tumor targeting and synergistic antiproliferative effects with paclitaxel in vitro (synergy score: 29.37). Transcriptomic analysis revealed significant alterations in immune-related pathways, particularly upregulation of the IL-17 signaling pathway. In vivo, the combination therapy markedly inhibited tumor growth, increased apoptosis, and elevated Th17 cell levels, aligning with the transcriptomic findings. CONCLUSION: MEVs@CuET significantly enhances paclitaxel's efficacy by inducing cuproptosis and modulating antitumor immunity, offering a promising strategy to overcome resistance in breast cancer treatment. © 2026 Guo et al.

A vitamin K3 (VK3)-loaded metal-organic framework (Cu/ZIF-8/VK3) was synthesized by a one-pot method. After the coencapsulation of Cu/ZIF-8/VK3 and 5-fluorouracil (5-FU) in the hyaluronate acid (HA)/carboxymethyl chitosan (CMCS) hydrogels formed via an amidation reaction, a drug-controlled release system (Cu/ZIF-8/VK3/5-FU/HA/CMCS) was obtained. In the weakly acidic media, the amide bonds in the HA/CMCS hydrogels are prone to be hydrolyzed, resulting in the release of 5-FU and Cu/ZIF-8/VK3; and the Cu/ZIF-8/VK3 is further degraded in the acidic environment, leading to the release of VK3 and Cu2+. The released Cu2+ can be reduced by glutathione (GSH) to Cu+, which can react with intracellular H2O2 to produce cytotoxic hydroxyl radicals (·OH) for chemodynamic therapy (CDT). On the other hand, H2O2 can be replenished through the redox cycling of VK3 in the presence of NAD(P)H: quinone oxidoreductase-1 (NQO1), generating stable ·OH for enhanced CDT. Cytotoxicity assay demonstrates that the developed drug-controlled release system has excellent biocompatibility, which can effectively inhibit the growth of mouse breast tumor cells 4T1 due to the synergistic chemotherapy and enhanced CDT.

The potential of copper nanoparticles (Cu-NPs) to counter fungicide resistance was investigated using five spontaneous Altrernaria alternata mutants highly resistant to fludioxonil. Resistant isolates carried mutations causing premature termination of AaHK1, the target gene of phenylpyrrole fungicides. Resistance mutations had no adverse effects on mycelial growth and virulence while fludioxonil-resistant isolates were more sensitive to osmotic stress and produced less conidia compared to the wild-type parental strains. Cu-NPs exerted a significant fungitoxic effect against both wild-type and resistant isolates, which was superior to that exerted by a reference fungicide containing Cu(OH)2. A profound synergistic effect against wild-type and resistant A. alternata isolates resulted from the combination of Cu-NPs with fludioxonil or iprodione, probably due to enhanced fungicide bioavailability. The fungitoxic mode of action of Cu-NPs extended beyond copper ion release as indicated by both the synergistic rather-than-antagonistic effect of the strong chelating agent EDTA when mixed with Cu-NPs and the lack of any correlation between Cu-NPs and Cu(OH)2. The enhanced antifungal activity of Cu-NPs + EDTA may stem from a reduction of NP size due to a capping effect of the chelating agent. Furthermore, ATP-dependent ion efflux may contribute to the fungitoxic effect of Cu-NPs against A. alternata, as indicated by the additive effect between NPs and the oxidative phosphorylation uncoupler fluazinam. Concluding, Cu-NPs can serve as an effective fungicide alternative against A. alternata, a promising anti-resistance strategy when combined with fludioxonil, and a means for minimizing the environmental impact of synthetic fungicides.

Treatment of breast cancer is severely hindered by dose-limiting toxicity and acquired Tamoxifen (Tam) resistance. This study investigated the synergistic anti-cancer effect and molecular mechanism of green-synthesized Copper Oxide Nanoparticles (CuO NPs) when combined with Tam against the MCF-7 human breast cancer cell line. CuO NPs were successfully produced using an aqueous extract of Artemisia sieberi as a dual reducing/capping agent. Characterization confirmed the formation of stable nanoparticles, evidenced by a Surface Plasmon Resonance (SPR) peak at 552 nm, an average size of ∼36 nm (TEM), and excellent colloidal stability with a highly negative Zeta Potential (-33.5 mV). The MTT assay demonstrated that the combination regimen exhibited a strong synergistic cytotoxic effect (CI<1) toward MCF-7 cells. Synergy was achieved even at low concentrations, such as 15.0 μg/mL CuO NPs:1.0 μM Tam (CI=0.99), with the most potent synergy (CI=0.69) observed at the maximum dose. Quantitative analysis via Annexin V/PI flow cytometry confirmed this enhancement, showing the combination reduced the viable cell population to a minimal 4.87 %. Mechanistically, RT-qPCR analysis revealed a maximal perturbation of the mitochondrial apoptotic pathway. The combined treatment simultaneously maximized the up-regulation of the pro-apoptotic gene BAX and the down-regulation of the anti-apoptotic gene BCL-2. This synergistic action resulted in a 16.74-fold increase in the critical BAX/BCL-2 ratio, approximately two times greater than either monotherapy. These findings validate CuO NPs co-administration with Tamoxifen as a promising strategy for overcoming acquired Tamoxifen resistance.

Heavy metals are ubiquitous in the environment due to both natural processes and anthropogenic activities. Nickel (Ni) and copper (Cu) commonly co-occur in contaminated environments, yet most toxicity studies focus on individual metals. We investigated the combined toxicity of Ni and Cu in Escherichia coli using environmentally relevant concentrations of each. While each metal alone caused minimal growth inhibition, their combination was synergistically toxic. Transcriptomic and metabolomic analyses revealed unique alterations in gene expression and metabolite abundances during the combined metal treatment. Key pathways uniquely impacted by the combined metal exposure included sulfur assimilation, cysteine biosynthesis, and the tricarboxylic acid cycle. Many of these responses appeared to be linked to dysregulation of iron-sulfur (Fe-S) cluster metabolism. We observed increased expression of the genes encoding ISC Fe-S cluster assembly machinery only during metal co-treatment. Growth experiments with deletion mutants confirmed that the ISC machinery was required for survival only under the combined metal stress. We also observed the activation of a sulfur starvation response during the combined metal stress that was consistent with increased sulfur demand for Fe-S cluster biosynthesis. Deletion of cysK, encoding cysteine synthase, impaired growth only under combined metal exposure. Because Fe-S clusters are universal across microbial taxa, the common co-occurrence of Ni and Cu in the environment represents a widespread and underrecognized threat to microbial life and the ecosystem processes they sustain. Our findings highlight the need to further assess the effects of metal mixtures, which can trigger emergent stress responses not yet predictable from single-metal exposures.IMPORTANCEMany environments are contaminated by metals. These metals are toxic to the microorganisms that inhabit these environments and carry out important ecosystem services. While much is known about bacterial responses to single metal stress, in most contaminated environments, metals typically exist as mixtures. Nickel (Ni) and copper (Cu) are common co-contaminants. We tested Ni and Cu i

Deoxynivalenol (DON) pollution remains a significant safety concern for humans and animals due to its widespread occurrence in grains and feedstuffs. Copper (Cu) plays a vital role as a trace element in maintaining biological functions in humans and animals. Nevertheless, the risks of DON and Cu co-exposure and the underlying mechanisms of intestinal toxicity remain unclear. Herein, IPEC-J2 cells and a mouse intestinal organoid model were used to evaluate the combined toxic effects of co-exposure to DON and Cu. Co-exposure to DON and Cu at low doses has significant synergistic toxic effects, which disrupt the intestinal barrier and significantly inhibit intestinal organoid development. Mechanistically, co-treatment with DON and Cu alters the levels of apoptosis and ferroptosis related proteins, and consequently activates apoptosis and ferroptosis in mouse intestinal organoids and IPEC-J2 cells. These activations are driven by DON + Cu exposure-induced mtROS accumulation, disrupted MMP and mPTP, and inhibited the expression of mitochondrial antioxidant proteins. Pretreatment with the mtROS-targeted scavenger MitoQ effectively assuaged DON + Cu exposure-caused mitochondrial injury and subsequently attenuated the apoptosis and ferroptosis. Overall, our research revealed the synergistic toxicity of DON + Cu exposure and confirmed the potential mechanism of DON + Cu exposure-induced intestinal toxicity, which will provide valuable insights into their potential combined toxic effects on humans and animals.

Candida albicans is an opportunistic fungal pathogen that causes millions of infections per year, for which more efficacious treatments are needed. Observations that azole antifungals incite C. albicans to adjust a variety of metal-dependent processes led us to hypothesize that vulnerabilities in metallohomeostasis incurred by drug stress could be leveraged by compounds that interrupt metal trafficking. Here, we show that tetrathiomolybdate (TTM), a copper (Cu) chelator that interferes with Cu trafficking and use, inhibits growth of C. albicans on its own and synergizes with select azoles to enhance antifungal activity. Proteomic and biochemical experiments revealed that TTM causes differential expression and stabilization of proteins involved in fermentation and oxidative stress responses in C. albicans. The synergy between TTM and azoles was found to arise from increased expression and stability of the nitric oxide dioxygenase Yhb1, a response driven by the decreased stability and activity incurred by TTM of CuZn superoxide dismutase 1. Addition of imidazole-based antifungals highjacks this stress response by inhibiting Yhb1. This study highlights the centrality of Cu homeostasis as a regulatory hub connecting energy production, oxidative stress management, and overall cellular fitness in ways that can be pharmacologically manipulated to enhance efficacy of existing antifungal agents.

Drug-resistant bacterial infections pose a significant threat to global health, creating an urgent need for new antimicrobial agents. Reusing approved drugs has gained attention as a strategy to address this issue. In this study, a nano antibacterial platform (DSF@HKUST-1@Dex) that responds to the infection microenvironment is proposed. This platform releases disulfiram (DSF), binds to copper ions in the mildly acidic conditions of infected areas, converting DSF from nontoxic to toxic in situ, thereby inducing bacterial death and enhancing copper ion absorption. Noncatalytic treatment is also initiated for a synergistic antibacterial effect. Excessive copper ions disrupt bacterial metabolism, inhibit the Tricarboxylic acid (TCA) cycle, reduce ATP levels, and induce cuproptosis-like death, significantly enhancing antibacterial efficacy. In a bacterial wound infection model, the platform exhibited excellent antibacterial activity, promoting wound healing and reducing inflammation. Proteomic analysis showed that the platform selectively targeted bacterial peptidoglycan, disrupted the bacterial cell wall, impacted energy metabolism, and inhibited bacterial growth. In conclusion, this nanoplatform offers a promising strategy for treating drug-resistant infections by repurposing old drugs, converting them to toxic forms, and providing a novel antimicrobial approach. © 2025 Wiley‐VCH GmbH.

Single-atom nanozymes (SANs), with their tunable metal active centers, enable the modulation of various enzyme activities for antitumor therapy. However, these materials encounter substantial challenges in cancer therapy owing to their limited biocompatibility and biodegradability. Additionally, the high-temperature pyrolysis process involved in their synthesis significantly restricts their practical, large-scale application. To address these challenges, we propose the construction of an LDH-based SAN exhibiting peroxidase-like (POD-like) activity and glutathione depletion capability. We successfully developed a SAN containing ruthenium (Ru) and copper (Cu) bimetallic atoms (MgAl-LDH/Ru/Cu), where Ru and Cu are distributed in single-atom dispersed states, forming nanodomains. The synergistic effects of the Ru/Cu bimetallic system enable MgAl-LDH/Ru/Cu to demonstrate superior POD-like and glutathione peroxidase-like (GPx-like) catalytic activities compared to those of MgAl-LDH/Ru or MgAl-LDH/Cu alone. Density functional theory calculations indicate that both Ru and Cu sites in MgAl-LDH/Ru/Cu exhibit lower energy barriers for POD-like and GPx-like reactions, likely due to enhanced electron loss states at the Ru/Cu bimetallic single-atom sites compared to those at Ru or Cu sites individually. Both in vitro and in vivo experiments demonstrate that the Ru/Cu bimetallic loading significantly outperforms the individual metal loadings of Ru or Cu in terms of anti-liver cancer efficacy. Importantly, by leveraging the precise correlation between the catalytic structural unit of MgAl-LDH-based SANs and enzyme activity, we further elucidated the potential contributions of POD-like and GPx-like activities to cancer therapy. MgAl-LDH-based multimetal SAN represents a synergistic multienzyme nanoplatform with a tunable elemental composition, paving the way for further investigations into the interplay between multienzyme activity and antitumor effects.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis, partly due to cancer stem cells (CSCs) that drive progression and treatment resistance. We explored the therapeutic potential of inducing cuproptosis, a copper-dependent, regulated cell death, in CSC-enriched PDAC models. Using human and murine PDAC models, we evaluated elesclomol, a copper transport enhancer. Elesclomol alone had minimal effects; combined with copper chloride (CuCl2), it significantly and irreversibly reduced CSC phenotypes without affecting non-transformed cells. Mechanistically, only the combination raised intracellular copper ions 2- to 4-fold, decreased iron-sulfur cluster proteins, and caused lipoylated dihydrolipoamide S-acetyltransferase (DLAT) accumulation in mitochondria, triggering cuproptosis, particularly in CSCs. It also selectively inhibited copper-dependent antioxidant SOD1 in PDAC cells, impairing oxidative stress defense and sensitizing them to copper-induced death. To enhance clinical relevance, CuCl2 was replaced with hollow mesoporous copper sulfide nanoparticles that release copper ions. Either combined with or loaded with elesclomol, these nanoparticles similarly increased copper levels and inhibited PDAC spheroid formation. In vivo, in aggressive immunocompetent murine PDAC models, this nanoparticle-based treatment significantly improved gemcitabine response. These findings identify nanoparticle-mediated cuproptosis induction, combined with standard chemotherapy, as an innovative CSC-targeting strategy to improve PDAC outcomes, offering new hope for patients with PDAC.

The copper-molybdenum-sulfur (Cu-Mo-S) interaction is one of the most important mineral antagonisms in ruminant nutrition because it can induce functional copper deficiency even when dietary copper intake appears adequate. In the rumen, dietary sulfur is reduced to sulfide, which reacts with molybdate to form thiomolybdates. These compounds bind copper within ruminal digesta and, when produced in excess, may also enter the circulation and interfere with systemic copper trafficking and cuproenzyme function. This review critically synthesizes evidence on ruminal thiomolybdate formation, post-absorptive copper sequestration, growth and immune consequences, rumen fermentation, and hair/wool follicle abnormalities. Practical mitigation requires more than increasing dietary copper: feed, forage, mineral supplements, and drinking water should be analyzed together for Cu, Mo, S, Fe, and Zn; dietary Cu:Mo:S balance should be interpreted in a species-specific manner; high Mo and sulfur exposure should be reduced when possible; and copper supplementation should be adjusted cautiously, particularly in sheep because of their narrow margin between deficiency and toxicity. Rumen-stable or less rumen-soluble copper sources, such as hydroxychloride or selected organic copper complexes, may reduce ruminal antagonism unde

GHK-Cu, the copper-bound form of the human tripeptide glycyl-L-histidyl-L-lysine has accumulated more than four decades of pre-clinical evidence for tissue regeneration, anti-inflammatory action, antioxidant capacity, and broad gene-expression remodeling. Yet despite this volume, the clinical literature in humans remains thin and fragmented: most randomized trials are small, conducted on facial cosmetic creams, and rarely paired with delivery technologies capable of reliably crossing the stratum corneum. The microneedle-mediated delivery route which has been shown in vitro and in porcine ex vivo models to dramatically enhance GHK-Cu skin uptake has yet to be evaluated in a single registered, adequately powered human randomized controlled trial published in the peer-reviewed literature. This systematic review synthesizes the body of GHK-Cu literature published between 2005 and 2026, mapped against the PRISMA framework. Searches across PubMed, Elsevier ScienceDirect, and the Cochrane CENTRAL Registry yielded 1,247 records; after deduplication and screening, 64 records were retained for qualitative synthesis. Studies were stratified by study model (in vitro, ex vivo, in vivo rodent, in vivo non-rodent, and human) so that comparator therapies could be matched on equivalent footing. A critical discussion is provided on the physiology and underlying mechanistic foundation of GHK-Cu activity, including its role as an endogenous matricryptin released from collagen Iα2 and SPARC, copper's essential cofactor function for the lysyl oxidase family of cross-linking enzymes, decorin and glycosaminoglycan organization of ne

Dear Editor, Viral hepatitis reactivation is one of the safety concerns for treatments based on biological agents. Hepatitis B (HBV) reactivation has been reported more frequently than hepatitis C (HCV) reactivation. It is more common with TNF-alpha inhibitors than with IL-17 inhibitors. The risk is higher, especially in those taking additional immunosuppressive drugs (systemic steroids, methotrexate, etc.) (1). Hair discoloration is a rare adverse effect observed with some medications. To our knowledge, hair discoloration developing under secukinumab treatment has not been previously reported in the literature. Herein, we describe a case of a patient who developed simultaneous HBV reactivation and hair discoloration under secukinumab treatment. A 36-year-old male patient was admitted to our clinic with a diagnosis of psoriasis. Secukinumab treatment was initiated, as the patient had not responded to previous treatments with cyclosporine, methotrexate, and ustekinumab. The patient had no known chronic diseases and/or arthritis. Hepatitis serology in baseline examinations before secukinumab treatment was as follows: positive (+) for hepatitis B surface antibodies (Anti-HBs), positive (+) for antibodies to hepatitis B core antigen (Anti Hbc IgG), negative (-) for hepatitis B surface antigen (Hbs Ag), and negative (-) HBV- DNA PCR. The patient was followed up every 3 months with HBV-DNA PCR monitoring, without prophylaxis. In the second year of treatment, although Hbs Ag was negative and liver transaminase levels were within the normal range in serum, the HBV-DNA PCR test became positive. The reddish discoloration in the patient's hair was also notable (Figure 1). The patient reported that this discoloration had occurred after secukinumab treatment. He reported that he did not dye his hair and did not use any additional medication during this

Menkes disease is an X-linked recessive condition characterized by seizures, failure to thrive, and rapid, progressive neurodegeneration beginning within weeks after birth. Death usually occurs by 3 years of age. The disorder is caused by genetic variants in ATP7A, an evolutionarily conserved copper transporter that is crucial for normal brain development. The mottled-brindled mouse recapitulates salient features of the human illness. Affected male mice typically die by 14 postnatal days. We evaluated a single-dose intravenous adeno-associated virus gene therapy approach to deliver working copies of a codon-optimized version of ATP7A to male mottled-brindled mice. In conjunction with subcutaneous injections of clinical-grade copper histidinate in the first month of life, 95% long-term survival was attained, which was correlated with improvements in serum and brain copper levels, brain neurochemical profiles, somatic growth, and neuromotor function. The notable results support a trial of this treatment combination in affected male newborns with Menkes disease.

OBJECTIVE: This study aimed to investigate the levels of ischaemia-modified albumin, an oxidative stress marker, and antioxidant vitamins and minerals in patients with Alopecia Areata (AA) to measure total antioxidant and oxidant capacity and to determine whether the obtained values were related to the severity of the disease. METHODS: This prospective, controlled study has enrolled 30 patients admitted to our institution's outpatient clinic with a clinical or histopathological diagnosis of AA and 30 individuals as the control group. Serum ischaemia-modified albumin, vitamin E, selenium, copper, zinc, total antioxidant capacity (TAC), and total oxidant capacity (TOC) levels of the individuals included in the study were evaluated, and their relationship with the severity of the disease was determined. RESULTS: Ischaemia-modified albumin level was significantly higher in the patient group compared to the control group (p = 0.002), and vitamin E level was significantly lower in the patient group compared to the control group (p = 0.017). Ischaemia-modified albumin levels were significantly higher in patients with severe disease than in those with mild disease (p = 0.027), while Zn was significantly lower (p = 0.014). No significant difference was found between Se, Cu, Zn, TAC, and TOC levels in the patient and control groups. No significant difference was found between the disease severity and vitamin E, Se, Cu, TAC, and TOC levels. CONCLUSION: In our study, the high ischaemia-modified albumin and low vitamin E levels in AA patients indicate that the oxidant-antioxidant balance in AA patients

CONTEXT: Evidence regarding the relationship between serum trace element levels and immune-mediated inflammatory skin diseases (IMSDs) is inconsistent. OBJECTIVE: In this systematic review and meta-analysis we aimed to evaluate the association between selected serum trace element levels (zinc [Zn], copper [Cu], iron [Fe], selenium [Se], and calcium [Ca]) and IMSDs (psoriasis, vitiligo, atopic dermatitis [AD], alopecia areata [AA], hidradenitis suppurativa, and bullous diseases). DATA SOURCES: We conducted a comprehensive search on the PubMed, EMBASE, Scopus, China National Knowledge Infrastructure, and Web of Science databases from the database inception date to May 2, 2024. Studies measuring serum, plasma, or whole-blood levels of Zn, Cu, Fe, Se, or Ca in patients with IMSD compared to those in healthy controls were included. DATA EXTRACTION: This study followed the guidelines of the Meta-analysis of Observational Studies in Epidemiology and the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. Two authors (X.Y.S. and Y.O.) independently reviewed the titles and abstracts of the identified studies using a standardized collection form. DATA ANALYSIS: The primary outcome was the standardized mean difference with a 95% CI in serum trace element levels (Zn, Cu, Fe, Se, and Ca) between patients with IMSDs and healthy controls. Overall, 113 studies involving 7014 patients with IMSD were included in the meta-analysis. Compared with those in the healthy control group, serum Zn levels decreased in patients with vitiligo, psoriasis, and AA; serum Cu levels increased in patients with psoriasis, AD, and AA; serum Se and Fe levels decreased in patients with psoriasis and AD. CONCLUSION: Serum trace element levels showed more significant changes in patients wit

CLINICAL CHARACTERISTICS: IDEDNIK syndrome is characterized by enteropathy, poor weight gain, growth deficiency, skin manifestations (ichthyosis, erythroderma, and keratoderma), sparse hair, global developmental delay, mild-to-severe intellectual disability, and deafness. Additional manifestations can include liver disease, recurrent infections, and hematologic and ocular manifestations (photophobia, corneal scarring, and keratitis). Reduced serum ceruloplasmin and total copper levels are common. Some individuals have findings on brain MRI (cerebral atrophy, basal ganglia abnormalities, and thin corpus callosum). Death prior to age two years occurs in some individuals due to severe enteropathy or sepsis; in others survival into adulthood is reported. DIAGNOSIS/TESTING: The diagnosis of IDEDNIK syndrome is established in a proband by identification of biallelic pathogenic variants in AP1B1 or AP1S1 by molecular genetic testing. MANAGEMENT: Targeted therapy: Treatment with oral zinc acetate therapy to reduce liver copper overload has been reported to improve behavioral disturbances, skin manifestations, and cognitive function in some individuals. Zinc sulfate may be an alternative, less expensive treatment option. Experience is limited with this targeted therapy. Supportive care: Dietary modification and potential parenteral supplementation for enteropathy; feeding therapy; gastrostomy tube placement as needed; treatment options for skin manifestations include low-dose oral acitretin, skin emollients and topical lactic acid, frequent emollient application and short courses of topical cortical steroids or pimecrolimus ointmen

AIM: The etiology of telogen effluvium (TE) includes situations that may cause physiological stress, surgical trauma, inflammatory, infectious, iatrogenic causes, medications and nutritional deficiencies. TE has been associated with iron deficiency, vitamin B12 deficiency and thyroid diseases. In recent years, the use of over-the-counter food supplements containing vitamins and minerals such as biotin, vitamin D, zinc (Zn), copper (Cu) and selenium (Se) has been increasing in TE patients. The aim of this study is to investigate whether there are differences in nutritional status, vitamin and mineral levels by comparing individuals with TE and a control group. MATERIALS AND METHODS: This case-control study included 90 female patients diagnosed with chronic telogen effluvium (CTE), and 90 female controls volunteered to participate in the study who consulted for reasons other than TE. Both groups aged 18 and over and applied to dermatology polyclinic between 01.09.2022 and 01.09.2023. A detailed anamnesis was taken from all patients, a hair pull test was performed, and TE was diagnosed after a dermoscopic examination was performed on all areas of the scalp. Then, serum vitamin D, Zn, Cu, Se levels and biotin levels in serum and urine were measured. Hemoglobin (Hb), ferritin, vitamin B12 and thyroid function tests were retrospectively scanned from the hospital database. RESULTS: It w

BACKGROUND: Alopecia areata is an autoimmune hair loss disorder with an incompletely understood etiology. Although trace elements, serum metabolites, and inflammatory factors are implicated in the disease, the potential causal relationships between these factors and alopecia areata require further investigation. METHODS: This study employed Mendelian randomization (MR), utilizing data from genome-wide association studies, to explore the causal relationships between 15 trace elements, 1400 serum metabolites, and 91 inflammatory factors and alopecia areata. The analysis was conducted using the inverse variance weighted (IVW) method complemented by various sensitivity analyses, including Cochran's Q test, MR-Egger regression intercept test, MR-PRESSO global test, and leave-one-out analysis, to assess the robustness of the results. RESULTS: MR analysis indicated a negative correlation between copper levels and the risk of developing alopecia areata (odds ratio = 0.86, 95% confidence interval: 0.75-0.99, p = 0.041). Additionally, causal relationships were identified between 15 serum metabolites and 6 inflammatory factors and the risk of alopecia areata (IVW, all p values < 0.05). CONCLUSION: This study provides genetic evidence of the relationships between trace elements, serum metabolites, and alopecia areata, underscoring the potential value of targeted therapeutic stra

BACKGROUND: Menkes disease (MD) is a rare, inherited, multisystemic copper metabolism disorder. Classical Menkes disease is characterized by low serum copper and ceruloplasmin concentrations, leading to multiple abnormalities in the whole-body, especially in connective tissue and central nervous system. However, serum copper and ceruloplasmin levels are not reliable diagnostic biomarkers due to the low concentrations in healthy newborns either. The featured imaging manifestations play an important role in diagnosing Menkes disease. To our knowledge, there are few reports on the systemic imaging manifestations of Menkes disease. CASE PRESENTATION: A 4-month-old male patient presented with recurrent seizures. He had cognitive, intellectual, growth, gross motor, precision movement, and language developmental lags. The patient's hemoglobin an

Copper peptides (GHK-Cu) are a powerful hair growth promoter with minimal side effects when compared with minoxidil and finasteride; however, challenges in delivering GHK-Cu topically limits their non-invasive applications. Using theoretical calculations and pseudo-ternary phase diagrams, we designed and constructed a thermodynamically stable ionic liquid (IL)-based microemulsion (IL-M), which integrates the high drug solubility of ILs and high skin permeability of microemulsions, thus improving the local delivery of copper peptides by approximately three-fold while retaining their biological function. Experiments in mice validated the effectiveness of our proposed IL-M system. Furthermore, the exact effects of the IL-M system on the expression of growth factors, such as vascular endothelial growth factor, were revealed, and it was found that microemulsion increased the activation of the Wnt/β-catenin signaling pathway, which includes factors involved in hair growth regulation. Overall, the safe and non-invasive IL microemulsion syste