Manganese

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: Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. Recent research has shown the importance of MNs in common pathologies, with significant deficiencies impacting the outcome. OBJECTIVE: This guideline aims to provide information for daily clinical nutrition practice regarding assessment of MN status, monitoring, and prescription. It proposes a consensus terminology, since many words are used imprecisely, resulting in confusion. This is particularly true for the words "deficiency", "repletion", "complement", and "supplement". METHODS: The expert group attempted to apply the 2015 standard operating procedures (SOP) for ESPEN which focuses on disease. However, this approach could not be applied due to the multiple diseases requiring clinical nutrition resulting in one text for each MN, rather than for diseases. An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL. The search focused on physiological data, historical evidence (published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS: There was a limited number of interventional trials, preventing meta-analysis and leading to a low level of evidence. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90% of votes. Altogether the guideline proposes sets of recommendations for 26 MNs, resulting in 170 single recommendations. Critical MNs were identified with deficiencies being present in numerous acute and chronic diseases. Monitoring and management strategies are proposed. CONCLUSION: This guideline should enable addressing suboptimal and deficient status of a bundle of MNs in at-risk diseases. In particular, it offers practical advice on MN provision and monitoring during nutritional support.

BACKGROUND & AIMS: Antioxidant micronutrients (AxMs) have been administered to critically ill adults attempting to counteract the oxidative stress imposed during critical illness. However, results are conflicting and relative effectiveness of AxMs regimens is unknown. We conducted a Bayesian multi-treatment comparison (MTC) meta-analysis to identify the best AxM treatment regimen that will improve clinical outcomes. METHODS: PubMed, EMBASE, Web of Science and Cochrane databases were searched from the inception of databases through August 2020. Randomized controlled trials (RCT) comparing AxMs supplementations with placebo among critically ill adults were included. Two authors assessed trial quality using Cochrane risk of bias tool and assessed certainty of evidence (CoE). A random effect model, non-informative priors Bayesian MTC meta-analysis using gemtc package in R version 3.6.2 was performed. AxMs treatment effect on clinical outcomes (mortality, infection rates, intensive care unit (ICU) and hospital stays and ventilator days) were represented by absolute risk differences (ARD) for dichotomous outcomes and mean differences (MD) for continuous outcomes. Prior to final analysis, we repeated the search through January 2021. RESULTS: 37 RCT (4905 patients) were included with 16 direct comparisons. With respect to mortality, the ARD for "vitamin E" compared with placebo was centred at -0.19 [95%CrI: -0.54,0.16; very low CoE] and was ranked the best treatment for mortality reduction as per surface under the cumulative ranking curve (SUCRA 0.71, 95%CrI: 0.07,1.00). A combination of "selenium, zinc and copper" was ranked the best for lowest ICU stay [-9.40, 95% CrI: -20.0,1.50; low CoE]. A combination of "selenium, zinc, copper and vitamin E" was ranked the best treatment for infection risk reduction [-0.22, 95% CrI: -0.61,0.17; very low CoE]. Ventilator days were least with a combination of "selenium, zinc and manganese" [2.80, 95% CrI: -6.30,0.89; low CoE]. Hospital stay was the lowest using a combination of "selenium, zinc and copper" [-13.00, 95% CrI: -38.00,13.00; very low CoE]. There is substantial uncertainty present in the rankings due to wide and overlappi

Manganese superoxide dismutase (MnSOD) has been identified as an important scavenger of reactive oxygen species (ROS), which can cause oxidative stress followed by breast cancer. A number of subsequent population-based studies have investigated the association between MnSOD Ala-9Val polymorphism and the risk of breast cancer. However, these studies have yielded conflicting results. This fact implies that the effect of MnSOD Ala-9Val polymorphism on the susceptibility to breast cancer may be modified by other risk factors. To provide a more definitive conclusion, a full meta-analysis combining and summarizing 16 studies was first performed using both traditional and Bayesian approaches. During this step, a recessive inheritance mode was determined after a biological justification. The capability of the Bayesian method was highlighted in the estimation of a pooled odds ratio and 95% confidence interval. As a result, no significant association was observed (OR = 0.978, CI = 0.914-1.046). Bayesian meta-regression and subgroup analysis were then conducted to find possible risk modifications by other factors, including menopausal status, ethnicity effect, use of oral contraceptives, use of hormone replacement therapy, fruits and vegetables intake, vitamin supplement, and body mass index. While the power of most subgroups may be insufficient to make a statistical statement, an evidence-based sample size calculation based upon updated meta-analysis was performed to power a future trial. For example, approximately 5,000 subjects are required for a new Asian study (2,500 cases and 2,500 controls) to achieve 80% power.

Background: Obesity is characterized by chronic low-grade systemic inflammation that contributes to metabolic dysfunction. Diet is a modifiable factor that can help reduce this inflammation. Nuts such as almonds are rich in unsaturated fats, and antioxidant and anti-inflammatory micronutrients, which may work synergistically to attenuate obesity-related inflammation. Hence, the objective of this study was to investigate whether daily almond consumption improves systemic inflammatory and immune markers in adults with obesity. Methods: In this randomized controlled parallel-arm trial (ClinicalTrials.gov ID NCT05530499), 69 adults (age 30-45 years) with obesity (BMI 30-45 kg/m2) were assigned to consume either 57 g/day of almonds (n = 38) or an isocaloric snack (cookie; n = 31) for six weeks. Fasting serum inflammatory cytokines, innate immune cell counts, body weight, serum glucose, insulin, lipid profile, and alpha-tocopherol were measured at baseline and week six. Dietary intake, compliance, palatability, acceptance, and appetite ratings were also assessed. Primary outcomes were analyzed using linear mixed models and baseline-adjusted linear models. Results: Subjective compliance was high in both groups, with greater acceptance of almonds (p < 0.05); however, serum alpha-tocopherol did not change. Almond consumption significantly decreased serum IL-6, TNF-α, and IFN-γ over 6 weeks compared with the cookie group (p < 0.05). No significant group differences were observed for innate immune cell counts, body weight, appetite ratings, blood pressure, or serum fasting glucose, insulin, total cholesterol (C), LDL-C, and triglycerides over six weeks. The almond group also increased intakes of monounsaturated fat, fiber, alpha-tocopherol, magnesium, zinc, and manganese, and improved diet quality indices relative to the cookie group (p < 0.05). Conclusions: Daily almond consumption for six weeks improved inflammatory cytokine profiles in adults with obesity, without changes in body weight under free-living conditions. These findings support recommending almonds as part of healthy dietary patterns to help attenuate obesity-related inflammation.

Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder in women. Oxidative stress (OS) plays a pivotal role in the pathogenesis of PCOS. Resveratrol, as a natural polyphenol, has several beneficial therapeutic effects for women with PCOS. In this study, we investigated the antioxidant effect of resveratrol on OS markers in follicular fluid (FF) and granulosa cells (GCs) of patients with PCOS. A total of fifty-six patients with PCOS were randomly assigned to receive 800 mg/day of resveratrol or placebo for 60 days. The main focus was on evaluating OS markers, such as malondialdehyde (MDA) and total thiol (sulfhydryl) content in FF, along with assessing the levels of total antioxidant capacity (TAC) and total oxidant status (TOS) in GCs. Additionally, secondary outcomes included measuring the expression of genes associated with OS responses (Manganese superoxide dismutase (Mn-SOD), catalase (CAT), and uncoupling protein 2 (UCP2)), as well as the expression of UCP2 protein in granulosa cells. Compared with the placebo group, resveratrol reduced MDA and conversely significantly increased total thiol (P = 0.6694 and P = 0.0318, respectively) in FF. Resveratrol significantly reduced TOS and oxidative stress index (OSI) (P = 0.0299 and P = 0.0144, respectively) and significantly increased TAC (P = 0.0484) in GCs. There were significant increases in CAT and UCP2 expression after resveratrol consumption (P = 0.0158 and P = 0.0004, respectively). Although resveratrol increased Mn-SOD expression (P = 0.0914), its effects were not statistically significant. Resveratrol significantly affected UCP2 protein levels (P = 0.0030). These findings suggested that 60 days of supplementation with 800 mg/day resveratrol improves markers of OS in the FF and GCs of patients with PCOS. Trial registration number: http://www.irct.ir ; IRCT20221106056417N1; 2023 February 09. © 2025. The Author(s), under exclusive licence to Society for Reproductive Investigation.

Tirzepatide induces weight reduction but the underlying mechanisms are unknown. This 6-week phase 1 study investigated early effects of tirzepatide on energy intake. Male and female adults without diabetes (n = 114) and a body mass index from 27 to 50 kg per m2 were randomized 1:1:1 to blinded once-weekly tirzepatide or placebo, or open-label once-daily liraglutide. The primary outcome was change from baseline to week 3 in energy intake during an ad libitum lunch with tirzepatide versus placebo. Secondary outcomes assessed self-reported ingestive behavior and blood-oxygenation-level-dependent functional magnetic resonance imaging with food photos. Tirzepatide reduced energy intake versus placebo at week 3 (estimated treatment difference -524.6 kcal (95% confidence interval -648.1 to -401.0), P < 0.0001). With regard to secondary outcomes versus placebo, tirzepatide decreased overall appetite, food cravings, tendency to overeat, perceived hunger and reactivity to foods in the environment but did not impact volitional restriction of dietary intake. At week 3 versus placebo, tirzepatide did not statistically significantly impact blood-oxygenation-level-dependent activation to highly palatable food photos (aggregated category of high-fat, high-sugar foods and high-fat, high-carbohydrate foods) but decreased activation to high-fat, high-sugar food photos in the medial frontal and cingulate gyri, orbitofrontal cortex and hippocampus. Our results suggest tirzepatide reduces food intake, potentially by impacting ingestive behavior. ClinicalTrials.gov registration: NCT04311411 . © 2025. The Author(s).

BACKGROUND: Many patients with biochemically recurrent prostate cancer (BCRPC) prefer to delay androgen deprivation therapy (ADT) due to its adverse effects, highlighting the need for better-tolerated, effective alternatives. A subgroup analysis of our prior Phase II trial showed that muscadine grape skin extract (MPX) increased PSA doubling time (PSADT) in patients with SOD2 Ala/Ala variant which provided the rationale for this trial. METHODS: This randomized, double-blind, placebo-controlled trial, conducted at 14 sites, evaluated patients with BCRPC and SOD2 Ala/Ala genotype. Patients received 4000 mg MPX or placebo daily. The primary endpoint was on-study PSA slope with comparisons between treatment arms. Secondary endpoints were PSADT, PSA response (≥ 50% decrease), and PSA progression free survival (PFS). Correlative studies included markers of oxidative stress and gastrointestinal microbiota composition. RESULTS: At interim analysis, fifty-nine patients were randomized (MPX, n = 29; placebo, n = 30). On-study PSA slopes at 12, 24, 36, and 48 weeks showed no significant differences between the MPX and placebo arms (p = 0.49). The study was stopped due to futility. No significant differences were observed in PSADT, PSA response, median PSA PFS, or oxidative stress biomarkers. MPX was well-tolerated, with no grade 3-4 AEs attributable to the study drug. Microbiome analysis showed no significant differences in alpha diversity but revealed increased relative abundance of Roseburia faecis and Akkermansia muciniphila in the MPX group. CONCLUSIONS: Although MPX supplementation had no significant effect on PSA slope in men with BCRPC and SOD2 Ala/Ala variant, this study provides a rigorous evaluation of a natural product and highlights the importance of well-designed clinical trials in advancing evidence-based integrative oncology. TRIAL REGISTRATION: ClinicalTrials. gov, NCT03535675. © 2025 Wiley Periodicals LLC.

OBJECTIVES: The primary objective of this study was to evaluate the visualization capability of orally administered manganese chloride tetrahydrate (ACE-MBCA [Ascelia Pharma-manganese-based contrast agent, also referred to as Orviglance or CMC-001]), a novel liver-specific contrast agent developed by Ascelia Pharma, as a liver-specific MRI contrast agent compared with that of the unenhanced MRI for focal liver lesions in a properly blinded study design. The secondary objective was to compare the performance of ACE-MBCA with gadobenate dimeglumine. MATERIALS AND METHODS: Three independent readers analyzed MRI examinations from a previously completed randomized crossover clinical trial in a blinded manner in a centralized setting. The study included 20 consecutive adult patients with known or suspected liver metastases, who received both ACE-MBCA and gadobenate dimeglumine. The readers evaluated 6 types of MRI scans (unenhanced, enhanced, and combined MRI for both contrast agents) with lesion visualization [lesion border delineation (LBD) and lesion contrast (LC)] as primary outcome. To maintain the blinded nature of the study, all statistical analyses were performed by an independent statistician who was not involved in the image reading process. Differences in primary outcomes were performed using 1-sided paired t tests at a significance level of 0.025 for both parameters. For secondary outcomes (ACE-MBCA enhanced MRI visualization, lesion detection, size measurements, reader confidence, quantitative parameters, and image quality were compared with that of the other scans), descriptive statistics and 95% confidence intervals were used to evaluate differences between categories in comparative analyses, without formal hypothesis testing for most secondary endpoints. RESULTS: ACE-MBCA-enhanced MRI demonstrated statistically significant superior scoring over unenhanced MRI for visualizing focal liver lesions, with mean LBD scores improving from 1.8-2.3 to 2.4-2.9 and LC scores ranging from 1.8-2.3 to 2.8-3.3 across all 3 readers ( P < 0.001). Compared with unenhanced MRI, ACE-MBCA detected significantly more lesions across all readers (mean differences 0.4-0.8 lesio

Diets high in red and processed meat and low in plant-based foods are associated with an increased risk of colorectal cancer. We investigated whether berry supplementation can impact gut metabolism to counteract the presumably cancer promoting luminal environment sustained by high red and processed meat consumption. Altogether 43 healthy adults were randomized either into Meat group (150 g/d red and processed pork meat) or Meat & Berries group (150 g/d red and processed meat and 200 g/d of mixed berries). Fecal samples and 3-d food records were collected at baseline and at the end of the four-week intervention. Intakes of vitamin C, vitamin E, manganese, insoluble fiber, and the polyphenols available in the database were significantly higher in the Meat & Berries than Meat group. While between-group comparisons found no significant differences in the gut microbiota, the within-group analyses showed that the relative abundances of beneficial Roseburia and Faecalibacterium were decreased and an unclassified group of Peptostreptococcaceae increased significantly in the Meat group. In comparison to the Meat group, berry consumption resulted in higher fecal concentrations of p-coumaric and protocatechuic acids and lower viability of fecal water (FW) -treated CV1-P fibroblastoma and human colon adenocarcinoma HCA-7 and Caco-2 cells (P<.05 with 30% FW). Berry consumption provided protective nutrients and mitigated potentially unfavourable gut microbiota changes seen in the Meat group, increased fecal polyphenol metabolites, and reduced viability of FW-treated colon adenocarcinoma cells, collectively suggesting that berries may protect against colorectal cancer development.

BACKGROUND: Manganese (Mn) is present in many parenteral nutrition (PN) ingredients, presumably as a contaminant during ingredient manufacturing. Exposure to Mn in PN may have negative health consequences in preterm neonates. The purpose of this study was to test the feasibility and safety of not adding supplemental Mn to PN prepared for extremely preterm and very preterm neonates compared with standard Mn supplementation. METHODS: Neonates <32 weeks' gestational age were randomized on postnatal day 1 to receive test PN prepared without adding Mn or standard PN prepared with Mn 5 mcg/kg/day using a commercially available neonatal multitrace element product. Randomization assignment was blinded to the clinical team. Whole blood Mn levels were measured at baseline, 2 weeks, and 8 weeks postnatal age. Growth parameters and nutrition intake were also collected. RESULTS: Twenty-six participants were enrolled and nineteen completed the trial. The median duration of PN was 11 days in the no Mn group and 12 days in the standard Mn group. Whole blood Mn levels were not significantly different between the two groups at any time point. Growth and nutrition outcomes were also not significantly different between the two groups. CONCLUSIONS: The provision of no-added-Mn PN in routine care was feasible and did not alter Mn blood levels or growth in the first 8 weeks of postnatal age compared with standard PN. © 2025 American Society for Parenteral and Enteral Nutrition.

BACKGROUND: Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype. METHODS: An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded sample, we compared MnSOD activity in 159 TD, 227 non-TD and 280 healthy controls, as well as the allele frequencies and genotypes for the MnSOD Ala-9Val polymorphism in 352 TD, 486 non-TD and 1150 healthy controls. RESULTS: EGb761 significantly reduced TD symptoms and increased MnSOD activity in TD patients compared to placebo (both p < 0.01). Moreover, we found an interaction between genotype and treatment response (p < 0.001). Furthermore, in the EGb761 group, patients carrying the Ala allele displayed a significantly lower AIMS total score than patients with the Val/Val genotype. In addition, MnSOD activity was significantly lower at baseline in TD patients compared with healthy controls or non-TD patients. CONCLUSION: EGb761 treatment enhanced low MnSOD activity in TD patients and produced greater improvement in TD symptoms in patients with the Ala allele of the MnSOD Ala-9Val polymorphism.

Aging is associated with a decline in physiological functions and an increased risk of age-related diseases, emphasizing the importance of identifying dietary strategies for healthy aging. Minerals play a crucial role in maintaining optimal health during aging, making them relevant targets for investigation. Therefore, we aimed to analyze the effect of different dietary pattern on mineral status in the elderly. We included 502 individuals aged 50-80 years in a 36-month randomized controlled trial (RCT) (NutriAct study). This article focuses on the results within the two-year intervention period. NutriAct is not a mineral-modulating-targeted intervention study, rather examining nutrition in the context of healthy aging in general. However, mineral status might be affected in an incidental manner. Participants were assigned to either NutriAct dietary pattern (proportionate intake of total energy consumption (%E) of 35-45 %E carbohydrates, 35-40 %E fats, and 15-25 %E protein) or the German Nutrition Society (DGE) dietary pattern (proportionate intake of total energy consumption (%E) of 55 %E carbohydrates, 30 %E fats, and 15 %E protein), differing in the composition of macronutrients. Data from 368 participants regarding dietary intake (energy, calcium, magnesium, iron, and zinc) and serum mineral concentrations of calcium, magnesium, iron, copper, zinc, selenium, iodine, and manganese, free zinc, and selenoprotein P were analyzed at baseline, as well as after 12 and 24 months to gain comprehensive insight into the characteristics of the mineral status. Additionally, inflammatory status - sensitive to changes in mineral status - was assessed by measurement of C-reactive protein and interleukin-6. At baseline, inadequate dietary mineral intake and low serum concentrations of zinc and selenium were observed in both dietary patterns. Throughout two years, serum zinc concentrations decreased, while an increase of serum selenium, manganese and magnesium concentrations was observable, likely influenced by both dietary interventions. No significant changes were observed for serum calcium, iron, copper, or iodine concentrations. In conclusion, long-term dietary interventio

PURPOSE: Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. EXPERIMENTAL DESIGN: Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI. RESULTS: Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI. CONCLUSIONS: Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.

Tetracycline antibiotics frequently co-occur with manganese (Mn) in freshwater environments, yet how Mn background gradients reshape mixture phytotoxicity remains insufficiently resolved. The objective of this study was to systematically investigate how varying Mn background levels modulate the phytotoxicity and interaction patterns of tetracycline antibiotics. Using Lemna minor as a model species, we employed full-factorial Mn × tetracycline concentration matrices (tetracycline, TC; oxytetracycline, OTC; and chlortetracycline, CTC) to quantify Mn-dependent modulation of tetracycline toxicity and identified operational Mn regimes supported by breakpoint robustness analysis. Growth-rate responses delineated a low-Mn window (0.10-0.40 mg·L⁻¹), a transition interval (0.40-1.60 mg·L⁻¹), and a high-Mn domain (≥1.60 mg·L⁻¹). Under low Mn conditions, Mn generally promoted antagonistic interactions, with inhibition weaker than expected, a pattern consistently observed across growth, pigment, and antioxidant endpoints. In contrast, under high Mn conditions, synergistic interactions emerged at specific Mn × antibiotic combinations, characterized by stronger-than-expected inhibition, forming spatially heterogeneous interaction "islands" on the response surfaces. These regime-dependent patterns were concordant between integrated multi-endpoint ΔBliss interaction landscapes, which quantify deviations from Bliss independence, and potency-surface validation using δZIP, a zero-interaction potency (ZIP)-based deviation metric, based on chlorophyll a. Overall, the results support a threshold-based, operational reporting framework linking Mn regimes to mixture interaction landscapes and indicate that mixture outcomes cannot be inferred from antibiotic dose alone when background metal levels vary, underscoring the need to explicitly incorporate metal gradients in mixture risk assessment.

Update of bioRxiv. 2025 Jul 10:2025.07.10.664208. doi: 10.1101/2025.07.10.664208. Halogenated phenazine (HP) compounds have shown promise as antimicrobial agents, particularly against biofilm-associated Gram-positive pathogens. Among these compounds, HP-29 demonstrates potent activity against methicillin-resistant Staphylococcus aureus by inducing rapid iron starvation. As maintenance of trace metals homeostasis is critical for the survival of Streptococcus mutans, this study investigated the antimicrobial efficacy of HP-29 and the impact of metal supplementation on this major oral and occasional systemic pathogen. As anticipated, HP-29 inhibited S. mutans growth in a dose-dependent manner, with iron supplementation alleviating the antimicrobial effect. Cobalt, manganese, or nickel supplementation also mitigated the inhibitory activity of HP-29, but, unexpectedly, the addition of zinc greatly enhanced HP-29 antimicrobial activity. This zinc-driven potentiation of HP-29 extended to other Gram-positive pathogens, including Enterococcus faecalis and S. aureus. Inductively coupled plasma mass spectrometry analysis revealed that intracellular iron content decreased significantly following exposure to HP-29. When combined with zinc, HP-29 triggered a 5-fold increase in intracellular zinc and reduced manganese levels by ~50%. Transcriptome analysis showed that HP-29 treatment, with or without zinc, altered expression of genes linked to iron and manganese uptake as well as zinc efflux, suggesting broad disruption of metal ion regulation. These findings highlight HP-29 as a potent antimicrobial that broadly impairs metal homeostasis. The unexpected synergy of HP-29 with zinc points toward a promising dual-agent therapeutic strategy against Gram-positive pathogens.IMPORTANCEWidespread development of antibiotic resistance has created a constantly moving target when combating infectious microbes. Here, we further explore an antimicrobial halogenated phenazine, HP-29, which is effective against Gram-positive bacteria through disruption of intracellular trace metal equilibrium. We showed that HP-29 inhibits growth of the oral and systemic pathogen Streptococcus mutans and th

Polyphenols are emerging as promising candidates for promoting healthy aging and neuroprotection. Here, we investigated the effects of quercetin (Q), luteolin (L), and 3-O-methylquercetin (3OMQ), individually and in combination (FORM), on lifespan, healthspan, and neurobehavioral functions in Caenorhabditis elegans. Wild-type and mutant strains (including daf-2, daf-16, and skn-1) were exposed to the compounds, followed by assessments of longevity, motility, senescence biomarkers (lipofuscin and red autofluorescence), and neuroprotection against PTZ- and methylmercury-induced damage. 3OMQ and FORM significantly extended lifespan (+ 20-24%) and improved motility and stress resilience, with effects dependent on the DAF-16/FOXO and SKN-1/Nrf2 pathways, but independent of DAF-2/IGF1R signalling. Both compounds induced DAF-16 nuclear translocation and upregulated SKN-1 expression. Furthermore, they attenuated neurodegeneration and cholinesterase hyperactivity following manganese and methylmercury exposure. These findings support the potential of 3OMQ and its polyphenol combination as anti-aging and neuroprotective agents, acting through conserved longevity and oxidative stress pathways. © 2025. The Author(s), under exclusive licence to Springer Nature B.V.

OBJECTIVES: Cisplatin (CDDP) therapy for glioblastoma (GBM) is linked with several limitations, which include poor penetration of the blood-brain barrier (BBB), systemic toxicity, and the development of drug resistance mechanisms implicating oxidative stress dysregulation and compromised apoptotic pathways. This study evaluates C-Phycocyanin (C-PC) as a potential adjuvant to enhance CDDP efficacy by modulating redox balance and apoptosis. METHODS: GBM cells (U87 and U87-EGFRvIII) were treated with CDDP, C-PC, or their combination. Cell viability was assessed by MTT assay; apoptosis was evaluated by DAPI staining and Western blot analysis of cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP). Both intracellular and extracellular reactive oxygen species (ROS) were measured using 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence and lucigenin chemiluminescence, respectively. Catalase activity was quantified via hydrogen peroxide (H2O2) decomposition assay, and manganese superoxide dismutase (MnSOD) expression by Western blot. RESULTS: C-PC selectively decreased U87 GBM cell viability while sparing normal cells. C-PC enhanced CDDP cytotoxicity, reducing viability to 26.5% vs. 53.2% for CDDP alone. This effect correlated with increased apoptosis, evidenced by DNA fragmentation and higher cleaved caspase-3 and PARP levels. Combined treatment lowered ROS below survival thresholds while upregulating MnSOD and catalase activity. In U87-EGFRvIII cells, CDDP reduced viability modestly (85.2%), C-PC alone decreased viability significantly (51.5%) and induced cell death, but the combination did not further increase apoptosis. Here, C-PC's pro-apoptotic effects, alone or with CDDP, were also associated with reduced oxidative stress in cells. CONCLUSION: We demonstrate that C-PC enhances CDDP cytotoxicity in sensitive U87 cells by promoting apoptosis and modulating ROS, suggesting potential for improved therapeutic efficacy with reduced systemic toxicity. Compared to the combination, C-PC monotherapy achieves superior cytotoxicity in CDDP-resistant U87-EGFRvIII cells, underscoring its potential as a standalone therapeutic approach for chemotherapy-resista

AIMS: Chelating agents are metal-sequestering compounds with antibacterial properties suitable for commercial and therapeutic applications. This study investigated the involvement of metal restriction and membrane disruption in the antibacterial mode of action of three chelators. METHODS AND RESULTS: The antibacterial, metal sequestration, and membrane disruptive effects of ethylenediaminetetraacetic acid, diethylenetriamine pentamethylene phosphonic acid, and fusaric acid were examined across five bacterial species. ICP-MS was used to determine the impact on bacterial metal composition, while RT-qPCR of selected genes allowed evaluation of changes in cellular responses to intracellular metal depletion. Mutants defective in metal import and export machinery were also examined to validate processes critical for resistance. Chelator-mediated disruption of membranes was investigated using 1-N-phenylnapthylamine and propidium iodide. Finally, the capacity of two of the chelators to potentiate the activity of ampicillin, chloramphenicol, tetracycline, and three aminoglycosides was assessed in chequerboards. The results show that these chelators restrict access to iron, zinc, manganese, and calcium to varying degrees in these bacterial species, reflecting important differences in envelope architectures and metal handling capabilities. CONCLUSIONS: This study shows that all three chelators behave differently in restricting metal access and possess antibacterial properties that often act synergistically in combination, notably with other antimicrobials. © The Author(s) 2025. Published by Oxford University Press on behalf of Applied Microbiology International.

Diabetic wound healing remains clinically challenging due to persistent oxidative stress and dysregulated inflammation caused by the pathological microenvironment, particularly excessive reactive oxygen species (ROS). A near-infrared (NIR)-responsive multifunctional microneedle system (Res@ZIF-67/Ce0.1Mn0.9-MMON, RZCM) integrating antioxidant, antibacterial, and angiogenic functionalities is developed. The microneedle substrate incorporates Ce0.1Mn0.9-MMON nanoparticles that synergistically exert antibacterial effects through peroxidase-mimetic activity and NIR-induced photothermal hyperthermia, while concurrently mimicking superoxide dismutase and catalase activities to scavenge ROS and alleviate hypoxia. The microneedle tips encapsulate pH-responsive Res@ZIF-67 nanoparticles that release cobalt ions (Co2+) and resveratrol in acidic environments, cooperatively stabilizing hypoxia-inducible factor 1α (HIF-1α) under normoxic conditions to promote angiogenesis. In vivo evaluations demonstrate that RZCM accelerates diabetic wound healing through coordinated mechanisms: photothermal bacterial eradication, ROS scavenging (85.7% reduction), macrophage M2 polarization (2.3 fold increase), HIF-1α-mediated neovascularization (2.1 fold higher CD31 density), and enhanced collagen remodeling (78.4% increased collagen I/III ratio). This multifunctional system achieves complete epithelialization within 14 days, outperforming conventional treatments. By integrating multi-enzyme mimetic nanomaterials with microenvironment-responsive drug delivery, RZCM establishes a novel therapeutic paradigm for chronic wound management, demonstrating significant translational potential for diabetic wound care through synergistic regulation of oxidative, inflammatory, and angiogenic pathways. © 2025 Wiley‐VCH GmbH.

Arsenic trioxide is a frontline drug for leukemia treatment; however, its successful application in solid tumors has not yet been fully achieved. Transferrin is an endogenous protein containing iron-binding sites that can be used for loading arsenic for targeted delivery to solid tumors. However, the nonspecific expression of the transferrin receptor greatly limits transferrin-based nanomedicines. Herein, the dynamic shielding of arsenic-loaded transferrin with calcium manganese carbonate is proposed to potentiate strong antitumor effects via self-enhanced synergistic therapy. The nanocloak enhances tumor accumulation and realizes responsive release in an acidic tumor microenvironment. The re-exposed arsenic-loaded transferrin penetrates deep into the tumor, binds specifically to the receptor, and exerts cytotoxicity via chemotherapy. Along with this process, the protein levels of NOX4, which is responsible for H2O2 production, are upregulated. This biological effect facilitates self-enhanced chemodynamic therapy and the co-loaded glucose oxidase further ensures the initiation of this reaction. The released manganese ions catalyze the conversion of H2O2 into hydroxyl radicals and effectively activate the cGAS-STING signaling pathway for tumor inhibition. Collectively, these findings reveal the potent antitumor effects of the biomineralized nanomedicine and pave the way for translating arsenic into solid tumor therapy via targeted delivery and synergistic therapy. © 2025 Wiley‐VCH GmbH.

BACKGROUND: Despite therapeutic benefits of anti-Programmed Death-Ligand 1 (PD-L1) therapy in triple-negative breast cancer (TNBC), low response rates and resistance limit its efficacy. Both manganese (Mn) and bisphosphonates (BPs) are known to induce immunogenic cell death (ICD). Strategies to synergistically enhance ICD induction and elucidate the underlying molecular mechanisms remain to be fully explored. METHODS: We analyzed the mode of apoptosis and immunogenicity of cancer cells post-treatment using Western blotting, flow cytometry, and confocal microscopy. RNA sequencing was employed to identify activated apoptotic pathways and elucidate the molecular mechanisms underlying ICD when Mn²+ and BPs act synergistically. In 4T1 tumor models, we evaluated the synergistic anti-tumor effect of Mn²+ and BPs with anti-PD-L1 antibodies. RESULTS: By leveraging the doping capacity of hydroxyapatite (HA) for Mn²+ and its high affinity for BPs, we developed MnHARis particles-a biocompatible slow-release system of biomineralized Mn²+ and risedronate (Ris). Compared to Mn2+ and Ris alone, MnHARis achieved a synergistic antitumor effect, manifesting as increased cytotoxicity (IC50 reduced by 17 times) and the emergence of more significant mitochondrial autophagic apoptosis (more pronounced nuclear fragmentation, increased ROS levels, significantly decreased ATP levels, depolarization of mitochondrial membrane potential, upregulation of autophagy markers (LC3B and Beclin), and obvious autophagosomes). MnHARis exerts its antitumor effects via the p38-MAPK pathway. Additionally, increased exposure of calreticulin and increased secretion of high mobility group box 1 indicated that MnHARis successfully induced ICD and promoted specific recognition and cross-presentation of damage-associated molecular patterns released by apoptotic tumor cells by activating dendritic cells and pattern recognition receptors, thereby altering TME of TNBC, increasing TILs, and sensitizing TNBC to anti-PD-L1 therapy. CONCLUSION: MnHARis effectively synergizes Mn²+ and Ris to promote autophagic apoptosis and ICD, increasing TILs and sensitizing TNBC to anti-PD-L1 therapy, thus offering a new therapeu

The emerging antibiotic-resistant bacteria, especially the "ESKAPE" pathogens, pose a continuous threat to global health. In this study, we explored metalloantibiotics as promising therapeutics and innovative antimicrobial agents. The role of metal in the antimicrobial activity of chloroxine (5,7-dichloro-8-hydroxyquinoline), as a metalloantibiotic, was investigated by minimal inhibit concentration (MIC) assay and a series of assays, including growth curve, time-killing, and UV-visible spectroscopy and PAR (4-(2-pyridylazo)-resorcinol) competition assays. Both chloroxine and its structural analogues exhibited increased antibacterial potency against Gram-positive bacteria compared to Gram-negative bacteria. The introduction of exogenous manganese or zinc ions significantly boosted chloroxine's antibacterial efficacy against Gram-negative bacteria, including the notorious ESKAPE pathogens. However, the enhanced antibacterial activity induced by zinc ions could be negated in the presence of copper or ferrous iron ions, as well as changes in oxygen availability, highlighting the involvement of proton motive force, oxidative and antioxidative systems. Notably, chloroxine effectively inhibited the enzymatic activity of superoxide dismutase (SOD). In addition, chloroxine could reverse polymyxin and carbapenem resistance in E. coli in vitro. Therefore, these results suggested that chloroxine with zinc ions are promising therapeutics and antibiotics potentiator to combat multidrug-resistant ESKAPE pathogens.

Triple-negative breast cancer (TNBC) is a relatively "cold" tumour with low immunogenicity compared to other tumour types. Especially, the immune checkpoint inhibitors to treat metastatic TNBC only shows the modest immune response rates. Here, we used Chlorella vulgaris as a bioreactor to synthesize an efficient nanobomb (Bio-MnSe) aimed at eliciting systemic anti-tumour immune response. Despite possessing extremely low Mn content, Bio-MnSe effectively produced more ROS and activated stronger cGAS-STING signal pathway compared to pure Se nanoparticles and free Mn2+ ions, promoting the infiltration of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) in tumour, effectively turning "cold" tumour into "hot" tumour, and achieving strong antitumour immunotherapy. Additionally, the use of αPD-L1 as an immune checkpoint antagonist further increased the anti-tumour immune response of Bio-MnSe, resulting in enhanced anti-tumour effects. Doxorubicin (Dox), an immunogenic cell death (ICD) inducer, was combined with Bio-MnSe to form Bio-MnSe@Dox. This Bio-MnSe@Dox not only directly damaged tumour cells and induced tumour ICD but also promoted dendritic cell maturation, cytotoxic T lymphocyte infiltration, and NK cell recruitment, synergistically intensifying anti-tumour immune responses and suppressing tumour relapse and lung metastasis. Collectively, our findings propose an effective strategy for transforming 'cold' tumours to 'hot' ones, thereby advancing the development of anti-tumour immune drugs. STATEMENT OF SIGNIFICANCE: A biogenic MnSe (Bio-MnSe) nanocomposite was synthesized using Chlorella vulgaris as a bioreactor for enhanced immunotherapy of TNBC. Bio-MnSe demonstrated a stronger ability to activate the cGAS-STING signalling pathway and generate more ROS compared to pure Se nanoparticles and free Mn2+ ions. Apoptotic cells induced by Bio-MnSe released a significant amount of interferon, leading to the activation of T and natural killer (NK) cells, ultimately transforming immunologically 'cold' breast tumours to 'hot' tumours and enhancing the tumour's response to immune checkpoint inhibitors. The combination of Bio-MnSe with Dox or αPD-L1 further enhance

BACKGROUND: Thyroid cancer is the most common endocrine malignancy worldwide, and recent studies suggest that environmental metal exposure may influence its development. However, existing evidence is mostly observational and lacks causal inference. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to assess the causal relationships between 21 metal elements and thyroid cancer risk in East Asian populations. Genetic instruments were selected from a GWAS of 2488 individuals, and thyroid cancer summary statistics were obtained from 361 cases and 178,362 controls. The inverse-variance weighted (IVW) method was used as the primary analysis, with MR-Egger, weighted median, MR-PRESSO, and sensitivity analyses to assess robustness. RESULTS: IVW results identified a positive causal association between serum lead levels, OR = 1.608 (95% CI: 1.165-2.219; P = 0.004) and plasma manganese levels, OR = 1.332 (95% CI: 1.087-1.633; P = 0.006) with thyroid cancer. In contrast, plasma titanium levels were inversely associated with thyroid cancer risk, OR = 0.834 (95% CI: 0.697-0.997; P = 0.046). No evidence of reverse causation was found. Sensitivity analyses showed no significant heterogeneity or pleiotropy, supporting the robustness of the findings. CONCLUSION: This study provides the first genetic evidence for causal links between specific metal exposures and thyroid cancer. Elevated lead and manganese levels may increase cancer risk, while titanium may have a protective effect. These findings warrant further validation through mechanistic and longitudinal studies across diverse populations. © 2025. The Author(s).

AIMS: Cancer metastasis is the major cause of cancer-related deaths. There are few prior studies reported on molecules targeting C-X-C chemokine receptor (CXCR) family and manganese superoxide dismutase (MnSOD). CXCRs are known to involve in angiogenesis, metastasis, cell survival and MnSOD is reported to be related in Epithelial-mesenchymal transition (EMT). MAIN METHODS: Cell viability and cell proliferation were measured by MTT and BrdU assay. Protein expression level of CXCR4/7, MMP-2/9, MnSOD, and EMT markers were evaluated by Western blot analysis. mRNA levels of Snail and Occludin were analyzed by Real-time RT-qPCR. Expression of EMT markers in cells was observed by immunocytochemistry. Cell invasion and migrations were evaluated by wound healing assay and boyden chamber assay. KEY FINDINGS: We noticed that LGA abolished proliferation, invasive ability, and cellular migration. LGA down-regulated the protein levels of mesenchymal markers such as Twist, Snail, Fibronectin, and Vimentin in CXCL12-treated HCC cells. It also suppressed the gelatinolytic activity of MMP-9/2. The amplification of MnSOD increased EMT-like phenotypes but with LGA treatment, these phenotypes were markedly attenuated. The overexpression of MnSOD increased the ROS levels significantly but ROS levels were decreased upon exposure to LGA and deletion of MnSOD suppressed the levels of various mesenchymal proteins. SIGNIFICANCE: LGA could function as a novel anti-metastatic agent by suppressing metastasis and EMT process via attenuation of MnSOD expression in hepatocellular carcinoma cells.

Loliolide (LL), a naturally occurring monoterpenoid lactone isolated from Vicia tenuifolia Roth, can exhibit numerous pharmacological effects such as those related to anti-Parkinson, anti-oxidant, anti-cholinesterase, and anti-depressant. Epithelial-mesenchymal transition (EMT) plays a pivotal role in regulating tumor metastasis. CXCR4 and CXCR7 are G-protein-coupled receptors (GPRs), which can be stimulated by CXCL12. CXCL12/CXCR4/CXCXR7 axis can cause activation of multiple pathways including MAPKs, JAK/STAT pathway, and manganese superoxide dismutase (MnSOD) signaling. These events can initiate EMT process and induce cell invasion and migration. Here, we investigated whether LL can modulate the CXCR4 and CXCR7 and EMT process in colon cancer and breast cancer cells. We found that LL suppressed levels of CXCR4 and CXCR7, and exerted an inhibitory effect on these chemokines even after stimulation by CXCL12. LL suppressed expression of MnSOD and mesenchymal markers, whereas induced epithelial markers. In addition, LL significantly attenuated cellular invasion, migration, and metastasis. We noted that LL inhibited CXCR4/7 and EMT process even after stimulation of CXCL12 and MnSOD overexpression. Therefore, in this study, we provide evidences that targeting CXCR4/7 and MnSOD could inhibit the invasion, migration, and metastasis of cancer cells as well as negatively regulate the EMT process. Overall, our study suggested that LL might act as a potent suppressor of EMT process against colon and breast cancer cells.

Recent studies have reported correlations between mineral intake and metabolic syndrome (MS), but accurate relationships and consistency in the results are difficult to confirm. Accordingly, this study aims to assess the dietary intakes of magnesium (Mg), manganese (Mn), and copper (Cu) to determine their relationship with MS. Data from a total of 5,136 adults (2,084 men, 3,052 women) was collected from the 2007-2008 Korea National Health and Nutrition Examination Survey (KNHANES), and the intakes of Mg, Mn, and Cu of the MS patients were compared with those of healthy adults. The relationship between the intakes of these minerals and the MS risks was analyzed. Diagnosis of MS was evaluated by the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) standards. Among all study subjects, 25.9 % (540 subjects) of the men and 24.5 % (748 subjects) of the women met diagnostic criteria for inclusion in the MS group. In the men, daily intakes of Mg and Cu in the MS group were significantly lower than those in control group, and in the women, daily intakes of energy, Mg, Mn, and Cu in the MS group were significantly lower than those of the control group. The women subjects with high blood pressure showed significantly lower intakes of Mg, Mn, and Cu than control subjects. In addition, in the women, the highest quartile of Mg and Cu was inversely associated with MS, but with adjustment were not maintained. However, in the postmenopausal women, MS was significant and inversely associated with the highest quartiles of Cu intake and the association remained significant after adjustments. Considering that MS incidence increases and dietary intake and nutrient density decrease with increasing age, and mineral intake is reduced accordingly, these results suggest that meal management with adequate mineral intake is advisable to control MS.

Erratum in Biol Trace Elem Res. 2012 Jul;148(1):133. In order to explore the associations between trace elements in dietary intake and the other three biological media (blood, urine, or feces) and inter-element interactions among the latter, we simultaneously collected 72-h diet duplicates, whole blood, and 72-h urine and feces from 120 free-living healthy males in China. Correlations among the toxic (cadmium [Cd], lead [Pb]), and nutritionally essential (zinc [Zn], copper [Cu], iron [Fe], manganese [Mn], selenium [Se], iodine [I]) elements were evaluated using Spearman rank correlation analysis based on analytical data determined by inductively coupled plasma-mass spectrometry. Dietary Cd intakes were highly correlated with the fecal Cd and blood Cd levels. Inverse correlations were found for Fe-Cd and Fe-Pb in both diet versus blood and diet versus feces. Cd-Zn and Cd-Se were significantly directly correlated in the urine and feces. Cd-Se and Pb-Se were negatively correlated in blood. In addition, there existed an extremely significant association between urinary Se and urinary I. Moreover, the other two highly direct correlations were found for Se-Fe and for I-Fe in urine. Improved knowledge regarding their mutual associations is considered to be of fundamental importance to understand more the complex interrelationships in trace element metabolism.

INTRODUCTION: We present data from Korean National Health and Nutritional Examination Survey (KNHANES) 2008 on the distribution of blood manganese (Mn) levels and their associations with iron deficiency in a representative sample of the adult Korean population. METHODS: This study was based on data obtained in KNHANES 2008, which was conducted for three years (2007-2009) using a rolling sampling design that involves a complex, stratified, multistage, probability-cluster survey of a representative sample of the noninstitutionalized civilian population in South Korea. RESULTS: Geometric means (GMs) of blood Mn in the low serum ferritin group in women, men, and all participants were significantly higher than in the normal group. GMs of blood Mn in the low-normal serum ferritin groups in women and all participants were significantly higher than in the normal group. In addition, multiple regression analysis after controlling for covariates including gender, age, regional area, education level, and smoking and drinking status showed that blood Mn was significantly higher in the low ferritin group in women, men, and all participants compared with the normal group, whereas blood Mn was significantly higher in the low-normal ferritin group only in women and all participants. DISCUSSION: The present study shows that iron deficiency increases blood Mn level in the general population. To the best of our knowledge, the present study is the first to show an association between blood Mn level and ferritin level in a representative sample of the adult population such as that evaluated in KNHANES.