Molybdenum

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.

The minerals Cu, Mo, and S are essential for metabolic functions related to cattle health and performance. The interaction between Cu, Mo, and S can determine the utilization of each mineral, in particular Cu, by ruminants. A meta-analysis was performed to evaluate the effects of dietary Cu, Mo, and S and their interactions on plasma and liver Cu, ADG, and G:F in growing-finishing cattle. Data were collated from 12 published studies. The model with the best fit to data indicated plasma Cu was positively affected by dietary Cu (P < 0.01) and negatively affected by both dietary Mo (P < 0.01) and S (P < 0.01). Another model also indicated that plasma Cu concentration is positively related to Cu:Mo ratio in the diet (P < 0.01). Dietary Cu had a positive effect on liver Cu (P < 0.01), whereas Mo showed a negative effect (P < 0.05), and no effect of dietary S on liver Cu was observed (P > 0.05). Average daily gain was negatively affected by dietary Mo (P < 0.05) and S (P < 0.01) and positively affected by Cu:Mo ratio (P < 0.01), likely because an increased Cu:Mo ratio minimizes the antagonistic effect of Mo on Cu. The feed conversion ratio was negatively affected by Mo (P < 0.05) and S (P < 0.01), whereas effects of the Cu:Mo ratio and dietary Cu were not significant (P > 0.05). The interaction between S and Mo affected (P < 0.01) G:F, which was likely related to a positive response with the proper balance between these minerals. In conclusion, dietary Cu, Mo, and S and the Cu:Mo ratio caused changes in plasma Cu. Only dietary Mo and S led to a negative response in the performance of growing-finishing cattle, whereas the diet Cu:Mo ratio has a linear and quadratic effect on ADG. Nutritionists and producers need to consider with caution the supplementation of growing-finishing cattle diets with Mo and S because of their potentially adverse effects on animal performance. An appropriate Cu:Mo ratio is desirable to minimize the effects of an impaired supply of Mo on Cu metabolism and ADG.

OBJECTIVE: To evaluate the evidence of the supplements vitamin C and vitamin E for treatment and prevention of cancer. METHODS: Systematic review of trials and meta-analysis. DATA SOURCES AND MAIN RESULTS: Thirty-eight studies showed scant evidence that vitamin C or vitamin E beneficially affects survival. In the ATBC Cancer Prevention Study Group, no statistically significant effect of treatment was seen for any cancer individually, and our pooled relative risk (regardless of tumor type) for alpha-tocopherol alone was 0.91 (95% confidence interval [CI]: 0.74, 1.12). All cause mortality was not significant. In the Linxian General Population Trial, the relative risks for cancer death for vitamin C (combined with molybdenum) was 1.06 (95% CI: 0.92, 1.21) and for vitamin E (combined with beta-carotene and selenium) was 0.87 (95% CI: 0.76, 1.00). We identified only 3 studies that reported statistically significant beneficial results: vitamin C (in combination with BCG) was found to be beneficial in a single trial of bladder cancer and vitamin E (in combination with omega-3 fatty acid) increased survival in patients with advanced cancer. In the ATBC trial, in analyses of 6 individual cancers, the prevention of prostate cancer in subjects treated with alpha-tocopherol was statistically significant (RR=0.64, 95% CI: 0.44, 0.94). CONCLUSIONS: The systematic review of the literature does not support the hypothesis that the use of supplements of vitamin C or vitamin E in the doses tested helps prevent and/or treat cancer in the populations tested. There were isolated findings of benefit, which require confirmation.

Background/Objectives: Excessive sugar, fat, and salt intake heighten susceptibility to metabolic syndrome and other chronic metabolic conditions. Biofortification (i.e., enhancing the nutritional content of crops) emerges as a sustainable new approach to address dietary deficiencies. Methods: This study evaluated the impact of an acute nutritional intervention in a controlled, randomized, single-blind trial involving healthy adults aged 50-79 years, in late middle age and early older adulthood utilizing biofortified vegetables enriched with iodine and molybdenum, aimed to explore short-term biochemical responses to the consumption of iodine- and molybdenum-biofortified lettuce. The study was designed as a controlled dietary intervention including both a biofortified and a non-biofortified lettuce group, matched for handling and composition. It was powered to detect short-term biochemical responses, providing initial insights into the physiological impact of micronutrient biofortification. Dietary intake was carefully monitored throughout the 12-day period to control for confounding dietary effects. Results: The intervention was associated with decreased plasma levels of triglycerides, AST, and ALT, and increased plasma levels of HDL-cholesterol and the satiety hormone PYY, suggesting enhanced metabolic regulation. Conclusions: These biochemical markers reflect early metabolic adaptations that may inform future research on the metabolic impact of micronutrient biofortification. This study also highlights the potential of crop biofortification as a sustainable, strategy to enhance the nutrient density of vegetables within controlled dietary patterns.

BACKGROUND: Gastrointestinal (GI) cancer patients undergoing surgery often face immunosuppression, increasing postoperative risk. Immunomodulatory enteral nutrition (IEN) may enhance immune function and recovery, but mechanisms remain unclear. This study compared plasma proteomic profiles of patients receiving IEN versus standard enteral nutrition (SEN) to explore pathways linked to outcomes. METHODS: This analysis extended a previously published randomized clinical trial in GI cancer patients who received SEN or IEN postoperatively, with 50 patients in each group. The IEN was rich in arginine, nucleotides, vitamin B12, chloride, vitamin C, selenium, chromium, and molybdenum. Plasma samples were analyzed using mass spectrometry-based proteomics (MassLynx v4.1 and Progenesis v4.1). Proteins consistently detected across replicates (database search P < 0.05) were identified. Clinical outcomes, including complications and biochemical markers, were integrated with proteomic findings to interpret biological mechanisms. RESULTS: Distinct proteomic profiles were observed. The IEN group showed higher levels of complement proteins (C3, C5, C9), inter-alpha-trypsin inhibitor heavy chain H2, pregnancy zone protein, immunoglobulins, and apolipoproteins-proteins linked to immune modulation, tissue repair, and inflammation control. The SEN group displayed elevated acute-phase proteins and coagulation factors, including fibrinogen and serum amyloid A-4, consistent with a pro-inflammatory, hypercoagulable state. These differences paralleled clinical results, with the IEN group experiencing fewer complications and improved albumin/globulin ratios. CONCLUSIONS: This exploratory study suggests that immunonutrition may modulate complement activation and immune pathways, supporting better postoperative outcomes in GI cancer patients. The proteomic profile provides evidence that supports a mechanistic hypothesis underlying the observed clinical benefits. Future quantitative proteomics with larger cohorts is warranted to validate these findings and optimize perioperative nutrition strategies.

AIM: To evaluate the three-dimensional position and root resorption of incisors after anterior segment retraction (ASR) using friction versus frictionless mechanics. PARTICIPANTS AND METHODS: Thirty female patients (13-18 years) with bimaxillary protrusion were randomly allocated into two groups. In the intervention group, ASR was undertaken using an elastomeric chain rendering 160 g/side extending between mini-screw implant and a hook crimped on 0.017 × 0.025-inch stainless-steel wire distal to the lateral incisor. In the comparison group, ASR was undertaken using closing T-loops fabricated from 0.017 × 0.025-inch titanium molybdenum alloy (TMA) wire rendering comparable retraction force. In both groups, the canine brackets were ligated after retraction to the mini-screw implants that were inserted in both the upper and lower arches bilaterally. The primary outcome was the three-dimensional changes in the position of the incisors. The secondary outcome was root resorption. These were measured from cone-beam computed tomography scans. RESULTS: Statistically significant decreases in the upper (UI) and lower incisors (LI) crown torque were seen in both groups; however, the difference between groups was not statistically or clinically significant (UI MD -2.04°; 95% confidence interval [CI] = -8.02-3.95; LI MD -0.49°; 95% CI = -7.06-6.08). Significant tipping of upper (MD -1.17°; 95% CI = -2.06--0.27) and lower (MD -1.13°; 95% CI = -1.66--0.60) incisors was found in the friction, but not the frictionless group after retraction; however, the changes were not clinically significant. Significant lower incisor intrusion was found in both groups after retraction; however, the difference between groups was not statistically or clinically significant (MD -0.61°; 95% CI = -1.99-0.77). Statistically significant decreases in the UI and LI root length were seen in both groups. The difference between groups for UI changes was statistically significant (MD 0.54 mm; 95% CI = -0.02-1.07) but probably not clinically significant. CONCLUSION: Considering the limitations in the current study, there was no advantage of either mechanics over the other regarding the final position of inc

BACKGROUND & AIMS: In Wilson disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may be associated with a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated its effects on copper absorption and biliary excretion. METHODS: In a double-blind randomized setting, hepatic 64Cu activity was examined after orally administered 64Cu by PET/CT in 16 healthy volunteers before and after seven days of TTM treatment (15 mg/d) or placebo. Oral 64Cu was administered one hour after the final TTM dose. Changes in hepatic 64Cu activity reflected changes in intestinal 64Cu uptake. Additionally, in four patients with WD, the distribution of 64Cu in venous blood, liver, gallbladder, kidney, and brain was followed after i.v. 64Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/day), using PET/MRI. Increased gallbladder 64Cu activity was taken as evidence of increased biliary 64Cu excretion. RESULTS: In healthy volunteers, TTM reduced intestinal 64Cu uptake by 82% 15 hours after the oral 64Cu dose. In patients with WD, gallbladder 64Cu activity was negligible before and after TTM, while TTM effectively retained 64Cu in the blood, significantly reduced hepatic 64Cu activity at all time-points and significantly reduced cerebral 64Cu activity two hours after the intravenous 64Cu dose. CONCLUSIONS: While we did not show an increase in biliary excretion of 64Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64Cu uptake and retained 64Cu in the blood stream, limiting the exposure of organs like the liver and brain to 64Cu. IMPACT AND IMPLICATIONS: Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator being developed for the treatment of Wilson disease. In animal models of Wilson disease, TTM has been shown to facilitate biliary copper excretion. In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significan

BACKGROUND: The use of poly-ether-ether-ketone (PEEK) prosthesis during total knee arthroplasty (TKA) is a relatively new concept. Several studies have suggested that the thickness of cement penetration during TKA may affect the stability of the implants. The present study aimed to compare the cement penetration and clinical performance between PEEK and traditional cobalt chromium molybdenum (CoCrMo) prosthesis during TKA. METHODS: This study was a randomized controlled trial with level I of evidence. A total of 48 patients were randomly assigned to either the PEEK group (n = 24) or the CoCrMo group (n = 24). Mean bone cement penetration under the tibial baseplate was assessed radiographically in four zones in the anteroposterior view and two zones in the lateral view, in accordance with the Knee Society Scoring System. Furthermore, parameters such as the Knee Society Score (KSS), visual analogue scale (VAS) scores, complications and survivorship at 1 year postoperatively were also compared. RESULTS: According to the results of this study, the mean bone cement penetration exhibited no significant difference between PEEK and CoCrMo groups (2.49 ± 0.61 mm vs. 2.53 ± 0.68 mm, p = 0.85). Additionally, there were no remarkable differences in the KSS clinical score, functional score, and VAS score between the two groups. Moreover, complications and survivorship were also statistically compared between the groups and presented no significant differences. CONCLUSIONS: Based on the current findings, it can be concluded that PEEK implant present similar bone cement penetration, short-term clinical outcomes, and survivorship with traditional CoCrMo implant in TKA without added complications. Trial registration Chinese Clinical Trial Registry (ChiCTR2100047563). © 2023. BioMed Central Ltd., part of Springer Nature.

BACKGROUND: This randomized-controlled trial was initiated to compare a new multilayer hypoallergenic coating system with the standard implant in total knee arthroplasty (TKA) in terms of serum metal ion levels, patient-reported outcomes (PROs), and implant survival. METHODS: A total of 120 patients were randomized to receive a coated or standard TKA of the same knee system. Serum metal ion levels (ie, cobalt, chromium, molybdenum, and nickel) as well as knee function (Oxford Knee Score, OKS), quality of life (SF-36), and physical activity (UCLA activity scale) were assessed before surgery and until the 10 year follow-up. A total of 24 patients died and there was one revision in each group. This resulted in 85 patients who completed follow-up. RESULTS: Both groups demonstrated equally good improvement in PROs after surgery and constant score values thereafter. The majority of patients had metal ion serum levels below detection limit. Only cobalt levels demonstrated a slight increase in the standard group at 5- and 10-year follow-up. However, all patients displayed values below 3 μg/L. The cumulative 10-year survival was 98% in both groups. CONCLUSION: There were no problems with the new coating system. No relevant increase in metal ion serum levels were measured. A slight increase in cobalt serum levels in the standard TKA was noted, thus not reaching critical values. The new coating system demonstrated equally good PROs as the standard TKA. Excellent implant survival was observed in both groups. LEVEL OF EVIDENCE: I.

BACKGROUND: In Germany, patients with contact allergy to implant components usually receive coated joint arthroplasties. Whether the treatment using these hypoallergenic implants achieves comparable results to standard treatment with implants consisting of cobalt-chromium alloy (CoCr) implants is controversially discussed internationally and has rarely been investigated in the mid-term. OBJECTIVES: Are there differences in blood metal ion concentrations, knee function, and patient-reported outcomes (PROM) between coated and standard implants? MATERIAL AND METHODS: 118 patients were randomized to receive either a coated or a standard implant. Knee function as well as patient-reported outcome measures were assessed. Metal ion concentrations in blood samples were additionally determined for chromium, cobalt, molybdenum, and nickel, preoperatively, one and five years after surgery. RESULTS: After five years, it was possible to analyse the results of 97 patients. In metal ion concentrations, as well as PRO, consistently good results were seen, without any difference between the groups. While in 13 patients there was an increase in chromium concentration above 2 µg/l one year after surgery, there was no measured value above 1 µg/l after five years. CONCLUSION: In our study, similar mid-term results were detected for coated (TiNiN) and standard (CoCr)TKA. With respect to metal ion concentrations and PRO there are no disadvantages in using coated TKA. Publisher: ZUSAMMENFASSUNG: HINTERGRUND: Patienten mit einer Kontaktallergie gegen Implantatbestandteile erhalten in Deutschland üblicherweise beschichtete Prothesen. Ob die Versorgung mit solchen hypoallergenen Implantaten vergleichbare Ergebnisse erzielt wie die Standardversorgung mit Implantaten aus Kobalt-Chrom-Legierungen (CoCr) ist international umstritten und mittelfristig bislang wenig untersucht. ZIEL DER ARBEIT (FRAGESTELLUNG): Gibt es Unterschiede hinsichtlich Metallionenkonzentration im Blut, Kniefunktion und patientenberichteter Ergebnisse (PROM) zwischen beschichteten Knieendoprothesen und Standardimplantaten? MATERIAL UND METHODEN: 118 Patienten erhielten randomisiert entweder eine beschichtete oder eine St

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.

Thiopurines, such as 6-mercaptopurine (6-MP) and azathioprine, are converted to the inactive metabolites 6-thioxanthin (6-TX) and 6-thiouric acid (6-TUA). Molybdenum-containing oxidoreductases, aldehyde oxidase (AOX) and xanthine oxidase (XO), are involved in the oxidation of 6-MP to 6-TX; XO inhibitors affect the therapeutic efficacy of thiopurines and the incidence of adverse effects, such as liver and blood disorders. However, the role of AOX in the pharmacokinetics of 6-MP remains unclear. To clarify the clinical importance of AOX-mediated drug-drug interactions, we evaluated whether drugs that inhibit AOX affect 6-MP metabolism. The metabolism of 6-MP to 6-TX was strongly inhibited by AOX inhibitors (amitriptyline, chlorpromazine, clomipramine, clozapine, hydralazine, quetiapine, and raloxifene) in a reaction mixture containing human liver cytosol. The inhibition of 6-TX production rate by each AOX inhibitor was 60-70% at high concentrations, although the XO inhibitor febuxostat showed an inhibition rate of 10-30%. Furthermore, the combination of febuxostat and each AOX inhibitor showed greater inhibition than when each compound was added alone. The AOX inhibitor did not alter 6-MP oxidation by recombinant XO. These results suggest that AOX inhibition may affect the pharmacokinetics of thiopurines. However, because of the lower activity of AOX in rats than that in humans, the contribution of AOX could not be assessed using in vivo experiments. Further studies are needed to evaluate the contribution of AOX to the therapeutic and adverse effects of thiopurines, both in clinical studies and in animal models of liver humanization.

The propensity for aldehyde oxidase (AO) substrates to be implicated in drug-drug interactions (DDIs) is not well understood due to the dearth of potent inhibitors that elicit in vivo inhibition of AO. Although there is only one reported instance of DDI that has been ascribed to the inhibition of AO to date, the supporting evidence for this clinical interaction is rather tenuous, and its veracity has been called into question. Our group recently reported that the epidermal growth factor receptor inhibitor erlotinib engendered potent time-dependent inhibition of AO with inactivation kinetic constants in the same order of magnitude as its free circulating plasma concentrations. At the same time, it was previously reported that the concomitant administration of erlotinib with the investigational drug OSI-930 culminated in a an approximately twofold increase in its systemic exposure. Although the basis underpinning this interaction remains unclear, the structure of OSI-930 contains a quinoline motif that is amenable to oxidation at the electrophilic carbon adjacent to the nitrogen atom by molybdenum-containing hydroxylases like AO. In this study, we conducted metabolite identification that revealed that OSI-930 undergoes AO metabolism to a mono-oxygenated 2-oxo metabolite and assessed its formation kinetics in human liver cytosol. Additionally, reaction phenotyping in human hepatocytes revealed that AO contributes nearly 50% to the overall metabolism of OSI-930. Finally, modeling the interaction between erlotinib and OSI-930 using a mechanistic static model projected an ∼1.85-fold increase in the systemic exposure of OSI-930, which accurately recapitulated clinical observations. SIGNIFICANCE STATEMENT: This study delineates an aldehyde oxidase (AO) metabolic pathway in the investigational drug OSI-930 for the first time and confirmed that it represented a major route of metabolism through reaction phenotyping in human hepatocytes. Our study provided compelling mechanistic and modeling evidence for the first instance of an AO-mediated clinical drug-drug interaction stemming from the in vivo inhibition of the AO-mediated quinoline 2-oxidation pathway in OSI-930 by erl

OBJECTIVES: Aldehyde oxidase (AO) is a molybdenum-containing redox enzyme similar to xanthine oxidase that is involved in the thiopurine metabolism. This study investigated the effects of drug-drug interactions (DDIs) between azathioprine (AZA) and AO inhibitors on hematologic and hepatic disorders using the U.S. Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report database. METHODS: The presence of DDI was assessed using the interaction signal scores (ISSs) calculated via the reporting odds ratios and 95% confidence intervals. The study used reports of 'azathioprine' as a suspect drug for adverse effects. AO inhibitors were selected based on previous in vitro reports. RESULTS: Some drugs tested positive for ISSs in each database and type of adverse effect (hematologic or hepatic disorder) analysis. Among these drugs, chlorpromazine, clozapine, hydralazine, and quetiapine could inhibit AZA metabolism via AO, given the previously reported clinical blood concentration and inhibitory effects of each drug. CONCLUSION: Concomitant use of AO inhibitors increased the signals for AZA-induced adverse effects. To date, no studies have evaluated the clinical importance of AO as a drug-metabolizing enzyme, and further in vitro and clinical research is needed to clarify the contribution of AO to the pharmacokinetics of thiopurines.

BACKGROUND: Child blood pressure (BP) is predictive of future cardiovascular risk. Prenatal exposure to metals has been associated with higher BP in childhood, but most studies have evaluated elements individually and measured BP at a single time point. We investigated impacts of prenatal metal mixture exposures on longitudinal changes in BP during childhood and elevated BP at 11 years of age. METHODS: The current study included 176 mother-child pairs from the Rhea Study in Heraklion, Greece and focused on eight elements (antimony, arsenic, cadmium, cobalt, lead, magnesium, molybdenum, selenium) measured in maternal urine samples collected during pregnancy (median gestational age at collection: 12 weeks). BP was measured at approximately 4, 6, and 11 years of age. Covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression and Bayesian Kernel Machine Regression (BKMR) were used to evaluate metal mixture impacts on baseline and longitudinal changes in BP (from ages 4 to 11) and the development of elevated BP at age 11, respectively. BKMR results were compared using static versus percentile-based cutoffs to define elevated BP. RESULTS: Molybdenum and lead were the mixture components most consistently associated with BP. J-shaped relationships were observed between molybdenum and both systolic and diastolic BP at age 4. Similar associations were identified for both molybdenum and lead in relation to elevated BP at age 11. For molybdenum concentrations above the inflection points (~ 40-80 μg/L), positive associations with BP at age 4 were stronger at high levels of lead. Lead was positively associated with BP measures at age 4, but only at high levels of molybdenum. Potential interactions between molybdenum and lead were also identified for BP at age 11, but were sensitive to the cutoffs used to define elevated BP. CONCLUSIONS: Prenatal exposure to high levels of molybdenum and lead, particularly in combination, may contribute to higher BP at age 4. These early effects appear to persist throughout childhood, contributing to elevated BP in adolescence. Future studies are needed to identify the major sources of molybdenum and lead in this population.

Here, we introduce an innovative "poison arrowhead" approach for disinfection based on a nanosheet bacterial inactivation system that acts synergistically to achieve sterilization rates of >99.99 % (Escherichia coli) over an ultrashort time period (≈0.5 min). The two-dimensional MoS2 "arrowhead" configuration has a sharp edge structure that enables the vigorous extraction of lipids from cell membranes and subsequent membrane disruptions. In the presence of permonosulfate, a strong oxidant, sulfur vacancies containing MoS2 activate the stable molecules, which in turn produce reactive oxygen species (ROS) from edge sites to basal areas. This process not only scavenges some portion of the phospholipids to allow for MoS2 surface refreshment but also directly attacks proteins thereby inflicting further damage to injured cells and amplifying the cell-membrane-destructive stresses toward pathogenic microorganisms. With small amounts of the new material, we successfully disinfected natural water (≈99.93 % inactivation in terms of total bacteria) within 30 s. © 2020 Wiley-VCH GmbH.

The principal unmet need in BRAFV600E-positive melanoma is lack of an adequate therapeutic strategy capable of overcoming resistance to clinically approved targeted therapies against oncogenic BRAF and/or the downstream MEK1/2 kinases. We previously discovered that copper (Cu) is required for MEK1 and MEK2 activity through a direct Cu-MEK1/2 interaction. Repurposing the clinical Cu chelator tetrathiomolybdate (TTM) is supported by efficacy in BRAFV600E-driven melanoma models, due in part to inhibition of MEK1/2 kinase activity. However, the antineoplastic activity of Cu chelators is cytostatic. Here, we performed high-throughput small-molecule screens to identify bioactive compounds that synergize with TTM in BRAFV600E-driven melanoma cells. Genetic perturbation or pharmacologic inhibition of specific members of the BCL2 family of antiapoptotic proteins (BCL-W, BCL-XL, and MCL1) selectively reduced cell viability when combined with a Cu chelator and induced CASPASE-dependent cell death. Further, in BRAFV600E-positive melanoma cells evolved to be resistant to BRAF and/or MEK1/2 inhibitors, combined treatment with TTM and the clinically evaluated BCL2 inhibitor, ABT-263, restored tumor growth suppression and induced apoptosis. These findings further support Cu chelation as a therapeutic strategy to target oncogene-dependent tumor cell growth and survival by enhancing Cu chelator efficacy with chemical inducers of apoptosis, especially in the context of refractory or relapsed BRAFV600E-driven melanoma. SIGNIFICANCE: This study unveils a novel collateral drug sensitivity elicited by combining copper chelators and BH3 mimetics for treatment of BRAFV600E mutation-positive melanoma. ©2020 American Association for Cancer Research.

Activation of peroxymonosulfate (PMS) and persulfate (PS) by Fe2+ is widely used for oxidizing organic pollutants. However, their application is limited by the slow conversion rate of Fe3+ to Fe2+ and the accumulation of Fe3+. Here, we introduce commercial molybdenum disulfide (MoS2) to promote the activation of PMS and PS by Fe2+, and explore the mechanism of this promotion using experimental and theoretical methods. The Fe2+/PMS/MoS2 and Fe2+/PS/MoS2 systems achieved faster rate of PMS and PS conversion and also higher degradation efficiency toward pollutants. About 94.7% and 87.6% of rhodamine B (RhB) could be degraded in Fe2+/PMS/MoS2 (54 μM Fe2+, 1 mM PMS) and Fe2+/PS/MoS2 (54 μM Fe2+, 0.25 mM PS) system, respectively. MoS2 addition simultaneously promoted the Fe3+/Fe2+ cycle, the PMS and PS conversion, and the RhB mineralization. As a co-catalyst, MoS2 exhibited excellent stability for eight successive cycles of use. The predominant oxidant was identified as SO4- in Fe2+/PMS/MoS2 and Fe2+/PS/MoS2 systems. Theoretical calculations and a kinetic model were employed to evaluate the catalytic performance of the systems. These novel findings indicate that the combination of a commercially available MoS2 catalyst with a low dosage of Fe2+ is a promising and effective approach for efficient activation of PMS and PS to produce SO4- and OH.

Platinum‑based antitumor agents have been widely used to treat head and neck squamous cell carcinoma (HNSCC) and numerous other malignancies. Cisplatin is the most frequently used platinum‑based antitumor agent, however drug resistance and numerous undesirable side effects limit its clinical efficacy for cancer patients. Cancer cells discharge cisplatin into the extracellular space via copper transporters such as ATPase copper transporting beta (ATP7B) in order to escape from cisplatin‑induced cell death. In the present study, it was demonstrated for the first time that the copper chelator ammonium tetrathiomolybdate (TM) has several promising effects on cisplatin and HNSCC. First, TM suppressed the ATP7B expression in HNSCC cell lines in vitro, thereby enhancing the accumulation and apoptotic effect of cisplatin in the cancer cells. Next, it was revealed that TM enhanced the antitumor effect of cisplatin in HNSCC cell tumor progression in a mouse model of bone invasion, which is important since HNSCC cells frequently invade to facial bone. Finally, it was demonstrated that TM was able to overcome the cisplatin resistance of a human cancer cell line, A431, via ATP7B depression in vitro.

Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson's disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo2S6O2 cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins.

Considered as the "King of spices", black pepper (Piper nigrum L.) is a widely used spice which adds flavor of its own to dishes, and also enhances the taste of other ingredients. Piper nigrum has also been extensively explored for its biological properties and its bioactive phyto-compounds. There is, however, no updated compilation of these available data to provide a complete profile of the medicinal aspects of P. nigrum. This study endeavors to systematically review scientific data on the traditional uses, phytochemical composition, and pharmacological properties of P. nigrum. Information was obtained using a combination of keywords via recognized electronic databases (e.g., Science Direct and Google Scholar). Google search was also used. Books and online materials were also considered, and the literature search was restricted to the English language. The country with the highest number of traditional reports of P. nigrum for both human and veterinary medicine was India, mostly for menstrual and ear-nose-throat disorders in human and gastrointestinal disorders in livestock. The seeds and fruits were mostly used, and the preferred mode of preparation was in powdered form, pills or tablets, and paste. Piper nigrum and its bioactive compounds were also found to possess important pharmacological properties. Antimicrobial activity was recorded against a wide range of pathogens via inhibition of biofilm, bacterial efflux pumps, bacterial swarming, and swimming motilities. Studies also reported its antioxidant effects against a series of reactive oxygen and nitrogen species including the scavenging of superoxide anion, hydrogen peroxide, nitric oxide, DPPH, ABTS, and reducing effect against ferric and molybdenum (VI). Improvement of antioxidant enzymes in vivo has also been reported. Piper nigrum also exhibited anticancer effect against a number of cell lines from breast, colon, cervical, and prostate through different mechanisms including cytotoxicity, apoptosis, autophagy, and interference with signaling pathways. Its antidiabetic property has also been confirmed in vivo as well as hypolipidemic activity as evidenced by decrease in the level of cholesterol, trigly

We performed a study to assess whether different bearing materials have an impact on femoral bone remodeling within the first four years after a hybrid total hip arthroplasty. 205 of 300 patients were available for 4 years follow-up after being randomly allocated to four prosthetic combinations: A: Zirconia ceramic head, polyethylene cup; B: Cobalt-Chrome-Molybdenum head and cup; C: Zirconia ceramic head, polyethylene moulded on the Titanium shell of the Asian cup; D: Alumina head and cup. Bone mineral density (BMD) was measured with Dual-Energy X-ray Absorptiometry in seven Gruen zones adjacent to the femoral implant. Scans were performed within one week after surgery and four years postoperatively. Clinical outcomes were monitored using the Oxford Hip Score (OHS). A high proportion of patients from group D were excluded due to re-operations (19 patients). BMD decreased significantly in all Gruen zones with the largest declines in group D. BMD changes in Gruen zones 1, 2, 3, 6, and 7 correlated with height, and body weight. Advanced age was associated with an increase in bone loss in Gruen zones 1, 2, 3, 6, and 7. A large stem size was associated with a decline in BMD in Gruen zones 1, 6, and 7.Bone remodeling after total hip arthroplasty may depend on the composition of bearing materials, but age, height, weight, and stem size are also related to changes in BMD.

BACKGROUND: Small vulnerable newborns (SVNs), defined as babies affected by preterm birth (PTB), small for gestational age (SGA), or low birth weight (LBW), face a substantially increased risk of chronic diseases over their lifespan and premature mortality. Gestational exposure to heavy metals may play a role in the aetiology of SVNs. Although previous limited systematic reviews have examined individual metal(loid)s and single SVN outcomes, their findings remain inconclusive. Given the recent surge in studies, the use of diverse biospecimens, and the narrow scope of prior search strategies, our study aims to addresses these gaps by comprehensively synthesizing evidence across multiple metal(loid)s, SVN outcomes, and biospecimen types, providing a more complete and up-to-date assessment. METHODS: We conducted a comprehensive search in three databases-PubMed, Web of Science, and Embase-for relevant articles published before 9th December 2025, investigating the associations between gestational exposure to metal(loid)s and outcomes of SVNs. Observational studies, including prospective and retrospective cohort studies, case-control studies, and cross-sectional studies, were included. Data were extracted from studies that assessed toxicologically relevant metal burdens using biomonitoring measurements. Meta-analysis was conducted and pooled odds ratios (ORs) and confidence intervals (CIs) were calculated using both fixed-effect and random-effects models, with further analyses stratified by biospecimen types. Two-stage dose-response analyses were performed. Publication bias and heterogeneity were assessed. The protocol was registered with PROSPERO, CRD42024571198. FINDINGS: Of the 43,695 publications identified and 102 studies with a total of 325,705 live births involving 20 heavy metals and either of SVNs outcomes met the inclusion criteria for final meta-analysis. Barium (Ba, n = 4541), Higher maternal Cadmium (Cd, n = 31,651), Mercury (Hg, n = 18,962), and lead (Pb, n = 92,082) exposure, defined based on study-specific exposure contrasts, were significantly related to increased risk of PTB, with pooled ORs (95% CIs) of 1.12 (1.01, 1.24) for Ba, 1.23 (1.10, 1.38) for

Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD-A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search. © 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Orofacial clefts (OFCs) have been linked to various toxic and essential trace elements (TETEs) worldwide. However, review estimation is absent. Therefore, addressing the hypothesis that TETEs are associated with OFCs is the main area of this review. A systematic literature search was conducted using electronic databases through PubMed, Web of Science, Scopus, Science Direct, and Google Scholar between 2004 and August 2022. The "AND" and "OR" operators were used to make our search results inclusive and restrictive as follows: ("Toxic element*" OR "Heavy metal*") AND ("Toxic element*" OR "Lead OR Arsenic OR Mercury*")) AND ("Essential trace element*" OR "Zinc OR Selenium OR Copper*")) AND ("Orofacial cleft*" OR "Cleft lip*" OR "Cleft palate*") AND ("Infant*" OR "Newborn*" OR "Neonate*")). The presence of toxic elements was linked to the development of OFCs. The results showed that higher levels of toxic elements in various biological sample types were related to increased risks for OFCs. Increased concentrations of essential trace elements (ETEs) lowered the risk of OFCs. Maternal consumption of diets rich in ETEs, including zinc (Zn), selenium (Se), copper (Cu), cobalt (Co), and molybdenum (Mo), was linked to a more pronounced reduction in the risk of OFCs. Based on the findings, it is acceptable to infer that maternal exposure to toxic elements, whether through environmental contaminants or dietary sources, was associated with an elevated risk of OFCs. Furthermore, the study revealed that ETEs exhibited a potential protective role in reducing the incidence of OFCs. This observation highlights the importance of reducing exposure to toxic elements during pregnancy and suggests that optimizing maternal intake of ETEs could be an effective preventive strategy. © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

The golden eagle (Aquila chrysaetos) and the white-tailed eagle (Haliaeetus albicilla), being apex predators and facultative scavengers, can bioaccumulate different environmental contaminants, including toxic elements that may adversely affect their health. We analyzed the levels of cadmium (Cd), lead (Pb), and other metals and metalloids, including arsenic (As), barium (Ba), beryllium (Be), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), selenium (Se), thorium (Th), thallium (Tl), uranium (U), vanadium (V), and zinc (Zn) in liver samples taken from three golden eagles and 36 white-tailed eagles that were found dead across Poland to verify their exposure. We also used a systematic review to summarize the available literature data on Cd, Pb, and other studied elements in the liver of both eagle species. Analyses of trace elements in the liver samples of the Polish eagles revealed interspecific differences in Cd, Cu, and Mn and differences in Co, Mn, Tl, and Zn among study regions. All elements tested except Pb were below the suggested thresholds linked with adverse health effects in birds. The hepatic Pb found in almost half of all the tested individuals suggests environmental exposure to this toxic element. One of the tested white-tailed eagles had hepatic Pb above the threshold of sublethal poisoning. Although our results seem optimistic, as previous Polish studies showed a higher prevalence of birds with hepatic Pb exceeding the toxicity threshold, they indicate that exposure to this toxic metal could still pose an additional threat to the health of Polish eagles. © 2022. The Author(s).

BACKGROUND: A balanced and optimized amount of nutrients in bread, which is the main food in many countries, is necessary to maintain human health. Considering the importance of nutritional values of bread in the food basket of Iranian households, the purpose of this study was to determine the nutrients and their concentrations in breads consumed in Iran. METHODS: This systematic review study was performed to determine the types of nutrients in breads consumed in Iran by searching reputable international databases including Scopus and Google scholar, PubMed, Science direct, ISI (Web of Science). Data were collected according to inclusion and exclusion criteria and by searching for relevant keywords, emphasizing the types of nutrients in breads consumed in Iran. Qualitative data were collected using the standard PRISMA checklist (preferential reporting items for systematic reviews and meta-analysis). After verifying the quality of the articles, the information was entered into a checklist such as the name of the first author and year of publication of the research, type of study, number of samples, type of nutrition, type of bread and amount of nutrition measured. RESULTS: After reviewing the information and quality of articles, 10 articles were qualified for systematic review. The review of the articles showed that different breads were experimented, including: Sangak, Barbari, Taftoon, Lavash, French and local bread. The highest number of experimented bread samples was Sangak. Examination of the articles showed that 6 nutrients were experimented in different breads such as Fe, K, Mg, Ca, Cu and Zn. The highest number of experimented in breads was related to the amount of Zn (13 times) and Cu (10 times), respectively. The results of quality assessment of articles showed that most of the studies were of good quality. The results of articles on the amount of nutrients measured in different breads showed that only in two articles the amount of nutrients was reported to be desirable. In most articles, the amount of nutrients in breads was reported to be lower or higher than standard. CONCLUSION: The results of this study showed that the concentration of nutrients in

The relationship between exposure to certain metals and the risk of hyperuricemia (HUA) has biological plausibility, yet prior studies have presented inconsistent findings. We aim to clarify the relationship between exposure to certain metals and HUA using a systematic review and meta-analysis approach. We searched the Web of Science, Embase, MEDLINE, Pubmed, Corchrane and China National Knowledge Infrastructure databases from inception through December, 2021 in order to identify studies that assessed the relationships between metals and the risk of HUA. Data were pooled by random-effects models and expressed as pooled odds ratios (OR) and 95% confidence intervals (CIs). The risk of bias was assessed using a tool from Agency for Healthcare Research and Quality (AHRQ). Twenty eligible articles (nineteen cross-sectional studies and one cohort) were included in our analysis, involving 63,283 participants in total. The studies showed that arsenic (pooled OR = 1.702, 95% CI: 1.44, 2.011; n = 6, I2 = 29.5%), calcium (pooled OR = 1.765, 1.111, 2.804; 4, 82.3%), cadmium (pooled OR = 1.199,1.020, 1.410; 11, 38.5%) and lead (pooled OR = 1.564,1.205, 2.030; 11, 72.9%) exposure were, all linked to an increased risk of HUA. Exposure to molybdenum (pooled OR = 0.804, 0.724, 0.975, 3, 0%) was linked to a decreased risk of HUA, however. Exposure to arsenic, calcium, cadmium and lead is associated with an increased risk of HUA. Molybdenum exposure was associated with a decreased prevalence of HUA; however, aluminum, cobalt, copper, iron, magnesium, manganese, mercury, selenium, thallium and zinc are not associated with HUA risk. Further experimental studies are warranted to decipher the mechanisms by which exposure to the above metals affect HUA risk. The findings reinforced the importance of metals in the HUA risk, and provided a reference for legislation to prevent HUA and protect people's health. © 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).

Nutrient imbalance (i.e., deficiency and toxicity) of microelements is an outstanding environmental issue that influences each aspect of ecosystems. Although the crucial roles of microelements in entire lifecycle of plants have been widely acknowledged, the effective control of microelements is still neglected due to the narrow safe margins. Selenium (Se) is an essential element for humans and animals. Although it is not believed to be indispensable for plants, many literatures have reported the significance of Se in terms of the uptake, accumulation, and detoxification of essential microelements in plants. However, most papers only concerned on the antagonistic effect of Se on metal elements in plants and ignored the underlying mechanisms. There is still a lack of systematic review articles to summarize the comprehensive knowledge on the connections between Se and microelements in plants. In this review, we conclude the bidirectional effects of Se on micronutrients in plants, including iron, zinc, copper, manganese, nickel, molybdenum, sodium, chlorine, and boron. The regulatory mechanisms of Se on these micronutrients are also analyzed. Moreover, we further emphasize the role of Se in alleviating element toxicity and adjusting the concentration of micronutrients in plants by altering the soil conditions (e.g., adsorption, pH, and organic matter), promoting microbial activity, participating in vital physiological and metabolic processes, generating element competition, stimulating metal chelation, organelle compartmentalization, and sequestration, improving the antioxidant defense system, and controlling related genes involved in transportation and tolerance. Based on the current understanding of the interaction between Se and these essential elements, future directions for research are suggested.