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Background: The iron(III)-quercetin complex, known as "IronQ", is an innovative MRI contrast agent composed of one Fe(III) ion and two quercetin molecules. IronQ is efficiently internalized by cells, enabling T1-weighted MRI tracking. It has demonstrated therapeutic benefits in reducing inflammation in an intracerebral hemorrhage (ICH) mouse model and offers a safer alternative to gadolinium-based agents by avoiding cytotoxicity and genotoxicity. These properties make IronQ a promising candidate for safe and effective MRI contrast enhancement., Purpose: This study aims to further the development of IronQ as an MRI contrast agent by investigating its biodistribution, pharmacokinetics, and acute toxicity in a preclinical animal model., Methods: The relaxivity of IronQ was measured in water and whole blood phantoms. Acute toxicity was evaluated in Sprague Dawley rats administered single intraperitoneal doses of IronQ (75, 150, and 225 µmol Fe/kg BW) over a 14-day period. Pharmacokinetic studies were performed at a dose of 150 µmol Fe/kg BW, with blood iron content analyzed using ICP-OES. For in vivo biodistribution, SD rats were administered an intravenous dose of IronQ (225 µmol Fe/kg BW), followed by MR imaging using a 1.5 T scanner and subsequent tissue-ICP analysis., Results: The longitudinal relaxivity (r 1 ) of IronQ was measured to be 2.17 mm⁻¹s⁻¹ in ultrapure water and 3.56 mm⁻¹s⁻¹ in whole blood. Acute toxicity studies showed no mortality, morbidity, or significant biochemical changes, with histopathology confirming no irreversible organ damage. Pharmacokinetics revealed peak blood iron content at 1.1 hours post-administration and clearance within 24 hours. MRI demonstrated enhanced T1 signal intensity, particularly in the liver and kidney., Conclusion: These findings provide valuable insights into the safety, pharmacokinetics, and imaging efficacy of IronQ, highlighting its potential as a robust and biocompatible MRI contrast agent., Competing Interests: The authors report no conflicts of interest in this work., (© 2025 Innuan et al.)

Iron is essential for every cell of the mammalian organism. Iron deficiency is a major public health issue worldwide. Intravenous (IV) iron therapy has been used to treat anemia. However, IV iron therapy is known far away from ideal because the quantitative relationship between the pharmacokinetics and biodistribution of IV iron under different iron statuses remains unclear. Patients are known to suffer adverse effects from excessive iron accumulation. Our objective was to develop a physiologically based pharmacokinetic (PBPK) model of iron in mice and validate its application for predicting iron disposition in rats and humans. Previously published data on iron were collected for constructing the PBPK model of iron in mice, and then extrapolated to rats and humans based on physiologically and chemically specific parameters relevant to each species. The PBPK model characterized the distribution of iron in mice successfully. The model based on extrapolation to rats accurately simulated the ferric carboxymaltose (FCM) PK profiles in rat tissues. Similarly, the observed and simulated serum PK of FCM in humans were in reasonable agreement. This mechanistic whole-body PBPK model is useful for understanding and predicting iron effects on different species. It also establishes a foundation for future research that incorporates iron kinetics and biodistribution, along with related clinical experiments. This approach could lead to the development of effective and personalized iron deficiency anemia treatments., Competing Interests: Declarations. Ethics approval and consent to participate: No ethical approval is required for this study. Consent for publication: All authors have agreed with publication of the manuscript. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Stable iron isotope techniques are critical for developing strategies to combat iron deficiency anemia, a leading cause of global disability. There are four primary stable iron isotope methods to assess ferrokinetics in humans. (i) The fecal recovery method applies the principles of a metabolic balance study but offers enhanced accuracy because the amount of iron isotope present in feces can be directly traced back to the labeled dose, distinguishing it from endogenous iron lost in stool from shed intestinal cells. (ii) In the plasma isotope appearance method, plasma samples are collected for several hours after oral dosing to evaluate the rate, quantity, and pattern of iron absorption. Key metrics include the time of peak isotope concentration and the area under the curve. (iii) The erythrocyte iron incorporation method measures iron bioavailability (absorption and erythrocyte iron utilization) from a whole blood sample collected 2 weeks after oral dosing. Simultaneous administration of oral and intravenous tracers allows for separate measurements of iron absorption and iron utilization. These three methods determine iron absorption by measuring tracer concentrations in feces, serum, or erythrocytes after administration of a tracer. In contrast, (iv) in iron isotope dilution, an innovative new approach, iron of natural composition acts as the tracer, diluting an ad hoc modified isotopic signature obtained via prior isotope administration and equilibration with body iron. This technique enables highly accurate long-term studies of iron absorption, loss, and gain. This review discusses the application of these kinetic methods and their potential to address important questions in hematology and iron biology., (© 2024. The Author(s).)

Purpose: Poor bioavailability may contribute to iron deficiency among children in high-resource countries, but iron bioavailability of Australian pre-schooler diets is unknown. This study aimed to estimate the bioavailability of Australian pre-schooler iron intakes across the day and by eating occasions to identify optimal timing for intervention, by using five previously developed algorithms, and to estimate the proportion of children with intakes of absorbable iron below the requirements., Methods: Dietary data of children aged 2 to < 6 y (n = 812) from the 2011-12 National Nutrition and Physical Activity Survey were collected via two 24-h recalls. Usual food and nutrient intakes were estimated via Multiple Source Method. Phytate, polyphenol, and heme iron values were sourced from international databases or the literature. Five previously published algorithms were applied to observed dietary data to estimate iron bioavailability and calculate the prevalence of children with intakes of absorbable iron below requirements., Results: Pre-schooler daily iron bioavailability was low (2.7-10.5%) and corresponded to intakes of 0.18-0.75 mg/d of absorbable iron. The proportion of children with inadequate intakes of absorbable iron ranged between 32 and 98%. For all eating occasions, dinner offered iron of the greatest bioavailability (4.2-16.4%), while iron consumed at breakfast was of the lowest bioavailability (1.2-5.6%)., Conclusion: Future strategies are required to improve intakes of bioavailable iron for pre-schoolers to prevent the risk of deficiency. These strategies could include the encouragement of concomitant consumption of enhancers of iron absorption with iron-rich sources, particularly at breakfast., (© 2024. The Author(s).)

Iron deficiency remains a top nutrient deficiency worldwide. Iron chlorophyllin (IC), a compound structurally analogous to heme, utilizes the protoporphyrin ring of chlorophyll to bind iron. IC has previously been shown to deliver more iron to Caco-2 cells than FeSO 4 , the most common form prescribed for supplementation. However, previous test conditions used digestive conditions outside of those observed in humans. This study sought to assess IC bioaccessibility and Caco-2 cell uptake using physiologically relevant digestive solutions, pH, and incubation time, as compared to other iron sources (i.e., FeSO 4 , and hemoglobin (Hb)). Co-digestion with ascorbic acid (AA) and albumin was also investigated. Following gastric, duodenal, and jejunal digestion, IC-bound iron was less bioaccessible than iron delivered as FeSO 4 , and IC-bound iron was less bioaccessible than Hb-bound iron. IC-bound iron bioaccessibility was not affected by AA and was enhanced 2x when co-digested with a low dose of albumin. However, Caco-2 cell incubation with IC-containing digesta increased cell ferritin 2.5x more than FeSO 4 alone, and less than Hb. IC with AA or with 400 mg albumin also increased cell ferritin more than IC alone, with the greatest increases observed following incubation of digesta containing IC + AA + 400 mg albumin. These results suggest IC can serve as an improved source of iron for supplementation as compared to FeSO 4. These results also support further in vivo investigations of IC-based iron delivery in populations at risk of iron deficiency., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Common beans (Phaseolus vulgaris L.) are among the most important legumes for human nutrition. The aim of the present study was to characterize the composition and in vitro bioaccessibility of tocochromanols, carotenoids, and iron from 14 different landraces and 2 commercial common bean varieties. Phytic acid, dietary fiber, and total (poly)phenolic content were determined as factors that can modify the bioaccessibility of the studied compounds. Two carotenoids were identified, namely lutein (4.6-315 ng/g) and zeaxanthin (12.2-363 ng/g), while two tocochromanols were identified, namely γ-tocopherol (2.62-18.01 µg/g), and δ-tocopherol (0.143-1.44 µg/g). The iron content in the studied samples was in the range of 58.7-144.2 µg/g. The contents of carotenoids, tocochromanols, and iron differed significantly among the studied samples but were within the ranges reported for commercial beans. After simulated gastrointestinal digestion, the average bioaccessibility of carotenoids was 30 %, for tocochromanols 50 %, and 17 % for iron. High variability in the bioaccessible content yielded by the bean varieties was observed. Dietary fiber, phytic acid and total (poly)phenol contents were negatively correlated with the bioaccessibility of carotenoids, while iron bioaccessibility was negatively correlated with the total (poly)phenol content. The principal component analysis indicated that the bioaccessibility of lutein was the main variable involved in class separations. The composition of the food matrix plays an important role in the bioaccessibility of carotenoids, tocochromanols and iron from cooked beans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Previous studies showed that pre- and probiotics may enhance iron absorption. Probiotics combined with prebiotics (synbiotics), including human-identical milk oligosaccharides (HiMOs), are commonly added to infant and follow-up formula (FUF). Whether these additions enhance iron absorption from iron-fortified commercial milk formula is uncertain., Objectives: We determined the effect of adding 1) a synbiotic [galacto-oligosaccharide [GOS] + Limosilactobacillus reuteri (L. reuteri)] or 2) the HiMO 2'-fucosyllactose (2'FL) to iron-fortified FUF on iron absorption in young Thai children., Methods: In a randomized, controlled, single-blinded (participants) crossover study, 82 Thai children aged 8-14 mo were enrolled to consume single servings (235 mL) of FUF with isotopically labeled ferrous sulfate (2.2 mg iron) with 1) the synbiotic (400 mg/100 mL GOS and L. reuteri DSM 17938), 2) the HiMO 2'FL (100 mg/100 mL), and 3) without synbiotic and 2'FL (control) in random order and a 3-d washout period between administrations. Fractional iron absorption [FIA (%)] was assessed by measuring erythrocyte incorporation of isotopic labels 14 d (n = 26) and 28 d (n = 76) after consumption of the last test FUF., Results: Median (IQR) FIA from iron-fortified FUF with the synbiotic [8.2 (5.2, 12.9)%] and with 2'FL [8.4 (5.5, 14.1)%] did not differ from the control FUF [8.1 (4.8,14.7)%] (synbiotic compared with control, P = 0.24; 2'FL compared with control, P = 0.95). FIA from all FUF did not differ when measured after 14 and 28 d of erythrocyte incorporation (Time, P = 0.368; FUF, P = 0.435; Time × FUF, P = 0.937). Fecal pH and hemoglobin were negatively associated with FIA., Conclusions: In young Thai children, the addition of a synbiotic (GOS + L. reuteri) or 2'FL to iron-fortified FUF did not impact FIA from a single serving. The study was registered at clinicaltrials.gov as NCT04774016., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The original aim of the study was to determine, in a double-blind 3-arm crossover human trial (n = 7), the effect of supplemental levels of iron (25 mg) and zinc (30 mg) on β-carotene (synthetic) bioavailability (10 h postprandial). However, despite the high dose of supplemental β-carotene (15 mg) consumed with the high fat (18 g), dairy-based breakfast test meal, there was a negligible postprandial response in plasma and triglyceride rich fraction β-carotene concentrations. We then systematically investigated the possible reasons for this low bioavailability of β-carotene., Methods: We determined (1) if the supplemental β-carotene could be micellised and absorbed by epithelial cells, using a Caco-2 cell model, (2) if the fat from the test meal was sufficiently bioavailable to facilitate β-carotene bioavailability, (3) the extent to which the β-carotene could have been metabolised and converted to retinoic acid/retinol and (4) the effect of the test meal matrix on the β-carotene bioaccessibility (in vitro digestion) and Caco-2 cellular uptake., Results: We found that (1) The supplemental β-carotene could be micellised and absorbed by epithelial cells, (2) the postprandial plasma triacylglycerol response was substantial (approximately 75-100 mg dL -1 over 10 h), indicating sufficient lipid bioavailability to ensure β-carotene absorption, (3) the high fat content of the meal (approximately 18 g) could have resulted in increased β-carotene metabolism, (4) β-carotene bioaccessibility from the dairy-based test meal was sixfold lower (p < 0.05) than when digested with olive oil., Conclusion: The low β-carotene bioavailability is probably due to a combination of the metabolism of β-carotene to retinol by BCMO1 and interactions of β-carotene with the food matrix, decreasing the bioaccessibility., Trail Registration: The human trail was retrospectively registered (ClinicalTrail.gov ID: NCT05840848)., (© 2024. The Author(s).)

Purpose: Iron absorption in sickle cell anemia (SCA) remains unclear and studies in adults with SCA are scarce. The aim of this study was to evaluate the iron absorption SCA adults and its association with iron status and hepcidin concentration., Methods: SCA patients (n = 13; SCA total ) and control participants (n = 10) ingested an oral stable iron isotope ( 57 Fe). Iron absorption was measured by inductively coupled plasma mass spectrometry (ICP-MS) 14 days after isotope administration. Patients with ≥ 1000 ng/mL serum ferritin were considered to present iron overload (IO) (SCAio+; n = 3) and others classified without IO (SCAio-; n = 10)., Results: Iron absorption in the control group ranged from 0.3 to 26.5% (median = 0.9%), while it varied from 0.3 to 5.4% in SCAio+ (median = 0.5%) and from 0.3 to 64.2% in the SCAio- (median = 6.9%). Hepcidin median values were 14.1 ng/mL (3.0-31.9 ng/mL) in SCAio-, 6.2 ng/mL (3.3-7.8 ng/mL) in SCAio + and 6.2 ng/mL (0.6-9.3 ng/mL) in control. Iron absorption was associated with ferritin level (r = - 0.641; p = 0.018) and liver iron concentration (LIC; r = - 0.786; p = 0.036) in the SCA total group., Conclusion: Our data suggest that SCAio- individuals may be at risk of developing primary IO. Simultaneously, secondary IO may induce physiological adaptation, resulting in reduced iron absorption. Further studies evaluating intestinal iron absorption using larger sample sizes should be conducted to help establish a safe nutrition approach to be adopted and to ensure the security of food-fortifying public policies for these patients., Trial Registration: This trial was registered at www.ensaiosclinicos.gov.br (Identifier RBR-4b7v8pt)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Iron is an essential mineral that supports biological functions like growth, oxygen transport, cellular function, and hormone synthesis. Insufficient dietary iron can lead to anemia and cause fatigue, cognitive impairment, and poor immune function. Animal-based foods provide heme iron, which is more bioavailable to humans, while plant-based foods typically contain less bioavailable non-heme iron. Edible insects vary in their iron content and may have heme or non-heme forms, depending on their diet. Edible insects have been proposed as a protein source that could address issues of food insecurity and malnutrition in low resource contexts; therefore, it is important to understand the bioavailability of iron from insect-based foods. In this study, we used Inductively Coupled Plasma and Mass Spectrometry (IPC-MS) and Caco-2 cell culture models to compare the soluble and bioavailable iron among five different lab-produced tempeh formulations featuring Tenebrio molitor (mealworm) with their non-fermented raw ingredient combinations. Finally, we compared the iron bioavailability of a mealworm tempeh with two sources of conventional beef (ground beef and sirloin steaks) and two commercially available plant-based meat alternatives. The results show that while plant-based meat alternatives had higher amounts of soluble iron, particularly in the Beyond Burger samples, the fermented mealworm-based tempeh had greater amounts of bioavailable iron than the other samples within the set. While all the samples presented varying degrees of iron bioavailability, all products within the sample set would be considered good sources of dietary iron.

The nutritional quality of plant-based meat analogues compared to traditional meat products has been questioned in recent commentary, particularly in relation to protein quality and micronutrient bioavailability. However, the attributes of specific products within this category are unclear. We therefore undertook a comprehensive assessment of the compositional and functional attributes of v2food ® (Sydney, Australia) plant-based mince, including an assessment of the effects of reformulation, including the addition of amino acids, ascorbic acid, and different forms of elemental iron. The protein digestibility and protein quality of v2food ® plant-based mince were comparable to beef mince in the standardized INFOGEST system, and favourable effects on microbiota composition and short-chain fatty acid (SCFA) production were demonstrated in an in vitro digestion system. The use of ferrous sulphate as an iron source improved in vitro intestinal iron absorption by ~50% in comparison to other forms of iron ( p < 0.05), although levels were ~3-fold lower than beef mince, even in the presence of ascorbic acid. In conclusion, the current study identified some favourable nutritional attributes of plant-based v2food ® mince, specifically microbiota and SCFA changes, as well as other areas where further reformulation could be considered to further enhance the bioavailability of key nutrients. Further studies to assess the effect of plant-based meat analogues on health measures in vivo will be important to improve knowledge in this area.

Background: Currently available intravenous iron preparations are not ideal, either because of safety concerns or dose limitations. We investigated the safety and pharmacokinetics of ferumoxytol, a new iron replacement therapy, in normal subjects and hemodialysis patients. Methods: In a randomized, double-blind, ascending-dose study in normal volunteers (n = 41), 6 subjects received placebo, and 8 subjects each received ferumoxytol, at 1, 2 or 4 mg iron/kg, injected at 60 mg iron/min. The remaining subjects received 4 mg iron/kg at injection rates of 90 (n = 3), 180 (n = 3) or 1,800 mg iron/min (n = 5). In the second, open-label, ascending-dose study, 20 hemodialysis patients received 125 or 250 mg of iron over 5 min. Results: In normal subjects, the blood half-life of ferumoxytol increased with increasing dose from 9.3 to 14.5 h (p < 0.05) but not with increasing rate of injection. The drug half-life in hemodialysis patients was similar to normal subjects. Ferumoxytol was not removed with hemodialysis. Serum iron (p < 0.001), transferrin saturation (p < 0.001) and ferritin increased in both populations. No serious adverse events were attributable to ferumoxytol. Conclusion: Ferumoxytol was well tolerated in this study. Its pharmacokinetic properties and simplicity of administration suggest that it will be an attractive form of iron replacement therapy. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Objective: Anemia caused by iron depletion is common in patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) patients. To maintain the iron levels, external administration of iron is essential. Ferric pyrophosphate citrate (FPC) is a novel, water-soluble complex iron salt. The present study was conducted to evaluate the pharmacokinetic (PK) parameters and safety of FPC in adult healthy Chinese subjects and patients with CKD-5HD., Methods: Two open-label, single-center studies were conducted in healthy subjects and patients with CKD-5HD. Healthy subjects received a single intravenous dose of 6.5 mg FPC solution, while CKD-5HD patients were randomized to two different sequences of FPC administration at two sequential hemodialysis (HD) treatments (dose 1 and dose 2). Patients received 27.2 mg of FPC at a dialysate concentration of 95 μg/L for 4 h or a single 6.5 mg dose of FPC administered intravenously via the pre-dialyzer blood circuit. The primary objective was to determine the PK parameters of total serum iron (Fe tot ), while the secondary objective was the safety of the FPC solution. PK parameters were calculated using Phoenix WinNonlin 8.1 and other parameters were analyzed using SAS 9.4 software. Comparison between HD dose 2 and HD dose 1 was performed using the Wilcoxon rank-sum test and analysis of variance (ANOVA)., Results: A total of 14 healthy subjects with a mean age of 30.8 ± 5.92 years and 12 HD patients with a mean age of 54.3 ± 16.47 years were included. In healthy subjects, the peak serum concentration was reached at the end of infusion of FPC, with an adjusted mean maximum concentration (C max, ) of 33.46 ± 4.83 μmol/L at a mean time to reach C max (T max ) of 4.09 ± 0.19 h. In patients with CKD-5HD, the adjusted mean C max of HD dose 2 was 25.37 ± 4.30 μmol/L at a T max, of 3.09 ± 0.32 h, whereas the C max, of HD dose 1 was 24.59 ± 4.77 μmol/L at a T max, of 3.96 ± 0.26 h. The Fe tot concentration-time curves were observed to be similar for both administration methods (HD doses 1 and 2), while the PK parameters differed significantly for T max (p = 0.001; baseline correction) and area under the concentration-time curve from time zero to time t (AUC t ) [p = 0.031 for cycle variance; without baseline correction] between HD doses 1 and 2. The geometric mean ratios (HD dose 1/HD dose 2) for C max and AUC t were within the 85-125% range (C max 96.56%; AUC t 96.07%). A total of three and two incidences of adverse events were reported in healthy subjects and patients with CKD-5HD, respectively., Conclusion: FPC showed a good PK and safety profile and hence can be used as maintenance therapy for patients with CKD-5HD by choosing a better method of administration based on clinical feasibility and requirement., Clinical Trial Registration: CTR20181113 and CTR20181119., (© 2022. The Author(s).)

Un-complexed polynuclear ferric oxyhydroxide cannot be administered safely or effectively to patients. When polynuclear iron cores are formed with carbohydrates of various structures, stable complexes with surface carbohydrates driven by multiple interacting sites and forces are formed. These complexes deliver iron in a usable form to the body while avoiding the serious adverse effects of un-complexed forms of iron, such as polynuclear ferric oxyhydroxide. The rate and extent of plasma clearance and tissue biodistribution is variable among the commercially available iron-carbohydrate complexes and is driven principally by the surface characteristics of the complexes which dictate macrophage opsonization. The surface chemistry differences between the iron-carbohydrate complexes results in significant differences in in vivo pharmacokinetic and pharmacodynamic profiles as well as adverse event profiles, demonstrating that the entire iron-carbohydrate complex furnishes the pharmacologic action for these complex products. Currently available physicochemical characterization methods have limitations in biorelevant matrices resulting in challenges in defining critical quality attributes for surface characteristics for this class of complex nanomedicines.

Background: Discrepancies are present in the findings from clinical trials evaluating a physiological role of iron status in the lead-exposed population., Objective: The purpose of this article was to summarize the current understanding of cellular mechanisms of lead toxicity and present a comprehensive review of existing clinical trials related to associations of lead poisoning and iron status. Although an association of iron metabolism pathways that are affected by lead intoxication has been studied, there are still aspects that remain to be elucidated. The existence of additional Pb uptake pathways besides DMT1 transporter-mediated is postulated to non-specifically regulate lead absorption., Methods: Authors performed a systematic search of PubMed, EMBASE® and Web of Science databases to identify studies that reported an association between health risks of non-organic lead that are associated with iron status markers as possible effect modifier., Results: There were 58 studies that met the pre-defined inclusion criteria for the systematic review. There is a strong body of evidence supporting the hypothesis that alleviated blood lead level can be correlated with a reduced body iron store and increasing the risk of anemia. This association is of a high significance in cases of a young adolescent, weaker in groups of older children and often without a statistical significance in adults., Discussion: Discrepancies in the observations may result from different specificities of lead absorption pathways in children and adults, as well as the power of the statistical tests in varying population sizes. It may be assumed that the extent of iron deficits coupled together with source, timing, and severity of lead exposure, significantly influence the correlation between these factors. Some of the intervention programs of counteracting lead poisoning by iron supplementation proved to be effective and may be a promising prevention strategy for the exposed population., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Iron-based nanoparticles have attracted much attention because of their ability to induce ferroptosis via a catalyzing Fenton reaction and to further potentiate immunotherapy. However, current iron-based nanoparticles need to be used in cooperation with other treatments or be applied in a high dose for effective therapy because of their low reactive oxygen species production efficacy. Here, we synthesized ultrasmall single-crystal Fe nanoparticles (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of an Fe 3 O 4 shell and the exposure of the Fe(0) core. The bcc-USINPs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. Intravenous injection of iRGD-bcc-USINPs at three doses of 1 mg/kg could effectively suppress the tumor growth, promote the maturation of dendritic cells, and trigger the adaptive T cell response. Combined with programmed death-ligand 1 (PD-L1) immune checkpoint blockade immunotherapy, the iRGD-bcc-USINP-mediated ferroptosis therapy greatly potentiated the immune response and developed strong immune memory. In addition, these USINPs were quickly renal excreted with no side effects in normal tissues. These iRGD-bcc-USINPs provide a simple, safe, effective, and selectively tumor-responsive Fe(0) delivery system for ferroptosis-based immunotherapy.

Although Zhusha Anshen Pill (ZSASP) is a commonly used traditional prescription for insomnia, the safety of cinnabar in the formula has always been controversial since its initial application in medical fields. Here, we developed a new prescription, Tieshuang Anshen Prescription (TSASP), by improving ZSASP with Fe 2+ instead of Hg 2+ . Besides, TSASP was further optimized by establishing and testing the HPLC fingerprint and its sedative-hypnotic effect of formulas with different compatibility ratios and performing correlation spectrum analysis. The safety of TSASP was also evaluated by HE staining of liver and kidney. In addition, a validated and robust UHPLC-MS/MS method was established to demonstrate the pharmacokinetic characteristics of berberine, palmatine, jatrorrhizine, ligustilide, catalpol, loganin, liquiritin and liquiritigenin after oral administration of TSASP. Our study originally provides a new non-toxic prescription, TSASP, with better sedative-hypnotic effect in comparison with ZSASP, revealing that Fe 2+ could replace Hg 2+ to eliminate its toxicity and play a sedative role. Meanwhile, we believe that our pharmacokinetics results may contribute valuable reference to both TSASP's specific mechanism of action and its further clinical efficacy and effectiveness research., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This work presents new findings on the nutritional quality of recently introduced biofortified and non-biofortified cowpea cultivars as well as some common beans. ICP-MS was used for the measurements. Biofortified cowpea cultivars showed high levels of Fe and Zn, greater than 60 and 40 mg kg -1 dry weight, respectively. The in vitro digestion protocol enabled simultaneous evaluation of bioaccessibility and bioavailability. Fe levels in cowpea cultivars were ca. 2.5-fold higher than in common beans. Cowpea seeds also had higher Zn levels, reaching 50.1% bioaccessibility and 44.2% bioavailability. Cooking improved the availability of micronutrients in bean seeds. The cooked biofortified Aracê cowpea showed a high Zn bioavailability above 60%. Consumption of 50 g of Aracê would contribute 27% and 48% of the Fe and Zn DRI for 1-3-year-old children. The new cowpea cultivars biofortified are a potential vehicle for improving the Fe and Zn status in groups in which the micronutrient deficiency is prevalent., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There has been an increase in the identification of cases of coal workers' pneumoconiosis (CWP) in recent years around the world. While there are a range of possible explanations for this, studies have implicated the pyrite content of coal as a key determinant of CWP risk. However, experimental studies to support this link are limited. The aim of this study was to assess the association between the pyrite content, and subsequent release of bioavailable iron, in coal particles and the response of lung cells involved in the pathogenesis of CWP (epithelial cells, macrophages and fibroblasts). Using real-world Australian coal samples, we found no evidence of an association between the pyrite content of the coal and the magnitude of the detrimental cell response. We did find evidence of an increase in IL-8 production by epithelial cells with increasing bioavailable iron (p = 0.01), however, this was not linked to the pyrite content of the coal (p = 0.75) and we did not see any evidence of a positive association in the other cell types. Given the lack of association between the pyrite content of real-world coal particles and lung cell cytotoxicity (epithelial cells and macrophages), inflammatory cytokine production (epithelial cells, macrophages and fibroblasts), and cell proliferation (fibroblasts) our data do not support the use of coal pyrite content as a predictor of CWP risk.

Chlorophyll is the vivid chromophore which imparts the green color to plant leaves, and is consumed by humans through green vegetables. The basic porphyrin structure of chlorophyll binds magnesium in plants, but can bind different divalent metals (e.g., copper, zinc, iron) facilitated by food processing techniques and/or chemical synthesis. This review covers the known elements of chlorophyll and metallo-chlorophyll absorption, distribution, metabolism, excretion in vitro and in vivo. The review discusses what is understood about the ability of these novel metallo-chlorophyll derivatives to deliver essential metals. This review also detail chlorophyll and metallo-chlorophyll toxin binding properties which largely occur during digestion, focusing on toxins including dioxins, heterocyclic aromatic amines, polyaromatic hydrocarbons, and aflatoxin. Finally, the article highlights the gaps in the understanding of the metabolism and metal and toxin-binding bioactivity of this family of molecules., (© 2021 Wiley-VCH GmbH.)

Iron is an essential micronutrient for life. In mammals, dietary iron is absorbed primarily in the small intestine. Currently, the impacts of dietary iron on the taxonomic structure and function of the gut microbiome and reciprocal effects on the animal host are not well understood. Here, we establish a mouse model of low-iron challenge in which intestinal biomarkers and reduced fecal iron reveal iron stress while serum iron and mouse behavioral markers indicate maintenance of iron homeostasis. We show that the diversity of the gut microbiome in conventional C57BL/6 mice changes dramatically during 2 weeks on a low-iron diet. We also show the effects of a low-iron diet on microbiome diversity are long lasting and not easily recovered when iron is returned to the diet. Finally, after optimizing taxon association methods, we show that some bacteria are unable to fully recover after the low-iron challenge and appear to be extirpated from the gut entirely. In particular, operational taxonomic units (OTUs) from the Prevotellaceae and Porphyromonadaceae families and Bacteroidales order are highly sensitive to low-iron conditions, while other seemingly insensitive OTUs recover. These results provide new insights into the iron requirements of gut microbiome members and add to the growing understanding of mammalian iron cycling. IMPORTANCE All cells need iron. Both too much and too little iron lead to diseases and unwanted outcomes. Although the impact of dietary iron on human cells and tissues has been well studied, there is currently a lack of understanding about how different levels of iron influence the abundant and diverse members of the human microbiome. This study develops a well-characterized mouse model for studying low-iron levels and identifies key groups of bacteria that are most affected. We found that the microbiome undergoes large changes when iron is removed from the diet but that many individual bacteria are able to rebound when iron levels are changed back to normal. That said, a select few members, referred to as iron-sensitive bacteria, seem to be lost. This study begins to identify individual members of the mammalian microbiome most affected by changes in dietary iron levels., (Copyright © 2021 Coe et al.)

Background: Beta-lactoglobulin (BLG) is a bovine lipocalin in milk with an innate defense function. The circumstances under which BLG is associated with tolerance of or allergy to milk are not understood., Objective: Our aims were to assess the capacity of ligand-free apoBLG versus loaded BLG (holoBLG) to protect mice against allergy by using an iron-quercetin complex as an exemplary ligand and to study the molecular mechanisms of this protection., Methods: Binding of iron-quercetin to BLG was modeled and confirmed by spectroscopy and docking calculations. Serum IgE binding to apoBLG and holoBLG in children allergic to milk and children tolerant of milk was assessed. Mice were intranasally treated with apoBLG versus holoBLG and analyzed immunologically after systemic challenge. Aryl hydrocarbon receptor (AhR) activation was evaluated with reporter cells and Cyp1A1 expression. Treated human PBMCs and human mast cells were assessed by fluorescence-activated cell sorting and degranulation, respectively., Results: Modeling predicted masking of major IgE and T-cell epitopes of BLG by ligand binding. In line with this modeling, IgE binding in children allergic to milk was reduced toward holoBLG, which also impaired degranulation of mast cells. In mice, only treatments with holoBLG prevented allergic sensitization and anaphylaxis, while sustaining regulatory T cells. BLG facilitated quercetin-dependent AhR activation and, downstream of AhR, lung Cyp1A1 expression. HoloBLG shuttled iron into monocytic cells and impaired their antigen presentation., Conclusion: The cargo of holoBLG is decisive in preventing allergy in vivo. BLG without cargo acted as an allergen in vivo and further primed human mast cells for degranulation in an antigen-independent fashion. Our data provide a mechanistic explanation why the same proteins can act either as tolerogens or as allergens., (Copyright © 2020. Published by Elsevier Inc.)

We report the first measurements of long-term iron absorption and loss during iron supplementation in African children using a stable isotope of iron ( 57 Fe). After uniform labelling of body iron with 57 Fe, iron absorption is proportional to the rate of decrease in the 57 Fe tracer concentration, while iron loss is proportional to the rate of decrease in the 57 Fe tracer amount. Anaemic Gambian toddlers were given 2 mg 57 Fe orally to equilibrate with total body iron over 8-11 months. After assignment to the positive control arm of the HIGH study, 22 toddlers consumed a micronutrient powder containing 12 mg iron for 12 weeks followed by 12 weeks without iron supplementation. Their daily iron absorption increased 3·8-fold during the iron supplementation period compared to the control period [median (interquartile range, IQR): 1·00 (0·82; 1·28) mg/day vs. 0·26 (0·22; 0·35) mg/day; P = 0·001]. Unexpectedly, during the supplementation period, daily iron loss also increased by 3·4-fold [0·75 (0·55; 0·87) mg/day vs. 0·22 (0·19; 0·29) mg/day; P = 0·005]. Consequently, most (~72%) of the absorbed iron was lost during supplementation. Long-term studies of iron absorption and loss are a promising and accurate method for assessing and quantifying long-term iron balance and may provide a reference method for evaluating iron intervention programs in vulnerable population groups. This study was registered as ISRCTN 0720906., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

The objective of this study was to explore potential microbial mechanisms associated with how water management may alter soil Cd availability under changing pe + pH environments. Four water regimes, aerobic [70% MWHC] + dissolved oxygen, aerobic, continuous flooding, and continuous flooding + N 2 , were applied to Cd-contaminated soil. The results show that the anoxic treatments were effective in decreasing soil pe + pH and in turn decreased Cd availability and increased soil S and Fe availability relative to those of the aerobic treatments. The decreased pe + pH enriched some anaerobic microorganisms such as those in the families Anaerolineaceae and Geobacteraceae. Conversely, other families, such as Gemmatimonadaceae and Sphingomonadaceae, appeared to be sensitive biomarkers that responded to aerobic treatments. Bacterial community structure and network interactions were altered to strengthen bacterial responses to different pe + pH environments as indicated by phylogenetic molecular ecological network (pMEN) analysis. The majority of predicted functional categories, such as metabolism, cell motility, and membrane transport, were affected by different irrigation regimes as indicated by a functional gene profile analysis. The categories were related to important traits that facilitated acclimation of bacteria to their local environment with altered soil pe + pH. Structural equation models revealed that soil pe + pH contributed significantly to soil enzyme activities and differences in bacterial community and function, and consequently, was responsible for the variation of soil Cd availability and iron or sulfur reduction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The provision or restriction of select nutrients in an athlete's diet can elicit a variety of changes in fuel utilization, training adaptation, and performance outcomes. Furthermore, nutrient availability can also influence athlete health, with one key system of interest being iron metabolism. The aim of this review was to synthesize the current evidence examining the impact of dietary manipulations on the iron regulatory response to exercise. Specifically, we assessed the impact of both acute and chronic carbohydrate (CHO) restriction on iron metabolism, with relevance to contemporary sports nutrition approaches, including models of periodized CHO availability and ketogenic low CHO high fat diets. Additionally, we reviewed the current evidence linking poor iron status and altered hepcidin activity with low energy availability in athletes. A cohesive understanding of these interactions guides nutritional recommendations for athletes struggling to maintain healthy iron stores, and highlights future directions and knowledge gaps specific to elite athletes.

Background: Iron deficiency is a major public health concern in Ethiopia, where the traditional diet is based on tef injera. Iron absorption from injera is low due to its high phytic acid (PA) content., Objectives: We investigated ways to increase iron absorption from FeSO4-fortified tef injera in normal-weight healthy women (aged 21-29 y)., Methods: Study A (n = 22) investigated the influence on fractional iron absorption (FIA) from FeSO4-fortified injera of 1) replacing 10% tef flour with whole wheat flour (a source of wheat phytase), or 2) adding an isolated phytase from Aspergillus niger. Study B (n = 18) investigated the influence on FIA of replacing FeSO4 in tef injera with different amounts of NaFeEDTA. In both studies, the iron fortificants were labeled with stable isotopes and FIA was calculated from erythrocyte incorporation of stable iron isotopes 14 d after administration., Results: In study A, the median (IQR) FIA from the 100% tef injera meal was 1.5% (0.7-2.8%). This increased significantly (P < 0.05) to 5.3% (2.4-7.1%) on addition of 10% whole wheat flour, and to 3.6% (1.6-6.2%) on addition of A. niger phytase. PA content of the 3 meals was 0.62, 0.20, and 0.02 g/meal, respectively. In study B, the median (IQR) FIA from the 100% tef injera meal was 3.3% (1.1-4.4%) and did not change significantly (P > 0.05) on replacing 50% or 75% of FeSO4 with NaFeEDTA., Conclusions: FIA from tef injera by young women was very low. NaFeEDTA was ineffective at increasing iron absorption, presumably due to the relatively low EDTA:Fe molar ratios. Phytate degradation, however, greatly increased during tef fermentation on addition of native or isolated phytases. Replacing 10% tef with whole wheat flour during injera fermentation tripled FIA in young women and should be considered as a potential strategy to improve iron status in Ethiopia., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Background: In adults, oral iron doses increase plasma hepcidin (PHep) for 24 h, but not for 48 h, and there is a circadian increase in PHep over the day. Because high PHep decreases fractional iron absorption (FIA), alternate day iron dosing in the morning may be preferable to consecutive day dosing. Whether these effects occur in infants is uncertain., Objective: Using stable iron isotopes in Kenyan infants, we compared FIA from morning and afternoon doses and from consecutive, alternate (every second day) and every third day iron doses., Methods: In prospective studies, we measured and compared FIA and the PHep response from 1) meals fortified with a 12-mg iron micronutrient powder given in the morning or afternoon (n = 22); 2) the same given on consecutive or alternate days (n = 21); and 3) a 12-mg iron supplement given on alternate days or every third day (n = 24)., Results: In total, 65.7% of infants were anemic. In study 1, PHep did not differ between morning and afternoon (P = 0.072), and geometric mean FIA[-SD, +SD](%) did not differ between the morning and afternoon doses [15.9 (8.9, 28.6) and 16.1 (8.7, 29.8), P = 0.877]. In study 2, PHep was increased 24 h after oral iron (P = 0.014), and mean FIA [±SD](%) from the baseline dose [23.3 (10.9)] was greater than that from the consecutive day dose (at 24 h) [20.1 (10.4); P = 0.042] but did not differ from the alternate day dose (at 48 h) [20.9 (13.4); P = 0.145]. In study 3, PHep was not increased 48 and 72 h after oral iron (P = 0.384), and the geometric mean FIA[-SD, +SD](%) from doses given at baseline, alternate days, and every third day did not differ [12.7 (7.3, 21.9), 13.8 (7.8, 24.2), and 14.8 (8.8, 24.8), respectively; P = 0.080]., Conclusions: In Kenyan infants given 12 mg oral iron, morning and afternoon doses are comparably absorbed, dosing on consecutive days increases PHep and modestly decreases iron absorption compared with alternate day dosing, and dosing on alternate days or every third day does not increase PHep or decrease absorption. This trial was registered at clinicaltrials.gov as NCT02989311 and NCT03617575., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Background: Although acute consumption of high doses of prebiotic galacto-oligosaccharides (GOS) increases fractional iron absorption (FIA) from ferrous fumarate (FeFum), it is uncertain if low doses of GOS have this effect. Furthermore, whether GOS improve iron absorption from other commonly used iron compounds and whether ascorbic acid (AA) enhances the effect of GOS on iron absorption from FeFum is unclear., Objectives: In iron-depleted women [serum ferritin (SF) <30 μg/L], we assessed: 1) whether the acute enhancing effect of GOS on FeFum is dose dependent; 2) if GOS would affect FIA from ferrous sulfate (FeSO4) or ferric pyrophosphate (FePP); and 3) if AA and GOS given together enhance FIA from FeFum to a greater extent compared with GOS alone., Methods: We recruited 46 women (mean age 22.0 y, mean BMI 21.3 kg/m2, median SF 17.1 μg/L), and measured FIA from 14 mg iron labeled with stable isotopes in the following conditions: 1) FIA from FeFum given with 3.5 g, 7 g GOS, and without GOS; 2) FIA from FeSO4 and FePP given with and without 15 g GOS; and 3) FIA from FeFum given with 7 g GOS with and without 93 mg AA. FIA was measured as erythrocyte incorporation of stable isotopes after 14 d. Comparisons were made using paired samples t-test or Wilcoxon rank sum test where appropriate., Results: Giving 7 g of GOS significantly increased FIA from FeFum (+26%; P = 0.039), whereas 3.5 g GOS did not (P = 0.130). GOS did not significantly increase FIA from FeSO4 (P = 0.998) or FePP (P = 0.059). FIA from FeFum given with GOS and AA was significantly higher compared with FeFum given with GOS alone (+30%; P <0.001)., Conclusions: In iron-depleted women, GOS does not increase FIA from FeSO4 or FePP, but it increases FIA from FeFum. Thus, a combination of FeFum and GOS may be a well-absorbed formula for iron supplements. The study was registered at clinicaltrials.gov as NCT03762148., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Background: Maternal iron absorption during pregnancy can be evaluated using RBC incorporation of orally administered stable iron isotope. This approach underestimates true maternal absorption of iron as it does not account for absorbed iron that is transferred to the fetus or retained within the placenta., Objective: Our objective was to re-evaluate maternal iron absorption after factoring in these losses and identify factors associated with iron partitioning between the maternal, neonatal, and placental compartments., Methods: This study utilized data from stable iron isotope studies carried out in 68 women during the third trimester of pregnancy. Iron status indicators and stable iron isotopic enrichment were measured in maternal blood, umbilical cord blood, and placental tissue when available. Factors associated with iron isotope partitioning between the maternal, neonatal, and placental compartments were identified., Results: On average, true maternal absorption of iron increased by 10% (from 19% to 21%) after accounting for absorbed iron present in the newborn (P < 0.001), and further increased by 7%, (from 39% to 42%, P < 0.001) after accounting for iron retained within the placenta. On average, 2% of recovered tracer was present in the placenta and 6% was found in the newborn. Net transfer of iron to the neonate was higher in women with lower total body iron (standardized β = -0.48, P < 0.01) and lower maternal hepcidin (standardized β = -0.66, P < 0.01). In women carrying multiple fetuses, neonatal hepcidin explained a significant amount of observed variance in net placental transfer of absorbed iron (R = 0.95, P = 0.03)., Conclusions: Maternal RBC iron incorporation of an orally ingested tracer underestimated true maternal iron absorption. The degree of underestimation was greatest in women with low body iron. Maternal hepcidin was inversely associated with maternal RBC iron utilization, whereas neonatal hepcidin explained variance in net transfer of iron to the neonatal compartment.These trials were registered at clinicaltrials.gov as NCT01019096 and NCT01582802., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Our previous studies have shown the existence of organophosphate hydrolase (OPH) as a part of the inner membrane associated Ton complex (ExbB/ExbD and TonB) of Sphingobium fuliginis. We now show its involvement in iron uptake by establishing direct interactions with ferric-enterobactin. The interactions between OPH and ferric-enterobactin were not affected even when the active site architecture is altered by substituting active site aspartate with either alanine or asparagine. Protein docking studies further substantiated these findings and predicted the existence of ferric-enterobactin binding site that is different from the catalytic site of OPH. A lysine residue (82K) found at the predicted ferric-enterobactin binding site facilitated interactions between OPH and ferric-enterobactin. Substitution of lysine with alanine did not affect triesterase activity, but it abrogated OPH ability to interact with both ferric-enterobactin and ExbD, strengthening further the fact that the catalytic site is not the site for binding of these ligands. In the absence of interactions between OPHK82A and ExbD, OPHK82A failed to target membrane in E. coli cells. The Sphingobium fuliginis TonB-dependent transport (SfTonBDT) system was reconstituted in E. coli GS027 cells generated by deleting the exbD and tonB genes. The E. coli GS030 cells having SfTonBDT system with OPH showed increased iron uptake. Such an increase was not seen in E. coli GS029, cells having SfTonBDT system generated either by omitting OPH or by including its variants, OPHD301A, OPHD301N suggesting a role for OPH in enhanced iron uptake., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Celiac disease (CD) is an autoimmune disorder characterized by intolerance to dietary gluten in genetically predisposed subjects. Iron deficiency anemia (IDA) is a common sign in CD, being the only abnormality in approximately 40% of celiac patients. A multifactorial etiology leads to IDA in CD. The two main causes are the villous atrophy of the mucosa at the site of iron absorption (the duodenum) and the resulting inflammation, which triggers the mechanism that leads to the anemia of chronic disease. Until now, it has been unclear why some patients with CD continue to have IDA despite a careful gluten-free diet (GFD) and the normalization of villous atrophy. Furthermore, some celiac patients are refractory to oral iron supplementation despite the healing of the mucosa, and they thus require periodic intravenous iron administration. The Marsh classification evaluates the degree of inflammation and villous atrophy, but it does not assess the possible persistence of ultrastructural and molecular alterations in enterocytes. The latter was found in CD in remission after adopting a GFD and could be responsible for the persistently reduced absorption of iron and IDA. Even in non-celiac gluten sensitivity, anemia is present in 18.5-22% of patients and appears to be related to ultrastructural and molecular alterations in intestinal microvilli. It is possible that a genetic component may also play a role in IDA. In this review, we evaluate and discuss the main mechanisms of IDA in CD and the possible causes of its persistence after adopting a GFD, as well as their therapeutic implications.

Iron deficiency in the human body is a global issue with an impact on more than two billion individuals worldwide. The most important functions ensured by adequate amounts of iron in the body are related to transport and storage of oxygen, electron transfer, mediation of oxidation-reduction reactions, synthesis of hormones, the replication of DNA, cell cycle restoration and control, fixation of nitrogen, and antioxidant effects. In the case of iron deficiency, even marginal insufficiencies may impair the proper functionality of the human body. On the other hand, an excess in iron concentration has a major impact on the gut microbiota composition. There are several non-genetic causes that lead to iron deficiencies, and thus, several approaches in their treatment. The most common methods are related to food fortifications and supplements. In this review, following a summary of iron metabolism and its health implications, we analyzed the scientific literature for the influence of iron fortification and supplementation on the gut microbiome and the effect of probiotics, prebiotics, and/or synbiotics in iron absorption and availability for the organism., Competing Interests: The authors declare no conflict of interest.

Australian Aboriginal populations have unacceptably high rates of bronchiectasis. This disease burden is associated with high rates of detection of pathogenic bacteria, particularly non-typeable Haemophilus influenzae (NTHi). While there is evidence to suggest that exposure to inorganic particulate matter (PM) is associated with worse respiratory infections, no studies have considered the direct effect of this PM on bacterial growth. Nine clinical isolates of pathogenic NTHi were used for this study. Isolates were exposed to two common iron oxides, haematite (Fe 2 O 3 ) or magnetite (Fe 3 O 4 ), or quartz (SiO 2 ), as the main constituents of environmental inorganic PM. NTHi isolates were exposed to PM with varying levels of heme to identify whether the response to PM was altered by iron availability. The maximal rate of growth and maximum supported growth were assessed. We observed that inorganic PM was able to modify the maximal growth of selected NTHi isolates. Magnetite and quartz were able to increase maximal growth, while haematite could both increase and suppress the maximal growth. However, these effects varied depending on iron availability and on the bacterial isolate. Our data suggest that inorganic PM may directly alter the growth of pathogenic NTHi. This observation may partly explain the link between exposure to high levels of crustal PM and chronic bacterial infection in Australian Aboriginals.

Black pepper ( Piper nigrum L.) has been employed in medicine (epilepsy, headaches, and diabetes), where its effects are mainly attributed to a nitrogen alkaloid called piperidine (1-(1-[1,3-benzodioxol-5-yl]-1-oxo-2,4 pentenyl) piperidine). Piperine co-administered with vitamins and minerals has improved its absorption. Therefore, this study aimed to describe the impact of the joint administration of iron (Fe) plus black pepper in physically active healthy individuals. Fe is a micronutrient that aids athletic performance by influencing the physiological functions involved in endurance sports by improving the transport, storage, and utilization of oxygen. Consequently, athletes have risk factors for Fe depletion, Fe deficiency, and eventually, anemia, mainly from mechanical hemolysis, gastrointestinal disturbances, and loss of Fe through excessive sweating. Declines in Fe stores have been reported to negatively alter physical capacities such as aerobic capacity, strength, and skeletal muscle recovery in elite athletes. Thus, there is a need to maintain Fe storage, even if Fe intake meets the recommended daily allowance (RDA), and Fe supplementation may be justified in physically active individuals, in states of Fe deficiency, with or without anemia. Females, in particular, should monitor their Fe hematological profile. The recommended oral Fe supplements are ferrous or ferric salts, sulfate, fumarate, and gluconate. These preparations constitute the first line of treatment; however, the high doses administered have gastrointestinal side effects that reduce tolerance and adherence to treatment. Thus, a strategy to counteract these adverse effects is to improve the bioavailability of Fe. Therefore, piperine may benefit the absorption of Fe through its bioavailability enhancement properties. Three research studies of Fe associated with black pepper have reported improvements in parameters related to the metabolism of Fe, without adverse effects. Although more research is needed, this could represent an advance in oral Fe supplementation for physically active individuals.

Iron (Fe) is an essential trace element. In daily veterinary practice, it plays a pivotal role e. g. due to its role in Fe deficiency anaemia. The bioavailability of Fe, for example for heme and hemoglobin synthesis, sets high demands on Fe homeostasis. The discovery of hepcidin as being an important regulative protein made a hormone-like regulation of the Fe metabolism evident. Hepcidin is synthesized by the liver and regulates the trans-membranous Fe-transporter ferroportin. An increase of hepcidin leads to a decrease of Fe export from the cell into the extracellular space, the consequence being an internalisation of Fe in the reticuloendothelial system as well as in mononuclear cells. Additionally, enteral Fe uptake decreases. The induction of hepatic hepcidin synthesis seems to be caused by high Fe- and transferrin concentrations in plasma. In addition to this, an increase of cytokines during inflammation similarly triggers hepatic hepcidin synthesis. This finding offers an explanation for the frequently observed decrease of Fe in serum/plasma during acute inflammation, the mechanism thus being termed as cytokine-hepcidin-link. Based on the fact that numerous pathogens require Fe for their own metabolism, internalisation of Fe into the intracellular compartment during inflammation has hence been categorised as being a part of the innate immunity. Iron supplementation, initiated by the veterinarian or the farmer, interferes with this regulation. Currently however, there is a lack of knowledge regarding the clinical and metabolic impacts of parenteral or oral Fe supplementation to farm animals. Therefore, the acquisition of added scientific data via prospective studies is warranted. In consequence, novel findings may lead to a reassessment of Fe supplementation strategies for ruminants, pigs and/or horses., Competing Interests: Die Autorin erklärt, dass keine geschützten finanziellen, beruflichen oder anderweitigen Interessen an einem Produkt oder einer Firma bestehen, welche die in dieser Veröffentlichung genannten Inhalte oder Meinungen beeinflussen könnten., (© Georg Thieme Verlag KG Stuttgart · New York.)

Although simultaneous supplementation with iron and folic acid is justified, the potential interactions between these micronutrients are unknown. The aim of this study was to determine the effects of oral iron and folic acid, administered together or separately, on iron concentration in tissues in rats with a deficiency of both these micronutrients. In the first stage of the experiment (28 days), 150 8-week-old female Wistar rats were randomly assigned to a control group (C; n = 30) fed the standard diet and to a study group (n = 120) fed a diet deficit in iron and folate. The study group was then randomly divided to four groups: D group fed a deficit diet, FE group fed a deficit diet with iron gluconate, the FOL group fed a deficit diet with folate acid, and the FEFOL group fed a deficit diet with iron gluconate and folate acid. After 2, 10, and 21 days of supplementation, ten animals from each group were killed. Morphological parameters were measured in whole blood. Iron concentration was assayed in serum, liver, spleen, pancreas, heart, and kidneys. Folic acid supplementation more significantly decreased iron concentrations in the pancreas and spleen than in the D group after 10 and 21 days of supplementation. Moreover, the combination of iron with folic acid markedly decreased iron levels in the liver and spleen, in comparison with iron alone, after 10 and 21 days of the experiment. In conclusion, folic acid affects iron status in female rats deficient in these micronutrients in moderate and long-term supplementation.

Purpose: A technological gap exists for the iron (Fe) fortification of difficult-to-fortify products, such as wet and acid food products containing polyphenols, with stable and bioavailable Fe. Fe picolinate, a novel food ingredient, was found to be stable over time in this type of matrix. The objective of this study was to measure the Fe bioavailability of Fe picolinate in a complementary fruit yogurt., Methods: The bioavailability of Fe picolinate was determined using stable iron isotopes in a double blind, randomized cross-over design in non-anemic Swiss women (n = 19; 25.1 ± 4.6 years). Fractional Fe absorption was measured from Fe picolinate (2.5 mg 57 Fe per serving in two servings given morning and afternoon) and from Fe sulfate (2.5 mg 54 Fe per serving in two servings given morning and afternoon) in a fortified dairy complementary food (i.e. yogurt containing fruits). Fe absorption was determined based on erythrocyte incorporation of isotopic labels 14 days after consumption of the last test meal., Results: Geometric mean (95% CI) fractional iron absorption from Fe picolinate and Fe sulfate were not significantly different: 5.2% (3.8-7.2%) and 5.3% (3.8-7.3%) (N.S.), respectively. Relative bioavailability of Fe picolinate versus Fe sulfate was 0.99 (0.85-1.15)., Conclusion: Therefore, Fe picolinate is a promising compound for the fortification of difficult-to-fortify foods, to help meet Fe requirements of infants, young children and women of childbearing age.

Background: The iron-based phosphate binders, sucroferric oxyhydroxide (SFOH) and ferric citrate (FC), effectively lower serum phosphorus in clinical studies, but gastrointestinal iron absorption from these agents appears to differ. We compared iron uptake and tissue accumulation during treatment with SFOH or FC using experimental rat models., Methods: Iron uptake was evaluated during an 8-h period following oral administration of SFOH, FC, ferrous sulphate (oral iron supplement) or control (methylcellulose vehicle) in rat models of anaemia, iron overload and inflammation. A 13-week study evaluated the effects of SFOH and FC on iron accumulation in different organs., Results: In the pharmacokinetic experiments, there was a minimal increase in serum iron with SFOH versus control during the 8-h post-treatment period in the iron overload and inflammation rat models, whereas a moderate increase was observed in the anaemia model. Significantly greater increases (P < 0.05) in serum iron were observed with FC versus SFOH in the rat models of anaemia and inflammation. In the 13-week iron accumulation study, total liver iron content was significantly higher in rats receiving FC versus SFOH (P < 0.01), whereas liver iron content did not differ between rats in the SFOH and control groups., Conclusions: Iron uptake was higher from FC versus SFOH following a single dose in anaemia, iron overload and inflammation rat models and 13 weeks of treatment in normal rats. These observations likely relate to different physicochemical properties of SFOH and FC and suggest distinct mechanisms of iron absorption from these two phosphate binders., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Iron deficiency (ID) is the most frequent nutritional deficiency in the whole population worldwide, and the second most common cause of anemia in the elderly. The prevalence of anemia is expecting to rise shortly, because of an ageing population. Even though WHO criteria define anemia as a hemoglobin serum concentration <12 g/dL in women and <13 g/dL in men, several authors propose different and specific cut-off values for the elderly. Anemia in aged subjects impacts health and quality of life, and it is associated with several negative outcomes, such as longer time of hospitalization and a higher risk of disability. Furthermore, it is an independent risk factor of increased morbidity and mortality. Even though iron deficiency anemia is a common disorder in older adults, it should be not considered as a normal ageing consequence, but a sign of underlying dysfunction. Relating to the molecular mechanism in Iron Deficiency Anemia (IDA), hepcidin has a key role in iron homeostasis. It downregulates the iron exporter ferroportin, inhibiting both iron absorption and release. IDA is frequently dependent on blood loss, especially caused by gastrointestinal lesions. Thus, a diagnostic algorithm for IDA should include invasive investigation such as endoscopic procedures. The treatment choice is influenced by the severity of anemia, underlying conditions, comorbidities, and the clinical state of the patient. Correction of anemia and iron supplementation should be associated with the treatment of the causal disease., Competing Interests: the authors declare no conflict of interest.

Zerovalent iron nanotechnologies are widely used for groundwater remediation and increasingly considered for advance oxidation treatment in drinking water applications. Iron nanoparticles have been detected in drinking water systems and considered for food fortification; therefore, the potential for human exposure through ingestion can be a concern. This study aimed to assess whether ingestion of iron nanoparticles from drinking water could be detected through flavor perception using in vitro salivary lipid oxidation as an indicator for metallic flavor perception. Ten female subjects, aged 29-59 years, donated saliva samples for use in the in vitro experiments. Test samples consisted of 1:1 mixture of saliva and bottled drinking water (control) and three treatment solutions, spiked with ferrous sulfate, stabilized zerovalent iron nanoparticles (nZVI), and an aggregated/microsized suspension of mixed zerovalent iron and microsized suspension of iron and iron oxide metal powder, (mZVI). Upon mixing, samples were subjected to 15 min incubation at 37 °C to resemble oral conditions. Salivary lipid oxidation (SLO) was measured in all samples as micromoles of thiobarbituric acid reactive substances (TBARS)/mg Fe. Exposure to iron in all three forms induced significant amount of SLO in all treatment samples as compared to the control ( p < 0.0001). The mean SLO levels were the highest in the ferrous treatment, followed by nZVI and mZVI treatments; the differences in the mean SLO levels were significant ( p < 0.05). The findings indicate that oral exposure to stabilized ZVI nanoparticles may induce sensory properties different from that of ferrous salt, likely predictive of diminished detection of metallic flavor by humans., Competing Interests: The author declares no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Background: Bouillon cubes are a potential vehicle for iron fortification. They are currently fortified with ferric pyrophosphate (FePP), which is known to be poorly absorbed. The objective of this study was to assess the iron absorption of Aspergillus oryzae grown in FePP (ASP-p) and compare it with FePP and ferrous sulfate (FeSO4)-fortified bouillon cubes., Methods: In 2 single-blinded, crossover studies, healthy women with serum ferritin concentrations <40 μg/L were randomly assigned to consume a rice-vegetable meal with iron-fortified chicken bouillon. Subjects in study I (n = 17, 18-26 y) consumed iron from both iron sources as 57FePP and 58ASP-p (intrinsically labeled with 58FePP) with a meal containing 4.2 mg of total iron provided for 3 d. Study II (n = 18, 18-29 y) was similar except that subjects consumed 57FeSO4 and 58ASP-p. Whole-blood stable isotope enrichment after 14 d was used to measure fractional iron absorption. Hemoglobin, hematocrit, serum ferritin, hepcidin, and serum C-reactive protein were analyzed at baseline and at 14 d. A t test was used to compare the mean differences in fractional absorptions within each study and baseline characteristics between studies., Results: Geometric mean (95% CI) fractional iron absorption of FePP [0.94% (0.63%, 1.40%)] was lower than ASP-p [2.20% (1.47%, 3.30%)] (P < 0.0001) in study I. In study II, ASP-p fractional absorption [2.98% (2.03%, 4.38%)] was lower than that of FeSO4 [9.88% (6.70%, 14.59%)] (P < 0.0001). Both ferritin (r = -0.41, P = 0.014) and hepcidin (r = -0.42, P = 0.01) concentrations were inversely correlated with ASP-p iron absorption. Fractional absorption of ASP-p was also positively correlated with FePP (r = 0.92, P < 0.0001) and FeSO4 (r = 0.52, P < 0.02) absorption., Conclusions: ASP-p-fortified bouillon provided 2.3-fold higher absorbable iron than the currently used FePP. Bouillon fortified with ASP-p may contribute sufficient bioavailable iron to meet the daily iron requirements in young women only if consumed with other iron-fortified staple foods. This trial was registered at clinicaltrials.gov as NCT03586245., (Copyright © The Author(s) 2020.)

Bouillon cubes are widely consumed and when fortified with iron could contribute in preventing iron deficiency. We report the development (part I) and evaluation (current part II) of a novel ferric phytate compound to be used as iron fortificant in condiments such as bouillon. Ferric pyrophosphate (FePP), is the compound of choice due to its high stability in foods, but has a modest absorption in humans. Our objective was to assess iron bioavailability from a novel iron fortificant consisting of ferric iron complexed with phytic acid and hydrolyzed corn protein (Fe-PA-HCP), used in bouillon with and without an inhibitory food matrix. In a randomised single blind, cross-over study, we measured iron absorption in healthy adult women (n = 22). In vitro iron bioaccessibility was assessed using a Caco-2 cell model. Iron absorption from Fe-PA-HCP was 1.5% and 4.1% in bouillon with and without inhibitory matrix, respectively. Relative iron bioavailability to FeSO 4 was 2.4 times higher than from FePP in bouillon (17% vs 7%) and 5.2 times higher when consumed with the inhibitory meal (41% vs 8%). Similar results were found in vitro. Fe-PA-HCP has a higher relative bioavailability versus FePP, especially when bouillon is served with an inhibitory food matrix.

Mycophenolic acid (MPA) is an immunosuppressive agent commonly prescribed during posttransplant periods for the prevention of acute and chronic rejection following organ transplantation. Compelling evidence has demonstrated a pivotal role of the exposure level of MPA in determining the rate of allograft rejection as well as the incidence of adverse outcomes, such as gastrointestinal complaints and myelosuppression. Because MPA has wide interindividual pharmacokinetic (PK) variability, the importance of maintaining the MPA concentration levels within its therapeutic range is clear. In addition, due to its complex PKs, MPA is prone to inadvertently develop PK drug-drug interactions (DDIs) with many agents, some of which are commonly used in organ transplant recipients. Failure to acknowledge such clinically significant PK DDIs between MPA and other coadministered drugs could potentially lead to devastating outcomes, ie, the occurrence of acute and chronic allograft rejection or the development of severe adverse events. The rationale to avoid concomitant use of certain drugs with MPA has been established; however, there is a lack of comprehensive literature to guide clinicians and medical professionals on the recognition and monitoring of potential PK DDIs when MPA is prescribed. In this article we comprehensively review, summarize, and discuss previous clinical studies that investigated the impact of coadministered drugs on the PK of MPA, with a major focus on the PK DDIs between MPA and commonly coadministered drugs., (© 2019, The American College of Clinical Pharmacology.)

Despite the great interest in RNA therapeutics, the development of a successful gene delivery process is still a major challenge. We propose an efficient nucleic acid entrapment into the mesopores of biocompatible nanoscaled metal-organic frameworks. Their rapid cellular uptake together with RNA protection and release led to a relevant in vitro gene activity.

Purpose: The aim of this study was to prepare zeolite/iron (III) oxide nanocomposites (zeolite/Fe 2 O 3 -NCs) as a smart fertilizer to improve crop yield and soil productivity., Methods: Zeolite/Fe 2 O 3 -NCs were successfully produced by loading of Fe 2 O 3 -NPs onto the zeolite surface using a quick green precipitation method. The production of zeolite/Fe 2 O 3 nanocomposites was performed under a mild condition using environmentally friendly raw materials as a new green chemistry method. The product was characterized using several techniques such as near and far Fourier-transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM) and transmission electron microscopy (TEM)., Results: The results confirmed the formation of Fe 2 O 3 -NPs with mean particle sizes of 1.45, 2.19, and 2.20 nm on the surface of the zeolite per amount of 4, 7 and 12 wt% Fe 2 O 3 -NPs, respectively. Such results indicated that the size of the Fe 2 O 3 -NPs did not significantly change when Fe amounts increased from 7 to 12 wt% for the zeolite/Fe 2 O 3 -NCs. In terms of medical applications, in vitro cell studies demonstrated that zeolites and zeolite/Fe 2 O 3 -NCs were generally non-toxic to human fibroblast cells and significantly pernicious to human malignant melanoma cells. From MTS cytotoxicity assays, the concentration of Fe 2 O 3 within the zeolite/Fe 2 O 3 -NCs that was effective at inhibiting the growth of malignant melanoma cells by 50% (the IC50 value) was ~14.9 wt%. The three types of nanocomposites were further tested as an iron smart nanofertilizer for the slow-release of iron ions., Conclusion: Advantages of this project include the production of non-toxic nanocomposites as a smart fertilizer to develop crops while the reaction involves the use of commercial and natural materials as low-cost raw materials with low energy usage due to a mild reaction condition, as well as the use of an environmentally friendly solvent (water) with no toxic residues., Competing Interests: The authors declare that they have no conflicts of interest in this work., (© 2020 Jahangirian et al.)

A poly(ethylene glycol)-based thermogel can capture an iron ion (Fe 3+ ) through a crown ether-like coordination bond between the oxygen atom and metal ions, thus, providing a sustained Fe 3+ -releasing system. Poly(ethylene glycol)-l-poly(alanine) thermogel was used in this study. The polypeptide forms a rather robust gel, and the degradation products are a neutral amino acid, which provides cyto-compatible neutral pH environments during the cell culture. During the heat-induced sol-to-gel transition at 37 °C, tonsil-derived mesenchymal stem cells (TMSCs) and iron ions were incorporated, leading to the formation of a three-dimensional matrix toward neuronal differentiation of the incorporated TMSCs. The initial concentration of the iron ions was varied between 0, 15, 30, and 60 mM. About 10% of the loaded iron ions was released over 21 days, which continuously supplied iron ions to the cells. The incorporation of iron ions not only increased the gel modulus at 37 °C from 107 to 680 Pa, but also promoted cell aggregation with a significant secretion of the cell adhesion signal of FAK. Expression of biomarkers related to the neuronal differentiation of TMSCs, including NFM, MAP2, GFAP, NURR1, NSE, and TUBB3, increased 4-35-fold at the mRNA level in the Fe 3+ -containing system compared to that of the system without Fe 3+ . Immunofluorescence studies also confirmed pronounced cell aggregation and a significant increase in neuronal biomarkers at the protein level. This study suggests that an iron ion-releasing thermogelling system can be a promising injectable scaffold toward neuronal differentiation of stem cells.

The present study analyzed the Peruvian scallop Argopecten purpuratus and its food sources for metal and fatty acid concentrations in order to determine spatial and temporal differences. Metals such as copper (Cu), manganese (Mn), and zinc (Zn) in gills and iron (Fe) and Zn in sediments were the most significant explaining factors for spatial differentiations (degree of contamination), while for fatty acids, it was C14:0, C15:0, C16:0 and C18:0 in A. purpuratus' muscle and in its food sources, which explained more temporal differences (El Niño-Southern Oscillation (ENSO) effect). Gills, digestive gland and intestine were the tissues where metal accumulation was the highest in A. purpuratus. Cd in digestive gland was always high, up to ∼250-fold higher than in other tissues, as previously reported in other bioindicator species for metal pollution. Fatty acids were good biomarkers when annual comparisons were performed, while metals when locations were compared. ENSO 2017 played an important role to disentangle A. purpuratus' biological conditions and food sources. A. purpuratus from Paracas locations mostly showed higher metal concentrations in gills and digestive glands, and lower fatty acid concentrations in muscle than those from Sechura and Illescas Reserved Zone., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

It is estimated that over 30% of the global population is anaemic, half of which is due to iron deficiency. The bioavailability of iron from vegetables is low and variable, and influenced by food composition and matrix. We have therefore determined the relative bioavailability of iron in five types of green vegetable, spinach, broccoli, savoy cabbage, curly kale and green pepper, by measuring the ferritin response in a simulated digestion/Caco-2 cell model. Savoy cabbage gave the highest ferritin response and analysis of the digest showed that the iron was present in low molecular weight fractions which contained glucose, fructose, organic acids and amino acids. The addition of fructose 1,6-biphosphate to the Caco-2 cells increased iron uptake 2-fold. These results demonstrate that cabbage was the best source of bioavailable iron out of the vegetables studied and suggest that the formation of complexes with fructose derivatives contribute to increase the iron bioavailability., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)