Iron-deficient Diet Research Articles

Pectin with Low Molecular Weight and High Degree of Esterification Increases Absorption of 58Fe in Growing Rats

Effects of pectins with different degrees of esterification (DE) and molecular weights (MW) on iron bioavailability were investigated in healthy growing rats by following erythrocyte incorporation of a dose of 58Fe. Rats were fed a control diet for 8 d and then deprived of food for 16 h. Two hours after the start of feeding iron-deficient diets, with or without pectin (80 g/kg diet), a dose of FeSO4 rich in 58Fe (60.28%) was intubated into the stomach; rats were then allowed to feed for an additional 4 h before withdrawal of food for 10 h. Rats were then fed iron-adequate diets for 9 d. The pectins differed in DE and MW, respectively, as follows: P-A (73%, 860,000), P-B (75%, 89,000), P-C (22%, 1,260,000) and P-D (24%, 114,000). Rats fed pectin-free diet with free access to food or restricted to the same quantity consumed by a respective pectin group served as controls. Iron absorption was 48% in the control group and 57% in rats fed P-B. Rats fed P-B had higher (P ≤ 0.05) serum iron, transferrin saturation, hematocrit and liver and spleen iron than the control group or the group fed P-C. These indices, except for transferrin saturation, were also higher in rats fed P-A and P-D compared with those fed P-C and controls, but to a lesser extent than in rats fed P-B. The data indicate that bioavailability of dietary non-heme iron was enhanced when pectin of low MW and high DE was added to the diet. This improvement was not evident with pectins having high MW and/or low DE.

Iron from Co-Encapsulation of Defatted Nannochloropsis Oceanica with Inulin Is Highly Bioavailable and Does Not Impact Wheat Flour Shelf Life or Sensorial Attributes.

Defatted green microalgae Nannochloropsis oceanica (DGM) is a rich source of bioavailable iron. However, its use in foods results in unacceptable color and taste development. Therefore, the purpose of this study was to investigate strategies to enhance the use of DGM in foods. DGM and inulin were encapsulated (EC) in an oil-in-water emulsion using high-pressure homogenization. To confirm iron bioavailability, C57BL/6 mice were fed an iron-deficient diet (ID) for 2 weeks. The mice were then fed one of the four diets: ID, ID + DGM (DGM), ID + EC (EC50 or EC100) for 4 weeks. To test the stability of DGM as an iron fortificant at two different fortification rates of 17.5 mg Fe/kg (50%) or 35 mg Fe/kg (100%), whole (DGM50/DGM100), encapsulated (EC50/EC100) and color-masked (CM50/CM100) DGM were added to wheat flour (WF) at two different temperatures: 20 °C and 45 °C and were examined for 30 days. Acceptability studies were conducted to determine sensory differences between rotis (Indian flat bread) prepared from WF/EC50/CM50/EC100. The mice consuming EC50/EC100 diets showed comparable iron status to DGM-fed mice, suggesting that encapsulation did not negatively impact iron bioavailability. Addition of EC to wheat flour resulted in the lowest Fe2+ oxidation and color change amongst treatments, when stored for 30 days. There were no differences in the overall liking and product acceptance of rotis amongst treatments at both day 0 and day 21 samples. Our results suggest that EC50 can be effectively used as an iron fortificant in WF to deliver highly bioavailable iron without experiencing any stability or sensory defects, at least until 30 days of storage.

Anemia Is Related to Iron Deficiency and Inflammation, But No to Global Overweight in Cuban Preschool Children

The main cause of anemia in the preschool population is dietary iron deficiency; however, there are other conditions that can lead to anemia such as diseases that produce chronic inflammation and obesity. The objective was to evaluate the prevalence of anemia and iron deficiency in children aged 6 to 59 months and the association with inflammation, global overweight and maternal educational level. A national sample of cross-sectional study design was carried out. Hemoglobin, ferritin, soluble transferrin receptors, leukocytes, C-reactive protein, and alpha-1 acid glycoprotein were assessed. Nutritional status was evaluated and level of mother education was collected by survey. A total of 1417 children were studied. Anemia prevalence was 22.5% and constitutes a moderate public health problem. Iron deficiency prevalence was 35.6% and erythropoietic dysfunction 13.3%; with elevated inflammation indicators 37.6% and leukocytosis 36.1%. Malnutrition occurred in 1.0% of the children, with a prevalence of overweight in 4.7% and obesity in 2.8%. Anemia was associated with iron storage deficiency OR=2.07 (1.45-2.97) and inflammation OR=2.01 (1.45-2.78). No associations were found between anemia OR=0.68 (95% CI= 0.35-1.32) and iron deficiency OR=0.96 (95% CI= 0.68-1.35) with global overweight. Global overweight does not explain the inflammation found OR=1.13 (95% CI= 0.54-2.37), neither by CRP OR=0.57 (0.24-1.37) or AGP OR=1.14 (0.54-2.42). Low education level of the mother was associated with anemia in the children (χ² trend= 4.327 p=0.037), but not with iron deficiency (χ² trend= 0.212 p=0.646). Anemia and iron deficiency in Cuban preschool children was a moderate public health problem associated with inflammation.

The state of health in Pakistan and its provinces and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Understanding health trends and estimating the burden of disease at the national and subnational levels helps policy makers track progress and identify disparities in overall health performance. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides comprehensive estimates for Pakistan. Comparison of health indicators since 1990 provides valuable insights about Pakistan's ability to strengthen its health-care system, reduce inequalities, improve female and child health outcomes, achieve universal health coverage, and meet the UN Sustainable Development Goals. We present estimates of the burden of disease, injuries, and risk factors for Pakistan provinces and territories from 1990 to 2019 based on GBD 2019 to improve health and health outcomes in the country. We used methods and data inputs from GBD 2019 to estimate socio-demographic index, total fertility rate, cause-specific deaths, years of life lost, years lived with disability, disability-adjusted life-years, healthy life expectancy, and risk factors for 286 causes of death and 369 causes of non-fatal health loss in Pakistan and its four provinces and three territories from 1990 to 2019. To generate estimates for Pakistan at the national and subnational levels, we used 68 location-years of data to estimate Pakistan-specific demographic indicators, 316 location-years of data for Pakistan-specific causes of death, 579 location-years of data for Pakistan-specific non-fatal outcomes, 296 location-years of data for Pakistan-specific risk factors, and 3089 location-years of data for Pakistan-specific covariates. Life expectancy for both sexes in Pakistan increased nationally from 61·1 (95% uncertainty interval [UI] 60·0-62·1) years in 1990 to 65·9 (63·8-67·8) years in 2019; however, these gains were not uniform across the provinces and federal territories. Pakistan saw a narrowing of the difference in healthy life expectancy between the sexes from 1990 to 2019, as health gains for women occurred at faster rates than for men. For women, life expectancy increased by 8·2% (95% UI 6·3-13·8) between 1990 and 2019, whereas the male life expectancy increased by 7·6% (3·5-11·8). Neonatal disorders, followed by ischaemic heart disease, stroke, diarrhoeal diseases, and lower respiratory infections were the leading causes of all-age premature mortality in 2019. Child and maternal malnutrition, air pollution, high systolic blood pressure, dietary risks, and tobacco consumption were the leading all-age risk factors for death and disability-adjusted life-years at the national level in 2019. Five non-communicable diseases-ischaemic heart disease, stroke, congenital defects, cirrhosis, and chronic kidney disease-were among the ten leading causes of years of life lost in Pakistan. Burden varied by socio-demographic index. Notably, Balochistan and Khyber Pakhtunkhwa had the lowest observed gains in life expectancy. Dietary iron deficiency was the leading cause of years lived with disability for both men and women in 1990 and 2019. Low birthweight and short gestation and particulate matter pollution were the leading contributors to overall disease burden in both 1990 and 2019 despite moderate improvements, with a 23·5% (95% UI 3·8-39·2) and 27·6% (14·3-38·6) reduction in age-standardised attributable DALY rates during the study period. Our study shows that progress has been made on reducing Pakistan's disease burden since 1990, but geographical, age, and sex disparities persist. Equitable investment in the health system, as well as the prioritisation of high-impact policy interventions and programmes, are needed to save lives and improve health outcomes. Pakistan is facing several domestic and foreign challenges-the Taliban's return to power in Afghanistan, political turmoil, catastrophic flooding, the COVID-19 pandemic-that will shape the trajectory of the country's health and development. Pakistan must address the burden of infectious disease and curb rising rates of non-communicable diseases. Prioritising these three areas will enhance Pakistan's ability to achieve universal health coverage, meet its Sustainable Development Goals, and improve the overall health outcomes. Bill & Melinda Gates Foundation. For the Urdu translation of the abstract see Supplementary Materials section.

Nutritional deficiencies in low-sociodemographic-index countries: a population-based study.

We aimed to estimate the burden of nutritional deficiency according to sex and age in countries with a low sociodemographic index (SDI). Following the methods of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019, estimated annual percentage changes (EAPCs) were calculated to determine trends in the age-standardized rates of incidence and disability-adjusted life-years (DALYs) of nutritional deficiency and its main subcategories from 1990 to 2019 in low-SDI countries. From 1990 to 2019, the age-standardized incidence and DALY rates of nutritional deficiency showed decreasing trends, with EAPCs of -0.90 [95% confidence interval (CI), 1.06 to -0.75] and -3.20 (95% CI, -3.29 to -3.10), respectively, in low-SDI countries. In 2019, of the subcategories analyzed, vitamin A deficiency had the highest age-standardized incidence rate and protein-energy malnutrition had the highest age-standardized DALY rate. From 1990 to 2019, the greatest decrease in the age-standardized incidence rate was observed for vitamin A deficiency and the greatest decrease in the age-standardized DALY rate was observed for protein-energy malnutrition. At the national level, from 1990 to 2019, the greatest increase in the age-standardized incidence rate of overall nutritional deficiency was observed in males in Afghanistan (EAPC: 0.28; 95% CI, 0.07 to 0.49). Of the age groups analyzed, the highest incidence and DALY rates of overall nutritional deficiency and dietary iron deficiency were observed in children aged 1-4 years. The age-standardized incidence and DALY rates of nutritional deficiency decreased significantly from 1990 to 2019, especially for vitamin A deficiency and protein-energy malnutrition. Overall nutritional deficiency and dietary iron deficiency occurred primarily in children aged 1-4 years.

PS-B11-10: IRON DEFICIENCY AFFECTS CARDIAC FUNCTION BUT HAS NO EFFECT ON BLOOD PRESSURE IN MICE WITH METABOLIC SYNDROME

Objective: Metabolic syndrome is a serious problem concerning public health, increasing the risk of cardiovascular diseases. Some epidemiological studies have reported that iron overload is associated with metabolic syndrome; however, it remains unknown whether iron deficiency affects the pathogenesis of metabolic syndrome. Therefore, in this study, we investigated the impact of dietary iron deficiency in genetically obese KKAy mice, a model of human metabolic syndrome. Methods: Four-week-old male KKAy mice and control C57BL/6J mice (wild-type mice, WT) were fed a normal or an iron-restricted diet, and the impact of dietary iron deficiency was investigated 12 weeks after diet initiation. Results: Compared with WT mice, systolic blood pressure presented an increasing trend in KKAy mice; however, the difference was not statistically significant between the two groups, and this trend did not change after iron restriction. Notably, some KKAy mice died following iron restriction, while no deaths were recorded in WT mice. Of interest, obese KKAy mice exhibited cardiac hypertrophy and cardiac dysfunction, thereby developing heart failure with pulmonary congestion after iron restriction. Conclusions: These results indicate that iron deficiency affects cardiac function in metabolic syndrome.

Effects of food-derived oligopeptide iron chelates on liver injury and gut microbiota homeostasis in iron-deficiency anemia female rats: a pilot study.

Iron deficiency (ID) is the biggest cause of anemia. This pilot study aimed to investigate the effects of food-derived oligopeptide iron chelates on ameliorating liver injury and restoring gut microbiota homeostasis in iron-deficiency anemia (IDA) female rats. Female Sprague-Dawley rats at 21 days old were selected and randomly divided into a control group (N = 4) and an ID model group (N = 16). The ID model group was fed an iron-deficient diet containing 4 mg kg-1 iron for 28 days to generate the IDA rat model and then randomly subdivided into four groups (N = 4 for each group): ID group, ferrous sulfate group, marine fish oligopeptide iron chelate (MCOP-Fe) group, and whey protein oligopeptide iron chelate (WPP-Fe) group. Iron supplements were given to rats in the three intervention groups once per day via intragastric administration for three weeks. After iron supplementation, the hemoglobin levels in the three intervention groups were significantly improved, with the MCOP-Fe and WPP-Fe groups returning to normal. The ALT and AST levels in the ID group increased significantly, while levels in all intervention groups decreased to normal levels. Liver glutathione in the WPP-Fe group was increased, while the activity of superoxide dismutase also tended to be higher. In addition, 16S rRNA gene sequencing showed that IDA resulted in changes to intestinal microbiota. After intervention, the WPP-Fe group showed increased alpha diversity of intestinal microbes. Therefore, MCOP-Fe and WPP-Fe may improve the iron status of IDA female rats as well as ameliorate liver damage, with WPP-Fe showing a greater potential in improving gut microbiota imbalance.

Effects of green tea polyphenols on inflammation and iron status.

Inflammation is an underlying problem for many disease states and has been implicated in iron deficiency (ID). This study aimed to determine whether iron status is improved by epigallocatechin-3-gallate (EGCG) through reducing inflammation. Thirty-two male Sprague-Dawley rats were fed an iron-deficient diet for 2 weeks and then randomly divided into four groups (n 8 each): positive controls, negative controls, lipopolysaccharide (LPS, 0⋅5 mg/kg body weight), and LPS + EGCG (LPS plus 600 mg EGCG/kg diet) for 3 additional weeks. The study involved testing two control groups, both treated with saline. One group (positive control) was fed a regular diet containing standard iron, while the negative control was fed an iron-deficient diet. Additionally, two treatment groups were tested. The first group was given LPS, while the second group was administered LPS and fed an EGCG diet. Iron status, hepcidin, C-reactive protein (CRP), serum amyloid A (SAA), and interleukin-6 (IL-6) were measured. There were no differences in treatment groups compared with control in CRP, hepcidin, and liver iron concentrations. Serum iron concentrations were significantly lower in the LPS (P = 0⋅02) and the LPS + EGCG (P = 0⋅01) than in the positive control group. Compared to the positive control group, spleen iron concentrations were significantly lower in the negative control (P < 0⋅001) but not with both LPS groups. SAA concentrations were significantly lower in the LPS + EGCG group compared to LPS alone group. EGCG reduced SAA concentrations but did not affect hepcidin or improve serum iron concentration or other iron markers.

Regulation of Iron Transport Is Required for Terminal Erythroid Differentiation Even Under Iron-Replete Conditions Sufficient for Hemoglobinization

Developing erythroid cells are the main consumer of iron in vertebrates, as their main function is to oxygenate tissues via hemoglobin. Iron metabolism is a key driver of erythroid development and hemoglobin synthesis. When iron deficient, or when iron metabolism is dysregulated, erythroid cells are both lacking in hemoglobin and exhibit differentiation defects. Currently, the efficacy of iron supplementation in patients is monitored by quantitating hemoglobin levels. However, the effect of iron supplementation on erythroid differentiation is less clear. As hemoglobinization and erythroid differentiation are inextricably intertwined with erythroid function, we sought to understand whether and how iron supplementation functions to restore erythroid differentiation during iron deficiency. Tackling this problem in vivo has been fraught with technical challenges as vertebrates with mutations in iron metabolism genes often die from anemia in utero. To circumvent this problem, we used zebrafish with genetic iron metabolism defects to determine if iron supplementation could rescue erythropoietic defects at both the cellular and systemic level. Zebrafish are tractable in vivo models for such studies as they develop externally and can easily be treated by exogenous iron in their water. To carry out this study, we designed a system to sort Tg(globin lcr:eGFP) erythrocytes from single zebrafish embryos onto slides for imaging, while keeping sufficient numbers of cells for genotyping of the same embryo. We used two zebrafish lines which carry loss of function mutations in the mfrn1 (carrying a mitochondrial iron trafficking defect) and fpn1 (carrying a defect in iron export from intestinal and yolk syncytial epithelium-a model of dietary iron deficiency). Both lines had decreased erythroid cell numbers. In addition, the erythroid cells were hemoglobin deficient and had erythroid differentiation defects which included enlarge nuclei. We showed that exogenous iron supplementation (labeled as "rescue) in mfrn1 mutant zebrafish restored hemoglobinization (benzidine staining) but not erythroid cell number (% lcr:eGFP) or terminal differentiation. However, iron supplementation in fpn1 mutant zebrafish, restored erythroid cell number but not terminal differentiation defects. The main difference in the 2 mutants is that the mfrn1 mutant has a defect in intracellular iron trafficking leading to defective iron metabolism, while the fpn1 mutant has defective iron export to erythroid cells but their erythroid cells have intact intracellular iron trafficking. mfrn1 mutants had defects in cell cycle progression and increased apoptosis in their erythroid cells which likely is a cause for decreased erythroid cell numbers. Our data suggests that in addition to adequate iron levels, correct regulation of iron trafficking is required for optimal erythroid iron utilization, terminal erythropoiesis and potentially, proliferation and differentiation of erythroid progenitors. This may indicate a role for iron transporters in directing iron fate, as well as signaling to developmental pathways. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Traumatic Bleeding and Mortality in Mice Are Intensified By Iron Deficiency Anemia and Can be Rescued with Tranexamic Acid Prophylaxis

Introduction Pre-traumatic anemia, particularly iron-deficiency anemia (IDA), is independently associated with poor outcomes and increased mortality. There is also mounting clinical evidence that anemia aggravates hemorrhage which may be particularly detrimental during trauma, where accelerated hemorrhage may worsen coagulopathy. In order to better understand what extent IDA could influence traumatic hemorrhaging, coagulopathy and mortality, we employed a model of traumatic liver injury in iron deficient mice, and evaluated the effects of prophylactic tranexamic acid (TXA) on bleeding and mortality in the setting of anemia. Materials and Methods Severe IDA was generated in C57BL/6J mice. Three week old mice were fed an iron-deficient diet for 6 weeks. Control mice (non-anemic) were fed a normal laboratory diet. Development of IDA was confirmed by complete blood count (CBC), red cell indices, and liver iron content. Mice were pre-treated with saline or TXA (10mg/kg) and subjected to liver laceration. Blood loss (determined by weighing blood-soaked sponges in the abdominal cavity), development of coagulopathy [APTT, Factor (F)II, FV, FVIII, FX and fibrinogen), thrombin-antithrombin (TAT) complexes and plasmin-antiplasmin (PAP) complexes] were analyzed at 15 and 60 minutes after trauma. All data were expressed as the median and were compared by Mann-Whitney test. The number of mice in each group was 8-20. Seven day survival was analyzed using Kaplan-Meier survival curves, which were compared using the Mantel-Cox log-rank test. Results IDA was ascertained by the development of hypochromic/microcytic anemia with significantly lower hematocrit (32% vs 48%, p=<0.0001) and hepatic iron content (20.04 µg/g vs. 72.41 µg/g, p=<0.0001) in anemic compared to non-anemic mice, respectively. Anemic mice demonstrated more rapid and increased blood loss when compared to non-anemic mice. At 15 and 60 minutes after liver laceration, median blood loss was 14.5 and 20.6 µL/g (p=<0.0001) in non-anemic mice and 20.3 and 24.5 µL/g (p=0.004), in anemic mice, respectively. Prophylaxis with TXA reduced blood loss significantly in both anemic and anemic mice to a threshold of ~15 µL/g. Bleeding led to a similar degree of acute traumatic coagulopathy (ATC) in both non-anemic and anemic mice, and was characterized by progressive APTT prolongation, TAT-complex formation, and depletion of FV, FVIII, and fibrinogen. FII and FX were not affected, consistent with the presence of ATC, rather than disseminated intravascular coagulation. In contrast, the extent of fibrinolysis differed between anemic and non-anemic mice in that PAP complex formation (not elevated at 15 minutes) rose significantly in anemic compared to non-anemic mice at 60 minutes (median 44 vs 28 ng/mL, p=0.0004). TXA prophylaxis promoted the correction of ATC by near-normalization of TAT-complexes, FV, FVIII, and fibrinogen in anemic and non-anemic mice alike. However, TXA only corrected PAP-complex formation and APTT in the non-anemic mice, without affecting these parameters in anemic mice. This suggests that anemia accelerated fibrinolysis which was not controlled by TXA. The 7-day survival of anemic mice was lower compared to non-anemic mice (50% vs 75%), but increased significantly with TXA (80%, p=0.04). Conclusion In a murine trauma model, IDA resulted in enhanced bleeding and mortality, which were both rescued by TXA prophylaxis. However, while ATC occurred to a similar extent in anemic and non-anemic mice and was corrected by TXA, only anemic mice developed exaggerated fibrinolysis that could not be suppressed by TXA. These findings suggest that hyper-fibrinolysis contributes to enhanced anemic bleeding, but that bleed and mortality rescue were not dependent on the anti-fibrinolytic effects of TXA alone. Therefore, less well defined properties of TXA (beyond fibrinolysis control) relating to vascular barrier stabilization and/or immune/cytokine modulation, may be involved in mitigation of early ATC (and, thereby, bleed control) and survival. These findings open new investigations into under-recognized pharmaco-dynamic effects of TXA beyond fibrinolysis mitigation, and could be critical for rescuing catastrophic bleeding situations (e.g. trauma, postpartum hemorrhage), especially in the presence of pre-existing anemia.

Might nontransferrin-bound iron in blood plasma and sera be a nonproteinaceous high-molecular-mass FeIII aggregate?

The HFE (Homeostatic Fe regulator) gene is commonly mutated in hereditary hemochromatosis. Blood of (HFE)(-/-) mice and of humans with hemochromatosis contains toxic nontransferrin-bound iron (NTBI) which accumulates in organs. However, the chemical composition of NTBI is uncertain. To investigate, HFE(-/-) mice were fed iron-deficient diets supplemented with increasing amounts of iron, with the expectation that NTBI levels would increase. Blood plasma was filtered to obtain retentate and flow-through solution fractions. Liquid chromatography detected by inductively coupled plasma mass spectrometry of flow-through solutions exhibited low-molecular-mass iron peaks that did not increase intensity with increasing dietary iron. Retentates yielded peaks due to transferrin (TFN) and ferritin, but much iron in these samples adsorbed onto the column. Retentates treated with the chelator deferoxamine (DFO) yielded a peak that comigrated with the Fe-DFO complex and originated from iron that adhered to the column in the absence of DFO. Additionally, plasma from younger and older 57Fe-enriched HFE mice were separately pooled and concentrated by ultrafiltration. After removing contributions from contaminating blood and TFN, Mössbauer spectra were dominated by features due to magnetically interacting FeIII aggregates, with greater intensity in the spectrum from the older mice. Similar features were generated by adding 57FeIII to "pseudo plasma". Aggregation was unaffected by albumin or citrate at physiological concentrations, but DFO or high citrate concentrations converted aggregated FeIII into high-spin FeIII complexes. FeIII aggregates were retained by the cutoff membrane and adhered to the column, similar to the behavior of NTBI. A model is proposed in which FeII entering blood is oxidized, and if apo-TFN is unavailable, the resulting FeIII ions coalesce into FeIII aggregates, a.k.a. NTBI.

An iron-deficient diet prevents alcohol- or diethylnitrosamine-induced acute hepatotoxicity in mice by inhibiting ferroptosis

An iron-deficient diet prevents alcohol- or diethylnitrosamine-induced acute hepatotoxicity in mice by inhibiting ferroptosis

A two-gene strategy increases iron and zinc concentrations in wheat flour, improving mineral bioaccessibility.

Dietary deficiencies of iron and zinc cause human malnutrition that can be mitigated by biofortified staple crops. Conventional breeding approaches to increase grain mineral concentrations in wheat (Triticum aestivum L.) have had only limited success, and our understanding of the genetic and physiological barriers to altering this trait is incomplete. Here we demonstrate that a transgenic approach combining endosperm-specific expression of the wheat VACUOLAR IRON TRANSPORTER gene TaVIT2-D with constitutive expression of the rice (Oryza sativa) NICOTIANAMINE SYNTHASE gene OsNAS2 significantly increases the total concentration of zinc and relocates iron to white-flour fractions. In two distinct bread wheat cultivars, we show that the so called VIT-NAS construct led to a two-fold increase in zinc in wholemeal flour, to ∼50 µg g-1. Total iron was not significantly increased, but redistribution within the grain resulted in a three-fold increase in iron in highly pure, roller-milled white flour, to ∼25 µg g-1. Interestingly, expression of OsNAS2 partially restored iron translocation to the aleurone, which is iron depleted in grain overexpressing TaVIT2 alone. A greater than three-fold increase in the level of the natural plant metal chelator nicotianamine in the grain of VIT-NAS lines corresponded with improved iron and zinc bioaccessibility in white flour. The growth of VIT-NAS plants in the greenhouse was indistinguishable from untransformed controls. Our results provide insights into mineral translocation and distribution in wheat grain and demonstrate that the individual and combined effects of the two transgenes can enhance the nutritional quality of wheat beyond what is possible by conventional breeding.

Burden of Nutritional Deficiencies in China: Findings from the Global Burden of Disease Study 2019.

From 1990 to 2019, the age-standardized incidence rate of nutritional deficiencies in China remained stable. However, the age-standardized disability-adjusted life-years (DALY) rate of nutritional deficiencies decreased from 1990 to 2019. Data were extracted from the GBD 2019 datasets. Estimated annual percentage changes (EAPCs) were calculated to assess the incidence rate, and DALY trends of nutritional deficiencies. Measures were stratified by subtypes, regions, and age groups. In 2019, the age-standardized DALY rates of dietary iron deficiency and protein-energy malnutrition reached their highest levels. The main population groups with protein-energy malnutrition and dietary iron deficiency were adults over the age of 70 and children under the age of five. The latter group also had a greater burden of vitamin A deficiency. Zhejiang, Beijing, and Guangdong reported the highest age-standardized incidence rates of nutritional deficiencies, which mainly pertained to protein-energy malnutrition and vitamin A deficiency. Tibet, Xinjiang, and Hainan had the highest age-standardized DALY rates of nutritional deficiencies, which mainly pertained to dietary iron deficiency and protein-energy malnutrition.

A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice.

The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in lipopolysaccharide (LPS)-treated wild type mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv-/- mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wild type animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv-/- mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen to stimulate ferroportin mRNA translation. Prolonged LPS treatment eliminated ferroportin mRNA and permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is a critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient when combined with iron depletion.

Influence of supplementation of probiotic bacteria Lactobacillus plantarum and Lactobacillus curvatus on selected parameters of liver iron metabolism in rats on high-fat iron-deficient diet

• Lactobacillus curvatus and L. plantarum increase serum ferroportin. • L. curvatus enhances the expression of the Tfrc gene in the liver. • Increased expression of Tfrc and SLC11A2 genes stimulates hepatic iron accumulation. • Fecal Lactobacillus content shows negative correlation with HJV gene expression. Iron deficiency constitutes the most frequent diet deficit. A high-fat diet also leads to disturbances in iron metabolism. There is evidence that probiotics favorably influence iron turnover. To compare the influence of supplementation with probiotic Lactobacillus plantarum and Lactobacillus curvatus with and without iron supply on liver iron metabolism in rats on high-fat iron-deficient diet. In the first stage (8 weeks), rats were fed a control diet (group C, n = 8), high-fat diet (group HF, n = 8), or high-fat iron-deficient diet (group HFDEF, n = 48). In the second stage (8 weeks), the rats in the C and HF groups were kept on the same diets, while the rats in the HFDEF group were divided into 6 groups (n = 8 each) and fed as follows: group HFDEF- high-fat iron-deficient diet, group HFDEFFe- high-fat iron-deficient diet with iron supplementation, groups HFDEFLp and HFDEFLc- high-fat iron-deficient diet with L. plantarum or L. curvatus supplementation, respectively, and groups HFDEFFeLp and HFDEFFeLc- high-fat iron-deficient diet supplemented with iron and L. plantarum or L. curvatus , respectively. The rats were subsequently sacrificed, and their serum and liver samples were collected for analysis. Serum ferroportin level was higher in the HFDEFFe, HFDEFLp, HFDEFLc, and HFDEFFeLp groups than in the C and HFDEF groups. The hepatic expression of type 1 transferrin receptor gene ( Tfrc ) was higher in the HFDEFFeLc group than in the C group. No differences in serum iron, hepcidin, hemojuvelin, transferrin, and ferritin levels and in hepatic type 2 transferrin receptor gene expression were observed between the groups. In rats on high-fat iron-deficient diet, the supplementation of L. curvatus and L. plantarum increased serum ferroportin concentration, and L. curvatus enhanced liver expression of the Tfrc gene.

Systemic iron reduction via an iron deficient diet decreases the severity of knee cartilage lesions in the Dunkin-Hartley guinea pig model of osteoarthritis

Iron accumulation is emerging as a player in aging-related disorders due to its propensity for generating reactive oxygen species (ROS). Studies investigating the role of iron in the pathogenesis of primary osteoarthritis (OA) are limited. We designed a proof-of-principle study to determine the effect of systemic iron deficiency, via an iron deficient diet, on knee OA in an animal model. Twelve-week-old male Hartley guinea pigs received the standard diet (n=6) or a diet devoid of iron (n=6) for 19-weeks. Iron levels were determined in the serum, liver, and articular cartilage. Knees were collected to assess structural changes related to OA (microcomputed tomography, histopathology). Immunohistochemistry was performed to evaluate the presence and distribution of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) and ROS-driven 4-hydroxynonenal (4-HNE)-induced protein adducts. Transcript expression was also assessed. Relative to control animals, an iron deficient diet reduced the concentration of this mineral in serum, liver, and articular cartilage. Iron deficient animals had lower histologic OA scores; decreased subchondral bone mineral density was also noted. This reduction in knee joint pathology was accompanied by a decrease in: ADAMTS4 in synovium; and 4-HNE protein adducts from lipid peroxidation in both the menisci and articular cartilage of iron deficient animals. Expression of iron-related genes in these tissues was also altered in treated animals. Results from this study suggest that systemic iron levels may play a role in knee OA pathogenesis, with a short-term deficit in dietary iron reducing the severity of knee cartilage lesions.

NCOA4-mediated ferritinophagy is involved in ionizing radiation-induced ferroptosis of intestinal epithelial cells

Ferroptosis is a newly recognized form of regulated cell death that is characterized by severe lipid peroxidation initiated by iron overload and the generation of reactive oxygen species (ROS). However, the role of iron in ionizing radiation (IR)-induced intestinal injury has not been fully illustrated yet. In this study, we found that IR induced ferroptosis in intestinal epithelial cells, as indicated by the increase in intracellular iron levels and lipid peroxidation, upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA, reduced glutathione peroxidase 4 (GPX4) mRNA and glutathione (GSH) levels, and significant mitochondrial damage. In addition, the iron chelator deferoxamine (DFO) attenuated IR-induced ferroptosis and intestinal injury in vitro and in vivo. Intriguingly, pharmacological inhibition of autophagy with 3-methyladenine (3-MA) mitigated IR-induced ferritin downregulation, iron overload and ferroptosis. IR increased the levels of nuclear receptor coactivator 4 (NCOA4) mRNA and protein. NCOA4 knockdown significantly inhibited the reduction of ferritin, decreased the level of intracellular free iron, and mitigated ferroptosis induced by IR in HIEC cells, indicating that NCOA4-mediated autophagic degradation of ferritin (ferritinophagy) was required for IR-induced ferroptosis. Furthermore, cytoplasmic iron further activated mitoferrin2 (Mfrn2) on the mitochondrial membrane, which in turn increased iron transport into the mitochondria, resulting in increased ROS production and ferroptosis. In addition, mice fed with an iron-deficient diet for 3 weeks showed a significant reversal in the intestinal injury induced by abdominal IR exposure. Taken together, ferroptosis is a novel mechanism of IR-induced intestinal epithelial cytotoxicity, and is dependent on NCOA4-mediated ferritinophagy.

Reticulocyte hemoglobin equivalent as a diagnostic parameter of iron deficiency anemia in infants age 1-4 months

IntroductionIron deficiency anemia (IDA) is still a major global health problem. The prevalence was highest among children under five years, 39.7%, with the most contributing cause being dietary iron deficiency (ID). Reticulocyte hemoglobin equivalent (Ret-He) assesses the amount of hemoglobin in reticulocytes. Ret-He is an easy, inexpensive, and applicable diagnostic parameter of iron deficiency. This study aims to determine the role of Ret-He as a diagnostic parameter of ID and IDA in infants 1-4 months old.Material and methodsThe study was conducted prospectively at 10 Community Health Centers in Banjarbaru, South Kalimantan, from August 2020 to August 2021. Total 403 infants aged 1, 2, 3, and 4 months met the inclusion and exclusion criteria. Venous blood samples were checked for Ret-He, complete blood count, and peripheral blood smears.ResultsThe incidence of ID and IDA in infants 1-4 months were 10,9% and 58,6%. Ret-He cut-off values for iron deficiency and IDA at 1, 2, 3 and 4 months were 22,25 pg, 20,3 pg, 19,05 pg and 17,55 pg; with sensitivity 7,8%, 2,5%, 7,4%, 8,2%; specificity 94,4%, 95,0%, 96,9%, 98,1%; positive predictive value 85,7%, 66,7%, 83,3%, 80,0%, and negative predictive value 18,1%, 19,6%, 33,0%, 53,6%.ConclusionsRet-He can detect iron deficiency and IDA in 1-4 months baby with high specificity and positive predictive value.

The effect of iron dextran on vitamin D3 metabolism in SD rats

BackgroundIron and vitamin D (VD) is essential to health. Previous studies have shown that iron homeostasis has a potential effect on VD metabolism, but the mechanism is not fully understood.ObjectivesTo explore the relationship between VD metabolism and iron metabolism, as well as the regulatory mechanism of iron on VD metabolism.Methods40 male rats were fed adaptively for 7 days and randomly divided into control (C, n = 6 normal diet) group and model (M, n = 24 iron deficient diet) by simple randomization, the latter was used to establish iron deficiency anemia (IDA) model. After 6 weeks of feeding, the M group was randomly divided into: iron deficiency group (DFe), low iron group (LFe), medium iron group (MFe) and high iron group (HFe) by block randomization. Different doses of iron dextran (based on iron content (100 g·bw·d)): 0, 1.1, 3.3 and 9.9 mg) were given respectively. After 4 weeks, the rats were anesthetized with 8% chloral hydrate, Blood (collected from the abdominal aorta), liver and kidney tissues were collected. The serum and tissues were separately packed and frozen at -80℃ for testing.ResultsThe results showed that the levels of hemoglobin (Hb), red blood cell (RBC), serum iron (SI), liver iron, and kidney iron in DFe group were lower than those in the other four groups, while the levels of total iron-binding capacity (TIBC), transferrin (TF) and transferrin receptor (Tfr) in DFe group were higher than those in other groups; The serum levels of 25-(OH)D3 and 1,25-(OH)2D3 in DFe group were significantly lower than those in C group (P < 0.05). The correlation analysis showed that the levels of 25-(OH)D3 and 1,25-(OH)2D3 were negatively correlated with TIBC, TF and Tfr no correlation with SI. Western blotting, immunofluorescence, and q-PCR results showed that compared with C group, the protein and gene expressions of CYP2R1, CYP27A1, and CYP24A1 in DFe group were down-regulated, and the expression of CYP27B1 protein and gene was up-regulated in DFe group.ConclusionIron may be involved in the metabolism of VD3 by regulating the expression of VD3 hydroxylase, suggesting that appropriate iron supplementation might promote the activation of VD3.