Spleen Iron Content Research Articles

Abdominal multi-organ iron content and the risk of Parkinson's disease: a Mendelian randomization study.

To evaluate the causal relationship between abdominal multi-organ iron content and PD risk using publicly available genome-wide association study (GWAS) data. We conducted MR analysis to assess the effects of iron content in various abdominal organs on PD risk, followed by reverse analysis. Additionally, MVMR analysis evaluated the independent effects of organ-specific iron content on PD. We utilized genetic variation data from the UK Biobank, including liver iron content (n = 32,858), spleen iron content (n = 35,324), and pancreas iron content (n = 25,617), as well as summary-level data for Parkinson's disease from the FinnGen (n = 218,473) and two other large GWAS datasets of European populations (First dataset n = 480,018; Second dataset n = 2,829). The primary MR analysis used the inverse variance-weighted (IVW) method, confirmed by MR-Egger and weighted median methods. Sensitivity analysis was performed to address potential pleiotropy and heterogeneity. Observational cohort results were validated through replication cohort analysis, followed by meta-analysis. IVW analysis revealed a causal relationship between increased liver iron content and elevated risk of PD (OR = 1.27; 95% CI: 1.05-1.53; p = 0.015). No significant causal relationship was observed between spleen (OR = 1.00; 95% CI: 0.76-1.32; p = 0.983) and pancreatic (OR = 0.93; 95% CI: 0.72-1.20; p = 0.573) iron content and increased risk of PD. Meta-analysis of GWAS data for PD from three different sources using the random-effects IVW method showed a statistically significant causal relationship between liver iron content and the occurrence of PD (OR = 1.17, 95% CI: 1.01-1.35; p = 0.012). This study presents evidence from Mendelian randomization (MR) analysis indicating a significant causal link between increased liver iron content and a higher risk of Parkinson's disease (PD). These findings suggest that interventions targeting body iron metabolism, particularly liver iron levels, may be effective in preventing PD.

Associations of genetically predicted iron status with 24 gastrointestinal diseases and gut microbiota: a Mendelian randomization study.

Iron status has been implicated in gastrointestinal diseases and gut microbiota, however, confounding factors may influence these associations. We performed Mendelian randomization (MR) to investigate the associations of iron status, including blood iron content, visceral iron content, and iron deficiency anemia with the incidence of 24 gastrointestinal diseases and alterations in gut microbiota. Independent genetic instruments linked with iron status were selected using a genome-wide threshold of p = 5 × 10-6 from corresponding genome-wide association studies. Genetic associations related to gastrointestinal diseases and gut microbiota were derived from the UK Biobank, the FinnGen study, and other consortia. Genetically predicted higher levels of iron and ferritin were associated with a higher risk of liver cancer. Higher levels of transferrin saturation were linked to a decreased risk of celiac disease, but a higher risk of non-alcoholic fatty liver disease (NAFLD) and liver cancer. Higher spleen iron content was linked to a lower risk of pancreatic cancer. Additionally, higher levels of liver iron content were linked to a higher risk of NAFLD and liver cancer. However, certain associations lost their statistical significance upon accounting for the genetically predicted usage of cigarettes and alcohol. Then, higher levels of iron and ferritin were associated with 11 gut microbiota abundance, respectively. In a secondary analysis, higher iron levels were associated with lower diverticular disease risk and higher ferritin levels with increased liver cancer risk. Higher levels of transferrin saturation were proven to increase the risk of NAFLD, alcoholic liver disease, and liver cancer, but decrease the risk of esophageal cancer. MR analysis showed no mediating relationship among iron status, gut microbiota, and gastrointestinal diseases. This study provides evidence suggesting potential causal associations of iron status with gastrointestinal diseases and gut microbiota, especially liver disease.

Sex similarities and divergences in systemic and muscle iron metabolism adaptations to extreme physical inactivity in rats.

Previous data in humans suggest that extreme physical inactivity (EPI) affects iron metabolism differently between sexes. Our objective was to deepen the underlying mechanisms by studying rats of both sexes exposed to hindlimb unloading (HU), the reference experimental model mimicking EPI. Eight-week-old male and female Wistar rats were assigned to control (CTL) or hindlimb unloading (HU) conditions (n=12/group). After 7days of HU, serum, liver, spleen, and soleus muscle were removed. Iron parameters were measured in serum samples, and ICP-MS was used to quantify iron in tissues. Iron metabolism genes and proteins were analysed by RT-qPCR and Western blot. Compared with control males, control females exhibited higher iron concentrations in serum (+43.3%, p<0.001), liver (LIC; +198%, P<0.001), spleen (SIC; +76.1%, P<0.001), and transferrin saturation (TS) in serum (+53.3%, P<0.001), contrasting with previous observations in humans. HU rat males, but not females, exhibited an increase of LIC (+54% P<0.001) and SIC (+30.1%, P=0.023), along with a rise of H-ferritin protein levels (+60.9% and +134%, respectively, in liver and spleen; P<0.05) and a decrease of TFRC protein levels (-36%; -50%, respectively, P<0.05). HU males also exhibited an increase of splenic HO-1 and NRF2 mRNA levels, (p<0.001), as well as HU females (P<0.001). Concomitantly to muscle atrophy observed in HU animals, the iron concentration increased in soleus in females (+26.7, P=0.004) while only a trend is observed in males (+17.5%, P=0.088). In addition, the H-ferritin and myoglobin protein levels in soleus were increased in males (+748%, P<0.001, +22%, P=0.011, respectively) and in females (+369%, P<0.001, +21.9%, P=0.007, respectively), whereas TFRC and ferroportin (FPN) protein levels were reduced in males (-68.9%, P<0.001, -76.8%, P<0.001, respectively) and females (-75.9%, P<0.001, -62.9%, P<0.001, respectively). Interestingly, in both sexes, heme exporter FLVCR1 mRNA increased in soleus, while protein levels decreased (-39.9% for males P=0.010 and -49.1% for females P<0.001). Taken together, these data support that, in rats (1) extreme physical inactivity differently impacts the distribution of iron in both sexes, (2) splenic erythrophagocytosis could play a role in this iron misdistribution. The higher iron concentrations in atrophied soleus from both sexes are associated with a decoupling between the increase in iron storage proteins (i.e., ferritin and myoglobin) and the decrease in levels of iron export proteins (i.e., FPN and FLVCR1), thus supporting an iron sequestration in skeletal muscle under extreme physical inactivity.

Tissue Iron Distribution in Anemic Patients with End-Stage Kidney Disease: Results of a Pilot Study.

Background/Objectives: Anemia is a frequent multifactorial co-morbidity in end-stage kidney disease (ESKD) associated with morbidity and poor QoL. Apart from insufficient erythropoietin formation, iron deficiency (ID) contributes to anemia development. Identifying patients in need of iron supplementation with current ID definitions is difficult since no good biomarker is available to detect actual iron needs. Therefore, new diagnostic tools to guide therapy are needed. Methods: We performed a prospective cohort study analyzing tissue iron content with MRI-based R2*-relaxometry in 20 anemic ESKD patients and linked it with iron biomarkers in comparison to 20 otherwise healthy individuals. Results: ESKD patients had significantly higher liver (90.1 s-1 vs. 36.1 s-1, p < 0.001) and spleen R2* values (119.8 s-1 vs. 19.3 s-1, p < 0.001) compared to otherwise healthy individuals, while their pancreas and heart R2* values did not significantly differ. Out of the 20 ESKD patients, 17 had elevated spleen and 12 had elevated liver R2* values. KDIGO guidelines (focusing on serum iron parameters) would recommend iron supplementation in seven patients with elevated spleen and four patients with elevated liver R2* values. Conclusions: These findings highlight that liver and especially spleen iron concentrations are significantly higher in ESKD patients compared to controls. Tissue iron overload diverged from classical iron parameters suggesting need of iron supplementation. Measurement of MRI-guided tissue iron distribution might help guide treatment of anemic ESKD patients.

Simvastatin-Mediated Nrf2 Activation Induces Fetal Hemoglobin and Antioxidant Enzyme Expression to Ameliorate the Phenotype of Sickle Cell Disease.

Sickle cell disease (SCD) is a pathophysiological condition of chronic hemolysis, oxidative stress, and elevated inflammation. The transcription factor Nrf2 is a master regulator of oxidative stress. Here, we report that the FDA-approved oral agent simvastatin, an inhibitor of hydroxymethyl-glutaryl coenzyme A reductase, significantly activates the expression of Nrf2 and antioxidant enzymes. Simvastatin also induces fetal hemoglobin expression in SCD patient primary erythroid progenitors and a transgenic mouse model. Simvastatin alleviates SCD symptoms by decreasing hemoglobin S sickling, oxidative stress, and inflammatory stress in erythroblasts. Particularly, simvastatin increases cellular levels of cystine, the precursor for the biosynthesis of the antioxidant reduced glutathione, and decreases the iron content in SCD mouse spleen and liver tissues. Mechanistic studies suggest that simvastatin suppresses the expression of the critical histone methyltransferase enhancer of zeste homolog 2 to reduce both global and gene-specific histone H3 lysine 27 trimethylation. These chromatin structural changes promote the assembly of transcription complexes to fetal γ-globin and antioxidant gene regulatory regions in an antioxidant response element-dependent manner. In summary, our findings suggest that simvastatin activates fetal hemoglobin and antioxidant protein expression, modulates iron and cystine/reduced glutathione levels to improve the phenotype of SCD, and represents a therapeutic strategy for further development.

Study on effect of millet milk on spleen iron concentration

Study on effect of millet milk on spleen iron concentration

Efficacy of polysaccharide iron complex in IDA rats: A comparative study with iron protein succinylate and ferrous succinate

Iron deficiency anemia (IDA) is the most common nutrient-related health problem in the world. There is still a lack of comprehensive comparative study on the efficacies of commonly used iron supplements such as polysaccharide iron complex (PIC), iron protein succinylate (IPS) and ferrous succinate (FS) for IDA. In this study, we compared the PIC, IPS and FS efficacies in IDA rats via intragastric administration. The results showed that the three iron supplements had similar efficacies. PIC/IPS/FS at a dose of 15 mg Fe/kg/d for 10 d increased the hematological and serum biochemical parameters to 2.15/2.12/2.18 (Hb), 1.71/1.67/1.69 (RBC), 2.10/2.11/2.12 (HCT), 1.26/1.22/1.22 (MCV), all 1.34 (MCH), 1.15/1.15/1.14 (MCHC), 1.94/1.82/1.91 (SF), 9.75/9.67/9.53 (SI), and 23.30/22.68/21.64 (TS) times, and reduced TIBC to 0.42/0.43/0.44 times, compared to untreated IDA rats. PIC performed slightly better than IPS and FS in restoring MCV level. Meanwhile, the heart, spleen and kidney coefficients reduced to 67%/74%/65% (heart), all 59% (spleen) and 87%/88%/88% (kidney), and the liver coefficient increased to 116%/115%/116%, compared to untreated IDA rats. The liver iron content was found to be more affected by IDA than the spleen iron content. PIC/IPS/FS at 15 mg Fe/kg/d increased organ iron contents to 4.20/3.97/4.03 times (liver) and 1.36/1.24/1.41 times (spleen) within 10 d compared to untreated IDA rats, and PIC-H and FS were slightly better than IPS in restoring spleen iron content. The results of this study can provide useful data information for the comparison of three iron supplements, PIC, IPS and FS.

Effect of pumpkin enriched with calcium lactate on iron status in an animal model of postmenopausal osteoporosis

Abstract The homeostasis of calcium (Ca) and iron (Fe) is disturbed during menopause. The present study aimed to determine the effects of Ca-enriched pumpkin on Fe status in ovariectomized rats. A total of 48 female Wistar rats were divided into six groups. One group was fed a standard diet (C), while the other five groups were ovariectomized and fed a standard diet (OVX), a calcium lactate diet (CaL_OVX), calcium lactate-enriched pumpkin (PCaL_OVX), calcium lactate and alendronate (CaL_OVX_B), and calcium lactate-enriched pumpkin and alendronate (PCaL_OVX_B), respectively. The nutritional intervention lasted 12 weeks and rats were euthanized. Tissue samples were collected, and the iron content in the samples was assessed. A comparison of all groups showed a reduction in iron concentrations in femurs, liver, hair, spleen, and kidneys in the ovariectomized groups than in the control group. The PCaL_OVX_B group had a significantly higher blood hemoglobin concentration than the control group. Moreover, spleen and liver Fe concentrations were the highest in PCaL_OVX and PCaL_OVX_B rats among the treated groups and were comparable with the control group. These results indicate that ovariectomy decreases Fe status in rats. Calcium lactate-enriched pumpkin with and without alendronate can increase Fe concentration in liver and spleen in ovariectomized rats.

Coenzyme Q10 and N-acetyl cysteine modulates the haematological parameters, markers of oxidative stress and membrane bound phosphatase in spleen toxicity induced by aniline hydrochloride

Aniline is widely used chemical for industrial purpose. Exposure to aniline can lead to various health issues in human being. The most common toxic effect of aniline is splenotoxicity which is produced via the generation of oxidative stress. The present study examines the protective effect of coenzyme Q10 and N-acetyl cysteine on spleen weight, body weight, endogenous antioxidants and membrane bound ATPases in aniline hydrochloride (AH) induced spleen toxicity in rats. Adult male albino rats were divided into five groups, each group consists of six rats. Toxicity was induced by administration of AH (100 ppm, p. o) in drinking water for 30 days. Body weight, markers of oxidative stress and haematological parameters were assessed at the end of treatment period. Treatment rats received Coenzyme Q10 (CoQ10, 10 mg/kg/day/p.o) and N- acetyl cysteine (NAC, 300mg/kg/ day p.o) alone and in combination for 30. AH toxic rats showed a significant elevation of spleen weight, WBC count, iron content, LPO level, NO level and Ca ATPase whereas a significant decrease in body weight, haemoglobin, RBCs level, Protein content, GSH and Na/ K and Mg ATPase were observed. Administration of Coenzyme Q10 (CoQ10, 10 mg/kg/day/p.o) and N- acetyl cysteine (NAC, 300mg/kg/ day p.o) together for 30 consecutive days shows a significant decrease in spleen weight, WBC level, iron content, LPO level, NO level whereas significant increase in body weight, hemoglobin level, RBCs level Protein content, GSH level, Na/ K ATPase, Ca and Mg ATPase when compared with aniline treated group and CoQ10 or NAC alone treated groups. These findings indicate the synergistic &amp; protective effect of CoQ10 and NAC in aniline induced spleen toxicity in rats compared to alone antioxidants.

Calcium-Deficit Diet Improves Iron Content in Ovariectomized Rats

In women, menopause is associated with disorders related to calcium and iron content, which may increase the risk of osteoporosis. This study aimed to determine the effect of calcium deficiency on the iron content in ovariectomized rats. This study included 30 3-month-old female rats, which were divided into three groups: group C (n = 10)—control group fed the standard diet; group O—ovariectomized rats fed the standard diet; and group D—ovariectomized rats fed the calcium-deficit diet. After 3 months of experimental intervention, the weight of the rats was measured, and blood and tissue samples were collected. Morphological parameters were analyzed in whole blood, and serum levels of leptin, estrogen and C-reactive protein, and total antioxidant status were determined. The iron content was measured in tissues, and histological analysis was performed in the femur. The results obtained demonstrated that ovariectomy significantly decreased the iron content in bones, hair, spleen, liver, and kidneys. The calcium-deficit diet increased the iron content in tissues and the hemoglobin level in ovariectomized rats and also enhanced the number of osteoblasts in bones compared with the O group. In conclusion, calcium deficiency improved the iron content in ovariectomized rats in this 12-week study.

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.

The Effect of Monoferric Transferrins on Hypoferremia in a Murine Model of Inflammation

Introduction: Modulation of iron metabolism and suppression of erythropoiesis are central components of the acute phase response (APR) and underlie the anemia of inflammation. Hypoferremia is characteristic of the APR and contributes to erythroid suppression by restricting the iron available for erythropoiesis. The role of transferrin (Tf) signaling in the APR has not been explored. We previously generated mice with transferrin mutations that prevent binding of iron to either the N-terminal (N-blocked) or C-terminal (C-blocked) lobe and demonstrated distinct effects on erythropoiesis and the status of the iron regulatory hormone hepcidin. We hypothesize that monoferric transferrins differentially affect modulation of iron metabolism during the APR. Methods: For a model of acute inflammation, 14 day old wild-type (wt), N-blocked and C-blocked Tf mutant mice were treated with 1mg/kg lipopolysaccharide (LPS) or carrier by intraperitoneal injection and sacrificed 6 hours later. A repeat dose regimen, consisting of seven consecutive daily intraperitoneal injections of 0.3 mg/kg LPS or carrier beginning at seven days of age, was used as a model of chronic inflammation. Results: In the acute model, wt and C-blocked mice demonstrate the expected decrease in serum iron in response to LPS administration (38 + 7 and 70 +6 ug/dL, respectively). In contrast, N-blocked mice fail to decrease serum iron following LPS administration (164 + 22 ug/dL; p <0.01). Liver and spleen iron concentrations are also significantly higher in N-blocked mice following LPS administration, compared to C-blocked and wild-type mice (LIC: 587 + 28 vs 311 + 53 and 243 + 9 ug Fe/g dry weight; p <0.0001; SIC: 471 + 16 vs 406 + 16 and 336 + 18 ug Fe/g dry weight; p <0.05). LPS administration increases hepcidin all three strains. In contrast, elevated Hamp1 expression is not sustained in the repeat dose model. Nevertheless, serum iron remains elevated in N-blocked mice (201.3 + 30 ug/dL; p <0.05) whereas it returns to baseline in wt and C-blocked mice (76.8 + 39 and 86.6 + 21.4 ug/dL, respectively). Liver and spleen iron concentrations also remain higher in the N-blocked mice relative to C-blocked and wt mice (764.7 + 202 vs 295.7 + 62.7 and 301.3 + 74.8 ug Fe/g dry weight; p <0.05 for liver and 511.9 + 36.2 vs 404.8 + 61.3 and 427.3 + 33.ug Fe/g dry weight; p < 0.05 for spleen). All mice demonstrate marked splenomegaly in response to repeated doses of endotoxin without significant differences between strains. Hemoglobin concentrations are decreased in all strains after repeated endotoxin dosing, with N-blocked mice presenting the most severe anemia (4.1 + .21 vs 5.1 + .42 and 5.3 + .28 g/dL for N-blocked, C-blocked and wt, respectively; p < 0.05). Conclusions: In LPS-mediated inflammation, mice unable to bind iron on the N-lobe of transferrin fail to develop hypoferremia and have elevated liver iron concentrations, despite increased hepcidin and splenic iron concentrations. We speculate that the iron excess observed in the Tf N-blocked mice arises from a more profound suppression of erythropoiesis, and relatively decreased utilization of iron in hemoglobin production. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rusfertide Analog-PN23114 As a Hepcidin Mimetic Provides Efficacy Benefits in Conjunction with Phlebotomy in Mouse Model for Hereditary Hemochromatosis

Hepcidin deficiency in hereditary hemochromatosis (HH) leads to hyperabsorption of dietary iron and primary iron overload (Nemeth E., Science 2004). Therapeutic phlebotomy is used to reduce organ iron-overload in HH patients. However, persistent high transferrin-saturation (TSAT%) may result in toxic labile iron that can deposit in organs, leading to tissue damage and subsequent organ dysfunction. Additionally, newly diagnosed patients with severe iron overload require frequent phlebotomies during the induction phase of therapy that can last for many months, during which TSAT% levels may continue to be high even when serum ferritin levels are reduced. Rusfertide is a hepcidin mimetic peptide that has demonstrated potential benefit in reducing the need for therapeutic maintenance phlebotomy in a Phase 2 trial with hemochromatosis subjects who have previously required chronic phlebotomies to reduce and maintain ferritin and liver iron values within normal range (Kowdley KV, AASLD Hepatology 2021). To evaluate the potential benefits of co-treatment of hepcidin mimetic during induction phase of clinical management, we evaluated additive effects of PN23114 in combination with phlebotomy in HJV-/- mouse model for HH (129S-Hjvtm1Nca/J; Andrews NC, J Clin Invest. 2005). PN23114 is an analog of rusfertide with a single amino acid change and with similar pharmacokinetic and pharmacodynamic characteristics. Male HJV-/- mice at 8-12 weeks of age were treated with either PN23114 (7.5 mg/kg, TIW), phlebotomy (~0.3mL blood drawn, QW), or combination of both for a total of 46 days. We found that all three treatment strategies reduced iron concentrations in both heart and kidney, as compared to a baseline group that was terminated at start of study. None of the treatments were able to reduce liver iron but all three prevented further iron deposition in the liver as compared to baseline. It's possible that the length of phlebotomy treatment is not sufficient to result in iron removal from liver. Treatment with PN23114 redistributed the excess iron into spleen and duodenum, thereby significantly elevating spleen iron concentration, while co-treatment of PN23114 and phlebotomy did not result in marked iron sequestration in spleen. Serum ferritin was reduced in all three treatment groups, the group that received the PN23114 and phlebotomy co-treatment showed the largest reduction. Serum iron was normalized with PN23114 treatment and with co-treatment with PN23114 and phlebotomy. Phlebotomy treatment was not able to lower serum iron to normal levels. Our data overall indicate that combining hepcidin mimetic treatment along with phlebotomy may be more effective in quickly lowering TSAT% and labile iron, and thereby quickly reversing tissue iron deposition in specific organs. Titration of rusfertide to the desired clinical effect may be effective in combination with phlebotomy during the induction phase of clinical management to reduce the frequency and duration of phlebotomy treatment as well as lower the lingering high TSAT% levels.

Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and hemolysis

SummaryThe spleen plays a key role in iron homeostasis. It is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this role, spleen iron concentration has not been measured in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank by using magnetic resonance imaging and provide a reference range for spleen iron in an unselected population. Through genome-wide association study, we identify associations between spleen iron and regulatory variation at two hereditary spherocytosis genes, ANK1 and SPTA1. Spherocytosis-causing coding mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while these common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes that have been observed clinically. Our genetic study also identifies a signal that co-localizes with a splicing quantitative trait locus for MS4A7, and we show this gene is abundantly expressed in the spleen and in macrophages. The combination of deep learning and efficient image processing enables non-invasive measurement of spleen iron and, in turn, characterization of genetic factors related to the lytic phase of the erythrocyte life cycle and iron reuptake in the spleen.

Effects of ferric carboxymaltose on phosphate and calcium homeostasis in a murine model of iron‐deficiency anemia

Iron deficiency anemia (IDA) can be caused by heavy uterine bleeding, inflammatory bowel disease, or chronic kidney disease. Ferric carboxymaltose (FCM) is an intravenous form of iron replacement therapy that has been shown clinically to induce severe hypophosphatemia. However, the mechanism by which this occurs is poorly understood. The objective of this study was to develop and characterize a mouse model that would allow investigating the effects of FCM on phosphate (Pi) and calcium (Ca2+) homeostasis. Female C57Bl/6J mice (n=40; 10/group) were randomized to either iron deficient (ID) diet (4 ppm iron) or control diet (48 ppm iron) for 4 weeks followed by intravenous bleeding (0.7% of body weight) 4 and 2 days prior to starting the study. Baseline blood and urine was collected for hematocrit, complete blood count, and serum and urine Pi and Ca2+ levels. Subsequently, mice were treated with a single IV injection of either vehicle (saline) or FCM (20 mg/kg) via retroorbital injection. One week later, terminal blood, urine, feces, liver, and spleen were collected. At baseline, compared with controls, ID mice had lower hematocrit (35±1% vs 39±1%; P&lt;0.05) and microcytic hypochromic anemia. After 7 days, FCM‐treated ID mice had significantly higher hematocrit compared with vehicle‐treated ID mice (43±1% vs 30±1%; P&lt;0.05). FCM treatment also significantly increased iron content in liver and spleen in control mice (18±1 vs 6±1 μmol/g and 36±2 vs 27±3 μmol/g, respectively; P&lt;0.05) and ID mice (16±1 vs 1±0.1 μmol/g and 21±2 vs 6±1 μmol/g, respectively; P&lt;0.05). At baseline, urinary Pi/creatinine ratios were significantly lower in ID mice compared with controls (30±5 vs 58±7 mmol/mmol; P&lt;0.05); however, FCM treatment in ID mice did not affect urinary Pi/creatinine ratios after 7 days (31±6 vs 18±5 mmol/mmol; not significant). There were no differences between groups for serum Pi, erythrocyte Pi, or fecal Pi. Under baseline conditions, no differences in plasma Ca2+ or urinary Ca2+/creatinine ratios were observed between groups; however, FCM‐treated ID mice had significantly lower plasma Ca2+ levels after 7 days compared with ID mice at baseline (2.3±0.1 vs 2.6±0.1 mmol; P&lt;0.05) and lower urinary Ca2+/creatinine ratios (0.1±0.1 vs 1.3±0.2 mmol/mmol; P&lt;0.05). We speculate this may be due to increased PTH and FGF23 levels in FCM‐treated ID mice. In summary, our study demonstrates for the first time that FCM affects Pi and Ca2+ homeostasis in a murine model of IDA. Further studies are needed to better understand the mechanisms of FCM on mineral homeostasis as well as the driving factors for species differences.

Precision MRI phenotyping enables detection of small changes in body composition for longitudinal cohorts

Longitudinal studies provide unique insights into the impact of environmental factors and lifespan issues on health and disease. Here we investigate changes in body composition in 3088 free-living participants, part of the UK Biobank in-depth imaging study. All participants underwent neck-to-knee MRI scans at the first imaging visit and after approximately two years (second imaging visit). Image-derived phenotypes for each participant were extracted using a fully-automated image processing pipeline, including volumes of several tissues and organs: liver, pancreas, spleen, kidneys, total skeletal muscle, iliopsoas muscle, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue, as well as fat and iron content in liver, pancreas and spleen. Overall, no significant changes were observed in BMI, body weight, or waist circumference over the scanning interval, despite some large individual changes. A significant decrease in grip strength was observed, coupled to small, but statistically significant, decrease in all skeletal muscle measurements. Significant increases in VAT and intermuscular fat in the thighs were also detected in the absence of changes in BMI, waist circumference and ectopic-fat deposition. Adjusting for disease status at the first imaging visit did not have an additional impact on the changes observed. In summary, we show that even after a relatively short period of time significant changes in body composition can take place, probably reflecting the obesogenic environment currently inhabited by most of the general population in the United Kingdom.

Lipopolysaccharide-induced splenic ferroptosis in goslings was alleviated by polysaccharide of atractylodes macrocephala koidz associated with proinflammatory factors

ABSRACTFerroptosis is a newly discovered form of cell death due to iron-dependent lipid peroxidation. In animal breeding, many environmental factors could lead to oxidative stress, which in turn reduce animal immunity and production performance. Polysaccharide of Atractylodes macrocephala Koidz (PAMK) has antioxidation, immunomodulatory, and inflammatory modulating effects. For investigating the effect of PAMK on splenic ferroptosis in gosling caused by lipopolysaccharide (LPS), 40 one-day-old Magang goslings were randomly divided into 4 groups (CON group, LPS group, PAMK group, and LPS+PAMK group). The protein expression of the ferroptosis marker Glutathione Peroxidase 4 (GPX4), the relative mRNA expression of ferroptosis-related genes and cytokines, and the oxidative stress and iron content of spleen tissues were examined. The correlation between ferroptosis and inflammatory factors was further analyzed by principal component analysis. The results showed that, compared with CON group, LPS caused alterations in the expression of the ferroptosis pathway genes and cytokines, which could upregulate levels of ferroptosis and inflammation. However, after treated with PAMK, the inflammation and ferroptosis was alleviated. Meanwhile, PAMK restored the expression and distribution of GPX4. In addition, PAMK alleviated the oxidative stress caused by LPS and reduced the iron content in spleen. Principal component analysis showed that cytokines were more closely related to antioxidant indexes. The CON, PAMK and LPS+PAMK groups had similar effects on the four components, with the LPS and PAMK groups showing the furthest difference in results. The result indicated that PAMK could reduce the level of oxidative stress and inflammatory cytokines in spleen of gosling caused by LPS, and jointly alleviate ferroptosis by regulating genes related to the ferroptosis pathway.

Iron supplementation ameliorates aloin-induced iron deficiency anemia in rats

Aloin, an anthraquinone glycoside, is one of other C-glycosides found in the leaf exudate of Aloe plant. Aloin possesses several biologic activities, including antitumor activity in vitro and in vivo. However, aloin treatment has shown iron deficiency anemia and erythropoiesis in vivo. The present study was undertaken to verify if iron supplementation could alleviate these perturbations, compared to doxorubicin, an anthracycline analog. Oral iron supplementation (20.56 mg elemental Fe/kg bw) to aloin-treated rats normalized red blood corpuscles count, hemoglobin concentration, and serum levels of total iron binding capacity and saturated transferrin, as well as hepatic iron content, hepcidin level, and mRNA expression of ferritin heavy chain (Ferr-H) and transferrin receptor-1 (TfR-1) genes. Although, serum hyperferremia, and leukocytosis were maintained, yet the spleen iron overload was substantially modulated. However, combined aloin and iron treatment increased iron storage levels in the heart and bone marrow, compared to aloin treatment per se. On other hand, oral iron supplementation to rats treated with doxorubicin (15 mg/kg bw) lessened the increase in the spleen iron content concomitantly with hepatic hepcidin level, rebound hepatic iron content to normal level, and by contrast augmented serum levels of iron and transferrin saturation. Also, activated Ferr-H mRNA expression and repressed TfR-1 mRNA expression were recorded, compared to doxorubicin treatment per se. Histopathological examination of the major body iron stores in rats supplemented with iron along with aloin or doxorubicin showed an increase in extramedullary hematopoiesis. In conclusion, iron supplementation restores the disturbances in iron homeostasis and erythropoiesis induced by aloin treatment.

Nutritional Yeast Ferritin-Iron Complex: A Novel Source of Dietary Iron

Iron deficiency anemia (IDA) is the leading nutritional disorder in the world. Iron deficiency (ID) occurs commonly in the US, particularly among children and women and in the elderly. Its impact on quality of life includes decreased cognitive ability and increased fatigue. Thus, there is clearly a need for effective and economical approaches to providing adequate dietary iron. We introduce nutritional yeast (S. cerevisiae) technologically modified to express human H-ferritin as a potential source of dietary iron. The efficacy of the yeast ferritin complex (YFC) was tested in established rat and monkey models of ID. In the rat model of ID, YFC improved hemoglobin (Hgb), hematocrit (Hct) levels as well as plasma iron and transferrin saturation and liver and spleen iron concentrations. Moreover, the YFC achieved a larger effect on Hgb and Hct with consumption of less iron compared to ferrous sulfate over a similar period. In the monkeys, YFC supplemented diet significantly improved Hgb levels within one month and increased mean corpuscular volume (MCV) by two months. To demonstrate that the Fe in the YFC was utilized by RBCs, we used a labeled isotope approach and found Fe from the ferritin in the monkeys’ RBCs with 5 days of consumption. This is the first attempt to use H-ferritin homopolymer as a nutritional iron source. Previous data from our laboratory and others have established H-ferritin as a significant iron delivery protein to the brain. Thus, H-ferritin appears to have a novel function as an iron delivery protein independent from its cooperation with L-ferritin to form an iron storage protein.

Iron Content and Cellular Proliferation in Thymus and Spleen of Hepatoma 22A Bearing Mice

Iron Content and Cellular Proliferation in Thymus and Spleen of Hepatoma 22A Bearing Mice