Changes In Iron Metabolism Research Articles

Mechanism of iron on the intestinal epithelium development in suckling piglets.

This study aimed to investigate the mechanism of iron on intestinal epithelium development of suckling piglets. Compared with newborn piglets, 7-day-old and 21-day-old piglets showed changes in the morphology of the jejunum, increased proliferation, differentiated epithelial cells, and expanded enteroids. Intestinal epithelium maturation markers and iron metabolism genes were significantly changed. These results suggest that lactation is a critical stage in intestinal epithelial development, accompanied by changes in iron metabolism. In addition, deferoxamine (DFO) treatment inhibited the activity of intestinal organoids at passage 4 (P4) of 0-day-old piglets, but no significant difference was observed in epithelial maturation markers at passage 1 (P1) and P4, and only argininosuccinate synthetase 1 (Ass1) and β-galactosidase (Gleb) were up-regulated at passage 7 (P7). These results in vitro show that iron deficiency may not directly affect intestinal epithelium development through intestinal stem cells (ISCs). The iron supplementation significantly down-regulated the mRNA expression of interleukin-22 receptor subunit alpha-2 (IL-22RA2) in the jejunum of piglets. Furthermore, the mRNA expression of IL-22 in 7-day-old piglets was significantly higher than that in 0-day-old piglets. Adult epithelial markers were significantly up-regulated in organoids treated with recombinant murine cytokine IL-22. Thus, IL-22 may play a key role in iron-affecting intestinal epithelium development.

Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells

Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. Although alterations in membrane lipid content are observed during ECM detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM detachment because of changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of ferritin sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy toward ECM-detached cells.

Abstract 1381: Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells

Abstract Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Ferroptosis is an iron dependent non-apoptotic cell death due to catastrophic accumulation of lipid peroxidation. While the mechanism that determines ferroptosis sensitivity has been extensively investigated in attached cells, how cells respond to ferroptosis under ECM detachment is largely unknown. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. While alterations in membrane lipid content are observed during ECM-detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM-detachment due to changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of iron storage proteins sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy towards ECM-detached cells. Citation Format: Jianping He, Abigail M. Abikoye, Brett P. McLaughlin, Ryan S. Middleton, Ryan Sheldon, Russell G. Jones, Zachary T. Schafer. Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1381.

Залізо: біохімічні, фармакологічні, клінічні дані

Iron is one of the most important macroelements in the body, which takes part in oxidation-reduction processes, and bioenergetics, and is a part of a number of enzymes. Iron deficiency is associated with food, pregnancy, fetal development, and some diseases. First of all, iron deficiency is established in iron-deficiency anemia, in addition to violations of biochemical indicators, immunological shifts and changes in the activity of vital organs and systems. The purpose of the study was to analyze the properties of iron and its preparations and their effects on the body. Materials and methods. On the topic of the study, a search and analysis of scientific literature was conducted in such databases as PubMed, Google Scholar, Scopus. Results and discussion. Iron reserves in the body are 3–6 g, the daily requirement is 20–30 mg. The need for iron increases in diseases with an increase in cardiac output, an increase in temperature, which requires taking drugs for oral and parenteral administration. In addition, if it is necessary to replenish iron reserves, it is recommended to take extracts from plants that contain it, such as common apricot (fruit pulp), blueberry fruits, beet roots, and common peach fruits. At the same time, it should be noted that iron can be in the oxidizing form of Fe2+ and the reduced form of Fe3+. It was determined that changes in iron metabolism and transport occur in pregnant women, which, in turn, is associated with changes in endothelial protective function. In modern methodological recommendations for the treatment of chronic heart failure, iron preparations are also included in the list of mandatory drugs, because in this condition, in addition to iron deficiency, disorders of the functions of the cardiovascular system have been found. A decrease in iron content has also been determined in various hypoxic conditions. Next they showed changes in iron metabolism in infectious diseases, such as COVID-19, tuberculosis, and HIV infection. In recent years, changes in iron content in neurodegenerative diseases have been noticed. Today, there are oral and parenteral iron preparations, but research is underway to create iron preparations that may have a more targeted effect and less toxicity. Conclusion. The current state of iron research in the functioning of vital organs and the occurrence of diseases presents scientists and clinicians with the task of involving new experimental and clinical methods to expand the understanding of the role of iron in pathobiochemical mechanisms, in pathological conditions, as well as the search for new approaches to treatment

Role of iron in the treatment of sepsis.

Iron is an important microelement in human and microbial life activities. During the pathophysiological process of sepsis, iron metabolism changes and the body undergoes a series of changes to fight microbial infection. Meanwhile, alterations in iron metabolism during sepsis lead to the development of some diseases, such as transfusion-induced siderosis and anemia. In recent years, several studies have demonstrated the use of iron-chelating agents to fight microbial infections, and new antimicrobial agents have been developed using "Trojan horse" and siderophores immunity. In addition, the use of iron-based nanomaterials as drug delivery systems for gene delivery may be applied to the treatment of sepsis in the future. In this review, we describe the pathophysiological changes in the development and course of sepsis, focusing on the potential of iron in the treatment of sepsis.

Direct effects of empagliflozin on erythropoiesis in heart failure: data from the Empire HF trial

Abstract Background Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a newly recommended treatment of heart failure with reduced ejection fraction (HFrEF). The consistently observed increase in haematocrit with SGLT2 inhibition is associated with a large proportion of the observed clinical benefit in different type 2 diabetes (T2D) populations. Whether the increase in haematocrit is caused by diuresis-associated haemoconcentration or is due to a direct effect on erythropoiesis is unknown. We have previously observed a decrease in ferritin alongside increases in haematocrit and haemoglobin with empagliflozin, thus indicating a direct effect on erythropoiesis. Purpose To investigate the effect of the SGLT2 inhibitor empagliflozin on erythropoiesis in patients with HFrEF. Methods The Empire HF trial was an investigator-initiated, double-blind, randomised, placebo-controlled trial conducted at two Danish university hospitals with enrolment of 190 patients from five outpatient heart failure clinics. Patients with a left ventricular ejection fraction (LVEF) of 40% or lower, with New York Heart Association (NYHA) Class I, II, or III symptoms, and on stable doses of guideline-directed HFrEF therapy were randomly assigned (1:1) to receive empagliflozin 10 mg or matching placebo once daily for 12 weeks. The present biomarker endpoints were analysed according to the intention-to-treat principle in analyses of covariance models with baseline adjustments. Results A minimum of 91 patients (96%) in each group had complete data and were included in the present analyses. Baseline characteristics were well-balanced between the allocated groups [mean age: 64 (SD 11) years; male: 85%; mean LVEF: 29 (SD 8) %; NYHA Class II: 78%; T2D: 13%; anaemia: 28%]. Serum-erythropoietin increased in the empagliflozin group compared to placebo from baseline to 12 weeks [adjusted mean difference 2.6 IU/L (95% CI 0.8–4.4; P=0.0052)]. Moreover, plasma-hepcidin decreased [adjusted ratio of change 0.68 (95% CI 0.22–1.02; P=0.067)], and mean corpuscular volume increased [adjusted ratio of change 1.01 (95% CI 1.00–1.02; P=0.0033)] compared to placebo, while no changes were observed for mean corpuscular haemoglobin concentration or plasma-iron (P>0.05). Conclusion The consistently observed increase in haematocrit with SGLT2 inhibitor treatment may not exclusively be due to diuresis-associated haemoconcentration as previously suspected. The present analyses suggest that empagliflozin increases erythropoiesis and induces changes in iron metabolism in a population of patients with HFrEF, primarily without diabetes. The observed decrease in hepcidin, and in ferritin as we have previously reported, further implies an anti-inflammatory effect, all of which may contribute to the cardioprotective properties of empagliflozin. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation;The A.P. Møller Foundation for the Advancement of Medical Science, Copenhagen, Denmark

DIFFERENCES IN THE FREQUENCY OF POLYMORPHISMS IN THE HFE GENE (H63D AND C282Y) IN A POPULATION GROUP FROM NORTHWEST SÃO PAULO, BRAZIL

Hereditary hemochromatosis (HH) is an autosomal recessive disease characterized by excess iron. People with polymorphisms in the HFE gene ( H63D and C282Y ) may develop inflammatory processes resulting from changes in iron metabolism. The ability of the HFE protein to make connections with transferrin receptors, located on cell membranes, allows it to help control the absorption of iron in the body. This work sought to investigate the frequency of HFE gene variants in a sample from the city of São José do Rio Preto, SP, Brazil. DNA samples from 105 people were subjected to molecular analysis to confirm mutations in the HFE gene ( H63D and C282Y ), using PCR-RFLP. The group was separated by male and female gender, age group of 10 in 10 years, and ethnic groups. Statistical analyzes were performed using the IBM SPSS Statistics 20 software and data were presented as percentages, with a significance level of 0.05. The associations between the wild-type homozygote, heterozygote, and mutant homozygote genotypes for each mutation were tested by the Chi-Square test. Then, the allele frequencies in the genotypes were calculated. Fisher's exact test was performed to verify the association between gender, age group, and ethnicity with mutations in the HFE gene. The sample included: 55 men (52.38%) and 50 women (47.62%), with ages ranging from 18 to 62 years, with an average of 30 years. A total of 210 alleles were evaluated and for the H63D mutation, 78 wild-type homozygotes, 26 heterozygotes, and 1 mutant homozygote were found. For the C282Y mutation, 99 wild-type homozygotes, 6 heterozygotes and no mutant homozygote were found. Allelic frequency analysis indicated the occurrence of significant differences between wild-type homozygous, heterozygous, and mutant homozygous genotypes for the mutations (p < 0.05). Fisher's exact test indicated no association between gender, age, and ethnicity for the H63D and C282Y polymorphisms (p > 0.05). The heterozygous genotype for H63D was more frequent in men (15-14%) than women 11 (10%). For C282Y equal frequencies (3-3%) were found for heterozygosity between men and women. H63D heterozygosity was more frequent in Caucasians (22-21%). In African-derived, only one individual was heterozygous for H63D . The frequency of HH genotypes varies among different populations. The low incidence or absence of homozygous alleles is due to the different degrees of miscegenation in the formation of the Brazilian population. The H63D mutation is an important marker for the Brazilian population, being frequent in Africa, although it has low phenotypic expression. The C282Y is predominantly associated with homozygosity for clinical cases, however, it is rare in African populations and frequent in Caucasians. Our results corroborate the data in the literature, with a predominance of the H63D mutation in Caucasians, African-derived, and Afro-descendants, and C282Y in Caucasians. The frequency of H63D and C282Y polymorphisms in the HFE gene showed a higher occurrence of heterozygotes for H63D in this population group. Studies to characterize HH are needed to devise strategies for effective support to patients and, therefore, improve quality of life.

Iron Metabolism Markers in Patients with Tuberculosis Combined with HIV Infection

Background. Changes of iron metabolism in patients with tuberculosis combined with HIV infection is an important task of phthisiology, since, on the one hand, iron deficiency can have a negative effect on the course of the tuberculous process. On the other hand, compensation for iron deficiency may be creating an iron overload situation, promoting replication of M. tuberculosis. Aims to study in a comparative aspect, changes in iron metabolism markers in patients with tuberculosis combined with HIV infection and without it. Methods. The study included 284 tuberculosis patients who were divided into 2 groups. The first group included 141 patients with tuberculosis combined with HIV (TB/HIV group). The comparison group consisted of 143 tuberculosis patients without HIV (TB group). The assessment of the bodys iron supply was carried out in terms of the concentration of serum iron, transferrin (TF), and ferritin (FT). The study was conducted separately in men and women, since the indicators of iron metabolism in healthy men and women differ significantly. Results. It was found that in men with TB/HIV patients, the decrease in serum iron less than the lower limit of the norm took place in 47.6%, and in the TB group in 27.3% of cases (p 0.01). The concentration of TF in the blood serum in the group of TB/HIV patients in men decreased in 69.9%, and in the group of TB patients in 31.2% of cases (p 0.01). The level of FT in the TB/HIV group increased in 19.4%, and in the TB group in 8.3% of cases (p 0.05). In women, a decrease in iron levels in the group of TB/HIV patients was observed in 39.5%, and in the TB group only in 2.2% of cases (p 0.01), a decrease in the level of TF was observed in 55.2% and 24.3% (p 0.01). A decrease in ferritin levels below 15 ng/ml was observed in 15.7% of women with TB/HIV and in 10.6% of TB patients. A negative relationship was found between iron content and CRP levels. Conclusion. The results of studied made it possible to conclude that in all cases the decrease in iron was caused not by a true deficiency of iron, but by its redistribution in the body. At the same time, a small number of women with tuberculosis combined with HIV infection and tuberculosis without HIV infection showed a significant decrease in ferritin levels, which indicated that they had a true iron deficiency.

Developmental changes in iron metabolism and erythropoiesis in mice with human gain-of-function erythropoietin receptor.

Iron availability for erythropoiesis is controlled by the iron-regulatory hormone hepcidin. Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain-of-function mutation of human EPO receptor (mtHEPOR) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3-6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age-related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive-mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose-dependent alterations of downstream EPOR stimulation.

Hypoxia inducible factor-prolyl hydroxylase inhibitors in anemic patients with non-dialysis dependent chronic kidney disease: a meta-analysis of randomized clinical trials.

Anemia persists as a challenge in chronic kidney disease (CKD) patients. Current therapies are the injectable erythropoietin stimulating agents (ESA). Concerns have been raised regarding ESA cardiovascular safety, therefore search for an alternative, convenient and safe therapy is underway. Hypoxia inducible factors-prolyl hydroxylase inhibitors (HIF-PHI) are oral agents with promising results. Numerous small studies reported favorable effects with lack of large, powered studies. We conducted a meta-analysis of randomized clinical trials to assess the efficacy and safety of HIF-PHI in non-dialysis-dependent CKD patients. Primary outcome was hemoglobin (Hb) concentration post intervention. Secondary outcomes were all-cause mortality, MACE, and changes in iron metabolism (ferritin, hepcidin). We reported total and serious adverse effects. Data were pooled using a random effect model via RevMan 5.4 software. We identified 7 trials comprising of 8228 patients (mean age 66.5 ± 13.2years, 42% were females, 53% used iron replacement) with a mean follow-up of 52weeks. Compared with the standard of care (ESA), HIF-PHI were non-inferior for treatment of anemia, with comparable effect on mortality and major adverse cardiovascular events. HIF-PHI showed no major safety concerns. Main side effect of HIF-PHI was diarrhea. HIF-PHI might represent a safe, and convenient alternative to ESA in non-dialysis dependent CKD patients with anemia.

P1597: THE DYNAMIC INTERACTION BETWEEN INFLAMMATION AND IRON SENSORS IN MALARIA-INDUCED ANEMIA

Background: Severe malarial anemia (SMA) is a complication developed during Plasmodium infection. It is often associated with increased rates of malaria-related morbidity and mortality, especially in children and pregnant women. Hence, it is fundamental to investigate new parameters to prevent this lethality. Aims: The occurrence of ineffective erythropoiesis, caused by a dysregulated erythropoietin (EPO)-erythropoietin receptor (EPOR) signaling pathway, is one of the main features of SMA. Therefore, to gain new insights into the pathogenesis of SMA, our study aims to better understand the dynamic interaction between erythropoiesis and inflammation in mice exposed to single or multiple infections, mimicking what occurs in endemic regions. Methods: Erythroid cell differentiation and immune cells activation were evaluated by flow cytometry. Changes in iron metabolism were assessed by the differences in expression of genes regulating iron homeostasis by qRT-PCR. Results: Flow cytometry analyses suggested that additional exposure to the parasite enhances erythropoiesis. Comparing infected with reinfected mice, we observed a faster erythropoietic response, induced by the bone marrow. It was also found that reinfected mice presented an earlier and robust immune response activation, as developing innate immune memory. Due to the fundamental role of iron in erythropoiesis and immune response activation, the expression of iron sensors, like HFE, was analyzed, detecting a strict correlation between disease severity and multiple infections exposure. The action of HFE in the pathogenesis of SMA and its role on the immune response activation, elicited to combat malaria, was also investigated. Preliminary data shows that when HFE knockout mice were infected with the parasite, their anemic profile improves. Summary/Conclusion: These reveals HFE as a potential target for drug therapy during hemolytic disorders, such as malaria infection.

Hemochromatosis Mimicked Gaucher Disease: Role of Hyperferritinemia in Evaluation of a Clinical Case.

Simple SummaryIn this paper, we describe the problem of diagnostic delay in Gaucher disease through the evaluation of a clinical case and how some clinical–instrumental parameters, such as hyperferritinemia should trigger an alarm bell in clinicians, inducing the clinical suspicion of Gaucher disease. In the described case of a 38-year-old man, the first diagnosis of hemochromatosis was updated to type 1 Gaucher disease years later. Analysis of the clinical case showed that the first diagnosis of hemochromatosis had been made almost exclusively based on a finding of high levels of ferritin and splenomegaly. Type 1 Gaucher disease and hereditary hemochromatosis show common clinical features, such as asthenia, joint pain, splenomegaly and hyperferritinemia. For this reason, in the presence of “unexplained hyperferritinemia” it is necessary to consider Gaucher disease in differential diagnosis, even if few typical signs and symptoms of the disease are present. The combination of a careful clinical history with simple first-level investigations may be sufficient to make differential diagnosis, also including rare conditions, such as Gaucher disease. Misdiagnosis and delayed diagnosis in metabolic diseases can lead to irreversible organ damage and a delayed start of specific therapy for these patients.Gaucher disease is a disorder of lysosomes caused by a functional defect of the glucocerebrosidase enzyme. The disease is mainly due to mutations in the GBA1 gene, which determines the gradual storage of glucosylceramide substrate in the patient’s macrophages. In this paper, we describe the case of a 38-year-old man who clinically presented with hyperferritinemia, thrombocytopenia, leukopenia, anemia and mild splenomegaly; a diagnosis of hemochromatosis was made 10 years earlier. Re-evaluation of the clinical case led to a suspicion of Gaucher disease, which was confirmed by enzymatic analysis, which was found to be below the normal range, and genetic evaluation, which identified compound heterozygosity N370S/RecNciI. We know that patients suffering from Gaucher disease can also have high ferritin levels. Even if the mechanism underlying the changes in iron metabolism is not yet elucidated, the chronic mild inflammatory state present in these patients probably causes the storage of ferritin in macrophages, resulting in hyperferritinemia. Therefore, in the presence of few typical signs and symptoms of the disease should raise an alarm bell in the clinicians, inducing clinical suspicion of Gaucher disease. Misdiagnosis and diagnostic delay in metabolic diseases could cause irreversible organ damage and delay the start of specific therapy for these patients.

Chronic Psychological Stress Disrupts Iron Metabolism and Enhances Hepatic Mitochondrial Function in Mice.

To explore the changes in iron metabolism and mitochondrial function exposed to chronic psychological stress, seventy-five male mice aged 5 ~ 6weeks were randomly sorted into 2 groups: control group and chronic psychological stress group. Mice were conducted by communication box to induce psychological stress for 21 consecutive days. The results showed that chronic psychological stress led to a significant reduction in average daily gain (P < 0.01) and the final weight (P < 0.05). Chronic psychological stress greatly increased plasma and duodenal iron level (P < 0.05), whereas markedly decreased hepatic iron content in mice (P < 0.05). Increasing expression of duodenal DCYTB and FPN (P < 0.05) was observed in mice exposed to chronic psychological stress. Moreover, chronic psychological stress greatly enhanced hepatic TFR1, FTL, and FPN protein expression (P < 0.05) in mice. Additionally, chronic psychological stress enhanced the levels of hepatic NADH, NAD + , ATP, mtDNA content, mtDNA-encoded genes, and the activity of mitochondrial complex I and II (P < 0.05). Taken together, chronic psychological stress impairs growth, disrupts iron metabolism, and enhances hepatic mitochondrial function in mice. These results will provide new insights for understanding the mechanisms of iron metabolism and mitochondrial function during chronic psychological stress.

ADHFE1 and C-MYC Association and Over-Expression in Different Stages of Human Breast Cancer Tissues

Chief enantiomer in breast tumors is D-2HG. Mitochondrial Alcohol Dehydrogenase (ADHFE I ) produces D-2HG. lt is the CA breast oncogene which leads to decreased patient survival. c-MYC can upregulate ADHFE I by changes in iron metabolism whereas co expression of c-MYC and ADHFE I greatly augment ort hotopic growth of tumor in MCF7 cells. Aims: To determine the expression levels and localization of c-M yc and ADHFE I in different stages of breast cancer tissue. Study Design: Cross-sectional comparative study. Methodology: Present study was conducted to enhance knowledge of c-Myc function in breast cancer by examination of relation between nuclear c-Myc and iron containing ADHFE I enz yme protein expression, using immunohist cichemistry. All this information was recorded on performa. Statistical analysis: Data was analyzed using SPSS version 25. Analysis of variance (ANOVA) test, was employed to observe mean difference between groups. Results: Nuclear c-Myc and cytoplasmic ADHFE I levels were significantly higher than controls and were positively correlated with each other in advancing stages of breast cancer. Conclusion: It was concluded that the association between the expression levels of c-Myc oncogene and ADHFE-1 enzyme existed in all advancing stages of CA Breast and the expression of both increased as the breast cancer advanced. Keywords: Breast cancer, c-Myc, ADHFE-I and Immunohistochemistry.

Iron promotes neurological function recovery in mice with ischemic stroke through endogenous repair mechanisms

The endogenous repair mechanisms play an important role in the recovery of nerve function after stroke, such as gliosis, synaptic plasticity, remyelination and nerve regeneration. Iron is the most abundant trace metal element in the brain and plays a crucial role in the maintenance of normal cerebral function. It is an important coenzyme factor in the process of cell metabolism, DNA synthesis, purine catabolism and neurotransmitter synthesis and decomposition. However, it is unclear what role iron plays in the long-term recovery of neurological function after stroke. In this study, we first observed that changes in iron metabolism occurred during neurological function recovery in the mice with distal middle cerebral artery occlusion (dMCAO). Our data showed that plasticity changes due to endogenous repair mechanisms resulted in improvements in cerebral cortex function. These changes involved gliosis, synaptic function reconstruction, remyelination, and activation of neural stem cells. In order to examine the potential role of iron, we synthesized liposomal-encapsulated deferoxamine (DFO) nanoparticles to further explore the effect and the mechanism of iron on the recovery of neurological function in dMCAO mice. Our results showed that liposome-DFO decreased iron deposition and reversed plasticity changes in cerebral cortex function after stroke, which delayed neurological function recovery. This experiment shows that the increasing iron level promotes endogenous repair in ischemic stroke. Our finding reveals the change regularity of iron and emphasizes the beneficial role of iron in the recovery process of neurological function, which provides an important basis for the prevention and/or treatment of ischemia-reperfusion and recovery after stroke.

MRI-Based Radiomic Signature Identifying Secondary Loss of Response to Infliximab in Crohn's Disease.

Up to 50% of patients with Crohn's disease (CD) experience secondary loss of response (SLR) to infliximab. Patients with SLR may show clinical signs of iron deficiency as a result of inflammation despite being iron-replete. The magnetic resonance imaging (MRI)-based radiomic index, R2*, can detect changes in iron metabolism. Therefore, the R2* parameter has considerable potential for detection of SLR to infliximab. The aims of this study were to explore the correlation between R2* and inflammation and to develop a non-invasive nomogram based on R2* to identify SLR to infliximab in patients with CD. Three hundred and twenty-two infliximab-treated patients with CD who underwent magnetic resonance enterography within 2 weeks before or after 54 weeks of infliximab therapy were divided into training and validation datasets at a ratio of 8:2. Point-biserial analysis was conducted to confirm the relationship between R2* and inflammation. A multivariate logistic regression model was created using R2*, CRP and hemoglobin (OR, 1.10, 1.04 and 0.98; P < 0.05). Receiver-operating characteristic curves and the Hosmer-Lemeshow test were used to assess the performance of the model. A correlation between R2* and inflammation was identified. Different trends in R2* and iron status indices were observed between patients with responsive and non-responsive CD, which is worthy of further study. The model was converted to a visualized nomogram that had a good ability to discriminate the outcomes of infliximab therapy with an area under the curve of 0.723 (95% CI, 0.661–0.785) in the training dataset and 0.715 (95% CI, 0.587–0.843) in the validation dataset. We confirmed a correlation between R2* and inflammation in patients with CD. Based on the MRI-based radiomic signature, a novel nomogram was established and validated to facilitate individualized identification of SLR to infliximab in patients with CD.

Effects of natural iron supplement intake on EPO, Hp, and iron metabolism during rapid weight loss in university wrestlers

Background: The purpose of this study was to determine the changes in erythropoiesis and iron metabolism indicators in order to improve the maintenance of athletic performance during rapid weight loss. Methods: The subjects were 23 university wrestlers (13 male, 10 female). The first measurements in the male and female groups after natural iron supplement intake indicated weight decreases of 6.2% and 5.8%, respectively. After the 3-week washout period, the weights in the male and female groups decreased by 6.1% and 6.2%, respectively. Results: Males in the intake group experienced changes in iron metabolism after weight loss, as shown by increases in the iron indicators (Fe, p &lt; 0.041; transferrin, p &lt; 0.004; total iron binding Capacity (TIBC), p &lt; 0.031), whereas the female group showed no significant changes. Both groups experienced decreases in erythropoietin (males, p &lt; 0.021; females, p &lt; 0.027) and VO2max (p &lt;0.001) after weight loss. Blood lactate in the intake group decreased after maximal exercise immediately after the test for the male group (p &lt;0.031) and during resting time and immediately after exercise in the female group (p &lt; 0.001 and p &lt; 0.050, respectively). Conclisions: These findings suggest that a 7% loss in weight does not positively affect athletic ability. Further research on methods for iron supplement intake, weight loss, and training is necessary to confirm our conclusions.

Relationship between Iron Profile and Thyroid Profile in Hypothyroid Patients

Introduction: Thyroid hormone biosynthesis is dependent on iron metabolism. Changes in iron metabolism and its deficiency may cause a change in the profile of thyroid hormone. Such interferences caused can lead to hypothyroidism in case of anaemia or the other way round. Aim: To find a relationship between various parameters of iron profile to that of thyroid profile in hypothyroid patients when compared to normal healthy subjects. Materials and Methods: Present case-control study was conducted on 50 hypothyroid patients and 50 healthy subjects of same age, in the Department of Endocrinology, IGIMS, Patna between April 2017 to June 2018. Serum ferritin and Serum T3, T4, and Thyroid Stimulating Hormone (TSH) were estimated by Chemiluminescence Immuno Assay (CLIA) method. Serum iron estimation was done using TPTZ (2,4,6-Tripyridyl-s-triazine) method and Total Iron Binding Capacity (TIBC) estimation was done by Nitroso PSAP method. All statistical test and analysis were performed in Statistical Package for the Social Science (SPSS) 16.0. The differences between mean values of groups for each test variable were tested by Student’s t-test after testing for homogeneity of variance and normality test (Kolmogorov-Smirnov test). Results: The mean age of the hypothyroid patients was 30.28±10.5 years while it was 31.14±10.4 years in control group. It was observed from the study that mean serum ferritin level and iron level were significantly lower in hypothyroid subjects compared to control groups (p&lt;0.001) while TIBC was significantly higher (p&lt;0.001). Serum ferritin and iron were found to be negatively correlated with TSH (-0.695 and -0.541) and positively correlated to T3 and T4, respectively. Conclusion: Evaluating iron profile in thyroid disorder may be an aid to the treatment modality and disease outcome

The disorder of the iron metabolism as a possible mechanism for the development of neurodegeneration after new coronavirus infection of SARS-CoV-2

The involvement of the nervous system in the pathological process that occurs when COVID-19 is infected is becoming more and more obvious. The question of the possibility of the debut or progression of the already developed Parkinsonism syndrome in patients who have undergone COVID-19 is regularly raised. A large number of hypotheses are put forward to explain this relationship. It is assumed that a violation of iron metabolism in the brain may underlie the development and progression of neurodegenerative diseases, including after the new coronavirus infection SARS-CoV-2. The analysis of stu dies on the possible influence of iron metabolism disorders on the occurrence and mechanism of development of neurodegenerative diseases after infection with SARS-CoV-2 has been carried out. The processes of physiological maintenance of iron homeostasis, as well as the influence of physiological aging on the accumulation of iron in the central nervous system are described. The relationship between hyperferritinemia occurring in COVID-19 and ferroptosis as the basis of the neurodegenerative process in Parkinsons disease and Alzheimers disease is discussed. The main molecular mechanisms involved in ferroptosis are described. Examples of involvement of metal homeostasis disorders in the process of altering the structure of -synuclein, synthesis of -amyloid, hyperphosphorylated tau- protein are given. The causes of excessive iron accumulation in certain brain structures are discussed. The question of the possibility of using the assessment of changes in iron metabolism as a new biomarker of the progression of Parkinsons disease is analyzed. (1 figure, bibliography: 62 refs)

Monthly Continuous Erythropoietin Receptor Activator Versus Weekly Epoetin-Beta, Similar Hemoglobinization but Different Anisocytosis Degree in Hemodialysis Patients: A Randomized Controlled Trial.

BackgroundThe monthly continuous erythropoietin receptor activator (CERA) utilization maintains stable hemoglobin (Hb) after conversion from weekly epoetin-β (EB); however, how the different pharmacologic properties affect the red blood cell (RBC) size determined by RBC distribution width (RDW) has not been evaluated yet. We assess the potential differences in iron metabolism, plasma erythropoietin (EPO), hepcidin, and soluble α-Klotho (α-Klotho) levels as an emergent hematopoiesis factor.MethodsThirty-seven chronic hemodialysis patients were included from January 2010 to November 2011 and randomized (1:1) to continue with EB or to convert to monthly CERA. Primary outcome was the mean change in Hb between groups at months 0, 3 and 6, and the percentage of patients who maintained stable Hb (Hb ± 1 g/dL from baseline level to month 6). Secondary outcomes were the influence on the erythropoietic process and iron metabolism markers. Thirty-one patients completed the study (CERA: n = 15, EB: n = 16).ResultsThe mean (95% confidence interval (CI)) Hb difference between groups was 0.28 g/dL (-0.36 to 0.93). There was no difference between the percentages of patients with stable Hb levels. In the CERA group RDW values increased progressively (interaction erythropoietin-stimulating agent (ESA) type and time on RDW values, F (1.57, 45.60) = 17.17, P < 0.01, partial η2 = 0.37) and the mean corpuscular volume changed at the different time points, (F (2, 28) = 29.12, P = 0.03, partial η2 = 0.23). During the evaluation period, in the CERA group, EPO was higher, and hepcidin and ferritin decreased significantly. α-Klotho decreased in both groups and correlated negatively with the changes on the RDW and positively with transferrin and serum iron. The number of serious adverse events was higher at the CERA group.ConclusionsMonthly CERA maintained Hb concentrations; however, it showed a significant effect on RDW, probably due to its impact on the EPO and hepcidin levels. α-Klotho decreased significantly in both groups, and its changes correlated with the changes in iron metabolism. Whether the RDW evolution was associated with the serious adverse events (SAEs) is a feasible hypothesis that needs to be confirmed in large studies.