Iron Stores Research Articles

Vitamin E Induces Liver Iron Depletion and Alters Iron Regulation in Mice

BackgroundVitamin E (vit E) is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat nonalcoholic fatty liver disease, where it suppresses oxidative damage and impedes the progression of steatosis and fibrosis. Mice lacking a critical liver iron–trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vit E supplements. ObjectivesWe aimed to examine the role of dietary vit E supplementation in modulating iron-sensing regulatory systems and nonheme iron levels in mouse liver. MethodsC57Bl/6 male mice, aged 6 wk, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R-α-tocopherol (vit E) for 18 d. Mouse plasma and liver were analyzed for nonheme iron, levels and activity of iron homeostatic proteins, and markers of oxidative stress. We compared means ± SD for iron and oxidative stress parameters between mice fed the control diet and those fed the vit E diet. ResultsThe Vit E–fed mice exhibited lower levels of liver nonheme iron (38% reduction, P < 0.0001) and ferritin (74% reduction, P < 0.01) than control-fed mice. The levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced to 42% and 57% of the control, respectively. The mRNA levels for targets of nuclear factor erythroid 2–related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in vit E livers. Hepcidin, an iron regulatory hormone, levels were lower in the plasma (P < 0.05), and ferroportin (FPN), the iron exporter regulated by hepcidin, was expressed at higher levels in the liver (P < 0.05). ConclusionsOral vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver FPN. Iron depletion may indirectly enhance the antioxidative effects of vit E.

Unraveling the structure and function of bacterioferritin in Candidatus Kuenenia stuttgartiensis: Iron storage sites maintain cellular iron homeostasis

Anammox bacteria rely heavily on iron and have many iron storage sites. However, the biological significance of these iron storage sites has not been clearly defined. In this study, we explored the properties and location of iron storage sites to better understand their cellular function. To do this, the Candidatus Kuenenia stuttgartiensis iron storage protein, bacterioferritin (K.S Bfr), was successfully expressed and purified. In vitro, correctly assembled globulins were observed by transmission electron microscopy. The self-assembled K.S Bfr has active redox and can bind Fe2+ and mineralize it in the protein cavity. In vivo, engineered bacteria with K.S Bfr showed good adaptability to Fe2+, with a survival rate of 78.9% when exposed to 5 mM Fe2+, compared with only 66.0% for wild-type bacteria lacking K.S Bfr. A potential iron regulatory strategy similar to that of Anammox was identified in transcriptomic analysis of engineered bacteria. This system may be controlled by the iron uptake regulator Furto transport Fe2+ via FeoB and store excess Fe2+ in K.S Bfr to maintain cellular homeostasis. K.S Bfr has superior iron storage capacity both intracellularly and in vitro. The discovery of K.S Bfr reveals the storage location of iron-rich nanoparticles, increases our understanding of the adaptability of iron-dependent bacteria to Fe2+, and suggests possible iron regulation strategies in Anammox bacteria.

Pengaruh Delay Cord Clamping Terhadap Kadar Hemoglobin Bayi Baru Lahir Di PMB Diah Rosita Kabupaten Bogor Tahun 2022

Introduction: Delay Cord Clamping can increase iron storage at birth so as to prevent iron deficiency anemia and can provide an additional 80-100 ml of blood in newborns. The purpose of this study was to determine the effect of Delay Cord Clamping on the hemoglobin level of newborns in PMB Diah Rosita, Bogor Regency in 2022 Methods: This research is quantitative research. The design used is a quasi-experimental research design with Posttest Only Control Design Group Design Results: The results of this study are newborn hemoglobin levels in the intervention group averaged 18,320 and newborn hemoglobin levels in the control group averaged 15,500; statistical tests using Independent T-Test obtained a value of p = 0,000 &lt; 0,05 which means Ho is rejected and Ha is accepted so that there is an effect of Delay Cord Clamping on newborn hemoglobin levels Discussion: This can have a positive impact on newborns which is expected to be an alternative to prevent iron deficiency anemia in newborns.

Targeted resequencing reveals high-level mosaicism for a novel frameshift variant in WDR45 associated with beta-propeller protein-associated neurodegeneration

Objectives Beta-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant neurodegenerative disease, which is characterized by iron accumulation in the basal ganglia. BPAN is associated with pathogenic variation in WDR45, which has been reported almost exclusively in females most probably due to male lethality in the hemizygous state. Methods Whole exome sequencing (WES) and targeted deep sequencing were performed for a male with a clinical diagnosis of BPAN at the age of 37. Results The novel frameshift variant in WDR45 detected by WES was further analyzed with targeted resequencing to detect a mosaic variant with a level of 85.5% in the blood sample of the proband. Discussion Although the main role of WDR45 remains elusive, recent studies show that WDR45 may contribute to neurodegeneration through defects in autophagy, iron storage and ferritin metabolism, mitochondria organization, and endoplasmic reticulum homeostasis. The extend of spatiotemporal haploinsufficiency of WDR45 frameshifting variants caused by mosaicism in males may lead to variable clinical severity, which may be hard to elaborate clinically. Promising genetic analysis strategies using targeted deep sequencing may help determine the clinical outcome of somatic mosaicism in neurological disorders including BPAN. Additionally, we suggest that deep sequencing should be conducted in cerebrospinal fluid samples to provide more reliable results in terms of reflecting the mosaicism level in the brain for future studies.

Exocarpium Citri Grandis alleviates the aggravation of NAFLD by mitigating lipid accumulation and iron metabolism disorders

Ethnopharmacological relevanceExocarpium Citri grandis (ECG, Huajuhong in Chinese), the epicarp of C. grandis ‘Tomentosa’, has been used for hundreds of years as an anti-inflammatory, expectorant, hypoglycemic, and lipid-lowering medication in China. Nevertheless, there have been few papers that have explored the mechanism behind ECG's hypolipidemic characteristics from the perspective of treating nonalcoholic fatty liver disease (NAFLD). Aim of studyThe purpose of our study was to confirm the therapeutic and preventative effects of ECG in NAFLD by regulating lipid accumulation and iron metabolism, and to explore the specific mechanism of ECG in enhancing hepatic iron transport and excretion capabilities. Study designWe constructed a NAFLD model by feeding male C57BL/6 J mice with a high-fat diet for 12 weeks. Mice were gavaged with ECG beginning in the seventh week of modeling, and three dosage gradients were established: low dose group (2.5 g/kg/d), medium dose group (5 g/kg/d) y, and high dose group (10 g/kg/d) until the end of model construction in week 12. Materials and methodsWe used network pharmacology to analyze the relationship between ECG and NAFLD. In addition, we constructed a nonalcoholic fatty liver disease model by feeding male C57BL/6 J mice a high-fat diet for 12 weeks. Finally, lipid accumulation, iron accumulation, inflammation and oxidative stress were evaluated by serological index detection, histological detection, immunofluorescent and immunohistochemical staining, and western blotting. ResultsNetwork pharmacology confirmed the treatment effect of ECG in NAFLD. Three active components of ECG, including Naringenin, Naringin and Neohesperidin, were detected by UHPLC-HRMS analysis. The results of serum TC, TG, LDL concentration, HE staining, Oil red staining and Nile red staining demonstrated that ECG could improve lipid metabolism disorders. The results of serum iron concentration, liver tissue iron concentration, iron metabolism-related proteins Ferritin light chain, Ferroportin1, Transferrin receptor, and Transferrin demonstrated that ECG improved the iron transport and storage capacities of hepatic cells. ConclusionsOur results demonstrated that ECG relieved liver injury by inhibiting lipid accumulation and iron accumulation in NAFLD.

Hydrogen sulfide antagonizes formaldehyde-induced ferroptosis via preventing ferritinophagy by upregulation of GDF11 in HT22 cells

Formaldehyde (FA) has neurotoxic characteristics and causes neurodegenerative disease. Our previous study demonstrated the neuroprotective effects of hydrogen sulfide (H2S) on FA-induced neurotoxicity in HT22 cells. Emerging evidence have supported that ferroptosis is involved in FA-induced neurotoxicity. To understand the mechanism of the protection of H2S against FA-induced neurotoxicity, this study explored the regulatory effect of H2S on FA-induced ferroptosis and the underlying mechanisms. We found that H2S (100, 200, and 400 μM, 30 min) reverses the ferroptosis induced by FA (100 μM, 24 h) in HT22 cells (a cell line of mouse hippocampal neurons), including decreases in free iron, reactive oxygen species (ROS), 4-hydroxy-2-trans-nominal (4-HNE), and malondialdehyde (MDA) contents, as well as an increase in glutathione (GSH) content. H2S (100, 200, and 400 μM, 30 min) also inhibited ferritinaphagy in FA-exposed HT22 cells, as evidenced by the downregulation of the ferritinophagy receptor nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain-3B (LC3B) as well as the upregulation of the main iron storage protein ferritin heavy chain 1 (FTH1) and p62. H2S (100, 200, and 400 μM, 30 min) also up-regulated the expression of growth differentiation factor-11 (GDF11) in FA-exposed HT22 cells. Furthermore, knockdown of GDF11 in HT22 cells cancelled the beneficial effects of H2S on FA-induced ferroptosis and ferritinaphagy. These data indicated that the protective mechanism underlying H2S-prevented neurotoxicity of FA is involved in alleviating FA-induced ferroptosis via inhibiting ferritinaphagy by upregulation of GDF11.

The prevalence and risk factors associated with Iron, vitamin B12 and folate deficiencies in pregnant women: A cross-sectional study in Mbeya, Tanzania.

Maternal nutrition is an important forecaster of infant's and mother's health status in most developing countries. This study aimed at assessing the prevalence and associated risk factors of iron, vitamin B12, and folate deficiencies among pregnant women in Mbeya Tanzania. A cross-sectional study using a cluster randomized sampling was conducted among 420 pregnant women. A structured questionnaire was used to collect socio-demographic and dietary assessment. Body iron store was assessed using serum ferritin measured by immunoturbidimetric assays using a Roche Cobas 400+ biochemistry analyzer. Serum folate was measured by folate microbiological assay, while serum vitamin B12 was measured by immunochemiluminescence assay using a Roche Cobas e411 immunoassay analyzer. Multivariate analysis was performed using Poisson regression. The prevalence of iron, folate, and vitamin B12 deficiencies among pregnant women in Mbeya was 37.8%, 24.0%, and 9.7% respectively. Higher odds of iron deficiency were seen in pregnant women aged 20-24 years older [Adjusted OR = 1.20 (95%CI 1.03, 1.35)], not employed [Adjusted OR = 3.0(95%CI 1.03-1.77)] and, not received iron/folic acid supplementation [Adjusted OR = 1.11 (95%CI 1.003-1.23)]. Pregnant women with highest and middle socio-economic statuses had lower odds of vitamin B12 deficiency [Adjusted OR = 0.83 (95%CI 0.76-0.92)] and [Adjusted OR = 0.89 (95%CI 0.81-0.98)] respectively. Pregnant women who were not employed, not received iron and folic acid supplement during pregnancy and, not consumed edible vegetable cooking oil had significant higher odds of serum folate deficiency [Adjusted OR = 3.0 (95%CI 1.58-5.68)], [Adjusted OR = 1.53 (95%CI 1.21-1.93)] and, [Adjusted OR = 2.77 (1.03-7.44)] respectively. This study confirms that iron, folate and vitamin B12 deficiencies are still a major challenge among pregnant women in Tanzania. We recommend for public health interventions for the provision of vitamin B12 along with iron and folic acid supplementations, especially in pregnant women belong to low socio-economic status and limited knowledge of healthy diet.

Review and assessment of the donor safety among plasma donors.

Review and assessment of the donor safety among plasma donors.

Association of Body Iron Metabolism with Type 2 Diabetes Mellitus in Chinese Women of Childbearing Age: Results from the China Adult Chronic Disease and Nutrition Surveillance (2015).

High iron stores have been reported to be associated with type 2 diabetes mellitus (T2DM). However, evidence for the associations of iron metabolism with T2DM is inconsistent, and whether there is a threshold effect remains controversial. In the present study, we aimed to examine the associations between various iron biomarkers and the risk of T2DM as well as impaired glucose metabolism (IGM) and hyperglycemia in Chinese women of childbearing age. A total of 1145 women were divided into three groups (normal blood glucose metabolism group; IGM group; T2DM group). Biomarkers of iron metabolism (serum ferritin (SF), transferrin, soluble transferrin receptor (sTfR), transferrin saturation, serum iron, total body iron, and sTfR-to-lgferritin index) were measured. After adjusting for various confounding risk factors, SF and sTfR were positively associated with the risk of IGM (fourth vs. first quartile: SF odds ratio (OR) = 1.93 (95% CI 1.17-3.20) and sTfR OR = 3.08 (95% CI 1.84-5.14)) and T2DM (SF OR = 2.39 (95% CI 1.40-4.06) and sTfR OR = 3.84 (95% CI 2.53-5.83)). There was a nonlinear relationship between SF and risk of T2DM and hyperglycemia (p for nonlinearity < 0.01). Our findings suggested that SF and sTfR could be independent predictors of T2DM risk.

Molecular insights into placental iron transfer mechanisms and maternofetal regulation.

Adequate iron transportation from the mother across the placenta is crucial for fetal growth and establishing sufficient iron stores in neonates at birth. The past decade has marked significant discoveries in iron metabolism with the identification of new players and mechanisms. Immunohistochemical studies rendered valuable data on the localization of substantial iron transporters on placental syncytiotrophoblasts. However, the function and regulation of maternal-placentofetal iron transporters and iron handling is still elusive and requires more attention. A thorough literature review was conducted to gather information about placental iron transfer, the role of regulators and maintenance of iron homeostasis. The role of classical and new players in maternal-fetal iron transport and the regulation in the placenta has been addressed in this review. Animal and human studies have been discussed. The role of placental iron regulation in thalassemia and hemochromatosis pregnancies has been reviewed. The current advances that highlight the mechanisms of placental iron regulation and transport in response to maternal and fetal signals have been presented.

Methionine alleviates heat stress-induced ferroptosis in bovine mammary epithelial cells through the Nrf2 pathway

Heat stress (HS) triggers mammary gland degradation, accompanied by apoptosis and autophagy in bovine mammary epithelial cells, negatively affecting milk performance and mammary gland health. Ferroptosis is iron-mediated regulated cell death caused by over production of lipid peroxides, however, the relationship between ferroptosis and HS in bovine mammary epithelial cells has not been clarified. Methionine (Met) plays a notable role in alleviating HS affecting the mammary glands in dairy cows, but the underlying mechanisms require further exploration. Therefore, we evaluated the regulatory effect and mechanism of Met in alleviating HS-induced ferroptosis by using bovine mammary epithelial cell line (MAC-T) as an in vitro model. The results showed that Met improved cell vitality, restored mitochondrial function; reduced the content of various reactive oxygen species (ROS), especially hydrogen peroxide (H2O2) and superoxide anion (O2·-); had positive effects on antioxidant enzyme activity, namely glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). More importantly, Met reduced labile iron protein (LIP) levels; increased iron storage and simultaneously decreased the levels of lipid reactive oxygen species (lipid ROS) and malondialdehyde (MDA), which all caused by HS in MAC-T. Mechanistically, Met increased the protein expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7, member 11 (SLC7A11) and ferritin heavy chain 1 (FTH1) by activating nuclear factor E2-related factor 2 (Nrf2) expression. Additionally, the protection effect of Met was cut off in MAC-T cells after interference with Nrf2, manifesting in decresing the protein expression levels of GPX4, SLC7A11 and FTH1,and increasing the levels of LIP and lipid ROS. Our findings indicate that Met eases HS-induced ferroptosis in MAC-T through the Nrf2 pathway, revealing that Met produces a marked effect on easing HS-induced bovine mammary gland injury in dairy cows.

Teaching Neuro Images : Neurodegeneration with brain iron accumulation in aceruloplasminemia

A 55-year-old African Canadian man with insulin-dependent diabetes mellitus and alcohol abuse presented with diabetic ketoacidosis. Progressive cognitive decline over the previous 5 years resulted in long-term care placement. Aside from pigmentary retinopathy, general examination was unremarkable. MRI demonstrated iron accumulation in the brain (figure 1) and liver (figure 2A). Ceruloplasmin, a ferroxidase enzyme important in iron homeostasis, was undetectable and associated with low serum iron, low serum copper, and 10-fold increase in serum ferritin. Liver biopsy confirmed increased hepatocyte iron storage (figure 2B). Aceruloplasminemia was diagnosed.1,2 Iron chelation was not administered given advanced dementia at presentation.

Dithiolethiones D3T and ACDT Protect Against Iron Overload-Induced Cytotoxicity and Serve as Ferroptosis Inhibitors in U-87 MG Cells.

Iron overload-induced oxidative stress is implicated in various neurodegenerative disorders. Given the numerous adverse effects associated with current iron chelators, natural antioxidants are being explored as alternative therapeutic options. Dithiolethiones found in cruciferous vegetables have emerged as promising candidates against a wide range of toxicants owing to their lipophilic and cytoprotective properties. Here, we test the dithiolethiones 3H-1,2-dithiole-3-thione (D3T) and 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) against ferric ammonium citrate (FAC)-induced toxicity in U-87 MG astrocytoma cells. Exposure to 15mM FAC for 24h resulted in 54% cell death. A 24-h pretreatment with 50μM D3T and ACDT prevented this cytotoxicity. Both dithiolethiones exhibited antioxidant effects by activating the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor and upregulating levels of intracellular glutathione (GSH). This resulted in the successful inhibition of FAC-induced reactive oxygen species, lipid peroxidation, and cell death. Additionally, D3T and ACDT upregulated expression of the Nrf2-mediated iron storage protein ferritin which consequently reduced the total labile iron pool. A 24-h pretreatment with D3T and ACDT also prevented cell death induced by the ferroptosis inducer erastin by upregulating the transmembrane cystine/glutamate antiporter (xCT) expression. The resulting increase in intracellular GSH and alleviation of lipid peroxidation was comparable to that caused by ferrostatin-1, a specific ferroptosis inhibitor. Collectively, our findings demonstrate that dithiolethiones may show promise as potential therapeutic options for the treatment of iron overload disorders.

Anaemia among pregnant women: a review in Africa

Iron-deficiency anemia is the most frequent form of anemia in pregnancy and can have serious consequences for both the mother and fetus. The majority of women do not have adequate iron stores to meet the dramatic increase in requirements during the second and third trimester of pregnancy. However, there is increasing evidence that intravenous iron is more effective, provides more rapid haemoglobin correction, corrects iron stores and is better tolerated than oral iron in treating iron-deficiency anemia during pregnancy. The reported prevalence of anemia in this study is high and routine screening of pregnant women is highly recommended and further studies to explore during pregnancy is a public health problem in developed and developing countries. Pregnant women are at risk of developing anemia due to increased nutrient needs which include iron, folate and Vitamin B12 and haemo-dilution during pregnancy. Keywords: Anemia, heamoglobin, red cells, pregnancy, Africa.

PTEN-induced kinase PINK1 supports colorectal cancer growth by regulating the labile iron pool

Mitophagy is a cargo-specific autophagic process that recycles damaged mitochondria to promote mitochondrial turnover. PTEN-induced putative kinase 1 (PINK1) mediates the canonical mitophagic pathway. However, the role of PINK1 in diseases where mitophagy has been purported to play a role, such as colorectal cancer, is unclear. Our results here demonstrate that higher PINK1 expression is positively correlated with decreased colon cancer survival, and mitophagy is required for colon cancer growth. We show that doxycycline-inducible knockdown (KD) of PINK1 in a panel of colon cancer cell lines inhibited proliferation, whereas disruption of other mitophagy receptors did not impact cell growth. We observed that PINK KD led to a decrease in mitochondrial respiration, membrane hyperpolarization, accumulation of mitochondrial DNA, and depletion of antioxidant glutathione. In addition, mitochondria are important hubs for the utilization of iron and synthesizing iron-dependent cofactors such as heme and iron sulfur clusters. We observed an increase in the iron storage protein ferritin and a decreased labile iron pool in the PINK1 KD cells, but total cellular iron or markers of iron starvation/overload were not affected. Finally, cellular iron storage and the labile iron pool are maintainedviaautophagic degradation of ferritin (ferritinophagy). We found overexpressing nuclear receptor coactivator 4, a key adaptor for ferritinophagy, rescued cell growth and the labile iron pool in PINK1 KD cells. These results indicate that PINK1 integrates mitophagy and ferritinophagy to regulate intracellular iron availability and is essential for maintaining intracellular iron homeostasis to support survival and growth in colorectal cancer cells.

Ferritin as a potential disease marker in patients with bipolar disorder

BackgroundLow-grade inflammation and oxidative stress have been implicated as potential pathophysiological processes in bipolar disorder, but the underlying mechanism is unknown. Ferritin is a marker of iron stores and involved in redox processes and inflammation but its role in bipolar disorder is unclear. MethodsWe investigated the possible association of increased plasma ferritin levels and bipolar disorder. We pooled two studies using similar longitudinal repeated measures designs and included 330 blood- and urinary samples from 95 patients with bipolar disorder across all affective states and 84 samples from 84 healthy control individuals. Plasma ferritin was measured along with multiple blood inflammatory markers and urinary markers of oxidatively generated damage to DNA and RNA. ResultsPlasma ferritin levels, adjusting for multiple demographical- and lifestyle variables, did not differ between patients with bipolar disorder compared with healthy control individuals (b = 1.09, 95 % CI: 0.86 to 1.39, p = 0.49). Within patients with bipolar disorder ferritin levels were higher in a depressed state compared with euthymia (b = 1.12, 95 % CI: 1.01 to 1.24, p < 0.04), and ferritin levels were positively associated with Interleukin-18 blood levels and urinary levels of 8-oxodG. LimitationsPatients with bipolar disorder received medication which could potentially influence iron metabolism. ConclusionElevated ferritin levels in depressed patients with bipolar disorder may point to a role for iron metabolism in bipolar disorder pathophysiology, and potentially as a biomarker, linking low-grade inflammation with redox biology and the well-known increased risk of medical comorbidity and reduced life expectancy.

Industrial solutions for developing low-carbon technologies and achieving carbon neutrality

Aim.The presented study aims to analyze Russian and international experience in the development of measures aimed at reducing the negative impact of climate change and adapting to it; to examine the impact of certain regulatory mechanisms on the business of domestic manufacturing companies.Tasks.The authors investigate the experience of several Russian companies (through the example of ferrous metallurgy and the pulp and paper industry) in the introduction of innovative decarbonization technologies; assess the prospects for their use to achieve decarbonization.Methods.This study analyzes Russian and foreign scientific literature, information from open sources, analytical materials and statistics of international organizations. The subject of the study is the approaches to solving the problem of decarbonization and achieving carbon neutrality.Results.The ways to achieve carbon neutrality in ferrous metallurgy and the pulp and paper industry — the two industries that are major environmental pollutants — are considered in the context of measures aimed at combating the global processes of climate change and Russia’s strategy of socio-economic development with low greenhouse gas emissions until 2050. The prospects of an inertial way of achieving decarbonization and innovative options for the strategic development of low-carbon technologies are described. The prospects of a wider introduction of direct recovery technology in ferrous metallurgy are shown. In the pulp and paper industry, the possibilities of developing technologies for the production of nanocellulose based on the use of industrial waste are identified.Conclusions.From the perspective of responding to climate challenges and achieving the optimal economic effect in ferrous metallurgy, the most strategically justified choice seems to be in favor of an innovative way of structural sectoral transformations aimed towards decarbonization and achieving carbon neutrality by reducing the carbon intensity of production through methods of carbon dioxide capture, use, and storage, and direct reduction of iron based on hydrogen. This conclusion corresponds to the strategy for the development of metallurgy adopted in 2022, which orients the industry toward the development and implementation of innovative lowcarbon technologies. In the pulp and paper industry, it seems promising to conduct further research to obtain innovative technologies for the production of nanocellulose.

Role of oral iron supplementation for anemia secondary to acute nonvariceal upper gastrointestinal bleeding: a randomized controlled trial.

Although acute upper gastrointestinal bleeding (UGIB) can lead to anemia, evidence regarding the effects of oral iron supplementation on UGIB-induced anemia following discharge remains lacking. The present study aimed to investigate the effects of oral iron supplementation on hemoglobin response and iron storage in patients with anemia secondary to nonvariceal UGIB. This randomized controlled trial included 151 patients with nonvariceal UGIB who had anemia at discharge. Patients were assigned to a 1:1 block in which they were either administered 6weeks of 600mg/d oral ferrous fumarate (treatment group, n=77) or treated without iron supplementation (control group, n=74). The primary outcome was composite hemoglobin response (hemoglobin elevation greater than 2g/dL or no anemia at the end of treatment [EOT]). The proportion of patients achieving composite hemoglobin response was greater in the treatment group than in the control group (72.7% vs 45.9%; adjusted risk ratio [RR], 2.980; P=0.004). At EOT, the percentage change in the hemoglobin level (34.2±24.8% vs 19.4±19.9%; adjusted coefficient, 11.543; P<0.001) was significantly higher in the treatment group than in the control group; however, the proportions of patients with a serum ferritin level <30μg/L and a transferrin saturation <16% were lower in the treatment group (all P<0.05). No significant differences in treatment-associated adverse effects and adherence rates were observed between the groups. Oral iron supplementation exerts beneficial effects on anemia and iron storage following nonvariceal UGIB without significantly impacting rates of adverse effects or adherence.

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.

Abstract 4824: Intracellular ferritin expression levels regulate growth and resistance to ferroptosis in pancreatic cancer cell lines

Abstract Background: Pancreatic cancer is one of the cancers with the highest mortality rate, and it is important to develop effective treatments and elucidate prognostic factors. It has been reported that elevated serum ferritin is associated with the prognosis of pancreatic cancer. However, there are few reports on how ferritin in pancreatic cancer tissue acts in pancreatic cancer. Ferritin heavy chain (FTH) is a major component of ferritin, which stores iron and plays a role in suppressing iron-induced generation of reactive oxygen species. In this study, we aimed to examine the expression level of FTH in pancreatic cancer cells and its prognostic and cell biological roles. Methods: We performed immunostaining of FTH in pancreatic cancer tissue specimens operated on at our hospital and classified the expression level of FTH by scoring the immunostaining intensity and staining rate. The expression levels and prognosis were then evaluated. The overexpression and knockout strains of FTH were generated using a human pancreatic cancer cell line (MIAPaCa-2), and their proliferative and stress tolerance abilities were compared with those of the control group. Results: Immunostaining of 149 pancreatic cancer surgical specimens showed that the group with high FTH had a significantly shorter overall survival rate than the group with low FTH (5-year survival rate; 16.8% vs. 36.9%, p = 0.018). In multivariate analysis, high FTH expression was also a prognostic factor: in vitro, cell lines overexpressing FTH had enhanced proliferative potential compared to controls, while knockout lines were suppressed. In addition, the knockout lines showed decreased resistance to RSL-3, an inducer of ferroptosis. Additional studies are currently underway to examine resistance to other drugs and the production of reactive oxygen species in the cells. Conclusion: In pancreatic cancer, high ferritin expression is associated with worse prognosis and may enhance cell proliferation and stress tolerance, and might be a new treatment or biomarker. Citation Format: Masataka Maruno, Yo-hei Kanamori, Takashi Matsumoto, Yuta Shiraishi, Toru Takematsu, Tatsunori Miyata, Kosuke Mima, Shigeki Nakagawa, Hidetoshi Nitta, Hiromitsu Hayashi, Toshiro Moroishi, Hideo Baba. Intracellular ferritin expression levels regulate growth and resistance to ferroptosis in pancreatic cancer cell lines. [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 4824.