Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway.

BACKGROUND AND AIMS: Intravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart. METHODS: A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells. RESULTS: In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1. CONCLUSIONS: Intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium's limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart.

Protective Role for Smooth Muscle Cell Hepcidin in Abdominal Aortic Aneurysm.

BACKGROUND: Hepcidin is a liver-derived hormone that controls systemic iron homeostasis, by inhibiting the iron exporter ferroportin in the gut and spleen, respective sites of iron absorption and recycling. Hepcidin is also expressed ectopically in the context of cardiovascular disease. However, the precise role of ectopic hepcidin in underlying pathophysiology is unknown. In patients with abdominal aortic aneurysm (AAA), hepcidin is markedly induced in smooth muscle cells (SMCs) of the aneurysm wall and inversely correlated with the expression of LCN2 (lipocalin-2), a protein implicated in AAA pathology. In addition, plasma hepcidin levels were inversely correlated with aneurysm growth, suggesting hepcidin has a potential disease-modifying role. METHODS: To probe the role of SMC-derived hepcidin in the setting of AAA, we applied AngII (Angiotensin-II)-induced AAA model to mice harbouring an inducible, SMC-specific deletion of hepcidin. To determine whether SMC-derived hepcidin acted cell-autonomously, we also used mice harboring an inducible SMC-specific knock-in of hepcidin-resistant ferroportinC326Y. The involvement of LCN2 was established using a LCN2-neutralizing antibody. RESULTS: Mice with SMC-specific deletion of hepcidin or knock-in of hepcidin-resistant ferroportinC326Y had a heightened AAA phenotype compared with controls. In both models, SMCs exhibited raised ferroportin expression and reduced iron retention, accompanied by failure to suppress LCN2, impaired autophagy in SMCs, and greater aortic neutrophil infiltration. Pretreatment with LCN2-neutralizing antibody restored autophagy, reduced neutrophil infiltration, and prevented the heightened AAA phenotype. Finally, plasma hepcidin levels were consistently lower in mice with SMC-specific deletion of hepcidin than in controls, indicating that SMC-derived hepcidin contributes to the circulating pool in AAA. CONCLUSIONS: Hepcidin elevation in SMCs plays a protective role in the setting of AAA. These findings are the first demonstration of a protective rather than deleterious role for hepcidin in cardiovascular disease. They highlight the need to further explore the prognostic and therapeutic value of hepcidin outside disorders of iron homeostasis.

"I Do Not Have the Time of Being sick": Para-Occupational Exposure and Women's Health Risk Perception in an Agricultural Community.

INTRODUCTION: Few studies have explored the relationship between para-occupational exposure and risk perception in farmers' families. Women are indirectly involved in agricultural activities, even though their roles most of the time are hidden. Women's para-occupational exposure and risk perceptions are important to describe, since women have a key gender role in the family's health care and possibly in the impact of acting regarding pesticide safety education. Furthermore, in farmer families, the impact of para-occupational pesticide exposure on women's health has been neglected. AIM: Analyze pesticide para-occupational exposure scenario, knowledge, and health risk perception among women living in a farmer community. METHODS: A mixed methodology was used. Two groups of women were identified to screen the exposure scenario: Women living in a farming family and women not living in a farming family. Data on para-occupational pesticide exposure and intradomicile practices were collected by questionnaire and semi-structured interviews to identify health risk perception and risk practices. RESULTS: We observed a complex pesticide exposure scenario. All women were potentially exposed to pesticides through several pathways. One-third of the participants lived near a farming family or in proximity to neighbors that used pesticides at home, and one of every three women referred to spending time in a farmer's home. Among the group of women in a farming family (n = 18) stored pesticides inside the home was common; having the "safety practice" of storing pesticides in high places to avoid children being exposed. Women not living in farmimg families (n = 11) felt overexposed due to living in an agricultural community and agricultural drift exposure. Women from this group also mentioned feeling fear of developing cancerous diseases as well as fertility problems. CONCLUSIONS: Knowledge and risk perception of pesticide exposure are similar between groups; however, women living in farming families were less willing to attend preventive health check-ups or educational programs than women not living in a farming family.

Ferulic acid protects HepG2 cells and mouse liver from iron-induced damage.

Liver as iron storage organ is particularly susceptible to oxidative stress-induced injury from excess iron. Thus, antioxidant therapies are often used to reverse oxidative damage and protect cells and tissues. This study investigated the protective effects of phenolic acids; ferulic acid (FA) and its metabolite, ferulic acid 4-O-sulfate disodium salt (FAS) against oxidative stress under iron overload conditions in mouse and HepG2 cells. Cells were exposed to FA or FAS and then treated with iron-induced oxidative stress complex of 50 µmol/L FAC and 20 µmol/L of 8-hydroxyquinoline 8HQ (8HQ-FAC). Iron dextran was injected intraperitoneally on alternate days for 10 days to induce the iron overload condition in BALB/c mice. The study revealed that the phenolic acids were protective against ROS production, lipid peroxidation and antioxidant depletion in HepG2 cells and liver tissues of BALB/c mice during iron-induced oxidative stress. The protective function of phenolic acids was achieved by the transcriptional activation of nuclear factor erythroid-2-related factor 2 (Nrf2) to regulate antioxidant genes. In conclusion, the study provides evidence that FA has the potential as a therapeutic agent against iron-related diseases such as T2D.

Curcumin and (-)- Epigallocatechin-3-Gallate Protect Murine MIN6 Pancreatic Beta-Cells Against Iron Toxicity and Erastin-Induced Ferroptosis.

Ferroptosis is a form of programmed cell death that is characterized by lipid peroxidation and is inducible by iron and the accumulation of reactive oxygen species (ROS). It is triggered by erastin but inhibited by antioxidants such as -tocopherol, -carotene, polyphenols, and iron chelators such as deferoxamine (DFO), nitrilotriacetic acid (NTA), and ethylenediaminetetraacetic acid (EDTA). This study investigated the protective effects of two polyphenols, curcumin and (-)- epigallocatechin-3-gallate (EGCG), against iron loading and erastin-mediated ferroptosis in MIN6 cells. Cells were treated with polyphenols before exposure to iron-induced oxidative stress comprising of 20 µmol/L of 8-hydroxyquinoline (8HQ) and 50 µmol/L of ferric ammonium citrate, (FAC) (8HQ+FAC) or Fenton reaction substrate (FS) (30 µmol/L of FeSO4 and 0.5 of mmol/L H2O2) and 20 µmol/L erastin. Cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, iron levels were measured by inductively-coupled plasma mass spectrometry (ICP-MS), glutathione and lipid peroxidation were assayed with commercially-available kits. Curcumin and EGCG both significantly protected pancreatic cells against iron-induced oxidative damage. Moreover, both compounds also protected against erastin-induced ferroptosis in pancreatic cells. The polyphenols enhanced cell viability in erastin-treated MIN6 cells in a dose- and time-dependent manner. Furthermore, MIN6 cells exposed to erastin alone showed elevated levels of iron, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) degradation and lipid peroxidation (p < 0.05) compared to cells that were protected by pre-treatment with curcumin or EGCG. Taken together, the data identify curcumin and EGCG as novel ferroptosis inhibitors, which might exert their protective effects by acting as iron chelators and preventing GSH depletion, GPX4 inactivation, and lipid peroxidation in MIN6 cells. The implications of the findings on the effects of iron overload and ferroptosis represent a potential therapeutic strategy against iron-related diseases.

Protective Role of Histidine Supplementation Against Oxidative Stress Damage in the Management of Anemia of Chronic Kidney Disease.

Anemia is a major health condition associated with chronic kidney disease (CKD). A key underlying cause of this disorder is iron deficiency. Although intravenous iron treatment can be beneficial in correcting CKD-associated anemia, surplus iron can be detrimental and cause complications. Excessive generation of reactive oxygen species (ROS), particularly by mitochondria, leads to tissue oxidation and damage to DNA, proteins, and lipids. Oxidative stress increase in CKD has been further implicated in the pathogenesis of vascular calcification. Iron supplementation leads to the availability of excess free iron that is toxic and generates ROS that is linked, in turn, to inflammation, endothelial dysfunction, and cardiovascular disease. Histidine is indispensable to uremic patients because of the tendency toward negative plasma histidine levels. Histidine-deficient diets predispose healthy subjects to anemia and accentuate anemia in chronic uremic patients. Histidine is essential in globin synthesis and erythropoiesis and has also been implicated in the enhancement of iron absorption from human diets. Studies have found that L-histidine exhibits antioxidant capabilities, such as scavenging free radicals and chelating divalent metal ions, hence the advocacy for its use in improving oxidative stress in CKD. The current review advances and discusses evidence for iron-induced toxicity in CKD and the mechanisms by which histidine exerts cytoprotective functions.

In Vitro Iron Availability from Insects and Sirloin Beef.

Interest in the consumption of insects (entomophagy) as an alternative environmentally sustainable source of protein in the diet of humans has recently witnessed a surge. Knowledge of the nutrient composition and, in particular, the bioavailability of minerals from insects is currently sparse. This study evaluated the availability of Fe, Ca, Cu, Mg, Mn, and Zn from four commonly eaten insects and compared these to sirloin beef. Soluble iron from the samples was measured by inductively coupled plasma optical emission spectrometry (ICP-OES). Iron bioavailability was determined using an in vitro simulated peptic-pancreatic digestion, followed by measurement of ferritin (a surrogate marker for iron absorption) in Caco-2 cells. Cricket and sirloin beef had comparably higher levels of Fe, Ca, and Mn than grasshopper, meal, and buffalo worms. However, iron solubility was significantly higher from the insect samples than from beef. The complementation of whole-wheat flour with insect or beef protein resulted in overall decreases in mineral content and iron solubility in the composite mixtures. Collectively, the data show that grasshopper, cricket, and mealworms contain significantly higher chemically available Ca, Cu, Mg, Mn, and Zn than sirloin. However, buffalo worms and sirloin exhibited higher iron bioavailability comparable to that of FeSO4. Commonly consumed insect species could be excellent sources of bioavailable iron and could provide the platform for an alternative strategy for increased mineral intake in the diets of humans.