Iron Metabolism Processes Research Articles

Ferroptosis and its role in gastric and colorectal cancers.

Ferroptosis is a novel mechanism of programmed cell death, characterized by intracellular iron overload, intensified lipid peroxidation, and abnormal accumulation of reactive oxygen species, which ultimately resulting in cell membrane impairment and demise. Research has revealed that cancer cells exhibit a greater demand for iron compared to normal cells, indicating a potential susceptibility of cancer cells to ferroptosis. Stomach and colorectal cancers are common gastrointestinal malignancies, and their elevated occurrence and mortality rates render them a global health concern. Despite significant advancements in medical treatments, certain unfavorable consequences and drug resistance persist. Consequently, directing attention towards the phenomenon of ferroptosis in gastric and colorectal cancers holds promise for enhancing therapeutic efficacy. This review aims to elucidate the intricate cellular metabolism associated with ferroptosis, encompassing lipid and amino acid metabolism, as well as iron metabolic processes. Furthermore, the significance of ferroptosis in the context of gastric and colorectal cancer is thoroughly examined and discussed.

TGF-β-regulated different iron metabolism processes in the development and cisplatin resistance of ovarian cancer.

The impact of different iron metabolism processes (DIMP) on ovarian cancer remains unclear. In this study, we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer. cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer. Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer. By analyzing 1669 serous ovarian cancer cases, we identified a range of mutations in iron metabolism genes, notably in those coding for the transferrin receptor (19%), melanotransferrin (19%), and ceruloplasmin (10%) in the iron import process, and glucose-6-phosphate isomerase (9%), hepcidin antimicrobial peptide (9%), metal regulatory transcription factor 1 (8%), and bone morphogenetic protein 6 (8%) in the iron regulation process. Compared to the unaltered group, the group with gene alterations exhibited a higher tumor mutation burden count (43 vs. 54) and more advanced histologic grade (78.19% vs. 87.90%). Compared to the normal ovarian counterparts, a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer; in contrast, an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer. Furthermore, in cisplatin-resistant cells compared to cisplatin-sensitive ones, the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased, while that of 8 out of the 10 genes in iron utilization was increased. In addition, survival curve analysis indicated that a higher expression in the majority of genes in the iron import process (12/21), or a reduced expression in most genes in the iron export process (4/5) correlated with poor progression-free survival. Additionally, TGF-β could regulate the expression of most iron metabolism-associated genes; particularly, expression of genes involved in the iron storage process (2/2) was inhibited after TGF-β1 or TGF-β2 treatment. In conclusion, DIMP plays multifaceted roles in the initiation, chemo-resistance, and prognosis of ovarian cancer. Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.

Nutrient vitamins enabled metabolic regulation of ferroptosis via reactive oxygen species biology.

Vitamins are dietary components necessary for cellular metabolic balance, especially redox homeostasis; deficient or excessive supply may give rise to symptoms of psychiatric disorders. Exploring the nutritional and metabolic pathways of vitamins could contribute to uncovering the underlying pathogenesis of ferroptosis-associated diseases. This mini-review aims to provide insights into vitamins closely linked to the regulation of ferroptosis from the perspective of cellular reactive oxygen species biology. The mainstream reprogramming mechanisms of ferroptosis are overviewed, focusing on unique biological processes of iron metabolism, lipid metabolism, and amino acid metabolism. Moreover, recent breakthroughs in therapeutic interventions targeting ferroptosis via fully utilizing vitamin-based pharmacological tools were overviewed, covering vitamins (B, C, E, and K). Finally, mechanism insight related to vitamin-associated nutrient signaling was provided, highlighting the pharmacological benefits of metabolically reprogramming ferroptosis-associated diseases.

The Interaction between Psychological Stress and Iron Status on Early-Life Neurodevelopmental Outcomes.

This review presents evidence from animal and human studies demonstrating the possible connection and significant impact of poor iron status and psychological distress on neurocognitive development during pregnancy and the neonatal period, with implications for long-term cognition. Stress and iron deficiency are independently prevalent and thus are frequently comorbid. While iron deficiency and early-life stress independently contribute to long-term neurodevelopmental alterations, their combined effects remain underexplored. Psychological stress responses may engage similar pathways as infectious stress, which alters fundamental iron metabolism processes and cause functional tissue-level iron deficiency. Psychological stress, analogous to but to a lesser degree than infectious stress, activates the hypothalamic-pituitary-adrenocortical (HPA) axis and increases proinflammatory cytokines. Chronic or severe stress is associated with dysregulated HPA axis functioning and a proinflammatory state. This dysregulation may disrupt iron absorption and utilization, likely mediated by the IL-6 activation of hepcidin, a molecule that impedes iron absorption and redistributes total body iron. This narrative review highlights suggestive studies investigating the relationship between psychological stress and iron status and outlines hypothesized mechanistic pathways connecting psychological stress exposure and iron metabolism. We examine findings regarding the overlapping impacts of early stress exposure to iron deficiency and children's neurocognitive development. We propose that studying the influence of psychological stress on iron metabolism is crucial for comprehending neurocognitive development in children exposed to prenatal and early postnatal stressors and for children at risk of early iron insufficiency. We recommend future directions for dual-exposure studies exploring iron as a potential mediating pathway between early stress and offspring neurodevelopment, offering opportunities for targeted interventions.

Негормональна профілактики і лікування функціональних порушень менструального циклу в пубертатний період

Introduction. Functional abnormalities of the menstrual cycle in the pubertal period can lead to deep disturbances with the subsequent formation of structural pathological changes in the reproductive system Aim. To study the possibilities of non-hormonal drug correction of menstrual cycle disorders and prevention of relapses and anemic syndrome in girls during puberty. Materials and methods. 180 girls aged 12-16 years with menstrual cycle disorders against the background of functioning atretic follicles were examined. A standardized approach was used during the interview of each patient, the data of the ultrasound examination of the pelvic organs, the condition of the hypothalamic-pituitary-ovarian system, the nature of the menogram, and the parameters of the hemogram were evaluated. In the first group, symptomatic treatment was recommended, in the second group, over the course of 6 months, the medicine tazalak was additionally prescribed according to the manufacturer's recommendations. Research results and their discussion. It has been found that menstrual cycle disorders are caused by hormonal imbalance and lead to iron deficiency anemia. The use of standard therapy does not give a sufficient clinical effect or is short-lived. In order to normalize the hormonal status and menstrual cycle and reduce menstrual blood loss, it is advisable to prescribe herbal preparations, which, in combination with the appointment of anti-anemic treatment, have shown significant advantages over generally accepted standard approaches in terms of normalizing the hormonal balance, parameters of the menstrual cycle, and processes of iron metabolism in the body. Conclusions. Advice on diet therapy, stress relief, lifestyle correction, and prescribing treatment according to current clinical protocols against the background of phytotherapy is necessary. Restoring normal menstrual function in adolescent girls is an essential measure for the prevention of reproductive health disorders in the future, which allows us to consider this issue as an important medical and social problem.

Серологический анализ протеома детей, рожденных от матерей с гестационным или второго типа сахарным диабетом

Objective. Determination the impact of pregnancy course on the background of gestational diabetes mellitus (GDM) or type 2 diabetes mellitus (T2DM) on the serological proteome of children under 1.5 years of age. Patients and methods. Blood plasma samples of 110 children aged 1.35 ± 0.4 years old (Me = 1.27 years old, 46 boys, 64 girls) from mothers with a pregnancy occurring against the background of T2DM (n = 32) or GDM established for the first time (n = 42, of which 20 – from mothers with insulin-dependent therapy, 22 – from mothers with diet therapy) and 36 children of the control group were studied. The study was performed using a semiquantitative proteomic approach with consideration of serological markers representation, redundancy and statistically significant differences betweeb groups of the study. Results. Children born to diabetic mothers are differed from the control group by a small part of the proteome. The proteins AFM, GSN, APOA2, TF, SERPINA7, RBP4, ORM1, and some elements of the complement system were most affected by mothers diabetic condition. The hange in proteins abundancy ranged betwee 20-80%. There was no correlation with the treatment strategy for the GDM group of patients. Conclusion. The degree of quantitiative alteration in the children proteome depends on the mothers diabetic condition over the pregnancy. The most profound alteration were observed amongst serological markers indicating the risk of metabolic disorders, carbohydrate metabolism, protein glycosylation and associated processes of iron metabolism and extracellular matrix organization. Key words: gestational diabetes, type 2 diabetes mellitus, children's serum proteome

Iron Metabolism, Pseudohypha Production, and Biofilm Formation through a Multicopper Oxidase in the Human-Pathogenic Fungus Candida parapsilosis.

Among all the essential micronutrients, iron plays an important role in mammalian biology. It is also essential for pathogens infecting mammalian hosts, including bacteria, fungi, and protozoans. As the availability of accessible iron is limited within the mammalian host, several human-pathogenic fungal pathogens, such as Candida albicans, Cryptococcus neoformans, Candida glabrata, and Aspergillus fumigatus, have developed various iron uptake mechanisms. Although Candida parapsilosis is the second or third most common non-albicans Candida species associated with systemic and superficial Candida infections in immunocompromised patients, the mechanisms of iron uptake and homoeostasis remain unknown in this fungus. In the current report, we show that a homologue of the multicopper oxidase gene FET3 is present in the genome of C. parapsilosis (CPAR2_603600) and plays a significant role in iron acquisition. We found that homozygous deletion mutants of CPAR2_603600 showed defects under low-iron conditions and were also sensitive to various stressors. Our results also revealed that the levels of pseudohypha formation and biofilm formation were reduced in the null mutants compared to the wild type. This phenotypic defect could be partially rescued by supplementation with excess iron in the growth medium. The expression levels of the orthologues of various iron metabolism-related genes were also altered in the mutants compared to the parental strain. In conclusion, our report describes the role of CPAR2_603600 in iron homoeostasis maintenance as well as morphology and biofilm formation regulation in this pathogenic fungus.IMPORTANCEC. parapsilosis is the second or third most common opportunistic human-pathogenic Candida species, being responsible for severe fungal infections among immunocompromised patients, especially low-birth-weight infants (0 to 2 years of age). Among the major virulence factors that pathogenic fungi possess is the ability to compete with the host for essential micronutrients, including iron. Accessible iron is required for the maintenance of several metabolic processes. In order to obtain accessible iron from the host, pathogenic fungi have developed several iron acquisition and metabolic mechanisms. Although C. parapsilosis is a frequent cause of invasive candidiasis, little is known about what iron metabolic processes this fungus possesses that could contribute to the species' virulent behavior. In this study, we identified the multicopper oxidase FET3 gene that regulates iron homeostasis maintenance and also plays important roles in the morphology of the fungus as well as in biofilm formation, two additional factors in fungal virulence.

Iron in neurodegenerative disorders: being in the wrong place at the wrong time?

Brain iron deposits have been reported consistently in imaging and histologic examinations of patients with neurodegenerative disorders. While the origins of this finding have not been clarified yet, it is speculated that impaired iron homeostasis or deficient transport mechanisms result in the accumulation of this highly toxic metal ultimately leading to formation of reactive oxygen species and cell death. On the other hand, there are also those who support that iron is just an incidental finding, a by product of neuronal loss. A literature review has been performed in order to present the key findings in support of the iron hypothesis of neurodegeneration, as well as to identify conditions causing or resulting from iron overload and compare and contrast their features with the most prominent neurodegenerative disorders. There is an abundance of experimental and observational findings in support of the hypothesis in question; however, as neurodegeneration is a rare incident of commonly encountered iron-associated disorders of the nervous system, and this metal is found in non-neurodegenerative disorders as well, it is possible that iron is the result or even an incidental finding in neurodegeneration. Understanding the underlying processes of iron metabolism in the brain and particularly its release during cell damage is expected to provide a deeper understanding of the origins of neurodegeneration in the years to come.

Research progress of iron metabolism in critical ill patients

Iron is an essential nutrient element for human, but has potential toxicity. Under physiological conditions, the processes of iron absorption, transportation, cellular uptake and utilization, storage, release, excretion as well as regulation of iron metabolism maintain the iron homeostasis. However under pathological conditions, the iron metabolism changes and is associated with the pathological states. In order to realize the relationship between the critical illness status and the iron metabolism, we start with an analysis of the basic processes of iron metabolism in human and the toxicity of iron, followed by summary on the alteration of iron metabolism in the settings of pathological conditions, such as inflammation, infection and anemia, which often occur in critical illness. Then, we discuss the relationship between the prognosis and the parameters of iron metabolism. Moreover, we review the current researches on treatments related to iron metabolism, which involve the iron supplementation, iron chelation and agents regulating iron metabolism.

New developments and controversies in iron metabolism and iron chelation therapy.

Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies.

Expression of ABCG2 (BCRP) in mouse models with enhanced erythropoiesis.

Haem is a structural component of numerous cellular proteins which contributes significantly to iron metabolic processes in mammals but its toxicity demands that cellular levels must be tightly regulated. Breast Cancer Resistance Protein (BCRP/ABCG2), an ATP Binding Cassette G-member protein has been shown to possess porphyrin/haem efflux function. The current study evaluated the expression and regulation of Abcg2 mRNA and protein levels in mouse tissues involved in erythropoiesis. Abcg2 mRNA expression was enhanced in bone marrow hemopoietic progenitor cells from mice that were treated with phenylhydrazine (PHZ). Abcg2 mRNA expression was increased particularly in the extramedullary haematopoietic tissues from all the mice models with enhanced erythropoiesis. Haem oxygenase (ho1) levels tended to increase in the liver of mice with enhanced erythropoiesis and gene expression patterns differed from those observed in the spleen. Efflux of haem biosynthetic metabolites might be dependent on the relative abundance of Abcg2 or ho1 during erythropoiesis. Abcg2 appears to act principally as a safety valve regulating porphyrin levels during the early stages of erythropoiesis and its role in systemic haem metabolism and erythrophagocytosis, in particular, awaits further clarification.

Iron Biomarker in Gestational Diabetes Pathogenesis

Gestational diabetes mellitus (GDM) is observed to be associated with increased perinatal morbidity and mortality. Screening for glucose intolerance during pregnancy provides an opportunity to offer management to those women diagnosed with gestational diabetes mellitus after first trimester. Elevated iron stores may induce diabetes through a variety of mechanisms, including oxidative damage to pancreatic beta cells, impairment of hepatic insulin extraction by the liver, and interference with insulin's ability to suppress hepatic glucose production. Raised Serum Ferritin could be related to the occurrence of long term complications of diabetes, both micro vascular and macro vascular. Iron affects glucose metabolism and glucose metabolism impinges on several iron metabolic processes. Iron overload decreases insulin sensitivity and cause earlier complications in diabetes mellitus. Iron plays a direct and causal role in diabetes pathogenesis mediated both by cell failure and insulin resistance. Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role.

Design of Iron chelators: Syntheses and iron (III) complexing abilities of tripodal tris-bidentate ligands

The interest in synthetic siderophore mimics includes therapeutic applications (iron chelation therapy), the design of more effective agents to deliver Fe to plants and the development of new chemical tools in order to study iron metabolism and iron assimilation processes in living systems. The design of ligands needs a rational approach for the understanding of the metal ion complexing abilities. The octahedral arrangement of donor atoms is the most favourable geometry, allowing the maximum possible distance between their formal or partial negative charges. Hexadentate chelators, usually of the tris-bidentate type, can accommodate the metal coordination sphere and are well-suited to obtain high pFe values. The first part of this review is dedicated to selected synthetic routes, taking into account (i) the nature of the chelating subunits, connecting groups and spacers, (ii) the water-solubility and hydrophilic/lipophilic balance, (iii) the chirality and (iv) the possibility of grafting probes or vectors. In the second part, we discuss the role of the molecular design on complexing abilities (thermodynamics and kinetics). The bidentate 8-hydroxyquinoline moiety offers an alternative to the usual coordinating hydroxamic acids, catechols and/or alpha-hydroxycarboxylic acids groups encountered in natural siderophores. The promizing results obtained with the tris-hydroxyquinoline-based ligand O-TRENSOX are summarized. O-TRENSOX exhibits a high and selective affinity for Fe(III) complexation. Its efficiency in delivering Fe to plants, iron mobilization, cell protection, and antiproliferative effects has been evidenced. Other chelators derived from O-TRENSOX (mixed catechol/8-hydroxyquinoline ligands, lipophilic ligands) are also described. Some results question the relevance of partition coefficients to foresee the activity of iron chelators. The development of probes (fluorescent, radioactive, spin labelled) based on the O-TRENSOX backbone is in progress in order to get insights in the complicated iron metabolism processes.

Iron uptake byBifidobacterium thermophilum protoplasts

Protoplasts of Bifidobacterium thermophilum were prepared by a combination of lysozyme and protease digestion, and ferrous iron uptake studies were carried out. Little, if any, iron was internalized by the protoplasts, although large amounts of iron were bound to the protoplast surface. This binding was much greater than that of intact cells, which prefer to internalize iron by an energy-dependent process. It was also found that the binding of iron by protoplasts of cells grown in an iron-deficient medium was much more extensive than that of cells grown in an iron-sufficient medium. Soluble and particulate fractions of protoplasts were prepared by grinding them in a glass homogenizer, and the particulate fraction was also subjected to iron binding studies. The amount of iron bound was the same as that in intact protoplasts, indicating that the particulate fraction membrane fragments bound iron on their outer surface only. Nevertheless, when iron-preloaded cells were protoplasted and their surface cleared of iron, their particulate fraction contained considerable amounts of iron, indicating that the inner surface of the membranes is capable of binding iron as long as the cell is intact. The amount of iron so bound was dose-dependent on the amount of iron entering the cell. The failure of the outer and inner surface iron pools to mix was confirmed by the fact that when iron-preloaded protoplasts were incubated with additional iron, only the latter (surface-bound) was elutable with nonradioactive 2 mM FeSO4. It is concluded that increasing bifidobacterial iron load increases the amount of iron bound to the inner surface of the membrane; the procedure, which is effective in forming bifidobacterial protoplasts, destroys their iron transport mechanism while uncovering surface iron-binding sites; and that such iron-binding sites may be of significance in the cellular iron metabolism processes.

Dynamics of iron metabolism in pregnancy

1 R 0 N I S A N essential element in the body as a major constituent of hemoglobin, myoglobin and the cellular enzymes such as cytochrome C, catalase, and aconitase. The total amount of body iron in the normal adult female ranges from 3.5 to 4.0 Gm., of which 60 to 70 per cent is contained in the mass of circulating hemoglobin, 20 to 30 per cent is storage iron, and the remaining 5 to 10 per cent is distributed as myoglobin, cellular iron, and transport iron. These estimates apply only to the female, inasmuch as body iron in the male is substantially greater because his mass of hemoglobin and depots of storage are larger. Iron is continuously absorbed, excreted, and transported in the plasma. It is liberated in the process of hemoglobin degradation and is reused as new hemoglobin is synthesized. Iron moves in and out of the storage sites. These are dynamic processes and they may be altered during pregnancy because of the demands for iron created by the fetus and the requirement for a larger hemoglobin mass. From knowledge concerning the processes of iron metabolism, meaningful information can be derived that is of value in the detection, prevention, and treatment of iron deficiency states and anemia during pregnancy.

Plasma Iron

This chapter introduces the iron metabolism and discusses the methods for the determination of iron and iron-binding capacity in serum or plasma. The results obtained by applying these methods in normal, experimental, and pathological circumstances are presented in the chapter. The methods for the extraction of iron from plasma use trichloroacetic acid, incubation with hydrochloric acid, and reducing agents. The major processes of iron metabolism, and the various ways in which they can be assessed quantitatively or semi-quantitatively have been outlined in the chapter. The picture of iron metabolism is uniform in other malignant diseases than in the various types of leukemia. Anemia is frequent, while plasma iron and total iron-binding capacity (TIBC) are both often slightly low, but there is no definite relation between the magnitudes of the changes. The determination of serum iron and TIBC is an excellent aid to the diagnosis of iron deficiency, but an aid that is rarely required by the physician.