Journal articles: 'Iron pathways'

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Conrad, Marcel E., Jay N. Umbreit, Elizabeth G. Moore, Lucille N. Hainsworth, Michael Porubcin, Marcia J. Simovich, Marian T. Nakada, Kevin Dolan, and Michael D. Garrick. "Separate pathways for cellular uptake of ferric and ferrous iron." American Journal of Physiology-Gastrointestinal and Liver Physiology 279, no. 4 (October 1, 2000): G767—G774. http://dx.doi.org/10.1152/ajpgi.2000.279.4.g767.

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Separate pathways for transport of nontransferrin ferric and ferrous iron into tissue cultured cells were demonstrated. Neither the ferric nor ferrous pathway was shared with either zinc or copper. Manganese shared the ferrous pathway but had no effect on cellular uptake of ferric iron. We postulate that ferric iron was transported into cells via β3-integrin and mobilferrin (IMP), whereas ferrous iron uptake was facilitated by divalent metal transporter-1 (DMT-1; Nramp-2). These conclusions were documented by competitive inhibition studies, utilization of a β3-integrin antibody that blocked uptake of ferric but not ferrous iron, development of an anti-DMT-1 antibody that blocked ferrous iron and manganese uptake but not ferric iron, transfection of DMT-1 DNA into tissue culture cells that showed enhanced uptake of ferrous iron and manganese but neither ferric iron nor zinc, hepatic metal concentrations in mk mice showing decreased iron and manganese but not zinc or copper, and data showing that the addition of reducing agents to tissue culture media altered iron binding to proteins of the IMP and DMT-1 pathways. Although these experiments show ferric and ferrous iron can enter cells via different pathways, they do not indicate which pathway is dominant in humans.

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Conrad, Marcel E., and Jay N. Umbreit. "Pathways of Iron Absorption." Blood Cells, Molecules, and Diseases 29, no. 3 (November 2002): 336–55. http://dx.doi.org/10.1006/bcmd.2002.0564.

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Miethke, Marcus, and Mohamed A. Marahiel. "Siderophore-Based Iron Acquisition and Pathogen Control." Microbiology and Molecular Biology Reviews 71, no. 3 (September 2007): 413–51. http://dx.doi.org/10.1128/mmbr.00012-07.

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SUMMARY High-affinity iron acquisition is mediated by siderophore-dependent pathways in the majority of pathogenic and nonpathogenic bacteria and fungi. Considerable progress has been made in characterizing and understanding mechanisms of siderophore synthesis, secretion, iron scavenging, and siderophore-delivered iron uptake and its release. The regulation of siderophore pathways reveals multilayer networks at the transcriptional and posttranscriptional levels. Due to the key role of many siderophores during virulence, coevolution led to sophisticated strategies of siderophore neutralization by mammals and (re)utilization by bacterial pathogens. Surprisingly, hosts also developed essential siderophore-based iron delivery and cell conversion pathways, which are of interest for diagnostic and therapeutic studies. In the last decades, natural and synthetic compounds have gained attention as potential therapeutics for iron-dependent treatment of infections and further diseases. Promising results for pathogen inhibition were obtained with various siderophore-antibiotic conjugates acting as “Trojan horse” toxins and siderophore pathway inhibitors. In this article, general aspects of siderophore-mediated iron acquisition, recent findings regarding iron-related pathogen-host interactions, and current strategies for iron-dependent pathogen control will be reviewed. Further concepts including the inhibition of novel siderophore pathway targets are discussed.

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Conrad, Marcel E., and Jay N. Umbreit. "Iron absorption: Relative importance of iron transport pathways." American Journal of Hematology 67, no. 3 (2001): 215. http://dx.doi.org/10.1002/ajh.1114.

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Shakoury-Elizeh, Minoo, John Tiedeman, Jared Rashford, Tracey Ferea, Janos Demeter, Emily Garcia, Ronda Rolfes, Patrick O. Brown, David Botstein, and Caroline C. Philpott. "Transcriptional Remodeling in Response to Iron Deprivation inSaccharomyces cerevisiae." Molecular Biology of the Cell 15, no. 3 (March 2004): 1233–43. http://dx.doi.org/10.1091/mbc.e03-09-0642.

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The budding yeast Saccharomyces cerevisiae responds to depletion of iron in the environment by activating Aft1p, the major iron-dependent transcription factor, and by transcribing systems involved in the uptake of iron. Here, we have studied the transcriptional response to iron deprivation and have identified new Aft1p target genes. We find that other metabolic pathways are regulated by iron: biotin uptake and biosynthesis, nitrogen assimilation, and purine biosynthesis. Two enzymes active in these pathways, biotin synthase and glutamate synthase, require an iron-sulfur cluster for activity. Iron deprivation activates transcription of the biotin importer and simultaneously represses transcription of the entire biotin biosynthetic pathway. Multiple genes involved in nitrogen assimilation and amino acid metabolism are induced by iron deprivation, whereas glutamate synthase, a key enzyme in nitrogen assimilation, is repressed. A CGG palindrome within the promoter of glutamate synthase confers iron-regulated expression, suggesting control by a transcription factor of the binuclear zinc cluster family. We provide evidence that yeast subjected to iron deprivation undergo a transcriptional remodeling, resulting in a shift from iron-dependent to parallel, but iron-independent, metabolic pathways.

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Perraud, Quentin, Paola Cantero, Béatrice Roche, Véronique Gasser, Vincent P. Normant, Lauriane Kuhn, Philippe Hammann, Gaëtan L. A. Mislin, Laurence Ehret-Sabatier, and Isabelle J. Schalk. "Phenotypic Adaption of Pseudomonas aeruginosa by Hacking Siderophores Produced by Other Microorganisms." Molecular & Cellular Proteomics 19, no. 4 (February 5, 2020): 589–607. http://dx.doi.org/10.1074/mcp.ra119.001829.

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Bacteria secrete siderophores to access iron, a key nutrient poorly bioavailable and the source of strong competition between microorganisms in most biotopes. Many bacteria also use siderophores produced by other microorganisms (exosiderophores) in a piracy strategy. Pseudomonas aeruginosa, an opportunistic pathogen, produces two siderophores, pyoverdine and pyochelin, and is also able to use a panel of exosiderophores. We first investigated expression of the various iron-uptake pathways of P. aeruginosa in three different growth media using proteomic and RT-qPCR approaches and observed three different phenotypic patterns, indicating complex phenotypic plasticity in the expression of the various iron-uptake pathways. We then investigated the phenotypic plasticity of iron-uptake pathway expression in the presence of various exosiderophores (present individually or as a mixture) under planktonic growth conditions, as well as in an epithelial cell infection assay. In all growth conditions tested, catechol-type exosiderophores were clearly more efficient in inducing the expression of their corresponding transporters than the others, showing that bacteria opt for the use of catechol siderophores to access iron when they are present in the environment. In parallel, expression of the proteins of the pyochelin pathway was significantly repressed under most conditions tested, as well as that of proteins of the pyoverdine pathway, but to a lesser extent. There was no effect on the expression of the heme and ferrous uptake pathways. Overall, these data provide precise insights on how P. aeruginosa adjusts the expression of its various iron-uptake pathways (phenotypic plasticity and switching) to match varying levels of iron and competition.

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Spencer, Michelle J. S., Andrew Hung, Ian K. Snook, and Irene Yarovsky. "Iron Surfaces: Pathways to Interfaces." Surface Review and Letters 10, no. 02n03 (April 2003): 169–74. http://dx.doi.org/10.1142/s0218625x03005025.

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We have used density functional theory to examine the effects of avalanche in adhesion between Fe(100) surfaces, in registry and out of registry. When the central layers of the two surfaces are constrained the surface layers are attracted towards each other, forming a strained crystal region at intermediate interfacial separations. When the constraints in the z-direction are lifted, the surfaces avalanche together. In addition, when the surfaces are allowed to move sideways, we find that an interface initially out of registry will tend to avalanche towards an interface that is in registry.

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Theil, Elizabeth C. "Mining ferritin iron: 2 pathways." Blood 114, no. 20 (November 12, 2009): 4325–26. http://dx.doi.org/10.1182/blood-2009-08-239913.

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Chen, Jen-Chih, Scott I. Hsieh, Janette Kropat, and Sabeeha S. Merchant. "A Ferroxidase Encoded by FOX1 Contributes to Iron Assimilation under Conditions of Poor Iron Nutrition in Chlamydomonas." Eukaryotic Cell 7, no. 3 (February 1, 2008): 541–45. http://dx.doi.org/10.1128/ec.00463-07.

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ABSTRACT When the abundance of the FOX1 gene product is reduced, Chlamydomonas cells grow poorly in iron-deficient medium, but not in iron-replete medium, suggesting that FOX1-dependent iron uptake is a high-affinity pathway. Alternative pathways for iron assimilation, such as those involving ZIP family transporters IRT1 and IRT2, may be operational.

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Mercier, Alexandre, and Simon Labbé. "Iron-Dependent Remodeling of Fungal Metabolic Pathways Associated with Ferrichrome Biosynthesis." Applied and Environmental Microbiology 76, no. 12 (April 30, 2010): 3806–17. http://dx.doi.org/10.1128/aem.00659-10.

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ABSTRACT The fission yeast Schizosaccharomyces pombe excretes and accumulates the hydroxamate-type siderophore ferrichrome. The sib1 + and sib2 + genes encode, respectively, a siderophore synthetase and an l-ornithine N5-oxygenase that participate in ferrichrome biosynthesis. In the present report, we demonstrate that sib1 + and sib2 + are repressed by the GATA-type transcriptional repressor Fep1 in response to high levels of iron. We further found that the loss of Fep1 results in increased ferrichrome production. We showed that a sib1Δ sib2Δ mutant strain exhibits a severe growth defect on iron-poor media. We determined that two metabolic pathways are involved in biosynthesis of ornithine, an obligatory precursor of ferrichrome. Ornithine is produced by hydrolysis of arginine by the Car1 and Car3 proteins. Although car3 + was constitutively expressed, car1 + transcription levels were repressed upon exposure to iron, with a concomitant decrease of Car1 arginase activity. Ornithine is also generated by transformation of glutamate, which itself is produced by two separate biosynthetic pathways which are transcriptionally regulated by iron in an opposite fashion. In one pathway, the glutamate dehydrogenase Gdh1, which produces glutamate from 2-ketoglutarate, was repressed under iron-replete conditions in a Fep1-dependent manner. The other pathway involves two coupled enzymes, glutamine synthetase Gln1 and Fe-S cluster-containing glutamate synthase Glt1, which were both repressed under iron-limiting conditions but were expressed under iron-replete conditions. Collectively, these results indicate that under conditions of iron deprivation, yeast remodels metabolic pathways linked to ferrichrome synthesis in order to limit iron utilization without compromising siderophore production and its ability to sequester iron from the environment.

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Dinkla, Inez J. T., Esther M. Gabor, and Dick B. Janssen. "Effects of Iron Limitation on the Degradation of Toluene by Pseudomonas Strains Carrying the TOL (pWWO) Plasmid." Applied and Environmental Microbiology 67, no. 8 (August 1, 2001): 3406–12. http://dx.doi.org/10.1128/aem.67.8.3406-3412.2001.

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ABSTRACT Most aerobic biodegradation pathways for hydrocarbons involve iron-containing oxygenases. In iron-limited environments, such as the rhizosphere, this may influence the rate of degradation of hydrocarbon pollutants. We investigated the effects of iron limitation on the degradation of toluene by Pseudomonas putida mt2 and the transconjugant rhizosphere bacterium P. putidaWCS358(pWWO), both of which contain the pWWO (TOL) plasmid that harbors the genes for toluene degradation. The results of continuous-culture experiments showed that the activity of the upper-pathway toluene monooxygenase decreased but that the activity of benzyl alcohol dehydrogenase was not affected under iron-limited conditions. In contrast, the activities of three meta-pathway (lower-pathway) enzymes were all found to be reduced when iron concentrations were decreased. Additional experiments in which citrate was used as a growth substrate and the pathways were induced with the gratuitous inducer o-xylene showed that expression of the TOL genes increased the iron requirement in both strains. Growth yields were reduced and substrate affinities decreased under iron-limited conditions, suggesting that iron availability can be an important parameter in the oxidative breakdown of hydrocarbons.

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Lönnerdal, Bo. "Alternative pathways for absorption of iron from foods." Pure and Applied Chemistry 82, no. 2 (February 1, 2010): 429–36. http://dx.doi.org/10.1351/pac-con-09-06-04.

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Iron is known to be absorbed from foods in two major forms, heme iron and non-heme iron. Iron status as well as dietary factors known to affect iron absorption has limited effect on heme iron absorption, whereas inhibitors and enhancers of iron absorption have pronounced effects on non-heme iron absorption. The enterocyte transporter for non-heme iron, DMT1, is strongly up-regulated during iron deficiency and down-regulated during iron overload. A transporter for heme iron, HCP1, was recently characterized and is present on the apical membrane of enterocytes. Two other pathways for iron absorption have been discovered and may serve to facilitate uptake of iron from two unique iron-binding proteins, lactoferrin and ferritin. Lactoferrin is an iron-binding protein in human milk and known to survive proteolytic digestion. It mediates iron uptake in breast-fed infants through endocytosis via a specific lactoferrin receptor (LfR). Recently, lactoferrin has become popular as a food additive and may enhance iron status in several age groups. Ferritin is present in meat, but also in plants. The ferritin content of plants can be enhanced by conventional breeding or genetic engineering, and thereby increase iron intake of populations consuming plant-based diets. Ferritin is a bioavailable source of iron, as shown in recent human studies. Ferritin can be taken up by intestinal cells via endocytosis, suggesting a receptor-mediated mechanism.

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Perraud, Quentin, Paola Cantero, Mathilde Munier, Françoise Hoegy, Nicolas Zill, Véronique Gasser, Gaëtan L. A. Mislin, Laurence Ehret-Sabatier, and Isabelle J. Schalk. "Phenotypic Adaptation of Pseudomonas aeruginosa in the Presence of Siderophore-Antibiotic Conjugates during Epithelial Cell Infection." Microorganisms 8, no. 11 (November 18, 2020): 1820. http://dx.doi.org/10.3390/microorganisms8111820.

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Iron acquisition pathways have often been considered to be gateways for the uptake of antibiotics into bacteria. Bacteria excrete chelators, called siderophores, to access iron. Antibiotic molecules can be covalently attached to siderophores for their transport into pathogens during the iron-uptake process. P. aeruginosa produces two siderophores and is also able to use many siderophores produced by other bacteria. We investigated the phenotypic plasticity of iron-uptake pathway expression in an epithelial cell infection assay in the presence of two different siderophore–antibiotic conjugates, one with a hydroxamate siderophore and the second with a tris-catechol. Proteomic and RT-qPCR approaches showed that P. aeruginosa was able to sense the presence of both compounds in its environment and adapt the expression of its iron uptake pathways to access iron via them. Moreover, the catechol-type siderophore–antibiotic was clearly more efficient in inducing the expression of its corresponding transporter than the hydroxamate compound when both were simultaneously present. In parallel, the expression of the proteins of the two iron uptake pathways using siderophores produced by P. aeruginosa was significantly repressed in the presence of both conjugates. Altogether, the data indicate that catechol-type siderophores are more promising vectors for antibiotic vectorization using a Trojan-horse strategy.

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Zhang, Tianrui, Zhidan Xiao, Chuanliang Liu, Chao Yang, Jiayi Li, Hongbo Li, Caiji Gao, and Wenjin Shen. "Autophagy Mediates the Degradation of Plant ESCRT Component FREE1 in Response to Iron Deficiency." International Journal of Molecular Sciences 22, no. 16 (August 16, 2021): 8779. http://dx.doi.org/10.3390/ijms22168779.

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Multivesicular body (MVB)-mediated endosomal sorting and macroautophagy are the main pathways mediating the transport of cellular components to the vacuole and are essential for maintaining cellular homeostasis. The interplay of these two pathways remains poorly understood in plants. In this study, we show that FYVE DOMAIN PROTEIN REQUIRED FOR ENDOSOMAL SORTING 1 (FREE1), which was previously identified as a plant-specific component of the endosomal sorting complex required for transport (ESCRT), essential for MVB biogenesis and plant growth, can be transported to the vacuole for degradation in response to iron deficiency. The vacuolar transport of ubiquitinated FREE1 protein is mediated by the autophagy pathway. As a consequence, the autophagy deficient mutants, atg5-1 and atg7-2, accumulate more endogenous FREE1 protein and display hypersensitivity to iron deficiency. Furthermore, under iron-deficient growth condition autophagy related genes are upregulated to promote the autophagic degradation of FREE1, thereby possibly relieving the repressive effect of FREE1 on iron absorption. Collectively, our findings demonstrate a unique regulatory mode of protein turnover of the ESCRT machinery through the autophagy pathway to respond to iron deficiency in plants.

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Lin, Min-Yu, Yen-Hua Chen, Jey-Jau Lee, and Hwo-Shuenn Sheu. "Reaction pathways of iron-sulfide mineral formation: an in situ X-ray diffraction study." European Journal of Mineralogy 30, no. 1 (February 1, 2018): 77–84. http://dx.doi.org/10.1127/ejm/2017/0029-2681.

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Aring, Luisa, Eun-kyeong Choi, and Young-Ah Seo. "WDR45 Contributes to Iron Accumulation Through Dysregulation of Neuronal Iron Homeostasis." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1188. http://dx.doi.org/10.1093/cdn/nzaa057_004.

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Abstract Objectives Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by an abnormal accumulation of brain iron and progressive degeneration of the nervous system. β-propeller protein-associated neurodegeneration (BPAN) (OMIM #300,894) is a recently identified subtype of NBIA. BPAN is caused by de novo mutations in the WD repeat domain 45 (WDR45) gene. WDR45 deficiency in BPAN patients and animal models has shown defects in autophagic flux, suggesting a role for WDR45 in autophagy. How WDR45 deficiency leads to brain iron overload remains unclear. The goal of the present study is to identify the pathogenic mechanisms of WDR45 deficiency that cause iron overload and neurodegeneration. Methods To elucidate the role of WDR45 in dopaminergic neuronal cells, we generated a WDR45-knockout (KO) SH-SY5Y cell line by CRISPR/Cas9-mediated genome editing. To identify mechanisms underlying iron homeostasis and transport, we examined two cellular iron acquisition pathways in these cells using radioactive isotope 59Fe: 1) the canonical transferrin-bound iron (TBI) uptake pathway and 2) the nontransferrin-bound iron (NTBI) pathway. Results Loss of WDR45 increased total iron levels with a concomitant increase in the iron storage protein ferritin in neuronal cells. Specifically, WDR45-KO cells preferentially took up NTBI compared to wild-type cells. Concordant with these functional data, the level of divalent metal transporter-1 (DMT1) expression was upregulated in WDR45-KO cells, providing a causal link to iron overload in WDR45 deficiency. In addition, loss of WDR45 led to defects in autophagic flux and impaired ferritinophagy, a lysosomal process that promotes ferritin degradation, suggesting that iron overload is driven by impaired ferritinophagy. Interestingly, WDR45 deficiency increased iron accumulation in the mitochondria, impaired mitochondrial function, and in turn, elevated reactive oxygen species generation. Conclusions Our study provides the first evidence that WDR45 deficiency alters cellular iron acquisition pathways thereby leading to iron accumulation in neuronal cells. These findings will serve as a basis for developing therapeutic strategies for patients with NBIA. Funding Sources NIH, NBIA Disorder Association.

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van Beers, Eduard J., Yanqin Yang, Susan Yuditskaya, Nalini Raghavachari, and Gregory J. Kato. "Turnover of Heme-Bound Iron Is Associated with Activation of TLR4 and Chemokine Receptor Pathways in the Peripheral Blood Mononuclear Cell Transcriptome in Sickle Cell Anemia." Blood 120, no. 21 (November 16, 2012): 819. http://dx.doi.org/10.1182/blood.v120.21.819.819.

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Abstract Abstract 819 Introduction It is widely accepted that inflammation plays an important role in the pathophysiology of Sickle Cell Anemia (SCA). Recently a number of studies indicated that peripheral blood mononuclear cell (PBMC) iron may contribute to inflammation in some diseases In SCA, PBMCs are continuously exposed to high turnover of iron in haptoglobin/hemoglobin complexes and free heme due to severe intravascular hemolysis. Therefore, we hypothesized that PBMC iron flux is marked by altered expression of iron-regulated genes, and in turn associated with the up regulation of genes in inflammatory pathways. To explore this hypothesis we correlated the expression of a predefined set of iron regulated genes to the SCA PBMC transcriptome as a whole. Methods Steady state patients with SCA were selected as published earlier. (Bereal-Williams et al. Haematologica 2012) Most noteworthy exclusion criteria were recent blood transfusion, liver or kidney dysfunction or a recent acute complication. Affymetrix Human Genome U133 Plus 2.0 arrays were used to measure PBMC mRNA profile. The primary source of free iron in PBMC in SCA is iron released from heme by heme oxygenase-1 (HMOX1), the first committed biochemical step in production of bilirubin. Therefore, we planned to validate the clustering of the study participants by correlating the cluster rank with bilirubin plasma levels. Genes which are published to be differentially expressed upon iron loading or chelation were used to prospectively create an ‘iron-regulated’ gene set (figure). Differentially expressed genes with the filter of a change greater than 40% between the clustering groups and 10% false discovery rate (FDR) were further analyzed with Ingenuity Pathway Analysis (IPA) System. Results Twenty-five subjects with SCA and 9 healthy subjects were analyzed. Hierarchical clustering using the predefined iron regulated gene list identified 3 groups of subjects with high, low and intermediate expression of iron activated genes (figure 1). As expected, none of the healthy controls was found in the high iron cluster. The cluster grouping was validated by correlation of serum bilirubin levels to the cluster rank (Spearman rho=0.358 p=0.044) and the expression of HMOX1 (Spearmen rho=0.387 p=0.034). In analysis of these three iron regulated gene clusters, we found 98 genes which were consistently and significantly differentially expressed, notably many genes important to crucial inflammatory pathways, especially Toll-like receptor 4 and 7 (TLR-4,7), chemokine receptor CCR1, and interleukin 15. The 98 markers identified ten canonical pathways in Ingenuity Pathway Analysis, most involving inflammation (each p<0.004, Table ). Expression profiling using a defined set of iron regulated genes identifies co-regulation of genes and pathways related to inflammatory cytokines, signaling cascades and innate immunity pathways. Our human PBMC findings confirm and extend recently presented data from several other groups linking TLR4-mediated heme-iron toxicity to pathological responses in sickle cell mice and in cultured cells. The role of heme-associated iron in sickle cell pathophysiology merits additional investigation. Disclosures: No relevant conflicts of interest to declare.

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Lenoir, Anne, Jean-Christophe Deschemin, Léon Kautz, Andrew J. Ramsay, Marie-Paule Roth, Carlos Lopez-Otin, Sophie Vaulont, and Gaël Nicolas. "Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6." Blood 117, no. 2 (January 13, 2011): 647–50. http://dx.doi.org/10.1182/blood-2010-07-295147.

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Abstract Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6−/− mice (characterized by increased hepcidin levels and anemia) and Bmp6−/− mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6−/− mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.

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Chhabra, Ravneet, Aishwarya Saha, Ashkon Chamani, Nicole Schneider, Riya Shah, and Meera Nanjundan. "Iron Pathways and Iron Chelation Approaches in Viral, Microbial, and Fungal Infections." Pharmaceuticals 13, no. 10 (September 25, 2020): 275. http://dx.doi.org/10.3390/ph13100275.

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Iron is an essential element required to support the health of organisms. This element is critical for regulating the activities of cellular enzymes including those involved in cellular metabolism and DNA replication. Mechanisms that underlie the tight control of iron levels are crucial in mediating the interaction between microorganisms and their host and hence, the spread of infection. Microorganisms including viruses, bacteria, and fungi have differing iron acquisition/utilization mechanisms to support their ability to acquire/use iron (e.g., from free iron and heme). These pathways of iron uptake are associated with promoting their growth and virulence and consequently, their pathogenicity. Thus, controlling microorganismal survival by limiting iron availability may prove feasible through the use of agents targeting their iron uptake pathways and/or use of iron chelators as a means to hinder development of infections. This review will serve to assimilate findings regarding iron and the pathogenicity of specific microorganisms, and furthermore, find whether treating infections mediated by such organisms via iron chelation approaches may have potential clinical benefit.

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Adhikari, Bishwo N., Kenneth A. Callicott, and Peter J. Cotty. "Conservation and Loss of a Putative Iron Utilization Gene Cluster among Genotypes of Aspergillus flavus." Microorganisms 9, no. 1 (January 9, 2021): 137. http://dx.doi.org/10.3390/microorganisms9010137.

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Iron is an essential component for growth and development. Despite relative abundance in the environment, bioavailability of iron is limited due to oxidation by atmospheric oxygen into insoluble ferric iron. Filamentous fungi have developed diverse pathways to uptake and use iron. In the current study, a putative iron utilization gene cluster (IUC) in Aspergillus flavus was identified and characterized. Gene analyses indicate A. flavus may use reductive as well as siderophore-mediated iron uptake and utilization pathways. The ferroxidation and iron permeation process, in which iron transport depends on the coupling of these two activities, mediates the reductive pathway. The IUC identified in this work includes six genes and is located in a highly polymorphic region of the genome. Diversity among A. flavus genotypes is manifested in the structure of the IUC, which ranged from complete deletion to a region disabled by multiple indels. Molecular profiling of A. flavus populations suggests lineage-specific loss of IUC. The observed variation among A. flavus genotypes in iron utilization and the lineage-specific loss of the iron utilization genes in several A. flavus clonal lineages provide insight on evolution of iron acquisition and utilization within Aspergillus section Flavi. The potential divergence in capacity to acquire iron should be taken into account when selecting A. flavus active ingredients for biocontrol in niches where climate change may alter iron availability.

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Adhikari, Bishwo N., Kenneth A. Callicott, and Peter J. Cotty. "Conservation and Loss of a Putative Iron Utilization Gene Cluster among Genotypes of Aspergillus flavus." Microorganisms 9, no. 1 (January 9, 2021): 137. http://dx.doi.org/10.3390/microorganisms9010137.

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Iron is an essential component for growth and development. Despite relative abundance in the environment, bioavailability of iron is limited due to oxidation by atmospheric oxygen into insoluble ferric iron. Filamentous fungi have developed diverse pathways to uptake and use iron. In the current study, a putative iron utilization gene cluster (IUC) in Aspergillus flavus was identified and characterized. Gene analyses indicate A. flavus may use reductive as well as siderophore-mediated iron uptake and utilization pathways. The ferroxidation and iron permeation process, in which iron transport depends on the coupling of these two activities, mediates the reductive pathway. The IUC identified in this work includes six genes and is located in a highly polymorphic region of the genome. Diversity among A. flavus genotypes is manifested in the structure of the IUC, which ranged from complete deletion to a region disabled by multiple indels. Molecular profiling of A. flavus populations suggests lineage-specific loss of IUC. The observed variation among A. flavus genotypes in iron utilization and the lineage-specific loss of the iron utilization genes in several A. flavus clonal lineages provide insight on evolution of iron acquisition and utilization within Aspergillus section Flavi. The potential divergence in capacity to acquire iron should be taken into account when selecting A. flavus active ingredients for biocontrol in niches where climate change may alter iron availability.

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Montejano-Ramírez, Vicente, Ernesto García-Pineda, and Eduardo Valencia-Cantero. "Bacterial Compound N,N-Dimethylhexadecylamine Modulates Expression of Iron Deficiency and Defense Response Genes in Medicago truncatula Independently of the Jasmonic Acid Pathway." Plants 9, no. 5 (May 14, 2020): 624. http://dx.doi.org/10.3390/plants9050624.

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Plants face a variety of biotic and abiotic stresses including attack by microbial phytopathogens and nutrient deficiencies. Some bacterial volatile organic compounds (VOCs) activate defense and iron-deficiency responses in plants. To establish a relationship between defense and iron deficiency through VOCs, we identified key genes in the defense and iron-deprivation responses of the legume model Medicago truncatula and evaluated the effect of the rhizobacterial VOC N,N-dimethylhexadecylamine (DMHDA) on the gene expression in these pathways by RT-qPCR. DMHDA increased M. truncatula growth 1.5-fold under both iron-sufficient and iron-deficient conditions compared with untreated plants, whereas salicylic acid and jasmonic acid decreased growth. Iron-deficiency induced iron uptake and defense gene expression. Moreover, the effect was greater in combination with DMHDA. Salicylic acid, Pseudomonas syringae, jasmonic acid, and Botrytis cinerea had inhibitory effects on growth and iron response gene expression but activated defense genes. Taken together, our results showed that the VOC DMHDA activates defense and iron-deprivation pathways while inducing a growth promoting effect unlike conventional phytohormones, highlighting that DMHDA does not mimic jasmonic acid but induces an alternative pathway. This is a novel aspect in the complex interactions between biotic and abiotic stresses.

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Mangani, S., I. Bertini, D. Lalli, C. Pozzi, C. Rosa, and P. Turano. "Structural insight into iron pathways in ferritin." Acta Crystallographica Section A Foundations of Crystallography 67, a1 (August 22, 2011): C772. http://dx.doi.org/10.1107/s0108767311080482.

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Williams, Gregory M., and Mark J. Pino. "Isomerization pathways of (acylcycloheptatriene)iron tricarbonyl complexes." Organometallics 11, no. 1 (January 1992): 345–49. http://dx.doi.org/10.1021/om00037a058.

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Szabo, Robert, Cristina Petrișor, Constantin Bodolea, Vlad Dobre, Sebastian Tranca, Simona Clichici, Iulia Szabo, Razvan Melinte, and Teodora Mocan. "Effects of Tocilizumab on Inflammation and Iron Metabolism in Critically Ill Patients with COVID-19." Pharmaceutics 15, no. 2 (February 14, 2023): 646. http://dx.doi.org/10.3390/pharmaceutics15020646.

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COVID-19 produces cytokine-mediated persistent inflammation and is associated with elevated iron stores and low circulating iron. It is believed that central to the pathophysiological mechanism is interleukin 6 and hepcidin. A state of iron overload, termed hyperferritinemia, and inflammatory anemia take place. Both conditions are linked to a worse result in critically ill patients. Blocking the interleukin 6—hepcidin pathway with Tocilizumab could present favorable outcomes. The aim of this study was to evaluate if Tocilizumab influences survival, the occurrence of sepsis, anemia and transfusions in critically ill patients suffering from COVID-19. This prospective observational study focused on levels of interleukin 6, hepcidin and blood iron parameters in patients treated with Tocilizumab. Data were compared before and after therapy as well as between treated and control groups. Results indicate that there is no difference in terms of survival nor in the rate of anemia or sepsis occurrence. Hepcidin was elevated and anemia ensued after treatment, which could indicate alternative pathways. In conclusion, when the classic interleukin 6—hepcidin pathway is blocked, inflammation seems to use alternative routes. Further understanding of these pathways is required and new pharmacological therapies need to be developed to treat persistent inflammation.

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Hwang, Lena H., Erica Seth, Sarah A. Gilmore, and Anita Sil. "SRE1Regulates Iron-Dependent and -Independent Pathways in the Fungal Pathogen Histoplasma capsulatum." Eukaryotic Cell 11, no. 1 (November 23, 2011): 16–25. http://dx.doi.org/10.1128/ec.05274-11.

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ABSTRACTRegulation of iron acquisition genes is critical for microbial survival under both iron-limiting conditions (to acquire essential iron) and iron-replete conditions (to limit iron toxicity). In fungi, iron acquisition genes are repressed under iron-replete conditions by a conserved GATA transcriptional regulator. Here we investigate the role of this transcription factor, Sre1, in the cellular responses of the fungal pathogenHistoplasma capsulatumto iron. We showed that cells in whichSRE1levels were diminished by RNA interference were unable to repress siderophore biosynthesis and utilization genes in the presence of abundant iron and thus produced siderophores even under iron-replete conditions. Mutation of a GATA-containing consensus site found in the promoters of these genes also resulted in inappropriate gene expression under iron-replete conditions. Microarray analysis comparing control andSRE1-depleted strains under conditions of iron limitation or abundance revealed both iron-responsive genes and Sre1-dependent genes, which comprised distinct but overlapping sets. Iron-responsive genes included those encoding putative oxidoreductases, metabolic and mitochondrial enzymes, superoxide dismutase, and nitrosative-stress-response genes; Sre1-dependent genes were of diverse functions. Genes regulated by iron levels and Sre1 included all of the siderophore biosynthesis genes, a gene involved in reductive iron acquisition, an iron-responsive transcription factor, and two catalases. Based on transcriptional profiling and phenotypic analyses, we conclude that Sre1 plays a critical role in the regulation of both traditional iron-responsive genes and iron-independent pathways such as regulation of cell morphology. These data highlight the evolving realization that the effect of Sre1 orthologs on fungal biology extends beyond the iron regulon.

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Tan, Xuelian, Timothy Cody Ashby, Yuqi Zhu, Can Li, Xuxing Shen, Qierra Brockman, Dongzheng Gai, et al. "Iron Trafficking through Macrophages Regulates Signaling Pathways in Myeloma." Blood 136, Supplement 1 (November 5, 2020): 2. http://dx.doi.org/10.1182/blood-2020-140372.

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Background Iron is an essential element for cell growth, including cancer cells, and is present in the microenvironment. We have shown that multiple myeloma (MM) cells have abnormal iron metabolism and harbor increased intracellular iron. However, the mechanism by which MM cells retain iron has remained largely elusive. Methods Expression and clinical relevance of the transferrin receptor in MM samples were analyzed in publicly available microarray and RNA-sequencing databases. Macrophages were isolated from C57BL/6J mice and were induced to specific subtypes by cytokines or culturing with MM cells. The 5TGM1-KaLwRij MM mice were used to confirm whether MM cells induce macrophage polarization in vivo. Specific subtypes of macrophage and transferrin receptor expression in MM cells were assessed by flow cytometry. Expression of ferroportin (FPN1) and ferritin in MM cells and/or macrophages were analyzed by Western blots. Single-cell RNA-sequencing (scRNA-seq), RNA-seq, and gene expression profiles (GEPs) were employed to identify ferroportin-signaling pathways in both tumor cells and macrophages of primary human MM samples. Results MM cells induced polarization with a significant increase of CD38+CD206- M1 macrophages both in vitro and in vivo. We also confirmed that the tumor associated macrophages (TAMs) were increased in the 5TGM1-KaLwRij MM mice. MM cells upregulated ferroportin expression in macrophages to provide iron to MM cells in co-culture studies and in vivo models. The transferrin receptor antibody treatment prevented MM cells from taking up iron from macrophages. scRNA-seq identified a subset of FPN1+ TAMs in human bone marrow aspirates, which are assumed to provide iron to MM cells. Using RNA-seq and GEPs analyses in primary human samples, multiple signaling pathways were differentially modulated in FPN1+ versus FPN1- TAMs, including those related to inflammation and apoptosis Conclusions Increased expression of the transferrin receptor in MM cells strongly suggests that tumor cells take up iron from its environment. MM cells promote intracellular iron mobilization in macrophages, which provide iron to MM cells in a transferrin-dependent manner. Blockade of iron trafficking between MM cells and macrophages might be a promising approach to MM therapy. Disclosures van Rhee: EUSA: Consultancy; CDCN: Consultancy; Karyopharm: Consultancy; Adaptive Biotech: Consultancy; Takeda: Consultancy.

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Gelvan, D., E. Fibach, EG Meyron-Holtz, and AM Konijn. "Ferritin uptake by human erythroid precursors is a regulated iron uptake pathway." Blood 88, no. 8 (October 15, 1996): 3200–3207. http://dx.doi.org/10.1182/blood.v88.8.3200.bloodjournal8883200.

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Iron delivery to mammalian cells is traditionally ascribed to diferric transferrin (Tf). We recently reported that human erythroid precursor cells possess specific membranes receptors that bind and internalize acid isoferritin. Here we show that ferritin uptake by these cells is highly regulated and that the internalized ferritin-iron is used for home synthesis and thus, this process could constitute a physiological pathway for iron assimilation. Ferritin was internalized by a specific, saturable process, distinct from the uptake of iron associated with albumin. Ferritin uptake downregulated transferrin-receptor expression, indicating that internalized ferritin-iron was recognized as an integral part of the cellular iron content. Ferritin receptor expression was coordinated to cell development and was tightly regulated by cellular iron status. Receptor abundance was increased by iron-depletion and decreased by iron-loading, while the affinity of the ferritin receptor for acid isoferritin remained nearly constant (kd = 4.1 +/- 0.5 x 10(-6) mol/L). Under all experimental conditions, ferritin- and transferrin-receptor expression was closely coordinated, suggesting that these pathways possess a common regulatory element. It is concluded that ferritin uptake by erythroid cells constitutes an iron uptake pathway in addition to the classical transferrin uptake pathway.

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Mladěnka, Přemysl, Radomír Hrdina, Mojmír Hübl, and Tomáš Šimůnek. "The Fate of Iron in The Organism and Its Regulatory Pathways." Acta Medica (Hradec Kralove, Czech Republic) 48, no. 3-4 (2005): 127–35. http://dx.doi.org/10.14712/18059694.2018.40.

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Iron is an essential element involved in many life-necessary processes. Interestingly, in mammals there is no active excretion mechanism for iron. Therefore iron kinetics has to be meticulously regulated. The most important step for regulation of iron kinetics is absorption. The absorption takes place in small intestine and it is implicated that it requires several proteins. Iron is then released from enterocytes into the circulation and delivered to the cells. Iron movement inside the cell is only partially elucidated and its traffic to mitochondia is not known. Surprisingly, the regulation of various proteins related to iron kinetics and energy metabolism at the molecular level is better described. On contrary, the complex control of iron absorption cannot be fully explicated with present knowledge.

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Lehmann, C., S. Islam, S. Jarosch, J. Zhou, D. Hoskin, A. Greenshields, N. Al-Banna, et al. "The Utility of Iron Chelators in the Management of Inflammatory Disorders." Mediators of Inflammation 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/516740.

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Since iron can contribute to detrimental radical generating processes through the Fenton and Haber-Weiss reactions, it seems to be a reasonable approach to modulate iron-related pathways in inflammation. In the human organism a counterregulatory reduction in iron availability is observed during inflammatory diseases. Under pathological conditions with reduced or increased baseline iron levels different consequences regarding protection or susceptibility to inflammation have to be considered. Given the role of iron in development of inflammatory diseases, pharmaceutical agents targeting this pathway promise to improve the clinical outcome. The objective of this review is to highlight the mechanisms of iron regulation and iron chelation, and to demonstrate the potential impact of this strategy in the management of several acute and chronic inflammatory diseases, including cancer.

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Ayala-Castro, Carla, Avneesh Saini, and F. Wayne Outten. "Fe-S Cluster Assembly Pathways in Bacteria." Microbiology and Molecular Biology Reviews 72, no. 1 (March 2008): 110–25. http://dx.doi.org/10.1128/mmbr.00034-07.

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SUMMARY Iron-sulfur (Fe-S) clusters are required for critical biochemical pathways, including respiration, photosynthesis, and nitrogen fixation. Assembly of these iron cofactors is a carefully controlled process in cells to avoid toxicity from free iron and sulfide. Multiple Fe-S cluster assembly pathways are present in bacteria to carry out basal cluster assembly, stress-responsive cluster assembly, and enzyme-specific cluster assembly. Although biochemical and genetic characterization is providing a partial picture of in vivo Fe-S cluster assembly, a number of mechanistic questions remain unanswered. Furthermore, new factors involved in Fe-S cluster assembly and repair have recently been identified and are expanding the complexity of current models. Here we attempt to summarize recent advances and to highlight new avenues of research in the field of Fe-S cluster assembly.

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Cheng, Ching-Feng, and Wei-Shiung Lian. "Prooxidant Mechanisms in Iron Overload Cardiomyopathy." BioMed Research International 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/740573.

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Iron overload cardiomyopathy (IOC), defined as the presence of systolic or diastolic cardiac dysfunction secondary to increased deposition of iron, is emerging as an important cause of heart failure due to the increased incidence of this disorder seen in thalassemic patients and in patients of primary hemochromatosis. At present, although palliative treatment by regular iron chelation was recommended; whereas IOC is still the major cause for mortality in patient with chronic heart failure induced by iron-overloading. Because iron is a prooxidant and the associated mechanism seen in iron-overload heart is still unclear; therefore, we intend to delineate the multiple signaling pathways involved in IOC. These pathways may include organelles such as calcium channels, mitochondria; paracrine effects from both macrophages and fibroblast, and novel mediators such as thromboxane A2 and adiponectin; with increased oxidative stress and inflammation found commonly in these signaling pathways. With further understanding on these complex and inter-related molecular mechanisms, we can propose potential therapeutic strategies to ameliorate the cardiac toxicity induced by iron-overloading.

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Pantopoulos, K., G. Weiss, and M. W. Hentze. "Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways." Molecular and Cellular Biology 16, no. 7 (July 1996): 3781–88. http://dx.doi.org/10.1128/mcb.16.7.3781.

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Several cellular mRNAs are regulated posttranscriptionally by iron-responsive elements (IREs) and the cytosolic IRE-binding proteins IRP-1 and IRP-2. Three different signals are known to elicit IRP-1 activity and thus regulate IRE-containing mRNAs: iron deficiency, nitric oxide (NO), and the reactive oxygen intermediate hydrogen peroxide (H2O2). In this report, we characterize the pathways for IRP-1 regulation by NO and H2O2 and examine their effects on IRP-2. We show that the responses of IRP-1 and IRP-2 to NO remarkably resemble those elicited by iron deficiency: IRP-1 induction by NO and by iron deficiency is slow and posttranslational, while IRP-2 induction by these inductive signals is slow and requires de novo protein synthesis. In contrast, H2O2 induces a rapid posttranslational activation which is limited to IRP-1. Removal of the inductive signal H2O2 after < or = 15 min of treatment (induction phase) permits a complete IRP-1 activation within 60 min (execution phase) which is sustained for several hours. This contrasts with the IRP-1 activation pathway by NO and iron depletion, in which NO-releasing drugs or iron chelators need to be present during the entire activation phase. Finally, we demonstrate that biologically synthesized NO regulates the expression of IRE-containing mRNAs in target cells by passive diffusion and that oxidative stress endogenously generated by pharmacological modulation of the mitochondrial respiratory chain activates IRP-1, underscoring the physiological significance of NO and reactive oxygen intermediates as regulators of cellular iron metabolism. We discuss models to explain the activation pathways of IRP-1 and IRP-2. In particular, we suggest the possibility that NO affects iron availability rather than the iron-sulfur cluster of IRP-1.

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Mardini, Louay, Jadwiga Gasiorek, Anna Derjuga, Lucie Carrière, Matthias Schranzhofer, Barry H. Paw, Prem Ponka, and Volker Blank. "Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1." Biochemical Journal 432, no. 1 (October 25, 2010): 145–51. http://dx.doi.org/10.1042/bj20100541.

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Late-stage erythroid cells synthesize large quantities of haemoglobin, a process requiring the co-ordinated regulation of globin and haem synthesis as well as iron uptake. In the present study, we investigated the role of the ERK (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) signalling pathways in MEL (mouse erythroleukaemia) cell differentiation. We found that treatment of HMBA (hexamethylene bisacetamide)-induced MEL cells with the ERK pathway inhibitor UO126 results in an increase in intracellular haem and haemoglobin levels. The transcript levels of the genes coding for βmajor-globin, the haem biosynthesis enzyme 5-aminolevulinate synthase 2 and the mitochondrial iron transporter mitoferrin 1 are up-regulated. We also showed enhanced expression of globin and transferrin receptor 1 proteins upon UO126 treatment. With respect to iron uptake, we found that ERK inhibitor treatment led to an increase in both haem-bound and total iron. In contrast, treatment of MEL cells with the p38 MAPK pathway inhibitor SB202190 had the opposite effect, resulting in decreased globin expression, haem synthesis and iron uptake. Reporter assays showed that globin promoter and HS2 enhancer-mediated transcription was under the control of MAPKs, as inhibition of the ERK and p38 MAPK pathways led to increased and decreased gene activity respectively. Our present results suggest that the ERK1/2 and p38α/β MAPKs play antagonistic roles in HMBA-induced globin gene expression and erythroid differentiation. These results provide a novel link between MAPK signalling and the regulation of haem biosynthesis and iron uptake in erythroid cells.

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Mancinelli, Romina, Luigi Rosa, Antimo Cutone, Maria Stefania Lepanto, Antonio Franchitto, Paolo Onori, Eugenio Gaudio, and Piera Valenti. "Viral Hepatitis and Iron Dysregulation: Molecular Pathways and the Role of Lactoferrin." Molecules 25, no. 8 (April 24, 2020): 1997. http://dx.doi.org/10.3390/molecules25081997.

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The liver is a frontline immune site specifically designed to check and detect potential pathogens from the bloodstream to maintain a general state of immune hyporesponsiveness. One of the main functions of the liver is the regulation of iron homeostasis. The liver detects changes in systemic iron requirements and can regulate its concentration. Pathological states lead to the dysregulation of iron homeostasis which, in turn, can promote infectious and inflammatory processes. In this context, hepatic viruses deviate hepatocytes’ iron metabolism in order to better replicate. Indeed, some viruses are able to alter the expression of iron-related proteins or exploit host receptors to enter inside host cells. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein belonging to the innate immunity, is endowed with potent antiviral activity, mainly related to its ability to block viral entry into host cells by interacting with viral and/or cell surface receptors. Moreover, Lf can act as an iron scavenger by both direct iron-chelation or the modulation of the main iron-related proteins. In this review, the complex interplay between viral hepatitis, iron homeostasis, and inflammation as well as the role of Lf are outlined.

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Lagaditis, Paraskevi O., Peter E. Sues, Alan J. Lough, and Robert H. Morris. "Exploring the decomposition pathways of iron asymmetric transfer hydrogenation catalysts." Dalton Transactions 44, no. 27 (2015): 12119–27. http://dx.doi.org/10.1039/c4dt02799j.

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Kontoghiorghes, George, and Christina Kontoghiorghe. "Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases." Cells 9, no. 6 (June 12, 2020): 1456. http://dx.doi.org/10.3390/cells9061456.

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Iron is essential for all living organisms. Many iron-containing proteins and metabolic pathways play a key role in almost all cellular and physiological functions. The diversity of the activity and function of iron and its associated pathologies is based on bond formation with adjacent ligands and the overall structure of the iron complex in proteins or with other biomolecules. The control of the metabolic pathways of iron absorption, utilization, recycling and excretion by iron-containing proteins ensures normal biologic and physiological activity. Abnormalities in iron-containing proteins, iron metabolic pathways and also other associated processes can lead to an array of diseases. These include iron deficiency, which affects more than a quarter of the world’s population; hemoglobinopathies, which are the most common of the genetic disorders and idiopathic hemochromatosis. Iron is the most common catalyst of free radical production and oxidative stress which are implicated in tissue damage in most pathologic conditions, cancer initiation and progression, neurodegeneration and many other diseases. The interaction of iron and iron-containing proteins with dietary and xenobiotic molecules, including drugs, may affect iron metabolic and disease processes. Deferiprone, deferoxamine, deferasirox and other chelating drugs can offer therapeutic solutions for most diseases associated with iron metabolism including iron overload and deficiency, neurodegeneration and cancer, the detoxification of xenobiotic metals and most diseases associated with free radical pathology.

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Varga, Edit, Ramóna Pap, Gergely Jánosa, Katalin Sipos, and Edina Pandur. "IL-6 Regulates Hepcidin Expression Via the BMP/SMAD Pathway by Altering BMP6, TMPRSS6 and TfR2 Expressions at Normal and Inflammatory Conditions in BV2 Microglia." Neurochemical Research 46, no. 5 (April 9, 2021): 1224–38. http://dx.doi.org/10.1007/s11064-021-03322-0.

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AbstractThe hormone hepcidin plays a central role in controlling iron homeostasis. Iron-mediated hepcidin synthesis is triggered via the BMP/SMAD pathway. At inflammation, mainly IL-6 pro-inflammatory cytokine mediates the regulation of hepcidin via the JAK/STAT signalling pathway. Microglial cells of the central nervous system are able to recognize a broad spectrum of pathogens via toll-like receptors and initiate inflammatory response. Although the regulation of hepcidin synthesis is well described in many tissues, little is known about the inflammation mediated hepcidin regulation in microglia. In this study, we investigated the pathways, which are involved in HAMP regulation in BV2 microglia due to inflammatory mediators and the possible relationships between the iron regulatory pathways. Our results showed that IL-6 produced by resting BV2 cells was crucial in maintaining the basal HAMP expression and hepcidin secretion. It was revealed that IL-6 neutralization decreased both STAT3 and SMAD1/5/9 phosphorylation suggesting that IL-6 proinflammatory cytokine is necessary to maintain SMAD1/5/9 activation. We revealed that IL-6 influences BMP6 and TMPRSS6 protein levels, moreover it modified TfR2 expression, as well. In this study, we revealed that BV2 microglia increased their hepcidin secretion upon IL-6 neutralization although the major regulatory pathways were inhibited. Based on our results it seems that both at inflammation and at normal condition the absence of IL-6 triggered HAMP transcription and hepcidin secretion via the NFκB pathway and possibly by the autocrine effect of TNFα cytokine on BV2 microglia.

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Kotla, Nikhil Kumar, Priyata Dutta, Sanjana Parimi, and Nupur K. Das. "The Role of Ferritin in Health and Disease: Recent Advances and Understandings." Metabolites 12, no. 7 (June 30, 2022): 609. http://dx.doi.org/10.3390/metabo12070609.

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Systemic iron homeostasis needs to be tightly controlled, as both deficiency and excess iron cause major global health concerns, such as iron deficiency anemia, hemochromatosis, etc. In mammals, sufficient dietary acquisition is critical for fulfilling the systemic iron requirement. New questions are emerging about whether and how cellular iron transport pathways integrate with the iron storage mechanism. Ferritin is the intracellular iron storage protein that stores surplus iron after all the cellular needs are fulfilled and releases it in the face of an acute demand. Currently, there is a surge in interest in ferritin research after the discovery of novel pathways like ferritinophagy and ferroptosis. This review emphasizes the most recent ferritin-related discoveries and their impact on systemic iron regulation.

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Maru, Devangkumar, Akhil Hothi, Chintan Bagariya, and Anmol Kumar. "Targeting Ferroptosis Pathways: A Novel Strategy for Cancer Therapy." Current Cancer Drug Targets 22, no. 3 (March 2022): 234–44. http://dx.doi.org/10.2174/1568009622666220211122745.

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Abstract: Ferroptosis is an iron-dependent nonapoptotic kind of regulated cell death resulting from the destruction of redox balance in the cytosol. Unlike apoptosis, ferroptosis is caused by an increase in intracellular iron and lipid peroxides that causes significant damage to the membrane lipid bilayer and mitochondria leading to cell death. Increased iron level in the cell promotes ROS production. Ferroptosis inducer molecules increase ROS production and inhibit the antioxidant defence mechanism to facilitate ferroptosis in cancer cells. Inhibition of GPX4, redox-active iron availability, and lipid peroxidation are major contributors to ferroptosis. Ferroptosis is involved in many diseases like heart disease, neurodegenerative disease, and cancer. Ferroptosis induction recently emerged as an attractive strategy for cancer therapy. In this review, we discuss the regulatory mechanism of ferroptosis, its different hallmarks, including genetic and metabolic regulators and inducers that promote ferroptosis in the cancer cells. Finally, the latest progress and development in ferroptosis research in different cancers focusing on proposing a novel strategy in cancer therapy are discussed.

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Meneghetti, Fiorella, Stefania Villa, Arianna Gelain, Daniela Barlocco, Laurent Roberto Chiarelli, Maria Rosalia Pasca, and Luca Costantino. "Iron Acquisition Pathways as Targets for Antitubercular Drugs." Current Medicinal Chemistry 23, no. 35 (November 10, 2016): 4009–26. http://dx.doi.org/10.2174/0929867323666160607223747.

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Schmidt, Wolfgang. "Iron Homeostasis in Plants: Sensing and Signaling Pathways." Journal of Plant Nutrition 26, no. 10-11 (September 2003): 2211–30. http://dx.doi.org/10.1081/pln-120024276.

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Martins, Telma S., Vítor Costa, and Clara Pereira. "Signaling pathways governing iron homeostasis in budding yeast." Molecular Microbiology 109, no. 4 (August 2018): 422–32. http://dx.doi.org/10.1111/mmi.14009.

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Monti, M., B. Santos, A. Mascaraque, O. Rodríguez de la Fuente, M. A. Niño, T. O. Menteş, A. Locatelli, K. F. McCarty, J. F. Marco, and J. de la Figuera. "Oxidation Pathways in Bicomponent Ultrathin Iron Oxide Films." Journal of Physical Chemistry C 116, no. 21 (May 17, 2012): 11539–47. http://dx.doi.org/10.1021/jp300702d.

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Flannery, Andrew R., Rebecca L. Renberg, and Norma W. Andrews. "Pathways of iron acquisition and utilization in Leishmania." Current Opinion in Microbiology 16, no. 6 (December 2013): 716–21. http://dx.doi.org/10.1016/j.mib.2013.07.018.

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Conroy, Brigid S., Jason C. Grigg, Maxim Kolesnikov, L. Daniela Morales, and Michael E. P. Murphy. "Staphylococcus aureus heme and siderophore-iron acquisition pathways." BioMetals 32, no. 3 (March 25, 2019): 409–24. http://dx.doi.org/10.1007/s10534-019-00188-2.

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Xiao, Yuanyou, Guocheng Wang, Hong Lei, and Seetharaman Sridhar. "Formation pathways for MgO·Al2O3 inclusions in iron melt." Journal of Alloys and Compounds 813 (January 2020): 152243. http://dx.doi.org/10.1016/j.jallcom.2019.152243.

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Chepelev, Nikolai L., and William G. Willmore. "Regulation of iron pathways in response to hypoxia." Free Radical Biology and Medicine 50, no. 6 (March 2011): 645–66. http://dx.doi.org/10.1016/j.freeradbiomed.2010.12.023.

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Li, Yikun, Xiali Huang, Jingjing Wang, Ruiling Huang, and Dan Wan. "Regulation of Iron Homeostasis and Related Diseases." Mediators of Inflammation 2020 (May 2, 2020): 1–11. http://dx.doi.org/10.1155/2020/6062094.

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The liver is the organ for iron storage and regulation; it senses circulating iron concentrations in the body through the BMP-SMAD pathway and regulates the iron intake from food and erythrocyte recovery into the bloodstream by secreting hepcidin. Under iron deficiency, hypoxia, and hemorrhage, the liver reduces the expression of hepcidin to ensure the erythropoiesis but increases the excretion of hepcidin during infection and inflammation to reduce the usage of iron by pathogens. Excessive iron causes system iron overload; it accumulates in never system and damages neurocyte leading to neurodegenerative diseases such as Parkinson’s syndrome. When some gene mutations affect the perception of iron and iron regulation ability in the liver, then they decrease the expression of hepcidin, causing hereditary diseases such as hereditary hemochromatosis. This review summarizes the source and utilization of iron in the body, the liver regulates systemic iron homeostasis by sensing the circulating iron concentration, and the expression of hepcidin regulated by various signaling pathways, thereby understanding the pathogenesis of iron-related diseases.

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Novikova, I. A. "IRON AND IMMUNE RESPONSE." Health and Ecology Issues, no. 4 (December 28, 2011): 42–48. http://dx.doi.org/10.51523/2708-6011.2011-8-4-7.

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The present-day data on possible pathways of iron influence on human immune response and susceptibility to infections have been considered. The article describes changes of immunologic resistance in conditions of low iron level and mechanisms of iron status disturbance as a consequence of immunostimulation.

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Journal articles on the topic 'Iron pathways'

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