High Iron Environments Research Articles

Creatine Promotes Endometriosis by Inducing Ferroptosis Resistance via Suppression of PrP.

Endometriosis, a chronic inflammatory disease, significantly impairs the quality of life of women in their reproductive years; however, its pathogenesis remains poorly understood. The accumulation of retrograde menstruation and recurrent bleeding fosters a high-iron environment in ectopic lesions, triggering ferroptosis in ectopic endometrial stromal cells (EESCs), thereby hindering the establishment of endometriosis. However, abnormal EESCs demonstrate resistance to ferroptosis in high-iron environments, promoting the progression of this disease. Here, novel findings on the accumulation of creatine, derived from endogenous synthesis, in both peritoneal fluid and EESCs of patients with endometriosis are presented. Creatine supplementation reduces cellular iron concentrations, mitigating oxidative stress and lipid peroxidation, thereby enhancing cell viability and preventing ferroptosis under high-iron conditions. Utilizing the drug affinity-responsive target stabilization (DARTS) assay, prion protein (PrP) as a potential creatine-sensing protein is identified. Mechanistically, creatine binds to the active site of PrP, inhibits the conversion of trivalent iron to divalent iron, and decreases iron uptake, promoting the tolerance of EESCs to ferroptosis. This interaction contributes to the development of endometriosis. The novel association between creatine and ferroptosis provides valuable insights into the role of creatine in endometriosis progression and highlights its potential as a therapeutic target for endometriosis.

Iron Stress Affects the Growth and Differentiation of Toxoplasma gondii.

Iron is an indispensable nutrient for the survival of Toxoplasma gondii; however, excessive amounts can lead to toxicity. The parasite must overcome the host's "nutritional immunity" barrier and compete with the host for iron. Since T. gondii can infect most nucleated cells, it encounters increased iron stress during parasitism. This study assessed the impact of iron stress, encompassing both iron depletion and iron accumulation, on the growth of T. gondii. Iron accumulation disrupted the redox balance of T. gondii while enhancing the parasite's ability to adhere in high-iron environments. Conversely, iron depletion promoted the differentiation of tachyzoites into bradyzoites. Proteomic analysis further revealed proteins affected by iron depletion and identified the involvement of phosphotyrosyl phosphatase activator proteins in bradyzoite formation.

Contribution of Autophagy to Cellular Iron Homeostasis and Stress Adaptation in Alternaria alternata.

The tangerine pathotype of Alternaria alternata produces the Alternaria citri toxin (ACT), which elicits a host immune response characterized by the increase in harmful reactive oxygen species (ROS) production. ROS detoxification in A. alternata relies on the degradation of peroxisomes through autophagy and iron acquisition using siderophores. In this study, we investigated the role of autophagy in regulating siderophore and iron homeostasis in A. alternata. Our results showed that autophagy positively influences siderophore production and iron uptake. The A. alternata strains deficient in autophagy-related genes 1 and 8 (ΔAaatg1 and ΔAaatg8) could not thrive without iron, and their adaptability to high-iron environments was also reduced. Furthermore, the ability of autophagy-deficient strains to withstand ROS was compromised. Notably, autophagy deficiency significantly reduced the production of dimerumic acid (DMA), a siderophore in A. alternata, which may contribute to ROS detoxification. Compared to the wild-type strain, ΔAaatg8 was defective in cellular iron balances. We also observed iron-induced autophagy and lipid peroxidation in A. alternata. To summarize, our study indicates that autophagy and maintaining iron homeostasis are interconnected and contribute to the stress resistance and the virulence of A. alternata. These results provide new insights into the complex interplay connecting autophagy, iron metabolism, and fungal pathogenesis in A. alternata.

Endometrial stromal cell autophagy-dependent ferroptosis caused by iron overload in ovarian endometriosis is inhibited by the ATF4-xCT pathway.

Ferroptosis is an iron-dependent programmed cell death process characterized by the accumulation of lethal oxidative damage. Localized iron overload is a unique clinical phenomenon in ovarian endometriosis (EM). However, the role and mechanism of ferroptosis in the course of ovarian EM remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian EM and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells (ESCs). Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse EM model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian EM can activate autophagy-related ferroptosis in ESCs, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the EM environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian EM.

Ferritin Is Secreted from Primary Cultured Astrocyte in Response to Iron Treatment via TRPML1-Mediated Exocytosis.

Impaired iron homeostasis has been proven to be one of the critical contributors to the pathology of Parkinson's disease (PD). Ferritin is considered an intracellular protein responsible for storing cytosolic iron. Recent studies have found that ferritin can be secreted from cells independent of the classical endoplasmic reticulum-Golgi system. However, the precise mechanisms underlying the secretion of ferritin in the brain were not elucidated. In the present study, we demonstrated that the primary cultured astrocytes do have the ability to secrete ferritin, which is enhanced by iron treatment. Increased ferritin secretion was accompanied by increased protein expression of ferritin response to iron stimulation. Further study showed that iron-induced expression and secretion of ferritin could be inhibited by CQ or 3-MA pretreatment. In addition, the knockdown of transient receptor potential mucolipin 1 (TRPML1) antagonized iron-induced ferritin secretion, accompanied by further increased intracellular protein levels of ferritin. Further study demonstrated that ferritin colocalized with LAMP1 in iron-treated astrocytes. On the contrary, ras-associated protein 27a (Rab27a) knockdown further enhanced iron-induced ferritin secretion and decreased intracellular protein levels of ferritin. Furthermore, we also showed that the secretory autophagy protein tripartite motif containing 16 (TRIM16) and sec22b decreased in iron-treated astrocytes. These results suggested that astrocytes might secrete ferritin via TRPML1-mediated exocytosis. This provides new evidence for the mechanisms underlying the secretion of ferritin in primary cultured astrocytes under a high iron environment.

Phosphatidylinositol 3-phosphate regulates iron transport via PI3P-binding CgPil1 protein

Iron homeostasis, which is pivotal to virulence, is regulated by the phosphatidylinositol 3-kinase CgVps34 inthe human fungal pathogen Candida glabrata. Here, we identify CgPil1 as a phosphatidylinositol 3-phosphate (PI3P)-binding protein and unveil its role in retaining the high-affinity iron transporter CgFtr1 at the plasma membrane (PM), with PI3P negatively regulating CgFtr1-CgPil1 interaction. PI3P production and its PM localization are elevated in the high-iron environment. Surplus iron also leads to intracellular distribution and vacuolar delivery of CgPil1 and CgFtr1, respectively, from the PM. Loss of CgPil1 or CgFtr1 ubiquitination at lysines 391 and 401 results in CgFtr1 trafficking to the endoplasmic reticulum and a decrease in vacuole-localized CgFtr1. The E3-ubiquitin ligase CgRsp5 interacts with CgFtr1 and forms distinct CgRsp5-CgFtr1 puncta at the PM, with high iron resulting in their internalization. Finally, PI3P controls retrograde transport of many PM proteins. Altogether, we establish PI3P as a key regulator of membrane transport in C.glabrata.

The Expression of GPR30 in Iron-Overloaded Atypical Ovarian Epithelium and Ectopic Endometrium Is Closely Correlated with Transferrin Receptor and Pi3K.

Background The mechanism of atypical hyperplasia of the ovarian epithelium and ectopic endometrium caused by iron overload remains unclear. Accordingly, we investigated possible effects on the human ovarian ectopic endometrium and ovarian epithelium by producing a high-iron environment with rat ovaries. Objective Human ovarian ectopic endometrium with atypical hyperplasia was collected, and the correlation between transferrin receptor GPR30 and Pi3K protein expression was studied by immunohistochemistry staining. Twenty SPF Sprague–Dawley female rats were microinjected with iron into one side of the ovary once a month, and the other ovary was used as the control. After 10 months of microinjection, the iron histological analysis was examined by Prussian blue staining, and ovarian endometrium morphology was assessed by HE staining. Abnormal lesion changes were measured by Pi3K staining. Evaluation of GPR30 was performed using reverse transcription PCR (RT-PCR) and western blotting, and the interrelationship between GPR30 and Pi3K was also assayed. Results GPR30 was significantly increased and correlated with the transferrin receptor and Pi3K in atypical human ovarian ectopic endometrium. Iron overload was confirmed in the 20 microinjected ovary cortexes, epithelial hyperplasia was observed in 12 ovaries, and papillary atypical hyperplasia was noted in eight ovaries. The RNA and protein levels of GPR30 were significantly increased in atypical hyperplasia compared to hyperplasia tissue samples. A positive relationship between GPR30 and Pi3K was found (P = 0.001). Conclusion The results suggest that persistent iron exposure may be a potential stimulus for ovarian endometriosis with atypical changes, and the abnormal increase in the new estrogen receptor GPR30 is closely related to this process.

A novel preparation for siderophore‐assisted copper and zinc enrichment in yeast

Copper and zinc are essential trace elements for several biological activities and play an important role in living organisms. In this study, the role of siderophores obtained from 16 microorganisms isolated from an iron-rich environment was evaluated in the transport of zinc and copper in yeast. In addition, siderophores showing relevant transport activity were used in the preparation of metal-enriched yeast. Siderophores TZT-SH5I and TZT-ZTH2X significantly improved tolerance of Saccharomyces cerevisiae during growth under high concentrations of zinc/copper. Strains producing siderophores TZT-SH5I and TZT-ZTH2X were identified as Aspergillus sp and Penicillium sp, respectively. The orthogonal method was used to determine optimized conditions for siderophore-assisted copper and zinc enrichment of S. cerevisiae. The final intracellular content of organic Cu and Zn in S. cerevisiae grown in a siderophore-containing medium was 60.76 and 44.22 mg/g. This study provides a convenient and feasible new strategy for the preparation of supplements rich in organic trace elements. Novelty impact statement Bioaccumulation of essential trace elements (TEs) by microorganisms is one of the most important ways to TEs from inorganic into organic forms which can be more efficiently absorbed by humans. In the current study, a novel method for preparing copper and zinc-enriched yeast using siderophores from high iron environment microorganisms has been optimized and established. Significantly higher intracellular content of organic Cu and Zn in Saccharomyces cerevisiae grown in a siderophore-containing medium was obtained, which would provide a new idea and platform for the preparation of organic trace elements.

The <i>Thermosynechococcus</i> Genus: Wide Environmental Distribution, but a Highly Conserved Genomic Core

Cyanobacteria thrive in diverse environments. However, questions remain about possible growth limitations in ancient environmental conditions. As a single genus, the Thermosynechococcus are cosmopolitan and live in chemically diverse habitats. To understand the genetic basis for this, we compared the protein coding component of Thermosynechococcus genomes. Supplementing the known genetic diversity of Thermosynechococcus, we report draft metagenome-assembled genomes of two Thermosynechococcus recovered from ferrous carbonate hot springs in Japan. We find that as a genus, Thermosynechococcus is genomically conserved, having a small pan-genome with few accessory genes per individual strain as well as few genes that are unique to the genus. Furthermore, by comparing orthologous protein groups, including an analysis of genes encoding proteins with an iron related function (uptake, storage or utilization), no clear differences in genetic content, or adaptive mechanisms could be detected between genus members, despite the range of environments they inhabit. Overall, our results highlight a seemingly innate ability for Thermosynechococcus to inhabit diverse habitats without having undergone substantial genomic adaptation to accommodate this. The finding of Thermosynechococcus in both hot and high iron environments without adaptation recognizable from the perspective of the proteome has implications for understanding the basis of thermophily within this clade, and also for understanding the possible genetic basis for high iron tolerance in cyanobacteria on early Earth. The conserved core genome may be indicative of an allopatric lifestyle—or reduced genetic complexity of hot spring habitats relative to other environments.

Novel and rapid osteoporosis model established in zebrafish using high iron stress

Osteoporosis is a global public health concern and, it can result from numerous pathogenic mechanisms, many of which are closely related with age, nutritional disorders, endocrine imbalance, or adverse drug side effects presented by glucocorticoids, heparin, and anti-epileptics. Given its wide range etiologies, it is crucial to establish an animal model of osteoporosis for use in screening potential drugs quickly and effectively. Previous research has reported that an accumulation of elevated iron in the body is an independent risk factor for osteoporosis. As such, we sought to use both zebrafish larvae and adults to model an osteoporosis phenotype using high iron stress (FAC, ferric ammonium citrate). Skeletal staining results suggested that iron-overload caused a significant decrease in bone calcification as well as severe developmental cartilage defects. In addition, osteoblast and cartilage-specific mRNA expression levels were downregulated after exposure to a high-iron environment. Most importantly, we demonstrated in both larval and adult fish that high iron-induced osteogenic defects were significantly rescued using alendronate (AL), a drug known to be effective against to human osteoporosis. Even more, the repair effect of AL was achieved by facilitating osteoblast differentiation and targeting Bmp signaling. Taken together, our findings propose an rapid and effective osteoporosis model, which could be used widely for future osteoporosis drug screening.

Hidden diversity revealed by genome-resolved metagenomics of iron-oxidizing microbial mats from L\u014d\u2019ihi Seamount, Hawai\u2019i

The Zetaproteobacteria are ubiquitous in marine environments, yet this class of Proteobacteria is only represented by a few closely-related cultured isolates. In high-iron environments, such as diffuse hydrothermal vents, the Zetaproteobacteria are important members of the community driving its structure. Biogeography of Zetaproteobacteria has shown two ubiquitous operational taxonomic units (OTUs), yet much is unknown about their genomic diversity. Genome-resolved metagenomics allows for the specific binning of microbial genomes based on genomic signatures present in composite metagenome assemblies. This resulted in the recovery of 93 genome bins, of which 34 were classified as Zetaproteobacteria. Form II ribulose 1,5-bisphosphate carboxylase genes were recovered from nearly all the Zetaproteobacteria genome bins. In addition, the Zetaproteobacteria genome bins contain genes for uptake and utilization of bioavailable nitrogen, detoxification of arsenic, and a terminal electron acceptor adapted for low oxygen concentration. Our results also support the hypothesis of a Cyc2-like protein as the site for iron oxidation, now detected across a majority of the Zetaproteobacteria genome bins. Whole genome comparisons showed a high genomic diversity across the Zetaproteobacteria OTUs and genome bins that were previously unidentified by SSU rRNA gene analysis. A single lineage of cosmopolitan Zetaproteobacteria (zOTU 2) was found to be monophyletic, based on cluster analysis of average nucleotide identity and average amino acid identity comparisons. From these data, we can begin to pinpoint genomic adaptations of the more ecologically ubiquitous Zetaproteobacteria, and further understand their environmental constraints and metabolic potential.

Iron acquisition and oxidative stress response in aspergillus fumigatus.

BackgroundAspergillus fumigatus is a ubiquitous airborne fungal pathogen that presents a life-threatening health risk to individuals with weakened immune systems. A. fumigatus pathogenicity depends on its ability to acquire iron from the host and to resist host-generated oxidative stress. Gaining a deeper understanding of the molecular mechanisms governing A. fumigatus iron acquisition and oxidative stress response may ultimately help to improve the diagnosis and treatment of invasive aspergillus infections.ResultsThis study follows a systems biology approach to investigate how adaptive behaviors emerge from molecular interactions underlying A. fumigatus iron regulation and oxidative stress response. We construct a Boolean network model from known interactions and simulate how changes in environmental iron and superoxide levels affect network dynamics. We propose rules for linking long term model behavior to qualitative estimates of cell growth and cell death. These rules are used to predict phenotypes of gene deletion strains. The model is validated on the basis of its ability to reproduce literature data not used in model generation.ConclusionsThe model reproduces gene expression patterns in experimental time course data when A. fumigatus is switched from a low iron to a high iron environment. In addition, the model is able to accurately represent the phenotypes of many knockout strains under varying iron and superoxide conditions. Model simulations support the hypothesis that intracellular iron regulates A. fumigatus transcription factors, SreA and HapX, by a post-translational, rather than transcriptional, mechanism. Finally, the model predicts that blocking siderophore-mediated iron uptake reduces resistance to oxidative stress. This indicates that combined targeting of siderophore-mediated iron uptake and the oxidative stress response network may act synergistically to increase fungal cell killing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0163-1) contains supplementary material, which is available to authorized users.

The mitogen-activated protein kinase CgHog1 is required for iron homeostasis, adherence and virulence in Candida glabrata.

Candida glabrata has emerged as a major fungal pathogen over the last two decades, although our understanding of its survival strategies inside the mammalian host remains rudimentary. An important requirement for survival in vivo is the ability to acquire critical nutrients such as iron from host niches of varied iron content. In the present study, we demonstrate for the first time that C. glabrata cells respond to high external iron levels via activation of two stress-responsive mitogen-activated protein kinases, CgHog1 and CgSlt2, and lack of either kinase results in sensitivity to the high-iron medium. Furthermore, we show that CgHOG1 deletion led to perturbed iron homeostasis (elevated intracellular iron content and high mitochondrial aconitase activity), reduced survival in macrophages and attenuated virulence in the murine model of disseminated candidiasis. Consistently, several genes implicated in iron acquisition and storage displayed deregulated expression in the Cghog1∆ mutant. Genome-wide transcriptional profiling analysis revealed upregulation of genes implicated in DNA repair, RNA processing and autophagy, and downregulation of genes related to cellular respiration and organonitrogen compound metabolism under iron-limiting conditions. In contrast, genes involved in the respiratory electron transport chain were induced under iron-replete conditions. Gene expression microarrays also identified a set of iron-responsive regulon in C. glabrata. Lastly, we present evidence for the iron-regulated expression of the major adhesin-encoding EPA1 gene, decreased histone deacetylase activity in a high-iron environment and increased adherence of iron-surplus-medium-grown C. glabrata cells to epithelial cells. Together, our findings yield novel insights into iron abundance-based regulation of transcriptional and mitogen-activated protein kinase signaling pathways in C. glabrata.

TonB-dependent heme iron acquisition in the tsetse fly symbiont Sodalis glossinidius.

Sodalis glossinidius is an intra- and extracellular symbiont of the tsetse fly (Glossina sp.), which feeds exclusively on vertebrate blood. S. glossinidius resides in a wide variety of tsetse tissues and may encounter environments that differ dramatically in iron content. The Sodalis chromosome encodes a putative TonB-dependent outer membrane heme transporter (HemR) and a putative periplasmic/inner membrane ABC heme permease system (HemTUV). Because these gene products mediate iron acquisition processes by other enteric bacteria, we characterized their regulation and physiological role in the Sodalis/tsetse system. Our results show that the hemR and tonB genes are expressed by S. glossinidius in the tsetse fly. Furthermore, transcription of hemR in Sodalis is repressed in a high-iron environment by the iron-responsive transcriptional regulator Fur. Expression of the S. glossinidius hemR and hemTUV genes in an Escherichia coli strain unable to use heme as an iron source stimulated growth in the presence of heme or hemoglobin as the sole iron source. This stimulation was dependent on the presence of either the E. coli or Sodalis tonB gene. Sodalis tonB and hemR mutant strains were defective in their ability to colonize the gut of tsetse flies that lacked endogenous symbionts, while wild-type S. glossinidius proliferated in this same environment. Finally, we show that the Sodalis HemR protein is localized to the bacterial membrane and appears to bind hemin. Collectively, this study provides strong evidence that TonB-dependent, HemR-mediated iron acquisition is important for the maintenance of symbiont homeostasis in the tsetse fly, and it provides evidence for the expression of bacterial high-affinity iron acquisition genes in insect symbionts.

Iron-dependent gene expression in Actinomyces oris

BackgroundActinomyces oris is a Gram-positive bacterium that has been associated with healthy and diseased sites in the human oral cavity. Most pathogenic bacteria require iron to survive, and in order to acquire iron in the relatively iron-scarce oral cavity A. oris has been shown to produce iron-binding molecules known as siderophores. The genes encoding these siderophores and transporters are thought to be regulated by the amount of iron in the growth medium and by the metal-dependent repressor, AmdR, which we showed previously binds to the promoter of proposed iron-regulated genes.ObjectiveThe purpose of this study was to characterize siderophore and associated iron transport systems in A. oris.DesignWe examined gene expression of the putative iron transport genes fetA and sidD in response to low- and high-iron environments. One of these genes, sidD, encoding a putative Fe ABC transporter protein, was insertionally inactivated and was examined for causing growth defects. To gain a further understanding of the role of iron metabolism in oral diseases, clinical isolates of Actinomyces spp. were examined for the presence of the gene encoding AmdR, a proposed global regulator of iron-dependent gene expression in A. oris.ResultsWhen A. oris was grown under iron-limiting conditions, the genes encoding iron/siderophore transporters fetA and sidD showed increased expression. One of these genes (sidD) was mutated, and the sidD::Km strain exhibited a 50% reduction in growth in late log and stationary phase cells in media that contained iron. This growth defect was restored when the sidD gene was provided in a complemented strain. We were able to isolate the AmdR-encoding gene in seven clinical isolates of Actinomyces. When these protein sequences were aligned to the laboratory strain, there was a high degree of sequence similarity.ConclusionsThe growth of the sidD::Km mutant in iron-replete medium mirrored the growth of the wild-type strain grown in iron-limiting medium, suggesting that the sidD::Km mutant was compromised in iron uptake. The known iron regulator AmdR is well conserved in clinical isolates of A. oris. This work provides additional insight into iron metabolism in this important oral microbe.

Genomic insights into the uncultivated marine Zetaproteobacteria at Loihi Seamount.

The Zetaproteobacteria are a candidate class of marine iron-oxidizing bacteria that are typically found in high iron environments such as hydrothermal vent sites. As much remains unknown about these organisms due to difficulties in cultivation, single-cell genomics was used to learn more about this elusive group at Loihi Seamount. Comparative genomics of 23 phylogenetically diverse single amplified genomes (SAGs) and two isolates indicate niche specialization among the Zetaproteobacteria may be largely due to oxygen tolerance and nitrogen transformation capabilities. Only Form II ribulose 1,5-bisphosphate carboxylase (RubisCO) genes were found in the SAGs, suggesting that some of the uncultivated Zetaproteobacteria may be adapted to low oxygen and/or high carbon dioxide concentrations. There is also genomic evidence of oxygen-tolerant cytochrome c oxidases and oxidative stress-related genes, indicating that others may be exposed to higher oxygen conditions. The Zetaproteobacteria also have the genomic potential for acquiring nitrogen from numerous sources including ammonium, nitrate, organic compounds, and nitrogen gas. Two types of molybdopterin oxidoreductase genes were found in the SAGs, indicating that those found in the isolates, thought to be involved in iron oxidation, are not consistent among all the Zetaproteobacteria. However, a novel cluster of redox-related genes was found to be conserved in 10 SAGs as well as in the isolates warranting further investigation. These results were used to isolate a novel iron-oxidizing Zetaproteobacteria. Physiological studies and genomic analysis of this isolate were able to support many of the findings from SAG analyses demonstrating the value of these data for designing future enrichment strategies.

When Nature Meets Nurture: Persistent Yersinia Infection

PRESENTATION When the patient’s symptoms are alleviated, it might seem that the causative infection has cleared. But that was not the case for a 62-year-old man with type 2 diabetes who presented with a 1-week history of constipation, lower abdominal cramping, rectal pressure, and hematochezia. In the emergency department, laboratory testing detected leukocytosis with a white blood cell count of 19 x 10 cells/mm and an elevated neutrophil count. Computed tomography (CT) of the patient’s abdomen and pelvis demonstrated marked inflammation of the rectal wall. He was admitted and underwent colonoscopy, which confirmed the presence of proctitis but was otherwise normal. Four days after admission, his stool culture grew pan-sensitive Yersinia enterocolitica. A diagnosis of Yersinia proctitis was made. Simple hepatic cysts seen on CT were felt to be incidental. The patient was prescribed a 5-day course of oral ciprofloxacin. He returned home and had complete symptom resolution. However, 3 weeks after completing treatment, he experienced gradual onset of severe pain that began in the right upper quadrant of the abdomen and radiated to his back and right shoulder. This was accompanied by malaise, intermittent fevers, and anorexia. He reported a 21-pound unintentional weight loss over the preceding 2 months. One month after discharge, he returned to the emergency department.

Pathways of ferrous iron mineral formation upon sulfidation of lepidocrocite surfaces

The interaction between S(-II) and ferric oxides exerts a major control for the sulphur and iron cycle and in particular for the carbon and electron flow in many aquatic systems. It is regarded to be a key reaction leading ultimately to pyrite formation, the pathways still remaining unresolved. We have studied the reaction between lepidocrocite (γ-FeOOH, 21–42mmolL−1) and dissolved S(-II) (3–9mmolL−1) in batch experiments at pH 7 in a glove box using TEM, XRD, Mössbauer spectroscopy, and wet chemistry extraction to explore the nanocrystalline products forming at different time steps in close contact to the lepidocrocite surface. S(0) and acid extractable Fe(II) (Fe(II)HCl) were the main products detected by wet chemistry extraction. The reaction could be divided into three steps: a rapid (<15min) consumption of dissolved S(-II), formation of S(0) and the build-up of an Fe(II)HCl pool. Then in the absence of dissolved S(-II) concentrations of S(0) and Fe(II)HCl increased only slightly. TEM measurements revealed the occurrence of a mackinawite rim covering the lepidocrocite crystals and being separated from the lepidocrocite surface by an interfacial magnetite layer that can be regarded as a steady state product of the interaction between lepidocrocite and mackinawite. A significant fraction of Fe(II) was formed in excess to FeS within the first 2h. The amount of this fraction increased with decreasing ratio between dissolved S(-II) concentration and the concentration of surface sites, which we attributed to a kinetic decoupling of S(-II) oxidation and Fe(II) detachment from the lepidocrocite surface. At low ratios, S(-II) seems to transfer electrons to lepidocrocite faster then stoichiometric amounts of FeS could. After 2days Fe(II)HCl and S(0) started to decrease resulting in pyrite formation accompanied by traces of magnetite. TEM measurements indicated that mackinawite completely dissolved and precipitation of pyrite occurred dislocated from the lepidocrocite surface. The absence of dissolved sulphide under these conditions suggest that excess Fe(II) is involved in the formation of polysulphides which are key precursors during pyrite formation. We propose that the occurrence of excess Fe(II) is a common phenomenon particularly in low sulphide – high iron environments attributing significant reactivity to ferric (hydr)oxides.

Molecular Analysis of Two Bacterioferritin Genes, bfr α and bfr β, in the Model Rhizobacterium Pseudomonas putida KT2440

The model rhizobacterium Pseudomonas putida KT2440 and other fluorescent pseudomonads possess two bacterioferritins, Bfralpha and Bfrbeta. However, the regulatory systems controlling the expression of these genes and the roles of these proteins in iron homeostasis are ill defined. Our studies show that both bfralpha and bfrbeta were monocistronic: promoter motifs and transcriptional start sites were identified, and Fur boxes and sigma(S)-dependent regulatory motifs were absent. The expressions of bfralpha and bfrbeta were enhanced by iron exposure and were maximal in cells rapidly growing in a high-iron environment. Both bfralpha and bfrbeta were positively regulated by Fur, and both were expressed independently of adjoining, functionally related genes. The loss of Bfralpha or Bfrbeta individually resulted in a significant reduction (ca. 17%) in cellular iron levels, and the deletion of both bfralpha and bfrbeta reduced cellular iron levels by 38% relative to those of the wild type. The mutants varied in their abilities to grow in low-iron medium; while growths (rate and final cell density) of single mutants and the wild type were similar, that of the double mutant was reduced significantly. Mutants lacking Bfralpha and/or Bfrbeta showed no change relative to the wild type in sensitivity to reactive oxygen species toxicity. Collectively, the data show that while Bfralpha and Bfrbeta could function independently of each other, an interaction-dependent function cannot be ruled out. Furthermore, regardless of the mechanism, a primary benefit of the bacterioferritins to P. putida KT2440 appears to be the enhancement of its survival in the environment by strengthening its tolerance to iron starvation.

Reproductive Toxicity: Too Much of a Good Thing?

Vol. 114, No. 10 EnvironewsOpen AccessReproductive Toxicity: Too Much of a Good Thing? Valerie J. Brown Valerie J. Brown Search for more papers by this author Published:1 October 2006https://doi.org/10.1289/ehp.114-a578aAboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Pregnant women are famously exhorted to faithfully take their daily prenatal vitamins, which often contain iron and other minerals. But new research suggests that a weekly iron supplement coinciding with the renewal of the small intestine’s mucosal lining cells (where nutrient absorption occurs) works better than a daily supplement and prevents problems resulting from too much iron at the wrong times.Maternal iron deficiency and anemia early in gestation can result in premature birth and low birth weight. These, in turn, can trigger further problems ranging from slow physical growth and motor development to impaired emotional control. In severe cases, both maternal and fetal survival can be threatened at or near birth. Thus, there exists a near-global public health policy of maternal iron supplementation during pregnancy.The new study appears in the July 2006 issue of Archives of Medical Research. A team including nutritionist and epidemiologist Esther Casanueva of the National Institute of Perinatology Isidro Espinosa de los Reyes (INPerIER) in Mexico City and colleagues elsewhere in Mexico City and California studied 116 women receiving prenatal care at INPerIER. All had come to INPerIER for prenatal care by gestational week 20.None of the women were anemic at that point, but 66% had low levels of ferritin (the principal form of stored iron), suggesting low iron nutritional status. Half took 60 mg of iron as ferrous sulfate with 200 μg of folic acid and 1 μg of vitamin B12 once a day; the others took double this dose once a week. The researchers checked the women’s levels of hemoglobin (which transports oxygen) and ferritin every four weeks through the end of pregnancy.More of the women taking the weekly dose were mildly anemic (with hemoglobin levels shown not to carry any risk for mothers and infants) compared with the women taking the daily dose. However, by weeks 28 to 36, women taking the daily supplement had a significantly higher prevalence of hemoconcentration, a condition defined as hemoglobin levels above 145 g/L. Ironically, both early gestational iron-deficiency anemia and hemoconcentration later in pregnancy increase the risk of premature birth and low birth weight. Thus, the researchers suggest that excess iron supplementation can cause the same problems it is supposed to correct.Animal studies suggest that excess iron can also trigger formation of free radicals in the intestinal mucosa and other tissues, and that both iron deficiency and iron overload can damage nuclear DNA and mitochondrial DNA. This kind of damage has been implicated in cancer induction.The intestinal mucosa is renewed every 5 to 6 days and will absorb as much iron as necessary to maintain iron balance; however, mature cells will stop absorbing iron entirely if they are flooded with it, even if there is an iron deficit. “Maintaining a high iron environment in the intestine by ingesting significantly more iron than needed every day overwhelms this safety system,” says coauthor Fernando E. Viteri. A more subtly calibrated iron supplementation during pregnancy may be as effective as current public health recommendations, and perhaps safer.FiguresReferencesRelatedDetails Vol. 114, No. 10 October 2006Metrics About Article Metrics Publication History Originally published1 October 2006Published in print1 October 2006 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.