Promotion of direct electron transfer between Shewanella putrefaciens CN32 and carbon fiber electrodes via in situ growth of α-Fe2O3 nanoarray.

The iron transport system plays a crucial role in the extracellular electron transfer process of Shewanella sp. In this study, we fabricated a vertically oriented α-Fe2O3 nanoarray on carbon cloth to enhance interfacial electron transfer in Shewanella putrefaciens CN32 microbial fuel cells. The incorporation of the α-Fe2O3 nanoarray not only resulted in a slight increase in flavin content but also significantly enhanced biofilm loading, leading to an eight-fold higher maximum power density compared to plain carbon cloth. Through expression level analyses of electron transfer-related genes in the outer membrane and core genes in the iron transport system, we propose that the α-Fe2O3 nanoarray can serve as an electron mediator, facilitating direct electron transfer between the bacteria and electrodes. This finding provides important insights into the potential application of iron-containing oxide electrodes in the design of microbial fuel cells and other bioelectrochemical systems, highlighting the role of α-Fe2O3 in promoting direct electron transfer.

A Haemophilus ducreyi strain lacking the yfeABCD iron transport system is virulent in human volunteers.

Haemophilus ducreyi causes the genital ulcer disease chancroid and painful cutaneous ulcers in children who live in the tropics. To acquire heme from the host, H. ducreyi expresses a TonB-dependent hemoglobin receptor, HgbA, which is necessary and sufficient for H. ducreyi to progress to the pustular stage of disease in a controlled human infection model. HgbA transports hemoglobin across the outer membrane; how heme is transported across the cytoplasmic membrane is unclear. In previous studies, transcripts encoding the YfeABCD heme transporter were upregulated in experimental lesions caused by H. ducreyi in human volunteers, suggesting the latter may have a role in virulence. Here we constructed a double deletion mutant, 35000HPΔyfeABΔyfeCD, which exhibited growth defects relative to its parent 35000HP in media containing human hemoglobin as an iron source. Five human volunteers were inoculated at three sites on the skin overlying the deltoid with each strain. The results of the trial showed that papules formed at 100% (95% CI, 71.5, 100) at both 35000HP and 35000HPΔyfeABΔyfeCD-inoculated sites (P = 1.0). Pustules formed at 60% (95% CI, 25.9, 94.1) at parent-inoculated sites and 53% (95% CI, 18.3, 88.4) at mutant-inoculated sites (P = 0.79). Thus, the ABC transporter encoded by yfeAB and yfeCD was dispensable for H. ducreyi virulence in humans. In the absence of YfeABCD, H. ducreyi likely utilizes other periplasmic binding proteins and ABC-transporters such as HbpA, SapABCDF, and DppBCDF to shuttle heme from the periplasm into the cytoplasm, underscoring the importance of redundancy of such systems in gram-negative pathogens.

Inhibition of Slc39a14/Slc39a8 reduce vascular calcification via alleviating iron overload induced ferroptosis in vascular smooth muscle cells.

BACKGROUND: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload. METHODS: R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification. RESULTS: Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs. CONCLUSIONS: Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment.

Exploring the Biological Pathways of Siderophores and Their Multidisciplinary Applications: A Comprehensive Review.

Siderophores are a class of small molecules renowned for their high iron binding capacity, essential for all life forms requiring iron. This article provides a detailed review of the diverse classifications, and biosynthetic pathways of siderophores, with a particular emphasis on siderophores synthesized via nonribosomal peptide synthetase (NRPS) and non-NRPS pathways. We further explore the secretion mechanisms of siderophores in microbes and plants, and their role in regulating bioavailable iron levels. Beyond biological functions, the applications of siderophores in medicine, agriculture, and environmental sciences are extensively discussed. These applications include biological pest control, disease treatment, ecological pollution remediation, and heavy metal ion removal. Through a comprehensive analysis of the chemical properties and biological activities of siderophores, this paper demonstrates their wide prospects in scientific research and practical applications, while also highlighting current research gaps and potential future directions.

Gene expression of iron transporters, markers of vascularization and structural integrity in placenta of mothers with and without anemia.

OBJECTIVE: To compare the mRNA expression of placental iron transporters (TfR-1 and FPN), markers of placental vascularization (VEGF and sFLT1) and marker of structural integrity (LMN-A) in term women with and without iron deficiency anemia. MATERIALS AND METHODS: A total of 30 pregnant women were enrolled; 15 cases of iron deficiency anemia (Hb 7-10.9 gm/dL) and 15 gestational age matched healthy controls (Hb ≥ 11 gm/dL). Peripheral venous blood was collected for assessment of hemoglobin levels and serum iron profile. Placental tissue was used for assessing the mRNA expression of TfR-1, FPN, VEGF, sFLT-1 and LMN-A via real time PCR. RESULTS: Placental expression of TfR-1, VEGF and LMN-A was increased in pregnant women with anemia compared to healthy pregnant controls. Placental expression of sFLT-1 was decreased in pregnant women with anemia compared to healthy pregnant controls. There was no change in the placental expression of FPN. CONCLUSION: The increased expression of TfR-1, VEGF and LMN-A in cases of iron deficiency anemia are most likely to be compensatory in nature to help maintain adequate fetal iron delivery. WHAT DOES THIS STUDY ADDS TO THE CLINICAL WORK: Compensatory changes in the placenta aimed at buffering transport of iron to the fetus are seen in pregnant women with anemia compared to healthy pregnant controls.

Specificity and mechanism of TonB-dependent ferric catecholate uptake by Fiu.

We studied the Escherichia coli outer membrane protein Fiu, a presumed transporter of monomeric ferric catecholates, by introducing Cys residues in its surface loops and modifying them with fluorescein maleimide (FM). Fiu-FM bound iron complexes of the tricatecholate siderophore enterobactin (FeEnt) and glucosylated enterobactin (FeGEnt), their dicatecholate degradation product Fe(DHBS)2 (FeEnt*), the monocatecholates dihydroxybenzoic acid (FeDHBA) and dihydroxybenzoyl serine (FeDHBS), and the siderophore antibiotics cefiderocol (FDC) and MB-1. Unlike high-affinity ligand-gated porins (LGPs), Fiu-FM had only micromolar affinity for iron complexes. Its apparent KD values for FeDHBS, FeDHBA, FeEnt*, FeEnt, FeGEnt, FeFDC, and FeMB-1 were 0.1, 0.7, 0.7, 1.0, 0.3, 0.4, and 4 µM, respectively. Despite its broad binding abilities, the transport repertoires of E. coli Fiu, as well as those of Cir and FepA, were less broad. Fiu only transported FeEnt*. Cir transported FeEnt* and FeDHBS (weakly); FepA transported FeEnt, FeEnt*, and FeDHBA. Both Cir and FepA bound FeGEnt, albeit with lower affinity. Related transporters of Acinetobacter baumannii (PiuA, PirA, BauA) had similarly moderate affinity and broad specificity for di- or monomeric ferric catecholates. Both microbiological and radioisotopic experiments showed Fiu's exclusive transport of FeEnt*, rather than ferric monocatecholate compounds. Molecular docking and molecular dynamics simulations predicted three binding sites for FeEnt*in the external vestibule of Fiu, and a fourth site deeper in its interior. Alanine scanning mutagenesis in the outermost sites (1a, 1b, and 2) decreased FeEnt* binding affinity as much as 20-fold and reduced or eliminated FeEnt* uptake. Finally, the molecular dynamics simulations suggested a pathway of FeEnt* movement through Fiu that may generally describe the process of metal transport by TonB-dependent receptors.

Siderophore-mediated iron acquisition by Klebsiella pneumoniae.

Microbes synthesize and secrete siderophores, that bind and solubilize precipitated or otherwise unavailable iron in their microenvironments. Gram (-) bacterial TonB-dependent outer membrane receptors capture the resulting ferric siderophores to begin the uptake process. From their similarity to fepA, the structural gene for the Escherichia coli ferric enterobactin (FeEnt) receptor, we identified four homologous genes in the human and animal ESKAPE pathogen Klebsiella pneumoniae (strain Kp52.145). One locus encodes IroN (locus 0027 on plasmid pII), and three other loci encode other FepA orthologs/paralogs (chromosomal loci 1658, 2380, and 4984). Based on the crystal structure of E. coli FepA (1FEP), we modeled the tertiary structures of the K. pneumoniae FepA homologs and genetically engineered individual Cys substitutions in their predicted surface loops. We subjected bacteria expressing the Cys mutant proteins to modification with extrinsic fluorescein maleimide (FM) and used the resulting fluorescently labeled cells to spectroscopically monitor the binding and transport of catecholate ferric siderophores by the four different receptors. The FM-modified FepA homologs were nanosensors that defined the ferric catecholate uptake pathways in pathogenic strains of K. pneumoniae. In Kp52.145, loci 1658 and 4984 encoded receptors that primarily recognized and transported FeEnt; locus 0027 produced a receptor that principally bound and transported FeEnt and glucosylated FeEnt (FeGEnt); locus 2380 encoded a protein that bound ferric catecholate compounds but did not detectably transport them. The sensors also characterized the uptake of iron complexes, including FeGEnt, by the hypervirulent, hypermucoviscous K. pneumoniae strain hvKp1. IMPORTANCE: Both commensal and pathogenic bacteria produce small organic chelators, called siderophores, that avidly bind iron and increase its bioavailability. Klebsiella pneumoniae variably produces four siderophores that antagonize host iron sequestration: enterobactin, glucosylated enterobactin (also termed salmochelin), aerobactin, and yersiniabactin, which promote colonization of different host tissues. Abundant evidence links bacterial iron acquisition to virulence and infectious diseases. The data we report explain the recognition and transport of ferric catecholates and other siderophores, which are crucial to iron acquisition by K. pneumoniae.

Iron Dysregulation in Alzheimer's Disease: LA-ICP-MS Bioimaging of the Distribution of Iron and Ferroportin in the CA1 Region of the Human Hippocampus.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by cognitive decline and neuropathological hallmarks, including ß-amyloid (Aß) plaques, Tau tangles, synaptic dysfunction and neurodegeneration. Emerging evidence suggests that abnormal iron (Fe) metabolism plays a role in AD pathogenesis, but the precise spatial distribution of the Fe and its transporters, such as ferroportin (FPN), within affected brain regions remains poorly understood. This study investigates the distribution of Fe and FPN in the CA1 region of the human hippocampus in AD patients with a micrometer lateral resolution using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). For this purpose, we visualized and quantified Fe and FPN in three separated CA1 layers: stratum molecular-radial (SMR), stratum pyramidal (SP) and stratum oriens (SO). Additionally, chromogenic immunohistochemistry was used to examine the distribution and colocalization with Tau and Aß proteins. The results show that Fe accumulation was significantly higher in AD brains, particularly in SMR and SO. However, FPN did not present significantly changes in AD, although it showed a non-uniform distribution across CA1 layers, with elevated levels in SP and SO. Interestingly, minimal overlap was observed between Fe and FPN signals, and none between Fe and areas rich in neurofibrillary tangles (NFTs) or neuritic plaques (NP). In conclusion, the lack of correlation between Fe and FPN signals suggests complex regulatory mechanisms in AD Fe metabolism and deposition. These findings highlight the complexity of Fe dysregulation in AD and its potential role in disease progression.

Dysregulation of iron transport-related biomarkers in blood leukocytes is associated with poor prognosis of early trauma.

Objective: The early targeted and effective diagnosis and treatment of severe trauma are crucial for patients' outcomes. Blood leukocytes act as significant effectors during the initial inflammation and activation of innate immunity in trauma. This study aims to identify hub genes related to patients' prognosis in blood leukocytes at the early stages of trauma. Methods: The expression profiles of Gene Expression Omnibus (GEO) Series (GSE) 36809 and GSE11375 were downloaded from the GEO database. R software, GraphPad Prism 9.3.1 software, STRING database, and Cytoscape software were used to process the data and identify hub genes in blood leukocytes of early trauma. Results: Gene Ontology (GO) analysis showed that the differentially expressed genes (DEGs) of blood leukocytes at the early stages of trauma (0-4 h, 4-8 h, and 8-12 h) were mainly involved in neutrophil activation and neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity, lymphocyte differentiation, and cell killing. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs were mainly involved in Osteoclast differentiation and Hematopoietic cell lineage. Sixty-six down-regulated DEGs and 148 up-regulated DEGs were identified and 37 hub genes were confirmed by Molecular Complex Detection (MCODE) of Cytoscape. Among the hub genes, Lipocalin 2 (LCN2), Lactotransferrin (LTF), Olfactomedin 4 (OLFM4), Resistin (RETN), and Transcobalamin 1 (TCN1) were related to prognosis and connected with iron transport closely. LCN2 and LTF were involved in iron transport and had a moderate predictive value for the poor prognosis of trauma patients, and the AUC of LCN2 and LTF was 0.7777 and 0.7843, respectively. Conclusion: As iron transport-related hub genes in blood leukocytes, LCN2 and LTF can be used for prognostic prediction of early trauma.

Dynamic Expressions of Yellow Stripe-Like (YSL) Genes During Pod Development Shed Light on Associations with Iron Distribution in Phaseolus vulgaris.

The global prevalence of iron deficiency-induced "hidden hunger" highlights a critical health concern, underscoring the pressing need to improve iron nutrition through safe and efficient means, such as increasing iron intake from plant-based foods. Yellow Stripe-Like (YSL) genes play a crucial role in long-distance iron transport between source and sink tissues in plants. Here, we report on the analysis of YSL family genes in the common bean (Phaseolus vulgaris L.), an iron-rich legume crop. We identified 9 YSL genes in the common bean genome using BLAST and HMM methods. Gene duplication analysis revealed that PvYSL7a and PvYSL7b originated through tandem duplication events. Structural analysis noted an absence of conservative motifs in PvYSL3b and PvYSL7a, which led to distinct predicted 3D protein structures. Leveraging publicly available RNA-seq data from developing bean pods, the expression patterns of PvYSL genes alongside pod and seed development were analyzed. Notably, PvYSL7a and PvYSL7b, as well as PvYSL1a and PvYSL1b, exhibited diverged expression patterns in seeds, signifying their functional divergence in this tissue. Moreover, PvYSL3a and PvYSL3b exhibited divergent expression patterns in both pod walls and seeds during pod development, underscoring their distinct roles in facilitating iron transportation between pods and seeds. This study provides valuable insights into the gene regulatory basis of iron accumulation in bean pods and seeds.

First detection of a cefiderocol-resistant and extensively drug-resistant Acinetobacter baumannii clinical isolate in Bulgaria.

Cefiderocol (CFDC) is a first-in-class siderophore cephalosporin with potent activity against multidrug-resistant Gram-negative bacteria including carbapenem-resistant Acinetobacter baumannii. The present study aimed to explore the CFDC resistance mechanisms of an extensively drug-resistant A. baumannii isolate from Bulgaria. The A. baumannii Aba52 strain (designated Aba52) was obtained in 2018 from a blood sample of a critically ill patient. The methodology included antimicrobial susceptibility testing, whole-genome sequencing (WGS), reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), multilocus sequence typing, and phylogenomic analysis. The isolate demonstrated high-level resistance to CFDC (MIC = 64 mg L-1), resistance to carbapenems, aminoglycosides, fluoroquinolones, sulfamethoxazole-trimethoprim, and tigecycline, as well as susceptibility only to colistin. WGS-based resistome analysis revealed the existence of blaOXA-23, blaOXA-66 and blaADC-73. Seven non-conservative missense mutations affecting iron transport-related genes were detected: exbD4 (p.Ser61Pro), tonB2 (p.Ala268Val), bauA (p.Thr61Ala), ftsI (p.Ala515Val), piuA (p.Gly216Val), and feoB (p.Ser429Pro and p.Thr595Ala). A variety of virulence factors associated with adherence, biofilm formation, enzyme production, immune invasion, iron uptake, quorum sensing, and two-component regulatory systems were identified, suggesting a significant pathogenic potential of Aba52. The performed RT-qPCR analysis showed diminished (0.17) and absent expression of the pirA and piuA genes, respectively, encoding TonB-dependent siderophore receptors. Aba52 belonged to the widespread high-risk sequence type ST2 (Pasteur scheme). To the best of our knowledge, this is the first documented case of CFDC-resistant A. baumannii in Bulgaria even though, CFDC has never been applied in our country. The emerging resistance highlights the crucial need for nationwide surveillance targeting the implementation of novel antibiotics.

Identification of a system for hydroxamate xenosiderophore-mediated iron transport in Burkholderia cenocepacia.

One of the mechanisms employed by the opportunistic pathogen Burkholderia cenocepacia to acquire the essential element iron is the production and release of two ferric iron chelating compounds (siderophores), ornibactin and pyochelin. Here we show that B. cenocepacia is also able to take advantage of a range of siderophores produced by other bacteria and fungi ('xenosiderophores') that chelate iron exclusively by means of hydroxamate groups. These include the tris-hydroxamate siderophores ferrioxamine B, ferrichrome, ferricrocin and triacetylfusarinine C, the bis-hydroxamates alcaligin and rhodotorulic acid, and the monohydroxamate siderophore cepabactin. We also show that of the 24 TonB-dependent transporters encoded by the B. cenocepacia genome, two (FhuA and FeuA) are involved in the uptake of hydroxamate xenosiderophores, with FhuA serving as the exclusive transporter of iron-loaded ferrioxamine B, triacetylfusarinine C, alcaligin and rhodotorulic acid, while both FhuA and FeuA are able to translocate ferrichrome-type siderophores across the outer membrane. Finally, we identified FhuB, a putative cytoplasmic membrane-anchored ferric-siderophore reductase, as being obligatory for utilization of all of the tested bis- and tris-hydroxamate xenosiderophores apart from alcaligin.

Role of transcriptomic and genomic analyses in improving the comprehension of cefiderocol activity in Acinetobacter baumannii.

The mechanisms of action and resistance of cefiderocol (FDC) in Acinetobacter baumannii are still not fully elucidated, but iron transport systems have been evoked in its entry into the cell to reach the penicillin-binding proteins (PBPs). To capture the dynamics of gene expression related to FDC action in various conditions, we report on the genomic and transcriptomic features of seven A. baumannii strains with different FDC susceptibility, focusing on the variants in genes associated with ß-lactam resistance and the expression of the siderophore biosynthesis and transport systems acinetobactin and baumannoferrin. We also investigated the expression of the TonB energy transduction system (ETS) and siderophore receptors piuA and pirA. The four clinical samples belonged to the same clonal complex (CC2), and the two strains with the highest FDC MICs showed peculiar variants in PBP2 and ampC. Similarly, the two clinical strains with the lowest MICs shared variants in an outer membrane protein as well as ampC. Gene expression analyses highlighted the up-regulation of the acinetobactin and baumannoferrin genes in response to iron depletion and a down-regulation in the presence of high iron concentrations. In response to FDC, gene expression seemed strain-dependent, probably due to the different metabolic features of each strain. Overall, FDC activates the ETS, confirming the active import of the drug; baumannoferrin, more than acinetobactin, appeared stimulated by FDC in an iron-depleted medium. In conclusion, iron transport systems play a clear role in the FDC uptake, and their expression likely contributes to MIC variation together with ß-lactam resistance determinants.IMPORTANCEAcinetobacter baumannii poses a threat to healthcare due to its ability to give difficult-to-treat infections as a consequence of our shortage of antibiotic molecules active on this multidrug-resistant bacterium. Cefiderocol (FDC) represents one of the few drugs active on A. baumannii, and to preserve its activity, this study explored the transcriptomic and genomic features of seven strains with varying susceptibility to FDC. Transcriptomic analyses revealed the different effects of FDC on iron transport systems, promoting mainly baumannoferrin expression-thus more likely related to FDC entry-and the energy transduction systems. These findings suggest that not all iron transport systems are equally involved in FDC entry into A. baumannii cells. Finally, mutations in PBPs and ß-lactamases may contribute to the resistance onset. Overall, the study sheds light on the importance of iron availability and metabolic differences in FDC resistance, offering insights into understanding the evolution of resistance in A. baumannii strains.

Quantitative Proteomics of Tissue-Infiltrating T Cells From CRC Patients Identified Lipocalin-2 Induces T-Cell Apoptosis and Promotes Tumor Cell Proliferation by Iron Efflux.

T cells play the most pivotal roles in antitumor immunity; the T-cell proteome and the differentially expressed proteins in the tumor immune microenvironment have rarely been identified directly from the clinical samples, especially for tumors that lack effective immunotherapy targets, such as colorectal cancer (CRC). In this study, we analyzed the protein expression pattern of the infiltrating T cells isolated from CRC patients using quantitative proteomics. CD4+ and CD8+ T cells were isolated from clinical samples and labeled by tandem mass tag reagents, and the differentially expressed proteins were quantified by mass spectrometry. The T-cell proteome profiling revealed dysfunctions in these tumor-infiltrating T cells. Specifically, antitumor immunity was suppressed because of differentially expressed metal ion transporters and immunity regulators. For the first time, lipocalin-2 (LCN2) was shown to be significantly upregulated in CD4+ T cells. Quantitative proteomic analysis of LCN2-overexpressed Jurkat cells showed that LCN2 damaged T cells by changes in iron transport. LCN2 induced T-cell apoptosis by reducing cellular iron concentration; moreover, the iron that was transported to the tumor microenvironment aided tumor cell proliferation, promoting tumor development. Meanwhile, LCN2 also influenced tumor progression through immune cytokines and cholesterol metabolism. Our results demonstrated that LCN2 has immunosuppressive functions that can promote tumor development; therefore, it is a potential immunotherapy target for CRC.

Dissecting components of the Campylobacter jejuni fetMP-fetABCDEF gene cluster under iron limitation.

IMPORTANCE: Campylobacter jejuni is a bacterium that is prevalent in the ceca of farmed poultry such as chickens. Consumption of ill-prepared poultry is thus the most common route by which C. jejuni infects the human gut to cause a typically self-limiting but severe gastrointestinal illness that can be fatal to very young, old, or immunocompromised people. The lack of a vaccine and an increasing resistance to current antibiotics highlight a need to better understand the mechanisms that make C. jejuni a successful human pathogen. This study focused on the functional components of one such mechanism-a molecular system that helps C. jejuni thrive despite the restriction on growth-available iron by the human body, which typically defends against pathogens. In providing a deeper understanding of how this system functions, this study contributes toward the goal of reducing the enormous global socioeconomic burden caused by C. jejuni.

Emergence of cefiderocol resistance during ceftazidime/avibactam treatment caused by a large genomic deletion, including ampD and piuCD genes, in Pseudomonas aeruginosa.

We report the emergence of cefiderocol resistance during the treatment of a ST312 Pseudomonas aeruginosa respiratory infection with ceftazidime/avibactam. whole genome sequencing (WGS) revealed that resistance was caused by a large genomic deletion, including PiuDC (iron transport system) and AmpD (ampC negative regulator), driven by the integration of phage DNA. Thus, our findings alert that this type of deletion could be an efficient (two mechanisms in one step) specific cefiderocol resistance mechanism that might occur nonspecifically upon treatment with ß-lactams that select for AmpC overexpression.

Molecular insights into placental iron transfer mechanisms and maternofetal regulation.

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

Iron Homeostasis in Azotobacter vinelandii.

Iron is an essential nutrient for all life forms. Specialized mechanisms exist in bacteria to ensure iron uptake and its delivery to key enzymes within the cell, while preventing toxicity. Iron uptake and exchange networks must adapt to the different environmental conditions, particularly those that require the biosynthesis of multiple iron proteins, such as nitrogen fixation. In this review, we outline the mechanisms that the model diazotrophic bacterium Azotobacter vinelandii uses to ensure iron nutrition and how it adapts Fe metabolism to diazotrophic growth.

Lipocalin-2: A Nurturer of Tumor Progression and a Novel Candidate for Targeted Cancer Therapy.

Within the tumor microenvironment (TME) exists a complex signaling network between cancer cells and stromal cells, which determines the fate of tumor progression. Hence, interfering with this signaling network forms the basis for cancer therapy. Yet, many types of cancer, in particular, solid tumors, are refractory to the currently used treatments, so there is an urgent need for novel molecular targets that could improve current anti-cancer therapeutic strategies. Lipocalin-2 (Lcn-2), a secreted siderophore-binding glycoprotein that regulates iron homeostasis, is highly upregulated in various cancer types. Due to its pleiotropic role in the crosstalk between cancer cells and stromal cells, favoring tumor progression, it could be considered as a novel biomarker for prognostic and therapeutic purposes. However, the exact signaling route by which Lcn-2 promotes tumorigenesis remains unknown, and Lcn-2-targeting moieties are largely uninvestigated. This review will (i) provide an overview on the role of Lcn-2 in orchestrating the TME at the level of iron homeostasis, macrophage polarization, extracellular matrix remodeling, and cell migration and survival, and (ii) discuss the potential of Lcn-2 as a promising novel drug target that should be pursued in future translational research.

The Role of Iron Overload in Diabetic Cognitive Impairment: A Review.

It is well documented that diabetes mellitus (DM) is strongly associated with cognitive decline and structural damage to the brain. Cognitive deficits appear early in DM and continue to worsen as the disease progresses, possibly due to different underlying mechanisms. Normal iron metabolism is necessary to maintain normal physiological functions of the brain, but iron deposition is one of the causes of some neurodegenerative diseases. Increasing evidence shows that iron overload not only increases the risk of DM, but also contributes to the development of cognitive impairment. The current review highlights the role of iron overload in diabetic cognitive impairment (DCI), including the specific location and regulation mechanism of iron deposition in the diabetic brain, the factors that trigger iron deposition, and the consequences of iron deposition. Finally, we also discuss possible therapies to improve DCI and brain iron deposition.