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Abstract: β-thalassemia is an iron-loading anemia caused by homozygous mutation of the hemoglobin subunit β (HBB) gene. In β-thalassemia intermedia (βTI), a non-transfusion-dependent form of the disease, iron overload is caused by excessive absorption of dietary iron due to inappropriately low production of the iron-regulatory hormone hepcidin. Low hepcidin stabilizes the iron exporter ferroportin (FPN) on the basolateral membrane of enterocytes. High FPN activity may deplete intracellular iron and enhance expression of the predominant iron importer divalent metal-ion transporter 1 (DMT1). In mice, DMT1 mediates normal iron absorption under physiological conditions and excessive iron absorption in pathological iron overload (eg, hereditary hemochromatosis). Here, we hypothesized that DMT1 drives elevated iron absorption in βTI. Accordingly, we crossed Hbbth3/+ mice, a preclinical model of βTI, with intestine-specific DMT1-knockout mice. Ablation of intestinal DMT1 in Hbbth3/+ mice caused a pathophysiological shift from iron overload to an iron-deficiency phenotype with exacerbated anemia. DMT1 is thus required for iron absorption and iron loading in Hbbth3/+ mice. Based upon these outcomes, we further logically postulated that in vivo knockdown of intestinal DMT1 would mitigate iron loading in Hbbth3/+ mice. Ginger-derived, lipid nanoparticles carrying DMT1-specific (or control) small interfering RNAs (siRNAs) were administered by oral, intragastric gavage to 4-week-old Hbbth3/+ mice daily for 16 days. siRNA treatment reduced DMT1 expression by >80% and blunted iron loading, as indicated by significant reductions in liver iron and serum ferritin (which reflect body iron stores). These notable experimental outcomes establish intestinal DMT1 as a plausible therapeutic target to mitigate iron overload in βTI., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Iron (Fe) plaque, which forms on the surface of rice roots, plays a crucial role in immobilizing heavy metal(loids), thus reducing their accumulation in rice plants. However, the principal factors influencing Fe plaque formation and its adsorption capacity for heavy metal(loid)s throughout the rice plant's lifecycle remain poorly understood. Thus, this study investigated the dynamics of Fe plaque formation and its ability to adsorb cadmium (Cd) and arsenic (As) across different growth stages, aiming to identify the key drivers behind these processes. The findings reveal that the rate of radial oxygen loss (ROL) and the abundance of plaque-associated microbes are the primary drivers of Fe plaque formation, with their relative importance ranging from 1.4% to 81%. Similarly, the adsorption of As by Fe plaque is principally determined by the rate of ROL and the quantity of Fe plaque, with subsequent effects from the total Fe in rhizospheric soil, arsenate-reducing bacteria, and organic matter-degrading bacteria. The relative importance of these factors ranges from 6.0% to 11.7%. By contrast, the adsorption of Cd onto Fe plaque is primarily affected by competition for adsorption sites with ammonium in soils and the presence of organic matter-degrading bacteria, contributing 25.5% and 23.5% to the adsorption process, respectively. These findings provide significant insights into the development of Fe plaque and its absorption of heavy metal(loid)s throughout the lifecycle of rice plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Heterogeneous reprogrammed nutrient metabolic networks formed by oncogenes exhibit the potential for exploring novel druggable targets and developing innovative anticancer therapeutics. Herein, based on the heterogeneous metabolic characteristics of glutamine (Gln) addiction in pancreatic cancer cells, an iron-delivery system (IDS) with enhanced endocytosis is designed for efficient ferroptosis therapy. The IDS is characterized by Gln modification and can be recognized as a source of Gln nutrients for efficient endocytic uptake by pancreatic tumor cells. Because the IDS is flexible to combine with amino acid-like components, the IDS with enhanced endocytosis is further produced by loading the Gln transporter inhibitor of V9302. V9302 is capable of suppressing molecular Gln uptake via transporter ASCT2, which generates Gln deprivation to direct metabolic reprogramming of cancer cells and enhances cellular uptake of Gln-modified IDS via RAS-stimulated macropinocytosis. The enhanced endocytosis and high iron content of IDS facilitate ferroptosis in mice pancreatic tumor models; thus, an amino acid-like ferroptosis inducer of l-buthionine sulfoximine (BSO) is further combined. The enhanced endocytosis resulting from the synergism of Gln and V9302 enables the efficient delivery of iron and BSO for ferroptosis tumor therapy. This work provides an alternative approach for enhancing intracellular drug delivery of the tumors with heterogeneous nutrient metabolism by virtue of combining nutrient-modified nanodrugs with the corresponding nutrient transporter inhibitors.

Chlamydia protein associating with death domains ( Ct CADD) is involved in the biosynthesis of p -aminobenzoic acid (pABA) for integration into folate, a critical cofactor that is required for pathogenic survival. CADD activates dioxygen and utilizes its own tyrosine and lysine as synthons to furnish the carboxylate, carbon backbone, and amine group of pABA in a complex multistep mechanism. Unlike other members of the heme oxygenase-like dimetal oxidase (HDO) superfamily that typically house an Fe 2 cofactor, previous activity studies have shown that Ct CADD likely uses a heterobimetallic Fe/Mn center. The structure of the Fe 2+ /Mn 2+ cofactor and how the conserved HDO scaffold mediates metal selectivity have remained enigmatic. Adopting an in crystallo metalation approach, Ct CADD was solved in the apo, Fe 2+ 2 , Mn 2+ 2 , and catalytically active Fe 2+ /Mn 2+ forms to identify the probable site for Mn binding. The analysis of Ct CADD active-site variants further reinforces the importance of the secondary coordination sphere on cofactor preference for competent pABA formation. Rapid kinetic optical and electron paramagnetic resonance (EPR) studies show that the heterobimetallic cofactor selectively reacts with dioxygen and likely initiates pABA assembly through the formation of a transient tyrosine radical intermediate and a resultant heterobimetallic Mn 3+ /Fe 3+ cluster.

Gastric cancer (GC) is the fifth most common cancer and the third most common cause of cancer death globally, with high invasiveness, high recurrence rate, and poor prognosis. Multiple studies have shown that Metallothionein-1G (MT1G) is closely associated with oxidative stress, ferroptosis, and autophagy. However, the role and potential mechanisms of MT1G in GC have not been fully elucidated. This study aims to explore the biological functions and regulatory mechanisms of MT1G in GC. Perform bioinformatics analysis using the TCGA database to investigate the expression of MT1G in GC. RT-qPCR and Western blot were used to detect the expression of MT1G, ferroptosis related proteins, autophagy related proteins and ARNTL clock autophagy related proteins in Hgc27, MKN45 and AGS cell lines. Exploring the biological functions of MT1G overexpressing GC cell lines through wound healing and transwell experiments. Use specific fluorescence probes to examine mitochondrial membrane potential and Fe 2+ fluorescence intensity. Using immunoprecipitation analysis (CO-IP) to elucidate the association between GC cell lines GPX4, SQSTM and ARNTL. Use flow cytometry to detect ROS expression. Observation of autophagy related morphological changes in cells using transmission electron microscopy. Compared with gastric mucosal cell lines, the expression of MT1G is decreased in three gastric cancer cell lines (Hgc27, MKN45 and AGS). Overexpression of MT1G inhibits the proliferation, migration, and invasion functions of GC cells, reduces SOD and GSH content, increases MDA content, cause the mitochondrial membrane potential to weaken and promote the transformation of JC-1 aggregates to JC-1 monomer, increases Fe 2+ , affects ROS, and reduces GPX4 and SLC7A11 protein expression, promoting ferroptosis. Overexpression of MT1G promotes the transformation of LC3B I to LC3B II, reduces SQSTM1 protein expression, and leads to the appearance of more autophagosomes and autolysosomes at low magnification. At high magnification, mitochondrial autophagy, endoplasmic reticulum autophagy, lipid droplet autophagy, and wrinkled mitochondrial cristae are observed, promoting autophagy. Overexpression of MT1G inhibits GPX4, thereby affecting SQSTM1 as a vector to promote ARNTL autophagy and EGLN2, promoting ARNTL clock autophagy through the GPX4/SQSTM1 axis. Our research findings elucidate that overexpression of MT1G promotes iron autophagy centered around ARNTL in GC cells via the GPX4/SQSTM1 axis, thereby inhibiting GC cell function and providing a new molecular mechanism and therapeutic target for the development of GC., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable., (© 2024. The Author(s).)

Non-heme mononuclear iron dependent (NHM-Fe) enzymes exhibit exceedingly diverse catalytic reactivities. Despite their catalytic versatilities, the mononuclear iron centers in these enzymes show a relatively simple architecture, in which an iron atom is ligated with 2-4 amino acid residues, including histidine, aspartic or glutamic acid. In the past two decades, a common high-valent reactive iron intermediate, the S=2 oxyferryl (Fe(IV)-oxo or Fe(IV)=O) species, has been repeatedly discovered in NHM-Fe enzymes containing a 2-His-Fe or 2-His-1-carboxylate-Fe center. However, for 3-His/4-His-Fe enzymes, no common reactive intermediate has been identified. Recently, we have spectroscopically characterized the first S=1 Fe(IV) intermediate in a 3-His-Fe containing enzyme, OvoA, which catalyzes a novel oxidative carbon-sulfur bond formation. In this review, we summarize the broad reactivities demonstrated by S=2 Fe(IV)-oxo intermediates, the discovery of the first S=1 Fe(IV) intermediate in OvoA and the mechanistic implication of such a discovery, and the intrinsic reactivity differences of the S=2 and the S=1 Fe(IV)-oxo species. Finally, we postulate the possible reasons to utilize an S=1 Fe(IV) species in OvoA and their implications to other 3-His/4-His-Fe enzymes., (© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

Iron is the most abundant trace metal in the human brain and consistently shown elevated in prevalent neurological disorders. Because of its paramagnetism, brain iron can be assessed in vivo by quantitative MRI techniques such as R 2 * mapping and Quantitative Susceptibility Mapping (QSM). While Inductively Coupled Plasma Mass Spectrometry (ICP-MS) has demonstrated good correlations of the total iron content to MRI parameters in gray matter, the relationship to ferritin levels as assessed by Electron Paramagnetic Resonance (EPR) has not been systematically analyzed. Therefore, we included 15 postmortem subjects (age: 26-91 years) which underwent quantitative in-situ MRI at 7 Tesla within a post-mortem interval of 24 h after death. ICP-MS and EPR were used to measure the total iron and ferritin content in 8 selected gray matter (GM) structures and the correlations to R 2 * and QSM were calculated. We found that R 2 * and QSM in the iron rich basal ganglia and the red nucleus were highly correlated with iron (R² > 0.7) and ferritin (R² > 0.6), whereas those correlations were lost in cortical regions and the hippocampus. The neuromelanin-rich substantia nigra showed a different behavior with a correlation with total iron only (R² > 0.5) but not with ferritin. Although qualitative results were similar for both qMRI techniques the observed correlation was always stronger for QSM than R 2 *. This study demonstrated the quantitative correlations between R 2 *, QSM, total iron and ferritin levels in an in-situ MRI setup and therefore aids to understand how molecular forms of iron are responsible for MRI contrast generation., Competing Interests: Declaration of competing interest None, (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The iron (Fe) biogeochemical cycle is critical for abiotic and biological environmental processes that overlap spatially and may compete with each other. The development of modern molecular biology technologies promoted the understanding of the electron transport mechanisms of Fe-cycling-related microorganisms. Recent studies have revealed a novel pathway for microaerophilic ferrous iron (Fe(II))-oxidizers in extracellular Fe(II) oxidation. In addition, OmcS, OmcZ, and OmcE nanowires on the cell surface have been shown to promote electron transfer between microorganisms and their environment. These processes affect the fate of pollutants in directly or indirectly ways, such as greenhouse gas emissions. In this review, these advances and the environmental implications of the Fe cycle process were discussed, with a particular focus on the mechanisms of intracellular or extracellular electron transport in microorganisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anaerobic microbiologically influenced corrosion (MIC) of Fe (0) metals causes great harm to the environment and economy, which depends on the key electron transfer process between anaerobic microorganisms and Fe (0) metals. However, the key electron transfer process in microbiota dominating MIC remains unclear, especially for methanogenic microbiota wildly distributed in the environment. Herein, three different methanogenic microbiota (Methanothrix, Methanospirillum, and Methanobacterium) were acclimated to systematically investigate electron transfer pathways on corroding Q235A steel coupons. Results indicated that microbiota dominated by Methanothrix, Methanospirillum, or Methanobacterium accelerated the steel corrosion mainly through direct electron transfer (DET) pathway, H 2 mediated electron transfer (HMET) pathway, and combined DET and HMET pathways, respectively. Compared with Methanospirillum dominant microbiota, Methanothrix or Methanobacterium dominant microbiota caused more methane production, higher weight loss, corrosion pits with larger areas, higher corrosion depth, and smaller corrosion pits density. Such results reflected that the DET process between microbiota and Fe (0) metals decided the biocorrosion degree and behavior of Fe (0) metals. This study insightfully elucidates the mechanisms of methanogenic microbiota on corroding steels, in turn providing new insights for anti-corrosion motives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study investigated the in vitro bioaccessibility of aluminum, copper, iron, manganese, lead, selenium, and zinc in three important species of farmed insects: the yellow mealworm (Tenebrio molitor), the house cricket (Acheta domesticus) and the migratory locust (Locusta migratoria). Results show that all three insect species constitute excellent sources of essential elements (Fe, Cu and Zn) for the human diet, contributing to the recommended dietary allowance, i.e., 10%, 50%, and 92%, respectively. A higher accumulation of Se (≥1.4 mg Se/kg) was observed with increasing exposure concentration in A. domesticus, showing the possibility of using insects as a supplements for this element. The presence of Al and Fe nanoparticles was confirmed in all three species using single particle-inductively coupled plasma-mass spectrometry and transmission electron microscopy. The results also indicate that Fe bioaccessibility declines with increasing Fe-nanoparticle concentration. These findings contribute to increase the nutritional and toxicological insights of farmed insects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Reversing the hypoxic microenvironment of tumors is an important method to enhance the synergistic effect of tumor treatment. In this work, we developed the nanoparticles called Ce6@HGMOF, which consists of a photosensitizer (Ce6), glucose oxidase (GOX), chemotherapy drugs (HCPT) and an iron-based metal-organic framework (MOF). Ce6@HGMOF can consume glucose in tumor cells through "starvation therapy", cut off their nutrition source, and produce gluconic acid and hydrogen peroxide (H 2 O 2 ). Utilizing this feature, Ce6@HGMOF can produce oxygen through catalase-like catalytic activity, thereby reversing the hypoxic microenvironment of tumors. This strategy of changing the hypoxic environment can help to slow down the growth of tumor blood vessels and improve the drug-resistant microenvironment to some extent. Meanwhile, increasing the supply of oxygen can enhance the effect of photodynamic therapy (PDT) and enhance the oxidative stress damage caused by reactive oxygen species (ROS) in tumor cells. On the other hand, cancer cells usually produce higher levels of glutathione (GSH) to adapt to high oxidative stress and protect themselves. The Ce6@HGMOF we designed can also consume GSH and induce ferroptosis of tumor cells through Fenton reaction with H 2 O 2 , while enhancing the effect of PDT. This innovative synergistic strategy, the combination of PDT/ferroptosis /starvation therapy, can complement each other and enhance each other. It has great potential as a powerful new anti-tumor paradigm in the future., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication All authors have given their consent for publication. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Cadmium (Cd) can harm the yield and quality of vegetables, threatening food safety. Essential microelements such as iron are crucial for plant growth and can help alleviate heavy metal stress. Recently, nanoparticles have been studied as eco-friendly solutions for mitigating heavy metal stress in plants. In the present study, iron nanoparticles (FeNPs) at 0, 100, and 300 mg/L were applied as soil drenches and foliar sprays to tomato plants under cadmium stress. A comparison was made between the application methods of FeNPs by evaluating the growth parameters of tomato plants, including shoot length (SL), root length (RL), number of branches (NB), number of leaves per plant (NL), and leaf area (LA), as well as by assessing biochemical and antioxidant enzyme parameters. In the Cd stress treatment, the protein content decreased by 24.71%, and the phenolic and flavonoid content of the tomato plants also decreased due to cadmium stress, with levels decreasing from 16.07 to 6.9 µg and from 0.36 to 0.16 µg, respectively. Compared with the soil drench, 100 mg/L FeNPs significantly improved the parameters of Cd-stressed plants when used as a foliar spray, leading to increases in shoot length, root length, fruit weight, number of fruits, number of leaves, and number of branches by 42%, 66%, 24%, 66%, 173%, and 45%, respectively. Tomato plants treated with this spray presented increased carotenoid and lycopene contents. FeNP foliar spray also reduced Cd accumulation in plant tissues. This technique shows promise in alleviating Cd stress in vulnerable vegetable plants such as tomatoes., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval and consent to participate We declare that the manuscript reporting studies do not involve any human participants, human data or human tissues. So, it is not applicable. Our experiment follows with the relevant institutional, national, and international guidelines and legislation., (© 2024. The Author(s).)

Iron is a crucial element integral to various fundamental biological molecular mechanisms, including magnetosome biogenesis in magnetotactic bacteria (MTB). Magnetosomes are formed through the internalization and biomineralization of iron into magnetite crystals. However, the interconnected mechanisms by which MTB uptake and regulate intracellular iron for magnetosome biomineralization remain poorly understood, particularly at the single-cell level. To gain insights we employed a holistic multiscale approach, i . e ., from elemental iron species to bacterial populations, to elucidate the interplay between iron uptake dynamics and magnetosome formation in Magnetospirillum gryphiswaldense MSR-1 under near-native conditions. We combined a correlative microscopy approach integrating light and X-ray tomography with analytical techniques, such as flow cytometry and inductively coupled plasma spectroscopy, to evaluate the effects of iron and oxygen availability on cellular growth, magnetosome biogenesis, and intracellular iron pool in MSR-1. Our results revealed that increased iron availability under microaerobic conditions significantly promoted the formation of longer magnetosome chains and increased intracellular iron uptake, with a saturation point at 300 μM iron citrate. Beyond this threshold, additional iron did not further extend the magnetosome chain length or increase total intracellular iron levels. Moreover, our work reveals (i) a direct correlation between the labile Fe 2+ pool size and magnetosome content, with higher intracellular iron concentrations correlating with increased magnetosome production, and (ii) the existence of an intracellular iron pool, distinct from magnetite, persisting during all stages of biomineralization. This study offers insights into iron dynamics in magnetosome biomineralization at a single-cell level, potentially enhancing the industrial biomanufacturing of magnetosomes.

Iron (Fe) is a trace nutrient required by nearly all organisms. As a result of the demand for Fe and the toxicity of non-chelated cytosolic ionic Fe, regulatory systems have evolved to tightly balance Fe acquisition and usage while limiting overload. In most bacteria, including the mammalian pathogen Staphylococcus aureus , the ferric uptake regulator (Fur) is the primary transcriptional regulator controlling the transcription of genes that code for Fe uptake and utilization proteins. Fpa (formerly YlaN) was demonstrated to be essential in Bacillus subtilis unless excess Fe is added to the growth medium, suggesting a role in Fe homeostasis. Here, we demonstrate that Fpa is essential in S. aureus upon Fe deprivation. Null fur alleles bypassed the essentiality of Fpa. The absence of Fpa abolished the derepression of Fur-regulated genes during Fe limitation. Bioinformatic analyses suggest that fpa was recruited to Gram-positive bacteria and, once acquired, was maintained in the genome as it co-evolved with Fur. Consistent with a role for Fpa in alleviating Fur-dependent repression, Fpa and Fur interacted in vivo , and Fpa decreased the DNA-binding ability of Fur in vitro . Fpa bound Fe(II) in vitro using oxygen or nitrogen ligands with an association constant that is consistent with a physiological role in Fe homeostasis. These findings have led to a model wherein Fpa is an Fe(II) binding protein that influences Fur-dependent regulation through direct interaction.IMPORTANCEIron (Fe) is an essential nutrient for nearly all organisms. If Fe homeostasis is not maintained, Fe may accumulate in the cytosol, which can be toxic. Questions remain about how cells efficiently balance Fe uptake and usage to prevent overload. Iron uptake and proper metalation of proteins are essential processes in the mammalian bacterial pathogen Staphylococcus aureus . Understanding the gene products involved in the genetic regulation of Fe uptake and usage and the physiological adaptations that S. aureus uses to survive in Fe-depleted conditions provides insight into pathogenesis. Herein, we demonstrate that the DNA-binding activity of the ferric uptake regulator transcriptional repressor is alleviated under Fe limitation, but uniquely, in S. aureus , alleviation requires the presence of Fpa., Competing Interests: The authors declare no conflict of interest.

The human pathogen Pseudomonas aeruginosa ( Pa ) poses a major risk for a range of severe infections, particularly lung infections in patients suffering from cystic fibrosis (CF). As previously reported, the virulent behavior of this pathogen is enhanced by elevated levels of Ca 2+ that are commonly present in CF nasal and lung fluids. In addition, a Ca 2+ -binding EF-hand protein, EfhP (PA4107), was partially characterized and shown to be critical for the Ca 2+ -regulated virulence in P. aeruginosa . Here, we describe the rapid (10 min, 60 min), and adaptive (12 h) transcriptional responses of PAO1 to elevated Ca 2+ detected by genome-wide RNA sequencing and show that efhP deletion significantly hindered both rapid and adaptive Ca 2+ regulation. The most differentially regulated genes included multiple Fe sequestering mechanisms, a large number of extracytoplasmic function sigma factors (ECFσ), and several virulence factors, such as the production of pyocins. The Ca 2+ regulation of Fe uptake was also observed in CF clinical isolates and appeared to involve the global regulator Fur. In addition, we showed that the efhP transcription is controlled by Ca 2+ and Fe, and this regulation required a Ca 2+ -dependent two-component regulatory system CarSR. Furthermore, the efhP expression is significantly increased in CF clinical isolates and upon pathogen internalization into epithelial cells. Overall, the results established for the first time that Ca 2+ controls Fe sequestering mechanisms in P. aeruginosa and that EfhP plays a key role in the regulatory interconnectedness between Ca 2+ and Fe signaling pathways, the two distinct and important signaling pathways that guide the pathogen's adaptation to the host.IMPORTANCE Pseudomonas aeruginosa ( Pa ) poses a major risk for severe infections, particularly in patients suffering from cystic fibrosis (CF). For the first time, kinetic RNA sequencing analysis identified Pa rapid and adaptive transcriptional responses to Ca 2+ levels consistent with those present in CF respiratory fluids. The most highly upregulated processes include iron sequestering, iron starvation sigma factors, and self-lysis factors pyocins. An EF-hand Ca 2+ sensor, EfhP, is required for at least 1/3 of the Ca 2+ response, including the majority of the iron uptake mechanisms and the production of pyocins. Transcription of efhP itself is regulated by Ca 2+ and Fe, and increases during interactions with host epithelial cells, suggesting the protein's important role in Pa infections. The findings establish the regulatory interconnectedness between Ca 2+ and iron signaling pathways that shape Pa transcriptional responses. Therefore, understanding Pa's transcriptional response to Ca 2+ and associated regulatory mechanisms will serve in the development of future therapeutics targeting Pa 's dangerous infections., Competing Interests: The authors declare no conflict of interest.

Osteoarthritis (OA) is the most prevalent degenerative joint disease, marked by cartilage degeneration, synovitis, and subchondral bone changes. The absence of effective drugs and treatments to decelerate OA's progression highlights a significant gap in clinical practice. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, has emerged as a research focus in osteoarthritic chondrocytes. This form of cell death is characterized by imbalances in iron and increased lipid peroxidation within osteoarthritic chondrocytes. Key antioxidant mechanisms, such as Glutathione Peroxidase 4 (GPX4) and the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) pathway, are vital in countering ferroptosis in osteoarthritic chondrocytes. This review collates recent findings on ferroptosis in osteoarthritic chondrocytes, emphasizing iron regulation, lipid peroxidation, and antioxidative responses. It also explores emerging therapeutics aimed at mitigating OA by targeting ferroptosis in chondrocytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Infection with drug-resistant bacteria and the formation of biofilms are the main factors contributing to wound healing insufficiency. Antibacterial agents with enzyme-like properties have exhibited considerable potential for efficient eradication of drug-resistant microorganisms due to their superior sensitivities and minimal side effects. In this work, we prepared a kind of Fe-centered single-atom nanozyme (Fe-SAzyme) with high biocompatibility and stability via a facile one-pot hydrothermal method, which was suitable for the treatment of wounds infected with drug-resistant bacteria. The Fe-SAzyme exhibited remarkable peroxidase-like catalytic activities, catalyzing the conversion of hydrogen peroxide (H 2 O 2 ) to highly toxic hydroxyl radicals ( • OH), which could not only damage bacterial cells but also inhibit, disrupt, and eradicate the formation of bacterial biofilms. Thus, Fe-SAzyme demonstrated a broad-spectrum antibacterial performance capable of effectively eliminating multidrug-resistant bacteria. The coexistence of ferrous (Fe 2+ ) and ferric (Fe 3+ ) ions in Fe-SAzyme conferred the nanozyme with anti-inflammatory activity, effectively suppressing excessive inflammation. Meanwhile, Fe-SAzyme could significantly downregulate inflammatory cytokines tumor necrosis factor-α and interleukin-1β and upregulate growth factors VEGF and epidermal growth factor, which can prevent bacterial infection, mitigate inflammation, promote fibroblast proliferation, and improve wound closure. Thus, Fe-SAzyme had shown favorable therapeutic efficiency in promoting bacteria-infected wound healing. This study provides Fe-SAzyme as a promising candidate for the development of new strategies to treat multidrug-resistant bacterial infections.

High-light stress strongly limits agricultural production in subtropical and tropical regions owing to photo-oxidative damage, decreased growth, and decreased yield. Here, we investigated whether beneficial microbes can protect plants under high-light stress. We found that Enterobacter sp. SA187 (SA187) supports the growth of Arabidopsis thaliana under high-light stress by reducing the accumulation of reactive oxygen species and maintaining photosynthesis. Under high-light stress, SA187 triggers dynamic changes in the expression of Arabidopsis genes related to fortified iron metabolism and redox regulation, thereby enhancing the antioxidative glutathione/glutaredoxin redox system of the plant. Genetic analysis showed that the enhancement of iron and sulfur metabolism by SA187 is coordinated by ethylene signaling. In summary, beneficial microbes could be an effective and inexpensive means of enhancing high-light-stress tolerance in plants., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This review aims to elucidate the multifaceted role of iron in the pathogenesis of atherosclerosis. The primary objective is to summarize recent advances in understanding how iron contributes to atherosclerosis through various cellular mechanisms. Additionally, the review explores the therapeutic implications of targeting iron metabolism in the prevention and treatment of cardiovascular diseases., Recent Findings: A growing body of literature suggests that excess iron accelerates the progression of atherosclerosis, with the deleterious form of iron, non-transferrin-bound iron (NTBI), particularly exacerbating this process. Furthermore, iron overload has been demonstrated to play a pivotal role in endothelial cells, vascular smooth muscle cells, and macrophages, contributing to plaque instability and disease progression by promoting lipid peroxidation, oxidative stress, inflammatory responses, and ferroptosis. Iron plays a complex role in atherosclerosis, influencing multiple cellular processes and promoting disease progression. By promoting oxidative stress, inflammation, and ferroptosis, iron exacerbates endothelial dysfunction, smooth muscle cell calcification, and the formation of macrophage-derived foam cells. Targeted therapies focusing on iron metabolism have proven effective in treating atherosclerosis and other cardiovascular diseases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To cause infection, bacterial pathogens must overcome host immune factors and barriers to nutrient acquisition. Reproducing these aspects of host physiology in vitro has shown great promise for antibacterial drug discovery. When used as a bacterial growth medium, human serum replicates several aspects of the host environment, including innate immunity and iron limitation. We previously reported that a high-throughput chemical screen using serum as the growth medium enabled the discovery of novel growth inhibitors overlooked by conventional screens. Here, we report that a subset of compounds from this high-throughput serum screen display an unexpected growth enhancing phenotype and are enriched for synthetic siderophores. We selected 35 compounds of diverse chemical structure and quantified their ability to enhance bacterial growth in human serum. We show that many of these compounds chelate iron, suggesting they were acting as siderophores and providing iron to the bacteria. For two different pharmacophores represented among these synthetic siderophores, conjugation to the β-lactam antibiotic ampicillin imparted iron-dependent enhancement in antibacterial activity. Conjugation of the most potent growth-enhancing synthetic siderophore with the monobactam aztreonam produced MLEB-22043, a broad-spectrum antibiotic with significantly improved activity against Klebsiella pneumoniae , Escherichia coli , Acinetobacter baumannii , and Pseudomonas aeruginosa . This synthetic siderophore-monobactam conjugate uses multiple TonB-dependent transporters for uptake into P. aeruginosa . Like aztreonam, MLEB-22043 demonstrated activity against metallo-β-lactamase expressing bacteria, and, when combined with the β-lactamase inhibitor avibactam, was active against clinical strains coexpressing the NDM-1 metallo-β-lactamase and serine β-lactamases. Our work shows that human serum is an effective bacterial growth medium for the high-throughput discovery of synthetic siderophores, enabling the development of novel Trojan Horse antibiotics.

Background and Aims: Intravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart., Methods: A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells., Results: In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1., Conclusions: Intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium's limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. falciparum requires nutritional iron to support essential metabolic pathways, but the critical mechanisms of iron acquisition and trafficking during RBC infection have remained obscure. Parasites internalize and liberate massive amounts of heme during large-scale digestion of RBC hemoglobin within an acidic food vacuole (FV) but lack a heme oxygenase to release porphyrin-bound iron. Although most FV heme is sequestered into inert hemozoin crystals, prior studies indicate that trace heme escapes biomineralization and is susceptible to nonenzymatic degradation within the oxidizing FV environment to release labile iron. Parasites retain a homolog of divalent metal transporter 1 (DMT1), a known mammalian iron transporter, but its role in P. falciparum iron acquisition has not been tested. Our phylogenetic studies indicate that P. falciparum DMT1 (PfDMT1) retains conserved molecular features critical for metal transport. We localized this protein to the FV membrane and defined its orientation in an export-competent topology. Conditional knockdown of PfDMT1 expression is lethal to parasites, which display broad cellular defects in iron-dependent functions, including impaired apicoplast biogenesis and mitochondrial polarization. Parasites are selectively rescued from partial PfDMT1 knockdown by supplementation with exogenous iron, but not other metals. These results support a cellular paradigm whereby PfDMT1 is the molecular gatekeeper to essential iron acquisition by blood-stage malaria parasites and suggest that therapeutic targeting of PfDMT1 may be a potent antimalarial strategy., Competing Interests: Competing interests statement:The authors declare no competing interest.

For bacteria, an intricate coordination between sensing and regulating iron levels and managing oxidative stress is required as their levels are tightly interlinked. While various oxidative stress and heme-based redox sensors have been reported for both pathogenic and non-pathogenic bacteria, the mechanisms governing the modulation of intracellular iron levels in response to changes in redox status remain unclear. In this study, a gene-inactivated strain of mycobacterial sensor kinase PdtaS showed dysregulated expression of genes associated with iron metabolism, including Fe-S clusters, NADH dehydrogenases, and iron uptake. The strain showed poor growth in nutrient-limiting conditions, a defect rescuable by heme but not by Fe 3+ supplementation. This observation was associated with the PAS domain of the PdtaS sensor kinase. Biochemical and biophysical experiments established heme-binding to the PAS domain and its inhibitory effect on PdtaS auto-kinase activity, suggesting that the absence of heme induces activation of this sensor kinase. Interestingly, despite having an endogenous heme biosynthetic pathway or even external heme supplementation, the ∆ pdtaS mutant exhibited persistent low intracellular iron levels concomitant with elevated oxidative stress. Antioxidant supplementation mitigated growth defects, emphasizing the link between oxidative stress, intracellular iron levels, and PdtaS activity. RNA-IP identified key targets associated with redox homeostasis and iron metabolism as targets of the PdtaR response regulator. The study proposes a novel role for the PdtaS-PdtaR TCS in sensing heme, regulation of intracellular iron levels, and redox balance.IMPORTANCEThe research article investigates the intricate interplay between bacteria's ability to take and utilize iron without inducing excess iron's toxic effects, including oxidative stress. The study shows that bacteria achieve this by sensing intracellular iron available as heme through a sensory protein PdtaS, which turns off when heme is in excess and prevents iron uptake and iron efflux. The process shields bacteria from generating Fe-dependent free radicals and allows it to maintain viability. The absence of sensor kinase abrogates all these processes, increasing bacteria susceptibility to ROS and thereby slowing growth. This feature of the sensor kinase PdtaS makes it an attractive co-therapeutic target for tuberculosis therapy, where its inhibition will prevent iron uptake, even in the presence of low iron, thereby halting bacterial proliferation., Competing Interests: The authors declare no conflict of interest.

Iron-sulfur cluster conversion and nitrosyl modification are involved in regulating their functions and play critical roles in signaling for biological systems. Hereby, the photo-induced dynamic process of (Me 4 N) 2 [Fe 2 S 2 (NO) 4 ] was monitored using time-resolved electron paramagnetic resonance (EPR) spectra, MS spectra and cellular imaging methods. Photo-irradiation and the solvent affect the reaction rates and products. Spectroscopic and kinetic studies have shown that the process involves at least three intermediates: spin-trapped NO free radical species with a g av at 2.040, and two other iron nitrosyl species, dinitrosyl iron units (DNICs) and mononitrosyl iron units (MNICs) with g av values at 2.031 and 2.024, respectively. Moreover, the [Fe 2 S 2 (NO) 4 ] 2- cluster could bind with ferritin and decompose gradually, and a binding state of dinitrosyl iron coordinated with Cys102 of the recombinant human heavy chain ferritin (rHuHF) was finally formed. This study provides insight into the photodynamic mechanism of nitrosyl iron - sulfur clusters to improve the understanding of physiological activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: We aimed to analyse the interplay between impaired iron uptake and β-lactamases on cefiderocol resistance in Pseudomonas aeruginosa., Methods: Thirty-one transferable β-lactamases and 16 intrinsic P. aeruginosa AmpC (PDC) variants were cloned and expressed in wild-type (PAO1) and iron uptake-deficient (PAO ΔpiuC) P. aeruginosa backgrounds. MICs of cefiderocol and antipseudomonal β-lactams were determined by reference broth microdilution., Results: Relative to PAO1, deletion of piuC caused a specific 16-fold decrease in cefiderocol activity but negligible effects on the activity of other β-lactams. Among transferable β-lactamases, SHV-12, KPC Ω-loop mutants, NDMs and OXA-15 showed cefiderocol MIC values above the clinical breakpoint (2 mg/L) when expressed in PAO1. When expressed in PAO ΔpiuC, these and the transformants harbouring PER-1, VEB-1, KPC-2, KPC-3, VIM-1, CMY-2, OXA-2 and OXA-14 showed increased MIC values from 16 to >256 mg/L. The PDC variants carrying the Ω-loop changes ΔP215-G222 (PDC-577), E219K (PDC-221 and PDC-558) and the H10 helix change L293P (PDC-219) had the greatest impact on cefiderocol resistance, with MICs of 2-4 mg/L in PAO1 and of up to 32-64 mg/L in PAO ΔpiuC. Widespread enzymes such as GES, CTX-M-9, CTX-M-15, VIM-2-like enzymes, IMPs, DHA-1, FOX-4, OXA-10, OXA-48 and the other PDC variants tested had weaker effects on cefiderocol resistance., Conclusion: We add evidence about the effect of the interplay between iron uptake and β-lactamases on the acquisition of cefiderocol resistance in P. aeruginosa. These findings may help to anticipate the emergence of resistance and optimize the use of cefiderocol against P. aeruginosa infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Genetic variation within a species can result in allelic expression for natural selection or breeding efforts. Here, we identified an iron (Fe) deficiency-inducible gene, AP2-like ABA repressor 1 (MdABR1), in apple (Malus domestica). MdABR1 exhibited differential expression at the allelic level (MdABR131A and MdABR131G) in response to Fe deficiency. The W-box insertion in the promoter of MdABR131A is essential for its induced expression and its positive role under Fe deficiency stress. MdABR1 binds to the promoter of basic helix-loop-helix 105 (MdbHLH105), participating in the Fe deficiency response, and activates its transcription. MdABR131A exerts a more pronounced transcriptional activation effect on MdbHLH105. Suppression of MdABR1 expression leads to reduced rhizosphere acidification in apple, and MdABR131A exhibits allelic expression under Fe deficiency stress, which is substantially upregulated and then activates the expression of MdbHLH105, promoting the accumulation of plasma membrane proton ATPase 8 (MdAHA8) transcripts in response to proton extrusion, thereby promoting rhizosphere acidification. Therefore, variation in the ABR1 alleles results in variable gene expression and enables apple plants to exhibit a wider tolerance capability and Fe deficiency response. These findings also shed light on the molecular mechanisms of allele-specific expression in woody plants., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Desert dust is an important source of essential metals for marine primary productivity, especially in oligotrophic systems surrounded by deserts, such as the Red Sea. However, there are very few studies on the effects of dust on reef-building corals and none on the response of corals to heat stress. We therefore supplied dust to two coral species (Stylophora pistillata and Turbinaria reniformis) kept under control conditions (26 °C) or heat stress (32 °C). Since dust releases large amounts of iron (Fe) in seawater, among other metals, the direct effect of different forms of Fe enrichment on coral photosynthesis was also tested. First, our results show that the desert dust altered the coral metallome by increasing the content of metals that are important for coral physiology (e.g. lithium (up to 5-fold), manganese (up to 4-fold in S. pistillata), iron (up to 3-fold in S. pistillata), magnesium (up to 1.3-fold), molybdenum (up to 1.5-fold in S. pistillata)). Overall, metal enrichment improved the photosynthetic performance of corals, especially under thermal stress (e.g. Pgross (up to 2-fold), Pnet (up to 10-fold), chlorophyll (up to 1.5-fold), symbionts (up to 1.6-fold)). However, Fe exposure (ferric chloride or ferric citrate) did not directly improve photosynthesis, suggesting that it is the combination of metals released by the dust, the so-called "metal cocktail effect", that has a positive impact on coral photophysiology. Dust also led to a decrease in Ni uptake (up to 1.4-fold in the symbionts), likely related to the nitrogen metabolism. Finally, we found that the isotopic signature of metals such as iron, zinc and copper is a good indicator of heat stress and dust exposure in corals. In conclusion, desert dust can increase coral resistance to bleaching by supplying corals with essential metals., (© 2024. The Author(s).)

Ferroptosis is a regulated cell death process characterized by iron ion catalysis and reactive oxygen species, leading to lipid peroxidation. This mechanism plays a crucial role in age-related diseases, including cancer and cardiovascular and neurological disorders. To better mimic iron-induced cell death, predict the effects of various elements, and identify drugs capable of regulating ferroptosis, it is essential to develop precise models of this process. Such drugs can be tested on cellular models. Systems biology offers a powerful approach to studying biological processes through modeling, which involves accumulating and analyzing comprehensive research data. Once a model is created, it allows for examining the system's response to various stimuli. Our goal is to develop a modular framework for ferroptosis, enabling the prediction and screening of compounds with geroprotective and antiferroptotic effects. For modeling and analysis, we utilized BioUML (Biological Universal Modeling Language), which supports key standards in systems biology, modular and visual modeling, rapid simulation, parameter estimation, and a variety of numerical methods. This combination fulfills the requirements for modeling complex biological systems. The integrated modular model was validated on diverse datasets, including original experimental data. This framework encompasses essential molecular genetic processes such as the Fenton reaction, iron metabolism, lipid synthesis, and the antioxidant system. We identified structural relationships between molecular agents within each module and compared them to our proposed system for regulating the initiation and progression of ferroptosis. Our research highlights that no current models comprehensively cover all regulatory mechanisms of ferroptosis. By integrating data on ferroptosis modules into an integrated modular model, we can enhance our understanding of its mechanisms and assist in the discovery of new treatment targets for age-related diseases. A computational model of ferroptosis was developed based on a modular modeling approach and included 73 differential equations and 93 species.

Iron (Fe) deficiency in calcareous soils is a significant agricultural challenge, affecting crop productivity and nutritional quality. This study aimed to isolate, characterize, and evaluate Fe solubilizing rhizobacterial isolates from maize rhizosphere in calcareous soils as potential biofertilizers. Forty bacterial isolates coded as SG1, SG2, …, SG40 were isolated and screened for siderophore production, with ten showing significant Fe solubilizing capabilities. These isolates were further assessed for phosphate solubilization and exopolysaccharides production. The selected bacterial isolates were also screened under axenic conditions for their ability to improve maize growth. The isolates SG8, SG13, SG24, SG30 and SG33 significantly enhanced growth parameters of maize. Notably, SG30 showed highest increment in shoot length (58%), root length (54%), root fresh and dry biomass (67% and 76%), SPAD value (67%), relative water contents (69%), root surface area (61%), and Fe concentration in shoots (79%) as compared to control. The biochemical characterization of these strains showed that all these strains have capability to solubilize insoluble phosphorus, produce indole-3-acetic acid (IAA), and ammonia with catalase, urease and protease activity. Molecular identification through 16s rRNA gene sequencing confirmed high similarity (99.7-100%) of the selected isolates to various Bacillus species, including B. pyramidoids, B. firmicutes, and B. cereus. The study provides a strong base for developing eco-friendly, cost-effective biofertilizers to address Fe deficiency in crops and promote sustainable agriculture., (© 2024. The Author(s).)

A high amount of iron in β-thalassemia patients can lead to oxidative stress and organ dysfunction, especially liver, the main iron accumulated organ. Iron catabolism causes the generation of reactive oxygen species (ROS), triggering liver inflammation, fibrosis, and cirrhosis. Deferiprone-resveratrol hybrid (DFP-RVT) is chemically synthesized by combining deferiprone (DFP) and resveratrol (RVT) which shows an iron-chelating property along with antioxidant activity. This study explored the hepatoprotective effect of DFP-RVT in iron overloaded β-knockout (BKO) thalassemic mice. The results revealed that DFP-RVT treatment improved liver function in iron-overloaded BKO mice by reducing liver enzymes and increasing hepcidin levels compared to iron overload control mice. Both DFP alone and DFP-RVT treatment groups demonstrated iron chelation effects by decreasing liver iron content (LIC), iron profiles, and iron deposition in the liver. Moreover, DFP-RVT powerfully showed antioxidant properties by decreasing liver and plasma thiobarbituric acid reactive substances (TBARs) and increasing reduced glutathione (GSH) and superoxide dismutase (SOD). Interestingly, transforming growth factor β1 (TGFβ1), which can contribute to chronic liver disease through liver injury, inflammation, fibrosis, and cirrhosis, is highly expressed in iron-overloaded mice. However, both DFP and DFP-RVT treatment significantly reduced TGFβ1 levels compared to the iron-overloaded group. Therefore, DFP-RVT could be a potent hepatoprotective compound through the mobilization of iron, reduction of ROS, improvement of liver enzymes, and alleviation of liver damage, potentially relieving liver dysfunction in iron-overloaded BKO mice., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this manuscript and there has been no significant financial support for this work that could have influenced its outcome, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Strenuous physical training increases total blood volume (BV) through expansion of plasma volume (PV) and red cell volume (RCV). In contrast, exogenous erythropoietin (EPO) treatment increases RCV but decreases PV, rendering BV stable or slightly decreased. This study aimed to determine the combined effects of strenuous training and EPO treatment on BV and markers of systemic and muscle iron homeostasis. In this longitudinal study, eight healthy nonanemic males were treated with EPO (50 IU/kg body mass, three times per week, sc) across 28 days of strenuous training (4 days/wk, exercise energy expenditures of 1,334 ± 24 kcal/day) while consuming a controlled, energy-balanced diet providing 39 ± 4 mg/day iron. Before (PRE) and after (POST) intervention, BV compartments were measured using carbon monoxide rebreathing, and markers of iron homeostasis were assessed in blood and skeletal muscle (vastus lateralis). Training + EPO increased ( P < 0.01) RCV (13 ± 6%) and BV (5 ± 4%), whereas PV remained unchanged ( P = 0.86). The expansion of RCV was accompanied by a large decrease in whole body iron stores, as indicated by decreased ( P < 0.01) ferritin (-77 ± 10%) and hepcidin (-49 ± 23%) concentrations in plasma. Training + EPO decreased ( P < 0.01) muscle protein abundance of ferritin (-25 ± 20%) and increased ( P < 0.05) transferrin receptor (47 ± 56%). These novel findings illustrate that strenuous training combined with EPO results in both increased total oxygen-carrying capacity and hypervolemia in young healthy males. The decrease in plasma and muscle ferritin suggests that the marked upregulation of erythropoiesis alters systemic and tissue iron homeostasis, resulting in a decline in whole body and skeletal muscle iron stores. NEW & NOTEWORTHY Strenuous exercise training combined with erythropoietin (EPO) treatment increases blood volume, driven exclusively by red cell volume expansion. This hematological adaptation results in increased total oxygen-carrying capacity and hypervolemia. The marked upregulation of erythropoiesis with training + EPO reduces whole body iron stores and circulating hepcidin concentrations. The finding that the abundance of ferritin in muscle decreased after training + EPO suggests that muscle may release iron to support red blood cell production.

High-solid anaerobic digestion (HSAD) of kitchen waste was generally faced to the common problems such as systemic acidification, prolonged lag-phase time and low methane production. Iron-carbon micro-electrolysis (ICME) materials exhibited advantages that porous structure, large specific surface area and excellent conductivity. It was beneficial for organic compounds to hydrolysis. Moreover, ICME materials could establish direct interspecies electron transfer (DIET) pathway between bacteria and methanogens. ICME materials were commonly used to enhance the AD of wastewater, but they were rarely applied to HSAD of kitchen waste. In this study, ICME materials were utilized to enhance HSAD of kitchen waste at different solid content conditions. The results showed that the highest cumulative biogas yield (705.23 mL/g VS) was obtained in the experimental group (TS = 10%), which was 94.15% higher than that of the control group. At the same time, the addiction of ICME could shorten lag-phase time. Electrochemical characteristics and XPS analysis showed that ICME materials promoted the release of Fe 2+ in the AD system and acceleration of direct interspecies electron transfer between microorganisms. Microbial community analysis showed that ICME materials enriched electroactive bacteria (Proteiniphilum), Methanosarcina, Methanobrevibacter and Methanofollis. Functional gene prediction revealed that ICME materials increased the relative abundance of carbohydrate transport and metabolism and coenzyme transport and metabolism. It provided a potential measure to treat kitchen waste., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Iron is essential for functioning of cells and of the body as a whole. Perls staining allows the histopathological identification of iron deposits. By classifying hepatic siderosis as parenchymal, mesenchymal or mixed, it may guide the search for its etiology. HFE1 hemochromatosis is the most common siderosis. Its diagnosis is currently based on genetic analysis. Its expressivity being variable and its penetrance incomplete, the demonstration of hepatic siderosis may represent a mode of discovery., (Copyright © 2024. Published by Elsevier Masson SAS.)

The biodegradability of dissolved organic carbon (DOC) is a crucial process in the migration and transformation of soil organic carbon (SOC), and play a vital role in the global soil carbon (C) cycle. Although the significance of DOC in SOC transportation and microbial utilization is widely acknowledged, the impact of long-term rice-crayfish (RC) farming on the content, quality, and biodegradability of DOC in paddy soils, as well as regulatory mechanisms involved, remains unclear. To address this gap, a space-for-time method was employed to investigate the effects of different RC farming durations (1-, 5-, 10-, 15-, and 20- years) on the quality and biodegradability of DOC, as well as their relationship with soil microbial metabolism and minerals in this study. The results revealed that continuous RC farming increased the soil DOC content, but reduced DOC biodegradability. Specifically, after 20 years of continuous RC farming, the DOC content increased by 52.7% compared to the initial year, whereas the DOC biodegradability decreased by 63.4%. Analysis using three-dimensional fluorescence and ultraviolet spectroscopy demonstrated that continuous RC farming resulted in a decrease in the relative abundance of humus-like fractions, humification, and aromaticity indexes in DOC, but increased the relative abundance of protein-like fractions, biological, and fluorescence index, indicating that long-term RC farming promoted the simple depolymerization of the molecular structure of DOC. Continuous RC farming increased the activity of hydrolase involved in soil nitrogen (N) and phosphorus (P) cycles and oxidase, but decreasing the hydrolase C/N and C/P acquisition ratios; moreover, it also stimulated an increase in soil iron oxides and exchangeable calcium content. Structural equation modeling suggests that soil hydrolases and iron oxides are the primary drivers of DOC quality change, with DOC biodegradability being driven solely by soil iron oxides and not regulated by DOC quality. In conclusion, long-term RC farming promotes the catalytic decomposition of DOC aromatic substances and the production of DOC protein-like components by increasing soil oxidase activity and decreasing the hydrolase C/N acquisition ratio; these processes collectively contribute to the simple depolymerization of DOC molecular structure. Additionally, long-term RC farming induced legacy effects of soil iron oxides and enhanced chemical protection role leading to reduced DOC biodegradability. These findings suggested that long-term RC farming may reduce the rapid turnover and loss of DOC, providing a negative feedback on climate warming., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Trichloroethylene (TCE) is a prevalent organic pollutant found in soil. The oxide passivation layer on the surface of micron iron powder inhibits the release of its reducing components, leading to ineffective reduction and purification of TCE in soil. To enhance TCE degradation, a slow-release reduction material "Escherichia sp. F1-micron iron powder" was developed. A novel iron-reducing bacterium, Escherichia sp. F1, was isolated from soil contaminated with chlorinated hydrocarbons. This bacterium demonstrated a sustained iron reduction capability, achieving a reduction rate of 38.7% for Fe(Ⅲ) within 15 days. Genome sequencing revealed that strain F1 harbors 53 functional iron reduction genes and 2 dehalogenation genes. Single-factor experiments identified the optimal conditions for TCE degradation in soil using the coupling material: glucose concentration at 40 mmol/kg, soil water content at 50%, and bacterial inoculum at 1% (v:w). Under these optimal conditions, the coupled material achieved 86.86% degradation of TCE in soil within 28 days. Further analysis using X-ray photoelectron spectroscopy of micron iron powder, soil Fe(Ⅱ) concentration, and soil physicochemical properties demonstrated that the addition of strain F1 to the soil could disrupt the passivation layer of iron oxide on the surface of micron iron powder, promoting the exposure of its reactive sites and internal reducing active components. This resulted in an in situ self-actuated activation of passivated micron iron powder, leading to an improved removal rate and complete dechlorination of TCE in the soil. Soil microbial high-throughput sequencing revealed that the addition of strain F1 regulated the soil bacterial community, significantly enriching of Escherichia-Shigella species associated with iron-reducing functions. This enrichment facilitated the degradation of TCE in the soil through coupling materials. The functional material plays a crucial role in achieving green treatment and risk control of sites contaminated with chlorinated organic pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bovine embryos by in vitro fertilization have become the primary source of commercial embryo transfers globally. However, the developmental capacity of in vitro maturation (IVM) oocytes is considerably lower than that of in vivo maturation (IVO) oocytes, owing to the production of reactive oxygen species (ROS) via mitochondrial metabolism, which was higher in IVM oocytes than in IVO oocytes. To avoid the negative effects of ROS on embryo quality, folic acid (FA) was supplemented directly into the IVM medium to antagonize ROS production, however, the mechanisms remain unknown. In the present study, five levels of FA (0, 25, 50, 100, and 200 µM) were supplemented into the bovine oocyte culture medium. The maturation, cleavage, and blastocyst formation rates increased by 8.95 %, 6.94 %, and 4.36 %, respectively, in the 50 µM group compared to the 0 µM group. Moreover, 7904 differential genes were identified between 0 µM and 50 µM groups by transcriptome sequencing, and they were mainly enriched in 8 pathways. The glutathione, ROS, and Fe 2+ levels in oocytes were found to be associated with ferroptosis. Our results revealed that 50 µM FA promoted the IVM of bovine oocytes and affected the expression of genes involved in the ferroptosis pathway. The downregulation of TFR1 and STEAP3 led to a decrease in intracellular Fe 2+ accumulation, and the upregulation of GCL increased oocyte GSH levels, thereby reducing the production of ROS in the ferroptosis pathway. Our study provides a new insight into the molecular mechanisms by which FA promotes bovine oocyte development in vitro., Competing Interests: Declaration of Competing Interest The authors confirm that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The activation of complement receptor 3 (CR3) in microglia contributes to neurodegeneration in neurological disorders, including Parkinson's disease (PD). However, it remains unclear for mechanistic knowledge on how CR3 mediates neuronal damage. In this study, the expression of CR3 and its ligands iC3b and ICAM-1 was found to be up-regulated in the midbrain of rotenone PD mice, which was associated with elevation of iron content and disruption of balance of iron metabolism proteins. Interestingly, genetic deletion of CR3 blunted iron accumulation and recovered the expression of iron metabolism markers in response to rotenone. Furthermore, reduced lipid peroxidation, ferroptosis of dopaminergic neurons and neuroinflammation were detected in rotenone-lesioned CR3 -/- mice compared with WT mice. The regulatory effect of CR3 on ferroptotic death of dopaminergic neurons was also mirrored in vitro. Mechanistic study revealed that iron accumulation in neuron but not the physiological contact between microglia and neurons was essential for microglial CR3-regulated neuronal ferroptosis. In a cell-culture system, microglial CR3 silence significantly dampened iron deposition in neuron in response to rotenone, which was accompanied by mitigated lipid peroxidation and neurodegeneration. Furthermore, ROS released from activated microglia via NOX2 was identified to couple microglial CR3-mediated iron accumulation and subsequent neuronal ferroptosis. Finally, supplementation with exogenous iron was found to recover the sensitivity of CR3 -/- mice to rotenone-induced neuronal ferroptosis. Altogether, our findings suggested that microglial CR3 regulates neuron ferroptosis through NOX2 -mediated iron accumulation in experimental Parkinsonism, providing novel points of the immunopathogenesis of neurological disorders., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Transferrin (TF) is a prototypical biological macromolecule protein known for its iron-binding properties. TF proteins play a crucial role in modulating host iron homeostasis and defending against pathogen invasion. In this study, we utilized common carp (Cyprinus carpio) tissues and Epithelioma papulosum cyprinid (EPC) cells to establish experimental models of iron overload with FeCl 3 or ferric amine citrate (FAC), and to establish experimental models of bacterial infection with Aeromonas hydrophila. The current research has successfully identified the CcTF-b gene in common carp, revealing an ORF of 2001 bp with N-terminal and C-terminal structures. CcTF-b exhibited inhibitory effects on the growth of LPS and LTA in vitro. In the experimental models, the upregulations of PTGS2a and PTGS2a-like mRNA and protein levels were observed. Overexpression or interference with CcTF-b levels can modulate the expression of ferroptosis-related genes, inflammatory cytokines, lipid reactive oxygen species, GSH/GSSH levels, and Fe 2+ concentration. Significantly, the expression levels of Nrf2 and GPX4 mRNA and protein, as well as the bacterial load of A. hydrophila, could be also modulated either by upregulating or downregulating CcTF-b factors. In conclusion, in this study, these findings suggest that CcTF-b plays a critical role in the innate immune response of common carp., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Although research on the role of iron in host immunity has a history spanning decades, it is only relatively recently that attention has been directed toward the biological effects of iron on the intestinal mucus layer, prompted by an evolving understanding of the role of this material in immune defense. The mucus layer, secreted by intestinal goblet cells, covers the intestinal epithelium, and given its unique location, interactions between the host and gut microbiota, as well as among constituent microbiota, occur frequently within the mucus layer. Iron, as an essential nutrient for the vast majority of life forms, regulates immune responses from both the host and microbial perspectives. In this review, we summarize the iron metabolism of both the host and gut microbiota and describe how iron contributes to intestinal mucosal homeostasis via the intestinal mucus layer with respect to both host and constituent gut microbiota. The findings described herein offer a new perspective on iron-mediated intestinal mucosal barrier function., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss. FECD pathogenesis is linked to impaired response to oxidative stress and environmental ultraviolet A (UVA) exposure. Although UVA is known to cause nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation, ferroptosis has not been characterized in FECD. We investigated the roles of genetic background and UVA exposure in causing CEC degeneration in FECD. Using ungenotyped FECD patient surgical samples, we found increased levels of cytosolic ferrous iron (Fe 2+ ) and lipid peroxidation in end-stage diseased tissues compared with healthy controls. Using primary and immortalized cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found altered gene and protein expression involved in ferroptosis compared to controls including elevated levels of Fe 2+ , basal lipid peroxidation, and the ferroptosis-specific marker transferrin receptor 1. Increased cytosolic Fe 2+ levels were detected after physiologically relevant doses of UVA exposure, indicating a role for ferroptosis in FECD disease progression. Cultured cells were more prone to ferroptosis induced by RSL3 and UVA than controls, indicating ferroptosis susceptibility is increased by both FECD genetic background and UVA. Finally, cell death was preventable after RSL3 induced ferroptosis using solubilized ubiquinol, indicating a role for anti-ferroptosis therapies in FECD. This investigation demonstrates that genetic background and UVA exposure contribute to iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated disease progression in FECD., Competing Interests: Declaration of competing interest Sanjib Saha, Declarations of interest: none. Jessica M. Skeie, Declarations of interest: none. Gregory A. Schmidt, Declarations of interest: none. Tim Eggleston, Declarations of interest: none. Hanna Shevalye, Declarations of interest: none. Christopher S. Sales, Declarations of interest: none. Pornpoj Phruttiwanichakun, Declarations of interest: none. Apurva Dusane, Declarations of interest: none. Matthew G. Field, Declarations of interest: none. Tommy A. Rinkoski, Declarations of interest: none. Michael P. Fautsch, Declarations of interest: none. Keith H. Baratz, Declarations of interest: none. Madhuparna Roy, Declarations of interest: none. Albert S. Jun, Declarations of interest: none. Chandler Pendleton, Declarations of interest: none. Aliasger K. Salem, Declarations of interest: none. Mark A. Greiner, Declarations of interest: none., (Published by Elsevier B.V.)

Iron is critical for neuronal activity and metabolism, and iron dysregulation alters these functions in age-related neurodegenerative disorders, such as Alzheimer's disease (AD). AD is a chronic neurodegenerative disease characterized by progressive neuronal dysfunction, memory loss and decreased cognitive function. AD patients exhibit elevated iron levels in the brain compared to age-matched non-AD individuals. However, the degree to which iron overload contributes to AD pathogenesis is unclear. Here, we evaluated the involvement of ferroptosis, an iron-dependent cell death process, in mediating AD-like pathologies in C. elegans. Results showed that iron accumulation occurred prior to the loss of neuronal function as worms age. In addition, energetic imbalance was an early event in iron-induced loss of neuronal function. Furthermore, the loss of neuronal function was, in part, due to increased mitochondrial reactive oxygen species mediated oxidative damage, ultimately resulting in ferroptotic cell death. The mitochondrial redox environment and ferroptosis were modulated by pharmacologic processes that exacerbate or abolish iron accumulation both in wild-type worms and worms with increased levels of neuronal amyloid beta (Aβ). However, neuronal Aβ worms were more sensitive to ferroptosis-mediated neuronal loss, and this increased toxicity was ameliorated by limiting the uptake of ferrous iron through knockout of divalent metal transporter 1 (DMT1). In addition, DMT1 knockout completely suppressed phenotypic measures of Aβ toxicity with age. Overall, our findings suggest that iron-induced ferroptosis alters the mitochondrial redox environment to drive oxidative damage when neuronal Aβ is overexpressed. DMT1 knockout abolishes neuronal Aβ-associated pathologies by reducing neuronal iron uptake., Competing Interests: Declaration of competing interest All the authors have no conflict of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Increased astrocytic lactoferrin (Lf) expression was observed in the brains of elderly individuals and Alzheimer's disease (AD) patients. Our previous study revealed that astrocytic Lf overexpression improved cognitive capacity by facilitating Lf secretion to neurons to inhibit β-amyloid protein (Aβ) production in APP/PS1 mice. Here, we further discovered that astrocytic Lf overexpression inhibited neuronal loss by decreasing iron accumulation and increasing glutathione peroxidase 4 (GPX4) expression in neurons within APP/PS1 mice. Furthermore, human Lf (hLf) treatment inhibited ammonium ferric citrate (FAC)-induced ferroptosis by chelating intracellular iron. Additionally, machine learning analysis uncovered a correlation between Lf and GPX4. hLf treatment boosted low-density lipoprotein receptor-related protein 1 (LRP1) internalization and facilitated its interaction with heat shock cognate 70 (HSC70), thereby inhibiting HSC70 binds to GPX4, and eventually attenuating GPX4 degradation and FAC-induced ferroptosis. Overall, astrocytic Lf overexpression inhibited neuronal ferroptosis through two pathways: reducing intracellular iron accumulation and promoting GPX4 expression via inhibiting chaperone-mediated autophagy (CMA)-mediated GPX4 degradation. Hence, upregulating astrocytic Lf expression is a promising strategy for combating AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To improve denitrification efficiency of microalgal-bacterial aggregates (MABAs) when treating low carbon to nitrogen (C/N) ratio wastewater, CK (the biological control), C1 (untreated corncobs), C2 (alkali-treated corncobs), CFe1 (C1 loaded iron nanoparticles) and CFe2 (C2 loaded iron nanoparticles) five groups of experiments were installed under artificial light (1600 lm). After 36 h of experiment, NO 3 - -N conversion rates were 6.2 and 3.4 times faster than the CK group, respectively. The result showed that the corncobs-loaded iron nanoparticles (CFe1, CFe2) had the potential to promote denitrification process and the CFe1 was more effective. Meanwhile, the CFe1 and CFe2 resulted in a decreased content in extracellular polymeric substances (EPS) secretion because iron nanoparticles (Fes) promoted electron transport and alleviated the nitrate stress. Moreover, the electrochemical analysis of EPS showed that the corncobs and corncobs-loaded iron nanoparticles improved the electron transport rate and redox active substances production. The increase in electron transport activity (ETSA), adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH) also indicated that the CFe1 and CFe2 promoted microbial metabolic activity and the electron transport rate in MABAs. In addition, the CFe1 group enhanced the enrichment of Proteobacteria, Patescibacteria, Chlorophyta and Ignavibacteriae, which was contributed to the nitrogen removal performance of MABAs. In summary, the enhancement mechanism of corncobs-loaded iron nanoparticles on denitrification process of MABAs was depicted through EPS secretion, electrochemical characteristics, microbial metabolic activity and microbial community. The article provides a viable program for enhancing the denitrification performance of MABAs when treating low C/N wastewater.3 - -N conversion rates were 6.2 and 3.4 times faster than the CK group, respectively. The result showed that the corncobs-loaded iron nanoparticles (CFe1, CFe2) had the potential to promote denitrification process and the CFe1 was more effective. Meanwhile, the CFe1 and CFe2 resulted in a decreased content in extracellular polymeric substances (EPS) secretion because iron nanoparticles (Fes) promoted electron transport and alleviated the nitrate stress. Moreover, the electrochemical analysis of EPS showed that the corncobs and corncobs-loaded iron nanoparticles improved the electron transport rate and redox active substances production. The increase in electron transport activity (ETSA), adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH) also indicated that the CFe1 and CFe2 promoted microbial metabolic activity and the electron transport rate in MABAs. In addition, the CFe1 group enhanced the enrichment of Proteobacteria, Patescibacteria, Chlorophyta and Ignavibacteriae, which was contributed to the nitrogen removal performance of MABAs. In summary, the enhancement mechanism of corncobs-loaded iron nanoparticles on denitrification process of MABAs was depicted through EPS secretion, electrochemical characteristics, microbial metabolic activity and microbial community. The article provides a viable program for enhancing the denitrification performance of MABAs when treating low C/N wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fe 2 plays a crucial role in biological systems as an essential trace element in the body. Iron is absorbed by the body through food and Fe + plays a crucial role in biological systems as an essential trace element in the body. Iron is absorbed by the body through food and Fe 2+ is also an important component of living cells; therefore, quantitative testing of Fe 2+ in food and in living cells is of great importance. This paper presents the development of a novel π-bridge EDOT-based N-oxide turn-on fluorescent probe, designated as FeE, for the detection of Fe 2+ . The probe has been shown to exhibit excellent sensitivity, a favorable linear relationship between fluorescence signal intensity and Fe 2+ concentration, and an effective immunity to interference. The probe has low cytotoxicity and has been successfully used to detect Fe 2+ in cells using laser confocal fluorescence microscopy. It is also possible to determine the presence of Fe 2+ in animal blood, spinach, apple juice, red wine, mineral water and metal cans., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Increased iron level is detected in rat kidney and human urine in diabetic condition and implicated in associated nephropathy. However, the biological cue and mechanism of the iron accumulation remain unclear. Here we reveal that glucose increases iron uptake by promoting transferrin receptor 1 (TFRC) in kidney cells by a translational mechanism but does not alter expression of endosomal iron transporter DMT1. Glucose decreases iron exporter ferroportin (FPN) by a protein degradation mechanism. Hepcidin is known to bind at Cys-326 residue in promoting degradation of human ferroportin. When Cys-326 was mutated to Ser in human-FPN-FLAG and expressed in kidney cells, glucose still could degrade FPN-FLAG implicating involvement of hepcidin independent mechanism in glucose induced ferroportin degradation. Chronic hyperglycemia was generated in rats by administering streptozotocin (STZ) with periodic insulin injection to determine the level of iron homeostasis components. Increased TFRC and decreased ferroportin levels were detected in hyperglycemic rat kidney by Western blot and immunohistochemistry analyses. Hepcidin mRNA was not significantly altered in kidney but was marginally decreased in liver. Perls' staining and non-heme iron estimation showed an elevated iron level in hyperglycemic rat kidney. These results suggest that high glucose dysregulates iron transport components resulting iron accumulation in diabetic kidney., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Proximal tubule endocytosis is essential to produce protein-free urine as well as to regulate system-wide metabolic pathways, such as the activation of Vitamin D. We have determined that the proximal tubule expresses an endolysosomal membrane protein, protein spinster homolog1 (Spns1), which engenders a novel iron conductance that is indispensable during embryonic development. Conditional knockout of Spns1 with a novel Cre-LoxP construct specific to megalin-expressing cells led to the arrest of megalin receptor-mediated endocytosis as well as dextran pinocytosis in proximal tubules. The endocytic defect was accompanied by changes in megalin phosphorylation as well as enlargement of lysosomes, confirming previous findings in Drosophila and Zebrafish. The endocytic defect was also accompanied by iron overload in proximal tubules. Remarkably, iron levels regulated the Spns1 phenotypes because feeding an iron-deficient diet or mating Spns1 knockout with divalent metal transporter1 knockout rescued the phenotypes. Conversely, iron-loading wild-type mice reproduced the endocytic defect. These data demonstrate a reversible, negative feedback for apical endocytosis and raise the possibility that regulation of endocytosis, pinocytosis, megalin activation, and organellar size and function is nutrient-responsive. NEW & NOTEWORTHY Spns1 mediates a novel iron conductance essential during embryogenesis. Spns1 knockout leads to endocytic and lysosomal defects, accompanied by iron overload in the kidney. Reversal of iron overload by restricting dietary iron or by concurrent knockout of the iron transporter, DMT1 rescued the endocytic and organellar defects and reverted markers of iron overload. These data suggest feedback between iron and proximal tubule endocytosis.

The inflammatory status of the kidneys, vasculature, and perivascular adipose tissue (PVAT) has a significant influence on blood pressure and hypertension. Numerous micronutrients play an influential role in hypertension-driving inflammatory processes, and recent reports have provided bases for potential targeted modulation of these micronutrients to reduce hypertension. Iron overload in adipose tissue macrophages and adipocytes engenders an inflammatory environment and may contribute to impaired anticontractile signalling, and thus a treatment such as chelation therapy may hold a key to reducing blood pressure. Similarly, magnesium intake has proven to greatly influence inflammatory signalling and concurrent hypertension in both healthy animals and in a model for chronic kidney disease, demonstrating its potential clinical utility. These findings highlight the importance of further research to determine the efficacy of micronutrient-targeted treatments for the amelioration of hypertension and their potential translation into clinical application., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Mitochondria perform vital biosynthetic processes, including fatty acid synthesis and iron-sulfur (FeS) cluster biogenesis. In Saccharomyces cerevisiae mitochondria, the acyl carrier protein Acp1 participates in type II fatty acid synthesis, requiring a 4-phosphopantetheine (PP) prosthetic group. Acp1 also interacts with the mitochondrial FeS cluster assembly complex that contains the cysteine desulfurase Nfs1. Here we investigated the role of Acp1 in FeS cluster biogenesis in mitochondria and cytoplasm. In the Acp1-depleted (Acp1↓) cells, biogenesis of mitochondrial FeS proteins was impaired, likely due to greatly reduced Nfs1 protein and/or its persulfide-forming activity. Formation of cytoplasmic FeS proteins was also deficient, suggesting a disruption in generating the (Fe-S) int intermediate, that is exported from mitochondria and is subsequently utilized for cytoplasmic FeS cluster assembly. Iron homeostasis was perturbed, with enhanced iron uptake into the cells and accumulation of iron in mitochondria. The Δppt2 strain, lacking the mitochondrial ability to add PP to Acp1, phenocopied the Acp1↓ cells. These data suggest that the holo form of Acp1 with the PP-conjugated acyl chain is required for stability of the Nfs1 protein and/or stimulation of its persulfide-forming activity. Thus, mitochondria lacking Acp1 (or Ppt2) cannot support FeS cluster biogenesis in mitochondria or cytoplasm, leading to disrupted iron homeostasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

T-2 toxin, a highly toxic trichothecene mycotoxin widely found in food and feed, poses a significant threat to human health as well as livestock and poultry industry. Liver, being a crucial metabolic organ, is particularly susceptible to T-2 toxin induced damage characterized by inflammation and oxidative stress. Despite the role of Sirtuin 5 (SIRT5) in mitigating liver injury has been confirmed, its specific impact on T-2 toxin induced liver injury remains to be elucidated. The objective of this study was to investigate the protective role of SIRT5 against T-2 toxin induced liver injury in mice. Following the oral administration of 1 mg/kg.bw of T-2 toxin for 21 consecutive days to SIRT5 knockout (SIRT5 -/- ) and wild-type (WT) male mice, liver assessments were conducted. Our findings demonstrated that aggravated hepatic pathological injury was observed in SIRT5 -/- mice, accompanied by elevated malondialdehyde (MDA) and Fe levels, as well as enhanced expression of glutathione peroxidase 4 (GPX4), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, Gasdermin-D (GSDMD), tumour necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β). These results indicated that SIRT5 alleviated hepatic structural damage and dysfunction, while inhibiting oxidative stress, iron accumulation, and NLRP3 inflammasome activation. Analysis revealed a positive correlation among NLRP3 inflammasome activation, iron accumulation, and oxidative stress. Overall, our study demonstrated that SIRT5 mitigated liver injury induced by T-2 toxin through inhibiting iron accumulation, oxidative stress, and NLRP3 inflammasome activation, providing novel insights into the management and prevention of T-2 toxin poisoning., Competing Interests: Declaration of competing interest Zhengkai Wei reports financial support was provided by the Guangdong Basic and Applied Basic Research Foundation. Zhengkai Wei reports financial support was provided by Foundation for Innovative Research Groups of the National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Anemia of Inflammation begins with the activation of the immune system and the subsequent release of cytokines that lead to an elevation of hepcidin, responsible for hypoferremia, and a suppression of erythropoiesis due to lack of iron. The anemia is usually mild/moderate, normocytic/normochromic and is the most prevalent, after iron deficiency anemia, and is the most common in patients with chronic diseases, in the elderly and in hospitalized patients. Anemia can influence the patient's quality of life and have a negative impact on survival. Treatment should be aimed at improving the underlying disease and correcting the anemia. Intravenous iron, erythropoietin and prolyl hydroxylase inhibitors are the current basis of treatment, but future therapy is directed against hepcidin, which is ultimately responsible for anemia., (Copyright © 2024 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)