Disruption Of Iron Homeostasis Research Articles

Ferroptosis in schizophrenia: Mechanisms and therapeutic potentials (Review).

Schizophrenia, a complex psychiatric disorder, presents with multifaceted symptoms and important challenges in treatment, primarily due to its pathophysiological complexity, which involves oxidative stress and aberrant iron metabolism. Recent insights into ferroptosis, a unique form of iron‑dependent cell death characterized by lipid peroxidation and antioxidant system failures, open new avenues for understanding the neurobiological foundation of schizophrenia. The present review explores the interplay between ferroptosis and schizophrenia, emphasizing the potential contributions of disrupted iron homeostasis and oxidative mechanisms to the pathology and progression of this disease. The emerging evidence linking ferroptosis with the oxidative stress observed in schizophrenia provides a compelling narrative for re‑evaluating current therapeutic strategies and exploring novel interventions targeting these molecular pathways, such as the glutathione peroxidase 4 pathway and the ferroptosis suppressor protein 1 pathway. By integrating recent advances in ferroptosis research, the current review highlights innovative therapeutic potentials, including N‑acetylcysteine, selenium, omega‑3 fatty acids and iron chelation therapy, which could address the limitations of existing treatments and improve clinical outcomes for individuals with schizophrenia.

An emerging double‑edged sword role of ferroptosis in cardiovascular disease (Review).

The pathophysiology of cardiovascular disease (CVD) is complex and presents a serious threat to human health. Cardiomyocyte loss serves a pivotal role in both the onset and progression of CVD. Among various forms of programmed cell death, ferroptosis, along with apoptosis, autophagy and pyroptosis, is closely linked to the advancement of CVD. Ferroptosis, a mechanism of cell death, is driven by the buildup of oxidized lipids and excess iron. This pathway is modulated by lipid, amino acid and iron metabolism. Key characteristics of ferroptosis include disrupted iron homeostasis, increased peroxidation of polyunsaturated fatty acids due to reactive oxygen species, decreased glutathione levels and inactivation of glutathione peroxidase 4. Treatments targeting ferroptosis could potentially prevent or alleviate CVD by inhibiting the ferroptosis pathway. Ferroptosis is integral to the pathogenesis of several types of CVD and inhibiting its occurrence in cardiomyocytes could be a promising therapeutic strategy for the future treatment of CVD. The present review provided an in‑depth analysis of advancements in understanding the mechanisms underlying ferroptosis. The present manuscript summarized the interplay between ferroptosis and CVDs, highlighting its dual roles in these conditions. Additionally, potential therapeutic targets within the ferroptosis pathway were discussed, alongside the current limitations and future directions of these novel treatment strategies. The present review may offer novel insights into preventive and therapeutic approaches for CVDs.

Advanced Quantitative MRI Unveils Microstructural Thalamic Changes Reflecting Disease Progression in Multiple Sclerosis.

In patients with multiple sclerosis (PwMS), thalamic atrophy occurs during the disease course. However, there is little understanding of the mechanisms leading to volume loss and of the relationship between microstructural thalamic pathology and disease progression. This cross-sectional and longitudinal study aimed to comprehensively characterize in vivo pathologic changes within thalamic microstructure in PwMS using advanced multiparametric quantitative MRI (qMRI). Thalamic microstructural integrity was evaluated using quantitative T1, magnetization transfer saturation, multishell diffusion, and quantitative susceptibility mapping (QSM) in 183 PwMS and 105 healthy controls (HCs). The same qMRI protocol was available for 127 PwMS and 73 HCs after a 2-year follow-up period. Inclusion criteria for PwMS encompassed either an active relapsing-remitting MS (RRMS) or inactive progressive MS (PMS) disease course. Thalamic alterations were compared between PwMS and HCs and among disease phenotypes. In addition, the study investigated the relationship between thalamic damage and clinical and conventional MRI measures of disease severity. Compared with HCs, PwMS exhibited substantial thalamic alterations, indicative of microstructural and macrostructural damage, demyelination, and disruption in iron homeostasis. These alterations extended beyond focal thalamic lesions, affecting normal-appearing thalamic tissue diffusely. Over the follow-up period, PwMS displayed an accelerated decrease in myelin volume fraction [mean difference in annualized percentage change (MD-ApC) = -1.50; p = 0.041] and increase in quantitative T1 (MD-ApC = 0.92; p < 0.0001) values, indicating heightened demyelinating and neurodegenerative processes. The observed differences between PwMS and HCs were substantially driven by the subgroup with PMS, wherein thalamic degeneration was significantly accelerated, even in comparison with patients with RRMS. Thalamic qMRI alterations showed extensive correlations with conventional MRI, clinical, and cognitive disease burden measures. Disability progression over follow-up was associated with accelerated thalamic degeneration, as reflected by enhanced diffusion (β = -0.067; p = 0.039) and QSM (β = -0.077; p = 0.027) changes. Thalamic qMRI metrics emerged as significant predictors of neurologic and cognitive disability even when accounting for other established markers including white matter lesion load and brain and thalamic atrophy. These findings offer deeper insights into thalamic pathology in PwMS, emphasizing the clinical relevance of thalamic damage and its link to disease progression. Advanced qMRI biomarkers show promising potential in guiding interventions aimed at mitigating thalamic neurodegenerative processes.

Mitochondrial acyl carrier protein, Acp1, required for iron-sulfur cluster assembly in mitochondria and cytoplasm in Saccharomyces cerevisiae

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 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.

Hepatitis B Virus-Associated Liver Carcinoma: The Role of Iron Metabolism and Its Modulation.

Hepatitis B virus (HBV) infection is a significant contributor to the development of hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide. Iron, a central co-factor in various metabolic pathways, plays an essential role in liver function, but its dysregulation can lead to severe health consequences. Accumulation of iron within hepatic cells over time is linked to increased liver injury and is strongly associated with sensitive exposure to a range of conditions, including cirrhosis, fibrosis and ultimately, HCC. This review explores the intricate interplay between iron metabolism and HCC within the context of HBV infection. Hepatic iron overload can arise from liver injury and disruptions in iron homeostasis, causing hepatic necrosis, inflammation, and fibrosis, ultimately culminating in carcinogenesis. Moreover, alterations in serum iron components in HBV-related scenarios have been observed to impact the persistence of HBV infection. Notably, the progression of HBV-associated liver damage exhibits distinct characteristics at various stages of liver disease. In addition to elucidating the complex relationship between iron metabolism and HCC in the context of HBV infection, this review also investigates the prognostic implications of systemic iron levels for HCC. Furthermore, it aims to provide a comprehensive understanding of the intricate interplay between iron metabolism and HCC, extending the discussion to the context of hepatitis C virus (HCV) infection. By shedding light on these multifaceted connections, this review aims to contribute to our understanding of the pathogenesis of HBV-associated HCC and potentially identify novel therapeutic avenues for intervention.

Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder.

Mutations in lysosomal genes cause neurodegeneration and neurological lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of the lysosome from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of novel lysosomal proteins and reveal the diversity of the lysosomal composition across brain cell types. Notably, we discovered SLC45A1, mutations in which cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. Mechanistically, SLC45A1 plays a dual role in lysosomal sugar transport and stabilization of V1 subunits of the V-ATPase. SLC45A1 deficiency depletes the V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as a LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution in the brain and its implications for neurodegeneration.

Role of iron homeostasis in the mutagenicity of disinfection by-products in mammalian cells

Disinfection by-products (DBPs) generated from water treatment have serious adverse effects on human health and natural ecosystems. However, research on the mutagenicity of DBPs with different chemical structures is still limited. In the present study, we compared the mutagenicity of 8 typical DBPs in human-hamster hybrid (AL) cells and clarified the mechanisms involved. Our data displayed that the rank order for mutagenicity was as follows: iodoacetamide (IAcAm) > iodoacetonitrile (IAN) > iodoacetic acid (IAA) > bromoacetamide (BAcAm) ≈ bromoacetonitrile (BAN) > bromoacetic acid (BAA), which was confirmed by DNA double strand breaks and oxidative DNA damage. In contrast, bromoform (TBM) and iodoform (TIM) had minimal mutagenicity. The mutation spectrum analysis further revealed that IAN, IAcAm, and IAA could induce multilocus deletions in mammalian cells. Interestingly, nitrogenous DBPs (N-DBPs) and IAA were found to cause varying degrees of iron overload and lipid peroxidation, which was mediated by the activation of the Nrf2/HO-1 signaling pathway. Moreover, the presence of deferoxamine (DFO), an iron ion inhibitor, effectively reduced γ-H2AX and 8-OHdG induced by N-DBPs and IAA. These results indicated that the variations in genotoxicity among DBPs with different structures were associated with their ability to disrupt iron homeostasis. This study provided new insights into the mechanisms underlying the structure-dependent toxicity of DBPs and established a foundation for a more comprehensive understanding and intervention of the health risks associated with DBPs.

Bismuth-based drugs sensitize Pseudomonas aeruginosa to multiple antibiotics by disrupting iron homeostasis.

Pseudomonas aeruginosa infections are difficult to treat due to rapid development of antibiotic drug resistance. The synergistic combination of already-in-use drugs is an alternative to developing new antibiotics to combat antibiotic-resistant bacteria. Here we demonstrate that bismuth-based drugs (bismuth subsalicylate, colloidal bismuth subcitrate) in combination with different classes of antibiotics (tetracyclines, macrolides, quinolones, rifamycins and so on) can eliminate multidrug-resistant P. aeruginosa and do not induce development of antibiotic resistance. Bismuth disrupts iron homeostasis by binding to P. aeruginosa siderophores. Inside cells, bismuth inhibits the electron transport chain, dissipates the proton motive force and impairs efflux pump activity by disrupting iron-sulfur cluster-containing enzymes, including respiration complexes. As a result, bismuth facilitates antibiotic accumulation inside bacteria, enhancing their efficacy. The combination therapy shows potent antibacterial efficacy and low toxicity in an ex vivo bacteraemia model and increases the survival rate of mice in in vivo mouse lung-infection models. Our findings highlight the potential of bismuth-based drugs to be repurposed to combat P. aeruginosa infections in combination with clinically used antibiotics.

Regulation of drought stress on nutrient cycle and metabolism of rhizosphere microorganisms in desert riparian forest

Microbial communities in desert riparian forest ecosystems have developed unique adaptive strategies to thrive in harsh habitats shaped by prolonged exposure to abiotic stressors. However, the influence of drought stress on the functional and metabolic characteristics of soil rhizosphere microorganisms remains unknown. Therefore, this study aimed to investigate the effects of drought stress on soil biogeochemistry and metabolism and analyze the relationship between the biogeochemical cycle processes and network of differentially-expressed metabolites. Using metagenomics and metabolomics, this study explored the microbial functional cycle and differential metabolic pathways within desert riparian forests. The predominant biogeochemical cycles in the study area were the Carbon and Nitrogen cycles, comprising 78.90 % of C, N, Phosphorus, Sulfur and Iron cycles. Drought led to increased soil C fixation, reduced C degradation and methane metabolism, weakened denitrification, and decreased N fixation. Furthermore, drought can disrupt iron homeostasis and reduce its absorption. The differential metabolic pathways of drought stress include flavonoid biosynthesis, arachidonic acid metabolism, steroid hormone biosynthesis, and starch and sucrose degradation. Network analysis of functional genes and metabolism revealed a pronounced competitive relationship between the C cycle and metabolic network, whereas the Fe cycle and metabolic network promoted each other, optimizing resource utilization. Partial least squares analysis revealed that drought hindered the expression and metabolic processes and functional genes, whereas the rhizosphere environment facilitated metabolic expression and the functional genes. The rhizosphere effect primarily promoted metabolic processes indirectly through soil enzyme activities. The integrated multi-omics analysis further revealed that the effects of drought and the rhizosphere play a predominant role in shaping soil functional potential and the accumulation of metabolites. These insights deepen our comprehension of desert riparian forest ecosystems and offer strong support for the functionality of nutrient cycling and metabolite dynamics.

A ferrous fluorescence lifetime response probe for monitoring changes in lipid droplets during ferroptosis and imaging in liver disease model

Ferrous ions (Fe2⁺) accumulation and abnormal alterations in lipid droplets (LDs) are closely associated with ferroptosis. In the liver, excessive iron accumulation promotes oxidative stress and exacerbates lipid droplet accumulation, while the disruption of iron homeostasis may also affect the formation and size of lipid droplets, their increased number and size can exacerbate the severity of disease under fatty liver conditions. The leads to hepatocyte damage, further triggering liver inflammation, fibrosis, and ultimately resulting in cirrhosis and hepatocellular carcinoma. Therefore, real-time monitoring of iron ion and lipid droplet changes is crucial for assessing the severity of liver disease, disease progression, and understanding the mechanisms of ferroptosis. We have developed a fluorescent probe, NRFep, for real-time monitoring of iron ion fluctuations and visualization of lipid droplet changes in ferroptosis and liver disease models. NRFep is specific and sensitive to iron ions and exhibits excellent stability in both cells and animal models. In addition, NRFep can be used to monitor changes in iron ions and lipid droplets in mouse liver injury and fatty liver models. Through fluorescence lifetime imaging technology, NRFep can also study the dynamic changes of intracellular iron ion content. NRFep provides a powerful tool for studying ferroptosis and related diseases, and its unique dual-monitoring function opens up new possibilities for developing new diagnostic and therapeutic strategies.

Association of urinary glyphosate levels with iron homeostasis among a representative sample of US adults: NHANES 2013–2018

PurposeGlyphosate and glyphosate-based herbicides (GBH), widely used globally, were initially considered harmless to humans. Experimental studies have suggested that these substances can disrupt iron homeostasis by interfering with iron uptake or triggering inflammatory responses. However, their potential impact on human iron homeostasis remains underexplored. Approach and resultsWe analyzed data from 5812 participants aged three and older from the 2013 to 2018 NHANES. We investigated the relationships between urinary glyphosate levels, oral iron intake, and markers of iron homeostasis, including serum iron, unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), transferrin saturation, ferritin, and transferrin receptor. Higher urinary glyphosate levels were positively associated with oral iron intake (β = 1.310, S.E. = 0.382, P = 0.001). A one-unit increase in the natural logarithm (ln)-glyphosate was associated with lower serum iron (β = − 4.236, 95 % CI = − 6.432 to − 2.039, P < 0.001) and ferritin (β = − 9.994, 95 % CI = − 17.342 to − 2.647, P = 0.009), and higher UIBC (β = 5.431, 95 % CI = 1.061–9.800, P = 0.018) and transferrin receptor levels (β = 0.139, 95 % CI = 0.015–0.263, P = 0.029). Increasing glyphosate exposure was associated with significant decreases in serum iron and ferritin across exposure quintiles (trend P-values = 0.003 and 0.018, respectively). ConclusionsHigher glyphosate exposure is associated with reduced iron availability, suggesting potential disruptions in iron absorption. These findings underscore the need for further research into the health implications of glyphosate exposure on iron homeostasis.

Hepcidin depending on astrocytic NEO1 ameliorates blood-brain barrier dysfunction after subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) significantly compromises the blood-brain barrier (BBB) and impairs patient recovery. This study elucidates the critical role of astrocytic Neogenin-1 (NEO1) in BBB integrity post-SAH and examines the regulatory effects of hepcidin on endothelial cell (EC) function amid NEO1-mediated disruptions in iron homeostasis. Proteomic analyses of cerebrospinal fluid (CSF) from SAH patients revealed a substantial decrease in NEO1 expression, identifying it as a key factor in BBB integrity. 111 CSF proteins were significantly reduced in early SAH stages (days 1–3), with NEO1 among the most significantly altered. This dysregulation was linked to poorer patient outcomes, as indicated by a negative correlation between NEO1 levels and Modified Rankin Scale scores six months post-SAH (R = −0.4743, P < 0.0001). Experimental models further highlighted the importance of NEO1: SAH model and NEO1GFAP-Cre mice exhibited exacerbated EC dysfunction and increased BBB permeability, evidenced by significant Evans Blue retention and dextran leakage in the parietal cortex, effects that were mitigated by hepcidin administration. Our findings highlight the complex interplay between astrocytic signaling and endothelial function in SAH pathophysiology. The loss of astrocytic NEO1 led to increased EC proliferation and altered BBB structure, as confirmed by transmission electron microscopy and immunostaining for PECAM-1, indicating heightened blood vessel density in the affected cortex. Hepcidin treatment effectively reversed the EC dysfunction and BBB disruption in both NEO1-cKO mice and the SAH model, highlighting its potential as a therapeutic agent to enhance recovery and improve prognosis following SAH.

Blue light photobiomodulation induced osteosarcoma cell death by facilitating ferroptosis and eliciting an incomplete tumor cell stress response

To investigate the potential of blue light photobiomodulation (PBM) in inducing ferroptosis, a novel form of regulated cell death, in OS cells, considering its known effectiveness in various cancer models. In this investigation, we exposed human OS cell lines, HOS and MG63, to different wavelengths (420, 460 and 480 nm) of blue light at varying irradiances, and examined cellular responses such as viability, apoptosis, levels of reactive oxygen species (ROS), and mitochondrial membrane potential (MMP). Transcriptome sequencing was employed to unravel the molecular mechanisms underlying blue light-induced effects, with validation via quantitative real-time PCR (qRT-PCR). Our findings revealed a wavelength- and time-dependent decrease in cell viability, accompanied by increased apoptosis and oxidative stress. Transcriptomic analysis identified differential expression of genes associated with ferroptosis, oxidative stress, and iron metabolism, further validated by qRT-PCR. These results implicated ferroptosis as a significant mechanism in the blue light-induced death of OS cells, potentially mediated by ROS generation and disruption of iron homeostasis. Also, An incomplete stress response was observed in MG63 cells induced by blue light exposure. Hence, blue light PBM holds promise as a therapeutic approach in OS clinical investigations; however, additional exploration of its underlying mechanisms remains imperative.

Iron Chelator Deferiprone Restores Iron Homeostasis and Inhibits Retinal Neovascularization in Experimental Neovascular Age-Related Macular Degeneration.

Retinal neovascularization is a significant feature of advanced age-related macular degeneration (AMD) and a major cause of blindness in patients with AMD. However, the underlying mechanism of this pathological neovascularization remains unknown. Iron metabolism has been implicated in various biological processes. This study was conducted to investigate the effects of iron metabolism on retinal neovascularization in neovascular AMD (nAMD). C57BL/6J and very low-density lipoprotein receptor (VLDLR) knockout (Vldlr-/-) mice, a murine model of nAMD, were used in this study. Bulk-RNA sequencing was used to identify differentially expressed genes. Western blot analysis was performed to test the expression of proteins. Iron chelator deferiprone (DFP) was administrated to the mice by oral gavage. Fundus fluorescein angiography was used to evaluate retinal vascular leakage. Immunofluorescence staining was used to detect macrophages and iron-related proteins. RNA sequencing (RNA-seq) results showed altered transferrin expression in the retina and RPE of Vldlr-/- mice. Disrupted iron homeostasis was observed in the retina and RPE of Vldlr-/- mice. DFP mitigated iron overload and significantly reduced retinal neovascularization and vascular leakage. In addition, DFP suppressed the inflammation in Vldlr-/- retinas. The reduced signals of macrophages were observed at sites of neovascularization in the retina and RPE of Vldlr-/- mice after DFP treatment. Further, the IL-6/JAK2/STAT3 signaling pathway was activated in the retina and RPE of Vldlr-/- mice and reversed by DFP treatment. Disrupted iron metabolism may contribute to retinal neovascularization in nAMD. Restoring iron homeostasis by DFP could be a potential therapeutic approach for nAMD.

Antimony trioxide nanoparticles promote ferroptosis in developing zebrafish (Danio rerio) by disrupting iron homeostasis

The widespread use of antimony trioxide (ATO) and ATO nanoparticles (nATO) has led to increasing ecological and health risks. However, there is relatively insufficient research on the aquatic ecotoxicology of nATO. This study revealed that nATO affects the development of zebrafish embryos and mainly induces ferroptosis through the dissolution of Sb(III). The size of nATO ranged from 50 to 250 nm, and it generated free radicals in water. It can be ingested and accumulate in zebrafish larvae and affects normal development. Compared with those in the control group, the levels of reactive oxygen species (ROS), cell apoptosis, mitochondrial damage and iron content in the group exposed to high concentrations of nATO were increased. The transcriptomics results indicated that nATO significantly altered the expression levels of key genes related to glutathione metabolism and ferroptosis. Quantitative polymerase chain reaction consistently demonstrated the reliability of the transcriptome data and revealed that nATO induced ferroptosis by disrupting iron homeostasis and the key factor is the dissolution of Sb(III). Furthermore, ferrostatin-1, an inhibitor of ferroptosis, decreased the levels of ROS, apoptosis and mitochondrial damage induced by nATO, which further prove that nATO can promote ferroptosis. This work deepens the understanding of the ecological toxicological effects of nATO in aquatic environments and its mechanisms, which is highly important for the development of antimony management strategies.

Erythroferrone in focus: emerging perspectives in iron metabolism and hematopathologies.

Beyond its core role in iron metabolism, erythroferrone (ERFE) has emerged as a key player with far-reaching implications in various hematologic disorders. Its regulatory effect on hepcidin underlines its significance in conditions characterized by disrupted iron homeostasis. In β-thalassemia and myelodysplastic syndromes, its dysregulation intricately contributes to the clinical challenges of anemia and iron overload which highlights its potential as a therapeutic target. In anemia of chronic disease and iron deficiency anemia, ERFE presents a unique profile. In chronic kidney disease (CKD), the intricate interplay between ERFE, erythropoietin, and hepcidin undergoes dysregulation, contributing to the complex iron imbalance characteristic of this condition. Recent research suggests that ERFE plays a multifaceted role in restoring iron balance in CKD, beyond simply suppressing hepcidin production. The potential to modulate ERFE activity offers a novel approach to treating a spectrum of disorders associated with iron dysregulation. As our understanding of ERFE continues to evolve, it is poised to become a key focus in the development of targeted treatments, making it an exciting and dynamic area of ongoing research. Modulating ERFE activity presents a groundbreaking approach to treat iron dysregulation in conditions like iron deficiency anemia, thalassemia, and hemochromatosis. As new research unveils its intricate roles, ERFE has rapidly emerged as a key target for developing targeted therapies like ERFE agonists and antagonists. With promising studies underway, this dynamic field holds immense potential to improve patient outcomes, reduce complications, and offer personalized treatment options in hematology research. This comprehensive overview of ERFE's role across various conditions underscores its pivotal function in iron metabolism and associated pathologies.

Toxicity and related molecular mechanisms of Sb(III) in the embryos and larvae of zebrafish (Danio rerio)

Antimony (Sb) pollution poses a severe threat to humans and ecosystems due to the extensive use of Sb in various fields. However, little is known about the toxic effects of Sb and its aquatic ecotoxicological mechanism. This study aimed to reveal the toxicity and related molecular mechanisms of trivalent Sb (Sb(III)) in zebrafish embryos/larvae. Sb(III) accumulated in larvae, which correlated with the exposure concentration. Although no significant lethal or teratogenic effects were observed, normal growth and development were affected. Exposure to 10 or 20 mg/L Sb(III) increased the levels of reactive oxygen species in the larvae while enhancing catalase activity and increasing cell apoptosis. Transcriptomic analysis revealed that Sb(III) promoted glutathione metabolism and the ferroptosis pathway. In addition, symptoms associated with ferroptosis, including mitochondrial damage, biochemical levels of related molecules and increased tissue iron content, were detected. Quantitative polymerase chain reaction (qPCR) analyses further confirmed that Sb(III) significantly altered the transcription levels of genes related to the ferroptosis pathway by disrupting iron homeostasis. Furthermore, ferrostatin-1 (Fer-1) mitigated the toxic effects induced by Sb(III) in zebrafish. Our research fills the gap in the literature on the toxicity and mechanism of Sb(III) in aquatic organisms, which is highly important for understanding the ecological risks associated with Sb.

Abnormality in Peripheral and Brain Iron Contents and the Relationship with Grey Matter Volumes in Major Depressive Disorder.

Major depressive disorder (MDD) is a prevalent mental illness globally, yet its etiology remains largely elusive. Recent interest in the scientific community has focused on the correlation between the disruption of iron homeostasis and MDD. Prior studies have revealed anomalous levels of iron in both peripheral blood and the brain of MDD patients; however, these findings are not consistent. This study involved 95 MDD patients aged 18-35 and 66 sex- and age-matched healthy controls (HCs) who underwent 3D-T1 and quantitative susceptibility mapping (QSM) sequence scans to assess grey matter volume (GMV) and brain iron concentration, respectively. Plasma ferritin (pF) levels were measured in a subset of 49 MDD individuals and 41 HCs using the Enzyme-linked immunosorbent assay (ELISA), whose blood data were simultaneously collected. We hypothesize that morphological brain changes in MDD patients are related to abnormal regulation of iron levels in the brain and periphery. Multimodal canonical correlation analysis plus joint independent component analysis (MCCA+jICA) algorithm was mainly used to investigate the covariation patterns between the brain iron concentration and GMV. The results of "MCCA+jICA" showed that the QSM values in bilateral globus pallidus and caudate nucleus of MDD patients were lower than HCs. While in the bilateral thalamus and putamen, the QSM values in MDD patients were higher than in HCs. The GMV values of these brain regions showed a significant positive correlation with QSM. The GMV values of bilateral putamen were found to be increased in MDD patients compared with HCs. A small portion of the thalamus showed reduced GMV values in MDD patients compared to HCs. Furthermore, the region of interest (ROI)-based comparison results in the basal ganglia structures align with the outcomes obtained from the "MCCA+jICA" analysis. The ELISA results indicated that the levels of pF in MDD patients were higher than those in HCs. Correlation analysis revealed that the increase in pF was positively correlated with the iron content in the left thalamus. Finally, the covariation patterns obtained from "MCCA+jICA" analysis as classification features effectively differentiated MDD patients from HCs in the support vector machine (SVM) model. Our findings indicate that elevated peripheral ferritin in MDD patients may disrupt the normal metabolism of iron in the brain, leading to abnormal changes in brain iron levels and GMV.

Establishment of the Diagnostic Signature of Ferroptosis Genes in Multiple Sclerosis.

Ferroptosis is a novel form of membrane-dependent cell death that differs from other cell death modalities such as necrosis, apoptosis, and autophagy. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system primarily affecting brain and spinal cord neurons. Although the pathogenesis of these two conditions may seem unrelated, recent studies have indicated a connection between ferroptosis and multiple sclerosis. In fact, ferroptosis plays a significant role in the development of MS, as evidenced by the presence of elevated iron levels and iron metabolism abnormalities in the brains, spinal cords, and other neurons of MS patients. These abnormalities disrupt iron homeostasis within cells, leading to the occurrence of ferroptosis. However, there is currently a lack of research on the diagnostic value of ferroptosis-related genes in multiple sclerosis. In this study, we employed bioinformatics methods to identify ferroptosis-related genes (ATM, GSK3B, HMGCR, KLF2, MAPK1, NFE2L1, NRAS, PCBP1, PIK3CA, RPL8, VDAC3) associated with the diagnosis of multiple sclerosis and constructed a diagnostic model. The results demonstrated that the diagnostic model accurately identified the patients' condition. Subsequently, subgroup analysis was performed based on the expression levels of ferroptosis-related genes, dividing patients into high and low expression groups. The results showed differences in immune function and immune cell infiltration between the two groups. Our study not only confirms the correlation between ferroptosis and multiple sclerosis but also demonstrates the diagnostic value of ferroptosis-related genes in the disease. This provides guidance for clinical practice and direction for further mechanistic research.

Iron metabolism and arthritis: Exploring connections and therapeutic avenues.

Iron is indispensable for the viablility of nearly all living organisms, and it is imperative for cells, tissues, and organisms to acquire this essential metal sufficiently and maintain its metabolic stability for survival. Disruption of iron homeostasis can lead to the development of various diseases. There is a robust connection between iron metabolism and infection, immunity, inflammation, and aging, suggesting that disorders in iron metabolism may contribute to the pathogenesis of arthritis. Numerous studies have focused on the significant role of iron metabolism in the development of arthritis and its potential for targeted drug therapy. Targeting iron metabolism offers a promising approach for individualized treatment of arthritis. Therefore, this review aimed to investigate the mechanisms by which the body maintains iron metabolism and the impacts of iron and iron metabolism disorders on arthritis. Furthermore, this review aimed to identify potential therapeutic targets and active substances related to iron metabolism, which could provide promising research directions in this field.