ABSTRACT
Iron overload is a risk factor for osteoporosis due to its oxidative toxicity. Previous studies have demonstrated that an excessive amount of iron increases osteocyte apoptosis and receptor activator of nuclear factor κ-B ligand (RANKL) production, which stimulates osteoclast differentiation in vitro. However, the effects of exogenous iron supplementation-induced iron overload on osteocytes in vivo and its role in iron overload-induced bone loss are unknown. This work aimed to develop an iron overloaded murine model of C57BL/6 mice by intraperitoneal administration of iron dextran for two months. The iron levels in various organs, bone, and serum, as well as the microstructure and strength of bone, apoptosis of osteocytes, oxidative stress in bone tissue, and bone formation and resorption, were assessed. The results showed that 2 months of exogenous iron supplementation significantly increased iron levels in the liver, spleen, kidney, bone tissue, and serum. Iron overload negatively affected bone microstructure and strength. Osteocyte apoptosis and empty lacunae rate were elevated by exogenous iron. Iron overload upregulated RANKL expression but had no significant impact on osteoprotegerin (OPG) and sclerostin levels. Static and dynamic histologic analyses and serum biochemical assay showed that iron overload increased bone resorption without significantly affecting bone formation. Exogenous iron promoted oxidative stress in osteocytes in vivo and in vitro. Additional supplementation of iron chelator (deferoxamine) or N-acetyl-l-cysteine (NAC) partially alleviated bone loss, osteocyte apoptosis, osteoclast formation, and oxidative stress due to iron overload. These findings, in line with prior in vitro studies, suggest that exogenous iron supplementation induces osteoclastogenesis and osteoporosis by promoting osteocyte apoptosis and RANKL production via oxidative stress.
Subject(s)
Apoptosis , Bone Resorption , Iron , Mice, Inbred C57BL , Osteocytes , Oxidative Stress , RANK Ligand , Animals , Osteocytes/drug effects , Osteocytes/metabolism , Oxidative Stress/drug effects , Apoptosis/drug effects , RANK Ligand/metabolism , Bone Resorption/metabolism , Bone Resorption/pathology , Mice , Iron/metabolism , Disease Models, Animal , Male , Iron Overload/metabolism , Iron Overload/pathology , Iron Overload/chemically induced , Osteoprotegerin/metabolism , Acetylcysteine/pharmacology , Adaptor Proteins, Signal TransducingABSTRACT
Tetrabromobisphenol S (TBBPS) is a brominated flame retardants (BFRs). TBBPS is widely used as a new type of BFR to replace TBBPA. Here, we used gastric cells as a model for evaluating the effect of TBBPS on the toxicology of gastric cells. Biochemical assays such as indirect immunofluorescence, cell proliferation assay were performed to analyze the toxicological effects of TBBPS on gastric cells. Cell proliferation analysis showed that TBBPS caused inhibition of gastric cell proliferation, and TBBPS induced gastric cell death. Further analysis showed that TBBPS led to ferroptosis and senescence of gastric cells by detecting ferroptosis-related marker molecules. Further work showed that TBBPS treatment resulted in lowered ferritin expression alongside heightened transferrin levels, which may be a potential molecular mechanism for TBBPS-induced ferroptosis and senescence in gastric cells. Here, our team investigates the effects of TBBPS on gastric cells in an in vitro model, and found that TBBPS caused toxicological damage to gastric cells. This study indicates potential toxic effects of TBBPS on the gastric cells, thereby providing a basis for further research into the toxicology of TBBPS.
Subject(s)
Cell Proliferation , Cellular Senescence , Ferroptosis , Flame Retardants , Iron Overload , Cellular Senescence/drug effects , Flame Retardants/toxicity , Ferroptosis/drug effects , Iron Overload/metabolism , Iron Overload/pathology , Humans , Cell Proliferation/drug effects , Inflammation/chemically induced , Inflammation/pathology , Inflammation/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Cell Line , Polybrominated Biphenyls/toxicity , Stomach/drug effects , Stomach/pathology , Ferritins/metabolismABSTRACT
Disease models of neurodegeneration with brain iron accumulation (NBIA) offer the possibility to explore the relationship between iron dyshomeostasis and neurodegeneration. We analyzed hiPS-derived astrocytes from PANK2-associated neurodegeneration (PKAN), an NBIA disease characterized by progressive neurodegeneration and high iron accumulation in the globus pallidus. Previous data indicated that PKAN astrocytes exhibit alterations in iron metabolism, general impairment of constitutive endosomal trafficking, mitochondrial dysfunction and acquired neurotoxic features. Here, we performed a more in-depth analysis of the interactions between endocytic vesicles and mitochondria via superresolution microscopy experiments. A significantly lower number of transferrin-enriched vesicles were in contact with mitochondria in PKAN cells than in control cells, confirming the impaired intracellular fate of cargo endosomes. The investigation of cytosolic and mitochondrial iron parameters indicated that mitochondrial iron availability was substantially lower in PKAN cells compared to that in the controls. In addition, PKAN astrocytes exhibited defects in tubulin acetylation/phosphorylation, which might be responsible for unregulated vesicular dynamics and inappropriate iron delivery to mitochondria. Thus, the impairment of iron incorporation into these organelles seems to be the cause of cell iron delocalization, resulting in cytosolic iron overload and mitochondrial iron deficiency, triggering mitochondrial dysfunction. Overall, the data elucidate the mechanism of iron accumulation in CoA deficiency, highlighting the importance of mitochondrial iron deficiency in the pathogenesis of disease.
Subject(s)
Astrocytes , Cytosol , Iron Overload , Iron , Mitochondria , Astrocytes/metabolism , Astrocytes/pathology , Humans , Mitochondria/metabolism , Cytosol/metabolism , Iron/metabolism , Iron Overload/metabolism , Iron Overload/pathology , Tubulin/metabolism , Phosphorylation , Iron Deficiencies , AcetylationABSTRACT
ß-Thalassaemia is one of the most common genetic diseases worldwide. During the past few decades, life expectancy of patients has increased significantly owing to advance in medical treatments. Cognitive impairment, once has been neglected, has gradually become more documented. Cognitive impairment in ß-thalassaemia patients is associated with natural history of the disease and socioeconomic factors. Herein, to determined effect of ß-thalassaemia intrinsic factors, 22-month-old ß-thalassaemia mouse was used as a model to assess cognitive impairment and to investigate any aberrant brain pathology in ß-thalassaemia. Open field test showed that ß-thalassaemia mice had decreased motor function. However, no difference of neuronal degeneration in primary motor cortex, layer 2/3 area was found. Interestingly, impaired learning and memory function accessed by a Morris water maze test was observed and correlated with a reduced number of living pyramidal neurons in hippocampus at the CA3 region in ß-thalassaemia mice. Cognitive impairment in ß-thalassaemia mice was significantly correlated with several intrinsic ß-thalassaemic factors including iron overload, anaemia, damaged red blood cells (RBCs), phosphatidylserine (PS)-exposed RBC large extracellular vesicles (EVs) and PS-exposed medium EVs. This highlights the importance of blood transfusion and iron chelation in ß-thalassaemia patients. In addition, to improve patients' quality of life, assessment of cognitive functions should become part of routine follow-up.
Subject(s)
Cognitive Dysfunction , Disease Models, Animal , Hippocampus , beta-Thalassemia , Animals , beta-Thalassemia/pathology , beta-Thalassemia/complications , beta-Thalassemia/genetics , Cognitive Dysfunction/etiology , Cognitive Dysfunction/pathology , Mice , Hippocampus/pathology , Hippocampus/metabolism , Male , Neurons/metabolism , Neurons/pathology , Iron Overload/pathology , Iron Overload/metabolism , Iron Overload/complications , Extracellular Vesicles/metabolism , Erythrocytes/metabolism , Erythrocytes/pathology , Pyramidal Cells/metabolism , Pyramidal Cells/pathology , Maze LearningABSTRACT
BACKGROUND: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload. METHODS: R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification. RESULTS: Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs. CONCLUSIONS: Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment.
Subject(s)
Cation Transport Proteins , Disease Models, Animal , Ferroptosis , Iron Chelating Agents , Mice, Inbred C57BL , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle , Vascular Calcification , Ferroptosis/drug effects , Vascular Calcification/metabolism , Vascular Calcification/pathology , Animals , Cation Transport Proteins/metabolism , Cation Transport Proteins/genetics , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/drug effects , Iron Chelating Agents/pharmacology , Iron Chelating Agents/therapeutic use , Signal Transduction , Male , Humans , Iron/metabolism , Iron Overload/metabolism , Iron Overload/pathologyABSTRACT
BACKGROUND: Amorphous silica nanoparticles (SiNPs) have been gradually proven to threaten cardiac health, but pathogenesis has not been fully elucidated. Ferroptosis is a newly defined form of programmed cell death that is implicated in myocardial diseases. Nevertheless, its role in the adverse cardiac effects of SiNPs has not been described. RESULTS: We first reported the induction of cardiomyocyte ferroptosis by SiNPs in both in vivo and in vitro. The sub-chronic exposure to SiNPs through intratracheal instillation aroused myocardial injury, characterized by significant inflammatory infiltration and collagen hyperplasia, accompanied by elevated CK-MB and cTnT activities in serum. Meanwhile, the activation of myocardial ferroptosis by SiNPs was certified by the extensive iron overload, declined FTH1 and FTL, and lipid peroxidation. The correlation analysis among detected indexes hinted ferroptosis was responsible for the SiNPs-aroused myocardial injury. Further, in vitro tests, SiNPs triggered iron overload and lipid peroxidation in cardiomyocytes. Concomitantly, altered expressions of TfR, DMT1, FTH1, and FTL indicated dysregulated iron metabolism of cardiomyocytes upon SiNP stimuli. Also, shrinking mitochondria with ridge fracture and ruptured outer membrane were noticed. To note, the ferroptosis inhibitor Ferrostatin-1 could effectively alleviate SiNPs-induced iron overload, lipid peroxidation, and myocardial cytotoxicity. More importantly, the mechanistic investigations revealed miR-125b-2-3p-targeted HO-1 as a key player in the induction of ferroptosis by SiNPs, probably through regulating the intracellular iron metabolism to mediate iron overload and ensuing lipid peroxidation. CONCLUSIONS: Our findings firstly underscored the fact that ferroptosis mediated by miR-125b-2-3p/HO-1 signaling was a contributor to SiNPs-induced myocardial injury, which could be of importance to elucidate the toxicity and provide new insights into the future safety applications of SiNPs-related nano products.
Subject(s)
Ferroptosis , Iron Overload , MicroRNAs , Nanoparticles , Humans , Myocytes, Cardiac , Silicon Dioxide/metabolism , Iron Overload/metabolism , Iron Overload/pathology , Iron/metabolism , Iron/pharmacology , MicroRNAs/metabolism , Nanoparticles/toxicityABSTRACT
Iron overload occurs due to excessive iron intake compared to the body's demand, leading to iron deposition and impairment of multiple organ functions. Our previous study demonstrated that chronic oral administration of ferric citrate (FC) caused colonic inflammatory injury. However, the precise mechanism underlying this inflammatory response remains unclear. The current study aims to investigate the mechanism by which iron overload induced by FC exposure leads to colonic inflammation. To accomplish this, mice were orally exposed to three different concentrations of FC (71â¯mg/kg/bw (L), 143â¯mg/kg/bw (M) and 286â¯mg/kg/bw (H)) for continuous 16 weeks, with the control group receiving ultrapure water (C). Exposure to FC caused disturbances in the excretory system, altered colonic flora alpha diversity, and enriched pathogenic bacteria, such as Mucispirillum, Helicobacter, Desulfovibrio, and Shigella. These changes led to structural disorders of the colonic flora and an inflammatory response phenotype characterized by inflammatory cells infiltration, atrophy of intestinal glands, and irregular thickening of the intestinal wall. Mechanistic studies revealed that FC-exposure activated the NF-κB signaling pathway by up-regulating TLR4, MyD88, and NF-κB mRNA levels and protein expression. This activation resulted in increased production of pro-inflammatory cytokines, further contributing to the colonic inflammation. Additionally, in vitro experiments in SW480 cells confirmed the activation of NF-κB signaling pathway by FC exposure, consistent with the in vivo findings. The significance of this study lies in its elucidation of the mechanism by which iron overload caused by FC exposure leads to colonic inflammation. By identifying the role of pathogenic bacteria and the NF-κB signaling pathway, this study could potentially offer a crucial theoretical foundation for the research on iron overload, as well as provide valuable insights for clinical iron supplementation.
Subject(s)
Ferric Compounds , Iron Overload , NF-kappa B , Mice , Animals , NF-kappa B/metabolism , Inflammation/chemically induced , Inflammation/pathology , Iron Overload/pathology , Iron/metabolismABSTRACT
Iron is an essential element for the normal functioning of living organisms, but excessive iron deposition can lead to organ damage. This study aims to investigate the interaction between the endoplasmic reticulum stress signaling pathway and the PI3K/AKT/mTOR signaling pathway in liver injury induced by iron overload in chicks. Rspectively, 150 one-day-old broilers were divided into three groups and supplemented with 50 (C), 500 (E1), and 1000 (E2) mg ferrous sulfate monohydrate/kg in the basal diet. Samples were taken after continuous feeding for 14 days. The results showed that iron overload could upregulate the levels of ALT and AST. Histopathological examination revealed bleeding in the central vein of the liver accompanied by inflammatory cell infiltration. Hoechst staining showed that the iron overload group showed significant bright blue fluorescence, and ultrastructural observations showed chromatin condensation as well as mitochondrial swelling and cristae disorganization in the iron overload group. RT-qPCR and Western blot results showed that iron overload upregulated the expression of Bax, Caspase-3, Caspase-9, GRP78, GRP94, P-PERK, ATF4, eIF2α, IRE1, and ATF6, while downregulating the expression of Bcl-2 and the PI3K/AKT/mTOR pathway. XBP-1 splicing experiment showed significant splicing of XBP-1 gene after iron overload. PCA and correlation analysis suggested a potential association between endoplasmic reticulum stress, the PI3K/AKT/mTOR signaling pathway, and liver injury in chicks. In summary, iron overload can induce cell apoptosis and liver injury by affecting endoplasmic reticulum stress and the PI3K/AKT/mTOR signaling pathway.
Subject(s)
Chickens , Endoplasmic Reticulum Stress , Iron Overload , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Signal Transduction , TOR Serine-Threonine Kinases , Animals , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Phosphatidylinositol 3-Kinases/metabolism , TOR Serine-Threonine Kinases/metabolism , Iron Overload/metabolism , Iron Overload/pathology , Liver/metabolism , Liver/pathologyABSTRACT
Age-related macular degeneration (AMD) is characterized by the degenerative senescence in the retinal pigment epithelium (RPE) and photoreceptors, which is accompanied by the accumulation of iron ions in the aging retina. However, current models of acute oxidative stress are still insufficient to simulate the gradual progression of AMD. To address this, we established chronic injury models by exposing the aRPE-19 cells, 661W cells, and mouse retina to iron ion overload over time. Investigations at the levels of cell biology and molecular biology were performed. It was demonstrated that long-term treatment of excessive iron ions induced senescence-like morphological changes, decreased cell proliferation, and impaired mitochondrial function, contributing to apoptosis. Activation of the mitogen-activated protein kinase (MAPK) pathway and the downstream molecules were confirmed both in the aRPE-19 and 661W cells. Furthermore, iron ion overload resulted in dry AMD-like lesions and decreased visual function in the mouse retina. These findings suggest that chronic exposure to overloading iron ions plays a significant role in the pathogenesis of retinopathy and provide a potential model for future studies on AMD.NEW & NOTEWORTHY To explore the possibility of constructing reliable research carriers on age-related macular degeneration (AMD), iron ion overload was applied to establish models in vitro and in vivo. Subsequent investigations into cellular physiology and molecular biology confirmed the presence of senescence in these models. Through this study, we hope to provide a better option of feasible methods for future researches into AMD.
Subject(s)
Disease Models, Animal , Iron , Macular Degeneration , Retinal Pigment Epithelium , Animals , Humans , Macular Degeneration/metabolism , Macular Degeneration/pathology , Macular Degeneration/genetics , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/pathology , Mice , Iron/metabolism , Mice, Inbred C57BL , Apoptosis , Oxidative Stress , Cell Line , Cellular Senescence , Iron Overload/metabolism , Iron Overload/pathology , Cell Proliferation , Retina/metabolism , Retina/pathology , Mitochondria/metabolism , Mitochondria/pathologyABSTRACT
Cold-inducible RNA binding protein (CIRBP), a stress response protein, protects cells from mild hypothermia or hypoxia by stabilizing specific mRNAs and promoting their translation. Neurons subjected to hypobaric hypoxia insult trigger various cell death programs. One of these is ferroptosis, a novel non-apoptotic form of programmed cell death, which is characterized by excessive iron ion accumulation and lipid peroxidation. Here, we establish that CIRBP can regulate neuronal ferroptosis both in vivo and in vitro. We observe that hypoxia leads to neuronal death via intracellular ferrous iron overload and impaired antioxidant systems, accompanied by suppressed CIRBP expression. Genetic enrichment of CIRBP in hippocampal neurons CIRBPTg mice bred with Emx1-Cre mice attenuates hypoxia-induced cognitive deficits and neuronal degeneration. Mechanistically, CIRBP alleviates neuronal ferroptosis and intracellular ferrous ion accumulation by binding to the mitochondrial ferritin (FTMT) 3'UTR to stabilize mRNA and promote its translation. Our novel study shows the critical role of CIRBP in the progression of ferroptosis, and provides promising therapeutic target for hypoxia-induced neurological diseases.
Subject(s)
Ferroptosis , Iron Overload , Neurons , RNA-Binding Proteins , Animals , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Mice , Neurons/metabolism , Neurons/pathology , Iron Overload/metabolism , Iron Overload/pathology , Hypoxia/metabolism , Mice, Inbred C57BL , Hippocampus/metabolism , Hippocampus/pathology , Iron/metabolism , HumansABSTRACT
RATIONALE AND OBJECTIVES: This study aimed to evaluate the technical success rate and stiffness measurement reliability of two specific hepatic magnetic resonance elastography (MRE) sequences dedicated to solving susceptibility artifacts in patients with various degrees of hepatic iron overload. MATERIALS AND METHODS: Thirty-seven patients with iron-overloaded liver confirmed by R2* value measurement who underwent two-dimensional (2D) spin-echo (SE) MRE and 2D SE-echo-planar-imaging (EPI) MRE were reviewed retrospectively. According to four categories based on R2* value (mild, moderate, severe elevation, and extremely severe iron overload), we compared the success rate, quality score, and liver stiffness of the two sequences. In addition, Spearman's correlation was performed to evaluate the relationship between the R2* value and liver stiffness. RESULTS: The overall success rates of SE MRE and SE-EPI MRE in patients with hepatic iron overload were 91.89% and 78.38%, respectively, and 100% and 78.57%, respectively, for severe elevation iron overload. In all patients, the MRE quality scores were 54 and 48 for SE MRE and SE-EPI MRE, respectively (P = 0.107). There were no significant differences in liver stiffness measurements between the two MRE methods in patients with mild, moderate, and severe elevation iron-overloaded livers (P > 0.6 for all), respectively. For both MRE methods, R2* value had no significant effect on the liver stiffness measurements (correlation coefficient <0.1, P >0.6 for both). CONCLUSION: In the mild and moderate elevation iron-overloaded liver, both SE MRE and fast SE-EPI MRE can provide successful and reliable liver stiffness measurement. In severe elevation iron-overloaded livers, SE MRE may be a better choice than SE-EPI MRE.
Subject(s)
Elasticity Imaging Techniques , Iron Overload , Humans , Elasticity Imaging Techniques/methods , Reproducibility of Results , Retrospective Studies , Liver/diagnostic imaging , Liver/pathology , Liver Cirrhosis/pathology , Magnetic Resonance Imaging/methods , Echo-Planar Imaging/methods , Iron Overload/diagnostic imaging , Iron Overload/pathology , IronABSTRACT
Magnetic resonance imaging (MRI) T2* is the gold standard for detecting iron deposition in cardiac tissue, but the technique has limitations and cannot be fully performed in paediatric thalassemia patients. The aim of this study was to analyse clinical data to identify other predictors of cardiac iron deposition. A retrospective analysis was performed on 370 children with ß-TM. According to the cardiac MRI results, patients were allocated to a cardiac deposition group and noncardiac deposition group. Multivariate analysis revealed that genotype and corrected QT interval were associated with cardiac iron deposition, indicating that the-ß0/ß0 genotype conferred greater susceptibility to cardiac iron deposition. Receiver operating characteristic curve (ROC) analysis was performed, and the area under the curve (AUC) of genotype was 0.651. The AUC for the corrected QT interval was 0.711, at a cut-off value of 418.5 ms. ROC analysis of the combined genotype and corrected QT interval showed an AUC of 0.762 with 81.3% sensitivity and 64.7% specificity. Compared to patients with the ß+/ß+ and ß0ß+ genotypes, ß0ß0 children with ß-TM were more likely to have cardiac iron deposition. Conclusion: The genotype and QTc interval can be used to predict cardiac iron deposition in children with ß-TM who are unable to undergo MRI T2 testing.
Subject(s)
Iron Overload , beta-Thalassemia , Humans , Child , beta-Thalassemia/complications , beta-Thalassemia/diagnosis , beta-Thalassemia/genetics , Iron Overload/complications , Iron Overload/diagnosis , Iron Overload/pathology , Retrospective Studies , ROC Curve , Magnetic Resonance Imaging/methods , Iron , Myocardium/pathologyABSTRACT
AIM: Haemophiliac arthritis (HA) is caused by spontaneous intra-articular hemorrhage and repeated intra-articular hematomas, leading to iron overload, which, in turn, induces M1 macrophage polarisation and inflammatory cytokine secretion, resulting in synovitis. Here, we explored the mechanism by which iron overload in HA induces the polarisation of M1 macrophages, providing a new approach for the treatment of HA synovitis. METHODS: The synovium from the knee joints of normal amputees and patients with HA was collected. Pathological changes in the synovial tissues were analysed using hematoxylin and eosin staining. Iron tissue deposition was evaluated using the iron assay kit and Prussia Blue staining, while macrophage phenotype was determined using immunofluorescence. The levels of pro-inflammatory cytokines and p53 acetylation were determine using western blotting. An in vitro iron overload model was established by inducing THP-1 macrophages with ferric ammonium citrate, and the involvement of acetylated p53 in M1 macrophage polarisation was investigated. RESULTS: Compared to control samples, the iron content in the synovium of patients with HA was significantly increased. The protein levels of M1 macrophage markers, pro-inflammatory cytokines, and acetylated p53, were also significantly elevated in the synovial tissues of patients with HA. Similar results were observed in the in vitro iron overload model. Furthermore, the inhibition of p53 acetylation in vitro reversed these iron overload-induced effects. CONCLUSION: In patients with HA, iron overload induced synovial p53 acetylation, leading to macrophage polarisation toward the M1 phenotype and increased inflammatory cytokine secretion, resulting in synovitis. HIGHLIGHTS: Synovial iron overload is associated with changes in P53 acetylation in hemophiliac arthritis (HA). Acetylated p53, a known regulator of macrophage polarization, is highly expressed in HA synovium, suggesting a potential role in M1 polarization. HA synovial macrophages predominantly polarize into the pro-inflammatory M1 phenotype, secreting elevated levels of pro-inflammatory cytokines.
Subject(s)
Iron Overload , Osteoarthritis , Synovitis , Humans , Tumor Suppressor Protein p53/metabolism , Synovial Membrane/pathology , Macrophages/metabolism , Macrophages/pathology , Synovitis/complications , Osteoarthritis/pathology , Phenotype , Iron Overload/complications , Iron Overload/metabolism , Iron Overload/pathology , Iron/metabolism , Cytokines/metabolismABSTRACT
BACKGROUND: Iron overload due to the excessive use of parenteral iron in haemodialysis is now an increasingly recognised clinical issue. Before erythropoiesis-stimulating agents (ESA) were introduced, a specific feature of patients treated by dialysis and having iron overload was that iron levels in the bone marrow were paradoxically low in most of them, despite severe hepatosplenic siderosis. Whether or not this paradox persists in the actual ESA era was unknown until recently, when an autopsy study in 21 patients treated by haemodialysis revealed similarities between liver and bone marrow iron content. The aim of this study was to further explore these recent findings in a cohort of alive patients on dialysis and to analyse the determinants of iron bone marrow. METHODS: Liver iron concentration (LIC) and vertebral T2∗ (a surrogate marker of bone marrow iron) were analysed retrospectively in 152 alive patients on dialysis (38.8% female) of whom 47.4% had iron overload by quantitative magnetic resonance imaging (MRI). FINDINGS: Vertebral T2∗ differed significantly between patients classified according to liver iron content at MRI: those with mild or moderate and severe liver iron overload had increased vertebral iron content at R2∗ relaxometry MRI (mild: vertebral T2∗ = 9.9 ms (4-24.8); moderate and severe: vertebral T2∗ = 8.5 ms (4.9-22.8)) when compared to patients with normal LIC (vertebral T2∗ = 13.2 ms (6.6-30.5) (p < 0.0001 Kruskal-Wallis test)). INTERPRETATION: The paradoxical discrepancy between bone marrow and liver iron-storage compartments observed in the pre-ESA era has disappeared today, as shown by a recent autopsy study and the present study in a cohort of alive patients treated by dialysis. FUNDING: None.
Subject(s)
Hemosiderosis , Iron Overload , Humans , Female , Male , Retrospective Studies , Bone Marrow/chemistry , Renal Dialysis/adverse effects , Hemosiderosis/etiology , Hemosiderosis/pathology , Iron , Iron Overload/pathology , Liver/pathology , Magnetic Resonance Imaging/methodsABSTRACT
Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA.
Subject(s)
Arthritis, Rheumatoid , Ferroptosis , Iron Overload , Humans , Mice , Animals , Arthritis, Rheumatoid/metabolism , Macrophages/metabolism , Iron Overload/pathology , Iron/metabolismABSTRACT
PURPOSE: Iron toxicity occurs under iron-overloaded settings, such as a high iron diet and blood transfusion, and damages important organs. Vanillin has been proven to have potential iron chelation capability. Given the negative effects of commonly used iron chelators like deferoxamine (DFO), we sought to examine the iron chelation potency of vanillin and evaluate its potential effect in the treatment of iron overload-related disorders. METHODS: 42 male NMRI mice were prepared for this purpose, and except for the negative control group, iron overload conditions were generated in them by injecting iron. Then normal saline (as a control), vanillin, and DFO (n = 7) were subsequently given to iron-overloaded mice. In the following, the activity of antioxidant enzymes catalase and superoxide dismutase were measured in the blood serum, brain, kidney, spleen, lung, and liver tissues of mice. Furthermore, the level of lipid peroxidation was determined by measuring the amount of malondialdehyde. Also, Perl's and H&E staining were used to examine the physiopathology changes of tissues. FINDINGS: Vanillin, a natural antioxidant compound, outperformed deferoxamine, a chemical iron chelator. Along with a decrease in iron content, the activity of catalase and superoxide dismutase enhanced in the iron-overloaded groups that were treated with vanillin. The level of lipid peroxidation was also declined in the iron-overloaded mice receiving vanillin. CONCLUSION: Vanillin can be used as a suitable substitute for chemical chelators with fewer side effects and equivalent efficiency. We encourage the use of this compound as a natural iron chelator following performing additional safety and efficacy studies.
Subject(s)
Deferoxamine , Iron Overload , Mice , Male , Animals , Deferoxamine/pharmacology , Catalase , Antioxidants/pharmacology , Antioxidants/therapeutic use , Iron Overload/drug therapy , Iron Overload/pathology , Iron Chelating Agents/pharmacology , Iron Chelating Agents/therapeutic use , Iron , Superoxide DismutaseABSTRACT
Ferroptosis is an iron-dependent programmed cell death process characterized by the accumulation of lethal oxidative damage. Localized iron overload is a unique clinical phenomenon in ovarian endometriosis (EM). However, the role and mechanism of ferroptosis in the course of ovarian EM remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian EM and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells (ESCs). Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse EM model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian EM can activate autophagy-related ferroptosis in ESCs, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the EM environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian EM.
Subject(s)
Endometriosis , Ferroptosis , Iron Overload , Female , Animals , Mice , Humans , Activating Transcription Factor 4/metabolism , Endometriosis/metabolism , Ferroptosis/genetics , Iron Overload/complications , Iron Overload/metabolism , Iron Overload/pathology , Iron/metabolism , Autophagy/genetics , Stromal Cells/metabolismABSTRACT
To investigate the value of T2* technique on 3.0 T magnetic resonance imaging (MRI) in evaluating the changes of cardiac and hepatic iron load before and after hematopoietic stem cell transplantation (HSCT) in patients with thalassemia (TM), the 141 TM patients were divided into 6 group for subgroup analysis: 6, 12, 18, 24 and > 24 months group, according to the postoperative interval. The T2* values of heart and liver (H-T2*, L-T2*) were quantified in TM patients before and after HSCT using 3.0 T MRI T2* technology, and the corresponding serum ferritin (SF) was collected at the same time, and the changes of the three before and after HSCT were compared. The overall H-T2* (P = 0.001) and L-T2* (P = 0.041) of patients after HSCT were higher than those before HSCT (mean relative changes = 19.63%, 7.19%). The H-T2* (P < 0.001) and L-T2* (P < 0.001) > 24 months after HSCT were significantly higher than those before HSCT (mean relative changes = 69.19%, 93.73%). The SF of 6 months (P < 0.001), 12 months (P = 0.008), 18 months (P = 0.002) and > 24 months (P = 0.001) were significantly higher than those before HSCT (mean relative changes = 57.93%, 73.84%, 128.51%, 85.47%). There was no significant improvement in cardiac and liver iron content in TM patients within 24 months after HSCT, while the reduction of cardiac and liver iron content in patients is obvious when > 24 months after HSCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Iron Overload , Thalassemia , beta-Thalassemia , Humans , Iron/metabolism , Ferritins , Iron Overload/pathology , beta-Thalassemia/diagnostic imaging , beta-Thalassemia/therapy , Thalassemia/diagnostic imaging , Thalassemia/therapy , Thalassemia/pathology , Magnetic Resonance Imaging/methods , Liver/metabolism , Myocardium/metabolismABSTRACT
Introduction: Raised serum ferritin levels often indicate iron overload, but they are not specific as the levels are elevated in inflammatory disorders, liver diseases, alcohol excess, or malignancy. If regular transfusions are required for the patient with thalassemia, this doubles the rate of iron accumulation leading to earlier massive iron overload and iron-related damage. The aim of this study aimed to find out the prevalence of high serum ferritin levels among blood-transfused thalassemic patients admitted to the Department of Paediatrics in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted at a tertiary care centre from 1 March 2022 to 31 December 2022. Ethical approval was taken from the Institutional Review Committee (Reference number: 078/79-017/HG). Children who were confirmed by haemoglobin electrophoresis on regular blood transfusion were included in the study. Those who did not gave consent were excluded from the study. Convenience sampling method was used. Point estimate and 90% Confidence Interval were calculated. Results: Out of 53 cases, the prevalence of high serum ferritin level was seen in 46 (88.79%) (80.30-97.28, 95% Confidence Interval). Among 46, 34 (73.91%) had serum ferritin levels of more than 1000 to 2500 ng/ml whereas 12 (26.09%) had more than 25000 ng/ml. Conclusions: The prevalence of high serum ferritin levels among blood transfused thalassemic patients admitted to the Department of Paediatrics in a tertiary care centre was found to be higher than in other studies done in similar settings. Keywords: blood transfusion; ferritin; thalassemia.
Subject(s)
Iron Overload , Pediatrics , Thalassemia , beta-Thalassemia , Humans , Child , Cross-Sectional Studies , Tertiary Care Centers , Iron , Thalassemia/epidemiology , Thalassemia/therapy , Iron Overload/pathology , FerritinsABSTRACT
We evaluated pattern and clinical correlates of renal T2* measurements in adult ß-thalassemia major (ß-TM) patients. Ninety ß-TM patients (48 females, 38.15 ± 7.94 years), consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network, underwent T2* magnetic resonance imaging (MRI) for quantification of iron overload (IO) in kidneys, liver, pancreas, and heart. Ten (11.1%) patients showed renal IO (T2* < 31 ms). Global kidney T2* values did not show a correlation with gender, age, splenectomy, regular transfusions or chelation starting age, pre-transfusion hemoglobin, and serum ferritin levels. Global kidney T2* values showed an inverse correlation with MRI liver iron concentration (LIC) values (R = - 0.349; p = 0.001) and a positive correlation with global pancreas T2* values (R = 0.212; p = 0.045). Frequency of renal IO was significantly higher in patients with cardiac IO than in patients without cardiac IO (50.0% vs. 6.3%; p = 0.001). A significant inverse association was detected between global kidneys T2* values and lactate dehydrogenase (LDH) (R = - 0.529; p < 0.0001). In multivariate regression analysis, MRI LIC and LDH were the strongest predictors of global kidney T2* values. A MRI LIC > 4.83 mg/g dw predicted the presence of renal IO (sensitivity = 90.0%; specificity = 61.2%). Global kidney T2* values were inversely correlated with uric acid (R = - 0.269; p = 0.025). In conclusion, in adult ß-TM patients, renal iron deposition is not common and is linked to both hemolysis and total body iron overload.