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Theranostics 2024Pulmonary fibrosis is a chronic progressive lung disease with limited therapeutic options. We previously revealed that there is iron deposition in alveolar epithelial...
Pulmonary fibrosis is a chronic progressive lung disease with limited therapeutic options. We previously revealed that there is iron deposition in alveolar epithelial type II cell (AECII) in pulmonary fibrosis, which can be prevented by the iron chelator deferoxamine. However, iron in the cytoplasm and the mitochondria has two relatively independent roles and regulatory systems. In this study, we aimed to investigate the role of mitochondrial iron deposition in AECII injury and pulmonary fibrosis, and to find potential therapeutic strategies. BLM-treated mice, MLE-12 cells, and primary AECII were employed to establish the mouse pulmonary fibrosis model and epithelial cells injury model, respectively. Mitochondrial transplantation, siRNA and plasmid transfection, western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), polymerase chain reaction (PCR), immunofluorescence, immunoprecipitation (IP), MitoSOX staining, JC-1 staining, oxygen consumption rate (OCR) measurement, and Cell Counting Kit-8 (CCK8) assay were utilized to elucidate the role of mitochondrial iron deposition in cell and lung fibrosis and determine its mechanism. This study showed that prominent mitochondrial iron deposition occurs within AECII in bleomycin (BLM)-induced pulmonary fibrosis mouse model and in BLM-treated MLE-12 epithelial cells. Further, the study revealed that healthy mitochondria rescue BLM-damaged AECII mitochondrial iron deposition and cell damage loss. Mitoferrin-2 (MFRN2) is the main transporter that regulates mitochondrial iron metabolism by transferring cytosolic iron into mitochondria, which is upregulated in BLM-treated MLE-12 epithelial cells. Direct overexpression of MFRN2 causes mitochondrial iron deposition and cell damage. In this study, decreased ubiquitination of the ubiquitin ligase F-box/LRR-repeat protein 5 (FBXL5) degraded iron-reactive element-binding protein 2 (IREB2) and promoted MFRN2 expression as well as mitochondrial iron deposition in damaged AECII. Activation of the prostaglandin E2 receptor EP4 subtype (EP4) receptor signaling pathway counteracted mitochondrial iron deposition by downregulating IREB2-MFRN2 signaling through upregulation of FBXL5. This intervention not only reduced mitochondrial iron content but also preserved mitochondrial function and protected against AECII damage after BLM treatment. Our findings highlight the unexplored roles, mechanisms, and regulatory approaches of abnormal mitochondrial iron metabolism of AECII in pulmonary fibrosis. Therefore, this study deepens the understanding of the mechanisms underlying pulmonary fibrosis and offers a promising strategy for developing effective therapeutic interventions using the EP4 receptor activator.
Topics: Animals; Bleomycin; Mitochondria; Pulmonary Fibrosis; Mice; Iron; Alveolar Epithelial Cells; Disease Models, Animal; Mice, Inbred C57BL; Cell Line; Male
PubMed: 38773980
DOI: 10.7150/thno.94072 -
Biological Trace Element Research May 2024In order to explore the effect of excessive iron supplementation on ferroptosis in mouse testes, Kunming mice received injections of varying concentrations of iron. The...
In order to explore the effect of excessive iron supplementation on ferroptosis in mouse testes, Kunming mice received injections of varying concentrations of iron. The organ weight, sperm density, and malformation rate were measured. Observations of pathological and ultrastructural alterations in spermatogenic tubules were conducted using haematoxylin eosin (HE) staining and transmission electron microscopy(TEM). Transcript levels of related genes and serum biochemical indicators were measured in mouse testicular tissue. The results showed that higher iron concentration inhibited the growth of mice; reduced the organ coefficients of the testis, heart, and liver; and increased the rate of sperm malformation and mortality. Supplementation with high levels of iron ions can adversely affect the male reproductive system by reducing sperm count, damaging the structure of the seminiferous tubules and causing sperm cell abnormalities. In addition, the iron levels also affected the immune response and blood coagulation ability by affecting the red blood cells, white blood cells and platelets. The results showed that iron ions can affect mouse testicular tissue and induce ferroptosis by altering the expression of ferroptosis-related genes. However, the degree of effect was different for the different concentrations of iron ions. The study also revealed the potential role of deferoxamine in inhibiting the occurrence of ferroptosis. Nevertheless, the damage caused to the testis by deferoxamine supplementation suggests the need for further research in this direction. This study provides reference for reproductive toxicity induced by environmental iron exposure and clarifies the mechanism of reproductive toxicity caused by iron overload and the important role of iron in the male reproductive system.
PubMed: 38771434
DOI: 10.1007/s12011-024-04192-7 -
Biological Trace Element Research May 2024The detrimental effects of fluoride on neurotoxicity have been widely recorded, yet the detailed mechanisms underlying these effects remain unclear. This study explores...
The detrimental effects of fluoride on neurotoxicity have been widely recorded, yet the detailed mechanisms underlying these effects remain unclear. This study explores lysosomal iron metabolism in fluoride-related neurotoxicity, with a focus on the Steap3/TRPML1 axis. Utilizing sodium fluoride (NaF)-treated human neuroblastoma (SH-SY5Y) and mouse hippocampal neuron (HT22) cell lines, our research demonstrates that NaF enhances the accumulation of ferrous ions (Fe) in these cells, disrupting lysosomal iron metabolism through the Steap3/TRPML1 axis. Notably, NaF exposure upregulated ACSL4 and downregulated GPX4, accompanied by reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity and increased malondialdehyde (MDA) levels. These changes indicate increased vulnerability to ferroptosis within neuronal cells. The iron chelator deferoxamine (DFO) mitigates this disruption. DFO binds to lysosomal Fe and inhibits the Steap3/TRPML1 axis, restoring normal lysosomal iron metabolism, preventing lysosomal membrane permeabilization (LMP), and reducing neuronal cell ferroptosis. Our findings suggest that interference in lysosomal iron metabolism may mitigate fluoride-induced neurotoxicity, underscoring the critical role of the Steap3/TRPML1 axis in this pathological process.
PubMed: 38760610
DOI: 10.1007/s12011-024-04226-0 -
Open Medicine (Warsaw, Poland) 2024Liver fibrosis is a key contributor to hepatic disease-related mortality. Exosomes derived from mesenchymal stem cells (MSCs) have been revealed to improve liver...
Liver fibrosis is a key contributor to hepatic disease-related mortality. Exosomes derived from mesenchymal stem cells (MSCs) have been revealed to improve liver fibrosis. To explore the effect and mechanism of MSC-derived exosomal miR-26a on liver fibrosis, exosomes were separated from bone marrow-derived MSCs (BMSCs) and used to treat with LX2 cells. The miR-26a level was decreased in BMSC-derived exosomes. Treatment with exosomes isolated from human BMSCs transfected with miR-26a mimics (miR-26a mimic-Exo) decreased the 5-ethynyl-2'-deoxyuridine-positive cell rate, the protein level of α-SMA and collagen I, and the glutathione (GSH) level but enhanced the apoptosis rate and the reactive oxide species (ROS) level in LX2 cells, which were reversed by the treatment of deferoxamine. Mechanically, miR-26a directly bound SLC7A11 mRNA and negatively modulated the level of SLC7A11 in LX2 cells. Overexpression of SLC7A11 reversed the miR-26a mimic-Exo-induced alterations in the level of ROS, Fe, malonaldehyde, and GSH in LX2 cells. , miR-26a mimic-Exo decreased the level of SLC7A11 and attenuated CCL4-induced liver fibrosis. Collectively, miR-26a mimic-Exo induced ferroptosis to alleviate liver fibrosis by regulating SLC7A11, which may provide new strategies for the treatment of liver fibrosis, and even other relevant diseases.
PubMed: 38756248
DOI: 10.1515/med-2024-0945 -
Pediatric Blood & Cancer Aug 2024In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent β-thalassemia (TDT) and explore the ideal timing for... (Review)
Review
In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent β-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.
Topics: Humans; beta-Thalassemia; Iron Chelating Agents; Child; Iron Overload; Chelation Therapy; Blood Transfusion; Child, Preschool; Deferoxamine; Deferiprone; Pyridones
PubMed: 38753107
DOI: 10.1002/pbc.31035 -
The Science of the Total Environment Jul 2024The brominated flame retardant 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is a ubiquitous environmental pollutant that causes neurotoxicity. However, incomplete...
The brominated flame retardant 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is a ubiquitous environmental pollutant that causes neurotoxicity. However, incomplete understanding of the underlying mechanisms has hampered the development of effective intervention strategies. Oxidative stress and related cell death are the modes of action for PBDE-47 neurotoxicity, which are also the characteristics of ferroptosis. Nonetheless, the role of ferroptosis in PBDE-47-induced neurotoxicity remains unclear. In the present study, we found that PBDE-47 triggered ferroptosis in neuron-like PC12 cells, as evidenced by intracellular iron overload, lipid peroxidation, and mitochondrial damage. This was confirmed by ferroptosis inhibitors including the lipid reactive oxygen species scavenger ferrostatin-1 and iron chelator deferoxamine mesylate. Mechanistically, PBDE-47 impaired ferritinophagy by disrupting nuclear receptor coactivator 4-mediated lysosomal degradation of the iron storage protein ferritin. Moreover, PBDE-47 disturbed iron metabolism by increasing cellular iron import via upregulation of transferrin receptor 1 and decreasing cellular iron export via downregulation of ferroportin 1 (FPN1). Intriguingly, rescuing lysosomal function by overexpressing cathepsin B (CatB) mitigated PBDE-47-induced ferroptosis by partially restoring dysfunctional ferritinophagy and enhancing iron excretion via the upregulation of FPN1. However, FPN1 knockdown reversed the beneficial effects of CatB overexpression on the PBDE-47-induced iron overload. Finally, network pharmacology integrated with experimental validation revealed that Canolol, the main phenolic compound in canola oil, protected against PBDE-47-evoked iron overload, resulting in ferroptosis by restoring defective ferritinophagy and improving abnormal iron metabolism via lowering iron uptake and facilitating iron excretion. Overall, these data suggest that ferroptosis is a novel mechanism of PBDE-47-induced neuronal death and that manipulation of ferritinophagy and iron metabolism via Canolol represents a promising therapeutic strategy.
Topics: Ferroptosis; Halogenated Diphenyl Ethers; Iron; Animals; PC12 Cells; Neurons; Rats; Ferritins; Flame Retardants; Oxidative Stress; Environmental Pollutants
PubMed: 38750757
DOI: 10.1016/j.scitotenv.2024.173118 -
Journal of Labelled Compounds &... Jun 2024A key aspect for the applicability of Zr-radioimmunoconjugates is inert modification and radiolabeling. The two commercially available bifunctional variants of the...
A key aspect for the applicability of Zr-radioimmunoconjugates is inert modification and radiolabeling. The two commercially available bifunctional variants of the siderophore desferrioxamine (DFO), Fe-DFO-N-suc-TFP-ester and p-NCS-Bz-DFO, are most often used for clinical Zr-immuno-PET. The use of Fe-DFO-N-suc-TFP-ester is advantageous with regard to higher radiolysis stability and more facile assessment of radiochemical purity as well as chelator-to-mAb ratio. However, not all mAbs withstand the Fe-removal step at relatively low pH (4-4.5) using EDTA, which is needed after conjugation to allow Zr labeling. In this study, it was investigated whether hydroxybenzyl ethylenediamine (HBED) or the clinically approved deferiprone (DFP) can serve as an alternative for EDTA to establish a pH-independent mild method for Fe-removal and thereby broaden the applicability of Fe-DFO-N-suc-TFP-ester. Carrier-added [Fe]Fe-DFO-N-suc-TFP-ester was used for mAb modification to enable direct tracking of the Fe-removal efficiency under various conditions. Whereas incomplete Fe-removal with HBED was observed at pH 5 or higher, Fe-removal with DFP was possible at a broad pH range (4-9). This provides a mild, pH-independent method for Fe-removal, improving the applicability and attractiveness of Fe-DFO-N-suc-TFP-ester for Zr-mAb preparation.
Topics: Zirconium; Deferoxamine; Radioisotopes; Iron; Positron-Emission Tomography; Pyridones; Deferiprone; Immunoconjugates; Radiopharmaceuticals; Antibodies, Monoclonal
PubMed: 38744538
DOI: 10.1002/jlcr.4097 -
Free Radical Biology & Medicine Aug 2024Bilirubin-induced brain damage is a serious clinical consequence of hyperbilirubinemia, yet the underlying molecular mechanisms remain largely unknown. Ferroptosis, an...
Bilirubin-induced brain damage is a serious clinical consequence of hyperbilirubinemia, yet the underlying molecular mechanisms remain largely unknown. Ferroptosis, an iron-dependent cell death, is characterized by iron overload and lipid peroxidation. Here, we report a novel regulatory mechanism of demethylase AlkB homolog 5 (ALKBH5) in acyl-coenzyme A synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis in hyperbilirubinemia. Hyperdifferential PC12 cells and newborn Sprague-Dawley rats were used to establish in vitro and in vivo hyperbilirubinemia models, respectively. Proteomics, coupled with bioinformatics analysis, first suggested the important role of ferroptosis in hyperbilirubinemia-induced brain damage. In vitro experiments showed that ferroptosis is activated in hyperbilirubinemia, and ferroptosis inhibitors (desferrioxamine and ferrostatin-1) treatment effectively alleviates hyperbilirubinemia-induced oxidative damage. Notably, we observed that the ferroptosis in hyperbilirubinemia was regulated by mA modification through the downregulation of ALKBH5 expression. MeRIP-seq and RIP-seq showed that ALKBH5 may trigger hyperbilirubinemia ferroptosis by stabilizing ACSL4 mRNA via mA modification. Further, hyperbilirubinemia-induced oxidative damage was alleviated through ACSL4 genetic knockdown or rosiglitazone-mediated chemical repression but was exacerbated by ACSL4 overexpression. Mechanistically, ALKBH5 promotes ACSL4 mRNA stability and ferroptosis by combining the 669 and 2015 mA modified sites within 3' UTR of ACSL4 mRNA. Our findings unveil a novel molecular mechanism of ferroptosis and suggest that mA-dependent ferroptosis could be an underlying clinical target for the therapy of hyperbilirubinemia.
Topics: Animals; Ferroptosis; Rats; Coenzyme A Ligases; AlkB Homolog 5, RNA Demethylase; PC12 Cells; Rats, Sprague-Dawley; RNA Stability; Cyclohexylamines; Humans; Deferoxamine; Oxidative Stress; Brain Injuries; Phenylenediamines; RNA, Messenger; Male; Disease Models, Animal; Lipid Peroxidation
PubMed: 38734267
DOI: 10.1016/j.freeradbiomed.2024.05.014 -
International Journal of Molecular... Apr 2024The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction... (Review)
Review
The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.
Topics: Humans; Iron Overload; Iron Chelating Agents; Anemia, Iron-Deficiency; Iron; Animals; Deferiprone
PubMed: 38731873
DOI: 10.3390/ijms25094654 -
Molecules (Basel, Switzerland) Apr 2024Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of... (Review)
Review
Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of studies have confirmed that deferoxamine can reduce inflammatory response and promote angiogenesis. Blood vessels play a crucial role in sustaining vital life by facilitating the delivery of immune cells, oxygen, and nutrients, as well as eliminating waste products generated during cellular metabolism. Dysfunction in blood vessels may contribute significantly to the development of life-threatening diseases. Anti-angiogenesis therapy and pro-angiogenesis/angiogenesis strategies have been frequently recommended for various diseases. Herein, we describe the mechanism by which deferoxamine promotes angiogenesis and summarize its application in chronic wounds, bone repair, and diseases of the respiratory system. Furthermore, we discuss the drug delivery system of deferoxamine for treating various diseases, providing constructive ideas and inspiration for the development of new treatment strategies.
Topics: Deferoxamine; Humans; Animals; Neovascularization, Physiologic; Regeneration; Wound Healing; Neovascularization, Pathologic; Angiogenesis
PubMed: 38731540
DOI: 10.3390/molecules29092050