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Antioxidants (Basel, Switzerland) Nov 2023The intracellular redox-active labile iron pool (LIP) is weakly chelated and available for integration into the iron metalloproteins that are involved in diverse...
The intracellular redox-active labile iron pool (LIP) is weakly chelated and available for integration into the iron metalloproteins that are involved in diverse cellular processes, including cancer cell-specific metabolic oxidative stress. Abnormal iron metabolism and elevated LIP levels are linked to the poor survival of lung cancer patients, yet the underlying mechanisms remain unclear. Depletion of the LIP in non-small-cell lung cancer cell lines using the doxycycline-inducible overexpression of the ferritin heavy chain (Ft-H) (H1299 and H292), or treatment with deferoxamine (DFO) (H1299 and A549), inhibited cell growth and decreased clonogenic survival. The Ft-H overexpression-induced inhibition of H1299 and H292 cell growth was also accompanied by a significant delay in transit through the S-phase. In addition, both Ft-H overexpression and DFO in H1299 resulted in increased single- and double-strand DNA breaks, supporting the involvement of replication stress in the response to LIP depletion. The Ft-H and DFO treatment also sensitized H1299 to VE-821, an inhibitor of ataxia telangiectasis and Rad2-related (ATR) kinase, highlighting the potential of LIP depletion, combined with DNA damage response modifiers, to alter lung cancer cell responses. In contrast, only DFO treatment effectively reduced the LIP, clonogenic survival, cell growth, and sensitivity to VE-821 in A549 non-small-cell lung cancer cells. Importantly, the Ft-H and DFO sensitized both H1299 and A549 to chemoradiation in vitro, and Ft-H overexpression increased the efficacy of chemoradiation in vivo in H1299. These results support the hypothesis that the depletion of the LIP can induce genomic instability, cell death, and potentiate therapeutic responses to chemoradiation in NSCLC.
PubMed: 38001858
DOI: 10.3390/antiox12112005 -
Antioxidants (Basel, Switzerland) Oct 2023The accumulation of the uremic toxin indoxyl sulfate (IS) is a key pathological feature of chronic kidney disease (CKD). The effect of IS on ferroptosis and the role of...
The accumulation of the uremic toxin indoxyl sulfate (IS) is a key pathological feature of chronic kidney disease (CKD). The effect of IS on ferroptosis and the role of IS-related ferroptosis in CKD are not well understood. We used a renal tubular cell model and an adenine-induced CKD mouse model to explore whether IS induces ferroptosis and injury and affects iron metabolism in the renal cells and the kidneys. Our results showed that exposure to IS induced several characteristics for ferroptosis, including iron accumulation, an impaired antioxidant system, elevated reactive oxygen species (ROS) levels, and lipid peroxidation. Exposure to IS triggered intracellular iron accumulation by upregulating transferrin and transferrin receptors, which are involved in cellular iron uptake. We also observed increased levels of the iron storage protein ferritin. The effects of IS-induced ROS generation, lipid peroxidation, ferroptosis, senescence, ER stress, and injury/fibrosis were effectively alleviated by treatments with an iron chelator deferoxamine (DFO) in vitro and the adsorbent charcoal AST-120 (scavenging the IS precursor) in vivo. Our findings suggest that IS triggers intracellular iron accumulation and ROS generation, leading to the induction of ferroptosis, senescence, ER stress, and injury/fibrosis in CKD kidneys. AST-120 administration may serve as a potential therapeutic strategy.
PubMed: 38001784
DOI: 10.3390/antiox12111931 -
Cell Death Discovery Nov 2023Cellular senescence is a hallmark of aging and has been linked to age-related diseases. Age-related macular degeneration (AMD), the most common aging-related retinal...
Cellular senescence is a hallmark of aging and has been linked to age-related diseases. Age-related macular degeneration (AMD), the most common aging-related retinal disease, is prospectively associated with retinal pigment epithelial (RPE) senescence. However, the mechanism of RPE cell senescence remains unknown. In this study, tert-butyl hydroperoxide (TBH)-induced ARPE-19 cells and D-galactose-treated C57 mice were used to examine the cause of elevated iron in RPE cell senescence. Ferric ammonium citrate (FAC)-treated ARPE-19 cells and C57 mice were used to elucidated the mechanism of iron overload-induced RPE cell senescence. Molecular biology techniques for the assessment of iron metabolism, cellular senescence, autophagy, and mitochondrial function in vivo and in vitro. We found that iron level was increased during the senescence process. Ferritin, a major iron storage protein, is negatively correlated with intracellular iron levels and cell senescence. NCOA4, a cargo receptor for ferritinophagy, mediates degradation of ferritin and contributes to iron accumulation. Besides, we found that iron overload leads to mitochondrial dysfunction. As a result, mitochondrial DNA (mtDNA) is released from damaged mitochondria to cytoplasm. Cytoplasm mtDNA activates the cGAS-STING pathway and promotes inflammatory senescence-associated secretory phenotype (SASP) and cell senescence. Meanwhile, iron chelator Deferoxamine (DFO) significantly rescues RPE senescence and retinopathy induced by FAC or D-gal in mice. Taken together, these findings imply that iron derived from NCOA4-mediated ferritinophagy causes cellular senescence via the cGAS-STING pathway. Inhibiting iron accumulation may represent a promising therapeutic approach for age-related diseases such as AMD.
PubMed: 37980349
DOI: 10.1038/s41420-023-01712-7 -
Scientific Reports Nov 2023Retinal ischemia‒reperfusion (I/R) injury can cause significant damage to human retinal neurons, greatly compromising their functions. Existing interventions have been...
Retinal ischemia‒reperfusion (I/R) injury can cause significant damage to human retinal neurons, greatly compromising their functions. Existing interventions have been proven to have little effect. Ferroptosis is a newly discovered type of programmed cell death that has been found to be involved in the process of ischemia‒reperfusion in multiple organs throughout the body. Studies have shown that it is also present in retinal ischemia‒reperfusion injury. A rat model of retinal ischemia‒reperfusion injury was constructed and treated with deferoxamine. In this study, we found the accumulation of Fe, reactive oxygen species (ROS), malondialdehyde (MDA), and the consumption of glutathione (GSH) via ELISA testing; increased expression of transferrin; and decreased expression of ferritin, SLC7A11, and GPX4 via Western blotting (WB) and real-time PCR testing. Structural signs of ferroptosis (mitochondrial shrinkage) were observed across multiple cell types, including retinal ganglion cells (RGCs), photoreceptor cells, and pigment epithelial cells. Changes in visual function were detected by F-VEP and ERG. The results showed that iron and oxidative stress were increased in the retinal ischemia‒reperfusion injury model, resulting in ferroptosis and tissue damage. Deferoxamine protects the structural and functional soundness of the retina by inhibiting ferroptosis through the simultaneous inhibition of hemochromatosis, the initiation of transferrin, and the degradation of ferritin and activating the antioxidant capacity of the System Xc-GSH-GPX4 pathway.
Topics: Humans; Animals; Rats; Ferroptosis; Deferoxamine; Reperfusion; Vision, Low; Reperfusion Injury; Ferritins; Glutathione; Transferrins; Reactive Oxygen Species
PubMed: 37978208
DOI: 10.1038/s41598-023-46104-0 -
BioMed Research International 2023[This retracts the article DOI: 10.1155/2019/9742765.].
[This retracts the article DOI: 10.1155/2019/9742765.].
PubMed: 37946739
DOI: 10.1155/2023/9895024 -
Molecular Medicine Reports Dec 2023Ferroptosis is driven by iron‑dependent accumulation of lipid hydroperoxides, and hemolytic hyperbilirubinemia causes accumulation of unconjugated bilirubin and iron....
Ferroptosis is driven by iron‑dependent accumulation of lipid hydroperoxides, and hemolytic hyperbilirubinemia causes accumulation of unconjugated bilirubin and iron. The present study aimed to assess the role of ferroptosis in hemolytic hyperbilirubinemia‑induced brain damage (HHIBD). Rats were randomly divided into the control, phenylhydrazine (PHZ) and deferoxamine (DFO) + PHZ groups, with 12 rats in each group. Ferroptosis‑associated biochemical and protein indicators were measured in the brain tissue of rats. We also performed tandem mass tag‑labeled proteomic analysis. The levels of iron and malondialdehyde were significantly higher and levels of glutathione (GSH) and superoxide dismutase activity significantly lower in the brain tissues of the PHZ group compared with those in the control group. HHIBD also resulted in significant increases in the expression of the ferroptosis‑related proteins acyl‑CoA synthetase long‑chain family member 4, ferritin heavy chain 1 and transferrin receptor and divalent metal transporter 1, as well as a significant reduction in the expression of ferroptosis suppressor protein 1. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis demonstrated that the differentially expressed proteins of rat brain tissues between the control and PHZ groups were significantly involved in ferroptosis, GSH metabolism and fatty acid biosynthesis pathways. Pretreatment with DFO induced antioxidant activity and alleviated lipid peroxidation‑mediated HHIBD. In addition, PC12 cells treated with ferric ammonium citrate showed shrinking mitochondria, high mitochondrial membrane density, and increased lipid reactive oxygen species and intracellular ferrous iron, which were antagonized by pretreatment with ferrostatin‑1 or DFO, which was reversed by pretreatment with ferrostatin‑1 or DFO. The present study demonstrated that ferroptosis is involved in HHIBD and provided novel insights into candidate proteins that are potentially involved in ferroptosis in the brain during hemolytic hyperbilirubinemia.
Topics: Rats; Animals; Ferroptosis; Proteomics; Apoptosis; Iron; Hyperbilirubinemia; Brain Injuries; Brain; Hemolysis; Glutathione; Lipids
PubMed: 37937619
DOI: 10.3892/mmr.2023.13123 -
Advanced Science (Weinheim,... Jan 2024The treatment of bone defects remains a substantial clinical challenge due to the lack of spatiotemporal management of the immune microenvironment, revascularization,...
The treatment of bone defects remains a substantial clinical challenge due to the lack of spatiotemporal management of the immune microenvironment, revascularization, and osteogenic differentiation. Herein, deferoxamine (DFO)-loaded black phosphorus nanosheets decorated by polydopamine layer are prepared (BPPD) and compounded into gelatin methacrylate/sodium alginate methacrylate (GA) hybrid hydrogel as a smart-responsive therapeutic system (GA/BPPD) for accelerated bone regeneration. The BPPD nanocomposites served as bioactive components and near-infrared (NIR) photothermal agents, which conferred the hydrogel with excellent NIR/pH dual-responsive properties, realizing the stimuli-responsive release of DFO and PO during bone regeneration. Under the action of NIR-triggered mild photothermal therapy, the GA/BPPD hydrogel exhibited a positive effect on promoting osteogenesis and angiogenesis, eliminating excessive reactive oxygen species, and inducing macrophage polarization to the M2 phenotype. More significantly, through macrophage M2 polarization-induced osteoimmune microenvironment, this hydrogel platform could also drive functional cytokine secretion for enhanced angiogenesis and osteogenesis. In vivo experiments further demonstrated that the GA/BPPD system could facilitate bone healing by attenuating the local inflammatory response, increasing the secretion of pro-healing factors, stimulating endogenous cell recruitment, and accelerating revascularization. Collectively, the proposed intelligent photothermal hydrogel platform provides a promising strategy to reshape the damaged tissue microenvironment for augmented bone regeneration.
Topics: Osteogenesis; Photothermal Therapy; Bone Regeneration; Hydrogels; Methacrylates
PubMed: 37933988
DOI: 10.1002/advs.202304641 -
Viruses Oct 2023Porcine epidemic diarrhea virus (PEDV) is a highly contagious coronavirus that induces diarrhea and death in neonatal piglets, resulting in substantial economic losses...
Porcine epidemic diarrhea virus (PEDV) is a highly contagious coronavirus that induces diarrhea and death in neonatal piglets, resulting in substantial economic losses to the global swine industry. The mechanisms of PEDV infection and the roles of host factors are still under exploration. In this study, we used the ferroptosis pathway downstream target activator (1S,3R)-RSL3 compound as a starting point, combined with the interactions of N-acetylcysteine and deferoxamine, to elucidate the effects of a series of compounds on PEDV proliferation. We also established glutathione peroxidase 4 (GPX4) gene overexpression to further elucidate the relationship between the ferroptosis pathway and PEDV. (1S,3R)-RSL3 inhibited PEDV replication in Vero cells, while N-acetylcysteine and deferoxamine promoted its proliferation. In addition, (1S,3R)-RSL3 mainly affected the replication stage of PEDV. Overexpression of GPX4 promoted PEDV proliferation, indicating that the ferroptosis pathway could influence PEDV replication in Vero cells. This study focused on the mechanism of (1S,3R)-RSL3 inhibition on PEDV, laying the foundation for exploring the pathogenic mechanisms of PEDV and drug development.
Topics: Chlorocebus aethiops; Animals; Swine; Vero Cells; Porcine epidemic diarrhea virus; Acetylcysteine; Deferoxamine; Ferroptosis; Coronavirus Infections; Diarrhea; Swine Diseases; Virus Replication
PubMed: 37896857
DOI: 10.3390/v15102080 -
Metabolites Oct 2023Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered...
Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various proteins by iron chelation, we investigated combination anticancer therapy targeting metabolic changes that are forcibly modified by iron chelator administration. The deferoxamine (DFO)-resistant cell lines were established by gradually increasing the DFO concentration. Metabolomic analysis was conducted to evaluate the metabolic alterations induced by DFO administration, aiming to elucidate the resistance mechanism in DFO-resistant strains and identify potential novel therapeutic targets. Metabolom analysis of the DFO-resistant Huh7 cells revealed enhanced glycolysis and salvage cycle, alternations in glutamine metabolism, and accumulation of dipeptides. Huh7 cultured in the absence of glutamine showed enhanced sensitivity to DFO, and glutaminase inhibitor (CB839) showed a synergistic effect with DFO. Furthermore, the effect of DFO was enhanced by an autophagy inhibitor (chloroquine) in vitro. DFO-induced metabolic changes are specific targets for the development of efficient anticancer combinatorial therapies using DFO. These findings will be useful for the development of new cancer therapeutics in refractory liver cancer.
PubMed: 37887398
DOI: 10.3390/metabo13101073 -
Current Medical Mycology Mar 2023Mucormycosis (previously called zygomycosis) is a diverse group of increasingly recognized and frequently fatal mycotic diseases caused by members of the class... (Review)
Review
Mucormycosis (previously called zygomycosis) is a diverse group of increasingly recognized and frequently fatal mycotic diseases caused by members of the class zygomycetes. Mucormycosis is around 80 times more common in India, compared to other developed countries, with a frequency of 0.14 cases per 1,000 population. The most frequent causative agent of mucormycosis is the following genera from the Order , , , , , , and . The major risk factors for the development of mucormycosis are diabetic ketoacidosis, deferoxamine treatment, cancer, solid organ or bone marrow transplantations, prolonged steroid use, extreme malnutrition, and neutropenia. The common clinical forms of mucormycosis are rhino-orbital-cerebral, pulmonary, cutaneous, and gastrointestinal. During the second wave of COVID-19, there was a rapid increase in mucormycosis with more severity than before. Amphotericin B is currently found to be an effective drug as it is found to have a broad-spectrum activity and posaconazole is used as a salvage therapy. Newer triazole isavuconazole is also found effective against mucormycosis. This study aimed to review various studies on the laboratory diagnosis and treatment of mucormycosis.
PubMed: 37867589
DOI: 10.18502/cmm.2023.345032.1400