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Human & Experimental Toxicology 2023Increasing evidence indicates that prolonged exposure to sulforaphane (SFN) can improve malignancies. However, the role of iron in SFN-triggered death in gastric...
OBJECTIVE
Increasing evidence indicates that prolonged exposure to sulforaphane (SFN) can improve malignancies. However, the role of iron in SFN-triggered death in gastric carcinoma cells and the underlying molecular mechanisms remain unclear. Thus, the current study explored the effects of SFN on iron overload-mediated ferroptosis and the PI3K/IRP2/DMT1 pathway in gastric carcinoma cells.
METHODS
We utilized the MGC-803 cell line to assess whether SFN affected iron metabolism and whether this effect contributed to cell death. Pharmacological inhibition of iron metabolism also was performed to determine the molecular mechanism underlying SFN-triggered iron overload and the disturbance in iron metabolism.
RESULTS
Our data revealed that SFN treatment altered iron homeostasis and led to iron overload . Interestingly, SFN-stimulated cell death resulted from ferroptosis, a recently identified iron-dependent form of regulated cell death. Furthermore, an iron chelator, deferiprone, ameliorated the SFN-triggered mitochondrial dysfunction and reduced the iron overload. In addition, we found that the SFN-triggered iron overload was regulated by the PI3K/IRP2/DMT1 signaling pathway.
CONCLUSION
We discovered that disturbance in iron metabolism might be involved in the SFN-triggered cell death in gastric carcinoma cells. Blockade of the PI3K/IRP2/DMT1 axis could provide a feedback effect on SFN-induced ferroptosis to protect tumor cells from growth.
Topics: Humans; Ferroptosis; Phosphatidylinositol 3-Kinases; Iron Overload; Iron; Carcinoma
PubMed: 37201195
DOI: 10.1177/09603271231177295 -
Scientific Reports May 2023Loosely bound iron, due to its contribution to oxidative stress and inflammation, has become an important therapeutic target for many diseases. A water-soluble...
Loosely bound iron, due to its contribution to oxidative stress and inflammation, has become an important therapeutic target for many diseases. A water-soluble chitosan-based polymer exhibiting both antioxidant and chelating properties due to the dual functionalization with DOTAGA and DFO has been developed to extract this iron therefore preventing its catalytic production of reactive oxygen species. This functionalized chitosan was shown to have stronger antioxidant properties compared to conventional chitosan, improved iron chelating properties compared to the clinical therapy, deferiprone, and provided promising results for its application and improved metal extraction within a conventional 4 h hemodialysis session with bovine plasma.
PubMed: 37193699
DOI: 10.1038/s41598-023-34251-3 -
Therapeutic Advances in Rare Disease 2022The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature... (Review)
Review
OBJECTIVES
The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease.
METHODS
Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched.
RESULTS
Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone ( = 11), followed by recombinant erythropoietin ( = 6), omaveloxolone ( = 3), and amantadine hydrochloride ( = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, = 12), the Scale for Assessment and Rating of Ataxia (SARA, = 7), and the Activities of Daily Living scale (ADL, = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation ( = 1), craniocerebral injury ( = 1), and ventricular tachycardia ( = 1).
CONCLUSION
Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.
PubMed: 37180421
DOI: 10.1177/26330040221139872 -
Blood Transfusion = Trasfusione Del... Jan 2024In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on...
Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.
BACKGROUND
In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months.
MATERIALS AND METHODS
We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique.
RESULTS
At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups.
DISCUSSION
In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.
Topics: Humans; Child, Preschool; Iron; Deferasirox; Deferiprone; Deferoxamine; Iron Chelating Agents; Pyridones; beta-Thalassemia; Benzoates; Triazoles; Drug Therapy, Combination; Thalassemia; Iron Overload; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Pancreas
PubMed: 37146300
DOI: 10.2450/BloodTransfus.485 -
PeerJ 2023The spread of artemisinin (ART)-resistant threatens the control of malaria. Mutations in the propeller domains of Kelch13 () are strongly associated with ART...
BACKGROUND
The spread of artemisinin (ART)-resistant threatens the control of malaria. Mutations in the propeller domains of Kelch13 () are strongly associated with ART resistance. Ferredoxin (Fd), a component of the ferredoxin/NADP reductase (Fd/FNR) redox system, is essential for isoprenoid precursor synthesis in the plasmodial apicoplast, which is important for K13-dependent hemoglobin trafficking and ART activation. Therefore, Fd is an antimalarial drug target and mutations may modulate ART sensitivity. We hypothesized that loss of Fd/FNR function enhances the effect of mutation on ART resistance.
METHODS
In this study, methoxyamino chalcone (C3), an antimalarial compound that has been reported to inhibit the interaction of recombinant Fd and FNR proteins, was used as a chemical inhibitor of the Fd/FNR redox system. We investigated the inhibitory effects of dihydroartemisinin (DHA), C3, and iron chelators including deferiprone (DFP), 1-(-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and deferiprone-resveratrol hybrid (DFP-RVT) against wild-type (WT), mutant, mutant, and double mutant parasites. Furthermore, we investigated the pharmacological interaction of C3 with DHA, in which the iron chelators were used as reference ART antagonists.
RESULTS
C3 showed antimalarial potency similar to that of the iron chelators. As expected, combining DHA with C3 or iron chelators exhibited a moderately antagonistic effect. No differences were observed among the mutant parasites with respect to their sensitivity to C3, iron chelators, or the interactions of these compounds with DHA.
DISCUSSION
The data suggest that inhibitors of the Fd/FNR redox system should be avoided as ART partner drugs in ART combination therapy for treating malaria.
Topics: Humans; Antimalarials; Plasmodium falciparum; Ferredoxins; Chalcone; Deferiprone; Malaria, Falciparum; Ferredoxin-NADP Reductase; Iron Chelating Agents
PubMed: 37131988
DOI: 10.7717/peerj.15187 -
Scientific Reports Apr 2023Iron, supplemented as iron-loaded transferrin (holotransferrin), is an essential nutrient in mammalian cell cultures, particularly for erythroid cultures. The high cost...
Iron, supplemented as iron-loaded transferrin (holotransferrin), is an essential nutrient in mammalian cell cultures, particularly for erythroid cultures. The high cost of human transferrin represents a challenge for large scale production of red blood cells (RBCs) and for cell therapies in general. We evaluated the use of deferiprone, a cell membrane-permeable drug for iron chelation therapy, as an iron carrier for erythroid cultures. Iron-loaded deferiprone (Def·Fe, at 52 µmol/L) could eliminate the need for holotransferrin supplementation during in vitro expansion and differentiation of erythroblast cultures to produce large numbers of enucleated RBC. Only the first stage, when hematopoietic stem cells committed to erythroblasts, required holotransferrin supplementation. RBCs cultured in presence of Def·Fe or holotransferrin (1000 µg/mL) were similar with respect to differentiation kinetics, expression of cell-surface markers CD235a and CD49d, hemoglobin content, and oxygen association/dissociation. Replacement of holotransferrin supplementation by Def·Fe was also successful in cultures of myeloid cell lines (MOLM13, NB4, EOL1, K562, HL60, ML2). Thus, iron-loaded deferiprone can partially replace holotransferrin as a supplement in chemically defined cell culture medium. This holds promise for a significant decrease in medium cost and improved economic perspectives of the large scale production of red blood cells for transfusion purposes.
Topics: Animals; Humans; Iron; Deferiprone; Erythrocytes; Iron Chelating Agents; Hemoglobins; Cells, Cultured; Mammals
PubMed: 37117329
DOI: 10.1038/s41598-023-32706-1 -
Chronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook.Cell Stress Feb 2023Myocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate...
Myocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate treatment by re-opening blocked arteries, they often develop chronic heart failure (CHF) in the aftermath of MI events. Yet, the factors that contribute to the development of MI-associated CHF are poorly understood. In our recent study (Nat Commun 13:6394), we link intramyocardial hemorrhage, an injury which can occur during reperfusion of areas affected by MI, to an increased risk of CHF. Mechanistically, our data suggest that an iron-induced adverse cascade of events after hemorrhagic MI drives fatty degeneration of infarcted tissue, which ultimately contributes to negative cardiac remodeling. In this Microreview, we discuss the implications of our findings regarding the molecular mechanism, more targeted treatment options as well as perspectives in the clinical care of CHF after hemorrhagic MI.
PubMed: 37063618
DOI: 10.15698/cst2023.02.276 -
BMC Chemistry Apr 2023This work aims to obtain the solubility, density and thermodynamic parameters of deferiprone in propylene glycol and ethanol. For this purpose, a shake-flask technique...
This work aims to obtain the solubility, density and thermodynamic parameters of deferiprone in propylene glycol and ethanol. For this purpose, a shake-flask technique was applied for solid-liquid equilibration and the spectrophotometry method was employed for solubility measurement. Solubility and density of deferiprone in non-aqueous mixtures of propylene glycol and ethanol were measured in the temperatures 293.2-313.2 K. Some equations including van't Hoff, the Jouyban-Acree, the Jouyban-Acree-van't Hoff, the mixture response surface and modified Wilson equations were used for the mathematical data modeling. The apparent thermodynamic parameters of the deferiprone dissolution process were computed and reported.
PubMed: 37061696
DOI: 10.1186/s13065-023-00950-1 -
BMC Neurology Mar 2023Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare and devastating disease caused by pathogenic mutations in C19orf12 gene. MPAN is...
BACKGROUND
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare and devastating disease caused by pathogenic mutations in C19orf12 gene. MPAN is characterized by pathological iron accumulation in the brain and fewer than 100 cases of MPAN have been described. Although the diagnosis of MPAN has achieved a great breakthrough with the application of the whole exome gene sequencing technology, the therapeutic effect of iron chelation therapy in MPAN remains controversial.
CASE PRESENTATION
We reported that two sisters from the same family diagnosed with MPAN had dramatically different responses to deferiprone (DFP) treatment. The diagnosis of MPAN were established based on typical clinical manifestations, physical examination, brain magnetic resonance imaging (MRI), cerebrospinal fluid analysis (CSF) and gene sequencing results. The clinical presentations of the two sisters with MPAN due to novel gene locus mutations were similar to those previously reported. There is no other difference in basic information except that the proband had a later onset age and fertility history. Both the proband and his second sister were treated with deferiprone (DFP), but they had dramatically different responses to the treatment. The proband's condition deteriorated sharply after treatment with DFP including psychiatric symptoms and movement disorders. However, the second sister of the proband became relatively stable after receiving the DFP treatment. After four years of follow-up, the patient still denies any new symptoms of neurological deficits.
CONCLUSION
The findings of this study enriched the MPAN gene database and indicated that DFP might ameliorate symptom progression in patients without severe autonomic neuropsychiatric impairment at the early stage of the disease.
Topics: Humans; Deferiprone; Mitochondrial Proteins; Neurodegenerative Diseases; Mutation; Membrane Proteins; Iron
PubMed: 37004026
DOI: 10.1186/s12883-023-03172-z