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Cureus Feb 2024This network meta-analysis was conducted with the aim of comparing the efficacy and safety of deferiprone (DFP), deferasirox (DFX), and deferoxamine (DFO) in individuals... (Review)
Review
Compare the Efficacy and Safety of Deferoxamine, Deferasirox, and Deferiprone in Patients With Sickle Cell Disease or Transfusion-Dependent Anemia: A Network Meta-Analysis of Randomized Control Trials.
This network meta-analysis was conducted with the aim of comparing the efficacy and safety of deferiprone (DFP), deferasirox (DFX), and deferoxamine (DFO) in individuals with sickle cell disease (SCD) or transfusion-dependent anemia. This systematic review and meta-analysis adhered to the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" guidelines. The search was conducted on electronic databases, including PubMed, CINAHIL, and EMBASE, from the inception of databases to January 10, 2024. Outcomes assessed in this study included a change in liver iron concentration (LIC) and a change in ferritin from baseline. For safety analysis, adverse events were compared among three treatment groups. A total of five studies were included in this meta-analysis. The pooled analysis showed that the change in LIC and serum ferritin from baseline was not significantly different in patients with SCD or other anemias. In terms of adverse events, deferiprone was the safest among all. In conclusion, deferiprone demonstrated noninferiority to deferoxamine and deferasirox in measures of iron load, presenting a viable treatment option. Safety outcomes revealed deferasirox carried a higher risk of adverse events compared to deferiprone, supporting its favorable safety profile.
PubMed: 38455804
DOI: 10.7759/cureus.53644 -
The Science of the Total Environment Dec 2023Microplastics and nanoplastics have become ubiquitous environmental pollutants. The threat these plastics pose to human health has fueled research focused on their...
Microplastics and nanoplastics have become ubiquitous environmental pollutants. The threat these plastics pose to human health has fueled research focused on their pathophysiology and toxicology, yet many of their fundamental properties - for example, their in vivo pharmacokinetics - remain poorly understood. In this investigation, we have harnessed positron emission tomography (PET) to track the in vivo fate of micro- and nanoplastics administered to mice intratracheally and intravenously. To this end, 1 μm and 20 nm diameter amine-functionalized polystyrene particles were modified with an isothiocyanate-bearing variant of desferrioxamine (DFO) and radiolabeled with the positron-emitting radiometal [Zr]Zr. Both radioplastics - [Zr]Zr-DFO-PS1000 and [Zr]Zr-DFO-PS20 - were produced in ∼95% radiochemical yield and found to be >85% stable to demetallation over one week at 37 °C in human serum and simulated lung fluid. The incubation of [Zr]Zr-DFO-PS1000 and [Zr]Zr-DFO-PS20 with MH-S cells revealed that the majority of the former were phagocytosed by alveolar macrophages within 4 h, while the latter largely evaded consumption. Finally, the in vivo behavior of the radioplastics was interrogated in mice upon intravenous and intratracheal administration. PET imaging and biodistribution experiments revealed that the intravenously injected plastics accumulated primarily in the liver and spleen, yielding hepatic radioactivity concentrations of 101 ± 48 %ID/g and 92 ± 22 %ID/g at 168 h post-injection for [Zr]Zr-DFO-PS1000 and [Zr]Zr-DFO-PS20 respectively. In contrast, the mice that received the radioplastics via intratracheal installation displayed the highest uptake in the lungs at the end of one week: 4 ± 2 %ID/g for [Zr]Zr-DFO-PS1000 and 32 ± 6 %ID/g for [Zr]Zr-DFO-PS20. Ultimately, this work illustrates the critical role that the route of exposure plays in the bioaccumulation of plastic particles, reveals that size dramatically influences the pulmonary retention of inhaled particles, and underscores the value of PET imaging as a tool for studying the pharmacokinetics of environmental pollutants.
Topics: Humans; Animals; Mice; Radioisotopes; Microplastics; Tissue Distribution; Plastics; Deferoxamine; Positron-Emission Tomography; Zirconium; Environmental Pollutants; Cell Line, Tumor
PubMed: 37586535
DOI: 10.1016/j.scitotenv.2023.166320 -
Anticancer Research Mar 2024Ferroptosis refers to an iron-dependent mechanism of regulated cell death that is attributable to lipid peroxidation. Ferroptosis has been documented as a therapeutic...
BACKGROUND/AIM
Ferroptosis refers to an iron-dependent mechanism of regulated cell death that is attributable to lipid peroxidation. Ferroptosis has been documented as a therapeutic target for various solid cancers; nonetheless, its implication in leukemia remains ambiguous. Therefore, this study aimed at investigating the impact of ferroptosis inducers and inhibitors on in vitro leukemia cell line proliferation.
MATERIALS AND METHODS
Six leukemia cell lines, including acute myeloid leukemia (AML)-derived MV4-11, THP-1, HL-60, and U-937, and T-lymphoblastic leukemia (T-ALL)-derived Jurkat and KOPT-K1 with activating NOTCH1 mutations, were assessed. Erastin, which interrupts cystine uptake and depletes intracellular glutathione, and RAS-selective lethal 3 (RSL3), which suppresses glutathione peroxidase 4 (GPX4), were employed as ferroptosis inducers. Lipid peroxidation-arresting ferrostatin-1 and deferoxamine were used as ferroptosis inhibitors. Cells were cultured with these compounds and cell proliferation was assessed using a colorimetric assay. Additionally, signaling protein expression was monitored using immunoblotting, and the outcome of GPX4 knockdown was evaluated.
RESULTS
Ferroptosis inducers suppressed proliferation in all cell lines except THP-1 for Erastin and THP-1 and Jurkat for RSL3. Although the ferroptosis inhibitors did not affect cell proliferation, they rescued inducer-mediated growth suppression. Ferroptosis inducers impeded MYC and cyclin D3 expression in certain cell lines and NOTCH1 signaling in T-ALL cells. GPX4 knockdown and RSL3 treatment interrupted MYC and cyclin D3 expression, respectively, in four cell lines.
CONCLUSION
Ferroptosis inducers may serve as potential candidates for novel molecular therapy against AML and T-ALL.
Topics: Humans; Cell Death; Ferroptosis; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Cyclin D3; Leukemia, Myeloid, Acute; Cell Proliferation
PubMed: 38423654
DOI: 10.21873/anticanres.16895 -
Free Radical Biology & Medicine Nov 2023Mechanical ventilation is an essential respiratory support in acute respiratory distress syndrome and intensive care cases. However, it is possible to cause...
Mechanical ventilation is an essential respiratory support in acute respiratory distress syndrome and intensive care cases. However, it is possible to cause ventilator-induced lung damage (VILI). In this work, we used a microfluidic device to provide a mechanical ventilation with cyclic stretch (30% total area change rate and 15 cycles per min) and oxygen (air) flux applied by a controlled pressured airflow. Compared to static control, the ventilation stretch resulted in significant death of A549 cells accompanied by increased lipid peroxidation, mitochondrial reactive oxygen species (ROS) production, and ferrous ion accumulation, while by decreased protein expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) proteins, as well as ratio of reduced-to-oxidized glutathione. The resulted A549 cell death could be alleviated by two ferroptosis inhibitors, deferoxamine and ferrostatin-1. These similar phenomena also occurred in other three types of human lung cells, such as primary alveolar type II epithelial cells, primary alveolar microvascular endothelial cells, and bronchial epithelial cell line. From the A549 RNA sequence analysis, the gene ontology (GO) based on 85 ferroptosis-related genes (FRGs) indicated that several iron homeostasis-related biological processes and molecular functions were involved in the ventilation-stretch-induced cell death, while the gene set enrichment analysis (GSEA) based on 2901 differentially expressed genes (DEGs) showed that glutathione metabolism was significantly suppressed. Finally, solute carrier family 39 member 14 (SLC39A14), a transporter of uptake extracellular divalent metal ion, was selected to be knocked down to verify its role in the ventilation-stretch-induced death of A549. Our results suggest that ferroptosis may be an alternative pathway for VILI, but it needs to be confirmed by further animal experiments and clinical data.
Topics: Animals; Humans; Ferroptosis; Endothelial Cells; Lung; Phospholipid Hydroperoxide Glutathione Peroxidase; Alveolar Epithelial Cells; Reactive Oxygen Species; Glutathione
PubMed: 37827457
DOI: 10.1016/j.freeradbiomed.2023.10.381 -
AMB Express Sep 2023The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is still difficult to be controlled. The spread of this virus and the emergence of new variants... (Review)
Review
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is still difficult to be controlled. The spread of this virus and the emergence of new variants are considered a great challenge worldwide. Disturbance in infection control guidelines implementation, use of steroids, antibiotics, hospital crowdedness, and repeated use of oxygen masks during the management of critically ill COVID-19 patients lead to an increase in the rate of opportunistic infections. So, patients need to fight both the virus with its different variants and opportunistic pathogens including bacteria and fungi especially patients with diabetes mellitus, malignancy, or those who undergo hemodialysis and receive deferoxamine. During the pandemic, many cases of Mucormycosis associated with COVID-19 infection were observed in many countries. In this review, we discuss risk factors that increase the chance of infection by opportunistic pathogens, especially fungal pathogens, recent challenges, and control measures.
PubMed: 37736777
DOI: 10.1186/s13568-023-01599-8 -
Ecotoxicology and Environmental Safety Nov 2023As the mechanism of paraquat (PQ) poisoning is still not fully elucidated, and no specific treatment has been developed in medical practice, the management of PQ...
As the mechanism of paraquat (PQ) poisoning is still not fully elucidated, and no specific treatment has been developed in medical practice, the management of PQ poisoning continues to present a medical challenge. In this study, the objective was to investigate the early metabolic changes in serum metabolism and identify the key metabolic pathways involved in patients with PQ poisoning. Quantitative analysis was conducted to determine the relevant metabolites. Additionally, experiments were carried out in both plasma and cell to elucidate the mechanisms underlying metabolic disorder and cell death in PQ poisoning. The study found that polyunsaturated fatty acids (PUFAs) and their metabolites, such as arachidonic acid (AA) and hydroxy eicosatetraenoic acids (HETEs), were significantly increased by non-enzymatic oxidative reaction. Reactive oxygen species (ROS) production increased rapidly at 2 h after PQ poisoning, followed by an increase in PUFAs at 12 h, and intracellular glutathione, cysteine (Cys), and Fe at 24 h. However, at 36 h later, intracellular glutathione and Cys decreased, HETEs increased, and the expression of SLC7A11 and glutathione peroxidase 4 (GPX4) decreased. Ultrastructural examination revealed the absence of mitochondrial cristae. Deferoxamine was found to alleviate lipid oxidation, and increase the viability of PQ toxic cells in the low dose. In conclusion, unsaturated fatty acids metabolism was the key metabolic pathways in PQ poisoning. PQ caused cell death through the induction of ferroptosis. Inhibition of ferroptosis could be a novel strategy for the treatment of PQ poisoning.
Topics: Humans; Paraquat; Lipid Metabolism; Ferroptosis; Reactive Oxygen Species; Glutathione
PubMed: 37827095
DOI: 10.1016/j.ecoenv.2023.115543 -
Molecular Neurobiology Dec 2023Previous studies have indicated that iron disorder, inflammation, and autophagy play an important role in traumatic brain injury (TBI). The triggering receptor expressed...
Previous studies have indicated that iron disorder, inflammation, and autophagy play an important role in traumatic brain injury (TBI). The triggering receptor expressed on myeloid cells 2 (TREM2), an immunoglobulin superfamily transmembrane receptor, is involved in inflammation. However, the role of TREM2 in modulating the microglia response in TBI has been rarely investigated. The present study aimed to investigate if the iron chelator deferoxamine (DFO) could ameliorate TBI through autophagy mediated by the TREM2. TBI was developed by the controlled cortical impact (CCI) mouse model and stretching of individual primary cortical microglia taken from the tissue of the rat brain. DFO was intraperitoneally used for intervention. Western blotting assay, qRT-PCR, TUNEL staining, immunofluorescence staining, confocal microscopy analysis, transmission electron microscopy, H&E staining, brain water content measurement, and the neurobehavioral assessments were performed. TREM2 expression was up-regulated in cortex of TBI mice model and in microglia stretching model, which was attenuated by DFO. After the mice were subjected to CCI, DFO treatment significantly up-regulated the protein levels of autophagy compared with the TBI group at 3 days and caused an increase of autophagic vacuoles. Treatment with DFO reduced TBI-induced cell apoptosis, cerebral edema, neuroinflammation, and motor function impairment in mice, at least partly via the mTOR signaling pathway that facilitates the TREM2 activity. The results indicated that the maintenance of iron homeostasis by DFO plays neuroprotection by modulating the inflammatory response to TBI through TREM2-mediated autophagy. This study suggested that TREM2-mediated autophagy might be a potential target for therapeutic intervention in TBI.
PubMed: 38110648
DOI: 10.1007/s12035-023-03875-x -
Digestive Diseases and Sciences Nov 2023Ischemia-reperfusion injury (IRI) is an important cause of graft dysfunction post-liver transplantation, where donor liver with severe steatosis is more sensitive to...
BACKGROUND
Ischemia-reperfusion injury (IRI) is an important cause of graft dysfunction post-liver transplantation, where donor liver with severe steatosis is more sensitive to IRI. Liver IRI involves ferroptosis and can be alleviated by heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs).
AIMS
To explore the role and mechanism of HO-1/BMMSCs in severe steatotic liver IRI.
METHODS
A severe steatotic liver IRI rat model and a hypoxia/reoxygenation (H/R) of severe steatosis hepatocyte model were established. Liver and hepatocyte damage was evaluated via liver histopathology and cell activity. Ferroptosis was evaluated through ferroptosis indexes. Nuclear factor erythroid 2-related factor 2 (Nrf2) was knocked down in severe steatotic hepatocytes. The role of Nrf2 and AMPK in HO-1/BMMSC inhibition of ferroptosis was examined using the AMP-activated protein kinase (AMPK) pathway inhibitor Compound C.
RESULTS
The HO-1/BMMSCs alleviated severe steatotic liver IRI and ferroptosis. HO-1/BMMSCs promoted ferritin heavy chain 1(FTH1), Nrf2, and phosphorylated (p)-AMPK expression in the H/R severe steatotic hepatocytes. Nrf2 knockdown decreased FTH1 expression levels but did not significantly affect p-AMPK expression levels. The protective effect of HO-1/BMMSCs against H/R injury in severe steatotic hepatocytes and the inhibitory effect on ferroptosis were reduced. Compound C decreased p-AMPK, Nrf2, and FTH1 expression levels, weakened the HO-1/BMMSC protective effect against severe steatotic liver IRI and H/R-injured severe steatotic hepatocytes, and reduced the inhibition of ferroptosis.
CONCLUSIONS
Ferroptosis was involved in HO-1/BMMSC reduction of severe steatotic liver IRI. HO-1/BMMSCs protected against severe steatotic liver IRI by inhibiting ferroptosis through the AMPK-Nrf2-FTH1 pathway. HO-1/BMMSCs activate AMPK, which activates Nrf2, promotes its nuclear transcription, then promotes the expression of its downstream protein FTH1, thereby inhibiting ferroptosis and attenuating severe steatotic liver IRI in rats. Glu: glutamic acid; Cys: cystine; GSH: glutathione; GPX4: glutathione peroxidase 4; HO-1/BMMSCs: HO-1-modified BMMSCs; Fer-1: ferrostatin-1; DFO: deferoxamine; FTH1: ferritin heavy chain1; p-AMPK: phosphorylated AMP-activated protein kinase; Nrf2: nuclear factor erythroid 2-related factor 2; IRI: ischemia-reperfusion injury; MCD: methionine-choline deficiency.
PubMed: 37707747
DOI: 10.1007/s10620-023-08102-0 -
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 -
Naunyn-Schmiedeberg's Archives of... Jul 2024Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer, accounting for the overwhelming majority of malignant liver tumors. Therefore, how to...
Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer, accounting for the overwhelming majority of malignant liver tumors. Therefore, how to effectively prevent and cure HCC has become a research hotspot. Many studies have shown that arenobufagin can induce apoptosis, ferroptosis, and autophagy of tumor cells. An increasing number of studies have shown that autophagy is closely linked to ferroptosis. In this study, HepG2 cells and BALB/c nude mice were used as research objects to explore the effect and preliminary mechanism of hepatoma cell autophagy and ferroptosis induced by arenobufagin. We found that arenobufagin can significantly inhibit tumor growth in vivo, and interestingly, we found that arenobufagin inhibited ferroptosis-related proteins Nrf2 and COX-2 in a dose-dependent manner and decreased the levels of reduced glutathione (GSH) and superoxide dismutase (T-SOD) in tissues, while increased the level of reduced malondialdehyde (MDA). In addition, we found that arenobufagin increased the levels of COX-2 and MDA in cells, decreased the levels of Nrf2, GSH, and T-SOD, increased the levels of tissue reactive oxygen species (ROS) and lipid ROS in a dose-dependent manner, and promoted ferroptosis in HepG2 cells. HepG2 cells were preprotected by autophagy inhibitor chloroquine (CQ) and ferroptosis inhibitor deferoxamine (DFO), and then treated with arenobufagin. It was found that CQ partially reversed the changes of COX-2 and Nrf2 expression and lipid peroxidation induced by arenobufagin-induced autophagy and HepG2 cells. Interestingly, CQ partially reversed the inhibition of arenobufagin on cytoplasmic junction protein (Keap1) and heme oxygenase-1 (HO-1) in p62-Keap1-Nrf2 pathway. At the same time, we found that the effect of arenobufagin on oxidative stress of HepG2 cells overexpressed by Nrf2 was significantly less than that of the control group. To sum up, arenobufagin promotes autophagy-dependent ferroptosis of HepG2 cells by inducing autophagy and regulating p62-Keap1-Nrf2 pathway. It is suggested that arenobufagin can be used as a potential intervention therapy.
Topics: Humans; Hep G2 Cells; Autophagy; NF-E2-Related Factor 2; Bufanolides; Animals; Ferroptosis; Mice, Inbred BALB C; Kelch-Like ECH-Associated Protein 1; Mice, Nude; Liver Neoplasms; Signal Transduction; Carcinoma, Hepatocellular; Mice; Sequestosome-1 Protein; Male; Xenograft Model Antitumor Assays; RNA-Binding Proteins
PubMed: 38165425
DOI: 10.1007/s00210-023-02916-5