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Nature Communications Aug 2023Radiation colitis is the leading cause of diarrhea and hematochezia in pelvic radiotherapy patients. This work advances the pathogenesis of radiation colitis from the...
Radiation colitis is the leading cause of diarrhea and hematochezia in pelvic radiotherapy patients. This work advances the pathogenesis of radiation colitis from the perspective of ferroptosis. An oral Pickering emulsion is stabilized with halloysite clay nanotubes to alleviate radiation colitis by inhibiting ferroptosis. Ceria nanozyme grown in situ on nanotubes can scavenge reactive oxygen species, and deferiprone was loaded into the lumen of nanotubes to relieve iron stress. These two strategies effectively inhibit lipid peroxidation and rescue ferroptosis in the intestinal microenvironment. The clay nanotubes play a critical role as either a medicine to alleviate colitis, a nanocarrier that targets the inflamed colon by electrostatic adsorption, or an interfacial stabilizer for emulsions. This ferroptosis-based strategy was effective in vitro and in vivo, providing a prospective candidate for radiotherapy protection via rational regulation of specific oxidative stress.
Topics: Humans; Clay; Ferroptosis; Drug Delivery Systems; Colitis; Gastritis
PubMed: 37607944
DOI: 10.1038/s41467-023-40794-w -
Human & Experimental Toxicology 2023Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a...
Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a wide range of oxidation - reduction activities. Whenever iron exceeds the cellular metabolic needs, its excess causes changes in the products of cellular respiration, such as superoxide, hydrogen peroxide and hydroxyl. The formation of these compounds causes cellular toxicity. Lack of control over reactive oxygen species causes damages to DNA, proteins, and lipids. Conversely, superoxide, hydrogen peroxide and hydroxyl are reactive oxygen species, using antioxidants, restoring DNA function, and controlling iron stores lead to natural conditions. Iron poisoning causes clinical manifestations in the gastrointestinal tract, liver, heart, kidneys, and hematopoietic system. When serum iron is elevated, serum iron concentrations, total iron-binding capacity (TIBC) and ferritin will also increase. Supportive care is provided by whole bowel irrigation (WBI), esophagogastroduodenoscopy is required to evaluate mucosal injury and remove undissolved iron tablets. The use of chelator agents such as deferoxamine mesylate, deferasirox, deferiprone, deferitrin are very effective in removing excess iron. Of course, the combined treatment of these chelators plays an important role in increasing iron excretion, and reducing side effects.
Topics: Humans; Iron; Iron Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Reactive Oxygen Species; Superoxides; Hydrogen Peroxide; Pyridones; Benzoates; Triazoles; DNA
PubMed: 37526177
DOI: 10.1177/09603271231192361 -
Caspian Journal of Internal Medicine 2023Growth retardation is a long-term complication in pediatric transfusion-dependent thalassemias (TDTs), presented as short-stature and upper body segment shortening. The...
BACKGROUND
Growth retardation is a long-term complication in pediatric transfusion-dependent thalassemias (TDTs), presented as short-stature and upper body segment shortening. The cause of this condition was chronic hypoxia, iron overload, endocrinopathy, inadequate transfusion, and iron chelation. We analyze the relationship between ferritin level and growth status of pediatric TDTs.
METHODS
This was a cross-sectional study on pediatric TDTs aged 2-18 years old at Dr. Soetomo General Academic Hospital Surabaya, Indonesia conducted in 2020. They required blood transfusion every 2-4 weeks. We evaluated the ratio of upper/lower body segments, weight for age Z-score (WAZ), height for age Z-score (HAZ), and body mass index (BMI) Z-score, based on CDC growth chart as growth status parameters. Serum ferritin was checked every three months to determine iron overload and iron chelation (deferiprone, deferasirox and deferoxamine). We used Spearman correlation and Mann-Whitney U test to analyze between variables (α=0.05).
RESULTS
We enrolled 15/29 males with median age 10.5 years. Serum Ferritin had negative correlation with the ratio of upper/lower body segments (rho=-0.552; P=0.002), but not for HAZ (rho=-0.078; P=0.694), WAZ (rho=-0.186; P=0.342), BMI Z-score (rho=-0.089; P=0.653) especially if serum ferritin was above 2500 µ/L. In deferiprone group (n=8), the WAZ (P=0.034) and BMI Z-score (P=0.031) were lower; but the ratio of upper/lower body segments was greater (P=0.039) than the deferasirox group.
CONCLUSION
Growth retardation was more visible in pediatric TDTs with high ferritin and in deferiprone group. The height and the ratio of upper/lower body segments of the body were more affected.
PubMed: 37520873
DOI: 10.22088/cjim.14.3.425 -
Pharmaceuticals (Basel, Switzerland) Jul 2023The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more... (Review)
Review
The Vital Role Played by Deferiprone in the Transition of Thalassaemia from a Fatal to a Chronic Disease and Challenges in Its Repurposing for Use in Non-Iron-Loaded Diseases.
The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood-brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs.
PubMed: 37513928
DOI: 10.3390/ph16071016 -
Tuberculosis (Edinburgh, Scotland) Sep 2023Non-Tuberculous Mycobacterial Pulmonary Disease (NTM-PD) caused by Mycobacterium abscessus is a frequent complication in patients with cystic fibrosis (CF) that worsens...
Non-Tuberculous Mycobacterial Pulmonary Disease (NTM-PD) caused by Mycobacterium abscessus is a frequent complication in patients with cystic fibrosis (CF) that worsens lung function over time. Currently, there is no cure for NTM-PD, hence new therapies are urgently required. Disrupting bacterial iron uptake pathways using gallium-protoporphyrin (IX) (GaPP), a heme analog, has been proposed as a novel antibacterial approach to tackle multi-drug resistant M. abscessus. However, the antibacterial activity of GaPP has been tested only in iron-deficient media, which cannot accurately mirror the potential activity in vivo. Herein, we investigated the potential synergistic activity between GaPP and the iron-chelating agent deferiprone (Def) in regular media against M. abscessus-infected macrophages. The safety of the treatment was assessed in vitro using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in Nuli-1 and THP-1 cell lines. Def-GaPP had synergistic activity against M. abscessus-infected macrophages where 10 mM-12.5 mg/L of Def-GaPP reduced the viability by up to 0.9 log. Furthermore, Def-GaPP showed no cytotoxicity to Nuli-1 and THP-1 cell lines at the effective antibacterial concentrations (10 mM-12.5 mg/L) of Def- GaPP. These data encourage future investigation of Def-GaPP as a novel antimicrobial against NTM-PD.
Topics: Deferiprone; Gallium; Protoporphyrins; Humans; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Iron Chelating Agents; THP-1 Cells; Drug Synergism
PubMed: 37506532
DOI: 10.1016/j.tube.2023.102390 -
Autophagy Nov 2023The selective autophagic degradation of mitochondria via mitophagy is essential for preserving mitochondrial homeostasis and, thereby, disease maintenance and...
The selective autophagic degradation of mitochondria via mitophagy is essential for preserving mitochondrial homeostasis and, thereby, disease maintenance and progression in acute myeloid leukemia (AML). Mitophagy is orchestrated by a variety of mitophagy receptors whose interplay is not well understood. Here, we established a pairwise multiplexed CRISPR screen targeting mitophagy receptors to elucidate redundancies and gain a deeper understanding of the functional interactome governing mitophagy in AML. We identified OPTN (optineurin) as sole non-redundant mitophagy receptor and characterized its unique role in AML. Knockdown and overexpression experiments demonstrated that OPTN expression is rate-limiting for AML cell proliferation. In a MN1-driven murine transplantation model, loss of OPTN prolonged overall median survival by 7 days (+21%). Mechanistically, we found broadly impaired mitochondrial respiration and function with increased mitochondrial ROS, that most likely caused the proliferation defect. Our results decipher the intertwined network of mitophagy receptors in AML for both ubiquitin-dependent and receptor-mediated mitophagy, identify OPTN as a non-redundant tool to study mitophagy in the context of leukemia and suggest OPTN inhibition as an attractive therapeutic strategy. AML: acute myeloid leukemia; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; CTRL: control; DFP: deferiprone; GI: genetic interaction; KD: knockdown; KO: knockout; ldMBM, lineage-depleted murine bone marrow; LFC: log2 fold change; LIR: LC3-interacting region; LSC: leukemic stem cell; MAGeCK: Model-based Analysis of Genome-wide CRISPR-Cas9 Knockout; MDIVI-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MOM: mitochondrial outer membrane; NAC: N-acetyl-L-cysteine; OA: oligomycin-antimycin A; OCR: oxygen consumption rate; OE: overexpression; OPTN: optineurin; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SEM: standard error of the mean; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; UBD: ubiquitin-binding domain; WT: wild type.
Topics: Animals; Mice; Autophagy; Leukemia, Myeloid, Acute; Mitophagy; Reactive Oxygen Species; Ubiquitin-Protein Ligases; Ubiquitins; Humans
PubMed: 37439113
DOI: 10.1080/15548627.2023.2230839 -
Heliyon Jun 2023This investigation dealt with the thermodynamic properties, saturated solubility values, and solvation behavior of deferiprone as an oral iron chelator agent in...
This investigation dealt with the thermodynamic properties, saturated solubility values, and solvation behavior of deferiprone as an oral iron chelator agent in non-aqueous mixtures of propylene glycol and 2-propanol using experimental measurements and mathematical correlations. The solubility of deferiprone demonstrated a positive correlation with both temperature and propylene glycol mass fraction. Four mathematical models were employed to correlate the solid-liquid equilibrium data, and the low mean relative deviation values of less than 3.6% illustrate the good agreement of computed data with the experimental data. The apparent thermodynamic behavior of deferiprone dissolution was also investigated according to van't Hoff and Gibbs equation.
PubMed: 37426787
DOI: 10.1016/j.heliyon.2023.e17402 -
International Journal of Molecular... Jun 2023Retinal ischemia-reperfusion (IR)-which ultimately results in retinal ganglion cell (RGC) death-is a common cause of visual impairment and blindness worldwide. IR...
Retinal ischemia-reperfusion (IR)-which ultimately results in retinal ganglion cell (RGC) death-is a common cause of visual impairment and blindness worldwide. IR results in various types of programmed cell death (PCD), which are of particular importance since they can be prevented by inhibiting the activity of their corresponding signaling cascades. To study the PCD pathways in ischemic RGCs, we used a mouse model of retinal IR and a variety of approaches including RNA-seq analysis, knockout animals, and animals treated with an iron chelator. In our RNA-seq analysis, we utilized RGCs isolated from retinas 24 h after IR. In ischemic RGCs, we found increased expression of many genes that regulate apoptosis, necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos. Our data indicate that genetic ablation of death receptors protects RGCs from IR. We showed that the signaling cascades regulating ferrous iron (Fe) metabolism undergo significant changes in ischemic RGCs, leading to retinal damage after IR. This data suggests that the activation of death receptors and increased Fe production in ischemic RGCs promote the simultaneous activation of apoptosis, necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos pathways. Thus, a therapy is needed that concurrently regulates the activity of the multiple PCD pathways to reduce RGC death after IR.
Topics: Mice; Animals; Retinal Ganglion Cells; Reperfusion Injury; Apoptosis; Ischemia; Retinal Diseases; Reperfusion; Receptors, Death Domain
PubMed: 37373037
DOI: 10.3390/ijms24129892 -
Blood Advances Jun 2023
Randomized Controlled Trial
Kwiatkowski JL, Hamdy M, El-Beshlawy A, et al. Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study. Blood Adv. 2022;6(4):1243-1254.
Topics: Humans; Anemia; Deferiprone; Deferoxamine; Iron Chelating Agents; Iron Overload
PubMed: 37368454
DOI: 10.1182/bloodadvances.2023009896 -
Biomedicine & Pharmacotherapy =... Aug 2023Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by massive loss of specific neurons. It is a progressive disabling, severe and fatal... (Review)
Review
Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by massive loss of specific neurons. It is a progressive disabling, severe and fatal complex disease. Due to its complex pathogenesis and limitations of clinical treatment strategies, it poses a serious medical challenge and medical burden worldwide. The pathogenesis of AD is not clear, and its potential biological mechanisms include aggregation of soluble amyloid to form insoluble amyloid plaques, abnormal phosphorylation of tau protein and formation of intracellular neurofibrillary tangles (NFT), neuroinflammation, ferroptosis, oxidative stress and metal ion disorders. Among them, ferroptosis is a newly discovered programmed cell death induced by iron-dependent lipid peroxidation and reactive oxygen species. Recent studies have shown that ferroptosis is closely related to AD, but the mechanism remains unclear. It may be induced by iron metabolism, amino acid metabolism and lipid metabolism affecting the accumulation of iron ions. Some iron chelating agents (deferoxamine, deferiprone), chloroiodohydroxyquine and its derivatives, antioxidants (vitamin E, lipoic acid, selenium), chloroiodohydroxyquine and its derivatives Fer-1, tet, etc. have been shown in animal studies to be effective in AD and exert neuroprotective effects. This review summarizes the mechanism of ferroptosis in AD and the regulation of natural plant products on ferroptosis in AD, in order to provide reference information for future research on the development of ferroptosis inhibitors.
Topics: Animals; Alzheimer Disease; Ferroptosis; Biological Products; Iron; Metals
PubMed: 37210894
DOI: 10.1016/j.biopha.2023.114312