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Brain & NeuroRehabilitation Nov 2023Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder characterized by progressive motor symptoms, such as dystonia and...
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder characterized by progressive motor symptoms, such as dystonia and spasticity. Classical PKAN is the most common subtype of neurodegeneration with brain iron accumulation (NBIA). Currently, there is no established treatment for PKAN. However, baclofen and botulinum toxin have been reported to improve motor symptoms and ease care in these patients. Additionally, Deferiprone is a well-tolerated iron chelator that has been shown to be effective in reducing brain iron accumulation. In this case report, we present the case of a seven-year-old boy who presented to our ward with spastic gait and extrapyramidal signs. Brain magnetic resonance imaging was performed, which showed features of neurodegeneration secondary to brain iron accumulation with a specific appearance of the eye-of-the-tiger sign. Genetic testing was positive for a homozygous mutation in PANK2, and the diagnosis of early-stage classical PKAN was made. This case report highlights the potent efficacy of baclofen, botulinum toxin, and deferiprone in slowing down the disease progression at an early stage and improving the severity of symptoms.
PubMed: 38047104
DOI: 10.12786/bn.2023.16.e25 -
Biomedicines Nov 2023The transition metal characteristics of iron allow it to play a fundamental role in several essential aspects of human life such as the transport of oxygen through... (Review)
Review
The transition metal characteristics of iron allow it to play a fundamental role in several essential aspects of human life such as the transport of oxygen through hemoglobin or the transport of electrons in the mitochondrial respiratory chain coupled to the synthesis of ATP. However, an excess or deficiency of iron is related to certain pathologies. The maintenance of iron homeostasis is essential to avoid certain pathologies related to iron excess or deficiency. The existence of iron deposits in postmortem tissues of Parkinson's patients has been interpreted as evidence that iron plays a fundamental role in the degenerative process of the nigrostriatal system in this disease. The use of iron chelators has been successful in the treatment of diseases such as transfusion-dependent thalassemia and pantothenate kinase-associated neurodegeneration. However, a clinical study with the iron chelator deferiprone in patients with Parkinson's disease has not shown positive effects but rather worsened clinical symptoms. This suggests that iron may not play a role in the degenerative process of Parkinson's disease.
PubMed: 38002094
DOI: 10.3390/biomedicines11113094 -
European Journal of Medicinal Chemistry Jan 2024Recent advances in understanding the role of iron and ROS in cell death suggest new therapeutic avenues to treat organ damage including acute kidney injury (AKI)....
Novel 3-hydroxypyridin-4(1H)-One derivatives as ferroptosis inhibitors with iron-chelating and reactive oxygen species scavenging activities and therapeutic effect in cisplatin-induced cytotoxicity.
Recent advances in understanding the role of iron and ROS in cell death suggest new therapeutic avenues to treat organ damage including acute kidney injury (AKI). Inhibiting ferroptosis was expected to have great potential for the treatment of this disease. Ferroptosis is characterized by iron-dependent lipid peroxidation and currently, a majority of reported ferroptosis inhibitors belong to either radical-trapping antioxidants or iron chelators. However, clinically used iron chelators such as deferoxamine and deferiprone have limited efficacy against ferroptosis (generally with EC > 100 μM), despite their proven safety. Herein, we present the rational design of novel ferroptosis inhibitors by incorporating the naturally occurring cinnamic acid scaffold and the 3-hydroxypyridin-4(1H)-one iron-chelating pharmacophore. Through ABTS˙ radical-scavenging assay, oxygen radical absorbance capacity (ORAC) measurement, Fe affinity evaluation, and anti-erastin-induced HT22 cell ferroptosis assays, we identified compound 9c as the most prospective ferroptosis inhibitor (ABTS˙, IC = 4.35 ± 0.05 μM; ORCA = 23.79 ± 0.56 TE; pFe = 18.59; EC = 14.89 ± 0.08 μM, respectively). Notably, 9c dose-dependently alleviated cell death in cisplatin-induced AKI model. Our results provide insight into the development of new ferroptosis inhibitors through rational incorporation of pharmacophores from existing ferroptosis inhibitors, and compound 9c could be a promising lead compound worth further investigation.
Topics: Humans; Reactive Oxygen Species; Cisplatin; Ferroptosis; Prospective Studies; Iron Chelating Agents; Iron; Acute Kidney Injury; Lipid Peroxidation
PubMed: 37976709
DOI: 10.1016/j.ejmech.2023.115945 -
European Journal of Medicinal Chemistry Jan 2024The important role of accumulated iron is well recognized in the pathophysiology of rhabdomyolysis-induced acute kidney injury (RM-AKI). Our previous work further...
The important role of accumulated iron is well recognized in the pathophysiology of rhabdomyolysis-induced acute kidney injury (RM-AKI). Our previous work further confirmed the labile iron triggered iron-dependent ferroptosis thus leading to the renal failure. In view of this, a series of hydroxypyridinones (HOPOs) with excellent iron chelation capability have been designed and synthesized in this study. A lead compound 6k was identified with good ferroptosis inhibition (EC = 20 μM) and no obvious cytotoxicity (CC > 100 μM), indicating a good therapeutic window (safety index = CC/EC > 5.00). Moreover, intraperitoneal treatment of 6k (10 mg/kg) displayed a superior protective effect than deferiprone (50 mg/kg) in glycerol-induced RM-AKI mice with alleviating kidney dysfunction and pathological injury, decreasing the renal iron level as well as downregulating the mRNA level of ferroptosis associated genes (Acls4 and Ptgs2). Also, 6k exhibited a good in vivo safety profile, even at single high dose up to 1 g/kg without inducing mortality or toxic symptoms. Importantly, 6k could significantly upregulate the protein hypoxia-inducible factor 1α, possibly involving HIF pathway against the ferroptosis. These results collectively highlighted that the strategy of iron chelation and downstream ferroptosis inhibition has a therapeutic potential against RM-AKI.
Topics: Mice; Animals; Acute Kidney Injury; Kidney; Rhabdomyolysis; Iron Chelating Agents; Iron
PubMed: 37976703
DOI: 10.1016/j.ejmech.2023.115933 -
Toxicology Letters Dec 2023
PubMed: 37953205
DOI: 10.1016/j.toxlet.2023.11.003 -
Auris, Nasus, Larynx Apr 2024The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT)...
OBJECTIVE
The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period.
METHODS
We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy.
RESULTS
A total of 42 adult TDT patients (18 male, 24 female; age range: 41-55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing.
CONCLUSION
This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients.
Topics: Adult; Humans; Male; Female; Middle Aged; beta-Thalassemia; Deferasirox; Deferiprone; Deferoxamine; Iron Overload; Follow-Up Studies; Retrospective Studies; Ototoxicity; Benzoates; Triazoles; Pyridones; Iron Chelating Agents; Iron; Hearing
PubMed: 37903661
DOI: 10.1016/j.anl.2023.10.005 -
DNA and Cell Biology Nov 2023Although the contribution of ferroptosis, an iron-dependent cell death, to ischemia reperfusion (IR)-induced retinal injury has been reported before, to optimize...
Although the contribution of ferroptosis, an iron-dependent cell death, to ischemia reperfusion (IR)-induced retinal injury has been reported before, to optimize therapeutic strategy, there is still an urgent need to identify potential candidates involved in this process. Androgen Receptor-Associated Protein of 70 kDa (ARA70) is a cargo receptor for ferritinophagy, and its role in retinal ferroptosis has not been revealed yet. Herein, we explored the role of ARA70 in IR-associated retinal lesions by (C57BL/6 J mice with intraocular pressure of 90-100 mmHg) and (retinal ganglion cells (RGCs) stimulated with tert-butyl hydroperoxide (tBH)) experiments. It was found that IR upregulated ARA70 expression and accelerated lipid peroxidation in retinal tissues. We first confirmed that two ferroptosis inhibitors, deferiprone or ferrostatin-1 (Fer-1), suppressed ferritin degradation, restrained apoptosis and inflammation, and protected mouse retinas against IR stress. Next, primary mouse RGCs were treated with tBH to simulate IR environment . ARA70 expression was decreased at lower concentrations of tBH (5-20 μM), but increased at higher concentrations (40-80 μM). Interestingly, the expression of ferritin-related proteins (ferritin heavy chain, FTH; ferritin light chain, FTL) showed an opposite alteration. Knockdown of ARA70 protected RGCs from tBH-induced damage. It inhibited the delivery of ferritin to lysosomes for ferritinophagy and thus reducing cellular Fe concentration. Besides, ARA70 knockdown suppressed autophagy and inflammation of tBH-treated RGCs. These findings provide novel insights into the pathogenesis of retinal IR, and may be helpful for treatment of retinal diseases.
Topics: Animals; Mice; Autophagy; Ferritins; Ferroptosis; Inflammation; Mice, Inbred C57BL; Nuclear Receptor Coactivators; Reperfusion Injury; Retinal Diseases; Retinal Ganglion Cells
PubMed: 37903234
DOI: 10.1089/dna.2023.0077 -
Scientific Reports Oct 2023NMDA excitotoxicity, as a part of glutamate excitotoxicity, has been proposed to contribute significantly to many retinal diseases. Therefore, understanding mechanisms...
NMDA excitotoxicity, as a part of glutamate excitotoxicity, has been proposed to contribute significantly to many retinal diseases. Therefore, understanding mechanisms of NMDA excitotoxicity will provide further insight into the mechanisms of many retinal diseases. To study mechanisms of NMDA excitotoxicity in vivo, we used an animal model in which NMDA (20 mM, 2 µL) was injected into the vitreous of mice. We also used high-throughput expression profiling, various animals with reduced expression of target genes, and animals treated with the oral iron chelator deferiprone. We found that the expression of many genes involved in inflammation, programmed cell death, free radical production, oxidative stress, and iron and calcium signaling was significantly increased 24 h after NMDA treatment. Meanwhile, decreased activity of the pro-inflammatory TNF signaling cascade and decreased levels of ferrous iron (Fe, required for free radical production) led to significant neuroprotection in NMDA-treated retinas. Since increased TNF signaling activity and high Fe levels trigger regulated necrosis, which, in turn, lead to inflammation, we proposed an important role in NMDA excitotoxicity of a positive feedback loop in which regulated necrosis promotes inflammation, which subsequently triggers regulated necrosis.
Topics: Mice; Animals; N-Methylaspartate; Retina; Retinal Diseases; Necrosis; Iron; Free Radicals; Inflammation
PubMed: 37891222
DOI: 10.1038/s41598-023-45855-0 -
Journal of Nuclear Medicine : Official... Dec 2023Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal...
Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. First, the optimal activity of [Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. The optimal [Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to Lu increased the Auger electron yield but not the absorbed dose. Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.
Topics: Mice; Animals; Humans; Female; Radioisotopes; Gadolinium; Peritoneal Neoplasms; Tissue Distribution; Trastuzumab; Radioimmunotherapy; Ovarian Neoplasms; Nanoparticles; Lutetium; Cell Line, Tumor
PubMed: 37857502
DOI: 10.2967/jnumed.123.265418 -
Medicine Oct 2023This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209...
This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209 patients, independent of the chelation regimen, ferritin, cardiac T2* and liver iron concentration changes were evaluated. We defined chelation success (ChS) as no iron load in the heart and acceptable levels in the liver. Over 3 early magnetic resonance imagings, the same parameters were assessed in 2 subgroups, the only 2 that had sufficient patients continuing on 1 regimen and for a significant period of time, 1 on deferrioxamine (low iron load patients n = 41, Group A) and 1 on deferoxamine-deferiprone (iron overloaded n = 60, Group B). Finally, 28 deaths and causes were compared to those of an earlier period. The 209 patients significantly optimized those indices, while the number of patients with chelation success, increased from 6% to 51% (P < .0001). In group A, ChS after about 8 years increased from 21 to 46% (P = .006), while in Group B, from 0% to 60% (P < .001) after about 7 years. Deaths over the 2 periods showed significant reduction. Combined clearance of cardiac and liver iron (ChS) is feasible and should become the new target for all patients. This requires, serial magnetic resonance imagings and often prolonged intensified chelation for patients.
Topics: Humans; Iron Chelating Agents; beta-Thalassemia; Deferoxamine; Deferiprone; Chelation Therapy; Pyridones; Iron; Liver
PubMed: 37832083
DOI: 10.1097/MD.0000000000035455