Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12928 - 12928

Published: Aug. 18, 2023

Iron is essential for all organisms and cells. Diseases of iron imbalance affect billions patients, including those with overload other forms toxicity. Excess load an adverse prognostic factor diseases can cause serious organ damage fatalities following chronic red blood cell transfusions in patients many conditions, hemoglobinopathies, myelodyspasia, hematopoietic stem transplantation. Similar toxicity excess body but at a slower rate disease progression found idiopathic haemochromatosis patients. deposition different regions the brain suspected has been identified by MRI T2* similar methods neurodegenerative diseases, Alzheimer’s Parkinson’s disease. Based on its role as major biological catalyst free radical reactions Fenton reaction, also implicated associated pathology tissue damage. Furthermore, recent discovery ferroptosis, which death program based generation membrane lipid oxidation, sparked thousands investigations association cardiac, kidney, liver, cancer infections. The implications labile, non-protein bound form complexes dietary molecules such vitamin C drugs doxorubicin xenobiotic relation to carcinogenesis are discussed. In each case toxicity, mechanistic insights, diagnostic criteria, molecular interactions design new effective therapeutic interventions future targeted strategies. particular, this approach successful treatment most loading conditions especially transition thalassemia from fatal due protocols resulting complete elimination

Language: Английский

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The Importance and Essentiality of Natural and Synthetic Chelators in Medicine: Increased Prospects for the Effective Treatment of Iron Overload and Iron Deficiency

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4654 - 4654

Published: April 25, 2024

The supply and control of iron is essential for all cells vital many physiological processes. All functions activities are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin chelator–iron complexes haem play major roles metabolism human physiology. Similarly, the mainstay treatments most common diseases metabolism, namely deficiency anaemia overload, involve iron–chelator iron-chelating drugs deferiprone (L1), deferoxamine (DF) deferasirox. Endogenous citric acid glutathione exogenous ascorbic also important homeostasis. Recent advances treatment effective ferric tri-maltol complex (feraccru or accrufer) transfusional overload using L1 L1/DF combinations have decreased associated mortality morbidity improved quality life millions patients. Many other chelating ciclopirox, dexrazoxane EDTA used daily by patients diseases. their metabolites iron-chelation capacity hydroxyurea, tetracyclines, anthracyclines aspirin, well dietary molecules gallic acid, caffeic quercetin, ellagic maltol phytochelators, known to interact affect related Different interactions observed presence essential, xenobiotic, diagnostic theranostic metal ions competing iron. Clinical trials Parkinson’s, Alzheimer’s neurodegenerative diseases, HIV infections, cancer, diabetic nephropathy inflammation, highlight importance chelation therapy clinical conditions. proposed use modulating ferroptosis signifies a new era design therapeutic strategies introduction artificial intelligence guidance optimal outcomes personalised medicine expected increase further impact medicine, survival metabolic disorders

Language: Английский

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Controlled release of deferiprone using iron-responsive nanoparticles integrated with dissolving microneedle for novel alternative treatments of β-thalassemia major

European Journal of Pharmaceutics and Biopharmaceutics, Journal Year: 2025, Volume and Issue: unknown, P. 114702 - 114702

Published: March 1, 2025

Language: Английский

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Integrated bioinformatics and experiment validation reveal cuproptosis-related biomarkers and therapeutic targets in sepsis-induced myocardial dysfunction

BMC Infectious Diseases, Journal Year: 2025, Volume and Issue: 25(1)

Published: March 31, 2025

Sepsis-induced myocardial dysfunction (SIMD) is a serious sepsis complication with high mortality, yet current diagnostic and therapeutic approaches remain limited. The lack of early, specific biomarkers effective treatments necessitates exploration novel mechanisms. Recently, cuproptosis has been implicated in various diseases, but its role SIMD unclear. This study aimed to identify cuproptosis-related potential agents, supported by animal model validation. Four GEO datasets (GSE79962, GSE267388, GSE229925, GSE229298) were analyzed using Limma WGCNA overlapping genes from differentially expressed (DEGs), DEGs (DE-CRGs), module-associated genes. Gene Set Enrichment Analysis (GSEA) single-sample GSEA (ssGSEA) performed assess biological functions immune cell infiltration, respectively. ceRNA transcription factor networks constructed explore gene regulatory mechanisms, while consensus clustering was employed define subtypes. Diagnostic selected through SVM–RFE, LASSO, random forest models. Additionally, gene-targeting agents predicted drug-gene interaction analysis. findings validated models qPCR immunohistochemical analysis confirm expression. PDHB DLAT emerged as key biomarkers. indicated upregulation oxidative phosphorylation downregulation chemokine signaling. ssGSEA revealed negative correlations several types. A network (51 nodes, 56 edges) constructed. Machine learning identified PDHB, NDUFA9, TIMMDC1 genes, showing accuracy (AUC = 0.995 GSE79962; AUC 0.960, 0.864, 0.984 external datasets). Using the DSigDB database, we six drugs that exhibit significant binding activity PDHB. immunohistochemistry confirmed reduced expression identifies biomarkers, addressing gaps unveiling molecular insights for early intervention targeted treatment. Not applicable.

Language: Английский

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Iron overload: the Achilles heel of β- thalassemia

Transfusion Clinique et Biologique, Journal Year: 2024, Volume and Issue: 31(3), P. 167 - 173

Published: June 6, 2024

Language: Английский

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Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 16749 - 16749

Published: Nov. 25, 2023

The design of clinical protocols and the selection drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal could ideally be designed in all diseases including millions patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well many variations limitations. EID is an adverse prognostic factor especially chronically red-blood-cell-transfused patients. Differences chelation therapy cause disappointing results neurodegenerative at low doses, but lifesaving outcomes thalassemia major (TM) when using higher doses. In particular, transformation TM from a fatal to chronic disease has been achieved effective doses oral deferiprone (L1), which improved compliance cleared toxic heart associated increased mortality TM. Furthermore, L1 L1/deferoxamine combination resulted complete elimination maintenance normal store levels monitored MRI T2* diagnosis different organs. Millions other iron-loaded sickle cell anemia, myelodysplasia haemopoietic stem transplantation, or non-iron-loaded categories organs also benefit such advances. Drawbacks include drug some wide use suboptimal protocols, resulting ineffective therapies. Drug metabolic effects, interactions metals, dietary molecules therapy. identification optimal dose essential positive chelating conditions, general toxicity.

Language: Английский

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Development of Nanocomposite Microspheres for Nasal Administration of Deferiprone in Neurodegenerative Disorders

Journal of Functional Biomaterials, Journal Year: 2024, Volume and Issue: 15(11), P. 329 - 329

Published: Nov. 5, 2024

Elevated brain iron levels are characteristic of many neurodegenerative diseases. As an chelator with short biological half-life, deferiprone leads to agranulocytosis and neutropenia a prolonged therapeutic course. Its inclusion in sustained-release dosage forms may reduce the frequency administration. On other hand, when administered by alternative route administration, such as nasal route, systemic exposure will be reduced, thereby reducing occurrence adverse effects. Direct nose-to-brain delivery has been raised non-invasive strategy deliver drugs brain, bypassing blood-brain barrier. The aim study was develop characterize nanocomposite microspheres suitable for intranasal administration combining nano- microparticle-based approaches. Nanoparticles average particle size 213 ± 56 nm based on biodegradable polymer poly-ε-caprolactone were developed using solvent evaporation method. To ensure deposition particles cavity avoid exhalation or into small airways, nanoparticles incorporated composite structures sodium alginate obtained spray drying. Deferiprone demonstrated sustained release from high iron-chelating activity.

Language: Английский

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Beyond blood transfusions: exploring iron chelation therapies in transfusion-dependent beta-thalassemia

Annals of Medicine and Surgery, Journal Year: 2024, Volume and Issue: 87(1), P. 13 - 17

Published: Dec. 11, 2024

Abnormal hemoglobin, or hemoglobinopathy, affects about 7% of the global population. Major hemoglobinopathies like beta-thalassemia and sickle cell disease require regular blood transfusions, leading to chronic iron overload. This review examines efficacy safety deferiprone, an oral chelator, in managing overload pediatric patients with transfusion-dependent conditions. Data were sourced from PubMed, Google Scholar, relevant articles, focusing on randomized controlled trials (RCTs) published between 2010 2023. The search terms included "deferiprone," "iron chelation," "transfusion," overload," "hemoglobinopathies," "thalassemia." Three RCTs met inclusion criteria, involving 521 patients. START trial demonstrated that early-start deferiprone significantly reduced load compared placebo, no severe adverse events. DEEP-2 study found non-inferior deferasirox safety. Another highlighted benefits early therapy delaying symptoms without serious side effects. Common effects pyrexia, nasopharyngitis, decreased neutrophil count, but significant differences growth parameters, creatinine, prolactin levels observed. Deferiprone shows promise patients, comparable effectiveness existing therapies a favorable profile. Its administration is advantageous for young children. However, long-term studies are needed fully understand its efficacy. Addressing challenges such as patient compliance through education, personalized medicine, advanced monitoring techniques can further improve treatment outcomes

Language: Английский

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New Insights into Aspirin’s Anticancer Activity: The Predominant Role of Its Iron-Chelating Antioxidant Metabolites

Antioxidants, Journal Year: 2024, Volume and Issue: 14(1), P. 29 - 29

Published: Dec. 29, 2024

Epidemiological studies have suggested that following long-term, low-dose daily aspirin (LTLDA) administration for more than 5 years at 75–100 mg/day, 20–30% of patients (50–80 old) had a lower risk developing colorectal cancer (CRC) and about the same proportion in iron deficiency anemia (IDA). In cases IDA, an increase excretion is suspected, which caused by chelating metabolites (ACMs): salicylic acid, salicyluric 2,5-dihydroxybenzoic 2,3-dihydroxybenzoic acid. The ACMs constitute 70% administered dose much longer half-lives blood tissues. mechanisms reduction LTLDA users likely due to ACM’s targeting involved free radical damage, iron-containing toxins, proteins, associated metabolic pathways such as ferroptosis. from non-absorbed (about 30%) may also mitigate toxicity heme nitroso-heme other toxins food, are responsible cause cancer. mode action antioxidant pro-drug ACMs, with continuous presence users, increases prospect prophylaxis diseases. It anticancer effects depend primarily on iron-chelating activity ACMs. role diseases incomplete without considering its rapid biotransformation half-life

Language: Английский

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Recent clinical studies on metals and metal antagonists

Side effects of drugs annual, Journal Year: 2024, Volume and Issue: unknown, P. 259 - 271

Published: Jan. 1, 2024

Language: Английский

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