Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various pathologies are characterized by the accumulation of toxic iron in cell compartments. In anemia of chronic disease, iron is withheld by macrophages, leaving extracellular fluids iron-depleted. In Friedreich ataxia, iron levels rise in the mitochondria of excitable cells but decrease in the cytosol. We explored the possibility of using deferiprone, a membrane-permeant iron chelator in clinical use, to capture labile iron accumulated in specific organelles of cardiomyocytes and macrophages and convey it to other locations for physiologic reuse. Deferiprone's capacity for shuttling iron between cellular organelles was assessed with organelle-targeted fluorescent iron sensors in conjunction with time-lapse fluorescence microscopy imaging. Deferiprone facilitated transfer of iron from extracellular media into nuclei and mitochondria, from nuclei to mitochondria, from endosomes to nuclei, and from intracellular compartments to extracellular apotransferrin. Furthermore, it mobilized iron from iron-loaded cells and donated it to preerythroid cells for hemoglobin synthesis, both in the presence and in the absence of transferrin. These unique properties of deferiprone underlie mechanistically its capacity to alleviate iron accumulation in dentate nuclei of Friedreich ataxia patients and to donate tissue-chelated iron to plasma transferrin in thalassemia intermedia patients. Deferiprone's shuttling properties could be exploited clinically for treating diseases involving regional iron accumulation.
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PMID:Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications. 1797 16

Free radical formation is primarily initiated from metal catalytic centers involving iron and copper. Under certain conditions, free radical reactions can lead to free radical cascades and oxidative stress, which can cause biomolecular, cellular and tissue damage (FRD). The use of natural antioxidants to prevent FRD is in most cases not effective. Many chelators have been shown to inhibit free radical reactions and toxicity in experimental models of both in vitro and in vivo. Deferiprone (L1) has been shown to be effective and safe in the reversal of accelerating oxidative stress related tissue damage in iron loading and non iron loading conditions such as cardiomyopathy in thalassaemia, acute kidney disease and Friedreich ataxia. The selection of chelating drugs and their combinations could be used as new strategies for antioxidant therapies. In vitro, in vivo and clinical data suggest that L1 is the most potent drug antioxidant because of its high therapeutic index, ability to reach extracellular and intracellular compartments of many tissues and ability to inhibit both iron and copper catalysed free radical reactions.
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PMID:Prospects for introducing deferiprone as potent pharmaceutical antioxidant. 1948 34

Highly active cardiomyocytes need iron for their metabolic activity. In physiological conditions, iron turnover is a delicate process which is dependent on global iron supply and local autonomous regulatory mechanisms. Though less is known about the autonomous regulatory mechanisms, data suggest that these mechanisms can preserve cellular iron turnover even in the presence of systemic iron disturbance. Therefore, activity of local iron protein machinery and its relationship with global iron metabolism is important to understand cardiac iron metabolism in physiological conditions and in cardiac disease. Our knowledge in this respect has helped in designing therapeutic strategies for different cardiac diseases. This review is a synthesis of our current knowledge concerning the regulation of cardiac iron metabolism. In addition, different models of cardiac iron dysmetabolism will be discussed through the examples of heart failure (cardiomyocyte iron deficiency), myocardial infarction (acute changes in cardiac iron turnover), doxorubicin-induced cardiotoxicity (cardiomyocyte iron overload in mitochondria), thalassaemia (cardiomyocyte cytosolic and mitochondrial iron overload) and Friedreich ataxia (asymmetric cytosolic/mitochondrial cardiac iron dysmetabolism). Finally, future perspectives will be discussed in order to resolve actual gaps in knowledge, which should be helpful in finding new treatment possibilities in different cardiac diseases.
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PMID:Keeping heart homeostasis in check through the balance of iron metabolism. 3116 83