1,721,058 research outputs found
Ipossia e stress ossidativo: l'omeostasi del ferro, strategie protettive e sopravvivenza cellulare.
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Transcriptional and post-transcriptional regulation of ferritin: modulation by oxalomalate.
No full textWith rare exceptions, virtually all studied organisms from Archaea to man are dependent on iron for survival. Despite the ubiquitous distribution and abundance of iron in the biosphere, iron-dependent life must contend with the paradoxical hazards of iron deficiency and iron overload, each with its serious or fatal consequences. Homeostatic mechanisms regulating the absorption, transport, storage, and mobilization of cellular iron are therefore of critical importance in iron metabolism, and a rich biology and chemistry underlie all of these mechanisms. Ferritins are among the most ancient proteins of iron metabolism, found substantially conserved in species from bacteria to plants to man. Ferritin is required for intracellular iron storage; its biosynthesis is regulated both transcriptionally, through iron–dependent and iron-independent factors, and translationally by the action of iron-regulatory proteins (IRP1 and IRP2). These regulations prevent iron excess from promoting the formation of reactive oxygen species (ROS). We have recently demonstrated that oxalomalate (OMA, -hydroxy--oxalosuccinic acid), a competitive inhibitor of aconitase, an enzyme of the citric acid cycle, remarkably decreases the RNA-binding activity of IRP1. The aim of the present study has been to investigate the effect of OMA on the translation of ferritin. In an attempt to verify this hypothesis, we evaluated the levels of ferritin in various cell types cultured with OMA and we found that this compound increases the intracellular ferritin content. In addition, we analyzed whether the OMA effect on the modulation of ferritin expression may result also from a transcriptional regulation. We observed an increase in ferritin mRNA levels and an enhanced transcription of H-ferritin gene induced by OMA. We suppose that OMA could play a role in controlling ferritin expression both at post-transcriptional and at transcriptional level, leading to a major amount of protein. Finally, the OMA-induced ferritin overexpression decreases ROS formation and cellular lipid peroxidation, thus protecting cells from iron-dependent oxidative injury. In conclusion, these data show that an inhibitor of aconitase, OMA, besides being involved in energetic metabolism, is able to control ferritin expression, probably through molecular mechanisms of either post-transcriptional regulation or transcriptional modulation, with advantageous consequences for the cell
Alterations of iron metabolism during hearth ischemia/reperfusion injury. Cytoprotective effects of simvastatin
No full textIschemic heart disease, the main cause of mortality and morbidity in industrialized countries, is a metabolic phenomenon due to an inadequate oxygenation of heart tissue caused by the closing or narrowing of the coronary arteries. However, the ischemic condition and the subsequent tissue reperfusion, lead to several functional and metabolic changes that globally define the so-called “ischemia/reperfusion injury”. This injury leads to metabolic and functional alterations, in particular due to the production of the Oxygen Reactive Species (ROS) that are able to promote cell damage. Because iron is involved in the ROS production by the Haber-Weiss-Fenton reaction, the aim of this study was to elucidate the molecular mechanisms underlying the iron metabolism during the cardiac ischemia/reperfusion. To this aim it has been analyzed the activity and the expression of the main proteins involved in iron homeostasis, such as the Iron Regulatory Proteins, Transferrin Receptor 1 (TfR1), and ferritin in an in vivo model of cardiac ischemia/reperfusion.
The results show that in rats hearts subjected to the ischemic/reperfusion injury, the activity of IRP1 was altered without changing its cellular content. The evaluation of the TfR1 levels showed an evident decrease of the expression of this protein during ischemia followed by a marked increase after the reperfusion phase, while regarding the ferritin expression it was observed a considerable decrease of the cytosolic levels of this protein only after the reperfusion phase.
Moreover, using rat cardyomyoblasts (H9c2 cell line) in an in vitro model of hypoxia and reoxygenation, it was evaluated the cellular levels of the “Labile Iron Pool” (LIP), showing a “free iron” increase after the reoxygenation phase, in accordance with the observed changes of the TfR1 and ferritin expression.
In addition, it was observed an increased ROS production after the hypoxia/reoxygenation damage and, using the iron chelator SIH (Salicylaldehyde Isonicotinoyl Hydrazone), it was showed that a significant part of these ROS depend by the higher levels of the LIP, strongly suggesting that iron is involved in the development of the cardiac damage induced by ischemia/reperfusion conditions.
Other aim of this study has been to evaluate the cytoprotective role of the cholesterol-lowering drug Simvastatin, during the ischemic/reperfusion injury, because of its anti-inflammatory and antioxidant effects (“pleiotropic effects”). Simvastatin, at concentration of 0,01μM, reduced the reactive nitrogen species levels and ROS productions in rat cardyomyoblasts (H9c2 cell line) subjected to hypoxia/reoxygenation conditions and also was able to reduce the cellular levels of the “Labile Iron Pool”, justifying the reduced production of the ROS and the resulting increased cell viability, observed after the drug treatment.
Moreover, Simvastatin increased the ferritin levels, in particular during hypoxia conditions, thus explaining the LIP reduction after treatment with this drug.
In conclusion, these results not only clarify the crucial role that iron plays in the progression of ischemic damage, but also show that proteins regulating the homeostasis of this metal, such as ferritin, may be a target of the Simvastatin, which could be used for the prevention of oxidative damage induced by cardiac ischemic conditions. Should this be the case, a new horizon as an antioxiodant opens for Simvastatin
Oxalomalate, a competitive inhibitor of aconitase, modulates the RNA-binding activity of iron regulatory proteins.
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Determination of pseudouridine and other nucleosides in human blood serum by high-performance liquid chromatography.
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