China
Africa
Explore chapters and articles related to this topic
Nitric Oxide as a Signaling Molecule in the Systemic Inflammatory Response to LPS
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Only recently has it become clear that NO can also regulate gene expression by a similar mechanism. This is illustrated by its effects on iron metabolism in mammalian cells. The iron-regulated biosynthesis of the transferrin receptor and ferritin, two proteins that control iron uptake and storage, is dependent on consensus iron-response elements (IRE) located in the 3′ or 5′ untranslated regions of their mRNAs. Two mammalian iron regulatory proteins, IRP-1 and IRP-2, that exist in all vertebrate tissues bind to the IREs and have been shown to be responsive to oxidative stress (16). For example, H2O2 can induce IRP-1 binding to the IRE of ferritin mRNA, which inhibits its translation efficiency and reduces intracellular ferritin levels (76). Similar high-affinity binding of IRP-1 to the IREs in the 3′ untranslated region of transferrin receptor mRNA reduces nucleolytic degradation of this message (77–79). Together, these two effects of H2O2 increase iron up-take and decrease the ability of the cell to store intra-cellular iron in a bound form, thus increasing the intracellular pool of free iron.
Congenital Causes of Erythrocytosis/Polycythemias and Thrombocytosis
Published in Richard T. Silver, Ayalew Tefferi, Myeloproliferative Disorders, 2007
Josef T. Prchal, Radek C. Skoda
HIF-1a and HIF-2a exhibit high sequence homology but have different mRNA expression patterns; HIF-1a is expressed ubiquitously whereas HIF-2a expression is restricted to certain tissues (6,13). Both HIF-1a and HIF-2a are regulated by an identical mechanism by hypoxia and form a dimer with the same HIF-1f3 subunit. Kidney is the main site of Epo production (i.e., renal interstitial cells) wherein HIF-1 is the principal regulator of EPO transcription (6), while in other tissues, such as brain (14) and liver (15) (that generates 20% of circulating Epo), EPO gene transcription is HIF-2 regulated (13). The recent discovery of an iron-responsive element in the 51 untranslated region of HIF-2a reveals a novel regulatory link between iron availability and HIF-2a expression (16) that may impact control of erythropoiesis. Thus, when iron supply is limited, HIF-2a would decrease, and when iron is abundant, the liver HIF-2a would increase, thus increasing liver-synthesized Epo production and promoting erythropoiesis by connecting to hepcidine function (17).
Metal Ion Dependent Antibiotics in Chemotherapy
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
David H. Petering, Chuanwu Xia, William E. Antholine
A surprising set of papers has implicated the iron-response element binding proteins (IRE-BP 1 and 2) as sites of reaction of the drug in cardiac cells [118–120]. In response to the cellular status of iron, IRE-BP 1 and 2 control the concentrations of ferritin and transferrin receptor proteins at the level of their mRNAs [121]. IRE-BP 1 cycles between two species: one contains a Fe4S4 cluster, exhibits cytosolic aconitase activity, and does not interact with either message [122]. The other, apo-protein structure binds to stem-loop, iron response elements in the 5′-untranslated region of the ferritin mRNA, inhibiting its translation, and to the 3′-untranslated region of the transferrin receptor message, stabilizing it and enhancing its translation. The stem-loops associate with IRE-BP 1 in the same region that forms the iron-sulfur center, thereby, making the structural linkage between the iron-status of the protein and its capacity to modulate translational events related to iron metabolism [122]. Incubation of H9c2 cardiac cells with lower concentrations of Dox resulted in the reversible conversion of the iron-form to the apoprotein [120]. At higher concentrations, apo-IRE-BP 1 and IRE-BP 2 were irreversibly degraded in reactions thought to involve Fe-dependent oxidation of key protein thiol groups. Related in vitro studies indicated that the active species in the degradation of the iron-sulfur cluster was Doxol, a 2-electron reduced species derived from Dox (Fig. 5) [119,120]. Another investigation also documented effects of Dox on IRE-BP 1 in several types of human tumor cell lines as well as primary cultures of rat cardiomyocytes [123].
Re-defining iron deficiency in patients with heart failure
Published in Expert Review of Cardiovascular Therapy, 2022
J. J. Cuthbert, N. Ransome, A. L. Clark
Iron homeostasis is controlled by three mechanisms; 1) hypoxia inducible factor-2 alpha which is secreted by enterocytes in response to low oxygen tension. It increases production of DMT-1 and ferroportin, thus increasing both iron uptake from the gut lumen and iron export into the serum; 2) iron regulatory proteins (IRP) 1 and 2 which bind to the iron responsive elements (IRE) of messenger RNA at low intracellular iron concentrations. They cause a fall in production of intracellular apoferritin, and increased production of DMT-1 and ferroportin in turn leading to reduced intracellular sequestration of iron as ferritin, increased uptake of iron from the gut, and increased export into the serum [30,33]; and 3) low serum iron concentrations detected as low concentrations of iron in transferrin molecules absorbed by TFR-1 on hepatocytes. In response, the liver reduces synthesis of hepcidin, a protein that binds to and causes endocytosis of ferroportin, thus reducing the capacity of a cell to export iron into the serum [34,35]. A fall in hepcidin secretion leads to increased iron release into the serum by enterocytes, hepatocytes, and macrophages (among other cell types) (Figure 3) [32].
Ferritin L-subunit gene mutation and hereditary hyperferritinaemia cataract syndrome (HHCS): a case report and literature review
Published in Hematology, 2021
Yunfan Yang, Ting Lin, Pu Kuang, Xinchuan Chen
It is currently believed that the pathogenesis of HHCS is mainly the mutation in the segment of Iron Response Element (IRE) that located in the 5’ untranslated region (UTR) of the ferritin L-subunit (FTL) gene, which is the critical sequence of the stem-loop motif [2]. This region can affect the binding affinity of Iron Regulatory Proteins (IRP) to IRE and deregulate the expression of the L-Ferritin, resulting in increased synthesis of L-Ferritin. The excessive ferritin subsequently accumulated in serum and crystalline lens, leading to hyperferritinemia and the early onset of bilateral cataracts [3]. Mumford and colleagues found that the level of ferritin in the lens of affected individuals was 10-fold higher than that in the normal group [4]. The severity of cataracts is related to the levels of serum ferritin and the clinical severity of HHCS (i.e. serum ferritin levels and cataract severity) is related to the location of the IRE mutation [2,5].
Of mitochondrion and COVID-19
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Khalid Omer Alfarouk, Sari T. S. Alhoufie, Abdelhameed Hifny, Laurent Schwartz, Ali S. Alqahtani, Samrein B. M. Ahmed, Ali M. Alqahtani, Saad S. Alqahtani, Abdel Khalig Muddathir, Heyam Ali, Adil H. H. Bashir, Muntaser E. Ibrahim, Maria Raffaella Greco, Rosa A. Cardone, Salvador Harguindey, Stephan Joel Reshkin
Iron is an essential nutrient and its levels differ from one tissue to another and also depend on the tissues pathological state48. Cellular iron homeostasis is a complexed process49, but generally, it could be described as: the entrance of iron to the cell through: (i) endocytosis of transferrin receptor 1 (TfR1), or (ii) ferrous iron (Fe+2) transporters e.g. divalent metal transporter 1 (DMT1)50 and Zinc transporters 8, 14 (ZIP8, ZIP14)51,52 with the assistance of the iron reductase enzyme Metalloreductase STEAP253, Duodenal cytochrome B (Dcytb)52, and Stromal cell-derived receptor 2 (SDR-2)54. After being taken-up, the iron is stored in ferritin55–57 for different biochemical functions including the formation of ROS58,59 and managing transcription through regulating the iron-responsive element-binding proteins (IRP1, IRP2)60,61. After that, iron export from the cell occurs via ferroportin-1 (also termed as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1))62.