- MeSH
- Child MeSH
- Adolescent MeSH
- Transferrin MeSH
- Binding Sites MeSH
- Iron analysis blood metabolism MeSH
- Check Tag
- Child MeSH
- Adolescent MeSH
Flavonoids have been demonstrated to possess miscellaneous health benefits which are, at least partly, associated with iron chelation. In this in vitro study, 26 flavonoids from different subclasses were analyzed for their iron chelating activity and stability of the formed complexes in four patho/physiologically relevant pH conditions (4.5, 5.5, 6.8, and 7.5) and compared with clinically used iron chelator deferoxamine. The study demonstrated that the most effective iron binding site of flavonoids represents 6,7-dihydroxy structure. This site is incorporated in baicalein structure which formed, similarly to deferoxamine, the complexes with iron in the stoichiometry 1:1 and was not inferior in all tested pH to deferoxamine. The 3-hydroxy-4-keto conformation together with 2,3-double bond and the catecholic B ring were associated with a substantial iron chelation although the latter did not play an essential role at more acidic conditions. In agreement, quercetin and myricetin possessing all three structural requirements were similarly active to baicalein or deferoxamine at the neutral conditions, but were clearly less active in lower pH. The 5-hydroxy-4-keto site was less efficient and the complexes of iron in this site were not stable at the acidic conditions. Isolated keto, hydroxyl, methoxyl groups or an ortho methoxy-hydroxy groups were not associated with iron chelation at all.
- MeSH
- Iron Chelating Agents chemistry MeSH
- Deferoxamine chemistry MeSH
- Flavanones chemistry MeSH
- Flavonoids chemistry MeSH
- Flavones chemistry MeSH
- Isoflavones chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Binding Sites MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Heart is a particularly sensitive organ to iron overload and cardiomyopathy due to the excessive cardiac iron deposition causes most deaths in disorders such as beta-thalassemia major. Free or loosely bound iron ions readily cycle between ferrous and ferric states and catalyze Haber-Weiss reaction that yields highly reactive and toxic hydroxyl radicals. Treatment with iron chelators (desferrioxamine, deferiprone, and deferasirox) substantially improved cardiovascular morbidity and mortality in iron overloaded patients. Furthermore, iron chelators have been studied in various cardiovascular disorders with known or presumed oxidative stress roles (e.g., ischemia/reperfusion injury) also in patients with normal body iron contents. The pharmacodynamic and pharmacokinetic properties of these chelators are critical for effective therapy. For example, the widely clinically used but hydrophilic chelator desferrioxamine suffers from poor plasma membrane permeability, which means that high and clinically unachievable concentrations/doses must be employed to obtain cardioprotection. Therefore, small-molecular and lipophilic chelators with oral availability are more suitable for this purpose, particularly in states without systemic iron overload. Apart from agents that are already used in clinical practice, aroylhydrazone iron chelators, namely salicylaldehyde isonicotinoyl hydrazone (SIH), have provided promising results. However, the use of classical iron-chelating agents is associated with a risk of toxicity due to indiscriminate iron depletion. Recent studies have therefore focused on "masked" prochelators that have little or no affinity for iron until site-specific activation by reactive oxygen species.
- MeSH
- Cell Line MeSH
- Iron Chelating Agents pharmacology therapeutic use MeSH
- Cardiotonic Agents pharmacology therapeutic use MeSH
- Humans MeSH
- Prodrugs pharmacology therapeutic use MeSH
- Iron Overload drug therapy MeSH
- Iron chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The iron-containing protein, acireductone dioxygenase 1 (ADI1), is a dioxygenase important for polyamine synthesis and proliferation. Using differential proteomics, the studies herein demonstrated that ADI1 was significantly down-regulated by cellular iron depletion. This is important, since ADI1 contains a non-heme, iron-binding site critical for its activity. Examination of multiple human cell-types demonstrated a significant decrease in ADI1 mRNA and protein after incubation with iron chelators. The decrease in ADI1 after iron depletion was reversible upon incubation of cells with the iron salt, ferric ammonium citrate (FAC). A significant decrease in ADI1 mRNA levels was observed after 14 h of iron depletion. In contrast, the chelator-mediated reduction in ADI1 protein occurred earlier after 10 h of iron depletion, suggesting additional post-transcriptional regulation. The proteasome inhibitor, MG-132, prevented the iron chelator-mediated decrease in ADI1 expression, while the lysosomotropic agent, chloroquine, had no effect. These results suggest an iron-dependent, proteasome-mediated, degradation mechanism. Poly r(C)-binding protein (PCBPs) 1 and 2 act as iron delivery chaperones to other iron-containing dioxygenases and were shown herein for the first time to be regulated by iron levels. Silencing of PCBP1, but not PCBP2, led to loss of ADI1 expression. Confocal microscopy co-localization studies and proximity ligation assays both demonstrated decreased interaction of ADI1 with PCBP1 and PCBP2 under conditions of iron depletion using DFO. These data indicate PCBP1 and PCBP2 interact with ADI1, but only PCBP1 plays a role in ADI1 expression. In fact, PCBP2 appeared to play an accessory role, being involved as a potential co-chaperone.
- MeSH
- Cell Line MeSH
- Dioxygenases genetics metabolism MeSH
- DNA-Binding Proteins genetics metabolism MeSH
- Down-Regulation MeSH
- Proteasome Inhibitors pharmacology MeSH
- Leupeptins MeSH
- Humans MeSH
- Membrane Potential, Mitochondrial MeSH
- Molecular Chaperones drug effects metabolism MeSH
- RNA-Binding Proteins genetics metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Gene Expression Regulation drug effects MeSH
- Binding Sites MeSH
- Iron metabolism MeSH
- Zinc metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs) that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs) of the 5'- or 3'-untranslated regions (UTR) of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP). The earthworm IRE site in 5'-UTR of ferritin mRNA most likely folds into a secondary structure that differs from the conventional IRE structures of ferritin due to the absence of a typically unpaired cytosine that participates in protein binding. Prepared recombinant EaIRP and proteins from mammalian liver extracts are able to bind both mammalian and Eisenia IRE structures of ferritin mRNA, although the affinity of the rEaIRP/Eisenia IRE structure is rather low. This result suggests the possible contribution of a conventional IRE structure. When IRP is supplemented with a Fe-S cluster, it can function as a cytosolic aconitase. Cellular cytosolic and mitochondrial fractions, as well as recombinant EaIRP, exhibit aconitase activity that can be abolished by the action of oxygen radicals. The highest expression of EaIRP was detected in parts of the digestive tract. We can assume that earthworms may possess an IRE/IRP regulatory network as a potential mechanism for maintaining cellular iron homeostasis, although the aconitase function of EaIRP is most likely more relevant.
- MeSH
- Aconitate Hydratase metabolism MeSH
- Ferritins metabolism MeSH
- Phylogeny MeSH
- Homeostasis physiology MeSH
- Nucleic Acid Conformation MeSH
- Real-Time Polymerase Chain Reaction MeSH
- RNA, Messenger genetics MeSH
- Molecular Sequence Data MeSH
- Oligochaeta growth & development metabolism MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Iron-Regulatory Proteins genetics metabolism MeSH
- Regulatory Sequences, Nucleic Acid genetics MeSH
- Amino Acid Sequence MeSH
- Sequence Homology, Amino Acid MeSH
- Protein Binding MeSH
- Iron metabolism MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
This mini-review summarizes the current information that has been published on the various effects of nano-scale zerovalent iron (nZVI) on microbial biota, with an emphasis on reports that highlight the positive aspects of its application or its stimulatory effects on microbiota. By nature, nZVI is a highly reactive substance; thus, the possibility of nZVI being toxic is commonly suspected. Accordingly, the cytotoxicity of nZVI and the toxicity of nZVI-related products have been detected by laboratory tests and documented in the literature. However, there are numerous other published studies on its useful nature, which are usually skipped in reviews that deal only with the phenomenon of toxicity. Therefore, the objective of this article is to review both recent publications reporting the toxic effects of nZVI on microbiota and studies documenting the positive effects of nZVI on various environmental remediation processes. Although cytotoxicity is an issue of general importance and relevance, nZVI can reduce the overall toxicity of a contaminated site, which ultimately results in the creation of better living conditions for the autochthonous microflora. Moreover, nZVI changes the properties of the site in a manner such that it can also be used as a tool in a tailor-made approach to support a specific microbial community for the decontamination of a particular polluted site.
Isoflavones are commonly consumed in many Asian countries and have potentially positive effects on human being. Only a few and rather controversial data on their interactions with copper and iron are available to date. 13 structurally related isoflavones were tested in the competitive manner for their Cu/Fe-chelating/reducing properties. Notwithstanding the 5-hydroxy-4-keto chelation site was associated with ferric, ferrous, and cupric chelation, the chelation potential of isoflavones was low and no cuprous chelation was observed. None of isoflavones was able to substantially reduce ferric ions, but the vast majority reduced cupric ions. The most important feature for cupric reduction was the presence of an unsubstituted 4'-hydroxyl; contrarily the presence of a free 5-hydroxyl decreased or abolished the reduction due to chelation of cupric ions. The results from this study may enable additional experiments which might clarify the effects of isoflavones on human being and/or mechanisms of copper absorption.
- MeSH
- Isoflavones metabolism MeSH
- Humans MeSH
- Copper metabolism MeSH
- In Vitro Techniques MeSH
- Iron metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
