Metal Ions, Metal Chelators and Metal Chelating Assay as Antioxidant Method

Heavy metals are essential for a wide range of biological processes, including the growth and reproduction of cells, synthesis of biomolecules, many enzymatic reactions, and the body’s immunity, but their excessive intake is harmful. Specifically, they cause oxidative stress (OS) and generate free radicals and reactive oxygen species (ROS) in metabolism. In addition, the accumulation of heavy metals in humans can cause serious damage to different organs, especially respiratory, nervous and reproductive and digestive systems. Biologically, metal chelation therapy is often used to treat metal toxicity. This process occurs through the interaction between the ligand and a central metal atom, forming a complex ring-like structure. After metals are chelated with appropriate chelating agents, their damage in metabolism can be prevented and efficiently removed from the body. On the other hand, heavy metals, including Zn, Fe and Cu, are necessary for the suitable functioning of different proteins including enzymes in metabolism. However, when the same metals accumulate at levels higher than the optimum level, they can easily become toxic and have harmful effects toward biomolecules. In this case, it induces the formation of ROS and nitrogen species (RNS) resulting in peroxidation of biological molecules such as lipids in the plasma membrane. Antioxidants have an increasing interest in many fields due to their protective effects, especially in food and pharmaceutical products. Screening of antioxidant properties of compounds needs appropriate methods including metal chelating assay. In this study, a general approach to the bonding and chelating properties of metals is described. For this purpose, the basic principles and chemical principles of metal chelation methods, both in vivo and in vitro, are outlined and discussed. Hence, in the main sections of this review, the descriptions related to metal ions, metal chelating, antioxidants, importance of metal chelating in biological system and definitions of metal chelating assays as widely used methods to determine antioxidant ability of compounds are provided. In addition, some chemical properties, technical and critical details of the used chelation methods are given.

Updated Prediction of Aggregators and Assay Interfering Substructures in Food Compounds

Positive outcomes in biochemical and biological assays of food compounds may appear due to the well-described capacity of some compounds to form colloidal aggregates that adsorb proteins, resulting in their denaturation and loss of function. This phenomenon can lead to wrongly ascribing mechanisms of biological action for these compounds (false positives), as the effect is non-specific and promiscuous. Similar false positives can show up due to chemical (photo)reactivity, redox cycling, metal chelation, interferences with the assay technology, membrane disruption, etc., which are more frequently observed when the tested molecule has some definite interfering substructures. Although discarding false positives can be achieved experimentally, it would be very useful to have in advance a prognostic value for possible aggregation and/or interference, based only in the chemical structure of the compound tested, in order to be aware of possible issues, help in prioritization of compounds to test, design of appropriate assays, etc. Previously, we applied cheminformatic tools derived from the drug discovery field to identify putative aggregators and interfering substructures in a database of food compounds, the FooDB, comprising 26457 molecules at that time. Here we provide an updated account of that analysis based on a current, much-expanded version of the FooDB, comprising a total of 70855 compounds. In addition, we also apply a novel machine learning model (the SCAM Detective) to predict aggregators with 46%-53% increased accuracies over previous models. In this way, we expect to provide the researchers in the mode of action of food compounds with a much improved, robust, and widened set of putative aggregators and interfering substructures of food compounds.

Iron Chelation by thiocytosine: Investigating electronic and structural features for describing tautomerism and metal chelation processes

This work was performed regarding the importance of iron (Fe) chelation for biological systems. This goal was investigated by assistance of a model of thiocytosine (TC) for participating in Fe-chelation processes. First, formations of tautomeric conformations were investigated to explore existence of possible structures of TC. Next, Fe-chelation processes were examined for all four obtained tautomers of TC. The results indicated that thiol tautomers could be seen at higher stability than thio tautomers, in which one of such thiol tautomers yielded the strongest Fe-chelation process to build FeTC3 model. As a consequence, parallel to the results of original TC tautomers, Fe-chelated models were found to be achievable for meaningful chelation processes or sensing the existence of Fe in media. Examining molecular orbital features could help for sensing purposes. The results of this work were obtained by performing density functional theory (DFT) calculations proposing TC compounds suitable for Fe-chelation purposes.

Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation

Background: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)—the only drug approved for its prevention—has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept. Methods: Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50). Results: Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10–100 µmol/L; P <0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; P <0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative. Conclusions: This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.

Fungal Melanins and Applications in Healthcare, Bioremediation and Industry

Melanin is a complex multifunctional pigment found in all kingdoms of life, including fungi. The complex chemical structure of fungal melanins, yet to be fully elucidated, lends them multiple unique functions ranging from radioprotection and antioxidant activity to heavy metal chelation and organic compound absorption. Given their many biological functions, fungal melanins present many possibilities as natural compounds that could be exploited for human use. This review summarizes the current discourse and attempts to apply fungal melanin to enhance human health, remove pollutants from ecosystems, and streamline industrial processes. While the potential applications of fungal melanins are often discussed in the scientific community, they are successfully executed less often. Some of the challenges in the applications of fungal melanin to technology include the knowledge gap about their detailed structure, difficulties in isolating melanotic fungi, challenges in extracting melanin from isolated species, and the pathogenicity concerns that accompany working with live melanotic fungi. With proper acknowledgment of these challenges, fungal melanin holds great potential for societal benefit in the coming years.

Hepatoprotective Effect of Costus Afer On Trace Metal Mixture Treated Rats Mediated By Regulation of Oxidative Stress Markers, Inflammatory Cytokines And Bio-Metal Chelation

Technological developments have led to exposure to various substances that are harmful to the environment and public health, including heavy metals. In the environment, these grades of metals are usually diverse mixtures shown to cause physiological, biochemical and neurological dysfunctions in humans and laboratory animals. Cadmium, Lead, and mercury have been envisaged to exhibit their hepatotoxic effects by oxidative induction damage and synthesis of reactive oxygen species (ROS). The current work evaluated the protective activity of aqueous leaf extract of Costus afer (ALECA)) on liver damage arsing from exposure to trace metal mixture (TMM): cadmium chloride (CdCl2), lead chloride (PbCl2), and mercury chloride (HgCl2). Five groups of weight matched Sprague Dawley rats were treated for 90 days. Metal mixture and deionized water were used to treat the 2 groups of rats whereas the other 3 groups were treated with various doses of the ALECA through oral gavage alongside the metal mixture. Hepatic function parameters, oxidative biomarkers, inflammatory cytokines, Morphological changes and trace metals (concentrations were monitored in the liver). TMM treatment resulted in significant increase in ALT, AST, ALP, bilirubin, IL-6, MDA, but decreased albumin, total protein, IL-10, SOD, CAT and GSH levels. TMM also caused some morphological changes and increased the heavy metal (Pb, Cd and Hg) concentrations in the liver. The leaf extract gave a reasonable protective effect on the hepatotoxicity caused by trace metal mixture - through the mechanisms of metal chelation, anti-inflammatory, and antioxidant although this depends on the dosage to the rats. ALECA may be beneficial in the management of liver toxicity.