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Bioinspired Magnetic Nanoparticles for Biomedical Applications
Published in Nguyễn T. K. Thanh, Clinical Applications of Magnetic Nanoparticles, 2018
Ferritin is an iron storage protein that exists in nearly all organisms. It plays a significant role in detoxification of Fe(II) and O2 by mineralizing a ferrihydrite core into a protein shell.57Figure 4.3 illustrates the secondary structure of the ferritin subunit is composed of four α helices (ABCD) that form a bundle and a short C-terminal α helix (E), and the three-dimensional structure of the ferritin shell is highly conserved with self-assembly of 24 subunits into 4-3-2 symmetry. The outer and inner diameter of ferritin cavity is about 12 and 8 nm, separately, which can accommodate up to 4500 iron atoms. Mammalian ferritin usually has two kinds of subunits, a heavy (H) chain and light (L) chain. For example, the human ferritin H-chain possesses a ferroxidase center to quickly oxidize Fe(II). The ferroxidase center is composed of two iron sites, site A (Glu27, His65, Glu62 and Gln141) and site B (Glu62, Glu61 and Glu107), with Glu62 bridging the two sites. While the L-chain has no ferroxidase center, it possesses more acidic amino acids than the H-chain does in the nucleation site (Glu107, Glu57, Glu60, Glu61, Glu64 and Glu67), which allows a more efficiently formed iron core.59–61 The H-chain and L-chain can be assembled at any ratio having a cooperative function for the iron uptake mechanism of ferritin. The self-assembled ferritin shell also has eight hydrophilic threefold channels and six hydrophobic fourfold channels. The threefold channel is lined at its narrowest part by Asp131 and Glu134, residues that are conserved in all mammalian ferritins. Mutation of these two residues causes a decreased amount of iron loading and decreased ferroxidase activity and indicates that the threefold channels are responsible for iron entry into the ferritin cavity.62
Ferroxidase-like and antibacterial activity of PtCu alloy nanoparticles
Published in Journal of Environmental Science and Health, Part C, 2019
Xiaowei Zhang, Xiumei Jiang, Timothy R. Croley, Mary D. Boudreau, Weiwei He, Junhui Cai, Peirui Li, Jun-Jie Yin
The catalytic activity of natural enzymes is often affected by certain anions, e.g. metal ions, temperature, pH. For example, the activity of ceruloplasmin (CP), a natural ferroxidase, is inhibited by Zn2+ via binding to the protein.29,44 In this study, the effects of different metal ions, temperature, and pH (pH is adjusted with sodium bicarbonate and 5% hydrochloric acid and determined by precision pH test paper) on the ferroxidase-like activity of PtCu NPs were examined. As shown in Figure 3a, the tested ions, except silver ions, have little influence on the ferroxidase-like activity of PtCu NPs. Silver ions significantly inhibited (65%) the ferroxidase-like activity of PtCu NPs. Therefore, silver ions should be eliminated when using PtCu NPs for the detection of Fe2+ in solutions. The ferroxidase-like activity of PtCu has high activity at pH values between 5 and 7 and peaked at pH 5 (Figure 3b). This value is close to the optimal pH of 6.0 for the natural enzyme, ceruloplasmin (CP),29 As expected from nanomaterial-based enzymatic activities, ferroxidase-like activity of PtCu NPs increased with increasing temperatures (Figure 3c). These results indicate that PtCu NPs have a strong ferroxidase-like activity, and other metal ions, except silver ions, do not interfere with this activity.
Asbestos fibers promote iron oxidation and compete with apoferritin enzymatic activity
Published in Journal of Toxicology and Environmental Health, Part A, 2023
Martina Zangari, Violetta Borelli, Annalisa Bernareggi, Giuliano Zabucchi
At present the mechanisms underlying the fiber ferroxidase activity are not known; however, it appears that the ferric iron is sequestered at least partially into the chrysotile fiber structure. It is conceivable that in the cell the fiber might compete with the enzyme for Fe oxidation and storage. Ghio et al. (1994) reported that chrysotile binds approximately 0.175 nmol of Fe(III)/µg), which is lower with respect to the 0.544 nmoles noted in this study. This discrepancy may be derived from incubation with Fe(II), which might be oxidized and subsequently incorporated into the chrysotile fiber. Our findings suggest that oxidized Fe is hindered from entry into the ferritin shell, which requires metallic chaperon involvement (Toyokuni et al. 2021). It is postulated that during cell-fiber interaction, in competition with apoferritin, Fe (II) may be oxidized and sequestered by the fibers and made unavailable for the cell; at the same time also ferritin is absorbed by the chrysotile fibers. Subsequently, and depending upon the fiber load, cells might experience Fe deficiency. The decrease of Fe availability may stimulate new apoferritin synthesis and more metal uptake, as shown by Ghio et al. (2016) in lung tissue of patients with asbestosis and in cell cultures (Ghio, Pavlisko, and Roggli 2015). A vicious cycle is triggered and maintained until the ferritin and Fe absorbing capacity of the fibers lasts. The first cell type which interacts with inhaled asbestos fibers is the alveolar macrophage (Toyokuni 2019). This cell undergoes Fe overload and increased ferritin synthesis upon asbestos exposure (Ghio, Churg, and Roggli 2004; Ghio, Pavlisko, and Roggli 2015; Ito et al. 2020, 2021) and exhibits an increased expression of molecules involved in Fe uptake. These macrophages are characterized by a high turnover due to the high level of ferroptotic cell death (Ito et al. 2021). Within these cells AB are formed and the secretion of extracellular vesicles containing Fe-loaded ferritin is triggered (Ito et al. 2021) which might induce persistent metal overload in bystander responsive target cells, creating tumor cells promoting conditions. In this complex scenario various events play a key role contemporaneously including ferritin absorption, ferritin ferroxidase activity, new ferritin synthesis, increase of Fe uptake, AB formation, fiber Fe uptake, Fe release from fibers, formation and secretion of extracellular vesicles.
Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes
Published in Journal of Toxicology and Environmental Health, Part A, 2019
F. Celsi, S. Crovella, R. R. Moura, M. Schneider, F. Vita, L. Finotto, G. Zabucchi, P. Zacchi, V. Borelli
Our study confirms the previous results obtained in individuals exposed to asbestos which developed mesothelioma and extends these findings to individuals who developed lung cancer. As indicated above, these results led us to hypothesize the presence of a common mechanism in developing an asbestos-related disease that needs further investigation. The Fe-metabolism pathway might be potentially involved in pleural mesothelioma and lung cancer development, with hephaestin playing a key role; expression of this protein was described as a prognostic marker in renal cancer and glioma, attributed to low expression correlating with increased survival (Uhlen et al. 2017)(The Human protein Atlas: www.proteinatlas.org). A possible scenario is conceivable in which the hypofunctional hephaestin is correlated with protection against cancer development; thus, its ferroxidase activity may be correlated with neoplastic transformation, i.e. via ROS increase, modulated by the other proteins linked to Fe metabolism; this scenario still needs a robust functional confirmation. The availability of well-characterized populations in regard to asbestos exposure that has been objectively quantitated during necroscopic examination, and availability of occupational data, enabled us to precisely select individuals with comparable levels of asbestos exposure. Numerous genetic investigations such as Wei et al. (2012) lack an exact quantitation of asbestos exposure, referring only to self-reported exposure or occupational data. Our study, in spite of the power analysis confirming the distribution in AE population of possible “protective” alleles in Fe-metabolism genes, with respect to both AEM and AELC populations, suffers limitations, due to the analysis of a limited number of genetic variants on a small-size sample instead of NGS approach as in most of the recent published studies. Nevertheless, DNA quality of many samples was too poor, due to significant degradation after aggressive fixation methods, to perform Whole Exome Sequencing or targeted re-sequencing focusing on sets of genes already considered in previous studies, as experienced when trying to perform NGS experiments. Therefore, in our experimental design, it was decided to use the robust Taqman technology, which is capable of working on extremely fragmented DNA thus allowing us to replicate previous findings obtained on another group of mesothelioma patients from the same geographic region (Monfalcone, North-East Italy). Of course, this approach does not permit any comparison with the recent GWAS literature results, thus limiting the strength of our observations that need to be considered cautiously.