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Ferrate (Fe(VI): HFeO 4 - /FeO 4 2- ), a potent oxidant, has been investigated as an alternative chemical disinfectant in water treatment due to its reduced production of disinfection by-products. In this study, we assessed the disinfecting ability of potassium ferrate against a variety of microorganisms, including waterborne pathogens, under varying pH and water temperature conditions. We presented CT values, a metric of ferrate concentrations (C) and contact time (T), to quantify microbial inactivation rates. Among the tested microorganisms, human adenovirus was the least resistant to ferrate, followed by waterborne bacteria such as Escherichia coli and Vibrio cholerae , and finally, the protozoan parasite Giardia duodenalis . We further investigated the impact of two pH values (7 and 8) and two temperatures (5 and 25 °C) on microbial inactivation rates, observing that inactivation rates increased with lower pH and higher temperature. In addition to showcasing ferrate's capacity to effectively inactivate a range of the tested microorganisms, we offer a ferrate CT table to facilitate the comparison of the effectiveness of various disinfection methods., Competing Interests: The authors declare there is no conflict., (© 2024 The Authors This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC BY 4.0), which permits copying, adaptation and redistribution, provided the original work is properly cited (http://creativecommons.org/licenses/by/4.0/).)

In this work a new donor of nitric oxide (NO) with antibacterial properties, namely nitrosyl iron complex of [Fe(C 6 H 5 C-SNH 2 ) 2 (NO) 2 ][Fe(C 6 H 5 C-SNH 2 )(S 2 O 3 )(NO) 2 ] composition (complex I ), has been synthesized and studied. Complex I was produced by the reduction of the aqueous solution of [Fe 2 (S 2 O 3 ) 2 (NO) 2 ] 2- dianion by the thiosulfate, with the further treatment of the mixture by the acidified alcohol solution of thiobenzamide. Based on the structural study of I (X-ray analysis, quantum chemical calculations by NBO and QTAIM methods in the frame of DFT), the data were obtained on the presence of the NO…NO interactions, which stabilize the DNIC dimer in the solid phase. The conformation properties, electronic structure and free energies of complex I hydration were studied using B3LYP functional and the set of 6-31 + G(d,p) basis functions. The effect of an aquatic surrounding was taken into account in the frame of a polarized continuous model (PCM). The NO-donating activity of complex I was studied by the amperometry method using an "amiNO-700" sensor electrode of the "inNO Nitric Oxide Measuring System". The antibacterial activity of I was studied on gram-negative ( Escherichia coli ) and gram-positive ( Micrococcus luteus ) bacteria. Cytotoxicity was studied using Vero cells. Complex I was found to exhibit antibacterial activity comparable to that of antibiotics, and moderate toxicity to Vero cells.

Un-complexed polynuclear ferric oxyhydroxide cannot be administered safely or effectively to patients. When polynuclear iron cores are formed with carbohydrates of various structures, stable complexes with surface carbohydrates driven by multiple interacting sites and forces are formed. These complexes deliver iron in a usable form to the body while avoiding the serious adverse effects of un-complexed forms of iron, such as polynuclear ferric oxyhydroxide. The rate and extent of plasma clearance and tissue biodistribution is variable among the commercially available iron-carbohydrate complexes and is driven principally by the surface characteristics of the complexes which dictate macrophage opsonization. The surface chemistry differences between the iron-carbohydrate complexes results in significant differences in in vivo pharmacokinetic and pharmacodynamic profiles as well as adverse event profiles, demonstrating that the entire iron-carbohydrate complex furnishes the pharmacologic action for these complex products. Currently available physicochemical characterization methods have limitations in biorelevant matrices resulting in challenges in defining critical quality attributes for surface characteristics for this class of complex nanomedicines.

Thanks to development of erlotinib and other target therapy drugs the lung cancer treatment have improved a lot in recent years. However, erlotinib-resistant lung cancer remains an unsolved clinical problem which demands for new therapeutics to be developed. Herein we report the synthesis of a library of 1,4- and 1,5-triazole ferrocenyl derivatives of erlotinib together with their anticancer activity studies against erlotinib-sensitive A549 and H1395 as well as erlotinib-resistant H1650 and H1975 cells. Studies showed that extend of anticancer activity is mainly related to the length of the spacer between the triazole and the ferrocenyl entity. Among the series of investigated compounds two isomers commonly bearing C(O)CH 2 CH 2 spacer have shown superior to erlotinib activity against erlotinib-resistant H1650 and H1975 cells whereas compound with short methylene spacer devoid of any activity. In-depth biological studies for the most active compound showed differences in its mechanism of action in compare to erlotinib. The latter is known EGFR inhibitor whereas their ferrocenyl congener exerts anticancer activity mainly as ROS-inducer which activates mitochondrial pathway of apoptosis in cancer cells. However, docking studies suggested that the most active compound can also binds to the active site of EGFR TK in a similar way as erlotinib., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Carbon monoxide (CO) can cause mitochondrial dysfunction, inducing apoptosis of cancer cells, which sheds light on a potential alternative for cancer treatment. However, the existing CO-based compounds are inherently limited by their chemical nature, such as high biological toxicity and uncontrolled CO release. Therefore, a nanoplatform - UmPF - that addresses such pain points is urgently in demand. In this study, we have proposed a nanoplatform irradiated by near-infrared (NIR) light to release CO. Iron pentacarbonyl (Fe(CO) 5 ) was loaded in the mesoporous polydopamine layer that was coated on rare-earth upconverting nanoparticles (UCNPs). The absorption wavelength of Fe(CO) 5 overlaps with the emission bands of the UCNPs in the UV-visible light range, and therefore the emissions from the UCNPs can be used to incite Fe(CO) 5 to control the release of CO. Besides, the catechol groups, which are abundant in the polydopamine structure, serve as an ideal locating spot to chelate with Fe(CO) 5 ; in the meantime, the mesoporous structure of the polydopamine layer improves the loading efficiency of Fe(CO) 5 and reduces its biological toxicity. The photothermal effect (PTT) of the polydopamine layer is highly controllable by adjusting the external laser intensity, irradiation time and the thickness of the polydopamine layer. The results illustrate that the combination of CO gas therapy (GT) and polydopamine PTT brought by the final nanoplatform can be synergistic in killing cancer cells in vitro . More importantly, the possible toxic side effects can be effectively prevented from affecting the organism, since CO will not be released in this system without near-infrared light radiation.

Magnetic nanoparticles are widely studied for their use in various therapeutic and diagnostic purposes. As biomaterials, their biocompatibility is as important as their magnetic properties. Iron nitride (Fe x N y ) has excellent magnetic properties, and thus Fe x N y nanoparticles could be useful as potential biomaterials. However, the biocompatibility of Fe x N y nanoparticles is yet to be investigated. In this study, we assessed the biocompatibility of Fe x N y nanoparticles by evaluating their direct-contact cytotoxicity compared with that of magnetite nanoparticles (MNPs). Rat fibroblasts were incubated with the nanoparticle samples dispersed in culture medium at concentrations of 10, 50, and 100 μg/ml. The DNA concentration measurement, MTT assay, and trypan blue exclusion test were conducted after days 1 and 3 of incubation. After day 1, the cell viability decreased, and cell death increased with increasing sample concentration when compared with the control. However, after day 3, there were no significant differences when compared with the control, irrespective of the sample concentrations. Further, there were no significant differences between the Fe x N y nanoparticles and MNPs at the same concentrations in all the cytotoxicity evaluation tests. Therefore, it is suggested that Fe x N y nanoparticles might be as cytocompatible as the conventional MNPs., (© 2021 Wiley Periodicals LLC.)

Cisplatin and its derivatives are commonly used in chemotherapeutic treatments of cancer, even though they suffer from many toxic side effects. The problems that emerge from the use of these metal compounds led to the search for new complexes capable to overcome the toxic side effects. Here, we report the evaluation of the antiproliferative activity of Fe(II) cyclopentadienyl complexes bearing n -heterocyclic carbene ligands in tumour cells and their in vivo toxicological profile. The in vitro antiproliferative assays demonstrated that complex Fe1 displays the highest cytotoxic activity both in human colorectal carcinoma cells (HCT116) and ovarian carcinoma cells (A2780) with IC 50 values in the low micromolar range. The antiproliferative effect of Fe1 was even higher than cisplatin. Interestingly, Fe1 showed low in vivo toxicity, and in vivo analyses of Fe1 and Fe2 compounds using colorectal HCT116 zebrafish xenograft showed that both reduce the proliferation of human HCT116 colorectal cancer cells in vivo.

Background: Iron administration has been evaluated in several randomized controlled trials for the potential of increasing baseline hemoglobin values and decreasing the incidence of red blood cell transfusion during cardiac surgery. We describe the protocol for a study aiming to evaluate the efficacy and safety of perioperative iron administration in patients undergoing cardiac surgery., Methods: We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science, from inception to Nov. 19, 2020, for randomized controlled trials in any language evaluating the perioperative administration of iron in adult patients undergoing cardiac surgery; we will also include the first 50 results from Google Scholar. The primary outcome will be the incidence of red blood cell transfusion from the study intervention time until 8 weeks postoperatively. The secondary outcomes will be the number of red blood cell units transfused; change in ferritin level, reticulocyte count and hemoglobin concentration after iron administration; and adverse events. We will assess the risk of bias with the Cochrane Collaboration Risk of Bias Tool, and will analyze the primary and secondary outcomes using a random-effects model., Interpretation: This study will summarize the current evidence about perioperative iron administration in patients undergoing cardiac surgery, help determine whether this intervention should be included in enhanced-recovery protocols, and shape future research if needed. The final manuscript will be submitted to a peer-reviewed journal., Trial Registration: PROSPERO no. CRD42020161927., Competing Interests: Competing interests: None declared., (© 2021 CMA Joule Inc. or its licensors.)

Hepcidin is the only known hormone negatively regulates systemic iron availability, its excess contributes to anemia of chronic disease (ACD).Heparin has been shown to be an efficient hepcidin inhibitor both in vitro and in vivo, but its powerful anticoagulant activity limits this therapeutic application. To this end, heparin-iron complex was prepared by electrostatic interaction and/or coordination between heparin and dihydroxy iron solution ([Fe(OH) 2 ] + ) under the condition of ultrasonic assisted. We assessed the anticoagulant activity of heparin-iron in vitro and vivo by sheep plasma, chromogenic substrate method and tail-bleeding in mice, respectively. Anti-hepcidin effect of heparin-iron was detected in HepG2 cell and LPS induced acute inflammation mice by qRT-PCR and ELISA. Turpentine-induced anemia mice were established to evaluate the effect of heparin-iron in ACD. Mice were treated with heparin-iron for 4 weeks. The results indicated that heparin-iron has significantly reduced anticoagulant activity in vitro and in vivo, strongly decreases hepcidin mRNA and IL-6 induced high level of secreted hepcidin in HepG2 cell. Heparin-iron was also found to cause a reduction on hepcidin expression through BMP/SMAD and JAK/STAT3 pathways in LPS induced acute inflammation model in mice. In ACD mice, heparin-iron could lower elevated serum hepcidin and improve anemia. These findings demonstrated low anticoagulant heparin-iron has potential applications for the treatment of ACD with high hepcidin levels., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This Account describes fundamental chemistry that promoted the discovery of new antibiotics. Specifically, the NH acidity of simple hydroxamic acid derivatives facilitated the syntheses of novel β-lactams (oxamazins and monobactams), siderophore mimics that limit bacterial iron uptake and bacterially targeted sideromycins (siderophore-antibiotic conjugates). The development of resistance to our current limited set of antibiotic scaffolds has created a dire medical situation. As recently stated, "if you weren't taking antibiotic resistance seriously before, now would be a good time to start." A project commissioned by the British government (https://amr-review.org/) has released estimates of the near-future global toll of antibiotic resistance that are jaw-dropping in their seriousness and scale: 10 million deaths per year and at least $100 trillion in sacrificed gross national product. The 2020 COVID pandemic confirmed that infectious disease problems are no longer localized but worldwide. Many classical antibiotics, especially β-lactams, previously provided economical cures, but the evolution of antibiotic destructive enzymes (i.e., β-lactamases), efflux pumps, and bacterial cell wall permeability barriers has made many types of bacteria, especially Gram-negative strains, resistant. Still, and in contrast to other therapies, the public expectation is that any new antibiotic must be inexpensive. This creates market limitations that have caused most major pharmaceutical companies to abandon antibiotic research. Much needs to be done to address this significant problem.The critical need for bacteria to sequester essential iron provides an Achilles' heel for new antibiotic development. Although ferric iron is extremely insoluble, bacteria need micromolar intracellular concentrations for growth and virulence. To this end, they biosynthesize siderophores (Gr. iron bearer) and excrete them into their environment, where they bind iron with high affinity. The iron complexes are recognized by specific outer-membrane transporters, and once actively internalized, the iron is released for essential processes. To conserve biosynthetic energy, some bacteria recognize and utilize siderophores made by competing strains. As a counter-revolution in the never-ending fight for survival, bacteria have also evolved sideromycins, which are siderophores conjugated to warheads that are lethal to rogue bacteria. While none are now used therapeutically, natural sideromycins called albomycins have been used clinically, and others have been shown to be well tolerated and active in animal infection models. Herein we describe practical methods to synthesize new antibiotics and artificial sideromycins with the generalized structure shown above (siderophore-linker drug). Utilizing the molecular-recognition-based siderophore/sideromycin bacterial assimilation processes, it is possible to design both broad spectrum and exquisitely narrow spectrum (targeted) sideromycins and even repurpose older or more classical antibiotics. Relevant microbiological assays, in vivo animal infection studies, and the recent FDA approval of cefiderocol demonstrate their effectiveness.

The fusion and fission behaviors of exosomes are essential for the cell-to-cell communication. Developing exosome-mimetic vesicles with such behaviors is of vital importance, but still remains a big challenge. Presented herein is an artificial supramolecular vesicle that exhibits redox-modulated reversible fusion-fission functions. These vesicles tend to fuse together and form large-sized vesicles upon oxidation, undergo a fission process and then return to small-sized vesicles through reduction. Noteworthy, the aggregation-induced emission (AIE) characteristics of the supramolecular building blocks enable the molecular configuration during vesicular transformation to be monitored by fluorescence technology. Moreover, the presented vesicles are excellent nanocarrier candidates to transfer siRNA into cancer cells., (© 2020 Wiley-VCH GmbH.)

In the paper, the results of the first regular studies of ultra-small iron oxide nanoparticles (IONPs) toxicity in vitro were presented. The influence of PEG-coated NPs with 5 nm magnetite core on six different cell lines was examined. These were: human bronchial fibroblasts, human embryonic kidney cells (HEK293T), two glioblastoma multiforme (GBM) cell lines as well as GBM cells isolated from a brain tumor of patient. Additionally, mouse macrophages were included in the study. The influence of IONPs in three different doses (1, 5 and 25 µg Fe/ml) on the viability, proliferation and migration activity of cells was assessed. Moreover, quantifying the intracellular ROS production, we determined the level of oxidative stress in cells exposed to IONPs. In the paper, for the first time, the effect of Fe in the form of IONPs was compared with the analogical data obtained for iron salts solutions containing the same amount of Fe, on the similar oxidation state. Our results clearly showed that the influence of iron on the living cells strongly depends not only on the used cell line, dose and exposure time but also on the form in which this element was administered to the culture. Notably, nanoparticles can stimulate the proliferation of some cell lines, including glioblastoma multiforme. Compared to Fe salts, they have a stronger negative impact on the viability of the cells tested. Ultra-small NPs, also, more often positively affect cell motility which seem to differ them from the NPs with larger core diameters.

Curcumin displays anticancer properties; however, some issues with the drug delivery mode limit its therapeutic use. Although reformulation and derivatization of curcumin have improved its bioavailability, curcumin derivatives may not retain the same anticancer properties as the parent compound. The present study investigated the anticancer properties of two curcumin complexes, the iron‑curcumin [Fe(Cur)3] and boron‑curcumin [B(Cur)2] complexes, in the MDA‑MB‑231 breast cancer cell line. The cellular localization of curcumin, B(Cur)2 and Fe(Cur)3 was determined by fluorescence microscopy. Cell proliferation, migration and invasion were also analysed. Furthermore, apoptosis‑associated proteins were detected by using a proteome profiler array, and ion channel gene expression was analysed by reverse transcription‑quantitative PCR. The results demonstrated that the three compounds were localized in the perinuclear and cytoplasmic regions of the cell, and displayed cytotoxicity with IC50 values of 25, 35 and 8 µM for curcumin, B(Cur)2 and Fe(Cur)3, respectively. In addition, the three compounds inhibited cell invasion, whereas only curcumin and B(Cur)2 inhibited cell migration. Furthermore, cell exposure to curcumin resulted in an increase in the relative expression of the two key proapoptotic proteins, cytochrome c and cleaved caspase‑3, as well as the antiapoptotic protein haem oxygenase‑1. In addition, curcumin increased the expression levels of the voltage‑gated potassium channels Kv2.1 and Kv3.2. Similarly, the expression levels of the chloride channel bestrophin‑1 and the calcium channel coding gene calcium voltage‑gated channel auxiliary subunit γ4 were increased following exposure to curcumin. Taken together, these results indicated that Fe(Cur)3 and B(Cur)2 may display similar anticancer properties as curcumin, suggesting that chemical complexation may be considered as a strategy for improving the potency of curcumin in the treatment of breast cancer.

Nanoformulations, prodrugs, and targeted therapies are among the most intensively investigated approaches to new cancer therapeutics. Human ferritin has been used extensively as a nanocarrier for the delivery of drugs and imaging agents to cancerous tumor cells both in vitro and in vivo. We report exploitation of the native properties of ferritin, which can be co-loaded with simple forms of iron (FeOOH) and arsenic (arsenate) in place of the native phosphate. The As(III) form arsenic trioxide has been successfully used to treat one blood cancer, but has so far proven too systemically toxic for use on solid tumors in the clinic. The As(V) form, arsenate, on the other hand, while much less systemically toxic upon bolus injection has also proven ineffective for cancer therapy. We extended the C-terminal ends of the human ferritin subunits with a tumor cell receptor targeting peptide and loaded this modified ferritin with ~ 800 arsenates and ~ 1100 irons. Our results demonstrate targeting and uptake of the iron, arsenate-loaded modified human ferritin by breast cancer cells. At the same arsenic levels, the cytotoxicity of the iron, arsenate-loaded human ferritin was equivalent to that of free arsenic trioxide and much greater than that of free arsenate. The iron-only loaded human ferritin was not cytotoxic at the highest achievable doses. The results are consistent with the receptor-targeted human ferritin delivering arsenate as a reductively activated 'prodrug'. This targeted delivery could be readily adapted to treat other types of solid tumor cancers.

A series of diiron/tetrairon compounds containing a S- or a Se-function ( 2a - d , 4a - d , 5a - b , 6 ), and the monoiron [FeCp(CO){SeC 1 (NMe 2 )C 2 HC 3 (Me)}] ( 3 ) were prepared from the diiron μ-vinyliminium precursors [Fe 2 Cp 2 (CO)( μ-CO){ μ-η 1 : η 3 -C 3 (R')C 2 HC 1 N(Me)(R)}]CF 3 SO 3 (R = R' = Me, 1a ; R = 2,6-C 6 H 3 Me 2 = Xyl, R' = Ph, 1b ; R = Xyl, R' = CH 2 OH, 1c ), via treatment with S 8 or gray selenium. The new compounds were characterized by elemental analysis, IR and multinuclear NMR spectroscopy, and structural aspects were further elucidated by DFT calculations. The unprecedented metallacyclic structure of 3 was ascertained by single crystal X-ray diffraction. The air-stable compounds ( 3 , 4a - d , 5a - b , 6 ) display fair to good stability in aqueous media, and thus were assessed for their cytotoxic activity towards A2780, A2780cisR, and HEK-293 cell lines. Cyclic voltammetry, ROS production and NADH oxidation studies were carried out on selected compounds to give insights into their mode of action.

Background: High serum phosphate (Pi) levels strongly associate with cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients with vascular calcification playing a major role in the pathogenesis of related cardiovascular disease. High-Pi challenged vascular smooth muscle cells (VSMCs) undergo simil-osteoblastic transformation and actively deposit calcium-phosphate crystals. Iron-based Pi-binders are used to treat hyperphosphatemia in CKD patients., Methods: In this study, we investigated the direct effect of iron citrate on extracellular matrix (ECM) modification induced by high-Pi, following either prophylactic or therapeutic approach., Results: Iron prophylactically prevents and therapeutically blocks high-Pi induced calcification. Masson's staining highlights the changes of muscular ECM that after high-Pi stimulation becomes fibrotic and which modifications are prevented or partially reverted by iron. Interestingly, iron preserves glycogen granules and either prevents or partially reverts the formation of non-glycogen granules induced by high-Pi. In parallel, iron addition is able to either prevent or block the high-Pi induced acid mucin deposition. Iron inhibited calcification also by preventing exosome osteo-chondrogenic shift by reducing phosphate load (0,61 ± 0.04vs0,45 ± 0.05, PivsPi + Fe, p < 0,05, nmol Pi/mg protein) and inducing miRNA 30c (0.62 ± 0.05vs3.07 ± 0.62; PivsPi + Fe, p < 0.01, relative expression). Studying aortic rings, we found that iron significantly either prevents or reverts the high-Pi induced collagen deposition and the elastin decrease, preserving elastin structure (0.7 ± 0.1 vs 1.2 ± 0.1; Pi vs Pi + Fe, p < 0.05, elastin mRNA relative expression)., Conclusions: Iron directly either prevents or partially reverts the high-Pi induced osteo-chondrocytic shift of ECM. The protection of muscular nature of VSMC ECM may be one of the mechanisms elucidating the anti-calcific effect of iron., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: 8-Hydroxyquinoline derivatives have highly sensitive fluorescent chemosensors for metal ions, which are associated with anti-oxidant, anti-tumor and anti-HIV-1 properties. Head and neck squamous cell carcinoma (HNSCC) is associated with a high rate of mortality and novel anti-HNSCC drugs must be developed. Therefore, effective chemotherapy agents are required to address this public health issue., Hypothesis/purpose: The aim of this study was to investigate the inhibitory effect of tris(8-hydroxyquinoline)iron (Feq 3 ) on the HNSCC and the underlying mechanism., Study Design/methods: A novel 8-hydroxyquinoline derivative, Feq 3 , was synthesized. The cell viabilities were analyzed using MTT reagent. Apoptosis and the cell cycle distributions were determined by flow cytometer. Reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, western blot, MitoSOX and CellROX stain assay were used to study the mechanism of Feq 3 . Feq 3 combined with antioxidants NAC (N-acetylcysteine) and BSO (buthionine sulfoximine) measured the cell viability and intracellular ROS., Results: Feq 3 induced the death of HNSCC cells and caused them to exhibit the morphological features of apoptosis. Feq 3 also induced apoptosis of SCC9 cells by cell cycle arrest during the G 2 /M phase and the induced arrest of SCC25 cells in the G 0 /G 1 and G 2 /M phases, which was associated with decreased cyclin B1/cdc2 and cyclin D/cdk4 expressions. Feq 3 increases reactive oxygen species (ROS) and reduces glutathione (GSH) levels, and responds to increased p53 and p21 expressions. Feq 3 induced apoptosis by mitochondria-mediated Bax and cytochrome c up-expression and down-expression Bcl-2. Feq 3 also up-regulated tBid, which interacts with the mitochondrial pathway and tumor necrosis factor-α (TNF-α)/TNF-Rs, FasL/Fas, and TNF-related apoptosis inducing ligand receptors (TRAIL-Rs)/TRAIL-dependent caspases apoptotic signaling pathway in HNSCC cells. However, Feq 3 activates Fas but not FasL in SCC25 cells. Feq 3 arrests the growth of HNSCC cells and is involved in the mitochondria- and death receptor (DR)-mediated caspases apoptotic pathway., Conclusion: This study is the first to suggest that apoptosis mediates the anti-HNSCC of Feq 3 . Feq 3 has potential as a cancer therapeutic agent against HNSCC., (Copyright © 2019. Published by Elsevier GmbH.)

Microbial exopolysaccharides (EPSs) have recently served as an efficient substrate for the production of biocompatible metal nanoparticles (NPs) given their favorable stabilizing and reducing properties due to the presence of polyanionic functional groups in their structure. In the present work, Pantoea sp. BCCS 001 GH was used to produce EPS-stabilized biogenic Fe NPs as a complex through a novel biosynthesis reaction. Physicochemical characterization of the EPS-Fe complex was performed, indicating high thermal stability, desirable magnetic properties due to the uniform distribution of the Fe NPs with the average size of ∼10 nm and spherical shape within the EPS matrix. In addition, the in vivo toxicity of the EPS-stabilized Fe NPs was evaluated to investigate their potential for the treatment of iron deficiency anemia. Biological blood parameters and organ histology studies confirmed very high safety of the biosynthesized composite, making EPS-Fe a suitable candidate with an economical and environment friendly synthesis method for a wide spectrum of potential fields in medicine.

Chlorido[ N , N '-disalicylidene-1,2-phenylenediamine]iron(III) complexes generate lipid-based ROS and induce ferroptosis in leukemia and neuroblastoma cell lines. The extent of ferroptosis on the mode of action is regulated by simple modifications of the substituents at the 1,2-phenylenediamine moiety. In HL-60 cells, the unsubstituted lead exclusively caused ferroptosis. For instance, a 4-F substituent shifted the mode of action toward both ferroptosis and necroptosis, while the analogously chlorinated derivative exerted only necroptosis. Remarkably, cell-death in NB1 neuroblastoma cells was solely induced by ferroptosis, independent of the used substituents. The effects were higher than that of the therapeutically applied drug cisplatin. These data clearly demonstrate for the first time that not only iron ions but also iron salophene complexes are potent ferroptosis inducers, which can be optimized as antitumor agents.

Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive cancers worldwide, especially in China, with poor prognosis due to the lack of effective therapeutic strategies. Here, the anticancer effect and pharmacological mechanism of a newly synthesized Fe(II) phenanthroline complex was studied in ESCC. Our data showed that transferrin receptor 1 (TFR1) was specifically overexpressed in ESCC tissues compared to its expression in normal esophageal tissues, a finding further supported by public datasets. The newly synthesized Fe(II) complex was selectively transported into ESCC cells overexpressing TFR1 through TFR1-mediated endocytosis and exhibited anticancer activity in a dose-dependent manner. The mechanistic study elucidated that the Fe(II) complex caused cell cycle arrest at the G0/G1 phase by blocking the CDK4/6-cyclin D1 complex and induced mitochondria-mediated apoptosis. Furthermore, exposure to the Fe(II) complex led to excessive reactive oxygen species (ROS) accumulation by thioredoxin reductase (TrxR) inhibition and DNA double-strand breaks (DSBs), which in turn sequentially activated ATM, CHK1/2 and p53. Moreover, combination treatment with cisplatin and the Fe(II) complex exhibited a synergistic effect in ESCC cells. Taken together, our results initially suggest the potential application of the Fe(II) complex in ESCC chemotherapy, especially for patients with TFR1 overexpression., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A multifunctional CO/thermo/chemotherapy nanoplatform is here reported, which is composed of mesoporous carbon nanoparticles (MCN) as near infrared (NIR)-responsive drug carrier, doxorubicin (DOX) as chemotherapeutic drug and triiron dodecacarbonyl (FeCO) as thermosensitive CO prodrug. The nanoplatform could absorb near-infrared (NIR) light and convert it into ample heat to trigger CO release and could also release DOX in the acidic tumor microenvironment. More importantly, the generated CO molecules successfully increase cancer cell sensitivity to chemotherapeutics by the ferroptosis pathway. Subsequently, under the guidance of photoacoustic imaging, the FeCO-DOX@MCN nanoplatform demonstrates high treatment efficacies in vitro and in vivo by combination of chemotherapy, photothermal therapy and gas therapy. This multifunctional platform with excellent antitumor efficacy has great potential in precision cancer therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A melanin-producing strain was identified as Streptomyces sp. ZL-24 by phylogenetic analysis of 16S rRNA gene sequences. Based on single factor experiment, NiCl 2 , FeSO 4 and soy peptone were selected as significant variables of melanin production. Subsequent biochemical and RT-qPCR analyses revealed that melanin production was markedly driven by moderate levels of ferrous and nickel ions. The central composite design indicated that the optimal medium was composed of 3.05 mM NiCl 2 , 1.33 g/L FeSO 4 and 20.31 g/L soy peptone. The maximum production of the insoluble melanin (189.90 mg/L) was obtained using 3% (v/v) inoculation size in the medium of pH 7.0 at 30 °C for 5 days. Under this optimal condition, an indigenous plate culture system was standardized and used to produce soluble melanin. The resulting pure melanin pigment was up to 4.24 g/L, which set a new record of soluble melanin production. Bioactivity assay in vitro showed that both melanin pigments had strong antimicrobial, anti-biofilm and antioxidant activity. To our best knowledge, the results provide novel data on soluble melanin production, and identify an excellent candidate for anti-biofilm application., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We previously identified a novel nanomagnetic particle, N,N'-bis(salicylidene)ethylenediamine iron [Fe(Salen)]. Fe(Salen) not only shows antitumor effects but also magnetic properties. We found that Fe(Salen) can be used for magnet-guided drug delivery and visualization of accumulated drug by magnetic resonance imaging (MRI) because of its magnetism. In addition, Fe(Salen) can generate heat by itself when exposed to an alternating current magnetic field (AMF), resulting in a hyperthermia effect. Herein, we partly elucidated the antitumor mechanism of Fe(Salen) and carried out an i.v. repeated dose toxicity study to decide the therapeutic amount. Furthermore, we evaluated the antitumor effect of selective intra-arterial injection or i.v. injection of Fe(Salen) by catheter and the hyperthermia effect of Fe(Salen) when exposed to AMF in vivo. We used a rabbit model grafted with VX2 cells (rabbit squamous cell carcinoma) on the right leg. Intra-arterial injection of Fe(Salen) showed a greater antitumor effect than did i.v. injection. The combination of Fe(Salen) intra-arterial injection and AMF exposure showed a greater antitumor effect than did either Fe(Salen) or methotrexate (MTX) without AMF exposure, suggesting that AMF exposure greatly enhanced the antitumor effect of Fe(Salen) by arterial injection by catheter. This is the first report that the effectiveness of Fe(Salen) was evaluated in the point of administration route; that is, selective intra-arterial injection by catheter. Taken together, these results indicate a new administration route; that is, selective arterial injection of Fe(Salen) by catheter, and the development of a new strategy of simultaneous hyperthermia-chemotherapy in the future., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The hydroferrate fluid MRN-100, an iron-based compound with potent antioxidant characteristics, was examined to identify its possible anti-inflammatory effects on human dendritic cells (DCs) in vitro. Human monocyte-derived DCs were treated with MRN-100 at two concentrations (50 and 100 μL/mL) for 24 h and then stimulated with or without lipopolysaccharides (LPS). The expression of DC maturation markers was assessed by flow cytometry and the production of cytokines was determined by enzyme-linked immunosorbent assay (ELISA). Functional assay was performed by co-culturing MRN-100-treated and untreated DCs with allogeneic naïve CD4+ T cells and assaying the T cells' cytokine production. Results show that treatment with MRN-100 significantly upregulated the co-stimulatory molecules CD80 and CD86 and increased human leukocyte antigen-DR (HLA-DR) though not significantly. MRN-100 treatment also significantly increased the production of the anti-inflammatory cytokine interleukin (IL)-10. On the other hand, MRN-100 significantly induced the secretion of pro-inflammatory cytokines such as IL-6 only at high concentrations. Furthermore, DCs pretreated with MRN-100 and either stimulated or not with LPS were able to prime CD4+ T cells to secrete significant amounts of IL-10 while inhibiting the secretion of pro-inflammatory cytokine tumor necrosis factor (TNF)-α. These results indicate that MRN-100 is a powerful anti-inflammatory agent that promotes the generation of an anti-inflammatory immune response in vitro. MRN-100 could be beneficial for treating patients with inflammatory diseases, including arthritis and type 1 diabetes, and its potential benefits should be examined in clinical trials.

Therapeutic nanosystems which can be triggered by the distinctive tumor microenvironment possess great selectivity and safety to treat cancers via in situ transformation of nontoxic prodrugs into toxic therapeutic agents. Here, we constructed intelligent, magnetic targeting, and tumor microenvironment-responsive nanocatalysts that can acquire oxidation therapy of cancer via specific reaction at tumor site. The magnetic nanoparticle core of iron carbide-glucose oxidase (Fe 5 C 2 -GOD) achieved by physical absorption has a high enzyme payload, and the manganese dioxide (MnO 2 ) nanoshell as an intelligent "gatekeeper" shields GOD from premature leaking until reaching tumor tissue. Fe 5 C 2 -GOD@MnO 2 nanocatalysts maintained inactive in normal cells upon systemic administration. On the contrary, after endocytosis by tumor cells, tumor acidic microenvironment induced decomposition of MnO 2 nanoshell into Mn 2+ and O 2 , meanwhile releasing GOD. Mn 2+ could serve as a magnetic resonance imaging (MRI) contrast agent for real-time monitoring treatment process. Then the generated O 2 and released GOD in nanocatalysts could effectively exhaust glucose in tumor cells, simultaneously generating plenty of H 2 O 2 which may accelerate the subsequent Fenton reaction catalyzed by the Fe 5 C 2 magnetic core in mildly acidic tumor microenvironments. Finally, we demonstrated the tumor site-specific production of highly toxic hydroxyl radicals for enhanced anticancer therapeutic efficacy while minimizing systemic toxicity in mice.

Peroxynitrite (ONOO - ), the reaction product derived from nitric oxide (NO) and superoxide (O 2 -• ), is a potent oxidizing and nitrating agent that modulates complex biological processes and promotes cell death. Therefore, it can be expected that the overproduction of ONOO - in tumors can be an efficient approach in cancer therapy. Herein, a multifunctional X-ray-controlled ONOO - generation platform based on scintillating nanoparticles (SCNPs) and UV-responsive NO donors Roussin's black salt is reported, and consequently the mechanism of their application in enhanced therapeutic efficacy of radiotherapy is illustrated. Attributed to the radioluminescence and high X-ray-absorbing property of SCNPs, the nanocomposite can produce NO and O 2 -• simultaneously when excited by X-ray irradiation. Such simultaneous release of NO and O 2 -• ensures the efficient X-ray-controlled generation of ONOO - in tumors. Meanwhile, the application of X-rays as the excitation source can achieve better penetration depth and induce radiotherapy in this nanotherapeutic platform. It is found that the X-ray-controlled ONOO - -generation platform can efficiently improve the radiotherapy efficiency via directly damaging DNA, downregulating the expression of the DNA-repair enzyme, and overcoming the hypoxia-associated resistance in radiotherapy. Therefore, this SCNP-based platform may provide a new combinatorial strategy of ONOO - and radiotherapy to improve cancer treatment., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new heterogeneous solar-Fenton catalyst, α-FeOOH-reduced graphene oxide (rGO) supported on active carbon fiber (ACF), was synthesized via in situ electrophoretic deposition in a self-assembly process. Optimization of the components (electrophoretic deposition time of GO and Fe, GO dosages), the effect of pH and the catalysts stability were investigated systematically. The results indicated that rGO-α-FeOOH composite is formed during the ferrous-ion-induced self-assembly process on ACF. FeOOH-rGO/ACF displayed excellent catalytic activity for degrading phenol and quinoline under the solar-driven photo-Fenton process in a wide range of pH values (4.5-9.5) and possess good stability in neutral condition. The phenol oxidation process on this catalyst was described by a pseudo-first-order kinetics model. Both the ACF support and solar irradiation promoted greater H 2 O 2 decomposition and produced more OH radicals, thus, significantly improving the catalytic capacity. The introduction of graphene improved the catalytic capacity of the catalyst under solar irradiation. The optimal electrophoretic deposition time of GO and the optimal Fe and initial GO content in deposition were 10 min, 9.8 wt% and 15.0 wt%, respectively. The degradation pathways of phenol and quinoline in the solar-driven photo-Fenton process were also elucidated., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

As a promising cell tracking technology, 19F MRI suffers from low sensitivity. Here, fluorinated nanoemulsions with a unified 19F signal and paramagnetic relaxation enhancement were developed as 19F MRI cellular tracers with high stability, size controllability, biocompatibility, cellular uptake, and dual-modality for sensitive in vivo RAW264.7 cell tracking.

Particulate adjuvants have shown increasing promise as effective, safe, and durable agents for the stimulation of immunity, or alternatively, the suppression of autoimmunity. Here we examined the potential of the adjuvant carbonyl iron (CI) for the modulation of organ-specific autoimmune disease-type 1 diabetes (T1D). T1D was induced by multiple low doses of streptozotocin (MLDS) that initiates beta cell death and triggers immune cell infiltration into the pancreatic islets. The results of this study indicate that the single in vivo application of CI to MLDS-treated DA rats, CBA/H mice, or C57BL/6 mice successfully counteracted the development of insulitis and hyperglycemia. The protective action was obtained either when CI was applied 7 days before, simultaneously with the first dose of streptozotocin, or 1 day after MLDS treatment. Ex vivo cell analysis of C57BL/6 mice showed that CI treatment reduced the proportion of proinflammatory F4/80 + CD40 + M1 macrophages and activated T lymphocytes in the spleen. Moreover, the treatment down-regulated the number of inflammatory CD4 + IFN-γ + cells in pancreatic lymph nodes, Peyer's patches, and pancreas-infiltrating mononuclear cells, while simultaneously potentiating proportion of CD4 + IL17 + cells. The regulatory arm of the immune system represented by CD3 + NK1.1 + (NKT) and CD4 + CD25 + FoxP3 + regulatory T cells was potentiated after CI treatment. In vitro analysis showed that CI down-regulated CD40 and CD80 expression on dendritic cells thus probably interfering with their antigen-presenting ability. In conclusion, particulate adjuvant CI seems to suppress the activation of the innate immune response, which further affects the adaptive immune response directed toward pancreatic beta cells., (© 2017 Wiley Periodicals, Inc.)

Background: The most commonly used definition of iron deficiency (ID; ferritin <100 ng/mL or ferritin 100-300 ng/mL and transferrin saturation [TSAT] <20%) has not been validated in patients with heart failure (HF). We aimed to define and validate the biomarker-based definition of ID in HF, using bone marrow iron staining as the gold standard. Second, we aimed to assess the prognostic value of the optimized definition., Methods and Results: Bone marrow aspiration with iron staining was performed in 42 patients with HF and a reduced left ventricular ejection fraction (≤45%) undergoing median sternotomy for coronary artery bypass grafting. Patients were mostly male (76%) with mild-to-moderate HF and a mean age of 68±10 years. Bone marrow ID was found in 17 (40%) of the HF patients. The most commonly used definition of ID had a sensitivity of 82% and a specificity of 72%. A definition solely based on TSAT ≤19.8% or serum iron ≤13 µmol/L had a sensitivity of 94% and specificity of 84% and 88%, respectively ( P <0.05 compared with the former definition). Subsequently, we assessed the incidence of all-cause mortality in 387 consecutive outpatient HF patients (left ventricular ejection fraction ≤45%). In these patients, TSAT ≤19.8% and serum iron ≤13 µmol/L, and not ferritin, were independently associated with mortality., Conclusions: A TSAT ≤19.8% or a serum iron ≤13 µmol/L shows the best performance in selecting patients with ID and identifies HF patients at the highest risk of death. Our findings validate the currently used TSAT cutoff of <20% for the identification of ID in HF patients, but question the diagnostic value of ferritin., (© 2018 American Heart Association, Inc.)

Laboratory tests, by following standardized Organization for Economic Co-operation and Development (OECD) protocols, were run for evaluating the acute effects of iron magnetic microparticles (MPs), recently proposed for lake restoration, on Chlorella sp. (algal growth) and on the rotifer B. calyciflorus (mortality). In addition, the MPs potential indirect effects on rotifer egg bank were assessed by performing hatching rate test with B. calyciflorus cysts in contact with dissolved iron (Tot-Fe dis ). In the algal growth test, no inhibition occurred at the two lowest MPs concentrations (0.01 and 0.05 g l -1 ) which would correspond, considering the adsorption efficiency ratio (Phosphorus: MPs), to P concentrations lower than 0.94 mg P l -1 , much higher than typical concentrations found in natural waters. For higher MPs dose (EC 50 for Chlorella sp. was 0.15 g l -1 ), no nutrient limitations but high turbidity and Tot-Fe dis values cause negative effects on algal growth. For the case of B. calyciflorus, LC 50 was 1.63 g MPs l -1 (corresponding to 30.7 mg P l -1 ). When analyzing Tot-Fe dis effect, the hatching rate of B. calyciflorus cysts was 100% for all treatments. To sum up our results for B. calyciflorus acute and chronic toxicity tests, it is extremely unlikely the mortality of adult organisms in contact with MPs as well as an affectation of the rotifer egg bank. In conclusion, it is expected that MPs addition in a real whole-lake application cause minor lethal and sublethal effects on both Chlorella sp. and B. calyciflorus., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Metal nanoparticles have been reported to influence plant growth and productivity. However, the molecular mechanisms underlying the effects have not been completely understood yet. Current work describes the physio-biochemical basis of iron sulfide nanoparticle induced growth and yield enhancement in Brassica juncea. Iron sulfide nanoparticles (0, 2, 4, 6, 8 and 10 ppm) were used for foliar treatment of B. juncea at 30, 45 and 60 days after sowing, under field conditions. Foliar treatment of 4 ppm iron sulfide nanoparticle solution at 30 days after sowing brought maximal enhancement in agronomic attributes of the treated plants. Results of assays i.e. total chlorophyll, electrolyte leakage, Malondialdehyde (MDA), proline, H 2 O 2 and antioxidant enzyme activities indicated the benign effect of iron sulfide nanoparticles on plants. Consequently, improved redox status of the treated plants, enabled them to assimilate higher photosynthate. The augmentation in growth and seed yield in iron sulfide nanoparticle treated plants was amply supported by activation of RUBISCO small subunit (rubisco S), RUBISCO large subunit (rubisco L), glutamine synthetase (gs) and glutamate synthase (gogat) genes. Thus, iron sulfide nanoparticle induced growth and yield enhancement is proposed to be mediated through activation of carbon and nitrogen assimilatory pathways at specific growth stage. The iron content in the leaves and root tissues of the treated plants was also significantly improved., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Importance: Iron-deficiency anemia (IDA) affects millions of persons worldwide, and is associated with impaired neurodevelopment in infants and children. Ferrous sulfate is the most commonly prescribed oral iron despite iron polysaccharide complex possibly being better tolerated., Objective: To compare the effect of ferrous sulfate with iron polysaccharide complex on hemoglobin concentration in infants and children with nutritional IDA., Design, Setting, and Participants: Double-blind, superiority randomized clinical trial of infants and children aged 9 to 48 months with nutritional IDA (assessed by history and laboratory criteria) that was conducted in an outpatient hematology clinic at a US tertiary care hospital from September 2013 through November 2015; 12-week follow-up ended in January 2016., Interventions: Three mg/kg of elemental iron once daily as either ferrous sulfate drops or iron polysaccharide complex drops for 12 weeks., Main Outcomes and Measures: Primary outcome was change in hemoglobin over 12 weeks. Secondary outcomes included complete resolution of IDA (defined as hemoglobin concentration >11 g/dL, mean corpuscular volume >70 fL, reticulocyte hemoglobin equivalent >25 pg, serum ferritin level >15 ng/mL, and total iron-binding capacity <425 μg/dL at the 12-week visit), changes in serum ferritin level and total iron-binding capacity, adverse effects., Results: Of 80 randomized infants and children (median age, 22 months; 55% male; 61% Hispanic white; 40 per group), 59 completed the trial (28 [70%] in ferrous sulfate group; 31 [78%] in iron polysaccharide complex group). From baseline to 12 weeks, mean hemoglobin increased from 7.9 to 11.9 g/dL (ferrous sulfate group) vs 7.7 to 11.1 g/dL (iron complex group), a greater difference of 1.0 g/dL (95% CI, 0.4 to 1.6 g/dL; P < .001) with ferrous sulfate (based on a linear mixed model). Proportion with a complete resolution of IDA was higher in the ferrous sulfate group (29% vs 6%; P = .04). Median serum ferritin level increased from 3.0 to 15.6 ng/mL (ferrous sulfate) vs 2.0 to 7.5 ng/mL (iron complex) over 12 weeks, a greater difference of 10.2 ng/mL (95% CI, 6.2 to 14.1 ng/mL; P < .001) with ferrous sulfate. Mean total iron-binding capacity decreased from 501 to 389 μg/dL (ferrous sulfate) vs 506 to 417 μg/dL (iron complex) (a greater difference of -50 μg/dL [95% CI, -86 to -14 μg/dL] with ferrous sulfate; P < .001). There were more reports of diarrhea in the iron complex group than in the ferrous sulfate group (58% vs 35%, respectively; P = .04)., Conclusions and Relevance: Among infants and children aged 9 to 48 months with nutritional iron-deficiency anemia, ferrous sulfate compared with iron polysaccharide complex resulted in a greater increase in hemoglobin concentration at 12 weeks. Once daily, low-dose ferrous sulfate should be considered for children with nutritional iron-deficiency anemia., Trial Registration: clinicaltrials.gov Identifier: NCT01904864.

The efficiency of natural minerals, i.e. zeolite, bentonite and goethite, regarding the retention of chromium, from maize was examined. Specifically, 1.0 kg of soil, 1.0 g of soil amendment and either 50 mg L -1 Cr(III) or 1 mg L -1 Cr(VI) were added in plant pots. Then, seeds of maize were cultivated. Each treatment was repeated three times. The statistical results of the experiments were analyzed by LSD test. Cr(III) addition in soil has shown that zeolite was the only amendment that increased the dry weight. Zeolite and bentonite reduced significantly the total chromium in plants after the addition of 50 mg L -1 Cr(III). The addition of Cr(VI) in soil has shown that bentonite was the only amendment that increased the dry weight of biomass and the plants' height. All soil amendments reduced to zero the total chromium concentration measured to plants after the addition of 1 mg L -1 Cr(VI).

Background: The similarities between swine and humans in physiological and genomic patterns, and the great correlation in size and anatomy, make pigs extremely useful in preclinical studies. New-born piglets can represent a model for congenital and genetic diseases in new-born children. It is known that piglets may have significant differences in clinicopathological results compared to adult pigs. Therefore, adult laboratory reference intervals cannot be applied to piglets. The aim of this study was to compare haematological and chemical variables in piglets of two ages and determinate age-related reference intervals for commercial hybrid young pigs. Blood samples were collected under general anaesthesia from 130 animals divided into five- (P5) and 30- (P30) day-old piglets. Only P30 animals were treated with parenteral iron after birth. Samples were analysed using automated haematology (ADVIA 2120) and chemistry analysers, and age-related reference intervals were calculated., Results: Significant higher values of RBC, Hb and HCT were observed in P30 animals when compared to P5, with an opposite trend for MCV. These results were associated with a reduction of the RBC regeneration process and the thrombopoietic response. The TSAT and TIBC were significantly higher in P30 compared to P5; however, piglets remained iron deficient compared to adult reference intervals reported previously., Conclusions: In conclusion, this paper emphasises the high variability occurring in clinicopathological variables between new-born and 30-day-old pigs, and between piglets and adult pigs. This study provides valuable reference data for piglets at precise ages and could be used in the future as historical control improving the Reduction in animal experiments, as suggested by the 3Rs principle.

Thioredoxin reductase (TrxR) is a selenoenzyme that could regulate intracellular oxidative balance and found to be overexpressed in many human tumor cells. Due to its important role in cancer progression, TrxR is becoming an attractive target in chemotherapeutic drug design. In this study, a new class of Fe(II) complexes with phenanthroline derivatives as ligands were synthesized and characterized. The mechanism of cell death induced by complex 3 revealed that the growth of cancer cells was suppressed by apoptosis and specifically inhibited the activities of TrxR. Furthermore, complex 3 exhibited brilliant antiangiogenic activity against HUVEC cells and inhibited cell migration and invasion. In addition, results of hematological analysis and H&E staining demonstrated that complex 3 has negligible toxicity on function of the major organs of mice. Taken together, this study provides a strategy for drug design to exploit Fe-based phenanthroline derivative as a chemotherapeutic agent in cancer treatment.

Background: Intravenous (IV) iron preparations are widely used in the treatment of anemia in patients undergoing hemodialysis (HD). All IV iron preparations carry a risk of causing hypersensitivity reactions. However, the pathophysiological mechanism is poorly understood. We hypothesize that a relevant number of these reactions are mediated by complement activation, resulting in a pseudo-anaphylactic clinical picture known as complement activation-related pseudo allergy (CARPA)., Methods: First, the in-vitro complement-activating capacity was determined for 5 commonly used IV iron preparations using functional complement assays for the 3 pathways. Additionally, the preparations were tested in an ex-vivo model using the whole blood of healthy volunteers and HD patients. Lastly, in-vivo complement activation was tested for one preparation in HD patients., Results: In the in-vitro assays, iron dextran, and ferric carboxymaltose caused complement activation, which was only possible under alternative pathway conditions. Iron sucrose may interact with complement proteins, but did not activate complement in-vitro. In the ex-vivo assay, iron dextran significantly induced complement activation in the blood of healthy volunteers and HD patients. Furthermore, in the ex-vivo assay, ferric carboxymaltose and iron sucrose only caused significant complement activation in the blood of HD patients. No in-vitro or ex-vivo complement activation was found for ferumoxytol and iron isomaltoside. IV iron therapy with ferric carboxymaltose in HD patients did not lead to significant in-vivo complement activation., Conclusion: This study provides evidence that iron dextran and ferric carboxymaltose have complement-activating capacities in-vitro, and hypersensitivity reactions to these drugs could be CARPA-mediated., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Background: Treatment of iron deficiency with intravenous (i.v.) iron is a first-line strategy to improve anaemia of chronic kidney disease. Previous in vitro experiments demonstrated that different i.v. iron preparations inhibit differentiation of haematopoietic stem cells to monocytes, but their effect on monocyte differentiation to macrophages and mature dendritic cells (mDCs) has not been assessed. We investigated substance-specific effects of iron sucrose (IS), sodium ferric gluconate (SFG), ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) on monocytic differentiation to M1/M2 macrophages and mDCs., Methods: Via flow cytometry and microRNA (miRNA) expression analysis, we morphologically and functionally characterized monocyte differentiation to M1/M2 macrophages and mDCs after monocyte stimulation with IS, SFG, FCM and IIM (0.133, 0.266 and 0.533 mg/mL, respectively). To assess potential clinical implications, we compared monocytic phagocytosis capacity in dialysis patients who received either 500 mg IS or IIM., Results: Phenotypically, IS and SFG dysregulated the expression of macrophage (e.g. CD40, CD163) and mDC (e.g. CD1c, CD141) surface markers. Functionally, IS and SFG impaired macrophage phagocytosis capacity. Phenotypic and functional alterations were less pronounced with FCM, and virtually absent with IIM. In miRNA expression analysis of mDCs, IS dysregulated miRNAs such as miR-146b-5p and miR-155-5p, which are linked to Toll-like receptor and mitogen-activated protein kinase signalling pathways. In vivo, IS reduced monocytic phagocytosis capacity within 1 h after infusion, while IIM did not., Conclusions: This study demonstrates that less stable i.v. iron preparations specifically affect monocyte differentiation towards macrophages and mDCs., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.)

Iron-copper interactions were described decades ago; however, molecular mechanisms linking the two essential minerals remain largely undefined. Investigations in humans and other mammals noted that copper levels increase in the intestinal mucosa, liver and blood during iron deficiency, tissues all important for iron homeostasis. The current study was undertaken to test the hypothesis that dietary copper influences iron homeostasis during iron deficiency and iron overload. We thus fed weanling, male Sprague-Dawley rats (n = 6-11/group) AIN-93G-based diets containing high (~8800 ppm), adequate (~80) or low (~11) iron in combination with high (~183), adequate (~8) or low (~0.9) copper for 5 weeks. Subsequently, the iron- and copper-related phenotype of the rats was assessed. Rats fed the low-iron diets grew slower than controls, with changes in dietary copper not further influencing growth. Unexpectedly, however, high-iron (HFe) feeding also impaired growth. Furthermore, consumption of the HFe diet caused cardiac hypertrophy, anemia, low serum and tissue copper levels and decreased circulating ceruloplasmin activity. Intriguingly, these physiologic perturbations were prevented by adding extra copper to the HFe diet. Furthermore, higher copper levels in the HFe diet increased serum nonheme iron concentration and transferrin saturation, exacerbated hepatic nonheme iron loading and attenuated splenic nonheme iron accumulation. Moreover, serum erythropoietin levels, and splenic erythroferrone and hepatic hepcidin mRNA levels were altered by the dietary treatments in unanticipated ways, providing insight into how iron and copper influence expression of these hormones. We conclude that high-iron feeding of weanling rats causes systemic copper deficiency, and further, that copper influences the iron-overload phenotype.

Recently, magnetic photothermal nanomaterials have emerged as a new class of bio-nanomaterials for application in cancer diagnosis and therapy. Hence, we developed a new kind of magnetic nanomaterials, iron diselenide (FeSe(2)) nanoparticles, for multimodal imaging-guided photothermal therapy (PTT) to improve the efficacy of cancer treatment. By controlling the reaction time and temperature, FeSe(2) nanoparticles were synthesized by a simple solution-phase method. After modification with polyethylene glycol (PEG), the obtained FeSe(2)-PEG nanoparticles showed high stability under various physiological conditions. FeSe(2)-PEG could serve as a T2-weighted magnetic resonance (MR) imaging contrast agent because of its strong superparamagnetic properties, with its r(2) relaxivity determined to be 133.38 mM(-1) S(-1), a value higher than that of the clinically used Feridex. On the other hand, with high absorbance in the near-infrared (NIR) region, FeSe(2)-PEG also appeared to be a useful contrast agent for photoacoustic imaging (PA) as well as an effective photothermal agent for PTT cancer treatment, as demonstrated in our animal tumor model experiments. Moreover, long-term toxicity tests have proven that FeSe(2)-PEG nanoparticles after systematic administration rendered no appreciable toxicity to the treated animals, and could be gradually excreted from the major organs of mice. Our work indicates that FeSe(2)-PEG nanoparticles would be a new class of theranostic agents promising for application in bioimaging and cancer therapy.

Polyoxometalates (POMs) have attracted a considerable attention due to their unique structural characteristics, physicochemical properties and biological activities. In this study, iron hepta-tungsten phosphate oxygen clusters complex Na12H[Fe(HPW7O28)2]·44H2O (IHTPO) was synthesized and evaluated for in vitro cytotoxic activities on human hepatoma HepG2, leukemia K562, lung carcinoma A549, and large cell lung cancer NCI-H460 cells, therapeutic efficacies on mice transplantable tumor, and immunomodulatory potentials on the immune response in tumor-bearing mice. IHTPO exhibited lower in vitro cytotoxic activities against four human tumor cell lines, with the IC50 values being higher than 62.5μM (ca. 300μg/ml). IHTPO, however, significantly inhibited the growth of S180 sarcoma transplanted in mice. It was further showed that IHTPO could not only significantly promote splenocytes proliferation, NK cell and CTL activity from splenocytes, but remarkably enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. IHTPO also significantly promoted Th1 cytokines IFN-γ and IL-2 production, and up-regulated the mRNA expression levels of IFN-γ, IL-2 and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. These results suggested that IHTPO significantly inhibited the growth of mice transplantable tumor, and that its in vivo antitumor activity might be achieved by improving Th1 protective cell-mediated immunity. IHTPO could act as antitumor agent with immunomodulatory activity., (Copyright © 2015. Published by Elsevier B.V.)

Protein disulfide isomerase (PDI) has two distinct CGHC redox-active sites; however, the contribution of these sites during different physiologic reactions, including thrombosis, is unknown. Here, we evaluated the role of PDI and redox-active sites of PDI in thrombosis by generating mice with blood cells and vessel wall cells lacking PDI (Mx1-Cre Pdifl/fl mice) and transgenic mice harboring PDI that lacks a functional C-terminal CGHC motif [PDI(ss-oo) mice]. Both mouse models showed decreased fibrin deposition and platelet accumulation in laser-induced cremaster arteriole injury, and PDI(ss-oo) mice had attenuated platelet accumulation in FeCl3-induced mesenteric arterial injury. These defects were rescued by infusion of recombinant PDI containing only a functional C-terminal CGHC motif [PDI(oo-ss)]. PDI infusion restored fibrin formation, but not platelet accumulation, in eptifibatide-treated wild-type mice, suggesting a direct role of PDI in coagulation. In vitro aggregation of platelets from PDI(ss-oo) mice and PDI-null platelets was reduced; however, this defect was rescued by recombinant PDI(oo-ss). In human platelets, recombinant PDI(ss-oo) inhibited aggregation, while recombinant PDI(oo-ss) potentiated aggregation. Platelet secretion assays demonstrated that the C-terminal CGHC motif of PDI is important for P-selectin expression and ATP secretion through a non-αIIbβ3 substrate. In summary, our results indicate that the C-terminal CGHC motif of PDI is important for platelet function and coagulation.

The inhibitory effects of iron-substituted phosphomolybdic acid (Na6PMo11FeO40, abbreviated as PMo11Fe) on mushroom tyrosinase were investigated. The Native-PAGE results show that PMo11Fe has an inhibitory effect on tyrosinase. A spectrophotometric analysis shows that PMo11Fe is a reversible and noncompetitive inhibitor with KI=KIS=0.47 mmol L(-1). The effects of PMo11Fe on the preservation of lotus root slices were studied. The results show that PMo11Fe can significantly slow the browning rate of lotus root slices, inhibit the activity of polyphenol oxidase (PPO), enhance the activity of peroxidase (POD) and superoxide dismutase (SOD), maintain high levels of glutathione (GSH), ascorbic acid (ASA) and sucrose and control the peroxidation degree of fresh-cut fruits and vegetables. This study may help to elucidate the design of mushroom tyrosinase inhibitors of polyoxometalates (abbreviated as POMs) and a theoretical basis for the use of POMs to inhibit fruit spoilage., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Hemojuvelin (Hjv) is a membrane protein that controls body iron metabolism by enhancing signaling to hepcidin. Hjv mutations cause juvenile hemochromatosis, a disease of systemic iron overload. Excessive iron accumulation in the liver progressively leads to inflammation and disease, such as fibrosis, cirrhosis, or hepatocellular cancer. Fatty liver (steatosis) may also progress to inflammation (steatohepatitis) and liver disease, and iron is considered as pathogenic cofactor. The aim of this study was to investigate the pathological implications of parenchymal iron overload due to Hjv ablation in the fatty liver. Wild-type (WT) and Hjv(-/-) mice on C57BL/6 background were fed a standard chow, a high-fat diet (HFD), or a HFD supplemented with 2% carbonyl iron (HFD+Fe) for 12 wk. The animals were analyzed for iron and lipid metabolism. As expected, all Hjv(-/-) mice manifested higher serum and hepatic iron and diminished hepcidin levels compared with WT controls. The HFD reduced iron indexes and promoted liver steatosis in both WT and Hjv(-/-) mice. Notably, steatosis was attenuated in Hjv(-/-) mice on the HFD+Fe regimen. Hjv(-/-) animals gained less body weight and exhibited reduced serum glucose and cholesterol levels. Histological and ultrastructural analysis revealed absence of iron-induced inflammation or liver fibrosis despite early signs of liver injury (expression of α-smooth muscle actin). We conclude that parenchymal hepatic iron overload does not suffice to trigger progression of liver steatosis to steatohepatitis or fibrosis in C57BL/6 mice., (Copyright © 2015 the American Physiological Society.)

Aim: Magnetic field guided drug targeting holds promise for more effective cancer treatment. Intravascular application of magnetic nanoparticles, however, bears the risk of potentially important, yet poorly understood side effects, such as off-target accumulation in endothelial cells., Materials & Methods: Here, we investigated the influence of shear stress (0-3.22 dyn/cm(2)), exposure time (5-30 min) and endothelial activation on the uptake of ferromagnetic carbon-encapsulated iron carbide nanomagnets into endothelial cells in an in vitro flow cell model., Results: We found that even moderate shear stresses typically encountered in the venous system strongly reduce particle uptake compared with static conditions. Interestingly, a pronounced particle uptake was observed in inflamed endothelial cells., Conclusion: This study highlights the importance of relevant exposure scenarios accounting for physiological conditions when studying particle-cell interactions as, for example, shear stress and endothelial activation are major determinants of particle uptake. Such considerations are of particular importance with regard to successful translation of in vitro findings into (pre-)clinical end points.

Novel derivatives were prepared by reaction of aromatic amines with 2-(4-ethylphenoxymethyl)benzoyl isothiocyanate, affording the N-[2-(4-ethylphenoxymethyl) benzoyl]-Nꞌ-(substituted phenyl)thiourea. Structural elucidation of these compounds was performed by IR, NMR spectroscopy and elemental analysis. The new compounds were used in combination with Fe3O4 and polyvinylpyrrolidone (PVP) for the coating of medical surfaces. In our experiments, catheter pieces were coated by Matrix Assisted Pulsed Laser Evaporation (MAPLE) technique. The microbial adherence ability was investigated in 6 multi-well plates by using culture based methods. The obtained surfaces were also assessed for their cytotoxicity with respect to osteoblast cells, by using fluorescence microscopy and MTT assay. The prepared surfaces by advanced laser processing inhibited the adherence and biofilm development ability of Staphylococcus aureus and Pseudomonas aeruginosa tested strains while cytotoxic effects on the 3T3-E1 preosteoblasts embedded in layer shaped alginate hydrogels were not observed. These results suggest that the obtained medical surfaces, based on the novel thiourea derivatives and magnetic nanoparticles with a polymeric shell could represent a promising alternative for the development of new and effective anti-infective strategies.

Phosphorus (P) is a limiting nutrient in many aquatic systems. The bioavailability of P in natural waters strongly depends on its speciation. In this study, structural properties of iron colloids were determined and related to their effect on P sorption and P bioavailability. The freshwater green alga Raphidocelis subcapitata was exposed to media spiked with radiolabelled (33)PO4, and the uptake of (33)P was monitored for 1 h. The media contained various concentrations of synthetic iron colloids with a size between 10 kDa and 0.45 μm. The iron colloids were stabilised by natural organic matter. EXAFS spectroscopy showed that these colloids predominantly consisted of ferrihydrite with small amounts of organically complexed Fe. In colloid-free treatments, the P uptake flux by the algae obeyed Michaelis-Menten kinetics. In the presence of iron colloids at 9 or 90 μM Fe, corresponding to molar P:Fe ratios between 0.02 and 0.17, the truly dissolved P (<10 kDa) was between 4 and 60% of the total dissolved P (<0.45 μm). These colloids reduced the P uptake flux by R. subcapitata compared to colloid-free treatments at the same total dissolved P concentration. However, the P uptake flux from colloid containing solutions equalled that from colloid-free ones when expressed as truly dissolved P. This demonstrates that colloidal P did not contribute to the P uptake flux. It is concluded that, on the short term, phosphate adsorbed to ferrihydrite colloids is not available to the green alga R. subcapitata., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Effect of hydrocortisone, NaF, and FeSO4 on ligninolytic and phosphatase activity of the fungus Lentinus (Panus) tigrinus VKM F-3616D was investigated, Hydrocortisone and NaF were shown to inhibit the enzymes of the ligninolytic complex-laccase (EC 1.10.3.2), secretory peroxidase (EC 1.11.1.7), and Mn peroxidase (EC 1.11.1.13). FeSO4 exhibited no significant effect on the activity of these enzymes. Decreased activity of the enzymes of the ligninolytic complex was associatedwith inhibition of the activity and changes in the substrate specificity of phospholipase A2 (EC 3.1.1.4) in the presence of hydrocortisone of NaF. Cultivation of L. tigrinus in the presence of these compounds resulted in higher affinity of this enzyme to saturated fatty acids, while in the control and in the presence of FeSO4 affinity to unsaturated fatty acids was higher.

Due to the high prevalence of iron and vitamin A deficiencies and to the controversy about the role of vitamin A and carotenoids in iron absorption, the objectives of this study were to evaluate the following: (1) the effect of a molar excess of vitamin A as well as the role of tannic acid on iron uptake by Caco-2 cells; (2) iron uptake and ferritin synthesis in presence of carotenoids without pro-vitamin A activity: lycopene, lutein, and zeaxantin; and (3) iron uptake and ferritin synthesis from ferrous fumarate and NaFe-EDTA. Cells were incubated 1 h at 37 °C in PBS pH 5.5, containing (59) Fe and different iron compounds. Vitamin A, ferrous fumarate, β-carotene, lycopene, lutein, zeaxantin, and tannic acid were added to evaluate uptake. Ferritin synthesis was measured 24 h after uptake experiments. Vitamin A had no effect on iron uptake by Caco-2 cells, and was significantly lower from NaFe-EDTA than from ferrous fumarate (15.2 ± 2.5 compared with 52.5 ± 8.3 pmol Fe/mg cell protein, respectively). Carotenoids increase uptake up to 50% from fumarate and up to 300% from NaFe-EDTA, since absorption from this compound is low when administered alone. We conclude the following: (1) There was no effect of vitamin A on iron uptake and ferritin synthesis by Caco-2cells. (2) Carotenoids significantly increased iron uptake from ferrous fumarate and NaFe-EDTA, and were capable of partially overcoming the inhibition produced by tannic acid. (3) Iron uptake by Caco-2 cell from NaFe-EDTA was significantly lower compared to other iron compounds, although carotenoids increased and tannic acid inhibited iron uptake comparably to ferrous fumarate., (© 2014 Institute of Food Technologists®)