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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.)

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.)

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.)

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.)

The severe deficiency of iron or ferric chlorosis is a serious problem of most citrus trees established in calcareous soils, as a result of the low availability of iron in these soils and the poor uptake and limited transport of this nutrient in trees. The objective of this study was to evaluate the response of chlorotic Italian lemon trees (Citrus lemon) to the application of iron compounds to roots and stems. On comparing the effects of aqueous solutions of ferric citrate, ferrous sulphate and FeEDDHA chelate, applied to 20% of the roots grown in soil and sand, of trees that were planted in pots containing calcareous soil, it was observed that the chelate fully corrected ferric chlorosis, while citrate and sulphate did not solve the problem. EDDHA induced the root uptake of iron as well as the movement of the nutrient up to the leaves. With the use of injections of ferric solutions into the secondary stem of adult trees, ferric citrate corrected chlorosis but ferrous sulphate did not. The citrate ion expanded the mobility of iron within the plant, from the injection points up to the leaves, whereas the sulphate ion did not sufficiently improve the movement of iron towards the leaf mesophyll.

Problems caused by the presence of adventitious metals in buffers and reagents are well recognized in studies of metal-catalyzed oxidation reactions. In most cases, metal contamination leads to an increase in rate, and chelating agents are inhibitory. In the present study, however, the rate of copper-catalyzed oxidation of cysteine was found to be increased by buffer purification with Chelex resin or by addition of micromolar concentrations of the specific iron chelator desferrioxamine (DFO). These effects are attributable to inhibition of copper-catalyzed oxidation by adventitious iron. In purified buffer at pH 7.25, containing 0.4 microM copper, cysteine was oxidized at a rate of 32 microM/min. Addition of iron salts to this buffer caused a dose-related decrease in this rate, up to a maximum of 85%. A 50% decrease in rate was recorded at an iron concentration of only 11 nM. Other transition metals were without effect. Similar effects of purification or addition of DFO on the rate of cysteine oxidation were seen in Tris, glycylglycine, Mops, and Pipes buffers. Catalase decreased the rate of cysteine oxidation, but the sensitivity to iron was similar in the presence and absence of catalase. Copper-catalyzed oxidation of cysteamine and reduced glutathione was much less sensitive to inhibition by iron. Our results offer an explanation for the conflicting literature reports of the effects of chelating agents and catalase on cysteine oxidation, and emphasize the need for buffer purification or addition of DFO in studies concerned with the oxidation or cytotoxicity of this thiol. The exceptional sensitivity of copper-catalyzed cysteine oxidation to iron makes this an attractive system for monitoring the iron content of buffers, and may also have application for determining the free iron content of physiological fluids.

Aquopentacyanoferrate(II), [Fe(II)H2O(CN)5]3-, is one of the photodegradation products of the vasodilator and nitric oxide donor nitroprusside. Earlier observations concerning the light dependence of N-methyl-D-aspartate (NMDA) receptor blockade by nitroprusside prompted us to examine the effects of this iron complex on the NMDA receptor. [Fe(II)H2O(CN)5]3- and two other related species, aminopentacyanoferrate(II) and aminopentacyanoferrate(III), were found to be highly potent, competitive, and selective NMDA receptor antagonists. In a binding assay for the transmitter recognition site on the NMDA receptor, these iron complexes displaced the radioligand [3H]CGP 39653 with nanomolar affinities. They did not displace radioligands labeling the channel ([3H]MK-801) or the glycine co-agonist ([3H]glycine) sites of the NMDA receptor, nor did they have any relevant affinities for a number of other neurotransmitter (alpha-adrenergic, 5-hydroxytryptamine, dopamine, opiate) receptors. The iron complexes blocked NMDA-induced depolarizations in rat cortical slices at submicromolar concentrations, whereas responses to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate were not affected. In another functional receptor assay (potentiation of [3H]MK-801 binding by glutamate under non-equilibrium conditions), Schild analysis demonstrated the competitive nature of the NMDA receptor antagonism. The pA2 values obtained from these experiments were similar to the pK(i) values derived from radioligand ([3H]CGP 39653) binding assays. To explain the high affinity and selectivity of these compounds for the NMDA receptor, a novel mechanism of antagonist-receptor interaction is proposed, involving a ligand exchange process in which a loosely bound species (here H2O or NH3) in the coordination sphere of the iron complex is replaced by a functional group of an amino acid side chain placed at the glutamate recognition site of the NMDA receptor, thereby hindering agonist binding.

Transferrin (Tf) is known primarily for its role in the transport and cellular uptake of iron (Fe). Tf is also the major serum binding protein for Al. In this study, primary rat oligodendrocyte, neuron and astrocyte cultures were found to differ in Tf mediated Fe and Al uptake and in the effect of Al-Tf on Fe-Tf uptake during 4 h incubation periods. When incubated with Al-Tf (1.25 microM), oligodendrocytes displayed a 3- to 4-fold increase (p=.0002) in Al, neurons demonstrated a much smaller (p=.06) increase, and no increase was seen for astrocytes. When incubated with equimolar Al citrate or Al chloride, no increase in cellular Al was seen in any of the three cell types. Oligodendrocytes, astrocytes and neurons all demonstrated greater 59Fe uptake from Fe-Tf than Fe chloride. This uptake could be inhibited by excess Fe-Tf in oligodendrocytes and neurons, but not astrocytes. A small but significant inhibition of 59Fe uptake from Fe-Tf was seen after addition of Al-Tf to the incubation medium of oligodendrocytes, but not neurons or astrocytes. Oligodendrocytes may be particularly vulnerable to the accumulation of excess intracellular Al, and to interference of Al with Fe uptake. Such effects could contribute to Al-induced neurotoxicity if they result in altered myelin formation or maintenance.

Photodynamic action of merocyanine 540, an antileukemic sensitizing dye, on murine L1210 cells results in the formation of lipid hydroperoxides and loss of cell viability. High-performance liquid chromatography with mercury cathode electrochemical detection was used for determining lipid oxidation products, including the following cholesterol-derived hydroperoxides: 5 alpha-OOH, 6 alpha-OOH, 6 beta-OOH, and unresolved 7 alpha, 7 beta-OOH. Among these species, 5 alpha-, 6 alpha-, and 6 beta-OOH (singlet oxygen adducts) were predominant in the early stages of photooxidation, whereas 7 alpha- and 7 beta-OOH (products of free radical reactions) became so after prolonged irradiation or during dark incubation after exposure to a light dose. These mechanistic changes were studied in a unique way by monitoring shifts in the peroxide ratio, i.e., 7-OOH/5 alpha-OOH, or 7-OOH/6-OOH. When cells (10(7)/ml) were exposed to a visible light fluence of 0.6 J/cm2 in the presence of 10 microM merocyanine 540, 7-OOH/5 alpha-OOH increased by approximately 100% after 2 h of dark incubation at 37 degrees C. The increase was much larger (approximately 250%) when cells were photooxidized after treatment with 1 microM ferric-8-hydroxyquinoline, a lipophilic iron donor, whereas no increase was observed when cells were pretreated with 100 microM desferrioxamine, an avid iron chelator/redox inhibitor. Correspondingly, postirradiation formation of thiobarbituric acid-reactive material was markedly enhanced by ferric-8-hydroxyquinoline and suppressed by desferrioxamine, as was the extent of cell killing. When added to cells after a light dose, chain-breaking antioxidants such as butylated hydroxytoluene and alpha-tocopherol strongly protected against cell killing and slowed the increase in 7-OOH/5 alpha-OOH ratio. It is apparent from these results that (1) the 7-OOH/5 alpha-OOH or 7-OOH/6-OOH ratio can be used as a highly sensitive index of singlet oxygen vs. free radical dominance in photodynamically stressed cells; and (2) that postirradiation chain peroxidation plays an important role in photodynamically initiated cell killing.

Ferritin protects endothelial cells from the damaging effects of iron-catalyzed oxidative injury. Regulation of ferritin occurs through the formation of an iron-sulfur cluster within a cytoplasmic protein, the iron regulatory protein (IRP) that controls ferritin mRNA translation. Nitric oxide has been shown to inhibit iron-sulfur proteins and is present at vascular sites of inflammation; therefore, we undertook a study to examine the influence of nitric oxide on changes in endothelial cell ferritin content in response to iron exposure, and the subsequent effects on susceptibility to oxidative injury. Iron-loaded endothelial cells (EC) exposed to nitric oxide donors synthesize markedly less ferritin. Treatment of EC with a nitric oxide donor increases IRP affinity for ferritin mRNA concomitant with a loss of cytoplasmic aconitase activity in iron-laden EC. Iron-treated EC exposed to NO donors were resistant to oxidative injury despite their low ferritin content when examined 1 h after the treatment period. In contrast, 24 h later, these same cells become sensitive to oxidants, whereas iron-treated EC that are ferritin-rich continue to be resistant. In conclusion, NO inhibits the increase of EC ferritin after exposure to iron but provides short-term protection against oxidants; ferritin, in turn, provides durable cytoprotection by inactivating reactive iron.

The antitumor activities of some Fe(II)/Fe(III) complexes containing 1,3-diacetyl-2H-benzimidazole-2-thione along with a few derivatives of 1,2,4-triazol, 1,3,4-oxadiazole and 1,3,4-thiadiazole as co-ligands have been investigated. Antibacterial and antifungal activities of disulfido-/dichloro-bridged dinuclear Fe(III)/Fe(II) complexes containing similar heterocycles as terminal ligands have also been investigated.