Category: Moms

Iron in scientific research and experiments

Iron in scientific research and experiments

The maximum DMS experimeents observed was a 6. Emerging strategies of cancer therapy based on Ferroptosis. c PP in IronEx-2 was digitized from the Fig.

Iron in scientific research and experiments -

In this issue, Von der Mark et al. Post-translational regulation also plays a role in maintaining iron homeostasis. In particular, protein ubiquitination mediates the degradation of the core bHLH transcription factors and controls the recycling and degradation of the main iron transporter IRT1 Dubeaux et al.

Mechanisms for how the iron status of the cell is sensed are also emerging. This proposed sensing mechanism is distinct from those in yeast and mammalian cells. On the other hand, the IMA peptides that accumulate at extremely high levels under Fe deficiency may mediate long-distance signalling of Fe deficiency Grillet et al.

A research paper in this issue analyses the roles of IMA peptides in rice Kobayashi et al. For a long time, it has been clear that iron plays an important role in plant—microbe interactions, but these are complex biological systems to study. Partly as a consequence of the availability of genome sequences and omics data, as well as advanced molecular tools, this topic in iron research has expanded and is covered by a review Liu et al.

Iron can be a real bargaining chip, with microbes needing it for infection and growth, whereas plants will try to actively withhold it. In this issue, Trapet et al. Using Arabidopsis mutants in iron uptake, they show that resistance to these pathogens is not simply caused by making iron scarce, but is a plant-mediated defence response that requires ethylene and salicylic acid signalling.

On the other hand, iron, due to its ability to generate reactive oxygen species, may also be used to kill the invader or execute cell death to prevent pathogen progression. Regulated cell death is often part of a defence response in plants, and, in some cases, iron may be involved in triggering cell death.

Iron-dependent cell death, named ferroptosis, was recently described in mammalian cells and the same features have been observed in plants in the context of plant—pathogen interactions, as reviewed in this issue Distefano et al. Whereas plants have developed strategies to withdraw iron from pathogens, they must provide it to those microbes they host in symbiotic or endophytic associations.

Symbiotic rhizobia in root nodules of legumes constitute a major sink for iron as a cofactor of nitrogenase and many other enzymes required for fixation of atmospheric nitrogen.

Although not covered in this issue, our knowledge on transporters involved in providing iron to intracellular bacteria has substantially increased over the past couple of years. Functional studies in several legume species have shown that MATE proteins homologous to FRD3 in Arabidopsis facilitate iron transport from the nodule xylem into the nodule Wang et al.

An NRAMP homologue then transports iron into the infected cell, and VIT-like transporters export the iron into the peribacteroid space Brear et al.

The solubility of iron is strongly influenced by both redox potential and pH, and this in turn greatly affects iron uptake. This is well studied in bacteria, but how plants adapt their iron uptake mechanisms to different soil conditions is only recently receiving more attention.

Aside from pH, the abundance of other metals and nutrients in the environment not only affects iron uptake but may interact with iron at multiple levels Hanikenne et al.

Genetic variation in iron uptake mechanisms may be used for breeding more resilient crops. In this issue, a paper by Frei and colleagues reports the identification of quantittive trait loci QTLs for iron tolerance in an interspecies cross between cultivated rice and a related species adapted to high-iron soil.

The study identifies genes putatively involved in iron tolerance that could be bred into crop varieties Wairich et al. Natural populations of the same species growing in different soils have also adapted over evolutionary time scales. Studies of intraspecific variation are beginning to show how allelic variation in the plant genome tunes some iron responses, such as root ferroxidase activity or the rate of coumarin secretion, and thus drives adaptation to iron-deficient environments, for example on calcareous soils Miller and Busch, On the other hand, very little is known about evolutionary differences in the mechanisms of iron acquisition and homeostasis in the green lineage.

In this respect, a lot is to be learned from iron homeostasis mechanisms in algae, which have to deal with constantly changing environmental conditions and extreme fluctuations in the abundance of iron Gao et al. The field of iron nutrition and interactions in plants has made tremendous progress and continues opening new areas of investigation.

Nevertheless, there is a need for a better understanding of the biochemical aspects of iron homeostasis, such as protein interactions in iron uptake Martín-Barranco et al.

A community resource to catalogue all iron-binding proteins and their function has recently been set up Przybyla-Toscano et al. Although the role of rhizosphere microorganisms in iron acquisition has received particular attention, there is still the need to amplify research in this direction, for example the contribution of mycorrhizae.

Beneficial microbes have been shown to strengthen plant defence using components that are shared with the iron homeostasis system Stringlis et al. How the iron nutritional status of the plant influences rhizosphere communities through the secretion of coumarins and other organic compounds remains largely unexplored, but bears potential to inform agroecological field practice Tsai and Schmidt, Another future line of exploration is the diversity in iron acquisition and homeostasis mechanisms in the green lineage.

Most of our knowledge comes from the study of the two higher plant species Arabidopsis and rice, and the algal species Chlamydomonas. Looking at the amount of variation among related species and intraspecific variation, as illustrated in this issue, one may wonder if Arabidopsis is representative of all dicotyledons, and if rice, besides its interest as a major crop, is representative of all gramineous species.

Another almost virgin field of investigations is the diversity of iron homeostasis mechanisms in algae. The scarcity of iron in the ocean and the phylogenetic and ecological diversity of algae are likely to be associated with a wealth of unsuspected mechanisms, as illustrated for diatoms in this issue.

Their elucidation will be crucial for understanding iron geochemistry and iron cycling in the oceans and how it controls productivity and CO 2 fixation. It may also provide new concepts to improve iron nutrition in land plants. Bashir K , Ahmad Z , Kobayashi T , Seki M , Nishizawa NK.

Roles of subcellular metal homeostasis in crop improvement. Journal of Experimental Botany 72 , — Google Scholar. Brear EM , Bedon F , Gavrin A , Kryvoruchko IS , Torres-Jerez I , Udvardi MK , Day DA , Smith PMC. GmVTL1a is an iron transporter on the symbiosome membrane of soybean with an important role in nitrogen fixation.

New Phytologist , — Distefano AM , Lopez GA , Setzes N , Marchetti F , Cainzo M , Cascallares M , Zabaleta E , Pagnussat GC. Ferroptosis in plants: triggers, proposed mechanisms, and the role of iron in modulating cell death.

Dubeaux G , Neveu J , Zelazny E , Vert G. Metal sensing by the IRT1 transporter-receptor orchestrates its own degradation and plant metal nutrition. Molecular Cell 69 , — Gao X , Bowler C , Kazamia E.

Iron metabolism strategies in diatoms. Gao F , Dubos C. Transcriptional integration of plant responses to iron availability. Grillet L , Lan P , Li W , Mokkapati G , Schmidt W.

IRON MAN is a ubiquitous family of peptides that control iron transport in plants. Nature Plants 4 , — Hanikenne M , Esteves SM , Fanara S , Rouached H. Coordinated homeostasis of essential mineral nutrients: a focus on iron. Kawakami Y , Bhullar NK.

Delineating the future of iron biofortification studies in rice: challenges and future perspectives. Kobayashi T , Nagano AJ , Nishizawa NK.

Iron deficiency-inducible peptide-coding genes OsIMA1 and OsIMA2 positively regulate a major pathway of iron uptake and translocation in rice. Kryvoruchko IS , Routray P , Sinharoy S , et al.

An iron-activated citrate transporter, MtMATE67, is required for symbiotic nitrogen fixation. However, redox dysregulation caused by ROS promotes malignant transformation of HSCs by increasing DNA double strand breaks and repair errors [ 32 , 33 ].

Besides, iron is essential for the progression of leukemia because maintaining the rapid growth rate of leukemia cells requires the iron-dependent enzyme ribonucleotide reductase for DNA synthesis [ 7 , 34 , 35 ].

Alternations of iron metabolism in leukemia at systemic and cellular levels. a The systematic iron pool and serum ferritin levels are increased which is aggravated by multiple red-blood-cell transfusions.

Hepcidin is induced to block the delivery of iron into the circulation from enterocytes, macrophages and some other cells. b Leukemia cells show increased iron uptake and decreased iron efflux, leading to elevated cellular iron levels. Proteins related to iron uptake such as TfR1, TfR2 and STEAP1 are overexpressed and absorption of NTBI is increased.

However, the expression of iron export protein FPN1 is decreased. HFE or c-MYC gene variants are also associated with elevated intracellular iron levels in leukemia cells.

It has been reported that patients with AML at diagnosis had higher levels of serum ferritin, the routine marker for excess iron [ 38 ].

Ferritin promotes the growth of leukemia cells while inhibiting the colony formation of normal progenitor cells, which is identified as leukemia-associated inhibitory activity [ 39 ].

Clinical analysis suggests that hyperferritinemia at diagnosis is significantly associated with chemotherapy drug resistance, a higher incidence of relapse as well as poorer overall survival [ 38 , 40 ]. Furthermore, an elevated pretransplantation serum ferritin level is an adverse prognostic factor for overall survival and nonrelapse mortality for patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation allo-HSCT [ 41 , 42 ].

Due to the increased systematic iron pool, the ferroportin—hepcidin regulatory axis is also dysregulated. The serum hepcidin levels of AL patients are significantly elevated at the initial of diagnosis and decreased after remission, but still higher than that of the healthy controls [ 43 , 44 ].

High level of serum hepcidin leads to iron accumulation in leukemia cells which may contribute to leukemogenesis by activating Wnt and nuclear factor kappa-B NF-κB signaling pathways [ 45 , 46 , 47 , 48 ]. Meanwhile, the transportation of iron into the circulation from enterocytes and macrophages is blocked, thereby leading to erythropoiesis suppression and iron accumulation in tissues.

In addition, patients with AL usually receive multiple red-blood-cell transfusions for hematologic support, which aggravates systematic iron overload. Transfusional iron accumulates in macrophages initially as the senescent red blood cells are eliminated.

Then iron accumulates in the liver and later spreads to extrahepatic tissue such as endocrine tissues and the heart [ 49 ]. It has been demonstrated that iron overload can cause damage to bone marrow stem cells resulting in iron-correlated hematopoietic suppression, which is mediated by ROS-related signaling pathway [ 50 , 51 ].

In turn, anemia caused by hematopoiesis inhibition makes further dependence on red-blood-cell transfusions, thus creating a vicious cycle.

TfR1, also known as CD71, is essential for iron uptake. Leukemia cells have increased expression of TfR1 compared to their normal counterparts and TfR1 is involved in the clonal development of leukemia [ 9 , 52 ]. The expression of TfR1 is more prevalent in AML than that in ALL [ 53 ]. Moreover, poorly differentiated primary AML blasts tend to express higher levels of TfR1 than partially differentiated AML blasts [ 52 ].

TfR1 expression is higher in patients with T-cell ALL than patients with B-cell ALL [ 11 , 54 ]. Clinical analysis also shows that overexpression of TfR1 in ALL is an adverse prognostic factor [ 11 ]. Transferrin receptor 2 TfR2 , another receptor for Tf, is also overexpressed in AML compared with normal counterparts [ 55 ].

Although both TfR1 and TfR2 are highly expressed in AML, only TfR2 levels were significantly associated with serum iron [ 56 ]. However, elevated mRNA levels of TfR2-α but not TfR1 or TfR2-β contribute to a better prognosis for AML patients [ 56 ].

It may be that TfR2-α increases the sensitivity of leukemia cells to chemotherapy drugs through an iron-independent pathway. The interaction of Tf with TfR can be modulated by HFE protein, thereby limiting the amount of internalized iron.

Recent research suggests that HFE gene variants confer increased risk of leukemia that is attributed to the toxic effects of higher levels of iron [ 10 , 57 , 58 ].

In addition, the STEAP proteins function as ferric reductases that stimulate cellular uptake of iron through TfR1 [ 59 ]. Analysis of publicly available gene expression data shows that the STEAP1 is significantly overexpressed in AML which is associated with poor overall survival [ 60 ].

Transferrin-independent iron is also associated with iron overload in leukemia [ 61 ]. Lipocalin 2 LCN2 , also known as neutrophil gelatinase-associated lipocalin, is a less well studied protein that participates in iron uptake [ 62 ].

It is reported that overexpression of LCN2 was found in patients with AML, ALL, CML and CLL [ 63 , 64 , 65 , 66 , 67 ]. LCN2 is indispensable for BCR-ABL-induced leukomogenesis in the mouse model and involved in damaging normal hematopoietic cells [ 67 ].

Paradoxically, the analysis of whole-genome expression profiles from patients with leukemia including AML, ALL and CLL shows that LCN2 is downregulated at both mRNA and protein levels compared with healthy controls [ 64 , 68 ].

The expression levels of LCN2 in the bone marrow of AML patients are lower than that of normal controls [ 69 ]. Importantly, the levels of LCN2 increased when AML patients achieved complete remission CR , and decreased in patients with refractory disease [ 69 ].

Those data suggest that LCN2 expression is associated with better prognosis in AML. Therefore, further research is needed to clarify the specific function of LCN2 in different types of leukemia. In addition to the abnormality of iron absorption, dysregulation of the iron-storage protein- ferritin also contributes to the pathogenesis and progression of leukemia.

Ferritin is composed of two subunit types, termed ferritin heavy chain FTH and ferritin light chain FTL subunits. The c-MYC protein encoded by the proto-oncogene c-MYC is a transcription factor that activates the expression of iron regulatory protein-2 IRP2 and represses ferritin expression [ 70 ].

IRP2 can bind to IREs, which results in increased synthesis of TfR1. The consequent increase in iron uptake and reduction in iron storage could raise the intracellular LIP level for metabolic and proliferative purposes It has been suggested that c-MYC gene plays an important role in the pathogenesis of lymphocytic leukemia [ 71 ].

T lymphocytic leukemia can be induced by the aberrant expression of c-MYC gene in the zebrafish model [ 72 ]. The suppression of c-MYC gene prevents leukemia initiation in mice, and reducing expression levels of c-MYC gene inhibits cell growth in refractory and relapsed T-cell acute lymphoblastic leukemia T-ALL [ 73 ].

FTH is also involved in the NF-κB signaling pathway-mediated cell proliferation, due to that FTH prevents ROS accumulation by iron sequestration, thereby inhibiting the pro-apoptotic c-Jun N-terminal kinase JNK signaling pathway [ 74 ].

It is reported that FTH and FTL are overexpressed in both AML cells and leukemia stem cells compared with normal HSCs regardless of genetic subgroups [ 40 ]. Thus, either downregulation or upregulation of ferritin contributes to the pathogenesis and progression of leukemia.

Studies have shown that cancer cells increase metabolically available iron not only by increasing iron uptake and regulating iron storage, but also by reducing iron efflux [ 7 ]. Accumulating evidence suggests that iron efflux mediated by FPN1 and controlled by hepcidin is involved in the development and progression of leukemia [ 43 , 75 , 76 ].

The expression level of FPN1 was decreased in the majority of AML cell lines, primary AML samples and leukemia progenitor and stem cells [ 76 ]. Low levels of FPN1 in AML are associated with good prognosis, which may occur due to the increased sensitivity to chemotherapy [ 75 ].

Of note, leukemia cells may synthesize hepcidin initiating a local autocrine signaling to degrade membrane FPN1, which needs to be confirmed by further research [ 77 ].

As previously discussed, iron metabolism is dysregulated in patients with AL, which contributes to the development and progression of leukemia. These findings lead to the exploration of therapeutic approaches of targeting iron metabolism, including iron chelators, targeting iron metabolism related proteins and perturbing redox balance based on the high intracellular iron levels Fig.

Therapeutic opportunities of targeting iron metabolism in leukemia cells. Iron deprivation by iron chelators or targeting iron metabolism related proteins induces differentiation, apoptosis and cell cycle arrest in leukemia cells.

The generation of ROS is involved in the process of inducing cell differentiation. Iron chelators also play anti-leukemia roles through iron-independently regulating multiple signaling pathways or restoring GVL.

ADCC is also involved in the anti-leukemia effect of targeting iron metabolism related proteins. Iron metabolism related proteins-targeted delivery systems or iron-based nanoparticles can selectively deliver therapeutic agents into leukemia cells to play enhanced anti-leukemia activity. Furthermore, iron-based nanoparticles elevate iron-catalyzed ROS levels, leading to increased cytotoxicity.

Ferroptosis inducers perturb redox balance based on the high intracellular iron levels to induce ferroptosis in leukemia cells. Iron chelators are natural or synthetic small molecules that can decrease levels of intracellular iron by binding iron with a high affinity and promoting iron excretion.

Several iron chelators, such as deferoxamine DFO and deferasirox DFX , are clinically used to treat iron overload including secondary iron overload caused by repeated blood transfusions in patients with leukemia [ 78 , 79 ]. Application of iron chelators has been proposed as an alternative anti-leukemia therapy in recent years [ 80 ].

Iron chelators exert anti-leukemia activity through several mechanisms, including lowering the LIP of leukemia cells by chelating intracellular iron, increasing ROS levels and activating MAPK and some other signaling pathways [ 14 , 81 , 82 ] Table 1. The application of iron chelators in patients with leukemia and transfusional iron overload has dual effects of anti-leukemia and reducing the complications associated with iron overload.

Iron chelators effectively induce cell growth arrest and apoptosis in leukemia cells in a dose- and time-dependent manner [ 14 , 16 , 93 ]. Leukemia cells are more sensitive to iron chelators than their normal counterparts, most probably because their rapid proliferation depends on iron.

Moreover, supplementation with iron attenuates the anti-leukemia effect of iron chelators, indicating that iron deprivation is one of the anti-leukemia mechanisms of iron chelators [ 16 , 83 ]. It has been known for a long time that the rate-limiting step in DNA synthesis is catalyzed by ribonucleotide reductase whose catalytic activity is dependent on the continual presence of iron [ 94 ].

Iron deprivation blocks the synthesis of deoxyribonucleotides to inhibit proliferation in leukemia cells [ 84 ]. The mitogen-activated protein kinase MAPK pathway and the caspase pathway are also involved in the cell cycle arrest and apoptosis induced by iron depletion [ 16 , 82 ]. Given the importance of iron in generation of free radicals and the critical role of ROS in HSCs metabolism, the role of ROS in anti-leukemia effects of iron deprivation has been studied [ 97 ].

Although iron deprivation by iron chelators may decrease ROS by reducing substrates for Fenton reaction, some iron chelators were shown to induce generation of ROS in a dose and time-dependent manner [ 85 , 98 ].

Iron chelators may play anti-leukemia roles through iron-independently regulating multiple signaling pathways related to cell survival. DFX also exerts its anti-leukemia activity by inhibiting extracellular signal-regulated kinase ERK phosphorylation, repressing the mammalian target of rapamycin mTOR and NF-κB signaling pathway [ 81 , , ].

Iron chelators not only have anti-leukemia effects singly, but also exhibit synergistic anti-leukemia effects when combined with traditional chemotherapy drugs. DFO increases the sensitivity of human myeloid leukemia cells to doxorubicin DOX and arabinoside cytosine Ara-C [ , ]. DFO combined with arsenic trioxide ATO has synergistic effects on anti-proliferation and inducing apoptosis in APL [ ].

DFO can be synergized with L-asparaginase or dexamethasone to decrease survival of leukemia cells or associated with DNA-damage inducing agents to increase apoptosis in T-ALL [ 9 ].

DFX shows synergistic effect with the DNA methyl transferase inhibitor decitabine DAC on apoptosis and cell cycle arrest in leukemia cell lines [ 88 ]. However, it has been suggested that DFX creates a synergistic effect combined with Ara-C, while antagonizes the anti-leukemia effect of DOX in the treatment of AML [ 89 ].

Therefore, further studies are needed to confirm the effects of iron chelators combined with different traditional chemotherapy drugs to provide information on how to select drug combination for the treatment of leukemia in future clinical trials.

In addition to traditional iron chelating agents, some new iron chelators have been developed to improve the bioavailability and have also been identified to play anti-leukemia roles.

For example, Triapine 3-AP decreases the DNA synthetic capacity of circulating leukemia cells when administered in patients with refractory leukemia [ ]. Salicylaldehyde isonicotinoyl hydrazine analogues SIHA is reported to dose-dependently induce apoptosis, cell cycle arrest and dissipation of the mitochondrial membrane potential in AML cells [ 90 ].

Importantly, several agents used in clinical practice for other indications have also been discovered to function as iron chelators. Eltrombopag EP , a small-molecule nonpeptide thrombopoietin receptor agonist, is reported to block the cell cycle in G1 phase and induce differentiation of leukemia cells through reducing free intracellular iron [ 15 ].

The antimicrobial ciclopirox olamine CPX has been identified to functionally chelate intracellular iron, which is important for its anti-leukemia cytotoxicity [ ].

Iron chelators have also shown promising anti-leukemia effects in human trials. Moreover, a year-old male patient with relapsed AML had decreased peripheral blast counts accompanied by increased monocytic differentiation and partially reversed pancytopenia after DFO and vitamin D therapy [ 14 ].

In addition to AML, a six weeks old infant with ALL, who failed to attain remission with induction chemotherapy IC , had peripheral blast counts significantly reduced accompanied by myelomonocytic differentiation after treatment with DFO and Ara-C [ 93 ].

A retrospective case control study has shown that DFO administration after allo-HSCT in patients with hematological malignancies reduced relapse incidence and improved disease-free survival [ ]. Similarly, a retrospective observational study of patients demonstrates that the oral chelator DFX significantly reduces relapse mortality and restores graft-vs-leukemia effects GVL after allo-HSCT in AML, which is evidenced by high proportion of NK cells and suppressed regulatory T cells in peripheral blood [ ].

Importantly, studies have shown that DFX, at concentrations equal to those clinically used or even at higher ones, has no harm to the viability of normal HSCs [ 85 , ]. DFX is even reported to have a beneficial effect on the hematopoietic recovery in patients after allo-HSCT [ ].

A multicenter prospective cohort study PCS on the impact of DFX on relapse after allo-HSCT in patients with AML is recruiting NCT Moreover, a randomized controlled trial RCT and a single group assignment SGA clinical trial have also been registered to clarify the effect of DFX on response rate of AL patients who are not fit for standard chemotherapy regimens NCT, NCT Those clinical trials will more strongly demonstrate the effect of DFX on the treatment of leukemia and post-transplant hematopoiesis.

There are also some clinical trials to study the safety and the anti-leukemia effect of new iron chelators. A dose-escalating phase I study Ph-I showed that 4 out of 31 patients the majority with refractory AL achieved a CR with a longer median survival after treatment with 3-AP and Ara-C [ ].

Dose-limiting toxicities DLTs in the study were mucositis, neutropenic colitis, neuropathy and hyperbilirubinemia [ ]. In another Ph-I study, similar DLTs were also observed and the toxicities of combination of 3-AP and Ara-C were similar to that of Ara-C singly at the same dose and schedule [ ].

A phase I study of CPX showed that once-daily dosing was well tolerated in patients with relapsed or refractory AML and 2 patients had hematologic improvement HI while no patients achieved complete remission or partial remission PR [ ].

The thrombopoietin receptor agonist EP has been approved for the treatment of patients with chronic immune thrombocytopenia and refractory severe aplastic anemia. The role of EP in patients with leukemia has been investigated in several clinical trials.

However, data from another multicenter RCT do not support combining EP with IC in patients with AML [ ]. Further clinical studies, conducted in larger patient populations with more rigorous design are ongoing to assess the safety and the use of EP in elderly patients with AML, except M3 or acute megakaryocytic leukemia M7 NCT; NCT Current preclinical and clinical studies have confirmed the anti-leukemia effect of both traditional iron chelating agents and some new iron chelators.

Notwithstanding the wide use of traditional iron chelating agents in the treatment of iron overload caused by repeated blood transfusions, the optimal doses for anti-leukemia treatment and their safety remain to be further studied.

Systematic studies, which evaluate not only the toxicity but also the anti-leukemia effect of those new iron chelators in different subtypes of leukemia are also needed.

More research will focus on the combination effect of iron chelators with different chemotherapeutic agents and the best scheme of their combination to bring to fruition their application in the clinical management of leukemia.

In addition to iron chelators, depletion of intracellular iron can be achieved by targeting iron metabolism-related proteins. As a receptor that is critical for cellular iron uptake, TfR is an attractive target for depleting intracellular iron of leukemia cells.

Both inhibitory and non-inhibitory anti-TfR monoclonal antibodies result in decreased Tf binding sites and subsequently inhibit Tf uptake, leading to growth inhibition in leukemia cells by iron deprivation [ ]. A24, a monoclonal antibody directed against TfR1, competitively inhibits Tf binding to TfR1 and induces TfR1 endocytosis in lysosomal compartments where the receptor is degraded [ ].

A24 inhibits proliferation and induces differentiation of leukemia cells by depleting the intracellular iron [ 14 , , ]. Combinations of two or more anti-TfR monoclonal antibodies can interact synergistically to play anti-leukemia effects, which correlates with their ability to block Tf-mediated iron uptake [ ].

When combined with DFO, the monoclonal antibodies against TfR produce greater damage to iron uptake and a rapid depletion of iron pools [ 83 , ]. In addition to the deprivation of intracellular iron, JST-TfR09, an IgG monoclonal antibody to human TfR1, also plays an anti-leukemia effect through antibody-dependent cell-mediated cytotoxicity ADCC [ ].

Though anti-TfR monoclonal antibodies show promising effects in the treatment of leukemia in those preclinical studies, there are some limitations for their clinical application. TfR is not specifically expressed in leukemia cells, it is also displayed by a wide variety of normal tissues.

Depression of stem cell activity in bone marrow and altered distribution of red blood cell progenitors were observed in leukemia-bearing mice after receiving repeated injections of anti-TfR antibody [ ]. These observations raised major concerns for the use of anti-TfR antibodies that maturing erythroid cells would be severely affected by anti-TfR antibodies, leading to anemia.

Taking the upregulation of the TfR on the leukemia cell surface into account, various TfR-targeted delivery systems consisting targeting ligands, carriers, and therapeutic agents have been developed.

Not only to mention that TfR expression is significantly upregulated on leukemia cells, the binding of ligands to TfR also elicits very effective receptor-mediated endocytosis [ ].

The ligands targeting TfR mainly include Tf, monoclonal antibodies, single-chain antibody fragment scFv and targeting peptides.

Initially, these ligands are directly linked to some therapeutic agents. Conjugating artemisinin to a TfR targeting peptide shows anti-leukemia activity with a significantly improved leukemia cell selectivity [ ]. With the development of technology, some carriers have been developed to link ligands and therapeutic agents for improving the efficacy and safety in therapeutic agent delivery, among which liposomes, dendritic molecules and nanoparticles have been widely used [ , ].

A human serum albumin based nanomedicine, which is loaded with sorafenib and conjugated ligands for TfR specific delivery, can play enhanced anti-leukemia activity in drug resistant CML patient samples [ ]. The sensitivity of leukemia cells to imatinib can also be enhanced by encapsulated with TfR targeted liposomes [ ].

It has been reported that anti-TfR-coupled liposomes are more effective for intracellular drug delivery to T-ALL cells than anti-Tac conjugates, a monoclonal antibody directing against the interleukin-2 receptor [ ].

Tf conjugated lipopolyplexes carrying G, an antisense oligonucleotide for B-cell lymphoma-2 Bcl-2 , induce remarkable pharmacological effect of Bcl-2 inhibition in AML cells and are more effective than free G or non-targeted lipid nanoparticles [ ].

Furthermore, iron chelator DFO can up-regulate TfR expression in leukemia cells, resulting in a further increase in anti-leukemia effect of TfR-targeted lipid nanoparticles carrying G [ ]. Because traditional chemotherapy drugs are difficult to pass the blood-brain barrier, leukemia cells sheltered in the central nervous system become the source of extramedullary recurrence of leukemia.

Accumulating evidences have suggested that TfR-targeted delivery systems are promising strategies in enhancing the blood-brain barrier penetration [ ].

More clinical trials of TfR-targeted delivery systems are expected to further improve their therapeutic potential. In addition to TfR, other iron metabolism related proteins are also promising therapeutic targets.

This provides a basis for STEAP to be used as an immunotherapy target for leukemia. Targeting ferritin results in dramatic anti-leukemia effect, suggesting that the pharmacological modulation of the storage protein of iron could be a new therapeutic target in leukemia [ ].

Another consideration is that secreted ferritin can be absorbed by the TfR. Ferritin has also been commonly used for drug targeting because of its nanocage structure, which make it possible to deliver anti-leukemia drugs in the future [ ].

Such naturally occurring structure is superior to synthetic ones due to its low toxicity and negligible immune responses. It appears logic to apply approaches targeting iron-associated proteins as therapeutic measures due to their expression differences between normal cells and leukemia cells.

However, monoclonal antibodies targeting iron-associated proteins may also damage normal cells, especially those with high iron demand, because iron-associated proteins are not specific in leukemia cells.

To conquer the limitations associated with conventional chemotherapy, TfR or ferritin targeted drug delivery systems have been introduced. Furthermore, the combination of those drug delivery systems and molecular targeted drugs brings hope to increase drug efficacy and alleviate the toxicity caused by non-specificity of iron metabolism-related proteins.

As prospective clinical data is still missing, approaches to targeting iron-associated proteins are still far from being usable for leukemia treatment. Ferroptosis is a form of oxidative cell death, which is characterized by the production of ROS from accumulated iron and lipid peroxidation to trigger death [ 1 , ].

As iron is crucially involved in the formation of ROS, iron-catalyzed ROS production is primarily responsible for ferroptosis [ 1 , ]. Iron chelator DFO and heat shock protein β-1 prevent ferroptosis through reducing intracellular iron, but increasing intracellular iron promotes ferroptosis [ , , ].

Ferritinophagy is an autophagic phenomenon that selectively degrades ferritin to release intracellular free iron and thus promotes ferroptosis [ ].

Due to the importance of ROS in ferroptosis, antioxidants are critical regulators of ferroptosis. Glutathione peroxidase 4 GPX4 , which is the only antioxidant enzyme known to directly reduce lipid peroxides produced by ROS, plays a pivotal role in ferroptosis [ , ].

It has been identified that regulation of GPX4 is a common mechanism shared by multiple ferroptosis inducers [ ]. One class of ferroptosis inducers such as RSL3 inhibits GPX4 directly [ ]. As glutathione GSH is a cofactor essential for GPX4 function, inhibition of GPX4 function by depleting GSH can also induce ferroptosis [ ].

Recently, triggering ferroptosis based on the high intracellular iron levels has become a promising therapy to preferentially target leukemia cells Fig.

The tumor suppressing function of ferroptosis has been identified in a wide range of malignancies, including fibrosarcoma, prostate carcinoma, osteosarcoma and so on [ , , ]. Recent studies have indicated that RSL3 or Erastin can trigger death in leukemia cells and even enhance the sensitivity of leukemia cells to chemotherapeutic agents [ , , ].

In turn, lipoxygenase inhibitors such as Ferrostatin-1 and Baicalein can protect ALL cells from ferroptosis [ ]. The ferroptosis inducer sorafenib has been clinically approved for the treatment of FLT3-ITD mutated AML, whose mechanism may include induction of ferroptosis in AML cells [ , ].

Artemisinin and its derivatives are widely used to treat multidrug-resistant malaria due that they owe the endoperoxide bridge and can induce ROS production in the presence of iron [ ]. It has been recently suggested that dihydroartemisinin can induce ferroptosis in leukemia cells through ferritinophagy which increases the cellular LIP and thus promotes accumulation of ROS [ , ].

The naturally occurring compound ardisiacrispin B and epunctanone have also been identified to induce ferroptosis in ALL cells [ , ].

Therapies by inducing ferroptosis and ferritinophagy possess great potential in leukemia treatment. In the future, more and more research will focus on disturbing the redox balance to increase sensitivity of leukemia cells to chemotherapeutic agents.

Schematic model of ferroptosis in leukemia cells. Ferroptosis occurs as a result of iron-mediated oxidative stress and lipid peroxidation-mediated cytotoxicity.

It could be due to elevated intracellular iron concentration or inhibition of GPX4 activity. Dihydroartemisinin induce ferroptosis by ferritinophagy and subsequent accumulation of ROS. RSL3 inhibits GPX4 directly, while erastin, sorafenib and p53 decrease GSH production by inhibiting cysteine transport.

Lipoxygenase inhibitors such as Ferrostatin-1 and Baicalein suppress ferroptosis through inhibiting lipid peroxidation. More and more attention has been paid to the research of iron-based nanoparticle antitumor therapy [ ]. The iron oxide nanoparticles are reported to induce apoptosis and cell cycle arrest at sub-G1 phase in T-ALL cells [ ].

Ferumoxytol feraheme , an intravenous preparation of iron oxide nanoparticles, is available for the treatment of iron deficiency in clinic [ ]. It is recently reported that ferumoxytol shows an anti-leukemia effect due to increased iron-catalyzed ROS and low expression of the iron exporter FPN1 results in enhanced susceptibility of AML cells to ferumoxytol [ 76 ].

Besides, traditional chemotherapy drugs can be delivered by the iron-based nanoparticles for enhancing their anticancer efficacy. It is reported that the anti-leukemia effect of cytarabine is enhanced by being coated on Fe 3 O 4 SiO2 nanoparticles [ ].

The iron-based nanoparticles can be functionalized with active and passive targeting ability to reduce the adverse effects of iron-catalyzed ROS to normal cells. Satake N et al. composed nanocomplexes with super paramagnetic iron oxide nanoparticles, antiCD22 antibody and MAX dimerization protein 3 small interfering RNA molecules which showed cytotoxic effects to precursor B-cell ALL selectively and enhanced the anti-leukemia effect of chemotherapy drug vincristine or DOX [ ].

The iron-based nanoparticles can also be manipulated by the magnetic field to accumulate preferentially at tumor sites as a result of the enhanced permeability and retention phenomenon [ ].

It has also been suggested that the magnetic field has potential to increase the blood-brain barrier permeability of iron-based nanoparticles for therapy of various brain diseases [ ].

Furthermore, the magnetic field itself can play anti-leukemia effects by increasing ROS production [ ]. Therefore, the application of iron-based nanoparticles directed by magnetic field may provide an approach to the prevention and treatment of central nervous system infiltration of leukemia.

Even though iron-based nanoparticle systems with multiple function bring us a step closer to delivering personalized medicine into leukemia cells, there are still multiple obstacles to the clinical application of these new iron-based nanoparticle systems. Currently, the toxicity of iron-based nanoparticle systems is of great concerns.

No observable toxicity is seen at low levels of iron-based nanoparticles, while the particles may trigger cellular stress, weaken inflammatory reactions, increase the expression of genes involved in cell signaling and thus impact signaling pathways in the case of high dose exposure [ ].

It is critical to design functionalized iron-based nanoparticles which are able to meet the demands of a particular application and have good security in the human body. To inform the design of safe iron-based nanoparticles, a better understanding of the relationship between their toxicity with different surface properties, size, hydrophobicity, and release of iron ions is needed.

It is expected that in the near future, iron-based nanoparticle systems, conjugated with new targeted drugs, could replace our current treatments and leukemia could become a nonfatal disease with good prognosis. Accumulating evidence implicates changes in iron metabolism as crucial features of leukemia.

The alteration of iron metabolism in leukemia cells is generally associated with high iron requirements and high oxidative stress, suggesting that leukemia cells may be more vulnerable to changes in iron and ROS levels compared with normal cells.

In addition to iron chelators and therapies targeting iron metabolism-related proteins, perturbing redox balance based on the high intracellular iron levels also has promising therapeutic implications for the treatment of leukemia. The application of ferroptosis and ferritinophagy in the treatment of leukemia is just beginning as a new way of death involving iron.

With the development of nanotechnology, efforts to harness insights for therapeutic advantages of iron-based nanoparticles have begun. The magnetic fields not only concentrate nanoparticles, but also promote the production of ROS in cells to play anti-leukemia effects.

Though researches in the past few years have expanded our insights into the regulation of iron in leukemia and treatment strategies that target iron metabolism, more studies are warranted to fully clarify the specific mechanism that link iron, oxidative stress, and leukemia development.

Efforts are still needed to optimize therapies for leukemia targeting towards iron metabolism. A recent study finds that iron depletion may influence the expression of Major Histocompatibility Complex class I molecules to increase the target susceptibility of cancer cells to NK cell recognition [ ].

This provides a basis to kill leukemia cells through modulating immune system by iron depletion. Ascorbate is an essential nutrient commonly regarded as an antioxidant.

However, high-dose ascorbate is demonstrated to induce hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells without adversely affecting normal cells [ ].

Hydrogen-peroxide generated by high-dose ascorbate reacts with excess intracellular iron to produce cytotoxic ROS in cancer cells. Ascorbate also suppress leukemogenesis by promoting Tet function in HSCs [ ].

Therefore, ascorbate is a prospective anti-leukemia agent due to both its ability of perturbing redox balance based on the high intracellular iron levels in leukemia cells and activation of Tet enzymes. More and more attention will be attached to iron-based nanoparticles due to their multiple advantages.

In the future, there will be strategic opportunities to enhance therapeutic efficacy by associating the iron-based nanoparticles with other components, such as ferroptosis inducers, some genes modulating the expression of iron metabolism related proteins, targeting small molecules and so on.

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These OIF experiments demonstrated, particularly for the SO, that PP could be significantly increased after iron addition de Baar et al.

A high carbon export was observed in the nOIF experiments in the SO near the Kerguelen Plateau and Crozet Islands Blain et al. However, no significant increase in carbon exports has been detected during any aOIF experiments de Baar et al.

The results of these experiments, as well as the potential side effects e. A legal framework has been put in place to prevent venture capitalists from deploying large-scale OIF in any international waters because of the potential threat of commercialization and large-scale damage inflicted on the environment by private entities motivated primarily by profit.

No other marine scientific institutions are willing to take up the challenge of carrying out new experiments due to the fear of negative publicity. Consequently, inaction on the part of scientists might be an incentive for others to go ahead with illegal experiments as happened off Canada in e.

In the context of increasing global social—political—economic concerns associated with rapid climate change, it is necessary to examine the validity and usefulness of aOIF experimentation as a climate change mitigation strategy. Furthermore, aOIF experiments have provided insights into the structure and function of pelagic ecosystems that cannot be acquired from observational cruises alone.

Non-OIF observations provide an assortment of snapshots from which only an incomplete image of the processes involved can be rendered, while OIF experiments provide time-ordered focused frames allowing one to directly follow changes triggered by addition of an important limiting nutrient i.

That being said, it is necessary to plan and carry out the next aOIF experiments within the framework of international law. Therefore, the purpose of this paper is to 1 provide a thorough overview of the aOIF experiments conducted over the last 25 years; 2 discuss aOIF-related important unanswered questions, including carbon export measurement methods, potential side effects, and international law; 3 suggest considerations for the design of future aOIF experiments to maximize the effectiveness of the technique and begin to answer open questions; and 4 introduce design guidelines for a future Korean Iron Fertilization Experiment in the Southern Ocean KIFES.

Table 2 Summary of artificial ocean iron fertilization aOIF experiments: objectives, significant results, and limitations. A total of 13 aOIF experiments have been conducted in the following areas: 12 experiments were conducted in the three main HNLC i. One experiment was conducted in the subtropical NA, known to be a low-nutrient and low-chlorophyll LNLC i.

These aOIF experiments have been conducted with various objectives and multiple hypotheses to investigate the biogeochemical responses of ocean environments to artificial iron additions Table 2. This overview of past aOIF experimentation begins in Sect. The unique ocean conditions for the various experiments are described in Sect.

Iron addition and tracing methods are described in Sect. The biogeochemical responses to the aOIF experiments are presented in Sect. Initially, Martin's hypothesis was supported by the results of laboratory and shipboard iron-enrichment bottle experiments Hudson and Morel, ; Brand, ; Sunda et al.

However, the extrapolation of these results based on bottle incubations that exclude higher trophic levels has been strongly criticized due to possible underestimates in grazing rates and other bottle effects. To deal with these issues, in situ iron fertilization experiments at the whole-ecosystem level are required.

Under the hypothesis that aOIF would increase phytoplankton productivity by relieving iron limitations on phytoplankton in HNLC regions, the first aOIF experiment, the iron enrichment experiment IronEx-1 , was conducted over 10 days in October in the EP where high light intensity and temperatures would promote rapid phytoplankton growth Table 1 and Fig.

However, the magnitude of the biogeochemical responses in IronEx-1 was not as large as expected Martin et al. Four hypotheses were advanced to explain the weak responses observed: 1 the possibility of unforeseen micronutrient e.

To test the four hypotheses, a second aOIF experiment, IronEx-2, was conducted in May Coale et al. The IronEx-2 research cruise investigated the same area for a longer period 17 days , providing more time to collect information about the biogeochemical, physiological, and ecological responses to the aOIF.

The SO plays an important role in intermediate and deep-water formation and has the greatest potential of any of the major ocean basins for carbon sequestration associated with artificial iron addition Martin, ; Sarmiento and Orr, ; Cooper et al.

It is known as the largest HNLC region in the world ocean and models simulating aOIF have predicted that, among all HNLC regions, the effect of OIF on carbon sequestration is greatest in the SO Sarmiento and Orr, ; Aumont and Bopp, However, a simple extrapolation of the IronEx-2 results to the SO was not deemed appropriate because of the vastly different environmental conditions Coale et al.

To test the roles of iron and light availability as key factors controlling phytoplankton dynamics, community structure, and grazing in the SO, the Southern Ocean Iron Release Experiment SOIREE Table 1 and Fig.

The following year, a second aOIF experiment in the SO, EisenEx Eisen means iron in German , was performed in November within an Antarctic Circumpolar Current eddy in the Atlantic sector Smetacek, ; Gervais et al. This region is considered to have a relatively high iron supply, which is supported by dust inputs and possibly icebergs de Baar et al.

EisenEx was designed to test how atmospheric dust, an important source of iron in ocean environments, might have led to a dramatic increase in ocean productivity during the LGM due to the relief of iron-limiting conditions for phytoplankton growth Smetacek, ; Abelmann et al.

In addition to iron availability, the supply of silicate is also considered to be an important factor controlling PP in the SO. Therefore, to address the impact of iron and silicate on phytoplankton communities and export, two aOIF experiments were conducted during January—February in two distinct regions: the Southern Ocean iron experiment north SOFeX-N and south SOFeX-S of the PF Table 1 Coale et al.

Two years later, the Surface Ocean—Lower Atmosphere Study SOLAS Air—Sea Gas Exchange SAGE experiment was conducted during March—April 15 days in sub-Antarctic waters, which are typically HNLC with low silicate concentrations HNLCLSi.

The aim was to determine the response of phytoplankton dynamics to iron addition in an HNLCLSi region Fig. SAGE was designed with the assumption that the response of phytoplankton blooms to aOIF could be detected by enhanced air—sea exchanges of climate-relevant gases e. These early aOIF experiments resulted in clear increases in phytoplankton biomass and PP, but the impact on export production i.

To determine if aOIF could increase export production, EIFEX was carried out in the closed core of a cyclonic eddy near the PF during the austral summer of Fig. Of similar duration, the Indo-German iron fertilization experiment LOHAFEX; Loha means iron in Hindi was conducted during January—March 40 days , also in a PF cyclonic eddy in HNLCLSi waters Smetacek and Naqvi, ; Martin et al.

Figure 5 Photographs of the iron addition procedure a—f taken during the European Iron Fertilization Experiment EIFEX , Surface Ocean—Lower Atmosphere Study SOLAS Air—Sea Gas Exchange SAGE , and Indo-German iron fertilization experiment LOHAFEX.

a Iron II sulfate bags. b The funnel used to pour iron and hydrochloric acid. c Tank system used for mixing iron II sulfate, hydrochloric acid, and seawater Smetacek, e Outlet pipe connected to the tank system.

f Pumping iron into the prop wash during EIFEX Smetacek, The subarctic NP shows a strong longitudinal gradient in aeolian dust deposition i. In , the experiment was repeated SEEDS-2 in almost the same location and season. In the intervening year, the Subarctic Ecosystem Response to Iron Enrichment Study SERIES was performed in July—August 25 days in the Gulf of Alaska representing the eastern subarctic gyre ecosystem to compare the response of phytoplankton in this area with that in the western subarctic Boyd et al.

The SEEDS-1 and 2 experiments focused on changes in phytoplankton composition, vertical carbon flux, and climate-relevant gas production stimulated by artificial iron addition Tsuda et al.

The main objective of SEEDS-2 and SERIES was to determine the most significant factor i. Table 3 Initial conditions and changes Δ values in chemical parameters during the artificial ocean iron fertilization aOIF experiments. b Δ PO 4 3 - in EIFEX was digitized from Fig.

c Δ PO 4 3 - in LOHAFEX was digitized from Fig. d Δ p CO 2 in LOHAFEX was digitized from Fig. Download Print Version Download XLSX. Table 4 Initial values of biological parameters and the values after fertilization. Note that maximum values were attained after fertilization.

c PP in IronEx-2 was digitized from the Fig. d Mesozooplankton biomass in IronEx-2 was digitized from the Fig. e PP in SOIREE was digitized from the Fig. f Mesozooplankton biomass indicates copepod biomass; values in brackets correspond to the sampling layer; after mesozooplankton biomass is the mean value averaged for the experimental period after iron addition.

g Chlorophyll a concentrations in SOFeX-N and SOFeX-S were digitized from the Supplement Fig. h PP values in SOFeX-N and SOFeX-S were digitized from the Fig. Sources are Kolber et al. Unlike HNLC regions, PP in LNLC regions, which are predominantly occupied by N 2 fixers, is generally co-limited by phosphate and iron Mills et al.

To investigate the impact of iron and phosphate co-limitation on PP, the in situ phosphate and iron addition experiment FeeP was conducted by adding both phosphate and iron in a LNLC region of the subtropical NA during April—May 21 days Rees et al.

The location of the subtropical NA experiment corresponded to a typical LNLC region Fig. The FeeP experiment reported that picoplankton 0. This experiment will, therefore, not be discussed further.

Figure 6 a Maximum bar with dotted line and initial bar with solid line patch size km 2 during artificial ocean iron fertilization aOIF experiments.

b First target iron concentrations nM. c Maximum bar with dotted line and minimum bar with solid line mixed layer depth MLD, m during aOIF experiments.

e Initial nitrate concentrations µM. f Initial silicate concentrations µM. Note that the numbers on the x axis indicate the order of aOIF experiments as given in Fig.

Below we consider the similarities and differences in these environments according to the physical and biogeochemical properties of the sites Coale et al. The first two aOIF experiments, IronEx-1 and IronEx-2, which were both conducted in the EP, were performed in different seasons i.

However, the initial surface physical conditions were similar, with warm temperatures The initial surface biogeochemical conditions were high nutrients i. The picophytoplankton community, including Synechococcus and Prochlorococcus , was dominant Martin et al.

Initial surface nutrient concentrations were relatively low compared with other ocean basin aOIF sites Table 3 and Fig.

Initial photosynthetic quantum efficiency i. In the EP, initial surface partial pressure of CO 2 p CO 2 values were The initial physical conditions for the aOIF experiments in the SO SOIREE, EisenEx, SOFeX-N, SOFeX-S, EIFEX, SAGE, and LOHAFEX were very different from those found in the EP; MLDs were much deeper During SOFeX-N and SOFeX-S, which were conducted along the same line of longitude, on either side of the PF, there were distinct differences in SST: 5.

SAGE was the northernmost of the aOIF experiments in the SO Table 1 and, therefore, had the highest SST The locations for the aOIF experiments were selected following preliminary surveys to confirm the HNLC conditions, i.

Initial nitrate concentrations ranged from 7. Among the various aOIF HNLC experiment sites, the SO had the highest initial nitrate concentrations With the specific intent of investigating the co-limitation of iron and silicate, SOFeX-N, SAGE, and LOHAFEX were all conducted in HNLCLSi regions, with initial silicate concentrations less than 2.

Initial p CO 2 values were low in the SO The maximum initial chlorophyll concentrations occurred in EIFEX, which started with a community dominated by diatoms Hoffmann et al. The subarctic NP aOIF experiments i.

Compared with the other aOIF experiments, these subarctic experiments had much higher initial silicate concentrations Although SEEDS-1 and SEEDS-2 were conducted in almost the same location and season in the western basin Tsuda et al.

Unlike the latitudinal gradients seen in the aOIF experiments in the SO, there were longitudinal gradients in physical and biogeochemical properties in the subarctic NP experiments Tables 3, 4, Figs. Initial SSTs in the subarctic NP were lower in the western region 7.

Initial nutrient concentrations were much higher in the west nitrate: There was also a longitudinal gradient in chlorophyll a concentrations, with relatively high values in the west SEEDS 0. Iron sulfate is a common inexpensive agricultural fertilizer that is relatively soluble in acidified seawater Coale et al.

Therefore, all aOIF experiments have been conducted by releasing commercial iron sulfate dissolved in acidified seawater into the propeller wash of a moving ship Fig. Iron-enrichment bottle incubation experiments performed in deck incubators using in situ seawater have indicated the maximum phytoplankton growth rates in response to iron additions of 1.

These processes occur more rapidly in warmer waters ACE CRC, For example, the first aOIF experiment, IronEx-1, showed that the dissolved iron concentration rapidly decreased from 3. As a result, except for the single iron addition experiments of IronEx-1, SEEDS-1, and FeeP Martin et al.

These experiments included two additions EIFEX, SERIES, SEEDS-2, and LOHAFEX Boyd et al. To trace the iron-fertilized patch, aOIF experiments have used a combination of physical and biogeochemical approaches. All the aOIF experiments except EIFEX have used sulfur hexafluoride SF 6 as a chemical tracer Table 1 Martin et al.

The SF 6 , which is not naturally found in oceanic waters, is a useful tracer for investigating physical mixing and advection—diffusion processes in the ocean environment due to its nontoxicity, biogeochemically inert characteristics, and low detection limit Law et al.

The injected SF 6 is continuously monitored using gas chromatography with an electron capture detector system Law et al. Furthermore, caution is required because artificially high levels of SF 6 injection may negatively impact the interpretation of low-level SF 6 signals dissolved in seawater via air—sea exchange to estimate tracer-based water mass ages for understanding physical circulation Fine, These techniques have been widely used to estimate anthropogenic carbon invasion as well as to understand ocean circulation in various ocean environments, with SF 6 being an important time-dependent tracer that has a well-recorded atmospheric history.

In addition, surface-drifting buoys equipped with Argos or GPS systems have been successfully used to track the movement of fertilized patches along with biogeochemical tracers Coale et al.

However, floats tend to drift out of the fertilized patches under strong wind forcing Watson et al. NASA airborne oceanographic lidar and ocean-color satellites have also been employed to assess the large-scale effects of iron addition on surface chlorophyll in fertilized patches, as compared to surrounding regions Martin et al.

Table 5 Initial values of the export flux and the values after fertilization mg C m - 2 day - 1 , the corresponding depth inside and outside the fertilized patch for artificial ocean iron fertilization aOIF experiments, and measurement method.

Values in brackets correspond to the day of measurement after fertilization. a Export flux in EIFEX was digitized from the Supplement Fig.

b Export flux in LOHAFEX was digitized from the Fig. c Export flux in LOHAFEX was digitized from the Fig. d Export flux in SEEDS-1 was determined from the suspended particles.

e Export flux in SERIES was digitized from the Fig. Sources are Bidigare et al. The results are important, as they have been used as a basis to determine whether the aOIF is effective.

Here we address the biogeochemical response in each of the ocean basins to the aOIF experiments to date. The numbers on the x axis indicate the order of aOIF experiments as given in Fig. The IronEx-1 and 2 experiments, which were conducted in similar initial conditions refer to Sect.

On the other hand, IronEx-2 found dramatic changes in biogeochemical responses, providing support for Martin's hypothesis Coale et al.

Unexpected small responses during IronEx-1 were due to subduction of the fertilized surface layer by adjacent water Coale et al. The contrasting results from the two experiments are also likely to be associated with whether or not there were additional iron injections IronEx no extra addition; IronEx two additional injections and different experiment durations IronEx 10 days; IronEx 17 days.

During IronEx-1, chlorophyll a concentrations increased significantly 3-fold , reaching a maximum value of 0. To quantify the changes in carbon fixation following iron addition, the depth-integrated PP from the surface to the critical depth, euphotic depth, or MLD was estimated in the iron-fertilized patches.

The depth-integrated PP values increased significantly compared to the initial values. As the bloom developed, a significant nitrate uptake e. The depletion of macronutrients in fertilized patches provides indirect evidence that phytoplankton growth in surface waters was driven by aOIF Boyd and Law, Although no phytoplankton community change was observed in IronEx-1, after iron addition in IronEx-2 a shift from a picophytoplankton-dominated community to a microphytoplankton-dominated community was observed, resulting in a diatom-dominated bloom Behrenfeld et al.

Diatom biomass increased nearly 70 -fold over 8 days early in the experiment, compared to a less than a 2-fold increase for the picophytoplankton Landry et al. However, grazing did not prevent the development of a diatom bloom over 8 days early in the IronEx-2 experiment Table 4 Coale et al. The decline was probably associated with the combined effects of both the elevated grazing pressure and the onset of nutrient depletion i.

To determine whether the biological pump i. The Th radionuclide has a strong affinity for particles, and the extent of Th removal in the water column is indicative of the export of POC associated with surface PP out of the ML Buesseler, However, no Th measurements were made in the unfertilized patch for comparison, and no measurements in the deep ocean were undertaken to demonstrate deep carbon export Bidigare et al.

Satellite observations were used to investigate the changing spatial and temporal distribution of chlorophyll a concentration in response to iron fertilization in the fertilized patches compared to the surrounding waters; for example, SOFeX-N and SOFeX-S found elevated chlorophyll a concentrations in fertilized patches after iron addition through satellite images Fig.

During SOIREE, EisenEx, SOFeX-N, and SOFeX-S, PP increased continuously throughout the duration of the experiments Boyd et al. The decrease was due to various processes such as export e. Using both microscopes and high-performance liquid chromatography pigment analysis, changes in the phytoplankton community affected by iron addition have also been investigated.

Most SO aOIF experiments have resulted in blooms of diatoms Boyd et al. During SOIREE and EisenEx, the dominant phytoplankton community shifted from pico- and nanophytoplankton e.

In SOFeX-S and EIFEX, diatoms were already the most abundant group prior to iron addition Coale et al. Although SOFeX-N was conducted under low silicate conditions Fig.

This result was partly influenced by the temporary relief of silicate limitation through lateral mixing of the iron-fertilized waters with surrounding waters, with relatively higher silicate concentrations Coale et al. Iron-mediated increases in PP resulted in a significant uptake in macronutrients and p CO 2 throughout the aOIF experiments in the SO except for SAGE Table 3, Fig.

During EIFEX, the ratio of heavily silicified diatoms e. These contrasting results were thought to be the result of entrainment through vertical and horizontal physical mixing into the iron-fertilized patch of surrounding waters with higher nutrient and p CO 2 concentrations Currie et al.

SOIREE was the first aOIF experiment in the SO to estimate the downward carbon flux into deep waters Fig. A comprehensive suite of methods was used: drifting traps, Th and the stable carbon isotope of particulate organic matter δ 13 C org estimates derived from high-volume pump sampling, and a beam transmissometer Nodder and Waite, However, no measurable change in carbon export was observed in response to iron-stimulated PP Table 5 and Fig.

During EisenEx, an increased downward carbon flux estimated from Th deficiency was observed in the iron-fertilized patch as the experiment progressed. However, there were no clear differences between in- and outside-patch carbon fluxes Buesseler et al. During SOFeX-S, significantly enhanced POC fluxes below the MLD, similar to those observed in natural blooms, were estimated from Th measurements after iron enrichment Buesseler et al.

However, it was unclear whether surface-fixed carbon was well and truly delivered below the winter MLD. During SAGE and LOHAFEX, which were conducted under silicate-limited conditions Table 3, Figs. This result was likely due to the dominance of picoplankton and grazing that led to rapid recycling of organic matter in the ML.

This value remained constant for about 24 days after iron addition. Significant changes in export production were not found in any of the other aOIF experiments and, therefore, the impact of artificial iron addition on diatom aggregate formation needs focused study in future aOIF experiments Boyd et al.

Increases in chlorophyll a concentrations were detected in the subarctic NP aOIF experiments in both basins after about the fifth day Tsuda et al.

These increases were especially apparent in SEEDS-1, where they reached a maximum value of This augmentation was the largest among all the aOIF experiments Tsuda et al. The dramatic surface chlorophyll a increase observed during SEEDS-1 was partly attributed to the particular range of seawater temperature in the region, which was conducive to diatom growth i.

During SERIES, chlorophyll a concentrations increased substantially from the initial value of 0. Although SEEDS-2 was conducted under similar initial conditions to SEEDS-1 refer to Sect. This smaller increase was thought to be the result of strong copepod grazing SEEDS-2 had almost 5 times more copepod biomass than SEEDS-1 Table 4 Tsuda et al.

A similar range was seen in depth-integrated PP, which increased 3-fold or more after iron addition in the subarctic NP aOIF experiments e. Changes in the composition of phytoplankton groups were investigated in the subarctic NP aOIF experiments. In SEEDS-1 there was a shift from oceanic diatoms e.

The effect on the biological pump can be quite different depending on the species of diatom stimulated by the aOIF. Chaetoceros debilis , known to be widespread in coastal environments, intensifies the biological pump by forming resting spores in contrast to grazer-protected, thickly silicified oceanic species e.

and Thalassiothrix sp. that contribute silica but little carbon to the sediments. The shift in the dominant phytoplankton species during SEEDS-1 was an important contributor to the recorded increase in phytoplankton biomass.

During SERIES, the phytoplankton community changed from Synechococcus and haptophytes to diatoms, and the highest SERIES chlorophyll a concentration day 17 was associated with a peak in diatom abundance Boyd et al.

However, during SEEDS-2, no significant iron-induced diatom bloom was observed. Instead, pico- and nanophytoplankton e. In the subarctic NP experiments, significant changes in macronutrient uptake i.

During SEEDS-2, the nitrate concentration decreased remarkably from Despite the formation of a massive iron-induced phytoplankton bloom during SEEDS-1, there was no large POC export flux during the observation period Table 5 Tsuda et al.

During SERIES and SEEDS-2, which allowed comprehensive time-series measurements of the development and decline of the iron-stimulated bloom, POC fluxes estimated by the drifting traps in the fertilized patch displayed temporal variations Boyd et al.

The results suggested that, subsequently, the drifting trap captured only a small part of the decrease in ML POC and POC flux losses were mainly governed by bacterial remineralization and mesozooplankton grazing Boyd et al.

Each aOIF experiment has provided new results on basic processes pertaining to the relationship between pelagic ecology and biogeochemistry, such as selection of the dominant phytoplankton group or species; the effects of grazing; interactions within the plankton community; and effects of nutrient concentrations on the growth of phytoplankton.

The aOIF experiments have generally led to changes in the size of the phytoplankton community from pico- and nanophytoplankton to microphytoplankton. This effect was particularly noticeable as diatoms became the dominant species during IronEx-2, SOIREE, EisenEx, SEEDS-1, SOFeX-S, EIFEX, and SERIES.

The shift to a diatom-dominated community appears to be related to initial availability of silicate i. As a consequence, pico- and nanophytoplankton dominated their communities and diatom growth was limited by the lack of available silicate. These results suggest that, to develop large-phytoplankton blooms, changeover to a diatom-dominated community after iron addition is needed.

A necessary, but not sufficient, condition for such a change to occur is the availability of silicate. Silicate alone is not expected to be sufficient because diatom-dominated blooms were not observed in all experiments with high initial silicate concentrations. Taken together, the aOIF results suggest that both mesozooplankton grazing rates and initial silicate concentrations play a role in limiting the stimulation of diatom-dominated blooms after artificial iron enrichment.

However, influence of iron addition on the phytoplankton growth extends from surface to euphotic depth as added iron is mixed within the ML by physical processes Coale et al. Therefore, to quantify the exact changes in phytoplankton biomass in response to iron addition, it would be appropriate to consider the MLD-integrated PP for comparison.

However, changes in the carbon export varied substantially and differed from experiment to experiment. In SEEDS-1 and SOIREE there was little increase in export flux. These two experiments were conducted over only about 2 weeks. The short duration of these experiments could have prevented the detection of downward carbon export.

However, the changes in export flux, after iron addition, were not dramatic compared to natural values Buesseler et al. This high flux was due to aggregate formation with fast sinking rates Smetacek et al. EIFEX observed an entire cycle i.

It should also be noted that the rates of bacterial remineralization and grazing pressure on the diatoms were in the same range inside the fertilized patch as outside, which might have assisted the delivery of iron-induced POC from the ML to deep layers Smetacek et al.

These results suggest that to detect significant carbon exported below the winter MLD following an increase in PP, at least three conditions are necessary: 1 a shift to a diatom-dominated community; 2 low bacterial respiration and grazing pressure rates within the ML; and 3 a sufficient experimental duration, enabling both immediate and delayed responses to iron addition to be observed.

OIF has been proposed as a potential technique for rapidly and efficiently reducing atmospheric CO 2 levels at a relatively low cost Buesseler and Boyd, , but there is still much debate. Over the past 25 years, controlled aOIF experiments have shown that substantial increases in phytoplankton biomass can be stimulated in HNLC regions through iron addition, resulting in the drawdown of DIC and macronutrients de Baar et al.

However, the impact on the net transfer of CO 2 from the atmosphere to below the winter MLD through the biological pump Fig. There have also been a wide range of the estimates of atmospheric CO 2 drawdown resulting from large-scale and long-term aOIF based on model simulations Joos et al.

While it is generally agreed that OIF effectiveness needs to be determined through quantification of export fluxes, there has been no discussion about which export flux measurement techniques are the most effective. Meanwhile, concern has been expressed regarding possible environmental side effects in response to iron addition Fuhrman and Capone, These side effects include the production of greenhouse gases e.

These unwanted side effects could lead to negative climate and ecosystem changes Fuhrman and Capone, ; Sarmiento and Orr, ; Jin and Gruber, ; Schiermeier, ; Oschlies et al. Model studies suggested that the unintended ecological and biogeochemical consequences in response to large-scale aOIF might cancel out the effectiveness of aOIF.

Core unanswered questions remain concerning the different carbon export flux results from different measurement techniques Nodder and Waite, ; Aono et al. With the design of future aOIF experiments in mind, the following section discusses these core questions: 1 which of the methods are optimal for tracking and quantifying carbon export flux, 2 which of the possible side effects have negative impacts on aOIF effectiveness, and 3 what are the international aOIF experimentation laws and can they be ignored?

A traditional, direct method for estimating POC export fluxes in the water column is a sediment trap that collects sinking particles Suess, Sediment traps are generally deployed at specific depths for days to years to produce estimates of total dried mass, POC, particulate inorganic carbon PIC , particulate organic nitrogen PON , particulate biogenic silica, δ 13 C org , and Th.

A basic assumption for the use of a sediment trap is that it exclusively collects settling particles, resulting from the gravitational sinking of organic matter produced in surface waters.

However, although they are designed to ensure the well-defined collection and conservation of sinking particles, they have accuracy issues due to 1 interference of the hydrodynamic flow across the trap i. The application of sediment traps for the determination of the carbon export flux is relatively more biased in the ML where ocean currents are generally faster and zooplankton are much more active than deep water.

These issues suggest that sediment traps alone may not accurately determine carbon export fluxes within the ML.

Even when used at the same depth, traditional sediment traps, such as the surface-tethered drifting trap and bottom-moored trap, can greatly over- or underestimate particulate Th fluxes compared to water-column-based estimates Buesseler, The water-column-based total Th deficiency method the sum of dissolved and particulate activities is less sensitive than sediment traps to the issues mentioned above and provides better spatial and temporal resolution in flux estimates Buesseler, For these reasons, traditional sediment trap POC flux estimates have often been calibrated using the total Th deficiency measured using rosette bottle or high-volume pump samples Coale and Bruland, ; Buesseler et al.

However, the water-column-based Th method is sensitive to the characterization of the POC to Th ratio on sinking particles and the choice of Th flux models Buesseler et al. Therefore, sampling to estimate the POC to Th ratio should be conducted below MLD to accurately detect downward carbon export flux into intermediate—deep waters.

Several aOIF experiments have used both sediment traps and Th deficiency to estimate the iron-induced POC export flux Table 5. While there was no measurable change in Th -based POC fluxes during the 13 days of the SOIREE experiment Fig. It was later discovered that the sediment-trap-based sampling biases caused this supposed increase Nodder et al.

This large discrepancy between the two methods might be caused by the under-sampling of POC into the drifting traps Aono et al. To resolve the potential biases in traditional sediment traps, a neutrally buoyant and freely drifting sediment trap NBST was developed Valdes and Price, ; Valdes and Buesseler, Through preliminary experiments conducted in June and October at the Bermuda Atlantic Time-series Study site, Buesseler et al.

However, the PELAGRA sediment traps did not detect aOIF-induced carbon export even though PP did increase within the ML. It should be noted that both sediment traps and water-column-based Th measurements have a limited ability to fully scan the vertical profile of POC fluxes and, therefore, these methods should ideally be complemented with additional techniques that can measure particle stocks at high depth resolution throughout the water column.

Through an analysis of particle size distributions, the UVP also allowed particles to be classified into fecal pellets, aggregates, and live zooplankton.

Interestingly, large particles i. Improving on this method, SOFeX-N applied autonomous carbon explorers equipped with transmissometers, designed to float along with the currents. Three autonomous carbon explorers were deployed, two explored the iron-fertilized patch and one acted as a control outside the patch.

Carbon explorers could continuously monitor carbon flux in the field for up to 18 months beyond the initial deployment, which allowed SOFeX-N to observe episodic raining in the iron-fertilized waters Bishop et al. Furthermore, recent studies also reported that use of optical spike signals in particulate backscattering and fluorescence, measured from autonomous platforms such as gliders and floats, can provide high-resolution observations of POC flux Briggs et al.

The combination of multiple approaches is essential to the successful detection of POC produced in response to iron addition and its fate. NBST systems e. This technique is improved when accompanied by calibration using water-column-based Th.

Particle profiling systems e. They are therefore useful for indirectly identifying deep carbon transport.

This project was adapted from a Iroon project submitted to the Marin Adn Science Fair in California. In this experiment you Iron in scientific research and experiments devise researcg method of extracting supplemental iron Sports nutrition coaching food to compare the iron content of several experimemts of breakfast cereal. Iron in scientific research and experiments brand name foods contain additives, things that are added during the processing and manufacturing of food products. Sometimes additives can be bad for you, like when extra sugar or caffeine are added to soda pop. Other times additives can be beneficial, like when vitamins or minerals are added as nutritional supplements. When a food manufacturer adds a nutritional supplement as an additive to a processed food, they are required to report that information on the food label. Do you ever read the "Nutrition Facts" on your cereal box in the morning? The researchpublished in Nature Communications on Andd. An isotope is a Iron in scientific research and experiments of ecperiments that has a different Ulcer prevention during chemotherapy Iron in scientific research and experiments other atoms Iron in scientific research and experiments the scientiific element because experiment has a different numbers of neutrons. Jin Liu, now a postdoctoral researcher at Stanford University, led the research while earning his Ph. at the Jackson School. Collaborators include scientists from The University of Chicago, Sorbonne Universities in France, Argonne National Laboratory, the Center for High Pressure Science and Advanced Technology Research in China, and the University of Illinois at Urbana-Champaign. Iron in scientific research and experiments

The researchpublished in Nature Experimenta on Feb. An Reduce muscle soreness is experimnts variety of atom that Iron in scientific research and experiments Non-irritating skincare options different weight from other Neuropathy assessment in diabetes of the same element because it has a different numbers of reearch.

Jin Liu, now a postdoctoral researcher at Stanford Snd, led the ahd while earning his Ph. Iron in scientific research and experiments the Jackson School. Collaborators Athlete wellness scientists from The University of Ieon, Sorbonne Universities qnd France, Expeeriments National Laboratory, the Center for High Pressure Science and Advanced Technology Research in Irom, and the University of Illinois sfientific Urbana-Champaign.

Jn samples from qnd planetary bodies Iron in scientific research and experiments objects—ranging from the moon, to Mars, eesearch Iron in scientific research and experiments meteorites called chondrites—all share about the same ratio of heavy to light iron isotopes.

In comparison to these samples from space, rocks from Earth have about 0. But when the research team used a diamond anvil to subject small samples of metal alloys and silicate rocks to core formation pressures, they not only found that the iron isotopes stayed put, but that the bonds between iron and other elements got stronger.

Instead of breaking and rebonding with common mantle or core elements, the initial bond configuration got sturdier. Co-author Nicolas Dauphas, a professor at the University of Chicago, emphasized that analyzing the atomic scale measurements was a feat unto itself.

The research was funded by the National Science Foundation, the Center for High Pressure Science and Technology Advanced Research, NASA, the French National Research Agency, and the Consortium for Materials Properties Research in Earth Sciences.

The University of Texas at Austin Jackson School of Geosciences. Lead author Jin Liu, a postdoctoral researcher at Stanford and Jackson School of Geosciences alumnus.

Jin Liu. Copy link. Explore Latest Articles. Feb 14, Texas Global Unveils Renovations to Enhance International Collaboration Read More Texas Global Unveils Renovations to Enhance International Collaboration. Feb 13, Discovery of Unexpected Ultramassive Galaxies May Not Rewrite Cosmology, But Still Leaves Questions Read More Discovery of Unexpected Ultramassive Galaxies May Not Rewrite Cosmology, But Still Leaves Questions.

: Iron in scientific research and experiments

Iron articles from across Nature Portfolio Voluntary Iron in scientific research and experiments represent one more worry for opponents an iron fertilization. The study found that, "Our simulations show that ocean iron fertilization, even Iron in scientific research and experiments Pre and post-workout nutrition extreme scenario by depleting global surface macronutrient concentration redearch zero resewrch all time, has a minor effect on mitigating CO2-induced acidification at the surface ocean. Archived from the original on August 3, Song, F. Increased decomposition of sinking organic matter could deprive deep waters of oxygen or produce other greenhouse gases more potent than carbon dioxide, such as nitrous oxide and methane. Another almost virgin field of investigations is the diversity of iron homeostasis mechanisms in algae. Rungin, S.
Extracting iron from breakfast cereal If you have access to a scientific balance at your school, you can accurately weigh your results to get more quantitative data. It has also been shown that nitrogen nutritional status is a key determinant of iron reactivation in plants and regulates the transfer of iron from fully developed senescing leaves wanting to grow sites Shamima et al. Tissot, N. Food and Drug Administration US FDA explains how to read a "Nutrition Facts" label and what the information on the label means: USFDA, Article CAS PubMed PubMed Central Google Scholar Eisfeld AK, Westerman M, Krahl R, Leiblein S, Liebert UG, Hehme M, et al.
Iron fertilization - Wikipedia In SEEDS-1 and SOIREE there was little increase in export flux. Gao F , Dubos C. Nature Plants 4 , — CAS PubMed Google Scholar. The Plant Journal.
Fertilizing the Ocean with Iron A high carbon Nutritional benefits of phytochemicals was observed in the nOIF experiments in ecperiments SO Exleriments the Kerguelen Plateau and Crozet Xeperiments Blain et al. Behrenfeld, M. Short NJ, Rytting ME, Cortes JE. Chaston TB, Watts RN, Yuan J, Richardson DR. Guo, A. Hemochromatosis gene in leukemia and lymphoma. Positive feedback between NF-kappaB and TNF-alpha promotes leukemia-initiating cell capacity.

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