Increased Iron Supply Research Articles

A single approach to targeting transferrin receptor 2 corrects iron and erythropoietic defects in murine models of anemia of inflammation and chronic kidney disease

Anemia is a common complication of systemic inflammation. Proinflammatory cytokines both decrease erythroblast sensitivity to erythropoietin (EPO) and increase the levels of the hepatic hormone hepcidin, sequestering iron in stores and causing functional iron deficiency. Anemia of chronic kidney disease (CKD) is a peculiar form of anemia of inflammation, characterized by impaired EPO production paralleling progressive kidney damage. Traditional therapy based on increased EPO (often in combination with iron) may have off-target effects due to EPO interaction with its non-erythroid receptors. Transferrin Receptor 2 (Tfr2) is a mediator of the iron-erythropoiesis crosstalk. Its deletion in the liver hampers hepcidin production, increasing iron absorption, whereas its deletion in the hematopoietic compartment increases erythroid EPO sensitivity and red blood cell production. Here, we show that selective hematopoietic Tfr2 deletion ameliorates anemia in mice with sterile inflammation in the presence of normal kidney function, promoting EPO responsiveness and erythropoiesis without increasing serum EPO levels. In mice with CKD, characterized by absolute rather than functional iron deficiency, Tfr2 hematopoietic deletion had a similar effect on erythropoiesis but anemia improvement was transient because of limited iron availability. Also, increasing iron levels by downregulating only hepatic Tfr2 had a minor effect on anemia. However, simultaneous deletion of hematopoietic and hepatic Tfr2, stimulating erythropoiesis and increased iron supply, was sufficient to ameliorate anemia for the entire protocol. Thus, our results suggest that combined targeting of hematopoietic and hepatic Tfr2 may be a therapeutic option to balance erythropoiesis stimulation and iron increase, without affecting EPO levels.

Manganese Limitation of Phytoplankton Physiology and Productivity in the Southern Ocean.

Although iron and light are understood to regulate the Southern Ocean biological carbon pump, observations have also indicated a possible role for manganese. Low concentrations in Southern Ocean surface waters suggest manganese limitation is possible, but its spatial extent remains poorly constrained and direct manganese limitation of the marine carbon cycle has been neglected by ocean models. Here, using available observations, we develop a new global biogeochemical model and find that phytoplankton in over half of the Southern Ocean cannot attain maximal growth rates because of manganese deficiency. Manganese limitation is most extensive in austral spring and depends on phytoplankton traits related to the size of photosynthetic antennae and the inhibition of manganese uptake by high zinc concentrations in Antarctic waters. Importantly, manganese limitation expands under the increased iron supply of past glacial periods, reducing the response of the biological carbon pump. Overall, these model experiments describe a mosaic of controls on Southern Ocean productivity that emerge from the interplay of light, iron, manganese and zinc, shaping the evolution of Antarctic phytoplankton since the opening of the Drake Passage.

Climate drivers of Southern Ocean phytoplankton community composition and potential impacts on higher trophic levels

Southern Ocean phytoplankton production supports rich Antarctic marine ecosystems comprising copepods, krill, fish, seals, penguins, and whales. Anthropogenic climate change, however, is likely to drive rearrangements in phytoplankton community composition with potential ramifications for the whole ecosystem. In general, phytoplankton communities dominated by large phytoplankton, i.e., diatoms, yield shorter, more efficient food chains than ecosystems supported by small phytoplankton. Guided by a large ensemble of Earth system model simulations run under a high emission scenario (RCP8.5), we present hypotheses for how anthropogenic climate change may drive shifts in phytoplankton community structure in two regions of the Southern Ocean: the Antarctic Circumpolar Current (ACC) region and the sea ice zone (SIZ). Though both Southern Ocean regions experience warmer ocean temperatures and increased advective iron flux under 21st century climate warming, the model simulates a proliferation of diatoms at the expense of small phytoplankton in the ACC, while the opposite patterns are evident in the SIZ. The primary drivers of simulated diatom increases in the ACC region include warming, increased iron supply, and reduced light from increased cloudiness. In contrast, simulated reductions in ice cover yield greater light penetration in the SIZ, generating a phenological advance in the bloom accompanied by a shift to more small phytoplankton that effectively consume available iron; the result is an overall increase in net primary production, but a decreasing proportion of diatoms. Changes of this nature may promote more efficient trophic energy transferviacopepods or krill in the ACC region, while ecosystem transfer efficiency in the SIZ may decline as small phytoplankton grow in dominance, possibly impacting marine food webs sustaining Antarctic marine predators. Despite the simplistic ecosystem representation in our model, our results point to a potential shift in the relative success of contrasting phytoplankton ecological strategies in different regions of the Southern Ocean, with ramifications for higher trophic levels.

Effectiveness of Dietary Interventions to Treat Iron-Deficiency Anemia in Women: A Systematic Review of Randomized Controlled Trials.

Iron-deficiency anemia is the most frequent nutritional deficiency, with women of reproductive age being particularly at risk of its development. The aim of the systematic review was to assess the effectiveness of dietary interventions to treat iron-deficiency anemia in women based on the randomized controlled trials. The systematic review was conducted according to the PRISMA guidelines and registered in the PROSPERO database (CRD42021261235). The searching procedure was based on PubMed and Web of Science databases, while it covered records published until June 2021. It included all randomized controlled trials assessing effectiveness of various dietary interventions on treatment of iron-deficiency anemia in women of childbearing age. The total number of 7825 records were screened, while 14 of them were finally included in the systematic review. The studies were screened, included, and reported, and the risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials by two independent researchers. The included studies compared the effectiveness of various dietary interventions with supplementation, placebo, control, or any other dietary intervention, while the assessed dietary interventions were based either on increasing iron supply and/or on increasing its absorption (by increasing vitamin C or vitamin D or decreasing phytate intake). The duration of applied intervention was diversified from 3 months or less, through 4 or 5 months, to half of a year or more. Among the assessed biochemical measures, the following were analyzed in majority of studies: hemoglobin, ferritin, transferrin receptor, hematocrit, and transferrin. The majority of included studies supported the influence of dietary interventions on the treatment of iron-deficiency anemia, as the applied dietary intervention was not effective in only three studies. The majority of included studies were assessed as characterized by medium risk of bias, while the overall risk was high for only four studies, which resulted from the randomization process, deviations from the intended interventions, and selection of the reported result. The majority of included studies were conducted for increasing iron supply and/or increasing vitamin C supply; however, only for the interventions including increasing iron supply and simultaneously increasing its absorption by vitamin C supply were all results confirmed effective. Vitamin D also seems to be an effective dietary treatment, but further studies are necessary to confirm the observations. Considering this fact, dietary interventions recommended for anemic female patients should include increased intake of iron and vitamin C.

Paleoproductivity variations and implications in the subarctic northwestern Pacific since MIS 7: Geochemical evidence

Knowledge of changes in marine primary productivity and export production in high-nutrient, low-chlorophyll regions of the subarctic NW Pacific Ocean is vital for understanding glacial-interglacial pCO2 variations induced by the biological pump mechanism. We conducted a multi-proxy of geochemical and biological productivity study of sedimentary core LV63-4-2, from the subarctic NW Pacific Ocean, spanning the last ~230 kyr (since ~MIS 7). The measurements included total organic carbon (TOC), opal, biogenic barium, and CaCO3 content as indicators of biological productivity; and the stable carbon isotope composition of TOC and trace elemental abundances to indicate sources of organic matter and redox conditions. The results reveal cyclic changes in paleoproductivity, with higher export production corresponding to periods of low Earth orbital obliquity and high winter insolation. Opal accumulation in core LV63-4-2 was higher during MIS 7, MIS 5d, and MIS 4, which differs from records from the Bering Sea, Okhotsk Sea, and the region to the south of the site LV63-4-2, but it is consistent with records from the Gulf of Alaska. We suggest that export production in the region is controlled by the combined effects of regional vertical convection associated with the formation of North Pacific Intermediate Water (NPIW), and the local iron supply sourced from the Gulf of Alaska. High export production is promoted by the coupling of weakened NPIW formation and an increased iron supply caused by enhanced upwelling in the Gulf of Alaska due to a strengthened Aleutian Low during warmer winters. By contrast, stronger NPIW formation dominated reduced export production during MIS 6 and MIS 2, despite an increased iron supply. Our results highlight the heterogeneity of export production in the subarctic North Pacific and the significant role of the local environment on productivity.

Soil chemistry determines whether defensive plant secondary metabolites promote or suppress herbivore growth

Plant secondary (or specialized) metabolites mediate important interactions in both the rhizosphere and the phyllosphere. If and how such compartmentalized functions interact to determine plant-environment interactions is not well understood. Here, we investigated how the dual role of maize benzoxazinoids as leaf defenses and root siderophores shapes the interaction between maize and a major global insect pest, the fall armyworm. We find that benzoxazinoids suppress fall armyworm growth when plants are grown in soils with very low available iron but enhance growth in soils with higher available iron. Manipulation experiments confirm that benzoxazinoids suppress herbivore growth under iron-deficient conditions and in the presence of chelated iron but enhance herbivore growth in the presence of free iron in the growth medium. This reversal of the protective effect of benzoxazinoids is not associated with major changes in plant primary metabolism. Plant defense activation is modulated by the interplay between soil iron and benzoxazinoids but does not explain fall armyworm performance. Instead, increased iron supply to the fall armyworm by benzoxazinoids in the presence of free iron enhances larval performance. This work identifies soil chemistry as a decisive factor for the impact of plant secondary metabolites on herbivore growth. It also demonstrates how the multifunctionality of plant secondary metabolites drives interactions between abiotic and biotic factors, with potential consequences for plant resistance in variable environments.

Long-term iron deprivation and subsequent recovery uncover heterogeneity in the response of cyanobacterial populations.

Cyanobacteria are globally important primary producers and nitrogen fixers. They are frequently limited by iron bioavailability in natural environments that often fluctuate due to rapid consumption and irregular influx of external Fe. Here we identify a succession of physiological changes in Synechocystis sp. PCC 6803 occurring over 14-16 days of iron deprivation and subsequent recovery. We observe several adaptive strategies that allow cells to push their metabolic limits under the restriction of declining intracellular Fe quotas. Interestingly, cyanobacterial populations exposed to prolonged iron deprivation showed discernible heterogeneity in cellular auto-fluorescence during the recovery process. Using FACS and microscopy techniques we revealed that only cells with high auto-fluorescence were able to grow and reconstitute thylakoid membranes. We propose that ROS-mediated damage is likely to be associated with the emergence of the two subpopulations, and, indeed, a rapid increase in intracellular ROS content was observed during the first hours following iron addition to Fe-starved cultures. These results suggest that an increasing iron supply is a double-edged sword - posing both an opportunity and a risk. Therefore, phenotypic heterogeneity within populations is crucial for the survival and proliferation of organisms facing iron fluctuations within natural environments.

Erythron to the Liver: Send Iron

For successful expansion of erythropoiesis, the activity of the hormone erythropoietin (EPO) must be coordinated with the supply of iron to erythroid precursors. Increased iron supply for erythropoiesis is ensured by the suppression of hepcidin, the iron-regulatory hormone produced by the liver. Low hepcidin levels allow greater absorption of dietary iron and greater mobilization of iron from the stores in the spleen and the liver. The mechanisms coordinating erythropoietic activity with iron delivery are not well understood. We recently identified erythroferrone as a new mediator of hepcidin suppression during stress erythropoiesis1. Erythroferrone (ERFE) is a member of the C1q/TNF-related protein (CTRP) family of metabolic mediators. ERFE is produced in response to EPO by erythroblasts of the bone marrow and spleen of mice. The induction of ERFE by EPO was dependent on Jak2/Stat5 signaling. Ex vivo treatment of human erythroblasts with EPO also resulted in a dramatic induction of ERFE expression. The essential role of ERFE in acute hepcidin suppression by erythropoiesis was demonstrated in ERFE-deficient mice. In contrast to wild-type mice which suppressed hepcidin ~10-fold within hours after hemorrhage or erythropoietin injection, no hepcidin suppression was observed in ERFE knockout mice within 24 h. As a consequence, ERFE-deficient mice exhibited delayed recovery of hemoglobin after hemorrhage or severe inflammation. Treatment of mice or hepatocytes with recombinant ERFE protein confirmed the hepcidin-suppressive activity of the protein. It remains to be seen whether administration of ERFE protein would be useful for the treatment of anemia of inflammation mediated by elevated hepcidin. In iron-loading anemias including β-thalassemia, hepcidin is chronically suppressed by the exuberant but ineffective erythropoietic activity. This is the cause of iron overload in untransfused thalassemia patients and may contribute to iron loading even in transfused patients. We found that ERFE expression is greatly increased in the bone marrow and spleen of mice with β-thalassemia intermedia (th3 model). Transgenic ablation of ERFE in th3 mice normalized hepcidin and partially corrected their iron overload. Although human studies of the role of ERFE in health and disease are clearly needed, ERFE is a promising candidate for the pathological suppressor of hepcidin in anemias with ineffective erythropoiesis.

The iron budget in ocean surface waters in the 20th and 21st centuries: projections by the Community Earth System Model version 1

Abstract. We investigated the simulated iron budget in ocean surface waters in the 1990s and 2090s using the Community Earth System Model version 1 and the Representative Concentration Pathway 8.5 future CO2 emission scenario. We assumed that exogenous iron inputs did not change during the whole simulation period; thus, iron budget changes were attributed solely to changes in ocean circulation and mixing in response to projected global warming, and the resulting impacts on marine biogeochemistry. The model simulated the major features of ocean circulation and dissolved iron distribution for the present climate. Detailed iron budget analysis revealed that roughly 70% of the iron supplied to surface waters in high-nutrient, low-chlorophyll (HNLC) regions is contributed by ocean circulation and mixing processes, but the dominant supply mechanism differed by region: upwelling in the eastern equatorial Pacific and vertical mixing in the Southern Ocean. For the 2090s, our model projected an increased iron supply to HNLC waters, even though enhanced stratification was predicted to reduce iron entrainment from deeper waters. This unexpected result is attributed largely to changes in gyre-scale circulations that intensified the advective supply of iron to HNLC waters. The simulated primary and export production in the 2090s decreased globally by 6 and 13%, respectively, whereas in the HNLC regions, they increased by 11 and 6%, respectively. Roughly half of the elevated production could be attributed to the intensified iron supply. The projected ocean circulation and mixing changes are consistent with recent observations of responses to the warming climate and with other Coupled Model Intercomparison Project model projections. We conclude that future ocean circulation has the potential to increase iron supply to HNLC waters and will potentially buffer future reductions in ocean productivity.

SKB1/PRMT5‐mediated histone H4R3 dimethylation of Ib subgroup bHLH genes negatively regulates iron homeostasis in Arabidopsis thaliana

Histone modifications play critical roles in the perception of environmental cues by plants. Here, we report that Shk1 binding protein 1 (SKB1/AtPRMT5), which catalyzes the symmetric dimethylation of histone H4R3 (H4R3sme2), is involved in iron homeostasis in Arabidopsis. The SKB1 lesion mutant exhibited higher iron accumulation in shoots and greater tolerance to iron deficiency than the wild type. The expression of SKB1 was not affected by iron, but the level of H4R3sme2 mediated by SKB1 was related to iron status in plants. We showed by chromatin immunoprecipitation (ChIP) and genome-wide ChIP-seq that SKB1 associated with the chromatin of the Ib subgroup bHLH genes (AtbHLH38, AtbHLH39, AtbHLH100 and AtbHLH101), and symmetrically dimethylated histone H4R3. The quantity of SKB1 that associated with chromatin of the Ib subgroup bHLH genes and the level of H4R3sme2 corresponded to the iron status of plants (higher with increased iron supply and lower when iron was removed). We conclude that SKB1-mediated H4R3sme2 regulates iron homeostasis in Arabidopsis in the context of increasing or decreasing expression of Ib subgroup bHLH genes. Iron deficiency may cause an increase in the disassociation of SKB1 from chromatin of the bHLH genes and a decrease in the level of H4R3sme2, thereby elevating their transcription and enhancing iron uptake. Our findings provide new insight into the molecular mechanisms of iron homeostasis in strategy I plants.

Effects of iron availability on pigment signature and biogenic silica production in the coastal diatomChaetoceros gracilis

The effects of iron availability on pigment signature and biogenic silica production were investigated for the first time in the coastal diatom Chaetoceros gracilis (isolated from the SW coast of the Bay of Bengal, India). Results revealed that increase in iron supply considerably increases chlorophyll a based specific growth rates, whereas, it decreases the values of diatoxanthin index and photoprotective to light harvesting pigment ratios. It is likely that, under iron stress C. gracilis activated a strong photoprotection mechanism by maximising the conversion of diadinoxanthin to diatoxanthin and by increasing overall amount of photoprotective pigments relative to light harvesting pigments. The xanthophyll cycle comprising of diadinoxanthin and diatoxanthin seems to be the principal photoprotective mechanism in C. gracilis and is consistent with some earlier studies. It is suggested that under iron limited conditions the diatoxanthin index and the ratio of photoprotective to light harvesting pigments can be used as physiological markers for iron stress in C. gracilis. The ratios of biogenic silica to chlorophyll a were considerably decreased with increasing iron supply indicating the possibility of reduced cellular silica content under iron enriched conditions; however, supplementary information is required to confirm this observation.

Effects of iron availability on pigment signature and biogenic silica production in the coastal diatom Chaetoceros gracilis

The effects of iron availability on pigment signature and biogenic silica production were investigated for the first time in the coastal diatom Chaetoceros gracilis (isolated from the SW coast of the Bay of Bengal, India). Results revealed that increase in iron supply considerably increases chlorophyll a based specific growth rates, whereas, it decreases the values of diatoxanthin index and photoprotective to light harvesting pigment ratios. It is likely that, under iron stress C. gracilis activated a strong photoprotection mechanism by maximising the conversion of diadinoxanthin to diatoxanthin and by increasing overall amount of photoprotective pigments relative to light harvesting pigments. The xanthophyll cycle comprising of diadinoxanthin and diatoxanthin seems to be the principal photoprotective mechanism in C. gracilis and is consistent with some earlier studies. It is suggested that under iron limited conditions the diatoxanthin index and the ratio of photoprotective to light harvesting pigments can be used as physiological markers for iron stress in C. gracilis. The ratios of biogenic silica to chlorophyll a were considerably decreased with increasing iron supply indicating the possibility of reduced cellular silica content under iron enriched conditions; however, supplementary information is required to confirm this observation.

Effect of iron intake on iron status: a systematic review and meta-analysis of randomized controlled trials

The response of status biomarkers to an increase in iron supply depends on several physiologic and environmental factors, which make it difficult to predict the outcome of an intervention. We assessed effects of baseline iron status, sex, menopausal status, duration of intervention, iron form, and daily dose on the change in iron status in response to iron supplementation. A systematic review of randomized controlled trials (RCTs) of iron-supplementation and -fortification trials that assessed effects on hemoglobin, serum ferritin (SF), soluble transferrin receptor, or body iron was conducted. Subgrouping and straight-line and curved metaregression were used to describe the magnitude and dose-responsiveness of effect modifiers with respect to changes in status. Forty-one RCTs were included; none of the RCTs were judged at low risk of bias. Random-effects meta-analyses showed that iron supplementation significantly improved iron status but with high levels of heterogeneity. Metaregression explained approximately one-quarter of between-study variance in effect size. There were clear effects on SF with study duration (increase in SF concentration/wk: 0.51 μg/L; 95% CI: 0.02, 1.00 μg/L; P = 0.04) and dose (increase in SF concentration/g Fe: 0.10 μg/L; 95% CI: 0.01, 0.20 μg/L; P = 0.036) and on hemoglobin concentrations with baseline iron status [-0.08 g/dL (95% CI: 0.15, 0.00 g/dL) per 10-μg/L increase in baseline SF concentration; P = 0.02]. Insufficient data were available to assess effects on body iron, sex, or menopausal status. Quantitative relations between baseline iron status, study duration, and iron dose on changes in iron-status biomarkers, which were generated from the meta-analyses, can be used to predict effects of trials of iron supplementation and fortification and to design iron-intervention programs.

Relationship between vitamin D deficiency, bone remodelling and iron status in iron-deficient young women consuming an iron-fortified food

Iron and vitamin D deficiencies are two of the most widespread nutritional disorders in the world. Our aim was to know whether the consumption of an iron-fortified fruit juice modifies bone remodelling and the possible influence of baseline vitamin D status on the recovery of iron status in a group of iron-deficient women. Iron biomarkers, 25-hydroxyvitamin D levels and dietary intake were measured in 123 iron-deficient menstruating women. A subgroup (n = 41) participated in a randomised double-blind placebo-controlled study of 16-weeks during winter. They consumed a placebo fruit juice (P) or iron-fortified fruit juice (F). Dietary intake, 25-hydroxyvitamin D, parathormone (PTH), bone alkaline phosphatase (ALP), aminoterminal telopeptide of collagen I (NTX) and iron biomarkers were determined. Ninety-two per cent of the iron-deficient women were vitamin D deficient or insufficient. Transferrin saturation and 25-hydroxyvitamin D were positively correlated. Iron status improved in F, 25-hydroxyvitamin D decreased in F and P, and PTH, ALP and NTX levels were within the normal range and did not vary. Women with 25-hydroxyvitamin D ≥ 50 nmol/L compared with 25-hydroxyvitamin D < 50 nmol/L showed a higher increase in transferrin saturation (a marker of iron supply to tissues) during iron recovery. The prevalence of vitamin D deficiency or insufficiency is very high in iron-deficient women. The recovery of iron status by consuming an iron-fortified food does not affect 25-hydroxyvitamin D levels; however, the increase in iron supply to tissues is lower if the women also present vitamin D deficiency. Although bone health does not seem to be affected in this group of women, correction of iron and vitamin D deficiencies should be promoted in young women to improve present and future health.

Magnetotactic bacterial response to Antarctic dust supply during the Palaeocene–Eocene thermal maximum

Distinct magnetic properties of marine sediments that record the Palaeocene–Eocene thermal maximum (PETM) have been suggested to be due to a bacterial magnetofossil signal that is linked to enhanced weathering conditions during the PETM. We document the dominance of bacterial magnetite in deep-sea sediments from southern Kerguelen Plateau (Ocean Drilling Program Hole 738C, southern Ocean) not only during the PETM, but also before and after the thermal event. This occurrence of magnetofossils throughout the PETM indicates that the occurrence of bacterial magnetosomes is not due to a preservation effect. Instead, we suggest that it is due to sustained mild iron-reducing conditions that dissolved the most labile aeolian-derived iron, which favoured continued magnetotactic bacterial activity without being strong enough to dissolve the less reactive magnetite and haematite. Enhanced aeolian haematite abundances at the beginning of the PETM indicate drier conditions on the neighbouring Antarctic continent at those times. Our results provide evidence that iron fertilisation by aeolian dust was the main limiting factor that conditioned proliferation of magnetotactic bacteria in the deep sea at the southern Kerguelen Plateau, with the exception of two short periods of rapidly changing palaeoenvironmental conditions at the onset and termination of the PETM. Increased iron supply from aeolian dust, that enhanced oceanic primary productivity and subsequent delivery of organic carbon to the seafloor, along with mild iron-reducing diagenetic conditions, seem to have been necessary to provide the iron needed for magnetite biomineralization by magnetotactic bacteria to drive their marked increase in abundance in the studied PETM record from southern Kerguelen Plateau. Our analyses of a deep-sea PETM record from Hole 1051B at Blake Nose (Atlantic Ocean) failed to identify magnetofossils despite evidence for the occurrence of magnetite and haematite of probable aeolian origin. Contrasting magnetic properties at these PETM sections indicate that further work is needed to understand the palaeoenvironmental and diagenetic factors whose interactions lead to production and preservation of magnetofossils in deep-sea sediments.

Seasonal and spatial dynamics of iron availability in the Scotia Sea

The Southern Ocean is the world's largest high nutrient low chlorophyll (HNLC) region. However, satellite images highlight several areas associated with island chains and shallow topographic features which display high phytoplankton biomass. Here we present the first study of seasonal variations in phytoplankton biomass and iron availability in the Scotia Sea over both austral spring and summer seasons. Based on dissolved iron (dFe) and Chlorophyll a (Chl a) concentrations, the study area is be divided into three regions: North of South Georgia, south of South Georgia and the vicinity of South Orkney Islands. The Scotia Sea to the south of South Georgia exhibited low dFe concentrations (<0.027–0.05nM) in surface waters during both the spring and summer seasons. Nevertheless, nitrate concentrations were considerably lower in spring compared to summer (difference ~8μM). Summer Chl a concentrations were ~1.4mgm−3 and in situ phytoplankton populations displayed evidence of iron stress, suggesting the development of seasonal iron limitation. Surface water dFe concentrations in the South Georgia bloom waters (north of the islands) were elevated and slightly lower during spring than summer (0.20nM compared to 0.31nM, P>0.05). Nitrate concentrations were 16μM lower in summer compared to spring, whilst Chl a standing stocks remained high. Enhanced dFe (~0.25nM) and Chl a concentrations were furthermore observed in the vicinity of the South Orkney Islands, located in the southern Scotia Sea. Iron addition experiments showed that in situ phytoplankton were iron replete spring and summer north of South Georgia and in the vicinity of South Orkney Islands during summer. We thus suggest that increased iron supply in high productivity areas including the area north of South Georgia and the South Orkney Islands, was sustained by a continuous benthic supply from their shelf systems, with a potential additional input from seasonally retreating sea ice in the South Orkney system.

Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project

AbstractIron is tightly connected to oxygen homeostasis and erythropoiesis. Our aim was to better understand how hypoxia regulates iron acquisition for erythropoiesis in humans, a topic relevant to common hypoxia-related disorders. Forty-seven healthy volunteers participated in the HIGHCARE project. Blood samples were collected at sea level and after acute and chronic exposure to high altitude (3400-5400 m above sea level). We investigated the modifications in hematocrit, serum iron indices, erythropoietin, markers of erythropoietic activity, interleukin-6, and serum hepcidin. Hepcidin decreased within 40 hours after acute hypoxia exposure (P < .05) at 3400 m, reaching the lowest level at 5400 m (80% reduction). Erythropoietin significantly increased (P < .001) within 16 hours after hypoxia exposure followed by a marked erythropoietic response supported by the increased iron supply. Growth differentiation factor-15 progressively increased during the study period. Serum ferritin showed a very rapid decrease, suggesting the existence of hypoxia-dependent mechanism(s) regulating storage iron mobilization. The strong correlation between serum ferritin and hepcidin at each point during the study indicates that iron itself or the kinetics of iron use in response to hypoxia may signal hepcidin down-regulation. The combined and significant changes in other variables probably contribute to the suppression of hepcidin in this setting.

Dissolved iron supply limits early growth of estuarine mangroves

Three mesocosm experiments were performed in an outdoor facility to quantify the responses of five mangrove species grown from seedling to sapling stage to increasing rates of dissolved iron supply. Stem extension and biomass of mangroves were measured in the first two experiments, and in the third experiment, rates of microbial iron reduction were measured in relation to stem extension of two mangrove species. In all experiments, mangrove growth was enhanced by increasing iron supply, although some species showed iron toxicity at the higher supply rates. In the first two experiments, stem extension rates of Rhizophora apiculata, Bruguiera gymnorrhiza, and Xylocarpus moluccensis best fit Gaussian curves with maximal growth at supply rates of 50-60 mmol Fe x m(-2) x d(-1), whereas growth of Avicennia marina and Ceriops tagal increased to the highest rate (100 mmol Fe x m(-2) x d(-1)) of iron supply. Changes in leaf chlorophyll concentrations and iron content of roots mirrored the growth responses. In the third experiment, rates of microbial iron reduction were greater with R. apiculata and A. marina than in controls without plants; for both species, there was a positive relationship between stem extension and iron reduction. The rates of iron reduction and rates of iron supplied to the plants were well within the range of interstitial iron concentrations and rates of iron reduction found in the natural mangrove soils from which the seedlings were obtained. The responses of these species show that mangroves growing from seedling to sapling stage have a strong nutritional requirement for iron, and that there is a close relationship between plant roots and the activities of iron-reducing bacteria. These results suggest that mangrove growth may be limited in some natural forests by the rate at which iron is solubilized by iron-reducing bacteria. Such biogeochemical conditions have significant implications for successful recruitment, establishment, and early growth of mangroves.

Quinolone compounds enhance -aminolevulinic acid-induced accumulation of protoporphyrin IX and photosensitivity of tumour cells

Exogenous δ-aminolevulinic acid (ALA)-induced photodynamic therapy (PDT) has been used in the treatment of cancer. To obtain a high efficacy of ALA-PDT, we have screened various chemicals affecting ALA-induced accumulation of protoporphyrin in cancerous cells. When HeLa cells were treated with quinolone chemicals including enoxacin, ciprofloxacin or norfloxacin, the ALA-induced photodamage accompanied by the accumulation of protoporphyrin was stronger than that with ALA alone. Thus, quinolone compounds such as enoxacin, ciprofloxacin and norfloxacin enhanced ALA-induced photodamage. The increased ALA-induced photodamage in enoxacin-treated HeLa cells was decreased by haemin or ferric-nitrilotriacetate (Fe-NTA), suggesting that an increase in iron supply cancels the accumulation of protoporphyrin. On the other hand, the treatment of the cells with ALA plus an inhibitor of haem oxygenase, Sn-protoporphyrin, led to an increase in the photodamage and the accumulation of protoporphyrin compared with those upon treatment with ALA alone, indicating that the cessation of recycling of iron from haem augments the accumulation. The use of quinolones plus Sn-protoporphyrin strongly enhances ALA-induced photodamage. To examine the mechanisms involved in the increased accumulation of protoporphyrin, we incubated ferric chloride with an equivalent amount of quinolones. Iron-quinolone complexes with visible colours with a maximum at 450 nm were formed. The levels of iron-metabolizing proteins in enoxacin- or ciprofloxacin-treated cells changed, indicating that quinolones decrease iron utilization for haem biosynthesis. Hence, we now propose that the use of quinolones in combination with ALA may be an extremely effective approach for the treatment modalities for PDT of various tumour tissues in clinical practice.

Inflammation, Multiple Blood Transfusions and Osteoclast Activation in Sickle Cell Disease Patients.

Abstract 1534Poster Board I-557 BackgroundLow bone mass density affects more than 65% of adult sickle cell disease patients and correlates with lower hemoglobin and higher ferritin concentrations (1). Increased iron supply promotes osteoclast differentiation and bone resorption (2). Proinflammatory cytokines also promote bone resorption (3). Tartrate resistant acid phosphatase isoform 5b (TRACP-5b) is produced only by activated osteoclasts and therefore serves as a marker of bone resorption (4). Sickle cell disease is a condition of chronic inflammation and patients often suffer from transfusional iron overload as well. In this study we aimed to determine the predictors of bone resorption in patients with sickle cell disease by measuring circulating levels of TRACP-5b. MethodsFifty-nine adult sickle cell disease patients and 22 apparently healthy controls were recruited at Howard University Hospital. Patients were at steady state with no crisis, hospitalization or blood transfusion in the last 3 weeks. Clinical and laboratory information was collected at the time of recruitment and TRACP-5b was measured in non-fasting serum samples using an enzyme immuno assay kit (Quidel, San Diego, CA). Serum concentrations of inflammatory cytokines and growth factors were measured by Multiplex assay (Bio-Rad, Hercules, CA).. ResultsSickle cell disease patients had elevated concentrations of TRACP-5b compared to controls (median values of 4.4 vs. 2.4 U/l, P < 0.0001). Among the patients, TRACP-5b concentrations correlated positively with number of blood transfusions (r = 0.19) and serum concentrations of alkaline phosphatase (r=0.46), endothelin-1 (r=0.39), interleukin-8 (r= 0.38), and interleukin-6 (r=0.25). TRACP-5b correlated negatively with RANTES (r = -0.42) and PDGF (r = -0.31). It did not correlate significantly with serum ferritin (r = -0.03), LDH (r = 0.13) or hemoglobin concentration (r = 0.11). Interestingly, TRACP-5b correlated positively with tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure (r = 0.30). ConclusionSickle cell patients have elevated steady-state osteoclast activity as reflected in serum TRACP-5b concentrations. Multiple blood transfusions and inflammation are associated findings. Among patients, higher TRACP-5b concentrations are associated with lower concentrations of RANTES and PDGF-BB, factors that influence function of osteoblasts. Further studies are needed to investigate whether common pathways may be involved in osteoclast activation and pulmonary changes in sickle cell disease.Supported by grants number 2 R25 HL003679-08 and 1 R01 HL079912-02 and 1U54HL090508-01 from NHLBI, by Howard University GCRC grant no 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, and by the intramural research program of the National Institutes of Health. DisclosuresGordeuk:Biomarin: Research Funding; TRF Pharma: Research Funding; Merck: Research Funding; Novartis: Speakers Bureau.