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Polycythemia and pulmonary hypertension are 2 human diseases for which better therapies are needed. Upregulation of hypoxia-inducible factor-2α (HIF-2α) and its target genes, erythropoietin (EPO) and endothelin-1, causes polycythemia and pulmonary hypertension in patients with Chuvash polycythemia who are homozygous for the R200W mutation in the von Hippel Lindau (VHL) gene and in a murine mouse model of Chuvash polycythemia that bears the same homozygous VhlR200W mutation. Moreover, the aged VhlR200W mice developed pulmonary fibrosis, most likely due to the increased expression of Cxcl-12, another Hif-2α target. Patients with mutations in iron regulatory protein 1 (IRP1) also develop polycythemia, and Irp1-knockout (Irp1-KO) mice exhibit polycythemia, pulmonary hypertension, and cardiac fibrosis attributable to translational derepression of Hif-2α, and the resultant high expression of the Hif-2α targets EPO, endothelin-1, and Cxcl-12. In this study, we inactivated Hif-2α with the second-generation allosteric HIF-2α inhibitor MK-6482 in VhlR200W, Irp1-KO, and double-mutant VhlR200W;Irp1-KO mice. MK-6482 treatment decreased EPO production and reversed polycythemia in all 3 mouse models. Drug treatment also decreased right ventricular pressure and mitigated pulmonary hypertension in VhlR200W, Irp1-KO, and VhlR200W;Irp1-KO mice to near normal wild-type levels and normalized the movement of the cardiac interventricular septum in VhlR200Wmice. MK-6482 treatment reduced the increased expression of Cxcl-12, which, in association with CXCR4, mediates fibrocyte influx into the lungs, potentially causing pulmonary fibrosis. Our results suggest that oral intake of MK-6482 could represent a new approach to treatment of patients with polycythemia, pulmonary hypertension, pulmonary fibrosis, and complications caused by elevated expression of HIF-2α.

Herein, we report the first Ni-catalyzed enantioselective deaminative alkylation of amino acid and peptide derivatives with unactivated olefins. Key for success was the discovery of a new sterically encumbered bis(oxazoline) ligand backbone, thus offering a de novo technology for accessing enantioenriched

To maintain an adequate iron supply for hemoglobin synthesis and essential metabolic functions while counteracting iron toxicity, humans and other vertebrates have evolved effective mechanisms to conserve and finely regulate iron concentration, storage, and distribution to tissues. At the systemic level, the iron-regulatory hormone hepcidin is secreted by the liver in response to serum iron levels and inflammation. Hepcidin regulates the expression of the sole known mammalian iron exporter, ferroportin, to control dietary absorption, storage and tissue distribution of iron. At the cellular level, iron regulatory proteins 1 and 2 (IRP1 and IRP2) register cytosolic iron concentrations and post-transcriptionally regulate the expression of iron metabolism genes to optimize iron availability for essential cellular processes, including heme biosynthesis and iron-sulfur cluster biogenesis. Genetic malfunctions affecting the iron sensing mechanisms or the main pathways that utilize iron in the cell cause a broad range of human diseases, some of which are characterized by mitochondrial iron accumulation. This review will discuss the mechanisms of systemic and cellular iron sensing with a focus on the main iron utilization pathways in the cell, and on human conditions that arise from compromised function of the regulatory axes that control iron homeostasis.

Ferroportin (FPN), the only known vertebrate iron exporter, transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues and cells in vivo. Most of the circulating iron is consumed by erythroid cells to synthesize hemoglobin. Here we found that erythroid cells not only consumed large amounts of iron, but also returned significant amounts of iron to the blood. Erythroblast-specific Fpn knockout (Fpn KO) mice developed lower serum iron levels in conjunction with tissue iron overload and increased FPN expression in spleen and liver without changing hepcidin levels. Our results also showed that Fpn KO mice, which suffer from mild hemolytic anemia, were sensitive to phenylhydrazine-induced oxidative stress but were able to tolerate iron deficiency upon exposure to a low-iron diet and phlebotomy, supporting that the anemia of Fpn KO mice resulted from erythrocytic iron overload and resulting oxidative injury rather than a red blood cell (RBC) production defect. Moreover, we found that the mean corpuscular volume (MCV) values of gain-of-function FPN mutation patients were positively associated with serum transferrin saturations, whereas MCVs of loss-of-function FPN mutation patients were not, supporting that erythroblasts donate iron to blood through FPN in response to serum iron levels. Our results indicate that FPN of erythroid cells plays an unexpectedly essential role in maintaining systemic iron homeostasis and protecting RBCs from oxidative stress, providing insight into the pathophysiology of FPN diseases.

Heme oxygenase 1 (HMOX1), the inducible enzyme that catabolizes the degradation of heme into biliverdin, iron, and carbon monoxide, plays an essential role in the clearance of senescent and damaged red blood cells, systemic iron homeostasis, erythropoiesis, vascular hemostasis, and oxidative and inflammatory stress responses. In humans, HMOX1 deficiency causes a rare and lethal disease, characterized by severe anemia, intravascular hemolysis, as well as vascular and tissue damage. Hmox1 knockout (KO) mice recapitulated the phenotypes of HMOX1-deficiency patients and could be rescued by bone marrow (BM) transplantation that engrafted donor’s hematopoietic stem cells into the recipient animals after myeloablation. To find better therapy and elucidate the contribution of macrophages to the pathogenesis of HMOX1-deficiency disease, we infused wild-type (WT) macrophages into Hmox1 KO mice. Results showed that WT macrophages engrafted and proliferated in the livers of Hmox1 KO mice, which corrected the microcytic anemia, rescued the intravascular hemolysis, restored iron homeostasis, eliminated kidney iron overload and tissue damage, and provided long-term protection. These results showed that a single macrophage infusion delivered a long-term curative effect in Hmox1 KO mice, obviating the need for BM transplantation, and suggested that the HMOX1 disease stems mainly from the loss of viable reticuloendothelial macrophages. Our work provides new insights into the etiology of HMOX1 deficiency and demonstrates the potential of infusion of WT macrophages to prevent disease in patients with HMOX1 deficiency and potentially other macrophage-related diseases.

Given the essential roles of iron-sulfur (Fe-S) cofactors in mediating electron transfer in the mitochondrial respiratory chain and supporting heme biosynthesis, mitochondrial dysfunction is a common feature in a growing list of human Fe-S cluster biogenesis disorders, including Friedreich ataxia and GLRX5-related sideroblastic anemia. Here, our studies showed that restriction of Fe-S cluster biogenesis not only compromised mitochondrial oxidative metabolism but also resulted in decreased overall histone acetylation and increased H3K9me3 levels in the nucleus and increased acetylation of α-tubulin in the cytosol by decreasing the lipoylation of the pyruvate dehydrogenase complex, decreasing levels of succinate dehydrogenase and the histone acetyltransferase ELP3, and increasing levels of the tubulin acetyltransferase MEC17. Previous studies have shown that the metabolic shift in Toll-like receptor (TLR)-activated myeloid cells involves rapid activation of glycolysis and subsequent mitochondrial respiratory failure due to nitric oxide (NO)-mediated damage to Fe-S proteins. Our studies indicated that TLR activation also actively suppresses many components of the Fe-S cluster biogenesis machinery, which exacerbates NO-mediated damage to Fe-S proteins by interfering with cluster recovery. These results reveal new regulatory pathways and novel roles of the Fe-S cluster biogenesis machinery in modifying the epigenome and acetylome and provide new insights into the etiology of Fe-S cluster biogenesis disorders.

Ti-6Al-4V (wt%) alloy samples with dog-bone and box shapes respectively were fabricated by selective laser melting (SLM). The microstructures and mechanical properties of the 3D printed Ti-6Al-4V samples with and without heat treatment were characterized and tested. The microstructures of the as-fabricated dog-bone shaped samples were mainly composed of acicular α’ phase. After annealing at 700°C, the acicular α’ phase changed into an α/β lamellar structure. After solution treatment at 955°C, water quenching and aging at 550°C, the microstructure was mainly composed of primary α phase and α/β lamellar structure. The optimum heat treatment is annealing, and the mechanical properties of the annealed sample are as follows: yield strength: 1015 MPa, ultimate tensile strength (UTS): 1083 MPa and elongation to fracture: 7.9%. The microstructures of the box-shaped samples after annealing mainly consist of α phase and α/β lamellar structure. When stretched along the direction parallel to the crystal growth direction, the yield strength and UTS of the sample are 1054 and 1090 MPa，and its elongation to fracture is 6.3%. When stretched along the direction perpendicular to the crystal growth direction, the yield strength and UTS of the sample are 1019 and 1068 MPa respectively, and its elongation to fracture is 8.7%.

Developing erythrocytes take up exceptionally large amounts of iron, which must be transferred to mitochondria for incorporation into heme. This massive iron flux must be precisely controlled to permit the coordinated synthesis of heme and hemoglobin while avoiding the toxic effects of chemically reactive iron. In cultured animal cells, iron chaperones poly rC-binding protein 1 (PCBP1) and PCBP2 deliver iron to ferritin, the sole cytosolic iron storage protein, and nuclear receptor coactivator 4 (NCOA4) mediates the autophagic turnover of ferritin. The roles of PCBP, ferritin, and NCOA4 in erythroid development remain unclear. Here, we show that PCBP1, NCOA4, and ferritin are critical for murine red cell development. Using a cultured cell model of erythroid differentiation, depletion of PCBP1 or NCOA4 impaired iron trafficking through ferritin, which resulted in reduced heme synthesis, reduced hemoglobin formation, and perturbation of erythroid regulatory systems. Mice lacking Pcbp1 exhibited microcytic anemia and activation of compensatory erythropoiesis via the regulators erythropoietin and erythroferrone. Ex vivo differentiation of erythroid precursors from Pcbp1-deficient mice confirmed defects in ferritin iron flux and heme synthesis. These studies demonstrate the importance of ferritin for the vectorial transfer of imported iron to mitochondria in developing red cells and of PCBP1 and NCOA4 in mediating iron flux through ferritin.

In this issue of Blood , Aschemeyer et al found that hepcidin bound to the central cavity of ferroportin (Fpn) and occluded its iron export activity, thereby revealing a previously unrecognized mechanism for Fpn regulation. 1

The microstructural evolution and tensile properties of nickel-silicon carbide nano-particles (Ni-3wt.% SiCNP) composites with milling time ranged from 8 to 48 h have been examined. High temperature aged and reference samples were investigated to clarify their high temperature stability. The TEM characterizations showed that the coarsening of dispersed SiCNP occurred with increasing milling time, whereas their sizes kept stable under different aging temperatures. The EBSD results indicated that the mean grain size decreased and increased respectively with increasing milling time and aging temperature. Two different recrystallization mechanisms, boundary bowing out and subgrain growth, were assumed to be responsible for the grain growth. The tensile test results showed that both the yield and tensile strengths of reference and aged samples increased as a function of the milling time. As milling time extended, the total elongations gradually decreased in the case of reference samples, but slightly decreased firstly and then increased in the case of the aged ones. The relationship between the microstructural evolution and the variations of tensile properties has been discussed in this study. (C) 2015 Elsevier B.V. All rights reserved.

Iron plays a role in cellular replication, metabolism, and growth. Although iron is needed, the imbalance of iron in the body can result in adverse health effects, including cancer. Interestingly, cancer cells have frequently been observed to express increased levels or activity of proteins that are associated with iron metabolism. Ferroportin (FPN), the only known mammalian cell iron exporter, is essential for iron homeostasis. Germline mutations in FPN occur more frequently in African and African American populations. A glutamine to histidine amino acid substitution at position 248 (Q248H) is the first and most prevalent gain-of-function mutation observed in FPN, with an allele frequency range of 2.2% to 13.4% in African and African Americans. However, it is unknown whether FPN Q248H is involved in cancer-associated reprogramming of iron metabolism, especially in individuals of African descent where the FPN Q248H mutation is enriched. The Q248H mutation traditionally renders FPN resistant to degradation. As a result, iron release is increased and aberrant uptake of iron across epithelial barriers of tissues can occur to cause iron overload, a risk factor for cancer. We hypothesize that patients with FPN Q248H have improper regulation of iron and thus increased unbound iron that will result in subsequent systemic and kidney-specific iron overload. We leveraged the repository of kidney cancer patients and banked samples of the Urologic Oncology Branch at the NIH to determine the association of FPN Q248H with kidney cancer. In our study, Black males with kidney cancer that expressed FPN Q248H had earlier onset of cancer compared to those without the variant. There were higher iron levels (p Citation Format: Samira Brooks, Cathy Vocke, Deliang Zhang, Victor Gordeuk, Tracey Rouault, Marston Linehan. Kidney iron overload in African American renal cancer patients with the ferroportin Q248H mutation [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-147.

The exact route of iron through the kidney and its regulation during iron overload are not completely elucidated. Under physiologic conditions, non-transferrin and transferrin bound iron passes the glomerular filter and is reabsorbed through kidney epithelial cells, so that hardly any iron is found in the urine. To study the route of iron reabsorption through the kidney, we analyzed the location and regulation of iron metabolism related proteins in kidneys of mice with iron overload, elicited by iron dextran injections. Transferrin Receptor 1 was decreased as expected, following iron overload. In contrast, the multi-ligand hetero-dimeric receptor-complex megalin/cubilin, which also mediates the internalization of transferrin, was highly up-regulated. Moreover, with increasing iron, intracellular ferritin distribution shifted in renal epithelium from an apical location to a punctate distribution throughout the epithelial cells. In addition, in contrast to many other tissues, the iron exporter ferroportin was not reduced by iron overload in the kidney. Iron accumulated mainly in interstitial macrophages, and more prominently in the medulla than in the cortex. This suggests that despite the reduction of Transferrin Receptor 1, alternative pathways may effectively mediate re-absorption of iron that cycles through the kidney during parenterally induced iron-overload. The most iron consuming process of the body, erythropoiesis, is regulated by the renal erythropoietin producing cells in kidney interstitium. We propose, that the efficient re-absorption of iron by the kidney, also during iron overload enables these cells to sense systemic iron and regulate its usage based on the systemic iron state.

Heme oxygenase 1 (HMOX1), the inducible enzyme that catabolizes the degradation of heme into biliverdin, iron, and carbon monoxide, plays an essential role in the clearance of senescent and damaged red blood cells, systemic iron homeostasis, erythropoiesis, vascular hemostasis, and oxidative and inflammatory stress responses. In humans, HMOX1 deficiency causes a rare and lethal disease, characterized by severe anemia, intravascular hemolysis, as well as vascular and tissue damage.

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by binding to RNA stem loops known as iron responsive elements (IREs) that are found in the untranslated regions of target mRNAs that encode proteins involved in iron metabolism. IRPs modify the expression of iron metabolism genes, and global and tissue-specific knockout mice have been made to evaluate the physiological significance of these iron regulatory proteins (Irps). Here, we will discuss the results of the studies that have been performed with mice engineered to lack the expression of one or both Irps and made in different strains using different methodologies. Both Irp1 and Irp2 knockout mice are viable, but the double knockout ( Irp1 −/− Irp2 −/− ) mice die before birth, indicating that these Irps play a crucial role in maintaining iron homeostasis. Irp1 −/− mice develop polycythemia and pulmonary hypertension, and when these mice are challenged with a low iron diet, they die early of abdominal hemorrhages, suggesting that Irp1 plays an essential role in erythropoiesis and in the pulmonary and cardiovascular systems. Irp2 −/− mice develop microcytic anemia, erythropoietic protoporphyria and a progressive neurological disorder, indicating that Irp2 has important functions in the nervous system and erythropoietic homeostasis. Several excellent review articles have recently been published on Irp knockout mice that mainly focus on Irp1 −/− mice (referenced in the introduction). In this review, we will briefly describe the phenotypes and physiological implications of Irp1 −/− mice and discuss the phenotypes observed for Irp2 −/− mice in detail with a particular emphasis on the neurological problems of these mice.

Silicon carbide nanoparticle-reinforced nickel-based composites (Ni–SiCNP), with a SiCNP content ranged from 1 to 3.5 wt%, were prepared using mechanical alloying and spark plasma sintering. In addition, unreinforced pure nickel samples were also prepared for comparative purposes. To characterize the microstructural properties of both the unreinforced pure nickel and the Ni–SiCNP composites transmission electron microscopy (TEM) was used, while their mechanical behavior was investigated using the Vickers pyramid method for hardness measurements and a universal tensile testing machine for tensile tests. TEM results showed an array of dislocation lines decorated in the sintered pure nickel sample, whereas, for the Ni–SiCNP composites, the presence of nano-dispersed SiCNP and twinning crystals was observed. These homogeneously distributed SiCNP were found located either within the matrix, between twins or on grain boundaries. For the Ni–SiCNP composites, coerced coarsening of the SiCNP assembly occurred with increasing SiCNP content. Furthermore, the grain sizes of the Ni–SiCNP composites were much finer than that of the unreinforced pure nickel, which was considered to be due to the composite ball milling process. In all cases, the Ni–SiCNP composites showed higher strengths and hardness values than the unreinforced pure nickel, likely due to a combination of dispersion strengthening (Orowan effects) and particle strengthening (Hall–Petch effects). For the Ni–SiCNP composites, the strength increased initially and then decreased as a function of SiCNP content, whereas their elongation percentages decreased linearly. Compared to all materials tested, the Ni–SiCNP composite containing 1.5% SiC was found more superior considering both their strength and plastic properties.

Chuvash polycythemia is an inherited disease caused by a homozygous germline VHLR200W mutation, which leads to impaired degradation of HIF2α, elevated levels of serum erythropoietin, and erythrocytosis/polycythemia. This phenotype is recapitulated by a mouse model bearing a homozygous VhlR200W mutation. We previously showed that iron-regulatory protein 1-knockout (Irp1-knockout) mice developed erythrocytosis/polycythemia through translational derepression of Hif2α, suggesting that IRP1 could be a therapeutic target to treat Chuvash polycythemia. Here, we fed VhlR200W mice supplemented with Tempol, a small, stable nitroxide molecule and observed that Tempol decreased erythropoietin production, corrected splenomegaly, normalized hematocrit levels, and increased the lifespans of these mice. We attribute the reversal of erythrocytosis/polycythemia to translational repression of Hif2α expression by Tempol-mediated increases in the IRE-binding activity of Irp1, as reversal of polycythemia was abrogated in VhlR200W mice in which Irp1 was genetically ablated. Thus, a new approach to the treatment of patients with Chuvash polycythemia may include dietary supplementation of Tempol, which decreased Hif2α expression and markedly reduced life-threatening erythrocytosis/polycythemia in the VhlR200W mice.

Substances extracted from the scutellaria based on the boiled were introduced to make the cotton fabrics achieve a good antibacterial properties. Specifically, the orthogonal experiment was designed based on four factors such as the concentration of extraction (compared with the original extraction), temperature, pH and mordant dyeing methods. It is proved that the cotton fabrics in such conditions, for instance, the scutellaria concentration of extraction of 80%, pH value of 9, at 80°C and the media reprocessing, can acquire a good antibacterial properties, and the bacillus subtilis antibacterial rate can reach 86.69%. Simultaneously, the rate of antibacterial against escherichia coli can reach 74.77%. It can still keep a good antibacterial properties after three times washing and ten times washing, and the bacillus subtilis inhibition rate is approximately 84.73% and 72.37% respectively, and the E. coli antibacterial rate is approximately 70.78% and 64.27% respectively.

SummaryIron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2α (HIF2α). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2α protein expression in kidneys of Irp1−/− mice, which led to increased erythropoietin (EPO) expression, polycythemia, and concomitant tissue iron deficiency. Increased HIF2α expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1−/− mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension.

Iron's grip on malaria Malaria parasites have coevolved with their human and mammalian hosts. These Plasmodium species invade the iron-rich environment of red blood cells. Zhang et al. found that the iron transporter ferroportin persists on the surface of mature mammalian red blood cells. Red blood cells are at risk of oxidative damage if their hemoglobin releases its iron; ferroportin is thus important to expel this iron. The authors also found that the transporter can deprive malaria parasites of the iron they need for proliferation. The Q248H mutation in the human ferroportin gene enhances ferroportin expression during development and seems to provide protection against malaria. This effect may explain the enrichment of the Q248H mutation among African populations. Science , this issue p. 1520

The iron-regulatory hormone, hepcidin, regulates systemic iron homeostasis by interacting with the iron export protein ferroportin (FPN1) to adjust iron absorption in enterocytes, iron recycling through reticuloendothelial macrophages, and iron release from storage in hepatocytes. We previously demonstrated that FPN1 was highly expressed in erythroblasts, a cell type that consumes most of the serum iron for use in hemoglobin synthesis. Herein, we have demonstrated that FPN1 localizes to the plasma membrane of erythroblasts, and hepcidin treatment leads to decreased expression of FPN1 and a subsequent increase in intracellular iron concentrations in both erythroblast cell lines and primary erythroblasts. Moreover, injection of exogenous hepcidin decreased FPN1 expression in BM erythroblasts in vivo, whereas iron depletion and associated hepcidin reduction led to increased FPN1 expression in erythroblasts. Taken together, hepcidin decreased FPN1 expression and increased intracellular iron availability of erythroblasts. We hypothesize that FPN1 expression in erythroblasts allows fine-tuning of systemic iron utilization to ensure that erythropoiesis is partially suppressed when nonerythropoietic tissues risk developing iron deficiency. Our results may explain why iron deficiency anemia is the most pronounced early manifestation of mammalian iron deficiency.

The serum ferritin concentration is a clinical parameter measured widely for the differential diagnosis of anemia. Its levels increase with elevations of tissue iron stores and with inflammation, but studies on cellular sources of serum ferritin as well as its subunit composition, degree of iron loading and glycosylation have given rise to conflicting results. To gain further understanding of serum ferritin, we have used traditional and modern methodologies to characterize mouse serum ferritin. We find that both splenic macrophages and proximal tubule cells of the kidney are possible cellular sources for serum ferritin and that serum ferritin is secreted by cells rather than being the product of a cytosolic leak from damaged cells. Mouse serum ferritin is composed mostly of L-subunits, whereas it contains few H-subunits and iron content is low. L-subunits of serum ferritin are frequently truncated at the C-terminus, giving rise to a characteristic 17-kD band that has been previously observed in lysosomal ferritin. Taken together with the fact that mouse serum ferritin is not detectably glycosylated, we propose that mouse serum ferritin is secreted through the nonclassical lysosomal secretory pathway.

A homozygous mutation in the complex III chaperone BCS1L causes GRACILE syndrome (intrauterine growth restriction, aminoaciduria, cholestasis, hepatic iron overload, lactacidosis). In control and patient fibroblasts we localized BCS1L in inner mitochondrial membranes. In patient liver, kidney, and heart BCS1L and Rieske protein levels, as well as the amount and activity of complex III, were decreased. Major histopathology was found in kidney and liver with cirrhosis and iron deposition, but of iron-related proteins only ferritin levels were high. In placenta from a GRACILE fetus, the ferrooxidases ceruloplasmin and hephaestin were upregulated suggesting association between iron overload and placental dysfunction.

SummaryFerroportin (FPN1), the sole characterized mammalian iron exporter, has an iron-responsive element (IRE) in its 5′ untranslated region, which ensures that its translation is repressed by iron regulatory proteins (IRPs) in iron-deficient conditions to maintain cellular iron content. However, here we demonstrate that duodenal epithelial and erythroid precursor cells utilize an alternative upstream promoter to express a FPN1 transcript, FPN1B, which lacks the IRE and is not repressed in iron-deficient conditions. The FPN1B transcript encodes ferroportin with an identical open reading frame and contributes significantly to ferroportin protein expression in erythroid precursors and likely also in the duodenum of iron-starved animals. The identification of FPN1B reveals how FPN1 expression can bypass IRP-dependent repression in intestinal iron uptake, even when cells throughout the body are iron deficient. In erythroid precursor cells, we hypothesize that FPN1B expression enhances real-time sensing of systemic iron status and facilitates restriction of erythropoiesis in response to low systemic iron.

In this paper, a new computational scheme for solving flows in porous media was proposed. The scheme was based on an improved CE/SE method (the space-time Conservation Element and Solution Element method). We described porous flows by adopting DFB (Brinkman-Forchheimer extended Darcy) equation. The comparison between our computational results and Ghia's confirmed the high accuracy, resolution, and efficiency of our CE/SE scheme. The proposed first-order CE/SE scheme is a new reliable way for numerical simulations of flows in porous media. After investigation of effects of Darcy number on porous flow, it shows that Darcy number has dominant influence on porous flow for the Reynolds number and porosity considered.

In mammalian cells, iron is required for the function of many prosthetic groups, including heme and iron-sulfur clusters. Mammals absorb dietary iron and heme across the apical mucosa of duodenal epithelial cells using a Fe2+ transporter known as divalent metal transporter 1 (DMT-1; also known as

It is believed that reactive oxygen species (ROS) play a very important role in the pathogenesis of acute respiratory distress syndrome (ARDS), but the mechanism has not been so clear, owing to the absence of direct measurable (experimental) data. In majority of the medical studies on free radicals, the analysis of ROS has generally been done by the way of measuring their secondary and breakdown products. In our study, we used electron spin resonance (ESR), a sensitive and accurate technique to detect ROS directly and also used some other sensitive techniques including ultra-weak luminescence and chemical luminescence to identify the species and relative amount of ROS. Furthermore, superoxide dismutase (SOD) was pre-administrated in ARDS rats to verify the results from the above studies and explore the possibility of the clinical application of SOD in ARDS. The spectra of ESR showed that the concentration of ROS increased at 10 min and reached a summit at 30 min after injection of oleic acid (OA), then dropped gradually. The scavenging effects of different scavenging agents on ROS by the analysis of ultra-weak luminescence proved that superoxide anion was the main species of ROS in the development of OA-induced ARDS. Moreover, the results of quantified measure of superoxide anion by chemical luminescence also showed the accordant tendency exhibited in ESR measurement. The pre-treatment of SOD might distinctly inhibit the production of superoxide anion, obviously improve the blood gas status, lung wet/dry ratio and lung/body ratio in ARDS rats. It is suggested that ROS may play a key role in the initiation phase of ARDS, while superoxide anion may be a leading actor in this process and SOD could effectively protect rats from ARDS. These results may provide helpful information for the treatment and prevention of ARDS.

Stroke is the third leading cause of death as dementia is a main symptom of Alzheimer's disease. One of the important mechanisms in the pathogeny of stroke is free radical production during the reperfusion period, therefore the effects of a type of natural antioxidant, i.e. Crataegus flavonoids (CF), on brain ischemic insults were investigated in Mongolian gerbil stroke model. Results showed that pretreatment of the animals with CF decreased reactive oxygen species (ROS) production, thiobarbituric acid reactive substances content, and nitrite/nitrate concentration in brain homogenate, increased the brain homogenate-associated antioxidant level in a dose-dependent manner. CF pretreatment increased the amount of biologically available NO by scavenging of superoxide anion produced during reperfusion. At same time, in the process of ischemia/reperfusion brain damage, the content of nitrite/nitrate (the end product of NO) increased, and of NO detected by ESR decreased. Oral pretreatment with CF decreased the nitrite/nitrate content in the brain homogenate and increased the biologically available NO concentration in a dose-dependent manner. The increasing effect of antioxidant on NO might be due to its scavenging effect on superoxide anion, which could react with NO into peroxynitrite. iNOS was implied in delayed neuron death after brain ischemic damage and it was found that pretreatment with CF could decrease the protein level of tumor necrosis factor (TNF)-alpha and nuclear factor-kappa B (NF-kappaB), and increase the mRNA level of NOS estimated by western blotting and RT-PCR. More neurons survived and fewer cells suffered apoptosis in the hippocampal CA1 region of CF treated animal brain. These results suggest that oral administration of this antioxidant increases the antioxidant level in the brain and protects the brain against delayed cell death caused by ischemia/reperfusion injury.

In this study the stability of the NO spin-trapping complex, (dithiocarbamate)2Fe2+NO and its interaction with rat peritoneal macrophages was investigated. The stability experiments showed that DTCS (dithiocarboxy sarcosine) trapping complex was more stable than that of MGD (N-methyl-D-glucamine-dithiocarbamate) in macrophages activated by PMA (phorbol-1,2-myristate-1,3-acetate) and L-arginine. Free radical species, O2•- and NO, generated in macrophages respiratory burst were causative for the instability of the NO trapping complex. Addition of more dithiocarbamate and ferrous salt could increase the stability of the trapping complex in the system. Dithiocarbamate and ferrous salt did not impair the oxygen consumption of macrophages. The increasing effects of dithiocarbamate derivatives and ferrous salt on the stability of the trapping complex may be due to their scavenging effects on the free radicals generated by macrophages and their ability to inhibit the oxidation of ferrous ion in the (dithiocarbamate)2Fe2+NO complex.

Despite large-scale anti-smoking campaigns throughout the world, the number of smokers remains high and cigarette smoking continues to represent a life-threatening health risk. Until a smoke-free society is achieved, reduction of cigarette smoke toxins may reduce the health burden. Current cigarette filter techniques are limited to the reduction of volatile tar constituents by dilution and by condensation on the filter surface. Vast quantities of harmful constituents, such as polycyclic aromatic hydrocarbons, heterocyclic (aromatic) amines, free radicals and reactive oxygen species, are inefficiently retained in the filter. We investigated whether neutralisation of free radicals in cigarette filters is feasible and accompanied by a reduction in smoke toxicity. Addition of the bioflavonoid pine bark extract Pycnogenolfi to cigarette filters depleted free radicals in a dose dependent manner. This was paralleled by a reduction of toxicity and mutagenicity in rodent test models. In this model system, the acute toxicity of cigarette smoke was markedly reduced by up to 70% in rodents with 0.4 mg Pycnogenolfi in filters. Chronic exposure to cigarette smoke for 75 days revealed that Pycnogenolfifilters significantly reduced mutagenicity by up to 48% and decreased pathological changes in lung tissue.

Iron regulatory proteins (IRPs) regulate the expression of genes involved in iron metabolism by binding to RNA stem-loop structures known as iron responsive elements (IREs) in target mRNAs. IRP binding inhibits the translation of mRNAs that contain an IRE in the 5'untranslated region of the transcripts, and increases the stability of mRNAs that contain IREs in the 3'untranslated region of transcripts. By these mechanisms, IRPs increase cellular iron absorption and decrease storage and export of iron to maintain an optimal intracellular iron balance. There are two members of the mammalian IRP protein family, IRP1 and IRP2, and they have redundant functions as evidenced by the embryonic lethality of the mice that completely lack IRP expression (Irp1 (-/-)/Irp2(-/-) mice), which contrasts with the fact that Irp1 (-/-) and Irp2 (-/-) mice are viable. In addition, Irp2 (-/-) mice also display neurodegenerative symptoms and microcytic hypochromic anemia, suggesting that IRP2 function predominates in the nervous system and erythropoietic homeostasis. Though the physiological significance of IRP1 had been unclear since Irp1 (-/-) animals were first assessed in the early 1990s, recent studies indicate that IRP1 plays an essential function in orchestrating the balance between erythropoiesis and bodily iron homeostasis. Additionally, Irp1 (-/-) mice develop pulmonary hypertension, and they experience sudden death when maintained on an iron-deficient diet, indicating that IRP1 has a critical role in the pulmonary and cardiovascular systems. This review summarizes recent progress that has been made in understanding the physiological roles of IRP1 and IRP2, and further discusses the implications for clinical research on patients with idiopathic polycythemia, pulmonary hypertension, and neurodegeneration.

In this work an improved method is described for using organic solvent extracting to detect nitric oxide. The partition coefficients of the diethylthiocarbamate (DETC)-Fe2+ complex between different organic solvents and water, the signal intensity of the same NO trapping complex concentration in different organic solvents, and the extracting abilities of the organic solvents were determined. It was found that ethyl acetate was the optimal organic solvent. With ethyl acetate as extracting solvent, the (DETC)2-Fe2+-NO complex was extracted from water phase to organic phase, and low concentration of nitric oxide in large volume could be detected by electron spin resonance (ESR) at room temperature. The ESR signal intensity had a good linear relationship with the concentration of nitric oxide, at a signal-to-noise ratio of 2. The detection threshold of this method was improved to lower than 50 nM, which was more sensitive than the usually used method. The (DETC)2-Fe2+-NO complex was stable in the dark at 0–4°C, and there was little change after days. Nitric oxide produced by cardiomyocytes cultured in media and other biological systems was firstly detected with this method.

Team-building of high-level talent is the core to promote the development of Shandong characteristic town. Based on the status quo analysis on team-building of high-level talent in Shandong characteristic industry town, this paper analyzes the problems existed in team-building of high-level talent in Shandong characteristic industry town, and puts forward with the measures to build up high-level talent team in Shandong characteristic industry town.

Team-building of science and technology innovative talent is the core to promote the development of characteristic industries in Shandong characteristic town. Based on the status quo analysis on team-building of science and technology innovative talent in Shandong characteristic industry town, this paper analyzes the problems existed in team-building of science and technology innovative talent in Shandong characteristic industry town, and puts forward with the measures to build up science and technology innovative talent team in Shandong characteristic industry town.

In mammals, two homologous cytosolic regulatory proteins, iron regulatory protein 1 (also known as IRP1 and Aco1) and iron regulatory protein 2 (also known as IRP2 and Ireb2), sense cytosolic iron levels and posttranscriptionally regulate iron metabolism genes, including transferrin receptor 1 (TfR1) and ferritin H and L subunits, by binding to iron-responsive elements (IREs) within target transcripts. Mice that lack IRP2 develop microcytic anemia and neurodegeneration associated with functional cellular iron depletion caused by low TfR1 and high ferritin expression. IRP1 knockout (IRP1 −/− ) animals do not significantly misregulate iron metabolism, partly because IRP1 is an iron-sulfur protein that functions mainly as a cytosolic aconitase in mammalian tissues and IRP2 activity increases to compensate for loss of the IRE binding form of IRP1. The neurodegenerative disease of IRP2 −/− animals progresses slowly as the animals age. In this study, we fed IRP2 −/− mice a diet supplemented with a stable nitroxide, Tempol, and showed that the progression of neuromuscular impairment was markedly attenuated. In cell lines derived from IRP2 −/− animals, and in the cerebellum, brainstem, and forebrain of animals maintained on the Tempol diet, IRP1 was converted from a cytosolic aconitase to an IRE binding protein that stabilized the TfR1 transcript and repressed ferritin synthesis. We suggest that Tempol protected IRP2 −/− mice by disassembling the cytosolic iron-sulfur cluster of IRP1 and activating IRE binding activity, which stabilized the TfR1 transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain.