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PubMed: 25411909

Title
Heme-regulated eIF2α kinase plays a crucial role in protecting erythroid cells against Pb-induced hemolytic stress.
Journal
Chemical research in toxicology
Volume
28
Issue
None
Pages
460-9
Date
2015-03-16
Authors
Liu S | Wang L | Wang X

Evidence 97306d76f8
JSON

With respect to the absence of Hri, there were slightly greater serum iron concentrations, total splenic iron content, and hepatic hepcidin expression level in Hri-deficient mice, relative to those in Wt mice (Figure 8A−C).

a(CHEBI:"iron(2+)") positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
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Serum
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a(CHEBI:"lead nitrate") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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erythroid progenitor cell
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a(CHEBI:"lead nitrate") positiveCorrelation p(MGI:Hamp) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Liver
Text Location
Results

p(MGI:Hamp) positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Liver
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Evidence 99f267eab3
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However, Pb exposure induced hepatic hepcidin expression by nearly 2- fold in Ko + Pb mice with a resultant significant increase of total splenic iron, compared to that in Ko − Pb mice (Figure 8 B and C; P < 0.05).

a(CHEBI:"iron(2+)") positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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a(CHEBI:"lead nitrate") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
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Spleen
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Results

a(CHEBI:"lead nitrate") positiveCorrelation p(MGI:Hamp) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Liver
Text Location
Results

p(MGI:Hamp) positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Liver
Text Location
Results

Evidence 6ceead9b02
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In contrast, Ko mice administrated with Pb(NO3)2 (Ko + Pb) developed significant anemia, evidenced by a great reduction of RBC count and hemoglobin concentration, compared to those of untreated Hri Ko mice (Ko − Pb) and Wt + Pb mice (Table 1; P < 0.05).

a(CHEBI:"lead nitrate") positiveCorrelation path(MESH:Anemia) View Subject | View Object

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path(MESH:Anemia) positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Evidence 3731af7150
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Analogous to phenotypic observations of anemia, the percentage of reticulocytes in peripheral blood of Ko + Pb mice was greatly induced by more than 2-fold relative to Ko − Pb mice (P < 0.05) and Wt + Pb mice (P < 0.001) (Figure 2A and B).

a(CHEBI:"lead nitrate") increases a(MESH:Reticulocytes) View Subject | View Object

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Evidence c4246ff822
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The serum levels of direct bilirubin (DBil) and total bilirubin (TBil) were significantly increased in Ko + Pb mice, compared to those in Ko − Pb mice and Wt + Pb mice (Figure 2C and D; P < 0.05).

a(CHEBI:"lead nitrate") increases a(CHEBI:bilirubin) View Subject | View Object

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Evidence 6c29e1e5e2
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Furthermore, the level of hematocrit (HCT) was also diminished by roughly 15% in Ko + Pb mice, compared to that in Wt + Pb mice (Table 1), and the mean corpuscular volume (MCV) in Ko + Pb mice was elevated by approximately 15% and 21%, compared to that in Ko − Pb mice and Wt + Pb mice, respectively (Table 1; P < 0.05).

a(CHEBI:"lead nitrate") decreases bp(MESH:Hematocrit) View Subject | View Object

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a(CHEBI:"lead nitrate") increases bp(MESH:"Erythrocyte Volume") View Subject | View Object

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Evidence 953ff7b944
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In stark contrast to Wt mice, there was an exuberant increase (57.9%) in Ter119+ cells in Ko + Pb mice, compared to that in Ko − Pb mice (Figure 3A; P = 0.01), suggesting enhanced medullary erythropoiesis in Ko mice upon Pb(NO3)2 administration.

a(CHEBI:"lead nitrate") increases g(MGI:Ly76) View Subject | View Object

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a(CHEBI:"lead nitrate") positiveCorrelation bp(MESH:Erythropoiesis) View Subject | View Object

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bp(MESH:Erythropoiesis) positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Evidence 529a89d5a1
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As shown in Figure 4B, Pb treatment resulted in an induction of splenic Ter119+ erythroid cells in Ko + Pb mice, compared to that in Wt + Pb mice (59.6% vs 36.5%, P < 0.001; Figure 4B).

a(CHEBI:"lead nitrate") increases g(MGI:Ly76) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

Evidence 0e48324f42
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Consistent with the FACS analysis results, abundant production of erythroblast and megakaryocytes in the sections of BM from Ko + Pb mice was observed, indicting enhanced medullary erythropoiesis (Figure 3C).

a(CHEBI:"lead nitrate") positiveCorrelation a(MESH:Erythroblasts) View Subject | View Object

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MeSH
Bone Marrow
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a(CHEBI:"lead nitrate") positiveCorrelation a(MESH:Megakaryocytes) View Subject | View Object

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MeSH
Bone Marrow
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a(MESH:Erythroblasts) positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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MeSH
Bone Marrow
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a(MESH:Megakaryocytes) positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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MeSH
Bone Marrow
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Results

Evidence 652229fcfa
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Examination of histological sections of spleens showed a dramatic expansion of erythroblasts in the red pulp of the spleens of Hri-null mice upon Pb administration (Figure 4C).

a(CHEBI:"lead nitrate") positiveCorrelation a(MESH:Erythroblasts) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

a(MESH:Erythroblasts) positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

Evidence 321265cf9c
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These results also indicated that, in spite of enforced extramedullary and medullary erythropoiesis in Ko + Pb mice, erythroid cells did not robustly survive and differentiate under Pb exposure as shown in Table 1, analogous to the observations in cadmium-treated mice.22

a(CHEBI:"lead nitrate") negativeCorrelation bp(GO:"erythrocyte differentiation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

a(CHEBI:cadmium) negativeCorrelation bp(GO:"erythrocyte differentiation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

bp(GO:"erythrocyte differentiation") negativeCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

bp(GO:"erythrocyte differentiation") negativeCorrelation a(CHEBI:cadmium) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

Evidence 877a801079
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Pb treatment has been demonstrated to reduce heme availability for globin assembly.38

a(CHEBI:"lead nitrate") decreases a(CHEBI:heme) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

Evidence e29942dc7d
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In Ko + Pb mice, apoptotic cells were increased by a greater degree, 79.4% in BM erythrocytes, compared to those in Ko − Pb mice (Figure 7B; P = 0.012).

a(CHEBI:"lead nitrate") positiveCorrelation bp(GO:"erythrocyte apoptotic process") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Bone Marrow
Text Location
Results

bp(GO:"erythrocyte apoptotic process") positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Bone Marrow
Text Location
Results

Evidence 61945ab177
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Apoptosis of splenic erythrocytes in Ko + Pb mice was enhanced by 19.0%, compared to that in Ko − Pb mice and by 55.4% in comparison to that in Wt + Pb mice (Figure 7C; P = 0.019).

a(CHEBI:"lead nitrate") positiveCorrelation bp(GO:"erythrocyte apoptotic process") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

bp(GO:"erythrocyte apoptotic process") positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

Evidence 8cbedac859
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Extramedullary and medullary erythropoiesis was enhanced in Hri-null mice upon Pb treatment.

a(CHEBI:"lead nitrate") positiveCorrelation path(MESH:"Hematopoiesis, Extramedullary") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Spleen
Text Location
Discussion

path(MESH:"Hematopoiesis, Extramedullary") positiveCorrelation a(CHEBI:"lead nitrate") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Spleen
Text Location
Discussion

Evidence 5aa1826b34
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These results suggest that Pb elicits direct inhibition of erythroid cell differentiation and that more importantly Hri takes a crucial role in promoting erythroid differentiation in response to Pb-induced toxicity.

a(CHEBI:"lead(2+)") decreases bp(GO:"erythrocyte differentiation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

bp(GO:"erythrocyte differentiation") positiveCorrelation p(MGI:Eif2ak1) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

p(MGI:Eif2ak1) positiveCorrelation bp(GO:"erythrocyte differentiation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

Evidence f0e773cfd0
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These data together demonstrated that Pb caused the inhibition of erythroid enucleation and that Hri seemingly surveilled the terminal differentiation of erythroblasts for appropriate hemoglobin production and final maturation before enucleation.

a(CHEBI:"lead(2+)") decreases bp(GO:"erythrocyte enucleation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

bp(GO:"erythrocyte differentiation") positiveCorrelation p(MGI:Eif2ak1) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

p(MGI:Eif2ak1) positiveCorrelation bp(GO:"erythrocyte differentiation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

Evidence c563b27bc9
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Elevated reticulocytes indicated markedly increased erythropoiesis in Ko mice challenged with Pb.29

a(MESH:Reticulocytes) positiveCorrelation bp(MESH:Erythropoiesis) View Subject | View Object

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bp(MESH:Erythropoiesis) positiveCorrelation a(MESH:Reticulocytes) View Subject | View Object

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Evidence dffe5a34e6
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Moreover, in the current study, we identified a crucial role of Hri in protecting erythroid precursors during differentiation by promoting terminal maturation including enucleation, preventing cell death, and increasing iron availability for erythropoiesis.

bp(GO:"cell death") negativeCorrelation p(MGI:Eif2ak1) View Subject | View Object

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erythroid progenitor cell
MeSH
Spleen
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Discussion

bp(GO:"erythrocyte enucleation") positiveCorrelation p(MGI:Eif2ak1) View Subject | View Object

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erythroid progenitor cell
MeSH
Spleen
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p(MGI:Eif2ak1) positiveCorrelation bp(GO:"erythrocyte enucleation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Discussion

p(MGI:Eif2ak1) negativeCorrelation bp(GO:"cell death") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Discussion

Evidence a56190fa38
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These data suggested that Pb-induced anemia should be ascribed to (at least partially) Pbinduced death of erythrocytes, and also stressed the critical role of Hri in assuring the survival of BM and spleen erythroid cells under Pb exposure.

bp(GO:"erythrocyte apoptotic process") negativeCorrelation p(MGI:Eif2ak1) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

p(MGI:Eif2ak1) negativeCorrelation bp(GO:"erythrocyte apoptotic process") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

Evidence 19f75b77c3
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Hri is activated to protect cells from oxidative stress-provoked apoptosis upon arsenic, cadmium, and iron deficiency.18,19,22

bp(GO:"erythrocyte apoptotic process") negativeCorrelation p(MGI:Eif2ak1) View Subject | View Object

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erythroid progenitor cell
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Spleen
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Discussion

p(MGI:Eif2ak1) negativeCorrelation bp(GO:"erythrocyte apoptotic process") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Discussion

Evidence 6de564b2a2
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In other words, Hri is necessary for erythroid differentiation and survival under oxidative stress.

bp(GO:"erythrocyte differentiation") positiveCorrelation p(HGNC:EIF2AK1) View Subject | View Object

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Introduction

bp(MESH:"Oxidative Stress") negativeCorrelation p(HGNC:EIF2AK1) View Subject | View Object

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Introduction

p(HGNC:EIF2AK1) positiveCorrelation bp(GO:"erythrocyte differentiation") View Subject | View Object

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Introduction

p(HGNC:EIF2AK1) negativeCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

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Introduction

Evidence acd67e1a9f
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These findings together led us to postulate that there could be disordered differentiation and survival for Hri-deficient erythroid cells upon Pb exposure.

bp(GO:"erythrocyte differentiation") positiveCorrelation p(MGI:Eif2ak1) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

p(MGI:Eif2ak1) positiveCorrelation bp(GO:"erythrocyte differentiation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

Evidence a392413457
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These results are similar to our findings in an earlier study where Hri deficiency resulted in the blockade of erythroid differentiation of FL cells from early and late basophilic erythroblasts into chromatophilic and orthochromatophilic erythroblasts.19

bp(GO:"erythrocyte differentiation") positiveCorrelation p(MGI:Eif2ak1) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Results

p(MGI:Eif2ak1) positiveCorrelation bp(GO:"erythrocyte differentiation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Results

Evidence 45897eecad
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Our combined results revealed that Hri functions to protect erythroid cells from Pb-induced toxicity through enhancing erythroid differentiation, enforcing cell survival, and orchestrating iron homeostasis.

bp(GO:"erythrocyte differentiation") positiveCorrelation p(MGI:Eif2ak1) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Discussion

p(MGI:Eif2ak1) positiveCorrelation bp(GO:"erythrocyte differentiation") View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
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Discussion

Evidence df3f93af87
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For example, the binding of Pb2+ to protein sulfydryl groups would result in inhibition of ALA-D activity, leading to heme deficiency, and reduction of heme supply is a known reason for lead-related pathology.10,11

complex(a(CHEBI:"lead(2+)"), a(CHEBI:thiol)) decreases p(HGNC:ALAD) View Subject | View Object

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erythroid progenitor cell
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Spleen
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Discussion

Evidence 96388b726e
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Moreover, loss of Hri gave rise to hepatic hepcidin induction, associated with iron retention in spleens.

p(MGI:Hamp) negativeCorrelation p(MGI:Eif2ak1) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Spleen
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Discussion

p(MGI:Eif2ak1) negativeCorrelation p(MGI:Hamp) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Spleen
Text Location
Discussion

Evidence 8510a10b2f
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Under Pb administration, Wt mice did not develop phenotypes of anemia; however, Hri-deficient mice developed severe anemia.

p(MGI:Eif2ak1) negativeCorrelation path(MESH:Anemia) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Discussion

path(MESH:Anemia) negativeCorrelation p(MGI:Eif2ak1) View Subject | View Object

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Cell Ontology (CL)
erythroid progenitor cell
MeSH
Spleen
Text Location
Discussion

Evidence 521169ca0d
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Extramedullary erythropoiesis is often switched on upon anemia, as characterized by splenomegaly.31

path(MESH:"Hematopoiesis, Extramedullary") positiveCorrelation path(MESH:Anemia) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Bone Marrow
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Results

path(MESH:Anemia) positiveCorrelation path(MESH:"Hematopoiesis, Extramedullary") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Bone Marrow
Text Location
Results

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