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a(CHEBI:"iron(2+)")

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Entity

Name
iron(2+)
Namespace
chebi
Namespace Version
20180906
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/chebi-names.belns

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Heme Curation v0.0.1-dev

Mechanistic knowledge surrounding heme

In-Edges 54

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

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). PubMed:25411909

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

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

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). PubMed:25411909

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

deg(a(CHEBI:heme)) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Within cells, heme is catabolized by the activity of heme oxygenases (inducible HO-1 and constitutive HO-2) into iron, carbon monoxide, and biliverdin. PubMed:26675351

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

a(CHEBI:heme) increases a(CHEBI:"iron(2+)") View Subject | View Object

Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Serum
MeSH
Porphyria, Erythropoietic
Text Location
Results

a(CHEBI:heme) negativeCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Under heme overload conditions, macrophages acquire an iron phenotype characterized by low intracellular iron and high ferroportin expression. PubMed:29212341

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Cell Ontology (CL)
macrophage
Text Location
Discussion

deg(a(CHEBI:heme)) increases a(CHEBI:"iron(2+)") View Subject | View Object

In subsequent reactions, metHb or metHb-derived heme participates in redox chain reactions that lead to the accumulation of modified lipids and proteins, as well as to heme degradation and to the release of free iron.19,25 PubMed:29610666

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Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

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

We showed that simulation of macrophages with LPS resulted in significant reduction in ferroportin mRNA and protein expression and enhanced intracellular iron deposition throughout all time points tested (Fig. 5A–D). PubMed:29212341

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Cell Ontology (CL)
macrophage
Text Location
Results

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

This dramatically contrasts the iron phenotype that develops in response to LPS, hallmarked by high intracellular iron levels and low ferroportin expression (10, 20, 48). PubMed:29212341

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Cell Ontology (CL)
macrophage
Text Location
Discussion

a(HM:"ruptured complicated lesions") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Concentrations of iron, conjugated dienes and lipid hydroperoxides were elevated by about 2- fold in ruptured complicated lesions, as compared to atheromatous lesions (0.433 ± 0.075 vs. 0.185 ± 0.096 nmol Fe/mg tissue; 0.047 ± 0.019 vs. 0.021 ± 0.003 A234 conjugated dienes/mg tissue and 0.465 ± 0.110 vs. 0.248 ± 0.106 nmol LOOH/mg tissue, respectively) and complicated lesions contained 5.6 times more TBARs than atheromatous lesions (0.028 ± 0.012 vs. 0.005 ± 0.001 nmol/mg tissue). PubMed:20378845

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Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"stored erythrocytes") increases a(CHEBI:"iron(2+)") View Subject | View Object

Stored RBCs undergo a complex structural and metabolic impairment that includes leakage of hemoglobin from the cells and hemolysis, reduced energy and NO production, formation of toxic products, such as lysophospholipids and free iron, phosphatidylserine exposure and shedding MPs [59]. PubMed:28458720

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Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Veins
MeSH
beta-Thalassemia
Text Location
Review

a(HM:"stored erythrocytes") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Fig 2 shows that free hemoglobin and free heme were higher 4 h after resuscitation with stored RBCs compared to fresh RBCs (n = 3±7 as indicated); NTBI level was also higher, but this difference did not reach statistical significance (p = 0.07). PubMed:29522519

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Results

a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively. PubMed:26794659

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Cell Ontology (CL)
epithelial cell
MeSH
Kidney Tubules
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135

Appears in Networks:
Annotations
MeSH
Kidney Cortex
MeSH
Hemorrhage
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Splenic iron content was greater in mice after resuscitation with SRBCs than in FRBC-transfused mice. PubMed:27515135

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Annotations
MeSH
Spleen
MeSH
Hemorrhage
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Taken together, these results indicate that haptoglobin co-transfusion prevented stored blood transfusion-associated renal iron uptake and led to increased weight and greater iron- accumulation in the spleens of mice. PubMed:27515135

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MeSH
Spleen
MeSH
Hemorrhage
Text Location
Results

a(MESH:"Blood Transfusion") increases a(CHEBI:"iron(2+)") View Subject | View Object

There is a clear need for, and medical benefit from, blood transfusions; nonetheless, administration of red blood cells (RBCs) does result in exposure to toxicants specific to hemoglobin (Hb) and its degradation components, hemin and iron. PubMed:30281034

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Text Location
Review

a(MESH:"Free Radicals") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Differently from biliverdin and CO, which have anti-inflammatory effects (Otterbein et al., 2000; Baranano et al., 2002), free Fe is highly oxidative and can promote free radicals generation through the Fenton reaction, which catalyzes hydroxyl radicals from the reaction of Fe with H2O2 (Fenton, 1894). PubMed:24904418

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Review

a(MESH:"Iron Chelating Agents") decreases a(CHEBI:"iron(2+)") View Subject | View Object

Because of large exposures to iron that occur in both disorders following transfusion, patients are inevitably prescribed small molecule iron chelation and the concomitant monitoring that is required. PubMed:30281034

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Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Anemia, Sickle Cell
MeSH
beta-Thalassemia
Text Location
Review

bp(GO:"heme catabolic process") increases a(CHEBI:"iron(2+)") View Subject | View Object

Once inside the cells, heme is catabolized by HO enzymes, generating equimolar amounts of biliverdin, carbon monoxide (CO), and Fe (Tenhunen et al., 1968). PubMed:24904418

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Text Location
Review

bp(GO:"inflammatory response") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Importantly, protoporphyrin did not induce TNFα, suggesting a critical proinflammatory role for iron within the heme moiety (supplemental Figure 8). PubMed:26675351

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

bp(HM:"macrophage M1 polarization") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Likewise, NAC was able to prevent iron-induced M1 polarization in M0, M1, and M2 BMDMs (supplemental Figure 13), indicating that the alteration of macrophage plasticity in response to iron is mostly explained by its pro-oxidant properties. PubMed:26675351

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

bp(MESH:"Cytotoxicity, Immunologic") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plasma
MeSH
Urine
MeSH
Anemia, Hemolytic, Autoimmune
Text Location
Review

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

This engenders the release of iron, which can promote further the oxidation of plaque lipids through redox cycling reactions. The result of these chemical reactions is the formation of deleterious oxidized ‘gruel’ which, among other things, leads to endothelial oxidative stress and ultimately to cytotoxicity. PubMed:20378845

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plasma
MeSH
Urine
MeSH
Anemia, Hemolytic, Autoimmune
Text Location
Review

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643

Appears in Networks:
Annotations
MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Abstract

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Hb and its degradation products – free heme and iron - perpetuate oxidative stress, and together with decreased NO availability promote many SCD complications. PubMed:28088643

Appears in Networks:
Annotations
MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Introduction

bp(MESH:"Platelet Activation") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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Text Location
Introduction

bp(MESH:Phagocytosis) increases a(CHEBI:"iron(2+)") View Subject | View Object

The causes for RBC-based toxicant exposures are multifactorial; however, following acute transfusion, the most common occurs during the processes of extravascular hemolysis, which includes macrophage erythrophagocytosis followed by macrophage death [1&&], release of iron, transferrin (Tf) saturation and, finally, accumulation of labile plasma iron (LPI) [2]. PubMed:30281034

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Annotations
Cell Ontology (CL)
erythrocyte
Text Location
Review

complex(a(CHEBI:"carbon monoxide"), a(CHEBI:"iron(2+)"), a(CHEBI:biliverdin)) hasComponent a(CHEBI:"iron(2+)") View Subject | View Object

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p(HGNC:HBB) increases a(CHEBI:"iron(2+)") View Subject | View Object

Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643

Appears in Networks:
Annotations
MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Abstract

p(HGNC:HBB) increases a(CHEBI:"iron(2+)") View Subject | View Object

Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Serum
MeSH
Porphyria, Erythropoietic
Text Location
Results

p(HGNC:HBB) increases a(CHEBI:"iron(2+)") View Subject | View Object

Another pathogenic mechanism involves the release of iron from cell-free hemoglobin with consecutive radical formation, which in turn can modify lipids, proteins, and DNA, leading to inflammation [39]. PubMed:29956069

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Annotations
MeSH
Arteries
MeSH
Sepsis
Text Location
Review

complex(a(CHEBI:"iron(2+)"), a(CHEBI:heme), a(MESH:"Reactive Oxygen Species")) hasComponent a(CHEBI:"iron(2+)") View Subject | View Object

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complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135

Appears in Networks:
Annotations
MeSH
Kidney Cortex
MeSH
Hemorrhage
Text Location
Results

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Only transfusion of SRBCs and haptoglobin prevented SRBC-induced renal iron accumulation (Figure 6A and B). PubMed:27515135

Appears in Networks:
Annotations
MeSH
Kidney Cortex
MeSH
Hemorrhage
Text Location
Results

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

In comparison to mice transfused with SRBCs alone, the spleens of mice resuscitated with SRBCs and haptoglobin contained more iron (Figure 6D). PubMed:27515135

Appears in Networks:
Annotations
MeSH
Spleen
MeSH
Hemorrhage
Text Location
Results

complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135

Appears in Networks:
Annotations
MeSH
Kidney Cortex
MeSH
Hemorrhage
Text Location
Results

p(MGI:Slc40a1) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

These data suggested that during severe hemolysis, heme mediated ferroportin induction and low hepcidin in HbS mice (11) served to elevate systemic iron availability, required to sustain high erythropoietic demands in these mice. PubMed:29212341

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Annotations
Cell Ontology (CL)
macrophage
Text Location
Results

p(HGNC:FTH1) decreases a(CHEBI:"iron(2+)") View Subject | View Object

Cells deficient on FtH are more susceptible to oxidative damage, while increased amounts of FtH protects cells from death induced by challenges such as Fe, tumor necrosis factor (TNF), heme, heme plus TNF, or oxidized low-density lipoprotein (LDL; Juckett et al., 1995; Pham et al., 2004; Gozzelino et al., 2012). PubMed:24904418

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Review

p(HGNC:TF) decreases a(CHEBI:"iron(2+)") View Subject | View Object

These studies do begin to suggest that apo-Tf administration could attenuate acute iron overload and hemochromatosis progression following chronic RBC transfusions. PubMed:30281034

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Anemia, Sickle Cell
MeSH
beta-Thalassemia
Text Location
Review

path(HP:"Intraventricular hemorrhage") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

In addition, iron and ferritin deposition are found in ependymal or subependymal location after neonatal IVH.7–9 PubMed:24667910

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Annotations
MeSH
Ependyma
Text Location
Introduction

path(HP:"Myocardial infarction") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Interestingly elevated levels of body iron stores are associated with an increased risk of myocardial infarction, and carriers of the hemochromatosis gene have an increased risk of myocardial infarction and cardiovascular death (20, 21). PubMed:19276082

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Text Location
Introduction

path(MESH:"Plaque, Atherosclerotic") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Earlier chemical investigations of gruel from advanced lesions revealed that it contains ceroid-like insoluble material composed mainly of hydoxyapatite, iron and calcium. PubMed:20378845

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

path(MESH:"Porphyria, Erythropoietic") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Using isolated duodenal loops to measure the transepithelial iron transport, we found that CEP mice presented a higher rate of iron absorption than the WT mice, although the differences between the area under the curves did not reach statistical significance (Figure 3D). PubMed:28143953

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Annotations
Cell Ontology (CL)
bone marrow cell
MeSH
Duodenum
MeSH
Porphyria, Erythropoietic
Text Location
Results

path(MESH:"Porphyria, Erythropoietic") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Serum iron was also increased in CEP mice, but this did not lead to elevated Tf saturation because Tf was also significantly increased, which is reminiscent of iron deficiency anemia and facilitates iron delivery to a larger number of erythroblasts (Table 1 and Figure 3G). PubMed:28143953

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Annotations
Cell Ontology (CL)
bone marrow cell
MeSH
Serum
MeSH
Porphyria, Erythropoietic
Text Location
Results

path(MESH:"Porphyria, Erythropoietic") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Serum
MeSH
Porphyria, Erythropoietic
Text Location
Results

path(MESH:"Porphyria, Erythropoietic") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

As expected, Perl’s staining of CEP kidneys showed significant accumulation of iron in the renal cortical part, particularly in the proximal tubules (Figure 6A). PubMed:28143953

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Kidney Cortex
MeSH
Porphyria, Erythropoietic
Text Location
Results

path(MESH:"Vascular Diseases") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

Appears in Networks:
Annotations
Text Location
Introduction

path(MESH:Hydrocephalus) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Twenty-four hours after injection, T2 MRI showed a significant bilateral ventricular enlargement in the iron-injected group (17.9±5.7mm3) compared with salineinjected rats (9.2±5.7mm3, Po0.01, Figure 4). PubMed:24667910

Appears in Networks:
Annotations
MeSH
Ependyma
Text Location
Results

path(MESH:Hydrocephalus) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

The major findings of this study are (1) intraventricular injection of lysed RBCs but not packed RBCs resulted in hydrocephalus; (2) lysed RBCs upregulated brain HO-1 and ferritin levels; (3) intraventricular injection of iron also caused hydrocephalus; and (4) iron chelation with deferoxamine reduced lysed RBC-induced hydrocephalus. PubMed:24667910

Appears in Networks:
Annotations
MeSH
Ependyma
Text Location
Discussion

path(MESH:Inflammation) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

Appears in Networks:
Annotations
Text Location
Introduction

path(MESH:Thrombosis) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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Annotations
Text Location
Introduction

rxn(reactants(a(CHEBI:"hydrogen peroxide"), a(CHEBI:"iron(2+)")), products(a(MESH:"Hydroxyl Radical"))) hasReactant a(CHEBI:"iron(2+)") View Subject | View Object

Appears in Networks:

rxn(reactants(a(CHEBI:"hydrogen peroxide"), a(CHEBI:"iron(2+)"), a(CHEBI:dioxygen)), products(a(MESH:ferrylhemoglobin))) hasReactant a(CHEBI:"iron(2+)") View Subject | View Object

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Out-Edges 51

a(CHEBI:"iron(2+)") increases a(MESH:"Reactive Oxygen Species") View Subject | View Object

ROS generation by haem is at least partially dependent on the Fenton reaction, in which iron catalyses the production of toxic ROS (Wagener et al, 2003). PubMed:25307023

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Plasma
MeSH
Urine
MeSH
Anemia, Hemolytic, Autoimmune
Text Location
Review

a(CHEBI:"iron(2+)") positiveCorrelation path(HP:"Myocardial infarction") View Subject | View Object

Interestingly elevated levels of body iron stores are associated with an increased risk of myocardial infarction, and carriers of the hemochromatosis gene have an increased risk of myocardial infarction and cardiovascular death (20, 21). PubMed:19276082

Appears in Networks:
Annotations
Text Location
Introduction

a(CHEBI:"iron(2+)") positiveCorrelation a(HM:"ruptured complicated lesions") View Subject | View Object

Concentrations of iron, conjugated dienes and lipid hydroperoxides were elevated by about 2- fold in ruptured complicated lesions, as compared to atheromatous lesions (0.433 ± 0.075 vs. 0.185 ± 0.096 nmol Fe/mg tissue; 0.047 ± 0.019 vs. 0.021 ± 0.003 A234 conjugated dienes/mg tissue and 0.465 ± 0.110 vs. 0.248 ± 0.106 nmol LOOH/mg tissue, respectively) and complicated lesions contained 5.6 times more TBARs than atheromatous lesions (0.028 ± 0.012 vs. 0.005 ± 0.001 nmol/mg tissue). PubMed:20378845

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(CHEBI:"iron(2+)") decreases act(a(CHEBI:antioxidant)) View Subject | View Object

Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023

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Annotations
Cell Ontology (CL)
macrophage
Text Location
Review

a(CHEBI:"iron(2+)") positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

This engenders the release of iron, which can promote further the oxidation of plaque lipids through redox cycling reactions. The result of these chemical reactions is the formation of deleterious oxidized ‘gruel’ which, among other things, leads to endothelial oxidative stress and ultimately to cytotoxicity. PubMed:20378845

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

a(CHEBI:"iron(2+)") positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plasma
MeSH
Urine
MeSH
Anemia, Hemolytic, Autoimmune
Text Location
Review

a(CHEBI:"iron(2+)") positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643

Appears in Networks:
Annotations
MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Abstract

a(CHEBI:"iron(2+)") positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Hb and its degradation products – free heme and iron - perpetuate oxidative stress, and together with decreased NO availability promote many SCD complications. PubMed:28088643

Appears in Networks:
Annotations
MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Introduction

a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:"Plaque, Atherosclerotic") View Subject | View Object

Earlier chemical investigations of gruel from advanced lesions revealed that it contains ceroid-like insoluble material composed mainly of hydoxyapatite, iron and calcium. PubMed:20378845

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

a(CHEBI:"iron(2+)") positiveCorrelation path(HP:"Intraventricular hemorrhage") View Subject | View Object

In addition, iron and ferritin deposition are found in ependymal or subependymal location after neonatal IVH.7–9 PubMed:24667910

Appears in Networks:
Annotations
MeSH
Ependyma
Text Location
Introduction

a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:Hydrocephalus) View Subject | View Object

Twenty-four hours after injection, T2 MRI showed a significant bilateral ventricular enlargement in the iron-injected group (17.9±5.7mm3) compared with salineinjected rats (9.2±5.7mm3, Po0.01, Figure 4). PubMed:24667910

Appears in Networks:
Annotations
MeSH
Ependyma
Text Location
Results

a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:Hydrocephalus) View Subject | View Object

The major findings of this study are (1) intraventricular injection of lysed RBCs but not packed RBCs resulted in hydrocephalus; (2) lysed RBCs upregulated brain HO-1 and ferritin levels; (3) intraventricular injection of iron also caused hydrocephalus; and (4) iron chelation with deferoxamine reduced lysed RBC-induced hydrocephalus. PubMed:24667910

Appears in Networks:
Annotations
MeSH
Ependyma
Text Location
Discussion

a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Free Radicals") View Subject | View Object

Differently from biliverdin and CO, which have anti-inflammatory effects (Otterbein et al., 2000; Baranano et al., 2002), free Fe is highly oxidative and can promote free radicals generation through the Fenton reaction, which catalyzes hydroxyl radicals from the reaction of Fe with H2O2 (Fenton, 1894). PubMed:24904418

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a(CHEBI:"iron(2+)") increases path(MESH:Inflammation) View Subject | View Object

These concepts challenged the idea that the cytotoxic and inflammatory effects of heme were exclusively mediated by the oxidative capability of the Fe associated with the amphipathic property of the porphyrin ring. PubMed:24904418

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erythrocyte
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a(CHEBI:"iron(2+)") increases path(MESH:Inflammation) View Subject | View Object

Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023

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macrophage
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a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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a(CHEBI:"iron(2+)") decreases bp(MESH:Vasodilation) View Subject | View Object

Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023

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macrophage
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a(CHEBI:"iron(2+)") increases bp(GO:"cell proliferation") View Subject | View Object

Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023

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macrophage
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a(CHEBI:"iron(2+)") increases a(MESH:"Reactive Oxygen Species") View Subject | View Object

We confirmed that the redox active iron, which is derived from heme catabolism in macrophages, is capable of catalyzing ROS formation (Fig. 7A) (19). PubMed:29212341

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macrophage
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a(CHEBI:"iron(2+)") increases bp(MESH:"Platelet Activation") View Subject | View Object

Finally, ferrous iron, through Fenton-derived hydroxyl radical species production and protein kinase C function, activates platelets (Iuliano et al, 1994). PubMed:25307023

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endothelial cell
MeSH
Plasma
MeSH
Urine
MeSH
Anemia, Hemolytic, Autoimmune
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Review

a(CHEBI:"iron(2+)") positiveCorrelation bp(MESH:"Platelet Activation") View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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a(CHEBI:"iron(2+)") positiveCorrelation bp(MESH:"Cytotoxicity, Immunologic") View Subject | View Object

Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023

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endothelial cell
MeSH
Plasma
MeSH
Urine
MeSH
Anemia, Hemolytic, Autoimmune
Text Location
Review

a(CHEBI:"iron(2+)") increases a(MESH:"Cell Adhesion Molecules") View Subject | View Object

Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023

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endothelial cell
MeSH
Plasma
MeSH
Urine
MeSH
Anemia, Hemolytic, Autoimmune
Text Location
Review

a(CHEBI:"iron(2+)") increases path(MESH:Thrombosis) View Subject | View Object

Thus, by participating in Fenton chemistry, non-transferrin-bound iron (i.e., iron not bound to the physiological iron transport protein, transferrin) causes oxidative damage, cytotoxicity and enhanced endothelial expression of adhesion molecules, thereby enhancing thrombotic risk (Hershko, 2007). PubMed:25307023

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endothelial cell
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Plasma
MeSH
Urine
MeSH
Anemia, Hemolytic, Autoimmune
Text Location
Review

a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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

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). PubMed:25411909

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erythroid progenitor cell
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Serum
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Results

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

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). PubMed:25411909

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erythroid progenitor cell
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Spleen
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Results

a(CHEBI:"iron(2+)") positiveCorrelation deg(a(CHEBI:heme)) View Subject | View Object

Within cells, heme is catabolized by the activity of heme oxygenases (inducible HO-1 and constitutive HO-2) into iron, carbon monoxide, and biliverdin. PubMed:26675351

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Anemia, Sickle Cell
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a(CHEBI:"iron(2+)") negativeCorrelation a(CHEBI:heme) View Subject | View Object

Under heme overload conditions, macrophages acquire an iron phenotype characterized by low intracellular iron and high ferroportin expression. PubMed:29212341

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macrophage
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a(CHEBI:"iron(2+)") positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

Importantly, protoporphyrin did not induce TNFα, suggesting a critical proinflammatory role for iron within the heme moiety (supplemental Figure 8). PubMed:26675351

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macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
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a(CHEBI:"iron(2+)") increases bp(GO:"inflammatory response") View Subject | View Object

Another pathogenic mechanism involves the release of iron from cell-free hemoglobin with consecutive radical formation, which in turn can modify lipids, proteins, and DNA, leading to inflammation [39]. PubMed:29956069

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Arteries
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Sepsis
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Review

a(CHEBI:"iron(2+)") positiveCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

Likewise, NAC was able to prevent iron-induced M1 polarization in M0, M1, and M2 BMDMs (supplemental Figure 13), indicating that the alteration of macrophage plasticity in response to iron is mostly explained by its pro-oxidant properties. PubMed:26675351

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macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
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Results

a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively. PubMed:26794659

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epithelial cell
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Kidney Tubules
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Results

a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135

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Kidney Cortex
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Hemorrhage
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a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Splenic iron content was greater in mice after resuscitation with SRBCs than in FRBC-transfused mice. PubMed:27515135

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Spleen
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Hemorrhage
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a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Taken together, these results indicate that haptoglobin co-transfusion prevented stored blood transfusion-associated renal iron uptake and led to increased weight and greater iron- accumulation in the spleens of mice. PubMed:27515135

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Spleen
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Hemorrhage
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a(CHEBI:"iron(2+)") positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) View Subject | View Object

Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135

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Kidney Cortex
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Hemorrhage
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Results

a(CHEBI:"iron(2+)") positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) View Subject | View Object

Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B). PubMed:27515135

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Kidney Cortex
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Hemorrhage
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Results

a(CHEBI:"iron(2+)") negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

Only transfusion of SRBCs and haptoglobin prevented SRBC-induced renal iron accumulation (Figure 6A and B). PubMed:27515135

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Kidney Cortex
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Hemorrhage
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a(CHEBI:"iron(2+)") positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

In comparison to mice transfused with SRBCs alone, the spleens of mice resuscitated with SRBCs and haptoglobin contained more iron (Figure 6D). PubMed:27515135

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Spleen
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Hemorrhage
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Results

a(CHEBI:"iron(2+)") decreases a(CHEBI:"nitric oxide") View Subject | View Object

Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643

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Erythrocytes
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Anemia, Sickle Cell
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Abstract

a(CHEBI:"iron(2+)") decreases a(CHEBI:"nitric oxide") View Subject | View Object

Hb and its degradation products – free heme and iron - perpetuate oxidative stress, and together with decreased NO availability promote many SCD complications. PubMed:28088643

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Erythrocytes
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Anemia, Sickle Cell
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Introduction

a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:"Porphyria, Erythropoietic") View Subject | View Object

Using isolated duodenal loops to measure the transepithelial iron transport, we found that CEP mice presented a higher rate of iron absorption than the WT mice, although the differences between the area under the curves did not reach statistical significance (Figure 3D). PubMed:28143953

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bone marrow cell
MeSH
Duodenum
MeSH
Porphyria, Erythropoietic
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a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:"Porphyria, Erythropoietic") View Subject | View Object

Serum iron was also increased in CEP mice, but this did not lead to elevated Tf saturation because Tf was also significantly increased, which is reminiscent of iron deficiency anemia and facilitates iron delivery to a larger number of erythroblasts (Table 1 and Figure 3G). PubMed:28143953

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bone marrow cell
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Serum
MeSH
Porphyria, Erythropoietic
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Results

a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:"Vascular Diseases") View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:"Porphyria, Erythropoietic") View Subject | View Object

Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953

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Cell Ontology (CL)
macrophage
MeSH
Serum
MeSH
Porphyria, Erythropoietic
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Results

a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:"Porphyria, Erythropoietic") View Subject | View Object

As expected, Perl’s staining of CEP kidneys showed significant accumulation of iron in the renal cortical part, particularly in the proximal tubules (Figure 6A). PubMed:28143953

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Cell Ontology (CL)
macrophage
MeSH
Kidney Cortex
MeSH
Porphyria, Erythropoietic
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Results

a(CHEBI:"iron(2+)") positiveCorrelation p(MGI:Slc40a1) View Subject | View Object

These data suggested that during severe hemolysis, heme mediated ferroportin induction and low hepcidin in HbS mice (11) served to elevate systemic iron availability, required to sustain high erythropoietic demands in these mice. PubMed:29212341

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macrophage
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a(CHEBI:"iron(2+)") positiveCorrelation a(CHEBI:lipopolysaccharide) View Subject | View Object

We showed that simulation of macrophages with LPS resulted in significant reduction in ferroportin mRNA and protein expression and enhanced intracellular iron deposition throughout all time points tested (Fig. 5A–D). PubMed:29212341

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macrophage
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a(CHEBI:"iron(2+)") positiveCorrelation a(CHEBI:lipopolysaccharide) View Subject | View Object

This dramatically contrasts the iron phenotype that develops in response to LPS, hallmarked by high intracellular iron levels and low ferroportin expression (10, 20, 48). PubMed:29212341

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macrophage
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Discussion

a(CHEBI:"iron(2+)") positiveCorrelation a(HM:"stored erythrocytes") View Subject | View Object

Fig 2 shows that free hemoglobin and free heme were higher 4 h after resuscitation with stored RBCs compared to fresh RBCs (n = 3±7 as indicated); NTBI level was also higher, but this difference did not reach statistical significance (p = 0.07). PubMed:29522519

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.