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p(MGI:Hpx)

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Entity

Name
Hpx
Namespace
mgi
Namespace Version
20181021
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/f2f993e599694ab5ce989cc39d789a499f75db99/external/mgi-names.belns

Appears in Networks 1

Heme Curation v0.0.1-dev

Mechanistic knowledge surrounding heme

In-Edges 32

a(CHEBI:"4-hydroxynon-2-enal") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Hepatic 4-hydroxynonenol (4-HNE), a marker of oxidative stress, was significantly lower in the liver microsomes of SSmice 24 hours after infusion of Hp or Hpx compared to vehicle-treated SS-mice (Fig 2G). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:"carbon monoxide") positiveCorrelation act(p(MGI:Hpx)) View Subject | View Object

The beneficial effects of Hp and Hpx were lost by inhibition of HO with SnPP, but could be restored by CO administration. PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

a(CHEBI:heme) negativeCorrelation p(MGI:Hpx) View Subject | View Object

The increase in hemopexin was associated with decreased plasma heme levels (Figure 3I). PubMed:27515135

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

a(MESH:"Blood Transfusion") negativeCorrelation p(MGI:Hpx) View Subject | View Object

In animals resuscitated with SRBCs, plasma hemopexin levels significantly decreased from 147.1±11.4 mg/dl at baseline to 86.7±12.2 and 76.3±5. 4 mg/dl at two and four hours after resuscitation, respectively (p<0.05 for both, Figure 2A). PubMed:27515135

Appears in Networks:
Annotations
MeSH
Hemorrhage
Text Location
Results

a(MESH:"Reactive Oxygen Species") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Importantly, by scavenging free heme, Hx prevents heme-induced M1 macrophage polarization and thus avoids both TLR4 activation and ROS formation. PubMed:26675351

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

bp(GO:"inflammatory response") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Taken together, these data suggest that Hx administration decreases heme-driven proinflammatory activation of macrophages. PubMed:26675351

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

bp(GO:"inflammatory response") negativeCorrelation p(MGI:Hpx) View Subject | View Object

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E). PubMed:26675351

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

bp(GO:"inflammatory response") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Our data support the idea that heme-induced phenotypic switching of macrophages toward a proinflammatory phenotype can contribute to the exacerbation of inflammation and chronic tissue injury in hemolytic disorders and that Hx therapy could alleviate these pathophysiologic consequences by preventing macrophage inflammatory activation. PubMed:26675351

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

bp(HM:"macrophage M1 polarization") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Importantly, by scavenging free heme, Hx prevents heme-induced M1 macrophage polarization and thus avoids both TLR4 activation and ROS formation. PubMed:26675351

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

bp(HM:"macrophage M1 polarization") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Our data support the idea that heme-induced phenotypic switching of macrophages toward a proinflammatory phenotype can contribute to the exacerbation of inflammation and chronic tissue injury in hemolytic disorders and that Hx therapy could alleviate these pathophysiologic consequences by preventing macrophage inflammatory activation. PubMed:26675351

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

bp(MESH:Apoptosis) negativeCorrelation p(MGI:Hpx) View Subject | View Object

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E). PubMed:26675351

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

complex(a(CHEBI:"tin atom"), a(CHEBI:protoporphyrin)) negativeCorrelation act(p(MGI:Hpx)) View Subject | View Object

The beneficial effects of Hp and Hpx were lost by inhibition of HO with SnPP, but could be restored by CO administration. PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

complex(a(CHEBI:heme), p(MGI:Hpx)) hasComponent p(MGI:Hpx) View Subject | View Object

Appears in Networks:

act(p(MGI:Tlr4)) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Importantly, by scavenging free heme, Hx prevents heme-induced M1 macrophage polarization and thus avoids both TLR4 activation and ROS formation. PubMed:26675351

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

complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) causesNoChange p(MGI:Hpx) View Subject | View Object

Resuscitation with SRBCs together with albumin did not alter plasma levels of hemoglobin, hemopexin, haptoglobin, or heme as compared to resuscitation with SRBCs alone (Figure 3C–E, I, Supplemental Material and Supplemental Figure II A–B). PubMed:27515135

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

complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) hasComponent p(MGI:Hpx) View Subject | View Object

Appears in Networks:

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

Infusion of hemopexin together with SRBCs resulted in a 6.4-fold (95% CI [5.2 – 7.6]) increase in plasma hemopexin levels at four hours after transfusion (Figure 3D). PubMed:27515135

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

complex(p(HGNC:HBB), p(MGI:Hpx)) hasComponent p(MGI:Hpx) View Subject | View Object

Appears in Networks:

act(p(MGI:Ccl5)) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Pro-inflammatory cytokine RANTES (chemokine ligand 5 or CCL5), which recruits leukocytes to pro-inflammatory sites, was lower in the plasma of SS-mice 24 hours after infusion of Hp or Hpx compared to vehicle-treated SS-mice (Fig 2F). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Flvcr1) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Consistently, Hx treatment blunted heme-mediated induction of the heme exporter Feline Leukemia Virus subgroup C Receptor 1(Flvcr1) [31, 38, 39] in H9c2 cells (see Figure 3 in [37]). PubMed:28400318

Appears in Networks:
Annotations
Cell Ontology (CL)
regular cardiac myocyte
Text Location
Results

p(MGI:Icam1) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Immunofluorescence staining of VCAM-1 and ICAM-1 was decreased in the dorsal skin of SS-mice 4h after infusion of Hb+Hp and Hb+Hpx compared to SS-mice infused with vehicle or Hb (Fig 2B and 2C). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

act(p(MGI:Nfkb1)) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Compared to Hb alone or Hb + albumin infused animals, sickle mice co-infused with Hb + Hp, Hb + Hpx, or Hb + Hp + Hpx had markedly diminished hepatic NF-κB activation 4h after infusion as evidenced by nuclear NF- κB phospho-p65 levels (Fig 2A). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Vcam1) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Immunofluorescence staining of VCAM-1 and ICAM-1 was decreased in the dorsal skin of SS-mice 4h after infusion of Hb+Hp and Hb+Hpx compared to SS-mice infused with vehicle or Hb (Fig 2B and 2C). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

path(HM:"vaso-occlusive crisis") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Thus a single infusion of Hp or Hpx inhibited stasis for 48h. PubMed:29694434

Appears in Networks:
Annotations
MeSH
Blood Platelets
MeSH
Anemia, Sickle Cell
Text Location
Results

path(HM:"vaso-occlusive crisis") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Sickle mice co-infused with Hb + Hp, Hb + Hpx or Hb + Hp + Hpx had less stasis 1h after infusion than mice infused with Hb + albumin or Hb (Fig 1B). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Blood Platelets
MeSH
Anemia, Sickle Cell
Text Location
Results

path(HM:"vaso-occlusive crisis") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Hp and Hpx significantly inhibited stasis in response H/R or LPS (Fig 5). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

path(HP:"Impaired myocardial contractility") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Cardiac contractility was severely impaired in 3 month-old Hx-/- mice compared to wild-type controls, as evidenced by significantly lower fractional shortening (FS) and ejection fraction (EF) (Figure 3A-C). PubMed:28400318

Appears in Networks:
Annotations
Cell Ontology (CL)
regular cardiac myocyte
Text Location
Results

path(HP:"Impaired myocardial contractility") negativeCorrelation p(MGI:Hpx) View Subject | View Object

As well as NAC, Hx co-treatment significantly improved systolic Ca2+ transients and accelerated Ca2+ transient decay kinetics, which resulted in a significant improvement of cardiomyocyte contractility (Figure 4A-E). PubMed:28400318

Appears in Networks:
Annotations
Cell Ontology (CL)
regular cardiac myocyte
Text Location
Results

path(MESH:"Porphyria, Erythropoietic") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Congenital erythropoietic porphyria mice showed increased serum bilirubin and LDH levels (Table 1), with almost undetectable levels of Hp and Hpx (Figure 1A and B, respectively), which was strongly indicative of hemolytic anemia. PubMed:28143953

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Serum
Text Location
Results

path(MESH:Fibrosis) negativeCorrelation p(MGI:Hpx) View Subject | View Object

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E). PubMed:26675351

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

path(MESH:Inflammation) negativeCorrelation p(MGI:Hpx) View Subject | View Object

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E). PubMed:26675351

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

path(MESH:Pneumonia) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Hemopexin improved post-pneumonia survival in mice that underwent massive resuscitation with stored RBCs (Fig 3A). PubMed:29522519

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Text Location
Results

Out-Edges 63

p(MGI:Hpx) decreases path(HM:"vaso-occlusive crisis") View Subject | View Object

These findings are consistent with a recent study which showed that both Hp and hemopexin (heme scavenger) were equally effective in preventing vasoocclusion in a sickle cell mouse model infused with Hb [73]. PubMed:24486321

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

p(MGI:Hpx) negativeCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

Thus a single infusion of Hp or Hpx inhibited stasis for 48h. PubMed:29694434

Appears in Networks:
Annotations
MeSH
Blood Platelets
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) negativeCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

Sickle mice co-infused with Hb + Hp, Hb + Hpx or Hb + Hp + Hpx had less stasis 1h after infusion than mice infused with Hb + albumin or Hb (Fig 1B). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Blood Platelets
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) negativeCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

Hp and Hpx significantly inhibited stasis in response H/R or LPS (Fig 5). PubMed:29694434

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) decreases a(CHEBI:heme) View Subject | View Object

Hp bound metHb and prevented heme loss and hemopexin captures any free heme released from metHb during its denaturation. PubMed:24486321

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

p(MGI:Hpx) negativeCorrelation a(CHEBI:heme) View Subject | View Object

The increase in hemopexin was associated with decreased plasma heme levels (Figure 3I). PubMed:27515135

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

p(MGI:Hpx) decreases a(CHEBI:heme) View Subject | View Object

Hx-heme-treated CMs were protected from heme accumulation, compared to cells treated with albumin-heme or heme alone (Figure 1A), indicating that Hx prevents heme entry in cardiac cells. PubMed:28400318

Appears in Networks:
Annotations
Cell Ontology (CL)
regular cardiac myocyte
Text Location
Results

p(MGI:Hpx) decreases p(MGI:Tnf) View Subject | View Object

Here we show that Hx treatment decreases expression of the M1 cytokine TNFα, the monocyte chemoattractant protein (MCP)1, and the profibrotic and mitogenic cytokines transforming growth factor (TGF)β and platelet-derived growth factor (PDGF) in the liver of sickle mice. PubMed:26675351

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

p(MGI:Hpx) decreases p(MGI:Ccl2) View Subject | View Object

Here we show that Hx treatment decreases expression of the M1 cytokine TNFα, the monocyte chemoattractant protein (MCP)1, and the profibrotic and mitogenic cytokines transforming growth factor (TGF)β and platelet-derived growth factor (PDGF) in the liver of sickle mice. PubMed:26675351

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

p(MGI:Hpx) decreases p(MGI:Tgfb1) View Subject | View Object

Here we show that Hx treatment decreases expression of the M1 cytokine TNFα, the monocyte chemoattractant protein (MCP)1, and the profibrotic and mitogenic cytokines transforming growth factor (TGF)β and platelet-derived growth factor (PDGF) in the liver of sickle mice. PubMed:26675351

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

p(MGI:Hpx) decreases p(PFAM:PDGF) View Subject | View Object

Here we show that Hx treatment decreases expression of the M1 cytokine TNFα, the monocyte chemoattractant protein (MCP)1, and the profibrotic and mitogenic cytokines transforming growth factor (TGF)β and platelet-derived growth factor (PDGF) in the liver of sickle mice. PubMed:26675351

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

p(MGI:Hpx) increases p(MGI:Mmp9) View Subject | View Object

Moreover, Hx administration increases hepatic expression of the matrix metalloproteinases MMP-9, MMP-12, and MMP-13 (mostly expressed by M2 macrophages). PubMed:26675351

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

p(MGI:Hpx) increases p(MGI:Mmp12) View Subject | View Object

Moreover, Hx administration increases hepatic expression of the matrix metalloproteinases MMP-9, MMP-12, and MMP-13 (mostly expressed by M2 macrophages). PubMed:26675351

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

p(MGI:Hpx) increases p(MGI:Mmp13) View Subject | View Object

Moreover, Hx administration increases hepatic expression of the matrix metalloproteinases MMP-9, MMP-12, and MMP-13 (mostly expressed by M2 macrophages). PubMed:26675351

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

p(MGI:Hpx) decreases p(MGI:Acta2) View Subject | View Object

It further increases the expression of a marker for resting HSCs, synaptophysin, and reduces the expression of a marker for activated myofibroblast-like HSCs, smooth muscle actin (SMA) (Figure 7B). PubMed:26675351

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

p(MGI:Hpx) increases p(MGI:Syp) View Subject | View Object

It further increases the expression of a marker for resting HSCs, synaptophysin, and reduces the expression of a marker for activated myofibroblast-like HSCs, smooth muscle actin (SMA) (Figure 7B). PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation bp(GO:"inflammatory response") View Subject | View Object

Taken together, these data suggest that Hx administration decreases heme-driven proinflammatory activation of macrophages. PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation bp(GO:"inflammatory response") View Subject | View Object

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E). PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation bp(GO:"inflammatory response") View Subject | View Object

Our data support the idea that heme-induced phenotypic switching of macrophages toward a proinflammatory phenotype can contribute to the exacerbation of inflammation and chronic tissue injury in hemolytic disorders and that Hx therapy could alleviate these pathophysiologic consequences by preventing macrophage inflammatory activation. PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation path(MESH:Inflammation) View Subject | View Object

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E). PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation path(MESH:Fibrosis) View Subject | View Object

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E). PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation bp(MESH:Apoptosis) View Subject | View Object

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E). PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

Importantly, by scavenging free heme, Hx prevents heme-induced M1 macrophage polarization and thus avoids both TLR4 activation and ROS formation. PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

Our data support the idea that heme-induced phenotypic switching of macrophages toward a proinflammatory phenotype can contribute to the exacerbation of inflammation and chronic tissue injury in hemolytic disorders and that Hx therapy could alleviate these pathophysiologic consequences by preventing macrophage inflammatory activation. PubMed:26675351

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

p(MGI:Hpx) negativeCorrelation act(p(MGI:Tlr4)) View Subject | View Object

Importantly, by scavenging free heme, Hx prevents heme-induced M1 macrophage polarization and thus avoids both TLR4 activation and ROS formation. PubMed:26675351

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

p(MGI:Hpx) decreases p(MGI:Tlr4) View Subject | View Object

The mechanism postulated for the beneficial effects 398 of hemopexin in mouse models of chronic hemolysis involves inhibition of heme399 dependent activation of TLR4 signaling and a combination of reduced endothelial 400 formation of reactive oxygen species and restored endothelial NOS-activity. PubMed:28314763

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
Text Location
Introduction

p(MGI:Hpx) negativeCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

Importantly, by scavenging free heme, Hx prevents heme-induced M1 macrophage polarization and thus avoids both TLR4 activation and ROS formation. PubMed:26675351

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

p(MGI:Hpx) decreases a(MESH:"Reactive Oxygen Species") View Subject | View Object

Being heme a well-known pro-oxidant agent [17], we then evaluated ROS levels in CMs exposed to heme alone or bound to either Hx or albumin. In the presence of Hx-heme complexes, CMs were protected from ROS formation, if compared to CMs treated with either albumin-heme complexes or heme alone (Figure 1D). PubMed:28400318

Appears in Networks:
Annotations
Cell Ontology (CL)
regular cardiac myocyte
Text Location
Results

p(MGI:Hpx) decreases p(MGI:Hmox1) View Subject | View Object

We found that Hpx effectively attenuated HO-1 induction by all redox forms of Hb. PubMed:26974230

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Annotations
MeSH
Mitochondria
Text Location
Results

p(MGI:Hpx) decreases p(MGI:Hmox1) View Subject | View Object

Consistently, HO-1 mRNA and protein levels were higher in hearts from Hx-/- mice than in controls (Figure 2B). Immunohistochemistry for HO-1 on heart sections indicated higher HO-1 expression in cardiomyocytes from Hx-/- mice than in wild-type animals (Figure 2B). PubMed:28400318

Appears in Networks:
Annotations
Cell Ontology (CL)
regular cardiac myocyte
Text Location
Results

p(MGI:Hpx) negativeCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

In animals resuscitated with SRBCs, plasma hemopexin levels significantly decreased from 147.1±11.4 mg/dl at baseline to 86.7±12.2 and 76.3±5. 4 mg/dl at two and four hours after resuscitation, respectively (p<0.05 for both, Figure 2A). PubMed:27515135

Appears in Networks:
Annotations
MeSH
Hemorrhage
Text Location
Results

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

Infusion of hemopexin together with SRBCs resulted in a 6.4-fold (95% CI [5.2 – 7.6]) increase in plasma hemopexin levels at four hours after transfusion (Figure 3D). PubMed:27515135

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

p(MGI:Hpx) negativeCorrelation path(MESH:"Porphyria, Erythropoietic") View Subject | View Object

Congenital erythropoietic porphyria mice showed increased serum bilirubin and LDH levels (Table 1), with almost undetectable levels of Hp and Hpx (Figure 1A and B, respectively), which was strongly indicative of hemolytic anemia. PubMed:28143953

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Serum
Text Location
Results

p(MGI:Hpx) increases path(MESH:Hemoglobinuria) View Subject | View Object

These results show that, in contrast to haptoglobin, hemopexin 247 was unable to prevent free hemoglobin-induced hemoglobinuria. PubMed:28314763

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Text Location
Introduction

p(MGI:Hpx) decreases bp(MESH:"Blood Pressure") View Subject | View Object

In mouse models associated with 392 chronic hemolysis and heme overload, such as in mice with a sickle hemoglobin 393 (HbS) gene knock-in or mouse models of β-thalassemia, repeated treatment with 394 hemopexin was shown to reduce chronically elevated blood pressure (21). PubMed:28314763

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
Text Location
Introduction

p(MGI:Hpx) decreases p(MGI:Slc40a1) View Subject | View Object

Moreover, in CMs the heme-mediated induction of the iron exporter Ferroportin (Fpn) was abrogated by Hx treatment while the down-regulation of the iron importer Transferrin receptor 1 (TfR1) was significantly reduced by Hx (see Figure 3 in [37]) further indicating that Hx limits heme-iron accumulation within the cell. PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) increases p(MGI:Tfrc) View Subject | View Object

Moreover, in CMs the heme-mediated induction of the iron exporter Ferroportin (Fpn) was abrogated by Hx treatment while the down-regulation of the iron importer Transferrin receptor 1 (TfR1) was significantly reduced by Hx (see Figure 3 in [37]) further indicating that Hx limits heme-iron accumulation within the cell. PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) increases p(MGI:Tfrc) View Subject | View Object

Moreover, the mRNA levels of Fpn and Flvcr1a were increased in Hx-/- mice, whereas those of the iron importers Divalent Metal Transporter 1 (Dmt1) and Tfr1 were decreased (see Figure 4 in [37]). PubMed:28400318

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p(MGI:Hpx) negativeCorrelation p(MGI:Flvcr1) View Subject | View Object

Consistently, Hx treatment blunted heme-mediated induction of the heme exporter Feline Leukemia Virus subgroup C Receptor 1(Flvcr1) [31, 38, 39] in H9c2 cells (see Figure 3 in [37]). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) decreases bp(MESH:"Oxidative Stress") View Subject | View Object

Staining of CMs with a fluorescent probe for specific detection of mitochondrial superoxide (Mito-sox) confirmed lower oxidative stress in cells exposed to Hx-heme than in those exposed to albumin-heme or heme alone (Figure 1E). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) decreases bp(MESH:"Oxidative Stress") View Subject | View Object

Both ROS and lipid peroxidation were increased in the heart of Hx-/- mice compared to that of wild-type animals (Figure 2C, D). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) decreases r(MGI:Gsr) View Subject | View Object

Consistently, the mRNA levels of Glutathione reductase (Gsr), -Glutamylcysteine synthetase (-Gcs) and thioredoxin reductase (Thiored red), anti-oxidant systems important in resistance of cardiac cell to oxidative damage [40, 41], were increased to a higher extent in CMs treated with either albumin heme or heme alone, compared to cells treated with Hx-heme (Figure 1F and see Figure 3 in [37]). PubMed:28400318

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p(MGI:Hpx) decreases r(MGI:Gclc) View Subject | View Object

Consistently, the mRNA levels of Glutathione reductase (Gsr), -Glutamylcysteine synthetase (-Gcs) and thioredoxin reductase (Thiored red), anti-oxidant systems important in resistance of cardiac cell to oxidative damage [40, 41], were increased to a higher extent in CMs treated with either albumin heme or heme alone, compared to cells treated with Hx-heme (Figure 1F and see Figure 3 in [37]). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) decreases complex(r(MGI:Txnrd1), r(MGI:Txnrd2), r(MGI:Txnrd3)) View Subject | View Object

Consistently, the mRNA levels of Glutathione reductase (Gsr), -Glutamylcysteine synthetase (-Gcs) and thioredoxin reductase (Thiored red), anti-oxidant systems important in resistance of cardiac cell to oxidative damage [40, 41], were increased to a higher extent in CMs treated with either albumin heme or heme alone, compared to cells treated with Hx-heme (Figure 1F and see Figure 3 in [37]). PubMed:28400318

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p(MGI:Hpx) decreases bp(GO:"protein nitrosylation") View Subject | View Object

The data were reproduced in H9c2 cells in which we were also able to demonstrate that Hx limits protein nitrosylation, another hallmark of cellular oxidative damage (see Figure 2 in [37]). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) decreases r(MGI:Hmox1) View Subject | View Object

Consistently, HO-1 mRNA and protein levels were higher in hearts from Hx-/- mice than in controls (Figure 2B). Immunohistochemistry for HO-1 on heart sections indicated higher HO-1 expression in cardiomyocytes from Hx-/- mice than in wild-type animals (Figure 2B). PubMed:28400318

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p(MGI:Hpx) decreases r(MGI:Slc40a1) View Subject | View Object

Moreover, the mRNA levels of Fpn and Flvcr1a were increased in Hx-/- mice, whereas those of the iron importers Divalent Metal Transporter 1 (Dmt1) and Tfr1 were decreased (see Figure 4 in [37]). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) decreases r(MGI:Flvcr1) View Subject | View Object

Moreover, the mRNA levels of Fpn and Flvcr1a were increased in Hx-/- mice, whereas those of the iron importers Divalent Metal Transporter 1 (Dmt1) and Tfr1 were decreased (see Figure 4 in [37]). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) increases p(MGI:Slc11a2) View Subject | View Object

Moreover, the mRNA levels of Fpn and Flvcr1a were increased in Hx-/- mice, whereas those of the iron importers Divalent Metal Transporter 1 (Dmt1) and Tfr1 were decreased (see Figure 4 in [37]). PubMed:28400318

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p(MGI:Hpx) decreases bp(MESH:"Lipid Peroxidation") View Subject | View Object

Both ROS and lipid peroxidation were increased in the heart of Hx-/- mice compared to that of wild-type animals (Figure 2C, D). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) decreases g(MGI:Gsr) View Subject | View Object

Consistently, the oxidative stress responsive gene Gsr was up-regulated in the heart of Hx-/- mice compared to wild-type animals (Figure 2E). PubMed:28400318

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p(MGI:Hpx) negativeCorrelation path(HP:"Impaired myocardial contractility") View Subject | View Object

Cardiac contractility was severely impaired in 3 month-old Hx-/- mice compared to wild-type controls, as evidenced by significantly lower fractional shortening (FS) and ejection fraction (EF) (Figure 3A-C). PubMed:28400318

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p(MGI:Hpx) negativeCorrelation path(HP:"Impaired myocardial contractility") View Subject | View Object

As well as NAC, Hx co-treatment significantly improved systolic Ca2+ transients and accelerated Ca2+ transient decay kinetics, which resulted in a significant improvement of cardiomyocyte contractility (Figure 4A-E). PubMed:28400318

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p(MGI:Hpx) decreases p(MGI:Ryr2, pmod(Ph, Ser, 2814)) View Subject | View Object

Consistently, CaMKII-dependent phosphorylation of RyR2 (Ser-2814) and Phospholamban (PLB) (Thr-17) were significantly higher in Hx-/- hearts than in wild-type controls (Figure 5C, D). PubMed:28400318

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p(MGI:Hpx) decreases p(MGI:Pln, pmod(Ph, Thr, 17)) View Subject | View Object

Consistently, CaMKII-dependent phosphorylation of RyR2 (Ser-2814) and Phospholamban (PLB) (Thr-17) were significantly higher in Hx-/- hearts than in wild-type controls (Figure 5C, D). PubMed:28400318

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regular cardiac myocyte
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p(MGI:Hpx) negativeCorrelation path(MESH:Pneumonia) View Subject | View Object

Hemopexin improved post-pneumonia survival in mice that underwent massive resuscitation with stored RBCs (Fig 3A). PubMed:29522519

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p(MGI:Hpx) negativeCorrelation act(p(MGI:Nfkb1)) View Subject | View Object

Compared to Hb alone or Hb + albumin infused animals, sickle mice co-infused with Hb + Hp, Hb + Hpx, or Hb + Hp + Hpx had markedly diminished hepatic NF-κB activation 4h after infusion as evidenced by nuclear NF- κB phospho-p65 levels (Fig 2A). PubMed:29694434

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MeSH
Liver
MeSH
Anemia, Sickle Cell
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p(MGI:Hpx) negativeCorrelation p(MGI:Vcam1) View Subject | View Object

Immunofluorescence staining of VCAM-1 and ICAM-1 was decreased in the dorsal skin of SS-mice 4h after infusion of Hb+Hp and Hb+Hpx compared to SS-mice infused with vehicle or Hb (Fig 2B and 2C). PubMed:29694434

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Liver
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Anemia, Sickle Cell
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p(MGI:Hpx) negativeCorrelation p(MGI:Icam1) View Subject | View Object

Immunofluorescence staining of VCAM-1 and ICAM-1 was decreased in the dorsal skin of SS-mice 4h after infusion of Hb+Hp and Hb+Hpx compared to SS-mice infused with vehicle or Hb (Fig 2B and 2C). PubMed:29694434

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Liver
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Anemia, Sickle Cell
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p(MGI:Hpx) negativeCorrelation act(p(MGI:Ccl5)) View Subject | View Object

Pro-inflammatory cytokine RANTES (chemokine ligand 5 or CCL5), which recruits leukocytes to pro-inflammatory sites, was lower in the plasma of SS-mice 24 hours after infusion of Hp or Hpx compared to vehicle-treated SS-mice (Fig 2F). PubMed:29694434

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Liver
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Anemia, Sickle Cell
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p(MGI:Hpx) negativeCorrelation a(CHEBI:"4-hydroxynon-2-enal") View Subject | View Object

Hepatic 4-hydroxynonenol (4-HNE), a marker of oxidative stress, was significantly lower in the liver microsomes of SSmice 24 hours after infusion of Hp or Hpx compared to vehicle-treated SS-mice (Fig 2G). PubMed:29694434

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Liver
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Anemia, Sickle Cell
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act(p(MGI:Hpx)) negativeCorrelation complex(a(CHEBI:"tin atom"), a(CHEBI:protoporphyrin)) View Subject | View Object

The beneficial effects of Hp and Hpx were lost by inhibition of HO with SnPP, but could be restored by CO administration. PubMed:29694434

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Liver
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Anemia, Sickle Cell
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Discussion

act(p(MGI:Hpx)) positiveCorrelation a(CHEBI:"carbon monoxide") View Subject | View Object

The beneficial effects of Hp and Hpx were lost by inhibition of HO with SnPP, but could be restored by CO administration. PubMed:29694434

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Liver
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Anemia, Sickle Cell
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Discussion

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.