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PubMed: 29694434

Title
Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction.
Journal
PloS one
Volume
13
Issue
None
Pages
e0196455
Date
2018-01-01
Authors
Chen C | Belcher JD | Vercellotti GM | Abdulla F | Brinkman N | Killeen T | Miescher SM | Nath KA | Nguyen H | Nguyen J | Nguyen P | Steer CJ | Zhang P

Evidence 3e40694b4b
JSON

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).

a(CHEBI:"4-hydroxynon-2-enal") positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

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

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

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

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

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

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:"4-hydroxynon-2-enal") View Subject | View Object

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

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

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

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

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

Evidence d7f6eba2ee
JSON

CO also inhibited stasis in mice treated with SnPP + Hb without Hp or Hpx.

a(CHEBI:"carbon monoxide") negativeCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

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

path(HM:"vaso-occlusive crisis") negativeCorrelation a(CHEBI:"carbon monoxide") View Subject | View Object

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

Evidence 98860d1309
JSON

SnPP and CO had similar inhibitory effects on NF-kB activation in the liver (data not shown).

a(CHEBI:"carbon monoxide") negativeCorrelation act(p(MGI:Nfkb1)) View Subject | View Object

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

complex(a(CHEBI:"tin atom"), a(CHEBI:protoporphyrin)) negativeCorrelation act(p(MGI:Nfkb1)) View Subject | View Object

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

act(p(MGI:Nfkb1)) negativeCorrelation a(CHEBI:"carbon monoxide") View Subject | View Object

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

act(p(MGI:Nfkb1)) negativeCorrelation complex(a(CHEBI:"tin atom"), a(CHEBI:protoporphyrin)) View Subject | View Object

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

Evidence 47cff2dc11
JSON

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Evidence 0cd1fcf925
JSON

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis.

a(CHEBI:heme) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

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Introduction

a(CHEBI:heme) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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Introduction

a(CHEBI:heme) positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

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Introduction

a(CHEBI:heme) positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

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Introduction

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Introduction

bp(MESH:"Oxidative Stress") positiveCorrelation p(HGNC:HBB) View Subject | View Object

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Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

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Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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Text Location
Introduction

p(HGNC:HBB) positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
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Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

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Text Location
Introduction

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

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Introduction

path(MESH:Hemolysis) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Introduction

path(MESH:Inflammation) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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path(MESH:Inflammation) positiveCorrelation p(HGNC:HBB) View Subject | View Object

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Introduction

path(MESH:Thrombosis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

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Introduction

path(MESH:Thrombosis) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 3e1a136113
JSON

The released heme can activate the innate immune pattern recognition receptor toll-like receptor 4 (TLR4) on inflammatory cells, platelets and endothelium, promoting a pro-inflammatory and pro-coagulant phenotype, ultimately leading to vaso-occlusion, ischemia-reperfusion physiology, tissue injury, and pain in murine models of SCD [5, 7±10].

a(CHEBI:heme) positiveCorrelation path(MESH:"Reperfusion Injury") View Subject | View Object

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

a(CHEBI:heme) positiveCorrelation act(p(HGNC:TLR4)) View Subject | View Object

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

a(CHEBI:heme) positiveCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

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

a(CHEBI:heme) positiveCorrelation path(MESH:Pain) View Subject | View Object

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

bp(GO:"inflammatory response") positiveCorrelation act(p(HGNC:TLR4)) View Subject | View Object

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

act(p(HGNC:TLR4)) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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

act(p(HGNC:TLR4)) positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

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

path(HM:"vaso-occlusive crisis") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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

path(MESH:"Reperfusion Injury") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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

path(MESH:Pain) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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

Evidence e90d415a5d
JSON

Infusion of exogenous hemoglobin into SS-mice can markedly increase stasis compared to the amount of spontaneous stasis [5].

p(HGNC:HBB) positiveCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

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

path(HM:"vaso-occlusive crisis") positiveCorrelation p(HGNC:HBB) View Subject | View Object

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

Evidence d417f17c82
JSON

Plasma haptoglobin and hemopexin levels are often depleted in SCD patients and mice due to chronic intravascular hemolysis [21±24].

p(HGNC:HPX) negativeCorrelation path(MESH:Hemolysis) View Subject | View Object

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

p(HGNC:HP) negativeCorrelation path(MESH:Hemolysis) View Subject | View Object

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

path(MESH:Hemolysis) negativeCorrelation p(HGNC:HP) View Subject | View Object

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

path(MESH:Hemolysis) negativeCorrelation p(HGNC:HPX) View Subject | View Object

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

Evidence 4f1fe7f0a5
JSON

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

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

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

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

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

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

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

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

Evidence c594ffbb68
JSON

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).

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

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

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

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

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

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

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

Evidence 6fec9a4981
JSON

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

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

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

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

path(HM:"vaso-occlusive crisis") positiveCorrelation path(MESH:Hypoxia) View Subject | View Object

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MeSH
Liver
MeSH
Anemia, Sickle Cell
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path(HM:"vaso-occlusive crisis") negativeCorrelation p(MGI:Hp) View Subject | View Object

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

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

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

path(MESH:Hypoxia) positiveCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence c044c7b4df
JSON

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).

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

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Liver
MeSH
Anemia, Sickle Cell
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p(MGI:Hp) negativeCorrelation act(p(MGI:Nfkb1)) View Subject | View Object

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Liver
MeSH
Anemia, Sickle Cell
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act(p(MGI:Nfkb1)) negativeCorrelation p(MGI:Hp) View Subject | View Object

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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

Evidence 7d80c2d105
JSON

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).

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
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Results

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 9ac4b4d3a3
JSON

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).

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
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Results

Evidence a51537e8a5
JSON

In contrast, albumin did not induce HO-1 or inhibit stasis and NF- κB.

p(MGI:Alb) causesNoChange p(MGI:Hmox1) View Subject | View Object

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Liver
MeSH
Anemia, Sickle Cell
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Discussion

p(MGI:Alb) causesNoChange act(p(MGI:Nfkb1)) View Subject | View Object

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Liver
MeSH
Anemia, Sickle Cell
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Discussion

Evidence c1606352a0
JSON

We have previously shown that induction of HO-1 expression or liver-directed HO-1 gene therapy inhibits stasis in sickle mice exposed to H/R [38, 45].

p(MGI:Hmox1) negativeCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

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Liver
MeSH
Anemia, Sickle Cell
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path(HM:"vaso-occlusive crisis") negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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MeSH
Liver
MeSH
Anemia, Sickle Cell
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Results

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