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PubMed: 23178521

Title
Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation.
Journal
European journal of pharmacology
Volume
698
Issue
None
Pages
145-53
Date
2013-01-05
Authors
Abdullah L | Ait-Ghezala G | Bachmeier C | Beaulieu-Abdelahad D | Crawford F | Mullan M | Paris D | Reed J | Verma M

Evidence c0527e8527
JSON

We observed that anatabine inhibits basal STAT3 phosphorylation levels (Mann– Whitney U=0, Z=-2.882, P=0.004) and reduces the induction of p65 NFkB phosphorylation by TNFa (Mann–Whitney U=0, Z=-2.882, P=0.004) within this 15 min time-frame (Fig. 1)

a(CHEBI:Anatabine) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 2d50d5ff58
JSON

Under these culture conditions, anatabine also inhibited both STAT3 and p65 NFkB phosphorylation induced by TNFa (Fig. 2)

a(CHEBI:Anatabine) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 517a336e2e
JSON

A significant inhibition of STAT3 phosphorylation was observed with 600 mg/ml of anatabine (Mann–Whitney U=0, Z=-2.309, P=0.021) and with 800 mg/ml of anatabine (Mann–Whitney U=0, Z=-2.309, P=0.021) and a significant inhibition of p65 NFkB phosphorylation was observed with 600 mg/ml of anatabine (Mann–Whitney U=1.0, Z=-2.021, P=0.043) and with 800 mg/ml of anatabine (Mann–Whitney U=0,Z=-2.309, P=0.021)

a(CHEBI:Anatabine) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 3383e1084d
JSON

We observed that anatabine significantly suppressed the stimulation of p65 NFkB and STAT3 phosphorylation by LPS in microglia (Fig. 3)

a(CHEBI:Anatabine) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

a(CHEBI:lipopolysaccharide) increases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

a(CHEBI:lipopolysaccharide) increases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence b0265753eb
JSON

Kruskal–Wallis test revealed that doses of anatabine significantly suppressed both LPS induced STAT3 phosphorylation (H=15.658, df=4, P=0.005) and p65 NFkB phosphorylation (H=14.150, df=4, P=0.007) in human microglia

a(CHEBI:Anatabine) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence 210f8f5bae
JSON

A significant inhibition of STAT3 phosphorylation was observed with 10 mg/ml of anatabine (Mann–Whitney U=1, Z=-2.021, P=0.043), with 100 mg/ml of anatabine (Mann–Whitney U=0, Z=-2.309, P=0.021), with 300 mg/ml of anatabine (Mann–Whitney U=0, Z=-2.309, P=0.021) and with 600 mg/ml of anatabine (Mann–Whitney U=0, Z=-2.309, P=0.021)

a(CHEBI:Anatabine) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence 1aeb963ed3
JSON

An inhibition of TNFa induced STAT3 (Mann–Whitney U=0, Z=-2.121, P=0.034), and p65 NFkB phosphorylation (Mann–Whitney U=0, Z=-2.121, P=0.034) was observed in these cells following the anatabine treatment (Fig. 4) suggesting that anatabine may also mediate its anti-inflammatory activity independently of nicotinic acetylcholine receptor expression

a(CHEBI:Anatabine) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293

a(CHEBI:Anatabine) regulates bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293

Evidence 915eca5f23
JSON

Anatabine appears to completely antagonize LPS induced STAT3 (Mann–Whitney U=0, Z=-3.077, P=0.002) and p65 NFkB phosphorylation (Mann–Whitney U=0, Z=-3.077, P=0.002) in human mononuclear cells

a(CHEBI:Anatabine) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
mononuclear cell

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
mononuclear cell

Evidence 9615f946f1
JSON

Similarly, LPS induced p65 NFkB phosphorylation in microglia was significantly inhibited with 10 mg/ml of anatabine (Mann–Whitney U=0, Z=-2.309, P=0.021), with 100 mg/ml of anatabine (Mann– Whitney U=0, Z=-2.309, P=0.021), with 300 mg/ml of anatabine (Mann–Whitney U=0, Z=-2.309, P=0.021)

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

a(CHEBI:lipopolysaccharide) increases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence 58aa9fe30b
JSON

Western-blot experiments revealed that LPS significantly stimulated of STAT3 phosphorylation in the spleen (Mann–Whitney U=0, Z=-2.309, P=0.021) (Fig. 8) and kidney (Mann–Whitney U=0, Z=-2.882, P=0.004) (data not shown) whereas anatabine significantly inhibited STAT3 phosphorylation in the spleen (Mann–Whitney U=1, Z=-2.021, P=0.043) and kidney (Mann– Whitney U=5, Z=-2.082, P=0.037) (data not shown)

a(CHEBI:Anatabine) decreases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Kidney
MeSH
Spleen

a(CHEBI:lipopolysaccharide) increases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Kidney
MeSH
Spleen

Evidence 230482eaae
JSON

A significant elevation of STAT3 phosphorylation was detected in the brain of Tg APPsw compared to their control littermates (Mann–Whitney U=1, Z=-3.767, p<0.001) and a significant reduction in STAT3 phosphorylation (Mann–Whitney U=8, Z=-2.066, p=0.039) was observed in the brain of Tg APPsw treated with anatabine compared to untreated Tg APPsw littermates (Fig. 10).

a(CHEBI:Anatabine) decreases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

Evidence 9678620723
JSON

Following 90 days of treatment with anatabine, a significant reduction in brain TNF-a (Mann–Whitney U=6, Z=-2.146, p=0.032) and in IL-6 (Mann–Whitney U=0, Z=-2.887, p=0.004) was observed in Tg APPsw mice compared to Tg APPsw that received regular drinking water (Fig. 9)

a(CHEBI:Anatabine) decreases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

a(CHEBI:Anatabine) decreases p(MGI:Il6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

Evidence a2043e5896
JSON

An increased STAT3 (Mann–Whitney U=0, Z=-2.309, P=0.021) and p65 NFkB phosphorylation (Mann–Whitney U=0, Z=-2.309, p=0.021) was observed in LPS treated microglia (Fig. 3)

a(CHEBI:lipopolysaccharide) increases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

a(CHEBI:lipopolysaccharide) increases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence 1b86a023ee
JSON

Following a 24 h incubation with LPS, a significant stimulation of STAT3 (Mann– Whitney U=0, Z=-2.882, P=0.004) and p65 NFkB phosphorylation was observed (Mann–Whitney U=1, Z=-2.722, P=0.006)

a(CHEBI:lipopolysaccharide) increases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
mononuclear cell

a(CHEBI:lipopolysaccharide) increases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
mononuclear cell

Evidence 128ab8ebec
JSON

Anatabine at 200 mg/ ml significantly lowered LPS induced IL-1b levels in whole blood (Mann–Whitney U=0.0, Z=-2.3, P=0.02)

a(CHEBI:lipopolysaccharide) increases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:

composite(a(CHEBI:Anatabine), a(MESH:Blood)) decreases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:

Evidence 7a7344e0de
JSON

Our results showed that intraperitoneal injection of LPS (1 mg/kg) caused a significant elevation of plasma IL-1b (Mann–Whitney U=3, Z=-2.988, P=0.003), IL-6 (Mann–Whitney U=0, Z=-3.366, P=0.001) and TNFa (Mann– Whitney U=0, Z=-3.508, P<0.001) 4 h after the LPS challenge whereas in mice co-treated with an intraperitoneal injection of anatabine (2 mg/kg) and LPS, a significant reduction in plasma IL-1b (Mann–Whitney U=7, Z=-2.645, P=0.008) and TNFa (Mann–Whitney U=4, Z=-2.941, P=0.003) levels was observed (Fig. 6)

a(CHEBI:lipopolysaccharide) increases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Plasma

a(CHEBI:lipopolysaccharide) increases p(MGI:Il6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Plasma

a(CHEBI:lipopolysaccharide) increases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Plasma

composite(a(CHEBI:Anatabine), a(CHEBI:lipopolysaccharide)) decreases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Plasma

composite(a(CHEBI:Anatabine), a(CHEBI:lipopolysaccharide)) decreases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Plasma

Evidence 036e29d5ba
JSON

An elevation of IL-6 (Mann–Whitney U=0, Z=-3.487, P<0.001), IL1b (Mann– Whitney U=0, Z=-3.24, P=0.001) and TNFa (Mann–Whitney U=0, Z=-3.361, P=0.001) was observed in the spleen of LPS challenged mice (Fig. 7)

a(CHEBI:lipopolysaccharide) increases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

a(CHEBI:lipopolysaccharide) increases p(MGI:Il6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

a(CHEBI:lipopolysaccharide) increases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

Evidence a10ff37bb9
JSON

Similarly, IL-1b (Mann–Whitney U=0, Z=-3.098, P=0.002), IL-6 (Mann–Whitney U=0, Z=-3.363, P<0.001) and TNF-a levels (Mann–Whitney U=0, Z=-3.361, P=0.001) were elevated in the kidney following the LPS challenge (data not shown)

a(CHEBI:lipopolysaccharide) increases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Kidney

a(CHEBI:lipopolysaccharide) increases p(MGI:Il6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Kidney

a(CHEBI:lipopolysaccharide) increases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Kidney

Evidence 4754f545b6
JSON

Nicotine has been shown to modulate inflammation by affecting STAT3 phosphorylation (Chatterjee et al., 2009; Hosur and Loring, 2011) and by opposing NFkB activation (Leite et al., 2010; Zhou et al., 2010)

a(CHEBI:nicotine) regulates bp(GO:"inflammatory response") View Subject | View Object

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a(CHEBI:nicotine) association p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

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a(CHEBI:nicotine) decreases act(p(FPLX:NFkappaB)) View Subject | View Object

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p(HGNC:STAT3, pmod(Ph)) association a(CHEBI:nicotine) View Subject | View Object

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Evidence baa1858960
JSON

As a positive control, we used stattic, a known inhibitor of STAT3 dimerization and phosphorylation

a(CHEBI:stattic) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(CHEBI:stattic) decreases complex(p(HGNC:STAT3), p(HGNC:STAT3)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence dc47eb9591
JSON

We found that stattic inhibited STAT3 phosphorylation (Mann–Whitney U=0, Z=-2.324, P=0.02) and also suppressed p65 NFkB phosphorylation (Mann–Whitney U¼0, Z¼2.324, P¼0.02) mimicking the effect of anatabine in SHSY5Y cells (Fig. 1)

a(CHEBI:stattic) decreases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(CHEBI:stattic) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 93fb063694
JSON

We next tested the impact of anatabine on STAT3 and p65 NFkB phosphorylation induced by a 24 h treatment with LPS on human microglial cells, a cell type known to express alpha7-nicotinic acetylcholine receptor subtype (Suzuki et al., 2006)

a(MESH:Microglia) increases a(MESH:"alpha7 Nicotinic Acetylcholine Receptor") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence 316707286c
JSON

Anatabine significantly inhibited LPS induced IL-6 (Mann–Whitney U=4, Z=-3.303, P=0.001), TNF-a (Mann–Whitney U=0, Z=-3.361, P=0.001) and IL-1b levels in the spleen (Mann–Whitney U=9, Z=-1.981, P=0.048) (Fig. 7)

composite(a(CHEBI:Anatabine), a(CHEBI:lipopolysaccharide)) decreases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

composite(a(CHEBI:Anatabine), a(CHEBI:lipopolysaccharide)) decreases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

composite(a(CHEBI:Anatabine), a(CHEBI:lipopolysaccharide)) decreases p(MGI:Il6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

Evidence 63f15d5cf0
JSON

A significant reduction in TNF-a (Mann–Whitney U=12, Z=-2.309, P=0.021) but no significant reduction in IL-6 levels (Mann–Whitney U=25, Z=-1.223, P=0.221) or IL-1b (Mann–Whitney U=8, Z=-1.857,P=0.063) were observed in the kidney of LPS and anatabine cotreated animals (data not shown)

composite(a(CHEBI:Anatabine), a(CHEBI:lipopolysaccharide)) decreases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Kidney

Evidence 0a0dca111b
JSON

Plasma IL-6 levels show a trend for a reduction but were not significantly affected (Mann–Whitney U=19, Z=-1.368, P=0.171) by the anatabine treatment (Fig. 6)

composite(a(CHEBI:Anatabine), a(CHEBI:lipopolysaccharide)) decreases p(MGI:Il6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Plasma

Evidence 377f948ef7
JSON

Higher doses of anatabine resulted in a complete suppression of IL-1b levels in LPS challenged human blood (Mann–Whitney U=0.0, Z=-2.5, P=0.01)

composite(a(CHEBI:Anatabine), a(CHEBI:lipopolysaccharide), a(MESH:Blood)) decreases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:

Evidence 405027a3d4
JSON

Following this 15 mins of stimulation with TNFa, an increased p65 NFkB phosphorylation (Mann–Whitney U=0, Z=-2.309, P=0.021) without a noticeable increase in STAT3 phosphorylation (Mann–Whitney U=7, Z=-0.289, P=0.773) was observed compared to the control conditions (Fig. 1)

p(HGNC:TNF) increases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

p(HGNC:TNF) causesNoChange p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 82889eb872
JSON

An increased in both STAT3 (Mann–Whitney U=0, Z=-2.309, P=0.021) and p65 NFkB phosphorylation (Mann–Whitney U=0, Z=-2.309, P=0.021) was observed following 24 h of treatment with TNFa

p(HGNC:TNF) increases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

p(HGNC:TNF) increases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 99c7cae9a4
JSON

TNFa significantly stimulated STAT3 (Mann–Whitney U=0, Z=-2.309, P=0.021) and p65 NFkB phosphorylation (Mann–Whitney U=0, Z=-2.309, P=0.021)

p(HGNC:TNF) increases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293

p(HGNC:TNF) increases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293

Evidence 679f3a1eef
JSON

An elevation of brain IL-6 (Mann–Whitney U=0, Z=-3, p=0.003) and TNF-a (Mann–Whitney U=0, Z=-2.887, p=0.004) was observed in Tg APPsw mice compared to their wild-type littermates (Fig. 9)

path(MESH:"Alzheimer Disease") increases p(MGI:Il6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

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