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23623790 | 23623790 | [
{
"id": "23623790_title",
"type": "title",
"text": [
"GABAA receptor modulation by piperine and a non-TRPV1 activating derivative."
],
"offsets": [
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0,
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]
},
{
"id": "23623790_abstract",
"type": "abstract",
"text": [
"The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABAA) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioral effects were investigated. GABAA receptor subtypes and TRPV1 receptors were expressed in Xenopus laevis oocytes. Modulation of GABA-induced chloride currents (IGABA) by piperine and SCT-66 and activation of TRPV1 was studied using the two-microelectrode-voltage-clamp technique and fast perfusion. Their effects on explorative behavior, thermoregulation and seizure threshold were analyzed in mice. Piperine acted with similar potency on all GABAA receptor subtypes (EC50 range: 42.8±7.6μM (α2β2)-59.6±12.3μM (α3β2)). IGABA modulation by piperine did not require the presence of a γ2S-subunit, suggesting a binding site involving only α and β subunits. IGABA activation was slightly more efficacious on receptors formed from β2/3 subunits (maximal IGABA stimulation through α1β3 receptors: 332±64% and α1β2: 271±36% vs. α1β1: 171±22%, p<0.05) and α3-subunits (α3β2: 375±51% vs. α5β2:136±22%, p<0.05). Replacing the piperidine ring by a N-di-isobutyl residue (SCT-66) prevents interactions with TRPV1 and simultaneously increases the potency and efficiency of GABAA receptor modulation. SCT-66 displayed greater efficacy on GABAA receptors than piperine, with different subunit-dependence. Both compounds induced anxiolytic, anticonvulsant effects and reduced locomotor activity; however, SCT-66 induced stronger anxiolysis without decreasing body temperature and without the proconvulsive effects of TRPV1 activation and thus may serve as a scaffold for the development of novel GABAA receptor modulators."
],
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] | [
{
"id": "23623790_T1",
"type": "CHEMICAL",
"text": [
"piperidine"
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{
"id": "23623790_T2",
"type": "CHEMICAL",
"text": [
"N-di-isobutyl"
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],
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{
"id": "23623790_T3",
"type": "CHEMICAL",
"text": [
"SCT-66"
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1333,
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],
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{
"id": "23623790_T4",
"type": "CHEMICAL",
"text": [
"SCT-66"
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{
"id": "23623790_T5",
"type": "CHEMICAL",
"text": [
"piperine"
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{
"id": "23623790_T6",
"type": "CHEMICAL",
"text": [
"piperine"
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},
{
"id": "23623790_T7",
"type": "CHEMICAL",
"text": [
"SCT-66"
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],
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},
{
"id": "23623790_T8",
"type": "CHEMICAL",
"text": [
"gamma-aminobutyric acid"
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]
],
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},
{
"id": "23623790_T9",
"type": "CHEMICAL",
"text": [
"GABA"
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268,
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],
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},
{
"id": "23623790_T10",
"type": "CHEMICAL",
"text": [
"GABA"
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],
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},
{
"id": "23623790_T11",
"type": "CHEMICAL",
"text": [
"chloride"
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],
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{
"id": "23623790_T12",
"type": "CHEMICAL",
"text": [
"piperine"
],
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]
],
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},
{
"id": "23623790_T13",
"type": "CHEMICAL",
"text": [
"SCT-66"
],
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],
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},
{
"id": "23623790_T14",
"type": "CHEMICAL",
"text": [
"Piperine"
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773,
781
]
],
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},
{
"id": "23623790_T15",
"type": "CHEMICAL",
"text": [
"SCT-66"
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153,
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],
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},
{
"id": "23623790_T16",
"type": "CHEMICAL",
"text": [
"((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide)"
],
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],
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{
"id": "23623790_T17",
"type": "CHEMICAL",
"text": [
"piperine"
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},
{
"id": "23623790_T18",
"type": "CHEMICAL",
"text": [
"piperine"
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],
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},
{
"id": "23623790_T19",
"type": "GENE-Y",
"text": [
"TRPV1"
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],
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},
{
"id": "23623790_T20",
"type": "GENE-N",
"text": [
"GABAA receptor"
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],
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},
{
"id": "23623790_T21",
"type": "GENE-N",
"text": [
"GABAA receptors"
],
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]
],
"normalized": []
},
{
"id": "23623790_T22",
"type": "GENE-N",
"text": [
"gamma-aminobutyric acid (GABA) type A (GABAA) receptors"
],
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[
243,
298
]
],
"normalized": []
},
{
"id": "23623790_T23",
"type": "GENE-Y",
"text": [
"TRPV1"
],
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1774,
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]
],
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},
{
"id": "23623790_T24",
"type": "GENE-N",
"text": [
"GABAA receptor"
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]
],
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},
{
"id": "23623790_T25",
"type": "GENE-Y",
"text": [
"transient-receptor-potential-vanilloid-1"
],
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300,
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]
],
"normalized": []
},
{
"id": "23623790_T26",
"type": "GENE-Y",
"text": [
"TRPV1"
],
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[
342,
347
]
],
"normalized": []
},
{
"id": "23623790_T27",
"type": "GENE-N",
"text": [
"GABAA receptor"
],
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401,
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]
],
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},
{
"id": "23623790_T28",
"type": "GENE-Y",
"text": [
"TRPV1"
],
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429,
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]
],
"normalized": []
},
{
"id": "23623790_T29",
"type": "GENE-Y",
"text": [
"TRPV1"
],
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581,
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]
],
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},
{
"id": "23623790_T30",
"type": "GENE-N",
"text": [
"GABAA receptor"
],
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816,
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]
],
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},
{
"id": "23623790_T31",
"type": "GENE-N",
"text": [
"GABAA receptor"
],
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[
0,
14
]
],
"normalized": []
},
{
"id": "23623790_T32",
"type": "GENE-Y",
"text": [
"TRPV1"
],
"offsets": [
[
48,
53
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23623790_0",
"type": "ACTIVATOR",
"arg1_id": "23623790_T18",
"arg2_id": "23623790_T32",
"normalized": []
},
{
"id": "23623790_1",
"type": "ACTIVATOR",
"arg1_id": "23623790_T7",
"arg2_id": "23623790_T23",
"normalized": []
}
] |
9486667 | 9486667 | [
{
"id": "9486667_title",
"type": "title",
"text": [
"Molecular determinants of dofetilide block of HERG K+ channels."
],
"offsets": [
[
0,
63
]
]
},
{
"id": "9486667_abstract",
"type": "abstract",
"text": [
"The human ether-a-go-go-related gene (HERG) encodes a K+ channel with biophysical properties nearly identical to the rapid component of the cardiac delayed rectifier K+ current (IKr). HERG/IKr channels are a prime target for the pharmacological management of arrhythmias and are selectively blocked by class III antiarrhythmic methanesulfonanilide drugs, such as dofetilide, E4031, and MK-499, at submicromolar concentrations. By contrast, the closely related bovine ether-a-go-go channel (BEAG) is 100-fold less sensitive to dofetilide. To identify the molecular determinants for dofetilide block, we first engineered chimeras between HERG and BEAG and then used site-directed mutagenesis to localize single amino acid residues responsible for block. Using constructs heterologously expressed in Xenopus oocytes, we found that transplantation of the S5-S6 linker from BEAG into HERG removed high-affinity block by dofetilide. A point mutation in the S5-S6 linker region, HERG S620T, abolished high-affinity block and interfered with C-type inactivation. Thus, our results indicate that important determinants of dofetilide binding are localized to the pore region of HERG. Since the loss of high-affinity drug binding was always correlated with a loss of C-type inactivation, it is possible that the changes observed in drug binding are due to indirect allosteric modifications in the structure of the channel protein and not to the direct interaction of dofetilide with the respective mutated site chains. However, the chimeric approach was not able to identify domains outside the S5-S6 linker region of the HERG channel as putative candidates involved in drug binding. Moreover, the reverse mutation BEAG T432S increased the affinity of BEAG K+ channels for dofetilide, whereas C-type inactivation could not be recovered. Thus, the serine in position HERG 620 may participate directly in dofetilide binding; however, an intact C-type inactivation process seems to be crucial for high-affinity drug binding."
],
"offsets": [
[
64,
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]
]
}
] | [
{
"id": "9486667_T1",
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"dofetilide"
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]
],
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{
"id": "9486667_T2",
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"dofetilide"
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{
"id": "9486667_T3",
"type": "CHEMICAL",
"text": [
"K+"
],
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[
230,
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]
],
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},
{
"id": "9486667_T4",
"type": "CHEMICAL",
"text": [
"K+"
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1810,
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]
],
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{
"id": "9486667_T5",
"type": "CHEMICAL",
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"dofetilide"
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]
],
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},
{
"id": "9486667_T6",
"type": "CHEMICAL",
"text": [
"serine"
],
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]
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"id": "9486667_T7",
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"dofetilide"
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},
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"id": "9486667_T8",
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"methanesulfonanilide"
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]
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"id": "9486667_T9",
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"dofetilide"
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"id": "9486667_T10",
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"text": [
"E4031"
],
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]
],
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},
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"id": "9486667_T11",
"type": "CHEMICAL",
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"MK-499"
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450,
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"id": "9486667_T12",
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"dofetilide"
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"id": "9486667_T13",
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"text": [
"K+"
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118,
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"id": "9486667_T14",
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"id": "9486667_T15",
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"text": [
"amino acid"
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"id": "9486667_T16",
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"id": "9486667_T17",
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"K+"
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51,
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},
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"id": "9486667_T18",
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"HERG"
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"type": "GENE-N",
"text": [
"rapid component of the cardiac delayed rectifier K+ current"
],
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181,
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],
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{
"id": "9486667_T20",
"type": "GENE-Y",
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"HERG"
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{
"id": "9486667_T21",
"type": "GENE-Y",
"text": [
"BEAG"
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]
],
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},
{
"id": "9486667_T22",
"type": "GENE-N",
"text": [
"T432S"
],
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1773,
1778
]
],
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},
{
"id": "9486667_T23",
"type": "GENE-Y",
"text": [
"BEAG"
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1805,
1809
]
],
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},
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"id": "9486667_T24",
"type": "GENE-N",
"text": [
"K+ channels"
],
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[
1810,
1821
]
],
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},
{
"id": "9486667_T25",
"type": "GENE-N",
"text": [
"IKr"
],
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[
242,
245
]
],
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},
{
"id": "9486667_T26",
"type": "GENE-Y",
"text": [
"HERG"
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248,
252
]
],
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},
{
"id": "9486667_T27",
"type": "GENE-Y",
"text": [
"HERG"
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1919,
1923
]
],
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},
{
"id": "9486667_T28",
"type": "GENE-N",
"text": [
"IKr"
],
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253,
256
]
],
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},
{
"id": "9486667_T29",
"type": "GENE-Y",
"text": [
"HERG"
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[
102,
106
]
],
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},
{
"id": "9486667_T30",
"type": "GENE-Y",
"text": [
"human ether-a-go-go-related gene"
],
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[
68,
100
]
],
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},
{
"id": "9486667_T31",
"type": "GENE-Y",
"text": [
"bovine ether-a-go-go channel"
],
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[
524,
552
]
],
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},
{
"id": "9486667_T32",
"type": "GENE-Y",
"text": [
"BEAG"
],
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[
554,
558
]
],
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},
{
"id": "9486667_T33",
"type": "GENE-N",
"text": [
"K+ channel"
],
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[
118,
128
]
],
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},
{
"id": "9486667_T34",
"type": "GENE-Y",
"text": [
"HERG"
],
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[
700,
704
]
],
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},
{
"id": "9486667_T35",
"type": "GENE-Y",
"text": [
"BEAG"
],
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[
709,
713
]
],
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},
{
"id": "9486667_T36",
"type": "GENE-Y",
"text": [
"BEAG"
],
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[
933,
937
]
],
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},
{
"id": "9486667_T37",
"type": "GENE-Y",
"text": [
"HERG"
],
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947
]
],
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},
{
"id": "9486667_T38",
"type": "GENE-Y",
"text": [
"HERG"
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]
],
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},
{
"id": "9486667_T39",
"type": "GENE-N",
"text": [
"S620T"
],
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[
1041,
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]
],
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},
{
"id": "9486667_T40",
"type": "GENE-Y",
"text": [
"HERG"
],
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46,
50
]
],
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},
{
"id": "9486667_T41",
"type": "GENE-N",
"text": [
"K+ channels"
],
"offsets": [
[
51,
62
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "9486667_0",
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},
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},
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"id": "9486667_9",
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},
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"id": "9486667_10",
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},
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},
{
"id": "9486667_12",
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},
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}
] |
17317527 | 17317527 | [
{
"id": "17317527_title",
"type": "title",
"text": [
"Role of combined administration of Tiron and glutathione against aluminum-induced oxidative stress in rat brain."
],
"offsets": [
[
0,
112
]
]
},
{
"id": "17317527_abstract",
"type": "abstract",
"text": [
"The current study was carried out to investigate the potential role of 4,5 dihydroxy benzene 1,3 disulfonic acid di sodium salt (Tiron) and glutathione (GSH) either individually or in combination against aluminum (Al)-induced toxicity in Wistar rats. Animals were exposed to aluminum chloride at a dose of 172.5mg/kg/d orally for 10 weeks. Tiron and GSH were administered at a dose of 471-mg/kg/d i.p. and 100mg/kg/d orally, respectively, for 7 consecutive days. Tiron is a diphenolic chelating compound which forms water soluble complexes with a large number of metal ions. Induction of oxidative stress was recorded in brain and serum after Al exposure. Significant decrease was recorded in reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GP(x)), catalase (CAT), superoxide dismutase (SOD), acetyl cholinesterase (AChE) and an increase was observed in thiobarbituric acid reacting substance (TBARS) and glutathione-S-transferase (GST) in brain and serum. Most of the above parameters responded positively to individual therapy with Tiron, but more pronounced beneficial effects on the above-described parameters were observed when Tiron was administered in combination with GSH. Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) studies also showed significantly high concentration of Al in brain and blood. Tiron was slightly more effective then GSH in reducing the concentration of Al from the brain and blood, however, no further improvement was recorded when Tiron was administered in combination with GSH in reducing the concentration of Al."
],
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113,
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]
]
}
] | [
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]
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253,
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]
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]
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]
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266,
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]
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]
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"Al"
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1705,
1707
]
],
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"id": "17317527_T14",
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"aluminum"
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317,
325
]
],
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327,
329
]
],
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388,
405
]
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453,
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]
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463,
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]
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576,
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]
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"id": "17317527_T20",
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587,
597
]
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"id": "17317527_T21",
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"glutathione"
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814,
825
]
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],
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184,
240
]
],
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"GSH"
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827,
830
]
],
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"glutathione"
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833,
844
]
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861,
872
]
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},
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"id": "17317527_T26",
"type": "CHEMICAL",
"text": [
"acetyl"
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937,
943
]
],
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],
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998,
1017
]
],
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},
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"glutathione"
],
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1049,
1060
]
],
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},
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"S"
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1061,
1062
]
],
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},
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"Tiron"
],
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35,
40
]
],
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},
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"id": "17317527_T31",
"type": "CHEMICAL",
"text": [
"glutathione"
],
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[
45,
56
]
],
"normalized": []
},
{
"id": "17317527_T32",
"type": "CHEMICAL",
"text": [
"aluminum"
],
"offsets": [
[
65,
73
]
],
"normalized": []
},
{
"id": "17317527_T33",
"type": "GENE-Y",
"text": [
"glutathione reductase"
],
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[
833,
854
]
],
"normalized": []
},
{
"id": "17317527_T34",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
856,
858
]
],
"normalized": []
},
{
"id": "17317527_T35",
"type": "GENE-N",
"text": [
"glutathione peroxidase"
],
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[
861,
883
]
],
"normalized": []
},
{
"id": "17317527_T36",
"type": "GENE-N",
"text": [
"GP(x)"
],
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[
885,
890
]
],
"normalized": []
},
{
"id": "17317527_T37",
"type": "GENE-Y",
"text": [
"catalase"
],
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[
893,
901
]
],
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},
{
"id": "17317527_T38",
"type": "GENE-Y",
"text": [
"CAT"
],
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[
903,
906
]
],
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},
{
"id": "17317527_T39",
"type": "GENE-N",
"text": [
"superoxide dismutase"
],
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[
909,
929
]
],
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},
{
"id": "17317527_T40",
"type": "GENE-N",
"text": [
"SOD"
],
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[
931,
934
]
],
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},
{
"id": "17317527_T41",
"type": "GENE-Y",
"text": [
"acetyl cholinesterase"
],
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[
937,
958
]
],
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},
{
"id": "17317527_T42",
"type": "GENE-Y",
"text": [
"AChE"
],
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[
960,
964
]
],
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},
{
"id": "17317527_T43",
"type": "GENE-N",
"text": [
"glutathione-S-transferase"
],
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[
1049,
1074
]
],
"normalized": []
},
{
"id": "17317527_T44",
"type": "GENE-N",
"text": [
"GST"
],
"offsets": [
[
1076,
1079
]
],
"normalized": []
}
] | [] | [] | [] |
11156594 | 11156594 | [
{
"id": "11156594_title",
"type": "title",
"text": [
"alpha(1B) adrenergic receptors in gonadotrophin-releasing hormone neurones: relation to Transport-P."
],
"offsets": [
[
0,
100
]
]
},
{
"id": "11156594_abstract",
"type": "abstract",
"text": [
"1. Peptidergic neurones accumulate amines via an unusual uptake process, designated Transport-P. [(3)H]-prazosin binds to alpha(1) adrenoceptors on these cells and is displaceable by unlabelled prazosin in concentrations up to 10(-7) M. However, at greater concentrations of prazosin, there is a paradoxical accumulation of [(3)H]-prazosin which we have attributed to Transport-P. Uptake of prazosin via Transport-P is detectable at 10(-10) M prazosin concentration, is linear up to 10(-7) M and at greater concentrations becomes non-linear. In contrast, in noradrenergic neurones, noradrenaline uptake is linear and saturates above 10(-7) M. In noradrenergic neurones and in non-neuronal cells, there is no uptake of prazosin in concentrations up to 10(-6) M, suggesting that Transport-P is a specialised function of peptidergic neurones. 2. Using a mouse peptidergic (gonadotrophin-releasing hormone, GnRH) neuronal cell line which possesses Transport-P, we have studied the interaction of alpha(1) adrenoceptors with Transport-P. Polymerase chain reactions and DNA sequencing of the products demonstrated that only the alpha(1B) sub-type of adrenoceptors is present in GnRH cells. 3. In COS cells transfected with alpha(1b) adrenoceptor cDNA and in DDT(1) MF-2 cells which express native alpha(1B) adrenoceptors, [(3)H]-prazosin was displaced by unlabelled prazosin in a normal equilibrium process, with no prazosin paradox in concentrations up to 10(-6) M. In DDT(1) MF-2 cells, [(3)H]-prazosin was displaced likewise by a series of alpha(1) adrenergic agonists, none of which increased the binding of [(3)H]-prazosin. Hence, the prazosin paradox is not due to some function of alpha(1) adrenoceptors, such as internalization of ligand-receptor complexes. 4. In neurones which possess Transport-P, transfection with alpha(1b) adrenoceptor cDNA resulted in over-expression of alpha(1B) adrenoceptors, but the prazosin paradox was unaltered. Thus, alpha(1) adrenoceptors and Transport-P mediate distinct functions in peptidergic neurones."
],
"offsets": [
[
101,
2141
]
]
}
] | [
{
"id": "11156594_T1",
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"GnRH"
],
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[
1273,
1277
]
],
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},
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"id": "11156594_T2",
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"[(3)H]-prazosin"
],
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1417,
1432
]
],
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},
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"id": "11156594_T3",
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"prazosin"
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1461,
1469
]
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},
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"id": "11156594_T4",
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"prazosin"
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1511,
1519
]
],
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},
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"[(3)H]-prazosin"
],
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1584,
1599
]
],
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},
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"id": "11156594_T6",
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"[(3)H]-prazosin"
],
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1707,
1722
]
],
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},
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"id": "11156594_T7",
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"prazosin"
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1735,
1743
]
],
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},
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"prazosin"
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2013,
2021
]
],
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"prazosin"
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295,
303
]
],
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"prazosin"
],
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376,
384
]
],
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},
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"[(3)H]-prazosin"
],
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425,
440
]
],
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},
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"id": "11156594_T12",
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"amines"
],
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136,
142
]
],
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},
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"prazosin"
],
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492,
500
]
],
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544,
552
]
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"noradrenaline"
],
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683,
696
]
],
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},
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819,
827
]
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},
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"gonadotrophin-releasing hormone"
],
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971,
1002
]
],
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},
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"GnRH"
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1004,
1008
]
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"[(3)H]-prazosin"
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198,
213
]
],
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},
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"gonadotrophin-releasing hormone"
],
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[
34,
65
]
],
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},
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"alpha(1B) sub-type of adrenoceptors"
],
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[
1223,
1258
]
],
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},
{
"id": "11156594_T22",
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"text": [
"GnRH"
],
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[
1273,
1277
]
],
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},
{
"id": "11156594_T23",
"type": "GENE-Y",
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"alpha(1b) adrenoceptor"
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1318,
1340
]
],
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},
{
"id": "11156594_T24",
"type": "GENE-N",
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"alpha(1) adrenoceptors"
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[
223,
245
]
],
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},
{
"id": "11156594_T25",
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"alpha(1B) adrenoceptors"
],
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[
1392,
1415
]
],
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},
{
"id": "11156594_T26",
"type": "GENE-N",
"text": [
"alpha(1)"
],
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[
1638,
1646
]
],
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},
{
"id": "11156594_T27",
"type": "GENE-N",
"text": [
"alpha(1) adrenoceptors"
],
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[
1783,
1805
]
],
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},
{
"id": "11156594_T28",
"type": "GENE-Y",
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"alpha(1b) adrenoceptor"
],
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[
1921,
1943
]
],
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},
{
"id": "11156594_T29",
"type": "GENE-Y",
"text": [
"alpha(1B) adrenoceptors"
],
"offsets": [
[
1980,
2003
]
],
"normalized": []
},
{
"id": "11156594_T30",
"type": "GENE-N",
"text": [
"alpha(1) adrenoceptors"
],
"offsets": [
[
2051,
2073
]
],
"normalized": []
},
{
"id": "11156594_T31",
"type": "GENE-Y",
"text": [
"gonadotrophin-releasing hormone"
],
"offsets": [
[
971,
1002
]
],
"normalized": []
},
{
"id": "11156594_T32",
"type": "GENE-Y",
"text": [
"GnRH"
],
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[
1004,
1008
]
],
"normalized": []
},
{
"id": "11156594_T33",
"type": "GENE-N",
"text": [
"alpha(1) adrenoceptors"
],
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[
1093,
1115
]
],
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},
{
"id": "11156594_T34",
"type": "GENE-Y",
"text": [
"alpha(1B) adrenergic receptors"
],
"offsets": [
[
0,
30
]
],
"normalized": []
},
{
"id": "11156594_T35",
"type": "GENE-Y",
"text": [
"gonadotrophin-releasing hormone"
],
"offsets": [
[
34,
65
]
],
"normalized": []
}
] | [] | [] | [
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"id": "11156594_6",
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"arg1_id": "11156594_T5",
"arg2_id": "11156594_T26",
"normalized": []
},
{
"id": "11156594_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "11156594_T6",
"arg2_id": "11156594_T26",
"normalized": []
}
] |
23432420 | 23432420 | [
{
"id": "23432420_title",
"type": "title",
"text": [
"SNAIL Induces Epithelial-to-Mesenchymal Transition and Cancer Stem Cell-like Properties in Aldehyde Dehydroghenase-Negative Thyroid Cancer Cells."
],
"offsets": [
[
0,
145
]
]
},
{
"id": "23432420_abstract",
"type": "abstract",
"text": [
"Background: Epithelial-to-mesenchymal transition (EMT) has been thought to play a critical role in invasion and metastasis of cancer and to be associated with cancer stem cell (CSC) properties. It is not clear if there is a link between EMT and CSCs in thyroid cancers. We therefore investigated CSC properties of thyroid cancers that underwent EMT. Method: To induce EMT (spindle-like cell morphology, loss and acquisition of expression of an epithelial marker E-cadherin and a mesenchymal marker vimentin, respectively) in an epithelial type thyroid cancer cell line ACT-1, we used transforming growth factor-beta (TGF-beta), BRAFV600E and/or Snail homolog 1 (SNAI1, also known as SNAIL) . CSC properties were analyzed with assays for cell proliferation, chemosensitivity, in vitro and in vivo tumor formation ability, cell surface antigens and intracellular aldehyde dehydrogenase (ALDH; a known CSC marker) activities. Results: EMT was induced most efficiently by SNAIL (ACT-SNAIL cells), whereas TGF-beta and BRAFV600E were less efficient. ACT-SNAIL cells showed slightly but significantly enhanced tumor formation ability in in vitro sphere assay (~3 fold) but not in vivo subcutaneous tumor growth assay, and showed comparable chemosensitivity, as compared to the parental ACT-1 cells. However, of interest, although in vitro sphere formation ability of ALDH+ cells was almost unchanged after SNAIL induction, SNAIL overexpression induced much higher (~14 fold) spheres in ALDH- cells. Thus, ALDH was no longer a CSC marker in ACT-SNAIL cells. Conclusions: All these data indicate that EMT confers CSC properties in ALDH- cells and appears to influence the ability of ALDH to enrich CSCs."
],
"offsets": [
[
146,
1841
]
]
}
] | [
{
"id": "23432420_T1",
"type": "CHEMICAL",
"text": [
"aldehyde"
],
"offsets": [
[
1007,
1015
]
],
"normalized": []
},
{
"id": "23432420_T2",
"type": "CHEMICAL",
"text": [
"Aldehyde"
],
"offsets": [
[
91,
99
]
],
"normalized": []
},
{
"id": "23432420_T3",
"type": "GENE-Y",
"text": [
"TGF-beta"
],
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1147,
1155
]
],
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{
"id": "23432420_T4",
"type": "GENE-Y",
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"BRAF"
],
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1160,
1164
]
],
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},
{
"id": "23432420_T5",
"type": "GENE-N",
"text": [
"V600E"
],
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[
1164,
1169
]
],
"normalized": []
},
{
"id": "23432420_T6",
"type": "GENE-Y",
"text": [
"SNAIL"
],
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[
1195,
1200
]
],
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"id": "23432420_T7",
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"ALDH"
],
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[
1507,
1511
]
],
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"id": "23432420_T8",
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"SNAIL"
],
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1546,
1551
]
],
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"id": "23432420_T9",
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"SNAIL"
],
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1563,
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]
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"id": "23432420_T10",
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"ALDH"
],
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[
1626,
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]
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"id": "23432420_T11",
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"ALDH"
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1645,
1649
]
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"id": "23432420_T12",
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"SNAIL"
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1684,
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]
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"id": "23432420_T13",
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"ALDH"
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]
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"ALDH"
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]
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"id": "23432420_T15",
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"text": [
"E-cadherin"
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608,
618
]
],
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},
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"id": "23432420_T16",
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"text": [
"vimentin"
],
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644,
652
]
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"id": "23432420_T17",
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"transforming growth factor-beta"
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730,
761
]
],
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"id": "23432420_T18",
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"TGF-beta"
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763,
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]
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"id": "23432420_T19",
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"text": [
"BRAF"
],
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774,
778
]
],
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},
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"id": "23432420_T20",
"type": "GENE-N",
"text": [
"V600E"
],
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778,
783
]
],
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},
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"id": "23432420_T21",
"type": "GENE-Y",
"text": [
"Snail homolog 1"
],
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[
791,
806
]
],
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},
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"id": "23432420_T22",
"type": "GENE-Y",
"text": [
"SNAI1"
],
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[
808,
813
]
],
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},
{
"id": "23432420_T23",
"type": "GENE-Y",
"text": [
"SNAIL"
],
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[
829,
834
]
],
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},
{
"id": "23432420_T24",
"type": "GENE-N",
"text": [
"aldehyde dehydrogenase"
],
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[
1007,
1029
]
],
"normalized": []
},
{
"id": "23432420_T25",
"type": "GENE-N",
"text": [
"ALDH"
],
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[
1031,
1035
]
],
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},
{
"id": "23432420_T26",
"type": "GENE-Y",
"text": [
"SNAIL"
],
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[
1114,
1119
]
],
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},
{
"id": "23432420_T27",
"type": "GENE-Y",
"text": [
"SNAIL"
],
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[
1125,
1130
]
],
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},
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"id": "23432420_T28",
"type": "GENE-Y",
"text": [
"SNAIL"
],
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[
0,
5
]
],
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},
{
"id": "23432420_T29",
"type": "GENE-N",
"text": [
"Aldehyde Dehydroghenase"
],
"offsets": [
[
91,
114
]
],
"normalized": []
}
] | [] | [] | [] |
23267011 | 23267011 | [
{
"id": "23267011_title",
"type": "title",
"text": [
"DNA polymerase minor groove interactions modulate mutagenic bypass of a templating 8-oxoguanine lesion."
],
"offsets": [
[
0,
103
]
]
},
{
"id": "23267011_abstract",
"type": "abstract",
"text": [
"A major base lesion resulting from oxidative stress is 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG) that has ambiguous coding potential. Error-free DNA synthesis involves 8-oxoG adopting an anti-conformation to base pair with cytosine whereas mutagenic bypass involves 8-oxoG adopting a syn-conformation to base pair with adenine. Left unrepaired the syn-8-oxoG/dAMP base pair results in a G-C to T-A transversion. During base excision repair of this mispair, DNA polymerase (pol) β is confronted with gap filling opposite 8-oxoG. To determine how pol β discriminates between anti- and syn-8-oxoG, we introduced a point mutation (R283K) to alter insertion specificity. Kinetic studies demonstrate that this substitution results in an increased fidelity opposite 8-oxoG. Structural studies with R283K pol β show that the binary DNA complex has 8-oxoG in equilibrium between anti- and syn-forms. Ternary complexes with incoming dCTP resemble the wild-type enzyme, with templating anti-8-oxoG base pairing with incoming cytosine. In contrast to wild-type pol β, the ternary complex of the R283K mutant with an incoming dATP-analogue and templating 8-oxoG resembles a G-A mismatched structure with 8-oxoG adopting an anti-conformation. These results demonstrate that the incoming nucleotide is unable to induce a syn-8-oxoG conformation without minor groove DNA polymerase interactions that influence templating (anti-/syn-equilibrium) of 8-oxoG while modulating fidelity."
],
"offsets": [
[
104,
1572
]
]
}
] | [
{
"id": "23267011_T1",
"type": "CHEMICAL",
"text": [
"cytosine"
],
"offsets": [
[
1121,
1129
]
],
"normalized": []
},
{
"id": "23267011_T2",
"type": "CHEMICAL",
"text": [
"dATP"
],
"offsets": [
[
1220,
1224
]
],
"normalized": []
},
{
"id": "23267011_T3",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
"offsets": [
[
1249,
1255
]
],
"normalized": []
},
{
"id": "23267011_T4",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
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[
1298,
1304
]
],
"normalized": []
},
{
"id": "23267011_T5",
"type": "CHEMICAL",
"text": [
"nucleotide"
],
"offsets": [
[
1380,
1390
]
],
"normalized": []
},
{
"id": "23267011_T6",
"type": "CHEMICAL",
"text": [
"syn-8-oxoG"
],
"offsets": [
[
1413,
1423
]
],
"normalized": []
},
{
"id": "23267011_T7",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
"offsets": [
[
1539,
1545
]
],
"normalized": []
},
{
"id": "23267011_T8",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
"offsets": [
[
275,
281
]
],
"normalized": []
},
{
"id": "23267011_T9",
"type": "CHEMICAL",
"text": [
"cytosine"
],
"offsets": [
[
330,
338
]
],
"normalized": []
},
{
"id": "23267011_T10",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
"offsets": [
[
373,
379
]
],
"normalized": []
},
{
"id": "23267011_T11",
"type": "CHEMICAL",
"text": [
"adenine"
],
"offsets": [
[
426,
433
]
],
"normalized": []
},
{
"id": "23267011_T12",
"type": "CHEMICAL",
"text": [
"syn-8-oxoG"
],
"offsets": [
[
455,
465
]
],
"normalized": []
},
{
"id": "23267011_T13",
"type": "CHEMICAL",
"text": [
"dAMP"
],
"offsets": [
[
466,
470
]
],
"normalized": []
},
{
"id": "23267011_T14",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
"offsets": [
[
627,
633
]
],
"normalized": []
},
{
"id": "23267011_T15",
"type": "CHEMICAL",
"text": [
"8-oxo-7,8-dihydro-2'-deoxyguanosine"
],
"offsets": [
[
159,
194
]
],
"normalized": []
},
{
"id": "23267011_T16",
"type": "CHEMICAL",
"text": [
"anti- and syn-8-oxoG"
],
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[
680,
700
]
],
"normalized": []
},
{
"id": "23267011_T17",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
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[
866,
872
]
],
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},
{
"id": "23267011_T18",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
"offsets": [
[
947,
953
]
],
"normalized": []
},
{
"id": "23267011_T19",
"type": "CHEMICAL",
"text": [
"dCTP"
],
"offsets": [
[
1030,
1034
]
],
"normalized": []
},
{
"id": "23267011_T20",
"type": "CHEMICAL",
"text": [
"8-oxoG"
],
"offsets": [
[
196,
202
]
],
"normalized": []
},
{
"id": "23267011_T21",
"type": "CHEMICAL",
"text": [
"anti-8-oxoG"
],
"offsets": [
[
1082,
1093
]
],
"normalized": []
},
{
"id": "23267011_T22",
"type": "CHEMICAL",
"text": [
"8-oxoguanine"
],
"offsets": [
[
83,
95
]
],
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},
{
"id": "23267011_T23",
"type": "GENE-Y",
"text": [
"pol β"
],
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[
1156,
1161
]
],
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},
{
"id": "23267011_T24",
"type": "GENE-N",
"text": [
"R283K"
],
"offsets": [
[
1190,
1195
]
],
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},
{
"id": "23267011_T25",
"type": "GENE-N",
"text": [
"minor groove"
],
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[
1445,
1457
]
],
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},
{
"id": "23267011_T26",
"type": "GENE-N",
"text": [
"DNA polymerase"
],
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[
1458,
1472
]
],
"normalized": []
},
{
"id": "23267011_T27",
"type": "GENE-Y",
"text": [
"DNA polymerase (pol) β"
],
"offsets": [
[
564,
586
]
],
"normalized": []
},
{
"id": "23267011_T28",
"type": "GENE-Y",
"text": [
"pol β"
],
"offsets": [
[
652,
657
]
],
"normalized": []
},
{
"id": "23267011_T29",
"type": "GENE-N",
"text": [
"R283K"
],
"offsets": [
[
734,
739
]
],
"normalized": []
},
{
"id": "23267011_T30",
"type": "GENE-N",
"text": [
"R283K"
],
"offsets": [
[
898,
903
]
],
"normalized": []
},
{
"id": "23267011_T31",
"type": "GENE-Y",
"text": [
"pol β"
],
"offsets": [
[
904,
909
]
],
"normalized": []
},
{
"id": "23267011_T32",
"type": "GENE-N",
"text": [
"DNA polymerase minor groove"
],
"offsets": [
[
0,
27
]
],
"normalized": []
}
] | [] | [] | [
{
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"arg2_id": "23267011_T32",
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},
{
"id": "23267011_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T14",
"arg2_id": "23267011_T27",
"normalized": []
},
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"id": "23267011_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T16",
"arg2_id": "23267011_T28",
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},
{
"id": "23267011_3",
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"arg1_id": "23267011_T18",
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"normalized": []
},
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"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T18",
"arg2_id": "23267011_T30",
"normalized": []
},
{
"id": "23267011_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T2",
"arg2_id": "23267011_T24",
"normalized": []
},
{
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"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T2",
"arg2_id": "23267011_T23",
"normalized": []
},
{
"id": "23267011_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T5",
"arg2_id": "23267011_T25",
"normalized": []
},
{
"id": "23267011_8",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T6",
"arg2_id": "23267011_T25",
"normalized": []
},
{
"id": "23267011_9",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T5",
"arg2_id": "23267011_T26",
"normalized": []
},
{
"id": "23267011_10",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T6",
"arg2_id": "23267011_T26",
"normalized": []
},
{
"id": "23267011_11",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T3",
"arg2_id": "23267011_T24",
"normalized": []
},
{
"id": "23267011_12",
"type": "DIRECT-REGULATOR",
"arg1_id": "23267011_T4",
"arg2_id": "23267011_T24",
"normalized": []
}
] |
17125913 | 17125913 | [
{
"id": "17125913_title",
"type": "title",
"text": [
"Cadmium induces mitogenic signaling in breast cancer cell by an ERalpha-dependent mechanism."
],
"offsets": [
[
0,
92
]
]
},
{
"id": "17125913_abstract",
"type": "abstract",
"text": [
"Breast cancer (BC) is linked to estrogen exposure. Estradiol (E2) stimulates BC cells proliferation by binding the estrogen receptor (ER). Hormone-related cancers have been linked to estrogenic environmental contaminants. Cadmium (Cd) a toxic pollutant, acts as estrogens in BC cells. Purpose of our study was to evaluate whether Cd regulates MCF-7 cell proliferation by activating ERK1/2, Akt and PDGFRalpha kinases. Cd increased cell proliferation and the ER-antagonist ICI 182,780 blunted it. To characterize an ER-dependent mechanism, ERalpha/beta expression was evaluated. Cd decreased ERalpha expression, but not ERbeta. Cd also increased ERK1/2, Akt and PDGFRalpha phosphorylation while ICI blocked it. Since stimulation of phosphorylation was slower than expected, c-fos and c-jun proto-oncogenes, and PDGFA were analyzed. Cd rapidly increased c-jun, c-fos and PDGFA expression. Cells were also co-incubated with the Cd and specific kinases inhibitors, which blocked the Cd-stimulated proliferation. In conclusion, our results indicate that Cd increases BC cell proliferation in vitro by stimulating Akt, ERK1/2 and PDGFRalpha kinases activity likely by activating c-fos, c-jun and PDGFA by an ERalpha-dependent mechanism."
],
"offsets": [
[
93,
1323
]
]
}
] | [
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"id": "17125913_T1",
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"Cd"
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1142,
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"id": "17125913_T2",
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"text": [
"Cadmium"
],
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[
315,
322
]
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"id": "17125913_T3",
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"Cd"
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"Cd"
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423,
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"Cd"
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511,
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"Estradiol"
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144,
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"Cd"
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155,
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"Cd"
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"Cd"
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] |
3124610 | 3124610 | [
{
"id": "3124610_title",
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],
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0,
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]
]
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"id": "3124610_abstract",
"type": "abstract",
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"We have used protein engineering and recombinant DNA methodologies to genetically replace the eukaryotic cell receptor binding domain of diphtheria toxin with interleukin 2 (IL-2). The toxin-related T cell growth factor fusion gene has been cloned in Escherichia coli K12. Recombinant strains of E coli produce a 68,086 K hybrid toxin, IL-2 toxin that retains immunologic properties intrinsic to both its diphtheria toxin and IL-2 components. IL-2 toxin has been found to selectively inhibit protein synthesis in both human and murine T cell lines that bear high affinity IL-2 receptors, whereas the hybrid toxin is not active against cells that do not bear this receptor. The cytotoxic action of IL-2 toxin is specifically blocked by free IL-2 and monoclonal antibodies that bind to the p55 (Tac antigen) subunit of the high affinity IL-2 receptor. In addition, IL-2 toxin, like diphtheria toxin itself, must pass through an acidic compartment in order to deliver its adenosine diphosphate ribosyl transferase activity to the cytosol of target T cells. In a murine delayed type hypersensitivity (DTH) model system, we have shown that IL-2 toxin treatment induces a marked immunosuppression."
],
"offsets": [
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63,
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]
]
}
] | [
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0,
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}
] | [] | [] | [] |
23455312 | 23455312 | [
{
"id": "23455312_title",
"type": "title",
"text": [
"Cerebrovascular Dilation via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1-Subunit by a Novel Nonsteroidal Agent."
],
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0,
148
]
]
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{
"id": "23455312_abstract",
"type": "abstract",
"text": [
"The Ca(2+)/voltage-gated K(+) large conductance (BK) channel β1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK β1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK β1 site that includes Thr169. Whether exogenous nonsteroidal agents can access this site to selectively activate β1-containing BK channels and evoke vasodilation remain unknown. We performed a chemical structure database similarity search using LCA as a template, along with a two-step reaction to generate sodium 3-hydroxyolean-12-en-30-oate (HENA). HENA activated the BK (cbv1 + β1) channels cloned from rat cerebral artery myocytes with a potency (EC50 = 53 μM) similar to and an efficacy (×2.5 potentiation) significantly greater than that of LCA. This HENA action was replicated on native channels in rat cerebral artery myocytes. HENA failed to activate the channels made of cbv1 + β2, β3, β4, or β1T169A, indicating that this drug selectively targets β1-containing BK channels via the BK β1 steroid-sensing site. HENA (3-45 μM) dilated the rat and C57BL/6 mouse pressurized cerebral arteries. Consistent with the electrophysiologic results, this effect was larger than that of LCA. HENA failed to dilate the arteries from the KCNMB1 knockout mouse, underscoring BK β1's role in HENA action. Finally, carotid artery-infusion of HENA (45 μM) dilated the pial cerebral arterioles via selective BK-channel targeting. In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates β1-containing BK channels by targeting the steroid-sensing site in BK β1, rendering vasodilation."
],
"offsets": [
[
149,
1938
]
]
}
] | [
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1156,
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]
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"id": "23455312_T4",
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"HENA"
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1509,
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"HENA"
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"HENA"
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1654,
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]
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"steroid"
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1884,
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]
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"steroid"
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401,
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]
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"id": "23455312_T10",
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"text": [
"K(+)"
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174,
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]
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"id": "23455312_T11",
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409,
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]
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"LCA"
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427,
430
]
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"id": "23455312_T13",
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"Thr"
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542,
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]
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"Ca(2+"
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153,
158
]
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"LCA"
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765,
768
]
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],
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827,
862
]
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"HENA"
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864,
868
]
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"HENA"
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871,
875
]
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{
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"LCA"
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[
1067,
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]
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{
"id": "23455312_T20",
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"HENA"
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1077,
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]
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},
{
"id": "23455312_T21",
"type": "CHEMICAL",
"text": [
"Cholane"
],
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[
56,
63
]
],
"normalized": []
},
{
"id": "23455312_T22",
"type": "CHEMICAL",
"text": [
"Steroid"
],
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[
64,
71
]
],
"normalized": []
},
{
"id": "23455312_T23",
"type": "GENE-N",
"text": [
"β1-containing BK channels"
],
"offsets": [
[
1278,
1303
]
],
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},
{
"id": "23455312_T24",
"type": "GENE-Y",
"text": [
"BK β1"
],
"offsets": [
[
1312,
1317
]
],
"normalized": []
},
{
"id": "23455312_T25",
"type": "GENE-Y",
"text": [
"KCNMB1"
],
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[
1553,
1559
]
],
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},
{
"id": "23455312_T26",
"type": "GENE-Y",
"text": [
"BK β1"
],
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[
1589,
1594
]
],
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},
{
"id": "23455312_T27",
"type": "GENE-Y",
"text": [
"BK β1"
],
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[
305,
310
]
],
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},
{
"id": "23455312_T28",
"type": "GENE-N",
"text": [
"BK-channel"
],
"offsets": [
[
1718,
1728
]
],
"normalized": []
},
{
"id": "23455312_T29",
"type": "GENE-N",
"text": [
"β1-containing BK channels"
],
"offsets": [
[
1841,
1866
]
],
"normalized": []
},
{
"id": "23455312_T30",
"type": "GENE-N",
"text": [
"BK channels"
],
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322,
333
]
],
"normalized": []
},
{
"id": "23455312_T31",
"type": "GENE-Y",
"text": [
"BK β1"
],
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[
1908,
1913
]
],
"normalized": []
},
{
"id": "23455312_T32",
"type": "GENE-N",
"text": [
"BK channel"
],
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462,
472
]
],
"normalized": []
},
{
"id": "23455312_T33",
"type": "GENE-Y",
"text": [
"BK β1"
],
"offsets": [
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517,
522
]
],
"normalized": []
},
{
"id": "23455312_T34",
"type": "GENE-Y",
"text": [
"Ca(2+)/voltage-gated K(+) large conductance (BK) channel β1"
],
"offsets": [
[
153,
212
]
],
"normalized": []
},
{
"id": "23455312_T35",
"type": "GENE-Y",
"text": [
"β1-containing BK channels"
],
"offsets": [
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633,
658
]
],
"normalized": []
},
{
"id": "23455312_T36",
"type": "GENE-Y",
"text": [
"BK (cbv1 + β1) channels"
],
"offsets": [
[
890,
913
]
],
"normalized": []
},
{
"id": "23455312_T37",
"type": "GENE-Y",
"text": [
"BK Channel β1-Subunit"
],
"offsets": [
[
96,
117
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23455312_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23455312_T21",
"arg2_id": "23455312_T37",
"normalized": []
},
{
"id": "23455312_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "23455312_T22",
"arg2_id": "23455312_T37",
"normalized": []
},
{
"id": "23455312_2",
"type": "PART-OF",
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"arg2_id": "23455312_T33",
"normalized": []
},
{
"id": "23455312_3",
"type": "ACTIVATOR",
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"arg2_id": "23455312_T36",
"normalized": []
},
{
"id": "23455312_4",
"type": "ACTIVATOR",
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"arg2_id": "23455312_T36",
"normalized": []
},
{
"id": "23455312_5",
"type": "ACTIVATOR",
"arg1_id": "23455312_T1",
"arg2_id": "23455312_T23",
"normalized": []
},
{
"id": "23455312_6",
"type": "DIRECT-REGULATOR",
"arg1_id": "23455312_T1",
"arg2_id": "23455312_T24",
"normalized": []
},
{
"id": "23455312_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "23455312_T9",
"arg2_id": "23455312_T33",
"normalized": []
},
{
"id": "23455312_8",
"type": "DIRECT-REGULATOR",
"arg1_id": "23455312_T11",
"arg2_id": "23455312_T33",
"normalized": []
},
{
"id": "23455312_9",
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"arg2_id": "23455312_T33",
"normalized": []
},
{
"id": "23455312_10",
"type": "DIRECT-REGULATOR",
"arg1_id": "23455312_T7",
"arg2_id": "23455312_T28",
"normalized": []
}
] |
17202666 | 17202666 | [
{
"id": "17202666_title",
"type": "title",
"text": [
"A novel vasopressin dual V1A/V2 receptor antagonist, conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH)."
],
"offsets": [
[
0,
182
]
]
},
{
"id": "17202666_abstract",
"type": "abstract",
"text": [
"We investigated the effects of intravenous administration of conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on blood electrolytes and plasma osmolality in rats with an experimental syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The experimental SIADH rat model was developed by means of continuous administration of arginine vasopressin (AVP) via a subcutaneously implanted osmotic mini pump, and hyponatremia was induced by additional water loading. This model possesses similar characteristics to those observed in patients with SIADH, specifically decreases in blood sodium concentration and plasma osmolality. In this experimental model, intravenous administration of conivaptan (0.1, 1 mg/kg) significantly increased blood sodium concentration and plasma osmolality. On the other hand, intravenous administration of furosemide (10 mg/kg) did not increase either blood sodium concentration or plasma osmolality in the SIADH rats. Moreover, furosemide significantly lowered blood potassium concentration. These results show that conivaptan improves hyponatremia in rats with SIADH, supporting the therapeutic potential of conivaptan in treatment of patients with hyponatremia associated with SIADH."
],
"offsets": [
[
183,
1436
]
]
}
] | [
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"id": "17202666_T1",
"type": "CHEMICAL",
"text": [
"potassium"
],
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[
1218,
1227
]
],
"normalized": []
},
{
"id": "17202666_T2",
"type": "CHEMICAL",
"text": [
"conivaptan"
],
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[
1267,
1277
]
],
"normalized": []
},
{
"id": "17202666_T3",
"type": "CHEMICAL",
"text": [
"conivaptan"
],
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[
1360,
1370
]
],
"normalized": []
},
{
"id": "17202666_T4",
"type": "CHEMICAL",
"text": [
"arginine vasopressin"
],
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[
551,
571
]
],
"normalized": []
},
{
"id": "17202666_T5",
"type": "CHEMICAL",
"text": [
"AVP"
],
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[
573,
576
]
],
"normalized": []
},
{
"id": "17202666_T6",
"type": "CHEMICAL",
"text": [
"conivaptan hydrochloride"
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[
244,
268
]
],
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},
{
"id": "17202666_T7",
"type": "CHEMICAL",
"text": [
"sodium"
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[
805,
811
]
],
"normalized": []
},
{
"id": "17202666_T8",
"type": "CHEMICAL",
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"conivaptan"
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907,
917
]
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},
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"id": "17202666_T9",
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"text": [
"sodium"
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963,
969
]
],
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},
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"id": "17202666_T10",
"type": "CHEMICAL",
"text": [
"furosemide"
],
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[
1056,
1066
]
],
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},
{
"id": "17202666_T11",
"type": "CHEMICAL",
"text": [
"sodium"
],
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[
1108,
1114
]
],
"normalized": []
},
{
"id": "17202666_T12",
"type": "CHEMICAL",
"text": [
"vasopressin"
],
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[
277,
288
]
],
"normalized": []
},
{
"id": "17202666_T13",
"type": "CHEMICAL",
"text": [
"furosemide"
],
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[
1179,
1189
]
],
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},
{
"id": "17202666_T14",
"type": "CHEMICAL",
"text": [
"conivaptan hydrochloride"
],
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53,
77
]
],
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},
{
"id": "17202666_T15",
"type": "CHEMICAL",
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"vasopressin"
],
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[
8,
19
]
],
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},
{
"id": "17202666_T16",
"type": "GENE-Y",
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"V2 receptor"
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297,
308
]
],
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},
{
"id": "17202666_T17",
"type": "GENE-Y",
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"antidiuretic hormone"
],
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433,
453
]
],
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},
{
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"type": "GENE-Y",
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"arginine vasopressin"
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551,
571
]
],
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},
{
"id": "17202666_T19",
"type": "GENE-Y",
"text": [
"AVP"
],
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573,
576
]
],
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},
{
"id": "17202666_T20",
"type": "GENE-Y",
"text": [
"vasopressin V1A"
],
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277,
292
]
],
"normalized": []
},
{
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"type": "GENE-Y",
"text": [
"antidiuretic hormone"
],
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153,
173
]
],
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},
{
"id": "17202666_T22",
"type": "GENE-Y",
"text": [
"V1A"
],
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25,
28
]
],
"normalized": []
},
{
"id": "17202666_T23",
"type": "GENE-Y",
"text": [
"V2 receptor"
],
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29,
40
]
],
"normalized": []
},
{
"id": "17202666_T24",
"type": "GENE-Y",
"text": [
"vasopressin"
],
"offsets": [
[
8,
19
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17202666_0",
"type": "ANTAGONIST",
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"arg2_id": "17202666_T22",
"normalized": []
},
{
"id": "17202666_1",
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"arg2_id": "17202666_T23",
"normalized": []
},
{
"id": "17202666_2",
"type": "ANTAGONIST",
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"arg2_id": "17202666_T20",
"normalized": []
},
{
"id": "17202666_3",
"type": "ANTAGONIST",
"arg1_id": "17202666_T6",
"arg2_id": "17202666_T16",
"normalized": []
}
] |
10353334 | 10353334 | [
{
"id": "10353334_title",
"type": "title",
"text": [
"Hyperammonemia: regulation of argininosuccinate synthetase and argininosuccinate lyase genes in aggregating cell cultures of fetal rat brain."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "10353334_abstract",
"type": "abstract",
"text": [
"Hyperammonemia in the brain leads to poorly understood alterations of nitric oxide (NO) synthesis. Arginine, the substrate of nitric oxide synthases, might be recycled from the citrulline produced with NO by argininosuccinate synthetase (AS) and argininosuccinate lyase (AL). The regulation of AS and AL genes during hyperammonemia is unknown in the brain. We used brain cell aggregates cultured from dissociated telencephalic cortex of rat embryos to analyze the regulation of AS and AL genes in hyperammonemia. Using RNase protection assay and non-radioactive in situ hybridization on aggregate cryosections, we show that both AS and AL genes are induced in astrocytes but not in neurons of aggregates exposed to 5 mM NH4Cl. Our work suggests that the hyperammonemic brain might increase its recycling of citrulline to arginine."
],
"offsets": [
[
142,
972
]
]
}
] | [
{
"id": "10353334_T1",
"type": "CHEMICAL",
"text": [
"nitric oxide"
],
"offsets": [
[
268,
280
]
],
"normalized": []
},
{
"id": "10353334_T2",
"type": "CHEMICAL",
"text": [
"citrulline"
],
"offsets": [
[
319,
329
]
],
"normalized": []
},
{
"id": "10353334_T3",
"type": "CHEMICAL",
"text": [
"NO"
],
"offsets": [
[
344,
346
]
],
"normalized": []
},
{
"id": "10353334_T4",
"type": "CHEMICAL",
"text": [
"argininosuccinate"
],
"offsets": [
[
350,
367
]
],
"normalized": []
},
{
"id": "10353334_T5",
"type": "CHEMICAL",
"text": [
"argininosuccinate"
],
"offsets": [
[
388,
405
]
],
"normalized": []
},
{
"id": "10353334_T6",
"type": "CHEMICAL",
"text": [
"nitric oxide"
],
"offsets": [
[
212,
224
]
],
"normalized": []
},
{
"id": "10353334_T7",
"type": "CHEMICAL",
"text": [
"NH4Cl"
],
"offsets": [
[
862,
867
]
],
"normalized": []
},
{
"id": "10353334_T8",
"type": "CHEMICAL",
"text": [
"citrulline"
],
"offsets": [
[
949,
959
]
],
"normalized": []
},
{
"id": "10353334_T9",
"type": "CHEMICAL",
"text": [
"arginine"
],
"offsets": [
[
963,
971
]
],
"normalized": []
},
{
"id": "10353334_T10",
"type": "CHEMICAL",
"text": [
"NO"
],
"offsets": [
[
226,
228
]
],
"normalized": []
},
{
"id": "10353334_T11",
"type": "CHEMICAL",
"text": [
"Arginine"
],
"offsets": [
[
241,
249
]
],
"normalized": []
},
{
"id": "10353334_T12",
"type": "CHEMICAL",
"text": [
"argininosuccinate"
],
"offsets": [
[
30,
47
]
],
"normalized": []
},
{
"id": "10353334_T13",
"type": "CHEMICAL",
"text": [
"argininosuccinate"
],
"offsets": [
[
63,
80
]
],
"normalized": []
},
{
"id": "10353334_T14",
"type": "GENE-N",
"text": [
"nitric oxide synthases"
],
"offsets": [
[
268,
290
]
],
"normalized": []
},
{
"id": "10353334_T15",
"type": "GENE-Y",
"text": [
"argininosuccinate synthetase"
],
"offsets": [
[
350,
378
]
],
"normalized": []
},
{
"id": "10353334_T16",
"type": "GENE-Y",
"text": [
"AS"
],
"offsets": [
[
380,
382
]
],
"normalized": []
},
{
"id": "10353334_T17",
"type": "GENE-Y",
"text": [
"argininosuccinate lyase"
],
"offsets": [
[
388,
411
]
],
"normalized": []
},
{
"id": "10353334_T18",
"type": "GENE-Y",
"text": [
"AL"
],
"offsets": [
[
413,
415
]
],
"normalized": []
},
{
"id": "10353334_T19",
"type": "GENE-Y",
"text": [
"AS"
],
"offsets": [
[
436,
438
]
],
"normalized": []
},
{
"id": "10353334_T20",
"type": "GENE-Y",
"text": [
"AL"
],
"offsets": [
[
443,
445
]
],
"normalized": []
},
{
"id": "10353334_T21",
"type": "GENE-Y",
"text": [
"AS"
],
"offsets": [
[
620,
622
]
],
"normalized": []
},
{
"id": "10353334_T22",
"type": "GENE-Y",
"text": [
"AL"
],
"offsets": [
[
627,
629
]
],
"normalized": []
},
{
"id": "10353334_T23",
"type": "GENE-Y",
"text": [
"AS"
],
"offsets": [
[
771,
773
]
],
"normalized": []
},
{
"id": "10353334_T24",
"type": "GENE-Y",
"text": [
"AL"
],
"offsets": [
[
778,
780
]
],
"normalized": []
},
{
"id": "10353334_T25",
"type": "GENE-Y",
"text": [
"argininosuccinate synthetase"
],
"offsets": [
[
30,
58
]
],
"normalized": []
},
{
"id": "10353334_T26",
"type": "GENE-Y",
"text": [
"argininosuccinate lyase"
],
"offsets": [
[
63,
86
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "10353334_0",
"type": "SUBSTRATE",
"arg1_id": "10353334_T11",
"arg2_id": "10353334_T14",
"normalized": []
},
{
"id": "10353334_1",
"type": "PRODUCT-OF",
"arg1_id": "10353334_T2",
"arg2_id": "10353334_T15",
"normalized": []
},
{
"id": "10353334_2",
"type": "PRODUCT-OF",
"arg1_id": "10353334_T2",
"arg2_id": "10353334_T16",
"normalized": []
},
{
"id": "10353334_3",
"type": "PRODUCT-OF",
"arg1_id": "10353334_T2",
"arg2_id": "10353334_T17",
"normalized": []
},
{
"id": "10353334_4",
"type": "PRODUCT-OF",
"arg1_id": "10353334_T2",
"arg2_id": "10353334_T18",
"normalized": []
},
{
"id": "10353334_5",
"type": "PRODUCT-OF",
"arg1_id": "10353334_T3",
"arg2_id": "10353334_T15",
"normalized": []
},
{
"id": "10353334_6",
"type": "PRODUCT-OF",
"arg1_id": "10353334_T3",
"arg2_id": "10353334_T16",
"normalized": []
},
{
"id": "10353334_7",
"type": "PRODUCT-OF",
"arg1_id": "10353334_T3",
"arg2_id": "10353334_T17",
"normalized": []
},
{
"id": "10353334_8",
"type": "PRODUCT-OF",
"arg1_id": "10353334_T3",
"arg2_id": "10353334_T18",
"normalized": []
}
] |
2453744 | 2453744 | [
{
"id": "2453744_title",
"type": "title",
"text": [
"Acute and long-term effects of acebutolol on systemic and renal hemodynamics, body fluid volumes, catecholamines, active renin, aldosterone, and lymphocyte beta-adrenoceptor density."
],
"offsets": [
[
0,
182
]
]
},
{
"id": "2453744_abstract",
"type": "abstract",
"text": [
"Acebutolol is a relatively new beta-adrenoceptor blocking antagonist, possessing both beta 1-adrenoceptor selectivity and partial agonist activity (PAA). Its acute (24 h, 400 mg, twice daily) and long-term effects (3 weeks) on systemic and renal hemodynamics, body fluid volumes, hormones, and beta-adrenoceptor density on lymphocytes were studied in a single-blind placebo-controlled trial, in 10 hypertensive patients. The initial response to acebutolol (1-2 h) was a fall in heart rate (HR) (-9.6 +/- 2.7%), cardiac output (-16.0 +/- 3%), and stroke volume (SV) (-10.7 +/- 0.2%), and an increase in systemic vascular resistance (SVR) (18.0 +/- 3.9%). Mean arterial pressure (MAP) began to fall 2-3 h after dosing in parallel with a decrease in SVR. At the end of the acute study, MAP and SVR were decreased by 18.1 +/- 2.7% and 15.6 +/- 5.6%, respectively. By that time, HR and SV had returned to control values despite blockade of beta-adrenoceptors. After 3 weeks of treatment (mean dose of acebutolol 480 mg twice daily), the fall in MAP was 10.1 +/- 2.7% and HR was decreased by 13.0 +/- 2.3%. Renal blood flow and glomerular filtration rate did not change. Acute and long-term treatment had no effect on the density of lymphocyte-membrane beta-adrenoceptors. This could be explained by acebutolol's beta 1 selectivity or, alternatively, this could be due to the drug's PAA."
],
"offsets": [
[
183,
1564
]
]
}
] | [
{
"id": "2453744_T1",
"type": "CHEMICAL",
"text": [
"Acebutolol"
],
"offsets": [
[
183,
193
]
],
"normalized": []
},
{
"id": "2453744_T2",
"type": "CHEMICAL",
"text": [
"acebutolol"
],
"offsets": [
[
628,
638
]
],
"normalized": []
},
{
"id": "2453744_T3",
"type": "CHEMICAL",
"text": [
"acebutolol"
],
"offsets": [
[
1179,
1189
]
],
"normalized": []
},
{
"id": "2453744_T4",
"type": "CHEMICAL",
"text": [
"aldosterone"
],
"offsets": [
[
128,
139
]
],
"normalized": []
},
{
"id": "2453744_T5",
"type": "CHEMICAL",
"text": [
"acebutolol"
],
"offsets": [
[
31,
41
]
],
"normalized": []
},
{
"id": "2453744_T6",
"type": "CHEMICAL",
"text": [
"catecholamines"
],
"offsets": [
[
98,
112
]
],
"normalized": []
},
{
"id": "2453744_T7",
"type": "GENE-N",
"text": [
"beta-adrenoceptors"
],
"offsets": [
[
1430,
1448
]
],
"normalized": []
},
{
"id": "2453744_T8",
"type": "GENE-N",
"text": [
"beta-adrenoceptor"
],
"offsets": [
[
477,
494
]
],
"normalized": []
},
{
"id": "2453744_T9",
"type": "GENE-N",
"text": [
"beta-adrenoceptor"
],
"offsets": [
[
214,
231
]
],
"normalized": []
},
{
"id": "2453744_T10",
"type": "GENE-Y",
"text": [
"beta 1-adrenoceptor"
],
"offsets": [
[
269,
288
]
],
"normalized": []
},
{
"id": "2453744_T11",
"type": "GENE-N",
"text": [
"beta-adrenoceptors"
],
"offsets": [
[
1118,
1136
]
],
"normalized": []
},
{
"id": "2453744_T12",
"type": "GENE-Y",
"text": [
"renin"
],
"offsets": [
[
121,
126
]
],
"normalized": []
},
{
"id": "2453744_T13",
"type": "GENE-N",
"text": [
"beta-adrenoceptor"
],
"offsets": [
[
156,
173
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "2453744_0",
"type": "ANTAGONIST",
"arg1_id": "2453744_T1",
"arg2_id": "2453744_T9",
"normalized": []
},
{
"id": "2453744_1",
"type": "AGONIST",
"arg1_id": "2453744_T1",
"arg2_id": "2453744_T10",
"normalized": []
}
] |
23246469 | 23246469 | [
{
"id": "23246469_title",
"type": "title",
"text": [
"Non-ionic Gd-based MRI contrast agents are optimal for encapsulation into phosphatidyldiglycerol-based thermosensitive liposomes."
],
"offsets": [
[
0,
129
]
]
},
{
"id": "23246469_abstract",
"type": "abstract",
"text": [
"Thermosensitive liposomes (TSL) with encapsulated magnetic resonance imaging (MRI) longitudinal relaxation time (T(1)) contrast agents (CAs) have been proposed for MRI assisted interventional thermotherapy in solid tumors. Here the feasibility of 6 clinically approved CAs (Gd-DTPA, Gd-BOPTA, Gd-DOTA, Gd-BT-DO3A, Gd-DTPA-BMA, and Gd-HP-DO3A) for formulation into TSL was investigated. CAs were passively encapsulated with 323 mOs kg(-1) into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1,2-distearoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol 50/20/30 (mol/mol) TSL (DPPG(2)-TSL) to obtain stable formulations. T(1) relaxivity (r(1)) and diffusive permeability to water (P(d)) across the membrane were determined. Shelf life at 4°C was investigated by determining lysolipid content up to 10 weeks after preparation. All preparations were monodispersed with comparable small vesicle sizes (~135 nm). Neither zeta potential nor phase transition temperature (T(m)) was affected by the CA. The formulations showed an increase in r(1) in the temperature range between 38 and 44°C. This correlated with the phase transition. Change in r(1) (Δr(1)=r(1)(45.3°C)-r(1)(37.6°C)) and r(1) (T<T(m)) depended on the encapsulated CA concentration. P(d) at T≤37.6°C was lower for DPPG(2)-TSL encapsulating non-ionic Gd-BT-DO3A, Gd-DTPA-BMA, and Gd-HP-DO3A. All CAs except Gd-DTPA-BMA induced phospholipid hydrolysis, which resulted in unwanted CA leakage. The serum proteins HSA and IgG both contributed to the increase of MRI signal at 30°C by increasing P(d). A high concentration of encapsulated CA is a prerequisite to achieve a sufficiently high Δr(1) during heat triggered CA release combined with a low r(1) at 37°C. Hence, the optimal CA is characterized by a non-ionic structure and a low contribution to osmolality."
],
"offsets": [
[
130,
1973
]
]
}
] | [
{
"id": "23246469_T1",
"type": "CHEMICAL",
"text": [
"Gd-DTPA"
],
"offsets": [
[
404,
411
]
],
"normalized": []
},
{
"id": "23246469_T2",
"type": "CHEMICAL",
"text": [
"Gd-BOPTA"
],
"offsets": [
[
413,
421
]
],
"normalized": []
},
{
"id": "23246469_T3",
"type": "CHEMICAL",
"text": [
"Gd-DOTA"
],
"offsets": [
[
423,
430
]
],
"normalized": []
},
{
"id": "23246469_T4",
"type": "CHEMICAL",
"text": [
"Gd-BT-DO3A"
],
"offsets": [
[
432,
442
]
],
"normalized": []
},
{
"id": "23246469_T5",
"type": "CHEMICAL",
"text": [
"Gd-DTPA-BMA"
],
"offsets": [
[
444,
455
]
],
"normalized": []
},
{
"id": "23246469_T6",
"type": "CHEMICAL",
"text": [
"Gd-HP-DO3A"
],
"offsets": [
[
461,
471
]
],
"normalized": []
},
{
"id": "23246469_T7",
"type": "CHEMICAL",
"text": [
"1,2-dipalmitoyl-sn-glycero-3-phosphocholine"
],
"offsets": [
[
573,
616
]
],
"normalized": []
},
{
"id": "23246469_T8",
"type": "CHEMICAL",
"text": [
"1,2-distearoyl-sn-glycero-3-phosphocholine"
],
"offsets": [
[
617,
659
]
],
"normalized": []
},
{
"id": "23246469_T9",
"type": "CHEMICAL",
"text": [
"1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol"
],
"offsets": [
[
660,
706
]
],
"normalized": []
},
{
"id": "23246469_T10",
"type": "CHEMICAL",
"text": [
"DPPG(2)"
],
"offsets": [
[
731,
738
]
],
"normalized": []
},
{
"id": "23246469_T11",
"type": "CHEMICAL",
"text": [
"Gd"
],
"offsets": [
[
10,
12
]
],
"normalized": []
},
{
"id": "23246469_T12",
"type": "CHEMICAL",
"text": [
"phosphatidyldiglycerol"
],
"offsets": [
[
74,
96
]
],
"normalized": []
}
] | [] | [] | [] |
23103563 | 23103563 | [
{
"id": "23103563_title",
"type": "title",
"text": [
"Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells."
],
"offsets": [
[
0,
107
]
]
},
{
"id": "23103563_abstract",
"type": "abstract",
"text": [
"There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism. Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity. In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1. We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells. Ibandronate attenuated cell proliferation in all cell lines tested. In the neoplastic cells we found up-regulation of caspases suggesting apoptosis. Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by re-isoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate. In contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells. Data suggest that bisphosphonates via modulation of the activity of small-GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression. In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway."
],
"offsets": [
[
108,
1564
]
]
}
] | [
{
"id": "23103563_T1",
"type": "CHEMICAL",
"text": [
"bisphosphonates"
],
"offsets": [
[
1205,
1220
]
],
"normalized": []
},
{
"id": "23103563_T2",
"type": "CHEMICAL",
"text": [
"CpG"
],
"offsets": [
[
1313,
1316
]
],
"normalized": []
},
{
"id": "23103563_T3",
"type": "CHEMICAL",
"text": [
"farnesyl"
],
"offsets": [
[
1454,
1462
]
],
"normalized": []
},
{
"id": "23103563_T4",
"type": "CHEMICAL",
"text": [
"aminobisphosphonates"
],
"offsets": [
[
139,
159
]
],
"normalized": []
},
{
"id": "23103563_T5",
"type": "CHEMICAL",
"text": [
"ibandronate"
],
"offsets": [
[
529,
540
]
],
"normalized": []
},
{
"id": "23103563_T6",
"type": "CHEMICAL",
"text": [
"ibandronate"
],
"offsets": [
[
165,
176
]
],
"normalized": []
},
{
"id": "23103563_T7",
"type": "CHEMICAL",
"text": [
"Ibandronate"
],
"offsets": [
[
703,
714
]
],
"normalized": []
},
{
"id": "23103563_T8",
"type": "CHEMICAL",
"text": [
"geranylgeranyl-pyrophosphate"
],
"offsets": [
[
1032,
1060
]
],
"normalized": []
},
{
"id": "23103563_T9",
"type": "CHEMICAL",
"text": [
"farnesylpyrophosphate"
],
"offsets": [
[
1065,
1086
]
],
"normalized": []
},
{
"id": "23103563_T10",
"type": "CHEMICAL",
"text": [
"ibandronate"
],
"offsets": [
[
1101,
1112
]
],
"normalized": []
},
{
"id": "23103563_T11",
"type": "CHEMICAL",
"text": [
"Ibandronate"
],
"offsets": [
[
0,
11
]
],
"normalized": []
},
{
"id": "23103563_T12",
"type": "GENE-Y",
"text": [
"FAS"
],
"offsets": [
[
1128,
1131
]
],
"normalized": []
},
{
"id": "23103563_T13",
"type": "GENE-Y",
"text": [
"DNMT1"
],
"offsets": [
[
1136,
1141
]
],
"normalized": []
},
{
"id": "23103563_T14",
"type": "GENE-N",
"text": [
"GTPases"
],
"offsets": [
[
1261,
1268
]
],
"normalized": []
},
{
"id": "23103563_T15",
"type": "GENE-N",
"text": [
"CpG"
],
"offsets": [
[
1313,
1316
]
],
"normalized": []
},
{
"id": "23103563_T16",
"type": "GENE-Y",
"text": [
"FAS"
],
"offsets": [
[
1350,
1353
]
],
"normalized": []
},
{
"id": "23103563_T17",
"type": "GENE-N",
"text": [
"farnesyl-transferase"
],
"offsets": [
[
1454,
1474
]
],
"normalized": []
},
{
"id": "23103563_T18",
"type": "GENE-N",
"text": [
"GTPases"
],
"offsets": [
[
297,
304
]
],
"normalized": []
},
{
"id": "23103563_T19",
"type": "GENE-N",
"text": [
"RAS-GTPase"
],
"offsets": [
[
364,
374
]
],
"normalized": []
},
{
"id": "23103563_T20",
"type": "GENE-Y",
"text": [
"FAS"
],
"offsets": [
[
472,
475
]
],
"normalized": []
},
{
"id": "23103563_T21",
"type": "GENE-Y",
"text": [
"DNMT1"
],
"offsets": [
[
510,
515
]
],
"normalized": []
},
{
"id": "23103563_T22",
"type": "GENE-N",
"text": [
"caspases"
],
"offsets": [
[
821,
829
]
],
"normalized": []
},
{
"id": "23103563_T23",
"type": "GENE-Y",
"text": [
"FAS"
],
"offsets": [
[
884,
887
]
],
"normalized": []
},
{
"id": "23103563_T24",
"type": "GENE-Y",
"text": [
"DNMT1"
],
"offsets": [
[
978,
983
]
],
"normalized": []
},
{
"id": "23103563_T25",
"type": "GENE-Y",
"text": [
"FAS"
],
"offsets": [
[
63,
66
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23103563_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23103563_T11",
"arg2_id": "23103563_T25",
"normalized": []
},
{
"id": "23103563_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23103563_T1",
"arg2_id": "23103563_T16",
"normalized": []
}
] |
7739347 | 7739347 | [
{
"id": "7739347_title",
"type": "title",
"text": [
"Opioid receptor interaction and adenylyl cyclase inhibition of dihydroetorphine: direct comparison with etorphine."
],
"offsets": [
[
0,
114
]
]
},
{
"id": "7739347_abstract",
"type": "abstract",
"text": [
"To find out the reason of weak addiction property of dihydroetorphine, we compared the affinities of dihydroetorphine to the type selective opioid receptor and inhibition effect on the adenylyl cyclase activity with those of etorphine. Dihydroetorphine and etorphine have almost the same binding affinities to all types (mu, delta, and kappa) of opioid receptors and antagonist binding sites, and have similar inhibition activities to forskolin stimulated adenylyl cyclase. However, dihydroetorphine showed significantly smaller value of DTNB-index compared with that of etorphine. This differentiation may explain partly the high analgesic with low dependence properties of dihydroetorphine."
],
"offsets": [
[
115,
807
]
]
}
] | [
{
"id": "7739347_T1",
"type": "CHEMICAL",
"text": [
"dihydroetorphine"
],
"offsets": [
[
216,
232
]
],
"normalized": []
},
{
"id": "7739347_T2",
"type": "CHEMICAL",
"text": [
"adenylyl"
],
"offsets": [
[
300,
308
]
],
"normalized": []
},
{
"id": "7739347_T3",
"type": "CHEMICAL",
"text": [
"etorphine"
],
"offsets": [
[
340,
349
]
],
"normalized": []
},
{
"id": "7739347_T4",
"type": "CHEMICAL",
"text": [
"Dihydroetorphine"
],
"offsets": [
[
351,
367
]
],
"normalized": []
},
{
"id": "7739347_T5",
"type": "CHEMICAL",
"text": [
"etorphine"
],
"offsets": [
[
372,
381
]
],
"normalized": []
},
{
"id": "7739347_T6",
"type": "CHEMICAL",
"text": [
"forskolin"
],
"offsets": [
[
550,
559
]
],
"normalized": []
},
{
"id": "7739347_T7",
"type": "CHEMICAL",
"text": [
"adenylyl"
],
"offsets": [
[
571,
579
]
],
"normalized": []
},
{
"id": "7739347_T8",
"type": "CHEMICAL",
"text": [
"dihydroetorphine"
],
"offsets": [
[
598,
614
]
],
"normalized": []
},
{
"id": "7739347_T9",
"type": "CHEMICAL",
"text": [
"dihydroetorphine"
],
"offsets": [
[
168,
184
]
],
"normalized": []
},
{
"id": "7739347_T10",
"type": "CHEMICAL",
"text": [
"DTNB"
],
"offsets": [
[
653,
657
]
],
"normalized": []
},
{
"id": "7739347_T11",
"type": "CHEMICAL",
"text": [
"etorphine"
],
"offsets": [
[
686,
695
]
],
"normalized": []
},
{
"id": "7739347_T12",
"type": "CHEMICAL",
"text": [
"dihydroetorphine"
],
"offsets": [
[
790,
806
]
],
"normalized": []
},
{
"id": "7739347_T13",
"type": "CHEMICAL",
"text": [
"etorphine"
],
"offsets": [
[
104,
113
]
],
"normalized": []
},
{
"id": "7739347_T14",
"type": "CHEMICAL",
"text": [
"adenylyl"
],
"offsets": [
[
32,
40
]
],
"normalized": []
},
{
"id": "7739347_T15",
"type": "CHEMICAL",
"text": [
"dihydroetorphine"
],
"offsets": [
[
63,
79
]
],
"normalized": []
},
{
"id": "7739347_T16",
"type": "GENE-N",
"text": [
"opioid receptor"
],
"offsets": [
[
255,
270
]
],
"normalized": []
},
{
"id": "7739347_T17",
"type": "GENE-N",
"text": [
"adenylyl cyclase"
],
"offsets": [
[
300,
316
]
],
"normalized": []
},
{
"id": "7739347_T18",
"type": "GENE-N",
"text": [
"(mu, delta, and kappa) of opioid receptors"
],
"offsets": [
[
435,
477
]
],
"normalized": []
},
{
"id": "7739347_T19",
"type": "GENE-N",
"text": [
"adenylyl cyclase"
],
"offsets": [
[
571,
587
]
],
"normalized": []
},
{
"id": "7739347_T20",
"type": "GENE-N",
"text": [
"Opioid receptor"
],
"offsets": [
[
0,
15
]
],
"normalized": []
},
{
"id": "7739347_T21",
"type": "GENE-N",
"text": [
"adenylyl cyclase"
],
"offsets": [
[
32,
48
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "7739347_0",
"type": "INHIBITOR",
"arg1_id": "7739347_T15",
"arg2_id": "7739347_T21",
"normalized": []
},
{
"id": "7739347_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "7739347_T1",
"arg2_id": "7739347_T16",
"normalized": []
},
{
"id": "7739347_2",
"type": "INHIBITOR",
"arg1_id": "7739347_T1",
"arg2_id": "7739347_T17",
"normalized": []
},
{
"id": "7739347_3",
"type": "INHIBITOR",
"arg1_id": "7739347_T3",
"arg2_id": "7739347_T17",
"normalized": []
},
{
"id": "7739347_4",
"type": "INHIBITOR",
"arg1_id": "7739347_T4",
"arg2_id": "7739347_T19",
"normalized": []
},
{
"id": "7739347_5",
"type": "INHIBITOR",
"arg1_id": "7739347_T5",
"arg2_id": "7739347_T19",
"normalized": []
}
] |
23616376 | 23616376 | [
{
"id": "23616376_title",
"type": "title",
"text": [
"Flexible Low-Voltage Organic Transistors with High Thermal Stability at 250 °C."
],
"offsets": [
[
0,
79
]
]
},
{
"id": "23616376_abstract",
"type": "abstract",
"text": [
"Low-operating-voltage flexible organic thin-film transistors with high thermal stability using DPh-DNTT and SAM gate dielectrics are reported. The mobility of the transistors are decreased by 23% after heating to 250 °C for 30 min. Furthermore, flexible organic pseudo-CMOS inverter circuits, which are functional after heating to 200 °C."
],
"offsets": [
[
80,
418
]
]
}
] | [
{
"id": "23616376_T1",
"type": "CHEMICAL",
"text": [
"DPh-DNTT"
],
"offsets": [
[
175,
183
]
],
"normalized": []
}
] | [] | [] | [] |
23604722 | 23604722 | [
{
"id": "23604722_title",
"type": "title",
"text": [
"Fructose-1,6-bisphosphate ameliorates lipopolysaccharide-induced dysfunction of blood-brain barrier."
],
"offsets": [
[
0,
100
]
]
},
{
"id": "23604722_abstract",
"type": "abstract",
"text": [
"Fructose-1,6-bisphosphate (FBP), a glycolytic intermediate, has neuroprotective effects in various brain injury models. However, its effects on blood-brain barrier (BBB) are largely unknown. In this study, we investigated the effects of FBP on lipopolysaccharide (LPS)-induced BBB dysfunction in in vitro BBB model comprising co-culture of mouse brain endothelial cell line, bEnd.3 and mouse primary astrocyte and explored its action mechanism therein involved. LPS induced the impairment of endothelial permeability and transendothelial electrical resistance (TEER). The functional changes were confirmed by alterations in immunostaining for junctional proteins occludin, ZO-1 and VE-cadherin, such as the loss of cortical staining pattern and appearance of intercellular gaps in endothelial cells. Co-administration of FBP alleviated the deleterious effects of LPS on BBB permeability and TEER in a dose dependent manner. And also FBP inhibited the LPS-induced changes in the distribution of endothelial junctional proteins, resulting in the better preservation of monolayer integrity. FBP suppressed the production of reactive oxygen species (ROS) but did not affect cyclooxygenase-2 expression and prostaglandin E2 production in endothelial cells stimulated with LPS. Taken together, these data suggest that FBP could ameliorate LPS-induced BBB dysfunction through the maintenance of junctional integrity, which might be mediated by downregulation of ROS production."
],
"offsets": [
[
101,
1571
]
]
}
] | [
{
"id": "23604722_T1",
"type": "CHEMICAL",
"text": [
"Fructose-1,6-bisphosphate"
],
"offsets": [
[
101,
126
]
],
"normalized": []
},
{
"id": "23604722_T2",
"type": "CHEMICAL",
"text": [
"FBP"
],
"offsets": [
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1189,
1192
]
],
"normalized": []
},
{
"id": "23604722_T3",
"type": "CHEMICAL",
"text": [
"oxygen"
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1231,
1237
]
],
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},
{
"id": "23604722_T4",
"type": "CHEMICAL",
"text": [
"prostaglandin E2"
],
"offsets": [
[
1303,
1319
]
],
"normalized": []
},
{
"id": "23604722_T5",
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"FBP"
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1413,
1416
]
],
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"id": "23604722_T6",
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"FBP"
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338,
341
]
],
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"id": "23604722_T7",
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"FBP"
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128,
131
]
],
"normalized": []
},
{
"id": "23604722_T8",
"type": "CHEMICAL",
"text": [
"FBP"
],
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922,
925
]
],
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},
{
"id": "23604722_T9",
"type": "CHEMICAL",
"text": [
"FBP"
],
"offsets": [
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1034,
1037
]
],
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},
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"id": "23604722_T10",
"type": "CHEMICAL",
"text": [
"Fructose-1,6-bisphosphate"
],
"offsets": [
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0,
25
]
],
"normalized": []
},
{
"id": "23604722_T11",
"type": "GENE-Y",
"text": [
"cyclooxygenase-2"
],
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1271,
1287
]
],
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},
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"id": "23604722_T12",
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"occludin"
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764,
772
]
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},
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"id": "23604722_T13",
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"text": [
"ZO-1"
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774,
778
]
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},
{
"id": "23604722_T14",
"type": "GENE-Y",
"text": [
"VE-cadherin"
],
"offsets": [
[
783,
794
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23604722_0",
"type": "PRODUCT-OF",
"arg1_id": "23604722_T4",
"arg2_id": "23604722_T11",
"normalized": []
}
] |
23122070 | 23122070 | [
{
"id": "23122070_title",
"type": "title",
"text": [
"Syzygium aqueum leaf extract and its bioactive compounds enhances pre-adipocyte differentiation and 2-NBDG uptake in 3T3-L1 cells."
],
"offsets": [
[
0,
130
]
]
},
{
"id": "23122070_abstract",
"type": "abstract",
"text": [
"The insulin-like and/or insulin-sensitising effects of Syzygium aqueum leaf extract and its six bioactive compounds; 4-hydroxybenzaldehyde, myricetin-3-O-rhamnoside, europetin-3-O-rhamnoside, phloretin, myrigalone-G and myrigalone-B were investigated in 3T3-L1 adipocytes. We observed that, S. aqueum leaf extract (0.04-5 μg/ml) and its six bioactive compounds (0.08-10 μM) at non-cytotoxic concentrations were effectively enhance adipogenesis, stimulate glucose uptake and increase adiponectin secretion in 3T3-L1 adipocytes. Clearly, the compounds myricetin-3-O-rhamnoside and europetin-3-O-rhamnoside showed insulin-like and insulin-sensitising effects on adipocytes from a concentration of 0.08 μM. These compounds were far better than rosiglitazone and the other isolated compounds in enhancing adipogenesis, stimulating 2-NBDG uptake and increasing adiponectin secretion at all the concentrations tested. These suggest the antidiabetic potential of S. aqueum leaf extract and its six bioactive compounds. However, further molecular interaction studies to explain the mechanisms of action are highly warranted."
],
"offsets": [
[
131,
1246
]
]
}
] | [
{
"id": "23122070_T1",
"type": "CHEMICAL",
"text": [
"4-hydroxybenzaldehyde"
],
"offsets": [
[
248,
269
]
],
"normalized": []
},
{
"id": "23122070_T2",
"type": "CHEMICAL",
"text": [
"myricetin-3-O-rhamnoside"
],
"offsets": [
[
271,
295
]
],
"normalized": []
},
{
"id": "23122070_T3",
"type": "CHEMICAL",
"text": [
"europetin-3-O-rhamnoside"
],
"offsets": [
[
297,
321
]
],
"normalized": []
},
{
"id": "23122070_T4",
"type": "CHEMICAL",
"text": [
"phloretin"
],
"offsets": [
[
323,
332
]
],
"normalized": []
},
{
"id": "23122070_T5",
"type": "CHEMICAL",
"text": [
"myrigalone-G"
],
"offsets": [
[
334,
346
]
],
"normalized": []
},
{
"id": "23122070_T6",
"type": "CHEMICAL",
"text": [
"myrigalone-B"
],
"offsets": [
[
351,
363
]
],
"normalized": []
},
{
"id": "23122070_T7",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
586,
593
]
],
"normalized": []
},
{
"id": "23122070_T8",
"type": "CHEMICAL",
"text": [
"myricetin-3-O-rhamnoside"
],
"offsets": [
[
681,
705
]
],
"normalized": []
},
{
"id": "23122070_T9",
"type": "CHEMICAL",
"text": [
"europetin-3-O-rhamnoside"
],
"offsets": [
[
710,
734
]
],
"normalized": []
},
{
"id": "23122070_T10",
"type": "CHEMICAL",
"text": [
"rosiglitazone"
],
"offsets": [
[
871,
884
]
],
"normalized": []
},
{
"id": "23122070_T11",
"type": "CHEMICAL",
"text": [
"2-NBDG"
],
"offsets": [
[
957,
963
]
],
"normalized": []
},
{
"id": "23122070_T12",
"type": "CHEMICAL",
"text": [
"2-NBDG"
],
"offsets": [
[
100,
106
]
],
"normalized": []
},
{
"id": "23122070_T13",
"type": "GENE-Y",
"text": [
"insulin"
],
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[
155,
162
]
],
"normalized": []
},
{
"id": "23122070_T14",
"type": "GENE-Y",
"text": [
"insulin"
],
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[
135,
142
]
],
"normalized": []
},
{
"id": "23122070_T15",
"type": "GENE-Y",
"text": [
"adiponectin"
],
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[
614,
625
]
],
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},
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"id": "23122070_T16",
"type": "GENE-Y",
"text": [
"insulin"
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[
742,
749
]
],
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},
{
"id": "23122070_T17",
"type": "GENE-Y",
"text": [
"insulin"
],
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[
759,
766
]
],
"normalized": []
},
{
"id": "23122070_T18",
"type": "GENE-Y",
"text": [
"adiponectin"
],
"offsets": [
[
986,
997
]
],
"normalized": []
}
] | [] | [] | [] |
17497253 | 17497253 | [
{
"id": "17497253_title",
"type": "title",
"text": [
"[Short QT syndrome]."
],
"offsets": [
[
0,
20
]
]
},
{
"id": "17497253_abstract",
"type": "abstract",
"text": [
"Short QT syndrome is a new genetic disorder associated with familial atrial fibrillation and/or sudden death or syncope. To date, different mutations in genes encoding for cardiac ion channels (KCNH2, KCNQ1, and KCNJ2) have been identified to cause the short QT syndrome. The mutations lead to a gain of function of the affected current (IKr, IKs, and IK1). The phenotype is characterized by a shortened QT interval<335 ms after correction for heart rate at rates<80 beats/min. Furthermore, the QT interval poorly adapts to heart rate. Patients exhibit shortened atrial and ventricular effective refractory periods and, in the majority, inducibility of ventricular fibrillation. Death occurs already in newborns. Therapy of choice seems to be the implantable cardioverter defibrillator because of the high incidence of sudden death. Pharmacological treatment has been studied and it could be demonstrated, that some mutant currents may be insufficiently suppressed by drugs targeted to block the specific current such as, e.g., sotalol or ibutilide in patients with a mutation in the IKr-coding gene KCNH2 (HERG). Quinidine proved to be efficient in prolonging the QT interval and normalizing the effective refractory periods in some patients."
],
"offsets": [
[
21,
1264
]
]
}
] | [
{
"id": "17497253_T1",
"type": "CHEMICAL",
"text": [
"sotalol"
],
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[
1049,
1056
]
],
"normalized": []
},
{
"id": "17497253_T2",
"type": "CHEMICAL",
"text": [
"ibutilide"
],
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[
1060,
1069
]
],
"normalized": []
},
{
"id": "17497253_T3",
"type": "CHEMICAL",
"text": [
"Quinidine"
],
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[
1135,
1144
]
],
"normalized": []
},
{
"id": "17497253_T4",
"type": "GENE-Y",
"text": [
"IKr"
],
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[
1105,
1108
]
],
"normalized": []
},
{
"id": "17497253_T5",
"type": "GENE-Y",
"text": [
"KCNH2"
],
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[
1121,
1126
]
],
"normalized": []
},
{
"id": "17497253_T6",
"type": "GENE-Y",
"text": [
"HERG"
],
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[
1128,
1132
]
],
"normalized": []
},
{
"id": "17497253_T7",
"type": "GENE-N",
"text": [
"cardiac ion channels"
],
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[
193,
213
]
],
"normalized": []
},
{
"id": "17497253_T8",
"type": "GENE-Y",
"text": [
"KCNH2"
],
"offsets": [
[
215,
220
]
],
"normalized": []
},
{
"id": "17497253_T9",
"type": "GENE-Y",
"text": [
"KCNQ1"
],
"offsets": [
[
222,
227
]
],
"normalized": []
},
{
"id": "17497253_T10",
"type": "GENE-Y",
"text": [
"KCNJ2"
],
"offsets": [
[
233,
238
]
],
"normalized": []
},
{
"id": "17497253_T11",
"type": "GENE-Y",
"text": [
"IKr"
],
"offsets": [
[
359,
362
]
],
"normalized": []
},
{
"id": "17497253_T12",
"type": "GENE-Y",
"text": [
"IKs"
],
"offsets": [
[
364,
367
]
],
"normalized": []
},
{
"id": "17497253_T13",
"type": "GENE-Y",
"text": [
"IK1"
],
"offsets": [
[
373,
376
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17497253_0",
"type": "INHIBITOR",
"arg1_id": "17497253_T1",
"arg2_id": "17497253_T4",
"normalized": []
},
{
"id": "17497253_1",
"type": "INHIBITOR",
"arg1_id": "17497253_T1",
"arg2_id": "17497253_T5",
"normalized": []
},
{
"id": "17497253_2",
"type": "INHIBITOR",
"arg1_id": "17497253_T1",
"arg2_id": "17497253_T6",
"normalized": []
},
{
"id": "17497253_3",
"type": "INHIBITOR",
"arg1_id": "17497253_T2",
"arg2_id": "17497253_T4",
"normalized": []
},
{
"id": "17497253_4",
"type": "INHIBITOR",
"arg1_id": "17497253_T2",
"arg2_id": "17497253_T5",
"normalized": []
},
{
"id": "17497253_5",
"type": "INHIBITOR",
"arg1_id": "17497253_T2",
"arg2_id": "17497253_T6",
"normalized": []
}
] |
18708991 | 18708991 | [
{
"id": "18708991_title",
"type": "title",
"text": [
"ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety."
],
"offsets": [
[
0,
111
]
]
},
{
"id": "18708991_abstract",
"type": "abstract",
"text": [
"Risperidone is metabolized to its active metabolite, 9-hydroxyrisperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisms in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype on the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisms have a moderate effect on those of 9-hydroxyrisperidone and the active moiety."
],
"offsets": [
[
112,
2027
]
]
}
] | [
{
"id": "18708991_T1",
"type": "CHEMICAL",
"text": [
"Risperidone"
],
"offsets": [
[
112,
123
]
],
"normalized": []
},
{
"id": "18708991_T2",
"type": "CHEMICAL",
"text": [
"risperidone"
],
"offsets": [
[
1311,
1322
]
],
"normalized": []
},
{
"id": "18708991_T3",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
1324,
1344
]
],
"normalized": []
},
{
"id": "18708991_T4",
"type": "CHEMICAL",
"text": [
"risperidone"
],
"offsets": [
[
1436,
1447
]
],
"normalized": []
},
{
"id": "18708991_T5",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
1477,
1497
]
],
"normalized": []
},
{
"id": "18708991_T6",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
1676,
1696
]
],
"normalized": []
},
{
"id": "18708991_T7",
"type": "CHEMICAL",
"text": [
"risperidone"
],
"offsets": [
[
1901,
1912
]
],
"normalized": []
},
{
"id": "18708991_T8",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
1984,
2004
]
],
"normalized": []
},
{
"id": "18708991_T9",
"type": "CHEMICAL",
"text": [
"risperidone"
],
"offsets": [
[
333,
344
]
],
"normalized": []
},
{
"id": "18708991_T10",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
349,
369
]
],
"normalized": []
},
{
"id": "18708991_T11",
"type": "CHEMICAL",
"text": [
"risperidone"
],
"offsets": [
[
376,
387
]
],
"normalized": []
},
{
"id": "18708991_T12",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
392,
412
]
],
"normalized": []
},
{
"id": "18708991_T13",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
165,
185
]
],
"normalized": []
},
{
"id": "18708991_T14",
"type": "CHEMICAL",
"text": [
"risperidone"
],
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[
689,
700
]
],
"normalized": []
},
{
"id": "18708991_T15",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
702,
722
]
],
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},
{
"id": "18708991_T16",
"type": "CHEMICAL",
"text": [
"risperidone"
],
"offsets": [
[
848,
859
]
],
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},
{
"id": "18708991_T17",
"type": "CHEMICAL",
"text": [
"risperidone"
],
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[
952,
963
]
],
"normalized": []
},
{
"id": "18708991_T18",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
968,
988
]
],
"normalized": []
},
{
"id": "18708991_T19",
"type": "CHEMICAL",
"text": [
"risperidone"
],
"offsets": [
[
1050,
1061
]
],
"normalized": []
},
{
"id": "18708991_T20",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
1063,
1083
]
],
"normalized": []
},
{
"id": "18708991_T21",
"type": "CHEMICAL",
"text": [
"9-hydroxyrisperidone"
],
"offsets": [
[
60,
80
]
],
"normalized": []
},
{
"id": "18708991_T22",
"type": "CHEMICAL",
"text": [
"risperidone"
],
"offsets": [
[
85,
96
]
],
"normalized": []
},
{
"id": "18708991_T23",
"type": "GENE-Y",
"text": [
"CYP3A5"
],
"offsets": [
[
1201,
1207
]
],
"normalized": []
},
{
"id": "18708991_T24",
"type": "GENE-N",
"text": [
"CYP2D6 and 3A4"
],
"offsets": [
[
225,
239
]
],
"normalized": []
},
{
"id": "18708991_T25",
"type": "GENE-Y",
"text": [
"CYP3A5"
],
"offsets": [
[
1258,
1264
]
],
"normalized": []
},
{
"id": "18708991_T26",
"type": "GENE-Y",
"text": [
"CYP3A5"
],
"offsets": [
[
1277,
1283
]
],
"normalized": []
},
{
"id": "18708991_T27",
"type": "GENE-Y",
"text": [
"CYP2D6"
],
"offsets": [
[
1373,
1379
]
],
"normalized": []
},
{
"id": "18708991_T28",
"type": "GENE-Y",
"text": [
"ABCB1"
],
"offsets": [
[
1610,
1615
]
],
"normalized": []
},
{
"id": "18708991_T29",
"type": "GENE-Y",
"text": [
"ABCB1"
],
"offsets": [
[
1768,
1773
]
],
"normalized": []
},
{
"id": "18708991_T30",
"type": "GENE-Y",
"text": [
"CYP2D6"
],
"offsets": [
[
1848,
1854
]
],
"normalized": []
},
{
"id": "18708991_T31",
"type": "GENE-Y",
"text": [
"ABCB1"
],
"offsets": [
[
1929,
1934
]
],
"normalized": []
},
{
"id": "18708991_T32",
"type": "GENE-N",
"text": [
"P-glycoprotein"
],
"offsets": [
[
431,
445
]
],
"normalized": []
},
{
"id": "18708991_T33",
"type": "GENE-N",
"text": [
"P-gp"
],
"offsets": [
[
447,
451
]
],
"normalized": []
},
{
"id": "18708991_T34",
"type": "GENE-Y",
"text": [
"CYP3A5"
],
"offsets": [
[
628,
634
]
],
"normalized": []
},
{
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"ABCB1"
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645,
650
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201,
216
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"text": [
"ABCB1"
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[
0,
5
]
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}
] | [] | [] | [
{
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}
] |
23421757 | 23421757 | [
{
"id": "23421757_title",
"type": "title",
"text": [
"p53-mediated autophagy adjustment is involved in the protection of silibinin against murine dermal inflammation and epidermal apoptosis induced by UVB irradiation."
],
"offsets": [
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0,
163
]
]
},
{
"id": "23421757_abstract",
"type": "abstract",
"text": [
"Apoptosis in murine dermal cells is retarded by ultraviolet B (UVB) irradiation-induced autophagic intervention while simultaneously epidermal cells commit apoptosis, during which inflammatory cytokines released from the lost epidermal cells promote immune responses of dermal inflammatory cells, forming morphological symptoms of acute cutaneous diseases. Autophagy is involved in prevention or provocation of apoptosis of dermal or epidermal cells of UVB-irradiated mice via modulation of intracellular metabolism, intervening the balance between cell death and survival in dermis and epidermis. p53 expressed in immune system affects autophagy function through activating or inactivating genes encoding apoptotic factors and inflammatory cytokines. Silibinin protects dermal and epidermal cells of UVB irradiated skin against abnormally autophagy-mediated apoptosis adjustments. In this study, how UVB irradiation intervenes autophagy in dermal and epidermal cells as well as how silibinin protects UVB irradiated skin through physiological recovering of autophagy function in dermis and epidermis are focused and elucidated preliminarily. Silibinin treatment (50 mg/kg/day for 4 days) reversed dermal and epidermal autophagy levels from UVB irradiation-induced improper autophagy intervention, repaired the balance between cell survival and death in dermis and epidermis, and protected skin against damage through mediation of p53 activation in dermal and epidermal cells."
],
"offsets": [
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164,
1640
]
]
}
] | [
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"id": "23421757_T1",
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"id": "23421757_T6",
"type": "GENE-N",
"text": [
"cytokines"
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0,
3
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}
] | [] | [] | [
{
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"arg2_id": "23421757_T5",
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}
] |
8986981 | 8986981 | [
{
"id": "8986981_title",
"type": "title",
"text": [
"Characterization of alpha-adrenoceptor activity in the preterm piglet mesentery."
],
"offsets": [
[
0,
80
]
]
},
{
"id": "8986981_abstract",
"type": "abstract",
"text": [
"To characterize neonatal mesenteric alpha-adrenoceptor populations, an extracorporeal perfusion circuit was established to control intestinal blood flow in prematurely delivered (by cesarean section at 90% of gestational age) piglets. Activation of alpha 1-adrenoceptors was documented by observing dose-dependent increases in mesenteric perfusion pressure after intramesenteric arterial injection of methoxamine; alpha 2-adrenoceptor activity was confirmed by finding similar increases in mesenteric perfusion pressure after intramesenteric arterial injections of BHT 933. Peripheral intravenous injections of WB 4101 (a competitive alpha 1A-adrenoceptor antagonist), but not clorethylclonidine (CEC, an alpha 1B-adrenoceptor antagonist), significantly blunted (P < .05, ANOVA) the mesenteric vasoconstrictor responses to methoxamine. The mesenteric vasoconstrictor response to BHT 933 (an alpha 2-adrenoceptor agonist) also was blunted by WB 4101, but not by CEC. These data suggest that alpha 1A- and alpha 2-adrenoceptors can be activated in the small intestinal mesentery of piglets well before they reach full-term maturation, although receptor specificity has not been fully established."
],
"offsets": [
[
81,
1275
]
]
}
] | [
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"id": "8986981_T1",
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"id": "8986981_T2",
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"BHT 933"
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646,
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]
],
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"id": "8986981_T3",
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"WB 4101"
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692,
699
]
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"id": "8986981_T4",
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"clorethylclonidine"
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758,
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]
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},
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"id": "8986981_T5",
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"CEC"
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778,
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]
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"methoxamine"
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"CEC"
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495,
515
]
],
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},
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"id": "8986981_T14",
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"alpha 1A-adrenoceptor"
],
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715,
736
]
],
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},
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"id": "8986981_T15",
"type": "GENE-Y",
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"alpha 1B-adrenoceptor"
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786,
807
]
],
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},
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"id": "8986981_T16",
"type": "GENE-N",
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"alpha 2-adrenoceptor"
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972,
992
]
],
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},
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"id": "8986981_T17",
"type": "GENE-N",
"text": [
"alpha-adrenoceptor"
],
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[
20,
38
]
],
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}
] | [] | [] | [
{
"id": "8986981_0",
"type": "ANTAGONIST",
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"arg2_id": "8986981_T14",
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},
{
"id": "8986981_1",
"type": "ANTAGONIST",
"arg1_id": "8986981_T4",
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"normalized": []
},
{
"id": "8986981_2",
"type": "ANTAGONIST",
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"arg2_id": "8986981_T15",
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},
{
"id": "8986981_3",
"type": "AGONIST",
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"arg2_id": "8986981_T16",
"normalized": []
},
{
"id": "8986981_4",
"type": "ACTIVATOR",
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},
{
"id": "8986981_5",
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"normalized": []
},
{
"id": "8986981_6",
"type": "INHIBITOR",
"arg1_id": "8986981_T8",
"arg2_id": "8986981_T16",
"normalized": []
}
] |
23265474 | 23265474 | [
{
"id": "23265474_title",
"type": "title",
"text": [
"Comparative formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in creatinine/phenylalanine and creatinine/phenylalanine/4-oxo-2-nonenal reaction mixtures."
],
"offsets": [
[
0,
171
]
]
},
{
"id": "23265474_abstract",
"type": "abstract",
"text": [
"The comparative formation of the heterocyclic aromatic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in both creatinine/phenylalanine (CRN/Phe) and creatinine/phenylalanine/4-oxo-2-nonenal (CRN/Phe/ON) systems was studied to analyse the ability of lipid-derived reactive carbonyls to promote PhIP formation. Although PhIP was produced to some extent in the CRN/Phe system, the presence of the oxidized lipid increased considerably the amount of PhIP produced. This increase seemed to be a consequence of the decrease in the E(a) of the reaction when the lipid was present, which diminished from 112.9 to 80.9 kJ/mol. On the other hand, the addition of the lipid did not seem to produce PhIP by an alternative mechanism because PhIP was formed analogously in both CRN/Phe and CRN/Phe/ON systems as a function of pH, creatinine concentration, phenylalanine concentration, time, temperature, oxygen concentration in the reaction atmosphere, and the addition of different amounts of ammonia. All these results suggest that the ability of lipid oxidation products to produce PhIP is related to their capacity to induce the Strecker degradation of phenylalanine to phenylacetaldehyde. Therefore, any other reactive carbonyl compound that can produce the Strecker degradation of phenylalanine should also be considered as a potential inducer of PhIP formation under appropriate conditions."
],
"offsets": [
[
172,
1569
]
]
}
] | [
{
"id": "23265474_T1",
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"PhIP"
],
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[
1257,
1261
]
],
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},
{
"id": "23265474_T2",
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"text": [
"PhIP"
],
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[
282,
286
]
],
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},
{
"id": "23265474_T3",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
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[
1329,
1342
]
],
"normalized": []
},
{
"id": "23265474_T4",
"type": "CHEMICAL",
"text": [
"phenylacetaldehyde"
],
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[
1346,
1364
]
],
"normalized": []
},
{
"id": "23265474_T5",
"type": "CHEMICAL",
"text": [
"carbonyl"
],
"offsets": [
[
1396,
1404
]
],
"normalized": []
},
{
"id": "23265474_T6",
"type": "CHEMICAL",
"text": [
"creatinine"
],
"offsets": [
[
296,
306
]
],
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},
{
"id": "23265474_T7",
"type": "CHEMICAL",
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"phenylalanine"
],
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[
1459,
1472
]
],
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},
{
"id": "23265474_T8",
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"phenylalanine"
],
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[
307,
320
]
],
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},
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"id": "23265474_T9",
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"PhIP"
],
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[
1525,
1529
]
],
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},
{
"id": "23265474_T10",
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"text": [
"CRN"
],
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[
322,
325
]
],
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},
{
"id": "23265474_T11",
"type": "CHEMICAL",
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"Phe"
],
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[
326,
329
]
],
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},
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"id": "23265474_T12",
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"creatinine"
],
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[
335,
345
]
],
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},
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"phenylalanine"
],
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[
346,
359
]
],
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},
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"4-oxo-2-nonenal"
],
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360,
375
]
],
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},
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"CRN"
],
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377,
380
]
],
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},
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"Phe"
],
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381,
384
]
],
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},
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"carbonyls"
],
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458,
467
]
],
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},
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"PhIP"
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479,
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]
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"PhIP"
],
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504,
508
]
],
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},
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"id": "23265474_T20",
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"CRN"
],
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[
544,
547
]
],
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},
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"id": "23265474_T21",
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"Phe"
],
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[
548,
551
]
],
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},
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"PhIP"
],
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632,
636
]
],
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},
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"2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine"
],
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233,
280
]
],
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},
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"id": "23265474_T24",
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"PhIP"
],
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[
873,
877
]
],
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},
{
"id": "23265474_T25",
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"PhIP"
],
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[
914,
918
]
],
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},
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"id": "23265474_T26",
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"CRN"
],
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[
950,
953
]
],
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},
{
"id": "23265474_T27",
"type": "CHEMICAL",
"text": [
"Phe"
],
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[
954,
957
]
],
"normalized": []
},
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"id": "23265474_T28",
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"CRN"
],
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[
962,
965
]
],
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},
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"id": "23265474_T29",
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"Phe"
],
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[
966,
969
]
],
"normalized": []
},
{
"id": "23265474_T30",
"type": "CHEMICAL",
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"creatinine"
],
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[
1002,
1012
]
],
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},
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"id": "23265474_T31",
"type": "CHEMICAL",
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"phenylalanine"
],
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[
1028,
1041
]
],
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},
{
"id": "23265474_T32",
"type": "CHEMICAL",
"text": [
"oxygen"
],
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[
1076,
1082
]
],
"normalized": []
},
{
"id": "23265474_T33",
"type": "CHEMICAL",
"text": [
"ammonia"
],
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[
1166,
1173
]
],
"normalized": []
},
{
"id": "23265474_T34",
"type": "CHEMICAL",
"text": [
"creatinine"
],
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[
112,
122
]
],
"normalized": []
},
{
"id": "23265474_T35",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
123,
136
]
],
"normalized": []
},
{
"id": "23265474_T36",
"type": "CHEMICAL",
"text": [
"4-oxo-2-nonenal"
],
"offsets": [
[
137,
152
]
],
"normalized": []
},
{
"id": "23265474_T37",
"type": "CHEMICAL",
"text": [
"2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine"
],
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[
25,
72
]
],
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},
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"id": "23265474_T38",
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"text": [
"PhIP"
],
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[
74,
78
]
],
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},
{
"id": "23265474_T39",
"type": "CHEMICAL",
"text": [
"creatinine"
],
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[
83,
93
]
],
"normalized": []
},
{
"id": "23265474_T40",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
94,
107
]
],
"normalized": []
}
] | [] | [] | [] |
10531013 | 10531013 | [
{
"id": "10531013_title",
"type": "title",
"text": [
"Caffeine inhibits the checkpoint kinase ATM."
],
"offsets": [
[
0,
44
]
]
},
{
"id": "10531013_abstract",
"type": "abstract",
"text": [
"The basis of many anti-cancer therapies is the use of genotoxic agents that damage DNA and thus kill dividing cells. Agents that cause cells to override the DNA-damage checkpoint are predicted to sensitize cells to killing by genotoxic agents. They have therefore been sought as adjuncts in radiation therapy and chemotherapy. One such compound, caffeine, uncouples cell-cycle progression from the replication and repair of DNA [1] [2]. Caffeine therefore servers as a model compound in establishing the principle that agents that override DNA-damage checkpoints can be used to sensitize cells to the killing effects of genotoxic drugs [3]. But despite more than 20 years of use, the molecular mechanisms by which caffeine affects the cell cycle and checkpoint responses have not been identified. We investigated the effects of caffeine on the G2/M DNA-damage checkpoint in human cells. We report that the radiation-induced activation of the kinase Cds1 [4] (also known as Chk2 [5]) is inhibited by caffeine in vivo and that ATM kinase activity is directly inhibited by caffeine in vitro. Inhibition of ATM provides a molecular explanation of the attenuation of DNA-damage checkpoint responses and for the increased radiosensitivity of caffeine-treated cells [6] [7] [8]."
],
"offsets": [
[
45,
1316
]
]
}
] | [
{
"id": "10531013_T1",
"type": "CHEMICAL",
"text": [
"caffeine"
],
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1115,
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"caffeine"
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1281,
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"caffeine"
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391,
399
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"Caffeine"
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482,
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]
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1044,
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"Caffeine"
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0,
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"kinase"
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"kinase"
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987,
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]
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"text": [
"Cds1"
],
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]
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"Chk2"
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1018,
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]
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"kinase"
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"text": [
"ATM"
],
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40,
43
]
],
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}
] | [] | [] | [
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},
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"type": "INHIBITOR",
"arg1_id": "10531013_T2",
"arg2_id": "10531013_T9",
"normalized": []
}
] |
23116938 | 23116938 | [
{
"id": "23116938_title",
"type": "title",
"text": [
"Endocrine disruptive potential of endosulfan on the reproductive axis of Cichlasoma dimerus (Perciformes, Cichlidae)."
],
"offsets": [
[
0,
117
]
]
},
{
"id": "23116938_abstract",
"type": "abstract",
"text": [
"Endosulfan (ES), a persistent organochlorine pesticide, is widely used despite its toxicity to non-target animals. Upon reaching water bodies, ES can cause negative effects on aquatic animals, including disruption of hormonal systems. However, the action of ES on fish reproductive axis has been hardly studied thus far. The aim of the present work was to assess the endocrine disruptive potential of endosulfan on the pituitary gonadotropins levels and on the testes function due to ES in the South American freshwater fish Cichlasoma dimerus, using in vitro and in vivo approaches. In vitro experiments showed that ES inhibited the LH-stimulated steroidogenesis in gonads; no change was observed in gonadotropins release from pituitaries in culture. Laboratory waterborne ES (0.1, 0.3 and 1 μg/L) exposure for two months caused decrease in βFSH pituitary content and γGT activity in the testes (Sertoli cell function marker). Testicular histology revealed pathologies such as scarce intermediate stages of spermatogenesis, release of immature germ cells into the lobular lumen, presence of foam cells and interstitial fibrosis. As FSH and FSH-mediated steroidogenesis regulate spermatogenesis and Sertoli cell function, the effect of ES on FSH could be responsible for the morphological alterations observed in testes. In vitro, ES disrupted steroidogenesis in gonads, therefore similar effects in vivo cannot be ruled out. Based on this evidence, ES exhibits an endocrine disruptive action on the reproductive axis of C. dimerus, causing disruption at the pituitary and/or at the gonad level. These effects could acquire ecological significance under prolonged exposure to the pesticide in nature."
],
"offsets": [
[
118,
1818
]
]
}
] | [
{
"id": "23116938_T1",
"type": "CHEMICAL",
"text": [
"Endosulfan"
],
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[
118,
128
]
],
"normalized": []
},
{
"id": "23116938_T2",
"type": "CHEMICAL",
"text": [
"organochlorine"
],
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[
148,
162
]
],
"normalized": []
},
{
"id": "23116938_T3",
"type": "CHEMICAL",
"text": [
"endosulfan"
],
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[
519,
529
]
],
"normalized": []
},
{
"id": "23116938_T4",
"type": "CHEMICAL",
"text": [
"endosulfan"
],
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[
34,
44
]
],
"normalized": []
},
{
"id": "23116938_T5",
"type": "GENE-N",
"text": [
"FSH"
],
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[
1251,
1254
]
],
"normalized": []
},
{
"id": "23116938_T6",
"type": "GENE-N",
"text": [
"FSH"
],
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[
1259,
1262
]
],
"normalized": []
},
{
"id": "23116938_T7",
"type": "GENE-N",
"text": [
"FSH"
],
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[
1360,
1363
]
],
"normalized": []
},
{
"id": "23116938_T8",
"type": "GENE-N",
"text": [
"gonadotropins"
],
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[
547,
560
]
],
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},
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"id": "23116938_T9",
"type": "GENE-N",
"text": [
"LH"
],
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[
752,
754
]
],
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},
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"id": "23116938_T10",
"type": "GENE-N",
"text": [
"gonadotropins"
],
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[
819,
832
]
],
"normalized": []
},
{
"id": "23116938_T11",
"type": "GENE-Y",
"text": [
"βFSH"
],
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[
960,
964
]
],
"normalized": []
},
{
"id": "23116938_T12",
"type": "GENE-N",
"text": [
"γGT"
],
"offsets": [
[
987,
990
]
],
"normalized": []
}
] | [] | [] | [] |
23639875 | 23639875 | [
{
"id": "23639875_title",
"type": "title",
"text": [
"Prostaglandin E2 acts via bone marrow macrophages to block PTH-stimulated osteoblast differentiation in vitro."
],
"offsets": [
[
0,
110
]
]
},
{
"id": "23639875_abstract",
"type": "abstract",
"text": [
"Intermittent PTH is the major anabolic therapy for osteoporosis while continuous PTH causes bone loss. PTH acts on the osteoblast (OB) lineage to regulate bone resorption and formation. PTH also induces cyclooxygenase-2 (COX-2), producing prostaglandin E2 (PGE2), that can act on both OBs and osteoclasts (OCs). Because intermittent PTH is more anabolic in Cox-2 knockout (KO) than wild type (WT) mice, we hypothesized COX-2 might contribute to the effects of continuous PTH by suppressing PTH-stimulated differentiation of mesenchymal stem cells into OBs. We compared effects of continuous PTH on bone marrow stromal cells (BMSCs) and primary OBs (POBs) from Cox-2 KO mice, mice with deletion of PGE2 receptors (Ptger4 and Ptger2 KO mice), and WT controls. PTH increased OB differentiation in BMSCs only in the absence of COX-2 expression or activity. In the absence of COX-2, PTH stimulated differentiation if added during the first week of culture. In Cox-2 KO BMSCs, PTH-stimulated differentiation was prevented by adding PGE2 to cultures. Co-culture of POBs with M-CSF-expanded bone marrow macrophages (BMMs) showed that the inhibition of PTH-stimulated OB differentiation required not only COX-2 or PGE2 but also BMMs. Sufficient PGE2 to mediate the inhibitory effect was made by either WT POBs or WT BMMs. The inhibitory effect mediated by COX-2/PGE2 was transferred by conditioned media from RANKL-treated BMMs and could be blocked by osteoprotegerin, which interferes with RANKL binding to its receptor on OC lineage cells. Deletion of Ptger4, but not Ptger2, in BMMs prevented the inhibition of PTH-stimulated OB differentiation. As expected, PGE2 also stimulated OB differentiation, but when given in combination with PTH, the stimulatory effects of both were abrogated. These data suggest that PGE2, acting via EP4R on BMMs committed to the OC lineage, stimulated secretion of a factor or factors that acted to suppress PTH-stimulated OB differentiation. This suppression of OB differentiation could contribute to the bone loss seen with continuous PTH in vivo."
],
"offsets": [
[
111,
2184
]
]
}
] | [
{
"id": "23639875_T1",
"type": "CHEMICAL",
"text": [
"PGE2"
],
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[
1137,
1141
]
],
"normalized": []
},
{
"id": "23639875_T2",
"type": "CHEMICAL",
"text": [
"PGE2"
],
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[
1316,
1320
]
],
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},
{
"id": "23639875_T3",
"type": "CHEMICAL",
"text": [
"PGE2"
],
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[
1347,
1351
]
],
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},
{
"id": "23639875_T4",
"type": "CHEMICAL",
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"PGE2"
],
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[
1464,
1468
]
],
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},
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"id": "23639875_T5",
"type": "CHEMICAL",
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"PGE2"
],
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1764,
1768
]
],
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},
{
"id": "23639875_T6",
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"PGE2"
],
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[
1917,
1921
]
],
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},
{
"id": "23639875_T7",
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"text": [
"prostaglandin E2"
],
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[
350,
366
]
],
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},
{
"id": "23639875_T8",
"type": "CHEMICAL",
"text": [
"PGE2"
],
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[
368,
372
]
],
"normalized": []
},
{
"id": "23639875_T9",
"type": "CHEMICAL",
"text": [
"PGE2"
],
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[
808,
812
]
],
"normalized": []
},
{
"id": "23639875_T10",
"type": "CHEMICAL",
"text": [
"Prostaglandin E2"
],
"offsets": [
[
0,
16
]
],
"normalized": []
},
{
"id": "23639875_T11",
"type": "GENE-Y",
"text": [
"PTH"
],
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[
214,
217
]
],
"normalized": []
},
{
"id": "23639875_T12",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
1255,
1258
]
],
"normalized": []
},
{
"id": "23639875_T13",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
1307,
1312
]
],
"normalized": []
},
{
"id": "23639875_T14",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
124,
127
]
],
"normalized": []
},
{
"id": "23639875_T15",
"type": "GENE-Y",
"text": [
"COX-2"
],
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[
1458,
1463
]
],
"normalized": []
},
{
"id": "23639875_T16",
"type": "GENE-Y",
"text": [
"RANKL"
],
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[
1511,
1516
]
],
"normalized": []
},
{
"id": "23639875_T17",
"type": "GENE-Y",
"text": [
"osteoprotegerin"
],
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[
1554,
1569
]
],
"normalized": []
},
{
"id": "23639875_T18",
"type": "GENE-Y",
"text": [
"RANKL"
],
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[
1593,
1598
]
],
"normalized": []
},
{
"id": "23639875_T19",
"type": "GENE-Y",
"text": [
"Ptger4"
],
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[
1656,
1662
]
],
"normalized": []
},
{
"id": "23639875_T20",
"type": "GENE-Y",
"text": [
"Ptger2"
],
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[
1672,
1678
]
],
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},
{
"id": "23639875_T21",
"type": "GENE-Y",
"text": [
"PTH"
],
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[
1716,
1719
]
],
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},
{
"id": "23639875_T22",
"type": "GENE-Y",
"text": [
"PTH"
],
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[
1840,
1843
]
],
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},
{
"id": "23639875_T23",
"type": "GENE-Y",
"text": [
"PTH"
],
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[
297,
300
]
],
"normalized": []
},
{
"id": "23639875_T24",
"type": "GENE-Y",
"text": [
"PTH"
],
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[
2043,
2046
]
],
"normalized": []
},
{
"id": "23639875_T25",
"type": "GENE-Y",
"text": [
"cyclooxygenase-2"
],
"offsets": [
[
314,
330
]
],
"normalized": []
},
{
"id": "23639875_T26",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
2172,
2175
]
],
"normalized": []
},
{
"id": "23639875_T27",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
332,
337
]
],
"normalized": []
},
{
"id": "23639875_T28",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
444,
447
]
],
"normalized": []
},
{
"id": "23639875_T29",
"type": "GENE-Y",
"text": [
"Cox-2"
],
"offsets": [
[
468,
473
]
],
"normalized": []
},
{
"id": "23639875_T30",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
530,
535
]
],
"normalized": []
},
{
"id": "23639875_T31",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
582,
585
]
],
"normalized": []
},
{
"id": "23639875_T32",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
601,
604
]
],
"normalized": []
},
{
"id": "23639875_T33",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
702,
705
]
],
"normalized": []
},
{
"id": "23639875_T34",
"type": "GENE-Y",
"text": [
"Cox-2"
],
"offsets": [
[
771,
776
]
],
"normalized": []
},
{
"id": "23639875_T35",
"type": "GENE-N",
"text": [
"PGE2 receptors"
],
"offsets": [
[
808,
822
]
],
"normalized": []
},
{
"id": "23639875_T36",
"type": "GENE-Y",
"text": [
"Ptger4"
],
"offsets": [
[
824,
830
]
],
"normalized": []
},
{
"id": "23639875_T37",
"type": "GENE-Y",
"text": [
"Ptger2"
],
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[
835,
841
]
],
"normalized": []
},
{
"id": "23639875_T38",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
869,
872
]
],
"normalized": []
},
{
"id": "23639875_T39",
"type": "GENE-Y",
"text": [
"PTH"
],
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[
192,
195
]
],
"normalized": []
},
{
"id": "23639875_T40",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
934,
939
]
],
"normalized": []
},
{
"id": "23639875_T41",
"type": "GENE-Y",
"text": [
"COX-2"
],
"offsets": [
[
982,
987
]
],
"normalized": []
},
{
"id": "23639875_T42",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
989,
992
]
],
"normalized": []
},
{
"id": "23639875_T43",
"type": "GENE-Y",
"text": [
"Cox-2"
],
"offsets": [
[
1066,
1071
]
],
"normalized": []
},
{
"id": "23639875_T44",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
1082,
1085
]
],
"normalized": []
},
{
"id": "23639875_T45",
"type": "GENE-Y",
"text": [
"PTH"
],
"offsets": [
[
59,
62
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23639875_0",
"type": "INHIBITOR",
"arg1_id": "23639875_T10",
"arg2_id": "23639875_T45",
"normalized": []
},
{
"id": "23639875_1",
"type": "PRODUCT-OF",
"arg1_id": "23639875_T7",
"arg2_id": "23639875_T25",
"normalized": []
},
{
"id": "23639875_2",
"type": "PRODUCT-OF",
"arg1_id": "23639875_T7",
"arg2_id": "23639875_T27",
"normalized": []
},
{
"id": "23639875_3",
"type": "PRODUCT-OF",
"arg1_id": "23639875_T8",
"arg2_id": "23639875_T25",
"normalized": []
},
{
"id": "23639875_4",
"type": "PRODUCT-OF",
"arg1_id": "23639875_T8",
"arg2_id": "23639875_T27",
"normalized": []
},
{
"id": "23639875_5",
"type": "INHIBITOR",
"arg1_id": "23639875_T1",
"arg2_id": "23639875_T44",
"normalized": []
},
{
"id": "23639875_6",
"type": "INHIBITOR",
"arg1_id": "23639875_T2",
"arg2_id": "23639875_T12",
"normalized": []
}
] |
15694653 | 15694653 | [
{
"id": "15694653_title",
"type": "title",
"text": [
"Atypical and typical antipsychotic drug interactions with the dopamine D2 receptor."
],
"offsets": [
[
0,
83
]
]
},
{
"id": "15694653_abstract",
"type": "abstract",
"text": [
"A model of the dopamine D2 receptor was used to study the receptor interactions of dopamine, the typical antipsychotics haloperidol and loxapine, and the atypical antipsychotics clozapine and melperone. The atypical antipsychotics interacted with the halogen atom of the ring system in the direction of the transmembrane helices (TMHs) 2, 3 and 7, while the typical had the corresponding halogen atom in the direction of TMH5. Molecular dynamics simulations indicated that the average helical displacement upon binding increased in the order: typical < atypical < dopamine. Upon binding, the atypical induced larger displacements into TMH5 than did the typical. The typical had stronger non-bonded interactions with the receptor than had the atypical, which is in agreement with the experimental observation that the atypical antipsychotic drugs dissociate faster from the receptor than the typical antipsychotic drugs."
],
"offsets": [
[
84,
1003
]
]
}
] | [
{
"id": "15694653_T1",
"type": "CHEMICAL",
"text": [
"haloperidol"
],
"offsets": [
[
204,
215
]
],
"normalized": []
},
{
"id": "15694653_T2",
"type": "CHEMICAL",
"text": [
"loxapine"
],
"offsets": [
[
220,
228
]
],
"normalized": []
},
{
"id": "15694653_T3",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
99,
107
]
],
"normalized": []
},
{
"id": "15694653_T4",
"type": "CHEMICAL",
"text": [
"clozapine"
],
"offsets": [
[
262,
271
]
],
"normalized": []
},
{
"id": "15694653_T5",
"type": "CHEMICAL",
"text": [
"melperone"
],
"offsets": [
[
276,
285
]
],
"normalized": []
},
{
"id": "15694653_T6",
"type": "CHEMICAL",
"text": [
"halogen"
],
"offsets": [
[
335,
342
]
],
"normalized": []
},
{
"id": "15694653_T7",
"type": "CHEMICAL",
"text": [
"halogen"
],
"offsets": [
[
472,
479
]
],
"normalized": []
},
{
"id": "15694653_T8",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
648,
656
]
],
"normalized": []
},
{
"id": "15694653_T9",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
167,
175
]
],
"normalized": []
},
{
"id": "15694653_T10",
"type": "CHEMICAL",
"text": [
"dopamine"
],
"offsets": [
[
62,
70
]
],
"normalized": []
},
{
"id": "15694653_T11",
"type": "GENE-Y",
"text": [
"dopamine D2 receptor"
],
"offsets": [
[
99,
119
]
],
"normalized": []
},
{
"id": "15694653_T12",
"type": "GENE-Y",
"text": [
"dopamine D2 receptor"
],
"offsets": [
[
62,
82
]
],
"normalized": []
}
] | [] | [] | [] |
23180341 | 23180341 | [
{
"id": "23180341_title",
"type": "title",
"text": [
"Chemical constituents from the fungus Amauroderma amoiensis and their in vitro acetylcholinesterase inhibitory activities."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "23180341_abstract",
"type": "abstract",
"text": [
"One new compound named amauroamoienin (1), together with thirteen known compounds (2-14), was isolated from the EtOAc extract of Amauroderma amoiensis. The structures of these compounds were elucidated by the analysis of 1D and 2D spectroscopic data and the MS technique. The bioassays of inhibitory activities of these isolates against acetylcholinesterase were evaluated, and compounds 1, 3, and 5 exhibited acetylcholinesterase inhibitory activities."
],
"offsets": [
[
123,
576
]
]
}
] | [
{
"id": "23180341_T1",
"type": "CHEMICAL",
"text": [
"EtOAc"
],
"offsets": [
[
235,
240
]
],
"normalized": []
},
{
"id": "23180341_T2",
"type": "CHEMICAL",
"text": [
"amauroamoienin"
],
"offsets": [
[
146,
160
]
],
"normalized": []
},
{
"id": "23180341_T3",
"type": "GENE-Y",
"text": [
"acetylcholinesterase"
],
"offsets": [
[
460,
480
]
],
"normalized": []
},
{
"id": "23180341_T4",
"type": "GENE-Y",
"text": [
"acetylcholinesterase"
],
"offsets": [
[
533,
553
]
],
"normalized": []
},
{
"id": "23180341_T5",
"type": "GENE-Y",
"text": [
"acetylcholinesterase"
],
"offsets": [
[
79,
99
]
],
"normalized": []
}
] | [] | [] | [] |
16851960 | 16851960 | [
{
"id": "16851960_title",
"type": "title",
"text": [
"Methyl transfer in glycine N-methyltransferase. A theoretical study."
],
"offsets": [
[
0,
68
]
]
},
{
"id": "16851960_abstract",
"type": "abstract",
"text": [
"Density functional theory calculations using the hybrid functional B3LYP have been performed to study the methyl transfer step in glycine N-methyltransferase (GNMT). This enzyme catalyzes the S-adenosyl-L-methionine (SAM)-dependent methylation of glycine to form sarcosine. The starting point for the calculations is the recent X-ray crystal structure of GNMT complexed with SAM and acetate. Several quantum chemical models with different sizes, employing up to 98 atoms, were used. The calculations demonstrate that the suggested mechanism, where the methyl group is transferred in a single S(N)2 step, is thermodynamically plausible. By adding or eliminating various groups at the active site, it was furthermore demonstrated that hydrogen bonds to the amino group of the glycine substrate lower the reaction barrier, while hydrogen bonds to the carboxylate group raise the barrier."
],
"offsets": [
[
69,
953
]
]
}
] | [
{
"id": "16851960_T1",
"type": "CHEMICAL",
"text": [
"methyl"
],
"offsets": [
[
175,
181
]
],
"normalized": []
},
{
"id": "16851960_T2",
"type": "CHEMICAL",
"text": [
"glycine"
],
"offsets": [
[
199,
206
]
],
"normalized": []
},
{
"id": "16851960_T3",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
207,
208
]
],
"normalized": []
},
{
"id": "16851960_T4",
"type": "CHEMICAL",
"text": [
"S-adenosyl-L-methionine"
],
"offsets": [
[
261,
284
]
],
"normalized": []
},
{
"id": "16851960_T5",
"type": "CHEMICAL",
"text": [
"SAM"
],
"offsets": [
[
286,
289
]
],
"normalized": []
},
{
"id": "16851960_T6",
"type": "CHEMICAL",
"text": [
"glycine"
],
"offsets": [
[
316,
323
]
],
"normalized": []
},
{
"id": "16851960_T7",
"type": "CHEMICAL",
"text": [
"sarcosine"
],
"offsets": [
[
332,
341
]
],
"normalized": []
},
{
"id": "16851960_T8",
"type": "CHEMICAL",
"text": [
"SAM"
],
"offsets": [
[
444,
447
]
],
"normalized": []
},
{
"id": "16851960_T9",
"type": "CHEMICAL",
"text": [
"hydrogen"
],
"offsets": [
[
802,
810
]
],
"normalized": []
},
{
"id": "16851960_T10",
"type": "CHEMICAL",
"text": [
"amino"
],
"offsets": [
[
824,
829
]
],
"normalized": []
},
{
"id": "16851960_T11",
"type": "CHEMICAL",
"text": [
"glycine"
],
"offsets": [
[
843,
850
]
],
"normalized": []
},
{
"id": "16851960_T12",
"type": "CHEMICAL",
"text": [
"hydrogen"
],
"offsets": [
[
895,
903
]
],
"normalized": []
},
{
"id": "16851960_T13",
"type": "CHEMICAL",
"text": [
"carboxylate"
],
"offsets": [
[
917,
928
]
],
"normalized": []
},
{
"id": "16851960_T14",
"type": "CHEMICAL",
"text": [
"Methyl"
],
"offsets": [
[
0,
6
]
],
"normalized": []
},
{
"id": "16851960_T15",
"type": "CHEMICAL",
"text": [
"glycine"
],
"offsets": [
[
19,
26
]
],
"normalized": []
},
{
"id": "16851960_T16",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
27,
28
]
],
"normalized": []
},
{
"id": "16851960_T17",
"type": "GENE-Y",
"text": [
"glycine N-methyltransferase"
],
"offsets": [
[
199,
226
]
],
"normalized": []
},
{
"id": "16851960_T18",
"type": "GENE-Y",
"text": [
"GNMT"
],
"offsets": [
[
228,
232
]
],
"normalized": []
},
{
"id": "16851960_T19",
"type": "GENE-Y",
"text": [
"GNMT"
],
"offsets": [
[
424,
428
]
],
"normalized": []
},
{
"id": "16851960_T20",
"type": "GENE-Y",
"text": [
"glycine N-methyltransferase"
],
"offsets": [
[
19,
46
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16851960_0",
"type": "SUBSTRATE",
"arg1_id": "16851960_T8",
"arg2_id": "16851960_T19",
"normalized": []
}
] |
23198819 | 23198819 | [
{
"id": "23198819_title",
"type": "title",
"text": [
"Bioinspired and highly oriented clay nanocomposites with a xyloglucan biopolymer matrix: extending the range of mechanical and barrier properties."
],
"offsets": [
[
0,
146
]
]
},
{
"id": "23198819_abstract",
"type": "abstract",
"text": [
"The development of clay bionanocomposites requires processing routes with nanostructural control. Moreover, moisture durability is a concern with water-soluble biopolymers. Here, oriented bionanocomposite coatings with strong in-plane orientation of clay platelets are for the first time prepared by continuous water-based processing. Montmorillonite (MTM) and a \"new\" unmodified biological polymer (xyloglucan (XG)) are combined. The resulting nanocomposites are characterized by FE-SEM, TEM, and XRD. XG adsorption on MTM is measured by quartz crystal microbalance analysis. Mechanical and gas barrier properties are measured, also at high relative humidity. The reinforcement effects are modeled. XG dimensions in composites are estimated using atomistic simulations. The nanostructure shows highly oriented and intercalated clay platelets. The reinforcement efficiency and effects on barrier properties are remarkable and are likely to be due to highly oriented and well-dispersed MTM and strong XG-MTM interactions. Properties are well preserved in humid conditions and the reasons for this are discussed."
],
"offsets": [
[
147,
1257
]
]
}
] | [
{
"id": "23198819_T1",
"type": "CHEMICAL",
"text": [
"MTM"
],
"offsets": [
[
1150,
1153
]
],
"normalized": []
},
{
"id": "23198819_T2",
"type": "CHEMICAL",
"text": [
"Montmorillonite"
],
"offsets": [
[
482,
497
]
],
"normalized": []
},
{
"id": "23198819_T3",
"type": "CHEMICAL",
"text": [
"MTM"
],
"offsets": [
[
499,
502
]
],
"normalized": []
},
{
"id": "23198819_T4",
"type": "CHEMICAL",
"text": [
"MTM"
],
"offsets": [
[
667,
670
]
],
"normalized": []
},
{
"id": "23198819_T5",
"type": "CHEMICAL",
"text": [
"quartz"
],
"offsets": [
[
686,
692
]
],
"normalized": []
},
{
"id": "23198819_T6",
"type": "CHEMICAL",
"text": [
"MTM"
],
"offsets": [
[
1132,
1135
]
],
"normalized": []
}
] | [] | [] | [] |
23592780 | 23592780 | [
{
"id": "23592780_title",
"type": "title",
"text": [
"Structural mechanism of ring opening reaction of glucose by human serum albumin."
],
"offsets": [
[
0,
80
]
]
},
{
"id": "23592780_abstract",
"type": "abstract",
"text": [
"Glucose reacts with proteins non-enzymatically under physiological conditions. Such glycation is exacerbated in diabetic patients with high level of blood sugar, and induces various complications. Human albumin serum (HSA) is the most abundant protein in plasma and is glycated by glucose. The glycation sites on HSA remain controversial among different studies. Here, we report two protein crystal structures of HSA in complex with either glucose or fructose. These crystal structures reveal that the presence of linear forms of sugar for both monosaccharides. The linear form of glucose forms a covalent bond to Lys195 of HSA, but not the case for fructose. Based on these structures, we propose a mechanism for glucose ring opening involving both residues Lys195 and Lys199. These results provide mechanistic insights to understand the glucose ring opening reaction and the glycation of proteins by monosaccharides."
],
"offsets": [
[
81,
999
]
]
}
] | [
{
"id": "23592780_T1",
"type": "CHEMICAL",
"text": [
"Glucose"
],
"offsets": [
[
81,
88
]
],
"normalized": []
},
{
"id": "23592780_T2",
"type": "CHEMICAL",
"text": [
"sugar"
],
"offsets": [
[
236,
241
]
],
"normalized": []
},
{
"id": "23592780_T3",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
362,
369
]
],
"normalized": []
},
{
"id": "23592780_T4",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
521,
528
]
],
"normalized": []
},
{
"id": "23592780_T5",
"type": "CHEMICAL",
"text": [
"fructose"
],
"offsets": [
[
532,
540
]
],
"normalized": []
},
{
"id": "23592780_T6",
"type": "CHEMICAL",
"text": [
"sugar"
],
"offsets": [
[
611,
616
]
],
"normalized": []
},
{
"id": "23592780_T7",
"type": "CHEMICAL",
"text": [
"monosaccharides"
],
"offsets": [
[
626,
641
]
],
"normalized": []
},
{
"id": "23592780_T8",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
662,
669
]
],
"normalized": []
},
{
"id": "23592780_T9",
"type": "CHEMICAL",
"text": [
"Lys"
],
"offsets": [
[
695,
698
]
],
"normalized": []
},
{
"id": "23592780_T10",
"type": "CHEMICAL",
"text": [
"fructose"
],
"offsets": [
[
731,
739
]
],
"normalized": []
},
{
"id": "23592780_T11",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
795,
802
]
],
"normalized": []
},
{
"id": "23592780_T12",
"type": "CHEMICAL",
"text": [
"Lys"
],
"offsets": [
[
840,
843
]
],
"normalized": []
},
{
"id": "23592780_T13",
"type": "CHEMICAL",
"text": [
"Lys"
],
"offsets": [
[
851,
854
]
],
"normalized": []
},
{
"id": "23592780_T14",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
920,
927
]
],
"normalized": []
},
{
"id": "23592780_T15",
"type": "CHEMICAL",
"text": [
"monosaccharides"
],
"offsets": [
[
983,
998
]
],
"normalized": []
},
{
"id": "23592780_T16",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
49,
56
]
],
"normalized": []
},
{
"id": "23592780_T17",
"type": "GENE-Y",
"text": [
"Human albumin serum"
],
"offsets": [
[
278,
297
]
],
"normalized": []
},
{
"id": "23592780_T18",
"type": "GENE-Y",
"text": [
"HSA"
],
"offsets": [
[
299,
302
]
],
"normalized": []
},
{
"id": "23592780_T19",
"type": "GENE-Y",
"text": [
"HSA"
],
"offsets": [
[
394,
397
]
],
"normalized": []
},
{
"id": "23592780_T20",
"type": "GENE-Y",
"text": [
"HSA"
],
"offsets": [
[
494,
497
]
],
"normalized": []
},
{
"id": "23592780_T21",
"type": "GENE-Y",
"text": [
"HSA"
],
"offsets": [
[
705,
708
]
],
"normalized": []
},
{
"id": "23592780_T22",
"type": "GENE-Y",
"text": [
"human serum albumin"
],
"offsets": [
[
60,
79
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23592780_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23592780_T4",
"arg2_id": "23592780_T20",
"normalized": []
},
{
"id": "23592780_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "23592780_T5",
"arg2_id": "23592780_T20",
"normalized": []
},
{
"id": "23592780_2",
"type": "PART-OF",
"arg1_id": "23592780_T9",
"arg2_id": "23592780_T21",
"normalized": []
},
{
"id": "23592780_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "23592780_T8",
"arg2_id": "23592780_T21",
"normalized": []
},
{
"id": "23592780_4",
"type": "DIRECT-REGULATOR",
"arg1_id": "23592780_T3",
"arg2_id": "23592780_T17",
"normalized": []
},
{
"id": "23592780_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "23592780_T3",
"arg2_id": "23592780_T18",
"normalized": []
}
] |
23313663 | 23313663 | [
{
"id": "23313663_title",
"type": "title",
"text": [
"Benzo[α]pyrene repressed DNA mismatch repair in human breast cancer cells."
],
"offsets": [
[
0,
74
]
]
},
{
"id": "23313663_abstract",
"type": "abstract",
"text": [
"DNA mismatch repair (MMR) has been recently implicated to play a significant role in breast cancer progression, however, few studies have examined how various carcinogens affect MMR system in breast cancer cells. The present study employs an in vivo MMR assay developed in our laboratory to assess how prevalent environmental carcinogens such as polycyclic aromatic hydrocarbons (PAHs) affect MMR activity in human breast carcinoma cells. Specifically, we quantitatively measured MMR activity in ZR75-1 cells after they were exposed to benzo[α]pyrene (BaP), a prototypical PAH, at various concentrations. Our findings revealed that BaP exposure at high concentrations of 1 and 5 μM induced significant inhibition of MMR activity in ZR75-1 cells. Further, we also identified that MMR repression induced by 5 μM BaP was mediated through one of the MMR key proteins MSH6 as significant reduction in protein level was detected by western blot. More importantly, ectopic expression of hMSH6 restored MMR activity in the BaP treated cells to the same level as in the control cells. Impaired MMR plays an important role in carcinogenesis. Our findings suggest that BaP induced repression of MMR activity may also contribute to the progression of mutagenesis event. Meanwhile, the present study also for the first demonstrated that our in vivo DNA MMR assay can be applied in the field of environmental toxicology."
],
"offsets": [
[
75,
1481
]
]
}
] | [
{
"id": "23313663_T1",
"type": "CHEMICAL",
"text": [
"BaP"
],
"offsets": [
[
1090,
1093
]
],
"normalized": []
},
{
"id": "23313663_T2",
"type": "CHEMICAL",
"text": [
"BaP"
],
"offsets": [
[
1233,
1236
]
],
"normalized": []
},
{
"id": "23313663_T3",
"type": "CHEMICAL",
"text": [
"polycyclic aromatic hydrocarbons"
],
"offsets": [
[
421,
453
]
],
"normalized": []
},
{
"id": "23313663_T4",
"type": "CHEMICAL",
"text": [
"PAHs"
],
"offsets": [
[
455,
459
]
],
"normalized": []
},
{
"id": "23313663_T5",
"type": "CHEMICAL",
"text": [
"benzo[α]pyrene"
],
"offsets": [
[
611,
625
]
],
"normalized": []
},
{
"id": "23313663_T6",
"type": "CHEMICAL",
"text": [
"BaP"
],
"offsets": [
[
627,
630
]
],
"normalized": []
},
{
"id": "23313663_T7",
"type": "CHEMICAL",
"text": [
"PAH"
],
"offsets": [
[
648,
651
]
],
"normalized": []
},
{
"id": "23313663_T8",
"type": "CHEMICAL",
"text": [
"BaP"
],
"offsets": [
[
707,
710
]
],
"normalized": []
},
{
"id": "23313663_T9",
"type": "CHEMICAL",
"text": [
"BaP"
],
"offsets": [
[
885,
888
]
],
"normalized": []
},
{
"id": "23313663_T10",
"type": "CHEMICAL",
"text": [
"Benzo[α]pyrene"
],
"offsets": [
[
0,
14
]
],
"normalized": []
},
{
"id": "23313663_T11",
"type": "GENE-Y",
"text": [
"MSH6"
],
"offsets": [
[
938,
942
]
],
"normalized": []
},
{
"id": "23313663_T12",
"type": "GENE-Y",
"text": [
"hMSH6"
],
"offsets": [
[
1055,
1060
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23313663_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23313663_T9",
"arg2_id": "23313663_T11",
"normalized": []
}
] |
12650833 | 12650833 | [
{
"id": "12650833_title",
"type": "title",
"text": [
"Effects of serine/threonine protein phosphatase inhibitors on morphine-induced antinociception in the tail flick test in mice."
],
"offsets": [
[
0,
126
]
]
},
{
"id": "12650833_abstract",
"type": "abstract",
"text": [
"The aim of this study was to evaluate the effects of serine/threonine protein phosphatase (PP) inhibitors on morphine-induced antinociception in the tail flick test in mice, and on [3H]naloxone binding to the forebrain crude synaptosome fraction. Neither okadaic acid nor cantharidin (1-10000 nM) displaced [3H]naloxone from its specific binding sites, which indicates that they do not interact at the opioid receptor level. The i.c.v. administration of very low doses of okadaic acid (0.001-1 pg/mouse) and cantharidin (0.001-1 ng/mouse), which inhibit PP2A, produced a dose-dependent antagonism of the antinociception induced by morphine (s.c.). However, L-nor-okadaone (0.001 pg/mouse-1 ng/mouse, i.c.v.), an analogue of okadaic acid lacking activity against protein phosphatases, did not affect the antinociceptive effect of morphine. On the other hand, high doses of okadaic acid (10 ng/mouse, i.c.v.) and cantharidin (1 microg/mouse, i.c.v.), which also block PP1, and calyculin-A (0.1 fg/mouse-1 ng/mouse, i.c.v.), which inhibits equally both PP1 and PP2A, did not modify the morphine-induced antinociception. These results suggest that the activation of type 2A serine/threonine protein phosphatases may play a role in the antinociceptive effect of morphine, and that PP1 might counterbalace this activity."
],
"offsets": [
[
127,
1441
]
]
}
] | [
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"id": "12650833_T1",
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1210,
1218
]
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236,
244
]
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1297,
1303
]
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1304,
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]
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],
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1384,
1392
]
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{
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"type": "CHEMICAL",
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"[3H]naloxone"
],
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[
308,
320
]
],
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[
382,
394
]
],
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"id": "12650833_T8",
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],
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[
399,
410
]
],
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"id": "12650833_T9",
"type": "CHEMICAL",
"text": [
"[3H]naloxone"
],
"offsets": [
[
434,
446
]
],
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],
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[
599,
611
]
],
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{
"id": "12650833_T11",
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[
635,
646
]
],
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"id": "12650833_T12",
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"serine"
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[
180,
186
]
],
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},
{
"id": "12650833_T13",
"type": "CHEMICAL",
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"threonine"
],
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[
187,
196
]
],
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},
{
"id": "12650833_T14",
"type": "CHEMICAL",
"text": [
"morphine"
],
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[
758,
766
]
],
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},
{
"id": "12650833_T15",
"type": "CHEMICAL",
"text": [
"L-nor-okadaone"
],
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[
784,
798
]
],
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"id": "12650833_T16",
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"okadaic acid"
],
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[
851,
863
]
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{
"id": "12650833_T17",
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"morphine"
],
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956,
964
]
],
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{
"id": "12650833_T18",
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"okadaic acid"
],
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[
999,
1011
]
],
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},
{
"id": "12650833_T19",
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"cantharidin"
],
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[
1038,
1049
]
],
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},
{
"id": "12650833_T20",
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],
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[
1102,
1113
]
],
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},
{
"id": "12650833_T21",
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"serine"
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11,
17
]
],
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},
{
"id": "12650833_T22",
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"threonine"
],
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[
18,
27
]
],
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{
"id": "12650833_T23",
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"text": [
"morphine"
],
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[
62,
70
]
],
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},
{
"id": "12650833_T24",
"type": "GENE-N",
"text": [
"PP1"
],
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[
1177,
1180
]
],
"normalized": []
},
{
"id": "12650833_T25",
"type": "GENE-N",
"text": [
"PP2A"
],
"offsets": [
[
1185,
1189
]
],
"normalized": []
},
{
"id": "12650833_T26",
"type": "GENE-N",
"text": [
"type 2A serine/threonine protein phosphatases"
],
"offsets": [
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1289,
1334
]
],
"normalized": []
},
{
"id": "12650833_T27",
"type": "GENE-N",
"text": [
"PP1"
],
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[
1403,
1406
]
],
"normalized": []
},
{
"id": "12650833_T28",
"type": "GENE-N",
"text": [
"opioid receptor"
],
"offsets": [
[
529,
544
]
],
"normalized": []
},
{
"id": "12650833_T29",
"type": "GENE-N",
"text": [
"serine/threonine protein phosphatase"
],
"offsets": [
[
180,
216
]
],
"normalized": []
},
{
"id": "12650833_T30",
"type": "GENE-N",
"text": [
"PP2A"
],
"offsets": [
[
681,
685
]
],
"normalized": []
},
{
"id": "12650833_T31",
"type": "GENE-N",
"text": [
"protein phosphatases"
],
"offsets": [
[
889,
909
]
],
"normalized": []
},
{
"id": "12650833_T32",
"type": "GENE-N",
"text": [
"PP"
],
"offsets": [
[
218,
220
]
],
"normalized": []
},
{
"id": "12650833_T33",
"type": "GENE-N",
"text": [
"PP1"
],
"offsets": [
[
1093,
1096
]
],
"normalized": []
},
{
"id": "12650833_T34",
"type": "GENE-N",
"text": [
"serine/threonine protein phosphatase"
],
"offsets": [
[
11,
47
]
],
"normalized": []
}
] | [] | [] | [
{
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"type": "INHIBITOR",
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},
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"type": "INHIBITOR",
"arg1_id": "12650833_T20",
"arg2_id": "12650833_T25",
"normalized": []
}
] |
23261677 | 23261677 | [
{
"id": "23261677_title",
"type": "title",
"text": [
"Shikonin induces programmed necrosis-like cell death through the formation of receptor interacting protein 1 and 3 complex."
],
"offsets": [
[
0,
123
]
]
},
{
"id": "23261677_abstract",
"type": "abstract",
"text": [
"An alternative cell demise programmed necrosis has also been proposed when apoptotic machinery is impaired or blocked during tumor necrosis factor alpha (TNFα) stimulation. Shikonin (SKN), an herbal extract from the Chinese plant, has been reported to induce either apoptosis or necrosis depending on cell types or its concentrations. In this presentation, SKN caused cell death of NIH3T3 in a dose-dependent manner. Intriguingly, SKN-mediated cell death was in part protected by necrostatin-1 (Nec-1), a specific inhibitor of programmed necrosis, but not zVAD a pan-caspase inhibitor. SKN directly mediated cell death via receptor interacting protein1 and 3 (RIP1-RIP3) complex formation, which is required for TNFα-mediated programmed necrosis. Additionally, SKN-caused cell death was reversed by a reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) whereas TNFα-mediated necrosis was successfully protected by butylated hydroxyanisole (BHA), implying that ROS may be differentially derived from death inducing agents. Concurrently with the protective effect of the ROS scavenger or Nec-1 on TNFα or SKN, the RIP1-RIP3 complex was significantly affected in the presence of those agents. Here, it is highlighted that SKN as well as TNFα can directly mediate cell death via a pronecrotic complex, but ROS were generated via different routes depending on cell death-inducing agents."
],
"offsets": [
[
124,
1517
]
]
}
] | [
{
"id": "23261677_T1",
"type": "CHEMICAL",
"text": [
"Nec-1"
],
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[
1221,
1226
]
],
"normalized": []
},
{
"id": "23261677_T2",
"type": "CHEMICAL",
"text": [
"SKN"
],
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[
1354,
1357
]
],
"normalized": []
},
{
"id": "23261677_T3",
"type": "CHEMICAL",
"text": [
"Shikonin"
],
"offsets": [
[
297,
305
]
],
"normalized": []
},
{
"id": "23261677_T4",
"type": "CHEMICAL",
"text": [
"SKN"
],
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[
307,
310
]
],
"normalized": []
},
{
"id": "23261677_T5",
"type": "CHEMICAL",
"text": [
"SKN"
],
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481,
484
]
],
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},
{
"id": "23261677_T6",
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"text": [
"SKN"
],
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[
555,
558
]
],
"normalized": []
},
{
"id": "23261677_T7",
"type": "CHEMICAL",
"text": [
"necrostatin-1"
],
"offsets": [
[
604,
617
]
],
"normalized": []
},
{
"id": "23261677_T8",
"type": "CHEMICAL",
"text": [
"Nec-1"
],
"offsets": [
[
619,
624
]
],
"normalized": []
},
{
"id": "23261677_T9",
"type": "CHEMICAL",
"text": [
"SKN"
],
"offsets": [
[
710,
713
]
],
"normalized": []
},
{
"id": "23261677_T10",
"type": "CHEMICAL",
"text": [
"SKN"
],
"offsets": [
[
885,
888
]
],
"normalized": []
},
{
"id": "23261677_T11",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
934,
940
]
],
"normalized": []
},
{
"id": "23261677_T12",
"type": "CHEMICAL",
"text": [
"N-acetylcysteine"
],
"offsets": [
[
965,
981
]
],
"normalized": []
},
{
"id": "23261677_T13",
"type": "CHEMICAL",
"text": [
"NAC"
],
"offsets": [
[
983,
986
]
],
"normalized": []
},
{
"id": "23261677_T14",
"type": "CHEMICAL",
"text": [
"butylated hydroxyanisole"
],
"offsets": [
[
1049,
1073
]
],
"normalized": []
},
{
"id": "23261677_T15",
"type": "CHEMICAL",
"text": [
"BHA"
],
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1075,
1078
]
],
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},
{
"id": "23261677_T16",
"type": "CHEMICAL",
"text": [
"Shikonin"
],
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[
0,
8
]
],
"normalized": []
},
{
"id": "23261677_T17",
"type": "GENE-Y",
"text": [
"TNFα"
],
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[
1230,
1234
]
],
"normalized": []
},
{
"id": "23261677_T18",
"type": "GENE-Y",
"text": [
"RIP1"
],
"offsets": [
[
1247,
1251
]
],
"normalized": []
},
{
"id": "23261677_T19",
"type": "GENE-Y",
"text": [
"RIP3"
],
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[
1252,
1256
]
],
"normalized": []
},
{
"id": "23261677_T20",
"type": "GENE-Y",
"text": [
"TNFα"
],
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[
1369,
1373
]
],
"normalized": []
},
{
"id": "23261677_T21",
"type": "GENE-Y",
"text": [
"tumor necrosis factor alpha"
],
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[
249,
276
]
],
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},
{
"id": "23261677_T22",
"type": "GENE-Y",
"text": [
"TNFα"
],
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[
278,
282
]
],
"normalized": []
},
{
"id": "23261677_T23",
"type": "GENE-N",
"text": [
"caspase"
],
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[
691,
698
]
],
"normalized": []
},
{
"id": "23261677_T24",
"type": "GENE-N",
"text": [
"receptor interacting protein1 and 3"
],
"offsets": [
[
747,
782
]
],
"normalized": []
},
{
"id": "23261677_T25",
"type": "GENE-Y",
"text": [
"RIP1"
],
"offsets": [
[
784,
788
]
],
"normalized": []
},
{
"id": "23261677_T26",
"type": "GENE-Y",
"text": [
"RIP3"
],
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[
789,
793
]
],
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},
{
"id": "23261677_T27",
"type": "GENE-Y",
"text": [
"TNFα"
],
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[
836,
840
]
],
"normalized": []
},
{
"id": "23261677_T28",
"type": "GENE-Y",
"text": [
"TNFα"
],
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[
996,
1000
]
],
"normalized": []
},
{
"id": "23261677_T29",
"type": "GENE-N",
"text": [
"receptor interacting protein 1 and 3"
],
"offsets": [
[
78,
114
]
],
"normalized": []
}
] | [] | [] | [] |
23558600 | 23558600 | [
{
"id": "23558600_title",
"type": "title",
"text": [
"Lixisenatide: first global approval."
],
"offsets": [
[
0,
36
]
]
},
{
"id": "23558600_abstract",
"type": "abstract",
"text": [
"The selective once-daily prandial glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide (Lyxumia(®)) is under development with Sanofi for the treatment of type 2 diabetes mellitus. Lixisenatide belongs to a class of GLP-1 compounds designed to mimic the endogenous hormone GLP-1. Native GLP-1 stimulates insulin secretion in a glucose-dependent manner, as well as suppressing glucagon production and slowing gastric emptying. A once-daily subcutaneous formulation of lixisenatide has been approved in the EU, Iceland, Liechtenstein, Norway and Mexico for the treatment of type 2 diabetes, and is under regulatory review in the USA, Switzerland, Brazil, Canada, Ukraine, South Africa, Japan and Australia. This article summarizes the milestones in the development of lixisenatide, leading to this first approval for use in adults with type 2 diabetes."
],
"offsets": [
[
37,
895
]
]
}
] | [
{
"id": "23558600_T1",
"type": "CHEMICAL",
"text": [
"glucose"
],
"offsets": [
[
372,
379
]
],
"normalized": []
},
{
"id": "23558600_T2",
"type": "GENE-Y",
"text": [
"GLP-1"
],
"offsets": [
[
261,
266
]
],
"normalized": []
},
{
"id": "23558600_T3",
"type": "GENE-Y",
"text": [
"GLP-1"
],
"offsets": [
[
318,
323
]
],
"normalized": []
},
{
"id": "23558600_T4",
"type": "GENE-Y",
"text": [
"GLP-1"
],
"offsets": [
[
332,
337
]
],
"normalized": []
},
{
"id": "23558600_T5",
"type": "GENE-Y",
"text": [
"insulin"
],
"offsets": [
[
349,
356
]
],
"normalized": []
},
{
"id": "23558600_T6",
"type": "GENE-Y",
"text": [
"glucagon-like peptide-1 (GLP-1) receptor"
],
"offsets": [
[
71,
111
]
],
"normalized": []
},
{
"id": "23558600_T7",
"type": "GENE-Y",
"text": [
"glucagon"
],
"offsets": [
[
421,
429
]
],
"normalized": []
}
] | [] | [] | [] |
15078100 | 15078100 | [
{
"id": "15078100_title",
"type": "title",
"text": [
"Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines."
],
"offsets": [
[
0,
96
]
]
},
{
"id": "15078100_abstract",
"type": "abstract",
"text": [
"Quinone oxidoreductase 2 (QR2) purified from human red blood cells was recently shown to be a potential target of the quinoline antimalarial compounds [Graves et al., (2002) Mol. Pharmacol. 62, 1364]. QR2 catalyzes the two-electron reduction of menadione via the oxidation of N-alkylated or N-ribosylated nicotinamides. To investigate the mechanism and consequences of inhibition of QR2 by the quinolines further, we have used steady-state and transient-state kinetics to define the mechanism of QR2. Importantly, we have shown that QR2 when isolated from an overproducing strain of E. coli is kinetically equivalent to the enzyme from the native human red blood cell source. We observe ping-pong kinetics consistent with one substrate/inhibitor binding site that shows selectivity for the oxidation state of the FAD cofactor, suggesting that selective inhibition of the liver versus red blood cell forms of malaria may be possible. The reductant N-methyldihydronicotinamide and the inhibitor primaquine bind exclusively to the oxidized enzyme. In contrast, the inhibitors quinacrine and chloroquine bind exclusively to the reduced enzyme. The quinone substrate menadione, on the other hand, binds nonspecifically to both forms of the enzyme. Single-turnover kinetics of the reductive half-reaction are chemically and kinetically competent and confirm the inhibitor selectivity seen in the steady-state experiments. Our studies shed light on the possible in vivo potency of the quinolines and provide a foundation for future studies aimed at creating more potent QR2 inhibitors and at understanding the physiological significance of QR2."
],
"offsets": [
[
97,
1734
]
]
}
] | [
{
"id": "15078100_T1",
"type": "CHEMICAL",
"text": [
"Quinone"
],
"offsets": [
[
97,
104
]
],
"normalized": []
},
{
"id": "15078100_T2",
"type": "CHEMICAL",
"text": [
"quinacrine"
],
"offsets": [
[
1170,
1180
]
],
"normalized": []
},
{
"id": "15078100_T3",
"type": "CHEMICAL",
"text": [
"chloroquine"
],
"offsets": [
[
1185,
1196
]
],
"normalized": []
},
{
"id": "15078100_T4",
"type": "CHEMICAL",
"text": [
"quinone"
],
"offsets": [
[
1241,
1248
]
],
"normalized": []
},
{
"id": "15078100_T5",
"type": "CHEMICAL",
"text": [
"menadione"
],
"offsets": [
[
1259,
1268
]
],
"normalized": []
},
{
"id": "15078100_T6",
"type": "CHEMICAL",
"text": [
"quinoline"
],
"offsets": [
[
215,
224
]
],
"normalized": []
},
{
"id": "15078100_T7",
"type": "CHEMICAL",
"text": [
"quinolines"
],
"offsets": [
[
1575,
1585
]
],
"normalized": []
},
{
"id": "15078100_T8",
"type": "CHEMICAL",
"text": [
"menadione"
],
"offsets": [
[
342,
351
]
],
"normalized": []
},
{
"id": "15078100_T9",
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"text": [
"N-alkylated"
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373,
384
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"id": "15078100_T10",
"type": "CHEMICAL",
"text": [
"N-ribosylated nicotinamides"
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388,
415
]
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"id": "15078100_T11",
"type": "CHEMICAL",
"text": [
"quinolines"
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491,
501
]
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"id": "15078100_T12",
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"N-methyldihydronicotinamide"
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1044,
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"id": "15078100_T13",
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"primaquine"
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"quinone"
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21,
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85,
95
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"id": "15078100_T16",
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97,
121
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"id": "15078100_T17",
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"QR2"
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1660,
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"QR2"
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1730,
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"QR2"
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298,
301
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123,
126
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480,
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"QR2"
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593,
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"QR2"
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630,
633
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"text": [
"quinone oxidoreductase 2"
],
"offsets": [
[
21,
45
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15078100_0",
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"arg2_id": "15078100_T24",
"normalized": []
},
{
"id": "15078100_1",
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},
{
"id": "15078100_2",
"type": "SUBSTRATE",
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"arg2_id": "15078100_T19",
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},
{
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"arg1_id": "15078100_T10",
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},
{
"id": "15078100_4",
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},
{
"id": "15078100_5",
"type": "INHIBITOR",
"arg1_id": "15078100_T7",
"arg2_id": "15078100_T17",
"normalized": []
}
] |
23473030 | 23473030 | [
{
"id": "23473030_title",
"type": "title",
"text": [
"Iron and diabetes risk."
],
"offsets": [
[
0,
23
]
]
},
{
"id": "23473030_abstract",
"type": "abstract",
"text": [
"Iron overload is a risk factor for diabetes. The link between iron and diabetes was first recognized in pathologic conditions-hereditary hemochromatosis and thalassemia-but high levels of dietary iron also impart diabetes risk. Iron plays a direct and causal role in diabetes pathogenesis mediated both by β cell failure and insulin resistance. Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role. The underlying molecular mechanisms mediating these effects are numerous and incompletely understood but include oxidant stress and modulation of adipokines and intracellular signal transduction pathways."
],
"offsets": [
[
24,
713
]
]
}
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24,
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"iron"
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"text": [
"Iron"
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252,
256
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"id": "23473030_T4",
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"text": [
"Iron"
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369,
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"id": "23473030_T5",
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"text": [
"iron"
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490,
494
]
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"id": "23473030_T6",
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"text": [
"iron"
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86,
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"id": "23473030_T7",
"type": "CHEMICAL",
"text": [
"Iron"
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0,
4
]
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"id": "23473030_T8",
"type": "GENE-Y",
"text": [
"insulin"
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[
349,
356
]
],
"normalized": []
},
{
"id": "23473030_T9",
"type": "GENE-N",
"text": [
"adipokines"
],
"offsets": [
[
655,
665
]
],
"normalized": []
}
] | [] | [] | [] |
17015817 | 17015817 | [
{
"id": "17015817_title",
"type": "title",
"text": [
"Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects."
],
"offsets": [
[
0,
81
]
]
},
{
"id": "17015817_abstract",
"type": "abstract",
"text": [
"CONTEXT: Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for insomnia treatment. Most approved insomnia medications have potential for abuse and cause motor and cognitive impairment. OBJECTIVE: To evaluate the potential for abuse, subjective effects, and motor and cognitive-impairing effects of ramelteon compared with triazolam, a classic benzodiazepine sedative-hypnotic drug. DESIGN: In this double-blind crossover study, each participant received oral doses of ramelteon (16, 80, or 160 mg), triazolam (0.25, 0.5, or 0.75 mg), and placebo during approximately 18 days. All participants received each treatment on different days. Most outcome measures were assessed at 0.5 hours before drug administration and repeatedly up to 24 hours after drug administration. SETTING: Residential research facility. PARTICIPANTS: Fourteen adults with histories of sedative abuse. MAIN OUTCOME MEASURES: Subject-rated measures included items relevant to potential for abuse (eg, drug liking, street value, and pharmacological classification), as well as assessments of a broad range of stimulant and sedative subjective effects. Observer-rated measures included assessments of sedation and impairment. Motor and cognitive performance measures included psychomotor and memory tasks and a standing balance task. RESULTS: Compared with placebo, ramelteon (16, 80, and 160 mg) showed no significant effect on any of the subjective effect measures, including those related to potential for abuse. In the pharmacological classification, 79% (11/14) of subjects identified the highest dose of ramelteon as placebo. Similarly, compared with placebo, ramelteon had no effect at any dose on any observer-rated or motor and cognitive performance measure. In contrast, triazolam showed dose-related effects on a wide range of subject-rated, observer-rated, and motor and cognitive performance measures, consistent with its profile as a sedative drug with abuse liability. CONCLUSION: Ramelteon demonstrated no significant effects indicative of potential for abuse or motor and cognitive impairment at up to 20 times the recommended therapeutic dose and may represent a useful alternative to existing insomnia medications."
],
"offsets": [
[
82,
2321
]
]
}
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]
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"ramelteon"
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1698,
1707
]
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"ramelteon"
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1754,
1763
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"id": "17015817_T4",
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"triazolam"
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1869,
1878
]
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"id": "17015817_T5",
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"Ramelteon"
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2084,
2093
]
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"id": "17015817_T6",
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"ramelteon"
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418,
427
]
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"id": "17015817_T7",
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"triazolam"
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442,
451
]
],
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},
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"id": "17015817_T8",
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"benzodiazepine"
],
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[
463,
477
]
],
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},
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"id": "17015817_T9",
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"ramelteon"
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588,
597
]
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},
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"id": "17015817_T10",
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"text": [
"triazolam"
],
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619,
628
]
],
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},
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"id": "17015817_T11",
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"text": [
"Ramelteon"
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91,
100
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"id": "17015817_T12",
"type": "CHEMICAL",
"text": [
"Ramelteon"
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0,
9
]
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},
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"id": "17015817_T13",
"type": "GENE-Y",
"text": [
"MT1"
],
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[
112,
115
]
],
"normalized": []
},
{
"id": "17015817_T14",
"type": "GENE-Y",
"text": [
"MT2 melatonin receptor"
],
"offsets": [
[
120,
142
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "17015817_0",
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"arg2_id": "17015817_T13",
"normalized": []
},
{
"id": "17015817_1",
"type": "AGONIST",
"arg1_id": "17015817_T11",
"arg2_id": "17015817_T14",
"normalized": []
}
] |
22830954 | 22830954 | [
{
"id": "22830954_title",
"type": "title",
"text": [
"Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism."
],
"offsets": [
[
0,
150
]
]
},
{
"id": "22830954_abstract",
"type": "abstract",
"text": [
"Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established."
],
"offsets": [
[
151,
1494
]
]
}
] | [
{
"id": "22830954_T1",
"type": "CHEMICAL",
"text": [
"sibutramine"
],
"offsets": [
[
1213,
1224
]
],
"normalized": []
},
{
"id": "22830954_T2",
"type": "CHEMICAL",
"text": [
"clarithromycin"
],
"offsets": [
[
1230,
1244
]
],
"normalized": []
},
{
"id": "22830954_T3",
"type": "CHEMICAL",
"text": [
"sibutramine"
],
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[
1277,
1288
]
],
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},
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"id": "22830954_T4",
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"text": [
"sibutramine"
],
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[
1405,
1416
]
],
"normalized": []
},
{
"id": "22830954_T5",
"type": "CHEMICAL",
"text": [
"sibutramine"
],
"offsets": [
[
176,
187
]
],
"normalized": []
},
{
"id": "22830954_T6",
"type": "CHEMICAL",
"text": [
"clopidogrel"
],
"offsets": [
[
418,
429
]
],
"normalized": []
},
{
"id": "22830954_T7",
"type": "CHEMICAL",
"text": [
"clarithromycin"
],
"offsets": [
[
433,
447
]
],
"normalized": []
},
{
"id": "22830954_T8",
"type": "CHEMICAL",
"text": [
"clopidogrel"
],
"offsets": [
[
471,
482
]
],
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},
{
"id": "22830954_T9",
"type": "CHEMICAL",
"text": [
"clarithromycin"
],
"offsets": [
[
487,
501
]
],
"normalized": []
},
{
"id": "22830954_T10",
"type": "CHEMICAL",
"text": [
"sibutramine"
],
"offsets": [
[
567,
578
]
],
"normalized": []
},
{
"id": "22830954_T11",
"type": "CHEMICAL",
"text": [
"clarithromycin"
],
"offsets": [
[
632,
646
]
],
"normalized": []
},
{
"id": "22830954_T12",
"type": "CHEMICAL",
"text": [
"sibutramine"
],
"offsets": [
[
716,
727
]
],
"normalized": []
},
{
"id": "22830954_T13",
"type": "CHEMICAL",
"text": [
"clopidogrel"
],
"offsets": [
[
782,
793
]
],
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},
{
"id": "22830954_T14",
"type": "CHEMICAL",
"text": [
"clarithromycin"
],
"offsets": [
[
834,
848
]
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},
{
"id": "22830954_T15",
"type": "CHEMICAL",
"text": [
"clopidogrel"
],
"offsets": [
[
901,
912
]
],
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},
{
"id": "22830954_T16",
"type": "CHEMICAL",
"text": [
"sibutramine"
],
"offsets": [
[
1031,
1042
]
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"normalized": []
},
{
"id": "22830954_T17",
"type": "CHEMICAL",
"text": [
"sibutramine"
],
"offsets": [
[
245,
256
]
],
"normalized": []
},
{
"id": "22830954_T18",
"type": "CHEMICAL",
"text": [
"clopidogrel"
],
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[
1130,
1141
]
],
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},
{
"id": "22830954_T19",
"type": "CHEMICAL",
"text": [
"clopidogrel"
],
"offsets": [
[
11,
22
]
],
"normalized": []
},
{
"id": "22830954_T20",
"type": "CHEMICAL",
"text": [
"clarithromycin"
],
"offsets": [
[
27,
41
]
],
"normalized": []
},
{
"id": "22830954_T21",
"type": "CHEMICAL",
"text": [
"sibutramine"
],
"offsets": [
[
64,
75
]
],
"normalized": []
},
{
"id": "22830954_T22",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
1337,
1343
]
],
"normalized": []
},
{
"id": "22830954_T23",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
320,
326
]
],
"normalized": []
},
{
"id": "22830954_T24",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
338,
344
]
],
"normalized": []
},
{
"id": "22830954_T25",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
662,
668
]
],
"normalized": []
},
{
"id": "22830954_T26",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
852,
858
]
],
"normalized": []
},
{
"id": "22830954_T27",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
873,
879
]
],
"normalized": []
},
{
"id": "22830954_T28",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
1096,
1102
]
],
"normalized": []
},
{
"id": "22830954_T29",
"type": "GENE-Y",
"text": [
"CYP2B6"
],
"offsets": [
[
128,
134
]
],
"normalized": []
}
] | [] | [] | [] |
23238103 | 23238103 | [
{
"id": "23238103_title",
"type": "title",
"text": [
"Age dependent differences in the regulation of hippocampal steroid hormones and receptor genes: relations to motivation and cognition in male rats."
],
"offsets": [
[
0,
147
]
]
},
{
"id": "23238103_abstract",
"type": "abstract",
"text": [
"Estrogen and estrogenic functions are age-dependently involved in the modulation of learning, memory and mood in female humans and animals. However, the investigation of estrogenic effects in males has been largely neglected. Therefore, we investigated the hippocampal gene expression of estrogen receptors α and β (ERα, β) in 8-week-old, 12-week-old and 24-week-old male rats. To control for possible interactions between the expression of the estrogen receptor genes and other learning-related steroid receptors, androgen receptors (AR), corticosterone-binding glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) were also measured. Furthermore, the concentrations of the ligands 17β-estradiol, testosterone and corticosterone were measured. The spatial training was conducted in a hole-board. The 8-week-old rats exhibited higher levels of general activity and exploration during the training and performed best with respect to spatial learning and memory, whereas no difference was found between the 12-week-old and 24-week-old rats. The trained 8-week-old rats exhibited increased gene expression of ERα compared with the untrained rats in this age group as well as the trained 12-week-old and 24-week-old rats. The concentrations of estradiol and testosterone, however, were generally higher in the 24-week-old rats than in the 8-week-old and 12-week-old rats. The ERα mRNA concentrations correlated positively with behavior that indicate general learning motivation. These results suggest a specific role of ERα in the age-related differences in motivation and subsequent success in the task. Thus, estrogen and estrogenic functions may play a more prominent role in young male behavior and development than has been previously assumed."
],
"offsets": [
[
148,
1906
]
]
}
] | [
{
"id": "23238103_T1",
"type": "CHEMICAL",
"text": [
"Estrogen"
],
"offsets": [
[
148,
156
]
],
"normalized": []
},
{
"id": "23238103_T2",
"type": "CHEMICAL",
"text": [
"estradiol"
],
"offsets": [
[
1402,
1411
]
],
"normalized": []
},
{
"id": "23238103_T3",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
1416,
1428
]
],
"normalized": []
},
{
"id": "23238103_T4",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
1769,
1777
]
],
"normalized": []
},
{
"id": "23238103_T5",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
436,
444
]
],
"normalized": []
},
{
"id": "23238103_T6",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
593,
601
]
],
"normalized": []
},
{
"id": "23238103_T7",
"type": "CHEMICAL",
"text": [
"steroid"
],
"offsets": [
[
644,
651
]
],
"normalized": []
},
{
"id": "23238103_T8",
"type": "CHEMICAL",
"text": [
"androgen"
],
"offsets": [
[
663,
671
]
],
"normalized": []
},
{
"id": "23238103_T9",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
"offsets": [
[
688,
702
]
],
"normalized": []
},
{
"id": "23238103_T10",
"type": "CHEMICAL",
"text": [
"17β-estradiol"
],
"offsets": [
[
845,
858
]
],
"normalized": []
},
{
"id": "23238103_T11",
"type": "CHEMICAL",
"text": [
"testosterone"
],
"offsets": [
[
860,
872
]
],
"normalized": []
},
{
"id": "23238103_T12",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
"offsets": [
[
877,
891
]
],
"normalized": []
},
{
"id": "23238103_T13",
"type": "CHEMICAL",
"text": [
"steroid"
],
"offsets": [
[
59,
66
]
],
"normalized": []
},
{
"id": "23238103_T14",
"type": "GENE-Y",
"text": [
"ERα"
],
"offsets": [
[
1268,
1271
]
],
"normalized": []
},
{
"id": "23238103_T15",
"type": "GENE-Y",
"text": [
"ERα"
],
"offsets": [
[
1534,
1537
]
],
"normalized": []
},
{
"id": "23238103_T16",
"type": "GENE-Y",
"text": [
"ERα"
],
"offsets": [
[
1678,
1681
]
],
"normalized": []
},
{
"id": "23238103_T17",
"type": "GENE-N",
"text": [
"estrogen receptors α and β"
],
"offsets": [
[
436,
462
]
],
"normalized": []
},
{
"id": "23238103_T18",
"type": "GENE-N",
"text": [
"ERα, β"
],
"offsets": [
[
464,
470
]
],
"normalized": []
},
{
"id": "23238103_T19",
"type": "GENE-Y",
"text": [
"estrogen receptor"
],
"offsets": [
[
593,
610
]
],
"normalized": []
},
{
"id": "23238103_T20",
"type": "GENE-N",
"text": [
"steroid receptors"
],
"offsets": [
[
644,
661
]
],
"normalized": []
},
{
"id": "23238103_T21",
"type": "GENE-Y",
"text": [
"androgen receptors"
],
"offsets": [
[
663,
681
]
],
"normalized": []
},
{
"id": "23238103_T22",
"type": "GENE-Y",
"text": [
"AR"
],
"offsets": [
[
683,
685
]
],
"normalized": []
},
{
"id": "23238103_T23",
"type": "GENE-Y",
"text": [
"glucocorticoid receptors"
],
"offsets": [
[
711,
735
]
],
"normalized": []
},
{
"id": "23238103_T24",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
737,
739
]
],
"normalized": []
},
{
"id": "23238103_T25",
"type": "GENE-Y",
"text": [
"mineralocorticoid receptors"
],
"offsets": [
[
745,
772
]
],
"normalized": []
},
{
"id": "23238103_T26",
"type": "GENE-Y",
"text": [
"MR"
],
"offsets": [
[
774,
776
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23238103_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "23238103_T9",
"arg2_id": "23238103_T23",
"normalized": []
},
{
"id": "23238103_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "23238103_T9",
"arg2_id": "23238103_T24",
"normalized": []
},
{
"id": "23238103_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "23238103_T9",
"arg2_id": "23238103_T25",
"normalized": []
},
{
"id": "23238103_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "23238103_T9",
"arg2_id": "23238103_T26",
"normalized": []
}
] |
11689471 | 11689471 | [
{
"id": "11689471_title",
"type": "title",
"text": [
"Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts."
],
"offsets": [
[
0,
133
]
]
},
{
"id": "11689471_abstract",
"type": "abstract",
"text": [
"Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. Aspirin and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa salicylate binding protein with sequence identity to immunoglobulin heavy chain binding protein (BiP). The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively. BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. Salicylates inhibited ATPase activity stimulated by this specific heptapeptide but did not block ATP binding or induce BiP expression. These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation."
],
"offsets": [
[
134,
1439
]
]
}
] | [
{
"id": "11689471_T1",
"type": "CHEMICAL",
"text": [
"Salicylic acid"
],
"offsets": [
[
134,
148
]
],
"normalized": []
},
{
"id": "11689471_T2",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
1205,
1208
]
],
"normalized": []
},
{
"id": "11689471_T3",
"type": "CHEMICAL",
"text": [
"salicylates"
],
"offsets": [
[
1271,
1282
]
],
"normalized": []
},
{
"id": "11689471_T4",
"type": "CHEMICAL",
"text": [
"SA"
],
"offsets": [
[
150,
152
]
],
"normalized": []
},
{
"id": "11689471_T5",
"type": "CHEMICAL",
"text": [
"Aspirin"
],
"offsets": [
[
354,
361
]
],
"normalized": []
},
{
"id": "11689471_T6",
"type": "CHEMICAL",
"text": [
"sodium salicylate"
],
"offsets": [
[
366,
383
]
],
"normalized": []
},
{
"id": "11689471_T7",
"type": "CHEMICAL",
"text": [
"salicylates"
],
"offsets": [
[
385,
396
]
],
"normalized": []
},
{
"id": "11689471_T8",
"type": "CHEMICAL",
"text": [
"SA"
],
"offsets": [
[
744,
746
]
],
"normalized": []
},
{
"id": "11689471_T9",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
951,
954
]
],
"normalized": []
},
{
"id": "11689471_T10",
"type": "CHEMICAL",
"text": [
"SA"
],
"offsets": [
[
1021,
1023
]
],
"normalized": []
},
{
"id": "11689471_T11",
"type": "CHEMICAL",
"text": [
"Salicylates"
],
"offsets": [
[
1108,
1119
]
],
"normalized": []
},
{
"id": "11689471_T12",
"type": "CHEMICAL",
"text": [
"Aspirin"
],
"offsets": [
[
0,
7
]
],
"normalized": []
},
{
"id": "11689471_T13",
"type": "CHEMICAL",
"text": [
"salicylate"
],
"offsets": [
[
12,
22
]
],
"normalized": []
},
{
"id": "11689471_T14",
"type": "GENE-Y",
"text": [
"BiP"
],
"offsets": [
[
1227,
1230
]
],
"normalized": []
},
{
"id": "11689471_T15",
"type": "GENE-Y",
"text": [
"BiP"
],
"offsets": [
[
1336,
1339
]
],
"normalized": []
},
{
"id": "11689471_T16",
"type": "GENE-N",
"text": [
"salicylate binding protein"
],
"offsets": [
[
624,
650
]
],
"normalized": []
},
{
"id": "11689471_T17",
"type": "GENE-Y",
"text": [
"immunoglobulin heavy chain binding protein"
],
"offsets": [
[
677,
719
]
],
"normalized": []
},
{
"id": "11689471_T18",
"type": "GENE-Y",
"text": [
"BiP"
],
"offsets": [
[
721,
724
]
],
"normalized": []
},
{
"id": "11689471_T19",
"type": "GENE-Y",
"text": [
"BiP"
],
"offsets": [
[
791,
794
]
],
"normalized": []
},
{
"id": "11689471_T20",
"type": "GENE-Y",
"text": [
"BiP"
],
"offsets": [
[
836,
839
]
],
"normalized": []
},
{
"id": "11689471_T21",
"type": "GENE-N",
"text": [
"chaperone protein"
],
"offsets": [
[
845,
862
]
],
"normalized": []
},
{
"id": "11689471_T22",
"type": "GENE-N",
"text": [
"heptapeptide sequence"
],
"offsets": [
[
922,
943
]
],
"normalized": []
},
{
"id": "11689471_T23",
"type": "GENE-N",
"text": [
"ATP binding site"
],
"offsets": [
[
951,
967
]
],
"normalized": []
},
{
"id": "11689471_T24",
"type": "GENE-N",
"text": [
"ATPase"
],
"offsets": [
[
1130,
1136
]
],
"normalized": []
},
{
"id": "11689471_T25",
"type": "GENE-Y",
"text": [
"immunoglobulin heavy chain binding protein"
],
"offsets": [
[
31,
73
]
],
"normalized": []
},
{
"id": "11689471_T26",
"type": "GENE-Y",
"text": [
"BiP"
],
"offsets": [
[
75,
78
]
],
"normalized": []
},
{
"id": "11689471_T27",
"type": "GENE-N",
"text": [
"ATPase"
],
"offsets": [
[
96,
102
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11689471_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "11689471_T12",
"arg2_id": "11689471_T25",
"normalized": []
},
{
"id": "11689471_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "11689471_T13",
"arg2_id": "11689471_T25",
"normalized": []
},
{
"id": "11689471_2",
"type": "INHIBITOR",
"arg1_id": "11689471_T12",
"arg2_id": "11689471_T27",
"normalized": []
},
{
"id": "11689471_3",
"type": "INHIBITOR",
"arg1_id": "11689471_T13",
"arg2_id": "11689471_T27",
"normalized": []
},
{
"id": "11689471_4",
"type": "DIRECT-REGULATOR",
"arg1_id": "11689471_T8",
"arg2_id": "11689471_T19",
"normalized": []
},
{
"id": "11689471_5",
"type": "INHIBITOR",
"arg1_id": "11689471_T11",
"arg2_id": "11689471_T24",
"normalized": []
},
{
"id": "11689471_6",
"type": "DIRECT-REGULATOR",
"arg1_id": "11689471_T3",
"arg2_id": "11689471_T15",
"normalized": []
},
{
"id": "11689471_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "11689471_T2",
"arg2_id": "11689471_T24",
"normalized": []
}
] |
17550897 | 17550897 | [
{
"id": "17550897_title",
"type": "title",
"text": [
"The calponin homology domain of Vav1 associates with calmodulin and is prerequisite to T cell antigen receptor-induced calcium release in Jurkat T lymphocytes."
],
"offsets": [
[
0,
159
]
]
},
{
"id": "17550897_abstract",
"type": "abstract",
"text": [
"Vav1 is a guanine nucleotide exchange factor that is expressed specifically in hematopoietic cells and plays important roles in T cell development and activation. Vav1 consists of multiple structural domains so as to facilitate both its guanine nucleotide exchange activity and scaffold function following T cell antigen receptor (TCR) engagement. Previous studies demonstrated that the calponin homology (CH) domain of Vav1 is required for TCR-stimulated calcium mobilization and thus downstream activation of nuclear factor of activated T cells. However, it remained obscure how Vav1 functions in regulating calcium flux. In an effort to explore molecules interacting with Vav1, we found that calmodulin bound to Vav1 in a calcium-dependent and TCR activation-independent manner. The binding site was mapped to the CH domain of Vav1. Reconstitution of vav1-null Jurkat T cells (J.Vav1) with CH-deleted Vav1 exhibited a severe deficiency in calcium release to the same extent as that of Jurkat cells treated with the calmodulin inhibitor or J.Vav1 cells. The defect persisted even when phospholipase-Cgamma1 was fully activated, indicating a prerequisite role of Vav1 CH domain in calcium signaling. The results suggest that Vav1 and calmodulin function cooperatively to potentiate TCR-induced calcium release. This study unveiled a mechanism by which the Vav1 CH domain is involved in calcium signaling and provides insight into our understanding of the role of Vav1 in T cell activation."
],
"offsets": [
[
160,
1650
]
]
}
] | [
{
"id": "17550897_T1",
"type": "CHEMICAL",
"text": [
"guanine nucleotide"
],
"offsets": [
[
170,
188
]
],
"normalized": []
},
{
"id": "17550897_T2",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
1342,
1349
]
],
"normalized": []
},
{
"id": "17550897_T3",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
1455,
1462
]
],
"normalized": []
},
{
"id": "17550897_T4",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
1547,
1554
]
],
"normalized": []
},
{
"id": "17550897_T5",
"type": "CHEMICAL",
"text": [
"guanine nucleotide"
],
"offsets": [
[
397,
415
]
],
"normalized": []
},
{
"id": "17550897_T6",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
616,
623
]
],
"normalized": []
},
{
"id": "17550897_T7",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
770,
777
]
],
"normalized": []
},
{
"id": "17550897_T8",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
885,
892
]
],
"normalized": []
},
{
"id": "17550897_T9",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
1102,
1109
]
],
"normalized": []
},
{
"id": "17550897_T10",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
119,
126
]
],
"normalized": []
},
{
"id": "17550897_T11",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
160,
164
]
],
"normalized": []
},
{
"id": "17550897_T12",
"type": "GENE-Y",
"text": [
"calmodulin"
],
"offsets": [
[
1178,
1188
]
],
"normalized": []
},
{
"id": "17550897_T13",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
1204,
1208
]
],
"normalized": []
},
{
"id": "17550897_T14",
"type": "GENE-N",
"text": [
"guanine nucleotide exchange factor"
],
"offsets": [
[
170,
204
]
],
"normalized": []
},
{
"id": "17550897_T15",
"type": "GENE-Y",
"text": [
"phospholipase-Cgamma1"
],
"offsets": [
[
1247,
1268
]
],
"normalized": []
},
{
"id": "17550897_T16",
"type": "GENE-N",
"text": [
"Vav1 CH domain"
],
"offsets": [
[
1324,
1338
]
],
"normalized": []
},
{
"id": "17550897_T17",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
1386,
1390
]
],
"normalized": []
},
{
"id": "17550897_T18",
"type": "GENE-Y",
"text": [
"calmodulin"
],
"offsets": [
[
1395,
1405
]
],
"normalized": []
},
{
"id": "17550897_T19",
"type": "GENE-N",
"text": [
"TCR"
],
"offsets": [
[
1443,
1446
]
],
"normalized": []
},
{
"id": "17550897_T20",
"type": "GENE-N",
"text": [
"Vav1 CH domain"
],
"offsets": [
[
1517,
1531
]
],
"normalized": []
},
{
"id": "17550897_T21",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
1624,
1628
]
],
"normalized": []
},
{
"id": "17550897_T22",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
323,
327
]
],
"normalized": []
},
{
"id": "17550897_T23",
"type": "GENE-N",
"text": [
"T cell antigen receptor"
],
"offsets": [
[
466,
489
]
],
"normalized": []
},
{
"id": "17550897_T24",
"type": "GENE-N",
"text": [
"TCR"
],
"offsets": [
[
491,
494
]
],
"normalized": []
},
{
"id": "17550897_T25",
"type": "GENE-N",
"text": [
"calponin homology (CH) domain"
],
"offsets": [
[
547,
576
]
],
"normalized": []
},
{
"id": "17550897_T26",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
580,
584
]
],
"normalized": []
},
{
"id": "17550897_T27",
"type": "GENE-Y",
"text": [
"TCR"
],
"offsets": [
[
601,
604
]
],
"normalized": []
},
{
"id": "17550897_T28",
"type": "GENE-N",
"text": [
"nuclear factor of activated T cells"
],
"offsets": [
[
671,
706
]
],
"normalized": []
},
{
"id": "17550897_T29",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
741,
745
]
],
"normalized": []
},
{
"id": "17550897_T30",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
835,
839
]
],
"normalized": []
},
{
"id": "17550897_T31",
"type": "GENE-Y",
"text": [
"calmodulin"
],
"offsets": [
[
855,
865
]
],
"normalized": []
},
{
"id": "17550897_T32",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
875,
879
]
],
"normalized": []
},
{
"id": "17550897_T33",
"type": "GENE-N",
"text": [
"TCR"
],
"offsets": [
[
907,
910
]
],
"normalized": []
},
{
"id": "17550897_T34",
"type": "GENE-N",
"text": [
"CH domain"
],
"offsets": [
[
977,
986
]
],
"normalized": []
},
{
"id": "17550897_T35",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
990,
994
]
],
"normalized": []
},
{
"id": "17550897_T36",
"type": "GENE-Y",
"text": [
"vav1"
],
"offsets": [
[
1014,
1018
]
],
"normalized": []
},
{
"id": "17550897_T37",
"type": "GENE-Y",
"text": [
"Vav1"
],
"offsets": [
[
1042,
1046
]
],
"normalized": []
},
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"CH"
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"Vav1"
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32,
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"calponin homology domain"
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"calmodulin"
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53,
63
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"id": "17550897_T43",
"type": "GENE-N",
"text": [
"T cell antigen receptor"
],
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[
87,
110
]
],
"normalized": []
}
] | [] | [] | [] |
23296101 | 23296101 | [
{
"id": "23296101_title",
"type": "title",
"text": [
"Lack of transient receptor potential melastatin 8 activation by phthalate esters that enhance contact hypersensitivity in mice."
],
"offsets": [
[
0,
127
]
]
},
{
"id": "23296101_abstract",
"type": "abstract",
"text": [
"We studied the involvement of sensory neurons in skin sensitization to allergens using a mouse model in which the T-helper type 2 response is essential. Skin sensitization to fluorescein isothiocyanate (FITC) has been shown to be enhanced by several phthalate esters, including dibutyl phthalate (DBP). For different types of phthalate esters, we found a correlation between the ability of transient receptor potential (TRP) A1 activation and that of enhancing skin sensitization. A TRPA1-specific antagonist, HC-030031, was shown to suppress skin sensitization in the presence of DBP. However, since phthalate esters also activate TRPV1, phthalate esters could activate other types of TRP channels non-selectively. Furthermore, sensitization to FITC is also enhanced by menthol, which activates TRPA1 and TRPM8. Here we established an in vitro system for measuring TRPM8 activation. The selectivity for TRPM8 was established by the fact that two TRPM8 agonists (menthol and icilin) induced calcium mobilization, whereas agonists of TRPA1 and TRPV1 did not. We demonstrated that phthalate esters do not activate TRPM8. TRPA1-antagonist HC-030031 did not inhibit TRPM8 activation induced by menthol or icilin. These results show that phthalate esters activate TRPA1 and TRPV1 with selectivity. TRPM8 activation is not likely to be involved in the sensitization to FITC."
],
"offsets": [
[
128,
1496
]
]
}
] | [
{
"id": "23296101_T1",
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"phthalate esters"
],
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[
1207,
1223
]
],
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},
{
"id": "23296101_T2",
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"text": [
"HC-030031"
],
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[
1264,
1273
]
],
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},
{
"id": "23296101_T3",
"type": "CHEMICAL",
"text": [
"menthol"
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1318,
1325
]
],
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},
{
"id": "23296101_T4",
"type": "CHEMICAL",
"text": [
"icilin"
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1329,
1335
]
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{
"id": "23296101_T5",
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"phthalate esters"
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[
1361,
1377
]
],
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},
{
"id": "23296101_T6",
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"text": [
"FITC"
],
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1491,
1495
]
],
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},
{
"id": "23296101_T7",
"type": "CHEMICAL",
"text": [
"fluorescein isothiocyanate"
],
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[
303,
329
]
],
"normalized": []
},
{
"id": "23296101_T8",
"type": "CHEMICAL",
"text": [
"FITC"
],
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[
331,
335
]
],
"normalized": []
},
{
"id": "23296101_T9",
"type": "CHEMICAL",
"text": [
"phthalate esters"
],
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[
378,
394
]
],
"normalized": []
},
{
"id": "23296101_T10",
"type": "CHEMICAL",
"text": [
"dibutyl phthalate"
],
"offsets": [
[
406,
423
]
],
"normalized": []
},
{
"id": "23296101_T11",
"type": "CHEMICAL",
"text": [
"DBP"
],
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[
425,
428
]
],
"normalized": []
},
{
"id": "23296101_T12",
"type": "CHEMICAL",
"text": [
"phthalate esters"
],
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[
454,
470
]
],
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},
{
"id": "23296101_T13",
"type": "CHEMICAL",
"text": [
"HC-030031"
],
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[
638,
647
]
],
"normalized": []
},
{
"id": "23296101_T14",
"type": "CHEMICAL",
"text": [
"DBP"
],
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[
709,
712
]
],
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},
{
"id": "23296101_T15",
"type": "CHEMICAL",
"text": [
"phthalate esters"
],
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[
729,
745
]
],
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},
{
"id": "23296101_T16",
"type": "CHEMICAL",
"text": [
"phthalate esters"
],
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[
767,
783
]
],
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},
{
"id": "23296101_T17",
"type": "CHEMICAL",
"text": [
"FITC"
],
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[
874,
878
]
],
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},
{
"id": "23296101_T18",
"type": "CHEMICAL",
"text": [
"menthol"
],
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[
899,
906
]
],
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},
{
"id": "23296101_T19",
"type": "CHEMICAL",
"text": [
"menthol"
],
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[
1091,
1098
]
],
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},
{
"id": "23296101_T20",
"type": "CHEMICAL",
"text": [
"icilin"
],
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[
1103,
1109
]
],
"normalized": []
},
{
"id": "23296101_T21",
"type": "CHEMICAL",
"text": [
"calcium"
],
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[
1119,
1126
]
],
"normalized": []
},
{
"id": "23296101_T22",
"type": "CHEMICAL",
"text": [
"phthalate esters"
],
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[
64,
80
]
],
"normalized": []
},
{
"id": "23296101_T23",
"type": "GENE-Y",
"text": [
"TRPA1"
],
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[
1161,
1166
]
],
"normalized": []
},
{
"id": "23296101_T24",
"type": "GENE-Y",
"text": [
"TRPV1"
],
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[
1171,
1176
]
],
"normalized": []
},
{
"id": "23296101_T25",
"type": "GENE-Y",
"text": [
"TRPM8"
],
"offsets": [
[
1240,
1245
]
],
"normalized": []
},
{
"id": "23296101_T26",
"type": "GENE-Y",
"text": [
"TRPA1"
],
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1247,
1252
]
],
"normalized": []
},
{
"id": "23296101_T27",
"type": "GENE-Y",
"text": [
"TRPM8"
],
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[
1290,
1295
]
],
"normalized": []
},
{
"id": "23296101_T28",
"type": "GENE-Y",
"text": [
"TRPA1"
],
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[
1387,
1392
]
],
"normalized": []
},
{
"id": "23296101_T29",
"type": "GENE-Y",
"text": [
"TRPV1"
],
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[
1397,
1402
]
],
"normalized": []
},
{
"id": "23296101_T30",
"type": "GENE-Y",
"text": [
"TRPM8"
],
"offsets": [
[
1421,
1426
]
],
"normalized": []
},
{
"id": "23296101_T31",
"type": "GENE-Y",
"text": [
"transient receptor potential (TRP) A1"
],
"offsets": [
[
518,
555
]
],
"normalized": []
},
{
"id": "23296101_T32",
"type": "GENE-Y",
"text": [
"TRPA1"
],
"offsets": [
[
611,
616
]
],
"normalized": []
},
{
"id": "23296101_T33",
"type": "GENE-Y",
"text": [
"TRPV1"
],
"offsets": [
[
760,
765
]
],
"normalized": []
},
{
"id": "23296101_T34",
"type": "GENE-N",
"text": [
"TRP channels"
],
"offsets": [
[
814,
826
]
],
"normalized": []
},
{
"id": "23296101_T35",
"type": "GENE-Y",
"text": [
"TRPA1"
],
"offsets": [
[
924,
929
]
],
"normalized": []
},
{
"id": "23296101_T36",
"type": "GENE-Y",
"text": [
"TRPM8"
],
"offsets": [
[
934,
939
]
],
"normalized": []
},
{
"id": "23296101_T37",
"type": "GENE-Y",
"text": [
"TRPM8"
],
"offsets": [
[
994,
999
]
],
"normalized": []
},
{
"id": "23296101_T38",
"type": "GENE-Y",
"text": [
"TRPM8"
],
"offsets": [
[
1032,
1037
]
],
"normalized": []
},
{
"id": "23296101_T39",
"type": "GENE-Y",
"text": [
"TRPM8"
],
"offsets": [
[
1075,
1080
]
],
"normalized": []
},
{
"id": "23296101_T40",
"type": "GENE-Y",
"text": [
"transient receptor potential melastatin 8"
],
"offsets": [
[
8,
49
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23296101_0",
"type": "ANTAGONIST",
"arg1_id": "23296101_T13",
"arg2_id": "23296101_T32",
"normalized": []
},
{
"id": "23296101_1",
"type": "ACTIVATOR",
"arg1_id": "23296101_T15",
"arg2_id": "23296101_T33",
"normalized": []
},
{
"id": "23296101_2",
"type": "ACTIVATOR",
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"arg2_id": "23296101_T34",
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},
{
"id": "23296101_3",
"type": "ACTIVATOR",
"arg1_id": "23296101_T17",
"arg2_id": "23296101_T35",
"normalized": []
},
{
"id": "23296101_4",
"type": "ACTIVATOR",
"arg1_id": "23296101_T17",
"arg2_id": "23296101_T36",
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},
{
"id": "23296101_5",
"type": "ACTIVATOR",
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"arg2_id": "23296101_T35",
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},
{
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"type": "ACTIVATOR",
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"arg2_id": "23296101_T36",
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},
{
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"type": "AGONIST",
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"arg2_id": "23296101_T39",
"normalized": []
},
{
"id": "23296101_8",
"type": "AGONIST",
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"arg2_id": "23296101_T39",
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},
{
"id": "23296101_9",
"type": "ACTIVATOR",
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"arg2_id": "23296101_T31",
"normalized": []
},
{
"id": "23296101_10",
"type": "ANTAGONIST",
"arg1_id": "23296101_T2",
"arg2_id": "23296101_T26",
"normalized": []
},
{
"id": "23296101_11",
"type": "ACTIVATOR",
"arg1_id": "23296101_T3",
"arg2_id": "23296101_T27",
"normalized": []
},
{
"id": "23296101_12",
"type": "ACTIVATOR",
"arg1_id": "23296101_T4",
"arg2_id": "23296101_T27",
"normalized": []
},
{
"id": "23296101_13",
"type": "ACTIVATOR",
"arg1_id": "23296101_T5",
"arg2_id": "23296101_T28",
"normalized": []
},
{
"id": "23296101_14",
"type": "ACTIVATOR",
"arg1_id": "23296101_T5",
"arg2_id": "23296101_T29",
"normalized": []
},
{
"id": "23296101_15",
"type": "ACTIVATOR",
"arg1_id": "23296101_T6",
"arg2_id": "23296101_T30",
"normalized": []
}
] |
23396090 | 23396090 | [
{
"id": "23396090_title",
"type": "title",
"text": [
"Overcoming chemotherapy resistance of ovarian cancer cells by liposomal cisplatin: molecular mechanisms unveiled by gene expression profiling."
],
"offsets": [
[
0,
142
]
]
},
{
"id": "23396090_abstract",
"type": "abstract",
"text": [
"Previously we reported that liposomal cisplatin (CDDP) overcomes CDDP resistance of ovarian A2780cis cancer cells (Krieger et al., Int. J. Pharm. 389, 2010, 10-17). Here we find that the cytotoxic activity of liposomal CDDP is not associated with detectable DNA platination in resistant ovarian cancer cells. This suggests that the mode of action of liposomal CDDP is different from the free drug. To gain insight into mechanisms of liposomal CDDP activity, we performed a transcriptome analysis of untreated A2780cis cells, and A2780cis cells in response to exposure with IC50 values of free or liposomal CDDP. A process network analysis of upregulated genes showed that liposomal CDDP induced a highly different gene expression profile in comparison to the free drug. p53 was identified as a key player directing transcriptional responses to free or liposomal CDDP. The free drug induced expression of essential genes of the intrinsic (mitochondrial) apoptosis pathway (BAX, BID, CASP9) most likely through p38MAPK activation. In contrast, liposomal CDDP induced expression of genes from DNA damage pathways and several genes of the extrinsic pathway of apoptosis (TNFRSF10B-DR5, CD70-TNFSF7). It thus appears that liposomal CDDP overcomes CDDP resistance by inducing DNA damage and in consequence programmed cell death by the extrinsic pathway. Predictions from gene expression data with respect to apoptosis activation were confirmed at the protein level by an apoptosis antibody array. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal CDDP as promising strategy for the treatment of CDDP resistant ovarian carcinomas."
],
"offsets": [
[
143,
1807
]
]
}
] | [
{
"id": "23396090_T1",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
1195,
1199
]
],
"normalized": []
},
{
"id": "23396090_T2",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
1370,
1374
]
],
"normalized": []
},
{
"id": "23396090_T3",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
1385,
1389
]
],
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},
{
"id": "23396090_T4",
"type": "CHEMICAL",
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"CDDP"
],
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[
1725,
1729
]
],
"normalized": []
},
{
"id": "23396090_T5",
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"CDDP"
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[
1773,
1777
]
],
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},
{
"id": "23396090_T6",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
362,
366
]
],
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},
{
"id": "23396090_T7",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
503,
507
]
],
"normalized": []
},
{
"id": "23396090_T8",
"type": "CHEMICAL",
"text": [
"cisplatin"
],
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[
181,
190
]
],
"normalized": []
},
{
"id": "23396090_T9",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
586,
590
]
],
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},
{
"id": "23396090_T10",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
192,
196
]
],
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},
{
"id": "23396090_T11",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
749,
753
]
],
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},
{
"id": "23396090_T12",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
208,
212
]
],
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},
{
"id": "23396090_T13",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
825,
829
]
],
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},
{
"id": "23396090_T14",
"type": "CHEMICAL",
"text": [
"CDDP"
],
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[
1005,
1009
]
],
"normalized": []
},
{
"id": "23396090_T15",
"type": "CHEMICAL",
"text": [
"cisplatin"
],
"offsets": [
[
72,
81
]
],
"normalized": []
},
{
"id": "23396090_T16",
"type": "GENE-N",
"text": [
"p38MAPK"
],
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[
1152,
1159
]
],
"normalized": []
},
{
"id": "23396090_T17",
"type": "GENE-Y",
"text": [
"TNFRSF10B"
],
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[
1310,
1319
]
],
"normalized": []
},
{
"id": "23396090_T18",
"type": "GENE-Y",
"text": [
"DR5"
],
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[
1320,
1323
]
],
"normalized": []
},
{
"id": "23396090_T19",
"type": "GENE-Y",
"text": [
"CD70"
],
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[
1325,
1329
]
],
"normalized": []
},
{
"id": "23396090_T20",
"type": "GENE-Y",
"text": [
"TNFSF7"
],
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[
1330,
1336
]
],
"normalized": []
},
{
"id": "23396090_T21",
"type": "GENE-Y",
"text": [
"p53"
],
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[
913,
916
]
],
"normalized": []
},
{
"id": "23396090_T22",
"type": "GENE-Y",
"text": [
"BAX"
],
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[
1115,
1118
]
],
"normalized": []
},
{
"id": "23396090_T23",
"type": "GENE-Y",
"text": [
"BID"
],
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[
1120,
1123
]
],
"normalized": []
},
{
"id": "23396090_T24",
"type": "GENE-Y",
"text": [
"CASP9"
],
"offsets": [
[
1125,
1130
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23396090_0",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23396090_T1",
"arg2_id": "23396090_T17",
"normalized": []
},
{
"id": "23396090_1",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23396090_T1",
"arg2_id": "23396090_T18",
"normalized": []
},
{
"id": "23396090_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23396090_T1",
"arg2_id": "23396090_T19",
"normalized": []
},
{
"id": "23396090_3",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23396090_T1",
"arg2_id": "23396090_T20",
"normalized": []
}
] |
2484931 | 2484931 | [
{
"id": "2484931_title",
"type": "title",
"text": [
"Evaluation of vitamin K3 feed additive for prevention of sweet clover disease."
],
"offsets": [
[
0,
78
]
]
},
{
"id": "2484931_abstract",
"type": "abstract",
"text": [
"Sweet clover poisoning in cattle is caused by an anticoagulant (dicumarol) that is formed in moldy sweet clover hay. Previous experiments with vitamin K3 and vitamin K1 in therapy trials indicated that vitamin K1 was effective in reducing prothrombin times but vitamin K3 was not. As a possible alternative in the use of toxic sweet clover hays, vitamin K3 was evaluated to see if it would prevent hemorrhagic crises when fed to cattle consuming toxic sweet clover hay. Vitamin K3 levels of 0, 0.45, 4.5, 11, and 45 mg/kg body weight/day were fed to 173-235-kg steers consuming toxic (40-50 ppm dicumarol) sweet clover. The 45-mg K3/kg/day supplement was not palatable and had to be discontinued. The 0.45, 4.5, and 11-mg K3/kg/day supplements did not significantly reduce the prothrombin times as compared to the 0-mg K3/kg/day group."
],
"offsets": [
[
79,
914
]
]
}
] | [
{
"id": "2484931_T1",
"type": "CHEMICAL",
"text": [
"vitamin K3"
],
"offsets": [
[
222,
232
]
],
"normalized": []
},
{
"id": "2484931_T2",
"type": "CHEMICAL",
"text": [
"vitamin K1"
],
"offsets": [
[
237,
247
]
],
"normalized": []
},
{
"id": "2484931_T3",
"type": "CHEMICAL",
"text": [
"vitamin K1"
],
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[
281,
291
]
],
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{
"id": "2484931_T4",
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"text": [
"vitamin K3"
],
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[
340,
350
]
],
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},
{
"id": "2484931_T5",
"type": "CHEMICAL",
"text": [
"vitamin K3"
],
"offsets": [
[
425,
435
]
],
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},
{
"id": "2484931_T6",
"type": "CHEMICAL",
"text": [
"Vitamin K3"
],
"offsets": [
[
549,
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]
],
"normalized": []
},
{
"id": "2484931_T7",
"type": "CHEMICAL",
"text": [
"dicumarol"
],
"offsets": [
[
674,
683
]
],
"normalized": []
},
{
"id": "2484931_T8",
"type": "CHEMICAL",
"text": [
"dicumarol"
],
"offsets": [
[
143,
152
]
],
"normalized": []
},
{
"id": "2484931_T9",
"type": "CHEMICAL",
"text": [
"vitamin K3"
],
"offsets": [
[
14,
24
]
],
"normalized": []
},
{
"id": "2484931_T10",
"type": "GENE-Y",
"text": [
"prothrombin"
],
"offsets": [
[
318,
329
]
],
"normalized": []
},
{
"id": "2484931_T11",
"type": "GENE-Y",
"text": [
"prothrombin"
],
"offsets": [
[
856,
867
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "2484931_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "2484931_T3",
"arg2_id": "2484931_T10",
"normalized": []
}
] |
23159479 | 23159479 | [
{
"id": "23159479_title",
"type": "title",
"text": [
"The impact of oxytocin administration and maternal love withdrawal on event-related potential (ERP) responses to emotional faces with performance feedback."
],
"offsets": [
[
0,
155
]
]
},
{
"id": "23159479_abstract",
"type": "abstract",
"text": [
"This is the first experimental study on the effect of oxytocin administration on the neural processing of facial stimuli conducted with female participants that uses event-related potentials (ERPs). Using a double-blind, placebo-controlled within-subjects design, we studied the effects of 16 IU of intranasal oxytocin on ERPs to pictures combining performance feedback with emotional facial expressions in 48 female undergraduate students. Participants also reported on the amount of love withdrawal they experienced from their mothers. Vertex positive potential (VPP) and late positive potential (LPP) amplitudes were more positive after oxytocin compared to placebo administration. This suggests that oxytocin increased attention to the feedback stimuli (LPP) and enhanced the processing of emotional faces (VPP). Oxytocin heightened processing of the happy and disgusted faces primarily for those reporting less love withdrawal. Significant associations with LPP amplitude suggest that more maternal love withdrawal relates to the allocation of attention toward the motivationally relevant combination of negative feedback with a disgusted face."
],
"offsets": [
[
156,
1305
]
]
}
] | [
{
"id": "23159479_T1",
"type": "CHEMICAL",
"text": [
"oxytocin"
],
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[
466,
474
]
],
"normalized": []
},
{
"id": "23159479_T2",
"type": "CHEMICAL",
"text": [
"oxytocin"
],
"offsets": [
[
210,
218
]
],
"normalized": []
},
{
"id": "23159479_T3",
"type": "CHEMICAL",
"text": [
"oxytocin"
],
"offsets": [
[
796,
804
]
],
"normalized": []
},
{
"id": "23159479_T4",
"type": "CHEMICAL",
"text": [
"oxytocin"
],
"offsets": [
[
860,
868
]
],
"normalized": []
},
{
"id": "23159479_T5",
"type": "CHEMICAL",
"text": [
"Oxytocin"
],
"offsets": [
[
973,
981
]
],
"normalized": []
},
{
"id": "23159479_T6",
"type": "CHEMICAL",
"text": [
"oxytocin"
],
"offsets": [
[
14,
22
]
],
"normalized": []
},
{
"id": "23159479_T7",
"type": "GENE-Y",
"text": [
"oxytocin"
],
"offsets": [
[
466,
474
]
],
"normalized": []
},
{
"id": "23159479_T8",
"type": "GENE-Y",
"text": [
"oxytocin"
],
"offsets": [
[
210,
218
]
],
"normalized": []
},
{
"id": "23159479_T9",
"type": "GENE-Y",
"text": [
"oxytocin"
],
"offsets": [
[
796,
804
]
],
"normalized": []
},
{
"id": "23159479_T10",
"type": "GENE-Y",
"text": [
"oxytocin"
],
"offsets": [
[
860,
868
]
],
"normalized": []
},
{
"id": "23159479_T11",
"type": "GENE-Y",
"text": [
"Oxytocin"
],
"offsets": [
[
973,
981
]
],
"normalized": []
},
{
"id": "23159479_T12",
"type": "GENE-Y",
"text": [
"oxytocin"
],
"offsets": [
[
14,
22
]
],
"normalized": []
}
] | [] | [] | [] |
23266452 | 23266452 | [
{
"id": "23266452_title",
"type": "title",
"text": [
"N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "23266452_abstract",
"type": "abstract",
"text": [
"Due to its efficient and specific gene silencing ability, RNA interference has shown great potential in the treatment of liver diseases. However, achieving in vivo delivery of siRNA to critical liver cells remains the biggest obstacle for this technique to be a real clinic therapeutic modality. Here, we describe a promising liver targeting siRNA delivery system based on N-acetylgalactosamine functionalized mixed micellar nanoparticles (Gal-MNP), which can efficiently deliver siRNA to hepatocytes and silence the target gene expression after systemic administration. The Gal-MNP were assembled in aqueous solution from mixed N-acetylgalactosamine functionalized poly(ethylene glycol)-b-poly(ε-caprolactone) and cationic poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) (PCL-b-PPEEA); the properties of nanoparticles, including particle size, zeta potential and the density of poly(ethylene glycol) could be easily regulated. The hepatocyte-targeting effect of Gal-MNP was demonstrated by significant enriching of fluorescent siRNA in primary hepatocytes in vitro and in vivo. Successful down-regulation of liver-specific apolipoprotein B (apoB) expression was achieved in mouse liver, at both the transcriptional and protein level, following intravenous injection of Gal-MNP/siapoB to BALB/c mice. Systemic delivery of Gal-MNP/siRNA did not induce the innate immune response or positive hepatotoxicity. The results of this study suggested therapeutic potential for the Gal-MNP/siRNA system in liver disease."
],
"offsets": [
[
107,
1630
]
]
}
] | [
{
"id": "23266452_T1",
"type": "CHEMICAL",
"text": [
"N-acetylgalactosamine"
],
"offsets": [
[
480,
501
]
],
"normalized": []
},
{
"id": "23266452_T2",
"type": "CHEMICAL",
"text": [
"N-acetylgalactosamine"
],
"offsets": [
[
736,
757
]
],
"normalized": []
},
{
"id": "23266452_T3",
"type": "CHEMICAL",
"text": [
"poly(ethylene glycol)-b-poly(ε-caprolactone)"
],
"offsets": [
[
773,
817
]
],
"normalized": []
},
{
"id": "23266452_T4",
"type": "CHEMICAL",
"text": [
"poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate)"
],
"offsets": [
[
831,
891
]
],
"normalized": []
},
{
"id": "23266452_T5",
"type": "CHEMICAL",
"text": [
"PCL-b-PPEEA"
],
"offsets": [
[
893,
904
]
],
"normalized": []
},
{
"id": "23266452_T6",
"type": "CHEMICAL",
"text": [
"poly(ethylene glycol)"
],
"offsets": [
[
999,
1020
]
],
"normalized": []
},
{
"id": "23266452_T7",
"type": "CHEMICAL",
"text": [
"N-acetylgalactosamine"
],
"offsets": [
[
0,
21
]
],
"normalized": []
},
{
"id": "23266452_T8",
"type": "GENE-Y",
"text": [
"apolipoprotein B"
],
"offsets": [
[
1244,
1260
]
],
"normalized": []
},
{
"id": "23266452_T9",
"type": "GENE-Y",
"text": [
"apoB"
],
"offsets": [
[
1262,
1266
]
],
"normalized": []
},
{
"id": "23266452_T10",
"type": "GENE-Y",
"text": [
"apoB"
],
"offsets": [
[
1400,
1404
]
],
"normalized": []
}
] | [] | [] | [] |
14722255 | 14722255 | [
{
"id": "14722255_title",
"type": "title",
"text": [
"The antileukemia drug 2-chloro-2'-deoxyadenosine: an intrinsic transcriptional antagonist."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "14722255_abstract",
"type": "abstract",
"text": [
"The nucleoside analog 2-chloro-2'-deoxyadenosine (CldAdo; cladribine) is effective in the treatment of hairy cell leukemia and chronic lymphocytic leukemia. CldAdo is phosphorylated and incorporated into cellular DNA but is not an absolute chain terminator. We demonstrated by in vitro gel-shift assays that binding interactions of the human TATA box-binding protein (TBP) were disrupted on 2-chlorodeoxyadenosine monophosphate (CldAMP)-substituted TATA box consensus sequences. We hypothesized that human RNA polymerase II (pol II) transcriptional processes would therefore be affected by 2-chlorodeoxyadenosine triphosphate (CldATP) incorporation into a promoter TATA element. Double-stranded DNA templates containing the adenovirus major late promoter and coding sequences were enzymatically synthesized as control or with site-specific CldAMP residues, incubated with HeLa extract, and the synthesis of radiolabeled 44-base transcripts was assessed. With increasing amounts of HeLa extract, CldAMP substitution for dAMP within the TATA box decreased in vitro pol II transcription by approximately 35% compared with control substrates. Time-course studies showed that transcript production increased in a linear fashion on control substrates. In contrast, transcription on CldAMP-substituted TATA sequences reached a plateau after 20 min. Furthermore, CldAMP-substituted promoter sequences trapped or sequestered TBP, preventing its dissociation from DNA and subsequent binding to additional TATA elements to reinitiate transcription. CldAdo thus represents the first example of a nucleoside analog that acts as a transcriptional antagonist. CldATP incorporation into gene regulatory sequences may provide a novel strategy to modulate specific protein/DNA interactions."
],
"offsets": [
[
91,
1863
]
]
}
] | [
{
"id": "14722255_T1",
"type": "CHEMICAL",
"text": [
"dAMP"
],
"offsets": [
[
1110,
1114
]
],
"normalized": []
},
{
"id": "14722255_T2",
"type": "CHEMICAL",
"text": [
"CldAMP"
],
"offsets": [
[
1367,
1373
]
],
"normalized": []
},
{
"id": "14722255_T3",
"type": "CHEMICAL",
"text": [
"CldAMP"
],
"offsets": [
[
1446,
1452
]
],
"normalized": []
},
{
"id": "14722255_T4",
"type": "CHEMICAL",
"text": [
"CldAdo"
],
"offsets": [
[
1629,
1635
]
],
"normalized": []
},
{
"id": "14722255_T5",
"type": "CHEMICAL",
"text": [
"CldAdo"
],
"offsets": [
[
248,
254
]
],
"normalized": []
},
{
"id": "14722255_T6",
"type": "CHEMICAL",
"text": [
"CldATP"
],
"offsets": [
[
1736,
1742
]
],
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},
{
"id": "14722255_T7",
"type": "CHEMICAL",
"text": [
"2-chloro-2'-deoxyadenosine"
],
"offsets": [
[
113,
139
]
],
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},
{
"id": "14722255_T8",
"type": "CHEMICAL",
"text": [
"2-chlorodeoxyadenosine monophosphate"
],
"offsets": [
[
482,
518
]
],
"normalized": []
},
{
"id": "14722255_T9",
"type": "CHEMICAL",
"text": [
"CldAMP"
],
"offsets": [
[
520,
526
]
],
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},
{
"id": "14722255_T10",
"type": "CHEMICAL",
"text": [
"CldAdo"
],
"offsets": [
[
141,
147
]
],
"normalized": []
},
{
"id": "14722255_T11",
"type": "CHEMICAL",
"text": [
"cladribine"
],
"offsets": [
[
149,
159
]
],
"normalized": []
},
{
"id": "14722255_T12",
"type": "CHEMICAL",
"text": [
"2-chlorodeoxyadenosine triphosphate"
],
"offsets": [
[
681,
716
]
],
"normalized": []
},
{
"id": "14722255_T13",
"type": "CHEMICAL",
"text": [
"CldATP"
],
"offsets": [
[
718,
724
]
],
"normalized": []
},
{
"id": "14722255_T14",
"type": "CHEMICAL",
"text": [
"CldAMP"
],
"offsets": [
[
931,
937
]
],
"normalized": []
},
{
"id": "14722255_T15",
"type": "CHEMICAL",
"text": [
"CldAMP"
],
"offsets": [
[
1086,
1092
]
],
"normalized": []
},
{
"id": "14722255_T16",
"type": "CHEMICAL",
"text": [
"2-chloro-2'-deoxyadenosine"
],
"offsets": [
[
22,
48
]
],
"normalized": []
},
{
"id": "14722255_T17",
"type": "GENE-N",
"text": [
"TATA box"
],
"offsets": [
[
1126,
1134
]
],
"normalized": []
},
{
"id": "14722255_T18",
"type": "GENE-N",
"text": [
"pol II"
],
"offsets": [
[
1154,
1160
]
],
"normalized": []
},
{
"id": "14722255_T19",
"type": "GENE-N",
"text": [
"TATA sequences"
],
"offsets": [
[
1386,
1400
]
],
"normalized": []
},
{
"id": "14722255_T20",
"type": "GENE-N",
"text": [
"TATA elements"
],
"offsets": [
[
1586,
1599
]
],
"normalized": []
},
{
"id": "14722255_T21",
"type": "GENE-Y",
"text": [
"human TATA box-binding protein"
],
"offsets": [
[
427,
457
]
],
"normalized": []
},
{
"id": "14722255_T22",
"type": "GENE-Y",
"text": [
"TBP"
],
"offsets": [
[
459,
462
]
],
"normalized": []
},
{
"id": "14722255_T23",
"type": "GENE-N",
"text": [
"TATA box consensus sequences"
],
"offsets": [
[
540,
568
]
],
"normalized": []
},
{
"id": "14722255_T24",
"type": "GENE-N",
"text": [
"human RNA polymerase II"
],
"offsets": [
[
591,
614
]
],
"normalized": []
},
{
"id": "14722255_T25",
"type": "GENE-N",
"text": [
"pol II"
],
"offsets": [
[
616,
622
]
],
"normalized": []
},
{
"id": "14722255_T26",
"type": "GENE-N",
"text": [
"TATA element"
],
"offsets": [
[
756,
768
]
],
"normalized": []
}
] | [] | [] | [] |
21318872 | 21318872 | [
{
"id": "21318872_title",
"type": "title",
"text": [
"Use of (Gyro) Gy and spermine synthase transgenic mice to study functions of spermine."
],
"offsets": [
[
0,
86
]
]
},
{
"id": "21318872_abstract",
"type": "abstract",
"text": [
"The polyamines putrescine, spermidine, and spermine are essential for mammalian cell growth, -differentiation, and cell death and have important physiological roles in all tissues. Many of the properties of polyamines that can be demonstrated in vitro are common to all three molecules with differences only in potency. Loss of any of the enzymes needed to make either putrescine or spermidine (which also -prevent the production of spermine) is lethal, but male mice lacking spermine synthase (SpmS) due to a deletion of part of the X chromosome are viable on the B6C3H background. These mice are termed Gyro (Gy) due to their circling behavior. They have a variety of abnormalities including deafness, neurological problems, small size, and a tendency to early death. They can therefore be used to evaluate the physiological function(s) uniquely provided by spermine. They also provide a potential animal model for Snyder-Robinson syndrome (SRS), a rare human inherited disease due to a loss of SpmS activity. An essential control in experiments using Gy mice is to demonstrate that the abnormal phenotypes exhibited by these mice are abolished by providing replacement spermine and this can be accomplished by breeding with CAG-SMS mice that express SpmS from a ubiquitous promoter. Techniques for identifying, characterizing, and using these mouse strains and limitations of this approach are described in this chapter."
],
"offsets": [
[
87,
1510
]
]
}
] | [
{
"id": "21318872_T1",
"type": "CHEMICAL",
"text": [
"spermine"
],
"offsets": [
[
1259,
1267
]
],
"normalized": []
},
{
"id": "21318872_T2",
"type": "CHEMICAL",
"text": [
"putrescine"
],
"offsets": [
[
102,
112
]
],
"normalized": []
},
{
"id": "21318872_T3",
"type": "CHEMICAL",
"text": [
"polyamines"
],
"offsets": [
[
294,
304
]
],
"normalized": []
},
{
"id": "21318872_T4",
"type": "CHEMICAL",
"text": [
"spermidine"
],
"offsets": [
[
114,
124
]
],
"normalized": []
},
{
"id": "21318872_T5",
"type": "CHEMICAL",
"text": [
"putrescine"
],
"offsets": [
[
456,
466
]
],
"normalized": []
},
{
"id": "21318872_T6",
"type": "CHEMICAL",
"text": [
"spermidine"
],
"offsets": [
[
470,
480
]
],
"normalized": []
},
{
"id": "21318872_T7",
"type": "CHEMICAL",
"text": [
"polyamines"
],
"offsets": [
[
91,
101
]
],
"normalized": []
},
{
"id": "21318872_T8",
"type": "CHEMICAL",
"text": [
"spermine"
],
"offsets": [
[
520,
528
]
],
"normalized": []
},
{
"id": "21318872_T9",
"type": "CHEMICAL",
"text": [
"spermine"
],
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[
130,
138
]
],
"normalized": []
},
{
"id": "21318872_T10",
"type": "CHEMICAL",
"text": [
"spermine"
],
"offsets": [
[
563,
571
]
],
"normalized": []
},
{
"id": "21318872_T11",
"type": "CHEMICAL",
"text": [
"spermine"
],
"offsets": [
[
947,
955
]
],
"normalized": []
},
{
"id": "21318872_T12",
"type": "CHEMICAL",
"text": [
"spermine"
],
"offsets": [
[
21,
29
]
],
"normalized": []
},
{
"id": "21318872_T13",
"type": "CHEMICAL",
"text": [
"spermine"
],
"offsets": [
[
77,
85
]
],
"normalized": []
},
{
"id": "21318872_T14",
"type": "GENE-Y",
"text": [
"SMS"
],
"offsets": [
[
1318,
1321
]
],
"normalized": []
},
{
"id": "21318872_T15",
"type": "GENE-Y",
"text": [
"SpmS"
],
"offsets": [
[
1340,
1344
]
],
"normalized": []
},
{
"id": "21318872_T16",
"type": "GENE-Y",
"text": [
"spermine synthase"
],
"offsets": [
[
563,
580
]
],
"normalized": []
},
{
"id": "21318872_T17",
"type": "GENE-Y",
"text": [
"SpmS"
],
"offsets": [
[
582,
586
]
],
"normalized": []
},
{
"id": "21318872_T18",
"type": "GENE-Y",
"text": [
"SpmS"
],
"offsets": [
[
1084,
1088
]
],
"normalized": []
},
{
"id": "21318872_T19",
"type": "GENE-Y",
"text": [
"spermine synthase"
],
"offsets": [
[
21,
38
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "21318872_0",
"type": "PRODUCT-OF",
"arg1_id": "21318872_T1",
"arg2_id": "21318872_T14",
"normalized": []
},
{
"id": "21318872_1",
"type": "PRODUCT-OF",
"arg1_id": "21318872_T1",
"arg2_id": "21318872_T15",
"normalized": []
}
] |
23387288 | 23387288 | [
{
"id": "23387288_title",
"type": "title",
"text": [
"Cytotoxic activity of Guettarda pohliana Müll. Arg. (Rubiaceae)."
],
"offsets": [
[
0,
64
]
]
},
{
"id": "23387288_abstract",
"type": "abstract",
"text": [
"The cytotoxic activity of crude extracts and their fractions from leaves and roots of G. pohliana was assessed against nine human cancer cell lines: melanoma (UACC-62), breast (MCF-7), breast expressing the multidrug resistance phenotype (NCI-ADR), lung (NCI-460), prostate (PCO-3), kidney (786-0), ovarian (OVCAR), colon (HT-29) and leukaemia (K-562). The hexane fraction from leaves (HL) and ethyl acetate (EAR), chloroform (CR) and hydromethanolic (HMR) fractions from roots were the most active fractions against K-562 with GI(50) values being lower than 1 μg mL(- 1). Also, CR and HMR fractions were active against UACC-62 cell line in the same order of magnitude. The phytochemical study of the CR fraction allowed identifying the known iridoids secoxyloganin, sweroside and loganin."
],
"offsets": [
[
65,
854
]
]
}
] | [
{
"id": "23387288_T1",
"type": "CHEMICAL",
"text": [
"hexane"
],
"offsets": [
[
422,
428
]
],
"normalized": []
},
{
"id": "23387288_T2",
"type": "CHEMICAL",
"text": [
"ethyl acetate"
],
"offsets": [
[
459,
472
]
],
"normalized": []
},
{
"id": "23387288_T3",
"type": "CHEMICAL",
"text": [
"chloroform"
],
"offsets": [
[
480,
490
]
],
"normalized": []
},
{
"id": "23387288_T4",
"type": "CHEMICAL",
"text": [
"iridoids"
],
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[
808,
816
]
],
"normalized": []
},
{
"id": "23387288_T5",
"type": "CHEMICAL",
"text": [
"secoxyloganin"
],
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[
817,
830
]
],
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},
{
"id": "23387288_T6",
"type": "CHEMICAL",
"text": [
"sweroside"
],
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[
832,
841
]
],
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},
{
"id": "23387288_T7",
"type": "CHEMICAL",
"text": [
"loganin"
],
"offsets": [
[
846,
853
]
],
"normalized": []
}
] | [] | [] | [] |
16765071 | 16765071 | [
{
"id": "16765071_title",
"type": "title",
"text": [
"Detection of 6-nitrotryptophan in proteins by Western blot analysis and its application for peroxynitrite-treated PC12 cells."
],
"offsets": [
[
0,
125
]
]
},
{
"id": "16765071_abstract",
"type": "abstract",
"text": [
"We have previously reported on the formation of 6-nitrotryptophan by the reaction of reactive nitrogen species with a tryptophan residue in human Cu, Zn-superoxide dismutase (SOD) (F. Yamakura et al., J. Biochem. 138 (2005) 57-69). Here, we report on the preparation of anti-6-nitrotryptophan antiserum by using synthesized 6-nitrotryptophan-conjugated keyhole limpet hemocyanin as an antigen and the purification of the antibody by using a 6-nitrotryptophan-conjugated affinity column. The purified antibody was immunoreactive with 6-nitrotryptophan residue containing Cu, Zn-SOD but not immunoreactive with Cu, Zn-SOD, Mn-SOD, bovine serum albumin, and 3-nitrotyrosine residue containing Mn-SOD. Nitro group of 6-nitrotryptophan was reduced by sodium hydrosulfite to form 6-aminotryptophan as a major product. The reduced 6-nitrotryptophan residues lost its immunoreactivity with the antibody. We detected different immunoreactive bands between using antibody for 6-nitrotryptophan residues and that for 3-nitrotyrosine residues in crude extracts of neuron-like PC12 cells treated with peroxynitrite by a Western blot analysis. Western blot analysis for two-dimensional gel electrophoresis showed nine intensively stained immunoreactive spots for 6-nitrotryptophan residues in the peroxynitrite-treated PC12 cells, which were subjected to trypsin digestion and LC-ESI-MS/MS analysis. We identified M2 pyruvate kinase, elongation factor 2, mitochondrial aconitase, pyruvate carboxylase, and heat shock protein HSP90alpha as candidates for 6-nitrotryptophan residues containing proteins, with peptide coverage over 10%, in crude extracts of peroxynitrite-treated PC12 cells."
],
"offsets": [
[
126,
1800
]
]
}
] | [
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"3-nitrotyrosine"
],
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[
1132,
1147
]
],
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},
{
"id": "16765071_T2",
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"text": [
"peroxynitrite"
],
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[
1214,
1227
]
],
"normalized": []
},
{
"id": "16765071_T3",
"type": "CHEMICAL",
"text": [
"tryptophan"
],
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[
244,
254
]
],
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},
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"6-nitrotryptophan"
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1375,
1392
]
],
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"peroxynitrite"
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[
1409,
1422
]
],
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"id": "16765071_T6",
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"text": [
"pyruvate"
],
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1529,
1537
]
],
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"id": "16765071_T7",
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"text": [
"Cu"
],
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272,
274
]
],
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},
{
"id": "16765071_T8",
"type": "CHEMICAL",
"text": [
"pyruvate"
],
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[
1592,
1600
]
],
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},
{
"id": "16765071_T9",
"type": "CHEMICAL",
"text": [
"Zn"
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[
276,
278
]
],
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},
{
"id": "16765071_T10",
"type": "CHEMICAL",
"text": [
"superoxide"
],
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[
279,
289
]
],
"normalized": []
},
{
"id": "16765071_T11",
"type": "CHEMICAL",
"text": [
"6-nitrotryptophan"
],
"offsets": [
[
1666,
1683
]
],
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},
{
"id": "16765071_T12",
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"text": [
"peroxynitrite"
],
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[
1767,
1780
]
],
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},
{
"id": "16765071_T13",
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"anti-6-nitrotryptophan"
],
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396,
418
]
],
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},
{
"id": "16765071_T14",
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"6-nitrotryptophan"
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[
450,
467
]
],
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"6-nitrotryptophan"
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567,
584
]
],
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"6-nitrotryptophan"
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174,
191
]
],
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659,
676
]
],
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"text": [
"Cu"
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696,
698
]
],
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},
{
"id": "16765071_T19",
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"Zn"
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[
700,
702
]
],
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},
{
"id": "16765071_T20",
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"text": [
"Cu"
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[
735,
737
]
],
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},
{
"id": "16765071_T21",
"type": "CHEMICAL",
"text": [
"Zn"
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[
739,
741
]
],
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},
{
"id": "16765071_T22",
"type": "CHEMICAL",
"text": [
"Mn"
],
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[
747,
749
]
],
"normalized": []
},
{
"id": "16765071_T23",
"type": "CHEMICAL",
"text": [
"3-nitrotyrosine"
],
"offsets": [
[
781,
796
]
],
"normalized": []
},
{
"id": "16765071_T24",
"type": "CHEMICAL",
"text": [
"Mn"
],
"offsets": [
[
816,
818
]
],
"normalized": []
},
{
"id": "16765071_T25",
"type": "CHEMICAL",
"text": [
"Nitro"
],
"offsets": [
[
824,
829
]
],
"normalized": []
},
{
"id": "16765071_T26",
"type": "CHEMICAL",
"text": [
"6-nitrotryptophan"
],
"offsets": [
[
839,
856
]
],
"normalized": []
},
{
"id": "16765071_T27",
"type": "CHEMICAL",
"text": [
"sodium hydrosulfite"
],
"offsets": [
[
872,
891
]
],
"normalized": []
},
{
"id": "16765071_T28",
"type": "CHEMICAL",
"text": [
"6-aminotryptophan"
],
"offsets": [
[
900,
917
]
],
"normalized": []
},
{
"id": "16765071_T29",
"type": "CHEMICAL",
"text": [
"6-nitrotryptophan"
],
"offsets": [
[
950,
967
]
],
"normalized": []
},
{
"id": "16765071_T30",
"type": "CHEMICAL",
"text": [
"nitrogen"
],
"offsets": [
[
220,
228
]
],
"normalized": []
},
{
"id": "16765071_T31",
"type": "CHEMICAL",
"text": [
"6-nitrotryptophan"
],
"offsets": [
[
1092,
1109
]
],
"normalized": []
},
{
"id": "16765071_T32",
"type": "CHEMICAL",
"text": [
"6-nitrotryptophan"
],
"offsets": [
[
13,
30
]
],
"normalized": []
},
{
"id": "16765071_T33",
"type": "CHEMICAL",
"text": [
"peroxynitrite"
],
"offsets": [
[
92,
105
]
],
"normalized": []
},
{
"id": "16765071_T34",
"type": "GENE-Y",
"text": [
"M2 pyruvate kinase"
],
"offsets": [
[
1526,
1544
]
],
"normalized": []
},
{
"id": "16765071_T35",
"type": "GENE-Y",
"text": [
"elongation factor 2"
],
"offsets": [
[
1546,
1565
]
],
"normalized": []
},
{
"id": "16765071_T36",
"type": "GENE-Y",
"text": [
"mitochondrial aconitase"
],
"offsets": [
[
1567,
1590
]
],
"normalized": []
},
{
"id": "16765071_T37",
"type": "GENE-Y",
"text": [
"pyruvate carboxylase"
],
"offsets": [
[
1592,
1612
]
],
"normalized": []
},
{
"id": "16765071_T38",
"type": "GENE-N",
"text": [
"heat shock protein"
],
"offsets": [
[
1618,
1636
]
],
"normalized": []
},
{
"id": "16765071_T39",
"type": "GENE-Y",
"text": [
"HSP90alpha"
],
"offsets": [
[
1637,
1647
]
],
"normalized": []
},
{
"id": "16765071_T40",
"type": "GENE-N",
"text": [
"superoxide dismutase"
],
"offsets": [
[
279,
299
]
],
"normalized": []
},
{
"id": "16765071_T41",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
301,
304
]
],
"normalized": []
},
{
"id": "16765071_T42",
"type": "GENE-N",
"text": [
"limpet hemocyanin"
],
"offsets": [
[
487,
504
]
],
"normalized": []
},
{
"id": "16765071_T43",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
703,
706
]
],
"normalized": []
},
{
"id": "16765071_T44",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
742,
745
]
],
"normalized": []
},
{
"id": "16765071_T45",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
750,
753
]
],
"normalized": []
},
{
"id": "16765071_T46",
"type": "GENE-Y",
"text": [
"bovine serum albumin"
],
"offsets": [
[
755,
775
]
],
"normalized": []
},
{
"id": "16765071_T47",
"type": "GENE-N",
"text": [
"SOD"
],
"offsets": [
[
819,
822
]
],
"normalized": []
}
] | [] | [] | [
{
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},
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},
{
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"arg2_id": "16765071_T42",
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},
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"id": "16765071_3",
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"arg2_id": "16765071_T40",
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},
{
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},
{
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"arg2_id": "16765071_T43",
"normalized": []
},
{
"id": "16765071_6",
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"arg2_id": "16765071_T44",
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},
{
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"arg2_id": "16765071_T47",
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},
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"id": "16765071_8",
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"arg2_id": "16765071_T34",
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},
{
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},
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"arg2_id": "16765071_T36",
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},
{
"id": "16765071_11",
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},
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"type": "PART-OF",
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"arg2_id": "16765071_T38",
"normalized": []
},
{
"id": "16765071_13",
"type": "PART-OF",
"arg1_id": "16765071_T11",
"arg2_id": "16765071_T39",
"normalized": []
}
] |
23371303 | 23371303 | [
{
"id": "23371303_title",
"type": "title",
"text": [
"Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination."
],
"offsets": [
[
0,
79
]
]
},
{
"id": "23371303_abstract",
"type": "abstract",
"text": [
"Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections."
],
"offsets": [
[
80,
3536
]
]
}
] | [
{
"id": "23371303_T1",
"type": "CHEMICAL",
"text": [
"Avibactam"
],
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[
80,
89
]
],
"normalized": []
},
{
"id": "23371303_T2",
"type": "CHEMICAL",
"text": [
"ceftazidime"
],
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[
1119,
1130
]
],
"normalized": []
},
{
"id": "23371303_T3",
"type": "CHEMICAL",
"text": [
"avibactam"
],
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[
1200,
1209
]
],
"normalized": []
},
{
"id": "23371303_T4",
"type": "CHEMICAL",
"text": [
"ceftazidime"
],
"offsets": [
[
1243,
1254
]
],
"normalized": []
},
{
"id": "23371303_T5",
"type": "CHEMICAL",
"text": [
"avibactam"
],
"offsets": [
[
1436,
1445
]
],
"normalized": []
},
{
"id": "23371303_T6",
"type": "CHEMICAL",
"text": [
"ceftazidime"
],
"offsets": [
[
1537,
1548
]
],
"normalized": []
},
{
"id": "23371303_T7",
"type": "CHEMICAL",
"text": [
"avibactam"
],
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[
1657,
1666
]
],
"normalized": []
},
{
"id": "23371303_T8",
"type": "CHEMICAL",
"text": [
"ceftazidime"
],
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[
1837,
1848
]
],
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},
{
"id": "23371303_T9",
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"text": [
"ceftazidime"
],
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[
1855,
1866
]
],
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},
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"id": "23371303_T10",
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"avibactam"
],
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[
1868,
1877
]
],
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},
{
"id": "23371303_T11",
"type": "CHEMICAL",
"text": [
"creatinine"
],
"offsets": [
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}
] | [] | [] | [
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}
] |
23395804 | 23395804 | [
{
"id": "23395804_title",
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0,
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]
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{
"id": "23395804_abstract",
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"text": [
"Prolactin (PRL) is a well-known regulator of ion and water transport within osmoregulatory tissues across vertebrate species, yet how PRL acts on some of its target tissues remains poorly understood. Using zebrafish as a model, we show that ionocytes in the gill directly respond to systemic PRL to regulate mechanisms of ion uptake. Ion-poor conditions led to increases in the expression of PRL receptor (prlra), Na(+)/Cl(-) cotransporter (ncc; slc12a10.2), Na(+)/H(+) exchanger (nhe3b; slc9a3.2), and epithelial Ca(2+) channel (ecac; trpv6) transcripts within the gill. Intraperitoneal injection of ovine PRL (oPRL) increased ncc and prlra transcripts, but did not affect nhe3b or ecac. Consistent with direct PRL action in the gill, addition of oPRL to cultured gill filaments stimulated ncc in a concentration-dependent manner, an effect blocked by a pure human PRL receptor antagonist (Δ1-9-G129R-hPRL). These results suggest that PRL signaling through PRL receptors in the gill regulates the expression of ncc, thereby linking this pituitary hormone with an effector of Cl(-) uptake in zebrafish for the first time."
],
"offsets": [
[
104,
1225
]
]
}
] | [
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]
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"Na(+)"
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]
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]
],
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]
],
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"H(+)"
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]
],
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"id": "23395804_T6",
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"Ca(2+)"
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618,
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]
],
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},
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"id": "23395804_T7",
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"Na+"
],
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[
52,
55
]
],
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},
{
"id": "23395804_T8",
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"Cl-"
],
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[
56,
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]
],
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},
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"id": "23395804_T9",
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"Prolactin"
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104,
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]
],
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},
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"id": "23395804_T10",
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"ncc"
],
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1116,
1119
]
],
"normalized": []
},
{
"id": "23395804_T11",
"type": "GENE-N",
"text": [
"pituitary hormone"
],
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[
1142,
1159
]
],
"normalized": []
},
{
"id": "23395804_T12",
"type": "GENE-Y",
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"PRL"
],
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115,
118
]
],
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},
{
"id": "23395804_T13",
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"PRL"
],
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238,
241
]
],
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},
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"id": "23395804_T14",
"type": "GENE-Y",
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"PRL"
],
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[
396,
399
]
],
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},
{
"id": "23395804_T15",
"type": "GENE-N",
"text": [
"PRL receptor"
],
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496,
508
]
],
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},
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"id": "23395804_T16",
"type": "GENE-Y",
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"prlra"
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510,
515
]
],
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},
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"id": "23395804_T17",
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"Na(+)/Cl(-) cotransporter"
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518,
543
]
],
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},
{
"id": "23395804_T18",
"type": "GENE-Y",
"text": [
"ncc"
],
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545,
548
]
],
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},
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"id": "23395804_T19",
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"slc12a10.2"
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550,
560
]
],
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},
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"id": "23395804_T20",
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"Na(+)/H(+) exchanger"
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[
563,
583
]
],
"normalized": []
},
{
"id": "23395804_T21",
"type": "GENE-Y",
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"nhe3b"
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[
585,
590
]
],
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},
{
"id": "23395804_T22",
"type": "GENE-Y",
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"slc9a3.2"
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[
592,
600
]
],
"normalized": []
},
{
"id": "23395804_T23",
"type": "GENE-Y",
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"epithelial Ca(2+) channel"
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[
607,
632
]
],
"normalized": []
},
{
"id": "23395804_T24",
"type": "GENE-Y",
"text": [
"ecac"
],
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[
634,
638
]
],
"normalized": []
},
{
"id": "23395804_T25",
"type": "GENE-Y",
"text": [
"trpv6"
],
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[
640,
645
]
],
"normalized": []
},
{
"id": "23395804_T26",
"type": "GENE-Y",
"text": [
"ovine PRL"
],
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[
705,
714
]
],
"normalized": []
},
{
"id": "23395804_T27",
"type": "GENE-Y",
"text": [
"oPRL"
],
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[
716,
720
]
],
"normalized": []
},
{
"id": "23395804_T28",
"type": "GENE-Y",
"text": [
"ncc"
],
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[
732,
735
]
],
"normalized": []
},
{
"id": "23395804_T29",
"type": "GENE-Y",
"text": [
"prlra"
],
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[
740,
745
]
],
"normalized": []
},
{
"id": "23395804_T30",
"type": "GENE-Y",
"text": [
"nhe3b"
],
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[
778,
783
]
],
"normalized": []
},
{
"id": "23395804_T31",
"type": "GENE-Y",
"text": [
"ecac"
],
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[
787,
791
]
],
"normalized": []
},
{
"id": "23395804_T32",
"type": "GENE-Y",
"text": [
"PRL"
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816,
819
]
],
"normalized": []
},
{
"id": "23395804_T33",
"type": "GENE-Y",
"text": [
"oPRL"
],
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[
852,
856
]
],
"normalized": []
},
{
"id": "23395804_T34",
"type": "GENE-Y",
"text": [
"ncc"
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895,
898
]
],
"normalized": []
},
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"id": "23395804_T35",
"type": "GENE-Y",
"text": [
"human PRL receptor"
],
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964,
982
]
],
"normalized": []
},
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"id": "23395804_T36",
"type": "GENE-N",
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"G129R"
],
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1000,
1005
]
],
"normalized": []
},
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"id": "23395804_T37",
"type": "GENE-Y",
"text": [
"hPRL"
],
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1006,
1010
]
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},
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"id": "23395804_T38",
"type": "GENE-Y",
"text": [
"PRL"
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1040,
1043
]
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},
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"id": "23395804_T39",
"type": "GENE-N",
"text": [
"PRL receptors"
],
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1062,
1075
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"id": "23395804_T40",
"type": "GENE-Y",
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"Prolactin"
],
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0,
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"id": "23395804_T41",
"type": "GENE-Y",
"text": [
"Na+/Cl- cotransporter"
],
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52,
73
]
],
"normalized": []
},
{
"id": "23395804_T42",
"type": "GENE-Y",
"text": [
"ncc"
],
"offsets": [
[
75,
78
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23395804_0",
"type": "SUBSTRATE",
"arg1_id": "23395804_T1",
"arg2_id": "23395804_T10",
"normalized": []
}
] |
8882618 | 8882618 | [
{
"id": "8882618_title",
"type": "title",
"text": [
"Interactions of 2,3-benzodiazepines and cyclothiazide at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices."
],
"offsets": [
[
0,
152
]
]
},
{
"id": "8882618_abstract",
"type": "abstract",
"text": [
"1. The 2,3-benzodiazepines GYKI 52466, GYKI 53405 and GYKI 53655 antagonized AMPA-induced currents in cultured superior colliculus neurones in a non use-dependent manner (steady state IC50s: GYKI 52466 9.8 +/- 0.6 microM; GYKI 53405 3.1 +/- 0.6 microM; GYKI 53655 0.8 +/- 0.1 microM). 2. Higher concentrations of all three antagonists slowed the onset kinetics and quickened the offset kinetics of AMPA-induced currents indicative of an allosteric interaction with the AMPA recognition site. 3. Cyclothiazide (3-300 microM) dramatically slowed desensitization of AMPA-induced currents and potentiated steady state currents (EC50 10.0 +/- 2.5 microM) to a much greater degree than peak currents. Both tau on and tau off were also increased by cyclothiazide in a concentration-dependent manner (EC50: tau on 42.1 +/- 4.5 microM; tau off 31.6 +/- 6.6 microM). 4. Cyclothiazide (10-100 microM) shifted the concentration-response curves of the 2,3-benzodiazepines to the right. For example, with 10 microM cyclothiazide the IC50s of GYKI 52466 and GYKI 53405 on steady-state AMPA-induced currents were 57.9 +/- 9.5 and 41.6 +/- 1.5 microM, respectively. 5. GYKI 53405 and GYKI 52466 concentration-dependently reversed the effects of cyclothiazide (100 microM) on offset kinetics (GYKI 53405 IC50 16.6 +/- 4.2 microM). However, the 2,3-benzodiazepines were unable to reintroduce desensitization in the presence of cyclothiazide and even concentration-dependently slowed the onset kinetics of AMPA responses further (GYKI 53405 EC50 8.0 +/- 2.8 microM). 6. GYKI 52466 decreased the peak amplitude of hippocampal area CA1 AMPA receptor-mediated excitatory postsynaptic currents (e.p.s.cs) (IC50 10.8 +/- 0.8 microM) with no apparent effect on response kinetics. Cyclothiazide prolonged the decay time constant of AMPA receptor-mediated e.p.s.cs (EC50 35.7 +/- 6.5 microM) with less pronounced effects in slowing e.p.s.c. onset kinetics and increasing e.p.s.c. amplitude. 7. Cyclothiazide (330 microM) shifted the concentration-response curve for the effects of GYKI 52466 on AMPA receptor-mediated e.p.s.c. peak amplitude to the right (GYKI 52466 IC50 26.9 +/- 9.4 microM). Likewise, GYKI 52466 (30-100 microM)) shifted the concentration-response curve for the effects of cyclothiazide on AMPA receptor-mediated e.p.s.c. decay time constants to the right. 8. In conclusion, cyclothiazide and the 2,3-benzodiazepines seem to bind to different sites on AMPA receptors but exert strong allosteric interactions with one another and with other domains such as the agonist recognition site. The interactions of GYKI 52466 and cyclothiazide on AMPA receptor-mediated e.p.s.cs in area CA1 of hippocampal slices provide evidence that the decay time constant of these synaptic events are not governed by desensitization."
],
"offsets": [
[
153,
2955
]
]
}
] | [
{
"id": "8882618_T1",
"type": "CHEMICAL",
"text": [
"cyclothiazide"
],
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[
1154,
1167
]
],
"normalized": []
},
{
"id": "8882618_T2",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
"offsets": [
[
1181,
1191
]
],
"normalized": []
},
{
"id": "8882618_T3",
"type": "CHEMICAL",
"text": [
"GYKI 53405"
],
"offsets": [
[
1196,
1206
]
],
"normalized": []
},
{
"id": "8882618_T4",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
1223,
1227
]
],
"normalized": []
},
{
"id": "8882618_T5",
"type": "CHEMICAL",
"text": [
"GYKI 53405"
],
"offsets": [
[
1305,
1315
]
],
"normalized": []
},
{
"id": "8882618_T6",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
"offsets": [
[
1320,
1330
]
],
"normalized": []
},
{
"id": "8882618_T7",
"type": "CHEMICAL",
"text": [
"cyclothiazide"
],
"offsets": [
[
1381,
1394
]
],
"normalized": []
},
{
"id": "8882618_T8",
"type": "CHEMICAL",
"text": [
"GYKI 53405"
],
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[
1428,
1438
]
],
"normalized": []
},
{
"id": "8882618_T9",
"type": "CHEMICAL",
"text": [
"2,3-benzodiazepines"
],
"offsets": [
[
1479,
1498
]
],
"normalized": []
},
{
"id": "8882618_T10",
"type": "CHEMICAL",
"text": [
"cyclothiazide"
],
"offsets": [
[
1561,
1574
]
],
"normalized": []
},
{
"id": "8882618_T11",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
1639,
1643
]
],
"normalized": []
},
{
"id": "8882618_T12",
"type": "CHEMICAL",
"text": [
"GYKI 53405"
],
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[
1663,
1673
]
],
"normalized": []
},
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"id": "8882618_T13",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
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[
1703,
1713
]
],
"normalized": []
},
{
"id": "8882618_T14",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
1767,
1771
]
],
"normalized": []
},
{
"id": "8882618_T15",
"type": "CHEMICAL",
"text": [
"Cyclothiazide"
],
"offsets": [
[
1907,
1920
]
],
"normalized": []
},
{
"id": "8882618_T16",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
1958,
1962
]
],
"normalized": []
},
{
"id": "8882618_T17",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
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[
344,
354
]
],
"normalized": []
},
{
"id": "8882618_T18",
"type": "CHEMICAL",
"text": [
"Cyclothiazide"
],
"offsets": [
[
2119,
2132
]
],
"normalized": []
},
{
"id": "8882618_T19",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
"offsets": [
[
2206,
2216
]
],
"normalized": []
},
{
"id": "8882618_T20",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
2220,
2224
]
],
"normalized": []
},
{
"id": "8882618_T21",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
"offsets": [
[
2281,
2291
]
],
"normalized": []
},
{
"id": "8882618_T22",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
"offsets": [
[
2329,
2339
]
],
"normalized": []
},
{
"id": "8882618_T23",
"type": "CHEMICAL",
"text": [
"GYKI 53405"
],
"offsets": [
[
375,
385
]
],
"normalized": []
},
{
"id": "8882618_T24",
"type": "CHEMICAL",
"text": [
"cyclothiazide"
],
"offsets": [
[
2417,
2430
]
],
"normalized": []
},
{
"id": "8882618_T25",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
2434,
2438
]
],
"normalized": []
},
{
"id": "8882618_T26",
"type": "CHEMICAL",
"text": [
"cyclothiazide"
],
"offsets": [
[
2519,
2532
]
],
"normalized": []
},
{
"id": "8882618_T27",
"type": "CHEMICAL",
"text": [
"2,3-benzodiazepines"
],
"offsets": [
[
2541,
2560
]
],
"normalized": []
},
{
"id": "8882618_T28",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
2596,
2600
]
],
"normalized": []
},
{
"id": "8882618_T29",
"type": "CHEMICAL",
"text": [
"GYKI 53655"
],
"offsets": [
[
406,
416
]
],
"normalized": []
},
{
"id": "8882618_T30",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
"offsets": [
[
2750,
2760
]
],
"normalized": []
},
{
"id": "8882618_T31",
"type": "CHEMICAL",
"text": [
"cyclothiazide"
],
"offsets": [
[
2765,
2778
]
],
"normalized": []
},
{
"id": "8882618_T32",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
2782,
2786
]
],
"normalized": []
},
{
"id": "8882618_T33",
"type": "CHEMICAL",
"text": [
"GYKI 52466"
],
"offsets": [
[
180,
190
]
],
"normalized": []
},
{
"id": "8882618_T34",
"type": "CHEMICAL",
"text": [
"GYKI 53405"
],
"offsets": [
[
192,
202
]
],
"normalized": []
},
{
"id": "8882618_T35",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
551,
555
]
],
"normalized": []
},
{
"id": "8882618_T36",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
622,
626
]
],
"normalized": []
},
{
"id": "8882618_T37",
"type": "CHEMICAL",
"text": [
"Cyclothiazide"
],
"offsets": [
[
648,
661
]
],
"normalized": []
},
{
"id": "8882618_T38",
"type": "CHEMICAL",
"text": [
"GYKI 53655"
],
"offsets": [
[
207,
217
]
],
"normalized": []
},
{
"id": "8882618_T39",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
716,
720
]
],
"normalized": []
},
{
"id": "8882618_T40",
"type": "CHEMICAL",
"text": [
"2,3-benzodiazepines"
],
"offsets": [
[
160,
179
]
],
"normalized": []
},
{
"id": "8882618_T41",
"type": "CHEMICAL",
"text": [
"cyclothiazide"
],
"offsets": [
[
895,
908
]
],
"normalized": []
},
{
"id": "8882618_T42",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
230,
234
]
],
"normalized": []
},
{
"id": "8882618_T43",
"type": "CHEMICAL",
"text": [
"Cyclothiazide"
],
"offsets": [
[
1013,
1026
]
],
"normalized": []
},
{
"id": "8882618_T44",
"type": "CHEMICAL",
"text": [
"2,3-benzodiazepines"
],
"offsets": [
[
1092,
1111
]
],
"normalized": []
},
{
"id": "8882618_T45",
"type": "CHEMICAL",
"text": [
"2,3-benzodiazepines"
],
"offsets": [
[
16,
35
]
],
"normalized": []
},
{
"id": "8882618_T46",
"type": "CHEMICAL",
"text": [
"cyclothiazide"
],
"offsets": [
[
40,
53
]
],
"normalized": []
},
{
"id": "8882618_T47",
"type": "CHEMICAL",
"text": [
"AMPA"
],
"offsets": [
[
57,
61
]
],
"normalized": []
},
{
"id": "8882618_T48",
"type": "GENE-N",
"text": [
"AMPA receptor"
],
"offsets": [
[
1767,
1780
]
],
"normalized": []
},
{
"id": "8882618_T49",
"type": "GENE-N",
"text": [
"AMPA receptor"
],
"offsets": [
[
1958,
1971
]
],
"normalized": []
},
{
"id": "8882618_T50",
"type": "GENE-N",
"text": [
"AMPA receptor"
],
"offsets": [
[
2220,
2233
]
],
"normalized": []
},
{
"id": "8882618_T51",
"type": "GENE-N",
"text": [
"AMPA receptor"
],
"offsets": [
[
2434,
2447
]
],
"normalized": []
},
{
"id": "8882618_T52",
"type": "GENE-N",
"text": [
"AMPA receptors"
],
"offsets": [
[
2596,
2610
]
],
"normalized": []
},
{
"id": "8882618_T53",
"type": "GENE-N",
"text": [
"AMPA receptor"
],
"offsets": [
[
2782,
2795
]
],
"normalized": []
},
{
"id": "8882618_T54",
"type": "GENE-N",
"text": [
"AMPA receptors"
],
"offsets": [
[
57,
71
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "8882618_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "8882618_T26",
"arg2_id": "8882618_T52",
"normalized": []
},
{
"id": "8882618_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "8882618_T27",
"arg2_id": "8882618_T52",
"normalized": []
},
{
"id": "8882618_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "8882618_T30",
"arg2_id": "8882618_T53",
"normalized": []
},
{
"id": "8882618_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "8882618_T31",
"arg2_id": "8882618_T53",
"normalized": []
}
] |
23318445 | 23318445 | [
{
"id": "23318445_title",
"type": "title",
"text": [
"Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi Anemia cells."
],
"offsets": [
[
0,
101
]
]
},
{
"id": "23318445_abstract",
"type": "abstract",
"text": [
"Fanconi Anemia (FA) is a rare genetic disorder associated with a bone-marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents. Majority of the 15 FA genes and encoded proteins characterized so far are integrated into DNA repair pathways, however, other important functions cannot be excluded. FA cells are sensitive to oxidants, and accumulation of oxidized proteins has been characterized for several FA subgroups. Clinical phenotypes of both FA and other closely related diseases suggest altered functions of mitochondria, organelles responsible for cellular energetic metabolism, and also serving as an important producer and the most susceptible target from reactive oxidative species (ROS). In this study, we have shown that elevated level of mitochondrial ROS in FA cells is in parallel with the decrease of mitochondrial membrane potential, the decrease of ATP production, impaired oxygen uptake and pathological changes in the morphology of mitochondria. This is accompanied by inactivation of enzymes that are essential for the energy production (F1F0ATPase and cytochrome C oxidase) and detoxification of ROS (superoxide dismutase, SOD1). In turn, overexpression of SOD1 could rescue oxygen consumption rate in FA-deficient cells. Importantly, the depletion of mitochondria improved survival rate of mitomycin C treated FA cells suggesting that hypersensitivity of FA cells to chemotherapeutic drugs could be in part due to the mitochondria-mediated oxidative stress. On the basis of our results, we propose that deficiency in FA genes lead to disabling mitochondrial ROS-scavenging machinery further affecting mitochondrial functions and suppressing cell respiration.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.583."
],
"offsets": [
[
102,
1889
]
]
}
] | [
{
"id": "23318445_T1",
"type": "CHEMICAL",
"text": [
"superoxide"
],
"offsets": [
[
1252,
1262
]
],
"normalized": []
},
{
"id": "23318445_T2",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
1326,
1332
]
],
"normalized": []
},
{
"id": "23318445_T3",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
1021,
1027
]
],
"normalized": []
},
{
"id": "23318445_T4",
"type": "GENE-N",
"text": [
"F1F0ATPase"
],
"offsets": [
[
1188,
1198
]
],
"normalized": []
},
{
"id": "23318445_T5",
"type": "GENE-N",
"text": [
"cytochrome C oxidase"
],
"offsets": [
[
1203,
1223
]
],
"normalized": []
},
{
"id": "23318445_T6",
"type": "GENE-N",
"text": [
"superoxide dismutase"
],
"offsets": [
[
1252,
1272
]
],
"normalized": []
},
{
"id": "23318445_T7",
"type": "GENE-Y",
"text": [
"SOD1"
],
"offsets": [
[
1274,
1278
]
],
"normalized": []
},
{
"id": "23318445_T8",
"type": "GENE-Y",
"text": [
"SOD1"
],
"offsets": [
[
1308,
1312
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23318445_0",
"type": "PRODUCT-OF",
"arg1_id": "23318445_T2",
"arg2_id": "23318445_T8",
"normalized": []
}
] |
17381051 | 17381051 | [
{
"id": "17381051_title",
"type": "title",
"text": [
"The role of glutathione transferases M1 and T1 in individual susceptibility to bladder cancer in a Tunisian population."
],
"offsets": [
[
0,
119
]
]
},
{
"id": "17381051_abstract",
"type": "abstract",
"text": [
"BACKGROUND: Susceptibility to bladder cancer is thought to depend on interplay between genetic factors and environmental chemical carcinogens. AIM: This study seeks to determine the role of the glutathione transferases M1 and T1 null genotypes (GSTM1*0 and GSTT1*0) in individual susceptibility to bladder cancer in a Tunisian population. METHOD: Sixty-two patients with transitional cell carcinoma of the bladder cancer and 79 controls were examined with respect to the frequency of GSTM1 and GSTT1 null genotypes. RESULTS: The frequencies of the GSTT1 null in the total group of bladder cancer cases vs. controls did not differ statistically. The proportion of GSTM1 null genotype in patients was 63% compared to 45% in controls group (OR = 2.03; 95% CI 0.97-4.24; p = 0.04). A significantly higher incidence of GSTM1 deletion genotype was found in smokers with bladder cancer compared to the controls (65.38% vs. 45.5%). Smokers lacking the GSTM1 gene are at an approximately 2.2-fold higher risk of bladder cancer (OR= 2.23, 95% CI 1-5.15; p = 0.03). CONCLUSION: This study suggests that in Tunisian subjects the GSTM1 null genotype may be associated with an increased risk of bladder cancer. This association appears to depend upon smoking status."
],
"offsets": [
[
120,
1372
]
]
}
] | [
{
"id": "17381051_T1",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
314,
325
]
],
"normalized": []
},
{
"id": "17381051_T2",
"type": "CHEMICAL",
"text": [
"glutathione"
],
"offsets": [
[
12,
23
]
],
"normalized": []
},
{
"id": "17381051_T3",
"type": "GENE-Y",
"text": [
"GSTM1"
],
"offsets": [
[
1237,
1242
]
],
"normalized": []
},
{
"id": "17381051_T4",
"type": "GENE-N",
"text": [
"glutathione transferases M1 and T1"
],
"offsets": [
[
314,
348
]
],
"normalized": []
},
{
"id": "17381051_T5",
"type": "GENE-Y",
"text": [
"GSTM1"
],
"offsets": [
[
365,
370
]
],
"normalized": []
},
{
"id": "17381051_T6",
"type": "GENE-Y",
"text": [
"GSTT1"
],
"offsets": [
[
377,
382
]
],
"normalized": []
},
{
"id": "17381051_T7",
"type": "GENE-Y",
"text": [
"GSTM1"
],
"offsets": [
[
604,
609
]
],
"normalized": []
},
{
"id": "17381051_T8",
"type": "GENE-Y",
"text": [
"GSTT1"
],
"offsets": [
[
614,
619
]
],
"normalized": []
},
{
"id": "17381051_T9",
"type": "GENE-Y",
"text": [
"GSTT1"
],
"offsets": [
[
668,
673
]
],
"normalized": []
},
{
"id": "17381051_T10",
"type": "GENE-Y",
"text": [
"GSTM1"
],
"offsets": [
[
783,
788
]
],
"normalized": []
},
{
"id": "17381051_T11",
"type": "GENE-Y",
"text": [
"GSTM1"
],
"offsets": [
[
934,
939
]
],
"normalized": []
},
{
"id": "17381051_T12",
"type": "GENE-Y",
"text": [
"GSTM1"
],
"offsets": [
[
1064,
1069
]
],
"normalized": []
},
{
"id": "17381051_T13",
"type": "GENE-N",
"text": [
"glutathione transferases M1 and T1"
],
"offsets": [
[
12,
46
]
],
"normalized": []
}
] | [] | [] | [] |
23557688 | 23557688 | [
{
"id": "23557688_title",
"type": "title",
"text": [
"Environmental pesticide exposure modulates cytokines, arginase and ornithine decarboxylase expression in human placenta."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "23557688_abstract",
"type": "abstract",
"text": [
"To evaluate the cytokine balance and enzymatic alterations induced by environmental pesticide exposure during pregnancy, this transversal study explored placentas derived from non-exposed women (control group-CG), and from women living in a rural area (rural group-RG), collected during intensive organophosphate (OP) pesticide spraying season (RG-SS) and during non-spraying season (RG-NSS). The exposure biomarkers blood cholinesterase and placental carboxylesterase (CaE) were significantly decreased in RG-SS. Among the cytokines studied IL-8, IL-6, TNFα, IL-10, TGFβ and IL-13, the expression frequency of IL-13 increased in RG-SS. Arginase and ornithine decarboxylase (ODC) enzymes were induced in syncytiotrophoblast and endothelial cells. Interestingly, the decrease in CaE activity was associated with arginase and ODC activity induction. These findings suggest that environmental pesticide exposure impacts the placenta by increasing the expression frequency of the anti-inflammatory cytokine IL-13, which may be related to the up-regulation of enzymes implicated in tissue repair."
],
"offsets": [
[
121,
1212
]
]
}
] | [
{
"id": "23557688_T1",
"type": "CHEMICAL",
"text": [
"organophosphate"
],
"offsets": [
[
418,
433
]
],
"normalized": []
},
{
"id": "23557688_T2",
"type": "CHEMICAL",
"text": [
"ornithine"
],
"offsets": [
[
771,
780
]
],
"normalized": []
},
{
"id": "23557688_T3",
"type": "CHEMICAL",
"text": [
"ornithine"
],
"offsets": [
[
67,
76
]
],
"normalized": []
},
{
"id": "23557688_T4",
"type": "GENE-Y",
"text": [
"IL-13"
],
"offsets": [
[
1124,
1129
]
],
"normalized": []
},
{
"id": "23557688_T5",
"type": "GENE-N",
"text": [
"cytokine"
],
"offsets": [
[
137,
145
]
],
"normalized": []
},
{
"id": "23557688_T6",
"type": "GENE-Y",
"text": [
"cholinesterase"
],
"offsets": [
[
544,
558
]
],
"normalized": []
},
{
"id": "23557688_T7",
"type": "GENE-N",
"text": [
"carboxylesterase"
],
"offsets": [
[
573,
589
]
],
"normalized": []
},
{
"id": "23557688_T8",
"type": "GENE-N",
"text": [
"CaE"
],
"offsets": [
[
591,
594
]
],
"normalized": []
},
{
"id": "23557688_T9",
"type": "GENE-N",
"text": [
"cytokines"
],
"offsets": [
[
645,
654
]
],
"normalized": []
},
{
"id": "23557688_T10",
"type": "GENE-Y",
"text": [
"IL-8"
],
"offsets": [
[
663,
667
]
],
"normalized": []
},
{
"id": "23557688_T11",
"type": "GENE-Y",
"text": [
"IL-6"
],
"offsets": [
[
669,
673
]
],
"normalized": []
},
{
"id": "23557688_T12",
"type": "GENE-Y",
"text": [
"TNFα"
],
"offsets": [
[
675,
679
]
],
"normalized": []
},
{
"id": "23557688_T13",
"type": "GENE-Y",
"text": [
"IL-10"
],
"offsets": [
[
681,
686
]
],
"normalized": []
},
{
"id": "23557688_T14",
"type": "GENE-Y",
"text": [
"TGFβ"
],
"offsets": [
[
688,
692
]
],
"normalized": []
},
{
"id": "23557688_T15",
"type": "GENE-Y",
"text": [
"IL-13"
],
"offsets": [
[
697,
702
]
],
"normalized": []
},
{
"id": "23557688_T16",
"type": "GENE-Y",
"text": [
"IL-13"
],
"offsets": [
[
732,
737
]
],
"normalized": []
},
{
"id": "23557688_T17",
"type": "GENE-N",
"text": [
"Arginase"
],
"offsets": [
[
758,
766
]
],
"normalized": []
},
{
"id": "23557688_T18",
"type": "GENE-Y",
"text": [
"ornithine decarboxylase"
],
"offsets": [
[
771,
794
]
],
"normalized": []
},
{
"id": "23557688_T19",
"type": "GENE-Y",
"text": [
"ODC"
],
"offsets": [
[
796,
799
]
],
"normalized": []
},
{
"id": "23557688_T20",
"type": "GENE-N",
"text": [
"CaE"
],
"offsets": [
[
899,
902
]
],
"normalized": []
},
{
"id": "23557688_T21",
"type": "GENE-Y",
"text": [
"ODC"
],
"offsets": [
[
945,
948
]
],
"normalized": []
},
{
"id": "23557688_T22",
"type": "GENE-N",
"text": [
"cytokine"
],
"offsets": [
[
1115,
1123
]
],
"normalized": []
},
{
"id": "23557688_T23",
"type": "GENE-N",
"text": [
"cytokines"
],
"offsets": [
[
43,
52
]
],
"normalized": []
},
{
"id": "23557688_T24",
"type": "GENE-N",
"text": [
"arginase"
],
"offsets": [
[
54,
62
]
],
"normalized": []
},
{
"id": "23557688_T25",
"type": "GENE-Y",
"text": [
"ornithine decarboxylase"
],
"offsets": [
[
67,
90
]
],
"normalized": []
}
] | [] | [] | [] |
23298577 | 23298577 | [
{
"id": "23298577_title",
"type": "title",
"text": [
"Synthesis, characterization and targeting potential of zidovudine loaded sialic acid conjugated-mannosylated poly(propyleneimine) dendrimers."
],
"offsets": [
[
0,
141
]
]
},
{
"id": "23298577_abstract",
"type": "abstract",
"text": [
"The present investigation was aimed at exploring dual targeting of anti-HIV drug, zidovudine (ZDV) via sialic acid conjugated-mannosylated poly(propyleneimine) (PPI) dendritic nano-constructs. Fourth generation PPI dendrimers, sialic acid conjugated PPI dendrimers (SPPI), mannose conjugated PPI dendrimers (MPPI) and dual ligand system i.e. sialic acid conjugated-mannosylated PPI dendrimers (SMPPI) were synthesized and characterized by FT-IR and (1)H NMR spectroscopies and were further confirmed by size exclusion chromatography and differential scanning calorimetry. Various parameters like drug loading, pH dependent in vitro release, hemolytic toxicity, macrophage uptake and cytotoxicity concerning PPI, SPPI, MPPI and SMPPI dendrimers were evaluated. ZDV loaded SMPPI, SPPI and MPPI have shown reduced hemolytic toxicity, cytotoxicity and in vitro drug release at pH 7.4. Extremely significant (P<0.001) increase in cellular uptake of ZDV by macrophage cells was observed in case of SMPPI as compared to PPI and free drug. The in vivo blood level and tissue distribution studies in albino rats also demonstrated potential of dual targeted system towards sialoadhesin and carbohydrate receptors. The drug concentration in lymph nodes was increased to about 28 times in case of SMPPI (1335 ± 17.6 ng/g) as compared to free drug (48 ± 5.8 ng/g) at 6th hr. The results suggested that such dual ligand dendritic system (SMPPI) hold potential to enhance biocompatibility and site specific delivery of antiretroviral drug, ZDV."
],
"offsets": [
[
142,
1671
]
]
}
] | [
{
"id": "23298577_T1",
"type": "CHEMICAL",
"text": [
"PPI"
],
"offsets": [
[
1155,
1158
]
],
"normalized": []
},
{
"id": "23298577_T2",
"type": "CHEMICAL",
"text": [
"sialic acid"
],
"offsets": [
[
245,
256
]
],
"normalized": []
},
{
"id": "23298577_T3",
"type": "CHEMICAL",
"text": [
"carbohydrate"
],
"offsets": [
[
1322,
1334
]
],
"normalized": []
},
{
"id": "23298577_T4",
"type": "CHEMICAL",
"text": [
"mannosylated poly(propyleneimine)"
],
"offsets": [
[
268,
301
]
],
"normalized": []
},
{
"id": "23298577_T5",
"type": "CHEMICAL",
"text": [
"ZDV"
],
"offsets": [
[
1667,
1670
]
],
"normalized": []
},
{
"id": "23298577_T6",
"type": "CHEMICAL",
"text": [
"PPI"
],
"offsets": [
[
303,
306
]
],
"normalized": []
},
{
"id": "23298577_T7",
"type": "CHEMICAL",
"text": [
"PPI"
],
"offsets": [
[
353,
356
]
],
"normalized": []
},
{
"id": "23298577_T8",
"type": "CHEMICAL",
"text": [
"sialic acid"
],
"offsets": [
[
369,
380
]
],
"normalized": []
},
{
"id": "23298577_T9",
"type": "CHEMICAL",
"text": [
"PPI"
],
"offsets": [
[
392,
395
]
],
"normalized": []
},
{
"id": "23298577_T10",
"type": "CHEMICAL",
"text": [
"mannose"
],
"offsets": [
[
415,
422
]
],
"normalized": []
},
{
"id": "23298577_T11",
"type": "CHEMICAL",
"text": [
"PPI"
],
"offsets": [
[
434,
437
]
],
"normalized": []
},
{
"id": "23298577_T12",
"type": "CHEMICAL",
"text": [
"sialic acid"
],
"offsets": [
[
484,
495
]
],
"normalized": []
},
{
"id": "23298577_T13",
"type": "CHEMICAL",
"text": [
"mannosylated PPI"
],
"offsets": [
[
507,
523
]
],
"normalized": []
},
{
"id": "23298577_T14",
"type": "CHEMICAL",
"text": [
"(1)H"
],
"offsets": [
[
591,
595
]
],
"normalized": []
},
{
"id": "23298577_T15",
"type": "CHEMICAL",
"text": [
"PPI"
],
"offsets": [
[
849,
852
]
],
"normalized": []
},
{
"id": "23298577_T16",
"type": "CHEMICAL",
"text": [
"ZDV"
],
"offsets": [
[
902,
905
]
],
"normalized": []
},
{
"id": "23298577_T17",
"type": "CHEMICAL",
"text": [
"zidovudine"
],
"offsets": [
[
224,
234
]
],
"normalized": []
},
{
"id": "23298577_T18",
"type": "CHEMICAL",
"text": [
"ZDV"
],
"offsets": [
[
1086,
1089
]
],
"normalized": []
},
{
"id": "23298577_T19",
"type": "CHEMICAL",
"text": [
"ZDV"
],
"offsets": [
[
236,
239
]
],
"normalized": []
},
{
"id": "23298577_T20",
"type": "CHEMICAL",
"text": [
"zidovudine"
],
"offsets": [
[
55,
65
]
],
"normalized": []
},
{
"id": "23298577_T21",
"type": "CHEMICAL",
"text": [
"sialic acid"
],
"offsets": [
[
73,
84
]
],
"normalized": []
},
{
"id": "23298577_T22",
"type": "CHEMICAL",
"text": [
"mannosylated poly(propyleneimine)"
],
"offsets": [
[
96,
129
]
],
"normalized": []
},
{
"id": "23298577_T23",
"type": "GENE-Y",
"text": [
"sialoadhesin"
],
"offsets": [
[
1305,
1317
]
],
"normalized": []
},
{
"id": "23298577_T24",
"type": "GENE-N",
"text": [
"carbohydrate receptors"
],
"offsets": [
[
1322,
1344
]
],
"normalized": []
}
] | [] | [] | [] |
9336833 | 9336833 | [
{
"id": "9336833_title",
"type": "title",
"text": [
"The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue."
],
"offsets": [
[
0,
120
]
]
},
{
"id": "9336833_abstract",
"type": "abstract",
"text": [
"Thymidine kinase from Herpes simplex virus type 1 (TK) was crystallized in an N-terminally truncated but fully active form. The structures of TK complexed with ADP at the ATP-site and deoxythymidine-5'-monophosphate (dTMP), deoxythymidine (dT), or idoxuridine-5'-phosphate (5-iodo-dUMP) at the substrate-site were refined to 2.75 A, 2.8 A, and 3.0 A resolution, respectively. TK catalyzes the phosphorylation of dT resulting in an ester, and the phosphorylation of dTMP giving rise to an anhydride. The presented TK structures indicate that there are only small differences between these two modes of action. Glu83 serves as a general base in the ester reaction. Arg163 parks at an internal aspartate during ester formation and binds the alpha-phosphate of dTMP during anhydride formation. The bound deoxythymidine leaves a 35 A3 cavity at position 5 of the base and two sequestered water molecules at position 2. Cavity and water molecules reduce the substrate specificity to such an extent that TK can phosphorylate various substrate analogues useful in pharmaceutical applications. TK is structurally homologous to the well-known nucleoside monophosphate kinases but contains large additional peptide segments."
],
"offsets": [
[
121,
1334
]
]
}
] | [
{
"id": "9336833_T1",
"type": "CHEMICAL",
"text": [
"Thymidine"
],
"offsets": [
[
121,
130
]
],
"normalized": []
},
{
"id": "9336833_T2",
"type": "CHEMICAL",
"text": [
"phosphorylate"
],
"offsets": [
[
1125,
1138
]
],
"normalized": []
},
{
"id": "9336833_T3",
"type": "CHEMICAL",
"text": [
"TK"
],
"offsets": [
[
1206,
1208
]
],
"normalized": []
},
{
"id": "9336833_T4",
"type": "CHEMICAL",
"text": [
"nucleoside monophosphate"
],
"offsets": [
[
1254,
1278
]
],
"normalized": []
},
{
"id": "9336833_T5",
"type": "CHEMICAL",
"text": [
"ADP"
],
"offsets": [
[
281,
284
]
],
"normalized": []
},
{
"id": "9336833_T6",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
292,
295
]
],
"normalized": []
},
{
"id": "9336833_T7",
"type": "CHEMICAL",
"text": [
"deoxythymidine-5'-monophosphate"
],
"offsets": [
[
305,
336
]
],
"normalized": []
},
{
"id": "9336833_T8",
"type": "CHEMICAL",
"text": [
"dTMP"
],
"offsets": [
[
338,
342
]
],
"normalized": []
},
{
"id": "9336833_T9",
"type": "CHEMICAL",
"text": [
"deoxythymidine"
],
"offsets": [
[
345,
359
]
],
"normalized": []
},
{
"id": "9336833_T10",
"type": "CHEMICAL",
"text": [
"dT"
],
"offsets": [
[
361,
363
]
],
"normalized": []
},
{
"id": "9336833_T11",
"type": "CHEMICAL",
"text": [
"idoxuridine-5'-phosphate"
],
"offsets": [
[
369,
393
]
],
"normalized": []
},
{
"id": "9336833_T12",
"type": "CHEMICAL",
"text": [
"5-iodo-dUMP"
],
"offsets": [
[
395,
406
]
],
"normalized": []
},
{
"id": "9336833_T13",
"type": "CHEMICAL",
"text": [
"TK"
],
"offsets": [
[
497,
499
]
],
"normalized": []
},
{
"id": "9336833_T14",
"type": "CHEMICAL",
"text": [
"dT"
],
"offsets": [
[
533,
535
]
],
"normalized": []
},
{
"id": "9336833_T15",
"type": "CHEMICAL",
"text": [
"ester"
],
"offsets": [
[
552,
557
]
],
"normalized": []
},
{
"id": "9336833_T16",
"type": "CHEMICAL",
"text": [
"dTMP"
],
"offsets": [
[
586,
590
]
],
"normalized": []
},
{
"id": "9336833_T17",
"type": "CHEMICAL",
"text": [
"anhydride"
],
"offsets": [
[
609,
618
]
],
"normalized": []
},
{
"id": "9336833_T18",
"type": "CHEMICAL",
"text": [
"TK"
],
"offsets": [
[
634,
636
]
],
"normalized": []
},
{
"id": "9336833_T19",
"type": "CHEMICAL",
"text": [
"ester"
],
"offsets": [
[
768,
773
]
],
"normalized": []
},
{
"id": "9336833_T20",
"type": "CHEMICAL",
"text": [
"aspartate"
],
"offsets": [
[
812,
821
]
],
"normalized": []
},
{
"id": "9336833_T21",
"type": "CHEMICAL",
"text": [
"ester"
],
"offsets": [
[
829,
834
]
],
"normalized": []
},
{
"id": "9336833_T22",
"type": "CHEMICAL",
"text": [
"alpha-phosphate"
],
"offsets": [
[
859,
874
]
],
"normalized": []
},
{
"id": "9336833_T23",
"type": "CHEMICAL",
"text": [
"dTMP"
],
"offsets": [
[
878,
882
]
],
"normalized": []
},
{
"id": "9336833_T24",
"type": "CHEMICAL",
"text": [
"anhydride"
],
"offsets": [
[
890,
899
]
],
"normalized": []
},
{
"id": "9336833_T25",
"type": "CHEMICAL",
"text": [
"N"
],
"offsets": [
[
199,
200
]
],
"normalized": []
},
{
"id": "9336833_T26",
"type": "CHEMICAL",
"text": [
"deoxythymidine"
],
"offsets": [
[
921,
935
]
],
"normalized": []
},
{
"id": "9336833_T27",
"type": "CHEMICAL",
"text": [
"TK"
],
"offsets": [
[
1118,
1120
]
],
"normalized": []
},
{
"id": "9336833_T28",
"type": "CHEMICAL",
"text": [
"thymidine"
],
"offsets": [
[
18,
27
]
],
"normalized": []
},
{
"id": "9336833_T29",
"type": "GENE-Y",
"text": [
"Thymidine kinase"
],
"offsets": [
[
121,
137
]
],
"normalized": []
},
{
"id": "9336833_T30",
"type": "GENE-Y",
"text": [
"TK"
],
"offsets": [
[
1206,
1208
]
],
"normalized": []
},
{
"id": "9336833_T31",
"type": "GENE-N",
"text": [
"nucleoside monophosphate kinases"
],
"offsets": [
[
1254,
1286
]
],
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"type": "GENE-Y",
"text": [
"thymidine kinase"
],
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[
18,
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]
],
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}
] | [] | [] | [
{
"id": "9336833_0",
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"arg2_id": "9336833_T35",
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},
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"id": "9336833_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "9336833_T5",
"arg2_id": "9336833_T32",
"normalized": []
}
] |
16940412 | 16940412 | [
{
"id": "16940412_title",
"type": "title",
"text": [
"Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin."
],
"offsets": [
[
0,
160
]
]
},
{
"id": "16940412_abstract",
"type": "abstract",
"text": [
"The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. Neither compound seemed to induce an aberrant tubulin assembly reaction, as occurs with vinblastine (tight spirals) or dolastatin 10 (aggregated rings and spirals). We modeled the two compounds into a shared binding site on tubulin consistent with their biochemical properties. Of the two tubulin structures available, we selected for modeling the complex of a stathmin fragment with two tubulin heterodimers with two bound colchicinoid molecules and a single bound vinblastine between the two heterodimers (Nature (Lond) 435:519-522, 2005). Halichondrin B and NSC 707389 fit snugly between the two heterodimers adjacent to the exchangeable site nucleotide. Fitting the compounds into this site, which was also close to the vinblastine site, resulted in enough movement of amino acid residues at the vinblastine site to cause the latter compound to bind less well to tubulin. The model suggests that halichondrin B and NSC 707389 most likely form highly unstable, small aberrant tubulin polymers rather than the massive stable structures observed with vinca alkaloids and antimitotic peptides."
],
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[
161,
1759
]
]
}
] | [
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"id": "16940412_T1",
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"Halichondrin B"
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1208,
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]
],
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"id": "16940412_T2",
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"NSC 707389"
],
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1227,
1237
]
],
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{
"id": "16940412_T3",
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"text": [
"nucleotide"
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1312,
1322
]
],
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"id": "16940412_T4",
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"vinblastine"
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1390,
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]
],
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"id": "16940412_T5",
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"text": [
"amino acid"
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1439,
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]
],
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},
{
"id": "16940412_T6",
"type": "CHEMICAL",
"text": [
"vinblastine"
],
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[
1466,
1477
]
],
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},
{
"id": "16940412_T7",
"type": "CHEMICAL",
"text": [
"ketone"
],
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[
298,
304
]
],
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},
{
"id": "16940412_T8",
"type": "CHEMICAL",
"text": [
"halichondrin B"
],
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1566,
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]
],
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"id": "16940412_T9",
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"text": [
"NSC 707389"
],
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1585,
1595
]
],
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"id": "16940412_T10",
"type": "CHEMICAL",
"text": [
"NSC 707389"
],
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376,
386
]
],
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},
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"id": "16940412_T11",
"type": "CHEMICAL",
"text": [
"halichondrin B"
],
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[
419,
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]
],
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},
{
"id": "16940412_T12",
"type": "CHEMICAL",
"text": [
"halichondrin B"
],
"offsets": [
[
196,
210
]
],
"normalized": []
},
{
"id": "16940412_T13",
"type": "CHEMICAL",
"text": [
"nucleotide"
],
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[
521,
531
]
],
"normalized": []
},
{
"id": "16940412_T14",
"type": "CHEMICAL",
"text": [
"vinblastine"
],
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[
624,
635
]
],
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},
{
"id": "16940412_T15",
"type": "CHEMICAL",
"text": [
"dolastatin"
],
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[
640,
650
]
],
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},
{
"id": "16940412_T16",
"type": "CHEMICAL",
"text": [
"vinblastine"
],
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[
754,
765
]
],
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},
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"id": "16940412_T17",
"type": "CHEMICAL",
"text": [
"dolastatin"
],
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[
785,
795
]
],
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},
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"id": "16940412_T18",
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"NSC 707389"
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229,
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]
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"text": [
"E7389"
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241,
246
]
],
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"id": "16940412_T20",
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"text": [
"vinblastine"
],
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1132,
1143
]
],
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},
{
"id": "16940412_T21",
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"text": [
"halichondrin B"
],
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[
46,
60
]
],
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{
"id": "16940412_T22",
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"text": [
"NSC 707389"
],
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[
68,
78
]
],
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{
"id": "16940412_T23",
"type": "CHEMICAL",
"text": [
"E7389"
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80,
85
]
],
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},
{
"id": "16940412_T24",
"type": "GENE-N",
"text": [
"tubulin"
],
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[
1533,
1540
]
],
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},
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"id": "16940412_T25",
"type": "GENE-N",
"text": [
"tubulin"
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1645,
1652
]
],
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},
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"id": "16940412_T26",
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"text": [
"tubulin"
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459,
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]
],
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},
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"id": "16940412_T27",
"type": "GENE-N",
"text": [
"tubulin"
],
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[
493,
500
]
],
"normalized": []
},
{
"id": "16940412_T28",
"type": "GENE-Y",
"text": [
"beta-tubulin"
],
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[
544,
556
]
],
"normalized": []
},
{
"id": "16940412_T29",
"type": "GENE-N",
"text": [
"tubulin"
],
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657,
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]
],
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},
{
"id": "16940412_T30",
"type": "GENE-N",
"text": [
"tubulin"
],
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712,
719
]
],
"normalized": []
},
{
"id": "16940412_T31",
"type": "GENE-N",
"text": [
"tubulin"
],
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[
890,
897
]
],
"normalized": []
},
{
"id": "16940412_T32",
"type": "GENE-N",
"text": [
"tubulin"
],
"offsets": [
[
955,
962
]
],
"normalized": []
},
{
"id": "16940412_T33",
"type": "GENE-Y",
"text": [
"stathmin"
],
"offsets": [
[
1027,
1035
]
],
"normalized": []
},
{
"id": "16940412_T34",
"type": "GENE-N",
"text": [
"tubulin"
],
"offsets": [
[
1054,
1061
]
],
"normalized": []
},
{
"id": "16940412_T35",
"type": "GENE-N",
"text": [
"tubulin"
],
"offsets": [
[
152,
159
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16940412_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T21",
"arg2_id": "16940412_T35",
"normalized": []
},
{
"id": "16940412_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T22",
"arg2_id": "16940412_T35",
"normalized": []
},
{
"id": "16940412_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T23",
"arg2_id": "16940412_T35",
"normalized": []
},
{
"id": "16940412_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T10",
"arg2_id": "16940412_T26",
"normalized": []
},
{
"id": "16940412_4",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T11",
"arg2_id": "16940412_T26",
"normalized": []
},
{
"id": "16940412_5",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T15",
"arg2_id": "16940412_T29",
"normalized": []
},
{
"id": "16940412_6",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T14",
"arg2_id": "16940412_T29",
"normalized": []
},
{
"id": "16940412_7",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T20",
"arg2_id": "16940412_T33",
"normalized": []
},
{
"id": "16940412_8",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T20",
"arg2_id": "16940412_T34",
"normalized": []
},
{
"id": "16940412_9",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T6",
"arg2_id": "16940412_T24",
"normalized": []
},
{
"id": "16940412_10",
"type": "PART-OF",
"arg1_id": "16940412_T5",
"arg2_id": "16940412_T24",
"normalized": []
},
{
"id": "16940412_11",
"type": "DIRECT-REGULATOR",
"arg1_id": "16940412_T4",
"arg2_id": "16940412_T24",
"normalized": []
}
] |
12522078 | 12522078 | [
{
"id": "12522078_title",
"type": "title",
"text": [
"Evidence against beta 3-adrenoceptors or low affinity state of beta 1-adrenoceptors mediating relaxation in rat isolated aorta."
],
"offsets": [
[
0,
127
]
]
},
{
"id": "12522078_abstract",
"type": "abstract",
"text": [
"1 The presence of beta(3)-adrenoceptors and the low affinity state of the beta(1)-adrenoceptor (formerly \"putative beta(4)-adrenoceptor\") was investigated in ring preparations of rat isolated aorta preconstricted with phenylephrine or prostaglandin F(2alpha) (PGF(2alpha)). Relaxant responses to isoprenaline, selective beta(3)-adrenoceptor agonists (BRL 37344, SR 58611A, CL 316243) and non-conventional partial agonists (CGP 12177A, cyanopindolol, pindolol) were obtained. 2 In phenylephrine-constricted, but not PGF(2alpha)-constricted rings, relaxations to isoprenaline showed a propranolol-resistant component. 3 In phenylephrine-constricted rings, relaxations to BRL 37344 (pEC(50), 4.64) and SR 58611A (pEC(50), 4.94) were not antagonized by the selective beta(3)-adrenoceptor antagonist SR 59230A (< or =1 microM). CL 316243 (< or =100 microM) failed to produce relaxation. In PGF(2alpha)-constricted rings only SR 58611A produced relaxation, which was not affected by SR 59230A (< or =3 microM). 4 Non-conventional partial agonists produced relaxation in phenylephrine-constricted but not PGF(2alpha)-constricted rings. The relaxation to CGP 12177A was unaffected by SR 59230A (< or =1 microM) or by CGP 20712A (10 microM), reported to block the low affinity state of the beta(1)-adrenoceptor. 5 beta-adrenoceptor antagonists also produced relaxation in phenylephrine-constricted rings with an order of potency of (pEC(50) values): bupranolol (5.5) approximately 38;SR 59230A (5.47) approximately 38;cyanopindolol (5.47)>pindolol (5.30)>alprenolol (5.10)>propranolol (4.83)>ICI 118551 (4.60)>CGP 12177A (4.38) approximately 38;CGP 20712A (4.35). Bupranolol (100 microM), alprenolol (30 microM), propranolol (100 microM) and SR 59230A (10 microM) produced no relaxation in PGF(2alpha)-constricted rings. 6 These results provide no evidence for the presence of functional beta(3)-adrenoceptors or the low affinity state of the beta(1)-adrenoceptor in rat aorta."
],
"offsets": [
[
128,
2096
]
]
}
] | [
{
"id": "12522078_T1",
"type": "CHEMICAL",
"text": [
"phenylephrine"
],
"offsets": [
[
1192,
1205
]
],
"normalized": []
},
{
"id": "12522078_T2",
"type": "CHEMICAL",
"text": [
"PGF(2alpha)"
],
"offsets": [
[
1226,
1237
]
],
"normalized": []
},
{
"id": "12522078_T3",
"type": "CHEMICAL",
"text": [
"CGP 12177A"
],
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[
1275,
1285
]
],
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},
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"id": "12522078_T4",
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"SR 59230A"
],
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1304,
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]
],
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},
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"id": "12522078_T5",
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"CGP 20712A"
],
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[
1337,
1347
]
],
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},
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"id": "12522078_T6",
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"text": [
"phenylephrine"
],
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1491,
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]
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"id": "12522078_T7",
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"bupranolol"
],
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]
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"id": "12522078_T8",
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"SR 59230A"
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1603,
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]
],
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"id": "12522078_T9",
"type": "CHEMICAL",
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"cyanopindolol"
],
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1637,
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]
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"id": "12522078_T10",
"type": "CHEMICAL",
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"pindolol"
],
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1658,
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]
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"id": "12522078_T11",
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"alprenolol"
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]
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"id": "12522078_T12",
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"propranolol"
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1703
]
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"ICI 118551"
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"CGP 20712A"
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1764,
1774
]
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"id": "12522078_T16",
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"Bupranolol"
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1783,
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"alprenolol"
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"propranolol"
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1832,
1843
]
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"id": "12522078_T19",
"type": "CHEMICAL",
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"SR 59230A"
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1861,
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]
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"id": "12522078_T20",
"type": "CHEMICAL",
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"PGF(2alpha)"
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1920
]
],
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},
{
"id": "12522078_T21",
"type": "CHEMICAL",
"text": [
"phenylephrine"
],
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[
346,
359
]
],
"normalized": []
},
{
"id": "12522078_T22",
"type": "CHEMICAL",
"text": [
"prostaglandin F(2alpha)"
],
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[
363,
386
]
],
"normalized": []
},
{
"id": "12522078_T23",
"type": "CHEMICAL",
"text": [
"PGF(2alpha)"
],
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[
388,
399
]
],
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},
{
"id": "12522078_T24",
"type": "CHEMICAL",
"text": [
"isoprenaline"
],
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[
424,
436
]
],
"normalized": []
},
{
"id": "12522078_T25",
"type": "CHEMICAL",
"text": [
"BRL 37344"
],
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[
479,
488
]
],
"normalized": []
},
{
"id": "12522078_T26",
"type": "CHEMICAL",
"text": [
"SR 58611A"
],
"offsets": [
[
490,
499
]
],
"normalized": []
},
{
"id": "12522078_T27",
"type": "CHEMICAL",
"text": [
"CL 316243"
],
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[
501,
510
]
],
"normalized": []
},
{
"id": "12522078_T28",
"type": "CHEMICAL",
"text": [
"CGP 12177A"
],
"offsets": [
[
551,
561
]
],
"normalized": []
},
{
"id": "12522078_T29",
"type": "CHEMICAL",
"text": [
"cyanopindolol"
],
"offsets": [
[
563,
576
]
],
"normalized": []
},
{
"id": "12522078_T30",
"type": "CHEMICAL",
"text": [
"pindolol"
],
"offsets": [
[
578,
586
]
],
"normalized": []
},
{
"id": "12522078_T31",
"type": "CHEMICAL",
"text": [
"phenylephrine"
],
"offsets": [
[
608,
621
]
],
"normalized": []
},
{
"id": "12522078_T32",
"type": "CHEMICAL",
"text": [
"PGF(2alpha)"
],
"offsets": [
[
643,
654
]
],
"normalized": []
},
{
"id": "12522078_T33",
"type": "CHEMICAL",
"text": [
"isoprenaline"
],
"offsets": [
[
689,
701
]
],
"normalized": []
},
{
"id": "12522078_T34",
"type": "CHEMICAL",
"text": [
"propranolol"
],
"offsets": [
[
711,
722
]
],
"normalized": []
},
{
"id": "12522078_T35",
"type": "CHEMICAL",
"text": [
"phenylephrine"
],
"offsets": [
[
749,
762
]
],
"normalized": []
},
{
"id": "12522078_T36",
"type": "CHEMICAL",
"text": [
"BRL 37344"
],
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[
797,
806
]
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"normalized": []
},
{
"id": "12522078_T37",
"type": "CHEMICAL",
"text": [
"SR 58611A"
],
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[
827,
836
]
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"normalized": []
},
{
"id": "12522078_T38",
"type": "CHEMICAL",
"text": [
"SR 59230A"
],
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923,
932
]
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},
{
"id": "12522078_T39",
"type": "CHEMICAL",
"text": [
"CL 316243"
],
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951,
960
]
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},
{
"id": "12522078_T40",
"type": "CHEMICAL",
"text": [
"PGF(2alpha)"
],
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[
1013,
1024
]
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},
{
"id": "12522078_T41",
"type": "CHEMICAL",
"text": [
"SR 58611A"
],
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[
1048,
1057
]
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},
{
"id": "12522078_T42",
"type": "CHEMICAL",
"text": [
"SR 59230A"
],
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1105,
1114
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},
{
"id": "12522078_T43",
"type": "GENE-Y",
"text": [
"putative beta(4)-adrenoceptor"
],
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234,
263
]
],
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},
{
"id": "12522078_T44",
"type": "GENE-Y",
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"beta(1)-adrenoceptor"
],
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1409,
1429
]
],
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},
{
"id": "12522078_T45",
"type": "GENE-N",
"text": [
"beta-adrenoceptor"
],
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1433,
1450
]
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},
{
"id": "12522078_T46",
"type": "GENE-Y",
"text": [
"beta(3)-adrenoceptors"
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146,
167
]
],
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},
{
"id": "12522078_T47",
"type": "GENE-Y",
"text": [
"beta(3)-adrenoceptors"
],
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[
2007,
2028
]
],
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},
{
"id": "12522078_T48",
"type": "GENE-Y",
"text": [
"beta(1)-adrenoceptor"
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2062,
2082
]
],
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},
{
"id": "12522078_T49",
"type": "GENE-Y",
"text": [
"beta(3)-adrenoceptor"
],
"offsets": [
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448,
468
]
],
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},
{
"id": "12522078_T50",
"type": "GENE-Y",
"text": [
"beta(1)-adrenoceptor"
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202,
222
]
],
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},
{
"id": "12522078_T51",
"type": "GENE-Y",
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"beta(3)-adrenoceptor"
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891,
911
]
],
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},
{
"id": "12522078_T52",
"type": "GENE-Y",
"text": [
"beta 3-adrenoceptors"
],
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17,
37
]
],
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},
{
"id": "12522078_T53",
"type": "GENE-Y",
"text": [
"beta 1-adrenoceptors"
],
"offsets": [
[
63,
83
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "12522078_0",
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},
{
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},
{
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},
{
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},
{
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},
{
"id": "12522078_5",
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},
{
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},
{
"id": "12522078_7",
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"arg2_id": "12522078_T51",
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},
{
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},
{
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"arg2_id": "12522078_T45",
"normalized": []
},
{
"id": "12522078_10",
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},
{
"id": "12522078_11",
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},
{
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"arg2_id": "12522078_T45",
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},
{
"id": "12522078_13",
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},
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},
{
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},
{
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"arg2_id": "12522078_T45",
"normalized": []
},
{
"id": "12522078_17",
"type": "ANTAGONIST",
"arg1_id": "12522078_T15",
"arg2_id": "12522078_T45",
"normalized": []
}
] |
23483103 | 23483103 | [
{
"id": "23483103_title",
"type": "title",
"text": [
"The induction of mitochondria-mediated apoptosis in cancer cells by ruthenium(ii) asymmetric complexes."
],
"offsets": [
[
0,
103
]
]
},
{
"id": "23483103_abstract",
"type": "abstract",
"text": [
"Four ruthenium(ii) asymmetric complexes, [Ru(bpy)2(PAIDH)](2+) (bpy = 2,2'-bipyridine, PAIDH = 2-pyridyl-1H-anthra[1,2-d]imidazole-6,11-dione, ), [Ru(phen)2(PAIDH)](2+) (phen = 1,10-phenanthroline, ), [Ru(dmp)2(PAIDH)](2+) (dmp = 4,7-dimethyl-1,10-phenanthroline, ) and [Ru(dip)2(PAIDH)](2+) (dip = 4,7-diphenyl-1,10-phenanthroline, ), have been synthesized and characterized. These complexes displayed potent anti-proliferation activity against various cancer cell lines and had high selectivity between tumor cells and normal cells. HeLa cells exhibited the highest sensitivity to complex , accounting for the greatest cellular uptake. Complex was shown to accumulate preferentially in the mitochondria of HeLa cells and induced apoptosis via the mitochondrial pathway, which involved ROS generation, mitochondrial membrane potential depolarisation, and Bcl-2 and caspase family members activation. These results demonstrated that complex induced cancer cell apoptosis by acting on mitochondrial pathways."
],
"offsets": [
[
104,
1111
]
]
}
] | [
{
"id": "23483103_T1",
"type": "CHEMICAL",
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"[Ru(phen)2(PAIDH)](2+)"
],
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[
250,
272
]
],
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},
{
"id": "23483103_T2",
"type": "CHEMICAL",
"text": [
"phen"
],
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[
274,
278
]
],
"normalized": []
},
{
"id": "23483103_T3",
"type": "CHEMICAL",
"text": [
"1,10-phenanthroline"
],
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[
281,
300
]
],
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},
{
"id": "23483103_T4",
"type": "CHEMICAL",
"text": [
"[Ru(dmp)2(PAIDH)](2+)"
],
"offsets": [
[
305,
326
]
],
"normalized": []
},
{
"id": "23483103_T5",
"type": "CHEMICAL",
"text": [
"dmp"
],
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[
328,
331
]
],
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},
{
"id": "23483103_T6",
"type": "CHEMICAL",
"text": [
"4,7-dimethyl-1,10-phenanthroline"
],
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334,
366
]
],
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},
{
"id": "23483103_T7",
"type": "CHEMICAL",
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"[Ru(dip)2(PAIDH)](2+)"
],
"offsets": [
[
374,
395
]
],
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},
{
"id": "23483103_T8",
"type": "CHEMICAL",
"text": [
"dip"
],
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[
397,
400
]
],
"normalized": []
},
{
"id": "23483103_T9",
"type": "CHEMICAL",
"text": [
"4,7-diphenyl-1,10-phenanthroline"
],
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[
403,
435
]
],
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},
{
"id": "23483103_T10",
"type": "CHEMICAL",
"text": [
"[Ru(bpy)2(PAIDH)](2+)"
],
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145,
166
]
],
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},
{
"id": "23483103_T11",
"type": "CHEMICAL",
"text": [
"ruthenium(ii)"
],
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[
109,
122
]
],
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},
{
"id": "23483103_T12",
"type": "CHEMICAL",
"text": [
"bpy"
],
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[
168,
171
]
],
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},
{
"id": "23483103_T13",
"type": "CHEMICAL",
"text": [
"2,2'-bipyridine"
],
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[
174,
189
]
],
"normalized": []
},
{
"id": "23483103_T14",
"type": "CHEMICAL",
"text": [
"PAIDH"
],
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[
191,
196
]
],
"normalized": []
},
{
"id": "23483103_T15",
"type": "CHEMICAL",
"text": [
"2-pyridyl-1H-anthra[1,2-d]imidazole-6,11-dione"
],
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[
199,
245
]
],
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},
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"id": "23483103_T16",
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"text": [
"ruthenium(ii)"
],
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[
68,
81
]
],
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},
{
"id": "23483103_T17",
"type": "GENE-Y",
"text": [
"Bcl-2"
],
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[
960,
965
]
],
"normalized": []
},
{
"id": "23483103_T18",
"type": "GENE-N",
"text": [
"caspase"
],
"offsets": [
[
970,
977
]
],
"normalized": []
}
] | [] | [] | [] |
23611835 | 23611835 | [
{
"id": "23611835_title",
"type": "title",
"text": [
"Molecular Mechanisms of the antitumor activity of SB225002: A novel microtubule inhibitor."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "23611835_abstract",
"type": "abstract",
"text": [
"SB225002 (SB) is an IL-8 receptor B (IL-8RB) antagonist that has previously been shown to inhibit IL-8-based cancer cell invasion, and to possess in vivo anti-inflammatory and anti-nociceptive effects. The present study presented an evidence for the cell cycle-targeting activity of SB in a panel of p53-mutant human cancer cell lines of different origin, and investigated the underlying molecular mechanisms. A combination of cell cycle analysis, immunocytometry, immunoblotting, and RNA interference revealed that SB induced a BubR1-dependent mitotic arrest. Mechanistically, SB was shown to possess a microtubule destabilizing activity evidenced by hyperphosphorylation of Bcl2 and BclxL, suppression of microtubule polymerization and induction of a prometaphase arrest. Molecular docking studies suggested that SB has a good affinity towards vinblastine-binding site on β-tubulin subunit. Of note, SB265610 which is a close structural analogue of SB225002 with a potent IL-8RB antagonistic activity did not exhibit a similar antimitotic activity. Importantly, in P-glycoprotein overexpressing NCI/Adr-Res cells the antitumor activity of SB was unaffected by multidrug resistance. Interestingly, the mechanisms of SB-induced cell death were cell-line dependent, where in invasive hepatocellular carcinoma HLE cells the significant contribution of BAK-dependent mitochondrial apoptosis was demonstrated. Conversely, SB activated p38 MAPK signaling in colorectal adenocarcinoma cells SW480, and pharmacologic inhibition of p38 MAPK activity revealed its key role in mediating SB-induced caspase-independent cell death. In summary, the present study introduced SB as a promising antitumor agent which has the potential to exert its activity through dual mechanisms involving microtubules targeting and interference with IL-8-drivin cancer progression."
],
"offsets": [
[
91,
1942
]
]
}
] | [
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"id": "23611835_T1",
"type": "CHEMICAL",
"text": [
"SB225002"
],
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[
91,
99
]
],
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},
{
"id": "23611835_T2",
"type": "CHEMICAL",
"text": [
"vinblastine"
],
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[
937,
948
]
],
"normalized": []
},
{
"id": "23611835_T3",
"type": "CHEMICAL",
"text": [
"SB265610"
],
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[
993,
1001
]
],
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},
{
"id": "23611835_T4",
"type": "CHEMICAL",
"text": [
"SB225002"
],
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[
1042,
1050
]
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},
{
"id": "23611835_T5",
"type": "CHEMICAL",
"text": [
"SB225002"
],
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[
50,
58
]
],
"normalized": []
},
{
"id": "23611835_T6",
"type": "GENE-Y",
"text": [
"P-glycoprotein"
],
"offsets": [
[
1158,
1172
]
],
"normalized": []
},
{
"id": "23611835_T7",
"type": "GENE-Y",
"text": [
"BAK"
],
"offsets": [
[
1441,
1444
]
],
"normalized": []
},
{
"id": "23611835_T8",
"type": "GENE-N",
"text": [
"p38"
],
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[
1522,
1525
]
],
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},
{
"id": "23611835_T9",
"type": "GENE-N",
"text": [
"MAPK"
],
"offsets": [
[
1526,
1530
]
],
"normalized": []
},
{
"id": "23611835_T10",
"type": "GENE-N",
"text": [
"p38"
],
"offsets": [
[
1615,
1618
]
],
"normalized": []
},
{
"id": "23611835_T11",
"type": "GENE-N",
"text": [
"MAPK"
],
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[
1619,
1623
]
],
"normalized": []
},
{
"id": "23611835_T12",
"type": "GENE-N",
"text": [
"caspase"
],
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[
1679,
1686
]
],
"normalized": []
},
{
"id": "23611835_T13",
"type": "GENE-Y",
"text": [
"IL-8"
],
"offsets": [
[
1911,
1915
]
],
"normalized": []
},
{
"id": "23611835_T14",
"type": "GENE-Y",
"text": [
"IL-8 receptor B"
],
"offsets": [
[
111,
126
]
],
"normalized": []
},
{
"id": "23611835_T15",
"type": "GENE-Y",
"text": [
"p53"
],
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[
391,
394
]
],
"normalized": []
},
{
"id": "23611835_T16",
"type": "GENE-Y",
"text": [
"IL-8RB"
],
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[
128,
134
]
],
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},
{
"id": "23611835_T17",
"type": "GENE-Y",
"text": [
"BubR1"
],
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[
620,
625
]
],
"normalized": []
},
{
"id": "23611835_T18",
"type": "GENE-Y",
"text": [
"Bcl2"
],
"offsets": [
[
767,
771
]
],
"normalized": []
},
{
"id": "23611835_T19",
"type": "GENE-Y",
"text": [
"BclxL"
],
"offsets": [
[
776,
781
]
],
"normalized": []
},
{
"id": "23611835_T20",
"type": "GENE-Y",
"text": [
"β-tubulin"
],
"offsets": [
[
965,
974
]
],
"normalized": []
},
{
"id": "23611835_T21",
"type": "GENE-Y",
"text": [
"IL-8RB"
],
"offsets": [
[
1065,
1071
]
],
"normalized": []
},
{
"id": "23611835_T22",
"type": "GENE-Y",
"text": [
"IL-8"
],
"offsets": [
[
189,
193
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23611835_0",
"type": "ANTAGONIST",
"arg1_id": "23611835_T1",
"arg2_id": "23611835_T14",
"normalized": []
},
{
"id": "23611835_1",
"type": "ANTAGONIST",
"arg1_id": "23611835_T1",
"arg2_id": "23611835_T16",
"normalized": []
},
{
"id": "23611835_2",
"type": "INHIBITOR",
"arg1_id": "23611835_T1",
"arg2_id": "23611835_T22",
"normalized": []
},
{
"id": "23611835_3",
"type": "DIRECT-REGULATOR",
"arg1_id": "23611835_T2",
"arg2_id": "23611835_T20",
"normalized": []
},
{
"id": "23611835_4",
"type": "ANTAGONIST",
"arg1_id": "23611835_T4",
"arg2_id": "23611835_T21",
"normalized": []
},
{
"id": "23611835_5",
"type": "ANTAGONIST",
"arg1_id": "23611835_T3",
"arg2_id": "23611835_T21",
"normalized": []
}
] |
22422627 | 22422627 | [
{
"id": "22422627_title",
"type": "title",
"text": [
"Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway."
],
"offsets": [
[
0,
104
]
]
},
{
"id": "22422627_abstract",
"type": "abstract",
"text": [
"The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels. Berberine only suppressed the expression of pp38 among the evaluated signaling molecules. SB203580 (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of collagen type I and α-SMA in TGF-β1-induced NPDFs. Berberine exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps."
],
"offsets": [
[
105,
1492
]
]
}
] | [
{
"id": "22422627_T1",
"type": "CHEMICAL",
"text": [
"SB203580"
],
"offsets": [
[
1141,
1149
]
],
"normalized": []
},
{
"id": "22422627_T2",
"type": "CHEMICAL",
"text": [
"Berberine"
],
"offsets": [
[
1286,
1295
]
],
"normalized": []
},
{
"id": "22422627_T3",
"type": "CHEMICAL",
"text": [
"berberine"
],
"offsets": [
[
372,
381
]
],
"normalized": []
},
{
"id": "22422627_T4",
"type": "CHEMICAL",
"text": [
"berberine"
],
"offsets": [
[
158,
167
]
],
"normalized": []
},
{
"id": "22422627_T5",
"type": "CHEMICAL",
"text": [
"berberine"
],
"offsets": [
[
921,
930
]
],
"normalized": []
},
{
"id": "22422627_T6",
"type": "CHEMICAL",
"text": [
"Berberine"
],
"offsets": [
[
1051,
1060
]
],
"normalized": []
},
{
"id": "22422627_T7",
"type": "CHEMICAL",
"text": [
"Berberine"
],
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0,
9
]
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"id": "22422627_T8",
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"kinase"
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"id": "22422627_T15",
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485
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"collagen type I"
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491,
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608
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"id": "22422627_T27",
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"pp38"
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"type": "GENE-N",
"text": [
"p38"
],
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[
92,
95
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "22422627_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "22422627_T5",
"arg2_id": "22422627_T23",
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},
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"id": "22422627_1",
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"id": "22422627_2",
"type": "INDIRECT-DOWNREGULATOR",
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},
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"id": "22422627_3",
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},
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"id": "22422627_5",
"type": "INHIBITOR",
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},
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"id": "22422627_6",
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"id": "22422627_8",
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"arg2_id": "22422627_T11",
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},
{
"id": "22422627_9",
"type": "INDIRECT-DOWNREGULATOR",
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"arg2_id": "22422627_T12",
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},
{
"id": "22422627_10",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "22422627_T5",
"arg2_id": "22422627_T22",
"normalized": []
}
] |
22406476 | 22406476 | [
{
"id": "22406476_title",
"type": "title",
"text": [
"Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells."
],
"offsets": [
[
0,
122
]
]
},
{
"id": "22406476_abstract",
"type": "abstract",
"text": [
"BACKGROUND & AIMS: Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: Aspirin reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. Aspirin changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. Aspirin induced autophagy, a feature of mTOR inhibition. Aspirin and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: Aspirin is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC."
],
"offsets": [
[
123,
1923
]
]
}
] | [
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"id": "22406476_T1",
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"text": [
"mTOR"
],
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1152,
1156
]
],
"normalized": []
},
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"id": "22406476_T2",
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"Aspirin"
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1184,
1191
]
],
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},
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"id": "22406476_T3",
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"mTOR"
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1251,
1255
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1397,
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]
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"id": "22406476_T6",
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"mTOR"
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1427,
1431
]
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"id": "22406476_T7",
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]
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"id": "22406476_T8",
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"id": "22406476_T9",
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"Aspirin"
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},
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"id": "22406476_T10",
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"text": [
"metformin"
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1502,
1511
]
],
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},
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"id": "22406476_T11",
"type": "CHEMICAL",
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"mTOR"
],
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[
1559,
1563
]
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"normalized": []
},
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"id": "22406476_T12",
"type": "CHEMICAL",
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"aspirin"
],
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1651,
1658
]
],
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},
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"id": "22406476_T13",
"type": "CHEMICAL",
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"Aspirin"
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1716,
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]
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},
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"id": "22406476_T14",
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"mTOR"
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1743,
1747
]
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},
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"id": "22406476_T15",
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"text": [
"rapamycin"
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310,
319
]
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"id": "22406476_T16",
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"Aspirin"
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142,
149
]
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"id": "22406476_T17",
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"mTOR"
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321,
325
]
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"id": "22406476_T18",
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"aspirin"
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383,
390
]
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},
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"id": "22406476_T19",
"type": "CHEMICAL",
"text": [
"adenosine monophosphate"
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399,
422
]
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"normalized": []
},
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"id": "22406476_T20",
"type": "CHEMICAL",
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"mTOR"
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459,
463
]
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"id": "22406476_T21",
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"aspirin"
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512,
519
]
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"id": "22406476_T22",
"type": "CHEMICAL",
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"mTOR"
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523,
527
]
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"normalized": []
},
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"id": "22406476_T23",
"type": "CHEMICAL",
"text": [
"aspirin"
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784,
791
]
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},
{
"id": "22406476_T24",
"type": "CHEMICAL",
"text": [
"mTOR"
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811,
815
]
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},
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"id": "22406476_T25",
"type": "CHEMICAL",
"text": [
"aspirin"
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1049,
1056
]
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},
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"id": "22406476_T26",
"type": "CHEMICAL",
"text": [
"Aspirin"
],
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[
1090,
1097
]
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"normalized": []
},
{
"id": "22406476_T27",
"type": "CHEMICAL",
"text": [
"mTOR"
],
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[
1106,
1110
]
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},
{
"id": "22406476_T28",
"type": "CHEMICAL",
"text": [
"Aspirin"
],
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[
0,
7
]
],
"normalized": []
},
{
"id": "22406476_T29",
"type": "CHEMICAL",
"text": [
"mTOR"
],
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[
17,
21
]
],
"normalized": []
},
{
"id": "22406476_T30",
"type": "CHEMICAL",
"text": [
"AMP"
],
"offsets": [
[
43,
46
]
],
"normalized": []
},
{
"id": "22406476_T31",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
1152,
1156
]
],
"normalized": []
},
{
"id": "22406476_T32",
"type": "GENE-Y",
"text": [
"S6K1"
],
"offsets": [
[
1167,
1171
]
],
"normalized": []
},
{
"id": "22406476_T33",
"type": "GENE-Y",
"text": [
"4E-BP1"
],
"offsets": [
[
1176,
1182
]
],
"normalized": []
},
{
"id": "22406476_T34",
"type": "GENE-N",
"text": [
"AMPK"
],
"offsets": [
[
1232,
1236
]
],
"normalized": []
},
{
"id": "22406476_T35",
"type": "GENE-Y",
"text": [
"mTOR"
],
"offsets": [
[
1251,
1255
]
],
"normalized": []
},
{
"id": "22406476_T36",
"type": "GENE-N",
"text": [
"AMPKalpha"
],
"offsets": [
[
1325,
1334
]
],
"normalized": []
},
{
"id": "22406476_T37",
"type": "GENE-N",
"text": [
"AMPK"
],
"offsets": [
[
1347,
1351
]
],
"normalized": []
},
{
"id": "22406476_T38",
"type": "GENE-N",
"text": [
"AMPK"
],
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[
1366,
1370
]
],
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},
{
"id": "22406476_T39",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
1427,
1431
]
],
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},
{
"id": "22406476_T40",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
1473,
1477
]
],
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},
{
"id": "22406476_T41",
"type": "GENE-N",
"text": [
"AMPK"
],
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[
1529,
1533
]
],
"normalized": []
},
{
"id": "22406476_T42",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
1559,
1563
]
],
"normalized": []
},
{
"id": "22406476_T43",
"type": "GENE-N",
"text": [
"Akt"
],
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[
1568,
1571
]
],
"normalized": []
},
{
"id": "22406476_T44",
"type": "GENE-Y",
"text": [
"S6K1"
],
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[
1690,
1694
]
],
"normalized": []
},
{
"id": "22406476_T45",
"type": "GENE-Y",
"text": [
"S6"
],
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[
1699,
1701
]
],
"normalized": []
},
{
"id": "22406476_T46",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
1743,
1747
]
],
"normalized": []
},
{
"id": "22406476_T47",
"type": "GENE-N",
"text": [
"AMPK"
],
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[
1768,
1772
]
],
"normalized": []
},
{
"id": "22406476_T48",
"type": "GENE-Y",
"text": [
"mechanistic target of rapamycin"
],
"offsets": [
[
288,
319
]
],
"normalized": []
},
{
"id": "22406476_T49",
"type": "GENE-Y",
"text": [
"mTOR"
],
"offsets": [
[
321,
325
]
],
"normalized": []
},
{
"id": "22406476_T50",
"type": "GENE-N",
"text": [
"adenosine monophosphate-activated protein kinase"
],
"offsets": [
[
399,
447
]
],
"normalized": []
},
{
"id": "22406476_T51",
"type": "GENE-N",
"text": [
"AMPK"
],
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[
449,
453
]
],
"normalized": []
},
{
"id": "22406476_T52",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
459,
463
]
],
"normalized": []
},
{
"id": "22406476_T53",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
523,
527
]
],
"normalized": []
},
{
"id": "22406476_T54",
"type": "GENE-Y",
"text": [
"ribosomal protein S6"
],
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[
543,
563
]
],
"normalized": []
},
{
"id": "22406476_T55",
"type": "GENE-Y",
"text": [
"S6 kinase 1"
],
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[
565,
576
]
],
"normalized": []
},
{
"id": "22406476_T56",
"type": "GENE-Y",
"text": [
"S6K1"
],
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[
578,
582
]
],
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},
{
"id": "22406476_T57",
"type": "GENE-Y",
"text": [
"eukaryotic translation initiation factor 4E binding protein 1"
],
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[
589,
650
]
],
"normalized": []
},
{
"id": "22406476_T58",
"type": "GENE-Y",
"text": [
"4E-BP1"
],
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[
652,
658
]
],
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},
{
"id": "22406476_T59",
"type": "GENE-N",
"text": [
"AMPK"
],
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[
725,
729
]
],
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},
{
"id": "22406476_T60",
"type": "GENE-N",
"text": [
"AMPKalpha"
],
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[
767,
776
]
],
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},
{
"id": "22406476_T61",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
811,
815
]
],
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},
{
"id": "22406476_T62",
"type": "GENE-N",
"text": [
"AMPK(alpha1/alpha2"
],
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[
888,
906
]
],
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},
{
"id": "22406476_T63",
"type": "GENE-N",
"text": [
"LC3"
],
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[
940,
943
]
],
"normalized": []
},
{
"id": "22406476_T64",
"type": "GENE-Y",
"text": [
"ULK1"
],
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[
948,
952
]
],
"normalized": []
},
{
"id": "22406476_T65",
"type": "GENE-Y",
"text": [
"mTOR"
],
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[
1106,
1110
]
],
"normalized": []
},
{
"id": "22406476_T66",
"type": "GENE-Y",
"text": [
"mTOR"
],
"offsets": [
[
17,
21
]
],
"normalized": []
},
{
"id": "22406476_T67",
"type": "GENE-N",
"text": [
"AMP-activated protein kinase"
],
"offsets": [
[
43,
71
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "22406476_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "22406476_T28",
"arg2_id": "22406476_T66",
"normalized": []
},
{
"id": "22406476_1",
"type": "ACTIVATOR",
"arg1_id": "22406476_T28",
"arg2_id": "22406476_T67",
"normalized": []
},
{
"id": "22406476_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "22406476_T26",
"arg2_id": "22406476_T65",
"normalized": []
},
{
"id": "22406476_3",
"type": "INHIBITOR",
"arg1_id": "22406476_T26",
"arg2_id": "22406476_T31",
"normalized": []
},
{
"id": "22406476_4",
"type": "INHIBITOR",
"arg1_id": "22406476_T26",
"arg2_id": "22406476_T32",
"normalized": []
},
{
"id": "22406476_5",
"type": "INHIBITOR",
"arg1_id": "22406476_T26",
"arg2_id": "22406476_T33",
"normalized": []
},
{
"id": "22406476_6",
"type": "ACTIVATOR",
"arg1_id": "22406476_T2",
"arg2_id": "22406476_T34",
"normalized": []
},
{
"id": "22406476_7",
"type": "INHIBITOR",
"arg1_id": "22406476_T4",
"arg2_id": "22406476_T35",
"normalized": []
},
{
"id": "22406476_8",
"type": "INHIBITOR",
"arg1_id": "22406476_T5",
"arg2_id": "22406476_T39",
"normalized": []
},
{
"id": "22406476_9",
"type": "INHIBITOR",
"arg1_id": "22406476_T7",
"arg2_id": "22406476_T40",
"normalized": []
},
{
"id": "22406476_10",
"type": "ACTIVATOR",
"arg1_id": "22406476_T9",
"arg2_id": "22406476_T41",
"normalized": []
},
{
"id": "22406476_11",
"type": "ACTIVATOR",
"arg1_id": "22406476_T10",
"arg2_id": "22406476_T41",
"normalized": []
},
{
"id": "22406476_12",
"type": "INHIBITOR",
"arg1_id": "22406476_T9",
"arg2_id": "22406476_T42",
"normalized": []
},
{
"id": "22406476_13",
"type": "INHIBITOR",
"arg1_id": "22406476_T9",
"arg2_id": "22406476_T43",
"normalized": []
},
{
"id": "22406476_14",
"type": "INHIBITOR",
"arg1_id": "22406476_T10",
"arg2_id": "22406476_T42",
"normalized": []
},
{
"id": "22406476_15",
"type": "INHIBITOR",
"arg1_id": "22406476_T10",
"arg2_id": "22406476_T43",
"normalized": []
},
{
"id": "22406476_16",
"type": "INHIBITOR",
"arg1_id": "22406476_T12",
"arg2_id": "22406476_T44",
"normalized": []
},
{
"id": "22406476_17",
"type": "INHIBITOR",
"arg1_id": "22406476_T12",
"arg2_id": "22406476_T45",
"normalized": []
},
{
"id": "22406476_18",
"type": "INHIBITOR",
"arg1_id": "22406476_T13",
"arg2_id": "22406476_T46",
"normalized": []
},
{
"id": "22406476_19",
"type": "ACTIVATOR",
"arg1_id": "22406476_T13",
"arg2_id": "22406476_T47",
"normalized": []
}
] |
17603545 | 17603545 | [
{
"id": "17603545_title",
"type": "title",
"text": [
"Alpha1-adrenoceptors are required for normal male sexual function."
],
"offsets": [
[
0,
66
]
]
},
{
"id": "17603545_abstract",
"type": "abstract",
"text": [
"BACKGROUND AND PURPOSE: Alpha(1)-adrenoceptor antagonists are extensively used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia. Among the side effects, ejaculatory dysfunction occurs more frequently with drugs that are relatively selective for alpha(1A)-adrenoceptors compared with other drugs of this class. This suggests that alpha(1A)-adrenoceptors may contribute to ejaculation. However, this has not been studied at the molecular level. EXPERIMENTAL APPROACH: The physiological contribution of each alpha(1)-adrenoceptor subtype was characterized using alpha(1)-adrenoceptor subtype-selective knockout (KO) mice (alpha(1A)-, alpha(1B)- and alpha(1D)-AR KO mice) since the subtype-specific drugs available are only moderately selective. We analysed the role of alpha(1)-adrenoceptors in the blood pressure and vascular response as well as ejaculation by determining these variables in alpha(1)-adrenoceptor subtype-selective KO mice and in mice with all their alpha(1)-adrenoceptor subtypes deleted (alpha(1)-AR triple-KO mice). KEY RESULTS: The pregnancy rate was reduced by 50% in alpha(1A)-adrenoceptor KO mice, and this reduction was dramatically enhanced in alpha(1)-adrenoceptor triple-KO mice. Contractile tension of the vas deferens in response to noradrenaline was markedly decreased in alpha(1A)-adrenoceptor KO mice, and this contraction was completely abolished in alpha(1)-adrenoceptor triple-KO mice. This attenuation of contractility was also observed in the electrically stimulated vas deferens. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that alpha(1)-adrenoceptors, particularly alpha(1A)-adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility."
],
"offsets": [
[
67,
1902
]
]
}
] | [
{
"id": "17603545_T1",
"type": "CHEMICAL",
"text": [
"noradrenaline"
],
"offsets": [
[
1390,
1403
]
],
"normalized": []
},
{
"id": "17603545_T2",
"type": "GENE-N",
"text": [
"alpha(1)-adrenoceptor"
],
"offsets": [
[
1094,
1115
]
],
"normalized": []
},
{
"id": "17603545_T3",
"type": "GENE-N",
"text": [
"alpha(1)-AR"
],
"offsets": [
[
1134,
1145
]
],
"normalized": []
},
{
"id": "17603545_T4",
"type": "GENE-Y",
"text": [
"alpha(1A)-adrenoceptor"
],
"offsets": [
[
1217,
1239
]
],
"normalized": []
},
{
"id": "17603545_T5",
"type": "GENE-N",
"text": [
"alpha(1)-adrenoceptor"
],
"offsets": [
[
1297,
1318
]
],
"normalized": []
},
{
"id": "17603545_T6",
"type": "GENE-Y",
"text": [
"alpha(1A)-adrenoceptor"
],
"offsets": [
[
1430,
1452
]
],
"normalized": []
},
{
"id": "17603545_T7",
"type": "GENE-N",
"text": [
"alpha(1)-adrenoceptor"
],
"offsets": [
[
1511,
1532
]
],
"normalized": []
},
{
"id": "17603545_T8",
"type": "GENE-N",
"text": [
"alpha(1)-adrenoceptors"
],
"offsets": [
[
1707,
1729
]
],
"normalized": []
},
{
"id": "17603545_T9",
"type": "GENE-Y",
"text": [
"alpha(1A)-adrenoceptors"
],
"offsets": [
[
1744,
1767
]
],
"normalized": []
},
{
"id": "17603545_T10",
"type": "GENE-N",
"text": [
"Alpha(1)-adrenoceptor"
],
"offsets": [
[
91,
112
]
],
"normalized": []
},
{
"id": "17603545_T11",
"type": "GENE-Y",
"text": [
"alpha(1A)-adrenoceptors"
],
"offsets": [
[
374,
397
]
],
"normalized": []
},
{
"id": "17603545_T12",
"type": "GENE-Y",
"text": [
"alpha(1A)-adrenoceptors"
],
"offsets": [
[
458,
481
]
],
"normalized": []
},
{
"id": "17603545_T13",
"type": "GENE-N",
"text": [
"alpha(1)-adrenoceptor"
],
"offsets": [
[
634,
655
]
],
"normalized": []
},
{
"id": "17603545_T14",
"type": "GENE-N",
"text": [
"alpha(1)-adrenoceptor"
],
"offsets": [
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688,
709
]
],
"normalized": []
},
{
"id": "17603545_T15",
"type": "GENE-N",
"text": [
"alpha(1A)-, alpha(1B)- and alpha(1D)-AR"
],
"offsets": [
[
748,
787
]
],
"normalized": []
},
{
"id": "17603545_T16",
"type": "GENE-N",
"text": [
"alpha(1)-adrenoceptors"
],
"offsets": [
[
895,
917
]
],
"normalized": []
},
{
"id": "17603545_T17",
"type": "GENE-N",
"text": [
"alpha(1)-adrenoceptor"
],
"offsets": [
[
1019,
1040
]
],
"normalized": []
},
{
"id": "17603545_T18",
"type": "GENE-N",
"text": [
"Alpha1-adrenoceptors"
],
"offsets": [
[
0,
20
]
],
"normalized": []
}
] | [] | [] | [] |
16199482 | 16199482 | [
{
"id": "16199482_title",
"type": "title",
"text": [
"Metabolite ligands of estrogen receptor-beta reduce primate coronary hyperreactivity."
],
"offsets": [
[
0,
85
]
]
},
{
"id": "16199482_abstract",
"type": "abstract",
"text": [
"Previous reports showed that 17beta-estradiol implants attenuate in vivo coronary hyperreactivity (CH), characterized by long-duration vasoconstrictions (in coronary angiographic experiments), in menopausal rhesus monkeys. Prolonged Ca2+ contraction signals that correspond with CH in coronary vascular muscle cells (VMC) to the same dual-constrictor stimulus, serotonin + the thromboxane analog U-46619, in estrogen-deprived VMC were suppressed by >72 h in 17beta-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor-beta (ER-beta) binding activity, estriol (E3), suppresses in vivo and in vitro CH. E3 treatment in vivo for 4 wk significantly attenuated the angiographically evaluated vasoconstrictor response to intracoronary serotonin + U-46619 challenge. In vitro treatment of rhesus coronary VMC for >72 h with nanomolar E3 attenuated late Ca2+ signals. This reduction of late Ca2+ signals also appeared after >72 h of treatment with subnanomolar 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), an endogenous dihydrotestosterone metabolite with ER-beta binding activity. R,R-tetrahydrochrysene, a selective ER-beta antagonist, significantly blocked the E3- and 3beta-Adiol-mediated attenuation of late Ca2+ signal increases. ER-beta and thromboxane-prostanoid receptor (TPR) were coexpressed in coronary arteries and aorta. In vivo E3 treatment attenuated aortic TPR expression. Furthermore, in vitro treatment with E3 or 3beta-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. E3- and 3beta-Adiol-mediated reduction in persistent Ca2+ signals is associated with ER-beta-mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle."
],
"offsets": [
[
86,
1909
]
]
}
] | [
{
"id": "16199482_T1",
"type": "CHEMICAL",
"text": [
"5alpha-androstane-3beta,17beta-diol"
],
"offsets": [
[
1100,
1135
]
],
"normalized": []
},
{
"id": "16199482_T2",
"type": "CHEMICAL",
"text": [
"3beta-Adiol"
],
"offsets": [
[
1137,
1148
]
],
"normalized": []
},
{
"id": "16199482_T3",
"type": "CHEMICAL",
"text": [
"dihydrotestosterone"
],
"offsets": [
[
1165,
1184
]
],
"normalized": []
},
{
"id": "16199482_T4",
"type": "CHEMICAL",
"text": [
"R,R-tetrahydrochrysene"
],
"offsets": [
[
1227,
1249
]
],
"normalized": []
},
{
"id": "16199482_T5",
"type": "CHEMICAL",
"text": [
"3beta-Adiol"
],
"offsets": [
[
1317,
1328
]
],
"normalized": []
},
{
"id": "16199482_T6",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
"offsets": [
[
1358,
1362
]
],
"normalized": []
},
{
"id": "16199482_T7",
"type": "CHEMICAL",
"text": [
"thromboxane"
],
"offsets": [
[
1393,
1404
]
],
"normalized": []
},
{
"id": "16199482_T8",
"type": "CHEMICAL",
"text": [
"prostanoid"
],
"offsets": [
[
1405,
1415
]
],
"normalized": []
},
{
"id": "16199482_T9",
"type": "CHEMICAL",
"text": [
"3beta-Adiol"
],
"offsets": [
[
1578,
1589
]
],
"normalized": []
},
{
"id": "16199482_T10",
"type": "CHEMICAL",
"text": [
"R,R-tetrahydrochrysene"
],
"offsets": [
[
1684,
1706
]
],
"normalized": []
},
{
"id": "16199482_T11",
"type": "CHEMICAL",
"text": [
"3beta-Adiol"
],
"offsets": [
[
1716,
1727
]
],
"normalized": []
},
{
"id": "16199482_T12",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
"offsets": [
[
1761,
1765
]
],
"normalized": []
},
{
"id": "16199482_T13",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
1863,
1871
]
],
"normalized": []
},
{
"id": "16199482_T14",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
"offsets": [
[
319,
323
]
],
"normalized": []
},
{
"id": "16199482_T15",
"type": "CHEMICAL",
"text": [
"17beta-estradiol"
],
"offsets": [
[
115,
131
]
],
"normalized": []
},
{
"id": "16199482_T16",
"type": "CHEMICAL",
"text": [
"serotonin"
],
"offsets": [
[
447,
456
]
],
"normalized": []
},
{
"id": "16199482_T17",
"type": "CHEMICAL",
"text": [
"thromboxane"
],
"offsets": [
[
463,
474
]
],
"normalized": []
},
{
"id": "16199482_T18",
"type": "CHEMICAL",
"text": [
"U-46619"
],
"offsets": [
[
482,
489
]
],
"normalized": []
},
{
"id": "16199482_T19",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
494,
502
]
],
"normalized": []
},
{
"id": "16199482_T20",
"type": "CHEMICAL",
"text": [
"17beta-estradiol"
],
"offsets": [
[
544,
560
]
],
"normalized": []
},
{
"id": "16199482_T21",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
622,
630
]
],
"normalized": []
},
{
"id": "16199482_T22",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
647,
655
]
],
"normalized": []
},
{
"id": "16199482_T23",
"type": "CHEMICAL",
"text": [
"estriol"
],
"offsets": [
[
698,
705
]
],
"normalized": []
},
{
"id": "16199482_T24",
"type": "CHEMICAL",
"text": [
"E3"
],
"offsets": [
[
707,
709
]
],
"normalized": []
},
{
"id": "16199482_T25",
"type": "CHEMICAL",
"text": [
"serotonin"
],
"offsets": [
[
876,
885
]
],
"normalized": []
},
{
"id": "16199482_T26",
"type": "CHEMICAL",
"text": [
"U-46619"
],
"offsets": [
[
888,
895
]
],
"normalized": []
},
{
"id": "16199482_T27",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
"offsets": [
[
993,
997
]
],
"normalized": []
},
{
"id": "16199482_T28",
"type": "CHEMICAL",
"text": [
"Ca2+"
],
"offsets": [
[
1030,
1034
]
],
"normalized": []
},
{
"id": "16199482_T29",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
22,
30
]
],
"normalized": []
},
{
"id": "16199482_T30",
"type": "GENE-Y",
"text": [
"ER-beta"
],
"offsets": [
[
1201,
1208
]
],
"normalized": []
},
{
"id": "16199482_T31",
"type": "GENE-Y",
"text": [
"ER-beta"
],
"offsets": [
[
1263,
1270
]
],
"normalized": []
},
{
"id": "16199482_T32",
"type": "GENE-Y",
"text": [
"ER-beta"
],
"offsets": [
[
1381,
1388
]
],
"normalized": []
},
{
"id": "16199482_T33",
"type": "GENE-Y",
"text": [
"thromboxane-prostanoid receptor"
],
"offsets": [
[
1393,
1424
]
],
"normalized": []
},
{
"id": "16199482_T34",
"type": "GENE-Y",
"text": [
"TPR"
],
"offsets": [
[
1426,
1429
]
],
"normalized": []
},
{
"id": "16199482_T35",
"type": "GENE-Y",
"text": [
"TPR"
],
"offsets": [
[
1519,
1522
]
],
"normalized": []
},
{
"id": "16199482_T36",
"type": "GENE-Y",
"text": [
"TPR"
],
"offsets": [
[
1604,
1607
]
],
"normalized": []
},
{
"id": "16199482_T37",
"type": "GENE-Y",
"text": [
"ER-beta"
],
"offsets": [
[
1793,
1800
]
],
"normalized": []
},
{
"id": "16199482_T38",
"type": "GENE-Y",
"text": [
"TPR"
],
"offsets": [
[
1825,
1828
]
],
"normalized": []
},
{
"id": "16199482_T39",
"type": "GENE-Y",
"text": [
"estrogen receptor-beta"
],
"offsets": [
[
647,
669
]
],
"normalized": []
},
{
"id": "16199482_T40",
"type": "GENE-Y",
"text": [
"(ER-beta"
],
"offsets": [
[
670,
678
]
],
"normalized": []
},
{
"id": "16199482_T41",
"type": "GENE-Y",
"text": [
"estrogen receptor-beta"
],
"offsets": [
[
22,
44
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16199482_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "16199482_T1",
"arg2_id": "16199482_T30",
"normalized": []
},
{
"id": "16199482_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "16199482_T2",
"arg2_id": "16199482_T30",
"normalized": []
},
{
"id": "16199482_2",
"type": "DIRECT-REGULATOR",
"arg1_id": "16199482_T3",
"arg2_id": "16199482_T30",
"normalized": []
},
{
"id": "16199482_3",
"type": "ANTAGONIST",
"arg1_id": "16199482_T4",
"arg2_id": "16199482_T31",
"normalized": []
},
{
"id": "16199482_4",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "16199482_T9",
"arg2_id": "16199482_T36",
"normalized": []
},
{
"id": "16199482_5",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "16199482_T11",
"arg2_id": "16199482_T38",
"normalized": []
}
] |
23161868 | 23161868 | [
{
"id": "23161868_title",
"type": "title",
"text": [
"Ras-dva is a novel Pit-1- and glucocorticoid-regulated gene in the embryonic anterior pituitary gland."
],
"offsets": [
[
0,
102
]
]
},
{
"id": "23161868_abstract",
"type": "abstract",
"text": [
"Glucocorticoids play a role in functional differentiation of pituitary somatotrophs and lactotrophs during embryogenesis. Ras-dva was identified as a gene regulated by anterior neural fold protein-1/homeobox expressed in embryonic stem cells-1, a transcription factor known to be critical in pituitary development, and has an expression profile in the chicken embryonic pituitary gland that is consistent with in vivo regulation by glucocorticoids. The objective of this study was to characterize expression and regulation of ras-dva mRNA in the developing chicken anterior pituitary. Pituitary ras-dva mRNA levels increased during embryogenesis to a maximum on embryonic day (e) 18 and then decreased and remained low or undetectable after hatch. Ras-dva expression was highly enriched in the pituitary gland on e18 relative to other tissues examined. Glucocorticoid treatment of pituitary cells from mid- and late-stage embryos rapidly increased ras-dva mRNA, suggesting it may be a direct transcriptional target of glucocorticoids. A reporter construct driven by 4 kb of the chicken ras-dva 5'-flanking region, containing six putative pituitary-specific transcription factor-1 (Pit-1) binding sites and two potential glucocorticoid receptor (GR) binding sites, was highly activated in embryonic pituitary cells and up-regulated by corticosterone. Mutagenesis of the most proximal Pit-1 site decreased promoter activity in chicken e11 pituitary cells, indicating regulation of ras-dva by Pit-1. However, mutating putative GR binding sites did not substantially reduce induction of ras-dva promoter activity by corticosterone, suggesting additional DNA elements within the 5'-flanking region are responsible for glucocorticoid regulation. We have identified ras-dva as a glucocorticoid-regulated gene that is likely expressed in cells of the Pit-1 lineage within the developing anterior pituitary gland."
],
"offsets": [
[
103,
2007
]
]
}
] | [
{
"id": "23161868_T1",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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1437,
1451
]
],
"normalized": []
},
{
"id": "23161868_T2",
"type": "CHEMICAL",
"text": [
"corticosterone"
],
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1715,
1729
]
],
"normalized": []
},
{
"id": "23161868_T3",
"type": "GENE-Y",
"text": [
"chicken ras-dva"
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1181,
1196
]
],
"normalized": []
},
{
"id": "23161868_T4",
"type": "GENE-N",
"text": [
"pituitary-specific transcription factor-1 (Pit-1) binding sites"
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1241,
1304
]
],
"normalized": []
},
{
"id": "23161868_T5",
"type": "GENE-N",
"text": [
"glucocorticoid receptor (GR) binding sites"
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1323,
1365
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],
"normalized": []
},
{
"id": "23161868_T6",
"type": "GENE-Y",
"text": [
"Ras-dva"
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225,
232
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},
{
"id": "23161868_T7",
"type": "GENE-N",
"text": [
"Pit-1 site"
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1486,
1496
]
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},
{
"id": "23161868_T8",
"type": "GENE-Y",
"text": [
"ras-dva"
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1582,
1589
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"id": "23161868_T9",
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"text": [
"Pit-1"
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1593,
1598
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"id": "23161868_T10",
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"text": [
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1627,
1643
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},
{
"id": "23161868_T11",
"type": "GENE-N",
"text": [
"ras-dva promoter"
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1686,
1702
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"normalized": []
},
{
"id": "23161868_T12",
"type": "GENE-N",
"text": [
"DNA elements"
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1753,
1765
]
],
"normalized": []
},
{
"id": "23161868_T13",
"type": "GENE-Y",
"text": [
"anterior neural fold protein-1/homeobox"
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271,
310
]
],
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},
{
"id": "23161868_T14",
"type": "GENE-Y",
"text": [
"ras-dva"
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1862,
1869
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},
{
"id": "23161868_T15",
"type": "GENE-Y",
"text": [
"Pit-1"
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"offsets": [
[
1946,
1951
]
],
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},
{
"id": "23161868_T16",
"type": "GENE-Y",
"text": [
"ras-dva"
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629,
636
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},
{
"id": "23161868_T17",
"type": "GENE-Y",
"text": [
"ras-dva"
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698,
705
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],
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},
{
"id": "23161868_T18",
"type": "GENE-Y",
"text": [
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851,
858
]
],
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},
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"id": "23161868_T19",
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"text": [
"ras-dva"
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1051,
1058
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},
{
"id": "23161868_T20",
"type": "GENE-Y",
"text": [
"Ras-dva"
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[
0,
7
]
],
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},
{
"id": "23161868_T21",
"type": "GENE-Y",
"text": [
"Pit-1"
],
"offsets": [
[
19,
24
]
],
"normalized": []
}
] | [] | [] | [
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{
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{
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},
{
"id": "23161868_4",
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"arg1_id": "23161868_T2",
"arg2_id": "23161868_T10",
"normalized": []
}
] |
8052854 | 8052854 | [
{
"id": "8052854_title",
"type": "title",
"text": [
"Inhibition of NF-kappa B by sodium salicylate and aspirin."
],
"offsets": [
[
0,
58
]
]
},
{
"id": "8052854_abstract",
"type": "abstract",
"text": [
"The transcription factor nuclear factor-kappa B (NF-kappa B) is critical for the inducible expression of multiple cellular and viral genes involved in inflammation and infection including interleukin-1 (IL-1), IL-6, and adhesion molecules. The anti-inflammatory drugs sodium salicylate and aspirin inhibited the activation of NF-kappa B, which further explains the mechanism of action of these drugs. This inhibition prevented the degradation of the NF-kappa B inhibitor, I kappa B, and therefore NF-kappa B was retained in the cytosol. Sodium salicylate and aspirin also inhibited NF-kappa B-dependent transcription from the Ig kappa enhancer and the human immunodeficiency virus (HIV) long terminal repeat (LTR) in transfected T cells."
],
"offsets": [
[
59,
796
]
]
}
] | [
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"id": "8052854_T1",
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"text": [
"sodium salicylate"
],
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[
327,
344
]
],
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},
{
"id": "8052854_T2",
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"text": [
"aspirin"
],
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349,
356
]
],
"normalized": []
},
{
"id": "8052854_T3",
"type": "CHEMICAL",
"text": [
"Sodium salicylate"
],
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596,
613
]
],
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},
{
"id": "8052854_T4",
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"aspirin"
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618,
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]
],
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},
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"id": "8052854_T5",
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247,
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]
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},
{
"id": "8052854_T6",
"type": "GENE-N",
"text": [
"IL-1"
],
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262,
266
]
],
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},
{
"id": "8052854_T7",
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"text": [
"IL-6"
],
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269,
273
]
],
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},
{
"id": "8052854_T8",
"type": "GENE-N",
"text": [
"nuclear factor-kappa B"
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84,
106
]
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"id": "8052854_T9",
"type": "GENE-N",
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385,
395
]
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},
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"id": "8052854_T10",
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"NF-kappa B"
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509,
519
]
],
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},
{
"id": "8052854_T11",
"type": "GENE-N",
"text": [
"I kappa B"
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531,
540
]
],
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},
{
"id": "8052854_T12",
"type": "GENE-N",
"text": [
"NF-kappa B"
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108,
118
]
],
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},
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"id": "8052854_T13",
"type": "GENE-N",
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"NF-kappa B"
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556,
566
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},
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"id": "8052854_T14",
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"NF-kappa B"
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641,
651
]
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},
{
"id": "8052854_T15",
"type": "GENE-Y",
"text": [
"Ig kappa"
],
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685,
693
]
],
"normalized": []
},
{
"id": "8052854_T16",
"type": "GENE-N",
"text": [
"NF-kappa B"
],
"offsets": [
[
14,
24
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "8052854_0",
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},
{
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},
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},
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"id": "8052854_3",
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},
{
"id": "8052854_4",
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},
{
"id": "8052854_5",
"type": "INHIBITOR",
"arg1_id": "8052854_T4",
"arg2_id": "8052854_T15",
"normalized": []
}
] |
14967461 | 14967461 | [
{
"id": "14967461_title",
"type": "title",
"text": [
"Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC."
],
"offsets": [
[
0,
112
]
]
},
{
"id": "14967461_abstract",
"type": "abstract",
"text": [
"Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer. Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate. Just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life. Newer agents, including the taxanes, vinorelbine, gemcitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer. Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%. It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates. The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies. Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux). Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PKI166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2). Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy. However, serious clinical challenges persist. These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds. Both gefitinib and erlotinib have shown clinical activity in pretreated, advanced non-small-cell lung cancer, but placebo-controlled randomized Phase III studies evaluating gefitinib in combination with standard cytotoxic therapy, to our chagrin, have failed to demonstrate a survival advantage compared with chemotherapy alone."
],
"offsets": [
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113,
2465
]
]
}
] | [
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]
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"id": "14967461_T5",
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1319,
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]
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"id": "14967461_T6",
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1328,
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]
],
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},
{
"id": "14967461_T7",
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"text": [
"cetuximab"
],
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1379,
1388
]
],
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},
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]
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"Erbitux"
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1399,
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"CI-1033"
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]
],
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},
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"id": "14967461_T11",
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"tyrosine"
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1510,
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]
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},
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"id": "14967461_T12",
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1541,
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1552,
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},
{
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301,
309
]
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2142,
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2156,
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2310,
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},
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540,
547
]
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},
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549,
560
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562,
573
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579,
589
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1505,
1509
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1510,
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1614,
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]
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},
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"id": "14967461_T27",
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"Her2"
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1651,
1655
]
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"id": "14967461_T28",
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1081,
1113
]
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},
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"epidermal growth factor receptor"
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17,
49
]
],
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}
] | [] | [] | [
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{
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{
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{
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},
{
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{
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},
{
"id": "14967461_8",
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},
{
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{
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"id": "14967461_12",
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"arg1_id": "14967461_T13",
"arg2_id": "14967461_T26",
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"id": "14967461_13",
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"arg2_id": "14967461_T27",
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},
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{
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"type": "INHIBITOR",
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"arg2_id": "14967461_T25",
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},
{
"id": "14967461_16",
"type": "INHIBITOR",
"arg1_id": "14967461_T13",
"arg2_id": "14967461_T25",
"normalized": []
}
] |
10368402 | 10368402 | [
{
"id": "10368402_title",
"type": "title",
"text": [
"Maturation of neuromuscular transmission during early development in zebrafish."
],
"offsets": [
[
0,
79
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]
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{
"id": "10368402_abstract",
"type": "abstract",
"text": [
"We have examined the rapid development of synaptic transmission at the neuromuscular junction (NMJ) in zebrafish embryos and larvae by patch-clamp recording of spontaneous miniature endplate currents (mEPCs) and single acetylcholine receptor (AChR) channels. Embryonic (24-36 h) mEPCs recorded in vivo were small in amplitude (<50 pA). The rate of mEPCs increased in larvae (3.5-fold increase measured by 6 days), and these mEPCs were mostly of larger amplitude (10-fold on average) with (</=5-fold) faster kinetics. Intracellular labeling with Lucifer yellow indicated extensive coupling between muscle cells in both embryos and larvae (</=10 days). Blocking acetylcholinesterase (AChE) with eserine had no effect on mEPC kinetics in embryos at 1 day and only partially slowed (by approximately 1/2) the decay rate in larvae at 6 days. In acutely dissociated muscle cells, we observed the same two types of AChR with conductances of 45 and 60 pS and with similar, brief (<0.5 ms) mean open times in both embryos and larvae. We conclude that AChR properties are set early during development at these early stages; functional maturation of the NMJ is only partly shaped by expression of AChE and may also depend on postsynaptic AChR clustering and presynaptic maturation."
],
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80,
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] | [
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"id": "10368402_T1",
"type": "CHEMICAL",
"text": [
"acetylcholine"
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"id": "10368402_T2",
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"id": "10368402_T3",
"type": "GENE-N",
"text": [
"AChR"
],
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323,
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]
],
"normalized": []
}
] | [] | [] | [] |
23578392 | 23578392 | [
{
"id": "23578392_title",
"type": "title",
"text": [
"The time point of β-catenin knockout in hepatocytes determines their response to xenobiotic activation of the constitutive androstane receptor."
],
"offsets": [
[
0,
143
]
]
},
{
"id": "23578392_abstract",
"type": "abstract",
"text": [
"The constitutive androstane receptor (CAR) controls the expression of drug-metabolizing enzymes and regulates hepatocyte proliferation. Studies with transgenic mice with an early postnatal conditional hepatocyte-specific knockout of the β-catenin gene Ctnnb1 revealed that β-catenin deficiency decreases the magnitude of induction of drug-metabolizing enzymes by CAR activators, abrogates zonal differences in the hepatocytes' susceptibility to these compounds, and impacts on hepatocyte proliferation. These data, however, do not allow distinguishing between effects caused by β-catenin deficiency during postnatal liver development and acute effects of β-catenin deficiency in the adult animal at the time point of CAR activation. Therefore, CAR activation was now studied in a different mouse model allowing for the hepatocyte-specific knockout of β-catenin in adult mice. Treatment of these mice with 3mg/kg body weight of the model CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) confirmed previous findings related to the coordinate regulation of drug metabolism by β-catenin and CAR. More importantly, the present study clarified that the impact of β-catenin signaling on CAR-mediated enzyme induction in the liver is not merely due to developmental defects caused by a postnatal lack of β-catenin, but depends on the presence of β-catenin at the time point of xenobiotic treatment. The study also revealed interesting differences between the two mouse models: hepatic zonation of TCPOBOP-dependent induction of drug-metabolizing enzymes was restored in mice with late knockout of β-catenin, and the strong proliferative response of female mice was exclusively abolished when using animals with a late β-catenin knockout. This suggests a β-catenin-dependent postnatal priming of hepatocytes during postnatal liver development, later affecting the proliferative response of adult animals to CAR-activating xenobiotics."
],
"offsets": [
[
144,
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]
]
}
] | [
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"id": "23578392_T1",
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"text": [
"TCPOBOP"
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]
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171
]
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]
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"id": "23578392_T7",
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"CAR"
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"id": "23578392_T8",
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"id": "23578392_T9",
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"CAR"
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]
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"id": "23578392_T10",
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"id": "23578392_T11",
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]
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"id": "23578392_T19",
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"CAR"
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507,
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]
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"id": "23578392_T20",
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182,
185
]
],
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},
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"id": "23578392_T21",
"type": "GENE-Y",
"text": [
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148,
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]
],
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"id": "23578392_T22",
"type": "GENE-Y",
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"β-catenin"
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722,
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]
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},
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"id": "23578392_T23",
"type": "GENE-Y",
"text": [
"β-catenin"
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799,
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]
],
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},
{
"id": "23578392_T24",
"type": "GENE-Y",
"text": [
"CAR"
],
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861,
864
]
],
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},
{
"id": "23578392_T25",
"type": "GENE-Y",
"text": [
"CAR"
],
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[
888,
891
]
],
"normalized": []
},
{
"id": "23578392_T26",
"type": "GENE-Y",
"text": [
"β-catenin"
],
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995,
1004
]
],
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},
{
"id": "23578392_T27",
"type": "GENE-Y",
"text": [
"CAR"
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1081,
1084
]
],
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},
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"id": "23578392_T28",
"type": "GENE-Y",
"text": [
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110,
142
]
],
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},
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"id": "23578392_T29",
"type": "GENE-Y",
"text": [
"β-catenin"
],
"offsets": [
[
18,
27
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23578392_0",
"type": "ACTIVATOR",
"arg1_id": "23578392_T3",
"arg2_id": "23578392_T27",
"normalized": []
},
{
"id": "23578392_1",
"type": "ACTIVATOR",
"arg1_id": "23578392_T4",
"arg2_id": "23578392_T27",
"normalized": []
}
] |
23164673 | 23164673 | [
{
"id": "23164673_title",
"type": "title",
"text": [
"The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells."
],
"offsets": [
[
0,
139
]
]
},
{
"id": "23164673_abstract",
"type": "abstract",
"text": [
"Cinobufagin, a major component of cinobufacini (huachansu), is an important cardenolidal steroid. Several studies have suggested that cinobufagin has potent anti-cancer effects. The present study examines the apoptosis-inducing activity and the underlying mechanism of action of cinobufagin in osteosarcoma (OS) cells. Our results showed that cinobufagin potently inhibited the proliferation of U2OS, MG63 and SaOS-2 cells. Significant increases in G2/M cell-cycle arrest and apoptosis in OS cells were also observed. The expression levels of several apoptotic proteins were assessed after cinobufagin treatment in U2OS cells. Among them, xIAP, cIAP-1, survivin and Bcl-2 levels decreased remarkably, while the levels of Bax and cleaved-PARP increased. Furthermore, we validated the inhibition of GSK-3β/NF-κB signaling following cinobufagin treatment. Western blots showed a decrease in nuclear p65 protein expression after exposure to different concentrations of cinobufagin, while the phosphorylation of GSK-3β was simultaneously increased. Transduction with constitutively active forms of GSK-3β could protect against the downregulation of p65 and upregulation of cleaved-PARP that are induced by cinobufagin treatment. However, combined treatment with cinobufagin and SB216367 resulted in a significant reduction in p65 and an increase in cleaved-PARP in U2OS cells. Altogether, these results show that cinobufagin is a promising agent for the treatment of OS. These studies are the first to reveal the involvement of the GSK-3β/NF-κB pathway in cinobufagin-induced apoptosis."
],
"offsets": [
[
140,
1721
]
]
}
] | [
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"id": "23164673_T1",
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140,
151
]
],
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},
{
"id": "23164673_T2",
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1341,
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]
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1397,
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1413,
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274,
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]
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"id": "23164673_T7",
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"cinobufagin"
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1691,
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419,
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]
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"id": "23164673_T9",
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483,
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]
],
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},
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"id": "23164673_T10",
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"text": [
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730,
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]
],
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},
{
"id": "23164673_T11",
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"text": [
"cardenolidal steroid"
],
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[
216,
236
]
],
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},
{
"id": "23164673_T12",
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"text": [
"cinobufagin"
],
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970,
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]
],
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},
{
"id": "23164673_T13",
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1105,
1116
]
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"id": "23164673_T14",
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"text": [
"cinobufagin"
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78,
89
]
],
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},
{
"id": "23164673_T15",
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"GSK-3β"
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1147,
1153
]
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},
{
"id": "23164673_T16",
"type": "GENE-Y",
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"GSK-3β"
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1233,
1239
]
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},
{
"id": "23164673_T17",
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"text": [
"p65"
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1284,
1287
]
],
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},
{
"id": "23164673_T18",
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"PARP"
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1316,
1320
]
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},
{
"id": "23164673_T19",
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"p65"
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1461,
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]
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},
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"id": "23164673_T20",
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},
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"id": "23164673_T22",
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785,
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]
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},
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793,
801
]
],
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},
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"id": "23164673_T26",
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806,
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]
],
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},
{
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"text": [
"Bax"
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861,
864
]
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},
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"id": "23164673_T28",
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877,
881
]
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},
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"id": "23164673_T29",
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937,
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]
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},
{
"id": "23164673_T30",
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"NF-κB"
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944,
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]
],
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},
{
"id": "23164673_T31",
"type": "GENE-Y",
"text": [
"p65"
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1036,
1039
]
],
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},
{
"id": "23164673_T32",
"type": "GENE-N",
"text": [
"nuclear factor-kappa B"
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[
32,
54
]
],
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},
{
"id": "23164673_T33",
"type": "GENE-Y",
"text": [
"glycogen synthase kinase-3β"
],
"offsets": [
[
4,
31
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23164673_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23164673_T12",
"arg2_id": "23164673_T29",
"normalized": []
},
{
"id": "23164673_1",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23164673_T12",
"arg2_id": "23164673_T30",
"normalized": []
},
{
"id": "23164673_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23164673_T13",
"arg2_id": "23164673_T31",
"normalized": []
},
{
"id": "23164673_3",
"type": "ACTIVATOR",
"arg1_id": "23164673_T13",
"arg2_id": "23164673_T15",
"normalized": []
},
{
"id": "23164673_4",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23164673_T2",
"arg2_id": "23164673_T17",
"normalized": []
},
{
"id": "23164673_5",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23164673_T2",
"arg2_id": "23164673_T18",
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},
{
"id": "23164673_6",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23164673_T4",
"arg2_id": "23164673_T19",
"normalized": []
},
{
"id": "23164673_7",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23164673_T3",
"arg2_id": "23164673_T19",
"normalized": []
},
{
"id": "23164673_8",
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"arg1_id": "23164673_T3",
"arg2_id": "23164673_T20",
"normalized": []
},
{
"id": "23164673_9",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23164673_T4",
"arg2_id": "23164673_T20",
"normalized": []
}
] |
16842172 | 16842172 | [
{
"id": "16842172_title",
"type": "title",
"text": [
"Dopaminergic enhancement of cognitive function."
],
"offsets": [
[
0,
47
]
]
},
{
"id": "16842172_abstract",
"type": "abstract",
"text": [
"The ascending dopamine system of the mammalian brain has been associated with motor, mnemonic and goal-directed or reward-related behaviour. The most progress in understanding the cortical mechanisms of dopaminergic modulation of function has been made with regards to short-term mnemonic (or working memory) function. Research in experimental animals strongly suggests that stimulation of dopamine D1 receptors in the prefrontal cortex can ameliorate spatial working memory related cognitive deficits, and may even enhance cognitive function in healthy animals. Research in humans has not been able to clearly replicate these findings, partly due to the lack of available agents that can safely be used. Low doses of dopamine D2 receptor agonists such as bromocriptine and pergolide may be able to enhance working memory and executive functions, but these effects may be dependent on the nature of the tasks used and the baseline performance levels of the subjects. Thus, the effects of dopaminergic cognitive enhancers may not be simple, or uniform across subjects. Systematic studies in humans carefully controlling task parameters are needed in order to specify the potential cognitive processes open to enhancement with dopaminergics. However, since the DA receptor subtypes in different brain regions appear to differentially influence similar functions, carefully defining the cognitive processes to be tested against potential therapeutics is an equally important goal. Studies in patients groups using selective dopaminergics are rather restricted, but show promise for designing large-scale clinical trials into the cognitive enhancing properties of potential therapeutic agents that act through the dopamine system."
],
"offsets": [
[
48,
1774
]
]
}
] | [
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"id": "16842172_T1",
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"DA"
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1307,
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]
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"dopamine"
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62,
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1758,
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"dopamine"
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"dopamine"
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"bromocriptine"
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"id": "16842172_T7",
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"text": [
"pergolide"
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822,
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]
],
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"DA receptor"
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"id": "16842172_T9",
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"dopamine D1 receptors"
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"dopamine D2 receptor"
],
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766,
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]
],
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}
] | [] | [] | [
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},
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"id": "16842172_1",
"type": "AGONIST",
"arg1_id": "16842172_T7",
"arg2_id": "16842172_T10",
"normalized": []
}
] |
23425969 | 23425969 | [
{
"id": "23425969_title",
"type": "title",
"text": [
"Synthesis, in vitro antiplatelet activity and molecular modelling studies of 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones."
],
"offsets": [
[
0,
149
]
]
},
{
"id": "23425969_abstract",
"type": "abstract",
"text": [
"The multistep preparation of the new 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones 6a-o, and of the two isomers 10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one 6p and 10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one 13, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca(2+) ionophore A23187 were here described. Nine out of fifteen 2-(1-piperazinyl)derivatives (6g-o) showed good inhibitory properties towards all the platelet aggregation agonists used. Moreover, a molecular modelling study has been performed on two of the best compounds of this series (6i and 6o) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor."
],
"offsets": [
[
150,
1036
]
]
}
] | [
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"id": "23425969_T1",
"type": "CHEMICAL",
"text": [
"10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one"
],
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[
288,
351
]
],
"normalized": []
},
{
"id": "23425969_T2",
"type": "CHEMICAL",
"text": [
"10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one"
],
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[
359,
422
]
],
"normalized": []
},
{
"id": "23425969_T3",
"type": "CHEMICAL",
"text": [
"10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones"
],
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187,
258
]
],
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},
{
"id": "23425969_T4",
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"ADP"
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556,
559
]
],
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},
{
"id": "23425969_T5",
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"Ca(2+)"
],
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[
577,
583
]
],
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},
{
"id": "23425969_T6",
"type": "CHEMICAL",
"text": [
"A23187"
],
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594,
600
]
],
"normalized": []
},
{
"id": "23425969_T7",
"type": "CHEMICAL",
"text": [
"2-(1-piperazinyl)"
],
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[
642,
659
]
],
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},
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"id": "23425969_T8",
"type": "CHEMICAL",
"text": [
"10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones"
],
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77,
148
]
],
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},
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"id": "23425969_T9",
"type": "GENE-N",
"text": [
"collagen"
],
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[
561,
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]
],
"normalized": []
},
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"id": "23425969_T10",
"type": "GENE-N",
"text": [
"human platelet PDE3"
],
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944,
963
]
],
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},
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"id": "23425969_T11",
"type": "GENE-Y",
"text": [
"PDE3B"
],
"offsets": [
[
993,
998
]
],
"normalized": []
}
] | [] | [] | [] |
23274898 | 23274898 | [
{
"id": "23274898_title",
"type": "title",
"text": [
"Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells."
],
"offsets": [
[
0,
127
]
]
},
{
"id": "23274898_abstract",
"type": "abstract",
"text": [
"Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance."
],
"offsets": [
[
128,
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]
]
}
] | [
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"id": "23274898_T1",
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"AS605240"
],
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1232,
1240
]
],
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},
{
"id": "23274898_T2",
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"ATP"
],
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1242,
1245
]
],
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},
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"id": "23274898_T3",
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"ATP"
],
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1479,
1482
]
],
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},
{
"id": "23274898_T4",
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"2-NBDG"
],
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[
1494,
1500
]
],
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},
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"id": "23274898_T5",
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"ATP"
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267,
270
]
],
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},
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"id": "23274898_T6",
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"ATP"
],
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1616,
1619
]
],
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},
{
"id": "23274898_T7",
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"text": [
"glucose"
],
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144,
151
]
],
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},
{
"id": "23274898_T8",
"type": "CHEMICAL",
"text": [
"glucose"
],
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[
422,
429
]
],
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},
{
"id": "23274898_T9",
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"ATP"
],
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462,
465
]
],
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},
{
"id": "23274898_T10",
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"2-NBD-Glucose"
],
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[
506,
519
]
],
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},
{
"id": "23274898_T11",
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"text": [
"2-NBDG"
],
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[
521,
527
]
],
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},
{
"id": "23274898_T12",
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"text": [
"ATP"
],
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[
593,
596
]
],
"normalized": []
},
{
"id": "23274898_T13",
"type": "CHEMICAL",
"text": [
"2-NBDG"
],
"offsets": [
[
607,
613
]
],
"normalized": []
},
{
"id": "23274898_T14",
"type": "CHEMICAL",
"text": [
"adenosine-phosphate"
],
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[
639,
658
]
],
"normalized": []
},
{
"id": "23274898_T15",
"type": "CHEMICAL",
"text": [
"suramin"
],
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[
708,
715
]
],
"normalized": []
},
{
"id": "23274898_T16",
"type": "CHEMICAL",
"text": [
"ATP"
],
"offsets": [
[
776,
779
]
],
"normalized": []
},
{
"id": "23274898_T17",
"type": "CHEMICAL",
"text": [
"suramin"
],
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[
857,
864
]
],
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},
{
"id": "23274898_T18",
"type": "CHEMICAL",
"text": [
"ATP"
],
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[
876,
879
]
],
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},
{
"id": "23274898_T19",
"type": "CHEMICAL",
"text": [
"ATP"
],
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[
1015,
1018
]
],
"normalized": []
},
{
"id": "23274898_T20",
"type": "CHEMICAL",
"text": [
"2-NBDG"
],
"offsets": [
[
1029,
1035
]
],
"normalized": []
},
{
"id": "23274898_T21",
"type": "CHEMICAL",
"text": [
"ATP"
],
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[
1068,
1071
]
],
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},
{
"id": "23274898_T22",
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"text": [
"2-NBDG"
],
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[
1082,
1088
]
],
"normalized": []
},
{
"id": "23274898_T23",
"type": "CHEMICAL",
"text": [
"ATP"
],
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[
27,
30
]
],
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},
{
"id": "23274898_T24",
"type": "CHEMICAL",
"text": [
"Glucose"
],
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[
67,
74
]
],
"normalized": []
},
{
"id": "23274898_T25",
"type": "GENE-Y",
"text": [
"phosphatidylinositol 3-kinase-γ"
],
"offsets": [
[
1182,
1213
]
],
"normalized": []
},
{
"id": "23274898_T26",
"type": "GENE-Y",
"text": [
"PI3Kγ"
],
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[
1215,
1220
]
],
"normalized": []
},
{
"id": "23274898_T27",
"type": "GENE-Y",
"text": [
"GLUT4"
],
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[
1270,
1275
]
],
"normalized": []
},
{
"id": "23274898_T28",
"type": "GENE-Y",
"text": [
"AS160"
],
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[
1364,
1369
]
],
"normalized": []
},
{
"id": "23274898_T29",
"type": "GENE-Y",
"text": [
"Rab8A"
],
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[
1370,
1375
]
],
"normalized": []
},
{
"id": "23274898_T30",
"type": "GENE-N",
"text": [
"Akt"
],
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[
1405,
1408
]
],
"normalized": []
},
{
"id": "23274898_T31",
"type": "GENE-Y",
"text": [
"PI3Kγ"
],
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[
1412,
1417
]
],
"normalized": []
},
{
"id": "23274898_T32",
"type": "GENE-N",
"text": [
"kinase"
],
"offsets": [
[
1418,
1424
]
],
"normalized": []
},
{
"id": "23274898_T33",
"type": "GENE-Y",
"text": [
"myristoylated PI3Kγ"
],
"offsets": [
[
1458,
1477
]
],
"normalized": []
},
{
"id": "23274898_T34",
"type": "GENE-Y",
"text": [
"insulin"
],
"offsets": [
[
1522,
1529
]
],
"normalized": []
},
{
"id": "23274898_T35",
"type": "GENE-Y",
"text": [
"insulin"
],
"offsets": [
[
1660,
1667
]
],
"normalized": []
},
{
"id": "23274898_T36",
"type": "GENE-N",
"text": [
"purinergic receptors"
],
"offsets": [
[
363,
383
]
],
"normalized": []
},
{
"id": "23274898_T37",
"type": "GENE-Y",
"text": [
"insulin"
],
"offsets": [
[
471,
478
]
],
"normalized": []
},
{
"id": "23274898_T38",
"type": "GENE-N",
"text": [
"adenosine-phosphate phosphatase"
],
"offsets": [
[
639,
670
]
],
"normalized": []
},
{
"id": "23274898_T39",
"type": "GENE-N",
"text": [
"purinergic receptor"
],
"offsets": [
[
678,
697
]
],
"normalized": []
},
{
"id": "23274898_T40",
"type": "GENE-N",
"text": [
"Akt"
],
"offsets": [
[
791,
794
]
],
"normalized": []
},
{
"id": "23274898_T41",
"type": "GENE-Y",
"text": [
"insulin"
],
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[
832,
839
]
],
"normalized": []
},
{
"id": "23274898_T42",
"type": "GENE-Y",
"text": [
"insulin"
],
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[
199,
206
]
],
"normalized": []
},
{
"id": "23274898_T43",
"type": "GENE-N",
"text": [
"Akt"
],
"offsets": [
[
902,
905
]
],
"normalized": []
},
{
"id": "23274898_T44",
"type": "GENE-N",
"text": [
"phosphatidylinositol 3-kinase"
],
"offsets": [
[
922,
951
]
],
"normalized": []
},
{
"id": "23274898_T45",
"type": "GENE-N",
"text": [
"PI3K"
],
"offsets": [
[
953,
957
]
],
"normalized": []
},
{
"id": "23274898_T46",
"type": "GENE-N",
"text": [
"Akt"
],
"offsets": [
[
962,
965
]
],
"normalized": []
},
{
"id": "23274898_T47",
"type": "GENE-N",
"text": [
"Akt"
],
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[
995,
998
]
],
"normalized": []
},
{
"id": "23274898_T48",
"type": "GENE-N",
"text": [
"Akt"
],
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[
1047,
1050
]
],
"normalized": []
},
{
"id": "23274898_T49",
"type": "GENE-N",
"text": [
"G protein βγ"
],
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[
1122,
1134
]
],
"normalized": []
},
{
"id": "23274898_T50",
"type": "GENE-Y",
"text": [
"GLUT4"
],
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[
43,
48
]
],
"normalized": []
},
{
"id": "23274898_T51",
"type": "GENE-Y",
"text": [
"PI3Kγ"
],
"offsets": [
[
86,
91
]
],
"normalized": []
},
{
"id": "23274898_T52",
"type": "GENE-N",
"text": [
"Akt"
],
"offsets": [
[
92,
95
]
],
"normalized": []
},
{
"id": "23274898_T53",
"type": "GENE-Y",
"text": [
"AS160"
],
"offsets": [
[
96,
101
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23274898_0",
"type": "SUBSTRATE",
"arg1_id": "23274898_T24",
"arg2_id": "23274898_T50",
"normalized": []
},
{
"id": "23274898_1",
"type": "INHIBITOR",
"arg1_id": "23274898_T15",
"arg2_id": "23274898_T38",
"normalized": []
},
{
"id": "23274898_2",
"type": "INHIBITOR",
"arg1_id": "23274898_T15",
"arg2_id": "23274898_T39",
"normalized": []
},
{
"id": "23274898_3",
"type": "INHIBITOR",
"arg1_id": "23274898_T17",
"arg2_id": "23274898_T40",
"normalized": []
},
{
"id": "23274898_4",
"type": "ACTIVATOR",
"arg1_id": "23274898_T18",
"arg2_id": "23274898_T43",
"normalized": []
},
{
"id": "23274898_5",
"type": "INHIBITOR",
"arg1_id": "23274898_T1",
"arg2_id": "23274898_T25",
"normalized": []
},
{
"id": "23274898_6",
"type": "INHIBITOR",
"arg1_id": "23274898_T1",
"arg2_id": "23274898_T26",
"normalized": []
}
] |
23244580 | 23244580 | [
{
"id": "23244580_title",
"type": "title",
"text": [
"Effects and mechanism of organ protection by cardiotrophin-1."
],
"offsets": [
[
0,
61
]
]
},
{
"id": "23244580_abstract",
"type": "abstract",
"text": [
"Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and profibrotic effects of CT-1 on the heart. Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them. Although many effects of CT-1 have been described on the heart, CT-1 has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system. CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFRβ) and a common signal transducer, the glycoprotein 130 (gp130). The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway(s) is involved in each particular effect of CT-1. In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated."
],
"offsets": [
[
62,
1642
]
]
}
] | [
{
"id": "23244580_T1",
"type": "CHEMICAL",
"text": [
"phosphatidylinositol 3-OH"
],
"offsets": [
[
1198,
1223
]
],
"normalized": []
},
{
"id": "23244580_T2",
"type": "GENE-Y",
"text": [
"Cardiotrophin-1"
],
"offsets": [
[
62,
77
]
],
"normalized": []
},
{
"id": "23244580_T3",
"type": "GENE-N",
"text": [
"p42/44 MAPK"
],
"offsets": [
[
1095,
1106
]
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"ERK1/2"
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"text": [
"Akt"
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"type": "GENE-Y",
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"CT-1"
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"id": "23244580_T19",
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"LIF receptor"
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"LIFRβ"
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"id": "23244580_T29",
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"text": [
"cardiotrophin-1"
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[
45,
60
]
],
"normalized": []
}
] | [] | [] | [] |
10212269 | 10212269 | [
{
"id": "10212269_title",
"type": "title",
"text": [
"Fibroblast growth factor-10. A second candidate stromal to epithelial cell andromedin in prostate."
],
"offsets": [
[
0,
98
]
]
},
{
"id": "10212269_abstract",
"type": "abstract",
"text": [
"Fibroblast growth factor (FGF)-10, a homologue of FGF-7, is expressed significantly in normal rat prostate tissue, well differentiated rat prostate tumors with an epithelial and stromal compartment and only in derived prostate stromal cells in culture. Similar to FGF-7, recombinant rat FGF-10 was a specific mitogen for prostate epithelial cells. In contrast to FGF-7 which is widely expressed among stromal cells in tissues, the expression of FGF-10 correlated with the presence of stromal cells of muscle origin. Radioreceptor binding assays and covalent cross-linking analysis revealed that FGF-10 binds with an affinity equal to FGF-7 to resident epithelial cell receptor, FGFR2IIIb, but unlike FGF-7 also binds the IIIb splice variant of FGFR1. Analysis of mRNA expression by RNase protection revealed that, similar to FGF-7, the expression of FGF-10 was responsive to androgen in stromal cells from normal prostate and non-malignant differentiated tumors. Although FGF-10 cDNA exhibits a signal sequence for secretion, cultured stromal cells exhibit strictly a cell-associated FGF-10 antigen that correlates with an alternately translated intracellular isoform. FGF-10 requires 1.4 times higher NaCl for elution from immobilized heparin than does FGF-7 and binds to four times the number of sites on the pericellular matrix of epithelial cells. The results show that prostate stromal cell-derived FGF-10, like FGF-7, exhibits the properties of an andromedin which may indirectly mediate control of epithelial cell growth and function by androgen. Although FGF-10 and FGF-7 bind and activate the same resident epithelial cell receptor (FGFR2IIIb), differences in cell type of origin, compartmentation by alternate translation, the affinity for FGFR1IIIb, and access to FGFR by differential interaction with pericellular matrix heparan sulfate suggest they may play both independent and compensatory roles in prostate homeostasis."
],
"offsets": [
[
99,
2034
]
]
}
] | [
{
"id": "10212269_T1",
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1301,
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]
],
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"id": "10212269_T2",
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"text": [
"androgen"
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]
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"id": "10212269_T3",
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"id": "10212269_T5",
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]
],
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"FGF-10"
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]
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"FGF-10"
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]
],
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"id": "10212269_T8",
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]
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},
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"id": "10212269_T10",
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1516,
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]
],
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},
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"id": "10212269_T11",
"type": "GENE-Y",
"text": [
"FGF-10"
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]
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"id": "10212269_T12",
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"text": [
"FGF-7"
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1673,
1678
]
],
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},
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"id": "10212269_T13",
"type": "GENE-N",
"text": [
"epithelial cell receptor"
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},
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"id": "10212269_T14",
"type": "GENE-Y",
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"FGFR2IIIb"
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]
],
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},
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"id": "10212269_T15",
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"FGFR1IIIb"
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"FGFR"
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"FGF-7"
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363,
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]
],
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},
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"id": "10212269_T18",
"type": "GENE-Y",
"text": [
"rat FGF-10"
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382,
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]
],
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},
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"id": "10212269_T19",
"type": "GENE-Y",
"text": [
"FGF-7"
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462,
467
]
],
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},
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"id": "10212269_T20",
"type": "GENE-Y",
"text": [
"FGF-10"
],
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[
544,
550
]
],
"normalized": []
},
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"id": "10212269_T21",
"type": "GENE-Y",
"text": [
"FGF-7"
],
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[
149,
154
]
],
"normalized": []
},
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"id": "10212269_T22",
"type": "GENE-Y",
"text": [
"FGF-10"
],
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[
694,
700
]
],
"normalized": []
},
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"id": "10212269_T23",
"type": "GENE-Y",
"text": [
"FGF-7"
],
"offsets": [
[
733,
738
]
],
"normalized": []
},
{
"id": "10212269_T24",
"type": "GENE-Y",
"text": [
"FGFR2IIIb"
],
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[
777,
786
]
],
"normalized": []
},
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"id": "10212269_T25",
"type": "GENE-Y",
"text": [
"FGF-7"
],
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[
799,
804
]
],
"normalized": []
},
{
"id": "10212269_T26",
"type": "GENE-Y",
"text": [
"IIIb splice variant of FGFR1"
],
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[
820,
848
]
],
"normalized": []
},
{
"id": "10212269_T27",
"type": "GENE-Y",
"text": [
"FGF-7"
],
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[
924,
929
]
],
"normalized": []
},
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"id": "10212269_T28",
"type": "GENE-Y",
"text": [
"FGF-10"
],
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[
949,
955
]
],
"normalized": []
},
{
"id": "10212269_T29",
"type": "GENE-Y",
"text": [
"FGF-10"
],
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[
1071,
1077
]
],
"normalized": []
},
{
"id": "10212269_T30",
"type": "GENE-Y",
"text": [
"Fibroblast growth factor-10"
],
"offsets": [
[
0,
27
]
],
"normalized": []
}
] | [] | [] | [] |
22397675 | 22397675 | [
{
"id": "22397675_title",
"type": "title",
"text": [
"Injectable PLA-based in situ forming implants for controlled release of Ivermectin a BCS Class II drug: solvent selection based on physico-chemical characterization."
],
"offsets": [
[
0,
165
]
]
},
{
"id": "22397675_abstract",
"type": "abstract",
"text": [
"In situ forming implants (ISI) prepared from biodegradable polymers such as poly(D,L-lactide) (PLA) and biocompatible solvents can be used to obtain sustained drug release after parenteral administration. The aim of this work was to study the effect of several biocompatible solvents with different physico-chemical properties on the release of ivermectin (IVM), an antiparasitic BCS II drug, from in situ forming PLA-based implants. The solvents evaluated were N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone (2P), triacetine (TA) and benzyl benzoate (BB). Hansen's solubility parameters of solvents were used to explain polymer/solvent interactions leading to different rheological behaviours. The stability of the polymer and drug in the solvents were also evaluated by size exclusion and high performance liquid chromatography, respectively. The two major factors determining the rate of IVM release from ISI were miscibility of the solvent with water and the viscosity of the polymer solutions. In general, the release rate increased with increasing water miscibility of the solvent and decreasing viscosity in the following order NMP>2P>TA>BB. Scanning electron microscopy revealed a relationship between the rate of IVM release and the surface porosity of the implants, release being higher as implant porosity increased. Finally, drug and polymer stability in the solvents followed the same trends, increasing when polymer-solvent affinities and water content in solvents decreased. IVM degradation was accelerated by the acid environment generated by the degradation of the polymer but the drug did not affect PLA stability."
],
"offsets": [
[
166,
1795
]
]
}
] | [
{
"id": "22397675_T1",
"type": "CHEMICAL",
"text": [
"NMP"
],
"offsets": [
[
1298,
1301
]
],
"normalized": []
},
{
"id": "22397675_T2",
"type": "CHEMICAL",
"text": [
"IVM"
],
"offsets": [
[
1385,
1388
]
],
"normalized": []
},
{
"id": "22397675_T3",
"type": "CHEMICAL",
"text": [
"IVM"
],
"offsets": [
[
1653,
1656
]
],
"normalized": []
},
{
"id": "22397675_T4",
"type": "CHEMICAL",
"text": [
"PLA"
],
"offsets": [
[
1781,
1784
]
],
"normalized": []
},
{
"id": "22397675_T5",
"type": "CHEMICAL",
"text": [
"ivermectin"
],
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[
511,
521
]
],
"normalized": []
},
{
"id": "22397675_T6",
"type": "CHEMICAL",
"text": [
"IVM"
],
"offsets": [
[
523,
526
]
],
"normalized": []
},
{
"id": "22397675_T7",
"type": "CHEMICAL",
"text": [
"PLA"
],
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[
580,
583
]
],
"normalized": []
},
{
"id": "22397675_T8",
"type": "CHEMICAL",
"text": [
"N-methyl-2-pyrrolidone"
],
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[
628,
650
]
],
"normalized": []
},
{
"id": "22397675_T9",
"type": "CHEMICAL",
"text": [
"NMP"
],
"offsets": [
[
652,
655
]
],
"normalized": []
},
{
"id": "22397675_T10",
"type": "CHEMICAL",
"text": [
"2-pyrrolidone"
],
"offsets": [
[
658,
671
]
],
"normalized": []
},
{
"id": "22397675_T11",
"type": "CHEMICAL",
"text": [
"triacetine"
],
"offsets": [
[
678,
688
]
],
"normalized": []
},
{
"id": "22397675_T12",
"type": "CHEMICAL",
"text": [
"benzyl benzoate"
],
"offsets": [
[
698,
713
]
],
"normalized": []
},
{
"id": "22397675_T13",
"type": "CHEMICAL",
"text": [
"poly(D,L-lactide)"
],
"offsets": [
[
242,
259
]
],
"normalized": []
},
{
"id": "22397675_T14",
"type": "CHEMICAL",
"text": [
"IVM"
],
"offsets": [
[
1054,
1057
]
],
"normalized": []
},
{
"id": "22397675_T15",
"type": "CHEMICAL",
"text": [
"PLA"
],
"offsets": [
[
261,
264
]
],
"normalized": []
},
{
"id": "22397675_T16",
"type": "CHEMICAL",
"text": [
"PLA"
],
"offsets": [
[
11,
14
]
],
"normalized": []
},
{
"id": "22397675_T17",
"type": "CHEMICAL",
"text": [
"Ivermectin"
],
"offsets": [
[
72,
82
]
],
"normalized": []
}
] | [] | [] | [] |
23274887 | 23274887 | [
{
"id": "23274887_title",
"type": "title",
"text": [
"Fetal PGC-1α overexpression programs adult pancreatic β-cell dysfunction."
],
"offsets": [
[
0,
73
]
]
},
{
"id": "23274887_abstract",
"type": "abstract",
"text": [
"Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1α represses genes important for β-cell development and function. More precisely, PGC-1α inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1α complex to the Pdx1 promoter. To explore PGC-1α function, we generated mice with inducible β-cell PGC-1α overexpression. Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypotrophy. Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult β-cell function whereas β-cell PGC-1α overexpression from adult age had no consequence on β-cell function. Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult β-cell function through inhibition of Pdx1 expression."
],
"offsets": [
[
74,
1479
]
]
}
] | [
{
"id": "23274887_T1",
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"text": [
"glucose"
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[
1023,
1030
]
],
"normalized": []
},
{
"id": "23274887_T2",
"type": "GENE-Y",
"text": [
"PGC-1α"
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[
1145,
1151
]
],
"normalized": []
},
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"id": "23274887_T3",
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"text": [
"PGC-1α"
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[
1244,
1250
]
],
"normalized": []
},
{
"id": "23274887_T4",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
1365,
1367
]
],
"normalized": []
},
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"id": "23274887_T5",
"type": "GENE-Y",
"text": [
"PGC-1α"
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[
1372,
1378
]
],
"normalized": []
},
{
"id": "23274887_T6",
"type": "GENE-Y",
"text": [
"Pdx1"
],
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[
1463,
1467
]
],
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},
{
"id": "23274887_T7",
"type": "GENE-Y",
"text": [
"peroxisome proliferator-activated receptor-γ coactivator-1α"
],
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[
426,
485
]
],
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},
{
"id": "23274887_T8",
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"text": [
"PGC-1α"
],
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[
487,
493
]
],
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},
{
"id": "23274887_T9",
"type": "GENE-Y",
"text": [
"GCs receptor"
],
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[
517,
529
]
],
"normalized": []
},
{
"id": "23274887_T10",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
531,
533
]
],
"normalized": []
},
{
"id": "23274887_T11",
"type": "GENE-Y",
"text": [
"PGC-1α"
],
"offsets": [
[
567,
573
]
],
"normalized": []
},
{
"id": "23274887_T12",
"type": "GENE-Y",
"text": [
"PGC-1α"
],
"offsets": [
[
653,
659
]
],
"normalized": []
},
{
"id": "23274887_T13",
"type": "GENE-Y",
"text": [
"pancreatic duodenal homeobox 1"
],
"offsets": [
[
724,
754
]
],
"normalized": []
},
{
"id": "23274887_T14",
"type": "GENE-Y",
"text": [
"Pdx1"
],
"offsets": [
[
756,
760
]
],
"normalized": []
},
{
"id": "23274887_T15",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
792,
794
]
],
"normalized": []
},
{
"id": "23274887_T16",
"type": "GENE-Y",
"text": [
"GR"
],
"offsets": [
[
833,
835
]
],
"normalized": []
},
{
"id": "23274887_T17",
"type": "GENE-Y",
"text": [
"PGC-1α"
],
"offsets": [
[
836,
842
]
],
"normalized": []
},
{
"id": "23274887_T18",
"type": "GENE-N",
"text": [
"Pdx1 promoter"
],
"offsets": [
[
858,
871
]
],
"normalized": []
},
{
"id": "23274887_T19",
"type": "GENE-Y",
"text": [
"PGC-1α"
],
"offsets": [
[
884,
890
]
],
"normalized": []
},
{
"id": "23274887_T20",
"type": "GENE-Y",
"text": [
"PGC-1α"
],
"offsets": [
[
941,
947
]
],
"normalized": []
},
{
"id": "23274887_T21",
"type": "GENE-Y",
"text": [
"PGC-1α"
],
"offsets": [
[
984,
990
]
],
"normalized": []
},
{
"id": "23274887_T22",
"type": "GENE-Y",
"text": [
"PGC-1α"
],
"offsets": [
[
6,
12
]
],
"normalized": []
}
] | [] | [] | [] |
15240882 | 15240882 | [
{
"id": "15240882_title",
"type": "title",
"text": [
"Thyroid hormone receptor alpha is a molecular switch of cardiac function between fetal and postnatal life."
],
"offsets": [
[
0,
106
]
]
},
{
"id": "15240882_abstract",
"type": "abstract",
"text": [
"Thyroid hormones are involved in the regulation of many physiological processes and regulate gene transcription by binding to their nuclear receptors TRalpha and TRbeta. In the absence of triiodothyronine (T3), the unliganded receptors (aporeceptors) do bind DNA and repress the transcription of target genes. The role of thyroid hormone aporeceptors as repressors was observed in hypothyroid adult mice, but its physiological relevance in nonpathological hypothyroid conditions remained to be determined. Here we show that, in the normal mouse fetus, TRalpha aporeceptors repress heart rate as well as the expression of TRbeta and several genes encoding ion channels involved in cardiac contractile activity. Right after birth, when T3 concentration sharply increases, liganded TRalpha (holoreceptors) turn on the expression of some of these same genes concomitantly with heart rate increase. These data describe a physiological situation under which conversion of TRalpha from apo-receptors into holo-receptors, upon changes in T3 availability, plays a determinant role in a developmental process."
],
"offsets": [
[
107,
1206
]
]
}
] | [
{
"id": "15240882_T1",
"type": "CHEMICAL",
"text": [
"Thyroid hormones"
],
"offsets": [
[
107,
123
]
],
"normalized": []
},
{
"id": "15240882_T2",
"type": "CHEMICAL",
"text": [
"T3"
],
"offsets": [
[
1137,
1139
]
],
"normalized": []
},
{
"id": "15240882_T3",
"type": "CHEMICAL",
"text": [
"triiodothyronine"
],
"offsets": [
[
295,
311
]
],
"normalized": []
},
{
"id": "15240882_T4",
"type": "CHEMICAL",
"text": [
"T3"
],
"offsets": [
[
313,
315
]
],
"normalized": []
},
{
"id": "15240882_T5",
"type": "CHEMICAL",
"text": [
"thyroid hormone"
],
"offsets": [
[
429,
444
]
],
"normalized": []
},
{
"id": "15240882_T6",
"type": "CHEMICAL",
"text": [
"T3"
],
"offsets": [
[
841,
843
]
],
"normalized": []
},
{
"id": "15240882_T7",
"type": "CHEMICAL",
"text": [
"Thyroid hormone"
],
"offsets": [
[
0,
15
]
],
"normalized": []
},
{
"id": "15240882_T8",
"type": "GENE-Y",
"text": [
"TRalpha"
],
"offsets": [
[
257,
264
]
],
"normalized": []
},
{
"id": "15240882_T9",
"type": "GENE-Y",
"text": [
"TRbeta"
],
"offsets": [
[
269,
275
]
],
"normalized": []
},
{
"id": "15240882_T10",
"type": "GENE-N",
"text": [
"thyroid hormone aporeceptors"
],
"offsets": [
[
429,
457
]
],
"normalized": []
},
{
"id": "15240882_T11",
"type": "GENE-Y",
"text": [
"TRalpha"
],
"offsets": [
[
659,
666
]
],
"normalized": []
},
{
"id": "15240882_T12",
"type": "GENE-Y",
"text": [
"TRbeta"
],
"offsets": [
[
728,
734
]
],
"normalized": []
},
{
"id": "15240882_T13",
"type": "GENE-Y",
"text": [
"TRalpha"
],
"offsets": [
[
886,
893
]
],
"normalized": []
},
{
"id": "15240882_T14",
"type": "GENE-Y",
"text": [
"TRalpha"
],
"offsets": [
[
1073,
1080
]
],
"normalized": []
},
{
"id": "15240882_T15",
"type": "GENE-Y",
"text": [
"Thyroid hormone receptor alpha"
],
"offsets": [
[
0,
30
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "15240882_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "15240882_T1",
"arg2_id": "15240882_T8",
"normalized": []
},
{
"id": "15240882_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "15240882_T1",
"arg2_id": "15240882_T9",
"normalized": []
}
] |
11237340 | 11237340 | [
{
"id": "11237340_title",
"type": "title",
"text": [
"Enzymatic determination of homocysteine in cell extracts."
],
"offsets": [
[
0,
57
]
]
},
{
"id": "11237340_abstract",
"type": "abstract",
"text": [
"Determination of homocysteine levels in cells and serum is important because high homocysteine is a risk factor for cardiovascular disease. The currently used methods for homocysteine analysis either are time consuming or rely on the use of expensive equipment. Described in this study is an enzymatic assay that determines levels of homocysteine in multiple samples in less than 30 min at levels from 5 to 50 pmol using only a spectrophotometer. The reproducibility of the assay is consistent with the other methods currently used. A second assay, that is about 5-fold more sensitive, follows the enzymatic catalyzed solvent exchange of protons on glycine, which requires a scintillation counter. Both the spectrophotometric and the radiometric methods are based on the conversion of 5-methyltetrahydrofolate to tetrahydrofolate by methionine synthase. The tetrahydrofolate is formed in stoichiometric amounts to the homocysteine in the sample. In the spectrophotometric method the tetrahydrofolate is used at catalytic levels by three enzymes to form a metabolic cycle that generates NADPH from NADP(+). In the radiometric assay tetrahydrofolate is required for the enzymatic exchange of the pro 2S proton of glycine with solvent. L-Cysteine, at levels more than 30-fold higher than the upper level of homocysteine used in these assays, does not give any measurable response."
],
"offsets": [
[
58,
1435
]
]
}
] | [
{
"id": "11237340_T1",
"type": "CHEMICAL",
"text": [
"NADPH"
],
"offsets": [
[
1144,
1149
]
],
"normalized": []
},
{
"id": "11237340_T2",
"type": "CHEMICAL",
"text": [
"NADP(+)"
],
"offsets": [
[
1155,
1162
]
],
"normalized": []
},
{
"id": "11237340_T3",
"type": "CHEMICAL",
"text": [
"tetrahydrofolate"
],
"offsets": [
[
1189,
1205
]
],
"normalized": []
},
{
"id": "11237340_T4",
"type": "CHEMICAL",
"text": [
"glycine"
],
"offsets": [
[
1269,
1276
]
],
"normalized": []
},
{
"id": "11237340_T5",
"type": "CHEMICAL",
"text": [
"L-Cysteine"
],
"offsets": [
[
1291,
1301
]
],
"normalized": []
},
{
"id": "11237340_T6",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
1362,
1374
]
],
"normalized": []
},
{
"id": "11237340_T7",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
229,
241
]
],
"normalized": []
},
{
"id": "11237340_T8",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
75,
87
]
],
"normalized": []
},
{
"id": "11237340_T9",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
392,
404
]
],
"normalized": []
},
{
"id": "11237340_T10",
"type": "CHEMICAL",
"text": [
"glycine"
],
"offsets": [
[
707,
714
]
],
"normalized": []
},
{
"id": "11237340_T11",
"type": "CHEMICAL",
"text": [
"5-methyltetrahydrofolate"
],
"offsets": [
[
843,
867
]
],
"normalized": []
},
{
"id": "11237340_T12",
"type": "CHEMICAL",
"text": [
"tetrahydrofolate"
],
"offsets": [
[
871,
887
]
],
"normalized": []
},
{
"id": "11237340_T13",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
140,
152
]
],
"normalized": []
},
{
"id": "11237340_T14",
"type": "CHEMICAL",
"text": [
"methionine"
],
"offsets": [
[
891,
901
]
],
"normalized": []
},
{
"id": "11237340_T15",
"type": "CHEMICAL",
"text": [
"tetrahydrofolate"
],
"offsets": [
[
916,
932
]
],
"normalized": []
},
{
"id": "11237340_T16",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
976,
988
]
],
"normalized": []
},
{
"id": "11237340_T17",
"type": "CHEMICAL",
"text": [
"tetrahydrofolate"
],
"offsets": [
[
1041,
1057
]
],
"normalized": []
},
{
"id": "11237340_T18",
"type": "CHEMICAL",
"text": [
"homocysteine"
],
"offsets": [
[
27,
39
]
],
"normalized": []
},
{
"id": "11237340_T19",
"type": "GENE-Y",
"text": [
"methionine synthase"
],
"offsets": [
[
891,
910
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11237340_0",
"type": "SUBSTRATE",
"arg1_id": "11237340_T11",
"arg2_id": "11237340_T19",
"normalized": []
},
{
"id": "11237340_1",
"type": "PRODUCT-OF",
"arg1_id": "11237340_T12",
"arg2_id": "11237340_T19",
"normalized": []
}
] |
23330847 | 23330847 | [
{
"id": "23330847_title",
"type": "title",
"text": [
"Hydroxy-terminated conjugated polymer nanoparticles have near-unity bright fraction and reveal cholesterol-dependence of IGF1R nanodomains."
],
"offsets": [
[
0,
139
]
]
},
{
"id": "23330847_abstract",
"type": "abstract",
"text": [
"Fluorescent nanoparticles have enabled many discoveries regarding how molecular machines function. Quantum dots have been the dominant class of fluorescent nanoparticles but suffer from blinking and from a substantial dark fraction--particles where the fluorescence is never seen--complicating any analysis of biological function. Nanoparticles composed of conjugated fluorescent polymers (Pdots) have recently been shown to have high brightness and no blinking. Here we develop a robust and efficient means to measure the dark fraction of Pdots, conjugating Atto dyes to the nanoparticles and testing fluorescence colocalization of dye and Pdot puncta. This established that the Pdots we generated had minimal dark fraction: ∼3%. The application of nanoparticles in biological environments is highly sensitive to surface functionalization. For Pdots we found that passivation with uncharged hydroxy-terminated polyethylene glycol caused a dramatic reduction in nonspecific cell binding and aggregation compared to a charged coating. Using carbonyl di-imidazole the hydroxy-Pdots were functionalized efficiently with streptavidin for high stability targeting, allowing specific labeling of mammalian cells. Type I insulin-like growth factor receptor (IGF1R) regulates cell survival and development, with roles in aging, heart disease, and cancer. We used hydroxy-Pdots to track the dynamics of IGF1R on a breast cancer cell-line, determining the diffusion characteristics and showing cholesterol-containing membrane nanodomains were important for receptor mobility at the plasma membrane. The near-unity bright fraction and low nonspecific binding of hydroxy-Pdots, combined with Pdot photostability and lack of blinking, provides many advantages for investigations at the single molecule level."
],
"offsets": [
[
140,
1935
]
]
}
] | [
{
"id": "23330847_T1",
"type": "CHEMICAL",
"text": [
"carbonyl di-imidazole"
],
"offsets": [
[
1180,
1201
]
],
"normalized": []
},
{
"id": "23330847_T2",
"type": "CHEMICAL",
"text": [
"hydroxy"
],
"offsets": [
[
1206,
1213
]
],
"normalized": []
},
{
"id": "23330847_T3",
"type": "CHEMICAL",
"text": [
"hydroxy"
],
"offsets": [
[
1495,
1502
]
],
"normalized": []
},
{
"id": "23330847_T4",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
1624,
1635
]
],
"normalized": []
},
{
"id": "23330847_T5",
"type": "CHEMICAL",
"text": [
"hydroxy"
],
"offsets": [
[
1791,
1798
]
],
"normalized": []
},
{
"id": "23330847_T6",
"type": "CHEMICAL",
"text": [
"hydroxy"
],
"offsets": [
[
1032,
1039
]
],
"normalized": []
},
{
"id": "23330847_T7",
"type": "CHEMICAL",
"text": [
"polyethylene glycol"
],
"offsets": [
[
1051,
1070
]
],
"normalized": []
},
{
"id": "23330847_T8",
"type": "CHEMICAL",
"text": [
"Hydroxy"
],
"offsets": [
[
0,
7
]
],
"normalized": []
},
{
"id": "23330847_T9",
"type": "CHEMICAL",
"text": [
"cholesterol"
],
"offsets": [
[
95,
106
]
],
"normalized": []
},
{
"id": "23330847_T10",
"type": "GENE-Y",
"text": [
"Type I insulin-like growth factor receptor"
],
"offsets": [
[
1347,
1389
]
],
"normalized": []
},
{
"id": "23330847_T11",
"type": "GENE-Y",
"text": [
"IGF1R"
],
"offsets": [
[
1391,
1396
]
],
"normalized": []
},
{
"id": "23330847_T12",
"type": "GENE-Y",
"text": [
"IGF1R"
],
"offsets": [
[
1534,
1539
]
],
"normalized": []
},
{
"id": "23330847_T13",
"type": "GENE-N",
"text": [
"IGF1R nanodomains"
],
"offsets": [
[
121,
138
]
],
"normalized": []
}
] | [] | [] | [] |
23587648 | 23587648 | [
{
"id": "23587648_title",
"type": "title",
"text": [
"Regulation of connexin hemichannel activity by membrane potential and the extracellular calcium in health and disease."
],
"offsets": [
[
0,
118
]
]
},
{
"id": "23587648_abstract",
"type": "abstract",
"text": [
"Connexins are thought to solely mediate cell-to-cell communication by forming gap junction channels composed of two membrane-spanning hemichannels positioned end-to-end. However, many if not all connexin isoforms also form functional hemichannels (i.e., the precursors of complete channels) that mediate the rapid exchange of ions, second messengers and metabolites between the cell interior and the interstitial space. Electrical and molecular signaling via connexin hemichannels is now widely recognized to be important in many physiological scenarios and pathological conditions. Indeed, mutations in connexins that alter hemichannel function have been implicated in several diseases. Here, we present a comprehensive overview of how hemichannel activity is tightly regulated by membrane potential and the external calcium concentration. In addition, we discuss the genetic mutations known to alter hemichannel function and their deleterious effects, of which a better understanding is necessary to develop novel therapeutic approaches for diseases caused by hemichannel dysfunction. This article is part of a Special Issue entitled 'Connexin based channels'."
],
"offsets": [
[
119,
1281
]
]
}
] | [
{
"id": "23587648_T1",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
937,
944
]
],
"normalized": []
},
{
"id": "23587648_T2",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
88,
95
]
],
"normalized": []
},
{
"id": "23587648_T3",
"type": "GENE-N",
"text": [
"Connexins"
],
"offsets": [
[
119,
128
]
],
"normalized": []
},
{
"id": "23587648_T4",
"type": "GENE-N",
"text": [
"hemichannel"
],
"offsets": [
[
1181,
1192
]
],
"normalized": []
},
{
"id": "23587648_T5",
"type": "GENE-N",
"text": [
"Connexin based channels"
],
"offsets": [
[
1256,
1279
]
],
"normalized": []
},
{
"id": "23587648_T6",
"type": "GENE-N",
"text": [
"hemichannels"
],
"offsets": [
[
253,
265
]
],
"normalized": []
},
{
"id": "23587648_T7",
"type": "GENE-N",
"text": [
"connexin"
],
"offsets": [
[
314,
322
]
],
"normalized": []
},
{
"id": "23587648_T8",
"type": "GENE-N",
"text": [
"connexin hemichannels"
],
"offsets": [
[
578,
599
]
],
"normalized": []
},
{
"id": "23587648_T9",
"type": "GENE-N",
"text": [
"connexins"
],
"offsets": [
[
723,
732
]
],
"normalized": []
},
{
"id": "23587648_T10",
"type": "GENE-N",
"text": [
"hemichannel"
],
"offsets": [
[
744,
755
]
],
"normalized": []
},
{
"id": "23587648_T11",
"type": "GENE-N",
"text": [
"hemichannel"
],
"offsets": [
[
856,
867
]
],
"normalized": []
},
{
"id": "23587648_T12",
"type": "GENE-N",
"text": [
"gap junction channels"
],
"offsets": [
[
197,
218
]
],
"normalized": []
},
{
"id": "23587648_T13",
"type": "GENE-N",
"text": [
"hemichannel"
],
"offsets": [
[
1021,
1032
]
],
"normalized": []
},
{
"id": "23587648_T14",
"type": "GENE-N",
"text": [
"connexin hemichannel"
],
"offsets": [
[
14,
34
]
],
"normalized": []
}
] | [] | [] | [] |
11103883 | 11103883 | [
{
"id": "11103883_title",
"type": "title",
"text": [
"In-vivo assessment of 5-HT2A and 5-HT2C antagonistic properties of newer antipsychotics."
],
"offsets": [
[
0,
88
]
]
},
{
"id": "11103883_abstract",
"type": "abstract",
"text": [
"The effects of serotonin (5-HT) receptor ligands on the MK 212 (6-chloro-2[1-piperazinyl]pyrazine) discriminative stimulus and quipazine-induced head twitches were studied in rats. 5-HT1A (8-OH-DPAT) and preferential 5-HT2A (DOI) receptor agonists did not generalize to the discriminative stimulus. The 5-HT2B/2C-receptor antagonist, SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole), and the 5-HT2A/2C-receptor antagonist, ritanserin, acted as potent antagonists, whereas the 5-HT2A-receptor antagonist, MDL 100.151 ([(+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4- piperidine-methanol), produced minor and inconsistent inhibition. SB 206553 was a weak antagonist against quipazine-induced head twitches, whereas MDL 100.151 and ritanserin were potent antagonists. This suggests that the MK 212 discriminative stimulus is mediated by 5-HT2C receptors, while quipazine-induced head twitches are mediated primarily by 5-HT2A receptors. The effects on quipazine-induced head twitches were comparable to previously published effects on the DOI discriminative stimulus. 5-HT2A- and 5-HT2C-receptor antagonistic potencies of clozapine, olanzapine, risperidone, sertindole and ziprasidone were compared in the same models. Clozapine showed similar potencies in both models, while sertindole, olanzapine and risperidone inhibited quipazine-induced effects more potently than the MK 212 discriminative stimulus. Ziprasidone exerted a minor preference for 5-HT2A- compared to 5-HT2C-receptor-mediated effects. The ratio between in vivo inhibitory potencies at 5-HT2A and 5-HT2C receptors did not correlate with corresponding ratios from in-vitro affinity and ex-vivo occupancy studies in the literature."
],
"offsets": [
[
89,
1834
]
]
}
] | [
{
"id": "11103883_T1",
"type": "CHEMICAL",
"text": [
"quipazine"
],
"offsets": [
[
1090,
1099
]
],
"normalized": []
},
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] |
23340252 | 23340252 | [
{
"id": "23340252_title",
"type": "title",
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"The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation."
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"type": "abstract",
"text": [
"Glucocorticoid signaling plays a critical role in regulating energy metabolism. Emerging data implicate environmental endocrine-disrupting chemicals as contributors to the obesity and diabetes epidemics. Previous studies have shown that the phenylsulfamide fungicide tolylfluanid (TF) augments glucocorticoid receptor (GR)-dependent luciferase expression in 3T3-L1 preadipocytes while modulating insulin action in primary murine and human adipocytes. Studies were performed to interrogate glucocorticoid signaling in primary adipocytes exposed to TF. TF mimicked the gene transcription profile of the murine glucocorticoid corticosterone (Cort). Cellular fractionation assays demonstrated that TF treatment promoted the activating serine phosphorylation of GR, augmenting its cytoplasmic-to-nuclear translocation as well as its enrichment at glucocorticoid response elements on the glucocorticoid-induced leucine zipper gene promoter. After acute treatment, Cort or TF promoted insulin receptor substrate-1 (IRS-1) gene and protein expression. Either treatment also enriched GR binding at an identified glucocorticoid response element in the IRS-1 gene. TF or Cort each increased insulin-stimulated lipogenesis, an effect resulting from increased lipogenic gene expression and enhanced insulin-stimulated dephosphorylation of acetyl-coenzyme A carboxylase. The augmentation of insulin-stimulated lipogenesis was mediated through a specific enhancement of Akt phosphorylation at T308. These findings support modulation of IRS-1 levels as a mechanism for glucocorticoid-mediated changes in insulin action in primary adipocytes. Albeit with less affinity than Cort, in silico analysis suggests that TF can interact with the ligand binding pocket of GR. Collectively, these studies identify TF as a structurally unique environmental glucocorticoid. Glucocorticoid signaling may thus represent a novel pathway by which environmental toxicants promote the development of metabolic diseases."
],
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115,
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]
}
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"id": "23340252_T1",
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1275,
1279
]
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"id": "23340252_T2",
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"acetyl-coenzyme A"
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1441,
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]
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"id": "23340252_T3",
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"Cort"
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1772,
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356,
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382,
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"id": "23340252_T6",
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"corticosterone"
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738,
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]
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754,
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"id": "23340252_T8",
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"serine"
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846,
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]
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"id": "23340252_T9",
"type": "CHEMICAL",
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"leucine"
],
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1020,
1027
]
],
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},
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"id": "23340252_T10",
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"Cort"
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1073,
1077
]
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"id": "23340252_T11",
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"tolylfluanid"
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[
34,
46
]
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},
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"id": "23340252_T12",
"type": "GENE-Y",
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"IRS-1"
],
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[
1123,
1128
]
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},
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"id": "23340252_T13",
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"GR"
],
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[
1190,
1192
]
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},
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"id": "23340252_T14",
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"glucocorticoid response element"
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1218,
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]
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},
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"IRS-1"
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1257,
1262
]
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},
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"id": "23340252_T16",
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"insulin"
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1295,
1302
]
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},
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"id": "23340252_T17",
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"insulin"
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1401,
1408
]
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"acetyl-coenzyme A carboxylase"
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1441,
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]
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"insulin"
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]
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"id": "23340252_T20",
"type": "GENE-N",
"text": [
"Akt"
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1570,
1573
]
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},
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"id": "23340252_T21",
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"IRS-1"
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1636,
1641
]
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"insulin"
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1703,
1710
]
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},
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"id": "23340252_T23",
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"GR"
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1861,
1863
]
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"id": "23340252_T24",
"type": "GENE-Y",
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"glucocorticoid receptor"
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409,
432
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"id": "23340252_T25",
"type": "GENE-Y",
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"GR"
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[
434,
436
]
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},
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"id": "23340252_T26",
"type": "GENE-N",
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"insulin"
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[
511,
518
]
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},
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"id": "23340252_T27",
"type": "GENE-Y",
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"GR"
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[
872,
874
]
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},
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"id": "23340252_T28",
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"glucocorticoid response elements"
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[
957,
989
]
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},
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"id": "23340252_T29",
"type": "GENE-N",
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"leucine zipper gene promoter"
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[
1020,
1048
]
],
"normalized": []
},
{
"id": "23340252_T30",
"type": "GENE-Y",
"text": [
"insulin receptor substrate-1"
],
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[
1093,
1121
]
],
"normalized": []
},
{
"id": "23340252_T31",
"type": "GENE-Y",
"text": [
"glucocorticoid receptor"
],
"offsets": [
[
79,
102
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23340252_0",
"type": "ACTIVATOR",
"arg1_id": "23340252_T11",
"arg2_id": "23340252_T31",
"normalized": []
},
{
"id": "23340252_1",
"type": "INDIRECT-UPREGULATOR",
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"arg2_id": "23340252_T24",
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},
{
"id": "23340252_2",
"type": "INDIRECT-UPREGULATOR",
"arg1_id": "23340252_T5",
"arg2_id": "23340252_T24",
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{
"id": "23340252_3",
"type": "INDIRECT-UPREGULATOR",
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"arg2_id": "23340252_T25",
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},
{
"id": "23340252_4",
"type": "INDIRECT-UPREGULATOR",
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"arg2_id": "23340252_T25",
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},
{
"id": "23340252_5",
"type": "PART-OF",
"arg1_id": "23340252_T8",
"arg2_id": "23340252_T27",
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},
{
"id": "23340252_6",
"type": "INDIRECT-UPREGULATOR",
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"id": "23340252_7",
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"arg2_id": "23340252_T16",
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},
{
"id": "23340252_9",
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"arg2_id": "23340252_T18",
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},
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}
] |
23394555 | 23394555 | [
{
"id": "23394555_title",
"type": "title",
"text": [
"Thymidylate kinase: an old topic brings new perspectives."
],
"offsets": [
[
0,
57
]
]
},
{
"id": "23394555_abstract",
"type": "abstract",
"text": [
"Thymidylate kinase (TMPK) is a key enzyme for pyrimidine synthesis that catalyzes the phosphorylation of thymidine 5'-monophosphate (dTMP) in the presence of ATP and Mg(2+) to form thymidine 5'-diphosphate (dTDP), which is then converted to thymidine 5'-triphosphate (dTTP) by nucleoside-diphosphate kinase (NDK). TMPK has an important function in cell proliferation and its enzyme kinetics and related structures have been determined in various organisms. TMPK is well recognized as a potential drug target, with the most notable function being in the activation of anti-HIV nucleoside prodrugs. Recent studies have shown that TMPK is a validated target for antibiotic development against gram-positive bacterium of Staphylococcus aureus. In addition, inhibition of human TMPK increases the potential of anticancer agent doxorubicin toward colon cancer cells regardless of p53 status. Following the rapid expanding knowledge on TMPKs and the rising interests in TMPKs as a drug target, in this review we try to describe current research on TMPKs in various organisms of eukaryotes, prokaryotes and viruses and to provide information for designing new potential inhibitors against TMPKs."
],
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58,
1245
]
]
}
] | [
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"id": "23394555_T1",
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"Thymidylate"
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58,
69
]
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"id": "23394555_T2",
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"thymidine 5'-monophosphate"
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163,
189
]
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},
{
"id": "23394555_T3",
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"dTMP"
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191,
195
]
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"id": "23394555_T4",
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"ATP"
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216,
219
]
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"id": "23394555_T5",
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"Mg(2+)"
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224,
230
]
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"id": "23394555_T6",
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"thymidine 5'-diphosphate"
],
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239,
263
]
],
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"id": "23394555_T7",
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"dTDP"
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265,
269
]
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"id": "23394555_T8",
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"thymidine 5'-triphosphate"
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299,
324
]
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"id": "23394555_T9",
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"dTTP"
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326,
330
]
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"id": "23394555_T10",
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"nucleoside-diphosphate"
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335,
357
]
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},
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"id": "23394555_T11",
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"text": [
"pyrimidine"
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104,
114
]
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},
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"id": "23394555_T12",
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"text": [
"nucleoside"
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634,
644
]
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},
{
"id": "23394555_T13",
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"text": [
"doxorubicin"
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880,
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]
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"id": "23394555_T14",
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0,
11
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"id": "23394555_T15",
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58,
76
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"id": "23394555_T16",
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"TMPKs"
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1099,
1104
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"id": "23394555_T17",
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"TMPKs"
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1239,
1244
]
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},
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"id": "23394555_T18",
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"TMPK"
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78,
82
]
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"id": "23394555_T19",
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"TMPK"
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372,
376
]
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},
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"id": "23394555_T20",
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"TMPK"
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515,
519
]
],
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},
{
"id": "23394555_T21",
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"TMPK"
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686,
690
]
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},
{
"id": "23394555_T22",
"type": "GENE-Y",
"text": [
"human TMPK"
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825,
835
]
],
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},
{
"id": "23394555_T23",
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"p53"
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932,
935
]
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},
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"id": "23394555_T24",
"type": "GENE-Y",
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"TMPKs"
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987,
992
]
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},
{
"id": "23394555_T25",
"type": "GENE-Y",
"text": [
"TMPKs"
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1021,
1026
]
],
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},
{
"id": "23394555_T26",
"type": "GENE-Y",
"text": [
"Thymidylate kinase"
],
"offsets": [
[
0,
18
]
],
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}
] | [] | [] | [
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},
{
"id": "23394555_10",
"type": "ACTIVATOR",
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"arg2_id": "23394555_T20",
"normalized": []
}
] |
17194761 | 17194761 | [
{
"id": "17194761_title",
"type": "title",
"text": [
"Structure of aspartoacylase, the brain enzyme impaired in Canavan disease."
],
"offsets": [
[
0,
74
]
]
},
{
"id": "17194761_abstract",
"type": "abstract",
"text": [
"Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. Deficiency in this activity leads to spongiform degeneration of the white matter of the brain and is the established cause of Canavan disease, a fatal progressive leukodystrophy affecting young children. We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8- and 1.8-A resolution, respectively. The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10-13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded beta-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N- and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypeptides in the active site. The structures revealed that residues 158-164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase."
],
"offsets": [
[
75,
1764
]
]
}
] | [
{
"id": "17194761_T1",
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"C"
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]
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},
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"id": "17194761_T2",
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"C"
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1105,
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]
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},
{
"id": "17194761_T3",
"type": "CHEMICAL",
"text": [
"zinc"
],
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[
1512,
1516
]
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},
{
"id": "17194761_T4",
"type": "CHEMICAL",
"text": [
"N-acetyl-l-aspartate"
],
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114,
134
]
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},
{
"id": "17194761_T5",
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"N"
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548,
549
]
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},
{
"id": "17194761_T6",
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"text": [
"zinc"
],
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625,
629
]
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},
{
"id": "17194761_T7",
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"aspartate"
],
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138,
147
]
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{
"id": "17194761_T8",
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"acetate"
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152,
159
]
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"id": "17194761_T9",
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"C"
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856,
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]
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"id": "17194761_T10",
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"N"
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977,
978
]
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"id": "17194761_T11",
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"N"
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1074,
1075
]
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},
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"id": "17194761_T12",
"type": "GENE-Y",
"text": [
"Aspartoacylase"
],
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[
75,
89
]
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},
{
"id": "17194761_T13",
"type": "GENE-Y",
"text": [
"aspartoacylase"
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[
1413,
1427
]
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},
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"id": "17194761_T14",
"type": "GENE-N",
"text": [
"carboxypeptidases"
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[
1460,
1477
]
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},
{
"id": "17194761_T15",
"type": "GENE-Y",
"text": [
"human aspartoacylase"
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[
1743,
1763
]
],
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},
{
"id": "17194761_T16",
"type": "GENE-N",
"text": [
"aspartoacylase"
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448,
462
]
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},
{
"id": "17194761_T17",
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"aspartoacylase"
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569,
583
]
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},
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"id": "17194761_T18",
"type": "GENE-N",
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"zinc-dependent hydrolases"
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625,
650
]
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},
{
"id": "17194761_T19",
"type": "GENE-N",
"text": [
"carboxypeptidases A"
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662,
681
]
],
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},
{
"id": "17194761_T20",
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"aspartoacylase"
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705,
719
]
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},
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"id": "17194761_T21",
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766,
783
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"id": "17194761_T22",
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"aspartoacylase"
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879,
893
]
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"id": "17194761_T23",
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"globular domain"
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901,
916
]
],
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},
{
"id": "17194761_T24",
"type": "GENE-Y",
"text": [
"aspartoacylase"
],
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[
13,
27
]
],
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}
] | [] | [] | [
{
"id": "17194761_0",
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},
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},
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},
{
"id": "17194761_3",
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},
{
"id": "17194761_4",
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"arg2_id": "17194761_T22",
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},
{
"id": "17194761_5",
"type": "PART-OF",
"arg1_id": "17194761_T10",
"arg2_id": "17194761_T23",
"normalized": []
}
] |
11350861 | 11350861 | [
{
"id": "11350861_title",
"type": "title",
"text": [
"The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist."
],
"offsets": [
[
0,
107
]
]
},
{
"id": "11350861_abstract",
"type": "abstract",
"text": [
"The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation."
],
"offsets": [
[
108,
1770
]
]
}
] | [
{
"id": "11350861_T1",
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"R(+)-7-OH-DPAT"
],
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[
1140,
1154
]
],
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},
{
"id": "11350861_T2",
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"apomorphine"
],
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1156,
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]
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"id": "11350861_T3",
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"morphine"
],
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]
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{
"id": "11350861_T4",
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"cisplatin"
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]
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"id": "11350861_T7",
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"cyclophosphamide"
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1499,
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]
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"id": "11350861_T8",
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"doxorubicin"
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1520,
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]
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"id": "11350861_T9",
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"id": "11350861_T10",
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"dopamine"
],
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1568,
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]
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},
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"id": "11350861_T11",
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"dopamine"
],
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[
306,
314
]
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"id": "11350861_T12",
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"5-hydroxytryptamine"
],
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[
326,
345
]
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"id": "11350861_T13",
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"AS-8112"
],
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443,
450
]
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"id": "11350861_T14",
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"2-methyl-5HT"
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518,
530
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"AS-8112"
],
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[
155,
162
]
],
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},
{
"id": "11350861_T16",
"type": "CHEMICAL",
"text": [
"(R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate"
],
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[
164,
284
]
],
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},
{
"id": "11350861_T17",
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"text": [
"granisetron"
],
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[
683,
694
]
],
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},
{
"id": "11350861_T18",
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"text": [
"ondansetron"
],
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[
696,
707
]
],
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"dopamine"
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"id": "11350861_T23",
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"R(+)-7-OH-DPAT"
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853,
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]
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"id": "11350861_T24",
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"R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline"
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869,
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]
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"Domperidone"
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]
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994,
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60,
68
]
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"5-HT3 receptors"
],
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80,
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]
],
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}
] | [] | [] | [
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}
] |
16801455 | 16801455 | [
{
"id": "16801455_title",
"type": "title",
"text": [
"Mitochondrial arginase II modulates nitric-oxide synthesis through nonfreely exchangeable L-arginine pools in human endothelial cells."
],
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0,
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]
]
},
{
"id": "16801455_abstract",
"type": "abstract",
"text": [
"Reduced synthesis of nitric oxide (NO) contributes to the endothelial dysfunction and may be related to limited availability of L-arginine, the common substrate of constitutive nitric-oxide synthase (NOS) and cytosolic arginase I and mitochondrial arginase II. To determine whether arginases modulate the endothelial NO synthesis, we investigated the effects of the competitive arginase inhibitor N(omega)-hydroxy-nor-L-arginine (Nor-NOHA) on the activity of NOS, arginases, and L-arginine transporter and on NO release at surface of human umbilical vein endothelial cells (HUVECs). In unstimulated cells, Nor-NOHA dose-dependently reduced the arginase activity with maximal inhibition at 20 microM. When HUVECs were stimulated by thrombin without extracellular L-arginine, Nor-NOHA dose-dependently increased the NOS activity and the NO release with maximal effects at 20 microM. Extracellular L-arginine also dose-dependently increased NO release and arginase activity. When HUVECs were stimulated by thrombin in the presence of 100 microM L-arginine, NOS activity and NO release were similar in untreated and Nor-NOHA-treated cells. However, despite activation of L-arginine uptake, the inhibition of arginase activity by Nor-NOHA was still significant. The depletion of freely exchangeable L-arginine pools with extracellular L-lysine did not prevent Nor-NOHA from increasing the NO release. This indicates the presence of pools, which are accessible to NOS and arginase, but not exchangeable. Interestingly, the mitochondrial arginase II was constitutively expressed, whereas the cytosolic arginase I was barely detectable in HUVECs. These data suggest that endothelial NO synthesis depends on the activity of arginase II in mitochondria and l-arginine carriers in cell membrane."
],
"offsets": [
[
135,
1919
]
]
}
] | [
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"id": "16801455_T1",
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"L-arginine"
],
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1177,
1187
]
],
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},
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"id": "16801455_T2",
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"text": [
"NO"
],
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1206,
1208
]
],
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"id": "16801455_T3",
"type": "CHEMICAL",
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"Nor-NOHA"
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1247,
1255
]
],
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"id": "16801455_T4",
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1302,
1312
]
],
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"id": "16801455_T5",
"type": "CHEMICAL",
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"Nor-NOHA"
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1360,
1368
]
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"id": "16801455_T6",
"type": "CHEMICAL",
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"L-arginine"
],
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263,
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]
],
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"id": "16801455_T7",
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"L-arginine"
],
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1439
]
],
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},
{
"id": "16801455_T8",
"type": "CHEMICAL",
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"L-lysine"
],
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[
1465,
1473
]
],
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},
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"id": "16801455_T9",
"type": "CHEMICAL",
"text": [
"Nor-NOHA"
],
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[
1490,
1498
]
],
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},
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"id": "16801455_T10",
"type": "CHEMICAL",
"text": [
"NO"
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1519,
1521
]
],
"normalized": []
},
{
"id": "16801455_T11",
"type": "CHEMICAL",
"text": [
"NO"
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1810,
1812
]
],
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},
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"id": "16801455_T12",
"type": "CHEMICAL",
"text": [
"l-arginine"
],
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[
1882,
1892
]
],
"normalized": []
},
{
"id": "16801455_T13",
"type": "CHEMICAL",
"text": [
"nitric-oxide"
],
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[
312,
324
]
],
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},
{
"id": "16801455_T14",
"type": "CHEMICAL",
"text": [
"nitric oxide"
],
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156,
168
]
],
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},
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"id": "16801455_T15",
"type": "CHEMICAL",
"text": [
"NO"
],
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452,
454
]
],
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},
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"id": "16801455_T16",
"type": "CHEMICAL",
"text": [
"NO"
],
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170,
172
]
],
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},
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"N(omega)-hydroxy-nor-L-arginine"
],
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532,
563
]
],
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},
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"id": "16801455_T18",
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"Nor-NOHA"
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565,
573
]
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"L-arginine"
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614,
624
]
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"id": "16801455_T20",
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"text": [
"NO"
],
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644,
646
]
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"id": "16801455_T21",
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"Nor-NOHA"
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741,
749
]
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"id": "16801455_T22",
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"L-arginine"
],
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897,
907
]
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},
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"id": "16801455_T23",
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"Nor-NOHA"
],
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909,
917
]
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},
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"id": "16801455_T24",
"type": "CHEMICAL",
"text": [
"NO"
],
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970,
972
]
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},
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"id": "16801455_T25",
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"L-arginine"
],
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1030,
1040
]
],
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},
{
"id": "16801455_T26",
"type": "CHEMICAL",
"text": [
"NO"
],
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1073,
1075
]
],
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},
{
"id": "16801455_T27",
"type": "CHEMICAL",
"text": [
"nitric-oxide"
],
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[
36,
48
]
],
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},
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"id": "16801455_T28",
"type": "CHEMICAL",
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"L-arginine"
],
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[
90,
100
]
],
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},
{
"id": "16801455_T29",
"type": "GENE-Y",
"text": [
"thrombin"
],
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[
1138,
1146
]
],
"normalized": []
},
{
"id": "16801455_T30",
"type": "GENE-N",
"text": [
"NOS"
],
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[
1189,
1192
]
],
"normalized": []
},
{
"id": "16801455_T31",
"type": "GENE-N",
"text": [
"arginase"
],
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[
1339,
1347
]
],
"normalized": []
},
{
"id": "16801455_T32",
"type": "GENE-N",
"text": [
"NOS"
],
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[
1593,
1596
]
],
"normalized": []
},
{
"id": "16801455_T33",
"type": "GENE-N",
"text": [
"arginase"
],
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[
1601,
1609
]
],
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},
{
"id": "16801455_T34",
"type": "GENE-Y",
"text": [
"mitochondrial arginase II"
],
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[
1652,
1677
]
],
"normalized": []
},
{
"id": "16801455_T35",
"type": "GENE-Y",
"text": [
"arginase I"
],
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[
1730,
1740
]
],
"normalized": []
},
{
"id": "16801455_T36",
"type": "GENE-Y",
"text": [
"constitutive nitric-oxide synthase"
],
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[
299,
333
]
],
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},
{
"id": "16801455_T37",
"type": "GENE-Y",
"text": [
"arginase II"
],
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1850,
1861
]
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},
{
"id": "16801455_T38",
"type": "GENE-N",
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"NOS"
],
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[
335,
338
]
],
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},
{
"id": "16801455_T39",
"type": "GENE-Y",
"text": [
"arginase I"
],
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[
354,
364
]
],
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},
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"id": "16801455_T40",
"type": "GENE-Y",
"text": [
"mitochondrial arginase II"
],
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[
369,
394
]
],
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},
{
"id": "16801455_T41",
"type": "GENE-N",
"text": [
"arginases"
],
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[
417,
426
]
],
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},
{
"id": "16801455_T42",
"type": "GENE-N",
"text": [
"arginase"
],
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[
513,
521
]
],
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},
{
"id": "16801455_T43",
"type": "GENE-N",
"text": [
"NOS"
],
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[
594,
597
]
],
"normalized": []
},
{
"id": "16801455_T44",
"type": "GENE-N",
"text": [
"arginases"
],
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[
599,
608
]
],
"normalized": []
},
{
"id": "16801455_T45",
"type": "GENE-N",
"text": [
"L-arginine transporter"
],
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[
614,
636
]
],
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},
{
"id": "16801455_T46",
"type": "GENE-N",
"text": [
"arginase"
],
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[
779,
787
]
],
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},
{
"id": "16801455_T47",
"type": "GENE-Y",
"text": [
"thrombin"
],
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[
866,
874
]
],
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},
{
"id": "16801455_T48",
"type": "GENE-N",
"text": [
"NOS"
],
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[
949,
952
]
],
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},
{
"id": "16801455_T49",
"type": "GENE-N",
"text": [
"arginase"
],
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[
1088,
1096
]
],
"normalized": []
},
{
"id": "16801455_T50",
"type": "GENE-Y",
"text": [
"Mitochondrial arginase II"
],
"offsets": [
[
0,
25
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "16801455_0",
"type": "PRODUCT-OF",
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"arg2_id": "16801455_T50",
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},
{
"id": "16801455_1",
"type": "SUBSTRATE",
"arg1_id": "16801455_T28",
"arg2_id": "16801455_T50",
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},
{
"id": "16801455_2",
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"arg2_id": "16801455_T36",
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},
{
"id": "16801455_3",
"type": "SUBSTRATE",
"arg1_id": "16801455_T6",
"arg2_id": "16801455_T38",
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},
{
"id": "16801455_4",
"type": "SUBSTRATE",
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"arg2_id": "16801455_T39",
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},
{
"id": "16801455_5",
"type": "SUBSTRATE",
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"id": "16801455_6",
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{
"id": "16801455_7",
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{
"id": "16801455_8",
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},
{
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},
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},
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"id": "16801455_13",
"type": "PRODUCT-OF",
"arg1_id": "16801455_T11",
"arg2_id": "16801455_T37",
"normalized": []
}
] |
23270990 | 23270990 | [
{
"id": "23270990_title",
"type": "title",
"text": [
"The interactions of apamin and tetraethylammonium are differentially affected by single mutations in the pore mouth of small conductance calcium-activated potassium (SK) channels."
],
"offsets": [
[
0,
179
]
]
},
{
"id": "23270990_abstract",
"type": "abstract",
"text": [
"Valine residues in the pore region of SK2 (V366) and SK3 (V520) were replaced by either an alanine or a phenylalanine to evaluate the impact on the interactions with the allosteric blocker apamin. Unlike TEA which showed high sensitivity to phenylalanine mutated channels, the binding affinity of apamin to the phenylalanine mutants was strongly reduced. In addition, currents from phenylalanine mutants were largely resistant to block by apamin. On the other hand, when the valine residue was replaced by an alanine residue, an increase of the binding affinity and the amount of block by apamin was observed for alanine mutated SK2 channels, but not for mutated SK3 channels. Interestingly, the VA mutation reduced the sensitivity to TEA. In silico data confirmed these experimental results. Therefore, such mutations in the pore region of SK channels show that the three-dimensional structure of the SK tetramers can be disorganized in the outer pore region leading to reduced interaction of apamin with its target."
],
"offsets": [
[
180,
1197
]
]
}
] | [
{
"id": "23270990_T1",
"type": "CHEMICAL",
"text": [
"Valine"
],
"offsets": [
[
180,
186
]
],
"normalized": []
},
{
"id": "23270990_T2",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
284,
297
]
],
"normalized": []
},
{
"id": "23270990_T3",
"type": "CHEMICAL",
"text": [
"TEA"
],
"offsets": [
[
384,
387
]
],
"normalized": []
},
{
"id": "23270990_T4",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
421,
434
]
],
"normalized": []
},
{
"id": "23270990_T5",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
491,
504
]
],
"normalized": []
},
{
"id": "23270990_T6",
"type": "CHEMICAL",
"text": [
"phenylalanine"
],
"offsets": [
[
562,
575
]
],
"normalized": []
},
{
"id": "23270990_T7",
"type": "CHEMICAL",
"text": [
"valine"
],
"offsets": [
[
655,
661
]
],
"normalized": []
},
{
"id": "23270990_T8",
"type": "CHEMICAL",
"text": [
"alanine"
],
"offsets": [
[
689,
696
]
],
"normalized": []
},
{
"id": "23270990_T9",
"type": "CHEMICAL",
"text": [
"alanine"
],
"offsets": [
[
793,
800
]
],
"normalized": []
},
{
"id": "23270990_T10",
"type": "CHEMICAL",
"text": [
"TEA"
],
"offsets": [
[
915,
918
]
],
"normalized": []
},
{
"id": "23270990_T11",
"type": "CHEMICAL",
"text": [
"alanine"
],
"offsets": [
[
271,
278
]
],
"normalized": []
},
{
"id": "23270990_T12",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
137,
144
]
],
"normalized": []
},
{
"id": "23270990_T13",
"type": "CHEMICAL",
"text": [
"potassium"
],
"offsets": [
[
155,
164
]
],
"normalized": []
},
{
"id": "23270990_T14",
"type": "CHEMICAL",
"text": [
"tetraethylammonium"
],
"offsets": [
[
31,
49
]
],
"normalized": []
},
{
"id": "23270990_T15",
"type": "GENE-Y",
"text": [
"apamin"
],
"offsets": [
[
369,
375
]
],
"normalized": []
},
{
"id": "23270990_T16",
"type": "GENE-Y",
"text": [
"apamin"
],
"offsets": [
[
477,
483
]
],
"normalized": []
},
{
"id": "23270990_T17",
"type": "GENE-Y",
"text": [
"SK2"
],
"offsets": [
[
218,
221
]
],
"normalized": []
},
{
"id": "23270990_T18",
"type": "GENE-Y",
"text": [
"apamin"
],
"offsets": [
[
619,
625
]
],
"normalized": []
},
{
"id": "23270990_T19",
"type": "GENE-Y",
"text": [
"SK3"
],
"offsets": [
[
233,
236
]
],
"normalized": []
},
{
"id": "23270990_T20",
"type": "GENE-Y",
"text": [
"apamin"
],
"offsets": [
[
769,
775
]
],
"normalized": []
},
{
"id": "23270990_T21",
"type": "GENE-Y",
"text": [
"SK2"
],
"offsets": [
[
809,
812
]
],
"normalized": []
},
{
"id": "23270990_T22",
"type": "GENE-Y",
"text": [
"SK3"
],
"offsets": [
[
843,
846
]
],
"normalized": []
},
{
"id": "23270990_T23",
"type": "GENE-N",
"text": [
"SK channels"
],
"offsets": [
[
1021,
1032
]
],
"normalized": []
},
{
"id": "23270990_T24",
"type": "GENE-N",
"text": [
"SK"
],
"offsets": [
[
1082,
1084
]
],
"normalized": []
},
{
"id": "23270990_T25",
"type": "GENE-Y",
"text": [
"apamin"
],
"offsets": [
[
1174,
1180
]
],
"normalized": []
},
{
"id": "23270990_T26",
"type": "GENE-N",
"text": [
"calcium-activated potassium (SK) channels"
],
"offsets": [
[
137,
178
]
],
"normalized": []
},
{
"id": "23270990_T27",
"type": "GENE-Y",
"text": [
"apamin"
],
"offsets": [
[
20,
26
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23270990_0",
"type": "PART-OF",
"arg1_id": "23270990_T1",
"arg2_id": "23270990_T17",
"normalized": []
},
{
"id": "23270990_1",
"type": "PART-OF",
"arg1_id": "23270990_T1",
"arg2_id": "23270990_T19",
"normalized": []
},
{
"id": "23270990_2",
"type": "PART-OF",
"arg1_id": "23270990_T11",
"arg2_id": "23270990_T17",
"normalized": []
},
{
"id": "23270990_3",
"type": "PART-OF",
"arg1_id": "23270990_T2",
"arg2_id": "23270990_T17",
"normalized": []
},
{
"id": "23270990_4",
"type": "PART-OF",
"arg1_id": "23270990_T11",
"arg2_id": "23270990_T19",
"normalized": []
},
{
"id": "23270990_5",
"type": "PART-OF",
"arg1_id": "23270990_T2",
"arg2_id": "23270990_T19",
"normalized": []
},
{
"id": "23270990_6",
"type": "DIRECT-REGULATOR",
"arg1_id": "23270990_T5",
"arg2_id": "23270990_T16",
"normalized": []
},
{
"id": "23270990_7",
"type": "PART-OF",
"arg1_id": "23270990_T9",
"arg2_id": "23270990_T21",
"normalized": []
}
] |
23562496 | 23562496 | [
{
"id": "23562496_title",
"type": "title",
"text": [
"2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells."
],
"offsets": [
[
0,
90
]
]
},
{
"id": "23562496_abstract",
"type": "abstract",
"text": [
"Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with chalcone, 2-hydroxychalcone, and xanthohumol for 24h inhibited the growth of MDA-MB-231cells with IC50 values of 18.1, 4.6, and 6.7μM, respectively. Similarly, Chalcone, 2-hydroxychalcone, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231cells. Xanthohumol and 2-hydroxychalcone induced apoptosis by Bcl-2 downregulation. Importantly, 2-hydroxychalcone and xanthohumol exerted more potent inhibitory effects on the proliferation, MMP-9 expression and invasive phenotype of MDA-MB-231 than chalcone. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC."
],
"offsets": [
[
91,
1706
]
]
}
] | [
{
"id": "23562496_T1",
"type": "CHEMICAL",
"text": [
"xanthohumol"
],
"offsets": [
[
1110,
1121
]
],
"normalized": []
},
{
"id": "23562496_T2",
"type": "CHEMICAL",
"text": [
"Neohesperidin dihydrochalcone"
],
"offsets": [
[
1183,
1212
]
],
"normalized": []
},
{
"id": "23562496_T3",
"type": "CHEMICAL",
"text": [
"4-methoxychalcone"
],
"offsets": [
[
1214,
1231
]
],
"normalized": []
},
{
"id": "23562496_T4",
"type": "CHEMICAL",
"text": [
"hesperidin methylchalcone"
],
"offsets": [
[
1237,
1262
]
],
"normalized": []
},
{
"id": "23562496_T5",
"type": "CHEMICAL",
"text": [
"Xanthohumol"
],
"offsets": [
[
1317,
1328
]
],
"normalized": []
},
{
"id": "23562496_T6",
"type": "CHEMICAL",
"text": [
"2-hydroxychalcone"
],
"offsets": [
[
1333,
1350
]
],
"normalized": []
},
{
"id": "23562496_T7",
"type": "CHEMICAL",
"text": [
"2-hydroxychalcone"
],
"offsets": [
[
1407,
1424
]
],
"normalized": []
},
{
"id": "23562496_T8",
"type": "CHEMICAL",
"text": [
"xanthohumol"
],
"offsets": [
[
1429,
1440
]
],
"normalized": []
},
{
"id": "23562496_T9",
"type": "CHEMICAL",
"text": [
"chalcone"
],
"offsets": [
[
1561,
1569
]
],
"normalized": []
},
{
"id": "23562496_T10",
"type": "CHEMICAL",
"text": [
"chalcones"
],
"offsets": [
[
1626,
1635
]
],
"normalized": []
},
{
"id": "23562496_T11",
"type": "CHEMICAL",
"text": [
"estrogen"
],
"offsets": [
[
270,
278
]
],
"normalized": []
},
{
"id": "23562496_T12",
"type": "CHEMICAL",
"text": [
"progesterone"
],
"offsets": [
[
279,
291
]
],
"normalized": []
},
{
"id": "23562496_T13",
"type": "CHEMICAL",
"text": [
"Chalcones"
],
"offsets": [
[
420,
429
]
],
"normalized": []
},
{
"id": "23562496_T14",
"type": "CHEMICAL",
"text": [
"flavonoids"
],
"offsets": [
[
462,
472
]
],
"normalized": []
},
{
"id": "23562496_T15",
"type": "CHEMICAL",
"text": [
"chalcones"
],
"offsets": [
[
612,
621
]
],
"normalized": []
},
{
"id": "23562496_T16",
"type": "CHEMICAL",
"text": [
"chalcones"
],
"offsets": [
[
692,
701
]
],
"normalized": []
},
{
"id": "23562496_T17",
"type": "CHEMICAL",
"text": [
"chalcone"
],
"offsets": [
[
802,
810
]
],
"normalized": []
},
{
"id": "23562496_T18",
"type": "CHEMICAL",
"text": [
"chalcone"
],
"offsets": [
[
917,
925
]
],
"normalized": []
},
{
"id": "23562496_T19",
"type": "CHEMICAL",
"text": [
"2-hydroxychalcone"
],
"offsets": [
[
927,
944
]
],
"normalized": []
},
{
"id": "23562496_T20",
"type": "CHEMICAL",
"text": [
"xanthohumol"
],
"offsets": [
[
950,
961
]
],
"normalized": []
},
{
"id": "23562496_T21",
"type": "CHEMICAL",
"text": [
"Chalcone"
],
"offsets": [
[
1077,
1085
]
],
"normalized": []
},
{
"id": "23562496_T22",
"type": "CHEMICAL",
"text": [
"2-hydroxychalcone"
],
"offsets": [
[
1087,
1104
]
],
"normalized": []
},
{
"id": "23562496_T23",
"type": "CHEMICAL",
"text": [
"2-Hydroxychalcone"
],
"offsets": [
[
0,
17
]
],
"normalized": []
},
{
"id": "23562496_T24",
"type": "CHEMICAL",
"text": [
"xanthohumol"
],
"offsets": [
[
22,
33
]
],
"normalized": []
},
{
"id": "23562496_T25",
"type": "GENE-Y",
"text": [
"Bcl-2"
],
"offsets": [
[
1372,
1377
]
],
"normalized": []
},
{
"id": "23562496_T26",
"type": "GENE-Y",
"text": [
"MMP-9"
],
"offsets": [
[
1502,
1507
]
],
"normalized": []
},
{
"id": "23562496_T27",
"type": "GENE-Y",
"text": [
"estrogen"
],
"offsets": [
[
270,
278
]
],
"normalized": []
},
{
"id": "23562496_T28",
"type": "GENE-Y",
"text": [
"progesterone receptors"
],
"offsets": [
[
279,
301
]
],
"normalized": []
},
{
"id": "23562496_T29",
"type": "GENE-Y",
"text": [
"ER"
],
"offsets": [
[
303,
305
]
],
"normalized": []
},
{
"id": "23562496_T30",
"type": "GENE-Y",
"text": [
"PR"
],
"offsets": [
[
306,
308
]
],
"normalized": []
},
{
"id": "23562496_T31",
"type": "GENE-Y",
"text": [
"human epidermal growth factor receptor 2"
],
"offsets": [
[
314,
354
]
],
"normalized": []
},
{
"id": "23562496_T32",
"type": "GENE-Y",
"text": [
"HER2"
],
"offsets": [
[
356,
360
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "23562496_0",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23562496_T5",
"arg2_id": "23562496_T25",
"normalized": []
},
{
"id": "23562496_1",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23562496_T6",
"arg2_id": "23562496_T25",
"normalized": []
},
{
"id": "23562496_2",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23562496_T7",
"arg2_id": "23562496_T26",
"normalized": []
},
{
"id": "23562496_3",
"type": "INDIRECT-DOWNREGULATOR",
"arg1_id": "23562496_T8",
"arg2_id": "23562496_T26",
"normalized": []
}
] |
23235156 | 23235156 | [
{
"id": "23235156_title",
"type": "title",
"text": [
"70-kDa heat shock cognate protein hsc70 mediates calmodulin-dependent nuclear import of the sex-determining factor SRY."
],
"offsets": [
[
0,
119
]
]
},
{
"id": "23235156_abstract",
"type": "abstract",
"text": [
"We recently showed that the developmentally important family of SOX (SRY (sex determining region on the Y chromosome)-related high mobility group (HMG) box) proteins require the calcium-binding protein calmodulin (CaM) for optimal nuclear accumulation, with clinical mutations in SRY that specifically impair nuclear accumulation via this pathway resulting in XY sex reversal. However, the mechanism by which CaM facilitates nuclear accumulation is unknown. Here, we show, for the first time, that the 70-kDa heat shock cognate protein hsc70 plays a key role in CaM-dependent nuclear import of SRY. Using a reconstituted nuclear import assay, we show that antibodies to hsc70 significantly reduce nuclear accumulation of wild type SRY and mutant derivatives thereof that retain CaM-dependent nuclear import, with an increased rate of nuclear accumulation upon addition of both CaM and hsc70, in contrast to an SRY mutant derivative with impaired CaM binding. siRNA knockdown of hsc70 in intact cells showed similar results, indicating clear dependence upon hsc70 for CaM-dependent nuclear import. Analysis using the technique of fluorescence recovery after photobleaching indicated that hsc70 is required for the maximal rate of SRY nuclear import in living cells but has no impact upon SRY nuclear retention/nuclear dynamics. Finally, we demonstrate direct binding of hsc70 to the SRY·CaM complex, with immunoprecipitation experiments from cell extracts showing association of hsc70 with wild type SRY, but not with a mutant derivative with impaired CaM binding, dependent on Ca(2+). Our novel findings strongly implicate hsc70 in CaM-dependent nuclear import of SRY."
],
"offsets": [
[
120,
1788
]
]
}
] | [
{
"id": "23235156_T1",
"type": "CHEMICAL",
"text": [
"Ca(2+)"
],
"offsets": [
[
1697,
1703
]
],
"normalized": []
},
{
"id": "23235156_T2",
"type": "CHEMICAL",
"text": [
"calcium"
],
"offsets": [
[
298,
305
]
],
"normalized": []
},
{
"id": "23235156_T3",
"type": "GENE-Y",
"text": [
"hsc70"
],
"offsets": [
[
1177,
1182
]
],
"normalized": []
},
{
"id": "23235156_T4",
"type": "GENE-Y",
"text": [
"CaM"
],
"offsets": [
[
1187,
1190
]
],
"normalized": []
},
{
"id": "23235156_T5",
"type": "GENE-Y",
"text": [
"hsc70"
],
"offsets": [
[
1307,
1312
]
],
"normalized": []
},
{
"id": "23235156_T6",
"type": "GENE-Y",
"text": [
"SRY"
],
"offsets": [
[
1349,
1352
]
],
"normalized": []
},
{
"id": "23235156_T7",
"type": "GENE-N",
"text": [
"high mobility group (HMG) box) proteins"
],
"offsets": [
[
246,
285
]
],
"normalized": []
},
{
"id": "23235156_T8",
"type": "GENE-Y",
"text": [
"SRY"
],
"offsets": [
[
1407,
1410
]
],
"normalized": []
},
{
"id": "23235156_T9",
"type": "GENE-Y",
"text": [
"hsc70"
],
"offsets": [
[
1489,
1494
]
],
"normalized": []
},
{
"id": "23235156_T10",
"type": "GENE-Y",
"text": [
"SRY"
],
"offsets": [
[
1502,
1505
]
],
"normalized": []
},
{
"id": "23235156_T11",
"type": "GENE-Y",
"text": [
"CaM"
],
"offsets": [
[
1506,
1509
]
],
"normalized": []
},
{
"id": "23235156_T12",
"type": "GENE-Y",
"text": [
"hsc70"
],
"offsets": [
[
1598,
1603
]
],
"normalized": []
},
{
"id": "23235156_T13",
"type": "GENE-Y",
"text": [
"SRY"
],
"offsets": [
[
1619,
1622
]
],
"normalized": []
},
{
"id": "23235156_T14",
"type": "GENE-Y",
"text": [
"CaM"
],
"offsets": [
[
1671,
1674
]
],
"normalized": []
},
{
"id": "23235156_T15",
"type": "GENE-Y",
"text": [
"hsc70"
],
"offsets": [
[
1743,
1748
]
],
"normalized": []
},
{
"id": "23235156_T16",
"type": "GENE-Y",
"text": [
"CaM"
],
"offsets": [
[
1752,
1755
]
],
"normalized": []
},
{
"id": "23235156_T17",
"type": "GENE-Y",
"text": [
"SRY"
],
"offsets": [
[
1784,
1787
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}
] | [] | [] | [] |
23410129 | 23410129 | [
{
"id": "23410129_title",
"type": "title",
"text": [
"Recurrent rearrangements in prostate cancer: causes and therapeutic potential."
],
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{
"id": "23410129_abstract",
"type": "abstract",
"text": [
"DNA damage and genetic rearrangements are hallmarks of cancer. However, gene fusions as driver mutations in cancer have classically been a distinction in leukemia and other rare instances until recently with the discovery of gene fusion events occurring in 50 to 75% of prostate cancer patients. The discovery of the TMPRSS2-ERG fusion sparked an onslaught of discovery and innovation resulting in a delineation of prostate cancer via a molecular signature of gene fusion events. The increased commonality of high-throughput sequencing data coupled with improved bioinformatics approaches not only elucidated the molecular underpinnings of prostate cancer progression, but the mechanisms of gene fusion biogenesis. Interestingly, the androgen receptor (AR), already known to play a significant role in prostate cancer tumorigenesis, has recently been implicated in the processes resulting in gene fusions by inducing the spatial proximity of genes involved in rearrangements, promoting the formation of double-strand DNA breaks (DSB), and facilitating the recruitment of proteins for non-homologous end-joining (NHEJ). Our increased understanding of the mechanisms inducing genomic instability may lead to improved diagnostic and therapeutic strategies. To date, the majority of prostate cancer patients can be molecularly stratified based on their gene fusion status thereby increasing the potential for tailoring more specific and effective therapies."
],
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}
] | [] | [] | [] |
22846225 | 22846225 | [
{
"id": "22846225_title",
"type": "title",
"text": [
"Matching biochemical and functional efficacies confirm ZIP as a potent competitive inhibitor of PKMζ in neurons."
],
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]
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"id": "22846225_abstract",
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"text": [
"PKMζ is an autonomously active, atypical protein kinase C (aPKC) isoform that is both necessary and sufficient for maintaining long-term potentiation (LTP) and long-term memory. The myristoylated ζ-pseudosubstrate peptide, ZIP, potently inhibits PKMζ biochemically in vitro, within cultured cells, and within neurons in hippocampal slices, and reverses LTP maintenance and erases long-term memory storage. A recent study (Wu-Zhang et al., 2012), however, suggested ZIP was not effective on a PKMζ fusion protein overexpressed in cultured cells. Chelerythrine, a redox-sensitive PKC inhibitor that inhibits PKMζ and disrupts LTP maintenance and memory storage, was also reported by Wu-Zhang et al. (2012) not to inhibit the expressed PKMζ fusion protein. However, the efficacy of inhibitors on endogenous enzymes in cells may not be adequately assessed in expression systems in which levels of expression of exogenous enzymes greatly exceed those of endogenous enzymes. Thus, we show, biochemically, that when PKMζ reaches a level beyond that necessary for substrate phosphorylation such that much of the enzyme is excess or 'spare' kinase, ZIP and chelerythrine do not effectively block substrate phosphorylation. We also show that the cellular overexpression techniques used by Wu-Zhang et al. (2012) increase kinase levels ~30-40 fold above normal levels in transfected cells. Using a mathematical model we show that at such level of overexpression, standard concentrations of inhibitor should have no noticeable effect. Furthermore, we demonstrate the standard concentrations of ZIP, but not scrambled ZIP, inhibit the ability of PKMζ to potentiate AMPAR responses at postsynaptic sites, the physiological function of the kinase. Wu-Zhang et al. (2012) had also claimed that staurosporine, a general kinase inhibitor that does not effectively inhibit PKMζ biochemically in vitro, nonetheless indirectly blocked the PKMζ fusion protein overexpressed in cultured cells by inhibiting phosphoinositide-dependent protein kinase-1 (PDK1). However, here we show that staurosporine does not affect PDK1 phosphorylation of the endogenous PKMζ in hippocampal slices. Thus, the biochemical in vitro effects of PKMζ inhibitors correspond with their intracellular effects, and ZIP and chelerythrine, together with scrambled ZIP and staurosporine as controls, are effective tools to examine the function of PKMζ in neurons. This article is part of a Special Issue entitled 'Cognitive Enhancers'."
],
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]
}
] | [
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172,
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96,
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],
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}
] | [] | [] | [
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}
] |
11791081 | 11791081 | [
{
"id": "11791081_title",
"type": "title",
"text": [
"Progestogens in hormonal replacement therapy: new molecules, risks, and benefits."
],
"offsets": [
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0,
81
]
]
},
{
"id": "11791081_abstract",
"type": "abstract",
"text": [
"While the benefits of progestogen use in hormone replacement therapy (HRT) are well recognized as far as endometrial protection is concerned, their risks and drawbacks have generated controversial articles. Several risks are attributed to progestogens as a class-effect; however, the progestogens used in HRT have varying pharmacological properties and do not induce the same side effects. Natural progesterone (P) and some of its derivatives, such as the 19-norprogesterones (Nestorone, nomegestrol acetate, trimegestone), do not bind to the androgen receptor and, hence, do not exert androgenic side effects. Newly synthesized molecules such as drospirenone or dienogest have no androgenic effect but do have a partial antiandrogenic effect. Drospirenone derives from spironolactone and binds to the mineralocorticoid receptor. When the cardiovascular risk factors are considered, some molecules with a higher androgenic potency than others attenuate the beneficial effects of estrogens on the lipid profile as well as the vasomotion. On the other hand, other progestogens devoid of androgenic properties do not exert these deleterious effects. The epidemiological data do not suggest any negative effect of the progestogens administered together with estrogens on cardiovascular morbidity or mortality. However, recent results suggest that in women with established coronary heart disease, HRT may not protect against further heart attacks when the progestogen selected possesses androgenic properties. The data related to the progestogen effect on breast tissue has been interpreted differently from country to country. However, it has been admitted that, according to the type of progestogen used and the dose and duration of its application, a predominant antiproliferative effect is observed in the human breast cells. As far as breast cancer risk is concerned, most epidemiological studies do not suggest any significant difference between the estrogens given alone or combined with progestogens in HRT. Complying with the classic contraindications of HRT and selecting molecules devoid of estrogenic, androgenic, or glucocorticoid effect should allow a larger use of the progestins without any major drawback."
],
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82,
2300
]
]
}
] | [
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"id": "11791081_T1",
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],
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},
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"id": "11791081_T2",
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"progestogens"
],
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1308
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],
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},
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"id": "11791081_T3",
"type": "CHEMICAL",
"text": [
"estrogens"
],
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[
1336,
1345
]
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"normalized": []
},
{
"id": "11791081_T4",
"type": "CHEMICAL",
"text": [
"progestogen"
],
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[
1534,
1545
]
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},
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"id": "11791081_T5",
"type": "CHEMICAL",
"text": [
"progestogen"
],
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1612,
1623
]
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"id": "11791081_T6",
"type": "CHEMICAL",
"text": [
"progestogen"
],
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[
1767,
1778
]
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"id": "11791081_T7",
"type": "CHEMICAL",
"text": [
"estrogens"
],
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[
2034,
2043
]
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},
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"id": "11791081_T8",
"type": "CHEMICAL",
"text": [
"progestogens"
],
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[
2073,
2085
]
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"id": "11791081_T9",
"type": "CHEMICAL",
"text": [
"progestins"
],
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2262,
2272
]
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"id": "11791081_T10",
"type": "CHEMICAL",
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"progestogen"
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104,
115
]
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"id": "11791081_T11",
"type": "CHEMICAL",
"text": [
"progestogens"
],
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321,
333
]
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{
"id": "11791081_T12",
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"text": [
"progestogens"
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[
366,
378
]
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},
{
"id": "11791081_T13",
"type": "CHEMICAL",
"text": [
"progesterone"
],
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[
480,
492
]
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},
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"id": "11791081_T14",
"type": "CHEMICAL",
"text": [
"19-norprogesterones"
],
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[
538,
557
]
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},
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"id": "11791081_T15",
"type": "CHEMICAL",
"text": [
"Nestorone"
],
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[
559,
568
]
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},
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"id": "11791081_T16",
"type": "CHEMICAL",
"text": [
"nomegestrol acetate"
],
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[
570,
589
]
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"id": "11791081_T17",
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"trimegestone"
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591,
603
]
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},
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"id": "11791081_T18",
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"androgen"
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625,
633
]
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{
"id": "11791081_T19",
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"drospirenone"
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729,
741
]
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"id": "11791081_T20",
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"dienogest"
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745,
754
]
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"id": "11791081_T21",
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"Drospirenone"
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826,
838
]
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},
{
"id": "11791081_T22",
"type": "CHEMICAL",
"text": [
"spironolactone"
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[
852,
866
]
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},
{
"id": "11791081_T23",
"type": "CHEMICAL",
"text": [
"Progestogens"
],
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[
0,
12
]
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"normalized": []
},
{
"id": "11791081_T24",
"type": "GENE-Y",
"text": [
"androgen receptor"
],
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[
625,
642
]
],
"normalized": []
},
{
"id": "11791081_T25",
"type": "GENE-Y",
"text": [
"mineralocorticoid receptor"
],
"offsets": [
[
884,
910
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11791081_0",
"type": "DIRECT-REGULATOR",
"arg1_id": "11791081_T22",
"arg2_id": "11791081_T25",
"normalized": []
},
{
"id": "11791081_1",
"type": "DIRECT-REGULATOR",
"arg1_id": "11791081_T21",
"arg2_id": "11791081_T25",
"normalized": []
}
] |
23143674 | 23143674 | [
{
"id": "23143674_title",
"type": "title",
"text": [
"Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction."
],
"offsets": [
[
0,
103
]
]
},
{
"id": "23143674_abstract",
"type": "abstract",
"text": [
"Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment."
],
"offsets": [
[
104,
1325
]
]
}
] | [
{
"id": "23143674_T1",
"type": "CHEMICAL",
"text": [
"clemizole"
],
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[
1165,
1174
]
],
"normalized": []
},
{
"id": "23143674_T2",
"type": "CHEMICAL",
"text": [
"clemizole"
],
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[
616,
625
]
],
"normalized": []
},
{
"id": "23143674_T3",
"type": "CHEMICAL",
"text": [
"clemizole"
],
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[
936,
945
]
],
"normalized": []
},
{
"id": "23143674_T4",
"type": "GENE-Y",
"text": [
"CYP3A4"
],
"offsets": [
[
1201,
1207
]
],
"normalized": []
}
] | [] | [] | [] |
11885959 | 11885959 | [
{
"id": "11885959_title",
"type": "title",
"text": [
"Differential binding mode of diverse cyclooxygenase inhibitors."
],
"offsets": [
[
0,
63
]
]
},
{
"id": "11885959_abstract",
"type": "abstract",
"text": [
"Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective COX inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of COX available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different COX inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of COX inhibitors, and are expected to contribute to the design of new selective compounds."
],
"offsets": [
[
64,
1349
]
]
}
] | [
{
"id": "11885959_T1",
"type": "CHEMICAL",
"text": [
"meclofenamic acid"
],
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[
1064,
1081
]
],
"normalized": []
},
{
"id": "11885959_T2",
"type": "CHEMICAL",
"text": [
"prostaglandins"
],
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[
204,
218
]
],
"normalized": []
},
{
"id": "11885959_T3",
"type": "CHEMICAL",
"text": [
"thromboxanes"
],
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[
223,
235
]
],
"normalized": []
},
{
"id": "11885959_T4",
"type": "CHEMICAL",
"text": [
"arachidonic acid"
],
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[
241,
257
]
],
"normalized": []
},
{
"id": "11885959_T5",
"type": "CHEMICAL",
"text": [
"steroidal"
],
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[
68,
77
]
],
"normalized": []
},
{
"id": "11885959_T6",
"type": "CHEMICAL",
"text": [
"rofecoxib"
],
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[
980,
989
]
],
"normalized": []
},
{
"id": "11885959_T7",
"type": "CHEMICAL",
"text": [
"ketoprofen"
],
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[
991,
1001
]
],
"normalized": []
},
{
"id": "11885959_T8",
"type": "CHEMICAL",
"text": [
"suprofen"
],
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[
1003,
1011
]
],
"normalized": []
},
{
"id": "11885959_T9",
"type": "CHEMICAL",
"text": [
"carprofen"
],
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[
1013,
1022
]
],
"normalized": []
},
{
"id": "11885959_T10",
"type": "CHEMICAL",
"text": [
"zomepirac"
],
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[
1024,
1033
]
],
"normalized": []
},
{
"id": "11885959_T11",
"type": "CHEMICAL",
"text": [
"indomethacin"
],
"offsets": [
[
1035,
1047
]
],
"normalized": []
},
{
"id": "11885959_T12",
"type": "CHEMICAL",
"text": [
"diclofenac"
],
"offsets": [
[
1049,
1059
]
],
"normalized": []
},
{
"id": "11885959_T13",
"type": "GENE-N",
"text": [
"COX"
],
"offsets": [
[
1261,
1264
]
],
"normalized": []
},
{
"id": "11885959_T14",
"type": "GENE-N",
"text": [
"COX-1 and -2"
],
"offsets": [
[
324,
336
]
],
"normalized": []
},
{
"id": "11885959_T15",
"type": "GENE-N",
"text": [
"COX"
],
"offsets": [
[
399,
402
]
],
"normalized": []
},
{
"id": "11885959_T16",
"type": "GENE-N",
"text": [
"COX"
],
"offsets": [
[
593,
596
]
],
"normalized": []
},
{
"id": "11885959_T17",
"type": "GENE-N",
"text": [
"cyclooxygenase"
],
"offsets": [
[
141,
155
]
],
"normalized": []
},
{
"id": "11885959_T18",
"type": "GENE-N",
"text": [
"COX"
],
"offsets": [
[
917,
920
]
],
"normalized": []
},
{
"id": "11885959_T19",
"type": "GENE-N",
"text": [
"COX"
],
"offsets": [
[
157,
160
]
],
"normalized": []
},
{
"id": "11885959_T20",
"type": "GENE-N",
"text": [
"cyclooxygenase"
],
"offsets": [
[
37,
51
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "11885959_0",
"type": "INHIBITOR",
"arg1_id": "11885959_T5",
"arg2_id": "11885959_T17",
"normalized": []
},
{
"id": "11885959_1",
"type": "INHIBITOR",
"arg1_id": "11885959_T5",
"arg2_id": "11885959_T19",
"normalized": []
},
{
"id": "11885959_2",
"type": "SUBSTRATE",
"arg1_id": "11885959_T4",
"arg2_id": "11885959_T17",
"normalized": []
},
{
"id": "11885959_3",
"type": "SUBSTRATE",
"arg1_id": "11885959_T4",
"arg2_id": "11885959_T19",
"normalized": []
},
{
"id": "11885959_4",
"type": "PRODUCT-OF",
"arg1_id": "11885959_T2",
"arg2_id": "11885959_T17",
"normalized": []
},
{
"id": "11885959_5",
"type": "PRODUCT-OF",
"arg1_id": "11885959_T2",
"arg2_id": "11885959_T19",
"normalized": []
},
{
"id": "11885959_6",
"type": "PRODUCT-OF",
"arg1_id": "11885959_T3",
"arg2_id": "11885959_T17",
"normalized": []
},
{
"id": "11885959_7",
"type": "PRODUCT-OF",
"arg1_id": "11885959_T3",
"arg2_id": "11885959_T19",
"normalized": []
},
{
"id": "11885959_8",
"type": "DIRECT-REGULATOR",
"arg1_id": "11885959_T6",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_9",
"type": "DIRECT-REGULATOR",
"arg1_id": "11885959_T7",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_10",
"type": "DIRECT-REGULATOR",
"arg1_id": "11885959_T8",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_11",
"type": "DIRECT-REGULATOR",
"arg1_id": "11885959_T9",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_12",
"type": "DIRECT-REGULATOR",
"arg1_id": "11885959_T10",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_13",
"type": "DIRECT-REGULATOR",
"arg1_id": "11885959_T11",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_14",
"type": "DIRECT-REGULATOR",
"arg1_id": "11885959_T12",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_15",
"type": "DIRECT-REGULATOR",
"arg1_id": "11885959_T1",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_16",
"type": "INHIBITOR",
"arg1_id": "11885959_T6",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_17",
"type": "INHIBITOR",
"arg1_id": "11885959_T7",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_18",
"type": "INHIBITOR",
"arg1_id": "11885959_T8",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_19",
"type": "INHIBITOR",
"arg1_id": "11885959_T9",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_20",
"type": "INHIBITOR",
"arg1_id": "11885959_T10",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_21",
"type": "INHIBITOR",
"arg1_id": "11885959_T11",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_22",
"type": "INHIBITOR",
"arg1_id": "11885959_T12",
"arg2_id": "11885959_T18",
"normalized": []
},
{
"id": "11885959_23",
"type": "INHIBITOR",
"arg1_id": "11885959_T1",
"arg2_id": "11885959_T18",
"normalized": []
}
] |
10755406 | 10755406 | [
{
"id": "10755406_title",
"type": "title",
"text": [
"A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C."
],
"offsets": [
[
0,
105
]
]
},
{
"id": "10755406_abstract",
"type": "abstract",
"text": [
"Mitomycin C (MMC) is a prototype bioreductive drug employed to treat a variety of cancers including head and neck cancer. Among the various enzymes, dicoumarol inhibitable cytosolic NAD(P)H:quinone oxidoreductase1 (NQO1) was shown to catalyse bioreductive activation of MMC leading to cross-linking of the DNA and cytotoxicity. However, the role of NQO1 in metabolic activation of MMC has been disputed. In this report, we present cellular and animal models to demonstrate that NQO1 may play only a minor role in metabolic activation of MMC. We further demonstrate that bioreductive activation of MMC is catalysed by a unique cytosolic activity which is related but distinct from NQO1. Chinese hamster ovary (CHO) cells were developed that permanently express higher levels of cDNA-derived NQO1. These cells showed significantly increased protection against menadione toxicity. However, they failed to demonstrate higher cytotoxicity due to exposure to MMC under oxygen (normal air) or hypoxia, as compared to the wild-type control CHO cells. Disruption of the NQO1 gene by homologous recombination generated NQO1-/- mice that do not express the NQO1 gene resulting in the loss of NQO1 protein and activity. The cytosolic fractions from liver and colon tissues of NQO1-/- mice showed similar amounts of DNA cross-linking upon exposure to MMC, as observed in NQO1+/+ mice. The unique cytosolic activity that activated MMC in cytosolic fractions of liver and colon tissues of NQO1-/- mice was designated as cytosolic MMC reductase. This activity, like NQO1, was inhibited by dicoumarol and immunologically related to NQO1."
],
"offsets": [
[
106,
1726
]
]
}
] | [
{
"id": "10755406_T1",
"type": "CHEMICAL",
"text": [
"Mitomycin C"
],
"offsets": [
[
106,
117
]
],
"normalized": []
},
{
"id": "10755406_T2",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
119,
122
]
],
"normalized": []
},
{
"id": "10755406_T3",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
1444,
1447
]
],
"normalized": []
},
{
"id": "10755406_T4",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
1523,
1526
]
],
"normalized": []
},
{
"id": "10755406_T5",
"type": "CHEMICAL",
"text": [
"dicoumarol"
],
"offsets": [
[
255,
265
]
],
"normalized": []
},
{
"id": "10755406_T6",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
1621,
1624
]
],
"normalized": []
},
{
"id": "10755406_T7",
"type": "CHEMICAL",
"text": [
"dicoumarol"
],
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[
1679,
1689
]
],
"normalized": []
},
{
"id": "10755406_T8",
"type": "CHEMICAL",
"text": [
"NAD(P)H"
],
"offsets": [
[
288,
295
]
],
"normalized": []
},
{
"id": "10755406_T9",
"type": "CHEMICAL",
"text": [
"quinone"
],
"offsets": [
[
296,
303
]
],
"normalized": []
},
{
"id": "10755406_T10",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
376,
379
]
],
"normalized": []
},
{
"id": "10755406_T11",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
487,
490
]
],
"normalized": []
},
{
"id": "10755406_T12",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
643,
646
]
],
"normalized": []
},
{
"id": "10755406_T13",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
703,
706
]
],
"normalized": []
},
{
"id": "10755406_T14",
"type": "CHEMICAL",
"text": [
"menadione"
],
"offsets": [
[
964,
973
]
],
"normalized": []
},
{
"id": "10755406_T15",
"type": "CHEMICAL",
"text": [
"MMC"
],
"offsets": [
[
1059,
1062
]
],
"normalized": []
},
{
"id": "10755406_T16",
"type": "CHEMICAL",
"text": [
"oxygen"
],
"offsets": [
[
1069,
1075
]
],
"normalized": []
},
{
"id": "10755406_T17",
"type": "CHEMICAL",
"text": [
"mitomycin C"
],
"offsets": [
[
93,
104
]
],
"normalized": []
},
{
"id": "10755406_T18",
"type": "GENE-N",
"text": [
"NQO1"
],
"offsets": [
[
1167,
1171
]
],
"normalized": []
},
{
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] |
23201179 | 23201179 | [
{
"id": "23201179_title",
"type": "title",
"text": [
"Aggression- and sex-induced neural activity across vasotocin populations in the brown anole."
],
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0,
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"id": "23201179_abstract",
"type": "abstract",
"text": [
"Activity within the social behavior neural network is modulated by the neuropeptide arginine vasotocin (AVT) and its mammalian homologue arginine vasopressin (AVP). However, central AVT/AVP release causes different behavioral effects across species and social environments. These differences may be due to the activation of different neuronal AVT/AVP populations or to similar activity patterns causing different behavioral outputs. We examined neural activity (assessed as Fos induction) within AVT neurons in male brown anole lizards (Anolis sagrei) participating in aggressive or sexual encounters. Lizards possess simple amniote nervous systems, and their examination provides a comparative framework to complement avian and mammalian studies. In accordance with findings in other species, AVT neurons in the anole paraventricular nucleus (PVN) were activated during aggressive encounters; but unlike in other species, a positive correlation was found between aggression levels and activation. Activation of AVT neurons within the supraoptic nucleus (SON) occurred nonspecifically with participation in either aggressive or sexual encounters. Activation of AVT neurons in the preoptic area (POA) and bed nucleus of the stria terminalis (BNST) was associated with engagement in sexual behaviors. The above findings are congruent with neural activation patterns observed in other species, even when the behavioral outputs (i.e., aggression level) differed. However, aggressive encounters also increased activation of AVT neurons in the BNST, which is incongruous with findings in other species. Thus, some species differences involve the encoding of social stimuli as different neural activation patterns within the AVT/AVP network, whereas other behavioral differences arise downstream of this system."
],
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}
] | [
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"id": "23201179_T1",
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"id": "23201179_T2",
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"AVT"
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"id": "23201179_T3",
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"id": "23201179_T4",
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"AVP"
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"id": "23201179_T7",
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"AVT"
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"AVP"
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"AVT"
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589,
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"id": "23201179_T14",
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"AVT"
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"arginine vasotocin"
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"Fos"
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"id": "23201179_T32",
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177,
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"vasotocin"
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51,
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]
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}
] | [] | [] | [] |